CN112351794A - 用于尿路上皮癌的免疫治疗方法 - Google Patents

用于尿路上皮癌的免疫治疗方法 Download PDF

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CN112351794A
CN112351794A CN201980024421.9A CN201980024421A CN112351794A CN 112351794 A CN112351794 A CN 112351794A CN 201980024421 A CN201980024421 A CN 201980024421A CN 112351794 A CN112351794 A CN 112351794A
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詹姆斯·宋
张韵
沈志荣
戚秦州
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Abstract

本发明公开了一种用于尿路上皮癌(urothelial carcinoma，UC)患者的免疫治疗方法，该方法包括向该患者施用抗PD‑1抗体，该抗体通过降低FcγR结合从而降低抗体依赖性吞噬作用。

Description

用于尿路上皮癌的免疫治疗方法
相关申请的交叉引用
本申请请求2018年2月9日申请的美国临时申请号US 62/628,648，2018年2月10日申请的国际申请PCT/CN 2018/076100的优先权，并将其全文援引并入本申请中。
电子提交文本文件说明
本申请电子递交文本文件的全部援引并入本申请：计算机可读形式的序列表(文件名称：BEIG_034_01WO_SeqList.TXT，数据记录于2019年2月8日，文件大小126千字节)。
技术领域
本文公开了一种用于尿路上皮癌(urothelial carcinoma，UC)患者的治疗方法，该方法包括向患者施用抗PD-1抗体，该抗体被特异性地工程化以降低FcγR与巨噬细胞的结合从而消除抗体依赖性吞噬作用。
背景技术
尿路上皮癌又称为尿路上皮(移行细胞)癌(UC)或尿路上皮癌(移行细胞肿瘤、或尿路上皮的移行细胞肿瘤)，以及膀胱癌。超过90％的尿路上皮肿瘤源自膀胱，8％源自肾盂，以及剩余2％起源自输尿管和尿道。
基于铂的联合化疗已被用于作为一线疗法用于患有晚期尿路上皮癌的患者数十年。例如，膀胱癌一线治疗的标准疗法包括甲氨蝶呤(methotrexate)、长春新碱(vinblastine)、多柔比星(doxorubicin)和顺铂(cisplatin)(MVAC)的联合化疗，其已被证明具有相当大的毒性。另一种联合化疗是顺铂-吉西他滨联合化疗，其已替代MVAC作为转移性膀胱癌的一线标准治疗，并且据报道90％的患者已复发并且预后极差。转移性UC的治疗进展在过去的三十年里停滞不前。
WO 2016064649 A1公开了抗-VEGF受体2抗体雷姆赛卢单抗(ramucirumab)与多西他赛(docetaxel)同时、单独或顺序联合治疗UC患者的组合疗法。其表明抗体疗法可作为治疗尿路上皮癌的有效药物。
已经证明针对免疫检查点抑制性受体(如程序性细胞死亡-1(PD-1))的单克隆抗体(monoclonal antibody，mAb)在多种恶性肿瘤中的有前景的抗肿瘤活性(Topalian SL,等人N Engl J Med.[新英格兰医学杂志]2012；366:2443-2454.)，该恶性肿瘤包括UC(Plimack ER,等人J Clin Oncol.[临床肿瘤学杂志]2015；33(增刊；摘要4502)；BellmuntJ,等人摘要470.在第31届癌症免疫治疗学会年会上发表,2016年11月9-13日,美国马里兰州国家海港；Balar A,等人Ann Oncol.[肿瘤学年鉴]2016；第27卷,增刊_6,2016年10月1日,LBA32 PR.；Sharma P,等人J Clin Oncol.[临床肿瘤学杂志]2016；34(增刊摘要4501)；Galsky MD,等人J Clin Oncol.[临床肿瘤学杂志]2016；LB:A31；以及Sharma P,等人Lancet Oncol.[柳叶刀·肿瘤学]2016；17:1590-1598)。
PD-1在CD8+效应子、肿瘤浸润的T淋巴细胞(TIL)上相对过表达；并且抗PD-1抗体诱导肿瘤微环境中CD8+T细胞百分比的增加(Ahmadzadeh M,等人Blood.[血液]2009；114:1537-1544)。
WO 2015/035606 A1公开了一种人源化IgG4单克隆抗体。该单克隆抗体对PD-1具有高亲和力和结合特异性，特别是与PD-1(包括残基K45和I93；或I93、L95和P97)特异性结合并抑制免疫细胞中PD-1介导的细胞信号传导(通过与其配体PD-L1结合所需的一组氨基酸残基结合)。WO 2015/035606公开了一种结合人PD-1的单克隆抗体，和经修饰的IgG4 Fc区，其中该经修饰的IgG4 Fc区降低了抗体与一个或多个Fcγ受体的结合。
Dahan R等人报道了体内证据表明，当抗体的Fc结构域与Fc-γ受体(FcγR)接合时，抗PD-1抗体显示肿瘤细胞毒性降低(Dahan R,等人Cancer Cell.[癌细胞]2015；28:285-295)。据报道，FcγR结合导致这些CD8+TIL的优先耗竭。这种降低可能与抗PD-1肿瘤活性降低有关。
WO 2015/035606 A1的抗体被特异性地工程化以降低FcγR与巨噬细胞和髓源性抑制细胞的结合；FcγR结合的降低可通过保存活化的T细胞来改善临床活性，而图1以图形方式显示了该提议的作用机理。
如UC治疗中的优势表明，本申请的发明人发现本发明的抗体可以作为一种新的免疫治疗方案，用于包括晚期或转移性尿路上皮癌的尿路上皮癌。
发明内容
本申请公开了一种用于尿路上皮癌(UC)患者的治疗方法，该方法包括向该患者施用治疗有效量的抗PD-1抗体或其抗原结合片段，该抗体或其抗原结合片段被特异性地工程化以使得降低FcγR与巨噬细胞的结合从而减少抗体依赖性吞噬作用。
在一个实施方案中，尿路上皮癌涉及输尿管、尿道、肾盂和/或膀胱。在另一个实施方案中，尿路上皮癌为移行细胞癌。在又另一个实施方案中，尿路上皮癌是晚期的或转移性的。
在一个实施方案中，该患者患有PD-L1+尿路上皮癌或PD-L1-尿路上皮癌。在另一个实施方案中，该患者患有PD-L1+尿路上皮癌。
在一个实施方案中，该抗PD-1抗体为WO 2015/035606 A1中公开的一种抗体。在WO2015/035606 A1中公开的抗体特异性地与程序性死亡-1(Programmed Death-1，PD-1)受体结合并抑制免疫细胞中PD-1介导的细胞信号传导和(通过与其配体PD-L1结合所需的一组氨基酸残基结合)。在另一个实施方案中，所述抗PD-1抗体是人源化的单克隆抗体，其是包含一个重链可变区(heavy chain variable region,VH)和一个轻链可变区(light chainvariable region,VL)(分别包含SEQ ID No 24和SEQ ID No 26)以及IgG4重链效应子或恒定结构域(SEQ ID NO:88)的人源化单克隆抗体，以下称为Mab-1，其特异性结合PD-1(包括PD-1受体残基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。
在另一个实施方案中，该抗PD-1抗体是结合人PD-1的单克隆抗体，其包含经修饰的IgG4 Fc区，其中该经修饰的IgG4 Fc区降低了抗体与一个或多个Fcγ受体的结合。在一个优选的实施方案中，该抗PD-1抗体是结合人PD-1的单克隆抗体，其包含IgG4 Fc区，该IgG4 Fc区包含在位置228处的S228P突变以及在位置233、234和235处的氨基酸突变，其中相对于仅具有在位置228处的突变而没有其他Fc区突变的参考IgG4抗体的Fc结合，该在位置233、234和235处的突变造成抗体表现出与至少一个Fcγ受体的降低的结合，如在WO2015/035606 A1中所公开的。在进一步的实施方案中，该IgG4 Fc区包含在位置228、233、234、235和265处的氨基酸突变，如在WO 2015/035606 A1中所公开的。在又进一步的实施方案中，该IgG4Fc区包含在位置228、233、234、235、265、309和409处的氨基酸突变，如在WO2015/035606 A1中所公开的。在另一个实施方案中，该IgG4 Fc区包含S228P、E233P、F234V和L235A的氨基酸突变，如在WO 2015/035606 A1中所公开的。在一个实施方案中，上述抗体可以进一步包含含有SEQ ID NO:83-88中任一项的IgG4重链恒定结构域。
本文申请的抗体，即Mab-1，先前已经表明其在如肝细胞癌的晚期实体瘤患者中是可耐受的，并且其毒性特征表明，不良事件(adverse events,AEs)通常为低至中度严重程度、可控的和可逆的；Desai J,等.J Immunother Cancer.[癌症免疫治疗杂志]2016；4(增刊1):P154；2019年1月3日公开的WO 2019/001417)。
本申请公开的治疗方法已被证明能够降低、延迟进展、并减轻人类患者的尿路上皮癌。
本发明的发明人已经发现，抗PD-1抗体，如Mab-1，可作为有效的免疫治疗方案用于治疗尿路上皮癌，尤其是PD-L1+尿路上皮癌，因为与PD-L1-UC相比，观察到PD-L1+UC的客观响应的速率更高。发明人还发现，Mab-1治疗在UC的预治疗患者中总体上是耐受良好，并且UC患者中报道的不良事件与研究中观察到的总体安全特征一致，并且一般为低或中度严重程度、可控的和可逆的。
附图说明
图1显示了本申请中所用的抗PD-1抗体的T细胞清除的潜在机制，即降低FcγR结合阻止了巨噬细胞介导的T细胞清除。
图2显示了本临床研究的设计方案。
图3显示了使用本发明的抗体治疗的UC患者的治疗的持续时间和响应。
图4显示了使用本发明的抗体治疗的UC患者的最大肿瘤减少。
图5显示了使用本发明的抗体治疗的UC患者的靶病变随时间的变化。
图6A-6H为74岁男性PD-L1阳性UC患者的射线照射图像，所述患者先前三种抗癌治疗方案失败且未包括任何免疫治疗。所述图像显示了从0天(基线)到46天治疗周期的UC肿瘤消退。
具体实施方式
缩写
贯穿发明的详细说明书和实施例，将使用以下缩写：
Ab 抗体
AE 不良事件
CD 分化簇
CDR 互补决定区
CR 完全响应
DPBS 杜尔贝科磷酸盐缓冲盐水
FcγR Fc-γ受体
i.p. 腹膜内或腹膜内地
i.v. 静脉内或静脉内地
IFN-γ 干扰素-γ
IgG 免疫球蛋白G
mAb 单克隆抗体
max 最大值
MHC 主要组织相容性复合体
min 最小值
NK 自然杀伤细胞
p.o. “口服”或“经口”
PD 进行性疾病
PD-1 程序性死亡1蛋白，Pdcd-1，或CD279
PD-L1 程序性细胞死亡配体-1
PDX 患者来源的异种移植物
PR 部分响应
Q2W 每2周一次
Q3W 每3周一次
Q4W 每4周一次
QW 每周一次
RP2D 2期推荐剂量
SD 稳定疾病
TILs 肿瘤浸润性淋巴细胞
UC 尿路上皮癌
VH 重链可变区
VL 轻链可变区
定义
除非在本文件的其他地方具体定义，否则本发明中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。
如本文使用的，包括所附权利要求，例如“一个”、“一种”和“该”的单数形式包括它们相应的复数指代，除非上下文另外明确说明。
本文术语“抗体”以最广义使用并且具体地涵盖抗体(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，但是还可以描述为不同特异性的，异特异性的，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定性抗原决定簇或表位结合。
本文中的术语“单克隆抗体”或“mAb”是指基本上同质的抗体的群体，即，除了可能少量存在的可能天然发生的突变外，该群体中包含的抗体分子在氨基酸序列上是相同的。相比之下，常规(多克隆)抗体制剂典型地包括在其可变结构域中具有不同氨基酸序列的多种不同抗体，特别地其CDR，它们通常对不同的表位具有特异性。修饰语“单克隆”指示获得自基本上均质的抗体群体的抗体的特征，并且不应理解为要求通过任何具体方法产生抗体。可以通过本领域技术人员已知的方法获得单克隆抗体(mAb)。参见，例如，Kohler和Milstein,Nature[自然](伦敦)256:495(1975)；美国专利号4,376,110；Ausubel等,ShortProtocols in Molecular Biology[精编分子生物学实验指南],第3版,Wiley&Sons[约翰威利父子公司],1995；Harlow和Lane,Using Antibodies,A Laboratory Manual[使用抗体:技术实验指南](1998)；和Colligan等,编辑,Current Protocols in Immunology[当代免疫学方案],Greene Publishing Assoc.and Wiley Interscience[格林出版联盟和威力跨学科],纽约,(1992,1993)。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在体内培养。高效价的mAb可以在体内产生中获得，其中将来自单个杂交瘤的细胞腹膜内注射到小鼠中，例如原始引发的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，基本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。典型地，人轻链被分类为κ和λ轻链。此外，人重链典型地分类为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(VL\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。
典型地，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两者都包含FR-1、CDR-1、FR-2、CDR-2、FR-3、CDR-3和FR-4。通常，每个结构域的氨基酸分配符合免疫学上感兴趣的蛋白质序列的定义，Kabat,等National Institutes of Health[国立卫生研究院],贝塞斯达,马里兰州；第5版；NIH公开号91-3242(1991)；Kabat(1978)Adv.Prot.Chem.[高级防护化学]32:1-75；Kabat,等,(1977)J.Biol.Chem.[生物化学杂志]252:6609-6616；Chothia,等人,(1987)JMol.Biol.[分子生物学杂志]196:901-917或Chothia,等,(1989)Nature[自然]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)。参见，Kabat等人(1991)Sequences of Proteins ofImmunological Interest[免疫学上感兴趣的蛋白质序列],第5版Public Health Service[公共卫生署],National Institutes of Health[国立卫生研究院],贝塞斯达,马里兰州(通过序列定义抗体的CDR区)；还参见Chothia和Lesk(1987)J.Mol.Biol.[分子生物学杂志]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。抗原结合位点的定义在下述文献中有描述：Ruiz等,IMGT,国际ImMunoGeneTics数据库.Nucleic Acid Res.[核酸研究],28,219-221(2000)；以及Lefranc,M.-P.IMGT,国际ImMunoGeneTics数据库.Nucleic AcidRes.[核酸研究],1月1日；29(1):207-09(2001)；MacCallum等,Antibody-antigeninteraction:Contact analysis and binding site topography[抗体-抗原相互作用：结合分析及结合位点分布],J Mol.Biol.[分子生物学杂志],262(5),732-745(1996)；和Martin等,Proc.Natl Acad.Sci.USA[美国国家科学院院刊],86,9268-9272(1989)；Martin,等,Methods Enzymol.[酶学方法],203,121-153,(1991)；Pedersen等,Immunomethods[免疫方法],1,126,(1992)；和Rees等，在Sternberg M.J.E.(编辑),Protein Structure Prediction[蛋白结构预测].牛津大学出版社,牛津,141-172 1996中)。
除非另外说明，“抗体片段”或“抗原结合片段”是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；纳米抗体以及从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至少2倍，优选高至少10倍，更优选高至少20倍，和最优选高至少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，如果其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”是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，人抗体可以含有鼠碳水化合物链。类似地，“小鼠抗体”或“大鼠抗体”是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”是指含有来自非人(例如鼠)抗体以及人抗体的序列的抗体形式。此类抗体含有源自非人免疫球蛋白的最小序列。通常，人源化抗体将包含基本上至少一个、并且典型地两个可变结构域的全部，其高变环的全部或基本上全部对应于非人类免疫球蛋白的那些，并且FR的全部或基本上全部是人类免疫球蛋白序列的那些。人源化抗体还将任选地包含免疫球蛋白恒定区(Fc)的至少一部分，典型地是人免疫球蛋白的至少一部分。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可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“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，缓和疾病状态，提供疾病的缓解(部分或全部)，降低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”也包括尿路上皮癌病理结果的减少。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。
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(VL)的抗体，该重链可变区(VH)和轻链可变区(VL)含有使用卡巴特(Kabat)编号系统定义的并且如下所列出的互补决定区(CDR)：
Figure BDA0002713600760000101
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(VL)的抗体，该重链可变区(VH)和轻链可变区(VL)含有如下所列出的CDR的任意组合：
Figure BDA0002713600760000111
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(VL)的抗体，该重链可变区(VH)和轻链可变区(VL)包含：
Figure BDA0002713600760000112
在一些实施方案中，该抗体包含在位置228(EU编号系统)处具有丝氨酸至脯氨酸突变的IgG4 Fc区。在一些实施方案中，该突变被称为S228P突变。在一些实施方案中，该抗体包含在位置233、234、235、265、309和409(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，该抗体包含在228和至少一个其他位置处具有突变的IgG4区，其中该至少一个其他突变导致与一种或多种FcγR的结合减少。在进一步的实施方案中，该抗体包含在位置228和至少2个、至少3个、至少4个、至少5个、或至少6个另外的位置处具有突变的IgG4区，其中该一个或多个另外的突变导致与一种或多种FcγR的结合减少。在一些实施方案中，该抗体包含在位置234和235处具有突变的IgG4区。在一些实施方案中，该抗体包含在位置233、235和235处具有突变的IgG4区。在一些实施方案中，该抗体包含在位置234、235和265处具有突变的IgG4区。在一些实施方案中，该抗体包含在位置233、234、235和265处具有突变的IgG4区。在一些实施方案中，该抗体包含在位置234、235、265和409处具有突变的IgG4区。在一些实施方案中，该抗体包含在位置233、234、235、265和409处具有突变的IgG4区。在一些实施方案中，该抗体包含在位置234、235、265、309和409处具有突变的IgG4区。在一些实施方案中，该抗体包含在位置233、234、235、265、309和409处具有突变的IgG4区。在位置234处的突变可以是苯丙氨酸取代缬氨酸或苯丙氨酸取代丙氨酸。在位置235处的突变可以是亮氨酸取代丙氨酸。在位置233处的突变可以是谷氨酸取代脯氨酸。在位置265处的突变可以是天冬氨酸取代缬氨酸或天冬氨酸取代苏氨酸。在位置309处的突变可以是亮氨酸取代缬氨酸。在位置409处的突变可以是精氨酸取代赖氨酸、苏氨酸或甲硫氨酸。
如本文所公开的，抗PD-1抗体包含含有SEQ ID NO:83-88或91-106中任一项的IgG4重链恒定结构域。
如本文所公开的，抗PD-1抗体是含有F(ab)或F(ab’)2的抗体，该F(ab)或F(ab’)2包含上述结构域(包括重链可变区(VH)、轻链可变区(VL)以及IgG4重链恒定结构域)。
如本文所公开的，抗PD-1抗体包含重链可变区(VH)和轻链可变区(VL)以及含有SEQID NO:87或88的IgG4重链恒定结构域，其中重链可变区(VH)和轻链可变区(VL)包含：
Figure BDA0002713600760000131
如本文所公开的，抗PD-1抗体包含重链可变区(VH)和轻链可变区(VL)以及含有SEQID NO:88的IgG4重链效应子或恒定结构域，其中重链可变区(VH)和轻链可变区(VL)分别包含SEQ ID NO:24和SEQ ID NO:26。
如本文所公开的，抗PD-1抗体包含独特工程化人源化IgG4 Fc结构域，该结构域可降低FcγR从而减少抗体依赖性吞噬作用，这是T细胞清除的潜在机制，从而提高了有效性。
抗PD1抗体及其抗原结合片段可以如WO 2015/035606 A1所述制备，将其通过援引并入本申请。
治疗方法
在本文公开的治疗方法中，以一定剂量向UC患者施用Mab-1抗体。在一个实施方案中，UC患者先前未通过免疫治疗方法分子治疗。在另一个实施方案中，UC患者接受了抗癌全身疗法(例如MVAC)治疗。在另一个实施方案中，患者先前进行了铂佐剂及新辅助疗法。
在针对UC的治疗方法中，抗PD-1抗体以0.5-10mg/kg QW或Q2W或Q3W或Q4W的剂量施用。在本文中的一些实施方案中，以0.5-10mg/kg QW或Q2W或Q3W的剂量施用Mab-1。在另一个治疗方案中，以2-10mg/kg Q2W或Q3W的剂量施用Mab-1或以200mg Mab-1的固定剂量施用Mab-1，还可以2.0mg/kg Q2W、5mg/kg Q2W、2mg/kg Q3W或5mg/kg Q3W的剂量或以Mab-1的200mg的固定剂量静脉内施用Mab-1。
在另一个实施方案中，将Mab-1与另一种或多种药剂联合来治疗UC。在一个实施方案中，将Mab-1与UC的标准疗法(甲氨蝶呤、长春新碱、多柔比星和顺铂(MVAC))联合来治疗UC。在又另一个实施方案中，用Mab-1和顺铂或顺铂和吉西他滨治疗UC。该治疗的一种变化是在顺铂和吉西他滨之前施用紫杉醇，在紫杉醇治疗之前或期间以及在顺铂和吉西他滨治疗之前或期间施用Mab-1。
实施例
研究设计-患者鉴别和招募
此研究设计的目的是招募UC患者以进行剂量确定和患者初步鉴别，分别在1A和1B期进行。本研究设计详述于图2中。在图2中，*显示剂量扩展方案；而
Figure BDA0002713600760000141
表示不超过最大耐受剂量的暴露量的固定剂量，并且
Figure BDA0002713600760000142
表示与1B期平行进行。
1A期用于确定Mab-1的安全性、RP2D和初步有效性。在1A期中，10mg/kg每两周一次(once every 2weeks,Q2W)是Mab-1最大施用剂量，并且未达到最大耐受剂量(maximumtolerated dose,MTD)。在1A期第1部分中，进行了从0.5mg/kg Q2W开始到10mg/kg Q2W的剂量递增研究。在1A期第2部分，用2mg/kg或5mg/kg的Mab-1 Q2W或Q3W进行了方案扩展研究。在1A期第3部分，用200mg的Mab-1 Q3W(在选择的肿瘤中的固定剂量不超过最大耐受剂量的暴露量)进行固定剂量扩展研究，并且该研究与1B期平行进行。所有1B期患者均接受Mab-1，5mg/kg静脉注射Q3W。根据实体肿瘤指南1.1版(RECIST v1.1)中的响应评估标准，每8周或9周进行一次放射照相评估，并且在图6A-6G中示出了它的一个实例。
UC亚群的关键资格标准
招募用组织学或细胞学证实UC的成年患者(年龄≥18岁)，其至少有一个可测量的病变(按照RECIST v1.1的定义)；其接受过标准治疗，但之前没有抗PD-1或程序性死亡配体1(PD-L1)治疗；并且东部肿瘤协作组(Eastern Cooperative Oncology Group,ECOG)行为状态≤1。
如果患者对其他抗体有严重超敏反应史，则将其排除。除UC外，过去2年内有既往恶性肿瘤活动的患者，以及明显治愈的局部可治愈癌症，如基底细胞或鳞状细胞皮肤癌、表浅性膀胱癌、或子宫颈或乳腺原位癌，也被排除在外。
在自动化平台上，通过进行免疫组织化学方法对预处理肿瘤标本进行PD-L1膜表达的回顾性评估。通过对肿瘤细胞(TC)或肿瘤相关免疫细胞(IC)进行任何强度的PD-L1膜染色，测定PD-L1的表达状态。如果≥25％Tc或≥25％IC表达膜PD-L1，PD-L1被定义为高表达；并且如果TC和IC都有<25％PD-L1膜染色，则PD-L1被定义为低/阴性。在临床试验中有十八(18)名UC患者(n＝18)被招募。
患者分布
在18名招募UC患者中，14名患者先前进行过至少一次化疗，并且6名患者先前进行过放射疗法，这表明在治疗UC方面存在困难。如图3和图5所示，总共有6名患者(33.3％)继续接受延长治疗，其中至少3名患者接受治疗超过36周。这些患者中的一位显示出完全缓解，而其他两位显示出良好的部分缓解(图5)。表1显示了UC患者的人口统计和疾病特征。
表1
Figure BDA0002713600760000151
Figure BDA0002713600760000161
抗肿瘤活性
在招募的18名UC患者中，有17名患者可评估。可评估的UC患者定义为具有可测量的基线肿瘤评估和至少一个可评估的基线后肿瘤响应评估，或者在初始肿瘤评估之前继续进展或死亡。
在下文的临床试验和结果中，所有患者均接受Mab-1，剂量为2.0、5.0或10.0mg/kg或固定剂量为200mg，静脉注射Q2W或Q3W。
在可评估的17名UC患者中，1名患者达到了确认的完全响应(CR)，4名达到了确认的部分响应(PR)，3名达到了稳定疾病(SD)。发现疾病控制率(DCR＝CR+PR+SD)为47.1％(n＝8/17)。中位治疗持续时间为3.0个月，最长持续时间为18.3个月，最短持续时间为0.7个月。Mab-1的抗肿瘤活性呈现在图3至5中。
PD-L1状态响应
还评估了用剂量为2.0、5.0或10.0mg/kg或固定剂量为200mg静脉注射Q2W或Q3W的Mab-1治疗的UC患者的PD-L1状态和临床响应。
共有10名患者具有可评估的PD-L1状态和临床响应。在PD-L1高表达和PD-L1低表达的患者中观察到临床响应(表2和图4)。表2显示了通过PD-L1状态确认的每个可评估患者的最佳总体响应。
表2：通过PD-L1状态确认的每个可评估患者的最佳总体响应
Figure BDA0002713600760000162
Figure BDA0002713600760000171
*由于肿瘤组织不足，PD-L1状态无法评估。PD-L1高定义为≥25％的肿瘤细胞(TC)或≥25％的肿瘤相关免疫细胞(IC)；如果TC和IC两者均具有<25％PD-L1染色，PD-L1低/阴性。
研究发现，与PD-L1-疾病相比，观察到PD-L1+疾病中的客观响应率的速率更高，这表明Mab-1对于PD-L1+UC患者可以是有效的。
安全性和耐受性
本临床研究还发现，在UC患者中Mab-1的治疗通常耐受性良好。18名UC患者中有15名出现治疗相关的不良事件(TRAEs)(表3)，其中疲劳(n＝1)、高血糖(n＝1)和1型糖尿病(n＝1)是唯一与严重程度≥3级的治疗相关的不良事件(无论归因)。
一名患者由于与Mab-1相关的输液相关反应而停止治疗，并且另一名患者具有治疗中出现的致命结果的紧急不良事件(肌肉无力)，这与Mab-1治疗无关。该数据示于表3中。
表3：≥2名UC患者发生的治疗相关不良事件
Figure BDA0002713600760000172
这些结果确认，本申请的抗体(Mab-1)是可耐受的，并且其毒性特征证明不良事件(AEs)通常是低严重程度、可控的和可逆的。
前述实例和某些实施方案的描述应被视为是说明性的，而非限制由权利要求书所限定的本发明。如将容易理解的，在不脱离如权利要求书中所阐述的本发明的情况下，可以使用上述特征的许多变化和组合。所有这些变化都意图包括在本发明的范围之内。引用的所有参考文献都通过引用以其全文并入本文。
应当理解，即使本文提到了现有技术出版物，但所述提及并不构成承认出版物形成任何国家的本领域公知常识的一部分。
序列表
<110> 百济神州有限公司
Song, James
Zhang, Yun
Shen, Zhirong
Qi, Qinzhou
<120> 用于尿路上皮癌的免疫治疗方法
<130> BEIG-034/01WO 317697-2105
<150> PCT/CN2018/076100
<151> 2018-02-10
<150> US 62/628,648
<151> 2018-02-09
<160> 107
<170> PatentIn版本3.5
<210> 1
<211> 444
<212> DNA
<213> 智人(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> 智人(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 or 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 or 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 or 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 or 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 or 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 or 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 or 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 or 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 region 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 region 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 region 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 region 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 region 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 region 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 region 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 region 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 region 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 region 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 region 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 region 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 region 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
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> 104
<211> 327
<212> PRT
<213> 人工序列
<220>
<223> IgG4 Fc region 228P-309V-409K
<400> 104
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
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> 105
<211> 327
<212> PRT
<213> 人工序列
<220>
<223> IgG4 Fc region 228P-265A-309V-409K
<400> 105
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 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> 106
<211> 327
<212> PRT
<213> 人工序列
<220>
<223> IgG4 Fc region 228P-233P-234A-235A-265A-309V-409K
<400> 106
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 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> 107
<211> 327
<212> PRT
<213> 智人(Homo sapiens)
<400> 107
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 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
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

Claims (27)

1.一种治疗尿路上皮癌患者的方法，该方法包括向该患者施用治疗有效量的抗PD-1抗体或其抗原结合片段，该抗PD-1抗体或其抗原结合片段降低FcγR结合并且降低抗体依赖性吞噬作用。
2.如权利要求1所述的方法，其中该抗PD-1抗体包含重链可变区(VH)和轻链可变区(VL)，该重链可变区(VH)和轻链可变区(VL)含有如下所示的互补决定区(CDR)：
a)mu317 CDR-H1、CDR-H2和CDR-H3(分别为SEQ ID NO:11、12、13)；以及
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)；以及
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)；以及
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)；以及
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)；以及
CDR-L1、CDR-L2和CDR-L3(分别为SEQ ID NO:14、15、16)；
f)317-4B2 CDR-H1、CDR-H2和CDR-H3(分别为SEQ ID NO:11、60、13)；以及
CDR-L1、CDR-L2和CDR-L3(分别为SEQ ID NO:61、15、16)；
g)317-4B5 CDR-H1、CDR-H2和CDR-H3(分别为SEQ ID NO:11、60、13)；以及
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)；以及
CDR-L1、CDR-L2和CDR-L3(分别为SEQ ID NO:61、15、16)；
i)326-1CDR-H1、CDR-H2和CDR-H3(分别为SEQ ID NO:17、62、19)；以及
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(分别为SEQ ID NO:17、62、19)；以及
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(分别为SEQ ID NO:17、62、19)；以及
CDR-L1、CDR-L2和CDR-L3(分别为SEQ ID NO:20、21、22)。
3.如权利要求1所述的方法，其中该抗PD-1抗体是包含重链可变区(VH)和轻链可变区(VL)的抗体，该重链可变区(VH)和轻链可变区(VL)含有如下所示的CDR：
(a)CDR-H1(SEQ ID NO 31)、CDR-H2(SEQ ID NO 32)和CDR-H3(SEQ ID NO 33)，
CDR-L1(SEQ ID NO 34)、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 38)和CDR-H3(SEQ ID NO 39)，
CDR-L1(SEQ ID NO 40)、CDR-L2(SEQ ID NO 41)和CDR-L3(SEQ ID NO 42)。
4.如权利要求1所述的方法，其中该抗PD-1抗体是包含重链可变区(VH)和轻链可变区(VL)的抗体，该重链可变区(VH)和轻链可变区(VL)包含：
a)mu317(分别为SEQ ID NO:4和p)317-3H1(分别为SEQ ID NO:696)；和26)；
b)mu326(分别为SEQ ID NO:8和q)317-311(分别为SEQ ID NO:7010)；和26)；
c)317-4B6(分别为SEQ ID NO:24和26)；r)317-4B1(分别为SEQ ID NO:71
d)326-4A3(分别为SEQ ID NO:28和26)；和30)；s)317-4B3(分别为SEQ ID NO:72
e)317-4B2(分别为SEQ ID NO:43和26)；和44)；t)317-4B4(分别为SEQ ID NO:73
f)317-4B5(分别为SEQ ID NO:45和26)；和46)；u)317-4A2(分别为SEQ ID NO:74
g)317-1(分别为SEQ ID NO:48和和26)；50)；
h)326-3B1(分别为SEQ ID NO:51v)326-3A 1(分别为SEQ ID NO:和52)；75和30)；
i)326-3GI(分别为SEQ ID NO:53w)326-3C1(分别为SEQ ID NO:76和54)；和30)；
j)326-1(分别为SEQ ID NO:56和x)326-3D1(分别为SEQ ID NO:7758)；和30)；
k)317-3A1(分别为SEQ ID NO:64y)326-3E1(分别为SEQ ID NO:78和26)；和30)；
l)317-3C1(分别为SEQ ID NO:65z)326-3F1(分别为SEQ ID NO:79和26)；和30)；
m)317-3E1(分别为SEQ ID NO:aa)326-3B N55D(分别为SEQ ID66和26)；NO:80和30)；
n)317-3F1(分别为SEQ ID NO:67ab)326-4A1(分别为SEQ ID NO:和26)；28和81)；或
o)317-3G1(分别为SEQ ID NO:68ac)326-4A2(分别为SEQ ID NO:和26)；28和82)。
5.如权利要求2-4中任一项所述的方法，其中该抗PD-1抗体包含SEQ ID NO:83-88或91-106中任一项所示的IgG4重链恒定结构域。
6.如权利要求2-3中任一项所述的方法，其中该抗PD-1抗体含有F(ab)或F(ab’)2，该F(ab)或F(ab’)2包含如权利要求2或3所述的CDR、或如权利要求4所述的重链可变区(VH)和轻链可变区(VL)。
7.如权利要求1所述的方法，其中该抗PD-1抗体包含SEQ ID NO:87或88所示的IgG4重链恒定结构域，并且其中该重链可变区(VH)和轻链可变区(VL)包含：
a)mu317(分别为SEQ ID NO:4和6)；p)317-3H1(分别为SEQ ID NO:69和26)；
b)mu326(分别为SEQ ID NO:8和10)；q)317-311(分别为SEQ ID NO:70和26)；
c)317-4B6(分别为SEQ ID NO:24和26)；
d)326-4A3(分别为SEQ ID NO:28和30)；r)317-4B1(分别为SEQ ID NO:71和26)；
e)317-4B2(分别为SEQ ID NO:43和44)；s)317-4B3(分别为SEQ ID NO:72和26)；
f)317-4B5(分别为SEQ ID NO:45和46)；t)317-4B4(分别为SEQ ID NO:73和26)；
g)317-1(分别为SEQ ID NO:48和50)；u)317-4A2(分别为SEQ ID NO:74和26)；
h)326-3B1(分别为SEQ ID NO:51和52)；v)326-3A1(分别为SEQ ID NO:75和30)；
i)326-3GI(分别为SEQ ID NO:53和54)；w)326-3C1(分别为SEQ ID NO:76和30)；
j)326-1(分别为SEQ ID NO:56和58)；x)326-3D1(分别为SEQ ID NO:77和30)；
k)317-3A1(分别为SEQ ID NO:64和26)；y)326-3E1(分别为SEQ ID NO:78和30)；
l)317-3C1(分别为SEQ ID NO:65和26)；z)326-3F1(分别为SEQ ID NO:79和30)；
m)317-3E1(分别为SEQ ID NO:66和26)；aa)326-3B N55D(分别为SEQ ID NO:80和30)；
n)317-3F1(分别为SEQ ID NO:67和26)；ab)326-4A1(分别为SEQ ID NO:28和81)；或
o)317-3G1(分别为SEQ ID NO:68和26)；ac)326-4A2(分别为SEQ ID NO:28和82)。
8.如权利要求1所述的方法，其中该抗PD-1抗体包含含有SEQ ID NO:88的IgG4重链结构域，并且其中该重链可变区(VH)和轻链可变区(VL)分别为SEQ ID NO:24和SEQ ID NO:26所示。
9.如权利要求1所述的方法，其中该抗PD-1抗体包含IgG4 Fc区，该IgG4 Fc区包含在位置228处的S228P突变以及在位置233、234和235处的氨基酸突变，其中相对于仅具有在位置228处的突变的参考IgG4抗体的Fcγ结合，该在位置233、234和235处的突变降低与至少一个Fcγ受体的结合。
10.如权利要求9所述的方法，其中该IgG4 Fc区包含在位置228、233、234、235和265处的氨基酸突变。
11.如权利要求9所述的方法，其中该IgG4 Fc区包含在位置228、233、234、235、265、309和409处的氨基酸突变。
12.如权利要求9所述的方法，其中该IgG4 Fc区由S228P、E233P、F234V和L235A的氨基酸突变组成。
13.如权利要求1所述的方法，其中该尿路上皮癌是输尿管、尿道、肾盂和/或膀胱的癌。
14.如权利要求13所述的方法，其中该尿路上皮癌是移行细胞癌。
15.如权利要求13所述的方法，其中该尿路上皮癌是晚期或转移性。
16.如权利要求13所述的方法，其中该尿路上皮癌是PD-L1+尿路上皮癌或PD-L1-尿路上皮癌。
17.如权利要求13所述的方法，其中该尿路上皮癌是PD-L1+尿路上皮癌。
18.如权利要求1所述的方法，其中该抗PD-1抗体以0.5-10mg/kg QW或Q2W或Q3W或Q4W的剂量胃肠外施用。
19.如权利要求18所述的方法，其中该抗PD-1抗体以2-10mg/kg QW或Q2W或Q3W的剂量施用。
20.如权利要求18所述的方法，其中该抗PD-1抗体以2-10mg/kg的剂量或以200mg Q2W或Q3W的固定剂量施用。
21.如权利要求18所述的方法，其中该抗PD-1抗体以2.0mg/kg Q2W、5mg/kg Q2W、2mg/kg Q3W或5mg/kg Q3W的剂量或以200mg Q2W或Q3W的固定剂量静脉内施用。
22.如权利要求1所述的方法，该方法进一步包括施用另外的治疗剂。
23.如权利要求22所述的方法，其中该另外的治疗剂是甲氨蝶呤、长春新碱、多柔比星和顺铂(MVAC)。
24.如权利要求22所述的方法，其中该另外的治疗剂是顺铂。
25.如权利要求24所述的方法，其中将顺铂与吉西他滨一起施用。
26.如权利要求22所述的方法，其中该另外的治疗剂是紫杉醇。
27.如权利要求25所述的方法，其中在施用顺铂和吉西他滨之前施用紫杉醇。
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