白介素-2变体及其使用方法

本申请要求于2018年11月2日提交的美国临时申请第62/755,016号和于2018年6月22日提交的美国临时申请第62/689,055号的权益，所述临时申请的每一项通过引用以其整体并入本文。

背景技术

白介素2(IL-2)是首次描述的针对T细胞的生长因子。自其发现以来，IL-2已被显示出在体外促进T细胞的增殖和存活(Smith,K A.(1988)Science.240,1169-76)以及在T病毒感染(Blattman,J N,等人(2003)Nat Med 9,540-7)或疫苗(Fishman,M.,等人(2008)JImmunother.31,72-80，Kudo-Saito,C.,等人(2007)Cancer Immunol Immunother.56,1897-910；Lin,C T.,等人(2007)Immunol Lett.114,86-93)的情况中加强免疫应答的能力。

IL-2已被用于癌症治疗。重组的人类IL-2是一种用于转移性黑素瘤和肾癌的有效的免疫疗法，约10％的患者有持久的响应。然而，短半衰期和严重毒性限制了IL-2的最佳给药。此外，IL-2还以较高的亲和力与其异源三聚体受体IL-2Rαβγ结合，优先扩增表达高组成型IL-2Rα水平的免疫抑制性调节性T细胞(Treg)。Treg的扩增代表了IL-2对癌症免疫疗法的不期望的影响。然而，IL-2即使在低剂量也能刺激Treg细胞的能力可以用于治疗自身免疫性紊乱和各种炎性紊乱。

Treg是免疫系统内稳态的核心，并且通过抑制(自身反应性)效应T细胞在维持外周免疫耐受中发挥主要作用。各种自身免疫性疾病和炎性疾病已被显示具有Treg细胞数量或Treg功能的缺陷。因此，在开发加强Treg细胞的数量和/或功能的疗法方面存在极大兴趣。正在研究的一种自身免疫性疾病的治疗方法是使用低剂量的IL-2以靶向Treg细胞，因为Treg细胞的IL-2Rα组成型水平(constitutive levels)较高，因此与许多其他免疫细胞类型相比，Treg细胞对较低浓度的IL-2有响应。(Klatzmann D,2015Nat Rev Immunol.15:283-94)。低剂量IL-2治疗各种GvHD(Koreth,J.,等人,2011,N Engl J Med.,365:2055-66)和HCV相关的自身免疫血管炎患者的临床试验(Saadoum,D.,等人,2011,N Engl J Med.,365:2067-77)已经展示出增加的Treg水平和临床效力的迹象。然而，即使这些较低的剂量也会导致严重的安全性和耐受性问题。因此，需要一种比IL-2更特异性地靶向Treg细胞、能够加强Treg细胞数量和功能的有效的自身免疫性/炎性疾病疗法。

最近发现，IL-2可以被修饰以选择性地刺激细胞毒性效应T细胞或Treg细胞。各种方法已经导致产生具有改进的和选择性免疫刺激能力的IL-2变体(参见例如，美国专利第7,186,804号、美国专利第7,105,653号、美国专利第6,955,807号、美国专利第5,229,109号、美国专利申请20050142106号)。在本发明中，IL-2变体被设计成增加该分子主要通过高亲和力受体(α链、β链和γ链)而不是通过中等亲和力受体(β链和γ链)进行信号传导的能力。基本理念是促进Treg细胞中的信号传导而不是效应T细胞和NK细胞中的信号传导，这被认为是观察到的毒性作用的原因。重要的是，现有技术公开内容中没有涉及基于IL-2变体的降低的刺激天然调节性T细胞的能力而具有大于天然IL-2的体内治疗功效的IL-2变体。然而，自从对IL-2变体的初步研究以来，本领域的研究更充分地确定，Treg细胞组成型表达高IL-2Rα(CD25)以及IL-2Rβ和γ

总之，IL-2是一种高度多效性细胞因子，与不同细胞群体的生物活性密切相关。这一特性使IL-2成为调节免疫应答的重要节点，这使IL-2成为治疗和复杂免疫调节的吸引人的靶。此外，可以制备受体亚基偏倚的IL-2变体以实现IL-2介导的选择性免疫调节，以促进调节性T细胞(Treg)的扩增和活性，同时使辅助性和细胞毒性T效应细胞(Teff)最小化，并导致较低的促炎信号传导分子水平。

在一方面，本发明涉及IL-2的突变变体的产生。这些变体的特征在于它们在刺激Treg(T CD4+CD25+FoxP3+)细胞方面比刺激常规CD4+T细胞、细胞毒性效应CD8+T淋巴细胞和NK细胞具有更高的选择性。特别地，这些变体将为改进自身免疫性紊乱和炎性紊乱的IL-2疗法提供实用的解决方案。本发明涉及除了一个至若干个被突变的氨基酸以外，与人类IL-2共有其一级序列的多肽。这些变体在对应于IL-2与IL-2Rβ和/或γ

在一方面，本发明涉及IL-2的突变变体的产生。这些变体具有Treg选择性活性、减少的聚集、增加的表达、改进的可制造性和可开发性的属性组合。这些变体还提供了改进的蛋白生物物理特性和降低的与IL-2分子相关的免疫原性风险。这些变体为改进IL-2疗法和降低在自身免疫性紊乱和炎性紊乱中的毒性提供了一种优越的解决方案。本发明涉及除了一个至若干个被突变的氨基酸以外，与人类IL-2共有其一级序列的多肽。

在一方面，本发明涉及IL-2突变变体的产生，该IL-2突变变体的特征在于去除了一个被提出类似于细菌毒素组分的‘

本发明允许在自身免疫性紊乱和各种炎性紊乱的疗法中基于IL-2的免疫调节的当前策略的实质性改进。特别地，本文描述的突变变体对天然IL-2的替代将导致对Treg细胞的CD25偏倚的选择性刺激。在各种实施方案中，IL-2变体(或突变体)包含源自如SEQ IDNO:3中列出的成熟的人类IL-2多肽序列的IL-2变体(或突变体)的序列。在各种实施方案中，IL-2变体起IL-2激动剂的作用。在各种实施方案中，IL-2变体起IL-2拮抗剂的作用。在各种实施方案中，IL-2变体包含SEQ ID NO:4-43、108-146和193-197中列出的序列。

本发明允许在Treg细胞缺乏性自身免疫性紊乱和各种炎性紊乱的疗法中基于IL-2的免疫调节的当前策略的实质性改进。特别地，本文描述的突变变体对天然IL-2的替代，将导致对Treg细胞的CD25偏倚的选择性刺激，并且预计会消除毒性基序，以及防止内皮细胞损伤并显著降低VLS。在各种实施方案中，IL-2变体(或突变体)包含源自如SEQ ID NO:3中列出的成熟的人类IL-2多肽序列的IL-2变体(或突变体)的序列。在各种实施方案中，IL-2变体起IL-2激动剂的作用。在各种实施方案中，IL-2变体起IL-2拮抗剂的作用。在各种实施方案中，IL-2变体包含SEQ ID NO:5-14、26-43、108-111、125-146和193-197。

在另一方面，本发明的IL-2变体与至少一种异源蛋白附接。在各种实施方案中，IL-2变体与至少一种赋予融合分子延长的半衰期的多肽融合。这样的多肽包括结合新生Fcγ/受体的IgG Fc或其他多肽、人类血清白蛋白或结合具有延长的血清半衰期的蛋白的多肽，包括IgG、非IgG免疫球蛋白、蛋白和非蛋白剂，其由于存在结合FcRn的IgG恒定结构域或其部分而具有增加的体内半衰期，其具有增加恒定结构域或片段对FcRn的亲和力的一个或更多个氨基酸修饰。这样的具有增加的半衰期的蛋白和分子具有这样的优点，即在这种分子的治疗、预防或诊断用途中需要更少的量和/或更少的给药频率(参见例如，美国专利第7,658,921号)。

在各种实施方案中，IL-2变体可以与异源蛋白的N末端或C末端连接。

在各种实施方案中，IL-2变体与IgG Fc分子融合。在各种实施方案中，Fc结构域是人类IgG Fc结构域。在各种实施方案中，Fc结构域源自SEQ ID NO:44中列出的人类IgG1重链恒定结构域序列。在各种实施方案中，Fc结构域为具有SEQ ID NO:45中列出的氨基酸序列的Fc结构域。在各种实施方案中，Fc结构域为具有SEQ ID NO:46中列出的氨基酸序列的Fc结构域。在各种实施方案中，Fc结构域为具有SEQ ID NO:47中列出的氨基酸序列的Fc结构域。在各种实施方案中，Fc结构域源自人类IgG2重链恒定结构域序列。在各种实施方案中，Fc结构域源自人类IgG4重链恒定结构域序列。

术语“Fc”是指包含完整抗体的非抗原结合片段的序列的分子或序列，无论是单体形式还是多聚体形式。天然Fc的原始免疫球蛋白来源优选地为人类来源，并且可以是本领域公开的任何免疫球蛋白。天然Fc由单体多肽组成，单体多肽可以通过共价(即二硫键)和非共价缔合连接成二聚体或多聚体形式。天然Fc分子的单体亚基之间的分子间二硫键的数目取决于类别(例如IgG、IgA、IgE)或亚类(例如IgG1、IgG2、IgG3、IgA1、IgGA2)而在从1至4的范围内。天然Fc的一种实例是由木瓜蛋白酶消化IgG产生的二硫键合的二聚体(参见Ellison等人(1982),Nucleic Acids Res.10:4071-9)。如本文使用的术语“天然Fc”是单体、二聚体和多聚体形式的总称。Fc结构域包含蛋白A、蛋白G、各种Fc受体和补体蛋白的结合位点。

在各种实施方案中，术语“Fc变体”是指从天然Fc修饰、但仍然包含补救受体FcRn的结合位点的分子或序列。国际申请WO 97/34631(1997年9月25日公布)和WO 96/32458描述了示例性的Fc变体以及与补救受体的相互作用，并特此通过引用并入。此外，天然Fc包含可被去除的位点，因为它们提供本发明的融合分子不需要的结构特征或生物活性。因此，在各种实施方案中，术语“Fc变体”包括缺乏一个或更多个天然Fc位点或残基的分子或序列，所述天然Fc位点或残基影响或参与(1)二硫键形成，(2)与所选宿主细胞的不相容性，(3)在所选宿主细胞中表达时的N末端异质性，(4)糖基化，(5)与补体的相互作用，(6)与补救受体以外的Fc受体的结合，或(7)抗体依赖性细胞毒性(ADCC)。

术语“Fc结构域”包括如上文定义的天然Fc和Fc变体分子和序列。如同Fc变体和天然Fc，术语“Fc结构域”包括单体或多聚体形式的分子，无论是从完整抗体消化的还是通过重组基因表达或通过其他方式产生的。在各种实施方案中，“Fc结构域”是指两个Fc结构域单体(SEQ ID NO:44)的二聚体，其通常包括全部或部分的铰链区。在各种实施方案中，Fc结构域可以被突变以缺乏效应子功能。在各种实施方案中，Fc结构域中的每个Fc结构域单体包含CH2抗体恒定结构域中的氨基酸取代，以减少Fc结构域和Fcγ受体之间的相互作用或结合。在各种实施方案中，Fc结构域的每个亚基包含两个氨基酸取代，这两个氨基酸取代减少与活化性Fc受体的结合和/或效应子功能，其中所述氨基酸取代是L234A、L235A。在各种实施方案中，Fc结构域的每个亚基包含三个氨基酸取代，这三个氨基酸取代减少与活化性Fc受体的结合和/或效应子功能，其中所述氨基酸取代是L234A、L235A和G237A(SEQ ID NO:45)。

在各种实施方案中，Fc结构域可以被突变以进一步延长体内半衰期。在各种实施方案中，Fc结构域的每个亚基包含增强与人类FcRn的结合的三个氨基酸取代，其中所述氨基酸取代是M252Y、S254T和T256E，公开于美国专利公布第7,658,921号中。在各种实施方案中，Fc结构域的每个亚基包含增强与人类FcRn的结合的一个氨基酸取代，其中所述氨基酸取代是N434A，公开于美国专利公布第7,371,826号中。在各种实施方案中，Fc结构域的每个亚基包含增强与人类FcRn的结合的一个氨基酸取代，其中所述氨基酸取代是M428L和N434S，公开于美国专利公布第8,546,543号中。在各种实施方案中，半衰期延长突变可以与减少与活化性Fc受体的结合和/或效应子功能的氨基酸取代组合。

在各种实施方案中，Fc结构域中的两个Fc结构域单体中的每一个包含促进两个单体异源二聚体化的氨基酸取代。在各种其他实施方案中，Fc结构域单体的异源二聚体化可以通过在两个Fc结构域单体中引入不同但相容的取代诸如“knob-into-hole”残基对来促进。“knob-into-hole”技术也公开于美国专利公布第8,216,805号中。在又另一种实施方案中，一个Fc结构域单体包含knob突变T366W，并且另一个Fc结构域单体包含hole突变T366S、L358A和Y407V。在各种实施方案中，引入形成稳定化的二硫桥的两个Cys残基(S354C在“knob”侧，并且Y349C在“hole”侧)。异源二聚体Fc的使用可以产生单价IL-2变体构建体。

在各种实施方案中，IL-2变体Fc-融合蛋白将是单体的，即，仅包含单个IL-2突变蛋白分子。在这样的实施方案中，融合蛋白与连接至IL-2变体的异源二聚体Knob-Fc和匹配的异源二聚体Hole Fc共表达。当两个含Fc的多肽的异源二聚体形成时，所得的蛋白仅包含单个IL-2变体。

在各种实施方案中，IL-2变体用于制备SEQ ID NO:69-107、147-189和198-208中列出的Fc-IL-2融合蛋白。

在各种实施方案中，本发明的IL-2变体可以附接至赋予融合分子延长的半衰期的抗体，诸如抗匙孔

在各种实施方案中，异源蛋白通过接头和/或铰链接头肽附接至IL-2变体。接头或铰链接头可以是相对地不含二级结构的在5个、10个、15个、20个、30个、40个或更多个氨基酸之间的人工序列。

在各种实施方案中，异源蛋白通过在10个、15个、20个、30个、40个或更多个氨基酸之间的刚性接头肽附接至IL-2变体，所述刚性连接肽展示出α-螺旋构象并可用作蛋白结构域之间的刚性间隔物。

在另一方面，IL-2变体可以以美国专利第4,640,835号、第4,496,689号、第4,301,144号、第4,670,417号、第4,791,192号或第4,179,337号中阐述的方式连接至各种非蛋白质聚合物，包括但不限于各种多元醇，诸如聚乙二醇、聚丙二醇或聚氧化烯。在各种实施方案中，可以在IL-2变体内的不同位置进行氨基酸取代，以促进聚合物诸如PEG的添加。在各种实施方案中，这样的PEG化的蛋白可以比非PEG化的蛋白具有增加的半衰期和/或降低的免疫原性。

“聚乙二醇”或“PEG”意指聚亚烷基二醇化合物或其衍生物，带有或不带有偶联剂或衍生化，所述衍生化带有偶联部分或活化部分(例如带有醛、羟基琥珀酰亚胺基、酰肼、硫醇、三氟甲磺酸酯、tresylate、氮丙啶、环氧乙烷、邻二硫吡啶(orthopyridyldisulphide)、乙烯基砜、碘乙酰胺或马来酰亚胺部分)。在各种实施方案中，PEG包括基本上线性的、直链PEG、支链PEG或树枝状PEG。PEG是一种公知的水溶性聚合物，可商购获得或可根据本领域公知的方法通过乙二醇的开环聚合制备(Sandler和Karo,Polymer Synthesis,Academic Press,New York,Vol.3,第138-161页)。

在各种实施方案中，Il-2变体可以在N末端或C末端处非共价或共价地连接至IgGFc或其他多肽(所述其他多肽结合至新生Fcγ/受体、人类血清白蛋白或与具有延长的血清半衰期的蛋白结合的多肽)或各种非蛋白质聚合物。

在另一方面，本公开内容提供了药物组合物，所述药物组合物包含与药学上可接受的载体混合的分离的IL-2变体。

在另一方面，IL-2变体可以被配制成用于缓释，诸如共价或非共价地被附接至水凝胶、纳米粒子等。

在另一方面，本公开内容提供了用于治疗受试者的自身免疫性疾病的方法，该方法包括向有相应需要的受试者施用治疗有效量的本发明的药物组合物。在一种实施方案中，受试者是人类受试者。与本发明相关的自身免疫性疾病是起因于个体的自身组织并针对个体的自身组织的疾病或紊乱，或其共分离系或表现或由其产生的状况。在各种实施方案中，自身免疫性疾病包括但不限于，移植物抗宿主病(GvHD)、免疫相关不良事件(irAE)、关节炎(包括类风湿性关节炎、反应性关节炎)、系统性红斑狼疮(SLE)、特应性皮炎、银屑病和炎症性肠病(IBD)、脑脊髓炎、葡萄膜炎、重症肌无力、多发性硬化、胰岛素依赖性糖尿病(1型糖尿病)、各种皮炎、爱迪生氏病、乳糜泻、慢性疲劳综合征、自身免疫性肝炎、自身免疫性脱发、强直性脊柱炎、溃疡性结肠炎、克罗恩病、纤维肌痛、寻常性天疱疮、干燥综合征、川崎病、甲状腺功能亢进/格雷夫斯病、甲状腺功能减退/桥本病、子宫内膜异位症、硬皮病、恶性贫血、肺出血肾炎综合征、格林-巴利综合征、韦格纳病、肾小球肾炎、再生障碍性贫血(包括多次输血的再生障碍性贫血患者)、阵发性夜间血红蛋白尿症、骨髓增生异常综合征、特发性血小板减少性紫癜(IPT)、自身免疫性溶血性贫血(AIHA)、埃文综合征、因子VIII抑制物综合征(Factor VIII inhibitor syndrome)、系统性血管炎、皮肌炎、多肌炎和风湿热、自身免疫性淋巴增生综合征(ALPS)、自身免疫性大疱性类天疱疮、帕金森病、结节病、白癜风、原发性胆汁性肝硬化和自身免疫性心肌炎。

在另一方面，本公开内容提供了用于治疗受试者的自身免疫性疾病的方法，所述方法包括施用与能够治疗自身免疫性疾病的第二治疗剂组合的治疗有效量的本发明的药物组合物。

在另一方面，本公开内容提供了用于治疗受试者的炎性疾病的方法，该方法包括向有相应需要的受试者施用治疗有效量的本发明的药物组合物。在一种实施方案中，受试者是人类受试者。在各种实施方案中，待治疗的炎性疾病包括但不限于，克罗恩病、结肠炎、皮炎、银屑病、憩室炎、肝炎、肠易激综合征(IBS)、红斑狼疮、肾炎、帕金森病、溃疡性结肠炎、胶原性结肠炎、淋巴细胞性结肠炎、缺血性结肠炎、改道性结肠炎、白塞氏综合征和未定型结肠炎多发性硬化(MS)、阿尔茨海默病、关节炎、类风湿性关节炎、哮喘和各种心血管疾病诸如动脉粥样硬化和血管炎。在各种实施方案中，炎性疾病选自由以下组成的组：类风湿性关节炎、糖尿病、痛风、cryopyrin相关周期性综合征和慢性阻塞性肺病。

在另一方面，本公开内容提供了用于治疗受试者的炎性疾病的方法，所述方法包括施用与能够治疗炎性疾病的第二治疗剂组合的治疗有效量的本发明的药物组合物。

在另一方面，本公开内容提供了用于受试者的器官移植或相关的移植物抗宿主病的方法，所述方法包括向有相应需要的受试者施用治疗有效量的本发明的药物组合物。在一种实施方案中，受试者是人类受试者。在各种实施方案中，移植选自心脏、肾、肝、肺、胰腺、肠和胸腺的器官移植，或选自骨、肌腱、角膜、皮肤、心脏瓣膜、神经和血管的组织移植。

在另一方面，本公开内容提供了IL-2变体用于制备用于治疗自身免疫性疾病的药物的用途。

在另一方面，本公开内容提供了IL-2变体用于制备用于治疗器官移植和GvHD的药物的用途。

在另一方面，本公开内容提供了IL-2变体用于制备用于治疗炎性紊乱的药物的用途。

在另一方面，本公开内容提供了分离的核酸分子，该分离的核酸分子包含编码本公开内容的IL-2变体的多核苷酸。在另一方面，本公开内容提供了包含本文描述的核酸的载体。在各种实施方案中，载体是表达载体。在另一方面，本公开内容提供了包含本公开内容的核酸的分离的细胞。在各种实施方案中，细胞是包含本公开内容的表达载体的宿主细胞。在另一方面，制备IL-2变体的方法通过在促进蛋白或多肽的表达的条件下培养宿主细胞来提供。

图1描绘了蛋白A纯化后的示例性IL-2Fc融合蛋白A)P-0250、B)P-0318、C)P-0317、D)P-0447和E)P-0511的尺寸排阻色谱图。图1D和图1E还说明了在还原剂的不存在(泳道2)和存在(泳道3)下各样品的SDS-PAGE。

图2描绘了在人类PBMC测定中，与野生型融合蛋白(P-0250)相比，在位置20处具有天冬氨酸的氨基酸取代的IL-2变体(D20X)的Fc融合蛋白对诱导CD4+Treg细胞(A)与Tconv细胞(B)中的STAT5磷酸化的不同作用。

图3描绘了在人类PBMC测定中，与野生型(P-0250)和基准蛋白相比，IL-2变体的Fc融合蛋白P-0375(N88Q)对诱导CD4+Treg细胞(A)与Tconv细胞(B)中的STAT5磷酸化的不同作用。

图4描绘了与野生型(P-0250)相比，在位置19处具有氨基酸取代的IL-2变体的Fc融合蛋白对STAT5磷酸化的不同作用。在人类PBMC测定中，通过FACS分析确定了诱导CD4+Treg细胞(A和C)与Tconv细胞(B和D)中的STAT5磷酸化的能力。

图5描绘了与野生型(P-0250)或基准-1蛋白相比，在位置19处(P-0424)或位置126处(P-0303)具有单个氨基酸取代或组合突变(P-0447)的IL-2变体的Fc融合蛋白对STAT5磷酸化的不同作用。通过FACS分析确定诱导CD4+Treg细胞(A、C和E)和CD4+Tconv细胞(B、D和F)中的STAT5磷酸化的能力。

图6描绘了与野生型(P-0250)相比，含有双重氨基酸取代的不同组合的IL-2变体的Fc融合蛋白(P-0419、P-0464、P-0471、P-0474、P-0417和P-0322)对STAT5磷酸化的不同作用。还将P-0417和P-0322的生物活性分别与其具有单个氨基酸取代的对应物P-0373和P-0363进行了比较。在人类PBMC测定中，通过FACS分析确定了诱导CD4+Treg细胞(A和C)与Tconv细胞(B和D)中的STAT5磷酸化的能力。

图7描绘了与野生型(P-0250)相比，在位置19处(P-0424)或位置126处(P-0303)具有单个氨基酸取代或组合突变(P-0447)的IL-2变体的Fc融合蛋白对STAT5磷酸化的不同作用，以及与野生型(P-0250)和基准Fc融合蛋白相比，含有不同组合氨基酸取代的IL-2变体的Fc融合蛋白(P-0419、P-0447、P-0448和P-0449)对STAT5磷酸化的不同作用。在人类PBMC测定中，通过FACS分析确定了诱导CD4+Treg细胞(A和C)与CD4+Tconv细胞(B和D)中的STAT5磷酸化的能力。

图8描绘了IL-2融合蛋白P-0250、P-0424和P-447与它们各自含有S125I取代的对应物P-0531、P-0491和P-0511的pSTAT5刺激活性的比较。在人类PBMC测定中，通过FACS分析确定了诱导CD4+Treg细胞(A、C和E)与CD4+Tconv细胞(B、D和F)中的STAT5磷酸化的能力。

图9描绘了与野生型(P-0250)和三种基准分子相比，IL-2变体Fc融合体(P-0511和P-0512)对三种CD4+T细胞亚群(A)CD4+FoxP3+CD25+Treg细胞、B)CD4+FoxP3-CD25+活化的Tconv细胞和C)CD4+FoxP3-CD25-初始Tconv细胞)中的STAT5磷酸化的不同作用。在人类PBMC测定中，通过FACS分析确定了诱导STAT5磷酸化的能力。

图10描绘了与野生型(P-0250)和基准分子相比，P-0511和P-0512对刺激A)CD8+T细胞和B)NK细胞的增殖的不同作用。在人类PBMC测定中，通过CFSE稀释的FACS分析来确定细胞增殖，并表示为分裂的细胞的百分比。

图11A-图11D描绘了与野生型等同物P-0531相比，IL-2变体Fc融合体P-0511诱导不同细胞类型中的STAT5磷酸化的不同作用。在人类PBMC测定中，通过FACS分析确定了诱导A)CD4+Treg细胞、B)CD4+Tconv细胞、C)CD8+T细胞和D)NK细胞中的STAT5磷酸化的能力。图11E描绘了在ELISA测定中，与P-0531和基准-1相比，P-511与IL-2Rβ和γc复合物的结合强度。

图12描绘了在单次皮下注射后，用IL-2变体的Fc融合蛋白和基准处理的小鼠中Treg细胞的增殖和扩增。在指示的时间点采集血液，以进行增殖测量和淋巴细胞表型分析。(A)增殖标志物Ki67阳性Treg细胞的百分比；(B)总CD4+T细胞群体中Treg细胞的百分比；(C)总血淋巴细胞中Treg细胞的百分比。数据表示为平均值±SEM。通过单因素ANOVA检验、随后Tukey事后检验进行统计分析。****p<0.0001；***p<0.001，在各自的时间点与PBS组相比。

图13描绘了在单次皮下注射后，用IL-2突变体Fc融合蛋白和基准处理的小鼠中效应T细胞和NK细胞的增殖。在指示的时间点采集血液，以测量淋巴细胞增殖。(A)Ki67阳性CD4+T常规(Tconv)细胞的百分比；(B)Ki67阳性CD8+T细胞的百分比；(C)Ki67阳性NK细胞的百分比。数据表示为平均值±SEM。通过单因素ANOVA检验、随后Tukey事后检验进行统计分析。****p<0.0001；***p<0.001，在各自的时间点与PBS组相比。

图14描绘了在单次皮下注射后，用IL-2突变体Fc融合蛋白和基准处理的小鼠中效应T细胞和NK细胞的扩增。(A-B)总CD4+T细胞(A)和总血淋巴细胞(B)中CD4+T常规(Tconv)细胞的百分比。(C)总血淋巴细胞中CD8+T细胞的百分比；(D)总血淋巴细胞中NK细胞的百分比。数据表示为平均值±SEM。

图15描绘了在用IL-2突变体Fc融合蛋白和基准处理的小鼠中，基于以下的Treg与Tconv细胞比率：A)Ki67阳性表达的百分比和B)细胞数目。数据用FACS获得，并表示为平均值±SEM。通过单因素ANOVA检验、随后Tukey事后检验进行统计分析。****p<0.0001；*p<0.05，在各自的时间点与PBS组相比。

图16描绘了在单次皮下注射后，用IL-2突变体Fc融合蛋白和基准处理的小鼠中Treg细胞上的CD25和Foxp3的表达。通过FACS分析对A)Foxp3和B)CD25的表达水平进行分析，并表示为平均荧光强度(MFI)。数据表示为平均值±SEM。****p<0.0001，在各自的时间点与PBS组相比。

图17描绘了在单次注射IL-2变体Fc融合蛋白P-0511后，小鼠中Treg细胞的增殖和扩增的剂量依赖性增加。在指示的时间点采集血液，以进行淋巴细胞表型分析和Ki67增殖标志物的测量。(A)增殖标志物Ki67阳性Treg细胞的百分比；(B)总CD4+T细胞中Treg细胞的百分比；(C)每微升全血中的Treg细胞数目；(D)每组的Treg细胞数目从基线的变化倍数。数据表示为平均值±SEM。通过单因素ANOVA检验、随后Tukey事后检验进行统计分析。****p<0.0001，***p<0.001，**p<0.01，*p<0.05，在各自的时间点与PBS组相比。

图18描绘了在单次注射后，IL-2变体Fc融合蛋白P-0511对小鼠的总淋巴细胞中Treg细胞(A)、CD4+Tconv细胞(B)、CD8 T细胞(C)和NK细胞(D)的百分比的剂量依赖性作用。在指示的时间点采集血液，以进行淋巴细胞表型分析。数据通过FACS分析来确定，并表示为平均值±SEM。通过单因素ANOVA检验、随后Tukey事后检验进行统计分析。****p<0.0001，**p<0.01，*p<0.05，在各自的时间点与PBS组相比。

图19描绘了在单次注射P-0511后，小鼠中A)Treg与T conv细胞数目的比率、B)Treg细胞上CD25的表达和C)Treg细胞上Foxp3的表达的剂量依赖性增加。数据通过FACS分析来确定，并表示为平均值±SEM。通过单因素ANOVA检验、随后Tukey事后检验进行统计分析。****p<0.0001，***p<0.001，**p<0.01，在各自的时间点与PBS组相比。

图20描绘了在接受重复剂量的IL-2变体的Fc融合蛋白(P-0511和P-0512)而不是野生型(P-0531)和基准的小鼠中Treg细胞的持续增殖和扩增。化合物每三天一次(Q3D)s.c.给予，并在第1次和第3次注射后3天采集血液，以进行淋巴细胞表型分析和增殖标志物Ki67的测量。(A)Ki67阳性Treg细胞的百分比；(B)总CD4+T细胞中Treg细胞的百分比；(C)总血淋巴细胞中Treg细胞的百分比。数据通过FACS分析来确定，并表示为平均值±SEM。通过单因素ANOVA检验、随后Tukey事后检验进行统计分析。****p<0.0001，*p<0.05，与各自的PBS组相比。

图21描绘了在接受重复给药的IL-2变体的Fc融合蛋白(P-0511和P-0512)而不是野生型(P-0531)和基准的小鼠中Treg细胞计数的持续升高。化合物每三天一次(Q3D)s.c.给予，并在第1次和第3次注射后3天采集血液，以进行淋巴细胞表型分析和增殖标志物Ki67的测量。(A)每微升全血中的Treg细胞数目；(B)与PBS对照组相比，Treg数目的变化倍数。数据通过FACS分析来确定，并表示为平均值±SEM。通过单因素ANOVA检验、随后Tukey事后检验进行统计分析。****p<0.0001，***p<0.001，**p<0.01，与各自的PBS组相比。

图22描绘了在接受重复给药的IL-2变体的Fc融合蛋白(P-0511和P-0512)而不是野生型(P-0531)和基准的小鼠中升高的Treg与Tconv的比率的维持。化合物每三天一次(Q3D)s.c.给予，并在第1次和第3次注射后3天采集血液，以进行Treg和Tconv细胞表型分析。比率基于总CD4细胞中的Treg％和Tconv％计算。数据通过FACS分析来确定，并表示为平均值±SEM。通过单因素ANOVA检验、随后Tukey事后检验进行统计分析。****p<0.0001，与各自的PBS组相比。

图23描绘了在由匙孔

图24描绘了在由KLH抗原诱导的DTH的小鼠模型中，与基准分子(基准-1)相比，P-0511对抗原驱动的炎症的抑制。在第0天对小鼠进行KLH免疫，并在第5天在右耳中再次攻击。从第-2天开始，用化合物Q5D处理小鼠。使用KLH攻击后不同时间的耳厚度相对于基线值的变化(Δ耳厚度)来说明DTH响应的动力学。数据表示为平均值±SEM。通过单因素ANOVA检验、随后Tukey事后检验进行统计分析。****p<0.0001，**p<0.01，*p<0.05，在各自的时间点与各自的PBS组相比。

本发明涉及除了一个至若干个被突变的氨基酸以外，与人类IL-2共有一级序列的多肽。一组IL-2变体包含相对于效应T细胞和NK细胞优先促进免疫抑制性调节性T细胞(TCD4+CD25+FoxP3+)的增殖、存活、活化和/或功能的突变。本发明还包括这样的IL-2选择性激动剂单独使用或与疾病组织靶向蛋白或肽组合使用以治疗自身免疫性紊乱和各种炎性紊乱的治疗用途。另一组IL-2变体包含大幅降低这些多肽刺激Treg细胞或Tconv细胞的能力，同时可具有受体结合活性并使其作为IL-2拮抗剂有效的突变。在另一方面，本发明涉及包含所公开的多肽的药物组合物。最后，本发明涉及所公开的多肽和药物组合物的治疗用途，这是由于它们对免疫系统对疾病如自身免疫性紊乱和炎性紊乱的选择性调节作用。

术语“多肽”、“肽”和“蛋白”在本文中可互换使用，以指氨基酸残基的聚合物。在各种实施方案中，“肽”、“多肽”和“蛋白”是其α碳通过肽键连接的氨基酸链。因此链的一个末尾(氨基末端)处的末端氨基酸具有游离氨基基团，而链的另一个末尾(羧基末端)处的末端氨基酸具有游离羧基基团。如本文使用的，术语“氨基末端”(缩写为N末端)是指在肽的氨基末端处的氨基酸上的游离α-氨基基团，或指在肽中的任何其他位置处的氨基酸的α-氨基基团(参与肽键时的氨基基团)。类似地，术语“羧基末端”是指肽的羧基末端上的游离羧基基团，或肽中任何其他位置处的氨基酸的羧基基团。肽还包括基本上任何多氨基酸，包括但不限于肽模拟物(peptide mimetic)，诸如通过醚键而非酰胺键连接的氨基酸。

本公开内容的多肽包括已经以任何方式和出于任何原因被修饰的多肽，例如，以：(1)降低对蛋白水解的敏感性，(2)降低对氧化的敏感性，(3)改变形成蛋白复合物的结合亲和力，(4)改变结合亲和力，和(5)赋予或改变其他物理化学特性或功能特性。

如本文使用的氨基酸“取代”是指用不同的氨基酸替换多肽中亲本多肽序列的特定位置处的一个氨基酸。氨基酸取代可以使用本领域熟知的遗传方法或化学方法来产生。例如，单氨基酸取代或多氨基酸取代(例如，保守氨基酸取代)可以在天然存在的序列中进行(例如，在形成分子间接触的结构域以外的多肽部分中)。“保守氨基酸取代”是指多肽中的氨基酸被功能上相似的氨基酸取代。以下六组各自包含互相为保守取代的氨基酸：

1)丙氨酸(A)、丝氨酸(S)和苏氨酸(T)

2)天冬氨酸(D)和谷氨酸(E)

3)天冬酰胺(N)和谷氨酰胺(Q)

4)精氨酸(R)和赖氨酸(K)

5)异亮氨酸(I)、亮氨酸(L)、甲硫氨酸(M)和缬氨酸(V)

6)苯丙氨酸(F)、酪氨酸(Y)和色氨酸(W)

“非保守氨基酸取代”是指这些类别之一的成员取代为来自另一类别的成员。在进行这样的改变时，根据各种实施方案，可以考虑氨基酸的亲水指数(hydropathic index)。基于氨基酸的疏水性和电荷特征，每种氨基酸已经被指定了亲水指数。它们是：异亮氨酸(+4.5)；缬氨酸(+4.2)；亮氨酸(+3.8)；苯丙氨酸(+2.8)；半胱氨酸/胱氨酸(+2.5)；甲硫氨酸(+1.9)；丙氨酸(+1.8)；甘氨酸(-0.4)；苏氨酸(-0.7)；丝氨酸(-0.8)；色氨酸(-0.9)；酪氨酸(-1.3)；脯氨酸(-1.6)；组氨酸(-3.2)；谷氨酸(-3.5)；谷氨酰胺(-3.5)；天冬氨酸(-3.5)；天冬酰胺(-3.5)；赖氨酸(-3.9)和精氨酸(-4.5)。

本领域理解亲水氨基酸指数在赋予蛋白相互作用的生物功能中的重要性(参见例如，Kyte等人,1982,J.Mol.Biol.157:105-131)。已知，某些氨基酸可以被具有相似亲水指数或评分的其他氨基酸取代，并且仍保持相似的生物活性。在基于亲水指数进行改变时，在各种实施方案中，包括了其亲水指数在±2内的氨基酸的取代。在各种实施方案中，包括在±1内的那些，并且在各种实施方案中，包括在±0.5内的那些。

本领域还理解，可以基于亲水性有效地进行相似氨基酸的取代，特别是当从而产生的生物功能蛋白或肽被意图用于在免疫学实施方案中使用时，如本文所公开的。在各种实施方案中，蛋白的最大局部平均亲水性(如由其相邻氨基酸的亲水性决定的)与其免疫原性和抗原性，即，与蛋白的生物学特性相关。

以下亲水性值(hydrophilicity values)被指定至这些氨基酸残基：精氨酸(+3.0)；赖氨酸(+3.0)；天冬氨酸(+3.0.+-.1)；谷氨酸(+3.0.+-.1)；丝氨酸(+0.3)；天冬酰胺(+0.2)；谷氨酰胺(+0.2)；甘氨酸(0)；苏氨酸(-0.4)；脯氨酸(-0.5.+-.1)；丙氨酸(-0.5)；组氨酸(-0.5)；半胱氨酸(-1.0)；甲硫氨酸(-1.3)；缬氨酸(-1.5)；亮氨酸(-1.8)；异亮氨酸(-1.8)；酪氨酸(-2.3)；苯丙氨酸(-2.5)和色氨酸(-3.4)。在基于相似亲水性值进行改变时，在各种实施方案中，包括其亲水性值在±2内的氨基酸的取代，在各种实施方案中，包括在±1内的那些，并且在各种实施方案中，包括在±0.5内的那些。

示例性的氨基酸取代在表1中列出。

技术人员将能够使用公知技术确定如本文列出的合适的多肽变体。在各种实施方案中，本领域技术人员可以通过靶向被认为对于活性不重要的区域来鉴定分子中可以被改变而不破坏活性的适合区域。在其他实施方案中，技术人员可以鉴定在相似多肽间保守的分子的残基和部分。在另外的实施方案中，即使可能对生物活性或对结构重要的区域也可以经历保守氨基酸取代，而不破坏生物活性或不会不利地影响多肽结构。

此外，本领域技术人员可以回顾鉴定相似多肽中对活性或结构重要的残基的结构-功能研究。鉴于这样的比较，技术人员可以预测对应于相似多肽中对活性或结构重要的氨基酸残基的多肽中的氨基酸残基的重要性。本领域技术人员可以选择对这样预测的重要氨基酸残基进行化学上相似的氨基酸取代。

本领域技术人员还可以分析相似多肽中与该结构相关的三维结构和氨基酸序列。鉴于这样的信息，本领域技术人员可以预测多肽的氨基酸残基在其三维结构方面的排列。在各种实施方案中，本领域技术人员可以选择不对预测在多肽表面上的氨基酸残基进行根本改变(radical changes)，因为此类残基可能参与与其他分子的重要相互作用。此外，本领域技术人员可以产生在每个期望的氨基酸残基处包含单个氨基酸取代的测试变体。然后可以使用本领域技术人员已知的活性测定来筛选变体。这些变体可以用于收集关于合适变体的信息。例如，如果人们发现，特定氨基酸残基的改变导致破坏的、不期望地减少的或不合适的活性，则可以避免具有这样的改变的变体。换句话说，基于从这样的常规实验收集的信息，本领域技术人员可以容易地确定应避免在该处单独的或与其他突变组合的进一步取代的氨基酸。

如本文使用的术语“多肽片段”和“截短的多肽”是指与对应的全长蛋白相比具有氨基末端缺失和/或羧基末端缺失的多肽。在各种实施方案中，片段的长度可以是例如，至少5个、至少10个、至少25个、至少50个、至少100个、至少150个、至少200个、至少250个、至少300个、至少350个、至少400个、至少450个、至少500个、至少600个、至少700个、至少800个、至少900个或至少1000个氨基酸。在各种实施方案中，片段的长度还可以是例如，最多1000个、最多900个、最多800个、最多700个、最多600个、最多500个、最多450个、最多400个、最多350个、最多300个、最多250个、最多200个、最多150个、最多100个、最多50个、最多25个、最多10个或最多5个氨基酸。片段还可以在其任一个或两个末端处包含一个或更多个另外的氨基酸，例如，来自不同的天然存在的蛋白的氨基酸的序列(例如，Fc或亮氨酸拉链结构域)或人工氨基酸序列(例如，人工接头序列)。

本文使用的术语“多肽变体”、“杂合多肽(hybrid polypeptide)”和“多肽突变体”是指包含这样的氨基酸序列的多肽，其中相对于另一个多肽序列，一个或更多个氨基酸残基被插入到该氨基酸序列中、从该氨基酸序列中缺失和/或被取代到该氨基酸序列中。在各种实施方案中，待被插入、缺失或取代的氨基酸残基的数目可以是例如，至少1个、至少2个、至少3个、至少4个、至少5个、至少10个、至少25个、至少50个、至少75个、至少100个、至少125个、至少150个、至少175个、至少200个、至少225个、至少250个、至少275个、至少300个、至少350个、至少400个、至少450个或至少500个氨基酸的长度。本公开内容的杂合体包括融合蛋白。

多肽的“衍生物”是已经被化学修饰的多肽，所述化学修饰例如，缀合至另一个化学部分(诸如例如，聚乙二醇、白蛋白(例如，人类血清白蛋白))、磷酸化和糖基化。

术语“％序列同一性”与术语“％同一性”在本文中可互换使用并且指当使用序列比对程序比对时，在两个或更多个肽序列之间的氨基酸序列同一性的水平或在两个或更多个核苷酸序列之间的核苷酸序列同一性的水平。例如，如本文使用的，通过定义的算法确定的80％同一性与80％序列同一性意指相同的意思，并且意指给定序列与另一长度的另一序列至少80％相同。在各种实施方案中，％同一性选自例如，与给定序列至少60％、至少65％、至少70％、至少75％、至少80％、至少85％、至少90％、至少95％或至少99％或更大的序列同一性。在各种实施方案中，％同一性在例如约60％至约70％、约70％至约80％、约80％至约85％、约85％至约90％、约90％至约95％或约95％至约99％的范围内。

术语“％序列同源性”与术语“％同源性”在本文中可互换使用并且指当使用序列比对程序比对时，在两个或更多个肽序列之间的氨基酸序列同源性的水平或在两个或更多个核苷酸序列之间的核苷酸序列同源性的水平。例如，如本文使用的，通过定义的算法确定的80％同源性与80％序列同源性意指相同的意思，并且因此给定序列的同源物具有相对于给定序列的长度大于80％的序列同源性。在各种实施方案中，％同源性选自例如，与给定序列至少60％、至少65％、至少70％、至少75％、至少80％、至少85％、至少90％、至少95％或至少99％或更大的序列同源性。在各种实施方案中，％同源性在例如约60％至约70％、约70％至约80％、约80％至约85％、约85％至约90％、约90％至约95％或约95％至约99％的范围内。

可以用于确定两个序列之间的同一性的示例性计算机程序包括但不限于在互联网在NCBI的网站上公开地可得的一套BLAST程序，例如BLASTN、BLASTX和TBLASTX、BLASTP和TBLASTN。另参见Altschul等人,J.Mol.Biol.215:403-10,1990(特别参考公布的默认设置，即参数w＝4、t＝17)和Altschul等人,Nucleic Acids Res.,25:3389-3402,1997。当相对于GenBank蛋白序列和其他公开数据库中的氨基酸序列评价给定氨基酸序列时，通常使用BLASTP程序进行序列检索。BLASTX程序优选用于针对在GenBank蛋白序列和其他公开数据库中的氨基酸序列检索在所有阅读框中已经被翻译的核酸序列。使用开放空位(gap)罚分为11.0和延伸空位罚分为1.0的默认参数并且使用BLOSUM-62矩阵运行BLASTP和BLASTX两者。

除了计算序列同一性百分比以外，BLAST算法还进行两个序列之间的相似性的统计分析(参见例如，Karlin&Altschul,Proc.Nat'l.Acad.Sci.USA,90:5873-5787,1993)。由BLAST算法提供的相似性的一个量度是最小总概率(P(N))，所述最小总概率提供在两个核苷酸序列或氨基酸序列之间的匹配偶然发生的概率的指示。例如，如果在测试核酸与参考核酸的比较中，最小总概率为例如小于约0.1、小于约0.01或小于约0.001，则该核酸被认为与参考序列相似。

如本文使用的术语“修饰”是指对肽骨架(例如氨基酸序列)的任何操作或对多肽的翻译后修饰(例如糖基化)。

如本文使用的术语“knob-into-hole修饰”是指两个免疫球蛋白重链的CH3结构域之间的界面内的修饰。在一种实施方案中，“knob-into-hole修饰”包含一条抗体重链中的氨基酸取代T366W和任选的氨基酸取代S354C，以及另一条抗体重链中的氨基酸取代T366S、L368A、Y407V和任选的Y349C。knob-into-hole技术在例如美国专利第5,731,168号；美国专利第7,695,936号；Ridgway等人,Prot Eng 9,617-621(1996)和Carter,J Immunol Meth248,7-15(2001)中描述。

如本文使用的术语“融合蛋白”是指包含两个或更多个最初编码不同蛋白的基因的融合多肽分子，其中融合蛋白的组分通过肽键直接彼此连接或通过肽接头彼此连接。如本文使用的术语“融合”是指通过肽键直接连接的组分或经由一个或更多个肽接头连接的组分。

“接头”是指共价地或通过离子键、范德华力或氢键连接两个其他分子的分子，例如在5'末端处与一个互补序列杂交并且在3'末端处与另一个互补序列杂交从而连接两个非互补序列的核酸分子。“可裂解的接头”是指可以被降解或以其他方式切断以使通过该可裂解的接头连接的两个组分分开的接头。可裂解的接头通常被酶，通常是肽酶、蛋白酶、核酸酶、脂肪酶等裂解。可裂解的接头还可以通过环境因素，诸如例如温度、pH、盐浓度等的改变来裂解。

如本文使用的术语“肽接头”是指包含一个或更多个氨基酸，通常为约2个-20个氨基酸的肽。肽接头是本领域已知的或在本文中被描述。合适的非免疫原性接头肽包括，例如，(G

“药物组合物”是指适于在动物中药物使用的组合物。药物组合物包含药理学有效量的活性剂和药学上可接受的载体。“药理学有效量”是指有效产生预期药理学结果的剂的量。“药学上可接受的载体”是指任何标准的药物载体、媒介物、缓冲剂和赋形剂，诸如磷酸盐缓冲盐水溶液、5％右旋糖的水性溶液，和乳液，诸如油/水乳液或水/油乳液，和各种类型的润湿剂和/或佐剂。合适的药学载体和制剂在Remington's Pharmaceutical Sciences,第21版2005,Mack Publishing Co,Easton中描述。“药学上可接受的盐”是可以被配制成用于药学用途的化合物的盐，包括例如金属盐(钠、钾、镁、钙等)和氨的盐或有机胺的盐。

如本文使用的，“治疗(treatment)”(及其语法变化形式诸如“治疗(treat)”或“治疗(treating)”)是指试图改变被治疗的个体的疾病的自然过程的临床干预，并且临床干预可以用于预防来进行或者在临床病理过程期间进行。期望的治疗效果包括但不限于，防止疾病的发生或复发、减轻症状、减轻疾病的任何直接或间接病理后果、防止转移、降低疾病进展速度、改善或缓和疾病状态以及缓解或改善预后。如本文使用的，“减轻”疾病、紊乱或状况意指降低疾病、紊乱或状况的症状的严重性和/或发生频率。另外，本文中述及“治疗”包括述及治愈性、缓解性和预防性治疗。

如本文使用的术语“有效量”或“治疗有效量”是指足以治疗特定紊乱、状况或疾病，诸如改善、缓和、减轻和/或延迟其一种或更多种症状的化合物或组合物的量。述及癌症或其他不需要的细胞增殖，有效量包括足以实现以下的量：(i)降低癌细胞的数目；(ii)降低肿瘤尺寸；(iii)在一定程度抑制、延缓、减缓并且优选地停止癌细胞浸润到外周器官中；(iv)抑制(即，在一定程度减缓并且优选地停止)肿瘤转移；(v)抑制肿瘤生长；(vi)预防或延迟肿瘤的发生和/或复发；和/或(vii)在一定程度减轻一种或更多种与癌症相关的症状。有效量可以以一次或更多次施用来施用。

措辞“施用”或“引起施用(cause to be administered)”是指由医学专业人员(例如医师)或控制患者的医疗护理的人员采取的控制和/或允许向患者施用所讨论的剂/化合物的行动。引起施用可以包括诊断和/或确定合适的治疗方案，和/或为患者开特定的剂/化合物的处方。这样的开处方可以包括例如起草处方形式、注释医疗记录等。当本文中描述施用时也设想了“引起施用”。

术语“患者”、“个体”和“受试者”可以互换地使用，并且指哺乳动物，优选人类或非人类灵长类动物，但也指家养哺乳动物(例如犬科动物或猫科动物)、实验室哺乳动物(例如小鼠、大鼠、兔、仓鼠、豚鼠)和农业哺乳动物(例如马科动物、牛科动物、猪、绵羊(ovine))。在各种实施方案中，患者可以是在医院、精神病护理机构如门诊或其他临床环境中的医师或其他卫生工作者的护理下的人类(例如，成年男性、成年女性、青少年男性、青少年女性、男性儿童、女性儿童)。在各种实施方案中，患者可以是免疫功能低下的患者或免疫系统减弱的患者，包括但不限于患有原发性免疫缺陷、AIDS的患者；服用某些免疫抑制药物的癌症患者和移植患者；以及患有影响免疫系统的遗传性疾病(例如，先天性无丙种球蛋白血症、先天性IgA缺乏症)的患者。在各种实施方案中，患者患有免疫原性癌症，包括但不限于膀胱癌、肺癌、黑素瘤和报道具有高突变率的其他癌症(Lawrence等人,Nature,499(7457):214-218,2013)。

如本文使用的术语“Fc结构域”或“Fc区”用于定义免疫球蛋白重链的C末端区域，其包含至少一部分恒定区。该术语包括天然序列Fc区和变体Fc区。IgG Fc区包含IgG CH2和IgG CH3结构域。本文中的CH3区可以是天然序列CH3结构域或变体CH3结构域(例如，在其一条链中具有引入的“突起(protuberance)”(“knob”)并且在其另一条链中具有相应的引入的“空腔(cavity)”(“hole”)的CH3结构域；参见美国专利第5,821,333号，通过引用明确并入本文)。这样的变体CH3结构域可以用于促进如本文描述的两个不同的免疫球蛋白重链的异源二聚体化。除非本文中另外规定，否则Fc区或恒定区中氨基酸残基的编号根据EU编号系统。

如本文使用的术语“效应子功能”是指可归因于免疫球蛋白的Fc区的那些生物活性，所述Fc区随免疫球蛋白亚型而不同。免疫球蛋白效应子功能的实例包括：C1q结合和补体依赖性细胞毒性(CDC)、Fc受体结合、抗体依赖性细胞介导的细胞毒性(ADCC)、抗体依赖性细胞吞噬作用(ADCP)、细胞因子分泌、免疫复合物介导的抗原呈递细胞的抗原摄取、细胞表面受体(例如B细胞受体)的下调和B细胞活化。

如本文使用的术语“调节性T细胞”或“Treg细胞”意指可以抑制其他T细胞(效应T细胞)的响应的专门类型的CD4+T细胞。Treg细胞的特征在于CD4、IL-2受体(CD25)的α亚基和转录因子叉头盒P3(FOXP3)的表达(Sakaguchi,Annu Rev Immunol 22,531-62(2004))，并在诱导和维持对抗原(包括由肿瘤表达的抗原)的外周自身耐受性中起关键作用。

如本文使用的术语“常规CD4+T细胞”意指调节性T细胞之外的CD4+T细胞。

如本文使用的术语“Treg细胞的选择性活化”意指基本上不伴随其他T细胞亚群(诸如CD4+辅助T细胞、CD8+细胞毒性T细胞)或自然杀伤(NK)细胞的活化的Treg细胞的活化。在实施例中描述了用于鉴定和区分这些细胞类型的方法。活化可包括诱导IL-2受体信号传导(如例如通过检测磷酸化的STAT5测量的)、诱导增殖(如例如通过检测Ki-67测量的)和/或上调活化标志物(诸如例如CD25)的表达以及细胞数量的扩增。

如本文使用的，“特异性结合”意指对抗原的结合是选择性的，并且可以与不需要的或非特异性的相互作用区分开。免疫球蛋白结合特定抗原的能力可以通过酶联免疫吸附测定(ELISA)或本领域技术人员熟悉的其他技术例如表面等离子体共振(SPR)技术来测量。

如本文使用的术语“亲和力”或“结合亲和力”是指分子(例如抗体)的单个结合位点与其结合配偶体(例如抗原)之间的非共价相互作用的总和的强度。分子X对其配偶体Y的亲和力一般可以通过解离常数(KD)来呈现，解离常数是解离速率常数和结合速率常数(分别为koff和kon)的比率。用于测量亲和力的一种特殊方法是表面等离子体共振(SPR)。

如本文使用的，术语“降低的结合”是指各自相互作用的亲和力的降低，如例如通过SPR测量的。相反，“增加的结合”是指各自相互作用的结合亲和力的增加。

如本文使用的术语“聚合物”通常包括但不限于均聚物；共聚物，诸如例如嵌段、接枝、无规和交替共聚物；和三元共聚物；以及它们的混合物和变化形式(modifications)。此外，除非另外明确限定，否则术语“聚合物”应包括材料的所有可能的几何构型。这些构型包括但不限于全同立构、间同立构和无规对称。

“多核苷酸”是指包含核苷酸单元的聚合物。多核苷酸包括天然存在的核酸，诸如脱氧核糖核酸(“DNA”)和核糖核酸(“RNA”)以及核酸类似物。核酸类似物包括包含以下的那些：非天然存在的碱基，以天然存在的磷酸二酯键以外的连接与其他核苷酸衔接(engage)的核苷酸，或包含通过除了磷酸二酯键以外的连接来附接的碱基的核苷酸。因此，核苷酸类似物包括例如并且不限于，硫代磷酸酯、二硫代磷酸酯、磷酸三酯(phosphorotriester)、氨基磷酸酯(phosphoramidate)、硼烷磷酸酯(boranophosphate)、甲基膦酸酯、手性甲基膦酸酯、2-O-甲基核糖核苷酸、肽核酸(PNA)等。这样的多核苷酸可以例如使用自动化的DNA合成仪来合成。术语“核酸”通常是指大的多核苷酸。术语“寡核苷酸”通常是指短的多核苷酸，通常不大于约50个核苷酸。将理解的是，当核苷酸序列由DNA序列(即，A、T、G、C)表示时，这还包括其中“U”代替“T”的RNA序列(即，A、U、G、C)。

本文使用常规符号描述多核苷酸序列：单链多核苷酸序列的左手末端为5'-末端；双链多核苷酸序列的左手方向被称作5'-方向。向新生RNA转录物5'至3'添加核苷酸的方向被称作转录方向。具有与mRNA相同的序列的DNA链被称作“编码链”；在具有与从该DNA转录的mRNA相同的序列的DNA链上并且位于RNA转录物的5'-末端的5'的序列被称作“上游序列”；在具有与RNA相同的序列的DNA链上并且在编码RNA转录物的3'-末端的3'的序列被称作“下游序列”。

“互补的”是指两个多核苷酸的相互作用表面的拓扑相容性或匹配在一起。因此，这两个分子可以被描述为互补的，并且更进一步地，接触表面特征是彼此互补的。如果第一多核苷酸的核苷酸序列与第二多核苷酸的多核苷酸结合配偶体的核苷酸序列基本上相同，或者如果第一多核苷酸可以与第二多核苷酸在严格杂交条件下杂交，则第一多核苷酸与第二多核苷酸是互补的。

“与...特异性杂交”或“特异性杂交”或“与...选择性杂交”是指当特定核苷酸序列存在于复杂混合物(例如，总细胞)DNA或RNA中时，在严格条件下核酸分子优先与该序列的结合、双链体化或杂交。术语“严格条件”是指这样的条件，在该条件下探针将优先与其靶子序列杂交，并且在较小程度上与其它序列杂交或根本不与其他序列杂交。在核酸杂交实验诸如DNA杂交和RNA杂交的背景下，“严格杂交”和“严格杂交洗涤条件”为序列依赖性的，并且在不同的环境参数下是不同的。对核酸杂交的广泛指导可见于：Tijssen,1993,Laboratory Techniques in Biochemistry and Molecular Biology--Hybridizationwith Nucleic Acid Probes,第I部分，第2章，“Overview of principles ofhybridization and the strategy of nucleic acid probe assays”,Elsevier,N.Y.；Sambrook等人,2001,Molecular Cloning:A Laboratory Manual,Cold Spring HarborLaboratory，第3增补版,NY；以及Ausubel等人，编著，现行版，Current Protocols inMolecular Biology,Greene Publishing Associates and Wiley Interscience,NY。

通常，高度严格的杂交和洗涤条件被选择为比在定义的离子强度和pH的特定序列的热解链点(Tm)低约5℃。Tm为50％的靶序列与完全匹配的探针杂交的温度(在定义的离子强度和pH条件下)。非常严格的条件被选择为等于特定探针的Tm。用于在DNA印迹或RNA印迹中的滤器上进行具有多于约100个互补残基的互补核酸的杂交的严格杂交条件的实例为在42℃，50％福尔马林与1mg肝素，过夜进行杂交。高度严格的洗涤条件的实例为在72℃，0.15M NaCl，持续约15分钟。严格洗涤条件的实例为在65℃，0.2x SSC洗涤，持续15分钟。参见Sambrook等人对于SSC缓冲液的描述。可以进行低严格洗涤以去除背景探针信号，然后进行高严格洗涤。对于例如多于约100个核苷酸的双链体的示例性中度严格洗涤为在45℃，1xSSC，持续15分钟。对于例如多于约100个核苷酸的双链体的示例性低严格洗涤为在40℃，4-6x SSC，持续15分钟。通常，在特定杂交测定中，与对不相关探针观察到的信噪比相比2x(或更高)的信噪比指示检测到特异性杂交。

“引物”是指能够与指定的多核苷酸模板特异性杂交并提供用于合成互补多核苷酸的起始点的多核苷酸。当多核苷酸引物被置于诱导合成的条件下(即，在核苷酸、互补多核苷酸模板和用于聚合的剂诸如DNA聚合酶的存在下)时，这样的合成发生。引物通常是单链的，但可以是双链的。引物通常为脱氧核糖核酸，但许多合成的和天然存在的引物可用于许多应用。引物与模板互补，引物被设计成与模板杂交以用作合成起始的位点，但不需要反映模板的精确序列。在这样的情况下，引物与模板的特异性杂交取决于杂交条件的严格度。引物可以用例如显色性、放射性或荧光性的部分标记并用作可检测的部分。

当用于述及多核苷酸使用时，“探针”是指能够与另一多核苷酸的指定序列特异性杂交的多核苷酸。探针与靶互补多核苷酸特异性杂交，但不需要反映模板的精确互补序列。在这样的情况下，探针与靶的特异性杂交取决于杂交条件的严格度。探针可以用例如显色性、放射性或荧光性的部分标记并用作可检测的部分。在其中探针提供用于合成互补多核苷酸的起始点的情况下，探针也可以是引物。

“载体”是可以被用于将与其连接的另一核酸引入到细胞中的多核苷酸。一种类型的载体是“质粒”，其是指可以将另外的核酸区段连接到其中的线性或环状双链DNA分子。另一种类型的载体是病毒载体(例如，复制缺陷型逆转录病毒、腺病毒和腺相关病毒)，其中另外的DNA区段可以被引入到病毒基因组中。某些载体能够在引入了它们的宿主细胞中自主复制(例如，包含细菌复制起点的细菌载体和附加型哺乳动物载体(episomal mammalianvector))。其他载体(例如，非附加型哺乳动物载体)在引入到宿主细胞中后被整合到宿主细胞的基因组中，并且从而与宿主基因组一起复制。“表达载体”是可以指导选择的多核苷酸的表达的一种类型的载体。

“调控序列”是影响与其可操作地连接的核酸的表达(例如，表达的水平、时机或位置)的核酸。调控序列可以例如直接对被调控的核酸发挥其作用，或通过一种或更多种其他分子(例如，与调控序列和/或核酸结合的多肽)的作用发挥其作用。调控序列的实例包括启动子、增强子和其他表达控制元件(例如多腺苷酸化信号)。调控序列的另外的实例描述于例如Goeddel,1990,Gene Expression Technology:Methods in Enzymology 185,Academic Press,San Diego；Calif.和Baron等人,1995,Nucleic Acids Res.23:3605-06中。如果调控序列影响核苷酸序列的表达(例如，表达的水平、时机或位置)，则核苷酸序列与调控序列“可操作地连接”。

“宿主细胞”是可以被用于表达本公开内容的多核苷酸的细胞。宿主细胞可以是原核生物，例如大肠杆菌(E.coli)，或者宿主细胞可以是真核生物，例如单细胞真核生物(例如，酵母或其他真菌)、植物细胞(例如，烟草或番茄植物细胞)、动物细胞(例如，人类细胞、猴细胞、仓鼠细胞、大鼠细胞、小鼠细胞或昆虫细胞)或杂交瘤。通常，宿主细胞是可以用编码多肽的核酸转化或转染的培养的细胞，所述核酸然后可以在宿主细胞中被表达。措辞“重组宿主细胞”可以被用于表示已经用待表达的核酸转化或转染的宿主细胞。宿主细胞还可以是包含核酸但不以期望的水平表达该核酸的细胞，除非调控序列被引入到宿主细胞中，使得调控序列变成与该核酸可操作地连接。应理解，术语宿主细胞不仅指特定的受试者细胞，而且还指这样的细胞的后代或潜在后代。因为某些修饰可以由于例如突变或环境影响而在随后世代中发生，这样的后代实际上可能与亲本细胞不相同，但仍然被包括在如本文使用的该术语的范围内。

术语“分离的分子”(其中分子是例如多肽或多核苷酸)是这样的分子：该分子凭借其起源或衍生的来源(1)不与在其天然状态中伴随其的、天然地缔合的组分缔合，(2)基本上不含来自相同物种的其他分子，(3)由来自不同物种的细胞表达，或(4)不存在于自然界中。因此，化学合成的或在与其天然起源的细胞不同的细胞系统中表达的分子将是与其天然缔合的组分“分离”的。也可以通过使用本领域熟知的纯化技术分离使分子基本上不含天然缔合的组分。分子纯度或均一性可以通过本领域熟知的许多手段来测定。例如，多肽样品的纯度可以使用本领域熟知的技术使用聚丙烯酰胺凝胶电泳和对凝胶染色以使多肽可视化来测定。为了某些目的，可以通过使用HPLC或本领域熟知的用于纯化的其他手段来提供更高的分辨率。

当样品的至少约60％至75％表现为单一种类的多肽时，蛋白或多肽是“基本上纯的”、“基本上均一的”或“基本上纯化的”。多肽或蛋白可以是单体的或多聚体的。基本上纯的多肽或蛋白将通常包含约50％、60％、70％、80％或90％W/W的蛋白样品，更通常约95％并且优选地将超过99％纯。蛋白纯度或均一性可以通过本领域熟知的许多手段来指示，所述手段诸如蛋白样品的聚丙烯酰胺凝胶电泳，随后用本领域熟知的染色剂对凝胶进行染色后使单个多肽条带可视化。为了某些目的，可以通过使用HPLC或本领域熟知的用于纯化的其他手段来提供更高的分辨率。

如本文使用的术语“标记”或“标记的”是指在抗体中掺入另一种分子。在一种实施方案中，标记物是可检测的标志物，例如掺入放射性标记的氨基酸或附接至可以通过标记的亲和素检测的生物素基部分的多肽(例如，包含荧光标志物的链霉亲和素或可以通过光学方法或量热法检测的酶活性)。在另一种实施方案中，标记物或标志物可以是治疗性的，例如药物缀合物或毒素。标记多肽和糖蛋白的各种方法是本领域中已知的并且可以被使用。用于多肽的标记物的实例包括但不限于以下：放射性同位素或放射性核素(例如

如本文使用的术语“异源”是指非天然的或在自然界不存在的组合或状态，所述组合或状态例如可以通过用源自另一来源的组分或状态替换现有的天然组分或状态来实现。类似地，在除了其中蛋白天然地表达的生物体之外的生物体中的蛋白表达构成异源表达系统和异源蛋白。

应理解，本文描述的本公开内容的方面和实施方案包括“由这些方面和实施方案组成”和/或“主要由这些方面和实施方案组成”。

本文中述及“约”值或参数包括(并且描述)针对该值或参数本身的变化。例如，述及“约X”的描述包括对“X”的描述。

除非上下文另外明确规定，否则如本文和所附的权利要求中使用的单数形式“一”、“或”和“该”包括复数指代物。应理解，本文描述的本公开内容的方面和变化形式包括“由这些方面和变化形式组成”和/或“主要由这些方面和变化形式组成”。

白介素-2(IL-2)是一种经典的Th1细胞因子，由T细胞通过T细胞抗原受体和共刺激分子CD28活化后产生。IL-2的调节通过作用于IL-2启动子以产生新的基因转录的信号传导途径和转录因子的活化而发生，但也涉及对IL-2mRNA的稳定性的调节。IL-2结合多链受体，包括通过Jak-STAT途径介导信号传导的高度调节的α链及β和γ链。IL-2向T细胞、B细胞和NK细胞递送活化、生长和分化信号。IL-2在介导活化诱导的T细胞的细胞死亡中也很重要，这一功能为终止免疫应答提供了关键机制。一种商业上可获得的未糖基化的人类重组IL-2产品阿地白介素(可从Prometheus Laboratories Inc.,San Diego Calif.以商标为

如本文使用的，术语“天然IL-2”和“天然白介素-2”在蛋白或多肽的上下文中是指任何天然存在的哺乳动物白介素-2氨基酸序列，包括未成熟形式或前体形式和成熟形式。各个物种的天然哺乳动物白介素-2的氨基酸序列的GenBank登录号的非限制性实例包括NP_032392.1(小家鼠(Mus musculus)，未成熟形式)、NP_001040595.1(猕猴(macacamulatta)，未成熟形式)、NP_000577.2(人类，前体形式)、CAA01199.1(人类，未成熟形式)、AAD48509.1(人类，未成熟形式)和AAB20900.1(人类)。在本发明的各种实施方案中，天然IL-2是天然存在的哺乳动物IL-2的未成熟或前体形式。在其他实施方案中，天然IL-2是天然存在的哺乳动物IL-2的成熟形式。在各种实施方案中，天然IL-2是天然存在的人类IL-2的前体形式。在各种实施方案中，天然IL-2是天然存在的人类IL-2的成熟形式。在各种实施方案中，IL-2源自SEQ ID NO:1中列出的人类IL-2前体序列的氨基酸序列：

在各种实施方案中，IL-2包含SEQ ID NO:3中列出的在位置125处包含半胱氨酸至丝氨酸的取代的人类IL-2成熟形式野生型序列的氨基酸序列，但是与天然存在的IL-2相比，不改变IL-2受体结合：

本发明涉及除了一个至若干个被突变的氨基酸以外，与人类IL-2共有一级序列的多肽。一组IL-2变体包含相对于效应T细胞和NK细胞优先促进免疫抑制性调节性T细胞(TCD4+CD25+FoxP3+)的增殖、存活、活化和/或功能的突变。还包括这样的IL-2选择性激动剂单独使用或与疾病组织靶向蛋白或肽组合使用以治疗Treg细胞缺乏性自身免疫性紊乱和各种炎性紊乱的治疗用途。在另一方面，本发明涉及包含所公开的多肽的药物组合物。最后，本发明涉及所公开的多肽和药物组合物的治疗用途，这是由于它们对免疫系统对疾病如自身免疫性紊乱和炎性紊乱或癌症和各种感染性疾病的选择性调节作用。

本发明涉及长度为100个至500个氨基酸的多肽，优选大小为140个残基，其表观分子量为至少15kD。这些多肽与天然IL-2保持多于90％的高序列同一性。在这些位置，这些多肽被突变，引入与天然IL-2中相同位置的氨基酸残基不同的氨基酸残基。

本发明的多肽可被称为免疫调节多肽、IL-2类似物或IL-2变体以及其他名称。这些多肽是基于IL-2受体复合物的3D结构(可在PDB公共数据库中获得)设计的，主要在与受体亚基β或γ或βγ相互作用的氨基酸对应的IL-2位置引入突变。

在各种实施方案中，IL-2变体(或突变体)包含源自如SEQ ID NO:3中列出的成熟的人类IL-2多肽序列的序列。在各种实施方案中，IL-2变体包含与天然(或野生型)IL-2蛋白不同的氨基酸序列。在各种实施方案中，IL-2变体结合IL-2Rα多肽，并且起IL-2激动剂或拮抗剂的作用。在各种实施方案中，具有激动剂活性的IL-2变体具有超级激动剂活性。在各种实施方案中，IL-2变体可以起IL-2激动剂或拮抗剂的作用，与其与IL-2Rα的缔合无关。IL-2激动剂通过与野生型IL-2相比生物活性相当或增加来例示。IL-2拮抗剂通过与野生型IL-2相比生物活性降低或通过抑制IL-2介导的响应的能力来例示。在各种实施方案中，与天然IL-2序列相比，IL-2变体的序列具有至少一个氨基酸变化，例如取代或缺失，这样的变化导致IL-2激动剂或拮抗剂活性。在各种实施方案中，作为Fc融合蛋白的IL-2变体具有SEQID NO:4-43、108-146和193-197中列出的氨基酸序列，具有减少的与IL-2Rβ和/或γ

示例性IL-2变体在表2A-表2F提供：

靶向IL-2Rβ界面和提出的毒性基序两者的IL-2单突变

靶向IL-2Rβ界面的IL-2单突变

靶向γc受体界面的IL-2单突变

靶向IL-2Rβ界面和提出的毒性基序两者的IL-2突变组合

靶向IL-2Rβ、γc界面和提出的毒性基序的IL-2突变组合

改进融合蛋白的可制造性并靶向IL-2Rβ和/或γc界面和提出的毒性基序的单个IL-2突变或组合IL-2突变

本发明还包括对以上提及的IL-2变体类别的另外修饰，尤其是对表2A-表2F中描述的IL-2变体的另外修饰。如技术人员可以理解的，组合表2A-表2F中描述的优选突变的另外的组合突变体可以产生更具Treg细胞选择性的IL-2激动剂。任何另外的组合突变都符合本发明的精神和范围，无论是增加它们对IL-2受体的特定组分的亲和力，还是改进它们的体内药效学：增加半衰期或减少它们被T细胞内化。这些另外的突变可以通过用生物信息学工具合理设计获得，或者通过使用不同性质的组合分子文库(噬菌体文库、酵母或细菌中的基因表达文库)获得。在另一方面，本发明涉及一种融合蛋白，该融合蛋白包含与载体蛋白偶联的上文描述的任何免疫调节多肽。载体蛋白可以是白蛋白或人类免疫球蛋白的Fc区。

IgG类的免疫球蛋白是人类血液中最丰富的蛋白之一。它们的循环半衰期可长达21天。已经报道了将IgG的Fc区与另一种蛋白(诸如各种细胞因子和受体)的结构域组合的融合蛋白(参见例如，Capon等人,Nature,337:525-531,1989；Chamow等人,TrendsBiotechnol.,14:52-60,1996)；美国专利第5,116,964号和第5,541,087号)。原型融合蛋白是通过IgG Fc的铰链区中的半胱氨酸残基连接的同源二聚体蛋白，产生类似于IgG分子、没有重链可变区和CH1结构域以及轻链的分子。包含Fc结构域的融合蛋白的二聚体性质在提供与其他分子的更高级相互作用(即二价或双特异性结合)方面可能是有利的。由于结构同源性，Fc融合蛋白表现出与具有相似同种型的人类IgG相当的体内药代动力学谱。

术语“Fc”是指包含完整抗体的非抗原结合片段的序列的分子或序列，无论是单体形式还是多聚体形式。天然Fc的原始免疫球蛋白来源优选地为人类来源，并且可以是任何免疫球蛋白，尽管IgG1和IgG2是优选的。天然Fc由单体多肽组成，单体多肽可以通过共价(即二硫键)和非共价缔合连接成二聚体或多聚体形式。天然Fc分子的单体亚基之间的分子间二硫键的数目取决于类别(例如IgG、IgA、IgE)或亚类(例如IgG1、IgG2、IgG3、IgA1、IgGA2)而在从1至4的范围内。天然Fc的一种实例是由木瓜蛋白酶消化IgG产生的二硫键合的二聚体(参见Ellison等人(1982),Nucleic Acids Res.10:4071-9)。如本文使用的术语“天然Fc”是单体、二聚体和多聚体形式的总称。Fc结构域包含蛋白A、蛋白G、各种Fc受体和补体蛋白的结合位点。

在各种实施方案中，术语“Fc变体”是指从天然Fc修饰、但仍然包含补救受体FcRn的结合位点的分子或序列。国际申请WO 97/34631(1997年9月25日公布)和WO 96/32478描述了示例性的Fc变体以及与补救受体的相互作用，并特此通过引用并入。此外，天然Fc包含可被去除的位点，因为它们提供本发明的融合分子不需要的结构特征或生物活性。因此，在各种实施方案中，术语“Fc变体”包括缺乏一个或更多个天然Fc位点或残基的分子或序列，所述天然Fc位点或残基影响或参与(1)二硫键形成，(2)与所选宿主细胞的不相容性，(3)在所选宿主细胞中表达时的N末端异质性，(4)糖基化，(5)与补体的相互作用，(6)与补救受体以外的Fc受体的结合，或(7)抗体依赖性细胞毒性(ADCC)。

术语“Fc结构域”包括如上文定义的天然Fc和Fc变体分子和序列。如同Fc变体和天然Fc，术语“Fc结构域”包括单体或多聚体形式的分子，无论是从完整抗体消化的还是通过重组基因表达或通过其他方式产生的。在各种实施方案中，“Fc结构域”是指两个Fc结构域单体(SEQ ID NO:44)的二聚体，其通常包括全部或部分的铰链区。在各种实施方案中，Fc结构域可以被突变以缺乏效应子功能。在各种实施方案中，Fc结构域中的每个Fc结构域单体包含CH2抗体恒定结构域中的氨基酸取代，以减少Fc结构域和Fcγ受体之间的相互作用或结合。在各种实施方案中，Fc结构域的每个亚基包含两个氨基酸取代，这两个氨基酸取代减少与活化性Fc受体的结合和/或效应子功能，其中所述氨基酸取代是L234A和L235A。在各种实施方案中，Fc结构域的每个亚基包含三个氨基酸取代，这三个氨基酸取代减少与活化性Fc受体的结合和/或效应子功能，其中所述氨基酸取代是L234A、L235A和G237A(SEQ ID NO:45)。

在各种实施方案中，Fc结构域中的两个Fc结构域单体中的每一个包含促进两个单体异源二聚体化的氨基酸取代。在各种其他实施方案中，Fc结构域单体的异源二聚体化可以通过在两个Fc结构域单体中引入不同但相容的取代诸如“knob-into-hole”残基对来促进。“knob-into-hole”技术也公开于美国专利公布第8,216,805号中。在又另一种实施方案中，一个Fc结构域单体包含knob突变T366W，并且另一个Fc结构域单体包含hole突变T366S、L358A和Y407V。在各种实施方案中，引入形成稳定化的二硫桥的两个Cys残基(S354C在“knob”侧，并且Y349C在“hole”侧)。异二聚体Fc的使用可以产生单价IL-2变体。

在各种实施方案中，Fc结构域可以被突变以进一步延长体内半衰期。在各种实施方案中，Fc结构域的每个亚基包含增强与人类FcRn的结合的三个氨基酸取代，其中所述氨基酸取代是M252Y、S254T和T256E(SEQ ID NO:156)，公开于美国专利公布第7,658,921号中。在各种实施方案中，Fc结构域的每个亚基包含增强与人类FcRn的结合的一个氨基酸取代，其中所述氨基酸取代是N434A，公开于美国专利公布第7,371,826号中。在各种实施方案中，Fc结构域的每个亚基包含增强与人类FcRn的结合的一个氨基酸取代，其中所述氨基酸取代是M428L和N434S，公开于美国专利公布第8,546,543号中。在各种实施方案中，半衰期延长突变可以与减少与活化性Fc受体的结合和/或效应子功能的氨基酸取代组合。

在各种实施方案中，用于制备IL-2变体Fc融合体的Fc结构域序列是SEQ ID NO:45中列出的具有和减少/消除的效应子功能的人类IgG1-Fc结构域序列：

其中SEQ ID NO:45包含消除FcγR和C1q结合的氨基酸取代(加下划线)。

在各种实施方案中，用于制备IL-2变体Fc融合体的Fc结构域序列是SEQ ID NO:46中列出的具有延长的半衰期和减少/消除的效应子功能的IgG1-Fc结构域

其中SEQ ID NO:46包含消除FcγR和C1q结合的氨基酸取代(加下划线)和延长融合蛋白血清半衰期的取代(粗体)。

在各种实施方案中，用于制备IL-2变体Fc融合体的Fc结构域序列是具有减少/消除的效应子功能和延长的半衰期的IgG1-Fc结构域并且具有SEQ ID NO:47中列出的氨基酸序列

其中SEQ ID NO:47包含消除FcγR和C1q结合的氨基酸取代(加下划线)和延长融合蛋白血清半衰期的取代(粗体)。

在各种实施方案中，用于制备IL-2变体Fc融合体的异源二聚体Fc结构域序列是SEQ ID NO:212中列出的具有延长的体内半衰期的Knob-Fc结构域序列：

其中SEQ ID NO:212包含消除FcγR和C1q结合的氨基酸取代(加下划线)和延长半衰期的氨基酸取代(粗体)。

在各种实施方案中，用于制备IL-2变体Fc融合体的异源二聚体Fc结构域序列是SEQ ID NO:213中列出的具有延长的体内半衰期的Hole-Fc结构域序列：

其中SEQ ID NO:213包含消除FcγR和C1q结合的氨基酸取代(加下划线)和延长半衰期的氨基酸取代(粗体)。

在各种实施方案中，异源蛋白通过接头和/或铰链接头肽附接至IL-2变体。接头或铰链接头可以是相对地不含二级结构或展示出α螺旋构象的在5个、10个、15个、20个、30个、40个或更多个氨基酸之间的人工序列。

肽接头在蛋白结构域之间提供共价连接和另外的结构和/或空间柔性。如本领域已知的，肽接头含有柔性氨基酸残基，诸如甘氨酸和丝氨酸。在各种实施方案中，肽接头可以包含1-100个氨基酸。在各种实施方案中，间隔物可以包含基序GGGSGGGS(SEQ ID NO:55)。在其他实施方案中，接头可以包含基序(GGGGS)n，其中n是1至10的整数。在其他实施方案中，接头还可以包含除甘氨酸和丝氨酸之外的氨基酸。在另一种实施方案中，接头可以包含其他蛋白基序，包括但不限于α-螺旋构象的序列，诸如AEAAAKEAAAKEAAAKA(SEQ ID NO：53)。在各种实施方案中，可以调节接头长度和组成以优化活性或可开发性，包括但不限于表达水平和聚集倾向。在另一种实施方案中，肽接头可以是简单的化学键，例如酰胺键(例如通过PEG的化学缀合)。

在表3中提供了示例性的肽接头：

在另一方面，本公开内容提供了分离的核酸分子，该分离的核酸分子包含编码本公开内容的IL-2、IL-2变体、IL-2融合蛋白或IL-2变体融合蛋白的多核苷酸。主题核酸可以是单链的或双链的。这样的核酸可以是DNA或RNA分子。DNA包括例如cDNA、基因组DNA、合成的DNA、通过PCR扩增的DNA及其组合。编码IL-2多肽的基因组DNA获取自基因组文库，该基因组文库对许多物种是可得的。合成的DNA从化学合成重叠的寡核苷酸片段然后组装片段以重构编码区和侧翼序列的部分或全部而可获得。可以从指导mRNA的高水平合成的原核表达载体，诸如使用T7启动子和RNA聚合酶的载体获得RNA。cDNA获取自从分离自表达IL-2的各种组织的mRNA制备的文库。本公开内容的DNA分子包括全长基因以及多核苷酸及其片段。全长基因还可以包含编码N末端信号序列的序列。此类核酸可以例如在用于制备新型IL-2变体的方法中使用。

在各种实施方案中，分离的核酸分子包含本文描述的多核苷酸，并且还包含编码本文描述的至少一种异源蛋白的多核苷酸。在各种实施方案中，核酸分子还包含编码本文描述的接头或铰链接头的多核苷酸。

在各种实施方案中，本公开内容的重组核酸可以可操作地连接至表达构建体中的一种或更多种调控核苷酸序列。调控序列是本领域所认知的并且被选择以指导IL-2变体的表达。相应地，术语调控序列包括启动子、增强子和其他表达控制元件。在Goeddel；GeneExpression Technology:Methods in Enzymology,Academic Press,San Diego,Calif.(1990)中描述了示例性的调控序列。通常，所述一种或更多种调控核苷酸序列可以包括但不限于启动子序列、前导或信号序列、核糖体结合位点、转录起始和终止序列、翻译起始和终止序列、以及增强子或激活序列。本公开内容设想了本领域已知的组成型或诱导型启动子。启动子可以是天然存在的启动子或者组合多于一个启动子的元件的杂合启动子。表达构建体可以存在于细胞中的附加体诸如质粒上，或者表达构建体可以插入染色体中。在各种实施方案中，表达载体包含选择性标志物基因以允许选择转化的宿主细胞。选择性标志物基因是本领域熟知的并且将随着使用的宿主细胞变化。

在本公开内容的另一方面，主题核酸在表达载体中提供，所述表达载体包含编码IL-2变体并可操作地连接到至少一个调控序列的核苷酸序列。术语“表达载体”是指用于从多核苷酸序列表达多肽的质粒、噬菌体、病毒或载体。适于在宿主细胞中表达的载体是容易地可得的并利用标准重组DNA技术将核酸分子插入到载体中。此类载体可以包括各种各样的表达控制序列，当被可操作地连接至DNA序列时，所述表达控制序列控制该DNA序列的表达，并可以在这些载体中使用以表达编码IL-2变体的DNA序列。此类有用的表达控制序列包括，例如，SV40的早期启动子和晚期启动子、tet启动子、腺病毒或巨细胞病毒介导的早期启动子、RSV启动子、lac系统、trp系统、TAC或TRC系统、其表达由T7 RNA聚合酶指导的T7启动子、λ噬菌体的主要操纵子和启动子区域、fd外壳蛋白的控制区域、3-磷酸甘油酸激酶或其他糖酵解酶的启动子、酸性磷酸酶例如PhoS的启动子、酵母a-交配因子的启动子、杆状病毒系统的多角体启动子和已知控制原核细胞或真核细胞或它们的病毒的基因表达的其他序列及其各种组合。应理解，表达载体的设计可能取决于诸如待转化的宿主细胞的选择和/或期望表达的蛋白的类型的因素。此外，还应考虑载体的拷贝数、控制该拷贝数的能力、以及载体编码的任何其他蛋白诸如抗生素标志物的表达。适用于表达vIL-2的示例性表达载体是包含vIL-2多核苷酸的pDSRa(描述于WO 90/14363，通过引用并入本文)及其衍生物，以及本领域已知的或下文描述的任何另外的合适的载体。

本公开内容的重组核酸可以通过将克隆的基因或其一部分连接到适于在原核细胞、真核细胞(酵母、鸟类、昆虫或哺乳动物)或两者中表达的载体中来产生。用于产生重组IL-2多肽的表达载体包括质粒和其他载体。例如，合适的载体包括以下类型的质粒：用于在原核细胞诸如大肠杆菌中表达的pBR322衍生的质粒、pEMBL衍生的质粒、pEX衍生的质粒、pBTac衍生的质粒和pUC衍生的质粒。

一些哺乳动物表达载体包含利于载体在细菌中增殖的原核序列以及在真核细胞中表达的一种或更多种真核转录单元两者。pcDNAI/amp、pcDNAI/neo、pRc/CMV、pSV2gpt、pSV2neo、pSV2-dhfr、pTk2、pRSVneo、pMSG、pSVT7、pko-neo和pHyg衍生的载体为适于转染真核细胞的哺乳动物表达载体的实例。这些载体中的一些被来自细菌质粒诸如pBR322的序列修饰，以利于在原核细胞和真核细胞两者中复制和药物抗性选择。可选地，病毒诸如牛乳头瘤病毒的衍生物(BPV-1)或Epstein-Barr病毒的衍生物(pHEBo、pREP衍生的和p205)可以用于蛋白在真核细胞中的瞬时表达。其他病毒(包括逆转录病毒)表达系统的实例可见于下文基因疗法递送系统的描述中。在质粒的制备方面和宿主生物体的转化方面所采用的各种方法是本领域熟知的。对于适于原核细胞和真核细胞两者的其他表达系统以及一般的重组程序，参见Sambrook、Fritsch和Maniatis的Molecular Cloning A Laboratory Manual,第2版(Cold Spring Harbor Laboratory Press,1989)第16和17章。在一些情形下，可能期望通过使用杆状病毒表达系统来表达重组多肽。此类杆状病毒表达系统的实例包括pVL衍生的载体(诸如pVL1392、pVL1393和pVL941)、pAcUW衍生的载体(诸如pAcUW1)以及pBlueBac衍生的载体(诸如含有B-gal的pBlueBac III)。

在各种实施方案中，载体将被设计成用于在CHO细胞中产生主题IL-2变体，诸如Pcmv-Script载体(Stratagene,La Jolla,Calif.)、pcDNA4载体(Invitrogen,Carlsbad,Calif.)和pCI-neo载体(Promega,Madison,Wis.)。将明显的是，主题基因构建体可以被用于引起主题IL-2变体在增殖于培养基中的细胞中表达，例如以产生用于纯化的蛋白，包括融合蛋白或变体蛋白。

本公开内容还涉及用重组基因转染的宿主细胞，所述重组基因包含编码一种或更多种主题IL-2变体的氨基酸序列的核苷酸序列。宿主细胞可以是原核细胞或真核细胞。例如，本公开内容的IL-2变体可以在细菌细胞诸如大肠杆菌、昆虫细胞(例如，使用杆状病毒表达系统)、酵母或哺乳动物细胞中表达。其他合适的宿主细胞是本领域技术人员已知的。

相应地，本公开内容还涉及产生主题IL-2变体的方法。例如，可以在允许发生IL-2变体的表达的适当条件下培养用编码IL-2变体的表达载体转染的宿主细胞。IL-2变体可以从含有IL-2变体的细胞分泌和从含有IL-2变体的细胞和培养基的混合物分离。可选地，IL-2变体可以保留在细胞质中或保留在膜级分中，并收获、裂解细胞和分离蛋白。细胞培养物包括宿主细胞、培养基和其他副产物。用于细胞培养的合适培养基是本领域熟知的。

本公开内容的多肽和蛋白可以根据本领域技术人员熟知的蛋白纯化技术来纯化。这些技术在一个层面上涉及蛋白质级分和非蛋白质级分的粗分级。将肽或多肽与其他蛋白分离后，可以利用色谱技术和电泳技术进一步纯化感兴趣的肽或多肽，以实现部分或完全纯化(或纯化至均一)。如本文使用的术语“分离的多肽”或“纯化的多肽”意图指可与其他组分分离的组合物，其中多肽被纯化至相对于其天然可获得状态的任何程度。因此纯化的多肽还指脱离其可能天然存在的环境的多肽。通常，“纯化的”将指已经经历分级以去除各种其他组分的多肽组合物，并且多肽该组合物基本上保留了其表达的生物活性。当使用术语“基本上纯化的”时，该指定将指这样的肽或多肽组合物，其中多肽或肽形成组合物的大部分组分，诸如构成组合物中的蛋白的约50％、约60％、约70％、约80％、约85％或约90％或更多。

适用于纯化的各种技术将是本领域技术人员熟知的。这些技术包括，例如，用硫酸铵、PEG、抗体(免疫沉淀)等沉淀或通过热变性沉淀，然后离心；色谱，诸如亲和色谱(蛋白A柱)、离子交换色谱、凝胶过滤色谱、反相色谱、羟基磷灰石色谱、疏水相互作用色谱；等电聚焦；凝胶电泳；以及这些技术的组合。如本领域一般已知的，认为进行各种纯化步骤的顺序可以改变，或者某些步骤可以省略，并且仍得到用于制备基本上纯化的多肽的合适方法。

在另一方面，本公开内容提供了药物组合物，所述药物组合物包含与药学上可接受的载体混合的IL-2变体或IL-2变体融合蛋白。此类药学上可接受的载体是本领域普通技术人员所熟知并理解的，并且已被广泛描述(参见例如，Remington's PharmaceuticalSciences,第18版,A.R.Gennaro编著,Mack Publishing Company,1990)。可以包括药学上可接受的载体以用于改变、保持或维持，例如，pH、摩尔渗透压浓度、黏度、澄清度、颜色、等渗性、气味、无菌性、稳定性、溶解或释放速率、组合物的吸收或渗透的目的。这样的药物组合物可以影响多肽的物理状态、稳定性、体内释放速率以及体内清除速率。合适的药学上可接受的载体包括但不限于，氨基酸(诸如甘氨酸、谷氨酰胺、天冬酰胺、精氨酸或赖氨酸)；抗菌剂；抗氧化剂(诸如抗坏血酸、亚硫酸钠或亚硫酸氢钠)；缓冲剂(诸如硼酸盐、碳酸氢盐、Tris-HCl、柠檬酸盐、磷酸盐、其他有机酸)；填充剂(bulking agents)(诸如甘露醇或甘氨酸)；螯合剂(诸如乙二胺四乙酸(EDTA))；复合剂(complexing agent)(诸如咖啡因、聚乙烯吡咯烷酮、β-环糊精或羟丙基-β-环糊精)；填料；单糖；二糖和其他碳水化合物(诸如葡萄糖、甘露糖或糊精)；蛋白(诸如血清白蛋白、明胶或免疫球蛋白)；着色剂；调味剂和稀释剂；乳化剂；亲水性聚合物(诸如聚乙烯吡咯烷酮)；低分子量多肽；盐形成抗衡离子(诸如钠)；防腐剂(诸如苯扎氯铵、苯甲酸、水杨酸、硫柳汞、苯乙醇、对羟基苯甲酸甲酯、对羟基苯甲酸丙酯、氯己定、山梨酸或过氧化氢)；溶剂(诸如甘油、丙二醇或聚乙二醇)；糖醇(诸如甘露醇或山梨醇)；悬浮剂；表面活性剂或润湿剂(诸如普朗尼克、PEG、山梨醇酐酯(sorbitanesters)、聚山梨醇酯诸如聚山梨醇酯20、聚山梨醇酯80、曲拉通(triton)、氨丁三醇、卵磷脂、胆固醇、tyloxapal)；稳定性增强剂(蔗糖或山梨醇)；张度增强剂(诸如碱金属卤化物(优选氯化钠或氯化钾)、甘露醇和山梨醇)；递送媒介物；稀释剂；赋形剂和/或药物佐剂(pharmaceutical adjuvants)。

药物组合物中的主要媒介物或载体实质上可以是水性的或非水性的。例如，合适的媒介物或载体可以是可能补充有用于肠胃外施用的组合物中常见的其他材料的注射用水、生理盐水溶液或人工脑脊液。中性缓冲盐水或与血清白蛋白混合的盐水是另外的示例性媒介物。其他的示例性药物组合物包含约pH 7.0-8.5的Tris缓冲液或约pH 4.0-5.5的乙酸盐缓冲液，其还可以包含山梨醇或山梨醇的合适替代物。在本公开内容的一种实施方案中，可以通过将选择的具有期望程度的纯度的组合物与任选的制剂用剂(formulationagent)(Remington's Pharmaceutical Sciences,同上)混合来制备组合物以便以冻干的块状物或水性溶液形式储存。另外，可以使用合适的赋形剂诸如蔗糖将治疗组合物配制为冻干物。最佳的药物组合物将取决于例如意图的施用途径、递送形式和期望的剂量由本领域普通技术人员确定。

当设想肠胃外施用时，治疗性药物组合物可以呈在药学上可接受的媒介物中包含期望的IL-2多肽或IL-2多肽融合蛋白的无致热原、肠胃外可接受的水性溶液的形式。用于肠胃外注射的特别合适的媒介物是无菌蒸馏水，其中多肽被配制为合适储存的无菌、等渗溶液。在各种实施方案中，适于可注射施用的药物制剂可以在水性溶液，优选地在生理上相容的缓冲液诸如Hanks溶液、Ringer溶液或生理缓冲盐水中配制。水性注射悬浮液可以包含增加悬浮液黏度的物质，诸如羧甲基纤维素钠、山梨醇或右旋糖酐。此外，活性化合物的悬浮液可以被制备为合适的油性注射悬浮液。任选地，悬浮液还可以包含合适的稳定剂或增加化合物的溶解度并允许制备高度浓缩的溶液的剂。

在各种实施方案中，可以使用胶体分散系统将治疗性药物组合物配制为用于靶向递送。胶体分散系统包括大分子复合体、纳米胶囊、微球、珠和基于脂质的系统，基于脂质的系统包括水包油乳液、胶束、混合的胶束和脂质体。在脂质体产生中有用的脂质的实例包括磷脂酰化合物，诸如磷脂酰甘油、磷脂酰胆碱、磷酯酰丝氨酸、磷脂酰乙醇胺、鞘脂、脑苷脂和神经节苷脂。示例性磷脂包括卵磷脂、二棕榈酰磷脂酰胆碱和二硬脂酰磷脂酰胆碱。脂质体的靶向还可以基于例如器官特异性、细胞特异性和细胞器特异性并且是本领域已知的。

在各种实施方案中，设想了药物组合物的口服施用。以该形式施用的药物组合物可以使用或不使用固体剂型诸如片剂和胶囊的复合中通常使用的那些载体配制。在用于口服施用的固体剂型(胶囊、片剂、丸剂、糖衣丸、粉末、颗粒等)中，本公开内容的一种或更多种治疗化合物可以与一种或更多种药学上可接受的载体诸如柠檬酸钠或磷酸氢钙(dicalcium phosphate)和/或以下中的任一种混合：(1)填料或增量剂(extender)，诸如淀粉、乳糖、蔗糖、葡萄糖、甘露醇和/或硅酸；(2)粘合剂，诸如例如羧甲基纤维素、藻酸盐(alginate)、明胶、聚乙烯吡咯烷酮、蔗糖和/或阿拉伯树胶；(3)保湿剂，诸如甘油；(4)崩解剂，诸如琼脂-琼脂、碳酸钙、马铃薯或木薯淀粉、藻酸、某些硅酸盐和碳酸钠；(5)溶液阻滞剂，诸如石蜡；(6)吸收加速剂，诸如季铵化合物；(7)润湿剂，诸如例如鲸蜡醇和单硬脂酸甘油酯；(8)吸收剂，诸如高岭土和膨润土；(9)润滑剂，诸如滑石、硬脂酸钙、硬脂酸镁、固体聚乙二醇、月桂基硫酸钠及其混合物；以及(10)着色剂。在胶囊、片剂和丸剂的情况下，药物组合物还可以包含缓冲剂。相似类型的固体组合物还可以用作使用诸如乳糖(lactose)或乳糖(milk sugar)以及高分子量聚乙二醇等的赋形剂软填充和硬填充的明胶胶囊中的填料。用于口服施用的液体剂型包括药学上可接受的乳液、微乳液、溶液、悬浮液、糖浆剂和酏剂。除了活性成分之外，液体剂型可以包含本领域中常用的惰性稀释剂，诸如水或其他的溶剂、增溶剂和乳化剂诸如乙醇、异丙醇、碳酸乙酯、乙酸乙酯、苄醇、苯甲酸苄酯、丙二醇、1,3-丁二醇、油(特别地，棉籽油、花生油、玉米油、胚芽油、橄榄油、蓖麻油和芝麻油)、甘油、四氢糠醇、聚乙二醇和脱水山梨醇的脂肪酸酯及其混合物。除惰性稀释剂之外，口服组合物还可以包含辅料(adjuvants)，诸如润湿剂、乳化剂和悬浮剂、增甜剂、调味剂、着色剂、增香剂和防腐剂。

在各种实施方案中，设想了将药物组合物局部施用(topical administration)至皮肤或施用至黏膜。局部制剂还可以包含已知作为皮肤或角质层渗透增强剂有效的各种各样的剂中的一种或更多种。这些剂的实例是2-吡咯烷酮、N-甲基-2-吡咯烷酮、二甲基乙酰胺、二甲基甲酰胺、丙二醇、甲醇或异丙醇、二甲基亚砜和氮酮。还可以包含另外的剂以使制剂在化妆品上可接受。这些剂的实例是脂肪、蜡、油、染料、芳香剂、防腐剂、稳定剂和表面活性剂。还可以包含角质软化剂(keratolytic agent)，诸如本领域已知的那些角质软化剂。实例是水杨酸和硫磺。用于局部或经皮施用的剂型包括粉末、喷雾剂、软膏剂(ointments)、糊剂、霜剂(creams)、洗剂、凝胶、溶液、贴剂和吸入剂。可以在无菌条件下将活性化合物与药学上可接受的载体以及与可能需要的任何防腐剂、缓冲剂或喷射剂混合。除了本公开内容的主题化合物(例如IL-2变体)之外，软膏剂、糊剂、霜剂和凝胶可以包含赋形剂，诸如动物和植物脂肪、油、蜡、石蜡、淀粉、黄芪胶、纤维素衍生物、聚乙二醇、硅酮、膨润土、硅酸、滑石和氧化锌或其混合物。

本文中设想的用于使用的另外的药物组合物包括在持续递送或控制递送的制剂中包含多肽的制剂。用于配制各种其他持续递送或控制递送工具诸如脂质体运载体、生物可侵蚀的微粒或多孔珠和贮库型注射剂的技术也是本领域技术人员已知的。

待被治疗上使用的药物组合物的有效量将取决于例如治疗背景和治疗目标。本领域技术人员将理解，用于治疗的适当剂量水平将因此部分地取决于所递送的分子、多肽所用于的适应症、施用途径、以及患者的尺寸(体重、体表或器官尺寸)和状况(年龄和总体健康)而变化。相应地，临床医师可以调整剂量并改变施用途径以获得最佳治疗效果。典型的剂量可以取决于上文提及的因素而在从约0.001mg/kg至最多约100mg/kg或更多的范围内。多肽组合物可以优选地注射或静脉内施用。长效药物组合物可以取决于特定制剂的半衰期和清除速率每三天至每四天一次、每周一次或每两周一次施用。给药频率将取决于使用的制剂中的多肽的药代动力学参数。通常，施用组合物直至达到实现期望的效果的剂量。因此组合物可以作为单剂量或作为随时间的多剂量(以相同或不同的浓度/剂量)或作为持续的输注施用。常规地进行适当剂量的进一步改进。适当的剂量可以通过使用适当的剂量-响应数据来确定。

药物组合物的施用途径根据已知方法，例如口服；通过静脉内、腹膜内、脑内(实质内)、脑室内、肌内、眼内、动脉内、门静脉内、病灶内途径，髓内、鞘内、心室内、经皮、皮下或腹膜内或瘤内注射；以及鼻内、肠内、局部、舌下、尿道、阴道或直肠方式；通过持续释放系统或通过植入装置。当期望时，组合物可以通过团注(bolus)注射施用，或通过输注持续施用，或通过植入装置施用。可选地或另外地，组合物可以经由期望的分子已经吸附或包封至其上的膜、海绵状物或另一种适当的材料的植入局部施用。当使用植入装置时，可以将该装置植入到任何合适的组织或器官中，并且期望的分子的递送可以经由扩散施用、缓释团注或持续施用。

本公开内容提供了用于治疗受试者的自身免疫性疾病的方法，该方法包括向所述受试者施用在药学上可接受的载体中的治疗有效量(作为单一疗法或在组合疗法方案中)的本公开内容的IL-2变体或IL-2变体融合蛋白。与本发明相关的自身免疫性疾病是起因于个体的自身组织并针对个体的自身组织的疾病或紊乱或其共分离系或表现或由其产生的状况。在各种实施方案中，自身免疫性疾病包括但不限于，关节炎(包括类风湿性关节炎、反应性关节炎)、系统性红斑狼疮(SLE)、银屑病和炎症性肠病(IBD)、脑脊髓炎、葡萄膜炎、重症肌无力、多发性硬化、胰岛素依赖性糖尿病、艾迪生氏病、乳糜泻、慢性疲劳综合征、自身免疫性肝炎、自身免疫性脱发、强直性脊柱炎、溃疡性结肠炎、克罗恩病、纤维肌痛、寻常性天疱疮、干燥综合征、川崎病、甲状腺机能亢进/格雷夫斯病、甲状腺功能减退/桥本病、子宫内膜异位症、硬皮病、恶性贫血、肺出血肾炎综合征、吉兰-巴雷综合征、韦格纳病、肾小球肾炎、再生障碍性贫血(包括多次输血的再生障碍性贫血患者)、阵发性夜间血红蛋白尿症、骨髓增生异常综合征、特发性血小板减少性紫癜、自身免疫性溶血性贫血、埃文综合征、因子VIII抑制物综合征、系统性血管炎、皮肌炎、多肌炎和风湿热、自身免疫性淋巴增生综合征(ALPS)、自身免疫性大疱性类天疱疮、帕金森病、结节病、白癜风、原发性胆汁性肝硬化和自身免疫性心肌炎。

在另一方面，本公开内容提供了用于治疗受试者的炎性疾病的方法，该方法包括向所述受试者施用在药学上可接受的载体中的治疗有效量(作为单一疗法或在组合疗法方案中)的本公开内容的IL-2变体或IL-2变体融合蛋白。“炎性疾病”包括与急性炎症或各种炎症相关的所有疾病。急性炎症是身体对有害刺激的初始反应，并且由血浆和白细胞(诸如例如粒细胞)从血液到损伤组织中的增加的移动引起。许多生物化学事件传播炎性反应并使炎性反应成熟，所述炎性反应涉及损伤组织内的局部血管系统、免疫系统和各种细胞。长期的炎症被称为慢性炎症，其导致存在于炎症部位处的细胞类型的进行性变化，并且其特征在于来自炎症过程的组织的同时破坏和愈合。在另一方面，本公开内容提供了用于治疗受试者的炎性疾病的方法，该方法包括向有相应需要的受试者施用治疗有效量的本发明的药物组合物。在一种实施方案中，受试者是人类受试者。在各种实施方案中，待治疗的炎性疾病包括但不限于，克罗恩病、结肠炎、皮炎、银屑病、憩室炎、肝炎、肠易激综合征(IBS)、红斑狼疮、肾炎、帕金森病、溃疡性结肠炎、胶原性结肠炎、淋巴细胞性结肠炎、缺血性结肠炎、改道性结肠炎(diversion colitis)、白塞氏综合征和未定型结肠炎多发性硬化(MS)、阿尔茨海默病、关节炎、类风湿性关节炎、哮喘和各种心血管疾病诸如动脉粥样硬化和血管炎。在各种实施方案中，炎性疾病选自由以下组成的组：类风湿性关节炎、糖尿病、痛风、cryopyrin相关周期性综合征和慢性阻塞性肺病。

在另一方面，本公开内容提供了用于受试者的器官移植或相关的移植物抗宿主病的方法，所述方法包括向有相应需要的受试者施用治疗有效量的本发明的药物组合物。在一种实施方案中，受试者是人类受试者。在各种实施方案中，移植选自心脏、肾、肝、肺、胰腺、肠和胸腺的器官移植，或选自骨、肌腱、角膜、皮肤、心脏瓣膜、神经和血管的组织移植。如本文使用的，术语“移植物抗宿主病”或“GvHD”是指一种状况，包括急性和慢性的，由移植的(移植物)细胞对宿主细胞和组织的由GVH引起的作用引起。换句话说，输注的移植物内的供体免疫细胞或由干细胞发育而来的供体免疫细胞，可能会将患者(宿主)细胞视为外来的并通过免疫应答来对抗它们。具体地，急性移植物抗宿主病(GvHD)是一种由经过同种异体骨髓或血细胞移植的患者体内的供体免疫细胞引起的紊乱。最常见的受影响组织是皮肤、肠和肝。在严重的情况下，GvHD可以引起皮肤起疱或过度腹泻和消瘦。泼尼松和/或其他免疫抑制药物用于治疗急性移植物抗宿主病。

治疗有效剂量可以通过确定EC

可以调整剂量方案以提供最佳的期望的响应(例如，治疗响应或预防响应)。例如，可以施用单次团注，可以随时间施用若干分次剂量(多个或重复或维持)并且剂量可以根据治疗情境的迫切需要所指示的按比例减少或增加。为了便于施用和剂量的一致性，配制呈剂量单位形式的肠胃外组合物是特别有益的。如本文使用的剂量单位形式是指适合作为用于待治疗的哺乳动物受试者的单一剂量的物理分散的单位；每一个单位包含与需要的药物载体一起的被计算产生期望的治疗作用的预定的量的活性化合物。本公开内容的剂量单位形式的规格将主要由抗体的独特特征和待实现的特定治疗作用或预防作用决定。

因此，技术人员将理解，基于本文提供的公开内容，根据治疗领域熟知的方法调整剂量和给药方案。即，最大可耐受剂量可以被容易地确定，并且向受试者提供可检测的治疗益处的有效量也可以被确定，向受试者提供可检测的治疗益处而施用每种剂的时间要求同样可以被确定。因此，尽管在本文中例举了某些剂量和施用方案，这些实例绝非限制在实践本公开内容时可以向受试者提供的剂量和施用方案。

应注意，剂量值可以随着待减轻的状况的类型和严重性而变化，并且可以包括单个剂量或多于一个剂量。还应理解，对于任何特定受试者，应根据个体需要和施用组合物或监督组合物的施用的人士的专业判断随时间调整具体剂量方案，并且本文列出的剂量范围仅是示例性的并且不意图限制所要求保护的组合物的范围或实践。另外，本公开内容的组合物的剂量方案可以基于多个因素，包括疾病的类型、受试者的年龄、体重、性别、医学状况、状况的严重性、施用途径和使用的特定抗体。因此，剂量方案可以广泛变化，但可以使用标准方法常规地确定。例如，剂量可以基于药代动力学或药效学参数调整，所述参数可以包括临床作用诸如毒性作用和/或实验值。因此，本公开内容包括如技术人员确定的受试者内的剂量递增(intra-subject dose-escalation)。确定适当的剂量和方案是相关技术领域熟知的并且将被理解为一旦提供本文所公开的教导，则由技术人员掌握。

取决于上文描述的因素，本公开内容的IL-2变体或IL-2变体融合蛋白的治疗或预防有效量的示例性、非限制性每日给药范围可以在从约0.1μg/kg至100mg/kg或更多的范围内。对于若干天或更长时间的重复施用，取决于状况，治疗通常会持续直到出现期望的疾病症状的抑制。在各种实施方案中，剂量将在从约0.0001mg/kg至100mg/kg、0.0001mg/kg至90mg/kg、0.0001mg/kg至80mg/kg、0.0001mg/kg至70mg/kg、0.0001mg/kg至60mg/kg、0.0001mg/kg至50mg/kg、0.0001mg/kg至40mg/kg、0.0001mg/kg至30mg/kg、0.0001mg/kg至20mg/kg、0.0001mg/kg至10mg/kg、0.0001mg/kg至5mg/kg、0.0001mg/kg至4mg/kg、0.0001mg/kg至3mg/kg、0.0001mg/kg至2mg/kg、0.0001mg/kg至1mg/kg、0.001mg/kg至50mg/kg、0.001mg/kg至40mg/kg、0.001mg/kg至30mg/kg、0.001mg/kg至20mg/kg、0.001mg/kg至10mg/kg、0.001mg/kg至5mg/kg、0.001mg/kg至4mg/kg、0.001mg/kg至3mg/kg、0.001mg/kg至2mg/kg、0.001mg/kg至1mg/kg、0.010mg/kg至50mg/kg、0.010mg/kg至40mg/kg、0.010mg/kg至30mg/kg、0.010mg/kg至20mg/kg、0.010mg/kg至10mg/kg、0.010mg/kg至5mg/kg、0.010mg/kg至4mg/kg、0.010mg/kg至3mg/kg、0.010mg/kg至2mg/kg、0.010mg/kg至1mg/kg、0.1mg/kg至50mg/kg、0.1mg/kg至40mg/kg、0.1mg/kg至30mg/kg、0.1mg/kg至20mg/kg、0.1mg/kg至10mg/kg、0.1mg/kg至5mg/kg、0.1mg/kg至4mg/kg、0.1mg/kg至3mg/kg、0.1mg/kg至2mg/kg、0.1mg/kg至1mg/kg、1mg/kg至50mg/kg、1mg/kg至40mg/kg、1mg/kg至30mg/kg、1mg/kg至20mg/kg、1mg/kg至10mg/kg、1mg/kg至5mg/kg、1mg/kg至4mg/kg、1mg/kg至3mg/kg、1mg/kg至2mg/kg或1mg/kg至1mg/kg体重等的范围中，可以基于以上描述的数量来施用。因此，可以向患者施用约0.5mg/kg、2.0mg/kg、5.0mg/kg或10mg/kg(或其任何组合)的一种或更多种剂量。应注意，剂量值可以随着待被缓解的状况的类型和严重性变化。还应理解，对于任何特定受试者，应根据个体需要和施用组合物或监督组合物的施用的人士的专业判断随时间调整具体剂量方案，并且本文列出的剂量范围仅是示例性的并且不意图限制所要求保护的组合物的范围或实践。

本公开内容的药物组合物的毒性和治疗指数可以在细胞培养物或实验动物中通过标准制药学程序确定，例如，确定LD

IL-2变体或IL-2变体融合蛋白药物组合物的施用的给药频率取决于疗法的性质和被治疗的特定疾病。受试者可以以规律间隔治疗，诸如每周两次、每周地或每月地，直到实现期望的治疗结果。示例性给药频率包括但不限于：无间断地每周一次；每2周一次；每3周一次；无间断地每周一次，持续2周，然后每月一次；无间断地每周一次，持续3周，然后每月一次；每月一次；每两个月一次；每3个月一次；每4个月一次；每5个月一次；或每6个月一次，或每年一次。

如本文使用的，提及本公开内容的IL-2变体或IL-2变体融合蛋白和一种或更多种其他治疗剂时，术语“共施用(co-administration)”、“共施用(co-administered)”和“与...组合(in combination with)”意图意指，并且的确是指并且包括以下：本公开内容的IL-2变体或IL-2变体融合蛋白和一种或更多种治疗剂的此类组合同时施用至需要治疗的受试者，其中这样的组分被一起配制成单一剂型，所述单一剂型在基本上相同的时间将所述组分释放至所述受试者；本公开内容的IL-2变体或IL-2变体融合蛋白和一种或更多种治疗剂的此类组合基本上同时施用至需要治疗的受试者，其中这样的组分彼此分开配制成单独的剂型，所述单独的剂型在基本上相同的时间被所述受试者服用，届时所述组分基本上在相同的时间释放至所述受试者；本公开内容的IL-2变体或IL-2变体融合蛋白和一种或更多种治疗剂的此类组合顺序施用至需要治疗的受试者，其中这样的组分彼此分开配制成单独的剂型，所述单独的剂型被所述受试者在连续的时间服用，每次施用之间具有显著的时间间隔，届时所述组分在基本上不同的时间释放至所述受试者；以及，本公开内容的IL-2变体或IL-2变体融合蛋白和一种或更多种治疗剂的此类组合顺序施用至需要治疗的受试者，其中这样的组分一起配制成单一剂型，所述单一剂型以受控方式释放所述组分，届时所述组分在相同和/或不同的时间同时、连续和/或重叠地释放至所述受试者，其中每个部分可以通过相同或不同的途径施用。

在另一方面，本公开内容提供了用于治疗受试者的自身免疫性疾病的方法，所述方法包括施用与能够治疗自身免疫性疾病的第二治疗剂组合的治疗有效量的本发明的药物组合物。在各种实施方案中，第二治疗剂选自由以下组成的组：免疫抑制剂(immunosuppressants)诸如皮质类固醇、环孢菌素、环磷酰胺、泼尼松、硫唑嘌呤、氨甲蝶呤、雷帕霉素、他克莫司、生物剂诸如TNF-α阻断剂或拮抗剂、IL-10激动剂或长半衰期延长的IL-10(PEG化的、抗体或Fc融合体IL-10)；免疫抑制剂(immunosuppressive agents)(例如，针对其他淋巴细胞表面标志物(例如CD40、α-4整联蛋白)的抗体或针对细胞因子的抗体)、其他融合蛋白(例如CTLA-4-Ig(ORENCIA.RTM.)、TNFR-Ig

在另一方面，本公开内容提供了一种用于治疗受试者的炎性疾病的方法，所述方法包括施用与第二治疗剂组合的治疗有效量的本发明的药物组合物，所述第二治疗剂能够抑制或减少Th1、Th17、Th22和/或其他细胞(分泌或导致其他细胞分泌炎性分子，包括但不限于IL-1β、TNF-α、TGF-β、IFN-γ、IL-17、IL-6、IL-23、IL-22、IL-21和MMP)的分化；抑制或减少以下细胞的活性：Th1、Th17、Th22和/或其他细胞(分泌或导致其他细胞分泌炎性分子，包括但不限于IL-1β、TNF-α、TGF-β、IFN-γ、IL-17、IL-6、IL-23、IL-22、IL-21和MMP)；抑制或减少Th1和/或Th17途径；抑制或减少以下细胞的细胞因子产生和/或分泌：Th1、Th17、Th22和/或其他细胞(分泌或导致其他细胞分泌炎性分子，包括但不限于IL-1β、TNF-α、TGF-β、IFN-γ、IL-17、IL-6、IL-23、IL-22、IL-21和MMP)；抑制或减少以下细胞的增殖：Th1、Th17、Th22和/或其他细胞(分泌或导致其他细胞分泌炎性分子，包括但不限于IL-1β、TNF-α、TGF-β、IFN-γ、IL-17、IL-6、IL-23、IL-22、IL-21和MMP)。在各种实施方案中，第二治疗剂是非类固醇抗炎剂，包括但不限于，昔康类(oxicams)，诸如吡罗昔康(piroxicam)、伊索昔康(isoxicam)、替诺昔康(tenoxicam)、舒多昔康(sudoxicam)；水杨酸类(salicylates)，诸如阿司匹林、双水杨酯(disalcid)、贝诺酯(benorylate)、三水杨酸胆碱镁(trilisate)、痛热宁(safapryn)、solprin、二氟尼柳(diflunisal)和芬度柳(fendosal)；乙酸衍生物，诸如双氯芬酸(diclofenac)、芬氯酸(fenclofenac)、吲哚美辛(indomethacin)、舒林酸(sulindac)、托美丁(tolmetin)、伊索克酸(isoxepac)、呋罗芬酸(furofenac)、硫平酸(tiopinac)、齐多美辛(zidometacin)、阿西美辛(acematacin)、芬替酸(fentiazac)、佐美酸(zomepirac)、clmdanac、奥昔平酸(oxepinac)、felbmac和酮咯酸(ketorolac)；芬那酸类(fenamates)，诸如甲芬那酸、甲氯芬那酸、氟芬那酸、尼氟灭酸和托芬那酸；丙酸衍生物，诸如布洛芬、萘普生、苯噁洛芬(benoxaprofen)、氟比洛芬(flurbiprofen)、酮洛芬(ketoprofen)、非诺洛芬(fenoprofen)、芬布芬(fenbufen)、吲哚洛芬(indopropfen)、吡洛芬(pirprofen)、卡洛芬(carprofen)、奥沙普秦(oxaprozin)、普拉洛芬(pranoprofen)、咪洛芬(miroprofen)、硫噁洛芬(tioxaprofen)、舒洛芬(suprofen)、阿明洛芬(alminoprofen)和噻洛芬酸(tiaprofenic)；吡唑类，诸如保泰松(phenylbutazone)、羟布宗(oxyphenbutazone)、非普拉宗(feprazone)、阿扎丙宗(azapropazone)和三甲保泰松(trimethazone)。也可以使用这些非类固醇抗炎剂的混合物。在各种实施方案中，第二治疗剂是类固醇抗炎药，包括但不限于皮质类固醇，诸如氢化可的松、羟基-曲安西龙(hydroxyl-triamcinolone)、α-甲基地塞米松、磷酸地塞米松、二丙酸倍氯米松(beclomethasone dipropionates)、戊酸氯倍他索(clobetasol valerate)、地奈德(desonide)、去氧米松(desoxymethasone)、醋酸去氧皮质酮(desoxycorticosteroneacetate)、地塞米松、二氯松(dichlorisone)、双醋酸二氟拉松(diflorasone diacetate)、戊酸二氟可龙(diflucortolone valerate)、氟氢缩松(fluadrenolone)、氟氯奈德(fluclorolone acetonide)、氟氢可的松(fludrocortisone)、氟美松新戊酸酯(flumethasone pivalate)、氟轻松(fluosinolone acetonide)、氟轻松醋酸酯(fluocinonide)、福可定丁酯(flucortine butylesters)、氟可龙(fluocortolone)、醋酸氟泼尼定(fluprednidene)(氟泼尼定(fluprednylidene))、氟氢缩松(flurandrenolone)、哈西奈德(halcinonide)、醋酸氢化可的松、丁酸氢化可的松、甲基泼尼龙(methylprednisolone)、曲安奈德(triamcinolone acetonide)、可的松、可托多松(cortodoxone)、醋酸氟轻松(flucetonide)、氟氢可的松、difluorosone diacetate、氟氢缩松、氟氢可的松、diflurosone diacetate、缩丙酮氟氢缩松(fluradrenoloneacetonide)、甲羟松(medrysone)、安西法尔(amcinafel)、安西非特(amcinafide)、倍他米松及其酯的平衡物、氯泼尼松、醋酸氯泼尼松、氯可托龙(clocortelone)、克西诺龙(clescinolone)、二氯松(dichlorisone)、二氟泼尼酯(diflurprednate)、氟二氯松(flucloronide)、氟尼缩松(flunisolide)、氟米龙(fluoromethalone)、氟培龙(fluperolone)、氟泼尼龙(fluprednisolone)、戊酸氢化可的松、环丙戊酸氢化可的松、氢可他酯(hydrocortamate)、甲泼尼松(meprednisone)、帕拉米松、泼尼松龙、泼尼松、二丙酸倍氯米松、曲安西龙、及其混合物。

在各种实施方案中，组合疗法包括同时施用在同一药物组合物中或在单独的药物组合物中的IL-2变体和第二剂组合物。在各种实施方案中，顺序施用IL-2变体组合物和第二剂组合物，即，在施用第二剂组合物之前或之后施用IL-2变体组合物。在各种实施方案中，IL-2变体组合物和第二剂组合物的施用是同时的，即，IL-2变体组合物和第二剂组合物的施用时间段彼此重叠。在各种实施方案中，IL-2变体组合物和第二剂组合物的施用是非同时的。例如，在各种实施方案中，终止IL-2变体组合物的施用，然后施用第二剂组合物。在各种实施方案中，终止施用第二剂组合物，然后施用IL-2变体组合物。

提供以下实施例以更充分地说明本公开内容，但不应解释为限制本公开内容的范围。

选择性靶向Treg细胞的IL-2变体的设计

在一方面，本发明涉及减弱IL-2对IL-2Rβ和/或γc受体亚基的亲和力的一种或更多种突变。在IL-2Rβγ相互作用减弱的情况下，由IL-2Rα表达赋予的Treg的增强的IL-2敏感性可以导致该细胞亚群的显著的生长优势。因此，在自身免疫性疾病和炎性疾病中，这些突变体可以用作Treg促进剂(promoters)。

这些变体是基于蛋白数据库中报道的人类IL-2的结构(PDB代码2B5I)通过计算设计的。设计了一组变体，在与IL-2Rβ或γc受体亚基进行直接接触的界面处或附近的残基中包含1个至3个突变(引入保守和非保守氨基酸取代)。例如，D20参与与IL-2Rβ界面处的受体亚基侧链的广泛的氢键网络。类似地，N88是IL-2/IL-2Rβ相互作用的能量热点，参与与受体链的关键氢键。Q126对γc相互作用是必需的，并且Q22类似地位于γc界面处。本发明人假设，在上述位点或邻近残基处的突变可以导致它们与IL-2中间亲和受体IL-2Rβγ相互作用的能力的缺陷。

令人感兴趣地，提出的类似于细菌毒素组分的‘

在本发明中，将具有以下1-3个氨基酸取代(D20T、D20E、D20N、D20Q、D20S、D20Y、D20I、L19Y、L19N、L19R、L19Q、L19H、L19D、L19P、L19S、L21S、L21N、L21R、N88R、N88G、N88I、N88Q、N88E、N88T、N88M、Q126E、Q126L、Q126N、Q126D、Q126M、Q126K、Q126H、Q126Y、Q125E、S125K、S125H、S125W、S125I、Q22N、Q22H、Q22K、Q22Y、Q22I、D20I/N88G、D20I/N88R、D20T/N88R、D20I/N88I、D20T/Q126E、D20T/N88R/Q126E、D20T/Q126L、D20T/N88R/Q126L、L19N/Q126E、L19R/Q126E、L19Y/Q126E、L19H/Q126E、L19Q/Q126E、L19S/Q126E、L19Y/Q126K、L19Y/Q126H、L19Y/Q126Y、L19Y/S125E、L19Y/S125K、L19Y/S125H、L19Y/S125W、L19Y/S125I、L19Y/Q22N、L19Y/Q22H、L19Y/Q22K、L19Y/Q22Y、L19Y/Q22I、L19H/Q126K、L19H/S125I、L19D/S125I、D20E/S25I、D20T/S125I、L19Y/S125I/Q126E、L19H/S125I/Q126E、L19H/S125I/Q126K、L19Q/S125I/Q126E、L19Q/Q126K、L19Q/S125I/Q126K、D20T/S125I/Q126K、L19N/S125I/Q126K和L19R/S125I/Q126K)的一组IL-2变体(SEQ ID NO:4-43、108-146和193-197)表达为经由“GGGSGGGS”接头(SEQ ID NO:55)与Fc同源二聚体的C末端融合体。具有D20I、D20I/N88G、D20E或L19N氨基酸取代的IL-2变体也被表达为经由刚性“AEAAAKEAAAKEAAAKA”接头(SEQ ID NO:53)与Fc同源二聚体的N末端融合体。总体上，这些IL-2变体Fc融合构建体的序列以SEQ ID NO:73-107、147-189和198-211列出。还制备了具有呈相同Fc融合形式(C末端和N末端两者)的野生型IL-2的构建体(SEQ ID NO:71和72)。

所有以上IL-2变体Fc融合分子被设计成向高表达IL-2Rα的细胞提供生长优势，导致Treg细胞优先于其他淋巴细胞(包括CD4+常规T细胞、CD8+T细胞和NK细胞)增殖。此外，预计在位置19、20或21处的突变会消除导致血管毒性的毒性基序，因此所得分子可具有两种有益特性，包括增强的Treg活化的选择性和减少的内皮细胞损伤。尽管如此，但对于调节效应T细胞和NK细胞的活化的损伤水平、同时保持足够高的Treg细胞活化潜能、并从而使Treg亚群的选择性靶向的窗口最大化，最佳的突变或突变组合至关重要。

此外，已经鉴定了单点突变，且该单点突变导致改进的蛋白稳定性、更高的表达水平、以及更低的聚集倾向。聚集减少和Treg靶向突变的结合导致了卓越的蛋白可开发性以及Treg细胞生长优势。

IL-2Fc融合构建体的构建和产生

对所有基因进行密码子优化以便在哺乳动物细胞中表达，合成这些基因并亚克隆到接受者哺乳动物表达载体(GenScript)中。蛋白表达由CMV启动子驱动，并且合成的SV40聚腺苷酸(polyA)信号序列存在于CDS的3'端。在构建体的N末端处工程化有前导序列，以确保合适的信号传导和加工以便分泌。

构建体通过使用聚乙烯亚胺(PEI，25,000MW线性，Polysciences)用哺乳动物表达载体共转染悬浮生长的HEK293-F细胞来产生。如果有两种或更多种表达载体，则载体以1:1的比转染。对于转染，将HEK293细胞在无血清FreeStyle

对于亲和色谱，将每种上清液加载到用25ml磷酸盐缓冲盐水pH 7.2(ThermoFisher)平衡的HiTrap MabSelectSure柱(CV＝5mL,GE Healthcare)上。通过用5倍柱体积的PBS pH 7.2洗涤来去除未结合的蛋白，并用25mM柠檬酸钠、25mM氯化钠，pH 3.2洗脱目标蛋白。蛋白溶液通过添加3％的1M Tris pH 10.2来中和。离子交换色谱术或混合模式色谱术，包括但不限于CaptoMMC(GE Healthcare)、陶瓷羟基磷灰石或陶瓷氟磷灰石(Bio-Rad)，也根据需要被用于对蛋白A材料进行精制。靶蛋白用

在具有还原剂和不存在还原剂的情况下，通过SDS-PAGE和用考马斯亮蓝(Coomassie)(ImperialR Stain)染色来分析所纯化的构建体的纯度和分子量。根据制造商的说明使用

值得注意的是，在具有不同突变位点的构建体或共有相同突变位点但残基取代不同的突变体之间，IL-2变体Fc融合体的表达谱和聚集倾向显著不同。

IL-2中的单个氨基酸取代导致融合体化合物的可开发性的普遍改进

当应用于IL-2时，寻找产生具有期望的生物学特性的变体蛋白的突变组合的工程化方法遇到了重大挑战。本领域已知，天然存在的IL-2蛋白往往不太稳定并且易于聚集。这在我们的实验中得到了展示，野生型IL-2Fc融合蛋白(P-0250)以低水平表达(在HEK-293F细胞中瞬时表达为约3mg/L)，具有高聚集倾向，通过图1A中描绘的SEC色谱图例示。工程化努力陷入困境，因为旨在期望的生物活性的IL-2的氨基酸取代通常导致突变蛋白甚至更不稳定。当前工作中的IL-2变体有很大一部分以极低水平表达，并且一些变体明显更容易聚集，通过图1B中描绘的P-0318(SEQ ID NO:95)的SEC色谱图例示。这对于治疗剂的制备和储存是有问题的。

还观察到，在具有不同突变位点的构建体或共有相同突变位点但残基取代不同的突变体之间，IL-2变体Fc融合体的表达谱和聚集倾向显著不同。该观察结果通过P-0317(SEQ ID NO:94)和P-0318(SEQ ID NO:95)例示。两种变体融合体在残基20和88处共有相同的突变位点，并且仅相差一个氨基酸。P-0317含有氨基酸取代D20I和N88R，而P-0318含有D20I和N88I突变。两种变体融合体以相似的低水平表达。如在图1B中可以观察到的，P-0318非常易于聚集：65％的高分子量物质，这使得预期的峰在色谱图中为次要物质，并用箭头标记。相比之下，P-0317相对纯净，具有7.5％的聚集体(图1C)。可以推断，N88R突变可以降低所得融合蛋白的聚集倾向。然而，IL-2具有N88R单突变或D20T/N88R双重突变所产生的融合蛋白P-0254(SEQ ID NO:71)和P-0324(SEQ ID NO:96)，分别具有30％-40％聚集体的聚集倾向。因此，单个氨基酸取代对蛋白稳定性的贡献表现为取决于背景。

对IL-2的氨基酸取代通常导致较不稳定的蛋白的事实因不同残基取代对蛋白稳定性的不可预测的贡献而更加复杂。因此，非常希望找到能够普遍增强蛋白可开发性(包括改进的稳定性、更高的表达水平和更低的聚集倾向)的残基取代。

在位置125处的氨基酸取代最初旨在调节IL-2选择性，因为该残基紧邻Q126，Q126对γc相互作用是必需的。天然存在的IL-2在位置125处含有未配对的半胱氨酸，该半胱氨酸在Proleukin中被丝氨酸替代，而在本发明中S125被认为是野生型IL-2残基。在位置125处含有丙氨酸取代的IL-2也被广泛使用。由于在位置125处对半胱氨酸的丝氨酸或丙氨酸取代保留了全部生物活性，因此在P-0372(SEQ ID NO:79)的位置125处引入了包括Glu、Lys、Try、His和Ile的大体积(bulky)带电残基或疏水残基以替代Ser旨在干扰Q126与γc的相互作用，从而实现改变的生物活性。除了P-0471(SEQ ID NO:178)以外，所有的所得融合分子表达水平太低，无法表征。相反，当P-0471与其S125对应物(P-0372)相比时，P-0471以显著更高的水平表达(19.3mg/L对比4.0mg/L滴度)，具有大幅降低的聚集倾向(1％对比21.7％聚集)。可开发性尤其是对产物纯度的令人印象深刻的改进，促使我们评价是否可以在不同的突变背景中重现位置125处异亮氨酸取代的这种提高。

因此将S125I取代引入到许多IL-2变体Fc融合分子中。在IL-2中含有Ile-125取代的构建体使用与其Ser-125对应物相同的载体并以相同的培养条件进行表达，并使用MabSelectSure进行纯化。在表4中总结了表达水平(mg/L)和通过SEC色谱术以示例性分子的聚集％评估的纯度。表4同一行中的两种分子共有相同的其他氨基酸取代，并且差异仅在于残基125处为丝氨酸或异亮氨酸。例如，P-0447(SEQ ID NO:168)及其Ile-125对应物P-0511(SEQ ID NO:198)的SEC色谱图和SDS-PAGE图在图1D和图1E中进一步说明。从表4清楚的是，在位置125处的异亮氨酸取代导致表达水平提高到4至11倍，并且聚集倾向一致地低。

125I取代使各种IL-2融合蛋白的聚集降低并且表达增加

从本发明明显的是，位置125处的异亮氨酸取代导致了IL-2融合构建体的可开发性的普遍改进，且完全保留了生物活性。在野生型IL-2和Fc融合形式中具有不同突变背景的IL-2变体的位置125处的Ile取代均导致表达水平的4至11倍提高，且聚集倾向一致地低。在表4中总结了表达水平(mg/L)和通过SEC色谱术以示例性分子的聚集％评估的蛋白A纯化物质的纯度。这一发现尤其有价值，因为改变临界稳定的野生型IL-2通常导致甚至更不稳定的突变蛋白的事实妨碍了为了获得期望的生物学特性的IL-2的工程化。IL-2工程化的固有挑战可以通过在位置125处用异亮氨酸单个氨基酸取代来缓解。总之，在IL-2或IL-2变体的位置125处的异亮氨酸取代显著改进了蛋白的可开发性谱，这通过IL-2构建体的蛋白表达增加和聚集倾向的大幅降低得到展示。

展示出对Treg淋巴细胞的不同选择性的单个氨基酸取代的IL-2变体的鉴定

在对应于与受体亚基β或γ或βγ相互作用的氨基酸的位置处向IL-2引入了单个氨基酸取代。这些取代旨在降低IL-2的通过中等亲和力IL-2Rβγ复合物的信号传导能力，并赋予来自高亲和力IL-2Rαβγ的信号传导特异性。检查了含有单个氨基酸取代的IL-2变体差异性地刺激CD4阳性Treg细胞和Tconv细胞中的STAT5磷酸化的能力。已知在IL-2结合跨膜IL-2受体后，STAT5参与下游信号级联。在FACS分析中，使用新鲜的人类外周血单核细胞(PBMC)测量限定的淋巴细胞亚群中的STAT5的磷酸化，并且使用叉头转录因子FOXP3来鉴定Treg群体。

简而言之，通过Ficoll-Hypaque离心法从健康供体的血沉棕黄层分离人类PBMC。在4℃使PBMC在无血清MACS缓冲液中饥饿1小时。然后在37℃将2×10

图2示出了与野生型融合蛋白相比，IL-2变体的示例性Fc融合蛋白对CD4阳性Treg细胞和Tconv细胞中的STAT5磷酸化的剂量响应效应。野生型IL-2Fc融合蛋白(P-0250)在Treg细胞和Teff细胞两者中诱导STAT5磷酸化，EC50值分别为0.1pM和25.4pM。野生型IL-2在Treg细胞中的效力比在CD4+Tconv细胞中高约250倍，与Treg细胞中高亲和力三聚体受体的较高表达水平一致。

在位置20处的天冬氨酸的各种取代P-0364(D20E)、P-0363(D20T)、P-0365(D20N)、P-0366(D20Q)和P-0367(D20S)展示出诱导Treg细胞中的STAT5磷酸化的能力，而这种活性在CD4+Tconv细胞中大幅减弱或消除(图2A和图2B)。这些变体是活化Treg细胞以用于治疗自身免疫性疾病的潜在的Treg偏倚的IL-2剂。此外，预计在所提出的毒素样基序的关键残基D20处的突变消除该毒性基序并防止内皮细胞损伤。因此，预计这些变体具有Treg选择活性，对VLS具有改进的安全性谱。此外，P-0368未显示出生物活性(图2A和图2B)。

图3示出了与分别含有V91K和N88R突变的基准-1和基准-2化合物相比，IL-2变体P-0375(N88Q)诱导CD4阳性Treg细胞和CD4+Tconv细胞中的STAT5磷酸化的能力。N88Q变体的活性谱与基准-2的活性谱相似。

图4示出了与野生型相比，在位置19处含有各种突变的IL-2变体的生物活性。变体P-0372(L19Y)、P-0373(L19N)、P-0374(L19R)、P-0423(L19Q)、P-0424(L19H)和P-0427(L19S)在诱导Treg细胞中的STAT5磷酸化中展示出与野生型相似的活性(图4A和图4C)。变体P-0372、P-0374、P-0423和P-0427还基本上保留了对CD4+Tconv细胞的生物活性(图4B和图4D)，而变体P-0373和P-0424对CD4+Tconv的这种活性降低。突变体P-0425(L19D)在诱导Treg细胞中的STAT5磷酸化中展示出稍微降低的能力，而对CD4+Tconv细胞这种活性显著受损(图4C和图4D)。突变体P-0373、P-0424和P-0425展示出的相对于CD4+Tconv细胞对Treg细胞的选择性活化，特别是P-0373和P-0425对Treg亚群的选择性靶向的宽窗口，使它们成为活化Treg细胞以用于治疗自身免疫性疾病的潜在的Treg偏倚的IL-2剂。重要地，L19是所提出的毒素样基序的一部分，并且还预计在该位点处的突变具有改进的安全性特征和减少的VLS。

IL-2中对Treg淋巴细胞的不同选择性的IL-2Rβ和γc靶向氨基酸取代的组合

在实施例4中展示了旨在减弱IL-2对IL-2Rβ或γc受体亚基的亲和力的定向突变可以产生对Treg淋巴细胞具有不同选择性的IL-2突变体。然后推断，经由组合靶向β受体的一个氨基酸取代和靶向γ受体的另一个氨基酸取代来调节IL-2对IL-2Rβ和γc受体亚基两者的亲和力，可以产生针对Treg淋巴细胞的期望的效力和选择性窗口。

在图5中展示了这种基本原理。图5A和图5B示出了与野生型IL-2融合蛋白P-0250相比，IL-2Rβ靶向变体P-0372(L19Y)对Treg细胞和CD4+Tconv细胞中的STAT5磷酸化的作用。类似地，图5C和图5D示出了含有靶向以干扰与γ受体的相互作用的氨基酸取代的P-0303(Q126E)的STAT5磷酸化活性。数据表明，每个单氨基酸取代最小地影响pSTAT5活化效力，但相对于野生型，也只显示出略微改进的针对Treg淋巴细胞亚群的选择性窗口。如图5E和图5F中展示的，在P-0419中通过组合L19Y和Q126E突变，对Treg细胞的选择性活化窗口显著扩大。Treg活化效力在P-0419中被大部分地保留，并且P-0419变体的活性谱与包含V91K突变的基准-1分子的活性谱非常相当。这种策略特别有吸引力，因为19L也是所提出的毒素样基序的一部分，并且还预计在该位点处的突变具有改进的安全性特征和减少的VLS。

然而，组合靶向β受体的一个氨基酸取代和靶向γ受体的另一个取代可能不总是产生期望的效力和选择性窗口。需要对每个方面进行适量的活性调节。图6A和图6B中的四种IL-2变体共有相同的靶向β受体的L19Y取代，并且被设计成靶向γc受体的另外的突变分别是P-0419中的Q126E、P-0464中的Q126K、P-0471中的S125I和P-0474中的Q22K。虽然所有突变体保留了相当的诱导Treg细胞中的STAT5磷酸化的效力(图6A)，但对CD4+Tconv细胞的这种活性变化显著(图6B)，展示了经由组合氨基酸取代来调节Treg活化选择性的不同能力。

然而，通过将Q126E取代组合至已经展示出对Treg亚群的偏倚的特异性的IL-2变体来复合另外的受体减弱，可以导致针对Treg细胞的活性显著减少或消除。如(图6C和图6D)中展示的，两种变体P-0373(L19N)和P-0363(D20T)已经显示出一些或显著的针对Treg细胞的偏倚的选择性窗口(图6C和图6D)。它们各自的具有另外的Q126E取代的对应物P-0417和P-0322显示出明显降低的Treg细胞活化效力。因此，找到正确的残基取代组合，以便将活性调节到针对Treg细胞的期望的效力和偏倚特异性是至关重要的。

评价了在位点L19和Q126处含有双重氨基酸取代的另外的变体，包括P-0447(L19H/Q126E)、P-0448(L19Q/Q126E)和P-0449(L19S/Q126E)，并且活性在图7A-图7D中示出。与各自含有一个单氨基酸取代的IL-2变体P-0424(L19H)和P-0303(Q126E)相比，含有两个氨基酸取代的组合的变体P-0447(L19H、Q126E)在刺激Treg细胞中STAT5磷酸化方面展示出强健的生物活性，而对Tconv细胞的这种活性几乎完全被消除(图7A和图7B)。在另一项评价P-0419、P-0447、P-0448和P-0449与两种基准化合物的比较的研究中，所有四种变体都展示出显著的诱导Treg细胞中的STAT5磷酸化的潜力，而对CD4+Tconv细胞的这种活性基本上被消除(图7C和图7D)。P-0419具有与基准-1相当的活性谱，这在图5E和图5F中得到类似的展示，而P-0447、P-0448和P-0449在针对Treg细胞的效力和选择性窗口方面与基准-3相当。

所有这些突变体都是活化Treg细胞以用于治疗自身免疫性疾病的潜在的Treg偏倚的IL-2剂。此外，由于潜在毒性基序的消除，还预计这些突变体具有改进的安全性谱和降低的VLS。

在位置125处具有异亮氨酸取代的IL-2变体保留了全部的生物活性

在实施例3中示出，在位置125处的异亮氨酸取代导致了IL-2融合构建体的可开发性的普遍改进。为了使S125I取代成为缓解IL-2工程化的可开发性挑战的可行方法，展示出这种氨基酸替代与其Ser-125对应物相比不会损害所得融合蛋白的生物活性是重要的。

然后将S125I取代引入野生型IL-2或已经含有1个或2个靶向受体亚基β或γ或βγ的突变的IL-2变体中。测试所得的在位置125处含有异亮氨酸的IL-2变体刺激Treg细胞和Tconv细胞中的STAT5磷酸化的能力，并与它们各自在位置125处为丝氨酸的对应物进行比较。表5列出了IL-2变体对Treg细胞的效力和选择性。表5同一行中的两种分子共有相同的其他氨基酸取代，并且差异仅在于位置125处为丝氨酸或异亮氨酸。数据展示，S125I取代完全保留或稍微提高了各种测试的IL-2变体的生物活性，而未改变Treg特异性。

含有S125I取代的IL-2变体保留了生物活性和Treg选择性

分别来自三种示例性构建体P-0250、P-0424和P-0447及其S125I等同物P-0531、P-0491和P-0511的数据在图8中示出。P-0250是野生型IL-2Fc融合分子，P-0424含有一个氨基酸取代L19H，并且P-0447含有两个氨基酸取代L19H/Q126E。它们对Treg细胞和CD4+Tconv细胞中的STAT5磷酸化的剂量依赖性效应在图8中说明。如图8A-图8F中示出的，S125I取代稍微增加了三种测试化合物的效力，而未改变P-0531和P-0491的Treg选择性；对于P-0511，S125I取代进一步扩大了Treg选择性窗口。

因此，数据展示出IL-2中的S125I取代保留了不同突变背景的IL-2融合蛋白的IL-2活性谱。总之，在IL-2的位置125处的异亮氨酸取代导致了IL-2、IL-2融合体、IL-2变体和IL-2变体融合体的普遍的可开发性改进(增加的产物产量、减少的聚集、降低的免疫原性潜力)以及生物活性和选择性的完全保留。这种特定的氨基酸取代代表了一种解决固有的IL-2工程化挑战的可行的缓解策略。

IL-2变体对CD25+CD4+T细胞、CD8细胞毒性T细胞和NK细胞的作用

与野生型IL-2(P-0250)和分别包含V91K、N88R、N88D的三种IL-2基准分子相比，除了评估两种变体P-0511和P-0512差异性刺激CD4阳性Treg(CD4+/Foxp3+/CD25

本发明的IL-2变体具有减弱的IL-2Rβγ相互作用，并且Treg对比CD4+Tconv的明显生长优势由Treg中的高组成型IL-2Rα(CD25)表达赋予。免疫刺激后，CD4+T效应细胞中的CD25表达可被诱导。因此，期望证实IL-2变体保留了相对于其他CD25+淋巴细胞亚群的Treg特异性。具有中等到高CD25表达水平的示例性淋巴细胞亚群包括CD4+效应T细胞(Teff)。

在用测试化合物的系列稀释液处理人类PBMC细胞，固定和透化，洗涤，并用抗CD25-PE抗体、抗FOXP3-APC抗体、抗pSTAT5-FITC抗体和抗CD4-PerCP-Cy5.5抗体的混合物染色后，流式细胞术分析对于Treg细胞、CD4效应细胞和CD4初始T细胞亚群分别门控为CD4+/Foxp3+/CD25+、CD4+/Foxp3-/CD25+、CD4+/Foxp3-/CD25-组。数据表示为门控的群体中pSTAT5阳性细胞的百分比，并在图9中说明。P-0512与基准-1针对所有三种T细胞亚群具有相当的活性谱，而在针对Treg细胞对比Teff细胞和初始CD4 T细胞两者的效力和选择性窗口方面，P-511优于基准-2和基准-3两者。基准-2在活化三个亚群中的每一个中都显示出弱得多的效力。尽管CD25在Teff上以中等到高水平表达，但在图9A和图9B中清楚地展示了，具有减弱的IL-2Rβγ相互作用的IL-2变体，尤其是P-0511，对Treg的活化优先于Teff。

此外，与野生型分子和基准分子相比，测试了P-0511和P-0512刺激NK细胞和CD8+T细胞增殖的能力。利用了细胞内荧光标记羧基荧光素二乙酸琥珀酰亚胺酯(CFSE)法。简而言之，将人类PBMC(1×10

如预计的，与野生型IL-2融合分子P-0250相比，所有IL-2变体都显示出减弱的刺激CD8+T细胞和NK细胞两者的效力。与STAT5磷酸化测定中的观察结果(图9)一致，在针对两种淋巴细胞亚群的效力方面，P-0512具有与基准-1相当的活性谱，并且P-0511与基准-3相当，而基准-2表现出弱得多的效力。

将P-0511对CD4+T细胞亚群以外的其他应答细胞(包括CD8+T细胞和NK细胞)的STAT5磷酸化活性与P-0531(野生型P-0250的S125I等同物)进行比较。与P-0531(图11A)相似，P-0511表现出显著的刺激Treg细胞中的STAT5磷酸化的活性，而对CD4+Tconv细胞(图11B)、CD8+T细胞(图11C)和NK细胞(图11D)的这种活性几乎完全被消除。CD4+Tconv细胞、CD8+T细胞和NK细胞上表达的IL-2受体主要是二聚体IL-2R，包括IL-2Rβ和γc。为了证实P-0511对CD8+T细胞和NK细胞的显著减弱的pSTAT5信号传导是由于其与IL-2Rβ和γc的相互作用受损，开发了一种ELISA测定。

简而言之，将IL-2Rβ-ECD(NP_000869)和γc-ECD(NP_000197)的非共价复合物通过异源二聚体Fc链以2μg/孔包被到Nunc Maxisorp 96孔微孔板的孔上。在4℃孵育过夜并用superblock(ThermoFisher)封闭后，以100μl/孔向每个孔添加从100nM或270nM开始的3倍系列稀释的IL-2Fc融合蛋白。在室温孵育1小时后，向每个孔添加1μg/ml的生物素小鼠抗人类IL-2Ab(BD BioSciences)，然后与1μg/ml的HRP-亲和素(ThermoFisher)一起孵育1小时。每一步骤后，将孔彻底抽吸，并用PBS/0.05％吐温-20洗涤三次。最后，向每个孔添加100μl TMB底物；将板在室温在黑暗中显影10分钟，并添加100μl/孔的停止溶液(2N硫酸，RiccaChemical)。确定450nm处的吸光度；使用Prism软件(GraphPad)拟合曲线，并在图11E中示出。

如图11E中示出的，可开发性改进的野生型IL-2融合蛋白P-0531以亚纳摩尔亲和力(EC

总之，表2A-表2F中列出的一系列IL-2变体被构建、表达，并在体外测定中被测试。在图2-图11中展示了示例性IL-2变体对Treg与其他淋巴细胞亚群(包括CD4+Tconv细胞、CD4+Teff细胞、CD8+T细胞和NK细胞)的生物活性。许多变体保留了针对Treg细胞的高效力，针对Tconv细胞和其他淋巴细胞亚群的活性降低或消除。一些变体具有与基准1相似的活性谱，而其他变体与基准-2或基准-3的活性特征相似。此外，大多数IL-2变体被消除了所提出的毒素样基序，旨在减少VLS。重要的是，S125I氨基酸取代的掺入产生了具有优异可开发性谱的IL-2变体融合体，同时保留了对Treg细胞的生物活性和选择性。这些变体潜在地是具有改进的安全性谱的用于治疗自身免疫性疾病的Treg偏倚的IL-2剂。

IL-2变体的Fc融合蛋白在小鼠体内优先增殖和扩增Treg细胞

向小鼠施用IL-2变体Fc融合蛋白，并在体内确定其优先于效应性T细胞和NK细胞增殖和扩增调节性T细胞(CD4+CD25+FoxP3+T细胞)的能力。

雌性C57/BL6小鼠(7周龄)从Charles River实验室接收，并且在机构内适应至少7天，然后进行研究。在第0天，向小鼠皮下施用媒介物(PBS)、0.3mg/kg的每种测试化合物或IL-2基准化合物。在处理后第3天、第5天和第7天，将外周血样品收集到肝素处理的管中。每组包含6只小鼠，并在处理前2天(第-2天)采集基线血液。红细胞裂解后，通过台盼蓝死细胞排除法对总存活单核血细胞进行计数，并继续进行细胞内染色，以便对免疫细胞表型和Ki67增殖标志物使用流式细胞术分析。将细胞分别用以下列出的两组抗体染色：1)对于CD4+调节性T细胞(Treg)，抗小鼠Foxp3-FITC、Ki67-PE、抗小鼠CD25-APC和抗小鼠CD4-Percpcy5.5(1:50稀释)；2)对于CD8+T细胞和NK细胞，抗小鼠CD3-FITC、Ki67-PE、抗小鼠CD335-APC和抗小鼠CD8-Percpcy5.5(1:50稀释)。

所有测试的IL-2化合物都刺激了Treg细胞增殖和扩增，如通过增加的Ki67阳性Treg细胞和升高的Treg细胞占总CD4+T细胞或总淋巴细胞的百分比所展示的(图12A-图12C)。在注射后3天观察到该效应，并持续至一次单次注射后的第5天或第7天。在诱导Treg磷酸化的IL-2变体中，与基准-1始终表现出最高效力的离体观察结果形成对比，在小鼠中，所有三种测试的变体P-0511、P-0512和P-0514展示出比基准分子更强的刺激Treg细胞增殖和扩增的体内功效。P-0511、P-0512和P-0514表现出相当的活性。三种基准之间的相对体内效力排序与离体人类PBMC细胞测定一致，即基准-1效力最高，其次是基准-3。基准-2在增殖和扩增Treg细胞方面弱得多。(图12A-图12C)。

对T效应细胞和NK细胞，基准-1对细胞毒性CD8 T细胞和NK细胞显示出强Ki67刺激，而基准-2和-3对CD8 T细胞和NK细胞显示出低效果(图13A-图13C)。变体P-0514对CD8+T细胞显示出与基准-1相似的Ki67刺激，而变体P-0511和P-0512对CD8 T细胞和NK细胞显示出如基准-2和基准-3的轻度Ki67刺激(图13A-图13C)。数据表明，变体P-0511和P-0512展示出优于基准1和基准2的对Treg的生物活性和选择性。基准-3对刺激和扩增Treg细胞和效应细胞两者无效。

在所有IL-2变体处理组中，由于Treg群体增加，CD4+T常规细胞的百分比降低(图14A)。在用任何Treg偏倚的IL-2变体(P-0511、P-0512和P-0514)或三种基准处理的小鼠中，均未观察到CD4+Tconv细胞、CD8 T细胞或NK细胞的显著扩增(图14B-图14D)。

在所有测量时间点，与三种基准相比，所有三种变体P-0511、P-0512和P-0514在Ki67刺激和基于细胞计数的细胞扩增两方面还表现出最有益的Treg/Tconv比率(图15A和图15B)。

注射后3天，所有测试的IL-2化合物均引起Treg细胞上的Foxp3表达增加(图16A)，并且所有三种变体均显示出比三种基准相对更高的CD25和Foxp3标志物的表达(图16A和图16B)，表明更佳的Treg活化和功能性。

在处理前和处理期间监测体重。未观察到显著的重量变化(数据未示出)。

总体上，数据展示，变体P-0511、P-0512和P-0514表现出促进免疫抑制性Treg细胞活化、增殖和扩增的能力，同时不影响CD4+常规细胞、细胞毒性效应T细胞和NK细胞。数据还证明了这三种变体在对Treg增殖和扩增的功效和选择性两方面优于基准分子。这些变体可以用作治疗剂来对抗自身免疫性疾病以及炎性疾病以及器官移植排斥。

对IL-2变体Fc融合蛋白在小鼠中单次注射后的剂量响应药效学研究

在对雌性Balb/C小鼠(n＝5只/组)单次皮下施用媒介物(PBS)或P-0511(1mg/kg、0.3mg/kg、0.1mg/kg或0.03mg/kg)后，在第-2天采集外周血作为基线，并在给药后第3天、第5天和第7天采集外周血。在第7天，处死小鼠，并收获脾。在每个时间点使用新鲜全血通过流式细胞术测量血淋巴细胞表型分析、增殖和扩增。

在任何处理组中，体重或脾重量均无显著变化(数据未示出)。

如图17中说明的，在以1mg/kg、0.3mg/kg或0.1mg/kg给药水平的P-0511处理的小鼠中，观察到Treg细胞增殖的剂量依赖性增加，如通过Ki67阳性细胞百分比增加所反映的(图17A)。以0.03mg/kg的处理具有极小的效果。以三个较高剂量水平，对Treg细胞中Ki67表达的刺激在第3天达到峰值，并且稳定直至第5天，然后下降。结果，P-0511处理导致Treg占总CD4+T细胞的百分比(图17B)、Treg细胞绝对数目(图17C)和细胞计数从基线的变化倍数(图17D)以剂量依赖性方式升高。Treg细胞扩增的增加遵循与增殖/活化Ki67标志物相似的动力学模式(图17)，即在第3天达到顶点，并进一步延伸至第5天。以1mg/kg给药刺激了较大的Treg幅度和持续时间，并且信号持续至第5天。

P-0511的处理还导致Treg占总淋巴细胞的百分比的剂量依赖性的且统计学显著的升高(图18A)，而未观察到CD4+Tconv细胞(图18B)、CD8Teff细胞(图18C)或NK细胞(图18D)占总淋巴细胞的百分比的统计学显著的变化。以1mg/kg单次剂量处理，在峰值时，Treg占总淋巴细胞的4.5％，对比剂量为0.3mg/kg时为3.1％，以及剂量为0.1mg/kg时为1.4％。在媒介物对照组中，Treg占总淋巴细胞的0.5％(图18A)。

基于细胞计数计算了Treg/Tconv比率(图19A)。Treg/Tconv比率的峰值在1mg/kg处理时为0.27，在0.3mg/kg处理时为0.18，并且在0.1mg/kg处理时为0.06，对比未处理时为0.027(图19A)，表明P-0511对Treg细胞的扩增优先于Tconv细胞。此外，Treg细胞功能标志物(包括CD25(图19B)和FoxP3(图19C))的表达剂量依赖性地增加。CD25和FoxP3的平均荧光强度(MFI)的增加在第3天达到峰值，并且在第5天减弱到较低水平。

总体上，数据展示，P-0511以剂量依赖性方式表现出有效和优先的Treg活化和扩增。需要仔细考虑，以实现最佳给药策略，以实现促进免疫抑制性Treg细胞的活化、增殖和扩增的最大效力，同时不影响细胞毒性效应T细胞和NK细胞。

在小鼠中重复施用IL-2变体Fc融合蛋白后的药效学研究

使雌性Balb/C小鼠(7周龄)在机构内适应5-7天，然后进行研究。在第0天、第3天和第6天，向小鼠(n＝5只/组)皮下施用媒介物(PBS)、0.3mg/kg的P-0511、P-0512、P-0531或基准-1化合物。在第3天和第9天，分别在第一次注射和多次(3次)注射后三天，采集外周血。基于较早的体内实验，预计Treg细胞的活化、增殖和扩增在第3天达到峰值，并且因此选择在注射后3天进行数据收集和分析。通过流式细胞术测量血淋巴细胞活化、增殖和扩增的变化。P-0531是野生型IL-2融合蛋白的S125I等同物。基准-1包含V91K突变。

在单次皮下施用IL-2融合蛋白后三天，在所有测试组中，接近90％的Treg细胞显示出阳性Ki67表达，并且在接受所有测试化合物的第三剂后，Ki67阳性细胞保持显著地高(图20A)。令人感兴趣地，在用P-0531和基准-1处理的小鼠中，以Treg占总CD4 T细胞或总淋巴细胞的％表示的Treg细胞显著下降到接近对照水平，而在用P-0511和P-0512处理的小鼠中，与一次处理相比，三次连续Q3D处理后，Treg细胞保持在显著高水平(图20B-图20C)。数据表明，由于对Treg刺激的效力更强，因此野生型IL-2或基准-1可以加速Treg细胞的消耗或促使Treg脱敏。另外的解释还可包括半衰期或非淋巴细胞上的“受体沉默(receptorsink)”的差异，导致非Treg选择性或较低Treg选择性的野生型IL-2或基准-1的改变的药物暴露。

对于Treg细胞计数和相对于PBS对照的变化倍数(图21A-图21B)以及Treg/Tconv比率(图22)，也获得了类似的观察结果。与P-0531和基准-1相比，P-0511和P-0512展示出更佳的维持Treg池和维持Treg选择性的能力。

总体上，数据说明，P-0511和P-0512是更佳的IL-2分子，在多次剂量后显示出优先和持续的体内Treg扩增。调节IL-2变体Fc融合体的给药方案，例如给药量和频率，可以进一步优化期望的相对于促炎性免疫活化的对Treg的效力和选择性。

IL-2变体Fc融合蛋白对迟发型超敏反应(DTH)小鼠模型中抗原驱动的炎症的抑制

在迟发型超敏反应(DTH)模型中评估了由IL-2变体诱导的Treg细胞在体内抑制T细胞抗原驱动的炎症的能力。使雌性Balb/C小鼠(7周龄)在机构内适应7天，并随机分组。在第-2天开始皮下施用媒介物(PBS)、0.1mg/kg或0.3mg/kg的P-0511，并且给予每3天一次(Q3D)的三次注射或每5天一次(Q5D)的两次注射。然后在第0天以皮下施用200μl盐水中的100克匙孔

在图23中，使用KLH攻击后不同时间的耳厚度相对于基线值的变化(Δ耳厚度)来说明DTH响应的动力学。

在皮下KLH抗原致敏后，耳廓皮内KLH攻击后24小时，明显的耳部炎症和肿胀达到峰值，并且PBS组中耳肿胀延长72小时。明显的是，免疫抑制性类固醇地塞米松在抑制KLH诱导的炎症反应中是有效的，连续4天每天以5mg/kg给药，在KLH攻击后72小时达到～85％的抑制。在KLH攻击后的所有时间点，在用0.3mg/kg的P-0511Q3D或Q5D处理的小鼠中，由P-0511诱导的Treg细胞对抗原驱动的炎症的抑制也是明显的(图23A-图23B)。对于以0.1mg/kg剂量Q3D和Q5D施用均观察到类似的减轻DTH炎症反应的趋势，但在大多数时间点效果未达到统计学显著性。Q3D和Q5D给药方案均有效。

在另一项研究中，确定了P-0511(0.1mg/kg、0.3mg/kg和1mg/kg，Q5D)对KLH诱导的DTH的抑制的剂量依赖性响应，并与基准-1(0.3mg/kg，Q5D)进行了比较。如图24中说明的，P-0511展示出对耳部炎症的剂量依赖性抑制。接受1mg/kg P-0511的小鼠展示出对KLH诱导的DTH的强耐受性，并且在KLH攻击后观察到最小的耳肿胀。对于0.3mg/kg和0.1mg/kg的P-0511分别观察到中度和轻度抑制。基准-1显示出对耳肿胀的轻度抑制，并且0.3mg/kg基准-1的效果与通过0.1mg/kg P-0511实现的效果相似(图24)。

总之，在DTH模型中，通过P-0511施用诱导的Treg细胞在抑制T细胞抗原驱动的炎症中有效。此外，Treg抑制在没有重复给药的情况下在KLH攻击后得以持续。从实施例还明显的是，调整给药方案以实现最佳功效至关重要。

P-0511在食蟹猴(cynomolgus monkey)体内的药效学/药代动力学效应

根据Q14D×3给药方案，评价IL-2变体Fc融合蛋白P-0511在食蟹猴体内的PK/PD特性。未经药物(Drug-

在第-7天、第-3天、第2天、第4天、第6天、第8天、第11天、第14天、第18天、第21天、第28天、第32天、第35天、第43天、第50天、第57天采集血液。将全血用于初始和记忆性外周血Treg、非调节性CD4 T细胞、CD8 T细胞和NK细胞的FACS免疫表型分析，以确定药效学。还通过测量CD69和Ki67来监测细胞活化和增殖。还将全血用于全血细胞计数(CBC)，分为5部分：中性粒细胞、淋巴细胞、单核细胞、嗜酸性粒细胞和嗜碱性粒细胞。

使用小鼠抗人类IL-2mAb(BD Pharmingen)包被96孔板以便捕获P-0511，通过测量全长的完整P-0511，在食蟹猴血浆样品中评估P-0511的PK特性。使用山羊抗人类Fc多克隆-HRP(ThermoFisher)检测P-0511，并且随后对P-0511的血浆浓度进行定量。除了在第-7天、第-3天、第2天、第4天、第6天、第8天、第11天、第14天、第18天、第21天、第28天、第32天、第35天、第43天、第50天、第57天采集的血浆样品之外，还在第1天第一次施用P-0511后的0.5小时、3小时和6小时采集了三个血浆样品。

来自第-8、第8天、第21天、第35天、第43天、第57天的血浆样品也被用于评价以下临床化学参数：天冬氨酸氨基转移酶、丙氨酸氨基转移酶、碱性磷酸酶、γ谷氨酰转移酶、白蛋白、总胆红素、肌酐、血尿素氮和C反应蛋白。

此外，在整个研究期间，每周一次或每周两次监测每只动物的体重和体温。

本文公开的和要求保护的所有物品和方法均可鉴于本公开内容被制备和执行而无需过度实验。尽管已根据优选的实施方案描述本公开内容的物品和方法，但对于本领域技术人员将明显是，变化形式可被应用到所述物品和方法而不偏离本公开内容的精神和范围。对于本领域技术人员明显的是，所有这样的变化和等效物，无论是现存的或以后开发的，都被认为是在由所附权利要求限定的本公开内容的精神和范围之内。说明书中提及的所有专利、专利申请和出版物指示本公开内容所属领域的普通技术人员的水平。为了所有目的，所有专利、专利申请和出版物通过引用以其整体并入本文，并且其程度如同每个单独出版物单独地且具体地被指示为了任何和所有目的通过引用以其整体并入本文。本文例证地表述的本公开内容可在本文未具体地公开的任何一个或更多个要素不存在的条件下被合适地实践。因此，应理解，尽管本公开内容已通过优选的实施方案和任选的特征被具体地公开，但是本领域技术人员可寻求本文公开的概念的改变和变化形式，并且认为此类改变和变化形式在由所附的权利要求限定的本公开内容的范围内。

序列表

在所附的序列表中列出的核酸序列和氨基酸序列按37C.F.R.1.822中规定的使用核苷酸碱基的标准字母缩写和氨基酸的单字母编码示出。

SEQ ID NO:1是人类IL-2前体氨基酸序列。

SEQ ID NO:2是人类IL-2成熟形式天然存在的氨基酸序列。

SEQ ID NO:3是人类IL-2成熟形式野生型氨基酸序列。

SEQ ID NO:4-43、108-146和193-197是各种IL-2变体的氨基酸序列。

SEQ ID NO:44是人类IgG1-Fc氨基酸序列。

SEQ ID NO:45是具有减少/消除的效应子功能的人类IgG1-Fc的氨基酸序列。

SEQ ID NO:46和47以及212-213是具有减少/消除的效应子功能和延长的半衰期的人类IgG1-Fc的氨基酸序列。

SEQ ID NO:48-67是各种肽接头序列的氨基酸序列。

SEQ ID NO:68是人类IL-2受体αSushi结构域氨基酸序列。

SEQ ID NO:69-107、147-189和198-211是各种Fc-IL-2融合蛋白的氨基酸序列。

SEQ ID NO:190-192是基准Fc-IL-2变体融合蛋白的氨基酸序列。

SEQ ID NO:214-222是各种Fc-IL-2融合蛋白的核苷酸序列。

序列表

人类IL-2前体序列

人类IL-2成熟形式天然存在的序列

人类IL-2成熟形式野生型序列

IL-2 N88R变体序列

IL-2 D20T变体序列

IL-2 D20E变体序列

IL-2 D20N变体序列

IL-2 D20Q变体序列

IL-2 D20S变体序列

IL-2 D20Y变体序列

IL-2 D20I变体序列

IL-2 L19Y变体序列

IL-2 L19N变体序列

IL-2 L19R变体序列

IL-2 N88G变体序列

IL-2 N88I变体序列

IL-2 N88Q变体序列

IL-2 N88E变体序列

IL-2 N88T变体序列

IL-2 N88M变体序列

IL-2 Q126E变体序列

IL-2 Q126L变体序列

IL-2 Q126N变体序列

IL-2 Q126D变体序列

IL-2 Q126M变体序列

IL-2 D20I/N88G变体序列

IL-2 D20I/N88R变体序列

IL-2 D20T/N88R变体序列

IL-2 D20I/N88I变体序列

IL-2 D20T/Q126E变体序列

IL-2 D20T/N88R/Q126E变体序列

IL-2 D20T/Q126L变体序列

IL-2 D20T/N88R/Q126L变体序列

IL-2 L19N/Q126E变体序列

IL-2 L19R/Q126E变体序列

IL-2 L19Y/Q126E变体序列

IL-2 L19Q变体序列

IL-2 L19H变体序列

IL-2 L19D变体序列

IL-2 L19P变体序列

IL-2 D20T/S125I/Q126K变体序列

IL-2 L19N/S125I/Q126K变体序列

IL-2 L19R/S125I/Q126K变体序列

人类IgG1-Fc

具有减少/消除的效应子功能的人类IgG1-Fc

具有减少/消除的效应子功能和延长的半衰期的人类IgG1-Fc

具有减少/消除的效应子功能和延长的半衰期的人类IgG1-Fc

肽接头序列GGGSGGGSGGGS(SEQ ID NO：48)

肽接头序列GGGS(SEQ ID NO：49)

肽接头序列GSSGGSGGSGGSG(SEQ ID NO：50)

肽接头序列GSSGT(SEQ ID NO：51)

肽接头序列GGGGSGGGGSGGGS(SEQ ID NO：52)

肽接头序列AEAAAKEAAAKEAAAKA(SEQ ID NO：53)

肽接头序列GGGGSGGGGSGGGGSGGGGS(SEQ ID NO：54)

肽接头序列GGGSGGGS(SEQ ID NO：55)

肽接头序列GS(SEQ ID NO：56)

肽接头序列GGS(SEQ ID NO：57)

肽接头序列GGGGS(SEQ ID NO：58)

肽接头序列GGSG(SEQ ID NO：59)

肽接头序列SGGG(SEQ ID NO：60)

肽接头序列GSGS(SEQ ID NO：61)

肽接头序列GSGSGS(SEQ ID NO：62)

肽接头序列GSGSGSGS(SEQ ID NO：63)

肽接头序列GSGSGSGSGS(SEQ ID NO：64)

肽接头序列GSGSGSGSGSGS(SEQ ID NO：65)

肽接头序列GGGGSGGGGS(SEQ ID NO：66)

肽接头序列GGGGSGGGGSGGGGS(SEQ ID NO：67)

人类IL-2Rα sushi结构域序列

P-0250

P-0305

P-0254

P-0363

P-0364

P-0365

P-0366

P-0367

P-0368

P-0252

P-0372

P-0373

P-0374

P-0253

P-0302

P-0375

P-0376

P-0377

P-0378

P-0303

P-0304

P-0369

P-0370

P-0371

P-0251

P-0317

P-0318

P-0324

P-0322

P-0323

P-0325

P-0326

P-0417

P-0418

P-0419

P-0416

P-0412

P-0306

P-0319

IL-2 L19S变体序列

IL-2 L21S变体序列

IL-2 L21N变体序列

IL-2 L21R变体序列

IL-2 Q126K变体序列

IL-2 Q126H变体序列

IL-2 Q126Y变体序列

IL-2 S125E变体序列

IL-2 S125K变体序列

IL-2 S125H变体序列

IL-2 S125W变体序列

IL-2 S125I变体序列

IL-2 Q22N变体序列

IL-2 Q22H变体序列

IL-2 Q22K变体序列

IL-2 Q22Y变体序列

IL-2 Q22I变体序列

IL-2 L19H/Q126E变体序列

IL-2 L19Q/Q126E变体序列

IL-2 L19S/Q126E变体序列

IL-2 L19Y/Q126K变体序列

IL-2 L19Y/Q126H变体序列

IL-2 L19Y/Q126Y变体序列

IL-2 L19Y/S125E变体序列

IL-2 L19Y/S125K变体序列

IL-2 L19Y/S125H变体序列

IL-2 L19Y/S125W变体序列

IL-2 L19Y/S125I变体序列

IL-2 L19Y/Q22N变体序列

IL-2 L19Y/Q22H变体序列

IL-2 L19Y/Q22K变体序列

IL-2 L19Y/Q22Y变体序列

IL-2 L19Y/Q22I变体序列

IL-2 L19H/Q126K变体序列

IL-2 L19H/S125I变体序列

IL-2 L19D/S125I变体序列

IL-2 D20E/S125I变体序列

IL-2 D20T/S125I变体序列

IL-2 L19Y/S125I/Q126E变体序列

P-0423

P-0424

P-0425

P-0426

P-0427

P-0428

P-0429

P-0430

P-0497

P-0498

P-0499

P-0500

P-0501

P-0502

P-0503

P-0531

P-0505

P-0506

P-0507

P-0508

P-0509

P-0447

P-0448

P-0449

P-0464

P-0465

P-0466

P-0467

P-0468

P-0469

P-0470

P-0471

P-0472

P-0473

P-0474

P-0475

P-0476

P-0480

P-0491

P-0492

P-0493

P-0494

P-0495

P-0496(基准-2)

基准-1

基准-3

IL-2 L19H/S125I/Q126E变体序列

IL-2 L19H/S125I/Q126K变体序列

IL-2 L19Q/Q126K变体序列

IL-2 L19Q/S125I/Q126E变体序列

IL-2 L19Q/S125I/Q126K变体序列

P-0511

P-0512

P-0513

P-0514

P-0515

P-0582

P-0583

P-0584

P-0585

P-0586

P-0616

P-0672Knob-Fc链

P-0673Knob-Fc链

P-0674

具有延长的体内半衰期的Knob-Fc结构域

具有延长的体内半衰期的Hole-Fc结构域

P-0511

P-0512

P-0514

P-0582

P-0583

P-0584

P-0585

P-0586

P-0616

序列表

<110> 科优基因公司

<120> 白介素-2变体及其使用方法

<130> CACCG1.0003WO

<160> 222

<170> PatentIn version 3.5

<210> 1

<211> 153

<212> PRT

<213> 智人(Homo sapiens)

<400> 1

Met Tyr Arg Met Gln Leu Leu Ser Cys Ile Ala Leu Ser Leu Ala Leu

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Val Thr Asn Ser Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu

20 25 30

Gln Leu Glu His Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile

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Asn Asn Tyr Lys Asn Pro Lys Leu Thr Arg Met Leu Thr Phe Lys Phe

50 55 60

Tyr Met Pro Lys Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu

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Glu Glu Leu Lys Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys

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Asn Phe His Leu Arg Pro Arg Asp Leu Ile Ser Asn Ile Asn Val Ile

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Val Leu Glu Leu Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala

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Asp Glu Thr Ala Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe

130 135 140

Cys Gln Ser Ile Ile Ser Thr Leu Thr

145 150

<210> 2

<211> 133

<212> PRT

<213> 智人(Homo sapiens)

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Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu His

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Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys

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Asn Pro Lys Leu Thr Arg Met Leu Thr Phe Lys Phe Tyr Met Pro Lys

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Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys

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Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu

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Arg Pro Arg Asp Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu

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Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala

100 105 110

Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Cys Gln Ser Ile

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Ile Ser Thr Leu Thr

130

<210> 3

<211> 133

<212> PRT

<213> 智人(Homo sapiens)

<400> 3

Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu His

1 5 10 15

Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys

20 25 30

Asn Pro Lys Leu Thr Arg Met Leu Thr Phe Lys Phe Tyr Met Pro Lys

35 40 45

Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys

50 55 60

Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu

65 70 75 80

Arg Pro Arg Asp Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu

85 90 95

Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala

100 105 110

Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Ser Gln Ser Ile

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Ile Ser Thr Leu Thr

130

<210> 4

<211> 133

<212> PRT

<213> 人工(Artificial)

<220>

<223> IL-2 N88R变体序列

<400> 4

Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu His

1 5 10 15

Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys

20 25 30

Asn Pro Lys Leu Thr Arg Met Leu Thr Phe Lys Phe Tyr Met Pro Lys

35 40 45

Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys

50 55 60

Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu

65 70 75 80

Arg Pro Arg Asp Leu Ile Ser Arg Ile Asn Val Ile Val Leu Glu Leu

85 90 95

Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala

100 105 110

Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Ser Gln Ser Ile

115 120 125

Ile Ser Thr Leu Thr

130

<210> 5

<211> 133

<212> PRT

<213> 人工(Artificial)

<220>

<223> IL-2 D20T变体序列

<400> 5

Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu His

1 5 10 15

Leu Leu Leu Thr Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys

20 25 30

Asn Pro Lys Leu Thr Arg Met Leu Thr Phe Lys Phe Tyr Met Pro Lys

35 40 45

Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys

50 55 60

Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu

65 70 75 80

Arg Pro Arg Asp Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu

85 90 95

Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala

100 105 110

Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Ser Gln Ser Ile

115 120 125

Ile Ser Thr Leu Thr

130

<210> 6

<211> 133

<212> PRT

<213> 人工(Artificial)

<220>

<223> IL-2 D20E变体序列

<400> 6

Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu His

1 5 10 15

Leu Leu Leu Glu Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys

20 25 30

Asn Pro Lys Leu Thr Arg Met Leu Thr Phe Lys Phe Tyr Met Pro Lys

35 40 45

Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys

50 55 60

Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu

65 70 75 80

Arg Pro Arg Asp Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu

85 90 95

Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala

100 105 110

Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Ser Gln Ser Ile

115 120 125

Ile Ser Thr Leu Thr

130

<210> 7

<211> 133

<212> PRT

<213> 人工(Artificial)

<220>

<223> IL-2 D20N变体序列

<400> 7

Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu His

1 5 10 15

Leu Leu Leu Asn Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys

20 25 30

Asn Pro Lys Leu Thr Arg Met Leu Thr Phe Lys Phe Tyr Met Pro Lys

35 40 45

Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys

50 55 60

Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu

65 70 75 80

Arg Pro Arg Asp Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu

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Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala

100 105 110

Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Ser Gln Ser Ile

115 120 125

Ile Ser Thr Leu Thr

130

<210> 8

<211> 133

<212> PRT

<213> 人工(Artificial)

<220>

<223> IL-2 D20Q变体序列

<400> 8

Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu His

1 5 10 15

Leu Leu Leu Gln Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys

20 25 30

Asn Pro Lys Leu Thr Arg Met Leu Thr Phe Lys Phe Tyr Met Pro Lys

35 40 45

Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys

50 55 60

Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu

65 70 75 80

Arg Pro Arg Asp Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu

85 90 95

Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala

100 105 110

Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Ser Gln Ser Ile

115 120 125

Ile Ser Thr Leu Thr

130

<210> 9

<211> 133

<212> PRT

<213> 人工(Artificial)

<220>

<223> IL-2 D20S变体序列

<400> 9

Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu His

1 5 10 15

Leu Leu Leu Ser Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys

20 25 30

Asn Pro Lys Leu Thr Arg Met Leu Thr Phe Lys Phe Tyr Met Pro Lys

35 40 45

Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys

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Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu

65 70 75 80

Arg Pro Arg Asp Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu

85 90 95

Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala

100 105 110

Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Ser Gln Ser Ile

115 120 125

Ile Ser Thr Leu Thr

130

<210> 10

<211> 133

<212> PRT

<213> 人工(Artificial)

<220>

<223> IL-2 D20Y变体序列

<400> 10

Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu His

1 5 10 15

Leu Leu Leu Tyr Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys

20 25 30

Asn Pro Lys Leu Thr Arg Met Leu Thr Phe Lys Phe Tyr Met Pro Lys

35 40 45

Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys

50 55 60

Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu

65 70 75 80

Arg Pro Arg Asp Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu

85 90 95

Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala

100 105 110

Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Ser Gln Ser Ile

115 120 125

Ile Ser Thr Leu Thr

130

<210> 11

<211> 133

<212> PRT

<213> 人工(Artificial)

<220>

<223> IL-2 D20I变体序列

<400> 11

Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu His

1 5 10 15

Leu Leu Leu Ile Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys

20 25 30

Asn Pro Lys Leu Thr Arg Met Leu Thr Phe Lys Phe Tyr Met Pro Lys

35 40 45

Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys

50 55 60

Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu

65 70 75 80

Arg Pro Arg Asp Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu

85 90 95

Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala

100 105 110

Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Ser Gln Ser Ile

115 120 125

Ile Ser Thr Leu Thr

130

<210> 12

<211> 133

<212> PRT

<213> 人工(Artificial)

<220>

<223> IL-2 L19Y变体序列

<400> 12

Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu His

1 5 10 15

Leu Leu Tyr Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys

20 25 30

Asn Pro Lys Leu Thr Arg Met Leu Thr Phe Lys Phe Tyr Met Pro Lys

35 40 45

Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys

50 55 60

Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu

65 70 75 80

Arg Pro Arg Asp Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu

85 90 95

Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala

100 105 110

Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Ser Gln Ser Ile

115 120 125

Ile Ser Thr Leu Thr

130

<210> 13

<211> 133

<212> PRT

<213> 人工(Artificial)

<220>

<223> IL-2 L19N变体序列

<400> 13

Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu His

1 5 10 15

Leu Leu Asn Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys

20 25 30

Asn Pro Lys Leu Thr Arg Met Leu Thr Phe Lys Phe Tyr Met Pro Lys

35 40 45

Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys

50 55 60

Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu

65 70 75 80

Arg Pro Arg Asp Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu

85 90 95

Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala

100 105 110

Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Ser Gln Ser Ile

115 120 125

Ile Ser Thr Leu Thr

130

<210> 14

<211> 133

<212> PRT

<213> 人工(Artificial)

<220>

<223> IL-2 L19R变体序列

<400> 14

Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu His

1 5 10 15

Leu Leu Arg Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys

20 25 30

Asn Pro Lys Leu Thr Arg Met Leu Thr Phe Lys Phe Tyr Met Pro Lys

35 40 45

Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys

50 55 60

Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu

65 70 75 80

Arg Pro Arg Asp Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu

85 90 95

Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala

100 105 110

Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Ser Gln Ser Ile

115 120 125

Ile Ser Thr Leu Thr

130

<210> 15

<211> 133

<212> PRT

<213> 人工(Artificial)

<220>

<223> IL-2 N88G变体序列

<400> 15

Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu His

1 5 10 15

Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys

20 25 30

Asn Pro Lys Leu Thr Arg Met Leu Thr Phe Lys Phe Tyr Met Pro Lys

35 40 45

Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys

50 55 60

Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu

65 70 75 80

Arg Pro Arg Asp Leu Ile Ser Gly Ile Asn Val Ile Val Leu Glu Leu

85 90 95

Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala

100 105 110

Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Ser Gln Ser Ile

115 120 125

Ile Ser Thr Leu Thr

130

<210> 16

<211> 133

<212> PRT

<213> 人工(Artificial)

<220>

<223> IL-2 N88I变体序列

<400> 16

Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu His

1 5 10 15

Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys

20 25 30

Asn Pro Lys Leu Thr Arg Met Leu Thr Phe Lys Phe Tyr Met Pro Lys

35 40 45

Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys

50 55 60

Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu

65 70 75 80

Arg Pro Arg Asp Leu Ile Ser Ile Ile Asn Val Ile Val Leu Glu Leu

85 90 95

Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala

100 105 110

Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Ser Gln Ser Ile

115 120 125

Ile Ser Thr Leu Thr

130

<210> 17

<211> 133

<212> PRT

<213> 人工(Artificial)

<220>

<223> IL-2 N88Q变体序列

<400> 17

Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu His

1 5 10 15

Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys

20 25 30

Asn Pro Lys Leu Thr Arg Met Leu Thr Phe Lys Phe Tyr Met Pro Lys

35 40 45

Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys

50 55 60

Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu

65 70 75 80

Arg Pro Arg Asp Leu Ile Ser Gln Ile Asn Val Ile Val Leu Glu Leu

85 90 95

Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala

100 105 110

Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Ser Gln Ser Ile

115 120 125

Ile Ser Thr Leu Thr

130

<210> 18

<211> 133

<212> PRT

<213> 人工(Artificial)

<220>

<223> IL-2 N88E变体序列

<400> 18

Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu His

1 5 10 15

Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys

20 25 30

Asn Pro Lys Leu Thr Arg Met Leu Thr Phe Lys Phe Tyr Met Pro Lys

35 40 45

Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys

50 55 60

Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu

65 70 75 80

Arg Pro Arg Asp Leu Ile Ser Glu Ile Asn Val Ile Val Leu Glu Leu

85 90 95

Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala

100 105 110

Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Ser Gln Ser Ile

115 120 125

Ile Ser Thr Leu Thr

130

<210> 19

<211> 133

<212> PRT

<213> 人工(Artificial)

<220>

<223> IL-2 N88T变体序列

<400> 19

Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu His

1 5 10 15

Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys

20 25 30

Asn Pro Lys Leu Thr Arg Met Leu Thr Phe Lys Phe Tyr Met Pro Lys

35 40 45

Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys

50 55 60

Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu

65 70 75 80

Arg Pro Arg Asp Leu Ile Ser Thr Ile Asn Val Ile Val Leu Glu Leu

85 90 95

Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala

100 105 110

Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Ser Gln Ser Ile

115 120 125

Ile Ser Thr Leu Thr

130

<210> 20

<211> 132

<212> PRT

<213> 人工(Artificial)

<220>

<223> IL-2 N88M变体序列

<400> 20

Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu His

1 5 10 15

Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys

20 25 30

Asn Pro Lys Leu Thr Arg Met Leu Thr Phe Lys Phe Tyr Met Pro Lys

35 40 45

Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys

50 55 60

Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu

65 70 75 80

Arg Pro Arg Asp Leu Ile Ser Met Ile Asn Val Ile Val Leu Glu Leu

85 90 95

Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala

100 105 110

Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Ser Gln Ser Ile

115 120 125

Ile Ser Thr Leu

130

<210> 21

<211> 133

<212> PRT

<213> 人工(Artificial)

<220>

<223> IL-2 Q126E变体序列

<400> 21

Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu His

1 5 10 15

Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys

20 25 30

Asn Pro Lys Leu Thr Arg Met Leu Thr Phe Lys Phe Tyr Met Pro Lys

35 40 45

Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys

50 55 60

Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu

65 70 75 80

Arg Pro Arg Asp Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu

85 90 95

Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala

100 105 110

Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Ser Glu Ser Ile

115 120 125

Ile Ser Thr Leu Thr

130

<210> 22

<211> 133

<212> PRT

<213> 人工(Artificial)

<220>

<223> IL-2 Q126L变体序列

<400> 22

Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu His

1 5 10 15

Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys

20 25 30

Asn Pro Lys Leu Thr Arg Met Leu Thr Phe Lys Phe Tyr Met Pro Lys

35 40 45

Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys

50 55 60

Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu

65 70 75 80

Arg Pro Arg Asp Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu

85 90 95

Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala

100 105 110

Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Ser Leu Ser Ile

115 120 125

Ile Ser Thr Leu Thr

130

<210> 23

<211> 133

<212> PRT

<213> 人工(Artificial)

<220>

<223> IL-2 Q126N变体序列

<400> 23

Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu His

1 5 10 15

Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys

20 25 30

Asn Pro Lys Leu Thr Arg Met Leu Thr Phe Lys Phe Tyr Met Pro Lys

35 40 45

Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys

50 55 60

Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu

65 70 75 80

Arg Pro Arg Asp Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu

85 90 95

Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala

100 105 110

Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Ser Asn Ser Ile

115 120 125

Ile Ser Thr Leu Thr

130

<210> 24

<211> 133

<212> PRT

<213> 人工(Artificial)

<220>

<223> IL-2 Q126D变体序列

<400> 24

Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu His

1 5 10 15

Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys

20 25 30

Asn Pro Lys Leu Thr Arg Met Leu Thr Phe Lys Phe Tyr Met Pro Lys

35 40 45

Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys

50 55 60

Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu

65 70 75 80

Arg Pro Arg Asp Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu

85 90 95

Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala

100 105 110

Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Ser Asp Ser Ile

115 120 125

Ile Ser Thr Leu Thr

130

<210> 25

<211> 133

<212> PRT

<213> 人工(Artificial)

<220>

<223> IL-2 Q126M变体序列

<400> 25

Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu His

1 5 10 15

Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys

20 25 30

Asn Pro Lys Leu Thr Arg Met Leu Thr Phe Lys Phe Tyr Met Pro Lys

35 40 45

Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys

50 55 60

Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu

65 70 75 80

Arg Pro Arg Asp Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu

85 90 95

Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala

100 105 110

Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Ser Met Ser Ile

115 120 125

Ile Ser Thr Leu Thr

130

<210> 26

<211> 133

<212> PRT

<213> 人工(Artificial)

<220>

<223> IL-2 D20I/N88G变体序列

<400> 26

Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu His

1 5 10 15

Leu Leu Leu Ile Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys

20 25 30

Asn Pro Lys Leu Thr Arg Met Leu Thr Phe Lys Phe Tyr Met Pro Lys

35 40 45

Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys

50 55 60

Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu

65 70 75 80

Arg Pro Arg Asp Leu Ile Ser Gly Ile Asn Val Ile Val Leu Glu Leu

85 90 95

Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala

100 105 110

Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Ser Gln Ser Ile

115 120 125

Ile Ser Thr Leu Thr

130

<210> 27

<211> 133

<212> PRT

<213> 人工(Artificial)

<220>

<223> IL-2 D20I/N88R变体序列

<400> 27

Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu His

1 5 10 15

Leu Leu Leu Ile Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys

20 25 30

Asn Pro Lys Leu Thr Arg Met Leu Thr Phe Lys Phe Tyr Met Pro Lys

35 40 45

Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys

50 55 60

Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu

65 70 75 80

Arg Pro Arg Asp Leu Ile Ser Arg Ile Asn Val Ile Val Leu Glu Leu

85 90 95

Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala

100 105 110

Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Ser Gln Ser Ile

115 120 125

Ile Ser Thr Leu Thr

130

<210> 28

<211> 133

<212> PRT

<213> 人工(Artificial)

<220>

<223> IL-2 D20T/N88R变体序列

<400> 28

Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu His

1 5 10 15

Leu Leu Leu Thr Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys

20 25 30

Asn Pro Lys Leu Thr Arg Met Leu Thr Phe Lys Phe Tyr Met Pro Lys

35 40 45

Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys

50 55 60

Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu

65 70 75 80

Arg Pro Arg Asp Leu Ile Ser Arg Ile Asn Val Ile Val Leu Glu Leu

85 90 95

Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala

100 105 110

Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Ser Gln Ser Ile

115 120 125

Ile Ser Thr Leu Thr

130

<210> 29

<211> 133

<212> PRT

<213> 人工(Artificial)

<220>

<223> IL-2 D20I/N88I变体序列

<400> 29

Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu His

1 5 10 15

Leu Leu Leu Ile Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys

20 25 30

Asn Pro Lys Leu Thr Arg Met Leu Thr Phe Lys Phe Tyr Met Pro Lys

35 40 45

Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys

50 55 60

Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu

65 70 75 80

Arg Pro Arg Asp Leu Ile Ser Ile Ile Asn Val Ile Val Leu Glu Leu

85 90 95

Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala

100 105 110

Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Ser Gln Ser Ile

115 120 125

Ile Ser Thr Leu Thr

130

<210> 30

<211> 133

<212> PRT

<213> 人工(Artificial)

<220>

<223> IL-2 D20T/Q126E变体序列

<400> 30

Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu His

1 5 10 15

Leu Leu Leu Thr Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys

20 25 30

Asn Pro Lys Leu Thr Arg Met Leu Thr Phe Lys Phe Tyr Met Pro Lys

35 40 45

Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys

50 55 60

Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu

65 70 75 80

Arg Pro Arg Asp Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu

85 90 95

Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala

100 105 110

Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Ser Glu Ser Ile

115 120 125

Ile Ser Thr Leu Thr

130

<210> 31

<211> 133

<212> PRT

<213> 人工(Artificial)

<220>

<223> IL-2 D20T/N88R/Q126E变体序列

<400> 31

Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu His

1 5 10 15

Leu Leu Leu Thr Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys

20 25 30

Asn Pro Lys Leu Thr Arg Met Leu Thr Phe Lys Phe Tyr Met Pro Lys

35 40 45

Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys

50 55 60

Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu

65 70 75 80

Arg Pro Arg Asp Leu Ile Ser Arg Ile Asn Val Ile Val Leu Glu Leu

85 90 95

Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala

100 105 110

Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Ser Glu Ser Ile

115 120 125

Ile Ser Thr Leu Thr

130

<210> 32

<211> 133

<212> PRT

<213> 人工(Artificial)

<220>

<223> IL-2 D20T/Q126L变体序列

<400> 32

Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu His

1 5 10 15

Leu Leu Leu Thr Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys

20 25 30

Asn Pro Lys Leu Thr Arg Met Leu Thr Phe Lys Phe Tyr Met Pro Lys

35 40 45

Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys

50 55 60

Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu

65 70 75 80

Arg Pro Arg Asp Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu

85 90 95

Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala

100 105 110

Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Ser Leu Ser Ile

115 120 125

Ile Ser Thr Leu Thr

130

<210> 33

<211> 133

<212> PRT

<213> 人工(Artificial)

<220>

<223> IL-2 D20T/N88R/Q126L变体序列

<400> 33

Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu His

1 5 10 15

Leu Leu Leu Thr Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys

20 25 30

Asn Pro Lys Leu Thr Arg Met Leu Thr Phe Lys Phe Tyr Met Pro Lys

35 40 45

Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys

50 55 60

Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu

65 70 75 80

Arg Pro Arg Asp Leu Ile Ser Arg Ile Asn Val Ile Val Leu Glu Leu

85 90 95

Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala

100 105 110

Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Ser Leu Ser Ile

115 120 125

Ile Ser Thr Leu Thr

130

<210> 34

<211> 133

<212> PRT

<213> 人工(Artificial)

<220>

<223> IL-2 L19N/Q126E变体序列

<400> 34

Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu His

1 5 10 15

Leu Leu Asn Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys

20 25 30

Asn Pro Lys Leu Thr Arg Met Leu Thr Phe Lys Phe Tyr Met Pro Lys

35 40 45

Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys

50 55 60

Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu

65 70 75 80

Arg Pro Arg Asp Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu

85 90 95

Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala

100 105 110

Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Ser Glu Ser Ile

115 120 125

Ile Ser Thr Leu Thr

130

<210> 35

<211> 133

<212> PRT

<213> 人工(Artificial)

<220>

<223> IL-2 L19R/Q126E变体序列

<400> 35

Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu His

1 5 10 15

Leu Leu Arg Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys

20 25 30

Asn Pro Lys Leu Thr Arg Met Leu Thr Phe Lys Phe Tyr Met Pro Lys

35 40 45

Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys

50 55 60

Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu

65 70 75 80

Arg Pro Arg Asp Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu

85 90 95

Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala

100 105 110

Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Ser Glu Ser Ile

115 120 125

Ile Ser Thr Leu Thr

130

<210> 36

<211> 133

<212> PRT

<213> 人工(Artificial)

<220>

<223> IL-2 L19Y/Q126E变体序列

<400> 36

Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu His

1 5 10 15

Leu Leu Tyr Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys

20 25 30

Asn Pro Lys Leu Thr Arg Met Leu Thr Phe Lys Phe Tyr Met Pro Lys

35 40 45

Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys

50 55 60

Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu

65 70 75 80

Arg Pro Arg Asp Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu

85 90 95

Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala

100 105 110

Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Ser Glu Ser Ile

115 120 125

Ile Ser Thr Leu Thr

130

<210> 37

<211> 133

<212> PRT

<213> 人工(Artificial)

<220>

<223> IL-2 L19Q变体序列

<400> 37

Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu His

1 5 10 15

Leu Leu Gln Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys

20 25 30

Asn Pro Lys Leu Thr Arg Met Leu Thr Phe Lys Phe Tyr Met Pro Lys

35 40 45

Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys

50 55 60

Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu

65 70 75 80

Arg Pro Arg Asp Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu

85 90 95

Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala

100 105 110

Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Ser Gln Ser Ile

115 120 125

Ile Ser Thr Leu Thr

130

<210> 38

<211> 133

<212> PRT

<213> 人工(Artificial)

<220>

<223> IL-2 L19H变体序列

<400> 38

Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu His

1 5 10 15

Leu Leu His Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys

20 25 30

Asn Pro Lys Leu Thr Arg Met Leu Thr Phe Lys Phe Tyr Met Pro Lys

35 40 45

Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys

50 55 60

Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu

65 70 75 80

Arg Pro Arg Asp Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu

85 90 95

Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala

100 105 110

Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Ser Gln Ser Ile

115 120 125

Ile Ser Thr Leu Thr

130

<210> 39

<211> 133

<212> PRT

<213> 人工(Artificial)

<220>

<223> IL-2 L19D变体序列

<400> 39

Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu His

1 5 10 15

Leu Leu Asp Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys

20 25 30

Asn Pro Lys Leu Thr Arg Met Leu Thr Phe Lys Phe Tyr Met Pro Lys

35 40 45

Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys

50 55 60

Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu

65 70 75 80

Arg Pro Arg Asp Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu

85 90 95

Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala

100 105 110

Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Ser Gln Ser Ile

115 120 125

Ile Ser Thr Leu Thr

130

<210> 40

<211> 133

<212> PRT

<213> 人工(Artificial)

<220>

<223> IL-2 L19P变体序列

<400> 40

Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu His

1 5 10 15

Leu Leu Pro Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys

20 25 30

Asn Pro Lys Leu Thr Arg Met Leu Thr Phe Lys Phe Tyr Met Pro Lys

35 40 45

Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys

50 55 60

Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu

65 70 75 80

Arg Pro Arg Asp Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu

85 90 95

Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala

100 105 110

Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Ser Gln Ser Ile

115 120 125

Ile Ser Thr Leu Thr

130

<210> 41

<211> 133

<212> PRT

<213> 人工(Artificial)

<220>

<223> IL-2 D20T/S125I/Q126K变体序列

<400> 41

Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu His

1 5 10 15

Leu Leu Leu Thr Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys

20 25 30

Asn Pro Lys Leu Thr Arg Met Leu Thr Phe Lys Phe Tyr Met Pro Lys

35 40 45

Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys

50 55 60

Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu

65 70 75 80

Arg Pro Arg Asp Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu

85 90 95

Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala

100 105 110

Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Ile Lys Ser Ile

115 120 125

Ile Ser Thr Leu Thr

130

<210> 42

<211> 133

<212> PRT

<213> 人工(Artificial)

<220>

<223> IL-2 L19N/S125I/Q126K变体序列

<400> 42

Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu His

1 5 10 15

Leu Leu Asn Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys

20 25 30

Asn Pro Lys Leu Thr Arg Met Leu Thr Phe Lys Phe Tyr Met Pro Lys

35 40 45

Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys

50 55 60

Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu

65 70 75 80

Arg Pro Arg Asp Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu

85 90 95

Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala

100 105 110

Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Ile Lys Ser Ile

115 120 125

Ile Ser Thr Leu Thr

130

<210> 43

<211> 133

<212> PRT

<213> 人工(Artificial)

<220>

<223> IL-2 L19R/S125I/Q126K变体序列

<400> 43

Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu His

1 5 10 15

Leu Leu Arg Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys

20 25 30

Asn Pro Lys Leu Thr Arg Met Leu Thr Phe Lys Phe Tyr Met Pro Lys

35 40 45

Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys

50 55 60

Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu

65 70 75 80

Arg Pro Arg Asp Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu

85 90 95

Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala

100 105 110

Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Ile Lys Ser Ile

115 120 125

Ile Ser Thr Leu Thr

130

<210> 44

<211> 226

<212> PRT

<213> 智人(Homo sapiens)

<400> 44

Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly

1 5 10 15

Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met

20 25 30

Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His

35 40 45

Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val

50 55 60

His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr

65 70 75 80

Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly

85 90 95

Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile

100 105 110

Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val

115 120 125

Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser

130 135 140

Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu

145 150 155 160

Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro

165 170 175

Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val

180 185 190

Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met

195 200 205

His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser

210 215 220

Pro Gly

225

<210> 45

<211> 226

<212> PRT

<213> 人工(Artificial)

<220>

<223> 具有减少/消除的效应子功能的人类IgG1-Fc

<400> 45

Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly

1 5 10 15

Ala Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met

20 25 30

Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His

35 40 45

Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val

50 55 60

His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr

65 70 75 80

Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly

85 90 95

Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile

100 105 110

Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val

115 120 125

Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser

130 135 140

Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu

145 150 155 160

Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro

165 170 175

Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val

180 185 190

Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met

195 200 205

His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser

210 215 220

Pro Gly

225

<210> 46

<211> 226

<212> PRT

<213> 人工(Artificial)

<220>

<223> 具有减少/消除的效应子功能并具有延长的半衰期的人类IgG1-Fc

<400> 46

Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly

1 5 10 15

Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Tyr

20 25 30

Ile Thr Arg Glu Pro Glu Val Thr Cys Val Val Val Asp Val Ser His

35 40 45

Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val

50 55 60

His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr

65 70 75 80

Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly

85 90 95

Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile

100 105 110

Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val

115 120 125

Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser

130 135 140

Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu

145 150 155 160

Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro

165 170 175

Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val

180 185 190

Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met

195 200 205

His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser

210 215 220

Pro Gly

225

<210> 47

<211> 226

<212> PRT

<213> 人工(Artificial)

<220>

<223> 具有减少/消除的效应子功能和延长的半衰期的人类IgG1-Fc

<400> 47

Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly

1 5 10 15

Ala Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met

20 25 30

Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His

35 40 45

Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val

50 55 60

His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr

65 70 75 80

Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly

85 90 95

Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile

100 105 110

Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val

115 120 125

Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser

130 135 140

Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu

145 150 155 160

Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro

165 170 175

Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val

180 185 190

Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met

195 200 205

His Glu Ala Leu His Ala His Tyr Thr Gln Lys Ser Leu Ser Leu Ser

210 215 220

Pro Gly

225

<210> 48

<211> 12

<212> PRT

<213> 人工(Artificial)

<220>

<223> 肽接头序列

<400> 48

Gly Gly Gly Ser Gly Gly Gly Ser Gly Gly Gly Ser

1 5 10

<210> 49

<211> 4

<212> PRT

<213> 人工(Artificial)

<220>

<223> 肽接头序列

<400> 49

Gly Gly Gly Ser

1

<210> 50

<211> 13

<212> PRT

<213> 人工(Artificial)

<220>

<223> 肽接头序列

<400> 50

Gly Ser Ser Gly Gly Ser Gly Gly Ser Gly Gly Ser Gly

1 5 10

<210> 51

<211> 5

<212> PRT

<213> 人工(Artificial)

<220>

<223> 肽接头序列

<400> 51

Gly Ser Ser Gly Thr

1 5

<210> 52

<211> 14

<212> PRT

<213> 人工(Artificial)

<220>

<223> 肽接头序列

<400> 52

Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser

1 5 10

<210> 53

<211> 17

<212> PRT

<213> 人工(Artificial)

<220>

<223> 肽接头序列

<400> 53

Ala Glu Ala Ala Ala Lys Glu Ala Ala Ala Lys Glu Ala Ala Ala Lys

1 5 10 15

Ala

<210> 54

<211> 20

<212> PRT

<213> 人工(Artificial)

<220>

<223> 肽接头序列

<400> 54

Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly

1 5 10 15

Gly Gly Gly Ser

20

<210> 55

<211> 8

<212> PRT

<213> 人工(Artificial)

<220>

<223> 肽接头序列

<400> 55

Gly Gly Gly Ser Gly Gly Gly Ser

1 5

<210> 56

<211> 2

<212> PRT

<213> 人工(Artificial)

<220>

<223> 肽接头序列

<400> 56

Gly Ser

1

<210> 57

<211> 3

<212> PRT

<213> 人工(Artificial)

<220>

<223> 肽接头序列

<400> 57

Gly Gly Ser

1

<210> 58

<211> 5

<212> PRT

<213> 人工(Artificial)

<220>

<223> 肽接头序列

<400> 58

Gly Gly Gly Gly Ser

1 5

<210> 59

<211> 4

<212> PRT

<213> 人工(Artificial)

<220>

<223> 肽接头序列

<400> 59

Gly Gly Ser Gly

1

<210> 60

<211> 4

<212> PRT

<213> 人工(Artificial)

<220>

<223> 肽接头序列

<400> 60

Ser Gly Gly Gly

1

<210> 61

<211> 4

<212> PRT

<213> 人工(Artificial)

<220>

<223> 肽接头序列

<400> 61

Gly Ser Gly Ser

1

<210> 62

<211> 6

<212> PRT

<213> 人工(Artificial)

<220>

<223> 肽接头序列

<400> 62

Gly Ser Gly Ser Gly Ser

1 5

<210> 63

<211> 8

<212> PRT

<213> 人工(Artificial)

<220>

<223> 肽接头序列

<400> 63

Gly Ser Gly Ser Gly Ser Gly Ser

1 5

<210> 64

<211> 10

<212> PRT

<213> 人工(Artificial)

<220>

<223> 肽接头序列

<400> 64

Gly Ser Gly Ser Gly Ser Gly Ser Gly Ser

1 5 10

<210> 65

<211> 12

<212> PRT

<213> 人工(Artificial)

<220>

<223> 肽接头序列

<400> 65

Gly Ser Gly Ser Gly Ser Gly Ser Gly Ser Gly Ser

1 5 10

<210> 66

<211> 10

<212> PRT

<213> 人工(Artificial)

<220>

<223> 肽接头序列

<400> 66

Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser

1 5 10

<210> 67

<211> 15

<212> PRT

<213> 人工(Artificial)

<220>

<223> 肽接头序列

<400> 67

Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser

1 5 10 15

<210> 68

<211> 165

<212> PRT

<213> 智人(Homo sapiens)

<400> 68

Glu Leu Cys Asp Asp Asp Pro Pro Glu Ile Pro His Ala Thr Phe Lys

1 5 10 15

Ala Met Ala Tyr Lys Glu Gly Thr Met Leu Asn Cys Glu Cys Lys Arg

20 25 30

Gly Phe Arg Arg Ile Lys Ser Gly Ser Leu Tyr Met Leu Cys Thr Gly

35 40 45

Asn Ser Ser His Ser Ser Trp Asp Asn Gln Cys Gln Cys Thr Ser Ser

50 55 60

Ala Thr Arg Asn Thr Thr Lys Gln Val Thr Pro Gln Pro Glu Glu Gln

65 70 75 80

Lys Glu Arg Lys Thr Thr Glu Met Gln Ser Pro Met Gln Pro Val Asp

85 90 95

Gln Ala Ser Leu Pro Gly His Cys Arg Glu Pro Pro Pro Trp Glu Asn

100 105 110

Glu Ala Thr Glu Arg Ile Tyr His Phe Val Val Gly Gln Met Val Tyr

115 120 125

Tyr Gln Cys Val Gln Gly Tyr Arg Ala Leu His Arg Gly Pro Ala Glu

130 135 140

Ser Val Cys Lys Met Thr His Gly Lys Thr Arg Trp Thr Gln Pro Gln

145 150 155 160

Leu Ile Cys Thr Gly

165

<210> 69

<211> 367

<212> PRT

<213> 人工(Artificial)

<220>

<223> P-0250

<400> 69

Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly

1 5 10 15

Ala Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met

20 25 30

Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His

35 40 45

Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val

50 55 60

His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr

65 70 75 80

Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly

85 90 95

Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile

100 105 110

Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val

115 120 125

Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser

130 135 140

Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu

145 150 155 160

Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro

165 170 175

Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val

180 185 190

Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met

195 200 205

His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser

210 215 220

Pro Gly Gly Gly Gly Ser Gly Gly Gly Ser Ala Pro Thr Ser Ser Ser

225 230 235 240

Thr Lys Lys Thr Gln Leu Gln Leu Glu His Leu Leu Leu Asp Leu Gln

245 250 255

Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys Asn Pro Lys Leu Thr Arg

260 265 270

Met Leu Thr Phe Lys Phe Tyr Met Pro Lys Lys Ala Thr Glu Leu Lys

275 280 285

His Leu Gln Cys Leu Glu Glu Glu Leu Lys Pro Leu Glu Glu Val Leu

290 295 300

Asn Leu Ala Gln Ser Lys Asn Phe His Leu Arg Pro Arg Asp Leu Ile

305 310 315 320

Ser Asn Ile Asn Val Ile Val Leu Glu Leu Lys Gly Ser Glu Thr Thr

325 330 335

Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala Thr Ile Val Glu Phe Leu

340 345 350

Asn Arg Trp Ile Thr Phe Ser Gln Ser Ile Ile Ser Thr Leu Thr

355 360 365

<210> 70

<211> 371

<212> PRT

<213> 人工(Artificial)

<220>

<223> P-0305

<400> 70

Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu His

1 5 10 15

Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys

20 25 30

Asn Pro Lys Leu Thr Arg Met Leu Thr Phe Lys Phe Tyr Met Pro Lys

35 40 45

Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys

50 55 60

Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu

65 70 75 80

Arg Pro Arg Asp Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu

85 90 95

Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala

100 105 110

Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Ser Gln Ser Ile

115 120 125

Ile Ser Thr Leu Thr Ala Glu Ala Ala Ala Lys Glu Ala Ala Ala Lys

130 135 140

Glu Ala Ala Ala Lys Ala Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala

145 150 155 160

Gly Ala Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu

165 170 175

Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser

180 185 190

His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu

195 200 205

Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr

210 215 220

Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn

225 230 235 240

Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro

245 250 255

Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln

260 265 270

Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val

275 280 285

Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val

290 295 300

Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro

305 310 315 320

Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr

325 330 335

Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val

340 345 350

Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu

355 360 365

Ser Pro Gly

370

<210> 71

<211> 367

<212> PRT

<213> 人工(Artificial)

<220>

<223> P-0254

<400> 71

Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly

1 5 10 15

Ala Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met

20 25 30

Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His

35 40 45

Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val

50 55 60

His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr

65 70 75 80

Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly

85 90 95

Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile

100 105 110

Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val

115 120 125

Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser

130 135 140

Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu

145 150 155 160

Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro

165 170 175

Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val

180 185 190

Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met

195 200 205

His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser

210 215 220

Pro Gly Gly Gly Gly Ser Gly Gly Gly Ser Ala Pro Thr Ser Ser Ser

225 230 235 240

Thr Lys Lys Thr Gln Leu Gln Leu Glu His Leu Leu Leu Asp Leu Gln

245 250 255

Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys Asn Pro Lys Leu Thr Arg

260 265 270

Met Leu Thr Phe Lys Phe Tyr Met Pro Lys Lys Ala Thr Glu Leu Lys

275 280 285

His Leu Gln Cys Leu Glu Glu Glu Leu Lys Pro Leu Glu Glu Val Leu

290 295 300

Asn Leu Ala Gln Ser Lys Asn Phe His Leu Arg Pro Arg Asp Leu Ile

305 310 315 320

Ser Arg Ile Asn Val Ile Val Leu Glu Leu Lys Gly Ser Glu Thr Thr

325 330 335

Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala Thr Ile Val Glu Phe Leu

340 345 350

Asn Arg Trp Ile Thr Phe Ser Gln Ser Ile Ile Ser Thr Leu Thr

355 360 365

<210> 72

<211> 367

<212> PRT

<213> 人工(Artificial)

<220>

<223> P-0363

<400> 72

Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly

1 5 10 15

Ala Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met

20 25 30

Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His

35 40 45

Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val

50 55 60

His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr

65 70 75 80

Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly

85 90 95

Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile

100 105 110

Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val

115 120 125

Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser

130 135 140

Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu

145 150 155 160

Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro

165 170 175

Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val

180 185 190

Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met

195 200 205

His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser

210 215 220

Pro Gly Gly Gly Gly Ser Gly Gly Gly Ser Ala Pro Thr Ser Ser Ser

225 230 235 240

Thr Lys Lys Thr Gln Leu Gln Leu Glu His Leu Leu Leu Thr Leu Gln

245 250 255

Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys Asn Pro Lys Leu Thr Arg

260 265 270

Met Leu Thr Phe Lys Phe Tyr Met Pro Lys Lys Ala Thr Glu Leu Lys

275 280 285

His Leu Gln Cys Leu Glu Glu Glu Leu Lys Pro Leu Glu Glu Val Leu

290 295 300

Asn Leu Ala Gln Ser Lys Asn Phe His Leu Arg Pro Arg Asp Leu Ile

305 310 315 320

Ser Asn Ile Asn Val Ile Val Leu Glu Leu Lys Gly Ser Glu Thr Thr

325 330 335

Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala Thr Ile Val Glu Phe Leu

340 345 350

Asn Arg Trp Ile Thr Phe Ser Gln Ser Ile Ile Ser Thr Leu Thr

355 360 365

<210> 73

<211> 367

<212> PRT

<213> 人工(Artificial)

<220>

<223> P-0364

<400> 73

Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly

1 5 10 15

Ala Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met

20 25 30

Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His

35 40 45

Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val

50 55 60

His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr

65 70 75 80

Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly

85 90 95

Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile

100 105 110

Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val

115 120 125

Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser

130 135 140

Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu

145 150 155 160

Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro

165 170 175

Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val

180 185 190

Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met

195 200 205

His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser

210 215 220

Pro Gly Gly Gly Gly Ser Gly Gly Gly Ser Ala Pro Thr Ser Ser Ser

225 230 235 240

Thr Lys Lys Thr Gln Leu Gln Leu Glu His Leu Leu Leu Glu Leu Gln

245 250 255

Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys Asn Pro Lys Leu Thr Arg

260 265 270

Met Leu Thr Phe Lys Phe Tyr Met Pro Lys Lys Ala Thr Glu Leu Lys

275 280 285

His Leu Gln Cys Leu Glu Glu Glu Leu Lys Pro Leu Glu Glu Val Leu

290 295 300

Asn Leu Ala Gln Ser Lys Asn Phe His Leu Arg Pro Arg Asp Leu Ile

305 310 315 320

Ser Asn Ile Asn Val Ile Val Leu Glu Leu Lys Gly Ser Glu Thr Thr

325 330 335

Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala Thr Ile Val Glu Phe Leu

340 345 350

Asn Arg Trp Ile Thr Phe Ser Gln Ser Ile Ile Ser Thr Leu Thr

355 360 365

<210> 74

<211> 367

<212> PRT

<213> 人工(Artificial)

<220>

<223> P-0365

<400> 74

Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly

1 5 10 15

Ala Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met

20 25 30

Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His

35 40 45

Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val

50 55 60

His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr

65 70 75 80

Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly

85 90 95

Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile

100 105 110

Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val

115 120 125

Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser

130 135 140

Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu

145 150 155 160

Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro

165 170 175

Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val

180 185 190

Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met

195 200 205

His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser

210 215 220

Pro Gly Gly Gly Gly Ser Gly Gly Gly Ser Ala Pro Thr Ser Ser Ser

225 230 235 240

Thr Lys Lys Thr Gln Leu Gln Leu Glu His Leu Leu Leu Asn Leu Gln

245 250 255

Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys Asn Pro Lys Leu Thr Arg

260 265 270

Met Leu Thr Phe Lys Phe Tyr Met Pro Lys Lys Ala Thr Glu Leu Lys

275 280 285

His Leu Gln Cys Leu Glu Glu Glu Leu Lys Pro Leu Glu Glu Val Leu

290 295 300

Asn Leu Ala Gln Ser Lys Asn Phe His Leu Arg Pro Arg Asp Leu Ile

305 310 315 320

Ser Asn Ile Asn Val Ile Val Leu Glu Leu Lys Gly Ser Glu Thr Thr

325 330 335

Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala Thr Ile Val Glu Phe Leu

340 345 350

Asn Arg Trp Ile Thr Phe Ser Gln Ser Ile Ile Ser Thr Leu Thr

355 360 365

<210> 75

<211> 367

<212> PRT

<213> 人工(Artificial)

<220>

<223> P-0366

<400> 75

Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly

1 5 10 15

Ala Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met

20 25 30

Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His

35 40 45

Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val

50 55 60

His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr

65 70 75 80

Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly

85 90 95

Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile

100 105 110

Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val

115 120 125

Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser

130 135 140

Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu

145 150 155 160

Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro

165 170 175

Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val

180 185 190

Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met

195 200 205

His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser

210 215 220

Pro Gly Gly Gly Gly Ser Gly Gly Gly Ser Ala Pro Thr Ser Ser Ser

225 230 235 240

Thr Lys Lys Thr Gln Leu Gln Leu Glu His Leu Leu Leu Gln Leu Gln

245 250 255

Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys Asn Pro Lys Leu Thr Arg

260 265 270

Met Leu Thr Phe Lys Phe Tyr Met Pro Lys Lys Ala Thr Glu Leu Lys

275 280 285

His Leu Gln Cys Leu Glu Glu Glu Leu Lys Pro Leu Glu Glu Val Leu

290 295 300

Asn Leu Ala Gln Ser Lys Asn Phe His Leu Arg Pro Arg Asp Leu Ile

305 310 315 320

Ser Asn Ile Asn Val Ile Val Leu Glu Leu Lys Gly Ser Glu Thr Thr

325 330 335

Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala Thr Ile Val Glu Phe Leu

340 345 350

Asn Arg Trp Ile Thr Phe Ser Gln Ser Ile Ile Ser Thr Leu Thr

355 360 365

<210> 76

<211> 367

<212> PRT

<213> 人工(Artificial)

<220>

<223> P-0367

<400> 76

Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly

1 5 10 15

Ala Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met

20 25 30

Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His

35 40 45

Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val

50 55 60

His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr

65 70 75 80

Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly

85 90 95

Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile

100 105 110

Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val

115 120 125

Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser

130 135 140

Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu

145 150 155 160

Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro

165 170 175

Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val

180 185 190

Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met

195 200 205

His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser

210 215 220

Pro Gly Gly Gly Gly Ser Gly Gly Gly Ser Ala Pro Thr Ser Ser Ser

225 230 235 240

Thr Lys Lys Thr Gln Leu Gln Leu Glu His Leu Leu Leu Ser Leu Gln

245 250 255

Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys Asn Pro Lys Leu Thr Arg

260 265 270

Met Leu Thr Phe Lys Phe Tyr Met Pro Lys Lys Ala Thr Glu Leu Lys

275 280 285

His Leu Gln Cys Leu Glu Glu Glu Leu Lys Pro Leu Glu Glu Val Leu

290 295 300

Asn Leu Ala Gln Ser Lys Asn Phe His Leu Arg Pro Arg Asp Leu Ile

305 310 315 320

Ser Asn Ile Asn Val Ile Val Leu Glu Leu Lys Gly Ser Glu Thr Thr

325 330 335

Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala Thr Ile Val Glu Phe Leu

340 345 350

Asn Arg Trp Ile Thr Phe Ser Gln Ser Ile Ile Ser Thr Leu Thr

355 360 365

<210> 77

<211> 367

<212> PRT

<213> 人工(Artificial)

<220>

<223> P-0368

<400> 77

Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly

1 5 10 15

Ala Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met

20 25 30

Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His

35 40 45

Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val

50 55 60

His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr

65 70 75 80

Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly

85 90 95

Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile

100 105 110

Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val

115 120 125

Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser

130 135 140

Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu

145 150 155 160

Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro

165 170 175

Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val

180 185 190

Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met

195 200 205

His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser

210 215 220

Pro Gly Gly Gly Gly Ser Gly Gly Gly Ser Ala Pro Thr Ser Ser Ser

225 230 235 240

Thr Lys Lys Thr Gln Leu Gln Leu Glu His Leu Leu Leu Tyr Leu Gln

245 250 255

Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys Asn Pro Lys Leu Thr Arg

260 265 270

Met Leu Thr Phe Lys Phe Tyr Met Pro Lys Lys Ala Thr Glu Leu Lys

275 280 285

His Leu Gln Cys Leu Glu Glu Glu Leu Lys Pro Leu Glu Glu Val Leu

290 295 300

Asn Leu Ala Gln Ser Lys Asn Phe His Leu Arg Pro Arg Asp Leu Ile

305 310 315 320

Ser Asn Ile Asn Val Ile Val Leu Glu Leu Lys Gly Ser Glu Thr Thr

325 330 335

Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala Thr Ile Val Glu Phe Leu

340 345 350

Asn Arg Trp Ile Thr Phe Ser Gln Ser Ile Ile Ser Thr Leu Thr

355 360 365

<210> 78

<211> 367

<212> PRT

<213> 人工(Artificial)

<220>

<223> P-0252

<400> 78

Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly

1 5 10 15

Ala Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met

20 25 30

Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His

35 40 45

Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val

50 55 60

His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr

65 70 75 80

Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly

85 90 95

Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile

100 105 110

Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val

115 120 125

Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser

130 135 140

Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu

145 150 155 160

Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro

165 170 175

Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val

180 185 190

Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met

195 200 205

His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser

210 215 220

Pro Gly Gly Gly Gly Ser Gly Gly Gly Ser Ala Pro Thr Ser Ser Ser

225 230 235 240

Thr Lys Lys Thr Gln Leu Gln Leu Glu His Leu Leu Leu Ile Leu Gln

245 250 255

Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys Asn Pro Lys Leu Thr Arg

260 265 270

Met Leu Thr Phe Lys Phe Tyr Met Pro Lys Lys Ala Thr Glu Leu Lys

275 280 285

His Leu Gln Cys Leu Glu Glu Glu Leu Lys Pro Leu Glu Glu Val Leu

290 295 300

Asn Leu Ala Gln Ser Lys Asn Phe His Leu Arg Pro Arg Asp Leu Ile

305 310 315 320

Ser Asn Ile Asn Val Ile Val Leu Glu Leu Lys Gly Ser Glu Thr Thr

325 330 335

Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala Thr Ile Val Glu Phe Leu

340 345 350

Asn Arg Trp Ile Thr Phe Ser Gln Ser Ile Ile Ser Thr Leu Thr

355 360 365

<210> 79

<211> 367

<212> PRT

<213> 人工(Artificial)

<220>

<223> P-0372

<400> 79

Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly

1 5 10 15

Ala Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met

20 25 30

Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His

35 40 45

Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val

50 55 60

His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr

65 70 75 80

Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly

85 90 95

Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile

100 105 110

Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val

115 120 125

Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser

130 135 140

Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu

145 150 155 160

Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro

165 170 175

Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val

180 185 190

Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met

195 200 205

His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser

210 215 220

Pro Gly Gly Gly Gly Ser Gly Gly Gly Ser Ala Pro Thr Ser Ser Ser

225 230 235 240

Thr Lys Lys Thr Gln Leu Gln Leu Glu His Leu Leu Tyr Asp Leu Gln

245 250 255

Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys Asn Pro Lys Leu Thr Arg

260 265 270

Met Leu Thr Phe Lys Phe Tyr Met Pro Lys Lys Ala Thr Glu Leu Lys

275 280 285

His Leu Gln Cys Leu Glu Glu Glu Leu Lys Pro Leu Glu Glu Val Leu

290 295 300

Asn Leu Ala Gln Ser Lys Asn Phe His Leu Arg Pro Arg Asp Leu Ile

305 310 315 320

Ser Asn Ile Asn Val Ile Val Leu Glu Leu Lys Gly Ser Glu Thr Thr

325 330 335

Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala Thr Ile Val Glu Phe Leu

340 345 350

Asn Arg Trp Ile Thr Phe Ser Gln Ser Ile Ile Ser Thr Leu Thr

355 360 365

<210> 80

<211> 367

<212> PRT

<213> 人工(Artificial)

<220>

<223> P-0373

<400> 80

Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly

1 5 10 15

Ala Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met

20 25 30

Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His

35 40 45

Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val

50 55 60

His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr

65 70 75 80

Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly

85 90 95

Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile

100 105 110

Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val

115 120 125

Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser

130 135 140

Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu

145 150 155 160

Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro

165 170 175

Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val

180 185 190

Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met

195 200 205

His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser

210 215 220

Pro Gly Gly Gly Gly Ser Gly Gly Gly Ser Ala Pro Thr Ser Ser Ser

225 230 235 240

Thr Lys Lys Thr Gln Leu Gln Leu Glu His Leu Leu Asn Asp Leu Gln

245 250 255

Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys Asn Pro Lys Leu Thr Arg

260 265 270

Met Leu Thr Phe Lys Phe Tyr Met Pro Lys Lys Ala Thr Glu Leu Lys

275 280 285

His Leu Gln Cys Leu Glu Glu Glu Leu Lys Pro Leu Glu Glu Val Leu

290 295 300

Asn Leu Ala Gln Ser Lys Asn Phe His Leu Arg Pro Arg Asp Leu Ile

305 310 315 320

Ser Asn Ile Asn Val Ile Val Leu Glu Leu Lys Gly Ser Glu Thr Thr

325 330 335

Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala Thr Ile Val Glu Phe Leu

340 345 350

Asn Arg Trp Ile Thr Phe Ser Gln Ser Ile Ile Ser Thr Leu Thr

355 360 365

<210> 81

<211> 367

<212> PRT

<213> 人工(Artificial)

<220>

<223> P-0374

<400> 81

Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly

1 5 10 15

Ala Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met

20 25 30

Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His

35 40 45

Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val

50 55 60

His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr

65 70 75 80

Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly

85 90 95

Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile

100 105 110

Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val

115 120 125

Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser

130 135 140

Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu

145 150 155 160

Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro

165 170 175

Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val

180 185 190

Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met

195 200 205

His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser

210 215 220

Pro Gly Gly Gly Gly Ser Gly Gly Gly Ser Ala Pro Thr Ser Ser Ser

225 230 235 240

Thr Lys Lys Thr Gln Leu Gln Leu Glu His Leu Leu Arg Asp Leu Gln

245 250 255

Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys Asn Pro Lys Leu Thr Arg

260 265 270

Met Leu Thr Phe Lys Phe Tyr Met Pro Lys Lys Ala Thr Glu Leu Lys

275 280 285

His Leu Gln Cys Leu Glu Glu Glu Leu Lys Pro Leu Glu Glu Val Leu

290 295 300

Asn Leu Ala Gln Ser Lys Asn Phe His Leu Arg Pro Arg Asp Leu Ile

305 310 315 320

Ser Asn Ile Asn Val Ile Val Leu Glu Leu Lys Gly Ser Glu Thr Thr

325 330 335

Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala Thr Ile Val Glu Phe Leu

340 345 350

Asn Arg Trp Ile Thr Phe Ser Gln Ser Ile Ile Ser Thr Leu Thr

355 360 365

<210> 82

<211> 367

<212> PRT

<213> 人工(Artificial)

<220>

<223> P-0253

<400> 82

Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly

1 5 10 15

Ala Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met

20 25 30

Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His

35 40 45

Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val

50 55 60

His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr

65 70 75 80

Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly

85 90 95

Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile

100 105 110

Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val

115 120 125

Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser

130 135 140

Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu

145 150 155 160

Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro

165 170 175

Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val

180 185 190

Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met

195 200 205

His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser

210 215 220

Pro Gly Gly Gly Gly Ser Gly Gly Gly Ser Ala Pro Thr Ser Ser Ser

225 230 235 240

Thr Lys Lys Thr Gln Leu Gln Leu Glu His Leu Leu Leu Asp Leu Gln

245 250 255

Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys Asn Pro Lys Leu Thr Arg

260 265 270

Met Leu Thr Phe Lys Phe Tyr Met Pro Lys Lys Ala Thr Glu Leu Lys

275 280 285

His Leu Gln Cys Leu Glu Glu Glu Leu Lys Pro Leu Glu Glu Val Leu

290 295 300

Asn Leu Ala Gln Ser Lys Asn Phe His Leu Arg Pro Arg Asp Leu Ile

305 310 315 320

Ser Gly Ile Asn Val Ile Val Leu Glu Leu Lys Gly Ser Glu Thr Thr

325 330 335

Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala Thr Ile Val Glu Phe Leu

340 345 350

Asn Arg Trp Ile Thr Phe Ser Gln Ser Ile Ile Ser Thr Leu Thr

355 360 365

<210> 83

<211> 367

<212> PRT

<213> 人工(Artificial)

<220>

<223> P-0302

<400> 83

Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly

1 5 10 15

Ala Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met

20 25 30

Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His

35 40 45

Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val

50 55 60

His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr

65 70 75 80

Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly

85 90 95

Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile

100 105 110

Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val

115 120 125

Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser

130 135 140

Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu

145 150 155 160

Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro

165 170 175

Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val

180 185 190

Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met

195 200 205

His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser

210 215 220

Pro Gly Gly Gly Gly Ser Gly Gly Gly Ser Ala Pro Thr Ser Ser Ser

225 230 235 240

Thr Lys Lys Thr Gln Leu Gln Leu Glu His Leu Leu Leu Asp Leu Gln

245 250 255

Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys Asn Pro Lys Leu Thr Arg

260 265 270

Met Leu Thr Phe Lys Phe Tyr Met Pro Lys Lys Ala Thr Glu Leu Lys

275 280 285

His Leu Gln Cys Leu Glu Glu Glu Leu Lys Pro Leu Glu Glu Val Leu

290 295 300

Asn Leu Ala Gln Ser Lys Asn Phe His Leu Arg Pro Arg Asp Leu Ile

305 310 315 320

Ser Ile Ile Asn Val Ile Val Leu Glu Leu Lys Gly Ser Glu Thr Thr

325 330 335

Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala Thr Ile Val Glu Phe Leu

340 345 350

Asn Arg Trp Ile Thr Phe Ser Gln Ser Ile Ile Ser Thr Leu Thr

355 360 365

<210> 84

<211> 367

<212> PRT

<213> 人工(Artificial)

<220>

<223> P-0375

<400> 84

Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly

1 5 10 15

Ala Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met

20 25 30

Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His

35 40 45

Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val

50 55 60

His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr

65 70 75 80

Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly

85 90 95

Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile

100 105 110

Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val

115 120 125

Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser

130 135 140

Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu

145 150 155 160

Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro

165 170 175

Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val

180 185 190

Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met

195 200 205

His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser

210 215 220

Pro Gly Gly Gly Gly Ser Gly Gly Gly Ser Ala Pro Thr Ser Ser Ser

225 230 235 240

Thr Lys Lys Thr Gln Leu Gln Leu Glu His Leu Leu Leu Asp Leu Gln

245 250 255

Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys Asn Pro Lys Leu Thr Arg

260 265 270

Met Leu Thr Phe Lys Phe Tyr Met Pro Lys Lys Ala Thr Glu Leu Lys

275 280 285

His Leu Gln Cys Leu Glu Glu Glu Leu Lys Pro Leu Glu Glu Val Leu

290 295 300

Asn Leu Ala Gln Ser Lys Asn Phe His Leu Arg Pro Arg Asp Leu Ile

305 310 315 320

Ser Gln Ile Asn Val Ile Val Leu Glu Leu Lys Gly Ser Glu Thr Thr

325 330 335

Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala Thr Ile Val Glu Phe Leu

340 345 350

Asn Arg Trp Ile Thr Phe Ser Gln Ser Ile Ile Ser Thr Leu Thr

355 360 365

<210> 85

<211> 367

<212> PRT

<213> 人工(Artificial)

<220>

<223> P-0376

<400> 85

Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly

1 5 10 15

Ala Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met

20 25 30

Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His

35 40 45

Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val

50 55 60

His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr

65 70 75 80

Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly

85 90 95

Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile

100 105 110

Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val

115 120 125

Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser

130 135 140

Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu

145 150 155 160

Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro

165 170 175

Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val

180 185 190

Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met

195 200 205

His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser

210 215 220

Pro Gly Gly Gly Gly Ser Gly Gly Gly Ser Ala Pro Thr Ser Ser Ser

225 230 235 240

Thr Lys Lys Thr Gln Leu Gln Leu Glu His Leu Leu Leu Asp Leu Gln

245 250 255

Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys Asn Pro Lys Leu Thr Arg

260 265 270

Met Leu Thr Phe Lys Phe Tyr Met Pro Lys Lys Ala Thr Glu Leu Lys

275 280 285

His Leu Gln Cys Leu Glu Glu Glu Leu Lys Pro Leu Glu Glu Val Leu

290 295 300

Asn Leu Ala Gln Ser Lys Asn Phe His Leu Arg Pro Arg Asp Leu Ile

305 310 315 320

Ser Glu Ile Asn Val Ile Val Leu Glu Leu Lys Gly Ser Glu Thr Thr

325 330 335

Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala Thr Ile Val Glu Phe Leu

340 345 350

Asn Arg Trp Ile Thr Phe Ser Gln Ser Ile Ile Ser Thr Leu Thr

355 360 365

<210> 86

<211> 367

<212> PRT

<213> 人工(Artificial)

<220>

<223> P-0377

<400> 86

Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly

1 5 10 15

Ala Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met

20 25 30

Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His

35 40 45

Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val

50 55 60

His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr

65 70 75 80

Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly

85 90 95

Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile

100 105 110

Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val

115 120 125

Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser

130 135 140

Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu

145 150 155 160

Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro

165 170 175

Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val

180 185 190

Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met

195 200 205

His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser

210 215 220

Pro Gly Gly Gly Gly Ser Gly Gly Gly Ser Ala Pro Thr Ser Ser Ser

225 230 235 240

Thr Lys Lys Thr Gln Leu Gln Leu Glu His Leu Leu Leu Asp Leu Gln

245 250 255

Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys Asn Pro Lys Leu Thr Arg

260 265 270

Met Leu Thr Phe Lys Phe Tyr Met Pro Lys Lys Ala Thr Glu Leu Lys

275 280 285

His Leu Gln Cys Leu Glu Glu Glu Leu Lys Pro Leu Glu Glu Val Leu

290 295 300

Asn Leu Ala Gln Ser Lys Asn Phe His Leu Arg Pro Arg Asp Leu Ile

305 310 315 320

Ser Thr Ile Asn Val Ile Val Leu Glu Leu Lys Gly Ser Glu Thr Thr

325 330 335

Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala Thr Ile Val Glu Phe Leu

340 345 350

Asn Arg Trp Ile Thr Phe Ser Gln Ser Ile Ile Ser Thr Leu Thr

355 360 365

<210> 87

<211> 367

<212> PRT

<213> 人工(Artificial)

<220>

<223> P-0378

<400> 87

Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly

1 5 10 15

Ala Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met

20 25 30

Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His

35 40 45

Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val

50 55 60

His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr

65 70 75 80

Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly

85 90 95

Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile

100 105 110

Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val

115 120 125

Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser

130 135 140

Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu

145 150 155 160

Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro

165 170 175

Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val

180 185 190

Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met

195 200 205

His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser

210 215 220

Pro Gly Gly Gly Gly Ser Gly Gly Gly Ser Ala Pro Thr Ser Ser Ser

225 230 235 240

Thr Lys Lys Thr Gln Leu Gln Leu Glu His Leu Leu Leu Asp Leu Gln

245 250 255

Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys Asn Pro Lys Leu Thr Arg

260 265 270

Met Leu Thr Phe Lys Phe Tyr Met Pro Lys Lys Ala Thr Glu Leu Lys

275 280 285

His Leu Gln Cys Leu Glu Glu Glu Leu Lys Pro Leu Glu Glu Val Leu

290 295 300

Asn Leu Ala Gln Ser Lys Asn Phe His Leu Arg Pro Arg Asp Leu Ile

305 310 315 320

Ser Met Ile Asn Val Ile Val Leu Glu Leu Lys Gly Ser Glu Thr Thr

325 330 335

Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala Thr Ile Val Glu Phe Leu

340 345 350

Asn Arg Trp Ile Thr Phe Ser Gln Ser Ile Ile Ser Thr Leu Thr

355 360 365

<210> 88

<211> 367

<212> PRT

<213> 人工(Artificial)

<220>

<223> P-0303

<400> 88

Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly

1 5 10 15

Ala Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met

20 25 30

Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His

35 40 45

Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val

50 55 60

His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr

65 70 75 80

Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly

85 90 95

Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile

100 105 110

Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val

115 120 125

Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser

130 135 140

Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu

145 150 155 160

Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro

165 170 175

Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val

180 185 190

Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met

195 200 205

His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser

210 215 220

Pro Gly Gly Gly Gly Ser Gly Gly Gly Ser Ala Pro Thr Ser Ser Ser

225 230 235 240

Thr Lys Lys Thr Gln Leu Gln Leu Glu His Leu Leu Leu Asp Leu Gln

245 250 255

Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys Asn Pro Lys Leu Thr Arg

260 265 270

Met Leu Thr Phe Lys Phe Tyr Met Pro Lys Lys Ala Thr Glu Leu Lys

275 280 285

His Leu Gln Cys Leu Glu Glu Glu Leu Lys Pro Leu Glu Glu Val Leu

290 295 300

Asn Leu Ala Gln Ser Lys Asn Phe His Leu Arg Pro Arg Asp Leu Ile

305 310 315 320

Ser Asn Ile Asn Val Ile Val Leu Glu Leu Lys Gly Ser Glu Thr Thr

325 330 335

Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala Thr Ile Val Glu Phe Leu

340 345 350

Asn Arg Trp Ile Thr Phe Ser Glu Ser Ile Ile Ser Thr Leu Thr

355 360 365

<210> 89

<211> 367

<212> PRT

<213> 人工(Artificial)

<220>

<223> P-0304

<400> 89

Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly

1 5 10 15

Ala Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met

20 25 30

Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His

35 40 45

Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val

50 55 60

His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr

65 70 75 80

Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly

85 90 95

Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile

100 105 110

Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val

115 120 125

Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser

130 135 140

Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu

145 150 155 160

Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro

165 170 175

Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val

180 185 190

Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met

195 200 205

His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser

210 215 220

Pro Gly Gly Gly Gly Ser Gly Gly Gly Ser Ala Pro Thr Ser Ser Ser

225 230 235 240

Thr Lys Lys Thr Gln Leu Gln Leu Glu His Leu Leu Leu Asp Leu Gln

245 250 255

Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys Asn Pro Lys Leu Thr Arg

260 265 270

Met Leu Thr Phe Lys Phe Tyr Met Pro Lys Lys Ala Thr Glu Leu Lys

275 280 285

His Leu Gln Cys Leu Glu Glu Glu Leu Lys Pro Leu Glu Glu Val Leu

290 295 300

Asn Leu Ala Gln Ser Lys Asn Phe His Leu Arg Pro Arg Asp Leu Ile

305 310 315 320

Ser Asn Ile Asn Val Ile Val Leu Glu Leu Lys Gly Ser Glu Thr Thr

325 330 335

Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala Thr Ile Val Glu Phe Leu

340 345 350

Asn Arg Trp Ile Thr Phe Ser Leu Ser Ile Ile Ser Thr Leu Thr

355 360 365

<210> 90

<211> 367

<212> PRT

<213> 人工(Artificial)

<220>

<223> P-0369

<400> 90

Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly

1 5 10 15

Ala Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met

20 25 30

Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His

35 40 45

Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val

50 55 60

His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr

65 70 75 80

Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly

85 90 95

Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile

100 105 110

Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val

115 120 125

Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser

130 135 140

Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu

145 150 155 160

Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro

165 170 175

Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val

180 185 190

Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met

195 200 205

His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser

210 215 220

Pro Gly Gly Gly Gly Ser Gly Gly Gly Ser Ala Pro Thr Ser Ser Ser

225 230 235 240

Thr Lys Lys Thr Gln Leu Gln Leu Glu His Leu Leu Leu Asp Leu Gln

245 250 255

Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys Asn Pro Lys Leu Thr Arg

260 265 270

Met Leu Thr Phe Lys Phe Tyr Met Pro Lys Lys Ala Thr Glu Leu Lys

275 280 285

His Leu Gln Cys Leu Glu Glu Glu Leu Lys Pro Leu Glu Glu Val Leu

290 295 300

Asn Leu Ala Gln Ser Lys Asn Phe His Leu Arg Pro Arg Asp Leu Ile

305 310 315 320

Ser Asn Ile Asn Val Ile Val Leu Glu Leu Lys Gly Ser Glu Thr Thr

325 330 335

Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala Thr Ile Val Glu Phe Leu

340 345 350

Asn Arg Trp Ile Thr Phe Ser Asn Ser Ile Ile Ser Thr Leu Thr

355 360 365

<210> 91

<211> 367

<212> PRT

<213> 人工(Artificial)

<220>

<223> P-0370

<400> 91

Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly

1 5 10 15

Ala Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met

20 25 30

Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His

35 40 45

Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val

50 55 60

His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr

65 70 75 80

Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly

85 90 95

Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile

100 105 110

Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val

115 120 125

Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser

130 135 140

Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu

145 150 155 160

Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro

165 170 175

Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val

180 185 190

Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met

195 200 205

His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser

210 215 220

Pro Gly Gly Gly Gly Ser Gly Gly Gly Ser Ala Pro Thr Ser Ser Ser

225 230 235 240

Thr Lys Lys Thr Gln Leu Gln Leu Glu His Leu Leu Leu Asp Leu Gln

245 250 255

Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys Asn Pro Lys Leu Thr Arg

260 265 270

Met Leu Thr Phe Lys Phe Tyr Met Pro Lys Lys Ala Thr Glu Leu Lys

275 280 285

His Leu Gln Cys Leu Glu Glu Glu Leu Lys Pro Leu Glu Glu Val Leu

290 295 300

Asn Leu Ala Gln Ser Lys Asn Phe His Leu Arg Pro Arg Asp Leu Ile

305 310 315 320

Ser Asn Ile Asn Val Ile Val Leu Glu Leu Lys Gly Ser Glu Thr Thr

325 330 335

Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala Thr Ile Val Glu Phe Leu

340 345 350

Asn Arg Trp Ile Thr Phe Ser Asp Ser Ile Ile Ser Thr Leu Thr

355 360 365

<210> 92

<211> 367

<212> PRT

<213> 人工(Artificial)

<220>

<223> P-0371

<400> 92

Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly

1 5 10 15

Ala Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met

20 25 30

Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His

35 40 45

Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val

50 55 60

His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr

65 70 75 80

Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly

85 90 95

Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile

100 105 110

Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val

115 120 125

Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser

130 135 140

Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu

145 150 155 160

Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro

165 170 175

Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val

180 185 190

Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met

195 200 205

His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser

210 215 220

Pro Gly Gly Gly Gly Ser Gly Gly Gly Ser Ala Pro Thr Ser Ser Ser

225 230 235 240

Thr Lys Lys Thr Gln Leu Gln Leu Glu His Leu Leu Leu Asp Leu Gln

245 250 255

Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys Asn Pro Lys Leu Thr Arg

260 265 270

Met Leu Thr Phe Lys Phe Tyr Met Pro Lys Lys Ala Thr Glu Leu Lys

275 280 285

His Leu Gln Cys Leu Glu Glu Glu Leu Lys Pro Leu Glu Glu Val Leu

290 295 300

Asn Leu Ala Gln Ser Lys Asn Phe His Leu Arg Pro Arg Asp Leu Ile

305 310 315 320

Ser Asn Ile Asn Val Ile Val Leu Glu Leu Lys Gly Ser Glu Thr Thr

325 330 335

Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala Thr Ile Val Glu Phe Leu

340 345 350

Asn Arg Trp Ile Thr Phe Ser Met Ser Ile Ile Ser Thr Leu Thr

355 360 365

<210> 93

<211> 367

<212> PRT

<213> 人工(Artificial)

<220>

<223> P-0251

<400> 93

Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly

1 5 10 15

Ala Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met

20 25 30

Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His

35 40 45

Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val

50 55 60

His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr

65 70 75 80

Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly

85 90 95

Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile

100 105 110

Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val

115 120 125

Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser

130 135 140

Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu

145 150 155 160

Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro

165 170 175

Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val

180 185 190

Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met

195 200 205

His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser

210 215 220

Pro Gly Gly Gly Gly Ser Gly Gly Gly Ser Ala Pro Thr Ser Ser Ser

225 230 235 240

Thr Lys Lys Thr Gln Leu Gln Leu Glu His Leu Leu Leu Ile Leu Gln

245 250 255

Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys Asn Pro Lys Leu Thr Arg

260 265 270

Met Leu Thr Phe Lys Phe Tyr Met Pro Lys Lys Ala Thr Glu Leu Lys

275 280 285

His Leu Gln Cys Leu Glu Glu Glu Leu Lys Pro Leu Glu Glu Val Leu

290 295 300

Asn Leu Ala Gln Ser Lys Asn Phe His Leu Arg Pro Arg Asp Leu Ile

305 310 315 320

Ser Gly Ile Asn Val Ile Val Leu Glu Leu Lys Gly Ser Glu Thr Thr

325 330 335

Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala Thr Ile Val Glu Phe Leu

340 345 350

Asn Arg Trp Ile Thr Phe Ser Gln Ser Ile Ile Ser Thr Leu Thr

355 360 365

<210> 94

<211> 367

<212> PRT

<213> 人工(Artificial)

<220>

<223> P-0317

<400> 94

Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly

1 5 10 15

Ala Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met

20 25 30

Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His

35 40 45

Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val

50 55 60

His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr

65 70 75 80

Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly

85 90 95

Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile

100 105 110

Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val

115 120 125

Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser

130 135 140

Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu

145 150 155 160

Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro

165 170 175

Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val

180 185 190

Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met

195 200 205

His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser

210 215 220

Pro Gly Gly Gly Gly Ser Gly Gly Gly Ser Ala Pro Thr Ser Ser Ser

225 230 235 240

Thr Lys Lys Thr Gln Leu Gln Leu Glu His Leu Leu Leu Ile Leu Gln

245 250 255

Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys Asn Pro Lys Leu Thr Arg

260 265 270

Met Leu Thr Phe Lys Phe Tyr Met Pro Lys Lys Ala Thr Glu Leu Lys

275 280 285

His Leu Gln Cys Leu Glu Glu Glu Leu Lys Pro Leu Glu Glu Val Leu

290 295 300

Asn Leu Ala Gln Ser Lys Asn Phe His Leu Arg Pro Arg Asp Leu Ile

305 310 315 320

Ser Arg Ile Asn Val Ile Val Leu Glu Leu Lys Gly Ser Glu Thr Thr

325 330 335

Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala Thr Ile Val Glu Phe Leu

340 345 350

Asn Arg Trp Ile Thr Phe Ser Gln Ser Ile Ile Ser Thr Leu Thr

355 360 365

<210> 95

<211> 367

<212> PRT

<213> 人工(Artificial)

<220>

<223> P-0318

<400> 95

Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly

1 5 10 15

Ala Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met

20 25 30

Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His

35 40 45

Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val

50 55 60

His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr

65 70 75 80

Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly

85 90 95

Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile

100 105 110

Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val

115 120 125

Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser

130 135 140

Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu

145 150 155 160

Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro

165 170 175

Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val

180 185 190

Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met

195 200 205

His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser

210 215 220

Pro Gly Gly Gly Gly Ser Gly Gly Gly Ser Ala Pro Thr Ser Ser Ser

225 230 235 240

Thr Lys Lys Thr Gln Leu Gln Leu Glu His Leu Leu Leu Ile Leu Gln

245 250 255

Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys Asn Pro Lys Leu Thr Arg

260 265 270

Met Leu Thr Phe Lys Phe Tyr Met Pro Lys Lys Ala Thr Glu Leu Lys

275 280 285

His Leu Gln Cys Leu Glu Glu Glu Leu Lys Pro Leu Glu Glu Val Leu

290 295 300

Asn Leu Ala Gln Ser Lys Asn Phe His Leu Arg Pro Arg Asp Leu Ile

305 310 315 320

Ser Ile Ile Asn Val Ile Val Leu Glu Leu Lys Gly Ser Glu Thr Thr

325 330 335

Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala Thr Ile Val Glu Phe Leu

340 345 350

Asn Arg Trp Ile Thr Phe Ser Gln Ser Ile Ile Ser Thr Leu Thr

355 360 365

<210> 96

<211> 367

<212> PRT

<213> 人工(Artificial)

<220>

<223> P-0324

<400> 96

Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly

1 5 10 15

Ala Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met

20 25 30

Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His

35 40 45

Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val

50 55 60

His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr

65 70 75 80

Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly

85 90 95

Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile

100 105 110

Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val

115 120 125

Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser

130 135 140

Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu

145 150 155 160

Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro

165 170 175

Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val

180 185 190

Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met

195 200 205

His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser

210 215 220

Pro Gly Gly Gly Gly Ser Gly Gly Gly Ser Ala Pro Thr Ser Ser Ser

225 230 235 240

Thr Lys Lys Thr Gln Leu Gln Leu Glu His Leu Leu Leu Thr Leu Gln

245 250 255

Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys Asn Pro Lys Leu Thr Arg

260 265 270

Met Leu Thr Phe Lys Phe Tyr Met Pro Lys Lys Ala Thr Glu Leu Lys

275 280 285

His Leu Gln Cys Leu Glu Glu Glu Leu Lys Pro Leu Glu Glu Val Leu

290 295 300

Asn Leu Ala Gln Ser Lys Asn Phe His Leu Arg Pro Arg Asp Leu Ile

305 310 315 320

Ser Arg Ile Asn Val Ile Val Leu Glu Leu Lys Gly Ser Glu Thr Thr

325 330 335

Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala Thr Ile Val Glu Phe Leu

340 345 350

Asn Arg Trp Ile Thr Phe Ser Gln Ser Ile Ile Ser Thr Leu Thr

355 360 365

<210> 97

<211> 367

<212> PRT

<213> 人工(Artificial)

<220>

<223> P-0322

<400> 97

Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly

1 5 10 15

Ala Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met

20 25 30

Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His

35 40 45

Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val

50 55 60

His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr

65 70 75 80

Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly

85 90 95

Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile

100 105 110

Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val

115 120 125

Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser

130 135 140

Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu

145 150 155 160

Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro

165 170 175

Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val

180 185 190

Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met

195 200 205

His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser

210 215 220

Pro Gly Gly Gly Gly Ser Gly Gly Gly Ser Ala Pro Thr Ser Ser Ser

225 230 235 240

Thr Lys Lys Thr Gln Leu Gln Leu Glu His Leu Leu Leu Thr Leu Gln

245 250 255

Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys Asn Pro Lys Leu Thr Arg

260 265 270

Met Leu Thr Phe Lys Phe Tyr Met Pro Lys Lys Ala Thr Glu Leu Lys

275 280 285

His Leu Gln Cys Leu Glu Glu Glu Leu Lys Pro Leu Glu Glu Val Leu

290 295 300

Asn Leu Ala Gln Ser Lys Asn Phe His Leu Arg Pro Arg Asp Leu Ile

305 310 315 320

Ser Asn Ile Asn Val Ile Val Leu Glu Leu Lys Gly Ser Glu Thr Thr

325 330 335

Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala Thr Ile Val Glu Phe Leu

340 345 350

Asn Arg Trp Ile Thr Phe Ser Glu Ser Ile Ile Ser Thr Leu Thr

355 360 365

<210> 98

<211> 367

<212> PRT

<213> 人工(Artificial)

<220>

<223> P-0323

<400> 98

Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly

1 5 10 15

Ala Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met

20 25 30

Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His

35 40 45

Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val

50 55 60

His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr

65 70 75 80

Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly

85 90 95

Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile

100 105 110

Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val

115 120 125

Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser

130 135 140

Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu

145 150 155 160

Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro

165 170 175

Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val

180 185 190

Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met

195 200 205

His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser

210 215 220

Pro Gly Gly Gly Gly Ser Gly Gly Gly Ser Ala Pro Thr Ser Ser Ser

225 230 235 240

Thr Lys Lys Thr Gln Leu Gln Leu Glu His Leu Leu Leu Thr Leu Gln

245 250 255

Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys Asn Pro Lys Leu Thr Arg

260 265 270

Met Leu Thr Phe Lys Phe Tyr Met Pro Lys Lys Ala Thr Glu Leu Lys

275 280 285

His Leu Gln Cys Leu Glu Glu Glu Leu Lys Pro Leu Glu Glu Val Leu

290 295 300

Asn Leu Ala Gln Ser Lys Asn Phe His Leu Arg Pro Arg Asp Leu Ile

305 310 315 320

Ser Asn Ile Asn Val Ile Val Leu Glu Leu Lys Gly Ser Glu Thr Thr

325 330 335

Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala Thr Ile Val Glu Phe Leu

340 345 350

Asn Arg Trp Ile Thr Phe Ser Leu Ser Ile Ile Ser Thr Leu Thr

355 360 365

<210> 99

<211> 367

<212> PRT

<213> 人工(Artificial)

<220>

<223> P-0325

<400> 99

Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly

1 5 10 15

Ala Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met

20 25 30

Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His

35 40 45

Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val

50 55 60

His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr

65 70 75 80

Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly

85 90 95

Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile

100 105 110

Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val

115 120 125

Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser

130 135 140

Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu

145 150 155 160

Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro

165 170 175

Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val

180 185 190

Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met

195 200 205

His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser

210 215 220

Pro Gly Gly Gly Gly Ser Gly Gly Gly Ser Ala Pro Thr Ser Ser Ser

225 230 235 240

Thr Lys Lys Thr Gln Leu Gln Leu Glu His Leu Leu Leu Thr Leu Gln

245 250 255

Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys Asn Pro Lys Leu Thr Arg

260 265 270

Met Leu Thr Phe Lys Phe Tyr Met Pro Lys Lys Ala Thr Glu Leu Lys

275 280 285

His Leu Gln Cys Leu Glu Glu Glu Leu Lys Pro Leu Glu Glu Val Leu

290 295 300

Asn Leu Ala Gln Ser Lys Asn Phe His Leu Arg Pro Arg Asp Leu Ile

305 310 315 320

Ser Arg Ile Asn Val Ile Val Leu Glu Leu Lys Gly Ser Glu Thr Thr

325 330 335

Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala Thr Ile Val Glu Phe Leu

340 345 350

Asn Arg Trp Ile Thr Phe Ser Glu Ser Ile Ile Ser Thr Leu Thr

355 360 365

<210> 100

<211> 367

<212> PRT

<213> 人工(Artificial)

<220>

<223> P-0326

<400> 100

Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly

1 5 10 15

Ala Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met

20 25 30

Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His

35 40 45

Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val

50 55 60

His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr

65 70 75 80

Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly

85 90 95

Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile

100 105 110

Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val

115 120 125

Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser

130 135 140

Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu

145 150 155 160

Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro

165 170 175

Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val

180 185 190

Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met

195 200 205

His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser

210 215 220

Pro Gly Gly Gly Gly Ser Gly Gly Gly Ser Ala Pro Thr Ser Ser Ser

225 230 235 240

Thr Lys Lys Thr Gln Leu Gln Leu Glu His Leu Leu Leu Thr Leu Gln

245 250 255

Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys Asn Pro Lys Leu Thr Arg

260 265 270

Met Leu Thr Phe Lys Phe Tyr Met Pro Lys Lys Ala Thr Glu Leu Lys

275 280 285

His Leu Gln Cys Leu Glu Glu Glu Leu Lys Pro Leu Glu Glu Val Leu

290 295 300

Asn Leu Ala Gln Ser Lys Asn Phe His Leu Arg Pro Arg Asp Leu Ile

305 310 315 320

Ser Arg Ile Asn Val Ile Val Leu Glu Leu Lys Gly Ser Glu Thr Thr

325 330 335

Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala Thr Ile Val Glu Phe Leu

340 345 350

Asn Arg Trp Ile Thr Phe Ser Leu Ser Ile Ile Ser Thr Leu Thr

355 360 365

<210> 101

<211> 367

<212> PRT

<213> 人工(Artificial)

<220>

<223> P-0417

<400> 101

Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly

1 5 10 15

Ala Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met

20 25 30

Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His

35 40 45

Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val

50 55 60

His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr

65 70 75 80

Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly

85 90 95

Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile

100 105 110

Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val

115 120 125

Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser

130 135 140

Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu

145 150 155 160

Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro

165 170 175

Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val

180 185 190

Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met

195 200 205

His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser

210 215 220

Pro Gly Gly Gly Gly Ser Gly Gly Gly Ser Ala Pro Thr Ser Ser Ser

225 230 235 240

Thr Lys Lys Thr Gln Leu Gln Leu Glu His Leu Leu Asn Asp Leu Gln

245 250 255

Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys Asn Pro Lys Leu Thr Arg

260 265 270

Met Leu Thr Phe Lys Phe Tyr Met Pro Lys Lys Ala Thr Glu Leu Lys

275 280 285

His Leu Gln Cys Leu Glu Glu Glu Leu Lys Pro Leu Glu Glu Val Leu

290 295 300

Asn Leu Ala Gln Ser Lys Asn Phe His Leu Arg Pro Arg Asp Leu Ile

305 310 315 320

Ser Asn Ile Asn Val Ile Val Leu Glu Leu Lys Gly Ser Glu Thr Thr

325 330 335

Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala Thr Ile Val Glu Phe Leu

340 345 350

Asn Arg Trp Ile Thr Phe Ser Glu Ser Ile Ile Ser Thr Leu Thr

355 360 365

<210> 102

<211> 367

<212> PRT

<213> 人工(Artificial)

<220>

<223> P-0418

<400> 102

Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly

1 5 10 15

Ala Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met

20 25 30

Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His

35 40 45

Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val

50 55 60

His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr

65 70 75 80

Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly

85 90 95

Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile

100 105 110

Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val

115 120 125

Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser

130 135 140

Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu

145 150 155 160

Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro

165 170 175

Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val

180 185 190

Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met

195 200 205

His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser

210 215 220

Pro Gly Gly Gly Gly Ser Gly Gly Gly Ser Ala Pro Thr Ser Ser Ser

225 230 235 240

Thr Lys Lys Thr Gln Leu Gln Leu Glu His Leu Leu Arg Asp Leu Gln

245 250 255

Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys Asn Pro Lys Leu Thr Arg

260 265 270

Met Leu Thr Phe Lys Phe Tyr Met Pro Lys Lys Ala Thr Glu Leu Lys

275 280 285

His Leu Gln Cys Leu Glu Glu Glu Leu Lys Pro Leu Glu Glu Val Leu

290 295 300

Asn Leu Ala Gln Ser Lys Asn Phe His Leu Arg Pro Arg Asp Leu Ile

305 310 315 320

Ser Asn Ile Asn Val Ile Val Leu Glu Leu Lys Gly Ser Glu Thr Thr

325 330 335

Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala Thr Ile Val Glu Phe Leu

340 345 350

Asn Arg Trp Ile Thr Phe Ser Glu Ser Ile Ile Ser Thr Leu Thr

355 360 365

<210> 103

<211> 367

<212> PRT

<213> 人工(Artificial)

<220>

<223> P-0419

<400> 103

Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly

1 5 10 15

Ala Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met

20 25 30

Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His

35 40 45

Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val

50 55 60

His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr

65 70 75 80

Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly

85 90 95

Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile

100 105 110

Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val

115 120 125

Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser

130 135 140

Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu

145 150 155 160

Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro

165 170 175

Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val

180 185 190

Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met

195 200 205

His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser

210 215 220

Pro Gly Gly Gly Gly Ser Gly Gly Gly Ser Ala Pro Thr Ser Ser Ser

225 230 235 240

Thr Lys Lys Thr Gln Leu Gln Leu Glu His Leu Leu Tyr Asp Leu Gln

245 250 255

Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys Asn Pro Lys Leu Thr Arg

260 265 270

Met Leu Thr Phe Lys Phe Tyr Met Pro Lys Lys Ala Thr Glu Leu Lys

275 280 285

His Leu Gln Cys Leu Glu Glu Glu Leu Lys Pro Leu Glu Glu Val Leu

290 295 300

Asn Leu Ala Gln Ser Lys Asn Phe His Leu Arg Pro Arg Asp Leu Ile

305 310 315 320

Ser Asn Ile Asn Val Ile Val Leu Glu Leu Lys Gly Ser Glu Thr Thr

325 330 335

Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala Thr Ile Val Glu Phe Leu

340 345 350

Asn Arg Trp Ile Thr Phe Ser Glu Ser Ile Ile Ser Thr Leu Thr

355 360 365

<210> 104

<211> 371

<212> PRT

<213> 人工(Artificial)

<220>

<223> P-0416

<400> 104

Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu His

1 5 10 15

Leu Leu Asn Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys

20 25 30

Asn Pro Lys Leu Thr Arg Met Leu Thr Phe Lys Phe Tyr Met Pro Lys

35 40 45

Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys

50 55 60

Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu

65 70 75 80

Arg Pro Arg Asp Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu

85 90 95

Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala

100 105 110

Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Ser Gln Ser Ile

115 120 125

Ile Ser Thr Leu Thr Ala Glu Ala Ala Ala Lys Glu Ala Ala Ala Lys

130 135 140

Glu Ala Ala Ala Lys Ala Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala

145 150 155 160

Gly Ala Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu

165 170 175

Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser

180 185 190

His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu

195 200 205

Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr

210 215 220

Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn

225 230 235 240

Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro

245 250 255

Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln

260 265 270

Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val

275 280 285

Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val

290 295 300

Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro

305 310 315 320

Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr

325 330 335

Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val

340 345 350

Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu

355 360 365

Ser Pro Gly

370

<210> 105

<211> 371

<212> PRT

<213> 人工(Artificial)

<220>

<223> P-0412

<400> 105

Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu His

1 5 10 15

Leu Leu Leu Glu Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys

20 25 30

Asn Pro Lys Leu Thr Arg Met Leu Thr Phe Lys Phe Tyr Met Pro Lys

35 40 45

Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys

50 55 60

Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu

65 70 75 80

Arg Pro Arg Asp Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu

85 90 95

Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala

100 105 110

Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Ser Gln Ser Ile

115 120 125

Ile Ser Thr Leu Thr Ala Glu Ala Ala Ala Lys Glu Ala Ala Ala Lys

130 135 140

Glu Ala Ala Ala Lys Ala Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala

145 150 155 160

Gly Ala Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu

165 170 175

Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser

180 185 190

His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu

195 200 205

Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr

210 215 220

Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn

225 230 235 240

Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro

245 250 255

Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln

260 265 270

Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val

275 280 285

Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val

290 295 300

Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro

305 310 315 320

Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr

325 330 335

Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val

340 345 350

Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu

355 360 365

Ser Pro Gly

370

<210> 106

<211> 371

<212> PRT

<213> 人工(Artificial)

<220>

<223> P-0306

<400> 106

Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu His

1 5 10 15

Leu Leu Leu Ile Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys

20 25 30

Asn Pro Lys Leu Thr Arg Met Leu Thr Phe Lys Phe Tyr Met Pro Lys

35 40 45

Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys

50 55 60

Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu

65 70 75 80

Arg Pro Arg Asp Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu

85 90 95

Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala

100 105 110

Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Ser Gln Ser Ile

115 120 125

Ile Ser Thr Leu Thr Ala Glu Ala Ala Ala Lys Glu Ala Ala Ala Lys

130 135 140

Glu Ala Ala Ala Lys Ala Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala

145 150 155 160

Gly Ala Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu

165 170 175

Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser

180 185 190

His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu

195 200 205

Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr

210 215 220

Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn

225 230 235 240

Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro

245 250 255

Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln

260 265 270

Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val

275 280 285

Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val

290 295 300

Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro

305 310 315 320

Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr

325 330 335

Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val

340 345 350

Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu

355 360 365

Ser Pro Gly

370

<210> 107

<211> 371

<212> PRT

<213> 人工(Artificial)

<220>

<223> P-0319

<400> 107

Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu His

1 5 10 15

Leu Leu Leu Ile Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys

20 25 30

Asn Pro Lys Leu Thr Arg Met Leu Thr Phe Lys Phe Tyr Met Pro Lys

35 40 45

Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys

50 55 60

Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu

65 70 75 80

Arg Pro Arg Asp Leu Ile Ser Arg Ile Asn Val Ile Val Leu Glu Leu

85 90 95

Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala

100 105 110

Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Ser Gln Ser Ile

115 120 125

Ile Ser Thr Leu Thr Ala Glu Ala Ala Ala Lys Glu Ala Ala Ala Lys

130 135 140

Glu Ala Ala Ala Lys Ala Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala

145 150 155 160

Gly Ala Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu

165 170 175

Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser

180 185 190

His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu

195 200 205

Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr

210 215 220

Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn

225 230 235 240

Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro

245 250 255

Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln

260 265 270

Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val

275 280 285

Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val

290 295 300

Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro

305 310 315 320

Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr

325 330 335

Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val

340 345 350

Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu

355 360 365

Ser Pro Gly

370

<210> 108

<211> 133

<212> PRT

<213> 人工(Artificial)

<220>

<223> IL-2 L19S变体序列

<400> 108

Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu His

1 5 10 15

Leu Leu Ser Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys

20 25 30

Asn Pro Lys Leu Thr Arg Met Leu Thr Phe Lys Phe Tyr Met Pro Lys

35 40 45

Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys

50 55 60

Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu

65 70 75 80

Arg Pro Arg Asp Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu

85 90 95

Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala

100 105 110

Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Ser Gln Ser Ile

115 120 125

Ile Ser Thr Leu Thr

130

<210> 109

<211> 133

<212> PRT

<213> 人工(Artificial)

<220>

<223> IL-2 L21S变体序列

<400> 109

Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu His

1 5 10 15

Leu Leu Leu Asp Ser Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys

20 25 30

Asn Pro Lys Leu Thr Arg Met Leu Thr Phe Lys Phe Tyr Met Pro Lys

35 40 45

Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys

50 55 60

Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu

65 70 75 80

Arg Pro Arg Asp Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu

85 90 95

Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala

100 105 110

Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Ser Gln Ser Ile

115 120 125

Ile Ser Thr Leu Thr

130

<210> 110

<211> 133

<212> PRT

<213> 人工(Artificial)

<220>

<223> IL-2 L21N变体序列

<400> 110

Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu His

1 5 10 15

Leu Leu Leu Asp Asn Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys

20 25 30

Asn Pro Lys Leu Thr Arg Met Leu Thr Phe Lys Phe Tyr Met Pro Lys

35 40 45

Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys

50 55 60

Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu

65 70 75 80

Arg Pro Arg Asp Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu

85 90 95

Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala

100 105 110

Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Ser Gln Ser Ile

115 120 125

Ile Ser Thr Leu Thr

130

<210> 111

<211> 133

<212> PRT

<213> 人工(Artificial)

<220>

<223> IL-2 L21R变体序列

<400> 111

Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu His

1 5 10 15

Leu Leu Leu Asp Arg Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys

20 25 30

Asn Pro Lys Leu Thr Arg Met Leu Thr Phe Lys Phe Tyr Met Pro Lys

35 40 45

Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys

50 55 60

Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu

65 70 75 80

Arg Pro Arg Asp Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu

85 90 95

Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala

100 105 110

Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Ser Gln Ser Ile

115 120 125

Ile Ser Thr Leu Thr

130

<210> 112

<211> 133

<212> PRT

<213> 人工(Artificial)

<220>

<223> IL-2 Q126K变体序列

<400> 112

Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu His

1 5 10 15

Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys

20 25 30

Asn Pro Lys Leu Thr Arg Met Leu Thr Phe Lys Phe Tyr Met Pro Lys

35 40 45

Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys

50 55 60

Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu

65 70 75 80

Arg Pro Arg Asp Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu

85 90 95

Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala

100 105 110

Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Ser Lys Ser Ile

115 120 125

Ile Ser Thr Leu Thr

130

<210> 113

<211> 133

<212> PRT

<213> 人工(Artificial)

<220>

<223> IL-2 Q126H变体序列

<400> 113

Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu His

1 5 10 15

Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys

20 25 30

Asn Pro Lys Leu Thr Arg Met Leu Thr Phe Lys Phe Tyr Met Pro Lys

35 40 45

Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys

50 55 60

Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu

65 70 75 80

Arg Pro Arg Asp Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu

85 90 95

Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala

100 105 110

Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Ser His Ser Ile

115 120 125

Ile Ser Thr Leu Thr

130

<210> 114

<211> 133

<212> PRT

<213> 人工(Artificial)

<220>

<223> IL-2 Q126Y变体序列

<400> 114

Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu His

1 5 10 15

Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys

20 25 30

Asn Pro Lys Leu Thr Arg Met Leu Thr Phe Lys Phe Tyr Met Pro Lys

35 40 45

Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys

50 55 60

Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu

65 70 75 80

Arg Pro Arg Asp Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu

85 90 95

Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala

100 105 110

Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Ser Tyr Ser Ile

115 120 125

Ile Ser Thr Leu Thr

130

<210> 115

<211> 133

<212> PRT

<213> 人工(Artificial)

<220>

<223> IL-2 S125E变体序列

<400> 115

Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu His

1 5 10 15

Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys

20 25 30

Asn Pro Lys Leu Thr Arg Met Leu Thr Phe Lys Phe Tyr Met Pro Lys

35 40 45

Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys

50 55 60

Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu

65 70 75 80

Arg Pro Arg Asp Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu

85 90 95

Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala

100 105 110

Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Glu Gln Ser Ile

115 120 125

Ile Ser Thr Leu Thr

130

<210> 116

<211> 133

<212> PRT

<213> 人工(Artificial)

<220>

<223> IL-2 S125K变体序列

<400> 116

Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu His

1 5 10 15

Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys

20 25 30

Asn Pro Lys Leu Thr Arg Met Leu Thr Phe Lys Phe Tyr Met Pro Lys

35 40 45

Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys

50 55 60

Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu

65 70 75 80

Arg Pro Arg Asp Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu

85 90 95

Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala

100 105 110

Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Lys Gln Ser Ile

115 120 125

Ile Ser Thr Leu Thr

130

<210> 117

<211> 133

<212> PRT

<213> 人工(Artificial)

<220>

<223> IL-2 S125H变体序列

<400> 117

Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu His

1 5 10 15

Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys

20 25 30

Asn Pro Lys Leu Thr Arg Met Leu Thr Phe Lys Phe Tyr Met Pro Lys

35 40 45

Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys

50 55 60

Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu

65 70 75 80

Arg Pro Arg Asp Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu

85 90 95

Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala

100 105 110

Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe His Gln Ser Ile

115 120 125

Ile Ser Thr Leu Thr

130

<210> 118

<211> 133

<212> PRT

<213> 人工(Artificial)

<220>

<223> IL-2 S125W变体序列

<400> 118

Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu His

1 5 10 15

Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys

20 25 30

Asn Pro Lys Leu Thr Arg Met Leu Thr Phe Lys Phe Tyr Met Pro Lys

35 40 45

Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys

50 55 60

Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu

65 70 75 80

Arg Pro Arg Asp Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu

85 90 95

Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala

100 105 110

Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Trp Gln Ser Ile

115 120 125

Ile Ser Thr Leu Thr

130

<210> 119

<211> 133

<212> PRT

<213> 人工(Artificial)

<220>

<223> IL-2 S125I变体序列

<400> 119

Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu His

1 5 10 15

Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys

20 25 30

Asn Pro Lys Leu Thr Arg Met Leu Thr Phe Lys Phe Tyr Met Pro Lys

35 40 45

Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys

50 55 60

Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu

65 70 75 80

Arg Pro Arg Asp Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu

85 90 95

Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala

100 105 110

Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Ile Gln Ser Ile

115 120 125

Ile Ser Thr Leu Thr

130

<210> 120

<211> 133

<212> PRT

<213> 人工(Artificial)

<220>

<223> IL-2 Q22N变体序列

<400> 120

Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu His

1 5 10 15

Leu Leu Leu Asp Leu Asn Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys

20 25 30

Asn Pro Lys Leu Thr Arg Met Leu Thr Phe Lys Phe Tyr Met Pro Lys

35 40 45

Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys

50 55 60

Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu

65 70 75 80

Arg Pro Arg Asp Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu

85 90 95

Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala

100 105 110

Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Ser Gln Ser Ile

115 120 125

Ile Ser Thr Leu Thr

130

<210> 121

<211> 133

<212> PRT

<213> 人工(Artificial)

<220>

<223> IL-2 Q22H变体序列

<400> 121

Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu His

1 5 10 15

Leu Leu Leu Asp Leu His Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys

20 25 30

Asn Pro Lys Leu Thr Arg Met Leu Thr Phe Lys Phe Tyr Met Pro Lys

35 40 45

Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys

50 55 60

Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu

65 70 75 80

Arg Pro Arg Asp Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu

85 90 95

Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala

100 105 110

Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Ser Gln Ser Ile

115 120 125

Ile Ser Thr Leu Thr

130

<210> 122

<211> 133

<212> PRT

<213> 人工(Artificial)

<220>

<223> IL-2 Q22K变体序列

<400> 122

Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu His

1 5 10 15

Leu Leu Leu Asp Leu Lys Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys

20 25 30

Asn Pro Lys Leu Thr Arg Met Leu Thr Phe Lys Phe Tyr Met Pro Lys

35 40 45

Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys

50 55 60

Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu

65 70 75 80

Arg Pro Arg Asp Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu

85 90 95

Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala

100 105 110

Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Ser Gln Ser Ile

115 120 125

Ile Ser Thr Leu Thr

130

<210> 123

<211> 133

<212> PRT

<213> 人工(Artificial)

<220>

<223> IL-2 Q22Y变体序列

<400> 123

Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu His

1 5 10 15

Leu Leu Leu Asp Leu Tyr Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys

20 25 30

Asn Pro Lys Leu Thr Arg Met Leu Thr Phe Lys Phe Tyr Met Pro Lys

35 40 45

Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys

50 55 60

Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu

65 70 75 80

Arg Pro Arg Asp Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu

85 90 95

Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala

100 105 110

Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Ser Gln Ser Ile

115 120 125

Ile Ser Thr Leu Thr

130

<210> 124

<211> 133

<212> PRT

<213> 人工(Artificial)

<220>

<223> IL-2 Q22I变体序列

<400> 124

Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu His

1 5 10 15

Leu Leu Leu Asp Leu Ile Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys

20 25 30

Asn Pro Lys Leu Thr Arg Met Leu Thr Phe Lys Phe Tyr Met Pro Lys

35 40 45

Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys

50 55 60

Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu

65 70 75 80

Arg Pro Arg Asp Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu

85 90 95

Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala

100 105 110

Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Ser Gln Ser Ile

115 120 125

Ile Ser Thr Leu Thr

130

<210> 125

<211> 133

<212> PRT

<213> 人工(Artificial)

<220>

<223> IL-2 L19H/Q126E变体序列

<400> 125

Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu His

1 5 10 15

Leu Leu His Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys

20 25 30

Asn Pro Lys Leu Thr Arg Met Leu Thr Phe Lys Phe Tyr Met Pro Lys

35 40 45

Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys

50 55 60

Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu

65 70 75 80

Arg Pro Arg Asp Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu

85 90 95

Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala

100 105 110

Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Ser Glu Ser Ile

115 120 125

Ile Ser Thr Leu Thr

130

<210> 126

<211> 133

<212> PRT

<213> 人工(Artificial)

<220>

<223> IL-2 L19Q/Q126E变体序列

<400> 126

Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu His

1 5 10 15

Leu Leu Gln Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys

20 25 30

Asn Pro Lys Leu Thr Arg Met Leu Thr Phe Lys Phe Tyr Met Pro Lys

35 40 45

Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys

50 55 60

Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu

65 70 75 80

Arg Pro Arg Asp Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu

85 90 95

Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala

100 105 110

Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Ser Glu Ser Ile

115 120 125

Ile Ser Thr Leu Thr

130

<210> 127

<211> 133

<212> PRT

<213> 人工(Artificial)

<220>

<223> IL-2 L19S/Q126E变体序列

<400> 127

Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu His

1 5 10 15

Leu Leu Ser Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys

20 25 30

Asn Pro Lys Leu Thr Arg Met Leu Thr Phe Lys Phe Tyr Met Pro Lys

35 40 45

Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys

50 55 60

Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu

65 70 75 80

Arg Pro Arg Asp Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu

85 90 95

Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala

100 105 110

Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Ser Glu Ser Ile

115 120 125

Ile Ser Thr Leu Thr

130

<210> 128

<211> 133

<212> PRT

<213> 人工(Artificial)

<220>

<223> IL-2 L19Y/Q126K变体序列

<400> 128

Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu His

1 5 10 15

Leu Leu Tyr Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys

20 25 30

Asn Pro Lys Leu Thr Arg Met Leu Thr Phe Lys Phe Tyr Met Pro Lys

35 40 45

Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys

50 55 60

Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu

65 70 75 80

Arg Pro Arg Asp Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu

85 90 95

Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala

100 105 110

Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Ser Lys Ser Ile

115 120 125

Ile Ser Thr Leu Thr

130

<210> 129

<211> 133

<212> PRT

<213> 人工(Artificial)

<220>

<223> IL-2 L19Y/Q126H变体序列

<400> 129

Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu His

1 5 10 15

Leu Leu Tyr Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys

20 25 30

Asn Pro Lys Leu Thr Arg Met Leu Thr Phe Lys Phe Tyr Met Pro Lys

35 40 45

Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys

50 55 60

Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu

65 70 75 80

Arg Pro Arg Asp Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu

85 90 95

Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala

100 105 110

Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Ser His Ser Ile

115 120 125

Ile Ser Thr Leu Thr

130

<210> 130

<211> 133

<212> PRT

<213> 人工(Artificial)

<220>

<223> IL-2 L19Y/Q126Y变体序列

<400> 130

Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu His

1 5 10 15

Leu Leu Tyr Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys

20 25 30

Asn Pro Lys Leu Thr Arg Met Leu Thr Phe Lys Phe Tyr Met Pro Lys

35 40 45

Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys

50 55 60

Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu

65 70 75 80

Arg Pro Arg Asp Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu

85 90 95

Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala

100 105 110

Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Ser Tyr Ser Ile

115 120 125

Ile Ser Thr Leu Thr

130

<210> 131

<211> 133

<212> PRT

<213> 人工(Artificial)

<220>

<223> IL-2 L19Y/S125E变体序列

<400> 131

Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu His

1 5 10 15

Leu Leu Tyr Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys

20 25 30

Asn Pro Lys Leu Thr Arg Met Leu Thr Phe Lys Phe Tyr Met Pro Lys

35 40 45

Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys

50 55 60

Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu

65 70 75 80

Arg Pro Arg Asp Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu

85 90 95

Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala

100 105 110

Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Glu Gln Ser Ile

115 120 125

Ile Ser Thr Leu Thr

130

<210> 132

<211> 133

<212> PRT

<213> 人工(Artificial)

<220>

<223> IL-2 L19Y/S125K变体序列

<400> 132

Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu His

1 5 10 15

Leu Leu Tyr Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys

20 25 30

Asn Pro Lys Leu Thr Arg Met Leu Thr Phe Lys Phe Tyr Met Pro Lys

35 40 45

Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys

50 55 60

Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu

65 70 75 80

Arg Pro Arg Asp Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu

85 90 95

Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala

100 105 110

Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Lys Gln Ser Ile

115 120 125

Ile Ser Thr Leu Thr

130

<210> 133

<211> 133

<212> PRT

<213> 人工(Artificial)

<220>

<223> IL-2 L19Y/S125H变体序列

<400> 133

Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu His

1 5 10 15

Leu Leu Tyr Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys

20 25 30

Asn Pro Lys Leu Thr Arg Met Leu Thr Phe Lys Phe Tyr Met Pro Lys

35 40 45

Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys

50 55 60

Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu

65 70 75 80

Arg Pro Arg Asp Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu

85 90 95

Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala

100 105 110

Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe His Gln Ser Ile

115 120 125

Ile Ser Thr Leu Thr

130

<210> 134

<211> 133

<212> PRT

<213> 人工(Artificial)

<220>

<223> IL-2 L19Y/S125W变体序列

<400> 134

Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu His

1 5 10 15

Leu Leu Tyr Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys

20 25 30

Asn Pro Lys Leu Thr Arg Met Leu Thr Phe Lys Phe Tyr Met Pro Lys

35 40 45

Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys

50 55 60

Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu

65 70 75 80

Arg Pro Arg Asp Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu

85 90 95

Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala

100 105 110

Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Trp Gln Ser Ile

115 120 125

Ile Ser Thr Leu Thr

130

<210> 135

<211> 133

<212> PRT

<213> 人工(Artificial)

<220>

<223> IL-2 L19Y/S125I变体序列

<400> 135

Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu His

1 5 10 15

Leu Leu Tyr Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys

20 25 30

Asn Pro Lys Leu Thr Arg Met Leu Thr Phe Lys Phe Tyr Met Pro Lys

35 40 45

Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys

50 55 60

Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu

65 70 75 80

Arg Pro Arg Asp Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu

85 90 95

Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala

100 105 110

Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Ile Gln Ser Ile

115 120 125

Ile Ser Thr Leu Thr

130

<210> 136

<211> 133

<212> PRT

<213> 人工(Artificial)

<220>

<223> IL-2 L19Y/Q22N变体序列

<400> 136

Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu His

1 5 10 15

Leu Leu Tyr Asp Leu Asn Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys

20 25 30

Asn Pro Lys Leu Thr Arg Met Leu Thr Phe Lys Phe Tyr Met Pro Lys

35 40 45

Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys

50 55 60

Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu

65 70 75 80

Arg Pro Arg Asp Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu

85 90 95

Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala

100 105 110

Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Ser Gln Ser Ile

115 120 125

Ile Ser Thr Leu Thr

130

<210> 137

<211> 133

<212> PRT

<213> 人工(Artificial)

<220>

<223> IL-2 L19Y/Q22H变体序列

<400> 137

Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu His

1 5 10 15

Leu Leu Tyr Asp Leu His Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys

20 25 30

Asn Pro Lys Leu Thr Arg Met Leu Thr Phe Lys Phe Tyr Met Pro Lys

35 40 45

Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys

50 55 60

Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu

65 70 75 80

Arg Pro Arg Asp Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu

85 90 95

Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala

100 105 110

Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Ser Gln Ser Ile

115 120 125

Ile Ser Thr Leu Thr

130

<210> 138

<211> 133

<212> PRT

<213> 人工(Artificial)

<220>

<223> IL-2 L19Y/Q22K变体序列

<400> 138

Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu His

1 5 10 15

Leu Leu Tyr Asp Leu Lys Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys

20 25 30

Asn Pro Lys Leu Thr Arg Met Leu Thr Phe Lys Phe Tyr Met Pro Lys

35 40 45

Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys

50 55 60

Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu

65 70 75 80

Arg Pro Arg Asp Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu

85 90 95

Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala

100 105 110

Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Ser Gln Ser Ile

115 120 125

Ile Ser Thr Leu Thr

130

<210> 139

<211> 133

<212> PRT

<213> 人工(Artificial)

<220>

<223> IL-2 L19Y/Q22Y变体序列

<400> 139

Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu His

1 5 10 15

Leu Leu Tyr Asp Leu Tyr Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys

20 25 30

Asn Pro Lys Leu Thr Arg Met Leu Thr Phe Lys Phe Tyr Met Pro Lys

35 40 45

Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys

50 55 60

Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu

65 70 75 80

Arg Pro Arg Asp Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu

85 90 95

Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala

100 105 110

Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Ser Gln Ser Ile

115 120 125

Ile Ser Thr Leu Thr

130

<210> 140

<211> 133

<212> PRT

<213> 人工(Artificial)

<220>

<223> IL-2 L19Y/Q22I变体序列

<400> 140

Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu His

1 5 10 15

Leu Leu Tyr Asp Leu Ile Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys

20 25 30

Asn Pro Lys Leu Thr Arg Met Leu Thr Phe Lys Phe Tyr Met Pro Lys

35 40 45

Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys

50 55 60

Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu

65 70 75 80

Arg Pro Arg Asp Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu

85 90 95

Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala

100 105 110

Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Ser Gln Ser Ile

115 120 125

Ile Ser Thr Leu Thr

130

<210> 141

<211> 133

<212> PRT

<213> 人工(Artificial)

<220>

<223> IL-2 L19H/Q126K变体序列

<400> 141

Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu His

1 5 10 15

Leu Leu His Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys

20 25 30

Asn Pro Lys Leu Thr Arg Met Leu Thr Phe Lys Phe Tyr Met Pro Lys

35 40 45

Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys

50 55 60

Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu

65 70 75 80

Arg Pro Arg Asp Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu

85 90 95

Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala

100 105 110

Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Ser Lys Ser Ile

115 120 125

Ile Ser Thr Leu Thr

130

<210> 142

<211> 133

<212> PRT

<213> 人工(Artificial)

<220>

<223> IL-2 L19H/S125I变体序列

<400> 142

Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu His

1 5 10 15

Leu Leu His Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys

20 25 30

Asn Pro Lys Leu Thr Arg Met Leu Thr Phe Lys Phe Tyr Met Pro Lys

35 40 45

Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys

50 55 60

Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu

65 70 75 80

Arg Pro Arg Asp Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu

85 90 95

Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala

100 105 110

Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Ile Gln Ser Ile

115 120 125

Ile Ser Thr Leu Thr

130

<210> 143

<211> 133

<212> PRT

<213> 人工(Artificial)

<220>

<223> IL-2 L19D/S125I变体序列

<400> 143

Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu His

1 5 10 15

Leu Leu Asp Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys

20 25 30

Asn Pro Lys Leu Thr Arg Met Leu Thr Phe Lys Phe Tyr Met Pro Lys

35 40 45

Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys

50 55 60

Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu

65 70 75 80

Arg Pro Arg Asp Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu

85 90 95

Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala

100 105 110

Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Ile Gln Ser Ile

115 120 125

Ile Ser Thr Leu Thr

130

<210> 144

<211> 133

<212> PRT

<213> 人工(Artificial)

<220>

<223> IL-2 D20E/S125I变体序列

<400> 144

Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu His

1 5 10 15

Leu Leu Leu Glu Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys

20 25 30

Asn Pro Lys Leu Thr Arg Met Leu Thr Phe Lys Phe Tyr Met Pro Lys

35 40 45

Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys

50 55 60

Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu

65 70 75 80

Arg Pro Arg Asp Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu

85 90 95

Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala

100 105 110

Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Ile Gln Ser Ile

115 120 125

Ile Ser Thr Leu Thr

130

<210> 145

<211> 133

<212> PRT

<213> 人工(Artificial)

<220>

<223> IL-2 D20T/S125I变体序列

<400> 145

Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu His

1 5 10 15

Leu Leu Leu Thr Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys

20 25 30

Asn Pro Lys Leu Thr Arg Met Leu Thr Phe Lys Phe Tyr Met Pro Lys

35 40 45

Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys

50 55 60

Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu

65 70 75 80

Arg Pro Arg Asp Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu

85 90 95

Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala

100 105 110

Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Ile Gln Ser Ile

115 120 125

Ile Ser Thr Leu Thr

130

<210> 146

<211> 133

<212> PRT

<213> 人工(Artificial)

<220>

<223> IL-2 L19Y/S125I/Q126E变体序列

<400> 146

Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu His

1 5 10 15

Leu Leu Tyr Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys

20 25 30

Asn Pro Lys Leu Thr Arg Met Leu Thr Phe Lys Phe Tyr Met Pro Lys

35 40 45

Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys

50 55 60

Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu

65 70 75 80

Arg Pro Arg Asp Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu

85 90 95

Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala

100 105 110

Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Ile Glu Ser Ile

115 120 125

Ile Ser Thr Leu Thr

130

<210> 147

<211> 367

<212> PRT

<213> 人工(Artificial)

<220>

<223> P-0423

<400> 147

Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly

1 5 10 15

Ala Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met

20 25 30

Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His

35 40 45

Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val

50 55 60

His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr

65 70 75 80

Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly

85 90 95

Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile

100 105 110

Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val

115 120 125

Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser

130 135 140

Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu

145 150 155 160

Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro

165 170 175

Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val

180 185 190

Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met

195 200 205

His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser

210 215 220

Pro Gly Gly Gly Gly Ser Gly Gly Gly Ser Ala Pro Thr Ser Ser Ser

225 230 235 240

Thr Lys Lys Thr Gln Leu Gln Leu Glu His Leu Leu Gln Asp Leu Gln

245 250 255

Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys Asn Pro Lys Leu Thr Arg

260 265 270

Met Leu Thr Phe Lys Phe Tyr Met Pro Lys Lys Ala Thr Glu Leu Lys

275 280 285

His Leu Gln Cys Leu Glu Glu Glu Leu Lys Pro Leu Glu Glu Val Leu

290 295 300

Asn Leu Ala Gln Ser Lys Asn Phe His Leu Arg Pro Arg Asp Leu Ile

305 310 315 320

Ser Asn Ile Asn Val Ile Val Leu Glu Leu Lys Gly Ser Glu Thr Thr

325 330 335

Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala Thr Ile Val Glu Phe Leu

340 345 350

Asn Arg Trp Ile Thr Phe Ser Gln Ser Ile Ile Ser Thr Leu Thr

355 360 365

<210> 148

<211> 367

<212> PRT

<213> 人工(Artificial)

<220>

<223> P-0424

<400> 148

Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly

1 5 10 15

Ala Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met

20 25 30

Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His

35 40 45

Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val

50 55 60

His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr

65 70 75 80

Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly

85 90 95

Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile

100 105 110

Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val

115 120 125

Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser

130 135 140

Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu

145 150 155 160

Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro

165 170 175

Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val

180 185 190

Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met

195 200 205

His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser

210 215 220

Pro Gly Gly Gly Gly Ser Gly Gly Gly Ser Ala Pro Thr Ser Ser Ser

225 230 235 240

Thr Lys Lys Thr Gln Leu Gln Leu Glu His Leu Leu His Asp Leu Gln

245 250 255

Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys Asn Pro Lys Leu Thr Arg

260 265 270

Met Leu Thr Phe Lys Phe Tyr Met Pro Lys Lys Ala Thr Glu Leu Lys

275 280 285

His Leu Gln Cys Leu Glu Glu Glu Leu Lys Pro Leu Glu Glu Val Leu

290 295 300

Asn Leu Ala Gln Ser Lys Asn Phe His Leu Arg Pro Arg Asp Leu Ile

305 310 315 320

Ser Asn Ile Asn Val Ile Val Leu Glu Leu Lys Gly Ser Glu Thr Thr

325 330 335

Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala Thr Ile Val Glu Phe Leu

340 345 350

Asn Arg Trp Ile Thr Phe Ser Gln Ser Ile Ile Ser Thr Leu Thr

355 360 365

<210> 149

<211> 367

<212> PRT

<213> 人工(Artificial)

<220>

<223> P-0425

<400> 149

Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly

1 5 10 15

Ala Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met

20 25 30

Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His

35 40 45

Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val

50 55 60

His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr

65 70 75 80

Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly

85 90 95

Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile

100 105 110

Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val

115 120 125

Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser

130 135 140

Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu

145 150 155 160

Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro

165 170 175

Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val

180 185 190

Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met

195 200 205

His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser

210 215 220

Pro Gly Gly Gly Gly Ser Gly Gly Gly Ser Ala Pro Thr Ser Ser Ser

225 230 235 240

Thr Lys Lys Thr Gln Leu Gln Leu Glu His Leu Leu Asp Asp Leu Gln

245 250 255

Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys Asn Pro Lys Leu Thr Arg

260 265 270

Met Leu Thr Phe Lys Phe Tyr Met Pro Lys Lys Ala Thr Glu Leu Lys

275 280 285

His Leu Gln Cys Leu Glu Glu Glu Leu Lys Pro Leu Glu Glu Val Leu

290 295 300

Asn Leu Ala Gln Ser Lys Asn Phe His Leu Arg Pro Arg Asp Leu Ile

305 310 315 320

Ser Asn Ile Asn Val Ile Val Leu Glu Leu Lys Gly Ser Glu Thr Thr

325 330 335

Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala Thr Ile Val Glu Phe Leu

340 345 350

Asn Arg Trp Ile Thr Phe Ser Gln Ser Ile Ile Ser Thr Leu Thr

355 360 365

<210> 150

<211> 367

<212> PRT

<213> 人工(Artificial)

<220>

<223> P-0426

<400> 150

Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly

1 5 10 15

Ala Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met

20 25 30

Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His

35 40 45

Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val

50 55 60

His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr

65 70 75 80

Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly

85 90 95

Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile

100 105 110

Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val

115 120 125

Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser

130 135 140

Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu

145 150 155 160

Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro

165 170 175

Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val

180 185 190

Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met

195 200 205

His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser

210 215 220

Pro Gly Gly Gly Gly Ser Gly Gly Gly Ser Ala Pro Thr Ser Ser Ser

225 230 235 240

Thr Lys Lys Thr Gln Leu Gln Leu Glu His Leu Leu Pro Asp Leu Gln

245 250 255

Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys Asn Pro Lys Leu Thr Arg

260 265 270

Met Leu Thr Phe Lys Phe Tyr Met Pro Lys Lys Ala Thr Glu Leu Lys

275 280 285

His Leu Gln Cys Leu Glu Glu Glu Leu Lys Pro Leu Glu Glu Val Leu

290 295 300

Asn Leu Ala Gln Ser Lys Asn Phe His Leu Arg Pro Arg Asp Leu Ile

305 310 315 320

Ser Asn Ile Asn Val Ile Val Leu Glu Leu Lys Gly Ser Glu Thr Thr

325 330 335

Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala Thr Ile Val Glu Phe Leu

340 345 350

Asn Arg Trp Ile Thr Phe Ser Gln Ser Ile Ile Ser Thr Leu Thr

355 360 365

<210> 151

<211> 367

<212> PRT

<213> 人工(Artificial)

<220>

<223> P-0427

<400> 151

Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly

1 5 10 15

Ala Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met

20 25 30

Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His

35 40 45

Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val

50 55 60

His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr

65 70 75 80

Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly

85 90 95

Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile

100 105 110

Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val

115 120 125

Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser

130 135 140

Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu

145 150 155 160

Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro

165 170 175

Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val

180 185 190

Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met

195 200 205

His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser

210 215 220

Pro Gly Gly Gly Gly Ser Gly Gly Gly Ser Ala Pro Thr Ser Ser Ser

225 230 235 240

Thr Lys Lys Thr Gln Leu Gln Leu Glu His Leu Leu Ser Asp Leu Gln

245 250 255

Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys Asn Pro Lys Leu Thr Arg

260 265 270

Met Leu Thr Phe Lys Phe Tyr Met Pro Lys Lys Ala Thr Glu Leu Lys

275 280 285

His Leu Gln Cys Leu Glu Glu Glu Leu Lys Pro Leu Glu Glu Val Leu

290 295 300

Asn Leu Ala Gln Ser Lys Asn Phe His Leu Arg Pro Arg Asp Leu Ile

305 310 315 320

Ser Asn Ile Asn Val Ile Val Leu Glu Leu Lys Gly Ser Glu Thr Thr

325 330 335

Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala Thr Ile Val Glu Phe Leu

340 345 350

Asn Arg Trp Ile Thr Phe Ser Gln Ser Ile Ile Ser Thr Leu Thr

355 360 365

<210> 152

<211> 367

<212> PRT

<213> 人工(Artificial)

<220>

<223> P-0428

<400> 152

Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly

1 5 10 15

Ala Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met

20 25 30

Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His

35 40 45

Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val

50 55 60

His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr

65 70 75 80

Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly

85 90 95

Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile

100 105 110

Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val

115 120 125

Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser

130 135 140

Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu

145 150 155 160

Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro

165 170 175

Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val

180 185 190

Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met

195 200 205

His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser

210 215 220

Pro Gly Gly Gly Gly Ser Gly Gly Gly Ser Ala Pro Thr Ser Ser Ser

225 230 235 240

Thr Lys Lys Thr Gln Leu Gln Leu Glu His Leu Leu Leu Asp Ser Gln

245 250 255

Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys Asn Pro Lys Leu Thr Arg

260 265 270

Met Leu Thr Phe Lys Phe Tyr Met Pro Lys Lys Ala Thr Glu Leu Lys

275 280 285

His Leu Gln Cys Leu Glu Glu Glu Leu Lys Pro Leu Glu Glu Val Leu

290 295 300

Asn Leu Ala Gln Ser Lys Asn Phe His Leu Arg Pro Arg Asp Leu Ile

305 310 315 320

Ser Asn Ile Asn Val Ile Val Leu Glu Leu Lys Gly Ser Glu Thr Thr

325 330 335

Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala Thr Ile Val Glu Phe Leu

340 345 350

Asn Arg Trp Ile Thr Phe Ser Gln Ser Ile Ile Ser Thr Leu Thr

355 360 365

<210> 153

<211> 367

<212> PRT

<213> 人工(Artificial)

<220>

<223> P-0429

<400> 153

Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly

1 5 10 15

Ala Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met

20 25 30

Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His

35 40 45

Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val

50 55 60

His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr

65 70 75 80

Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly

85 90 95

Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile

100 105 110

Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val

115 120 125

Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser

130 135 140

Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu

145 150 155 160

Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro

165 170 175

Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val

180 185 190

Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met

195 200 205

His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser

210 215 220

Pro Gly Gly Gly Gly Ser Gly Gly Gly Ser Ala Pro Thr Ser Ser Ser

225 230 235 240

Thr Lys Lys Thr Gln Leu Gln Leu Glu His Leu Leu Leu Asp Asn Gln

245 250 255

Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys Asn Pro Lys Leu Thr Arg

260 265 270

Met Leu Thr Phe Lys Phe Tyr Met Pro Lys Lys Ala Thr Glu Leu Lys

275 280 285

His Leu Gln Cys Leu Glu Glu Glu Leu Lys Pro Leu Glu Glu Val Leu

290 295 300

Asn Leu Ala Gln Ser Lys Asn Phe His Leu Arg Pro Arg Asp Leu Ile

305 310 315 320

Ser Asn Ile Asn Val Ile Val Leu Glu Leu Lys Gly Ser Glu Thr Thr

325 330 335

Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala Thr Ile Val Glu Phe Leu

340 345 350

Asn Arg Trp Ile Thr Phe Ser Gln Ser Ile Ile Ser Thr Leu Thr

355 360 365

<210> 154

<211> 367

<212> PRT

<213> 人工(Artificial)

<220>

<223> P-0430

<400> 154

Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly

1 5 10 15

Ala Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met

20 25 30

Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His

35 40 45

Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val

50 55 60

His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr

65 70 75 80

Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly

85 90 95

Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile

100 105 110

Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val

115 120 125

Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser

130 135 140

Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu

145 150 155 160

Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro

165 170 175

Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val

180 185 190

Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met

195 200 205

His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser

210 215 220

Pro Gly Gly Gly Gly Ser Gly Gly Gly Ser Ala Pro Thr Ser Ser Ser

225 230 235 240

Thr Lys Lys Thr Gln Leu Gln Leu Glu His Leu Leu Leu Asp Arg Gln

245 250 255

Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys Asn Pro Lys Leu Thr Arg

260 265 270

Met Leu Thr Phe Lys Phe Tyr Met Pro Lys Lys Ala Thr Glu Leu Lys

275 280 285

His Leu Gln Cys Leu Glu Glu Glu Leu Lys Pro Leu Glu Glu Val Leu

290 295 300

Asn Leu Ala Gln Ser Lys Asn Phe His Leu Arg Pro Arg Asp Leu Ile

305 310 315 320

Ser Asn Ile Asn Val Ile Val Leu Glu Leu Lys Gly Ser Glu Thr Thr

325 330 335

Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala Thr Ile Val Glu Phe Leu

340 345 350

Asn Arg Trp Ile Thr Phe Ser Gln Ser Ile Ile Ser Thr Leu Thr

355 360 365

<210> 155

<211> 367

<212> PRT

<213> 人工(Artificial)

<220>

<223> P-0497

<400> 155

Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly

1 5 10 15

Ala Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met

20 25 30

Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His

35 40 45

Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val

50 55 60

His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr

65 70 75 80

Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly

85 90 95

Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile

100 105 110

Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val

115 120 125

Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser

130 135 140

Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu

145 150 155 160

Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro

165 170 175

Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val

180 185 190

Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met

195 200 205

His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser

210 215 220

Pro Gly Gly Gly Gly Ser Gly Gly Gly Ser Ala Pro Thr Ser Ser Ser

225 230 235 240

Thr Lys Lys Thr Gln Leu Gln Leu Glu His Leu Leu Leu Asp Leu Gln

245 250 255

Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys Asn Pro Lys Leu Thr Arg

260 265 270

Met Leu Thr Phe Lys Phe Tyr Met Pro Lys Lys Ala Thr Glu Leu Lys

275 280 285

His Leu Gln Cys Leu Glu Glu Glu Leu Lys Pro Leu Glu Glu Val Leu

290 295 300

Asn Leu Ala Gln Ser Lys Asn Phe His Leu Arg Pro Arg Asp Leu Ile

305 310 315 320

Ser Asn Ile Asn Val Ile Val Leu Glu Leu Lys Gly Ser Glu Thr Thr

325 330 335

Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala Thr Ile Val Glu Phe Leu

340 345 350

Asn Arg Trp Ile Thr Phe Ser Lys Ser Ile Ile Ser Thr Leu Thr

355 360 365

<210> 156

<211> 367

<212> PRT

<213> 人工(Artificial)

<220>

<223> P-0498

<400> 156

Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly

1 5 10 15

Ala Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met

20 25 30

Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His

35 40 45

Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val

50 55 60

His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr

65 70 75 80

Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly

85 90 95

Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile

100 105 110

Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val

115 120 125

Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser

130 135 140

Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu

145 150 155 160

Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro

165 170 175

Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val

180 185 190

Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met

195 200 205

His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser

210 215 220

Pro Gly Gly Gly Gly Ser Gly Gly Gly Ser Ala Pro Thr Ser Ser Ser

225 230 235 240

Thr Lys Lys Thr Gln Leu Gln Leu Glu His Leu Leu Leu Asp Leu Gln

245 250 255

Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys Asn Pro Lys Leu Thr Arg

260 265 270

Met Leu Thr Phe Lys Phe Tyr Met Pro Lys Lys Ala Thr Glu Leu Lys

275 280 285

His Leu Gln Cys Leu Glu Glu Glu Leu Lys Pro Leu Glu Glu Val Leu

290 295 300

Asn Leu Ala Gln Ser Lys Asn Phe His Leu Arg Pro Arg Asp Leu Ile

305 310 315 320

Ser Asn Ile Asn Val Ile Val Leu Glu Leu Lys Gly Ser Glu Thr Thr

325 330 335

Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala Thr Ile Val Glu Phe Leu

340 345 350

Asn Arg Trp Ile Thr Phe Ser His Ser Ile Ile Ser Thr Leu Thr

355 360 365

<210> 157

<211> 367

<212> PRT

<213> 人工(Artificial)

<220>

<223> P-0499

<400> 157

Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly

1 5 10 15

Ala Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met

20 25 30

Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His

35 40 45

Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val

50 55 60

His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr

65 70 75 80

Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly

85 90 95

Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile

100 105 110

Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val

115 120 125

Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser

130 135 140

Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu

145 150 155 160

Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro

165 170 175

Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val

180 185 190

Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met

195 200 205

His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser

210 215 220

Pro Gly Gly Gly Gly Ser Gly Gly Gly Ser Ala Pro Thr Ser Ser Ser

225 230 235 240

Thr Lys Lys Thr Gln Leu Gln Leu Glu His Leu Leu Leu Asp Leu Gln

245 250 255

Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys Asn Pro Lys Leu Thr Arg

260 265 270

Met Leu Thr Phe Lys Phe Tyr Met Pro Lys Lys Ala Thr Glu Leu Lys

275 280 285

His Leu Gln Cys Leu Glu Glu Glu Leu Lys Pro Leu Glu Glu Val Leu

290 295 300

Asn Leu Ala Gln Ser Lys Asn Phe His Leu Arg Pro Arg Asp Leu Ile

305 310 315 320

Ser Asn Ile Asn Val Ile Val Leu Glu Leu Lys Gly Ser Glu Thr Thr

325 330 335

Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala Thr Ile Val Glu Phe Leu

340 345 350

Asn Arg Trp Ile Thr Phe Ser Tyr Ser Ile Ile Ser Thr Leu Thr

355 360 365

<210> 158

<211> 367

<212> PRT

<213> 人工(Artificial)

<220>

<223> P-0500

<400> 158

Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly

1 5 10 15

Ala Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met

20 25 30

Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His

35 40 45

Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val

50 55 60

His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr

65 70 75 80

Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly

85 90 95

Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile

100 105 110

Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val

115 120 125

Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser

130 135 140

Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu

145 150 155 160

Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro

165 170 175

Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val

180 185 190

Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met

195 200 205

His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser

210 215 220

Pro Gly Gly Gly Gly Ser Gly Gly Gly Ser Ala Pro Thr Ser Ser Ser

225 230 235 240

Thr Lys Lys Thr Gln Leu Gln Leu Glu His Leu Leu Leu Asp Leu Gln

245 250 255

Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys Asn Pro Lys Leu Thr Arg

260 265 270

Met Leu Thr Phe Lys Phe Tyr Met Pro Lys Lys Ala Thr Glu Leu Lys

275 280 285

His Leu Gln Cys Leu Glu Glu Glu Leu Lys Pro Leu Glu Glu Val Leu

290 295 300

Asn Leu Ala Gln Ser Lys Asn Phe His Leu Arg Pro Arg Asp Leu Ile

305 310 315 320

Ser Asn Ile Asn Val Ile Val Leu Glu Leu Lys Gly Ser Glu Thr Thr

325 330 335

Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala Thr Ile Val Glu Phe Leu

340 345 350

Asn Arg Trp Ile Thr Phe Glu Gln Ser Ile Ile Ser Thr Leu Thr

355 360 365

<210> 159

<211> 367

<212> PRT

<213> 人工(Artificial)

<220>

<223> P-0501

<400> 159

Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly

1 5 10 15

Ala Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met

20 25 30

Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His

35 40 45

Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val

50 55 60

His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr

65 70 75 80

Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly

85 90 95

Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile

100 105 110

Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val

115 120 125

Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser

130 135 140

Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu

145 150 155 160

Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro

165 170 175

Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val

180 185 190

Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met

195 200 205

His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser

210 215 220

Pro Gly Gly Gly Gly Ser Gly Gly Gly Ser Ala Pro Thr Ser Ser Ser

225 230 235 240

Thr Lys Lys Thr Gln Leu Gln Leu Glu His Leu Leu Leu Asp Leu Gln

245 250 255

Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys Asn Pro Lys Leu Thr Arg

260 265 270

Met Leu Thr Phe Lys Phe Tyr Met Pro Lys Lys Ala Thr Glu Leu Lys

275 280 285

His Leu Gln Cys Leu Glu Glu Glu Leu Lys Pro Leu Glu Glu Val Leu

290 295 300

Asn Leu Ala Gln Ser Lys Asn Phe His Leu Arg Pro Arg Asp Leu Ile

305 310 315 320

Ser Asn Ile Asn Val Ile Val Leu Glu Leu Lys Gly Ser Glu Thr Thr

325 330 335

Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala Thr Ile Val Glu Phe Leu

340 345 350

Asn Arg Trp Ile Thr Phe Lys Gln Ser Ile Ile Ser Thr Leu Thr

355 360 365

<210> 160

<211> 367

<212> PRT

<213> 人工(Artificial)

<220>

<223> P-0502

<400> 160

Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly

1 5 10 15

Ala Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met

20 25 30

Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His

35 40 45

Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val

50 55 60

His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr

65 70 75 80

Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly

85 90 95

Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile

100 105 110

Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val

115 120 125

Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser

130 135 140

Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu

145 150 155 160

Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro

165 170 175

Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val

180 185 190

Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met

195 200 205

His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser

210 215 220

Pro Gly Gly Gly Gly Ser Gly Gly Gly Ser Ala Pro Thr Ser Ser Ser

225 230 235 240

Thr Lys Lys Thr Gln Leu Gln Leu Glu His Leu Leu Leu Asp Leu Gln

245 250 255

Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys Asn Pro Lys Leu Thr Arg

260 265 270

Met Leu Thr Phe Lys Phe Tyr Met Pro Lys Lys Ala Thr Glu Leu Lys

275 280 285

His Leu Gln Cys Leu Glu Glu Glu Leu Lys Pro Leu Glu Glu Val Leu

290 295 300

Asn Leu Ala Gln Ser Lys Asn Phe His Leu Arg Pro Arg Asp Leu Ile

305 310 315 320

Ser Asn Ile Asn Val Ile Val Leu Glu Leu Lys Gly Ser Glu Thr Thr

325 330 335

Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala Thr Ile Val Glu Phe Leu

340 345 350

Asn Arg Trp Ile Thr Phe His Gln Ser Ile Ile Ser Thr Leu Thr

355 360 365

<210> 161

<211> 367

<212> PRT

<213> 人工(Artificial)

<220>

<223> P-0503

<400> 161

Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly

1 5 10 15

Ala Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met

20 25 30

Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His

35 40 45

Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val

50 55 60

His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr

65 70 75 80

Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly

85 90 95

Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile

100 105 110

Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val

115 120 125

Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser

130 135 140

Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu

145 150 155 160

Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro

165 170 175

Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val

180 185 190

Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met

195 200 205

His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser

210 215 220

Pro Gly Gly Gly Gly Ser Gly Gly Gly Ser Ala Pro Thr Ser Ser Ser

225 230 235 240

Thr Lys Lys Thr Gln Leu Gln Leu Glu His Leu Leu Leu Asp Leu Gln

245 250 255

Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys Asn Pro Lys Leu Thr Arg

260 265 270

Met Leu Thr Phe Lys Phe Tyr Met Pro Lys Lys Ala Thr Glu Leu Lys

275 280 285

His Leu Gln Cys Leu Glu Glu Glu Leu Lys Pro Leu Glu Glu Val Leu

290 295 300

Asn Leu Ala Gln Ser Lys Asn Phe His Leu Arg Pro Arg Asp Leu Ile

305 310 315 320

Ser Asn Ile Asn Val Ile Val Leu Glu Leu Lys Gly Ser Glu Thr Thr

325 330 335

Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala Thr Ile Val Glu Phe Leu

340 345 350

Asn Arg Trp Ile Thr Phe Trp Gln Ser Ile Ile Ser Thr Leu Thr

355 360 365

<210> 162

<211> 367

<212> PRT

<213> 人工(Artificial)

<220>

<223> P-0531

<400> 162

Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly

1 5 10 15

Ala Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met

20 25 30

Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His

35 40 45

Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val

50 55 60

His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr

65 70 75 80

Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly

85 90 95

Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile

100 105 110

Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val

115 120 125

Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser

130 135 140

Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu

145 150 155 160

Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro

165 170 175

Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val

180 185 190

Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met

195 200 205

His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser

210 215 220

Pro Gly Gly Gly Gly Ser Gly Gly Gly Ser Ala Pro Thr Ser Ser Ser

225 230 235 240

Thr Lys Lys Thr Gln Leu Gln Leu Glu His Leu Leu Leu Asp Leu Gln

245 250 255

Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys Asn Pro Lys Leu Thr Arg

260 265 270

Met Leu Thr Phe Lys Phe Tyr Met Pro Lys Lys Ala Thr Glu Leu Lys

275 280 285

His Leu Gln Cys Leu Glu Glu Glu Leu Lys Pro Leu Glu Glu Val Leu

290 295 300

Asn Leu Ala Gln Ser Lys Asn Phe His Leu Arg Pro Arg Asp Leu Ile

305 310 315 320

Ser Asn Ile Asn Val Ile Val Leu Glu Leu Lys Gly Ser Glu Thr Thr

325 330 335

Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala Thr Ile Val Glu Phe Leu

340 345 350

Asn Arg Trp Ile Thr Phe Ile Gln Ser Ile Ile Ser Thr Leu Thr

355 360 365

<210> 163

<211> 367

<212> PRT

<213> 人工(Artificial)

<220>

<223> P-0505

<400> 163

Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly

1 5 10 15

Ala Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met

20 25 30

Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His

35 40 45

Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val

50 55 60

His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr

65 70 75 80

Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly

85 90 95

Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile

100 105 110

Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val

115 120 125

Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser

130 135 140

Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu

145 150 155 160

Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro

165 170 175

Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val

180 185 190

Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met

195 200 205

His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser

210 215 220

Pro Gly Gly Gly Gly Ser Gly Gly Gly Ser Ala Pro Thr Ser Ser Ser

225 230 235 240

Thr Lys Lys Thr Gln Leu Gln Leu Glu His Leu Leu Leu Asp Leu Asn

245 250 255

Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys Asn Pro Lys Leu Thr Arg

260 265 270

Met Leu Thr Phe Lys Phe Tyr Met Pro Lys Lys Ala Thr Glu Leu Lys

275 280 285

His Leu Gln Cys Leu Glu Glu Glu Leu Lys Pro Leu Glu Glu Val Leu

290 295 300

Asn Leu Ala Gln Ser Lys Asn Phe His Leu Arg Pro Arg Asp Leu Ile

305 310 315 320

Ser Asn Ile Asn Val Ile Val Leu Glu Leu Lys Gly Ser Glu Thr Thr

325 330 335

Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala Thr Ile Val Glu Phe Leu

340 345 350

Asn Arg Trp Ile Thr Phe Ser Gln Ser Ile Ile Ser Thr Leu Thr

355 360 365

<210> 164

<211> 367

<212> PRT

<213> 人工(Artificial)

<220>

<223> P-0506

<400> 164

Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly

1 5 10 15

Ala Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met

20 25 30

Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His

35 40 45

Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val

50 55 60

His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr

65 70 75 80

Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly

85 90 95

Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile

100 105 110

Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val

115 120 125

Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser

130 135 140

Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu

145 150 155 160

Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro

165 170 175

Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val

180 185 190

Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met

195 200 205

His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser

210 215 220

Pro Gly Gly Gly Gly Ser Gly Gly Gly Ser Ala Pro Thr Ser Ser Ser

225 230 235 240

Thr Lys Lys Thr Gln Leu Gln Leu Glu His Leu Leu Leu Asp Leu His

245 250 255

Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys Asn Pro Lys Leu Thr Arg

260 265 270

Met Leu Thr Phe Lys Phe Tyr Met Pro Lys Lys Ala Thr Glu Leu Lys

275 280 285

His Leu Gln Cys Leu Glu Glu Glu Leu Lys Pro Leu Glu Glu Val Leu

290 295 300

Asn Leu Ala Gln Ser Lys Asn Phe His Leu Arg Pro Arg Asp Leu Ile

305 310 315 320

Ser Asn Ile Asn Val Ile Val Leu Glu Leu Lys Gly Ser Glu Thr Thr

325 330 335

Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala Thr Ile Val Glu Phe Leu

340 345 350

Asn Arg Trp Ile Thr Phe Ser Gln Ser Ile Ile Ser Thr Leu Thr

355 360 365

<210> 165

<211> 367

<212> PRT

<213> 人工(Artificial)

<220>

<223> P-0507

<400> 165

Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly

1 5 10 15

Ala Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met

20 25 30

Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His

35 40 45

Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val

50 55 60

His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr

65 70 75 80

Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly

85 90 95

Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile

100 105 110

Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val

115 120 125

Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser

130 135 140

Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu

145 150 155 160

Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro

165 170 175

Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val

180 185 190

Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met

195 200 205

His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser

210 215 220

Pro Gly Gly Gly Gly Ser Gly Gly Gly Ser Ala Pro Thr Ser Ser Ser

225 230 235 240

Thr Lys Lys Thr Gln Leu Gln Leu Glu His Leu Leu Leu Asp Leu Lys

245 250 255

Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys Asn Pro Lys Leu Thr Arg

260 265 270

Met Leu Thr Phe Lys Phe Tyr Met Pro Lys Lys Ala Thr Glu Leu Lys

275 280 285

His Leu Gln Cys Leu Glu Glu Glu Leu Lys Pro Leu Glu Glu Val Leu

290 295 300

Asn Leu Ala Gln Ser Lys Asn Phe His Leu Arg Pro Arg Asp Leu Ile

305 310 315 320

Ser Asn Ile Asn Val Ile Val Leu Glu Leu Lys Gly Ser Glu Thr Thr

325 330 335

Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala Thr Ile Val Glu Phe Leu

340 345 350

Asn Arg Trp Ile Thr Phe Ser Gln Ser Ile Ile Ser Thr Leu Thr

355 360 365

<210> 166

<211> 367

<212> PRT

<213> 人工(Artificial)

<220>

<223> P-0508

<400> 166

Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly

1 5 10 15

Ala Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met

20 25 30

Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His

35 40 45

Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val

50 55 60

His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr

65 70 75 80

Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly

85 90 95

Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile

100 105 110

Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val

115 120 125

Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser

130 135 140

Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu

145 150 155 160

Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro

165 170 175

Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val

180 185 190

Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met

195 200 205

His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser

210 215 220

Pro Gly Gly Gly Gly Ser Gly Gly Gly Ser Ala Pro Thr Ser Ser Ser

225 230 235 240

Thr Lys Lys Thr Gln Leu Gln Leu Glu His Leu Leu Leu Asp Leu Tyr

245 250 255

Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys Asn Pro Lys Leu Thr Arg

260 265 270

Met Leu Thr Phe Lys Phe Tyr Met Pro Lys Lys Ala Thr Glu Leu Lys

275 280 285

His Leu Gln Cys Leu Glu Glu Glu Leu Lys Pro Leu Glu Glu Val Leu

290 295 300

Asn Leu Ala Gln Ser Lys Asn Phe His Leu Arg Pro Arg Asp Leu Ile

305 310 315 320

Ser Asn Ile Asn Val Ile Val Leu Glu Leu Lys Gly Ser Glu Thr Thr

325 330 335

Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala Thr Ile Val Glu Phe Leu

340 345 350

Asn Arg Trp Ile Thr Phe Ser Gln Ser Ile Ile Ser Thr Leu Thr

355 360 365

<210> 167

<211> 367

<212> PRT

<213> 人工(Artificial)

<220>

<223> P-0509

<400> 167

Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly

1 5 10 15

Ala Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met

20 25 30

Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His

35 40 45

Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val

50 55 60

His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr

65 70 75 80

Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly

85 90 95

Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile

100 105 110

Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val

115 120 125

Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser

130 135 140

Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu

145 150 155 160

Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro

165 170 175

Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val

180 185 190

Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met

195 200 205

His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser

210 215 220

Pro Gly Gly Gly Gly Ser Gly Gly Gly Ser Ala Pro Thr Ser Ser Ser

225 230 235 240

Thr Lys Lys Thr Gln Leu Gln Leu Glu His Leu Leu Leu Asp Leu Ile

245 250 255

Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys Asn Pro Lys Leu Thr Arg

260 265 270

Met Leu Thr Phe Lys Phe Tyr Met Pro Lys Lys Ala Thr Glu Leu Lys

275 280 285

His Leu Gln Cys Leu Glu Glu Glu Leu Lys Pro Leu Glu Glu Val Leu

290 295 300

Asn Leu Ala Gln Ser Lys Asn Phe His Leu Arg Pro Arg Asp Leu Ile

305 310 315 320

Ser Asn Ile Asn Val Ile Val Leu Glu Leu Lys Gly Ser Glu Thr Thr

325 330 335

Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala Thr Ile Val Glu Phe Leu

340 345 350

Asn Arg Trp Ile Thr Phe Ser Gln Ser Ile Ile Ser Thr Leu Thr

355 360 365

<210> 168

<211> 367

<212> PRT

<213> 人工(Artificial)

<220>

<223> P-0447

<400> 168

Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly

1 5 10 15

Ala Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met

20 25 30

Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His

35 40 45

Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val

50 55 60

His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr

65 70 75 80

Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly

85 90 95

Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile

100 105 110

Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val

115 120 125

Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser

130 135 140

Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu

145 150 155 160

Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro

165 170 175

Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val

180 185 190

Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met

195 200 205

His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser

210 215 220

Pro Gly Gly Gly Gly Ser Gly Gly Gly Ser Ala Pro Thr Ser Ser Ser

225 230 235 240

Thr Lys Lys Thr Gln Leu Gln Leu Glu His Leu Leu His Asp Leu Gln

245 250 255

Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys Asn Pro Lys Leu Thr Arg

260 265 270

Met Leu Thr Phe Lys Phe Tyr Met Pro Lys Lys Ala Thr Glu Leu Lys

275 280 285

His Leu Gln Cys Leu Glu Glu Glu Leu Lys Pro Leu Glu Glu Val Leu

290 295 300

Asn Leu Ala Gln Ser Lys Asn Phe His Leu Arg Pro Arg Asp Leu Ile

305 310 315 320

Ser Asn Ile Asn Val Ile Val Leu Glu Leu Lys Gly Ser Glu Thr Thr

325 330 335

Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala Thr Ile Val Glu Phe Leu

340 345 350

Asn Arg Trp Ile Thr Phe Ser Glu Ser Ile Ile Ser Thr Leu Thr

355 360 365

<210> 169

<211> 367

<212> PRT

<213> 人工(Artificial)

<220>

<223> P-0448

<400> 169

Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly

1 5 10 15

Ala Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met

20 25 30

Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His

35 40 45

Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val

50 55 60

His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr

65 70 75 80

Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly

85 90 95

Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile

100 105 110

Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val

115 120 125

Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser

130 135 140

Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu

145 150 155 160

Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro

165 170 175

Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val

180 185 190

Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met

195 200 205

His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser

210 215 220

Pro Gly Gly Gly Gly Ser Gly Gly Gly Ser Ala Pro Thr Ser Ser Ser

225 230 235 240

Thr Lys Lys Thr Gln Leu Gln Leu Glu His Leu Leu Gln Asp Leu Gln

245 250 255

Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys Asn Pro Lys Leu Thr Arg

260 265 270

Met Leu Thr Phe Lys Phe Tyr Met Pro Lys Lys Ala Thr Glu Leu Lys

275 280 285

His Leu Gln Cys Leu Glu Glu Glu Leu Lys Pro Leu Glu Glu Val Leu

290 295 300

Asn Leu Ala Gln Ser Lys Asn Phe His Leu Arg Pro Arg Asp Leu Ile

305 310 315 320

Ser Asn Ile Asn Val Ile Val Leu Glu Leu Lys Gly Ser Glu Thr Thr

325 330 335

Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala Thr Ile Val Glu Phe Leu

340 345 350

Asn Arg Trp Ile Thr Phe Ser Glu Ser Ile Ile Ser Thr Leu Thr

355 360 365

<210> 170

<211> 367

<212> PRT

<213> 人工(Artificial)

<220>

<223> P-0449

<400> 170

Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly

1 5 10 15

Ala Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met

20 25 30

Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His

35 40 45

Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val

50 55 60

His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr

65 70 75 80

Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly

85 90 95

Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile

100 105 110

Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val

115 120 125

Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser

130 135 140

Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu

145 150 155 160

Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro

165 170 175

Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val

180 185 190

Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met

195 200 205

His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser

210 215 220

Pro Gly Gly Gly Gly Ser Gly Gly Gly Ser Ala Pro Thr Ser Ser Ser

225 230 235 240

Thr Lys Lys Thr Gln Leu Gln Leu Glu His Leu Leu Ser Asp Leu Gln

245 250 255

Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys Asn Pro Lys Leu Thr Arg

260 265 270

Met Leu Thr Phe Lys Phe Tyr Met Pro Lys Lys Ala Thr Glu Leu Lys

275 280 285

His Leu Gln Cys Leu Glu Glu Glu Leu Lys Pro Leu Glu Glu Val Leu

290 295 300

Asn Leu Ala Gln Ser Lys Asn Phe His Leu Arg Pro Arg Asp Leu Ile

305 310 315 320

Ser Asn Ile Asn Val Ile Val Leu Glu Leu Lys Gly Ser Glu Thr Thr

325 330 335

Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala Thr Ile Val Glu Phe Leu

340 345 350

Asn Arg Trp Ile Thr Phe Ser Glu Ser Ile Ile Ser Thr Leu Thr

355 360 365

<210> 171

<211> 367

<212> PRT

<213> 人工(Artificial)

<220>

<223> P-0464

<400> 171

Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly

1 5 10 15

Ala Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met

20 25 30

Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His

35 40 45

Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val

50 55 60

His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr

65 70 75 80

Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly

85 90 95

Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile

100 105 110

Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val

115 120 125

Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser

130 135 140

Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu

145 150 155 160

Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro

165 170 175

Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val

180 185 190

Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met

195 200 205

His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser

210 215 220

Pro Gly Gly Gly Gly Ser Gly Gly Gly Ser Ala Pro Thr Ser Ser Ser

225 230 235 240

Thr Lys Lys Thr Gln Leu Gln Leu Glu His Leu Leu Tyr Asp Leu Gln

245 250 255

Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys Asn Pro Lys Leu Thr Arg

260 265 270

Met Leu Thr Phe Lys Phe Tyr Met Pro Lys Lys Ala Thr Glu Leu Lys

275 280 285

His Leu Gln Cys Leu Glu Glu Glu Leu Lys Pro Leu Glu Glu Val Leu

290 295 300

Asn Leu Ala Gln Ser Lys Asn Phe His Leu Arg Pro Arg Asp Leu Ile

305 310 315 320

Ser Asn Ile Asn Val Ile Val Leu Glu Leu Lys Gly Ser Glu Thr Thr

325 330 335

Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala Thr Ile Val Glu Phe Leu

340 345 350

Asn Arg Trp Ile Thr Phe Ser Lys Ser Ile Ile Ser Thr Leu Thr

355 360 365

<210> 172

<211> 367

<212> PRT

<213> 人工(Artificial)

<220>

<223> P-0465

<400> 172

Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly

1 5 10 15

Ala Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met

20 25 30

Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His

35 40 45

Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val

50 55 60

His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr

65 70 75 80

Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly

85 90 95

Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile

100 105 110

Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val

115 120 125

Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser

130 135 140

Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu

145 150 155 160

Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro

165 170 175

Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val

180 185 190

Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met

195 200 205

His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser

210 215 220

Pro Gly Gly Gly Gly Ser Gly Gly Gly Ser Ala Pro Thr Ser Ser Ser

225 230 235 240

Thr Lys Lys Thr Gln Leu Gln Leu Glu His Leu Leu Tyr Asp Leu Gln

245 250 255

Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys Asn Pro Lys Leu Thr Arg

260 265 270

Met Leu Thr Phe Lys Phe Tyr Met Pro Lys Lys Ala Thr Glu Leu Lys

275 280 285

His Leu Gln Cys Leu Glu Glu Glu Leu Lys Pro Leu Glu Glu Val Leu

290 295 300

Asn Leu Ala Gln Ser Lys Asn Phe His Leu Arg Pro Arg Asp Leu Ile

305 310 315 320

Ser Asn Ile Asn Val Ile Val Leu Glu Leu Lys Gly Ser Glu Thr Thr

325 330 335

Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala Thr Ile Val Glu Phe Leu

340 345 350

Asn Arg Trp Ile Thr Phe Ser His Ser Ile Ile Ser Thr Leu Thr

355 360 365

<210> 173

<211> 367

<212> PRT

<213> 人工(Artificial)

<220>

<223> P-0466

<400> 173

Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly

1 5 10 15

Ala Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met

20 25 30

Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His

35 40 45

Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val

50 55 60

His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr

65 70 75 80

Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly

85 90 95

Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile

100 105 110

Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val

115 120 125

Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser

130 135 140

Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu

145 150 155 160

Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro

165 170 175

Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val

180 185 190

Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met

195 200 205

His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser

210 215 220

Pro Gly Gly Gly Gly Ser Gly Gly Gly Ser Ala Pro Thr Ser Ser Ser

225 230 235 240

Thr Lys Lys Thr Gln Leu Gln Leu Glu His Leu Leu Tyr Asp Leu Gln

245 250 255

Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys Asn Pro Lys Leu Thr Arg

260 265 270

Met Leu Thr Phe Lys Phe Tyr Met Pro Lys Lys Ala Thr Glu Leu Lys

275 280 285

His Leu Gln Cys Leu Glu Glu Glu Leu Lys Pro Leu Glu Glu Val Leu

290 295 300

Asn Leu Ala Gln Ser Lys Asn Phe His Leu Arg Pro Arg Asp Leu Ile

305 310 315 320

Ser Asn Ile Asn Val Ile Val Leu Glu Leu Lys Gly Ser Glu Thr Thr

325 330 335

Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala Thr Ile Val Glu Phe Leu

340 345 350

Asn Arg Trp Ile Thr Phe Ser Tyr Ser Ile Ile Ser Thr Leu Thr

355 360 365

<210> 174

<211> 367

<212> PRT

<213> 人工(Artificial)

<220>

<223> P-0467

<400> 174

Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly

1 5 10 15

Ala Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met

20 25 30

Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His

35 40 45

Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val

50 55 60

His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr

65 70 75 80

Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly

85 90 95

Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile

100 105 110

Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val

115 120 125

Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser

130 135 140

Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu

145 150 155 160

Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro

165 170 175

Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val

180 185 190

Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met

195 200 205

His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser

210 215 220

Pro Gly Gly Gly Gly Ser Gly Gly Gly Ser Ala Pro Thr Ser Ser Ser

225 230 235 240

Thr Lys Lys Thr Gln Leu Gln Leu Glu His Leu Leu Tyr Asp Leu Gln

245 250 255

Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys Asn Pro Lys Leu Thr Arg

260 265 270

Met Leu Thr Phe Lys Phe Tyr Met Pro Lys Lys Ala Thr Glu Leu Lys

275 280 285

His Leu Gln Cys Leu Glu Glu Glu Leu Lys Pro Leu Glu Glu Val Leu

290 295 300

Asn Leu Ala Gln Ser Lys Asn Phe His Leu Arg Pro Arg Asp Leu Ile

305 310 315 320

Ser Asn Ile Asn Val Ile Val Leu Glu Leu Lys Gly Ser Glu Thr Thr

325 330 335

Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala Thr Ile Val Glu Phe Leu

340 345 350

Asn Arg Trp Ile Thr Phe Glu Gln Ser Ile Ile Ser Thr Leu Thr

355 360 365

<210> 175

<211> 367

<212> PRT

<213> 人工(Artificial)

<220>

<223> P-0468

<400> 175

Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly

1 5 10 15

Ala Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met

20 25 30

Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His

35 40 45

Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val

50 55 60

His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr

65 70 75 80

Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly

85 90 95

Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile

100 105 110

Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val

115 120 125

Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser

130 135 140

Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu

145 150 155 160

Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro

165 170 175

Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val

180 185 190

Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met

195 200 205

His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser

210 215 220

Pro Gly Gly Gly Gly Ser Gly Gly Gly Ser Ala Pro Thr Ser Ser Ser

225 230 235 240

Thr Lys Lys Thr Gln Leu Gln Leu Glu His Leu Leu Tyr Asp Leu Gln

245 250 255

Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys Asn Pro Lys Leu Thr Arg

260 265 270

Met Leu Thr Phe Lys Phe Tyr Met Pro Lys Lys Ala Thr Glu Leu Lys

275 280 285

His Leu Gln Cys Leu Glu Glu Glu Leu Lys Pro Leu Glu Glu Val Leu

290 295 300

Asn Leu Ala Gln Ser Lys Asn Phe His Leu Arg Pro Arg Asp Leu Ile

305 310 315 320

Ser Asn Ile Asn Val Ile Val Leu Glu Leu Lys Gly Ser Glu Thr Thr

325 330 335

Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala Thr Ile Val Glu Phe Leu

340 345 350

Asn Arg Trp Ile Thr Phe Lys Gln Ser Ile Ile Ser Thr Leu Thr

355 360 365

<210> 176

<211> 367

<212> PRT

<213> 人工(Artificial)

<220>

<223> P-0469

<400> 176

Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly

1 5 10 15

Ala Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met

20 25 30

Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His

35 40 45

Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val

50 55 60

His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr

65 70 75 80

Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly

85 90 95

Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile

100 105 110

Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val

115 120 125

Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser

130 135 140

Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu

145 150 155 160

Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro

165 170 175

Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val

180 185 190

Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met

195 200 205

His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser

210 215 220

Pro Gly Gly Gly Gly Ser Gly Gly Gly Ser Ala Pro Thr Ser Ser Ser

225 230 235 240

Thr Lys Lys Thr Gln Leu Gln Leu Glu His Leu Leu Tyr Asp Leu Gln

245 250 255

Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys Asn Pro Lys Leu Thr Arg

260 265 270

Met Leu Thr Phe Lys Phe Tyr Met Pro Lys Lys Ala Thr Glu Leu Lys

275 280 285

His Leu Gln Cys Leu Glu Glu Glu Leu Lys Pro Leu Glu Glu Val Leu

290 295 300

Asn Leu Ala Gln Ser Lys Asn Phe His Leu Arg Pro Arg Asp Leu Ile

305 310 315 320

Ser Asn Ile Asn Val Ile Val Leu Glu Leu Lys Gly Ser Glu Thr Thr

325 330 335

Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala Thr Ile Val Glu Phe Leu

340 345 350

Asn Arg Trp Ile Thr Phe His Gln Ser Ile Ile Ser Thr Leu Thr

355 360 365

<210> 177

<211> 367

<212> PRT

<213> 人工(Artificial)

<220>

<223> P-0470

<400> 177

Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly

1 5 10 15

Ala Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met

20 25 30

Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His

35 40 45

Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val

50 55 60

His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr

65 70 75 80

Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly

85 90 95

Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile

100 105 110

Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val

115 120 125

Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser

130 135 140

Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu

145 150 155 160

Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro

165 170 175

Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val

180 185 190

Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met

195 200 205

His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser

210 215 220

Pro Gly Gly Gly Gly Ser Gly Gly Gly Ser Ala Pro Thr Ser Ser Ser

225 230 235 240

Thr Lys Lys Thr Gln Leu Gln Leu Glu His Leu Leu Tyr Asp Leu Gln

245 250 255

Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys Asn Pro Lys Leu Thr Arg

260 265 270

Met Leu Thr Phe Lys Phe Tyr Met Pro Lys Lys Ala Thr Glu Leu Lys

275 280 285

His Leu Gln Cys Leu Glu Glu Glu Leu Lys Pro Leu Glu Glu Val Leu

290 295 300

Asn Leu Ala Gln Ser Lys Asn Phe His Leu Arg Pro Arg Asp Leu Ile

305 310 315 320

Ser Asn Ile Asn Val Ile Val Leu Glu Leu Lys Gly Ser Glu Thr Thr

325 330 335

Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala Thr Ile Val Glu Phe Leu

340 345 350

Asn Arg Trp Ile Thr Phe Trp Gln Ser Ile Ile Ser Thr Leu Thr

355 360 365

<210> 178

<211> 367

<212> PRT

<213> 人工(Artificial)

<220>

<223> P-0471

<400> 178

Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly

1 5 10 15

Ala Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met

20 25 30

Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His

35 40 45

Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val

50 55 60

His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr

65 70 75 80

Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly

85 90 95

Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile

100 105 110

Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val

115 120 125

Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser

130 135 140

Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu

145 150 155 160

Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro

165 170 175

Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val

180 185 190

Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met

195 200 205

His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser

210 215 220

Pro Gly Gly Gly Gly Ser Gly Gly Gly Ser Ala Pro Thr Ser Ser Ser

225 230 235 240

Thr Lys Lys Thr Gln Leu Gln Leu Glu His Leu Leu Tyr Asp Leu Gln

245 250 255

Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys Asn Pro Lys Leu Thr Arg

260 265 270

Met Leu Thr Phe Lys Phe Tyr Met Pro Lys Lys Ala Thr Glu Leu Lys

275 280 285

His Leu Gln Cys Leu Glu Glu Glu Leu Lys Pro Leu Glu Glu Val Leu

290 295 300

Asn Leu Ala Gln Ser Lys Asn Phe His Leu Arg Pro Arg Asp Leu Ile

305 310 315 320

Ser Asn Ile Asn Val Ile Val Leu Glu Leu Lys Gly Ser Glu Thr Thr

325 330 335

Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala Thr Ile Val Glu Phe Leu

340 345 350

Asn Arg Trp Ile Thr Phe Ile Gln Ser Ile Ile Ser Thr Leu Thr

355 360 365

<210> 179

<211> 367

<212> PRT

<213> 人工(Artificial)

<220>

<223> P-0472

<400> 179

Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly

1 5 10 15

Ala Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met

20 25 30

Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His

35 40 45

Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val

50 55 60

His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr

65 70 75 80

Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly

85 90 95

Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile

100 105 110

Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val

115 120 125

Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser

130 135 140

Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu

145 150 155 160

Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro

165 170 175

Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val

180 185 190

Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met

195 200 205

His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser

210 215 220

Pro Gly Gly Gly Gly Ser Gly Gly Gly Ser Ala Pro Thr Ser Ser Ser

225 230 235 240

Thr Lys Lys Thr Gln Leu Gln Leu Glu His Leu Leu Tyr Asp Leu Asn

245 250 255

Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys Asn Pro Lys Leu Thr Arg

260 265 270

Met Leu Thr Phe Lys Phe Tyr Met Pro Lys Lys Ala Thr Glu Leu Lys

275 280 285

His Leu Gln Cys Leu Glu Glu Glu Leu Lys Pro Leu Glu Glu Val Leu

290 295 300

Asn Leu Ala Gln Ser Lys Asn Phe His Leu Arg Pro Arg Asp Leu Ile

305 310 315 320

Ser Asn Ile Asn Val Ile Val Leu Glu Leu Lys Gly Ser Glu Thr Thr

325 330 335

Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala Thr Ile Val Glu Phe Leu

340 345 350

Asn Arg Trp Ile Thr Phe Ser Gln Ser Ile Ile Ser Thr Leu Thr

355 360 365

<210> 180

<211> 367

<212> PRT

<213> 人工(Artificial)

<220>

<223> P-0473

<400> 180

Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly

1 5 10 15

Ala Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met

20 25 30

Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His

35 40 45

Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val

50 55 60

His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr

65 70 75 80

Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly

85 90 95

Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile

100 105 110

Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val

115 120 125

Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser

130 135 140

Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu

145 150 155 160

Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro

165 170 175

Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val

180 185 190

Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met

195 200 205

His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser

210 215 220

Pro Gly Gly Gly Gly Ser Gly Gly Gly Ser Ala Pro Thr Ser Ser Ser

225 230 235 240

Thr Lys Lys Thr Gln Leu Gln Leu Glu His Leu Leu Tyr Asp Leu His

245 250 255

Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys Asn Pro Lys Leu Thr Arg

260 265 270

Met Leu Thr Phe Lys Phe Tyr Met Pro Lys Lys Ala Thr Glu Leu Lys

275 280 285

His Leu Gln Cys Leu Glu Glu Glu Leu Lys Pro Leu Glu Glu Val Leu

290 295 300

Asn Leu Ala Gln Ser Lys Asn Phe His Leu Arg Pro Arg Asp Leu Ile

305 310 315 320

Ser Asn Ile Asn Val Ile Val Leu Glu Leu Lys Gly Ser Glu Thr Thr

325 330 335

Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala Thr Ile Val Glu Phe Leu

340 345 350

Asn Arg Trp Ile Thr Phe Ser Gln Ser Ile Ile Ser Thr Leu Thr

355 360 365

<210> 181

<211> 367

<212> PRT

<213> 人工(Artificial)

<220>

<223> P-0474

<400> 181

Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly

1 5 10 15

Ala Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met

20 25 30

Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His

35 40 45

Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val

50 55 60

His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr

65 70 75 80

Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly

85 90 95

Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile

100 105 110

Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val

115 120 125

Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser

130 135 140

Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu

145 150 155 160

Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro

165 170 175

Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val

180 185 190

Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met

195 200 205

His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser

210 215 220

Pro Gly Gly Gly Gly Ser Gly Gly Gly Ser Ala Pro Thr Ser Ser Ser

225 230 235 240

Thr Lys Lys Thr Gln Leu Gln Leu Glu His Leu Leu Tyr Asp Leu Lys

245 250 255

Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys Asn Pro Lys Leu Thr Arg

260 265 270

Met Leu Thr Phe Lys Phe Tyr Met Pro Lys Lys Ala Thr Glu Leu Lys

275 280 285

His Leu Gln Cys Leu Glu Glu Glu Leu Lys Pro Leu Glu Glu Val Leu

290 295 300

Asn Leu Ala Gln Ser Lys Asn Phe His Leu Arg Pro Arg Asp Leu Ile

305 310 315 320

Ser Asn Ile Asn Val Ile Val Leu Glu Leu Lys Gly Ser Glu Thr Thr

325 330 335

Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala Thr Ile Val Glu Phe Leu

340 345 350

Asn Arg Trp Ile Thr Phe Ser Gln Ser Ile Ile Ser Thr Leu Thr

355 360 365

<210> 182

<211> 367

<212> PRT

<213> 人工(Artificial)

<220>

<223> P-0475

<400> 182

Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly

1 5 10 15

Ala Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met

20 25 30

Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His

35 40 45

Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val

50 55 60

His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr

65 70 75 80

Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly

85 90 95

Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile

100 105 110

Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val

115 120 125

Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser

130 135 140

Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu

145 150 155 160

Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro

165 170 175

Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val

180 185 190

Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met

195 200 205

His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser

210 215 220

Pro Gly Gly Gly Gly Ser Gly Gly Gly Ser Ala Pro Thr Ser Ser Ser

225 230 235 240

Thr Lys Lys Thr Gln Leu Gln Leu Glu His Leu Leu Tyr Asp Leu Tyr

245 250 255

Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys Asn Pro Lys Leu Thr Arg

260 265 270

Met Leu Thr Phe Lys Phe Tyr Met Pro Lys Lys Ala Thr Glu Leu Lys

275 280 285

His Leu Gln Cys Leu Glu Glu Glu Leu Lys Pro Leu Glu Glu Val Leu

290 295 300

Asn Leu Ala Gln Ser Lys Asn Phe His Leu Arg Pro Arg Asp Leu Ile

305 310 315 320

Ser Asn Ile Asn Val Ile Val Leu Glu Leu Lys Gly Ser Glu Thr Thr

325 330 335

Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala Thr Ile Val Glu Phe Leu

340 345 350

Asn Arg Trp Ile Thr Phe Ser Gln Ser Ile Ile Ser Thr Leu Thr

355 360 365

<210> 183

<211> 367

<212> PRT

<213> 人工(Artificial)

<220>

<223> P-0476

<400> 183

Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly

1 5 10 15

Ala Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met

20 25 30

Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His

35 40 45

Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val

50 55 60

His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr

65 70 75 80

Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly

85 90 95

Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile

100 105 110

Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val

115 120 125

Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser

130 135 140

Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu

145 150 155 160

Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro

165 170 175

Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val

180 185 190

Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met

195 200 205

His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser

210 215 220

Pro Gly Gly Gly Gly Ser Gly Gly Gly Ser Ala Pro Thr Ser Ser Ser

225 230 235 240

Thr Lys Lys Thr Gln Leu Gln Leu Glu His Leu Leu Tyr Asp Leu Ile

245 250 255

Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys Asn Pro Lys Leu Thr Arg

260 265 270

Met Leu Thr Phe Lys Phe Tyr Met Pro Lys Lys Ala Thr Glu Leu Lys

275 280 285

His Leu Gln Cys Leu Glu Glu Glu Leu Lys Pro Leu Glu Glu Val Leu

290 295 300

Asn Leu Ala Gln Ser Lys Asn Phe His Leu Arg Pro Arg Asp Leu Ile

305 310 315 320

Ser Asn Ile Asn Val Ile Val Leu Glu Leu Lys Gly Ser Glu Thr Thr

325 330 335

Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala Thr Ile Val Glu Phe Leu

340 345 350

Asn Arg Trp Ile Thr Phe Ser Gln Ser Ile Ile Ser Thr Leu Thr

355 360 365

<210> 184

<211> 367

<212> PRT

<213> 人工(Artificial)

<220>

<223> P-0480

<400> 184

Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly

1 5 10 15

Ala Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met

20 25 30

Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His

35 40 45

Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val

50 55 60

His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr

65 70 75 80

Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly

85 90 95

Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile

100 105 110

Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val

115 120 125

Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser

130 135 140

Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu

145 150 155 160

Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro

165 170 175

Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val

180 185 190

Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met

195 200 205

His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser

210 215 220

Pro Gly Gly Gly Gly Ser Gly Gly Gly Ser Ala Pro Thr Ser Ser Ser

225 230 235 240

Thr Lys Lys Thr Gln Leu Gln Leu Glu His Leu Leu His Asp Leu Gln

245 250 255

Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys Asn Pro Lys Leu Thr Arg

260 265 270

Met Leu Thr Phe Lys Phe Tyr Met Pro Lys Lys Ala Thr Glu Leu Lys

275 280 285

His Leu Gln Cys Leu Glu Glu Glu Leu Lys Pro Leu Glu Glu Val Leu

290 295 300

Asn Leu Ala Gln Ser Lys Asn Phe His Leu Arg Pro Arg Asp Leu Ile

305 310 315 320

Ser Asn Ile Asn Val Ile Val Leu Glu Leu Lys Gly Ser Glu Thr Thr

325 330 335

Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala Thr Ile Val Glu Phe Leu

340 345 350

Asn Arg Trp Ile Thr Phe Ser Lys Ser Ile Ile Ser Thr Leu Thr

355 360 365

<210> 185

<211> 367

<212> PRT

<213> 人工(Artificial)

<220>

<223> P-0491

<400> 185

Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly

1 5 10 15

Ala Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met

20 25 30

Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His

35 40 45

Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val

50 55 60

His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr

65 70 75 80

Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly

85 90 95

Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile

100 105 110

Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val

115 120 125

Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser

130 135 140

Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu

145 150 155 160

Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro

165 170 175

Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val

180 185 190

Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met

195 200 205

His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser

210 215 220

Pro Gly Gly Gly Gly Ser Gly Gly Gly Ser Ala Pro Thr Ser Ser Ser

225 230 235 240

Thr Lys Lys Thr Gln Leu Gln Leu Glu His Leu Leu His Asp Leu Gln

245 250 255

Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys Asn Pro Lys Leu Thr Arg

260 265 270

Met Leu Thr Phe Lys Phe Tyr Met Pro Lys Lys Ala Thr Glu Leu Lys

275 280 285

His Leu Gln Cys Leu Glu Glu Glu Leu Lys Pro Leu Glu Glu Val Leu

290 295 300

Asn Leu Ala Gln Ser Lys Asn Phe His Leu Arg Pro Arg Asp Leu Ile

305 310 315 320

Ser Asn Ile Asn Val Ile Val Leu Glu Leu Lys Gly Ser Glu Thr Thr

325 330 335

Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala Thr Ile Val Glu Phe Leu

340 345 350

Asn Arg Trp Ile Thr Phe Ile Gln Ser Ile Ile Ser Thr Leu Thr

355 360 365

<210> 186

<211> 367

<212> PRT

<213> 人工(Artificial)

<220>

<223> P-0492

<400> 186

Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly

1 5 10 15

Ala Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met

20 25 30

Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His

35 40 45

Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val

50 55 60

His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr

65 70 75 80

Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly

85 90 95

Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile

100 105 110

Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val

115 120 125

Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser

130 135 140

Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu

145 150 155 160

Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro

165 170 175

Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val

180 185 190

Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met

195 200 205

His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser

210 215 220

Pro Gly Gly Gly Gly Ser Gly Gly Gly Ser Ala Pro Thr Ser Ser Ser

225 230 235 240

Thr Lys Lys Thr Gln Leu Gln Leu Glu His Leu Leu Asp Asp Leu Gln

245 250 255

Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys Asn Pro Lys Leu Thr Arg

260 265 270

Met Leu Thr Phe Lys Phe Tyr Met Pro Lys Lys Ala Thr Glu Leu Lys

275 280 285

His Leu Gln Cys Leu Glu Glu Glu Leu Lys Pro Leu Glu Glu Val Leu

290 295 300

Asn Leu Ala Gln Ser Lys Asn Phe His Leu Arg Pro Arg Asp Leu Ile

305 310 315 320

Ser Asn Ile Asn Val Ile Val Leu Glu Leu Lys Gly Ser Glu Thr Thr

325 330 335

Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala Thr Ile Val Glu Phe Leu

340 345 350

Asn Arg Trp Ile Thr Phe Ile Gln Ser Ile Ile Ser Thr Leu Thr

355 360 365

<210> 187

<211> 367

<212> PRT

<213> 人工(Artificial)

<220>

<223> P-0493

<400> 187

Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly

1 5 10 15

Ala Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met

20 25 30

Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His

35 40 45

Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val

50 55 60

His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr

65 70 75 80

Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly

85 90 95

Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile

100 105 110

Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val

115 120 125

Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser

130 135 140

Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu

145 150 155 160

Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro

165 170 175

Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val

180 185 190

Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met

195 200 205

His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser

210 215 220

Pro Gly Gly Gly Gly Ser Gly Gly Gly Ser Ala Pro Thr Ser Ser Ser

225 230 235 240

Thr Lys Lys Thr Gln Leu Gln Leu Glu His Leu Leu Leu Glu Leu Gln

245 250 255

Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys Asn Pro Lys Leu Thr Arg

260 265 270

Met Leu Thr Phe Lys Phe Tyr Met Pro Lys Lys Ala Thr Glu Leu Lys

275 280 285

His Leu Gln Cys Leu Glu Glu Glu Leu Lys Pro Leu Glu Glu Val Leu

290 295 300

Asn Leu Ala Gln Ser Lys Asn Phe His Leu Arg Pro Arg Asp Leu Ile

305 310 315 320

Ser Asn Ile Asn Val Ile Val Leu Glu Leu Lys Gly Ser Glu Thr Thr

325 330 335

Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala Thr Ile Val Glu Phe Leu

340 345 350

Asn Arg Trp Ile Thr Phe Ile Gln Ser Ile Ile Ser Thr Leu Thr

355 360 365

<210> 188

<211> 367

<212> PRT

<213> 人工(Artificial)

<220>

<223> P-0494

<400> 188

Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly

1 5 10 15

Ala Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met

20 25 30

Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His

35 40 45

Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val

50 55 60

His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr

65 70 75 80

Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly

85 90 95

Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile

100 105 110

Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val

115 120 125

Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser

130 135 140

Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu

145 150 155 160

Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro

165 170 175

Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val

180 185 190

Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met

195 200 205

His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser

210 215 220

Pro Gly Gly Gly Gly Ser Gly Gly Gly Ser Ala Pro Thr Ser Ser Ser

225 230 235 240

Thr Lys Lys Thr Gln Leu Gln Leu Glu His Leu Leu Leu Thr Leu Gln

245 250 255

Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys Asn Pro Lys Leu Thr Arg

260 265 270

Met Leu Thr Phe Lys Phe Tyr Met Pro Lys Lys Ala Thr Glu Leu Lys

275 280 285

His Leu Gln Cys Leu Glu Glu Glu Leu Lys Pro Leu Glu Glu Val Leu

290 295 300

Asn Leu Ala Gln Ser Lys Asn Phe His Leu Arg Pro Arg Asp Leu Ile

305 310 315 320

Ser Asn Ile Asn Val Ile Val Leu Glu Leu Lys Gly Ser Glu Thr Thr

325 330 335

Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala Thr Ile Val Glu Phe Leu

340 345 350

Asn Arg Trp Ile Thr Phe Ile Gln Ser Ile Ile Ser Thr Leu Thr

355 360 365

<210> 189

<211> 367

<212> PRT

<213> 人工(Artificial)

<220>

<223> P-0495

<400> 189

Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly

1 5 10 15

Ala Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met

20 25 30

Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His

35 40 45

Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val

50 55 60

His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr

65 70 75 80

Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly

85 90 95

Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile

100 105 110

Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val

115 120 125

Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser

130 135 140

Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu

145 150 155 160

Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro

165 170 175

Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val

180 185 190

Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met

195 200 205

His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser

210 215 220

Pro Gly Gly Gly Gly Ser Gly Gly Gly Ser Ala Pro Thr Ser Ser Ser

225 230 235 240

Thr Lys Lys Thr Gln Leu Gln Leu Glu His Leu Leu Tyr Asp Leu Gln

245 250 255

Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys Asn Pro Lys Leu Thr Arg

260 265 270

Met Leu Thr Phe Lys Phe Tyr Met Pro Lys Lys Ala Thr Glu Leu Lys

275 280 285

His Leu Gln Cys Leu Glu Glu Glu Leu Lys Pro Leu Glu Glu Val Leu

290 295 300

Asn Leu Ala Gln Ser Lys Asn Phe His Leu Arg Pro Arg Asp Leu Ile

305 310 315 320

Ser Asn Ile Asn Val Ile Val Leu Glu Leu Lys Gly Ser Glu Thr Thr

325 330 335

Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala Thr Ile Val Glu Phe Leu

340 345 350

Asn Arg Trp Ile Thr Phe Ile Glu Ser Ile Ile Ser Thr Leu Thr

355 360 365

<210> 190

<211> 374

<212> PRT

<213> 人工(Artificial)

<220>

<223> P-0496 (基准-2)

<400> 190

Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu His

1 5 10 15

Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys

20 25 30

Asn Pro Lys Leu Thr Arg Met Leu Thr Phe Lys Phe Tyr Met Pro Lys

35 40 45

Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys

50 55 60

Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu

65 70 75 80

Arg Pro Arg Asp Leu Ile Ser Arg Ile Asn Val Ile Val Leu Glu Leu

85 90 95

Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala

100 105 110

Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Ser Gln Ser Ile

115 120 125

Ile Ser Thr Leu Thr Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly

130 135 140

Gly Gly Gly Ser Gly Gly Gly Gly Ser Cys Pro Pro Cys Pro Ala Pro

145 150 155 160

Glu Ala Ala Gly Ala Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys

165 170 175

Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val

180 185 190

Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp

195 200 205

Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr

210 215 220

Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp

225 230 235 240

Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu

245 250 255

Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg

260 265 270

Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys

275 280 285

Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp

290 295 300

Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys

305 310 315 320

Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser

325 330 335

Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser

340 345 350

Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser

355 360 365

Leu Ser Leu Ser Pro Gly

370

<210> 191

<211> 367

<212> PRT

<213> 人工(Artificial)

<220>

<223> 基准-1

<400> 191

Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly

1 5 10 15

Ala Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met

20 25 30

Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His

35 40 45

Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val

50 55 60

His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr

65 70 75 80

Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly

85 90 95

Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile

100 105 110

Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val

115 120 125

Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser

130 135 140

Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu

145 150 155 160

Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro

165 170 175

Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val

180 185 190

Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met

195 200 205

His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser

210 215 220

Pro Gly Gly Gly Gly Ser Gly Gly Gly Ser Ala Pro Thr Ser Ser Ser

225 230 235 240

Thr Lys Lys Thr Gln Leu Gln Leu Glu His Leu Leu Leu Asp Leu Gln

245 250 255

Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys Asn Pro Lys Leu Thr Arg

260 265 270

Met Leu Thr Phe Lys Phe Tyr Met Pro Lys Lys Ala Thr Glu Leu Lys

275 280 285

His Leu Gln Cys Leu Glu Glu Glu Leu Lys Pro Leu Glu Glu Val Leu

290 295 300

Asn Leu Ala Gln Ser Lys Asn Phe His Leu Arg Pro Arg Asp Leu Ile

305 310 315 320

Ser Asn Ile Asn Lys Ile Val Leu Glu Leu Lys Gly Ser Glu Thr Thr

325 330 335

Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala Thr Ile Val Glu Phe Leu

340 345 350

Asn Arg Trp Ile Thr Phe Ser Gln Ser Ile Ile Ser Thr Leu Thr

355 360 365

<210> 192

<211> 367

<212> PRT

<213> 人工(Artificial)

<220>

<223> 基准-3

<400> 192

Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly

1 5 10 15

Ala Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met

20 25 30

Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His

35 40 45

Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val

50 55 60

His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr

65 70 75 80

Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly

85 90 95

Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile

100 105 110

Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val

115 120 125

Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser

130 135 140

Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu

145 150 155 160

Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro

165 170 175

Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val

180 185 190

Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met

195 200 205

His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser

210 215 220

Pro Gly Gly Gly Gly Ser Gly Gly Gly Ser Ala Pro Thr Ser Ser Ser

225 230 235 240

Thr Lys Lys Thr Gln Leu Gln Leu Glu His Leu Leu Leu Asp Leu Gln

245 250 255

Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys Asn Pro Lys Leu Thr Arg

260 265 270

Met Leu Thr Phe Lys Phe Tyr Met Pro Lys Lys Ala Thr Glu Leu Lys

275 280 285

His Leu Gln Cys Leu Glu Glu Glu Leu Lys Pro Leu Glu Glu Val Leu

290 295 300

Asn Leu Ala Gln Ser Lys Asn Phe His Leu Arg Pro Arg Asp Leu Ile

305 310 315 320

Ser Asp Ile Asn Val Ile Val Leu Glu Leu Lys Gly Ser Glu Thr Thr

325 330 335

Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala Thr Ile Val Glu Phe Leu

340 345 350

Asn Arg Trp Ile Thr Phe Ser Gln Ser Ile Ile Ser Thr Leu Thr

355 360 365

<210> 193

<211> 133

<212> PRT

<213> 人工(Artificial)

<220>

<223> IL-2 L19H/S125I/Q126E变体序列

<400> 193

Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu His

1 5 10 15

Leu Leu His Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys

20 25 30

Asn Pro Lys Leu Thr Arg Met Leu Thr Phe Lys Phe Tyr Met Pro Lys

35 40 45

Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys

50 55 60

Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu

65 70 75 80

Arg Pro Arg Asp Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu

85 90 95

Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala

100 105 110

Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Ile Glu Ser Ile

115 120 125

Ile Ser Thr Leu Thr

130

<210> 194

<211> 133

<212> PRT

<213> 人工(Artificial)

<220>

<223> IL-2 L19H/S125I/Q126K变体序列

<400> 194

Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu His

1 5 10 15

Leu Leu His Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys

20 25 30

Asn Pro Lys Leu Thr Arg Met Leu Thr Phe Lys Phe Tyr Met Pro Lys

35 40 45

Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys

50 55 60

Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu

65 70 75 80

Arg Pro Arg Asp Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu

85 90 95

Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala

100 105 110

Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Ile Lys Ser Ile

115 120 125

Ile Ser Thr Leu Thr

130

<210> 195

<211> 133

<212> PRT

<213> 人工(Artificial)

<220>

<223> IL-2 L19Q/Q126K变体序列

<400> 195

Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu His

1 5 10 15

Leu Leu Gln Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys

20 25 30

Asn Pro Lys Leu Thr Arg Met Leu Thr Phe Lys Phe Tyr Met Pro Lys

35 40 45

Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys

50 55 60

Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu

65 70 75 80

Arg Pro Arg Asp Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu

85 90 95

Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala

100 105 110

Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Ser Lys Ser Ile

115 120 125

Ile Ser Thr Leu Thr

130

<210> 196

<211> 133

<212> PRT

<213> 人工(Artificial)

<220>

<223> IL-2 L19Q/S125I/Q126E变体序列

<400> 196

Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu His

1 5 10 15

Leu Leu Gln Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys

20 25 30

Asn Pro Lys Leu Thr Arg Met Leu Thr Phe Lys Phe Tyr Met Pro Lys

35 40 45

Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys

50 55 60

Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu

65 70 75 80

Arg Pro Arg Asp Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu

85 90 95

Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala

100 105 110

Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Ile Glu Ser Ile

115 120 125

Ile Ser Thr Leu Thr

130

<210> 197

<211> 133

<212> PRT

<213> 人工(Artificial)

<220>

<223> IL-2 L19Q/S125I/Q126K变体序列

<400> 197

Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu His

1 5 10 15

Leu Leu Gln Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys

20 25 30

Asn Pro Lys Leu Thr Arg Met Leu Thr Phe Lys Phe Tyr Met Pro Lys

35 40 45

Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys

50 55 60

Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu

65 70 75 80

Arg Pro Arg Asp Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu

85 90 95

Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala

100 105 110

Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Ile Lys Ser Ile

115 120 125

Ile Ser Thr Leu Thr

130

<210> 198

<211> 367

<212> PRT

<213> 人工(Artificial)

<220>

<223> P-0511

<400> 198

Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly

1 5 10 15

Ala Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met

20 25 30

Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His

35 40 45

Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val

50 55 60

His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr

65 70 75 80

Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly

85 90 95

Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile

100 105 110

Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val

115 120 125

Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser

130 135 140

Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu

145 150 155 160

Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro

165 170 175

Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val

180 185 190

Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met

195 200 205

His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser

210 215 220

Pro Gly Gly Gly Gly Ser Gly Gly Gly Ser Ala Pro Thr Ser Ser Ser

225 230 235 240

Thr Lys Lys Thr Gln Leu Gln Leu Glu His Leu Leu His Asp Leu Gln

245 250 255

Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys Asn Pro Lys Leu Thr Arg

260 265 270

Met Leu Thr Phe Lys Phe Tyr Met Pro Lys Lys Ala Thr Glu Leu Lys

275 280 285

His Leu Gln Cys Leu Glu Glu Glu Leu Lys Pro Leu Glu Glu Val Leu

290 295 300

Asn Leu Ala Gln Ser Lys Asn Phe His Leu Arg Pro Arg Asp Leu Ile

305 310 315 320

Ser Asn Ile Asn Val Ile Val Leu Glu Leu Lys Gly Ser Glu Thr Thr

325 330 335

Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala Thr Ile Val Glu Phe Leu

340 345 350

Asn Arg Trp Ile Thr Phe Ile Glu Ser Ile Ile Ser Thr Leu Thr

355 360 365

<210> 199

<211> 367

<212> PRT

<213> 人工(Artificial)

<220>

<223> P-0512

<400> 199

Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly

1 5 10 15

Ala Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met

20 25 30

Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His

35 40 45

Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val

50 55 60

His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr

65 70 75 80

Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly

85 90 95

Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile

100 105 110

Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val

115 120 125

Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser

130 135 140

Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu

145 150 155 160

Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro

165 170 175

Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val

180 185 190

Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met

195 200 205

His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser

210 215 220

Pro Gly Gly Gly Gly Ser Gly Gly Gly Ser Ala Pro Thr Ser Ser Ser

225 230 235 240

Thr Lys Lys Thr Gln Leu Gln Leu Glu His Leu Leu His Asp Leu Gln

245 250 255

Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys Asn Pro Lys Leu Thr Arg

260 265 270

Met Leu Thr Phe Lys Phe Tyr Met Pro Lys Lys Ala Thr Glu Leu Lys

275 280 285

His Leu Gln Cys Leu Glu Glu Glu Leu Lys Pro Leu Glu Glu Val Leu

290 295 300

Asn Leu Ala Gln Ser Lys Asn Phe His Leu Arg Pro Arg Asp Leu Ile

305 310 315 320

Ser Asn Ile Asn Val Ile Val Leu Glu Leu Lys Gly Ser Glu Thr Thr

325 330 335

Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala Thr Ile Val Glu Phe Leu

340 345 350

Asn Arg Trp Ile Thr Phe Ile Lys Ser Ile Ile Ser Thr Leu Thr

355 360 365

<210> 200

<211> 367

<212> PRT

<213> 人工(Artificial)

<220>

<223> P-0513

<400> 200

Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly

1 5 10 15

Ala Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met

20 25 30

Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His

35 40 45

Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val

50 55 60

His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr

65 70 75 80

Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly

85 90 95

Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile

100 105 110

Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val

115 120 125

Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser

130 135 140

Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu

145 150 155 160

Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro

165 170 175

Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val

180 185 190

Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met

195 200 205

His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser

210 215 220

Pro Gly Gly Gly Gly Ser Gly Gly Gly Ser Ala Pro Thr Ser Ser Ser

225 230 235 240