CN107011441A - 抗pd1抗体及其作为治疗剂与诊断剂的用途 - Google Patents

抗pd1抗体及其作为治疗剂与诊断剂的用途 Download PDF

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CN107011441A
CN107011441A CN201710207300.0A CN201710207300A CN107011441A CN 107011441 A CN107011441 A CN 107011441A CN 201710207300 A CN201710207300 A CN 201710207300A CN 107011441 A CN107011441 A CN 107011441A
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宋兢
李康
张彤
徐兰兰
刘琦
彭浩
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Abstract

本发明涉及抗PD1抗体及其作为治疗剂与诊断剂的用途。本发明提供特异性结合程序性死亡‑1(PD1、Pdcd‑1或CD279)、抑制免疫细胞中PD1介导的细胞信号传导及活性，并结合PD1的配体所需要的一套氨基酸残基的抗体，及这些抗体治疗或诊断由PD1介导的功能所调控的癌症、传染性疾病或其他病理病症的用途。

Description

抗PD1抗体及其作为治疗剂与诊断剂的用途
本申请是申请日为2013年09月13日、中国申请号为201380079581.6、发明名称为“抗PD1抗体及其作为治疗剂与诊断剂的用途”的发明申请的分案申请。
发明背景
程序性死亡-1(Programmed Death-1；PD-1，也称为CD279)是一种与CD28/CTLA4共同刺激/抑制受体家族相关的55KD受体蛋白质(Blank等人，2005Cancer ImmunolImmunother 54:307-314)。在小鼠及人类中克隆及表征了编码PD-1的基因及cDNA(Ishida等人，1992EMBO J 11:3887-3395；Shinohara等人，1994Genomics 23:704-706)。全长PD-1含有288个氨基酸残基(NCBI登录号：NP_005009)。它的胞外域由氨基酸残基1-167组成，而胞质C末端尾部包含残基191-288，该尾部具有两个假设性免疫调节基序，一个是基于免疫受体酪氨酸的抑制基序(ITIM；Vivier等人，1997Immunol Today 18:286-291)，一个是免疫受体酪氨酸转换基序(ITSM；Chemnitz等人，2004J Immunol 173:945-954)。
迄今为止，两个序列相关配体PD-L1(B7-H1)与PD-L2(B7-DC)已被鉴定为与PD-1特异性相互作用，诱导细胞内信号转导，该细胞内信号转导抑制CD3及CD28介导的T细胞激活(Riley,2009Immunol Rev 229:114-125)，继而削弱T细胞活性(例如，减少细胞增殖、IL-2与IFN-γ分泌，以及其他生长因子及细胞因子分泌)。
经常在诸如T细胞、B细胞、单核细胞及天然杀伤(NK)细胞等免疫细胞中发现PD-1的表达。PD-1很少在诸如肌肉、上皮、神经元组织等其他人类组织中表达。此外，高水平的PD-1表达常常与免疫细胞的激活关联。举例而言，当藉由植物血球凝集素(PHA)或佛波醇酯(12-O-十四酰基佛波醇-13-乙酸酯或TPA)激活人类T细胞系Jurkat时，在Western印迹中可见PD-1的表达上调(Vibharka等人，1997Exp Cell Res 232:25-28)。在被抗CD3抗体刺激后，在受刺激鼠类T淋巴细胞及B淋巴细胞中及在原代人类CD4+T细胞中观察到相同现象(Agata等人，1996Int Immunol 8:765-772；Bennett等人，2003J Immunol170:711-118)。T效应细胞刺激后的PD-1表达增强使得朝耗竭及减少免疫活性方向再导向激活的T效应细胞。因此，PD-1介导的抑制信号在免疫耐受方面起到重要作用(Bour-Jordan等人，2011Immunol Rev 241:180-205)。
在各种涉及不同类型组织及器官的癌症方面，报告了肿瘤浸润淋巴细胞(TIL)中的PD-1表达及肿瘤细胞中的PD-1配体表达的增强，所述组织及器官诸如肺(Konishi等人，2004Clin Cancer Res 10:5094-5100)、肝(Shi等人，2008Int J Cancer 128:887-896；Gao等人，2009Clin Cancer Res 15:971-979)、胃(Wu等人，2006Acta Histochem 108:19-24)、肾(Thompson等人，2004Proc Natl Acad Sci 101:17174-17179；Thompson等人，2007ClinCancer Res 13:1757-1761)、乳腺(Ghebeh等人，2006Neoplasia 8:190-198)、卵巢(Hamanishi等人，2007Proc Natl Acad Sci 104:3360-3365)、胰腺(Nomi等人，2007ClinCancer Res13:2151-2157)、黑素细胞(Hino等人，2010Cancer 116:1757-1766)及食道(Ohigashi等人，2005Clin Cancer Res 11:2947-2953)。更经常地，那些癌症中的PD-1及PD-L1增强表达与患者生存结果的不良预后关联。具有抑制异体移植癌细胞生长的PD-1基因敲除的转基因小鼠进一步阐明在癌症根治或耐受的免疫系统调控中PD-1信号传导的重要性(Zhang等人，2009Blood 114:1545-1552)。
PD-1信号传导上调不仅导致对癌生长的免疫耐受，而且导致人类中的病毒感染及扩充。流行性肝感染病毒HBV及HCV诱导肝细胞中的PD-1配体的过度表达及激活T效应细胞中的PD-1信号传导，从而引起T细胞耗竭及对病毒感染的耐受(Boni等人，2007J Virol81:4215-4225；Golden-Mason等人，2008J Immunol 180:3637-3641)。同样地，HIV感染常常藉由类似机制避开人类免疫系统。拮抗剂分子对PD-1信号传导的治疗性调控可从耐受中反转免疫细胞，并经再激活以根治癌症及慢性病毒感染(Blank等人，2005Cancer ImmunolImmunother 54:307-314；Okazaki等人，2007Int Immunol 19:813-824)。
发明概述
本发明提供PD-1的免疫抑制的方法及组合物。在一个方面中，本发明提供一种抗体抗原结合域，该抗体抗原结合域特异性结合人类PD-1，且包含具有选自序列编号11-22、31-42及59-63的序列的互补决定区(CDR)。
CDR可经历重组成为重链可变区(Vh)及轻链可变区(Vκ)，所述区分别包含(CDR-H1、CDR-H2及CDR-H3)及(CDR-L1、CDR-L2及CDR-L3)序列，且保持特异于PD-1的结合及/或功能性。
在特定实施方案中，域包含重链可变区(Vh)或轻链可变区(Vκ)，所述可变区包含：
在特定实施方案中，域包含重链可变区(Vh)及/或轻链可变区(Vκ)，所述可变区包含：
a)mu317 CDR-H1、CDR-H2及CDR-H3(序列编号11-13)；
CDR-L1、CDR-L2及CDR-L3(序列编号14-16)；
b)mu326 CDR-H1、CDR-H2及CDR-H3(序列编号17-19)；
CDR-L1、CDR-L2及CDR-L3(序列编号20-22)；
c)317-4B6 CDR-H1、CDR-H2及CDR-H3(序列编号31-33)；
CDR-L1、CDR-L2及CDR-L3(序列编号34-36)；
d)326-4A3 CDR-H1、CDR-H2及CDR-H3(序列编号37-39)；
CDR-L1、CDR-L2及CDR-L3(序列编号40-42)；
e)317-1 CDR-H1、CDR-H2及CDR-H3(序列编号11、59、13)；
CDR-L1、CDR-L2及CDR-L3(序列编号14-16)；
f)317-4B2 CDR-H1、CDR-H2及CDR-H3(序列编号11、60、13)；
CDR-L1、CDR-L2及CDR-L3(序列编号61、15、16)；
g)317-4B5 CDR-H1、CDR-H2及CDR-H3(序列编号11、60、13)；
CDR-L1、CDR-L2及CDR-L3(序列编号61、15、16)；
h)317-4B6 CDR-H1、CDR-H2及CDR-H3(序列编号11、32、13)；
CDR-L1、CDR-L2及CDR-L3(序列编号61、15、16)；
i)326-1 CDR-H1、CDR-H2及CDR-H3(序列编号17、62、19)；
CDR-L1、CDR-L2及CDR-L3(序列编号20-22)；
j)326-3B1 CDR-H1、CDR-H2及CDR-H3(序列编号17、62、19)；
CDR-L1、CDR-L2及CDR-L3(序列编号20-22)；
k)326-3G1 CDR-H1、CDR-H2及CDR-H3(序列编号17、62、19)；及
CDR-L1、CDR-L2及CDR-L3(序列编号20-22)。
在特定实施方案中，域包含重链可变区(Vh)及轻链可变区(Vκ)，所述可变区包含：
(a)CDR-H1(序列编号31)、CDR-H2(序列编号12、32、59或60)及CDR-H3(序列编号33)，
CDR-L1(序列编号14、34或61)、CDR-L2(序列编号35)及CDR-L3(序列编号36)；或
(b)CDR-H1(序列编号37)、CDR-H2(序列编号18、38或62)及CDR-H3(序列编号39)，
CDR-L1(序列编号40)、CDR-L2(序列编号41)及CDR-L3(序列编号42)。在特定实施方案中，域包含重链可变区(Vh)或轻链可变区(Vκ)，所述可变区包含：
在特定实施方案中，域包含重链可变区(Vh)及轻链可变区(Vκ)，所述可变区包含：
在特定实施方案中，域特异性结合PD1残基：(a)K45及I93(基于2008PNAS,105:10483进行AA编号；相当于序列编号2中的K58及I106)；或(b)I93、L95及P97(基于2008PNAS,105:10483进行AA编号；相当于序列编号2中的I106、L108及P110)。
在特定实施方案中，域诱导与HEK293/OS8/PD-L1细胞或与HEK293/OS8/PD-L2细胞共同培养的HuT78/PD-1细胞中的IL-2释放，及/或抑制与HEK293/PD-L1细胞或与HEK293/PD-L2细胞共同培养的HuT78/P3Z细胞中的IL-2分泌。
本发明还提供一种抗体IgG4重链效应器或恒定域，该效应器或恒定域包含序列编号83-88中的任一者，尤其是序列编号87或88。
本发明还提供包含专属PD-1结合域的抗体、F(ab)或F(ab)2。
本发明还提供抗体，所述抗体包含专属PD-1结合域及IgG4重链效应器或恒定域，该效应器或恒定域包含序列编号83-88中的任一者，尤其是序列编号87或88。
本发明还提供一种编码专属PD-1结合域的多核苷酸，尤其是cDNA序列。
本发明提供使用该专属域的方法，该方法藉由向确定患有癌症或病毒感染或确定另外需要PD-1拮抗作用的个人施用该域。
本发明还提供融合蛋白，所述融合蛋白包含：(a)融合至小鼠CD8α的C末端域(113-220)的抗人类CD3单抗OKT3的单链可变片段(scFv)(序列编号89)；或(b)融合至人类CD3ζ链的胞质域的人类PD-1的胞外域及跨膜域(序列编号90)。
本发明还提供使用该专属融合蛋白的方法，该方法包含用表达融合蛋白的细胞系检定、筛选或选择抗PD-1抗体。
附图简述
图1：PD-1/Fc(上图)及PD-1/His(下图)的示意性呈现。ECD：胞外域。L：接头。H：His标签。Fc：人类IgG4中的γ4Fc片段。N：N末端。C：C末端。
图2：在ELISA中结合至人类PD-1的鼠类单抗的剂量依赖型反应曲线。各图的左上角指示鼠类单抗。单抗317及517共享重链及轻链的可变区的高度同源性。藉由直接OD450读数指示结合信号强度。抗原PD-1/His以50微升的体积中增加浓度，至高达每孔70纳克来包被。在实施例1中描述该方法。
图3：藉由FACS分析产生的结合至活细胞上所表达的人类PD-1的鼠类单抗的剂量依赖型反应曲线。在各个小图上指示鼠类抗体代码及EC50。MFI代表荧光强度均值。使HuT78/PD-1细胞以每孔5x104个细胞悬浮于96孔板中用于FACS。如实施例1中所描述执行PD-1单抗结合至细胞表面靶点及FACS检测。
图4：用于检定抗PD-1单抗的功能活性的细胞共同培养系统的示意性表示。T细胞(CD4+或CD8+)表示HuT78/PD-1或PBMC中的原代T细胞。TCR：T细胞受体。N：细胞核。C：细胞质。
图5：与HEK293/OS8/PD-L1细胞共同培养的HuT78/PD-1细胞中鼠类单抗诱导的IL-2分泌的剂量依赖型反应曲线。基线：在所有受测试浓度下由mIgG所诱导的平均IL-2释放。顶线：基于Prizm Software回归计算所得的最高IL-2释放。
图6：(A)图示与细胞系HEK293/OS8/PD-L1共同培养的PBMC(供体19)中抗PD-1单抗所诱导的IFN-γ分泌的直方图。(B)图示与细胞系HEK293/OS8/PD-L1共同培养的PBMC(供体20)中抗PD-1单抗所诱导的IFN-γ分泌的直方图。
图7：(A)与(B)藉由共同培养效应细胞(NK92MI/PD-1)及靶细胞(HuT78/PD-1)所得的抗PD-1单抗的ADCC活性。由代表性实验的两个数据点计算均值。将单抗添加到10μg/ml的浓度。如实施例9中所描述执行实验。
图8：藉由ELISA(上图)及Western印迹(下图)定位抗PD-1单抗的结合表位。使用含有WT或Mt PD-1的条件培养基藉由ELISA及Western印迹评估结合活性。**指示单抗结合活性降低至WT PD-1的25-50％的AA残基。***指示单抗结合活性降低至WT PD-1的25％以下的AA残基。
图9：来自不同健康供体的原代人类PBMC中由人源化抗PD-1单抗所诱导的IFN-γ释放，原代人类PBMC与HEK293/OS8/PD-L1细胞共同培养。
图10：由人源化抗PD-1单抗hu317(A)及hu326(B)增强的NK92MI/PD-1细胞的细胞毒性。靶肺癌细胞SK-MES-1/PD-L1与效应细胞以1:2的(T比E)比率共同培养，以及如实施例12所述进行检定。
图11：三个治疗群组：媒剂(PBS)、人类IgG(huIgG)及抗PD-1单抗(hu317-1/IgG4mt2)中的个体肿瘤生长曲线。各个曲线表示肿瘤生长路径，藉由各小图右侧指示数字对负有肿瘤小鼠编代码。在第1天时接种Hep3B/OS8/PD-L1细胞(自肝细胞癌系Hep3B建立)，在第15天时植入PBMC，及在第18天、第28天及第38天时分别注射三剂hu317-1/IgG4mt2。在实施例12中描述方法。
发明详述
当被PD-1的配体PD-L1或PD-L2接合时，PD-1启动免疫细胞中的抑制性信号传导。在癌长出及病毒感染的情况下，PD-1信号传导的激活促进了免疫耐受，导致癌症或病毒感染细胞逃避免疫监视及癌症转移或病毒负荷增长。藉由治疗剂抑制PD-1介导的细胞信号传导可激活包括T细胞、B细胞及NK细胞在内的免疫细胞，并因此增强抑制癌细胞生长或病毒感染的免疫细胞功能，及恢复免疫监视及免疫记忆功能以治疗此类人类疾病。
本发明提供抗体，这些抗体的功能拮抗免疫细胞中配体诱导及PD-1介导的细胞信号传导。鼠类抗PD-1抗体经人源化为在框架区中高度类似于人类抗体。以经修饰的人类IgG4变体形式产生的全抗体在效应器功能及物理化学特性的方面中具有独特的特征集合。所揭露抗PD-1抗体适合于癌症治疗、控制病毒感染及机制上涉及加剧免疫耐受的其他人类疾病中的治疗用途。
定义
除非上下文另有指示，否则术语“抗体”是用于广义上，且具体覆盖抗体(包括全长单克隆抗体)及抗体片段，只要它们识别PD-1即可。抗体分子通常为单特异性，但也可描述为独特特异性、异种特异性或多特异性。抗体分子经由特异性结合位点结合至抗原上的特定抗原决定簇或表位。“抗体片段”包含全长抗体的一部分，大体而言为全长抗体的抗原结合或可变区。抗体片段的实例包括Fab、Fab'、F(ab')2及Fv片段；双抗体；线性抗体；单链抗体分子；及由抗体片段形成的多特异性抗体。
可藉由熟悉此项技术者已知的方法获得单克隆抗体(单抗)。请参看例如，Kohler等人(1975)；美国专利第4,376,110号；Ausubel等人(1987-1999)；Harlow等人(1988)；及Colligan等人(1993)。本发明的单抗可以是任何免疫球蛋白类别，包括IgG、IgM、IgE、IgA及上述的任何亚类。可在体外或体内培养产生单抗的杂交瘤。在体内产生中可获得高滴度的单抗，其中将来自个别杂交瘤中的细胞经腹膜内注射至小鼠(诸如原始致敏Balb/c小鼠)体内以产生含有高浓度所欲单抗的腹水液。可使用熟习此项技术者所熟知的柱层析法自此类腹水液或自培养物上清液中纯化同种型IgM或IgG的单抗。
“经分离多核苷酸”是指已与天然产生状态下位于侧翼的序列分开的多核苷酸区段或片段，例如已自正常邻接于片段的序列移除的DNA片段，例如在天然产生片段的基因组中邻接于片段的序列。因此，该术语包括(例如)并入载体中、并入自主复制质粒或病毒中或并入原核生物或真核生物的基因组DNA中的重组DNA，或作为独立于其他序列的单独分子存在(例如，作为cDNA或由PCR或限制酶消化产生的基因组或cDNA片段)的重组DNA。还包括如下重组DNA，该重组DNA为杂合基因中编码额外多肽序列的一部分。
“构建体”意谓任何重组多核苷酸分子(诸如质粒、粘粒、病毒、自主复制多核苷酸分子、噬菌体或线性或环状单链或双链DNA或RNA多核苷酸分子)，衍生自任何来源，能够基因组整合或自主复制，构成如下多核苷酸分子，其中已经以功能操作的方式连接(即，可操作地连接)一或多个多核苷酸分子。重组构建体通常会包含可操作地连接至转录起始调节序列的本发明的多核苷酸，这些序列会导引多核苷酸在所欲宿主细胞中的转录。可使用异源及非异源(即，内源)启动子两者导引本发明的核酸的表达。
“载体”是指任何重组多核苷酸构建体，该构建体可用于转化的目的(即，将异源DNA引入到宿主细胞中)。一种类型的载体为“质粒”，是指环状双链DNA环，可将额外DNA区段连接至该环中。另一类型的载体为病毒载体，其中可将额外DNA区段连接至病毒基因组中。某些载体能够在被引入到的宿主细胞中自主复制(例如，具有细菌复制起点的细菌载体及游离型哺乳动物载体)。在引入到宿主细胞中后，其他载体(例如，非游离型哺乳动物载体)整合至宿主细胞的基因组中，且因此与宿主基因组一起复制。此外，某些载体能够导引被操作性连接的基因的表达。本文将此类载体称为“表达载体”。
本文所使用的“表达载体”是指能够在转化、转染或转导至宿主细胞中时复制及表达感兴趣基因的核酸分子。表达载体包含一或多个表型选择标记及复制起点，以确保维护载体及以在需要的情况下于宿主内提供扩增。表达载体进一步包含启动子，以驱动多肽在细胞内的表达。适宜表达载体可为衍生自pBR322的质粒或各种pUC质粒，这些质粒为市售。其他表达载体可衍生自噬菌体、噬菌粒或粘粒表达载体。
本发明的额外实施方案
在特定实施方案中，本发明提供自筛选本文所揭露的鼠类杂交瘤克隆所鉴定的小鼠单克隆抗体。
在其他实施方案中，本发明提供以下多核苷酸及蛋白质序列的组合物：
a)编码鼠类单抗317的重链可变区的cDNA序列，序列编号3；
b)mu317_Vh或鼠类单抗317的重链可变区的蛋白质序列(序列编号4)；
c)编码鼠类单抗317的轻链可变区的cDNA序列，序列编号5；
d)mu317_Vκ或鼠类单抗317的轻链可变区的蛋白质序列(序列编号6)；
e)编码鼠类单抗326的重链可变区的cDNA序列，序列编号7；
f)mu326_Vh或鼠类单抗326的重链可变区的蛋白质序列(序列编号8)；
g)编码鼠类单抗326的轻链可变区的cDNA序列，序列编号9；
h)mu326_Vκ或鼠类单抗326的轻链可变区的蛋白质序列(序列编号10)。
在一个方面中，本发明提供包含互补决定区(CDR)序列的组合物，这些序列介导结合至靶抗原PD-1，包括mu317及mu326的CDR序列：
a)mu317重链的CDR1(mu317H-CDR1)含有氨基酸序列GFSLTSYGVH(序列编号11)；
b)mu317H-CDR2含有氨基酸序列VIWAGGSTNYNSALMS(序列编号12)；
c)mu317H-CDR3含有氨基酸序列ARAYGNYWYIDV(序列编号13)；
d)mu317轻链的CDR1(mu317L-CDR1)含有氨基酸序列KASQSVSNDVA(序列编号14)；
e)mu317L-CDR2含有氨基酸序列YAFHRFT(序列编号15)；
f)mu317L-CDR3含有氨基酸序列HQAYSSPYT(序列编号16)；
g)mu326H-CDR1含有氨基酸序列GYTFTNYGMN(序列编号17)；
h)mu326H-CDR2含有氨基酸序列WINNNNGEPTYAEEFKG(序列编号18)；
i)mu326H-CDR3含有氨基酸序列ARDVMDY(序列编号19)；
j)mu326L-CDR1含有氨基酸序列RASESVDNYGYSFMH(序列编号20)；
k)mu326L-CDR2含有氨基酸序列RASNLES(序列编号21)；
l)mu326L-CDR3含有氨基酸序列QQSKEYPT(序列编号22)。
在另一实施方案中，本发明提供包含源自鼠类单抗mu317及mu326的人源化单克隆抗体的序列的组合物，包括：
a)人源化单抗hu317-4B6包含作为序列编号24的重链可变区(Vh)的蛋白质序列，该重链可变区由以下编码：
b)hu317-4B6_Vh的cDNA(序列编号23)；
c)人源化单抗hu317-4B6还包含作为序列编号26的轻链可变区(Vκ)的蛋白质序列，该轻链可变区由以下编码：
d)hu317-4B6的cDNA(序列编号25)；
e)人源化单抗hu326-4A3包含作为序列编号28的Vh的蛋白质序列，该Vh由以下编码：
f)hu326-4A3-Vh的cDNA(序列编号27)；
g)人源化单抗hu326-4A3还包含作为序列编号30的Vκ的蛋白质序列，该Vκ由以下编码：
h)hu326-4A3_Vκ的cDNA(序列编号29)；
i)hu317-4B2_Vh的蛋白质序列(序列编号43)与hu317-4B2_Vκ的蛋白质序列(序列编号44)；
j)hu317-4B5_Vh的蛋白质序列(序列编号45)与hu317-4B5_Vκ的蛋白质序列(序列编号46)；
k)hu317-1_Vh的蛋白质序列(序列编号48)与编码hu317-1_Vh的cDNA(序列编号47)；
l)hu317-1_Vκ的蛋白质序列(序列编号50)与编码hu317-1_Vκ的cDNA(序列编号49)；
m)hu326-3B1_Vh的蛋白质序列(序列编号51)与hu326-3B1_Vκ的蛋白质序列(序列编号52)；
n)hu326-3G1_Vh的蛋白质序列(序列编号53)与hu326-3G1_Vκ的蛋白质序列(序列编号54)；
o)hu326-1_Vh的蛋白质序列(序列编号56)与编码hu326-1_Vh的cDNA(序列编号55)；
p)hu326-1_Vκ的蛋白质序列(序列编号58)与编码hu326-1_Vκ的cDNA(序列编号57)；
q)源自mu317的其他人源化单抗的蛋白质序列(序列编号63-74)；
r)源自mu326的其他人源化单抗的蛋白质序列(序列编号75-82)。
在一个方面中，本发明提供包含人源化单克隆抗体的CDR序列的组合物。在相同系列的人源化单抗(诸如hu317或hu326)中可共享CDRs(参看表15-16)。以下列出非冗余CDRs：
a)H-CDR1序列GFSLTSYGVH(序列编号31)，为所有人源化单抗hu317及mu317重链所共享；
b)H-CDR3序列ARAYGNYWYIDV(序列编号33)，为所有人源化单抗hu317及mu317重链所共享；
c)L-CDR1序列KSSESVSNDVA(序列编号34)，为所有人源化单抗hu317-4B2、hu317-4B5及hu317-4B6轻链所共享；
d)L-CDR2序列YAFHRFT(序列编号35)，为所有人源化单抗hu317及mu317轻链所共享；
e)L-CDR3序列HQAYSSPYT(序列编号36)，为所有人源化单抗hu317及mu317轻链所共享；
f)hu317-4B6_Vh中的H-CDR2序列VIYADGSTNYNPSLKS(序列编号32)；
g)hu317-4B2_Vh与hu317-4B5_Vh中的H-CDR2序列VIYAGGSTNYNPSLKS(序列编号60)；
h)hu317-1_Vh中的H-CDR2序列VIWAGGSTNYNPSLKS(序列编号59)；
i)hu317-1_Vk中的L-CDR1序列KASQSVSNDVA(序列编号11)；
j)H-CDR1序列GYTFTNYGMN(序列编号37)，为所有人源化单抗hu326及mu326重链所共享；
k)H-CDR3序列ARDVMDY(序列编号39)，为所有人源化单抗hu326及mu326重链所共享；
l)L-CDR1序列RASESVDNYGYSFMH(序列编号40)，为所有人源化单抗hu326及mu326轻链所共享；
m)L-CDR2序列RASNLES(序列编号41)，为所有人源化单抗hu326及mu326轻链所共享；
n)L-CDR3序列QQSKEYPT(序列编号42)，在为所有人源化单抗hu326及mu326轻链所共享；
o)hu326_4A3_Vh中的H-CDR2序列WINNNNAEPTYAQDFRG(序列编号38)；
p)hu326_1及其他hu317单抗的Vh中的H-CDR2序列WINNNNGEPTYAQGFRG(序列编号62)。
在另一方面中，本发明提供抗原上人源化抗PD-1单抗的特定结合表位及其功能用途。使PD-1中配体结合所需要的六个关键氨基酸(AA)残基个别突变，及使用突变体与野生型PD-1蛋白质评估结合表位。将突变使抗体结合明显削弱的残基视为关键或明显结合表位。单抗hu317-4B5及hu317-4B6的明显结合表位为K45及I93(基于2008PNAS,105:10483进行AA编号；相当于序列编号2中的K58及I106)；及单抗hu326-3B1及hu317-4A3的明显结合表位为I93、L95及P97(基于2008PNAS,105:10483进行AA编号；相当于序列编号2中的I106、L108及P110)。
在又一方面中，本发明提供包含重组人类IgG4变体的恒定区序列的组合物，该恒定区序列可连接至特定抗体(包括人源化抗PD-1单抗)的可变区，这些恒定区序列展示出优选的效应器功能及物理化学特性。序列如下：
IgG4mt10的恒定区序列(序列编号88)；
a)IgG4mt1的参考序列(序列编号83)；
b)IgG4mt2的参考序列(序列编号84)；
c)IgG4mt6的参考序列(序列编号85)；
d)IgG4mt8的参考序列(序列编号86)；
e)IgG4mt9的参考序列(序列编号87)。
在另一实施方案中，本发明提供检定抗PD-1抗体功能的方法，该方法使用表达重组融合蛋白OS8的质粒产生稳定细胞系HEK293/OS8/PD-L1或HEK293/OS8/PD-L2，该稳定细胞系共同表达OS8(一种T细胞激活分子)及PD-1配体。使用细胞系藉由共同培养接合T细胞及PBMCs，以评估抗PD-1单抗的功能性(参看实施例3及实施例4)。或者，使用表达重组融合蛋白P3Z的另一质粒产生稳定细胞系HuT78/P3Z，其中P3Z用作分子传感器及信号转导介体。当由PD-1配体接合P3Z时，P3Z会传导细胞内信号以激活HuT78细胞中的IL-2释放。这些系统可用于评估抗PD-1单抗的抑制效果(参看实施例3)。
在一个方面中，本发明提供包含重组融合蛋白的氨基酸序列的组合物，这些序列如下：
a)OS8的蛋白质序列(序列编号89)；
b)P3Z的蛋白质序列(序列编号90)。
在另一方面中，本发明提供产生表达本文所描述的重组融合蛋白的稳定细胞系的方法，及使用该系统定量检定抗PD-1单抗的功能活性的方法。
在另一实施方案中，本发明提供编码主题蛋白质的多核苷酸。可将多核苷酸可操作地连接至异源转录调节序列用于表达及可并入载体、细胞等中。
在另一实施方案中，本发明提供鼠类抗PD-1抗体及人源化型式的抗PD-1抗体，这些人源化型式的抗PD-1抗体包括hu317-4B6、hu317-4B5、hu317-4B2等及hu326-4A3、hu326-3B1、hu326-3G1等，这些抗体具有抑制PD-1介导的信号转导及激活免疫细胞的功能，这些功能触发包括细胞因子分泌及对靶细胞(诸如癌细胞)的细胞毒性的级联免疫反应，及提供这些抗体的此类功能用途。
在一个方面中，本发明提供激活表达PD-1的若干类型免疫细胞的人源化抗PD-1抗体，这些免疫细胞包括人类T细胞、NK细胞及PBMCs，这些免疫细胞的功能为放大免疫应答信号，调动免疫系统，及充当免疫效应细胞以便清除癌细胞及病毒感染，及提供这些抗体的此类功能用途。
在另一方面中，将人源化抗PD-1单抗用作治疗剂来治疗涉及由PD-1介导的细胞内信号传导抑制免疫细胞而导致病情恶化的人类疾病，尤其是癌症及病毒感染。
本发明的组合物对于治疗癌症、神经退化性疾病及传染性疾病(尤其是病毒性疾病)及人类PD-1的不适宜或不利表达是其病因学或病理学的组份的其他疾患是有用的。因此，本发明提供用专属抗PD-1蛋白质在有需要的受试者中治疗癌症或抑制肿瘤发展的方法。本发明进一步提供专属多核苷酸制造在受试者中治疗癌症或抑制肿瘤发展的药剂中的用途。
本发明包括所叙述特定实施方案的所有组合。本发明的进一步实施方案及可应用性的完整范畴将自下文所提供的详细描述变得显而易见。然而，应理解，尽管详细描述及特定实施例指示本发明的优选实施方案，但仅以说明的方式提供这些描述及实施例，因为本发明的精神及范畴内的各种改变及修改将自此详细描述对熟悉此项技术者变得显而易见。出于所有目的，包括引文在内的本文所引用的所有公开物、专利及专利申请将以引用的方式全部并入本文。
实施例
实施例1：抗PD-1单克隆抗体的产生
基于常规杂交瘤融合技术(Kohler与Milstein 1976Eur J Immunol 6:511-519；de St Groth与Sheidegger 1980，J Immunol Methods 35:1-21；Mechetner 2007MethodsMol Biol378:1-13)并略作修改产生抗PD-1单克隆抗体(单抗)。选择在酶联免疫吸附检定(ELISA)及荧光激活细胞分选(FACS)检定中具有高结合活性的单抗以便进一步作表征。
用于免疫及结合检定的PD-1重组蛋白质
含有全长人类PD-1cDNA的表达质粒购自Origene(产品编号SC117011，NCBI登录号：NM_005018.1，中国，北京)。PCR扩增由PD-1的氨基酸(AA)1-168(序列编号1、序列编号2)组成的胞外域，在基于pcDNA3.1的表达载体(Invitrogen，Carlsbad，CA，USA)中亚克隆，其中C末端融合至His6标签或者融合至人类IgG4重链的γFc域，从而产生两个重组融合蛋白表达质粒PD-1-EC/His与PD-1-EC/Fc(缩写为PD-1/His与PD-1/Fc)。图1图示免疫原/抗原蛋白质的示意性呈现。针对重组融合蛋白产生，在1-3升培养基(Invitrogen)中将PD-1/His与PD-1/Fc质粒瞬时转染入293-F细胞，及在配备有旋转振动器的CO2培育箱中培养5-7天。收集含有重组蛋白质的上清液及在15000g下离心处理30分钟使该上清液透明。经由使用Ni-Sepharose Fast Flow(产品编号17531801，GE Lifesciences，中国，上海)的固定化金属亲和层析法，然后使用HiLoad 16/60Superdex 200柱(产品编号17106901，GE Lifesciences，中国，上海)执行大小排阻层析法纯化PD-1/His。使用蛋白G Sepharose Fast Flow柱(产品编号17061805，GE Lifesciences)纯化PD-1/Fc。用磷酸盐缓冲盐水(PBS)透析PD-1/His与PD-1/Fc蛋白质两者，并以小等分试样储存于-80℃冷冻箱中。
基于已公开序列(NCBI登录号：NM_014143)，藉由Genescript(中国，南京)化学合成编码人类PD-L1的cDNA。PD-L2表达质粒购自Origene(产品编号SC108873，NCBI登录号：NM_025239.2，中国，北京)。在pcDNA3.1/潮霉素(产品编号V870-20，Invitrogen)及pcDNA3.1/V5-His(产品编号V810-20，Invitrogen)中分别克隆两个cDNA。
稳定表达细胞系
藉由分别将含有PD-1、PD-L1及PD-L2的pcDNA3.1质粒转染至HuT78(ATCC，Manassas，VA，USA)及HEK293(ATCC)，及然后用含有每毫升200微克潮霉素(产品编号10687-010，Invitrogen)或1mg G418(Sigma)的培养基选择来建立表达人类PD-1、PD-L1或PD-L2的稳定细胞系。藉由常规方法分离单个克隆，该方法为有限稀释或从培养皿表面采集单个群落。分别使用抗PD-1、PD-L1及PD-L2抗体(产品编号12-9969、17-5983、12-5888，eBioscience，San Diego，USA)藉由Western印迹及FACS分析筛选所有克隆，及选择顶级表达克隆用于FACS结合检定以筛选杂交瘤单克隆抗体，或在功能性检定中使用。
免疫、杂交瘤融合及克隆
用含有5微克PD-1/Fc的100μl佐剂(产品编号KX0210041，康碧泉公司，中国，北京)皮下注射使八至十二周大Balb/c小鼠(购自北京华阜康生物科技股份有限公司，中国，北京)免疫。间隔三周注射上述免疫原两次来实施免疫。在第二次免疫后两周，藉由FACS(下文中)评估小鼠血清的PD-1结合。选择血清中具有高抗PD-1抗体滴度的小鼠及在腹膜内注射无任何佐剂的50微克PD-1/Fc进行强化。在强化后三天，使用标准技术(Gefter,M.L.等人，1977Somat Cell Genet，3:231-236)使脾细胞分离及与鼠类骨髓瘤细胞系SP2/0细胞(ATCC)融合。
藉由ELISA及FACS评估抗体的PD-1结合活性
如在“Flanagan,M.L.等人，2007Methods in Molecular Biology 378:33-52”中所描述的并略作修改，最初藉由酶联免疫吸附检定(ELISA)筛选杂交瘤克隆的上清液。简而言之，在96孔板(深圳市金灿华实业有限公司，中国，深圳)中的每个孔基底上包被50微升磷酸盐缓冲盐水(PBS)中50-200纳克PD-1/His或PD-1/Fc蛋白质。使用HRP偶联抗小鼠IgG抗体(产品编号7076S，Cell Signaling Technology，USA与中国上海)及化学发光试剂(产品编号PA107-01，TIANGEN，中国)检测及显现ELISA信号，该信号在450nm的波长处由读板仪(PHREAstar FS，BMG LABTECH，Germany)读取。使用常规方法藉由荧光激活细胞分选(FACS)进一步验证ELISA阳性抗体产生者克隆。在V形底96孔板(产品编号3897，Corning，USA与中国上海)中用来自抗PD-1杂交瘤的上清液染色上文所描述的PD-1稳定表达细胞系HuT78/PD-1(105个细胞/孔)。为了封闭人类Fc受体，用人类IgG(20μg/ml)(产品编号H11296，LifeHolder，USA与中国上海)预温育细胞。用DylightTM649标记山羊抗小鼠IgG抗体(产品编号405312，Biolegend，Sandy Diego，USA)检测PD-1抗体及使用流式细胞仪(GuavaeasyCyte 8HT，Merck-Millipore，USA与中国上海)检测细胞荧光。
在ELISA与FACS检定两者中展示阳性信号的杂交瘤细胞的条件培养基经受功能性检定以鉴定在基于人类免疫细胞的检定中(在本文中)具有良好功能活性的抗体。进一步亚克隆及表征具有阳性功能活性的抗体。
亚克隆及对无血清或低血清培养基的适应
藉由受限稀释的常规方法亚克隆来自经由ELISA、FACS及功能性检定的初级筛选的阳性杂交瘤克隆。在96孔板中放入各个阳性克隆，在CO2培育箱中，在具有10％胎牛血清(FBS，产品编号SH30084.03，Hyclone，中国，北京)的RPMI1640培养基(产品编号SH30809.01B，Hyclone，中国，上海)中培养。选择各个有限稀释板中的三个亚克隆及藉由FACS及功能性检定表征这些亚克隆。将经由功能性检定所选择的亚克隆定义为单克隆抗体。顶级亚克隆经适应在具有1-3％FBS的CDM4MAb培养基(产品编号SH30801.02，Hyclone)中生长。
单克隆抗体的表达及纯化
在37℃的CO2培育箱中，在CDM4MAb培养基(产品编号SH30801.02，Hyclone)或Freestyle293表达培养基(产品编号12338018，Invitrogen)内分别培养产生鼠类单克隆抗体的杂交瘤细胞或重组抗体质粒转染的293-F细胞(产品编号R79007，Invitrogen)5至7天。经由在10,000g下离心处理30分钟移除所有细胞及细胞碎片收集条件培养基，并在纯化前经由0.22μm薄膜过滤。遵循制造商规则，将鼠类或重组抗体加入及结合至蛋白A柱(产品编号17127901，GE Life Sciences)，用PBS清洗，在含有20mM柠檬酸盐、150mM NaCl的缓冲液(pH3.5)中洗脱。用1M Tris pH8.0中和所洗脱物质，这些物质通常含有90％以上纯度的抗体。用PBS透析或使用HiLoad 16/60Superdex200柱(产品编号17531801，GE LifeSciences)进一步纯化经蛋白A亲和纯化的抗体以移除聚集体。藉由在280nm处测量吸收率或藉由Bradford检定(产品编号1856210，Thermo Scientific，Rockford，IL，USA)测定蛋白质浓度，使用所界定浓度的牛IgG(产品编号23212，Thermo Scientific)作为标准品。在-80℃的冷冻箱中以等分试样储存纯化抗体。
实施例2：抗PD-1抗体中的结合活性的比较
经由筛选数千种杂交瘤克隆，发明人鉴定出一些顶级单克隆抗体(单抗)，这些单克隆抗体以高特异性及强度结合人类PD-1。如ELISA检定(图2)所示，顶级抗体中的三者引发此结合强度及特异性。FACS分析结果表明，选定单克隆抗体结合至表达于细胞表面上的天然PD-1蛋白质。鼠类单抗317(mu317)、mu326及mu150展示出浓度依赖型结合活性，且其结合EC50(50％活性处的有效浓度)明显比对照mu55更低(图3)。
藉由表面等离子共振(SPR)评定单抗结合亲和力
对在ELISA及FACS中具有高结合活性以及在基于细胞的检定中(在本文中)具有有力功能活性的单抗在实时结合反应中检查结合动力学常数。使用蛋白A Flow柱(产品编号17531801，GE Life Sciences)，然后使用HiLoad 16/60Superdex200柱(产品编号17106901，GE Life Sciences)执行排阻层析法从杂交瘤上清液中纯化鼠类抗PD-1单抗。将纯化抗PD-1抗体浓缩至PBS中0.5-1mg/mL及以等份试样储存于-80℃冷冻箱中。
为了测定PD-1单抗的结合亲和力，使用BIAcoreTMT-200仪器(GE Life Sciences)在HBS-N缓冲液(10mM HEPES pH 7.4，0.15M NaCl，3mM EDTA，0.005％v/v表面活性剂P20，GE Healthcare)中执行SPR测量。使用标准伯胺偶联规程产生抗小鼠Fc CM5生物传感器芯片(GE Healthcare)。以10μl/分钟在抗小鼠Fc表面上捕捉0.3μg/ml的PD-1单抗达1分钟。以30μl/分钟在抗体结合表面上注射自3.3nM连续稀释至120nM的PD-1/Fc达3分钟，然后经历10分钟解离阶段。使用一对一朗谬(Langmuir)结合模型(BIA Evaluation Software,GELife Sciences)计算结合速率(Ka或kon)及解离速率(Kd或koff)。以比率koff/kon来计算平衡解离常数(KD)。
如表1所示，与mu317相关的关联序列家族成员mu326及mu517两者具有分别等于0.324nM及0.289nM的亚纳摩尔KD，此情况明显比mu134更佳。表1中所列出的三个单抗的kon速率相似，但koff速率明显不同，mu134中所观察到的解离速率快得多。
表1：某些顶级抗体的结合常数
藉由SPR测定抗PD-1Fab的亲和力
藉由PCR将抗PD-1单抗转换成Fab形式以使重链及轻链的可变区分别融合至人类IgG2-CH1及κ链恒定区的N末端，及在pcDNA3.1载体(Invitrogen)中亚克隆。使用与整个抗体的瞬时表达类似的瞬时转染方法在293-F细胞中共同表达两个表达载体。简而言之，PCR扩增Fabκ链及在基于pcDNA3.1的表达载体(Invitrogen，Carlsbad，CA，USA)中亚克隆。在另一质粒中，藉由交叠PCR将重链可变区(VH)以及来自人类IgG2中的CH1编码序列与C末端c-Myc-His8标签融合，及随后在表达载体中亚克隆。在IgG2重链中引入C232S及C233S(Kabat残基编号，Kabat等人，Sequence of proteins of immunologic interest，第5版，Bethesda,MD,NIH 1991)突变以防止二硫键交换及稳定人类IgG2处于IgG2-A构象(Lightle等人，2010Protein Sci 19(4):753-762)。两个构建体含有Fab成熟序列上游的信号肽。藉由上述2个质粒共同转染入293-F细胞实现Fab的分泌表达及在转染后6-7天收获细胞培养物上清液。使用Ni-Sepharose Fast Flow柱(产品编号17531801，GE Life Sciences)，然后使用HiLoad 16/60Superdex200柱(产品编号17106901，GE Life Sciences)执行大小排阻层析法从细胞培养物上清液中纯化带有His8标签的Fab。将纯化Fab浓缩至PBS中0.5-5mg/mL及以等份试样储存于-80℃冷冻箱中。
针对抗PD-1Fab的亲和力测定，使用BIAcoreTMT-200仪器(GE Life Sciences)进行SPR检定。简而言之，将人类PD-1/His或食蟹猴PD-1/His偶联至已活化的CM5生物传感器芯片(产品编号BR100530，GE Life Sciences)以实现大约100-200个响应单位(RU)，然后用1M乙醇胺封闭未反应基团。以30μL/分钟在SPR运行缓冲液(10mM HEPES,150mM NaCl,0.05％Tween20,pH7.4)中注射自0.12nM至90nM递增浓度的Fab样品，且藉由减去来自空白流动室的RU来计算人类PD-1/His或猴PD-1/His上的结合响应。使用一对一朗谬结合模型(BIAEvaluation Software,GE Life Sciences)计算结合速率(kon)及解离速率(koff)。以比率koff/kon来计算平衡解离常数(KD)。
表18中列出SPR测定的抗PD-1Fab的结合亲和力。各个抗PD-1Fab以高亲和力(KD＝0.15-1nM)结合至人类PD-1。除326-3G1外的所有Fab以略微较低但相当(KD的5倍内)亲和力结合至食蟹猴PD-1。
实施例3：抗PD-1抗体在人类T细胞中的功能活性
稳定细胞系的产生
逆转录病毒封装细胞系PT67、人类T细胞系HuT78及HEK293购自美国典型培养物保藏中心(ATCC,Rockville,MD)。根据前述操作程序(Zhang等人，2005Blood 106:1544-1551)，使用含有PD-1基因的pFB-neo载体(Strategene/Agilent Tech，Santa Clara，CA)藉由逆转录病毒转导产生表达PD-1的HuT78亚株HuT78/PD-1。藉由将抗人类CD3单抗OKT3的单链可变片段(scFv)(Kipriyanov等人，1997，PEDS 10:445-453)融合至小鼠CD8α的C末端域(113-220)(NCBI登录号：NP_001074579.1)建构T细胞接合物，膜锚定嵌合抗体(OS8)，该小鼠CD8α的C末端域包括铰链、跨膜及胞质域。藉由此举，将抗CD3scFv锚定至细胞表面作为T细胞激活物。将人类PD-L1、PD-L2及OS8cDNA亚克隆入pcDNA3.1载体。藉由用成对质粒共同转染HEK293及Hep3B细胞(ATCC)，然后用潮霉素或G418选择10-14天来产生共同表达OS8与PD-L1或PD-L2cDNA两者的稳定细胞系HEK293/OS8/PD-L1、Hep3B/OS8/PD-L1及HEK293/OS8/PD-L2。随后藉由如先前所描述的有限稀释法克隆细胞系(Fuller SA等人，Curr ProtocMol Biol.，第11章：第11.8.单元，2001)。藉由将人类PD-1的胞外域及跨膜域融合至人类CD3ζ链的胞质域(NCBI登录号：NP_932170.1)构建称为P3Z的嵌合PD-1受体。将P3Z编码cDNA序列克隆入pFB-neo，并经由逆转录病毒转导输送入HuT78细胞中以产生HuT78/P3Z细胞。
藉由HuT78/PD-1细胞中的IL-2释放测定PD-1抗体功能
为了测定抗PD-1抗体是否能阻断PD-L1诱导的PD-1信号传导的相互作用，用杂交瘤上清液或PD-1抗体预温育HuT78/PD-1细胞(在96孔板中每孔1.5x104个细胞)15分钟，之后在37℃下于平底板中与HEK293/OS8/PD-L1或HEK293/OS8/PD-L2细胞(每孔4x104)共同培养，每孔以200μl RPMI1640生长培养基供给营养。在16-18小时后，收集共同培养物上清液。藉由ELISA使用人类IL-2Ready-Set-Go！ELISA试剂盒(产品编号88-7025，eBiosciences，San Diego，CA)检定IL-2。在此检定中，用抗PD-1抗体阻断PD-1信号传导引发增强的TCR信号传导及IL-2产生(图4)。
如图5及表2所示，鼠类抗PD-1单抗mu317及mu326引发比mu30明显更高的功能活性，抑制PD-L1诱导的PD-1信号传导，从而导致IL-2分泌增加。两者比mu30抗体皆具有较高IL-2分泌(顶线，表2)，分别为675及634pg/ml，且两者皆具有更低的EC50(在IL-2分泌诱导的50％水平上的单抗的有效浓度)。
表2：与HEK293/OS8/PD-L1细胞共同培养的HuT78/PD-1细胞中藉由抗PD-1单抗所诱导的IL-2释放
由抗PD-1单抗结合HuT78/PD-1细胞不仅阻断了PD-L1诱导的T细胞激活，而且阻断了PD-L2诱导的IL-2释放。表3呈现数据，这些数据展示，mu317及mu326在激活T细胞中具有比mu476高得多的效能，如IL-2分泌的参数(EC50)所指示。
表3：与HEK293/OS8/PD-L2细胞共同培养的HuT78/PD-1细胞中藉由抗PD-1单抗所诱导的IL-2释放
藉由HuT78/P3Z细胞中的IL-2释放的反向信号传导测定PD-1抗体功能
在嵌合受体P3Z中，用CD3ζ的胞质域替换PD-1信号传导域。因此，P3Z在与PD-L1结合后介导激活，而非像原始PD-1受体那样产生抑制。在此检定中，用杂交瘤上清液或PD-1抗体预温育HuT78/P3Z细胞(3x104/孔)15分钟，之后在37℃于96孔平底板(总体积200μl/孔)中与HEK293/PD-L1或HEK293/PD-L2细胞(5x104/孔)共同培养。在16-18小时后，收集上清液及藉由如上所述的ELISA检定IL-2产生。
藉由在上文所描述的反向信号传导检定中直接读出T细胞激活进一步证实鼠类抗PD-1单抗的功能活性。与上文所描述的结果一致，mu317及mu326在发明人所筛选的单抗中具有最佳功能活性。如表4及表5所示，就IC50及最大抑制两方面而言，mu317及mu326比低活性单抗之一的mu37有力得多。
表4：在与HEK293/PD-L1细胞共同培养的HuT78/P3Z细胞中藉由抗PD-1单抗抑制IL-2分泌
表5：在与HEK293/PD-L2细胞共同培养的HuT78/P3Z细胞中藉由抗PD-1单抗抑制IL-2分泌
实施例4：与HEK293/OS8/PD-L1细胞共同培养的原代人类PBMC中藉由抗PD-1单抗激活IFN-γ分泌
为了验证针对PD-1选定的顶级单抗是否也对原代人类免疫细胞施加功能性效果，发明人藉由使用新鲜分离的外周血单个核细胞(PBMC)检定抗体功能，这些PBMC主要由T细胞(50-70％)、B细胞及NK细胞(15-30％)及单核细胞(2-10％)组成。根据制造商说明书，藉由使用Ficoll淋巴细胞分离介质(Histopaque-1077；Sigma-Aldrich，MO)的密度梯度离心处理而从健康供体中分离人类PBMC。所有人类血液采集遵循Beigene的内部程序。随后用抗CD3单抗(40ng/mL)OKT3(产品编号16-0037，eBioscience，CA)刺激PBMCs达3天，之后进行检定。FACS分析(实施例1)显示，激活的PBMC(原代T细胞)上的PD-1表达均有不同程度的增加，取决于不同供体(表6)。为了测定在结合TCR/CD3复合物后预激活T细胞对PD-1配体阳性肿瘤细胞的反应，在96孔平底板中将PBMCs(1x104)与HEK293/OS8/PD-L1或HEK293/OS8/PD-L2细胞(3x104)共同培养15-18小时。藉由ELISA使用Ready-Set-Go！ELISA试剂盒(产品编号88-7316，eBiosciences)对无细胞上清液检定IFN-γ水平，此IFN-γ水平为T细胞激活以及其他免疫细胞激活的最突出指标(Thakur A.等人，2012Vaccine，30:4907-4920)。
图6表明预激活PBMCs与HEK293/OS8/PD-L1细胞的共同培养液中存在单抗mu317及mu326导致以剂量依赖型方式增加IFN-γ累积。尽管用对照鼠类IgG处理的IFN-γ的基础水平在不同供体间各异，但由mu317或mu326处理的PBMC，在0.1至10μg/ml抗体处理范围内，IFN-γ分泌的增加在统计学上是明显的。与mIgG处理的PBMCs的对应水平相比，由介于0.1至10μg/ml浓度水平之间的mu317及mu326所诱导的IFN-γ分泌分别在供体-19的PBMCs中增加2.5至3.2倍及在供体-20的PBMCs中增加1.4至2.3倍。
实施例5：藉由抗PD1单抗激活人类NK细胞
用于NK细胞中的功能性检定的稳定细胞系
先前报告了原代人类NK细胞响应IL-2处理表达PD-1蛋白质及抑制PD-1介导的信号传导，增强了NK细胞的细胞毒性(2010Blood,116:2286)。为了定量检定NK细胞中由抗PD-1单抗所施加的功能效果，人类NK细胞系NK92MI(ATCC)及肺癌细胞系SK-Mes-1(ATCC)经工程设计以根据先前所描述的操作程序，藉由逆转录病毒转导分别稳定表达人类PD-1及PD-L1(Zhang等人，2005，Blood 106:1544-1551；Zhang等人，2006，Cancer Res，66:5927)。两个稳定细胞系被命名为NK92MI/PD-1及SK-Mes-1/PD-L1。
抗PD-1抗体促进NK92MI/PD-1细胞中的IFN-γ产生及分泌
藉由定量测量NK92MI/PD-1细胞中的IFN-γ产生及分泌检定抗PD-1单抗对NK细胞的功能活性，在96孔平底板中将这些NK92MI/PD-1细胞与肺癌细胞系SK-MES-1/PD-L1以1:2的比率共同培养，每孔总计6x104个细胞。在共同培养开始前15分钟，将抗PD-1单抗添加至NK92MI/PD-1细胞，随后在CO2培育箱中将这些细胞共同培养过夜。藉由实施例4中所描述的ELISA对无细胞上清液检定IFN-γ水平。
所有抗PD-1单抗触发IFN-γ产生，自具有低浓度抗体处理的基线明显增加至具有高浓度抗体处理的顶线。两个顶级抗体mu317及mu326具有比参照抗体5C更低的EC50，显示这些抗体具有对NK细胞有力得多的激活效果(表7)。
表7：在抗PD-1单抗及SK-MES-1/PD-L1细胞存在下，NK92MI/PD-1细胞在培养基中分泌的IFN-γ(pg/ml)
抗PD-1抗体增强由NK92MI/PD-1细胞所介导的癌细胞杀死
藉由使用CytoTox 96非放射性细胞毒性检定试剂盒(Promega，Madison，WI)的乳酸脱氢酶(LDH)释放检定测定NK92MI/PD-1细胞针对SK-MES-1/PD-L1细胞的细胞毒性。简言之，用抗PD-1单抗以最终浓度为0.004-10μg/ml的范围将NK92MI/PD-1细胞(105)预温育15分钟，并以效应细胞与肿瘤细胞(E:T)成5:1的比率将SK-MES-1/PD-L1细胞(2x104)添加至96孔V形底板中的免疫细胞培养物中，随后共同培养5小时。将完全肿瘤细胞裂解设定为最大细胞杀死，将各个样品的LDH释放检定读值计算为最大细胞杀死的百分比。使用基线的10％作为共同标准，跨板标准化所有样品的细胞杀死(％)。
在上文所设定的特异性细胞毒性检定中，所选定抗PD-1单抗以高浓度的单抗输入引发净肿瘤细胞杀死(＝顶线-基线)，范围自19％至20.2％。Mu317及mu326具有比mu336更低的EC50，显示触发NK92MI/PD-1细胞介导的肿瘤细胞杀死的较佳效力(表8)。
表8：由抗PD-1单抗诱导的NK92MI/PD-1细胞对肿瘤细胞的细胞毒性
实施例6：PD-1单抗的克隆及序列分析
在100mm组织培养皿中将分泌特定单抗的鼠类杂交瘤克隆培养至3x106至10x106个细胞的密度，经由在摇摆桶旋转器中以1500rpm离心处理来收获细胞。遵循制造商操作程序，使用Ultrapure RNA试剂盒(产品编号CW0581，CWBIOTECH，中国，北京)分离总细胞RNA。在二次去离子水中再悬浮RNA，藉由NanoDrop(ThermoFisher，中国，上海)测量浓度。
基于先前所报告的序列(Brocks等人，2001Mol Med 7:461-469)，藉由Invitrogen(中国，北京)合成用于单抗cDNA克隆的PCR引物。使用逆转录酶(产品编号AH301-02，Transgen Biotech，中国，北京)合成第一链cDNA。使用PCR试剂盒(产品编号Ap221-12，Transgen Biotech，中国，北京)且遵循制造商操作程序进行特定单抗cDNA的PCR扩增。由服务提供商对PCR产物直接测序(GeneWiz，中国，北京)或将PCR产物亚克隆入pCR载体(Invitrogen)，随后测序(GeneWiz)。
藉由序列同源性比对分析鼠类单抗的蛋白质序列。基于序列同源性及表位定位结果(实施例13)将单抗分组。基于Kabat(Wu,T.T.及Kabat,E.A.,1970J.Exp.Med.132:211-250)及IMGT系统(Lefranc M.-P.等人，1999Nucleic Acids Research，27，209-212)，藉由序列批注及藉由基于因特网的序列分析(http://www.imgt.org/IMGT_vquest/share/textes/index.html与http://www.ncbi.nlm.nih.gov/igblast/)鉴定互补决定区(CDR)。如表9所示，mu317及mu326的CDR在序列长度及同源性上极为不同。
表9：mu317及mu326的CDR
实施例7：鼠类单抗的人源化
抗体3D结构的模拟
针对mu317及mu326的可变域模拟三维结构，以便鉴定对于支持CDR环结构可能重要的框架残基。在第一轮抗体人源化中将潜在重要的框架残基保持为原始鼠类残基。采用先前建立的针对抗体的结构建模方法(Morea等人，Methods 2000 20:267-279)基于抗体的已知规范结构模拟抗PD-1单抗的3D结构(Al-Lazikani等人，1997Journal of MolecularBiology 273:927-948)。简而言之，在PDB数据库(Protein Data Bank，http://blast.ncbi.nlm.nih.gov/)中检索(blast)鼠类抗体的各个可变域(Vk及Vh)的序列以鉴定具有已知高分辨率结构(分辨率小于2.5埃)的最同源抗体序列。针对mu317及mu326建模选定的结构模板(表10中列出)在L-CDR1、L-CDR2、L-CDR3、H-CDR1及H-CDR2中具有与待建模的靶抗体相同类别的规范环结构。若Vκ及Vh的模板来自不同的免疫球蛋白，则藉由主链原子的最小平方拟合将这些模板堆叠(pack)在一起，以形成Vκ-Vh界面残基的杂合结构，该结构被Swiss模型程序用作结构同源性建模的模板(Kiefer等人，2009Nucleic Acids Research37，D387-D392)。在保持主链构象的同时，调整某些侧链构象。在亲本结构与建模结构具有相同残基的位点处，保持侧链构象。在残基为不同的位点处，在模板结构、旋转异构体库及堆叠考虑的基础上对侧链构象建模。在同源性建模后，使用PLOP程序(Jacobson等人，2002Journal of Physical Chemistry 106:11673-11680)细化同源性模型以最小化所有原子能量及优化Vκ及Vh界面。执行此步骤以改良立体化学，尤其是在来自不同抗体的结构的区段已被结合在一起的那些区域中。
表10：用于抗体结构模拟的结构模板
也针对CDR嫁接317-1及326-1模拟结构，以便导引更多轮抗体工程设计以增强人源化的程度及/或增强抗体稳定性。表10也列出选定结构模板。以与上文程序类似的方式实行结构模拟，所不同的是分别从针对317-1的PDB模板1AY1及针对326-1的模板3CXD中取得H-CDR3的可能构象，这些模板含有相似大小及躯干(torso)区域的H-CDR3。使用PLOP实行嫁接H-CDR3残基的能量最小化。
人源化
对于抗PD-1单抗的人源化，发明人藉由检索IMGT(http://www.imgt.org/IMGT_vquest/share/textes/index.html)及NCBI(http://www.ncbi.nlm.nih.gov/igblast/)网站中的人类免疫球蛋白基因数据库搜寻与mu317及mu326可变区的cDNA序列同源的人类种系IgG基因。将与PD-1单抗具有高同源性的人类IGVH及IGVκ选为人源化模板。
原则上藉由CDR嫁接实施人源化。在第一轮人源化中，如上文所描述的，藉由模拟3D结构导引可变区的框架序列中鼠类至人类氨基酸残基的突变，且仅使得其变化保持了总体抗体及CDR环结构的鼠类氨基酸残基突变至人类序列。人源化单抗的初始型式为hu317-1(序列编号47-50)及hu326-1(序列编号55-58)，它们包含：重链，其中人源化可变重链(Vh)融合至人类IgG2恒定区(NCBI登录号：P01859)；及轻链，其中人源化可变轻链κ(Vκ)融合至人类IgκC区(NCBI登录号：P01834)。同样地，发明人从mu317及mu326中产生嵌合抗体，这些嵌合抗体由融合至人类IgG2恒定区的鼠类VH及融合至人类IgκC区的鼠类Vκ组成。将全嵌合抗体分别命名为ch317及ch326。如实施例1所描述表达及纯化所有重组单抗。
FACS及功能性检定表明，单抗hu317-1几乎保持了与mu317及ch317相同的结合及功能活性。可藉由在FACS中使用两个不同检测抗体(山羊抗小鼠IgG及山羊抗人类IgG)的事实解读mu317对比ch317与hu317-1之间在FACS分析中的EC50差异。在两个功能性检定中，更同等地处理317的所有三个型式，且结果也接近于彼此(表11)。
作为针对mu326的初轮人源化的结果，单抗hu326-1保持了与亲本ch326及mu326相似的功能特征，尽管FACS结合检定及基于HuT78/PD-1细胞的IL-2释放检定中的功能活性可比ch326略微更弱(表12)。
表11：藉由FACS及功能性检定比较mu317、ch317及hu317-1
表12：藉由FACS及功能性检定比较mu326、ch326及hu326-1
基于第一轮人源化，发明人进一步使hu317-1_Vh及_Vκ的框架(FR)中的其他鼠类氨基酸(AA)残基个别突变，以评估对抗体功能的影响。如表13所示，hu317-1的Vh中的七个个体突变及Vκ中的一个突变皆具有相似功能活性。在一些Vh突变中仅观察到较小变化，诸如hu317-2_K71V在突变中具有略微较弱的抑制功能。然而，当所有鼠类氨基酸残基一起突变成人类时(hu317-3A)，在FACS及IL-2释放检定中功能比其余突变明显更弱。
在上文所描述的初期试验中，除留下少数鼠类AA残基外，hu326-1在FR中达到明显的人源化水平。然而，hu326-1具有比mu326更弱的功能。因此，发明人实行更个别的突变，这些突变返回到鼠类残基或者朝向人类残基，以探索各个个体AA对单抗326功能的贡献。表14呈现基于hu326-1_Vh模板(序列编号56、序列编号57)产生的所有单个AA突变及其功能性检定结果。大多数突变展示出比hu326-1更好的功能活性，匹配原始mu326单抗。一对突变(E46K及F95Y)展示出EC50或IC50上略微较少的效力，表明那些残基在抗体结构及功能中的作用。
表13：hu317-1框架中具有人源化突变的Fab的功能活性的比较
表14：hu326-1框架中具有突变的单抗的功能活性的比较
为了探索可在人类中用作治疗剂的单抗317及326的最佳可能Vh及Vκ序列组成，发明人考虑到抗体特征实行各种组合突变(包括在CDR序列中的一些突变)，这些抗体特征诸如FR中的人源化水平、功能活性、物理化学特性、抗体依赖性细胞介导的细胞毒性(ADCC)及补体依赖性细胞毒性(CDC)。认为突变中的大多数未通过合格标准。经由工程设计过程，出于它们的潜在治疗效用选择人源化重组单抗中的六个：hu317-4B2(序列编号43-44)、hu317-4B5(序列编号45-46)、hu317-4B6(序列编号23-26)、hu326-3B1(序列编号51-52)、hu326-3G1(序列编号53-54)及hu326-4A3(序列编号27-30)。将单抗的CDRs与原始鼠类抗体相比较，展示于表15及表16中。
在六个单抗中，hu317-4B2、hu317-4B5及hu317-4B6在序列上彼此密切相关且在功能活性及强度上极为相似。另一方面，hu326-3B1、hu326-3G1及hu326-4A3在序列及功能性上彼此相当接近(表17-18)。在两组单抗的各者内，尽管存在一些较小差异，但它们也共享在序列及功能以外的许多其他特征，诸如物理化学特性及结合表位(实施例10及11中所描述)。
表15：单抗317的不同型式间的CDR比较
表16：单抗326的不同型式间的CDR比较
表17：藉由ELISA及FAC S检定的人源化单抗的结合活性
表18：藉由SPR检定的Fab的结合亲和力
藉由SPR的人源化抗PD-1Fab的亲和力测定
藉由PCR将抗PD-1单抗转换成Fab型式以使重链及轻链的可变区分别融合至人类IgG2-CH1及κ链恒定区的N末端，及在pcDNA3.1载体(Invitrogen)中亚克隆。使用与整个抗体的瞬时表达类似的瞬时转染方法在293-F细胞中共同表达两个表达载体。简而言之，PCR扩增Fabκ链及在基于pcDNA3.1的表达载体(Invitrogen，Carlsbad，CA，USA)中亚克隆。在另一质粒中，藉由交叠PCR将重链可变区(VH)以及来自人类IgG2中的CH1编码序列与C末端c-Myc-His8标签融合，及随后在表达载体中次克隆。在IgG2重链中引入C232S及C233S(Kabat残基编号，Kabat等人，Sequence of proteins of immunologic interest，第5版，Bethesda,MD,NIH 1991)突变以防止二硫键交换及稳定人类IgG2处于IgG2-A构象(Lightle等人，2010Protein Sci 19(4):753-762)。两个构建体含有Fab成熟序列上游的信号肽。藉由上述2个质粒共同转染入293-F细胞实现Fab的分泌表达及在转染后6-7天收获细胞培养物上清液。使用Ni-Sepharose Fast Flow柱(产品编号17531801，GE Life Sciences)，然后使用HiLoad 16/60Superdex200柱(产品编号17106901，GE Life Sciences)执行大小排阻层析法从细胞培养物上清液中纯化带His8标签的Fab。将纯化Fab浓缩至PBS中0.5-5mg/mL及以等份试样储存于-80℃冷冻箱中。
为了抗PD-1Fab的亲和力测定，使用BIAcoreTMT-200仪器(GE Life Sciences)进行SPR检定。简而言之，将人类PD-1/His或食蟹猴PD-1/His偶联至已活化的CM5生物传感器芯片(产品编号BR100530，GE Life Sciences)以实现大约100-200个响应单位(RU)，然后用1M乙醇胺封闭未反应基团。以30μL/分钟在SPR运行缓冲液(10mM HEPES,150mM NaCl,0.05％Tween20,pH7.4)中注射自0.12nM至90nM递增浓度的Fab样品，且藉由减去来自空白流动室的RU来计算在人类PD-1/His或猴PD-1/His上的结合响应。使用一对一朗谬结合模型(BIAEvaluation Software,GE Life Sciences)计算结合速率(kon)及解离速率(koff)。以比率koff/kon来计算平衡解离常数(KD)。
表18中列出SPR测定的抗PD-1Fab的结合亲和力。各个抗PD-1Fab以高亲和力(KD＝0.15-1nM)结合至人类PD-1。除326-3G1外的所有Fab以略微较低但相当(KD的5倍内)亲和力结合至食蟹猴PD-1。
实施例8：具有经修饰人类IgG4恒定区的重组抗PD-1单抗的产生及表达
由于PD-1主要表达于激活T细胞中，连接至天然产生类型IgG-Fc模块的PD-1阻断性抗体预期取决于IgG亚类会以不同程度诱导Fc介导的效应器功能(诸如ADCC及CDC)，从而导致消除激活T细胞(Natsume A等人，2009Drug Des Devel Ther.3:7-16)。在许多先前报告中已展示人类抗体亚类IgG4，IgG4具有适度ADCC且几乎没有CDC效应器功能(Moore GL等人，2010MAbs，2:181-189)。另一方面，已发现天然IgG4在压力条件下(诸如在酸性缓冲液中或在上升的温度下)不太稳定(Angal,S.1993Mol Immunol，30:105-108；Dall'Acqua,W.等人，1998Biochemistry，37:9266-9273；Aalberse等人，2002Immunol，105:9-19)。为了使PD-1+T细胞免遭杀死及改良抗PD-1抗体的物理化学特性，将人源化单抗连接至由突变组合所设计的IgG4以具有减小的或零FcγR结合或C1q结合活性，因此减弱或消除ADCC及CDC效应器功能。考虑到抗体作为生物学药物的物理化学特性，IgG4的不太理想的固有特性之一为其在溶液中动态分离两个重链而形成半抗体，此举导致经由称为“Fab臂交换”的过程在体内产生双特异性抗体(Van der Neut Kolfschoten M等人，2007Science，317:1554-157)。在位置228(EU编号系统)处的丝氨酸至脯氨酸的突变呈现对IgG4重链分离的抑制(Angal,S.1993Mol Immunol，30:105-108；Aalberse等人，2002Immunol，105:9-19)。已报告铰链及γFc区中的一些氨基酸残基对抗体与Fcγ受体的相互作用具有影响(Chappel SM等人，1991Proc.Natl.Acad.Sci.USA，88:9036-9040；Mukherjee,J.等人，1995FASEB J，9:115-119；Armour,K.L.等人，1999Eur J Immunol，29:2613-2624；Clynes,R.A.等人，2000NatureMedicine，6:443-446；Arnold J.N.，2007Annu Rev Immunol，25:21-50)。此外，人类群体中一些罕见发生的IgG4同等型也可引发不同的物理化学特性(Brusco,A.等人，1998Eur JImmunogenet，25:349-55；Aalberse等人，2002Immunol，105:9-19)。然而，将先前发现的所有突变及同等型集中成特定抗体并不保证理想抗体分子共享诸如上文所描述的用作治疗剂的所有特征，原因可为组合突变的矛盾效果及可变区对抗体的效应器功能及物理化学特性的影响(Igawa T.等人，2010Prot Eng Design Select，23:385-392；Perchiacca J.M.与Tessier P.M.，2012Ann Rev Biomol Eng 3:263-286)。
为了产生具有最小ADCC、CDC及不稳定性的抗PD-1单抗，发明人藉由引入一定数目突变组合来修饰人类IgG4的铰链及γFc区，创建IgG4mt1至IgG4mt12。如发明人的检定结果所示，一些经修饰的IgG4变体显然不太理想，表19中列出若干相关IgG4变体及修饰后序列。本文描述这些抗体的评估。
表19：IgG4变体的序列修饰
实施例9：IgG4mt10没有FcγR结合、具有最低的ADCC及CDC效应器功能
当抗体结合至细胞表面靶蛋白质，然后连接至效应细胞上所表达的Fcγ受体(FcγR)时，启动ADCC。很清楚地记载了人类IgG1对FcγR具有比IgG2及IgG4明显更高的结合亲和力，尤其是结合FcγR-I及FcγR-IIIA，该亲和力与IgG1激活ADCC的强度相关联。联想到ADCC，当抗体交联细胞表面靶点及C1q蛋白质，继之以补体复合物形成及靶细胞裂解的级联反应时，激活CDC。作为ADCC及CDC的代理，抗体结合至FcγR及C1q的检定可充当ADCC及CDC的基本指标。因此，发明人系统地评估单抗对所有主要FcγR的结合。
FcγR结合
藉由流式细胞术测定各种IgG4突变体对FcγR的结合。简言之，建立表达人类FcγR的一系列HEK293转染子。这些转染子表达FcγRI、FcγRIIA、FcγRIIB或FcγRIIIA。与FcRγ共同表达多亚基FcγR(即，FcγRI及FcγRIIIA)。还包括多态性变体(即，FcγRIIA H131与R131、FcγRIIIA F158与V158)。使用二体(山羊抗人类IgG F(ab)'2-Alexa Fluor 488，Jackson Immuno Research，West Grove，PA，USA)检测抗PD-1单抗与经修饰IgG4变体(表19)对FcγR+HEK293细胞的结合。如预期，IgG1型式的抗PD-1单抗(hu317-1/IgG1及hu317-4B6/IgG1)强有力地结合所有FcγR，包括FcγRI、FcγRIIA(H131及R131等位基因)、FcγRIIB及FcγRIIIA(V158及F158等位基因)(表20)。有趣的是，当以相同IgG4变体型式(诸如IgG4mt1或者IgG4mt6型式)产生两个不同型式的人源化单抗，即hu317-1及hu317-4B6(在Vh及Vκ两者中具有差异)时，它们的结合强度(MFI)自2倍至接近于100倍的范围变化(例如，455.2/115.7＝3.9倍；13.6/1.0＝13.6倍；434.6/4.9＝88.7倍；等等，参看表20)。与其他人的先前发现一致的是，抗体的可变区对与FcR的结合具有明显影响，因此，对诸如ADCC的效应器功能施加影响(Igawa T.等人，2010Prot Eng Design Select，23:385-392；Perchiacca J.M.与Tessier P.M.，2012Ann Rev Biomol Eng 3:263-286)。
如表20中所表明，当以IgG4mt10型式产生hu317-4B6及hu326-4A3时，它们在表中所列出的PD-1单抗及IgG变体型式中以及研究中已测试的许多其他人源化单抗及IgG型式中具有对FcγR的最低结合活性。IgG4mt10型式的hu317-4B6及hu326-4A3在这个方面的独特性不可延伸至具有某些远序列同源性的人源化单抗的相同家族(诸如hu317-1)，如上文所描述。
表20：由FACS所测定的抗PD-1单抗对FcγR的结合强度(MFI*)
ADCC
经典ADCC涉及藉由抗体结合至FcγRIIIA或CD16而激活NK细胞。为了验证人源化抗PD-1单抗是否诱导ADCC，将NK92MI/CD16V细胞用作效应细胞，该细胞藉由共同转导含有CD16(V158等位基因)与FcRγ基因的表达质粒自NK92MI细胞(ATCC)产生，及将表达PD-1的T细胞系HuT78/PD-1用作靶细胞。在96孔V形底板中将NK92MI/CD16V细胞(4x104)与相等数目的HuT78/PD-1细胞共同培养5小时。由前文中所描述的LDH释放检定测定细胞毒性。结果确认，与阳性对照相比较，hu317-4B2/IgG4mt6、hu317-4B6/IgG4mt6、hu317-4B6/IgG4mt10及hu326-4A3/IgG4mt10全部具有ADCC的基础水平(图7)。那4个单抗之间ADCC的较小差异可归因于实验误差(参看图7中的误差棒)。
CDC
大体而言，人类IgG4抗体并不经由经典路径诱导任何CDC。使用PD-1表达T细胞系HuT78/PD-1及来自健康供体的新鲜人类血清评估IgG4mt10型式的抗PD-1单抗是否会触发CDC。藉由Celltiter glo检定试剂盒(Promega，中国，北京)测定CDC的细胞裂解。简言之，在96孔平底板中，在37℃在具有抗PD-1抗体(10μg/ml)的无血清RPMI1640(Invitrogen)中温育HuT78/PD-1细胞(2x104)15分钟，随后添加正常人类血清(NHS)，终浓度为15％或50％，总体积为120μl。在37℃过夜温育后，细胞裂解并检定ATP浓度。为了测试IgG4mt10的人源化抗PD-1单抗是否能经由CDC杀死PD-1+原代T细胞，用抗CD3抗体OKT3(40ng/ml)预激活自健康供体分离的PBMCs达3天，随后与抗PD-1抗体加NHS共同培养。ATP量与培养液中存在的细胞数目成正比。使用96孔荧光计(PHERA Star FS,BMG LABTECH)读取荧光。以与活细胞数目成比例的相对荧光单位(RFU)表述这些结果。百分比CDC活性计算如下：％CDC活性＝[(RFU测试-RFU背景)/(完全细胞裂解下的RFU-背景下的RFU)]x100。大体而言，发明人未能检测由结合至激活PBMCs的IgG4mt10型式的抗PD-1单抗所介导的任何ADCC。在高度敏感性实验条件下，诸如使用PD-1高表达细胞系、高血清与抗体浓度，发明人在一些场合中检测到极低水平的CDC，且不同型式与抗PD-1单抗之间不存在太多差异，此指示IgG4变体型式的抗PD-1单抗保持与常见形式的IgG4相同的低CDC活性或无CDC活性的特征。
实施例10：IgG4mt10型式的人源化抗PD-1单抗在压力条件下具有增强的稳定性
抗PD-1抗体在高温及酸性条件中的稳定性
用于稳定性研究的抗PD-1抗体全部由前文中所描述的蛋白A柱及随后的大小排阻层析法(SEC)纯化。在纯化后，在分析性大小排阻层析法-高效液体层析法(SEC-HPLC)中监测纯化抗体样品的聚集体含量，这些含量处于0％-0.5％的范围内。
对于SEC-HPLC分析，在等度洗脱条件下(洗脱缓冲液0.2M磷酸钠，pH7.2)，使用TSKgel G3000SWXL柱(7.8x300mm，产品编号08541，Tosoh Bioscience，中国，上海)分析抗体样品，随后在UV-215nm处检测。在各次执行中，将10微升抗体样品加载到柱上并以1mL/分钟的流速洗脱。将抗体的二聚体或较大聚集体种类与单体种类分开，并基于UV线的积分峰面积测定二聚体及聚集体的百分比。
对于速度增强的贮存稳定性研究，将抗PD-1抗体(PBS中10-40mg/mL)保存于40-50℃的培育箱中长达4-7天，以便测试抗体在高温条件中的稳定性。随后在SEC-HPLC中针对热诱导形成二聚体及聚集体分析抗体样品。对于所分析的各个抗PD-1抗体，2％以下变成较高分子量种类(二聚体及聚集体)，说明抗PD-1抗体在高温条件下具有良好稳定性。
在下游制造过程中，酸性条件中的抗体稳定性已成为关键性挑战(Liu等人，2010mAbs 2:480-499)。自蛋白A的抗体洗脱及病毒的灭活通常需要在低pH(2.5-4)条件中温育抗体。然而，此类酸性条件可潜在引发抗体变性及聚集。已知人类IgG4比IgG1及IgG2稳定性低(2002Immunology 105:9)。因此，发明人检定用各种IgG4突变体型式所产生的人源化单抗。简而言之，藉由1:1体积的各个抗体样品(PBS中10mg/mL)与低pH缓冲液混合研究低pH条件中的抗体稳定性，这些缓冲液含有50mM柠檬酸钠，100mM NaCl，pH分别为3.6、3.3、3.0或2.7。在室温下温育1小时后，藉由1:5稀释入含有0.2M磷酸钠(pH7.2)的SEC-HPLC洗脱缓冲液中和低pH条件中的抗体样品。如上文所描述进行SEC-HPLC分析及量化由低pH条件所诱导的二聚体及聚集体的百分比。IgG1型式的抗PD-1单抗317-4B6在生物工艺相关的酸性条件中最稳定，即使当pH值低到2.7时亦如此。在若干IgG4变体中产生的抗PD-1单抗之中，hu317-4B6/IgG4mt10与hu326-4A3/IgG4mt10在酸性缓冲液条件下最稳定(表21)，因为酸诱导的聚集体明显减少到与IgG1型式的抗PD-1单抗317-4B6及326-4A3相当的水平(即，可溶性聚集体小于2％(表21))。
表21：在酸性缓冲液中形成及藉由SEC-HPLC检定的二聚体及可溶性聚集体
实施例11：定位抗PD-1单抗的结合表位
关于PD-1/PD-L1及PD-1/PD-L2复合物的晶体结构的先前报告已经阐明而理解PD-1上配体结合所需要的关键氨基酸(AA)残基(Zhang等人，2004Immunity，20:337-347；LinD.Y.等人，2008PNAS 105:3011-3016；Lazar-Molnar E.等人，2008PNAS，105:10483-10488)。事实上，在受体上经由点突变分析鉴定此类AA残基中的六个是PD-L1结合所需要的。六个AA残基中的五个也是PD-L2结合所需要的(Lin D.Y.等人，2008PNAS 105:3011-3016)。基于结构导引突变分析中的信息，发明人假设，功能性单抗阻断PD-1介导的信号传导的最有效方式为藉由结合至六个关键AA残基，从而占据配体结合所需要的结合表位而与PD-1配体竞争。为了探索该假设及理解功能性PD-1抗体的作用机制，发明人已藉由将六个关键AA的每一个个别地替换成Ala，产生PD-1的六个突变体，即K45A、I93A、L95A、P97A、I101A及E103A(基于Lin D.Y.等人，2008PNAS 105:3011-3016进行的AA残基编号)。将突变型PD-1/Fc及PD-1/His(图1)作为模板，用于使用快速诱变系统(产品编号FM111，TransgenBiotech，中国，北京)的PCR导引诱变或滚环诱变。在发明人基于pcDNA的表达载体中亚克隆所有突变体，并藉由测序验证。藉由瞬时转染(实施例1中所描述)表达突变型及野生型PD-1蛋白质，并在培养4-6天后制备这些蛋白质。藉由Western印迹分析条件培养基(CM)，以就质量与数量而言验证PD-1蛋白质表达。在清除细胞碎片后，在ELISA分析或Western印迹中直接使用上清液(CM)以进行表位定位。
为了研究人源化抗PD-1单抗的结合表位，执行使用野生型(WT)及突变型(Mt)PD-1的ELISA检定以评估hu317-4B5、hu317-4B6、hu326-3B1及hu326-4A3的结合活性。为了进行比较以检查抗体结合签名的独特性，在研究中包括两个参考抗体(分别来自US8008449B2及US8168757B2的参考抗体-1与参考抗体-2)。在相同ELISA检定中，在用于所有单抗的96孔板中包被相等体积的含有WT或Mt PD-1的CM。使用WT PD-1结合信号的平均ELISA读数作为标准，标准化所有ELISA结果。针对对某特定Mt PD-1的最高抗体结合读数(设定为100％)进一步标准化针对该特定Mt PD-1的ELISA结合信号。为了便于数据分析，当单抗针对特定突变体的ELISA结合信号相对于WT PD-1下降到50％以下时，将该氨基酸残基定义为明显结合表位，因为其突变明显消除了抗体结合。同样地，若单抗针对特定突变体的ELISA结合信号下降到25％以下，则定义为极其明显。如图8所示，PD-1中关键AA残基中的两者K45及I93为单抗hu317-4B5及hu317-4B6结合的明显或极其明显表位，且三个AA残基I93、L95及P97为hu326-3B1及hu326-4A3的明显或极其明显表位。另一方面，两个参考抗体具有可区别的结合表位，P97对于参考抗体-1明显，而L95及P97对于参考抗体-2明显。
有趣的是，当PD-1蛋白质在Western印迹中变性后，单抗hu317-4B5及hu317-4B6仍然能够结合至WT PD-1，虽然关键结合表位(K45及I93)彼此并不接近(非线性)。此表明，在Western印迹过程的SDS-PAGE中变性后，PD-1蛋白质在某种程度上复性，从而允许抗PD-1单抗识别及结合它。利用此观察结果，发明人针对上文ELISA研究中所使用的所有六个抗体执行Western印迹分析。Western印迹的总体结果很好地印证了ELISA结果，即，，其突变在ELISA中引发弱结合信号的明显或极其明显表位也提供与其他突变型PD-1的结合相比最弱的Western印迹带(图8)。还观察到ELISA与Western印迹之间的一些较小差异，例如，由参考抗体-2在I93A及E103A上的ELISA结合信号比Western印迹中的信号相对更强。这可能指示，那些AA残基还可帮助结合，因为那些AA残基突变影响结合，但仅在压力条件下(即，变性或丧失天然构象)。如表22中所归纳的，本发明中的抗PD-1单抗具有与其他抗PD-1抗体不同的可鉴定结合表位。
表22：抗PD-1单抗的关键表位的归纳*
实施例12：抗PD-1单抗在异种移植物小鼠模型中激活原代人类PBMC及抑制肿瘤生长
人源化抗PD-1单抗激活人类PBMC
贯穿人源化过程，人源化抗PD-1单抗在各种阶段处保持相似功能活性，由ELISA、FACS及基于免疫细胞的细胞因子释放检定评估该功能活性。为了确认人源化单抗的最终型式的功能，发明人使用原代人类PBMCs检定了hu317-4B5、hu317-4B6、hu326-3B1及hu326-4A3的激活功能。结果表明，尽管因个体遗传背景不同造成四个供体之间的激活程度不同，但贯穿人源化的那些单抗维持了原始鼠类单抗激活原代PBMC的功能(图9)。
人源化抗PD-1单抗增强基于NK细胞的对癌细胞的细胞毒性
联想到原始鼠类单抗，人源化抗PD-1单抗hu317-4B5、hu317-4B6、hu326-3B1及hu326-3G1以剂量依赖型方式增强针对靶肺癌细胞SK-MES-1/PD-L1的NK92MI/PD-1细胞介导的细胞毒性(图10，表23)。很明显，原理上人源化抗PD-1单抗可发挥破坏由PD-1信号传导所介导的免疫细胞耐受的功能，从而增强免疫细胞(例如，NK细胞及细胞毒性T淋巴细胞)的杀癌活性。
人源化抗PD-1单抗在小鼠异种移植物癌症模型中体内激活人类PBMCs及抑制肿瘤生长
所有上述实验证据显示，抗PD-1单抗可在小鼠癌症模型中起作用，这些模型利用异种移植有人类癌细胞的免疫受损小鼠，随后植入人类PBMCs及应用单抗处理，以抑制体内癌细胞生长。实验设计如下。在七至八周大SCID雄性小鼠(Vital River Laboratories，中国)右体侧处皮下接种50％Matrigel(BD Biosciences，New Jesey，USA)中的3x106个Hep3B/OS8-PD-L1细胞。在肿瘤接种后15天，使带肿瘤大小100-250mm3的小鼠随机分为三个处理组。瘤内注射来自2个健康供体的100微升汇集PBMCs(5x105)。在PBMCs植入后3天，经由皮下注射以10mg/kg的剂量分别施用抗PD-1抗体(Hu317-IgG4mt2)及人类IgG。抗体处理每10天重复一次，共计3次。在平行组中注射PBS作为阴性对照。在第7天开始，使用测径规每周两次测量肿瘤。使用以下公式计算肿瘤体积：[D x(d2)]/2，其中D表示肿瘤的大直径，及d表示小直径。所有动物研究皆遵循Beigene动物护理及使用程序执行。
在体内研究中，尽管对照组中的60％肿瘤为自动消退，但体内实验的剩余部分仍相当具有教益，此呈现于图11中。在对照组中，媒剂处理组或人类IgG(huIgG)处理组各具有40％的肿瘤(5只小鼠中的2只)比在起始点处的基线长出更大。PBS处理组中的两个肿瘤生长大得多(2000mm3以上，由于超过规程的肿瘤大小限制，提前终止一只带肿瘤小鼠)。huIgG处理组中的两个肿瘤生长到800及1370mm3的大小，明显超过164mm3的平均基线，但比PBS处理的肿瘤小。另一方面，在抗PD-1单抗(hu317-1/IgG4mt2)处理组中，肿瘤完全消退或者接近于基线大小(一个肿瘤＝200mm3，该肿瘤在自PBMC植入起两周时消退到基线的50％后缓慢重新生长)。结果显示，上文所描述的抗PD-1单抗能在小鼠体内癌症模型中激活抑制肿瘤细胞生长的人类免疫细胞，该结果与上文所描述的体外实验结果一致。
序列表
<110> 百济神州有限公司
李康
张彤
宋兢
徐兰兰
刘琦
彭浩
<120> 抗PD1抗体及其作为治疗剂与诊断剂的用途
<130> BGB 108
<160> 90
<170> PatentIn version 3.5
<210> 1
<211> 444
<212> DNA
<213> 人（Homo sapiens）
<400> 1
ccaggatggt tcttagactc cccagacagg ccctggaacc cccccacctt ctccccagcc 60
ctgctcgtgg tgaccgaagg ggacaacgcc accttcacct gcagcttctc caacacatcg 120
gagagcttcg tgctaaactg gtaccgcatg agccccagca accagacgga caagctggcc 180
gccttccccg aggaccgcag ccagcccggc caggactgcc gcttccgtgt cacacaactg 240
cccaacgggc gtgacttcca catgagcgtg gtcagggccc ggcgcaatga cagcggcacc 300
tacctctgtg gggccatctc cctggccccc aaggcgcaga tcaaagagag cctgcgggca 360
gagctcaggg tgacagagag aagggcagaa gtgcccacag cccaccccag cccctcaccc 420
aggccagccg gccagttcca aacc 444
<210> 2
<211> 148
<212> PRT
<213> 人（Homo sapiens）
<400> 2
Pro Gly Trp Phe Leu Asp Ser Pro Asp Arg Pro Trp Asn Pro Pro Thr
1 5 10 15
Phe Ser Pro Ala Leu Leu Val Val Thr Glu Gly Asp Asn Ala Thr Phe
20 25 30
Thr Cys Ser Phe Ser Asn Thr Ser Glu Ser Phe Val Leu Asn Trp Tyr
35 40 45
Arg Met Ser Pro Ser Asn Gln Thr Asp Lys Leu Ala Ala Phe Pro Glu
50 55 60
Asp Arg Ser Gln Pro Gly Gln Asp Cys Arg Phe Arg Val Thr Gln Leu
65 70 75 80
Pro Asn Gly Arg Asp Phe His Met Ser Val Val Arg Ala Arg Arg Asn
85 90 95
Asp Ser Gly Thr Tyr Leu Cys Gly Ala Ile Ser Leu Ala Pro Lys Ala
100 105 110
Gln Ile Lys Glu Ser Leu Arg Ala Glu Leu Arg Val Thr Glu Arg Arg
115 120 125
Ala Glu Val Pro Thr Ala His Pro Ser Pro Ser Pro Arg Pro Ala Gly
130 135 140
Gln Phe Gln Thr
145
<210> 3
<211> 354
<212> DNA
<213> 小家鼠（Mus musculus）
<400> 3
caggtgcagc tgaaggagtc aggacctggc ctggtggcgc cctcaaagaa cctgtccatc 60
acttgcactg tctctgggtt ttcattaacc agctatggtg tacactggat tcgccagcct 120
ccaggaaagg gactggaatg gctgggagta atatgggccg gtggaagcac aaattataat 180
tcggctctca tgtccagact gagcatcagc aaagacaact ccaggagcca agttttctta 240
agaatgaaca gtctgcaaac tgatgacaca gccatgtact actgtgccag agcctatggt 300
aactactggt acatcgatgt ctggggcgca gggaccacgg tcaccgtctc ctca 354
<210> 4
<211> 118
<212> PRT
<213> 小家鼠（Mus musculus）
<400> 4
Gln Val Gln Leu Lys Glu Ser Gly Pro Gly Leu Val Ala Pro Ser Lys
1 5 10 15
Asn Leu Ser Ile 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 Ser Ala Leu Met
50 55 60
Ser Arg Leu Ser Ile Ser Lys Asp Asn Ser Arg Ser Gln Val Phe Leu
65 70 75 80
Arg Met Asn Ser Leu Gln Thr Asp Asp Thr Ala Met Tyr Tyr Cys Ala
85 90 95
Arg Ala Tyr Gly Asn Tyr Trp Tyr Ile Asp Val Trp Gly Ala Gly Thr
100 105 110
Thr Val Thr Val Ser Ser
115
<210> 5
<211> 321
<212> DNA
<213> 小家鼠（Mus musculus）
<400> 5
gacattgtga tgacccagac tcccaaattc ctgcttgtat cagcaggaga cagggttacc 60
ataacctgca aggccagtca gagtgtgagt aatgatgtag cttggtacca acagaagcca 120
gggcagtctc ctaaactgct gataaactat gcatttcatc gcttcactgg agtccctgat 180
cgtttcactg gcagtggata tgggacggat ttcattttca ccatcagcac tgtgcaggct 240
gaagacctgg cagtttattt ctgtcaccag gcttatagtt ctccgtacac gttcggaggg 300
gggaccaagc tggaaatgaa a 321
<210> 6
<211> 107
<212> PRT
<213> 小家鼠（Mus musculus）
<400> 6
Asp Ile Val Met Thr Gln Thr Pro Lys Phe Leu Leu Val Ser Ala Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Lys Ala Ser Gln Ser Val Ser Asn Asp
20 25 30
Val Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ser Pro Lys Leu Leu Ile
35 40 45
Asn Tyr Ala Phe His Arg Phe Thr Gly Val Pro Asp Arg Phe Thr Gly
50 55 60
Ser Gly Tyr Gly Thr Asp Phe Ile Phe Thr Ile Ser Thr Val Gln Ala
65 70 75 80
Glu Asp Leu Ala Val Tyr Phe Cys His Gln Ala Tyr Ser Ser Pro Tyr
85 90 95
Thr Phe Gly Gly Gly Thr Lys Leu Glu Met Lys
100 105
<210> 7
<211> 342
<212> DNA
<213> 小家鼠（Mus musculus）
<400> 7
cagatccagt tggtgcagtc tggacctgag ctgaagaagc ctggagagac agtcaagatc 60
tcctgcaagg cttctgggta taccttcaca aactatggaa tgaactgggt gaagcaggct 120
ccaggaaagg gtttaaagtg gatgggctgg ataaacaata ataatggaga gccaacatat 180
gctgaagagt tcaagggacg gtttgccttc tctttggaaa cctctgccag cactgcctat 240
ttgcagatca acaacctcaa aaatgaggac acggctacat atttctgtgc aagagatgtt 300
atggactatt ggggtcaagg aacctcagtc accgtctcct ca 342
<210> 8
<211> 114
<212> PRT
<213> 小家鼠（Mus musculus）
<400> 8
Gln Ile Gln Leu Val Gln Ser Gly Pro Glu Leu Lys Lys Pro Gly Glu
1 5 10 15
Thr Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Tyr
20 25 30
Gly Met Asn Trp Val Lys Gln Ala Pro Gly Lys Gly Leu Lys Trp Met
35 40 45
Gly Trp Ile Asn Asn Asn Asn Gly Glu Pro Thr Tyr Ala Glu Glu Phe
50 55 60
Lys Gly Arg Phe Ala Phe Ser Leu Glu Thr Ser Ala Ser Thr Ala Tyr
65 70 75 80
Leu Gln Ile Asn Asn Leu Lys Asn Glu Asp Thr Ala Thr Tyr Phe Cys
85 90 95
Ala Arg Asp Val Met Asp Tyr Trp Gly Gln Gly Thr Ser Val Thr Val
100 105 110
Ser Ser
<210> 9
<211> 330
<212> DNA
<213> 小家鼠（Mus musculus）
<400> 9
gacattgtgc tgacccaatc tccagcttct ttggctgtgt ctctagggca gagggccacc 60
atatcctgca gagccagtga aagtgttgat aattatggct atagttttat gcactggtac 120
cagcagaaac caggacagcc accccaactc ctcatctatc gtgcatccaa cctagaatct 180
gggatccctg ccaggttcag tggcagtggg tctaggacag gcttcaccct caccattaat 240
cctgtggagg ctgatgatgt tgcaacctat tactgtcagc aaagtaaaga atatccgacg 300
ttcggtggag gcaccaagct ggaagtcaaa 330
<210> 10
<211> 110
<212> PRT
<213> 小家鼠（Mus musculus）
<400> 10
Asp Ile Val Leu Thr Gln Ser Pro Ala Ser Leu Ala Val Ser Leu Gly
1 5 10 15
Gln Arg Ala Thr Ile Ser 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
Gln Leu Leu Ile Tyr Arg Ala Ser Asn Leu Glu Ser Gly Ile Pro Ala
50 55 60
Arg Phe Ser Gly Ser Gly Ser Arg Thr Gly Phe Thr Leu Thr Ile Asn
65 70 75 80
Pro Val Glu Ala Asp Asp Val Ala Thr Tyr Tyr Cys Gln Gln Ser Lys
85 90 95
Glu Tyr Pro Thr Phe Gly Gly Gly Thr Lys Leu Glu Val Lys
100 105 110
<210> 11
<211> 10
<212> PRT
<213> 小家鼠（Mus musculus）
<400> 11
Gly Phe Ser Leu Thr Ser Tyr Gly Val His
1 5 10
<210> 12
<211> 16
<212> PRT
<213> 小家鼠（Mus musculus）
<400> 12
Val Ile Trp Ala Gly Gly Ser Thr Asn Tyr Asn Ser Ala Leu Met Ser
1 5 10 15
<210> 13
<211> 12
<212> PRT
<213> 小家鼠（Mus musculus）
<400> 13
Ala Arg Ala Tyr Gly Asn Tyr Trp Tyr Ile Asp Val
1 5 10
<210> 14
<211> 11
<212> PRT
<213> 小家鼠（Mus musculus）
<400> 14
Lys Ala Ser Gln Ser Val Ser Asn Asp Val Ala
1 5 10
<210> 15
<211> 7
<212> PRT
<213> 小家鼠（Mus musculus）
<400> 15
Tyr Ala Phe His Arg Phe Thr
1 5
<210> 16
<211> 9
<212> PRT
<213> 小家鼠（Mus musculus）
<400> 16
His Gln Ala Tyr Ser Ser Pro Tyr Thr
1 5
<210> 17
<211> 10
<212> PRT
<213> 小家鼠（Mus musculus）
<400> 17
Gly Tyr Thr Phe Thr Asn Tyr Gly Met Asn
1 5 10
<210> 18
<211> 17
<212> PRT
<213> 小家鼠（Mus musculus）
<400> 18
Trp Ile Asn Asn Asn Asn Gly Glu Pro Thr Tyr Ala Glu Glu Phe Lys
1 5 10 15
Gly
<210> 19
<211> 7
<212> PRT
<213> 小家鼠（Mus musculus）
<400> 19
Ala Arg Asp Val Met Asp Tyr
1 5
<210> 20
<211> 15
<212> PRT
<213> 小家鼠（Mus musculus）
<400> 20
Arg Ala Ser Glu Ser Val Asp Asn Tyr Gly Tyr Ser Phe Met His
1 5 10 15
<210> 21
<211> 7
<212> PRT
<213> 小家鼠（Mus musculus）
<400> 21
Arg Ala Ser Asn Leu Glu Ser
1 5
<210> 22
<211> 8
<212> PRT
<213> 小家鼠（Mus musculus）
<400> 22
Gln Gln Ser Lys Glu Tyr Pro Thr
1 5
<210> 23
<211> 354
<212> DNA
<213> 人工序列
<220>
<223> 317-4B6 cDNA-Vh
<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（Mus musculus）
<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（Mus musculus）
<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（Mus musculus）
<400> 35
Tyr Ala Phe His Arg Phe Thr
1 5
<210> 36
<211> 9
<212> PRT
<213> 小家鼠（Mus musculus）
<400> 36
His Gln Ala Tyr Ser Ser Pro Tyr Thr
1 5
<210> 37
<211> 10
<212> PRT
<213> 小家鼠（Mus musculus）
<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（Mus musculus）
<400> 39
Ala Arg Asp Val Met Asp Tyr
1 5
<210> 40
<211> 15
<212> PRT
<213> 小家鼠（Mus musculus）
<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（Mus musculus）
<400> 41
Arg Ala Ser Asn Leu Glu Ser
1 5
<210> 42
<211> 8
<212> PRT
<213> 小家鼠（Mus musculus）
<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

Claims (10)

1.一种抗体抗原结合域，该抗体抗原结合域特异性结合人类PD-1，且该抗体抗原结合域包含具有选自序列编号11-22、31-42及59-63的序列的互补决定区(CDR)。
2.如权利要求1所述的域，该域包含重链可变区(Vh)或轻链可变区(Vκ)，所述可变区包含：
a)mu317 CDR-H1、CDR-H2及CDR-H3(序列编号11-13)；或
CDR-L1、CDR-L2及CDR-L3(序列编号14-16)；
b)mu326 CDR-H1、CDR-H2及CDR-H3(序列编号17-19)；或
CDR-L1、CDR-L2及CDR-L3(序列编号20-22)；
c)317-4B6 CDR-H1、CDR-H2及CDR-H3(序列编号31-33)；或
CDR-L1、CDR-L2及CDR-L3(序列编号34-36)；
d)326-4A3 CDR-H1、CDR-H2及CDR-H3(序列编号37-39)；或
CDR-L1、CDR-L2及CDR-L3(序列编号40-42)；
e)317-1H CDR-H1、CDR-H2及CDR-H3(序列编号11、59、13)；或
CDR-L1、CDR-L2及CDR-L3(序列编号14-16)；
f)317-4B2 CDR-H1、CDR-H2及CDR-H3(序列编号11、60、13)；或
CDR-L1、CDR-L2及CDR-L3(序列编号61、15、16)；
g)317-4B5 CDR-H1、CDR-H2及CDR-H3(序列编号11、60、13)；或
CDR-L1、CDR-L2及CDR-L3(序列编号61、15、16)；
h)317-4B6 CDR-H1、CDR-H2及CDR-H3(序列编号11、32、13)；或
CDR-L1、CDR-L2及CDR-L3(序列编号61、15、16)；
i)326-1 CDR-H1、CDR-H2及CDR-H3(序列编号17、62、19)；或
CDR-L1、CDR-L2及CDR-L3(序列编号20-22)；
j)326-3B1 CDR-H1、CDR-H2及CDR-H3(序列编号17、62、19)；或
CDR-L1、CDR-L2及CDR-L3(序列编号20-22)；
k)326-3G1 CDR-H1、CDR-H2及CDR-H3(序列编号17、62、19)；或
CDR-L1、CDR-L2及CDR-L3(序列编号20-22)。
3.如权利要求1所述的域，该域包含重链可变区(Vh)及轻链可变区(Vκ)，所述可变区包含：
a)mu317 CDR-H1、CDR-H2及CDR-H3(序列编号11-13)；及
CDR-L1、CDR-L2及CDR-L3(序列编号14-16)；
b)mu326 CDR-H1、CDR-H2及CDR-H3(序列编号17-19)；及
CDR-L1、CDR-L2及CDR-L3(序列编号20-22)；
c)317-4B6 CDR-H1、CDR-H2及CDR-H3(序列编号31-33)；及
CDR-L1、CDR-L2及CDR-L3(序列编号34-36)；
d)326-4A3 CDR-H1、CDR-H2及CDR-H3(序列编号37-39)；及
CDR-L1、CDR-L2及CDR-L3(序列编号40-42)；
e)317-1H CDR-H1、CDR-H2及CDR-H3(序列编号11、59、13)；及
CDR-L1、CDR-L2及CDR-L3(序列编号14-16)；
f)317-4B2 CDR-H1、CDR-H2及CDR-H3(序列编号11、60、13)；及
CDR-L1、CDR-L2及CDR-L3(序列编号61、15、16)；
g)317-4B5 CDR-H1、CDR-H2及CDR-H3(序列编号11、60、13)；及
CDR-L1、CDR-L2及CDR-L3(序列编号61、15、16)；
h)317-4B6 CDR-H1、CDR-H2及CDR-H3(序列编号11、32、13)；及
CDR-L1、CDR-L2及CDR-L3(序列编号61、15、16)；
i)326-1 CDR-H1、CDR-H2及CDR-H3(序列编号17、62、19)；及
CDR-L1、CDR-L2及CDR-L3(序列编号20-22)；
j)326-3B1 CDR-H1、CDR-H2及CDR-H3(序列编号17、62、19)；及
CDR-L1、CDR-L2及CDR-L3(序列编号20-22)；
k)326-3G1 CDR-H1、CDR-H2及CDR-H3(序列编号17、62、19)；及
CDR-L1、CDR-L2及CDR-L3(序列编号20-22)。
4.如权利要求1所述的域，该域包含重链可变区(Vh)或轻链可变区(Vκ)，所述可变区包含：
5.如权利要求1所述的域，该域包含重链可变区(Vh)及轻链可变区(Vκ)，所述可变区包含：
6.一种抗体IgG4重链效应器或恒定域，该效应器或恒定域包含序列编号83-88中的任一者。
7.一种抗体、F(ab)或F(ab)2，其包含如权利要求1-5中任一项所述的域。
8.一种抗体，该抗体包含如权利要求5所述的域及包含序列编号87或88的IgG4重链效应器或恒定域。
9.一种多核苷酸，该多核苷酸编码如权利要求1所述的域。
10.一种使用如权利要求1所述的域的方法，该方法包含向确定患有癌症或病毒感染或确定另外需要PD-1拮抗作用的人施用该域的步骤。
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