CN110799543A - 肝细胞癌的免疫治疗 - Google Patents
肝细胞癌的免疫治疗 Download PDFInfo
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- CN110799543A CN110799543A CN201880042740.8A CN201880042740A CN110799543A CN 110799543 A CN110799543 A CN 110799543A CN 201880042740 A CN201880042740 A CN 201880042740A CN 110799543 A CN110799543 A CN 110799543A
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Abstract
本文公开的是用于在受试者中对肝细胞癌进行预防、延迟其进展或治疗的方法，其包括向有此需要的受试者施用治疗有效量的抗PD‑1抗体，其为特异性结合人PD‑1的抗体或其抗原结合片段。
Description
对相关申请的交叉引用
本申请要求美国临时专利申请号62/524,967和国际专利申请号PCT/CN2017/090397的优先权的权益，将其中每一篇的公开内容通过提述以其整体由此并入用于所有目的。
技术领域
本文公开的是用于患有肝细胞癌(HCC)的患者的免疫治疗的方法，其包括向所述受试者施用抗PD-1抗体，其经特异性工程改造以最小化巨噬细胞上的FcγR结合来消除抗体依赖性吞噬作用。
背景技术
肝细胞癌(HCC)是世界上最常见的癌症之一，并且由于其恶性，是全球癌症相关死亡率的第三大原因。HCC形成与患有慢性肝炎的患者中，或者是由于慢性乙型或丙型肝炎病毒感染，或者是由于摄入黄曲霉毒素后的炎症，或者是过量饮酒。
大多数HCC患者首先被诊断患有晚期疾病或存在有肝功能差的患者，从而阻止了潜在的治愈性治疗的使用。患有晚期疾病的患者的治疗选择仅限于化疗栓塞或全身治疗，其中包括索拉非尼(sorafenib)，这是唯一获得批准的一线治疗，疗效适中且毒性相当大[Samonakis DN,Kouroumalis EA.Systemic treatment for hepatocellular carcinoma:Still unmet expectations.World J Hepatol.2017；9(2):80–90.]。尽管这些方法已经产生改善的临床结果，但对于患有晚期疾病患者，HCC患者中的存活率仍然不到一年，并且患者在潜在的治愈性手术和消融后仍然存在疾病复发的高风险。由于肝功能障碍，这些患者通常不能很好地耐受有毒化学疗法，因此新型免疫疗法有望用于晚期HCC。抗免疫检查点抑制受体，程序性细胞死亡-1(PD-1)的单克隆抗体已经展现了跨多种恶性肿瘤的抗肿瘤活性[Topalian SL,Hodi FS,Brahmer JR,et al.Safety,activity,and immune correlatesof anti-PD-1antibody in cancer.N Engl J Med.2012；366(26):2443–2454.]，包括HCC[El-Khoueiry AB,Sangro B,Yau T,et al.Nivolumab in patients with advancedhepatocellular carcinoma(CheckMate 040):an open-label,non-comparative,phase1/2dose escalation and expansion trial.Lancet.2017；389(10088):2492–2502]。然而，据报道，Nivolumab的HBV感染组的响应率相对较低(7％)[M.Kudo,Immune CheckpointBlockade in Hepatocellular Carcinoma:2017Update,Liver Cancer2017；6:1-12]。到目前为止，HBV感染的HCC与预后不良有关。因此，需要一种新的用于晚期HCC的，特别是对感染的HCC具有高响应率的免疫疗法。
发明概述
本文公开的是用于患有肝细胞癌(HCC)的患者的免疫治疗的方法，其包括向所述患者施用治疗有效量的抗PD-1抗体或其抗原结合片段。在一些实施方案中，所述抗PD-1抗体或其抗原结合片段经特异性工程改造以最小化巨噬细胞上的FcγR结合来消除抗体依赖性吞噬作用。
在一个实施方案中，HCC是晚期HCC和/或转移性HCC。在其他实施方案中，晚期HCC是HBV感染的HCC，或HCV感染的HCC，或HBV/HCV共感染的HCC。优选地，晚期HCC是晚期HBV感染的HCC，转移性HBV感染的HCC，HCV感染的HCC或转移性HCV感染的HCC。
在一些实施方案中，抗PD-1抗体是WO2015/035606A1或美国专利号8,735,553中公开的抗体，其全部内容通过提述并入本文。WO2015/035606A1和美国专利号8,735,553中公开的抗体特异性结合程序性死亡-1(PD-1)并抑制免疫细胞中PD-1介导的细胞信号传导和活性。在一些实施方案中，抗体结合其配体(程序性死亡-配体1，PD-L1)结合所需的一组氨基酸残基。特别地，抗PD-1抗体是人源化单克隆抗体，其包含重链可变区(Vh)和轻链可变区(Vk)(分别包含SEQ ID No 24和SEQ ID No 26)和IgG4重链效应子或恒定结构域(包含SEQID NO:88)，以下称为Mab-1，其特异性结合PD-1。在一些实施方案中，抗体结合PD-1残基，包括K45和I93；或，I93，L95和P97，并抑制免疫细胞中PD-1介导的细胞信号传导和活性，该抗体与其配体结合所需的一组氨基酸残基结合。
已经证明本文公开的免疫治疗的方法可预防HCC、延迟HCC进展、减轻HCC并因此治疗HCC，或甚至晚期HCC，特别是感染的晚期HCC，并且本文公开的抗PD-1抗体的毒性概况(profile)证明了不良事件(AE)通常严重程度低，可控制且可逆。因此，本公开提供了相对于其他PD-1抗体在HCC中具有卓越效果的PD-1抗体。
本申请的发明人已经发现，在患有晚期HCC的预治疗的患者中，使用Mab-1的治疗通常是良好耐受的。初步安全性概况和抗肿瘤活性支持Mab-1在患有晚期HCC的患者中(特别是在患有感染性HCC，包括HBV感染的HCC、HCV感染的HCC和HBV/HCV共感染的HCC的患者中)的持续开发。
附图说明
图1显示了本申请中使用的抗PD-1抗体的T细胞清除的潜在机制，即缺乏或降低的FcγR结合防止巨噬细胞介导的T细胞清除。
图2显示了1a/1b期研究的研究设计的示意图。
图3显示1a/1b期研究中肝炎病毒感染状态的肿瘤大小的最佳变化。
图4显示了1a/1b期研究中的治疗持续时间和响应。
图5显示了在1a/1b期研究中具有部分响应的三名患者的基线和最近的CT评估。
图6显示1a/1b期研究中肿瘤负荷随时间的变化。
图7显示1a/1b期研究中甲胎蛋白(AFP)从基线的变化。
图8显示了3期研究的研究设计。
发明详述
缩写
在本文公开的详细描述和实施例中，将使用表1中提供的以下缩写：
表1.缩写
定义
除非在本文件的其他地方具体限定，否则本文使用的所有其他技术和科学术语具有本发明所属领域的普通技术人员通常理解的含义。
如本文(包括所附专利申请范围)所使用的，除非上下文另有明确规定，否则诸如“一”、“一个”和“该”的单数形式的词语包括其对应的复数形式。
本文的术语“抗体”以最广泛的意义使用，并且具体涵盖抗体(包括全长单克隆抗体)和抗体片段，只要它们识别PD-1。抗体分子通常是单特异性的，但也可以描述为不同特异性的(idiospecific)、异种特异性的或多特异性的。抗体分子通过特异性结合位点与抗原上的特异性抗原决定簇或表位结合。“抗体片段”或“抗原结合片段”包含全长抗体的一部分，通常是其抗原结合区或可变区。抗体片段的实例包括Fab、Fab'、F(ab')2和Fv片段；双抗体(diabody)；线性抗体；单链抗体分子；和由抗体片段形成的多特异性抗体。
本文中的术语“单克隆抗体”或“mAb”或“Mab”意指基本上同质的抗体的群体，即群体中包含的抗体分子在氨基酸序列上是相同的，除了少量出现的可能的天然发生的突变。相反，常规(多克隆)抗体制剂通常包括在其可变结构域(特别是其CDR，其通常对不同表位为特异性的)中具有不同氨基酸序列的多种不同抗体。修饰语“单克隆”表示抗体的特征是从基本上同质的抗体群体获得的，并且不应解释为需要通过任何特定方法产生抗体。单克隆抗体(mAb)可通过本领域技术人员已知的方法获得。参见，例如，Kohler et al(1975)；U.S.Pat.No.4,376,110；Ausubel et al(1987-1999)；Harlow et al(1988)；和Colliganet al(1993)。本文公开的mAb可以是任何免疫球蛋白类，包括IgG、IgM、IgD、IgE、IgA及其任何亚类。产生mAb的杂交瘤可以在体外或体内培养。在体内产生中可以获得高效价的mAb，其中将来自单个杂交瘤的细胞腹膜内注射到小鼠中，诸如原始诱导的Balb/c小鼠，以产生含有高浓度所需mAb的腹水。可以使用本领域技术人员熟知的柱层析方法从这样的腹水，或从培养上清液中纯化同种型IgM或IgG的MAb。
通常，碱性抗体结构单元包含四聚体。每个四聚体包括两对相同的多肽链，每对具有一条“轻链”(约25kDa)和一条“重链”(约50-70kDa)。每条链的氨基末端部分包括主要负责抗原识别的约100至110或更多氨基酸的可变区。重链的羧基末端部分可以定义为主要负责效应子功能的恒定区。通常，人轻链被分类为κ和λ轻链。此外，人重链通常分类为α、δ、ε、γ或μ，并且分别将抗体的同种型定义为IgA、IgD、IgE、IgG和IgM。在轻链和重链内，可变区和恒定区通过约12个或更多个氨基酸的“J”区连接，重链还包括约10个以上氨基酸的“D”区。
每个轻链/重链(Vk/Vh)对的可变区形成抗体结合位点。因此，一般而言，完整抗体具有两个结合位点。除了双功能或双特异性抗体外，一般而言两个结合位点是相同的。
一般地，重链和轻链的可变结构域包含三个高变区，也称为“互补决定区(CDR)”，其位于相对保守的框架区(FR)内。CDR通常由框架区对齐，使得能够结合特异性表位。一般而言，从N末端到C末端，轻链和重链可变结构域均包含FR-1、CDR-1、FR-2、CDR-2、FR-3、CDR-3和FR-4。一般地，每个结构域的氨基酸分配符合免疫学感兴趣的蛋白质序列的定义，Kabat,et al.National Institutes of Health,Bethesda,Md.5th ed.,NIH Publ.No.91-3242(1991)；Kabat(1978)Adv.Prot.Chem.32:1-75；Kabat,et al.,(1977)J.Biol.Chem.252:6609-6616；Chothia,et al,(1987)J.Mol.Biol.196:901-917或Chothia,et al,(1989)Nature 342:878-883。
术语“高变区”是指抗体中负责抗原结合的氨基酸残基。高变区包含来自“互补决定区”或“CDR”的氨基酸残基(即，轻链可变结构域中的CDR-L1、CDR-L2和CDR-L3和重链可变结构域中的CDR-H1、CDR-H2和CDR-H3)。在)。参见，Kabat et al.(1991)Sequences ofProteins of Immunological Interest,5th Ed.Public Health Service,NationalInstitutes of Health,Bethesda,Md.(通过序列定义抗体的CDR区)；还参见Chothia andLesk(1987)J.Mol.Biol.196:901-917(通过结构定义抗体的CDR区)。术语“框架”或“FR”残基意指除了本文定义为CDR残基的高变区残基之外的那些可变结构域残基。
除非另有说明，“抗体片段”或“抗原结合片段”意指抗体的抗原结合片段，即保留与全长抗体结合的抗原特异性结合的能力的抗体片段，例如保留一个或多个CDR区的片段。抗体结合片段的实例包括但不限于Fab、Fab'、F(ab')2和Fv片段；双抗体；线性抗体；单链抗体分子，例如sc-Fv；纳米抗体和由抗体片段形成的多特异性抗体。
“特异性地结合”特定靶蛋白的抗体是表现出与其他蛋白质相比优先结合该靶标的抗体，但该特异性不需要绝对结合特异性。如果抗体的结合决定了样品中靶蛋白的存在，例如，没有产生不希望的结果，诸如假阳性，则抗体被认为是对其预期靶标为“特异性的”。可用于本发明的抗体或其结合片段会以比非靶蛋白的亲和力高2倍，优选至少10倍，更优选至少20倍，和最优选至少100倍的亲和力结合至靶蛋白。将本文的抗体称作与包含给定氨基酸序列(例如成熟人PD-1分子的氨基酸序列)的多肽特异性结合，如果它与包含该序列的多肽结合但不与缺乏该序列的蛋白质结合。
本文中的术语“人抗体”意指仅包含人免疫球蛋白蛋白质序列的抗体。如果在小鼠、小鼠细胞或源自小鼠细胞的杂交瘤中产生，人抗体可含有鼠碳水化合物链。类似地，“小鼠抗体”或“大鼠抗体”意指分别仅包含小鼠或大鼠免疫球蛋白序列的抗体。
术语“人源化抗体”意指含有来自非人(例如鼠)抗体以及人抗体的序列的抗体形式。这样的抗体含有源自非人免疫球蛋白的最小序列。一般而言，人源化抗体会包含基本上全部的至少一个，通常为两个可变结构域，其中所有或基本上所有高变环对应于非人免疫球蛋白和所有或基本上所有FR区的那些是人免疫球蛋白序列的那些。人源化抗体任选地还会包含至少一部分免疫球蛋白恒定区(Fc)，通常是人免疫球蛋白的恒定区。当有必要区分人源化抗体与亲本啮齿动物抗体时，将前缀“hum”，“hu”或“h”添加到抗体克隆名称中。人源化形式的啮齿动物抗体会通常包含亲本啮齿动物抗体的相同CDR序列，但是可包括某些氨基酸取代以增加亲和力，增加人源化抗体的稳定性，或出于其他原因。
术语“肝细胞癌(HCC)”具有其在本领域中的一般含义，并且指在肝细胞中发展的癌症。一般而言，肝癌表示肝细胞癌。HCC可能由过量饮酒(酒精性脂肪性肝炎)或黄曲霉毒素摄入后的炎症(非酒精性脂肪性肝炎，有时称为NASH)引起。HCC可能由感染(诸如乙型肝炎病毒(有时称为HBV感染的HCC)或丙型肝炎病毒(有时称为HCV感染的HCC))或由HBV和HCV一起感染(有时称为HBV/HCV共感染的HCC)引起。在一些实施方案中，HCC由慢性乙型肝炎、慢性丙型肝炎、黄曲霉毒素、酒精中毒、肝脏的肝硬化、非酒精性脂肪性肝炎、血色素沉着症、α1-抗胰蛋白酶缺乏威尔逊氏病、2型糖尿病、血友病等发展而来。在一些实施方案中，HCC是早期HCC、非转移性HCC、原发性HCC、晚期HCC、局部晚期HCC、转移性HCC、缓解期HCC或复发性HCC。
术语“治疗(treatment)”或“治疗(treating)”是获得有益或所希望的临床结果的方法，包括但不限于以下一种或多种：减轻由疾病引起的一种或多种症状，减小疾病程度，稳定疾病(例如，预防或延迟疾病的恶化)，预防或延迟疾病的传播(例如，转移)，预防或延迟疾病的复发，延迟或减缓疾病的进展，改善疾病状态，提供疾病的缓解(部分或全部)，减少治疗疾病所需的一种或多种其他药物的剂量，延迟疾病的进展，提高生活质量，和/或延长生存期。因此，术语“治疗”也包括HCC病理结果的减少。本文公开的方法涵盖了这些治疗方面中的任何一个或多个。
术语“患者”在本文中可与术语“受试者”等互换使用。在某些实施方案中，患者是人类患者。在特定实施方案中，患者是已被诊断患有HCC，需要HCC的治疗和/或处于HCC风险中的人类患者。
除非另有说明，术语“CDR”意指使用Kabat编号系统定义的免疫球蛋白可变区中的互补决定区。
抗PD-1抗体
如本文所公开的，抗PD-1抗体是抗体或其抗原结合片段，其特异性地结合人PD-1。
如本文所公开的，抗PD-1抗体是包含重链可变区(Vh)和轻链可变区(Vk)的抗体，所述重链可变区和轻链可变区含有表2中提供的互补决定区(CDR)：
表2.本文提供的示例性抗体的CDR
如本文所公开的，在一些实施方案中，抗PD-1抗体是包含重链可变区(Vh)和轻链可变区(Vk)的抗体，所述重链可变区和轻链可变区含有表3中提供的CDR的任何组合：
表3.本文提供的示例性抗体的CDR
如本文所公开的，抗PD-1抗体是包含重链可变区(Vh)和轻链可变区(Vk)的抗体，所述重链可变区和轻链可变区包含选自表4中提供的序列的序列：
表4.本文提供的示例性抗体的Vh和Vk序列
在一些实施方案中，本文提供的抗PD-1抗体包含重链效应子或恒定结构域，其包括减少与FcγR结合的氨基酸突变。抗体可以进一步包含效应子或恒定域中的一个或多个突变，其提供增强的稳定性。在一些实施方案中，抗体包含IgG4 Fc区。在一些实施方案中，抗体包含IgG4 Fc区，其包含一个或多个减少与FcγR结合的氨基酸突变。例如，在一些实施方案中，抗体包含IgG4Fc区，其包含减少或消除与FcγRI、FcγRIIA、FcγRIIB、FcγRIIIA和/或FcγRIIIB结合的突变。
在一些实施方案中，抗体包含在第228位(EU编号系统)具有丝氨酸至脯氨酸突变的IgG4 Fc区。在一些实施方案中，该突变称为S228P突变。在一些实施方案中，抗体包含在第233、234、235、265、309和409位(EU编号系统)中的一个或多个处具有突变的IgG4 Fc区。例如，在一些实施方案中，抗体包含在228和至少一个其他位置具有突变的IgG4区，其中所述至少一个其他突变导致与一个或多个FcγR的结合降低。在进一步的实施方案中，抗体包含IgG4区，其在228位和至少2个、至少3个、至少4个、至少5个或至少6个另外的位置具有突变，其中一个或多个另外的突变导致与一种或多种FcγR的结合降低。在一些实施方案中，抗体包含在234和235位具有突变的IgG4区。在一些实施方案中，抗体包含在233、234和235位具有突变的IgG4区。在一些实施方案中，抗体包含在234、235和265处具有突变的IgG4区。在一些实施方案中，抗体包含在233、234、235和265位具有突变的IgG4区。在一些实施方案中，抗体包含在234、235、265和409位具有突变的IgG4区。在一些实施方案中，抗体包含在233、234、235、265和409位具有突变的IgG4区。在一些实施方案中，抗体包含在234、235、265、309和409位具有突变的IgG4区。在一些实施方案中，抗体包含在第233、234、235、265、309和409位具有突变的IgG4区。第234位的突变可以是苯丙氨酸至缬氨酸的取代或苯丙氨酸至丙氨酸的取代。235位的突变可以是亮氨酸至丙氨酸的取代。第233位的突变可以是谷氨酸至脯氨酸的取代。第265位的突变可以是天冬氨酸至缬氨酸取代或天冬氨酸至苏氨酸的取代。第309位的突变可以是亮氨酸至缬氨酸的取代。第409位的突变可以是精氨酸至赖氨酸、苏氨酸或甲硫氨酸的取代。示例性的IgG4 Fc区在下表5中提供。
表5.示例性IgG4 Fc区序列
如本文所公开的，抗PD-1抗体是包含含有SEQ ID NO:83-88中任一个的IgG4重链效应子或恒定结构域的抗体。
如在以上各方面中所公开的，抗PD-1抗体是含有包含上述结构域的F(ab)或F(ab)2的抗体，其包括重链可变区(Vh)，轻链可变区(Vk)和IgG4重链效应子或恒定结构域。
如本文所公开的，抗PD-1抗体是包含重链可变区(Vh)和轻链可变区(Vk)，和包含选自SEQ ID NO:83-88和91-106的序列的IgG4重链效应子或恒定结构域的抗体，其中重链可变区(Vh)和轻链可变区(Vk)包含选自表6中提供的序列的序列：
表6.示例性的Vh和Vk序列
如本文所公开的，在一些实施方案中，抗PD-1抗体是包含分别根据SEQ ID NO:11、32和13的重链CDR-H1、CDR-H2和CDR-H3；分别根据SEQ ID NO:61、15和16的轻链CDR-L1，CDR-L2和CDR-L3；和包含SEQ ID NO:88的IgG4重链效应子或恒定结构域的抗体。
如本文所公开的，在一些实施方案中，抗PD-1抗体是包含重链可变区(Vh)和轻链可变区(Vk)，以及包含SEQ ID NO:88的IgG4重链效应子或恒定结构域的抗体，其中重链可变区(Vh)和轻链可变区(Vk)分别包含SEQ ID NO:24和SEQ ID NO:26。
如本文所公开的，在一些实施方案中，抗PD-1抗体是经独特地工程改造的人源化IgG4单克隆抗体，具有针对PD-1的高亲和力和结合特异性，经特异性地工程改造以最小化巨噬细胞上的FcγR结合以消除抗体依赖性吞噬作用，即一种T细胞清除的潜在机制。
本文公开的抗PD1抗体及其抗体片段可根据WO2015/035606A1或美国专利号8,735,553的公开制备，其全部公开内容明确地通过提述并入本文。
治疗方法
在本文公开的治疗方法中，将一定剂量的抗PD-1抗体静脉内施用于患有HCC的患者。在一些实施方案中，患有HCC的患者先前未用PD-1或PD-L1靶向治疗治疗。在一些实施方案中，患有HCC的患者先前用另一种治疗剂(例如索拉非尼)治疗。
在一些实施方案中，本公开提供了在有此需要的受试者中治疗HCC的方法，该方法包括向受试者施用抗PD-1抗体或其抗原结合片段，其中所述抗体经工程改造以减少、最小化或消除巨噬细胞或其他抗原呈递细胞上的FcγR结合。在一些实施方案中，抗体包含本文提供的工程改造的IgG4区。例如，在一些实施方案中，抗体包含工程改造的IgG4区，其具有选自SEQ ID NO:83-88和91-106的氨基酸序列。在一些实施方案中，抗体包含分别根据SEQID NO:11、32和13的重链CDR1、CDR2和CDR3序列；分别根据SEQ ID NO:61、15和16的轻链CDR1、CDR2和CDR3序列；以及已被工程改造为具有降低的FcγR的IgG4区域。在一些实施方案中，抗体包含分别根据SEQ ID NO:11、32和13的重链CDR1、CDR2和CDR3序列；分别根据SEQID NO:61、15和16的轻链CDR1、CDR2和CDR3序列；以及具有选自SEQ ID NO:83-88和91-106的氨基酸序列的IgG4区。在一些实施方案中，抗体分别包含根据SEQ ID NO:24和26的重链和轻链可变区序列，以及已经工程化以具有降低的FcγR的IgG4区。在一些实施方案中，抗体包含分别根据SEQ ID NO:24和26的重链和轻链可变区序列，以及具有选自SEQ ID NO:83-88和91-106的氨基酸序列的IgG4区。在一些实施方案中，抗PD-1抗体是Mab-1。
在一些实施方案中，本公开提供了本文提供的抗体，其用于治疗患者中的HCC。在一些实施方案中，本公开提供了本文提供的抗体，其用于HCC患者中的免疫治疗。在一些实施方案中，本公开提供了本文提供的抗体，其用于制备用于治疗HCC的药物。在一些实施方案中，本公开提供了本文提供的抗体，其用于制备用于HCC患者中的免疫治疗的药物。
在一些实施方案中，本公开提供了用于治疗患者中的HCC的方法，其包括施用本文提供的抗体，其中相对于未接受所述抗体的患者，抗体的施用提供了以下改善：总存活率(OS)、客观响应率(ORR)、完全响应率(CR)、部分缓解率(PR)、稳定疾病(SD)、无进展存活(PFS)、无病存活(DFS)、无事件存活(EFS)、反应持续时间(DoR)、进展时间(TTP)、疾病控制率(DCR)、临床受益率(CBR)或它们的任何组合。在特定的实施方案中，抗体的施用提供了OS的改善。
在一些实施方案中，OS定义为从临床试验随机化到任何原因死亡的时间。在一些实施方案中，ORR定义为肿瘤尺寸减小预定量和达到最小时间段的患者的百分比。在一些实施方案中，CR定义为所有癌症指征响应于治疗而消失。在一些实施方案中，PR定义为可检测疾病(例如，肿瘤大小)的至少30％的减少。在一些实施方案中，SD被定义为既没有疾病的充分减少而有资格作为PR，也没有疾病的充分增加而有资格作为进行性疾病(例如，可检测疾病的不到25％的增加至30％的减少(例如，肿瘤大小))。在一些实施方案中，TTP定义为从随机化到肿瘤进展的时间。在一些实施方案中，PFS定义为从随机化到肿瘤进展或到死亡发生的时间。在一些实施方案中，DFS定义为从随机化到肿瘤复发或任何原因死亡的时间。在一些实施方案中，EFS定义为由于任何原因从随机化到疾病进展、死亡或中断治疗的时间。在一些实施方案中，DoR定义为从记录肿瘤响应到疾病进展的时间段。在一些实施方案中，DCR和CBR均定义为已达到完全响应、部分响应或稳定疾病的患者的百分比。
在一些实施方案中，RECIST v.1.1(实体瘤中的响应评估标准)，一组公布的规则，其定义治疗期间或之后癌症患者中的疾病响应、进展或稳定性，其用于评估用本文提供的抗体治疗的患者。
在一些实施方案中，本公开提供了治疗患有HCC的患者的方法，其包括向患者施用本文提供的抗体，其中所述方法实现至少约20％、至少约25％、至少约30％、至少约35％、至少约40％、至少约45％、至少约50％、至少约55％、至少约60％、至少约65％、至少约70％、至少约75％、至少约80％或更多的ORR和/或CR和/或PR和/或DCR和/或CBR(或肿瘤患者的任何其他已知的基于比率的结果测量值)。
在一些实施方案中，本公开提供了治疗患者中的HCC的方法，其包括施用本文提供的抗体，其中所述抗体的施用相对于安慰剂治疗或相对于另一种抗肿瘤或抗癌治疗提供了统计学上显著的治疗效果。在一些实施方案中，统计学上显著的效果包括治疗功效与对毒性或耐受性参数的统计学显著影响的组合。在一些实施方案中，统计学上显著的效果进一步包含改善的OS、ORR、CR、PR、SD、PFS、DFS、EFS、DoR、TTP、DCR、CBR或它们的任何组合。在一些实施方案中，与索拉非尼相比，本文提供的方法提供统计学上显著的效果。在一些实施方案中，本文提供的方法包括施用约200mg IV Q3W的本文提供的抗体(例如，Mab-1)，其中与口服BID施用约400mg索拉非尼相比，所述方法提供了统计学显著的效果。在一些实施方案中，与另外的PD-1或PD-L1靶向治疗相比，本文提供的方法提供了统计学上显著的效果。术语“统计学上显著的治疗效果”等指导致受试者中的临床或医学改善的治疗结果。“统计上显著的”意指结果不可能偶然发生。统计显著性可通过本领域已知的任何方法确定。常用的重要度量包括p值，如果零假设为真，则p值是观察事件会发生的频率或概率。如果获得的p值小于显著性水平，则否定零假设。在简单的情况下，显著性水平定义为p值为0.05或更小。
在一些实施方案中，抗PD-1抗体以0.5-10mg/kg QW，或Q2W，或Q3W或Q4W的剂量施用。在本文的一些实施方案中，抗PD-1抗体是Mab-1，并且Mab-1以0.5-10mg/kg QW或Q2W或Q3W的剂量施用。优选地，Mab-1以0.5-5mg/kg Q2W，5-10mg/kg Q2W或2-5mg/kg Q3W的剂量施用。最优选地，Mab-1以0.5mg/kg Q2W，5mg/kg Q2W，10mg/kg Q2W，2mg/kg Q3W或5mg/kgQ3W的剂量肠胃外施用。
在一些实施方案中，本公开提供了用于治疗HCC的方法，其包括以约50mg、约75mg、约100mg、约125mg、约150mg、约175mg、约200mg、约225mg、约250mg、约300mg、约325mg、约350mg、约375mg、约400mg、约425mg、约450mg、约475mg或约500mg的剂量施用本文提供的抗PD-1抗体。在一些实施方案中，每天，每隔一天、每3天、每4天、每5天、每6天或每7天施用抗体。在一些实施方案中，每周、每10天、每2周、每3周、每4周、每5周、每6周、每7周或每8周施用抗体。在一些实施方案中，每月或每隔一个月施用抗体。在一些实施方案中，根据患者的临床阶段、实现的治疗效果和其他患者特征，将抗体一次或多次施用于受试者，和/或以增加或减少的抗体剂量施用。在特定实施方案中，将抗体施用于受试者QW、Q2W、Q3W或Q4W。
在一些实施方案中，药物组合物的施用途径根据已知方法，例如，通过静脉内、腹膜内、脑内(实质内)、脑室内、肌内、皮下、眼内、动脉内、门内或病灶内途径注射；通过持续释放系统或通过植入装置。在某些实施方案中，所述组合物可以通过推注(bolusinjection)或持续地通过输注或通过植入装置施用。
在某些实施方案中，本公开提供了用于治疗HCC的方法，其包括每3周(Q3W)以约200mg的剂量静脉内(IV)向有此需要的受试者施用本文提供的抗PD-1抗体。
实施例
实施例1：在患有晚期肝细胞癌(HCC)患者中对Mab-1的1A/1B期研究
研究设计-患者鉴别(patient differentiation)和招募
研究设计的目的是通过选择肿瘤来招募HCC患者用于推荐的2期剂量(RP2D)确定和初步鉴别(由1A期和1B期组成)。研究设计详见图2。
在1A期中，10mg/kg Q2W的Mab-1(除非另有说明，临床试验中使用的抗体是Mab-1)是最大施用剂量；未达到最大耐受剂量(MTD)。1B期的所有患者均以5mg/kg IV输注Q3W接受了Mab-1。射线照相评估每9周进行一次。这里给出的结果包括用5mg/kg Q3W治疗的晚期HCC患者。最后，在临床试验中招募了40名HCC患者(n＝40)。
汇集的HCC人群亚组的关键合格性
招募没有接受过在先PD-1或PD-L1治疗的具有组织学或细胞学上确认的晚期/转移性HCC的成年患者(年龄≥18岁)。
具体的纳入标准包括巴塞罗那临床肝癌(Barcelona Clinic Liver Cancer)C期或B期，难治性/不适合局部区域治疗，并且不适用于治愈性治疗方法，以及Child-Pugh A，无任何级别脑病。
合格患者必须具有<200IU/mL(～1000cps/mL)的乙型肝炎病毒(HBV)病毒载量，并且具有活动性HBV感染的受试者在整个治疗期间和治疗后6个月需要进行抗HBV抑制≥3个月。
未经治疗的患有活动性丙型肝炎病毒(HCV)感染的患者不允许进行研究。
患者处置
40名患有晚期HCC的患者(其中大多数是HBV阳性的(n＝28/40))被招募进该研究中(表7)。总共有24名患者在本分析时仍然进行治疗。
表7：患者人口统计学和疾病特征
初步抗肿瘤活性
在招募的40名晚期HCC患者中，总共27名患者可被评价，其中25名患者具有可测量的疾病，并且至少有1名可评价的基线后肿瘤评估；2名在第1个预定肿瘤评估日期之前死亡。
在以下的临床试验和结果中，所有患者以5mg/kg IV输注Q3W接受Mab-1，每9周进行放射照相评估。在27名可评价的
患者中：3名患者实现了至少部分响应(PR)，且9名患者实现了稳定疾病(SD)。包括部分响应(PR)和稳定疾病(SD)的初始疾病控制率(DCR)为44％，如图3所示，其显示根据肝炎病毒感染状态的肿瘤大小的最佳变化。
用Mab-1治疗的持续时间和患者的响应示于图4。它显示出最大持续时间是28周。
如上所述，发现三名患者实现至少部分响应，这通过图5中具有部分响应的三名患者中的基线和最近的CT评估中得到证实。
图6还显示出HBV感染的HCC患者中肿瘤负荷随时间的变化是有希望的。
图7显示出在HCC患者中通过放射照相证据的最佳总体响应，其中一名患者显示出具有受控的、稳定的疾病超过60周。
耐受性概况
还研究了与本文公开的Mab-1的施用相关的不良事件(AE)。
40名HCC患者中有21名发生了与治疗相关的AE(表8)。除了这些事件的其中之一外，所有事件均为≤2级。最常见的事件是皮疹(n＝8)和瘙痒(n＝5)。
表8：与治疗相关的不良事件
两名患者由于任何治疗中出现的AE而停止治疗，其中之一被研究者认为是与治疗相关的5级AE。一名49岁的亚洲男性患有HBV和HCC，广泛转移到脑、肝和肺，在第一且唯一一次Mab-1剂量后不久发展出进展的证据(意识障碍、腹痛和胸部X光的变化)。尽管用甲基强的松龙和恩替卡韦治疗，患者在进入研究后约5周死亡。病毒血清学阴性；没有进行尸检。死因归因于急性肝炎，并且受到快速疾病进展的混淆。
这些结果证实，本文公开的抗体(Mab-1)是可耐受的；其毒性概况证实不良事件(AE)通常严重性低，可控且可逆。
在该早期报道中，超过一半的患者仍在研究中(n＝24/40)；中位数治疗持续时间为64天(范围：1-471天)；与治疗相关的AE引起的治疗中断率低(n＝1/40。该群组中报告的不良事件与研究中观察到的总体安全性概况一致，并且通常严重性低，可控且可逆。大多数患者有潜在的病毒感染(HBV+，n＝28；HCV+/HBV+，n＝6；HCV+，n＝2)。在3名患者中观察到符合“部分响应”(即，定义为肿瘤负荷的至少30％的减少)的定义的肿瘤减少；且9名患者实现了稳定疾病，其中的一些还具有显著减少的AFP。
实施例2在患有不能切除的肝细胞癌(HCC)的患者中对Mab-1的2期研究
研究设计
设计2期研究以评价在先治疗过的HCC患者中Mab-1的功效、安全性/耐受性和药代动力学(PK)。安全性/耐受性评估会包括监测不良事件(AE)，包括与免疫相关的AE。
研究人群
年龄≥18岁的成年患者如果符合以下条件会被招募：
(a)组织学上确认的HCC；
(b)患有巴塞罗那临床肝癌(BCLC)C期或BCLC B期，不适合局部区域治疗或局部区域治疗后复发，且不适合治愈性治疗方法；
(c)已针对无法切除的HCC接受过至少1线的全身治疗；
(d)具有如根据RECIST v1.1所定义的至少1个可测量的病变；
(e)child-Pugh得分A；
(f)东部合作肿瘤学组(Eastern Cooperative Oncology Group，ECOG)表现状态≤1；
(g)足够的器官功能。
患者如果符合以下条件会被排除：
(a)已知的纤维板层状HCC，肉瘤样HCC或混合胆管癌和HCC组织学；
(b)在先靶向PD-1或PD-L1的治疗；
(c)已知大脑或柔脑膜转移；
(d)涉及门静脉或下腔静脉主干的肿瘤血栓；
(e)在招募前4周内对肝脏进行的局部区域治疗；
(f)间质性肺病、非感染性肺炎或未受控制的全身性疾病的病史，包括糖尿病、高血压、肺纤维化、急性肺病等；
(g)在第一次研究药物施用的28天或5个半衰期(以较短者为准)内接受过：任何化学疗法、免疫疗法(例如，白细胞介素、干扰素、胸腺素)或任何研究性治疗；在第一次研究药物施用后14天内接受过：索拉非尼，瑞戈非尼(regorafenib)或任何用于控制癌症的中草药或中成药；
(h)活动性自身免疫性疾病或可能复发的自身免疫性疾病的病史；
(i)在研究药物施用前14天内，患有任何需要用皮质类固醇(每日>10mg的泼尼松(prednisone)或等效物)或其他免疫抑制药物进行全身治疗的病况。
治疗
会用Mab-1 200mg IV Q3W治疗患者。
实施例3在患有不可切除的肝细胞癌(HCC)的患者中比较Mab-1与索拉非尼作为一线治疗的功效和安全性的3期研究
研究设计
设计3期研究以评价与索拉非尼相比作为晚期HCC的一线治疗的Mab-1的功效和安全性(图8)。
主要目的会是比较两个治疗组之间的总存活率(OS)。根据RECIST v1.1通过设盲的独立审查委员会来评估的客观响应率(ORR)是一个关键的次要目标。其他次要目标将包括Mab-1和索拉非尼在各种效力评估(无进展生存[PFS]、响应的持续时间[DoR]、进展时间[TTP]、疾病控制率[DCR]和临床受益率[CBR])、与健康相关的生活质量的衡量标准以及安全性和耐受性方面的比较。
研究人群
年龄≥18的成年患者如果符合以下条件将被招募：
(a)无法切除的、组织学证实的HCC，
(b)东部合作肿瘤学组(ECOG)评分≤1，Child-Pugh A分类，
(c)巴塞罗那临床肝癌(BCLC)C期疾病或BCLC，B期疾病，及不适合局部区域治疗或在局部区域治疗后已经进展，并且不适合治愈性治疗方法，
(d)未接受过在先的全身治疗。
患者如果符合以下条件将被排除：
(a)已知的纤维板层状HCC、肉瘤样HCC或混合胆管癌和HCC组织学，
(b)涉及门静脉或下腔静脉主干的肿瘤血栓，
(c)在随机化前28天内接受过肝脏的局部区域治疗或任何在先免疫治疗，或在随机化后14天内接受过用于控制癌症的任何中草药或成药，
(d)2级或更高级的肝性脑病(筛查时或以前的病史)，
(e)筛查时的心包积液、无法控制的胸腔积液或临床上显著的腹水。
治疗
患者会按1:1随机分组以接受Mab-1 200mg IV Q3W或索拉非尼400mg每日两次(BID)口服，其中随机化通过大血管侵入的存在、肝外扩散的存在、ECOG表现状态、病因和地理来分层。会施用治疗直至疾病进展、无法忍受的毒性或由于其他原因治疗中止。
研究评估和统计分析
(a)根据RECIST v1.1，会在第1年每9周评价一次肿瘤响应，从第2年开始每12周评估一次肿瘤响应。
(b)会就Mab-1相对于索拉非尼评估主要疗效终点OS的非劣效性。
(c)会就治疗比较评价次要终点(诸如由设盲的独立审查委员会评估的ORR、PFS、DoR和TTP)
(d)所有测试会以单侧α＝0.025(或2侧α＝0.05)进行。
(e)安全性和耐受性(次要终点)会通过监测不良事件(AE)，包括与免疫相关的AE，以及通过身体检查、生命体征和心电图来评估。
(f)欧洲癌症研究和治疗组织生活质量癌症调查问卷-肝细胞癌18个问题(EORTCQLQ-HCC18)和欧洲癌症研究和治疗组织生活质量问卷-核心30会用于使用混合模型评估在两个治疗组之间的与健康相关的生活质量。欧洲生活质量五维也会被总结。
应当将前述实施例和某些实施方案的描述作为示例说明，而不作为限制由权利要求限定的本发明。如将容易理解的，在不脱离如权利要求中所述的本发明的情况下，可以利用上述特征的许多变化和组合。所有这样的变化都意图包括在本发明的范围内。引用的所有参考文献都通过提述以其整体并入本文。
应理解的是，如果本文提及任何现有技术出版物，这样的参考文献并不构成承认该出版物形成任何国家的本领域公知常识的一部分。
在以下和在本发明的前述描述中的权利要求中，除非上下文由于明确的语言或必要的含义而另有要求，否则词语“包含(comprise)”或诸如“包含(comprises)”或“包含(comprising)”的变体用于包括的意义，即指定所述特征的存在但不排除在本发明的各种实施方案中存在或添加其他特征。
本文通过鉴定引用提及的所有出版物、专利、专利申请和公开的专利申请的公开内容均通过提述以其整体并入本文。
序列表
<110> 百济神州有限公司
Wang, Lai
Li, Kang
Qi, Qinzhou
Hou, Jeannie
Wu, Zhong
<120> 肝细胞癌的免疫治疗
<130> F18W0404TW
<150> PCT/CN2017/090397
<151> 2017-06-27
<150> US 62/524,967
<151> 2017-06-26
<160> 107
<170> PatentIn version 3.5
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<400> 23
caggtgcagc tgcaggagtc gggaccagga ctggtgaagc cttcggagac cctgtccctc 60
acctgcactg tctctgggtt ttcattaacc agctatggtg tacactggat ccggcagccc 120
ccagggaagg gactggagtg gatcggggtc atatacgccg atggaagcac aaattataat 180
ccctccctca agagtcgagt gaccatatca aaagacacct ccaagaacca ggtttccctg 240
aagctgagct ctgtgaccgc tgcggacacg gccgtgtatt actgtgcgag agcctatggt 300
aactactggt acatcgatgt ctggggccaa gggaccacgg tcaccgtctc ctca 354
<210> 24
<211> 118
<212> PRT
<213> 人工序列
<220>
<223> 317-4B6 pro-Vh
<400> 24
Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu
1 5 10 15
Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Phe Ser Leu Thr Ser Tyr
20 25 30
Gly Val His Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Ile
35 40 45
Gly Val Ile Tyr Ala Asp Gly Ser Thr Asn Tyr Asn Pro Ser Leu Lys
50 55 60
Ser Arg Val Thr Ile Ser Lys Asp Thr Ser Lys Asn Gln Val Ser Leu
65 70 75 80
Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala
85 90 95
Arg Ala Tyr Gly Asn Tyr Trp Tyr Ile Asp Val Trp Gly Gln Gly Thr
100 105 110
Thr Val Thr Val Ser Ser
115
<210> 25
<211> 321
<212> DNA
<213> 人工序列
<220>
<223> 317-4B6 cDNA-Vk
<400> 25
gacatcgtga tgacccagtc tccagactcc ctggctgtgt ctctgggcga gagggccacc 60
atcaactgca agtccagcga gagtgtgagt aatgatgtag cttggtacca gcagaaacca 120
ggacagcctc ctaagctgct cattaactat gcatttcatc gcttcactgg ggtccctgac 180
cgattcagtg gcagcgggta tgggacagat ttcactctca ccatcagcag cctgcaggct 240
gaagatgtgg cagtttatta ctgtcaccag gcttatagtt ctccgtacac gtttggccag 300
gggaccaagc tggagatcaa a 321
<210> 26
<211> 107
<212> PRT
<213> 人工序列
<220>
<223> 317-4B6 pro-Vk
<400> 26
Asp Ile Val Met Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly
1 5 10 15
Glu Arg Ala Thr Ile Asn Cys Lys Ser Ser Glu Ser Val Ser Asn Asp
20 25 30
Val Ala Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro Lys Leu Leu Ile
35 40 45
Asn Tyr Ala Phe His Arg Phe Thr Gly Val Pro Asp Arg Phe Ser Gly
50 55 60
Ser Gly Tyr Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Ala
65 70 75 80
Glu Asp Val Ala Val Tyr Tyr Cys His Gln Ala Tyr Ser Ser Pro Tyr
85 90 95
Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys
100 105
<210> 27
<211> 342
<212> DNA
<213> 人工序列
<220>
<223> 326-4A3 cDNA-Vh
<400> 27
caggtgcagc tggtgcagag cggcagcgag ctgaagaagc ccggcgccag cgtgaaggtg 60
agctgcaagg ccagcggcta caccttcacc aactacggca tgaactgggt gagacaggcc 120
cccggccagg gcctgaagtg gatgggctgg atcaacaaca acaacgccga gcccacctac 180
gcccaggact tcagaggcag attcgtgttc agcctggaca ccagcgccag caccgcctac 240
ctgcagatca gcagcctgaa gaccgaggac accgccgtgt actactgcgc cagagacgtg 300
atggactact ggggccaggg caccctggtg accgtgagca gc 342
<210> 28
<211> 114
<212> PRT
<213> 人工序列
<220>
<223> 326-4A3 pro-Vh
<400> 28
Gln Val Gln Leu Val Gln Ser Gly Ser Glu Leu Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Tyr
20 25 30
Gly Met Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Lys Trp Met
35 40 45
Gly Trp Ile Asn Asn Asn Asn Ala Glu Pro Thr Tyr Ala Gln Asp Phe
50 55 60
Arg Gly Arg Phe Val Phe Ser Leu Asp Thr Ser Ala Ser Thr Ala Tyr
65 70 75 80
Leu Gln Ile Ser Ser Leu Lys Thr Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Asp Val Met Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val
100 105 110
Ser Ser
<210> 29
<211> 330
<212> DNA
<213> 人工序列
<220>
<223> 326-4A3 cDNA-Vk
<400> 29
gacattgtgc tgacccagtc tccagcctcc ttggccgtgt ctccaggaca gagggccacc 60
atcacctgca gagccagtga aagtgttgat aattatggct atagttttat gcactggtat 120
cagcagaaac caggacaacc tcctaaactc ctgatttacc gtgcatccaa cctagaatct 180
ggggtcccag ccaggttcag cggcagtggg tctgggaccg atttcaccct cacaattaat 240
cctgtggaag ctgaggatac tgcaaattat tactgtcagc aaagtaaaga atatccgacg 300
ttcggcggag ggaccaaggt ggagatcaaa 330
<210> 30
<211> 110
<212> PRT
<213> 人工序列
<220>
<223> 326-4A3 pro-Vk
<400> 30
Asp Ile Val Leu Thr Gln Ser Pro Ala Ser Leu Ala Val Ser Pro Gly
1 5 10 15
Gln Arg Ala Thr Ile Thr Cys Arg Ala Ser Glu Ser Val Asp Asn Tyr
20 25 30
Gly Tyr Ser Phe Met His Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro
35 40 45
Lys Leu Leu Ile Tyr Arg Ala Ser Asn Leu Glu Ser Gly Val Pro Ala
50 55 60
Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Asn
65 70 75 80
Pro Val Glu Ala Glu Asp Thr Ala Asn Tyr Tyr Cys Gln Gln Ser Lys
85 90 95
Glu Tyr Pro Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105 110
<210> 31
<211> 10
<212> PRT
<213> 小家鼠
<400> 31
Gly Phe Ser Leu Thr Ser Tyr Gly Val His
1 5 10
<210> 32
<211> 16
<212> PRT
<213> 人工序列
<220>
<223> 317-4B6 H-CDR2或CDR-H2
<400> 32
Val Ile Tyr Ala Asp Gly Ser Thr Asn Tyr Asn Pro Ser Leu Lys Ser
1 5 10 15
<210> 33
<211> 12
<212> PRT
<213> 小家鼠
<400> 33
Ala Arg Ala Tyr Gly Asn Tyr Trp Tyr Ile Asp Val
1 5 10
<210> 34
<211> 11
<212> PRT
<213> 人工序列
<220>
<223> 317-4B6 L-CDR1或CDR-L1
<400> 34
Lys Ser Ser Glu Ser Val Ser Asn Asp Val Ala
1 5 10
<210> 35
<211> 7
<212> PRT
<213> 小家鼠
<400> 35
Tyr Ala Phe His Arg Phe Thr
1 5
<210> 36
<211> 9
<212> PRT
<213> 小家鼠
<400> 36
His Gln Ala Tyr Ser Ser Pro Tyr Thr
1 5
<210> 37
<211> 10
<212> PRT
<213> 小家鼠
<400> 37
Gly Tyr Thr Phe Thr Asn Tyr Gly Met Asn
1 5 10
<210> 38
<211> 17
<212> PRT
<213> 人工序列
<220>
<223> 326-4A3 H-CDR2或CDR-H2
<400> 38
Trp Ile Asn Asn Asn Asn Ala Glu Pro Thr Tyr Ala Gln Asp Phe Arg
1 5 10 15
Gly
<210> 39
<211> 7
<212> PRT
<213> 小家鼠
<400> 39
Ala Arg Asp Val Met Asp Tyr
1 5
<210> 40
<211> 15
<212> PRT
<213> 小家鼠
<400> 40
Arg Ala Ser Glu Ser Val Asp Asn Tyr Gly Tyr Ser Phe Met His
1 5 10 15
<210> 41
<211> 7
<212> PRT
<213> 小家鼠
<400> 41
Arg Ala Ser Asn Leu Glu Ser
1 5
<210> 42
<211> 8
<212> PRT
<213> 小家鼠
<400> 42
Gln Gln Ser Lys Glu Tyr Pro Thr
1 5
<210> 43
<211> 118
<212> PRT
<213> 人工序列
<220>
<223> 317-4B2 pro-Vh
<400> 43
Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu
1 5 10 15
Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Phe Ser Leu Thr Ser Tyr
20 25 30
Gly Val His Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Ile
35 40 45
Gly Val Ile Tyr Ala Gly Gly Ser Thr Asn Tyr Asn Pro Ser Leu Lys
50 55 60
Ser Arg Val Thr Ile Ser Lys Asp Thr Ser Lys Asn Gln Phe Ser Leu
65 70 75 80
Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala
85 90 95
Arg Ala Tyr Gly Asn Tyr Trp Tyr Ile Asp Val Trp Gly Gln Gly Thr
100 105 110
Thr Val Thr Val Ser Ser
115
<210> 44
<211> 107
<212> PRT
<213> 人工序列
<220>
<223> 317-4B2 pro-Vk
<400> 44
Asp Ile Val Met Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly
1 5 10 15
Glu Arg Ala Thr Ile Asn Cys Lys Ser Ser Glu Ser Val Ser Asn Asp
20 25 30
Val Ala Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro Lys Leu Leu Ile
35 40 45
Asn Tyr Ala Phe His Arg Phe Thr Gly Val Pro Asp Arg Phe Ser Gly
50 55 60
Ser Gly Tyr Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Ala
65 70 75 80
Glu Asp Val Ala Val Tyr Tyr Cys His Gln Ala Tyr Ser Ser Pro Tyr
85 90 95
Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys
100 105
<210> 45
<211> 118
<212> PRT
<213> 人工序列
<220>
<223> 317-4B5 pro-Vh
<400> 45
Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu
1 5 10 15
Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Phe Ser Leu Thr Ser Tyr
20 25 30
Gly Val His Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Ile
35 40 45
Gly Val Ile Tyr Ala Gly Gly Ser Thr Asn Tyr Asn Pro Ser Leu Lys
50 55 60
Ser Arg Val Thr Ile Ser Lys Asp Thr Ser Lys Asn Gln Val Ser Leu
65 70 75 80
Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala
85 90 95
Arg Ala Tyr Gly Asn Tyr Trp Tyr Ile Asp Val Trp Gly Gln Gly Thr
100 105 110
Thr Val Thr Val Ser Ser
115
<210> 46
<211> 107
<212> PRT
<213> 人工序列
<220>
<223> 317-4B5 pro-Vk
<400> 46
Asp Ile Val Met Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly
1 5 10 15
Glu Arg Ala Thr Ile Asn Cys Lys Ser Ser Glu Ser Val Ser Asn Asp
20 25 30
Val Ala Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro Lys Leu Leu Ile
35 40 45
Asn Tyr Ala Phe His Arg Phe Thr Gly Val Pro Asp Arg Phe Ser Gly
50 55 60
Ser Gly Tyr Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Ala
65 70 75 80
Glu Asp Val Ala Val Tyr Tyr Cys His Gln Ala Tyr Ser Ser Pro Tyr
85 90 95
Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys
100 105
<210> 47
<211> 354
<212> DNA
<213> 人工序列
<220>
<223> 317-1 cDNA-Vh
<400> 47
caggtgcagc tgcaggagtc gggaccagga ctggtgaagc cttcggagac cctgtccctc 60
acctgcactg tctctgggtt ttcattaacc agctatggtg tacactggat ccggcagccc 120
ccagggaagg gactggagtg gctgggggtc atatgggccg gtggaagcac aaattataat 180
ccctccctca agagtcgact gaccatatca aaagacaact ccaagagcca ggtttccctg 240
aagatgagct ctgtgaccgc tgcggacacg gccgtgtatt actgtgcgag agcctatggt 300
aactactggt acatcgatgt ctggggccaa gggaccacgg tcaccgtctc ctca 354
<210> 48
<211> 118
<212> PRT
<213> 人工序列
<220>
<223> 317-1 pro-Vh
<400> 48
Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu
1 5 10 15
Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Phe Ser Leu Thr Ser Tyr
20 25 30
Gly Val His Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Leu
35 40 45
Gly Val Ile Trp Ala Gly Gly Ser Thr Asn Tyr Asn Pro Ser Leu Lys
50 55 60
Ser Arg Leu Thr Ile Ser Lys Asp Asn Ser Lys Ser Gln Val Ser Leu
65 70 75 80
Lys Met Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala
85 90 95
Arg Ala Tyr Gly Asn Tyr Trp Tyr Ile Asp Val Trp Gly Gln Gly Thr
100 105 110
Thr Val Thr Val Ser Ser
115
<210> 49
<211> 321
<212> DNA
<213> 人工序列
<220>
<223> 317-1 cDNA-Vk
<400> 49
gacatcgtga tgacccagtc tccagactcc ctggctgtgt ctctgggcga gagggccacc 60
atcaactgca aggccagcca gagtgtgagt aatgatgtag cttggtacca gcagaaacca 120
ggacagcctc ctaagctgct cattaactat gcatttcatc gcttcactgg ggtccctgac 180
cgattcagtg gcagcgggta tgggacagat ttcactctca ccatcagcag cctgcaggct 240
gaagatgtgg cagtttatta ctgtcaccag gcttatagtt ctccgtacac gtttggcggg 300
gggaccaagc tggagatcaa a 321
<210> 50
<211> 107
<212> PRT
<213> 人工序列
<220>
<223> 317-1 pro-Vk
<400> 50
Asp Ile Val Met Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly
1 5 10 15
Glu Arg Ala Thr Ile Asn Cys Lys Ala Ser Gln Ser Val Ser Asn Asp
20 25 30
Val Ala Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro Lys Leu Leu Ile
35 40 45
Asn Tyr Ala Phe His Arg Phe Thr Gly Val Pro Asp Arg Phe Ser Gly
50 55 60
Ser Gly Tyr Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Ala
65 70 75 80
Glu Asp Val Ala Val Tyr Tyr Cys His Gln Ala Tyr Ser Ser Pro Tyr
85 90 95
Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
100 105
<210> 51
<211> 114
<212> PRT
<213> 人工序列
<220>
<223> 326-3B1 pro-Vh
<400> 51
Gln Val Gln Leu Val Gln Ser Gly Ser Glu Leu Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Tyr
20 25 30
Gly Met Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Lys Trp Met
35 40 45
Gly Trp Ile Asn Asn Asn Asn Gly Glu Pro Thr Tyr Ala Gln Asp Phe
50 55 60
Arg Gly Arg Phe Val Phe Ser Leu Asp Thr Ser Ala Ser Thr Ala Tyr
65 70 75 80
Leu Gln Ile Ser Ser Leu Lys Thr Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Asp Val Met Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val
100 105 110
Ser Ser
<210> 52
<211> 110
<212> PRT
<213> 人工序列
<220>
<223> 326-3B1 pro-Vk
<400> 52
Asp Ile Val Leu Thr Gln Ser Pro Ala Ser Leu Ala Val Ser Pro Gly
1 5 10 15
Gln Arg Ala Thr Ile Thr Cys Arg Ala Ser Glu Ser Val Asp Asn Tyr
20 25 30
Gly Tyr Ser Phe Met His Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro
35 40 45
Lys Leu Leu Ile Tyr Arg Ala Ser Asn Leu Glu Ser Gly Val Pro Ala
50 55 60
Arg Phe Ser Gly Ser Gly Ser Arg Thr Asp Phe Thr Leu Thr Ile Asn
65 70 75 80
Pro Val Glu Ala Asn Asp Thr Ala Asn Tyr Tyr Cys Gln Gln Ser Lys
85 90 95
Glu Tyr Pro Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105 110
<210> 53
<211> 114
<212> PRT
<213> 人工序列
<220>
<223> 326-3G1 pro-Vh
<400> 53
Gln Val Gln Leu Val Gln Ser Gly Pro Glu Leu Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Tyr
20 25 30
Gly Met Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Lys Trp Met
35 40 45
Gly Trp Ile Asn Asn Asn Asn Gly Glu Pro Thr Tyr Ala Gln Asp Phe
50 55 60
Arg Gly Arg Phe Val Phe Ser Leu Asp Thr Ser Ala Ser Thr Ala Tyr
65 70 75 80
Leu Gln Ile Ser Ser Leu Lys Thr Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Asp Val Met Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val
100 105 110
Ser Ser
<210> 54
<211> 110
<212> PRT
<213> 人工序列
<220>
<223> 326-3G1 pro-Vk
<400> 54
Asp Ile Val Leu Thr Gln Ser Pro Ala Ser Leu Ala Val Ser Pro Gly
1 5 10 15
Gln Arg Ala Thr Ile Thr Cys Arg Ala Ser Glu Ser Val Asp Asn Tyr
20 25 30
Gly Tyr Ser Phe Met His Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro
35 40 45
Lys Leu Leu Ile Tyr Arg Ala Ser Asn Leu Glu Ser Gly Val Pro Ala
50 55 60
Arg Phe Ser Gly Ser Gly Ser Arg Thr Asp Phe Thr Leu Thr Ile Asn
65 70 75 80
Pro Val Glu Ala Asn Asp Thr Ala Asn Tyr Tyr Cys Gln Gln Ser Lys
85 90 95
Glu Tyr Pro Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105 110
<210> 55
<211> 342
<212> DNA
<213> 人工序列
<220>
<223> 326-1 cDNA-Vh
<400> 55
caggtgcagc tggtgcagag cggcagcgag ctgaagaagc ccggcgccag cgtgaaggtg 60
agctgcaagg ccagcggcta caccttcacc aactacggca tgaactgggt gagacaggcc 120
cccggccagg gcctggagtg gatgggctgg atcaacaaca acaacggcga gcccacctac 180
gcccagggct tcagaggcag attcgtgttc agcctggaca ccagcgccag caccgcctac 240
ctgcagatca gcagcctgaa gaccgaggac accgccgtgt acttctgcgc cagagacgtg 300
atggactact ggggccaggg caccaccgtg accgtgagca gc 342
<210> 56
<211> 114
<212> PRT
<213> 人工序列
<220>
<223> 326-1 pro-Vh
<400> 56
Gln Val Gln Leu Val Gln Ser Gly Ser Glu Leu Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Tyr
20 25 30
Gly Met Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Trp Ile Asn Asn Asn Asn Gly Glu Pro Thr Tyr Ala Gln Gly Phe
50 55 60
Arg Gly Arg Phe Val Phe Ser Leu Asp Thr Ser Ala Ser Thr Ala Tyr
65 70 75 80
Leu Gln Ile Ser Ser Leu Lys Thr Glu Asp Thr Ala Val Tyr Phe Cys
85 90 95
Ala Arg Asp Val Met Asp Tyr Trp Gly Gln Gly Thr Thr Val Thr Val
100 105 110
Ser Ser
<210> 57
<211> 330
<212> DNA
<213> 人工序列
<220>
<223> 326-1 cDNA-Vk
<400> 57
gacattgtgc tgacccagtc tccagcctcc ttggccgtgt ctccaggaca gagggccacc 60
atcacctgca gagccagtga aagtgttgat aattatggct atagttttat gcactggtat 120
cagcagaaac caggacaacc tcctaaactc ctgatttacc gtgcatccaa cctagaatct 180
ggggtcccag ccaggttcag cggcagtggg tctaggaccg atttcaccct cacaattaat 240
cctgtggaag ctaatgatac tgcaaattat tactgtcagc aaagtaaaga atatccgacg 300
ttcggcggag ggaccaaggt ggagatcaaa 330
<210> 58
<211> 110
<212> PRT
<213> 人工序列
<220>
<223> 326-1 pro-Vk
<400> 58
Asp Ile Val Leu Thr Gln Ser Pro Ala Ser Leu Ala Val Ser Pro Gly
1 5 10 15
Gln Arg Ala Thr Ile Thr Cys Arg Ala Ser Glu Ser Val Asp Asn Tyr
20 25 30
Gly Tyr Ser Phe Met His Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro
35 40 45
Lys Leu Leu Ile Tyr Arg Ala Ser Asn Leu Glu Ser Gly Val Pro Ala
50 55 60
Arg Phe Ser Gly Ser Gly Ser Arg Thr Asp Phe Thr Leu Thr Ile Asn
65 70 75 80
Pro Val Glu Ala Asn Asp Thr Ala Asn Tyr Tyr Cys Gln Gln Ser Lys
85 90 95
Glu Tyr Pro Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105 110
<210> 59
<211> 16
<212> PRT
<213> 人工序列
<220>
<223> 317-1 H-CDR2或CDR-H2
<400> 59
Val Ile Trp Ala Gly Gly Ser Thr Asn Tyr Asn Pro Ser Leu Lys Ser
1 5 10 15
<210> 60
<211> 16
<212> PRT
<213> 人工序列
<220>
<223> 317-4B2 H-CDR2或CDR-H2
<400> 60
Val Ile Tyr Ala Gly Gly Ser Thr Asn Tyr Asn Pro Ser Leu Lys Ser
1 5 10 15
<210> 61
<211> 11
<212> PRT
<213> 人工序列
<220>
<223> 317-4B2 L-CDR1或CDR-L1
<400> 61
Lys Ser Ser Glu Ser Val Ser Asn Asp Val Ala
1 5 10
<210> 62
<211> 17
<212> PRT
<213> 人工序列
<220>
<223> 326-1 H-CDR2或CDR-H2
<400> 62
Trp Ile Asn Asn Asn Asn Gly Glu Pro Thr Tyr Ala Gln Gly Phe Arg
1 5 10 15
Gly
<210> 63
<211> 17
<212> PRT
<213> 人工序列
<220>
<223> 326-3G1 H-CDR2或CDR-H2
<400> 63
Trp Ile Asn Asn Asn Asn Gly Glu Pro Thr Tyr Ala Gln Asp Phe Arg
1 5 10 15
Gly
<210> 64
<211> 118
<212> PRT
<213> 人工序列
<220>
<223> 317-3A1 pro-Vh
<400> 64
Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu
1 5 10 15
Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Phe Ser Leu Thr Ser Tyr
20 25 30
Gly Val His Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Ile
35 40 45
Gly Val Ile Trp Ala Gly Gly Ser Thr Asn Tyr Asn Pro Ser Leu Lys
50 55 60
Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe Ser Leu
65 70 75 80
Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala
85 90 95
Arg Ala Tyr Gly Asn Tyr Trp Tyr Ile Asp Val Trp Gly Gln Gly Thr
100 105 110
Thr Val Thr Val Ser Ser
115
<210> 65
<211> 118
<212> PRT
<213> 人工序列
<220>
<223> 317-3C1 pro-Vh
<400> 65
Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu
1 5 10 15
Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Phe Ser Leu Thr Ser Tyr
20 25 30
Gly Val His Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Leu
35 40 45
Gly Val Ile Trp Ala Gly Gly Ser Thr Asn Tyr Asn Pro Ser Leu Lys
50 55 60
Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe Ser Leu
65 70 75 80
Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala
85 90 95
Arg Ala Tyr Gly Asn Tyr Trp Tyr Ile Asp Val Trp Gly Gln Gly Thr
100 105 110
Thr Val Thr Val Ser Ser
115
<210> 66
<211> 118
<212> PRT
<213> 人工序列
<220>
<223> 317-3E1 pro-Vh
<400> 66
Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu
1 5 10 15
Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Phe Ser Leu Thr Ser Tyr
20 25 30
Gly Val His Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Ile
35 40 45
Gly Val Ile Trp Ala Gly Gly Ser Thr Asn Tyr Asn Pro Ser Leu Lys
50 55 60
Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys Ser Gln Phe Ser Leu
65 70 75 80
Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala
85 90 95
Arg Ala Tyr Gly Asn Tyr Trp Tyr Ile Asp Val Trp Gly Gln Gly Thr
100 105 110
Thr Val Thr Val Ser Ser
115
<210> 67
<211> 118
<212> PRT
<213> 人工序列
<220>
<223> 317-3F1 pro-Vh
<400> 67
Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu
1 5 10 15
Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Phe Ser Leu Thr Ser Tyr
20 25 30
Gly Val His Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Ile
35 40 45
Gly Val Ile Trp Ala Gly Gly Ser Thr Asn Tyr Asn Pro Ser Leu Lys
50 55 60
Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Val Ser Leu
65 70 75 80
Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala
85 90 95
Arg Ala Tyr Gly Asn Tyr Trp Tyr Ile Asp Val Trp Gly Gln Gly Thr
100 105 110
Thr Val Thr Val Ser Ser
115
<210> 68
<211> 118
<212> PRT
<213> 人工序列
<220>
<223> 317-3G1 pro-Vh
<400> 68
Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu
1 5 10 15
Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Phe Ser Leu Thr Ser Tyr
20 25 30
Gly Val His Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Ile
35 40 45
Gly Val Ile Trp Ala Gly Gly Ser Thr Asn Tyr Asn Pro Ser Leu Lys
50 55 60
Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys Ser Gln Val Ser Leu
65 70 75 80
Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala
85 90 95
Arg Ala Tyr Gly Asn Tyr Trp Tyr Ile Asp Val Trp Gly Gln Gly Thr
100 105 110
Thr Val Thr Val Ser Ser
115
<210> 69
<211> 118
<212> PRT
<213> 人工序列
<220>
<223> 317-3H1 pro-Vh
<400> 69
Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu
1 5 10 15
Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Phe Ser Leu Thr Ser Tyr
20 25 30
Gly Val His Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Ile
35 40 45
Gly Val Ile Trp Ala Gly Gly Ser Thr Asn Tyr Asn Pro Ser Leu Lys
50 55 60
Ser Arg Val Thr Ile Ser Lys Asp Thr Ser Lys Ser Gln Val Ser Leu
65 70 75 80
Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala
85 90 95
Arg Ala Tyr Gly Asn Tyr Trp Tyr Ile Asp Val Trp Gly Gln Gly Thr
100 105 110
Thr Val Thr Val Ser Ser
115
<210> 70
<211> 118
<212> PRT
<213> 人工序列
<220>
<223> 317-3I1 pro-Vh
<400> 70
Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu
1 5 10 15
Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Phe Ser Leu Thr Ser Tyr
20 25 30
Gly Val His Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Ile
35 40 45
Gly Val Ile Trp Ala Gly Gly Ser Thr Asn Tyr Asn Pro Ser Leu Lys
50 55 60
Ser Arg Val Thr Ile Ser Lys Asp Thr Ser Lys Asn Gln Val Ser Leu
65 70 75 80
Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala
85 90 95
Arg Ala Tyr Gly Asn Tyr Trp Tyr Ile Asp Val Trp Gly Gln Gly Thr
100 105 110
Thr Val Thr Val Ser Ser
115
<210> 71
<211> 118
<212> PRT
<213> 人工序列
<220>
<223> 317-4B1 pro-Vh
<400> 71
Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu
1 5 10 15
Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Phe Ser Leu Thr Ser Tyr
20 25 30
Gly Val His Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Ile
35 40 45
Gly Val Ile Trp Ala Gly Gly Ser Thr Asn Tyr Asn Pro Ser Leu Lys
50 55 60
Ser Arg Val Thr Ile Ser Lys Asp Thr Ser Lys Asn Gln Phe Ser Leu
65 70 75 80
Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala
85 90 95
Arg Ala Tyr Gly Asn Tyr Trp Tyr Ile Asp Val Trp Gly Gln Gly Thr
100 105 110
Thr Val Thr Val Ser Ser
115
<210> 72
<211> 118
<212> PRT
<213> 人工序列
<220>
<223> 317-4B3 pro-Vh
<400> 72
Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu
1 5 10 15
Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Phe Ser Leu Thr Ser Tyr
20 25 30
Gly Val His Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Ile
35 40 45
Gly Val Ile Asn Ala Gly Gly Ser Thr Asn Tyr Asn Pro Ser Leu Lys
50 55 60
Ser Arg Val Thr Ile Ser Lys Asp Thr Ser Lys Asn Gln Phe Ser Leu
65 70 75 80
Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala
85 90 95
Arg Ala Tyr Gly Asn Tyr Trp Tyr Ile Asp Val Trp Gly Gln Gly Thr
100 105 110
Thr Val Thr Val Ser Ser
115
<210> 73
<211> 118
<212> PRT
<213> 人工序列
<220>
<223> 317-4B4 pro-Vh
<400> 73
Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu
1 5 10 15
Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Phe Ser Leu Thr Ser Tyr
20 25 30
Gly Val His Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Ile
35 40 45
Gly Val Ile Trp Ala Gly Gly Ser Thr Asn Tyr Asn Pro Ser Leu Lys
50 55 60
Ser Arg Val Thr Ile Ser Lys Asp Thr Ser Lys Asn Gln Phe Ser Leu
65 70 75 80
Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala
85 90 95
Arg Ala Tyr Gly Asn Tyr Pro Tyr Ile Asp Val Trp Gly Gln Gly Thr
100 105 110
Thr Val Thr Val Ser Ser
115
<210> 74
<211> 107
<212> PRT
<213> 人工序列
<220>
<223> 317-4A2 pro-Vk
<400> 74
Asp Ile Val Met Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly
1 5 10 15
Glu Arg Ala Thr Ile Asn Cys Lys Ser Ser Gln Ser Val Ser Asn Asp
20 25 30
Val Ala Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro Lys Leu Leu Ile
35 40 45
Asn Tyr Ala Phe His Arg Phe Thr Gly Val Pro Asp Arg Phe Ser Gly
50 55 60
Ser Gly Tyr Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Ala
65 70 75 80
Glu Asp Val Ala Val Tyr Tyr Cys His Gln Ala Tyr Ser Ser Pro Tyr
85 90 95
Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys
100 105
<210> 75
<211> 114
<212> PRT
<213> 人工序列
<220>
<223> 326-3A1 pro-Vh
<400> 75
Gln Val Gln Leu Val Gln Ser Gly Pro Glu Leu Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Tyr
20 25 30
Gly Met Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Trp Ile Asn Asn Asn Asn Gly Glu Pro Thr Tyr Ala Gln Gly Phe
50 55 60
Arg Gly Arg Phe Val Phe Ser Leu Asp Thr Ser Ala Ser Thr Ala Tyr
65 70 75 80
Leu Gln Ile Ser Ser Leu Lys Thr Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Asp Val Met Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val
100 105 110
Ser Ser
<210> 76
<211> 114
<212> PRT
<213> 人工序列
<220>
<223> 326-3C1 pro-Vh
<400> 76
Gln Val Gln Leu Val Gln Ser Gly Pro Glu Leu Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Tyr
20 25 30
Gly Met Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Lys Trp Met
35 40 45
Gly Trp Ile Asn Asn Asn Asn Gly Glu Pro Thr Tyr Ala Gln Asp Phe
50 55 60
Arg Gly Arg Phe Val Phe Ser Leu Asp Thr Ser Ala Ser Thr Ala Tyr
65 70 75 80
Leu Gln Ile Ser Ser Leu Lys Thr Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Asp Val Met Asp Tyr Trp Gly Gln Gly Thr Thr Val Thr Val
100 105 110
Ser Ser
<210> 77
<211> 114
<212> PRT
<213> 人工序列
<220>
<223> 326-3D1 pro-Vh
<400> 77
Gln Val Gln Leu Val Gln Ser Gly Ser Glu Leu Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Tyr
20 25 30
Gly Met Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Trp Ile Asn Asn Asn Asn Gly Glu Pro Thr Tyr Ala Gln Gly Phe
50 55 60
Arg Gly Arg Phe Val Phe Ser Leu Asp Thr Ser Ala Ser Thr Ala Tyr
65 70 75 80
Leu Gln Ile Ser Ser Leu Lys Thr Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Asp Val Met Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val
100 105 110
Ser Ser
<210> 78
<211> 114
<212> PRT
<213> 人工序列
<220>
<223> 326-3E1 pro-Vh
<400> 78
Gln Val Gln Leu Val Gln Ser Gly Ser Glu Leu Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Tyr
20 25 30
Gly Met Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Lys Trp Met
35 40 45
Gly Trp Ile Asn Asn Asn Asn Gly Glu Pro Thr Tyr Ala Gln Asp Phe
50 55 60
Arg Gly Arg Phe Val Phe Ser Leu Asp Thr Ser Ala Ser Thr Ala Tyr
65 70 75 80
Leu Gln Ile Ser Ser Leu Lys Thr Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Asp Val Met Asp Tyr Trp Gly Gln Gly Thr Thr Val Thr Val
100 105 110
Ser Ser
<210> 79
<211> 114
<212> PRT
<213> 人工序列
<220>
<223> 326-3F1 pro-Vh
<400> 79
Gln Val Gln Leu Val Gln Ser Gly Pro Glu Leu Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Tyr
20 25 30
Gly Met Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Trp Ile Asn Asn Asn Asn Gly Glu Pro Thr Tyr Ala Gln Gly Phe
50 55 60
Arg Gly Arg Phe Val Phe Ser Leu Asp Thr Ser Ala Ser Thr Ala Tyr
65 70 75 80
Leu Gln Ile Ser Ser Leu Lys Thr Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Asp Val Met Asp Tyr Trp Gly Gln Gly Thr Thr Val Thr Val
100 105 110
Ser Ser
<210> 80
<211> 114
<212> PRT
<213> 人工序列
<220>
<223> 326-3B N55D pro-Vh
<400> 80
Gln Val Gln Leu Val Gln Ser Gly Ser Glu Leu Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Tyr
20 25 30
Gly Met Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Lys Trp Met
35 40 45
Gly Trp Ile Asn Asn Asn Asp Gly Glu Pro Thr Tyr Ala Gln Asp Phe
50 55 60
Arg Gly Arg Phe Val Phe Ser Leu Asp Thr Ser Ala Ser Thr Ala Tyr
65 70 75 80
Leu Gln Ile Ser Ser Leu Lys Thr Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Asp Val Met Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val
100 105 110
Ser Ser
<210> 81
<211> 110
<212> PRT
<213> 人工序列
<220>
<223> 326-4A1 pro-Vk
<400> 81
Asp Ile Val Leu Thr Gln Ser Pro Ala Ser Leu Ala Val Ser Pro Gly
1 5 10 15
Gln Arg Ala Thr Ile Thr Cys Arg Ala Ser Glu Ser Val Asp Asn Tyr
20 25 30
Gly Tyr Ser Phe Met His Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro
35 40 45
Lys Leu Leu Ile Tyr Arg Ala Ser Asn Leu Glu Ser Gly Val Pro Ala
50 55 60
Arg Phe Ser Gly Ser Gly Ser Arg Thr Asp Phe Thr Leu Thr Ile Asn
65 70 75 80
Pro Val Glu Ala Glu Asp Thr Ala Asn Tyr Tyr Cys Gln Gln Ser Lys
85 90 95
Glu Tyr Pro Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105 110
<210> 82
<211> 110
<212> PRT
<213> 人工序列
<220>
<223> 326-4A2 pro-Vk
<400> 82
Asp Ile Val Leu Thr Gln Ser Pro Ala Ser Leu Ala Val Ser Pro Gly
1 5 10 15
Gln Arg Ala Thr Ile Thr Cys Arg Ala Ser Glu Ser Val Asp Asn Tyr
20 25 30
Gly Tyr Ser Phe Met His Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro
35 40 45
Lys Leu Leu Ile Tyr Arg Ala Ser Asn Leu Glu Ser Gly Val Pro Ala
50 55 60
Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Asn
65 70 75 80
Pro Val Glu Ala Asn Asp Thr Ala Asn Tyr Tyr Cys Gln Gln Ser Lys
85 90 95
Glu Tyr Pro Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105 110
<210> 83
<211> 327
<212> PRT
<213> 人工序列
<220>
<223> huIgG4mt1 pro
<400> 83
Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg
1 5 10 15
Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr
20 25 30
Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser
35 40 45
Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser
50 55 60
Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Lys Thr
65 70 75 80
Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys
85 90 95
Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro
100 105 110
Glu Phe Glu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys
115 120 125
Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val
130 135 140
Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp
145 150 155 160
Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe
165 170 175
Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp
180 185 190
Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu
195 200 205
Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg
210 215 220
Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys
225 230 235 240
Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp
245 250 255
Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys
260 265 270
Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser
275 280 285
Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser
290 295 300
Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser
305 310 315 320
Leu Ser Leu Ser Leu Gly Lys
325
<210> 84
<211> 327
<212> PRT
<213> 人工序列
<220>
<223> huIgG4mt2 pro
<400> 84
Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg
1 5 10 15
Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr
20 25 30
Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser
35 40 45
Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser
50 55 60
Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Lys Thr
65 70 75 80
Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys
85 90 95
Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro
100 105 110
Pro Val Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys
115 120 125
Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val
130 135 140
Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp
145 150 155 160
Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe
165 170 175
Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp
180 185 190
Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu
195 200 205
Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg
210 215 220
Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys
225 230 235 240
Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp
245 250 255
Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys
260 265 270
Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser
275 280 285
Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser
290 295 300
Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser
305 310 315 320
Leu Ser Leu Ser Leu Gly Lys
325
<210> 85
<211> 327
<212> PRT
<213> 人工序列
<220>
<223> huIgG4mt6 pro
<400> 85
Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg
1 5 10 15
Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr
20 25 30
Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser
35 40 45
Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser
50 55 60
Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Lys Thr
65 70 75 80
Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys
85 90 95
Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro
100 105 110
Pro Val Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys
115 120 125
Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val
130 135 140
Ala Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp
145 150 155 160
Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe
165 170 175
Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp
180 185 190
Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu
195 200 205
Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg
210 215 220
Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys
225 230 235 240
Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp
245 250 255
Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys
260 265 270
Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser
275 280 285
Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser
290 295 300
Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser
305 310 315 320
Leu Ser Leu Ser Leu Gly Lys
325
<210> 86
<211> 327
<212> PRT
<213> 人工序列
<220>
<223> huIgG4mt8 pro
<400> 86
Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg
1 5 10 15
Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr
20 25 30
Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser
35 40 45
Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser
50 55 60
Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Lys Thr
65 70 75 80
Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys
85 90 95
Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro
100 105 110
Pro Val Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys
115 120 125
Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val
130 135 140
Thr Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp
145 150 155 160
Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe
165 170 175
Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp
180 185 190
Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu
195 200 205
Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg
210 215 220
Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys
225 230 235 240
Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp
245 250 255
Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys
260 265 270
Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser
275 280 285
Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser
290 295 300
Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser
305 310 315 320
Leu Ser Leu Ser Leu Gly Lys
325
<210> 87
<211> 327
<212> PRT
<213> 人工序列
<220>
<223> huIgG4mt9 pro
<400> 87
Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg
1 5 10 15
Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr
20 25 30
Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser
35 40 45
Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser
50 55 60
Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Lys Thr
65 70 75 80
Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys
85 90 95
Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro
100 105 110
Pro Val Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys
115 120 125
Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val
130 135 140
Ala Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp
145 150 155 160
Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe
165 170 175
Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp
180 185 190
Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu
195 200 205
Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg
210 215 220
Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys
225 230 235 240
Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp
245 250 255
Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys
260 265 270
Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser
275 280 285
Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser
290 295 300
Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser
305 310 315 320
Leu Ser Leu Ser Leu Gly Lys
325
<210> 88
<211> 327
<212> PRT
<213> 人工序列
<220>
<223> huIgG4mt10 pro
<400> 88
Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg
1 5 10 15
Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr
20 25 30
Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser
35 40 45
Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser
50 55 60
Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Lys Thr
65 70 75 80
Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys
85 90 95
Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro
100 105 110
Pro Val Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys
115 120 125
Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val
130 135 140
Ala Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp
145 150 155 160
Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe
165 170 175
Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Val His Gln Asp
180 185 190
Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu
195 200 205
Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg
210 215 220
Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys
225 230 235 240
Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp
245 250 255
Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys
260 265 270
Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser
275 280 285
Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser
290 295 300
Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser
305 310 315 320
Leu Ser Leu Ser Leu Gly Lys
325
<210> 89
<211> 367
<212> PRT
<213> 人工序列
<220>
<223> OS8 pro
<400> 89
Met Glu Arg His Trp Ile Phe Leu Leu Leu Leu Ser Val Thr Ala Gly
1 5 10 15
Val His Ser Gln Val Gln Leu Gln Gln Ser Gly Ala Glu Leu Ala Arg
20 25 30
Pro Gly Ala Ser Val Lys Met Ser Cys Lys Ala Ser Gly Tyr Thr Phe
35 40 45
Thr Arg Tyr Thr Met His Trp Val Lys Gln Arg Pro Gly Gln Gly Leu
50 55 60
Glu Trp Ile Gly Tyr Ile Asn Pro Ser Arg Gly Tyr Thr Asn Tyr Asn
65 70 75 80
Gln Lys Phe Lys Asp Lys Ala Thr Leu Thr Thr Asp Lys Ser Ser Ser
85 90 95
Thr Ala Tyr Met Gln Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val
100 105 110
Tyr Tyr Cys Ala Arg Tyr Tyr Asp Asp His Tyr Cys Leu Asp Tyr Trp
115 120 125
Gly Gln Gly Thr Thr Leu Thr Val Ser Ser Gly Gly Gly Gly Ser Gly
130 135 140
Gly Gly Gly Ser Gly Gly Gly Gly Ser Gln Ile Val Leu Thr Gln Ser
145 150 155 160
Pro Ala Ile Met Ser Ala Ser Pro Gly Glu Lys Val Thr Met Thr Cys
165 170 175
Ser Ala Ser Ser Ser Val Ser Tyr Met Asn Trp Tyr Gln Gln Lys Ser
180 185 190
Gly Thr Ser Pro Lys Arg Trp Ile Tyr Asp Thr Ser Lys Leu Ala Ser
195 200 205
Gly Val Pro Ala His Phe Arg Gly Ser Gly Ser Gly Thr Ser Tyr Ser
210 215 220
Leu Thr Ile Ser Gly Met Glu Ala Glu Asp Ala Ala Thr Tyr Tyr Cys
225 230 235 240
Gln Gln Trp Ser Ser Asn Pro Phe Thr Phe Gly Ser Gly Thr Lys Leu
245 250 255
Glu Ile Asn Ser Ser Val Val Pro Val Leu Gln Lys Val Asn Ser Thr
260 265 270
Thr Thr Lys Pro Val Leu Arg Thr Pro Ser Pro Val His Pro Thr Gly
275 280 285
Thr Ser Gln Pro Gln Arg Pro Glu Asp Cys Arg Pro Arg Gly Ser Val
290 295 300
Lys Gly Thr Gly Leu Asp Phe Ala Cys Asp Ile Tyr Ile Trp Ala Pro
305 310 315 320
Leu Ala Gly Ile Cys Val Ala Leu Leu Leu Ser Leu Ile Ile Thr Leu
325 330 335
Ile Cys Tyr His Arg Ser Arg Lys Arg Val Cys Lys Cys Pro Arg Pro
340 345 350
Leu Val Arg Gln Glu Gly Lys Pro Arg Pro Ser Glu Lys Ile Val
355 360 365
<210> 90
<211> 304
<212> PRT
<213> 人工序列
<220>
<223> P3Z pro
<400> 90
Met Gln Ile Pro Gln Ala Pro Trp Pro Val Val Trp Ala Val Leu Gln
1 5 10 15
Leu Gly Trp Arg Pro Gly Trp Phe Leu Asp Ser Pro Asp Arg Pro Trp
20 25 30
Asn Pro Pro Thr Phe Ser Pro Ala Leu Leu Val Val Thr Glu Gly Asp
35 40 45
Asn Ala Thr Phe Thr Cys Ser Phe Ser Asn Thr Ser Glu Ser Phe Val
50 55 60
Leu Asn Trp Tyr Arg Met Ser Pro Ser Asn Gln Thr Asp Lys Leu Ala
65 70 75 80
Ala Phe Pro Glu Asp Arg Ser Gln Pro Gly Gln Asp Cys Arg Phe Arg
85 90 95
Val Thr Gln Leu Pro Asn Gly Arg Asp Phe His Met Ser Val Val Arg
100 105 110
Ala Arg Arg Asn Asp Ser Gly Thr Tyr Leu Cys Gly Ala Ile Ser Leu
115 120 125
Ala Pro Lys Ala Gln Ile Lys Glu Ser Leu Arg Ala Glu Leu Arg Val
130 135 140
Thr Glu Arg Arg Ala Glu Val Pro Thr Ala His Pro Ser Pro Ser Pro
145 150 155 160
Arg Pro Ala Gly Gln Phe Gln Thr Leu Val Val Gly Val Val Gly Gly
165 170 175
Leu Leu Gly Ser Leu Val Leu Leu Val Trp Val Leu Ala Val Ile Arg
180 185 190
Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr Gln Gln Gly Gln
195 200 205
Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr Asp
210 215 220
Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met Gly Gly Lys Pro
225 230 235 240
Gln Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln Lys
245 250 255
Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu Arg
260 265 270
Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu Ser Thr Ala
275 280 285
Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu Pro Pro Arg
290 295 300
<210> 91
<211> 327
<212> PRT
<213> 人工序列
<220>
<223> IgG4 Fc区228P-233P
<400> 91
Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg
1 5 10 15
Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr
20 25 30
Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser
35 40 45
Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser
50 55 60
Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Lys Thr
65 70 75 80
Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys
85 90 95
Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro
100 105 110
Pro Glu Phe Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys
115 120 125
Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val
130 135 140
Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp
145 150 155 160
Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe
165 170 175
Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp
180 185 190
Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu
195 200 205
Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg
210 215 220
Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys
225 230 235 240
Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp
245 250 255
Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys
260 265 270
Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser
275 280 285
Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser
290 295 300
Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser
305 310 315 320
Leu Ser Leu Ser Leu Gly Lys
325
<210> 92
<211> 327
<212> PRT
<213> 人工序列
<220>
<223> IgG4 Fc区228P-234V
<400> 92
Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg
1 5 10 15
Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr
20 25 30
Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser
35 40 45
Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser
50 55 60
Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Lys Thr
65 70 75 80
Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys
85 90 95
Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro
100 105 110
Glu Val Phe Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys
115 120 125
Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val
130 135 140
Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp
145 150 155 160
Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe
165 170 175
Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp
180 185 190
Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu
195 200 205
Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg
210 215 220
Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys
225 230 235 240
Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp
245 250 255
Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys
260 265 270
Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser
275 280 285
Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser
290 295 300
Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser
305 310 315 320
Leu Ser Leu Ser Leu Gly Lys
325
<210> 93
<211> 327
<212> PRT
<213> 人工序列
<220>
<223> IgG4 Fc区228P-235A
<400> 93
Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg
1 5 10 15
Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr
20 25 30
Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser
35 40 45
Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser
50 55 60
Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Lys Thr
65 70 75 80
Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys
85 90 95
Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro
100 105 110
Glu Phe Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys
115 120 125
Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val
130 135 140
Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp
145 150 155 160
Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe
165 170 175
Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp
180 185 190
Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu
195 200 205
Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg
210 215 220
Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys
225 230 235 240
Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp
245 250 255
Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys
260 265 270
Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser
275 280 285
Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser
290 295 300
Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser
305 310 315 320
Leu Ser Leu Ser Leu Gly Lys
325
<210> 94
<211> 327
<212> PRT
<213> 人工序列
<220>
<223> IgG4 Fc区228P-234V-235A
<400> 94
Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg
1 5 10 15
Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr
20 25 30
Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser
35 40 45
Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser
50 55 60
Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Lys Thr
65 70 75 80
Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys
85 90 95
Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro
100 105 110
Glu Val Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys
115 120 125
Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val
130 135 140
Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp
145 150 155 160
Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe
165 170 175
Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp
180 185 190
Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu
195 200 205
Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg
210 215 220
Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys
225 230 235 240
Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp
245 250 255
Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys
260 265 270
Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser
275 280 285
Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser
290 295 300
Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser
305 310 315 320
Leu Ser Leu Ser Leu Gly Lys
325
<210> 95
<211> 327
<212> PRT
<213> 人工序列
<220>
<223> IgG4 Fc区228P-234A
<400> 95
Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg
1 5 10 15
Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr
20 25 30
Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser
35 40 45
Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser
50 55 60
Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Lys Thr
65 70 75 80
Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys
85 90 95
Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro
100 105 110
Glu Ala Phe Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys
115 120 125
Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val
130 135 140
Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp
145 150 155 160
Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe
165 170 175
Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp
180 185 190
Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu
195 200 205
Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg
210 215 220
Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys
225 230 235 240
Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp
245 250 255
Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys
260 265 270
Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser
275 280 285
Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser
290 295 300
Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser
305 310 315 320
Leu Ser Leu Ser Leu Gly Lys
325
<210> 96
<211> 327
<212> PRT
<213> 人工序列
<220>
<223> IgG4 Fc区228P-234A-235A
<400> 96
Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg
1 5 10 15
Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr
20 25 30
Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser
35 40 45
Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser
50 55 60
Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Lys Thr
65 70 75 80
Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys
85 90 95
Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro
100 105 110
Glu Ala Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys
115 120 125
Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val
130 135 140
Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp
145 150 155 160
Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe
165 170 175
Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp
180 185 190
Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu
195 200 205
Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg
210 215 220
Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys
225 230 235 240
Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp
245 250 255
Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys
260 265 270
Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser
275 280 285
Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser
290 295 300
Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser
305 310 315 320
Leu Ser Leu Ser Leu Gly Lys
325
<210> 97
<211> 327
<212> PRT
<213> 人工序列
<220>
<223> IgG4 Fc区228P-233P-234A-235A
<400> 97
Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg
1 5 10 15
Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr
20 25 30
Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser
35 40 45
Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser
50 55 60
Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Lys Thr
65 70 75 80
Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys
85 90 95
Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro
100 105 110
Pro Ala Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys
115 120 125
Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val
130 135 140
Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp
145 150 155 160
Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe
165 170 175
Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp
180 185 190
Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu
195 200 205
Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg
210 215 220
Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys
225 230 235 240
Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp
245 250 255
Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys
260 265 270
Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser
275 280 285
Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser
290 295 300
Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser
305 310 315 320
Leu Ser Leu Ser Leu Gly Lys
325
<210> 98
<211> 327
<212> PRT
<213> 人工序列
<220>
<223> IgG4 Fc区228P-234V-235A-265A
<400> 98
Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg
1 5 10 15
Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr
20 25 30
Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser
35 40 45
Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser
50 55 60
Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Lys Thr
65 70 75 80
Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys
85 90 95
Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro
100 105 110
Glu Val Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys
115 120 125
Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val
130 135 140
Ala Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp
145 150 155 160
Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe
165 170 175
Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp
180 185 190
Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu
195 200 205
Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg
210 215 220
Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys
225 230 235 240
Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp
245 250 255
Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys
260 265 270
Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser
275 280 285
Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser
290 295 300
Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser
305 310 315 320
Leu Ser Leu Ser Leu Gly Lys
325
<210> 99
<211> 327
<212> PRT
<213> 人工序列
<220>
<223> IgG4 Fc区228P-234A-235A-265A
<400> 99
Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg
1 5 10 15
Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr
20 25 30
Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser
35 40 45
Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser
50 55 60
Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Lys Thr
65 70 75 80
Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys
85 90 95
Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro
100 105 110
Glu Ala Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys
115 120 125
Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val
130 135 140
Ala Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp
145 150 155 160
Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe
165 170 175
Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp
180 185 190
Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu
195 200 205
Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg
210 215 220
Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys
225 230 235 240
Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp
245 250 255
Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys
260 265 270
Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser
275 280 285
Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser
290 295 300
Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser
305 310 315 320
Leu Ser Leu Ser Leu Gly Lys
325
<210> 100
<211> 327
<212> PRT
<213> 人工序列
<220>
<223> IgG4 Fc区228P-233P-234A-235A-265A
<400> 100
Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg
1 5 10 15
Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr
20 25 30
Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser
35 40 45
Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser
50 55 60
Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Lys Thr
65 70 75 80
Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys
85 90 95
Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro
100 105 110
Pro Ala Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys
115 120 125
Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val
130 135 140
Ala Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp
145 150 155 160
Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe
165 170 175
Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp
180 185 190
Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu
195 200 205
Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg
210 215 220
Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys
225 230 235 240
Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp
245 250 255
Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys
260 265 270
Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser
275 280 285
Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser
290 295 300
Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser
305 310 315 320
Leu Ser Leu Ser Leu Gly Lys
325
<210> 101
<211> 327
<212> PRT
<213> 人工序列
<220>
<223> IgG4 Fc区228P-265A
<400> 101
Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg
1 5 10 15
Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr
20 25 30
Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser
35 40 45
Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser
50 55 60
Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Lys Thr
65 70 75 80
Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys
85 90 95
Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro
100 105 110
Glu Phe Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys
115 120 125
Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val
130 135 140
Ala Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp
145 150 155 160
Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe
165 170 175
Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp
180 185 190
Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu
195 200 205
Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg
210 215 220
Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys
225 230 235 240
Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp
245 250 255
Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys
260 265 270
Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser
275 280 285
Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser
290 295 300
Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser
305 310 315 320
Leu Ser Leu Ser Leu Gly Lys
325
<210> 102
<211> 327
<212> PRT
<213> 人工序列
<220>
<223> IgG4 Fc区228P-309V
<400> 102
Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg
1 5 10 15
Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr
20 25 30
Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser
35 40 45
Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser
50 55 60
Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Lys Thr
65 70 75 80
Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys
85 90 95
Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro
100 105 110
Glu Phe Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys
115 120 125
Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val
130 135 140
Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp
145 150 155 160
Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe
165 170 175
Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Val His Gln Asp
180 185 190
Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu
195 200 205
Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg
210 215 220
Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys
225 230 235 240
Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp
245 250 255
Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys
260 265 270
Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser
275 280 285
Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser
290 295 300
Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser
305 310 315 320
Leu Ser Leu Ser Leu Gly Lys
325
<210> 103
<211> 327
<212> PRT
<213> 人工序列
<220>
<223> IgG4 Fc区228P-409K
<400> 103
Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg
1 5 10 15
Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr
20 25 30
Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser
35 40 45
Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser
50 55 60
Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Lys Thr
65 70 75 80
Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys
85 90 95
Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro
100 105 110
Glu Phe Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys
115 120 125
Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val
130 135 140
Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp
145 150 155 160
Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe
165 170 175
Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp
180 185 190
Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu
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Ala Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp
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Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys
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245 250 255
Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys
260 265 270
Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser
275 280 285
Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser
290 295 300
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305 310 315 320
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<210> 107
<211> 327
<212> PRT
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Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg
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Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr
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35 40 45
Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser
50 55 60
Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Lys Thr
65 70 75 80
Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys
85 90 95
Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys Pro Ser Cys Pro Ala Pro
100 105 110
Glu Phe Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys
115 120 125
Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val
130 135 140
Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp
145 150 155 160
Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe
165 170 175
Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp
180 185 190
Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu
195 200 205
Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg
210 215 220
Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys
225 230 235 240
Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp
245 250 255
Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys
260 265 270
Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser
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Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser
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Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser
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Claims (23)
1.一种用于患有肝细胞癌(HCC)的患者的免疫治疗的方法，其包括向所述患者施用治疗有效量的抗PD-1抗体或其抗原结合片段，其经特异性工程改造以最小化巨噬细胞上的FcγR结合来消除抗体依赖性吞噬作用。
2.权利要求1的方法，其中所述抗PD-1抗体是包含重链可变区(Vh)和轻链可变区(Vk)的抗体，所述重链可变区和轻链可变区含有如下所列的互补决定区(CDR)：
a)mu317 CDR-H1、CDR-H2和CDR-H3(分别为SEQ ID NO:11、12、13)；和
CDR-L1、CDR-L2和CDR-L3(分别为SEQ ID NO:14、15、16)；
b)mu326 CDR-H1、CDR-H2和CDR-H3(分别为SEQ ID NO:17、18、19)；和
CDR-L1、CDR-L2和CDR-L3(分别为SEQ ID NO:20、21、22)；
c)317-4B6 CDR-H1、CDR-H2和CDR-H3(分别为SEQ ID NO:31、32、33)；和
CDR-L1、CDR-L2和CDR-L3(分别为SEQ ID NO:34、35、36)；
d)326-4A3 CDR-H1、CDR-H2和CDR-H3(分别为SEQ ID NO:37、38、39)；和
CDR-L1、CDR-L2和CDR-L3(分别为SEQ ID NO:40、41、42)；
e)317-1H CDR-H1、CDR-H2和CDR-H3(分别为SEQ ID NO:11、59、13)；和
CDR-L1、CDR-L2和CDR-L3(分别为SEQ ID NO:14、15、16)；
f)317-4B2 CDR-HL CDR-H2和CDR-H3(分别为SEQ ID NO:11、60、13)；和
CDR-L1、CDR-L2和CDR-L3(分别为SEQ ID NO:61、15、16)；
g)317-4B5 CDR-Hl、CDR-H2和CDR-H3(分别为SEQ ID NO:11、60、13)；和
CDR-L1、CDR-L2和CDR-L3(分别为SEQ ID NO:61、15、16)；
h)317-4B6 CDR-H1、CDR-H2和CDR-H3(分别为SEQ ID NO:11、32、13)；和
CDR-L1、CDR-L2和CDR-L3(分别为SEQ ID NO:61、15、16)；
i)326-1 CDR-H1、CDR-H2和CDR-H3(分别为SEQ ID NO:17、62、19)；和
CDR-L1、CDR-L2和CDR-L3(分别为SEQ ID NO:20、21、22)；
j)326-3B1 CDR-H1、CDR-H2和CDR-H3(SEQ ID NO:17、62、19分别为)；和
CDR-L1、CDR-L2和CDR-L3(分别为SEQ ID NO:20、21、22)；或
k)326-3G1 CDR-H1、CDR-H2和CDR-H3(SEQ ID NO:17、62、19分别为)；和
CDR-L1、CDR-I 2和CDR-L3(分别为SEQ ID NO:20、21、22)。
3.权利要求1的方法，其中所述抗PD-1抗体是包含重链可变区(Vh)和轻链可变区(Vk)的抗体，所述重链可变区和轻链可变区含有如下所列的CDR的任何组合：
(a)CDR-H1(SEQ ID NO 31)、CDR-H2(SEQ ID NO 12、32、59或60)和CDR-H3(SEQ ID NO33)，
CDR-L1(SEQ ID NO 14、34或61)、CDR-L2(SEQ ID NO 35)和CDR-L3(SEQ ID NO 36)；或
(b)CDR-H1(SEQ ID NO 37)、CDR-H2(SEQ ID NO 18、38或62)和CDR-H3(SEQ ID NO39)，
CDR-L1(SEQ ID NO 40)、CDR-L2(SEQ ID NO 41)和CDR-L3(SEQ ID NO 42)。
4.权利要求2-3中任一项的方法，其中所述抗PD-1抗体是包含重链可变区(Vh)和轻链可变区(Vk)的抗体，所述重链可变区和轻链可变区包含：
a)mu317(分别为SEQ ID NO:4和6)；
b)mu326(分别为SEQ ID NO:8和10)；
c)317-4B6(分别为SEQ ID NO:24和26)；
d)326-4A3(分别为SEQ ID NO:28和30)；
e)317-4B2(分别为SEQ ID NO:43和44)；
f)317-4B5(分别为SEQ ID NO:45和46)；
g)317-1(分别为SEQ ID NO:48和50)；
h)326-3B1(分别为SEQ ID NO:51和52)；
i)326-3GI(分别为SEQ ID NO:53和54)；
j)326-1(分别为SEQ ID NO:56和58)；
k)317-3A1(分别为SEQ ID NO:64和26)；
l)317-3C1(分别为SEQ ID NO:65和26)；
m)317-3E1(分别为SEQ ID NO:66和26)；
n)317-3F1(分别为SEQ ID NO:67和26)；
o)317-3G1(分别为SEQ ID NO:68和26)；
p)317-3H1(分别为SEQ ID NO:69和26)；
q)317-311(分别为SEQ ID NO:70和26)；
r)317-4B 1(分别为SEQ ID NO:71和26)；
s)317-4B3(分别为SEQ ID NO:72和26)；
t)317-4B4(分别为SEQ ID NO:73和26)；
u)317-4A2(分别为SEQ ID NO:74和26)；
v)326-3A 1(分别为SEQ ID NO:75和30)；
w)326-3C1(分别为SEQ ID NO:76和30)；
x)326-3D1(分别为SEQ ID NO:77和30)；
y)326-3E1(分别为SEQ ID NO:78和30)；
z)326-3F1(分别为SEQ ID NO:79和30)；
aa)326-3B N55D(分别为SEQ ID NO:80和30)；
ab)326-4A1(分别为SEQ ID NO:28和81)；
或
ac)326-4A2(分别为SEQ ID NO:28和82)。
5.权利要求2-3中任一项的方法，其中所述抗PD-1抗体是含有包含SEQ ID NO:83-88或91-106中任一个的IgG4重链效应子或恒定结构域的抗体。
6.权利要求2-3中任一项的方法，其中所述抗PD-1抗体是含有F(ab)或F(ab)2的抗体，所述F(ab)或F(ab)2包含权利要求2-5中任一项的结构域。
7.根据权利要求1的方法，其中所述抗PD-1抗体是包含重链可变区(Vh)和轻链可变区(Vk)，和包含SEQ ID NO:87或88的IgG4重链效应子或恒定结构域的抗体，其中所述重链可变区(Vh)和所述轻链可变区(Vk)包含：
a)mu317(分别为SEQ ID NO:4和6)；
b)mu326(分别为SEQ ID NO:8和10)；
c)317-4B6(分别为SEQ ID NO:24和26)；
d)326-4A3(分别为SEQ ID NO:28和30)；
e)317-4B2(分别为SEQ ID NO:43和44)；
f)317-4B5(分别为SEQ ID NO:45和46)；
g)317-1(分别为SEQ ID NO:48和50)；
h)326-3B1(分别为SEQ ID NO:51和52)；
i)326-3GI(分别为SEQ ID NO:53和54)；
j)326-1(分别为SEQ ID NO:56和58)；
k)317-3A1(分别为SEQ ID NO:64和26)；
l)317-3C1(分别为SEQ ID NO:65和26)；
m)317-3E1(分别为SEQ ID NO:66和26)；
n)317-3F1(分别为SEQ ID NO:67和26)；
o)317-3G1(分别为SEQ ID NO:68和26)；
p)317-3H1(分别为SEQ ID NO:69和26)；
q)317-311(分别为SEQ ID NO:70和26)；
r)317-4B 1(分别为SEQ ID NO:71和26)；
s)317-4B3(分别为SEQ ID NO:72和26)；
t)317-4B4(分别为SEQ ID NO:73和26)；
u)317-4A2(分别为SEQ ID NO:74和26)；
v)326-3A 1(分别为SEQ ID NO:75和30)；
w)326-3C1(分别为SEQ ID NO:76和30)；
x)326-3D1(分别为SEQ ID NO:77和30)；
y)326-3E1(分别为SEQ ID NO:78和30)；
z)326-3F1(分别为SEQ ID NO:79和30)；
aa)326-3B N55D(分别为SEQ ID NO:80和30)；
ab)326-4A1(分别为SEQ ID NO:28和81)；
或
ac)326-4A2(分别为SEQ ID NO:28和82)。
8.根据权利要求1的方法，其中所述抗PD-1抗体是包含重链可变区(Vh)和轻链可变区(Vk)，和包含SEQ ID NO:88的IgG4重链效应子或恒定结构域的抗体，其中所述重链可变区(Vh)和所述轻链可变区(Vk)分别包含SEQ ID NO:24和SEQ ID NO:26。
9.权利要求1-8中任一项的方法，其中所述HCC是晚期HCC和/或转移性HCC。
10.权利要求1-8中任一项的方法，其中所述HCC是一种与病毒感染有关的HCC。
11.权利要求10的方法，其中所述HCC是HBV感染的HCC、HCV感染的HCC或HBV/HCV共感染的HCC。
12.权利要求1-8中任一项的方法，其中所述HCC是晚期HBV感染的HCC，转移性HBV感染的HCC、HCV感染的HCC或转移性HCV感染的HCC。
13.权利要求1-8中任一项的方法，其中所述HCC是晚期HBV感染的HCC或转移性HBV感染的HCC。
14.权利要求9的方法，其中所述HCC没有通过先前的PD-1或PD-L1治疗。
15.权利要求1-14中任一项的方法，其中所述抗PD-1抗体以0.5-10mg/kg QW，或Q2W，或Q3W，或Q4W的剂量肠胃外施用。
16.权利要求1-14中任一项的方法，其中所述抗PD-1抗体以0.5-10mg/kg QW或Q2W或Q3W的剂量施用。
17.权利要求1-14中任一项的方法，其中所述抗PD-1抗体以0.5-10mg/kg Q2W或Q3W的剂量施用。
18.权利要求1-14中任一项的方法，其中所述抗PD-1抗体以0.5-5mg/kg Q2W、5-10mg/kg Q2W或2-5mg/kg Q3W的剂量肠胃外施用。
19.权利要求1-14中任一项的方法，其中所述抗PD-1抗体以0.5mg/kg Q2W、5mg/kgQ2W、10mg/kg Q2W、2mg/kg Q3W或5mg/kg Q3W的剂量肠胃外施用。
20.权利要求1-14中任一项的方法，其中所述抗PD-1抗体以约200mg的剂量肠胃外施用。
21.权利要求20的方法，其中所述抗PD-1抗体Q3W施用。
22.权利要求1的方法，其中所述患有HCC的患者具有HBV病毒载量<200IU/mL(～1000cps/mL)。
23.权利要求1的方法，其中所述患有HCC的患者具有活动性HBV感染需要在整个治疗期间和治疗后6个月内进行抗HBV抑制≥3个月。
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| PCT/CN2018/092827 WO2019001417A1 (en) | 2017-06-26 | 2018-06-26 | IMMUNOTHERAPY FOR HEPATOCELLULAR CARCINOMA |
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| CN111808194A (zh) * | 2020-07-13 | 2020-10-23 | 北京凯因科技股份有限公司 | 一种结合密蛋白的用于治疗癌症的人源化抗体 |
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| SG11201901141WA (en) | 2016-08-16 | 2019-03-28 | Beigene Ltd | Crystalline form of (s)-7-(1-acryloylpiperidin-4-yl)-2-(4-phenoxyphenyl)-4,5,6,7-tetra-hydropyrazolo[1,5-a]pyrimidine-3-carboxamide, preparation, and uses thereof |
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| TWI774726B (zh) | 2017-01-25 | 2022-08-21 | 英屬開曼群島商百濟神州有限公司 | (S)-7-(1-(丁-2-炔醯基)哌啶-4-基)-2-(4-苯氧基苯基)-4,5,6,7-四氫吡唑并[1,5-a]嘧啶-3-甲醯胺的晶型、及其製備和用途 |
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| JP2020525411A (ja) | 2020-08-27 |
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