CN115052884A - 单特异性和多特异性抗体 - Google Patents

单特异性和多特异性抗体 Download PDF

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CN115052884A
CN115052884A CN202080082179.3A CN202080082179A CN115052884A CN 115052884 A CN115052884 A CN 115052884A CN 202080082179 A CN202080082179 A CN 202080082179A CN 115052884 A CN115052884 A CN 115052884A
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梁延斌
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Beijing Shuoxing Biomedical Technology Co ltd
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Abstract

本文公开了对CD47、PD‑L1、HSA、CD33、LAG3和CD16中的一者或多者具有特异性的单特异性和多特异性单链抗体。

Description

单特异性和多特异性抗体
相关申请的交叉引用
本申请要求2019年9月27日提交的美国临时专利申请62/907,275和2020年3月13日提交的美国临时专利申请62/989,327的权益，该两个美国临时专利申请的全部内容均全文以引用方式并入。
发明内容
本文公开了对CD47、人血清白蛋白(HSA)、PD-L1、CD33、CD16和LAG3具有特异性的单特异性仅重链抗体(HCAb)；以及多价单链抗体，所述多价单链抗体并入了对这些抗原中的一种或多种抗原具有特异性的两个或更多个HCAb可变结构域。
一些实施方式是单结构域抗体，所述单结构域抗体专门或主要包含骆驼科抗体的VHH结构域。这些实施方式是单特异性和一价的。
一些实施方式是HCAb，或包含与一个或多个来自常规抗体的恒定结构域融合的VHH结构域(例如人IgG抗体的Fc区)。这些实施方式是单特异性的，但通常是二价的。取决于例如恒定结构域的选择，其他效价也是可能的。IgA和IgM的Fc区可以赋予更高的效价。
一些实施方式包含在单个氨基酸链中接合的两个对相同抗原具有特异性的VHH结构域(多价单链抗体)。这些实施方式也是单特异性的和二价的。可接合附加VHH结构域以实现更高的效价。
一些实施方式包含两个(或更多个)VHH结构域，其中每个VHH结构域对在单个氨基酸链中接合的不同抗原具有特异性(多价、多特异性的单链抗体)。这些实施方式是多价和多特异性的。在包含三个或更多个VHH结构域的其他实施方式中，两个或更多个VHH结构域可以对同一抗原具有特异性，而一个或多个其他VHH结构域对不同的抗原具有特异性。此类构建体具有比特异性更高阶的效价。
单特异性实施方式中的每个单特异性实施方式将对CD47、HSA、PD-L1、CD33、CD16或LAG3具有特异性。多特异性实施方式中的每个多特异性实施方式对CD47、HSA、PD-L1、CD33、CD16和LAG3中的一者或多者具有特异性，但也可对一种或多种其他抗原具有特异性。
一些实施方式对HSA和一种或多种其他抗原具有特异性。在这些实施方式的一个方面中，HSA特异性结构域赋予延长的体内半衰期，而其他结构域提供治疗效应。在这些实施方式的另一方面中，HSA特异性结构域可以部分或完全地抑制相邻结构域的结合活性。HSA特异性结构域可以通过可切割的接头接合，该可切割的接头被存在于预期作用位点(例如在肿瘤中)的蛋白酶切割，使得切割解除了对相邻结构域的抑制。一些多特异性实施方式是三特异性的。
在包含多个抗原结合结构域的一些实施方式中，可以使用源自常规VL-VH配对的抗原结合结构域来代替上述实施方式中的一个或多个(但不是全部)VHH结构域。
本文所公开的对特定抗原具有特异性的抗原结合结构域可被称为用于结合抗原的手段。
附图说明
图1描绘了抗CD47 HCAb A09-10和B6H12对过表达CD47的细胞系的结合亲和力的流式细胞术分析。
图2描绘了对CD47具有结合特异性的多特异性抗体1511(SEQ ID NO:156)和3321(SEQ ID NO:157)的竞争性ELISA结合分析。
图3描绘了在Jurkat细胞系上使用流式细胞术对结合CD47的多特异性分子1511和3321进行竞争性结合分析。
图4A描绘了使用结合CD47的多特异性分子1511和3321的人红细胞(RBC)血细胞凝集测定。Hu5F9用作对照。图4B描绘了1511和3321与HL-60细胞和人RBC的结合。
图5描绘了结合CD47的多特异性分子3321在Raja-Luc异种移植小鼠中的抗肿瘤活性。
图6描绘了在过表达PD-L1的CHO细胞上进行的抗PD-L1 HCAb、PL14和PL16的流式细胞术结合分析。阿特朱单抗(Atezolizumab)用作对照。
图7.对PD-L1具有结合特异性的多特异性分子1511和作为对照的阿特朱单抗的基于细胞的功能测定。
图8描绘了结合PD-L1的多特异性分子1518(SEQ ID NO:135)对B-hPD-L1小鼠中MC38-hPD-L1肿瘤生长的抑制。
图9描绘了抗HSA VHH抗体的
Figure BDA0003664798220000031
结合分析。
图10A至图10B描绘了抗CD33 VHH抗体的
Figure BDA0003664798220000032
结合亲和力分析。
图11A至图11B描绘了抗CD16A VHH分子CD16F1(图11A)和CD16E11(图11B)的
Figure BDA0003664798220000033
结合分析。
图12描绘了使用IgG1 B6H12和IgG4 B6H12作为对照，在Jurkat NFAT CD16报道基因测定(ADCC测定)中进行的多特异性分子1511和3321的基于细胞的功能测定。
图13A至图13C描绘了具有HSA结合结构域和CD47结合结构域的分子(图13A)、具有HSA结合结构域和LAG3结合结构域的分子(图13B)和具有HSA结合结构域和CD16结合结构域的分子(图13C)的三特异性分子形式。
图14A至图14B描绘了三特异性分子形式(图14A)和由肿瘤蛋白酶活化的pro-CD47的SDS-PAGE分析(图14B)。
图15描绘了PD-L1/pro-CD47对比PD-L1/活性CD47的实时动力学
Figure BDA0003664798220000034
结合分析。
图16描绘了多特异性分子的形式。Mon＝单价结合结构域；BiV＝包含两个相同单价结合结构域的二价结合结构域。
图17A至图17D描绘了四特异性抗体的形式(四种特异性，图14A至图14D)。两个VHH3可以是针对相同抗原结合不同表位的相同VHH或不同VHH。两个VHH4可以是针对相同抗原结合不同表位的相同VHH或不同VHH。在一些实施方式中，VHH2总是为结合HSA的结构域。在一些实施方式中，VHH1是有效负载，例如CD16A激动剂VHH。图17C和图17D表示前药形式的四特异性抗体。
图18描述了在HL60细胞系上进行的结合CD47的多特异性分子1518-HS5(SEQ IDNO:173)和1518-HS5-GS15(SEQ ID NO 184)的流式细胞术结合分析。
图19描绘了多特异性分子1511的
Figure BDA0003664798220000035
结合分析。
图20描绘了多特异性分子3321的
Figure BDA0003664798220000041
结合分析。
图21描述了抗CD47 VHH序列的氨基酸序列比对。
图22描绘了抗PD-L1 VHH序列的氨基酸序列比对。
图23描绘了抗HSA VHH序列的氨基酸序列比对。
图24描绘了抗CD33 VHH序列的氨基酸序列比对。
图25描绘了抗LAG3 VHH序列的氨基酸序列比对。
图26描述了抗CD16A VHH序列的氨基酸序列比对。
具体实施方式
本文公开了对CD47、人血清白蛋白(HSA)、PD-L1、CD33、CD16和LAG3具有特异性的单特异性仅重链抗体(HCAb)或其可变结构域(称为VHH单结构域抗体[sdAb])；以及多价单链抗体(MVSCA)，所述多价单链抗体并入了两个或更多个HCAb的可变结构域，所述可变结构域对这些抗原中的一种或多种抗原具有特异性。
在一些实施方式中，MVSCA包含对同一抗原具有特异性的两个或更多个HCAb可变结构域。也就是说，MVSCA是多价的，但对抗原是单特异性的。在这些实施方式中的一些实施方式中，MVSCA包含两个或更多个重复的相同HCAb可变结构域或多个HCAb可变结构域，各个HCAb可变结构域对相同表位具有特异性。也就是说，它们是多价，但关于表位而言是单特异性的。这种MVSCA将仅与抗原单体上的单个位点结合，但可以交联该单体的多个拷贝。在这些实施方式中的其它实施方式中，MVSCA包含两个或更多个HCAb可变结构域，各个HCAb可变结构域对同一抗原的不同表位具有特异性。也就是说，它们是多价，但是关于表位而言是多特异性的。此类MVSCA可与抗原单体上的多个位点结合，或交联该单体的多个拷贝。
在一些实施方式中，MVSCA包含两个或更多个对不同抗原具有特异性的HCAb可变结构域，也就是说，它们是多价的且关于抗原而言是多特异性的。在进一步的实施方式中，MVSCA包含任意组合的多个HCAb可变结构域，其中附加可变结构域与第一HCAb可变结构域相同，其中附加HCAb可变结构域与第一HCAb可变结构域不同，但对同一抗原上的不同表位具有特异性，或者其中附加HCAb可变结构域与第一HCAb可变结构域不同，但对不同抗原具有特异性。
包含两个或更多个HCAb可变结构域的MVSCA可进一步包含HCAb恒定结构域。例如，C末端HCAb可变结构域可保持与其原始HCAb恒定结构域的附接。或者，C末端HCAb可变结构域可附接至更常规的抗体(例如人抗体，如人IgG抗体)的恒定区或Fc区。在一些实施方式中，如本领域技术人员将熟悉的，恒定结构域或完整Fc区可赋予特定的功能性。在其它实施方式中，包含两个或更多个HCAb可变结构域的MVSCA可进一步包含HCAb恒定结构域，其中HCAb恒定结构域位于HCAb可变结构域之间或HCAb可变结构域的N末端，而不是位于HCAb可变结构域的C末端，或除位于HCAb可变结构域的C末端之外。。
抗原
CD47(分化群簇47)，也称为整合素相关蛋白(integrin associated protein,IAP)，是一种50KDa的跨膜蛋白，其在人类中由CD47基因编码。CD47属于免疫球蛋白超家族，与膜整合素合作，并且还结合配体血小板反应蛋白-1(TSP-1)和信号调节蛋白α(SIRPα)。血小板反应蛋白-1是一种分泌型糖蛋白，其在血管发育和血管生成中发挥作用，并且在后一种能力中，TSP1-CD47相互作用在血管细胞中以多水平抑制一氧化氮信号传导。TSP-1与CD47的结合影响几种基本的细胞功能，包括细胞迁移和粘附、细胞增殖或凋亡，并在血管生成和炎症的调节中起作用。信号调节蛋白α是一种存在于骨髓细胞上的跨膜受体。CD47/SIRPα相互作用导致双向信号传导，从而导致不同的细胞至细胞反应，包括对吞噬作用的抑制、对细胞至细胞融合的刺激、以及T细胞活化。CD47充当发送给免疫系统的巨噬细胞的“不要吃我”信号，这使CD47成为一些癌症中的潜在治疗靶标。
程序性细胞死亡蛋白1(PD-1)，也称为CD279，是在人类中由PDCD1基因编码的I型膜蛋白。它有两个配体PD-L1和PD-L2。PD-L1，也称为CD274或B7同源物1(B7-H1)，是一种40kDa的I型跨膜蛋白，其在人类中由CD274基因编码。PD-1在活化的T细胞的表面上表达，PD-L1在抗原呈递细胞(antigen presenting cell,APC)(例如树突状细胞和巨噬细胞)的表面上表达。PD-L1也在几种肿瘤(包括乳腺癌、肺癌、膀胱癌、头颈癌和其他癌症)中过表达。当PD-L1或PD-L2与PD-1结合时，抑制信号被传递到T细胞中，这减少细胞因子产生并抑制T细胞增殖。
PD-1通路是T细胞耗竭的关键免疫抑制介体。PD-1作用以在对感染的炎症反应期间限制外周中已活化的T细胞的活性，以限制自体免疫。阻断这一通路可导致T细胞活化、扩增，以及增强的效应子功能。因此，PD-1负调节T细胞应答。PD-1已被确定为慢性疾病状态下被耗竭的T细胞的标志物，并且阻断PD-1:PD-L1相互作用已被证明可部分恢复T细胞功能。(Sakuishi等人，JEM,207:2187-2194,2010)。WO 2006/133396中公开了用于通过抑制PD-1通路来治疗持续性感染和癌症的方法和组合物。在WO 2007/005874、US2011/209230、US 8,217,149和WO2014/055897中描述了针对PD-L1的人单克隆抗体。
人血清白蛋白(HSA)是人血浆中最丰富的蛋白质；其构成血清蛋白的约一半。白蛋白运输激素、脂肪酸和其他化合物，缓冲pH，并且维持膨胀压，以及其他功能。白蛋白在肝脏中合成为前白蛋白原，该前白蛋白原具有N末端肽，该N末端肽在初生蛋白被从粗面内质网释放之前被去除。产物前白蛋白，继而在高尔基小囊泡中被切割，以产生分泌型白蛋白。它的血清半衰期为约20天。白蛋白的长血清半衰期是部分地通过其大小而实现的，该大小阻止了通过肾脏进行的清除；以及是通过与新生Fc受体(FcRn)的相互作用而实现的。与抗白蛋白sdAb(单结构域抗体)的融合已经被用于将抗肿瘤单链抗体的半衰期从1-2小时增加到约10天。
CD33或Siglec-3(结合唾液酸的免疫球蛋白样凝集素3、SIGLEC3、SIGLEC-3、gp67、p67)是一种在髓系细胞上表达的跨膜受体。其通常被认为是骨髓特异性的，但其也能在一些淋巴样细胞上发现。它结合唾液酸，因此是凝集素类SIGLEC家族的成员。这种受体的细胞外部分含有两个免疫球蛋白结构域(一个IgV和一个IgC2结构域)，从而将CD33置于免疫球蛋白超家族内。CD33的细胞内部分含有基于免疫受体酪氨酸的抑制基序(immunoreceptortyrosine-based inhibitory motif,ITIM)，该ITIM与细胞活性的抑制有关。可以通过靶向CD33而治疗的疾病包括但不限于阿尔茨海默氏病和视网膜疾病，例如黄斑水肿(例如，糖尿病性黄斑水肿)和年龄相关性黄斑变性(AMD)(例如，干性AMD和湿性AMD)。
CD33是吉妥珠单抗奥佐米星(
Figure BDA0003664798220000071
Pfizer/Wyeth-Ayerst Laboratories)的靶标，吉妥珠单抗奥佐米星是一种用于治疗急性髓性白血病患者的抗体-药物缀合物(antibody-drug conjugate,ADC)。CD33也是瓦他妥昔单抗他利林(SGN-CD33A)的靶标，瓦他妥昔单抗他利林是一种由Seattle Genetics利用该公司的ADC技术开发的新颖抗体-药物缀合物。
淋巴细胞活化基因3(LAG-3)，一种503个氨基酸的跨膜蛋白，是一种免疫检查点受体蛋白，其存在于效应T细胞和调节T细胞(Treg)的细胞表面上并且作用以控制T细胞应答、活化和生长。LAG3是免疫球蛋白(Ig)超家族的成员。LAG3与MHC II类分子的结合导致向表达LAG3的细胞递送负信号，并下调抗原依赖性CD4和CD8T细胞应答。LAG3负调节T细胞增殖、产生细胞因子和裂解靶细胞的能力，被称为T细胞的‘耗竭’。由于LAG3在肿瘤免疫和感染免疫中起重要作用，因此它是免疫疗法的理想靶标。已经在癌症和慢性病毒感染的治疗中研究了用拮抗剂(包括单克隆抗体)阻断LAG3。
CD16，也称为FcγRIII，是在自然杀伤细胞、嗜中性粒细胞、单核细胞和巨噬细胞的表面上存在的分化簇分子。CD16被鉴定为Fc受体，以以下两种由单独基因编码的形式存在：FcγRIIIa(CD16a)，一种跨膜蛋白；以及FcγRIIIb(CD16b)，一种GPI锚定蛋白；并且参与信号转导。与由NK细胞触发裂解有关的被最充分研究的膜受体，CD16，是参与抗体依赖性细胞毒性(antibody-dependent cellular cytotoxicity,ADCC)的免疫球蛋白超家族(immunoglobulin superfamily,IgSF)的分子。它可用于通过荧光活化细胞分选(fluorescent-activated cell sorting,FACS)或磁活化细胞分选，使用针对CD16的抗体来分离特定免疫细胞群体。这些受体与IgG抗体的Fc部分结合，这随后活化人NK细胞中的抗体依赖性细胞介导的细胞毒性(ADCC)。CD16是由人类单核细胞进行的ADCC过程所必需的。在人类中，表达CD16的单核细胞在特异性抗体存在下具有多种ADCC能力，并且可以杀死原代白血病细胞、癌细胞系和被乙型肝炎病毒感染的细胞。此外，CD16能够介导在没有抗体的情况下直接杀死一些病毒感染的细胞和癌细胞。在与配体(例如IgG抗体的保守区段)结合后，人NK细胞上的CD16诱导表面活化分子如IL-2-R(CD25)和炎性细胞因子如IFN-γ和TNF的基因转录。这种CD16诱导的细胞因子mRNA在NK细胞中的表达是由活化T细胞核因子(NFATp)介导的，该NFATp是一种调节各种细胞因子的转录的环孢菌素A(CsA)敏感因子。特定细胞因子基因的上调表达经由CsA敏感性和钙依赖性机制发生。
CD16在疫苗接种后自然杀伤(NK)细胞的早期活化中起重要作用。此外，CD16下调代表了在T细胞和抗体依赖性信号传导通路两者中调节NK细胞应答和维持免疫稳态的一种可能方式。在正常健康个体中，由免疫复合物交联CD16(FcγRIII)在NK细胞中诱导了抗体依赖性细胞毒性(ADCC)。然而，该途径也可以通过免疫疗法靶向癌细胞或患病细胞。在流感疫苗接种后，CD16下调与流感特异性血浆抗体的显著上调相关联，并且与NK细胞的去颗粒作用呈正相关。
CD16经常被用作可靠地识别人类免疫细胞的不同亚群的附加标记物。几种其他CD分子，例如CD11b和CD33，传统上被用作人髓源性抑制细胞(myeloid-derived suppressorcell,MDSC)的标记物。然而，由于这些标记物也在NK细胞和所有其他来源于髓细胞的细胞上表达，因此需要其他标记物，例如CD14和CD15。发现嗜中性粒细胞是CD14低并且CD15高的，而单核细胞是CD14高并且CD15低的。虽然这两种标记物足以区分嗜中性粒细胞与单核细胞，但是嗜酸性粒细胞与嗜中性粒细胞具有相似的CD15表达。因此，CD16被用作识别嗜中性粒细胞的进一步标志物：成熟的嗜中性粒细胞是CD16高的，而嗜酸性粒细胞和单核细胞都是CD16低的。CD16允许区分这两种类型的粒细胞。此外，CD16表达在嗜中性粒细胞发育的不同阶段之间有所不同：具有分化能力的嗜中性粒细胞祖细胞是CD16低的，而CD16分别在晚幼粒细胞、带状和成熟嗜中性粒细胞中的表达不断增加。
由于CD16在嗜中性粒细胞上的表达，CD16代表了癌症免疫疗法中的一个可能靶标。马格图希单抗(Margetuximab)是一种Fc优化的单克隆抗体，其识别乳腺、膀胱和其他实体瘤癌症中的肿瘤细胞上表达的人表皮生长因子受体2(HER2)，优先于CD16B而靶向CD16A。此外，CD16可以在抗体靶向癌症疗法中发挥作用。双特异性抗体片段，例如抗CD19/CD16，允许免疫治疗药物靶向癌细胞。抗CD19/CD16双抗已被证明增强自然杀伤细胞对B细胞淋巴瘤的应答。此外，将外源因子如FasL或TRAIL靶向肿瘤细胞表面会触发死亡受体，从而通过自分泌和旁分泌过程诱导凋亡。
抗体
抗体及其用于治疗疾病的用途是在本领域中众所周知的。如本文所用，术语“抗体”是指包含一条或多条包含抗原结合位点的多肽链的单体或多聚体蛋白质。抗体与抗原特异性结合，并且可能能够调节抗原的生物活性。如本文所用，术语“抗体”可包括“全长抗体”和“抗体片段”。如本文所用的术语“结合位点”或“抗原结合位点”表示配体实际结合的抗体分子区域。术语“抗原结合位点”包含抗体重链可变结构域(VH)和抗体轻链可变结构域(VL)，或者在仅重链抗体的情况下，包含抗体重链可变区。
抗体特异性是指抗体对抗原的特定表位的选择性识别。天然抗体是例如单特异性的。如本文所用的术语“单特异性”抗体表示这样的抗体，所述抗体具有一个或多个结合位点，所述结合位点中的每个结合位点与相同抗原的相同表位结合。本文所公开的单特异性抗体对CD47、HSA、PD-L1、CD33、CD16或LAG3具有特异性。在一些实施方式中，单特异性抗体是仅重链抗体(HCAb)。在其他实施方式中，单特异性抗体包含与一个或多个蛋白结构域(包括例如人Fc区)融合的VHH结构域。在其他实施方式中，单特异性抗体包含VHH作为唯一完整的蛋白结构域，即单结构域抗体。在一些实施方式中，单结构域抗体可另外包含短肽，例如His标签。术语“VHH结构域”和“HCAb可变结构域”可以可互换地使用。VHH结构域可以被称作用于结合特定靶标(例如，CD47、HSA、PD-L1、CD33、CD16或LAG3)的手段。因此，本文所公开的含有VHH结构域或被构建为含有VHH结构域的各种抗体结构、形式或构建体中的任何一者都可以被称为包含用于结合指定靶标的手段的抗体。一些实施方式可具体包括一种或多种特定的抗体结构、形式或构建体。其他实施方式可以具体排除一种或多种特定的抗体结构、形式或构建体。
如本文所用，“对……具有特异性的抗体”、“识别……的抗体”、“对……具有亲和力的抗体”、“具有与……的结合位点的抗体”以及类似的结构可以可互换地使用。
“多特异性抗体”指具有两种或更多种抗原结合特异性的抗体。本文所公开的多特异性抗体对CD47、HSA、PD-L1、CD33、CD16和LAG3中的至少两者是特异性的，或者对前述特异性中的至少一者和至少第二种特异性是特异性的。在一些实施方式中，本文所公开的多特异性抗体可包括两个、三个、四个或更多个能够结合抗原的结构域。此外，多特异性抗体可包括相同抗原结合序列的至少两个拷贝，或者对相同抗原上的不同表位具有特异性的两个抗原结合序列(双互补位的)，只要该多特异性抗体对CD47、HSA、PD-L1、CD33、CD16和LAG3中的至少一者和至少一种第二抗原具有特异性即可。在一些实施方式中，多特异性抗体(MVSCA)对CD47、HSA、PD-L1、CD33、CD16和LAG3中的至少两者具有特异性。在一些实施方式中，本文所公开的多特异性抗体是单链抗体。因此，一些多特异性抗体可被称为包含用于结合第一靶标的手段和用于结合第二靶标的手段等的抗体。
“双特异性抗体”是指具有两种不同抗原结合特异性的抗体。在一些实施方式中，本文所公开的双特异性抗体对CD47、HSA、PD-L1、CD33、CD16和LAG3中的两者是特异性的。编码双特异性抗体的抗原结合部分的氨基酸序列可以以各种构型连接。在一些实施方式中，编码双特异性抗体的抗体结合部分的氨基酸序列通过如本文所公开的接头连接。
“三特异性抗体”是指具有三种不同抗原结合特异性的抗体。在一些实施方式中，本文所公开的三特异性抗体对CD47、HSA、PD-L1、CD33、CD16和LAG3中的三者是特异性的。编码三特异性抗体的抗原结合部分的氨基酸序列可以以各种构型连接。在一些实施方式中，编码三特异性抗体的抗体结合部分的氨基酸序列通过如本文所公开的接头连接。在一些实施方式中，使用两种接头，该两种接头可以相同或不同。
“四特异性抗体”是指具有四种不同抗原结合特异性的抗体。在一些实施方式中，本文所公开的四特异性抗体对CD47、HSA、PD-L1、CD33、CD16和LAG3中的四者是特异性的。编码四特异性抗体的抗原结合部分的氨基酸序列可以各种构型连接。在一些实施方式中，编码四特异性抗体的抗体结合部分的氨基酸序列通过本文所公开的接头连接。在一些实施方式中，使用两种接头，该两种接头可以相同或不同。
如本文所使用的术语“价”表示抗体分子中存在指定数量的结合位点。因此，术语“二价”、“三价”、“四价”、“五价”、“六价”、“七价”和“八价”分别表示抗体分子中存在两个结合位点、三个结合位点、四个结合位点、五个结合位点、六个结合位点、七个结合位点和八个结合位点。本文所公开的双特异性抗体是“二价的”。本文所公开的三特异性抗体是“三价的”本文所公开的四特异性抗体是“四价的”然而，单特异性多价抗体，例如二价、三价和四价抗体，在本公开的范围内，其中多个抗原结合位点结合相同的抗原。单特异性二价和三价(或更高价)抗体的抗原结合位点可结合抗原上的相同表位或不同表位。类似地，通过将多个单特异性结合位点与用于一种或多种其他特异性的结合位点组合，可以构建抗体，在所述抗体中效价比多特异性更高阶，例如三价双特异性抗体。
“全长抗体”在本文中是指构成抗体的天然生物形式的结构，包括可变区和恒定区。例如，在大多数哺乳动物，包括人和小鼠中，IgG类的全长抗体是四聚体，并且由两对相同的两条免疫球蛋白链组成，每对具有一条轻链和一条重链，每条轻链包含免疫球蛋白结构域VL和C1，并且每条重链包含免疫球蛋白结构域VH、CH1、CH2和CH3。在一些哺乳动物中，例如在骆驼和美洲驼中，IgG抗体也可以仅由两条重链(HCAb)组成，每条重链包含附接至Fc区的可变结构域(CH2和CH3结构域)。
四聚体抗体通常由两对相同的多肽链构成，每对多肽链具有一条“轻链”(分子量通常为约25kDa)和一条“重链”(分子量通常为约50-70kDa)。轻链和重链中的每一者都由被称为可变区和恒定区的两个不同区域组成。对于IgG类免疫球蛋白，重链由从N末端至C末端以VH-CH1-CH2-CH3次序连接的四个免疫球蛋白结构域构成，该四个免疫球蛋白结构域分别指重链可变结构域、重链恒定结构域1、重链恒定结构域2和重链恒定结构域3(也称为VH-Cγ1-Cγ2-Cγ3，分别是指重链可变结构域、恒定γ1结构域、恒定γ2结构域和恒定γ3结构域)。IgG轻链由以VL-CL次序从N末端连接到C末端的两个免疫球蛋白结构域构成，该两个免疫球蛋白结构域分别指轻链可变结构域和轻链恒定结构域。恒定区显示出较少的序列多样性，并负责结合许多天然蛋白质以引发重要的生物化学事件。
抗体的可变区含有分子的抗原结合决定簇，并且因此决定抗体对其靶抗原的特异性。可变区如此命名是因为它在序列上与相同类别的其它抗体最不同。在可变区中，重链和轻链的每个V结构域聚集三个环，以形成抗原结合位点。所述环中的每个环被称为互补决定区(下文称为“CDR”)，在所述互补决定区中氨基酸序列的变化最显著。总共有六个CDR，每条重链和轻链各三个，命名为VH CDR1、VH CDR2、VH CDR3、VL CDR1、VL CDR2和VL CDR3。CDR外部的可变区被称为骨架(FR)区。虽然不像CDR那样多样，但是不同抗体之间的FR区确实存在序列变异性。总的来说，抗体的这种特征性架构提供了稳定的支架(FR区)，在此基础上，可由免疫系统探索大量的抗原结合多样性(CDR)以获得对多种抗原的特异性。
编码免疫球蛋白基因座的基因包含多个V区序列以及被命名为“D”和“J”的较短核苷酸序列，并且正是V、D和J核苷酸序列的组合产生了VH多样性。
如由恒定区遗传决定的，抗体被分成几类，也称为同种型。人类恒定轻链被分类为κ(Cκ)和λ(Cλ)轻链。重链被分类为缪(μ)、德尔塔(δ)、伽马(γ)、阿尔法(α)或依普西隆(ε)，并将抗体的同种型分别定义为IgM、IgD、IgG、IgA和IgE。IgG类别是最常用于治疗目的的。在人类中，这种类别包括亚类IgG1、IgG2、IgG3和IgG4。在小鼠中，这种类别包括亚类IgG1、IgG2a、IgG2b、IgG3。IgM具有亚类，包括但不限于IgM1和IgM2。IgA有几个子类，包括但不限于IgA1和IgA2。因此，如本文所用的“同种型”是指由免疫球蛋白的恒定区的化学和抗原特性定义的所述免疫球蛋白的任何类别或亚类。已知的人免疫球蛋白同种型是IgG1、IgG2、IgG3、IgG4、IgA1、IgA2、IgM1、IgM2、IgD和IgE。所公开的HCAb抗体、双特异性抗体和多特异性抗体可以具有包含上述同种型中的全部或部分同种型的恒定区。
包括但不限于以下的抗体片段也在本公开的范围内：(i)包含VL、CL、VH和CH1结构域的Fab片段；(ii)包含VH和CH1结构域的Fd片段；(iii)包含单个抗体的VL和VH结构域的Fv片段；(iv)包含单一可变区的dAb片段；(v)分离的CDR区；(vi)F(ab′)2片段，一种包含两个连接的Fab片段的二价片段；以及(vii)单链Fv分子(scFv)，其中VH结构域和VL结构域通过肽接头连接，该肽接头允许两个结构域缔合形成抗原结合位点。还公开了包含具有三种不同的特异性并通过可切割或不可切割的接头连接的可变结构域的三价或四价抗体片段。在某些实施方式中，通过重组DNA技术产生抗体。在另外的实施方式中，通过天然存在的抗体的酶促或化学切割产生抗体。
如本文所用的“单链抗体”是指通常通过接头肽连接的抗体的抗原结合部分(即，可变区)的融合蛋白。本文公开了多价单特异性和多特异性单链抗体。单特异性多价抗体对CD47、HSA、PD-L1、CD33、CD16和LAG3中的至少一者具有特异性。多特异性单链抗体对CD47、HSA、PD-L1、CD33、CD16和LAG3中的至少一者具有特异性，加上至少一种进一步的特异性。在一些实施方式中，多特异性单链抗体对CD47、HSA、PD-L1、CD33、CD16和LAG3中的至少两者具有特异性。
如本文所用的“人源化”抗体是指包含人骨架区(FR)和一个或多个来自非人抗体的互补决定区(CDR’)的抗体。提供CDR’的非人抗体被称为“供体”，并且提供骨架的人免疫球蛋白被称为“受体”。在某些实施方式中，人源化主要依赖于将供体CDR移植到受体(人)VL或VH骨架上。这种策略被称为“CDR移植”。通常需要将选定的受体骨架残基“回复突变”成对应的供体残基，以重新获得最初移植的构建体中丧失的亲和力。人源化抗体最佳地还将包含免疫球蛋白恒定区(通常是人免疫球蛋白的恒定区)的至少一部分，并且通常将包含人Fc区。人源化或其他降低非人抗体可变区的免疫原性的方法可包括表面再塑方法。在一个实施方式中，可采用基于选择的方法来对抗体可变区进行人源化和/或亲和成熟，即以增加可变区对其靶抗原的亲和力。其他人源化方法可能涉及仅部分CDR的移植，包括但不限于在US6,797,492中描述的方法，该专利公开的所有关于CDR移植的内容以引入方式并入本文。可采用基于结构的方法来进行人源化和亲和力成熟，例如如在US 7,117,096中所述，该专利公开的所有关于人源化和亲和力成熟的内容以引入方式并入本文。
在本文的各种实施方式中，抗体是仅重链抗体(HCAb)。除了含有常规的重链和轻链抗体(一个抗体中含有2条轻链和2条重链)外，骆驼科动物(骆驼、单峰骆驼和美洲驼)还含有双链抗体(仅含有变异重链)。二聚体抗体由一组独特的被称为VHH基因的VH区段编码。VH和VHH散布在基因组中(即，它们看起来混合在彼此之间)。在VH和VHH cDNA中鉴定出相同的D区段表明VH和VHH共同使用D区段。天然含VHH的抗体缺少重链恒定区的整个CH1结构域。编码CH1结构域的外显子存在于基因组中，但由于CH1外显子的5′侧处的功能性剪接受体序列的缺少而被剪接掉。结果，VDJ区域被剪接到CH2外显子上。当VHH重组到此类恒定区(CH2、CH3)上时，产生了这样的抗体，在所述抗体中，半抗体是单链而不是轻链/重链对(即，具有两条重链而没有轻链相互作用的抗体)。抗原的结合不同于使用常规抗体时看到的结合，但高亲和力是以同样的方式实现的，即通过可变区的超突变和对表达此类高亲和力抗体的细胞的选择。
在一个示例性实施方式中，所公开的HCAb是通过对转基因小鼠进行免疫而产生的，其中内源性鼠抗体表达已经被消除并且已经引入了骆驼科转基因。在US8,883,150、US8,921,524、US8,921,522、US8,507,748、US8,502,014、US2014/0356908、US2014/0033335、US2014/0037616、US2014/0356908、US2013/0344057、US2013/0323235、US2011/0118444、和US2009/0307787中公开了HCAb小鼠，所有这些专利都因所有它们的关于仅重链抗体及所述仅重链抗体在转基因小鼠中的生产的公开内容而以引用方式并入本文。对HCAb小鼠进行免疫，并将所得的致敏脾细胞与鼠骨髓瘤细胞融合以形成杂交瘤。
在其他实施方式中，通过以下方式来生产HCAb：用所需抗原对美洲驼进行免疫，以及分离编码所得抗原结合抗体的VHH区的测序。在一个实施方式中，使用噬菌体展示文库分离VHH。参见例如，WO 91/17271；WO 92/01047；和WO 92/06204(这些专利中的每一者的关于对制备噬菌体文库的描述的全部内容以引用方式并入)。
本文还公开了多特异性或多价抗体，在所述多特异性或多价抗体中两个或更多个抗原结合结构域接合在单个融合蛋白中。多特异性抗体可以采取多种形式，包括(i)多特异性Fv片段；(ii)具有第一特异性的重链，该重链具有与其缔合(或与其融合)的具有第二特异性的第二VH结构域；(iii)具有第一特异性的四聚体单克隆抗体，所述四聚体单克隆抗体具有与其缔合的具有第二特异性的第二VH结构域，其中所述第二VH结构域与第一VH结构域缔合)；(iv)具有第一特异性的Fab片段(VH-CH1/VL-CL)，其具有与其缔合的具有第二特异性的第二VH结构域。示例性Fab片段包括这样的Fab片段，在所述Fab片段中具有第二特异性的第二VH序列与第一VH结构域的C末端或N末端缔合，或者与第一CH1或第一CL结构域的C末端或N末端缔合。在另外的实施方式中，具有第二和/或第三特异性(或更多特异性)的VH序列可以与第一VH结构域的C末端或N末端缔合(或融合)，或者与第一CH1或第一CL结构域的C末端或N末端缔合(或融合)。在各种实施方式中，这些形式中的任何一种形式都可包括本文所公开的HCAb可变结构域中的至少一种HCAb可变结构域。
多特异性或多价抗体可包括接头序列，所述接头序列将特定抗原结合结构域(例如VH或VHH)连接到另一抗原结合结构域，并且允许氨基酸序列正确折叠以产生所需的三维构象和抗原结合谱。通常，接头序列将是短氨基酸序列，所述短氨基酸序列在结构域之间提供足够的空间和灵活性以便所述结构域正确折叠。接头也可引起空间位阻以便于与每个结构域的靶标结合。合适的接头包括但不限于表15的接头(SEQ ID No:100至SEQ ID No:119)、EPKSCD(SEQ ID NO:224)和ASTKGP(SEQ ID NO:225)。本领域技术人员将知道更多的接头。
本文所公开的单特异性或多特异性抗体的氨基酸序列变体也在本公开的范围内。所述氨基酸序列变体是通过将适当的核苷酸改变引入编码抗体的DNA中，或通过肽合成而制备的。此类变体包括例如对本文示例的抗体的氨基酸序列内的残基的缺失和/或插入和/或取代。可以进行缺失、插入和取代的任何组合以达成最终构建体，前提条件是最终构建体具有所需的特征。氨基酸变化还可改变人源化或变异抗体的翻译后过程，例如改变糖基化位点的数目或位置。
用于鉴定为优选诱变位置的某些抗体残基或区域的有用方法称为“丙氨酸扫描诱变”。鉴定出一个残基或一组靶残基(例如，带电荷的残基，例如Arg、Asp、His、Lys以及Glu)，并替换成中性氨基酸(最优选地丙氨酸或聚丙氨酸)以影响氨基酸与抗原的相互作用。然后通过在取代位点处或针对取代位点引入进一步或其他变异来改善那些对取代表现出功能敏感性的氨基酸位置。因此，虽然预先确定了用于引入氨基酸序列变异的位点，但是突变本身的性质无需预先确定。例如，为了分析给定位点处的突变的性能，在靶密码子或区域进行丙氨酸扫描或随机诱变，并对表达的抗体变体进行所需活性筛选。
氨基酸序列插入包括从一个残基到含有一百个或更多个残基的多肽的长度范围内的氨基和/或羧基末端融合，以及单个或多个氨基酸残基的序列内插入。末端插入的示例包括具有N末端甲硫酰基残基的本文所公开的抗体，或与表位标签融合的抗体。抗体分子的其他插入变体包括将延长抗体的血清半衰期的酶或多肽融合到所述抗体的N末端或C末端。
变体的另一种类型是氨基酸取代变体。这些变体在抗体分子中具有至少一个氨基酸残基被去除并且在其位置中插入了不同的残基。最感兴趣的替代诱变位点包括高变区，但也考虑FR改变。保守取代显示在表1的“优选取代基”表头下。如果此类取代导致生物活性改变，则可以引入在表1中命名为“示例性取代”或者如以下参考氨基酸类别进一步描述的更实质性改变，并筛选产物。
表1
Figure BDA0003664798220000161
对抗体的生物学特性的实质性修饰是通过以下方式实现的：选择在维持(a)取代区域中的多肽主链的结构(例如呈片状或螺旋构象)，(b)在靶位点处分子的电荷或疏水性，或(c)侧链的体积方面的效应显著不同的取代。天然存在的残基基于常见的侧链特性分为以下各组：
(1)疏水性：正亮氨酸、Met、Ala、Val、Leu、Ile；
(2)中性亲水性：Cys、Ser、Thr；
(3)酸性：Asp、Glu；
(4)碱性：Asn、Gin、His、Lys、Arg；
(5)影响链取向的残基：Gly、Pro；以及
(6)芳香族：Trp、Tyr、Phe。
非保守取代将需要将这些类别中的一种类别的成员交换为另一种类别。
也可以通常用丝氨酸取代不参与维持单特异性或多特异性抗体的适当构象的任何半胱氨酸残基，以改善分子的氧化稳定性并防止异常交联。相反，可将一个或多个半胱氨酸键添加至抗体以改善其稳定性(特别是当抗体是例如Fv片段等抗体片段时)。
另一种类型的替代变体涉及取代亲本抗体(例如，人源化或骆驼科抗体)的一个或多个高变区残基。通常，选择用于进一步开发的所得变体将相对于产生它们的亲本抗体具有改善的生物学特性。产生此类取代变体的方便方式是使用噬菌体展示进行亲和力成熟。简而言之，几个高变区位点(例如，6-7个位点)经突变以产生每个位点处所有可能的氨基取代。如此产生的抗体变体以单价形式从丝状噬菌体颗粒展示为与包装在每个颗粒中的M13的基因III产物的融合体。然后如本文所公开的，对经噬菌体展示的变体进行针对它们的生物学活性(例如，结合亲和力)的筛选。为了鉴定用于修饰的候选高变区位点，可以执行丙氨酸扫描诱变以鉴定对抗原结合有显著贡献的高变区残基。替代地或另外，可为有益的是分析抗原-抗体复合物的晶体结构以鉴定抗体与抗原之间的接触点。根据本文详述的技术，此类接触残基和邻近残基是取代的候选者。一旦产生了此类变体，就对该组变体进行如本文所述的筛选，并且可以选择在一项或多项相关测定中具有优异特性的抗体用于进一步开发。
抗体的另一种氨基酸变体改变了抗体的原始糖基化模式。改变是指使抗体中发现的一个或多个碳水化合物部分缺失，和/或添加抗体中不存在的一个或多个糖基化位点。
抗体的糖基化通常是N-连接的或O-连接的。N-连接的是指碳水化合物部分附接至天冬酰胺残基的侧链。三肽序列天冬酰胺-X-丝氨酸和天冬酰胺-X-苏氨酸，其中X是除脯氨酸外的任何氨基酸，是将碳水化合物部分酶促附接至天冬酰胺侧链的识别序列。因此，多肽中这些三肽序列中任一者的存在产生潜在的糖基化位点。O-连接的糖基化是指糖N-乙酰半乳糖胺、半乳糖或木糖中的一者附接至羟基氨基酸(最通常为丝氨酸或苏氨酸)，尽管也可以使用5-羟基脯氨酸或5-羟基赖氨酸。
通过改变氨基酸序列以使其含有上述三肽序列中的一个或多个，可以方便地实现将糖基化位点添加至抗体(对于N-连接的糖基化位点)。也可以通过对原始抗体的序列添加或取代一个或多个丝氨酸或苏氨酸残基来进行改变(对于O-连接的糖基化位点)。
通过本领域已知的多种方法来制备编码单特异性或多特异性抗体的氨基酸序列变体的核酸分子。这些方法包括但不限于从天然来源分离(在天然存在的氨基酸序列变体的情况下)，或通过对先前制备的本文所公开的抗体的变异或非变异版本进行寡核苷酸介导的(或定点)诱变、PCR诱变和盒式诱变来制备。
设想了单特异性或多特异性抗体的其他修饰。例如，可能需要在效应子功能方面对抗体进行修饰，例如以增强抗体在治疗疾病方面的功效。例如，可以将一个或多个半胱氨酸残基引入Fc区，从而允许在该区域中形成链间二硫键。如此产生的同二聚体抗体可能具有改善的内化能力和/或增加的补体介导的细胞杀伤和抗体依赖性细胞毒性(ADCC)。也可以使用异双功能交联剂制备具有增强的抗肿瘤活性的同二聚体抗体。或者，抗体可以经工程化为具有双Fc区，并可由此具有增强的补体裂解和ADCC能力。
在另一个实施方式中，抗体可以与“受体”(例如链霉亲和素)缀合以用于预靶向，其中将抗体-受体缀合物施用于患者，之后使用清除剂从循环中去除未结合的缀合物，然后施用与细胞毒性剂(例如，放射性核素)缀合的“配体”(例如，亲和素)。
单特异性或多特异性抗体的共价修饰也被包括在本公开的范围内。如果适用的话，它们可以通过化学合成或通过抗体的酶促或化学切割来制备。通过使抗体的靶向氨基酸残基与有机衍生剂反应来将抗体的其它类型的共价修饰引入分子中，所述有机衍生剂能够与选定的侧链或N末端或C末端残基反应。多肽的示例性共价修饰在US5,534,615中有所描述，该专利出于其关于多肽共价修饰的公开内容而特别地以引用方式并入本文。示例性的抗体共价修饰类型包括以US4,640,835、US4,496,689、US4,301,144、US4,670,417、US4,791,192、或US4,179,337中所述的方式将抗体连接到多种非蛋白聚合物(例如聚乙二醇、聚丙二醇或聚氧化烯)中的一种非蛋白聚合物。
本文所公开的单特异性或多特异性抗体可以通过重组手段产生。因此，本文公开了编码抗体的核酸、包含编码抗体的核酸的表达载体，以及包含编码抗体的核酸的细胞。重组生产的方法在现有技术中是众所周知的，并且包括在原核和真核细胞中进行蛋白质表达，随后分离抗体，并通常纯化至药学上可接受的纯度。为了在宿主细胞中如上所述表达抗体，通过标准方法将编码抗体序列的核酸插入表达载体。在合适的原核或真核宿主细胞(如CHO细胞、NS0细胞、SP2/0细胞、HEK293细胞、COS细胞、PER.C6细胞、酵母或大肠杆菌(E.coli)细胞)中执行表达，并从所述细胞中回收抗体(裂解后的上清液或细胞)。应当理解的是，任何重组表达的蛋白质在其N末端都需要引发剂甲硫氨酸(或甲酰甲硫氨酸)或信号序列，具体取决于所使用的表达系统以及该蛋白质是在细胞质中表达还是被分泌。因此，在一些实施方式中，本文所公开的蛋白质序列在其N末端用此类附加氨基酸进行了修饰。在一些实施方式中，此类N末端序列被从完全成熟的序列上切割下来(全部或部分地)，而在其它实施方式中，它们被保留下来。
因此，本文所公开的某些实施方式包括一种制备单特异性或多特异性抗体的方法，所述方法包括以下步骤：a)用至少一种包含编码抗体的核酸分子的表达载体转化宿主细胞；b)在允许抗体分子合成的条件下培养宿主细胞；以及c)从培养物中回收所述抗体分子。
通过常规的免疫球蛋白纯化方法，例如蛋白A-琼脂糖凝胶、羟磷灰石层析、凝胶电泳、透析或亲和层析，将抗体与培养基适当地分离。
如本文所用，表述“细胞”、“细胞系”和“细胞培养物”可互换地使用，并且所有此类名称均包括子代。因此，词语“转化体”和“转化细胞”包括原代受试者细胞和来源于其的培养物，而与转移次数无关。还应理解，由于故意或无意的突变，所有子代的DNA含量可能不是精确相同的。包括具有与原始转化细胞中筛选的功能或生物学活性相同的功能或生物学活性的变异子代。在旨在使用不同的名称的情况下，将从上下文中明晰。
如本文所用的术语“转化”是指将载体/核酸转移到宿主细胞中的过程。如果将没有强大的细胞壁屏障的细胞用作宿主细胞，则可以例如通过磷酸钙沉淀法进行转染。然而，也可以使用例如通过核注射或通过原生质体融合将DNA引入细胞中的其他方法。如果使用原核细胞或含有大量细胞壁构造的细胞，则例如一种转染方法是使用氯化钙进行钙处理。
如本文所用，“表达”是指将核酸转录成mRNA的过程和/或将经转录的mRNA(也称为转录物)随后翻译成肽、多肽或蛋白质的过程。转录物和编码的多肽统称为基因产物。如果多核苷酸来源于基因组DNA，则在真核细胞中表达可包括mRNA的剪接。
“载体”是核酸分子，尤其是自我复制的核酸分子，其将插入的核酸分子转移到宿主细胞内和/或之间。该术语包括主要起将DNA或RNA插入细胞中(例如，染色体整合)的功能的载体，主要起复制DNA或RNA的功能的载体的复制，以及作用为转录和/或翻译DNA或RNA的表达载体。还包括提供如所述功能中的多于一种功能的载体。
“表达载体”是这样的多核苷酸，所述多核苷酸当被引入合适的宿主细胞中时，可以被转录并翻译成多肽。“表达系统”通常是指由可作用以产生所需表达产物的表达载体组成的合适宿主细胞。
如本文所用的术语“宿主细胞”表示可以经工程化以产生本文所公开的抗体的任何类型的细胞系统。在一个实施方式中，HEK293细胞和CHO细胞用作宿主细胞。
适用于原核生物的控制序列例如包括启动子、任选地操纵子序列，以及核糖体结合位点。已知真核细胞利用启动子、增强子和多腺苷酸化信号。
当核酸被放置为与另一核酸序列呈功能关系时，该核酸是“可操作地连接的”。例如，如果前序列或分泌前导序列的DNA表达为参与多肽分泌的前蛋白，则所述前序列或分泌前导序列的DNA与所述多肽的DNA可操作地连接；如果启动子或增强子影响编码序列的转录，则所述启动子或增强子与所述序列可操作地连接；或者如果核糖体结合位点经定位以促进翻译，则所述核糖体结合位点与编码序列可操作地连接。通常，“可操作地连接的”是指被连接的DNA序列是连续的，并且在分泌前导序列的情况下，是连续的并且在阅读框中。然而，增强子不必是连续的。连接是通过在方便的限制性位点连接完成的。如果此类位点不存在，则根据常规实践使用合成的寡核苷酸衔接子或接头。
本文还公开了编码单特异性或多特异性抗体的分离核酸，包含所述核酸的载体和宿主细胞，以及用于产生所述抗体的重组技术。
为了重组产生抗体，可以将编码所述抗体的核酸分离，并插入到可复制载体中以进一步克隆(DNA扩增)或表达。在一些实施方式中，抗体可以通过同源重组产生，例如如在US 5,204,244中所述，该专利关于抗体产生的所有公开内容以引用方式特别地并入本文。使用常规工序(例如，通过使用能够与编码抗体的重链和轻链的基因特异性结合的寡核苷酸探针)容易地分离编码抗体的DNA并进行测序。许多载体可用。载体组分通常包括但不限于以下中的一种或多种：信号序列、复制起点、一个或多个标记基因、增强子元件、启动子，以及转录终止序列，例如如在US 5,534,615中描述的，该专利关于蛋白质表达的所有公开内容以引用方式明确地并入本文。
用于克隆或表达本文的载体中的DNA的合适宿主细胞是上述原核生物、酵母，或更高等的真核细胞。用于此目的的合适原核生物包括真细菌，例如革兰氏阴性或革兰氏阳性生物体，例如肠杆菌科(Enterobacteriaceae)(例如埃希氏菌属(Escherichia)，例如大肠杆菌)、肠杆菌属(Enterobacter)、欧文氏菌属(Erwinia)、克雷伯氏菌属(Klebsiella)、变形杆菌属(Proteus)、沙门氏菌属(Salmonella)(例如，鼠伤寒沙门氏菌(Salmonellatyphimurium))、沙雷氏菌属(Serratia)(例如，粘质沙雷氏菌(Serratia marcescans))和志贺氏菌属(Shigella)，以及芽孢杆菌属(Bacilli)(例如枯草芽孢杆菌(B.subtilis)和地衣芽孢杆菌(B.licheniformis))、假单胞菌属(Pseudomonas)(例如铜绿假单胞菌(P.aeruginosa))、以及链霉菌属(Streptomyces)。一种示例性的大肠杆菌克隆宿主是大肠杆菌294(ATCC 31,446)，但是其他菌株，例如大肠杆菌B、大肠杆菌X1776(ATCC 31,537)和大肠杆菌W3110(ATCC 27,325)也是合适的。这些示例是说明性的而不是限制性的。
除原核生物外，真核微生物，例如丝状真菌或酵母菌，也是编码单特异性或多特异性抗体的载体的合适克隆或表达宿主。酿酒酵母(Saccharomyces cerevisiae)，或普通的面包酵母，是低等真核宿主微生物中最常用的酵母。然而，许多其他属、物种和菌株是本文中普遍可得和有用的，例如粟酒裂殖酵母(Schizosaccharomyces pombe)；克鲁维酵母(Kluyveromyces)宿主，例如乳酸克鲁维酵母(K.lactis)、脆壁克鲁维酵母(K.fragilis)(ATCC 12,424)、保加利亚克鲁维酵母(K.bulgaricus)(ATCC 16,045)、威克克鲁维酵母(K.wickeramii)(ATCC 24,178)、瓦尔特克鲁维酵母(K.waltii)(ATCC 56,500)、果蝇克鲁维酵母(K.drosophilarum)(ATCC 36,906)、耐热克鲁维酵母(K.thermotolerans)、以及马克斯克鲁维酵母(K.marxianus)；耶氏酵母属(yarrowia)(EP 402,226)；巴斯德毕赤酵母(Pichia pastoris)(EP 183,070)；念珠菌属(Candida)；里氏木霉(Trichoderma reesia)(EP 244,234)；粗糙脉孢菌(Neurospora crassa)；许旺酵母属(Schwanniomyces)，例如西方许旺酵母(Schwanniomyces occidentalis)；以及丝状真菌，例如脉孢菌属(Neurospora)、青霉菌属(Penicillium)、弯颈霉属(Tolypocladium)、以及曲霉属(Aspergillus)宿主，例如构巢曲霉(A.nidulans)和黑曲霉(A.niger)。
用于表达糖基化单特异性或多特异性抗体的合适宿主细胞来源于多细胞生物，包括无脊椎动物细胞，例如植物细胞和昆虫细胞。已经鉴定出来自宿主的许多杆状病毒株和变体以及相应的允许昆虫宿主细胞，所述宿主为例如草地夜蛾(Spodoptera frugiperda)(毛虫)、埃及伊蚊(Aedes aegypti)(蚊子)、白纹伊蚊(Aedes albopictus)(蚊子)、黑腹果蝇(Drosophila melanogaster)(果蝇)以及中国桑蚕(Bombyx mori)。用于转染的各种病毒株是可公开获得的，例如，苜蓿银纹夜蛾(Autographa californica)NPV的L-1变体和中国桑蚕NPV的Bm-5株，并且此类病毒可用作本文中根据本发明的病毒，特别是用于草地夜蛾细胞的转染。棉花、玉米、马铃薯、大豆、矮牵牛、番茄和烟草的植物细胞培养物也可以用作宿主。
然而，对脊椎动物细胞的兴趣最大，并且脊椎动物细胞在培养(组织培养)中的增殖已成为常规程序。有用的哺乳动物宿主细胞系的示例是通过SV40(COS-7、ATCC CRL1651)转化的猴肾CV1系；人胚胎肾细胞系(经亚克隆以在悬浮培养中生长的293或293细胞)；幼仓鼠肾细胞(BHK、ATCC CCL 10)；中国仓鼠卵巢细胞/-DHFR(CHO)；小鼠塞尔托利氏细胞(TM4)；猴肾细胞(CV1ATCC CCL 70)；非洲绿猴肾细胞(VERO-76、ATCC CRL-1587)；人宫颈癌细胞(HELA、ATCC CCL 2)；犬肾细胞(MDCK、ATCC CCL 34)；布法罗大鼠肝细胞(BRL 3A、ATCC CRL 1442)；人肺细胞(W138、ATCC CCL 75)；人肝细胞(Hep G2、HB 8065)；小鼠乳腺肿瘤(MMT 060562、ATCC CCL51)；TRI细胞；MRC 5细胞；FS4细胞；以及人类肝癌细胞系(HepG2)。
用上述表达载体转化宿主细胞以进行单特异性或多特异性抗体生产，并在经适当修饰以诱导启动子、选择转化体或扩增编码所需序列的基因的常规营养培养基中培养。
用于生产单特异性或多特异性抗体的宿主细胞可以在多种培养基中培养。商业可用的培养基，例如Ham′s F10(Sigma)、基本必需培养基(MEM)(Sigma)、RPMI-1640(Sigma)和杜氏改良的伊格尔培养基(DMEM)(Sigma)，都适合用于培养宿主细胞。此外，US4,767,704；US4,657,866；US4,927,762；US4,560,655；或US5,122,469；WO 90/03430；WO 87/00195；或US Re.30,985可用作宿主细胞的培养基。这些培养基中的任何一种都可以根据需要补充激素和/或其他生长因子(例如胰岛素、转铁蛋白或表皮生长因子)、盐(例如氯化钠、钙、镁，以及磷酸盐)、缓冲剂(例如HEPES)、核苷酸(例如腺苷和胸苷)、抗生素(例如GENTAMYCINTM)、微量元素(定义为通常以微摩尔范围的最终浓度存在的无机化合物)，以及葡萄糖或等效能源。也可以以本领域技术人员已知的适当浓度包含任何其他必要的补充剂。培养条件，诸如温度、pH等，是先前与经选择用于表达的宿主细胞一起使用的那些条件，并且对于普通技术人员而言将是显而易见的。
当使用重组技术时，抗体可以在细胞内、在周质间隙中产生，或直接分泌到培养基中。如果抗体在细胞内产生，则作为第一步，例如通过离心或超滤去除为宿主细胞或裂解片段的微粒碎片。
可以使用例如羟基磷灰石层析、凝胶电泳、透析和亲和层析来纯化由细胞制备的抗体组合物，其中亲和层析是优选的纯化技术。蛋白A作为亲和配体的适用性取决于抗体中存在的任何免疫球蛋白Fc结构域的种类和同种型。蛋白A可用于纯化基于人γ1、γ2或γ4重链的抗体，尽管蛋白A可用于纯化不含Fc区的抗体。蛋白G可用于所有小鼠同种型和人γ3。亲和配体所附接至的基质最通常是琼脂糖，但也可以使用其他基质。机械稳定的基质(诸如受控的孔玻璃或聚(苯乙烯二乙烯基)苯)允许实现比使用琼脂糖能够实现的更快的流率和更短的处理时间。如果抗体包含CH3结构域，则Bakerbond ABXTM树脂可用于纯化。本文所公开的抗体和抗体片段也可合成为具有组氨酸标签，并通过金属亲和层析进行亲和纯化。
取决于要回收的抗体，也可以使用其他蛋白质纯化技术，诸如离子交换柱上的分馏、乙醇沉淀、反相HPLC、硅胶上的层析、在肝素SEPHAROSETM上的层析、在阴离子或阳离子交换树脂上的色谱(例如聚天冬氨酸柱)、层析聚焦、SDS-PAGE，以及硫酸铵沉淀。
在任何初步纯化步骤之后，可以使用洗脱缓冲液在约2.5-4.5之间的pH下对包含感兴趣的抗体和污染物的混合物进行低pH疏水相互作用层析，优选在低盐浓度(例如，约0-0.25M的盐)下执行。
本文还公开了在肿瘤微环境中可切割的多特异性单链抗体。在一些实施方式中，一旦多特异性单链抗体到达肿瘤，肿瘤靶向结构域(例如肿瘤抗原结合结构域)或其他功能结构域(例如抗HSA结构域，其可以延长全身半衰期)在接头处被切割下，以便释放带来治疗效应的其他结构域。肿瘤微环境含有大量能够切割本文所公开的接头的蛋白酶。肿瘤蛋白酶的非限制性示例包括但不限于基质金属蛋白酶(例如，MMP1、MMP2、MMP3、MMP7、MMP8、MMP9、MMP12和MMP14)、ADAM(去整合素和金属蛋白酶；例如，ADAM10和ADAM17)、激肽释放酶相关的肽酶(例如，KLK1、KLK2、KLK3和KLK6)、组织蛋白酶(例如，CTS-B、CTS-L和CTS-S)、尿激酶纤溶酶原活化剂(uPA)、hepsin(HPN)、马曲肽酶(matriptase)、豆荚蛋白或二肽基肽酶(例如，DDP4)。
抗体组合物
本文还公开了包含单特异性或多特异性抗体的药物组合物，在所述单特异性或多特异性抗体中特异性包括CD47、HSA、PD-L1、CD33、CD16或LAG3。还公开了本文所述的抗体用于制造药物组合物的用途。还公开了使用所公开的抗体和包含所述抗体的药物组合物来治疗各种疾病和疾患的方法。
药物组合物是旨在用于并适合用于治疗人类疾病的药物组合物。也就是说，它提供了总体有益效应，并且不含有导致与有益效应的提供无关的毒性或其它非期望效应的量的成分或污染物。药物组合物将含有一种或多种活性剂，并且可进一步含有溶剂、缓冲剂、稀释剂、载剂和其他赋形剂，以有助于活性剂或整个组合物的施用、溶解度、吸收或生物利用度和/或稳定性等。
本文所公开的单特异性或多特异性抗体也可以在脂质体中配制。含有抗体的脂质体是通过本领域已知的方法，例如在US4,485,045、US4,544,545、和US5,013,556中描述的方法制备。特别有用的脂质体可以用包含磷脂酰胆碱、胆固醇和PEG衍生的磷脂酰乙醇胺(PEG-derivatized phosphatidylethanolamine,PEG-PE)的脂质组合物，通过反相蒸发法产生。将脂质体通过规定孔径的过滤器挤出，以得到具有所需直径的脂质体。抗体的Fab′片段可以经由二硫键交换反应与脂质体缀合。
如本文所用，“药物载体”包括生理上相容的任何和所有溶剂、分散介质、包衣、抗细菌剂和抗真菌剂、等渗剂和吸收延迟剂等。优选地，载体适于静脉内、肌内、眼内、玻璃体内、皮下、肠胃外、脊柱或表皮施用(例如通过注射或输注)。在一些实施方式中，载体是水性的。
本文所公开的组合物可以通过本领域已知的多种方法施用。如本领域技术人员应理解的，施用的途径和/或模式将取决于所需的结果而变化。为了通过某些施用途径施用所公开的抗体，可能有必要将抗体与防止其失活的物质缔合或将所述抗体与所述物质共施用。例如，抗体可以在合适的载体，例如脂质体或稀释剂中施用于受试者。药学上可接受的稀释剂包括盐水和缓冲水溶液。药物载体包括无菌水溶液或分散体以及用于临时制备无菌可注射溶液或分散体的无菌粉末。用于药学活性物质的此类介质和药剂的用途是本领域已知的。
如本文所用的短语“胃肠外施用”和“胃肠外地施用”是指除肠内和局部施用以外的施用模式(通常通过注射)，并且包括但不限于静脉内、肌内、动脉内、鞘内、囊内、眶内、心内、眼内、玻璃体内、皮内、腹膜内、经气管、皮下、表皮下、关节内、囊下、蛛网膜下、脊柱内、硬膜外和胸骨内注射和输注。
这些组合物还可含有赋形剂，诸如防腐剂、润湿剂、乳化剂和分散剂。通过上文的灭菌程序和通过包含各种抗细菌剂和抗真菌剂(例如对羟基苯甲酸酯、氯丁醇、苯酚山梨酸等)，可以确保防护微生物的存在。还可能需要在组合物中包含等渗剂，诸如糖、氯化钠等。此外，可以通过包含延迟吸收的试剂(例如单硬脂酸铝和明胶)来延长可注射药物形式的吸收。
在一些实施方式中，包含抗体的药物组合物是冻干饼。该冻干饼可进一步包含填充剂、缓冲剂和/或盐，或其它赋形剂，例如本文所述。冻干组合物可以通过加入无菌水或水性缓冲液来重构，以用于施用于患者。
不管所选择的施用途径如何，可以以合适的水合形式使用的所公开的抗体和/或含有所述抗体的药物组合物，被通过本领域技术人员已知的常规方法配制成药学上可接受的剂型。
药物组合物中活性成分的实际剂量水平可以变化，以便获得一定量活性成分，该量有效实现对特定患者、组合物和施用模式的所需治疗反应，而对患者没有毒性。所选择的剂量水平将取决于多种药代动力学因素，包括所采用的本发明的特定组合物的活性、施用途径、施用时间、所采用的特定化合物的排泄速率、治疗持续时间、与所采用的特定组合物联合使用的其它药物、化合物和/或材料、所治疗的患者的年龄、性别、体重、状况、总体健康和既往病史，以及医学领域中众所周知的类似因素。
所公开的MVSCA及其组成抗体结构域和接头的功能
抗HSA的VHH
MVSCA内的抗HSA结构域的主要功能是结合HSA，并由此延长MVSCA在体内的半衰期。包含抗HSA结构域可延长半衰期，否则半衰期可能只有几个小时到大于一周。通常情况下，单个抗HSA结构域就足以满足这一目的。因此，抗HSA结构域构成了用于延长MVSCA半衰期的手段。
通过结合HSA，抗HSA结构域可以介导相邻结合结构域的部分或完全阻断，从而抑制或调节其活性(有效亲和力)。阻断是基本上完全的还是仅仅部分的取决于两个结构域之间的接头的长度，接头越短，则抗原结合的阻断越完全。部分阻断往往可以观察到是VHH对其抗原的表观或有效亲和力降低。在一些情况下，部分阻断被观察到是VHH的特异性的增加，因为该结构域继续结合其具有较高亲和力的抗原，但未能表现出对较低亲和力抗原的显著结合。因此，抗HSA结构域构成了用于抑制相邻结合结构域的结合活性的手段。
该阻断也可为可逆的。通过将抗HSA结构域置于MVSCA中的末端位置，并将其与可切割的接头附接，可以去除抗HSA结构域，并恢复相邻的结合结构域的全部结合活性。此类抗体构建体是有效的前药。例如，如果接头被在所需作用位点发现的蛋白酶切割，则MVSCA可以在邻近结合位点无活性的情况下行进通过身体，但是在到达其作用位点(例如，肿瘤)时，接头被切割，抗HSA结构域被释放，并且对邻近结构域的结合活性的抑制被逆转。因此，当与可切割的接头配对时，抗HSA结构域构成了用于可逆地抑制MVSCA或多特异性抗体中的相邻结合结构域的结合活性的手段。
抗CD47
抗CD47结构域的功能是抑制肿瘤细胞上CD47的“不要吃我”信号，使得所述肿瘤细胞可以被巨噬细胞吞噬。CD47广泛表达，并且如果与正常健康细胞有实质性结合，则抗CD47活性可能会有问题。有几种方式可以避免这种情况。显然存在CD47的多种构象，并且通常在肿瘤细胞上发现的构象不同于例如在RBC上发现的构象。如实施例1所示，本文所公开的VHH结合在肿瘤细胞上表达的CD47，但不结合在RBC上表达的CD47。避免与RBC结合也很重要，以便MVSCA不会在血流中被捕获并且被阻止而无法到达其靶标。
另一种避免MVSCA与CD47的不期望或有害结合的方式可以通过以下方式来实现：将MVSCA以某一方式放置在抗HSA结构域附近，使得与CD47的结合被减少或被阻止，如上所述。一旦MVSCA通过其结合结构域中的另一个结合结构域与肿瘤细胞结合，并且抗HSA结构域被局部蛋白酶切割并释放，抗CD47结构域就可以结合CD47并阻止其与巨噬细胞的吞噬抑制相互作用。
因此，抗CD47结构域构成了用于降低对吞噬作用的抑制的手段。
抗CD16
抗CD16结构域的功能是上调NK细胞的ADCC活性。然而CD16B具有广泛的组织分布，CD16A在NK细胞中特异性表达。对CD16A有特异性的抗体是优选的，因为它们将只与NK细胞(所需的靶细胞)结合。然而，结合CD16A和CD16B两者的抗体和仅结合CD16A的抗体都是能够促进NK细胞的ADCC活性的激动剂。
CD16通常与抗体的Fc部分相互作用。当NK细胞上的CD16A被抗体的Fc部分接合时，NK细胞的溶细胞活性变得针对抗体的可变结构域已经结合的细胞或微生物。然而，存在多种Fc序列和多种类型的Fc受体，从而导致由Fc区介导的多种可能的效应。通过使用抗CD16结构域而不是Fc区，MVSCA可以特异性地募集NK介导的ADCC来对抗它所携带的其他特异性的靶标。因此，抗CD16结构域构成了用于募集NK介导的ADCC的手段。
抗PD-L1
抗PD-L1结构域作为免疫检查点抑制剂和抗肿瘤抗原抗体两者起作用。抗PD-L1结构域充当PD-1结合拮抗剂。通过阻断PD-L1(例如，在肿瘤细胞上)与PD-1(例如，在T细胞上)的结合，抗PD-L1结构域抑制相关联的免疫检查点，从而释放T细胞介导的免疫应答的发展。使用抗PD-1或抗PD-L1抗体的PD-1阻断是一种众所周知的癌症治疗方式。因此，抗PD-L1结构域构成了用于PD-1阻断的手段或用于释放PD-1免疫检查点的手段。
抗PD-L1结构域，作为抗肿瘤抗原的抗体，可介导MVSCA与肿瘤细胞的结合。如果MVSCA还包含抗CD16结构域，则促进了NK介导的ADCC。在MVSCA还包含抗CD47结构域的情况下，促进了巨噬细胞介导的吞噬作用。与肿瘤细胞的多价结合提高了结合亲和力和ADCC。这可以通过具有抗PD-L1结构域的多个拷贝和/或一个或多个靶向其他肿瘤抗原的结合结构域来实现。因此，抗PD-L1结构域构成了用于结合肿瘤细胞的手段、用于结合肿瘤抗原的手段或用于结合PD-L1肿瘤抗原的手段。
抗LAG3
抗LAG3结构域作为免疫检查点抑制剂起作用。抗LAG3结构域充当LAG3与II类MHC蛋白结合的拮抗剂。通过阻断T细胞上的LAG3与肿瘤细胞上的II类MHC的结合，抗LAG3结构域抑制相关联的免疫检查点，从而释放T细胞介导的免疫应答的发展。因此，抗LAG3结构域构成了用于释放LAG3免疫检查点的手段。
抗CD33
抗CD33结构域可以以两种方式使用。CD33在髓样细胞和一些淋巴样细胞上表达，其在一些血液系统癌，例如急性髓样白血病(AML)中表达，因此是肿瘤抗原。抗CD33结构域，作为抗肿瘤抗原的抗体，可介导MVSCA与肿瘤细胞的结合。如果MVSCA还包含抗CD16结构域，则促进了NK介导的ADCC。在MVSCA还包含抗CD47结构域的情况下，促进了巨噬细胞介导的吞噬作用。与肿瘤细胞的多价结合提高了结合亲和力和ADCC。这可以通过具有抗CD33结构域的多个拷贝和/或一个或多个靶向其他肿瘤抗原的结合结构域来实现。因此，抗CD33结构域构成了用于结合肿瘤细胞的手段、用于结合肿瘤抗原的手段或用于结合CD33肿瘤抗原的手段。
此外，当CD33与唾液酸残基接合时，例如在β-淀粉样蛋白或糖脂沉积的其他糖蛋白中，抑制性信号传导级联导致对吞噬活性的抑制。包含抗CD33结构域的抗体可以充当CD33刺激的拮抗剂，从而促进吞噬活性和β-淀粉样蛋白的清除，以便治疗阿尔茨海默氏病。视网膜疾病，例如干性年龄相关性黄斑变性(AMD)，也涉及可通过小胶质细胞吞噬作用清除的不溶性沉积物。因此，包含抗CD33结构域的抗体也可用于治疗干性AMD和其他视网膜疾病。因此，抗CD33结构域构成了用于促进吞噬活性(在表达CD33的细胞中)的手段、用于促进β-淀粉样蛋白的清除的手段或用于清除不溶性沉积物的手段。
适用于治疗阿尔茨海默氏病和视网膜疾病的MVSCA优选为对于CD33是二价的，并包含抗HSA结构域以提高半衰期。它们也可包含FC5纳米抗体结构域(Rissiek等人，Front.Cell.Neurosci.8:344,2014)以促进跨越人血脑屏障的迁移。
接头
在许多实施方式中，各个结合结构域不直接彼此连接，而是具有插置在它们之间的短氨基酸序列，即接头。接头的示例在表15中显示。接头的长度和序列可对MVSCA的表达水平和结构以及所连接的结构域的结合亲和力有显著影响。长度可调的接头L2和L4(参见表15)可用于根据这些参数优化MVSCA。接头L1、L2和L4可称为不可切割的接头手段、柔性接头手段或柔性不可切割的接头手段。
当同一个VHH结构域的两个拷贝在MVSCA中彼此相邻放置时，它们会频繁地不利地相互作用。这可以通过在两个拷贝之间插置相对较短且刚性的接头来避免。在一些实施方式中，短的刚性接头具有序列AAA(表15中的L3)。这种接头可以称为短刚性接头手段或不可切割的短刚性接头手段。
当抗HSA结构域-HSA复合物被用于产生与相邻结合结构域的结合活性相关的前药时，可切割的接头应该被插置在两个结构域之间。L11*3至L11*18(参见表15)是具有各种长度和对由不同蛋白酶切割的易感性的可切割接头的示例，所述可切割接头可用于在MVSCA的表达水平和结构、所连接的结构域的结合亲和力和切割方面对MVSCA进行优化。接头L11*3至L11*18可被称为可切割接头手段、柔性接头手段或柔性可切割接头手段。
MVSCA
本文所述的结合结构域和接头可以组合以产生多功能MVSCA，所述多功能MVSCA适用于特定疾病的治疗。所述结合结构域和接头也可以进一步与其他结合域结合。MVSCA也可被称为包括用于实现与结合结构域的每种组分类型相关联的各种功能的手段，和/或包括用于实现它们的相关功能的接头手段。下面将立即简要讨论示例性设计。
HSA/CD47/PD-L1：这种设计适用于治疗表达PD-L1的肿瘤，将促进吞噬作用，将释放PD-1免疫检查点，并将具有延长的循环半衰期。在各种实施方式中，MVSCA对于抗CD47和/或抗PD-L1结合结构域可为二价的。取决于所用的接头，抗HSA结构域(一旦结合了HSA)将抑制或将不抑制与CD47的结合，并且抑制(如果存在的话)可以通过切割可切割的接头来逆转。在一些实施方式中，结合结构域以不同的次序排列，但是如果要被切割，则抗HSA结构域应该在末端位置。除了将这种设计的MVSCA描述为包括用于其组成部分的功能中的一种或多种功能的手段之外，MVSCA还可以被称为用于促进表达PD-L1的肿瘤的吞噬作用(和释放PD-1免疫检查点)的手段。这种设计的几个实施方式在实施例7中阐述。
HSA/LAG3/PD-L1：这种设计适用于治疗表达PD-L1的肿瘤，将释放LAG3和PD-1免疫检查点，并将具有延长的循环半衰期。在各种实施方式中，MVSCA对于抗LAG3和/或抗PD-L1结合结构域可为二价的。在一些实施方式中，结合结构域以不同的次序排列。除了将这种设计的MVSCA描述为包括用于其组成部分的功能中的一种或多种功能的手段之外，MVSCA还可以被称为用于将T效应细胞募集到表达PD-L1的肿瘤(并释放LAG3和PD-1免疫检查点)的手段。这种设计的几个实施方式在实施例7中阐述。
CD16A/HSA/CD47/PD-L1：这种设计适用于治疗表达PD-L1的肿瘤，将促进吞噬作用，将募集NK细胞来介导ADCC，将释放PD-1免疫检查点，并将具有延长的循环半衰期。在各种实施方式中，MVSCA对于抗CD47和/或抗PD-L1结合结构域可为二价的。在一些实施方式中，结合结构域以不同的次序排列，但是如果要被切割，则抗HSA结构域应该被放置在末端位置。取决于所用的接头，抗HSA结构域(一旦结合了HSA)将抑制或将不抑制与CD47的结合，并且抑制(如果存在的话)可以通过切割可切割的接头来逆转。除了将这种设计的MVSCA描述为包括用于其组成部分的功能中的一种或多种功能的手段之外，MVSCA还可以被称为用于促进对表达PD-L1的肿瘤的吞噬作用并将NK介导的ADCC募集到表达PD-L1的肿瘤(和释放PD-1免疫检查点)的手段。这种设计的几个实施方式在实施例8中阐述。
CD16A/HSA/CD47/CD33：这种设计适用于治疗表达CD33的肿瘤，将促进吞噬作用，将募集NK细胞来介导ADCC，并将具有延长的循环半衰期。在各种实施方式中，MVSCA对于抗CD47和/或抗CD33结合结构域可为二价的。在一些实施方式中，结合结构域以不同的次序排列，但是如果要被切割，则抗HSA结构域应该被放置在末端位置。取决于所用的接头，抗HSA结构域(一旦结合了HSA)将抑制或将不抑制与CD47的结合，并且抑制(如果存在的话)可以通过切割可切割的接头来逆转。除了将这种设计的MVSCA描述为包括用于其组成部分的功能中的一种或多种功能的手段之外，MVSCA还可以被称为用于促进对表达CD33的肿瘤的吞噬作用并将NK介导的ADCC募集到表达CD33的肿瘤的手段。这种设计的几个实施方式在实施例8中阐述。
双价抗CD33MVSCA：这些设计适合于通过例如由小胶质细胞阻断对吞噬作用的抑制来治疗与不溶性物质沉积相关联的疾病。此类疾病包括阿尔茨海默氏病和干性AMD。HSA/CD33/CD33设计具有延长的循环半衰期。FC5/CD33/CD33设计将跨越血脑屏障。FC5/CD33/CD33/HAS设计将具有延长的循环半衰期并跨越血脑屏障。简单的CD33/CD33设计适合于局部注射到眼睛或大脑中，在这种情况下，延长的循环半衰期或跨越血脑屏障的能力具有可忽略不计的价值。在一些实施方式中，结合结构域以不同的次序排列。除了将这种设计的MVSCA描述为包括用于其组成部分的功能中的一种或多种功能的手段之外，MVSCA还可以被称为用于促进对不溶性沉积物的(小胶质细胞)吞噬作用的手段。这种设计的几个实施方式在实施例9中阐述。
所公开的抗体的用途
所公开的抗体是在医学上可用的。术语“治疗”等是指对患者进行医疗管理，意图是治愈、改善、稳定化或预防疾病、病理状况或疾患。该术语包括积极治疗，即专门针对改善疾病、病理状况或疾患的治疗，并且还包括病因治疗，即针对去除相关疾病、病理状况或疾患的病因的治疗。此外，该术语还包括姑息治疗，即被设计用于缓解症状而非治愈疾病、病理状况或疾患的治疗；预防性治疗，即旨在最小化或部分或完全抑制相关联的疾病、病理状况或疾患的发展的治疗；和支持性治疗，即用于补充另一种旨在改善相关联的疾病、病理状况或疾患的特定疗法的治疗。各种实施方式可以具体包括或排除这些治疗模式中的一种或多种治疗模式。
还考虑了本文所公开的抗体在诊断和成像中的用途。
此外，术语“治疗(treating/treatment)”广泛地包括任何类型的治疗活动，包括对人或其他动物的疾病的诊断、缓解或预防，或其方面，或者以其他方式影响人或其他动物的身体的结构或任何功能的任何活动。治疗活动包括特别地根据本文所公开的各种治疗方法，无论是由医疗保健专业人员、患者本人还是任何其他人向患者施用本文所述的药物、剂型和药物组合物。治疗活动包括医疗保健专业人员(诸如医师、医师的助手、护士从业人员等)的医嘱、指示和建议，所述医嘱、指示和建议然后由包括其他医疗保健专业人员或患者本人在内的任何其他人执行操作。这包括例如指导患者接受或指导临床实验室执行诊断程序，例如用于癌症诊断和分期，以便最终患者可接受有益的适当治疗。在一些实施方式中，治疗活动的医嘱、指示和建议方面还可以包括鼓励、诱导或强制选择特定药物或其组合来治疗病症，并且药物通过以下方式被实际使用：批准药物的保险范围、拒绝替代药物的范围，包括药物在药物处方集上，或从药物处方集中排除替代药物，或提供使用药物的财务激励，如可由保险公司或药房福利管理公司等所做的。在一些实施方式中，治疗活动还可以包括鼓励、诱导或强制选择特定的药物来治疗疾病—并且该药物实际上是按照如可由医院、诊所、健康维护组织、医疗实践或医师团体等建立的政策或实践标准使用的。所有此类医嘱、指示和建议都被视为以遵守指示为条件接受治疗的益处。在一些情况下，患者还会因为遵从此类医嘱、指示和建议而获得经济利益。在一些情况下，健康护理专业人员还会因为遵从此类医嘱、指示和建议而获得经济利益。
所公开的对CD47、HSA、PD-L1、CD33、CD16和LAG3具有特异性的单特异性HCAb和多价单链抗体可用于治疗癌症。每种抗体基于抗体中所包含的抗原结合特异性而被设计用于治疗特定类别的癌症。
本发明提供了一种治疗癌症的方法，所述方法包括向需要此类治疗的患者施用有效量的本文所公开的抗体或包含所述抗体的药物组合物。
可以通过所公开的方法治疗的癌症的示例包括急性成淋巴细胞性白血病；急性髓性白血病；肾上腺皮质癌；AIDS相关淋巴瘤；AIDS相关恶性肿瘤；肛门癌；星形细胞瘤；胆管癌、膀胱癌；骨癌；脑干胶质瘤；脑瘤；乳腺癌；支气管腺瘤/类癌瘤；类癌肿瘤；胰岛细胞癌；原发灶不明肿瘤；中枢神经系统淋巴瘤；小脑星形细胞瘤；脑星形细胞瘤/恶性胶质瘤；宫颈癌；慢性淋巴细胞白血病；慢性髓性白血病；慢性骨髓增生性疾患；结肠癌；结直肠癌；经皮肤T细胞淋巴瘤；子宫内膜癌、室管膜瘤；卵巢上皮癌；食道癌；尤文肉瘤家族肿瘤(Ewing′sfamily of tumors)；颅外生殖细胞肿瘤；眼内黑素瘤；成视网膜细胞瘤；胆囊癌；胃癌；生殖细胞肿瘤；妊娠滋养细胞肿瘤；毛细胞白血病；头颈癌；肝细胞癌；霍奇金氏淋巴瘤；下咽癌；卡波西氏肉瘤；肾癌；喉癌；非小细胞肺癌；小细胞肺癌；非霍奇金氏淋巴瘤；瓦氏巨球蛋白血症；恶性间皮瘤；恶性胸腺瘤；成神经管细胞瘤；黑素瘤；默克尔细胞癌；鳞状颈部癌；多发性内分泌肿瘤综合征；多发性骨髓瘤/浆细胞肿瘤；蕈样肉芽肿；骨髓增生异常综合征；鼻咽癌；成神经细胞瘤；口腔癌；口咽癌；骨肉瘤；胰腺癌；甲状旁腺癌；阴茎癌；嗜铬细胞瘤；垂体瘤；胸膜肺母细胞瘤；前列腺癌；直肠癌；横纹肌肉瘤；唾液腺癌；软组织肉瘤；塞扎里综合征；皮肤癌；鳞状颈部癌；睾丸癌；胸腺瘤；甲状腺癌；滋养细胞肿瘤；尿道癌；子宫癌；阴道癌；外阴癌；和维尔姆斯瘤。
癌症疗法的有效性通常根据“反应”来衡量。监测反应的技术可以类似于用于诊断癌症的测试，例如但不限于：
·涉及一些淋巴结的肿块或肿瘤可以通过身体检查从外部感觉和测量。
·一些内部癌症肿瘤将会在x射线或CT扫描中显示出来，并且可以用尺子测量。
·可以执行血液测试，包括测量器官功能的那些测试。
·可以对某些癌症进行肿瘤标记物测试。
无论使用何种测试，无论是血液测试、细胞计数还是肿瘤标记物测试，都要以特定的时间间隔重复进行，以便将结果与早期的同类测试进行比较。
对癌症治疗的反应以以下几种定义方式：
·完全反应—所有的癌症或肿瘤消失；没有疾病的迹象。肿瘤标志物(如果适用的话)的表达水平可落在正常范围内。
·部分反应—癌症缩小了某一百分比，但疾病仍然存在。肿瘤标志物(如果适用的话)的水平可能已经下降(或升高，基于肿瘤标志物，作为肿瘤负荷降低的指标)，但疾病的迹象仍然存在。
·稳定的疾病—癌症既没有生长也没有缩小；疾病的量没有变化。肿瘤标志物(如果适用的话)没有显著变化。
·疾病进展—癌症已经生长；现在的疾病比治疗前多。肿瘤标志物测试(如果适用的话)显示肿瘤标志物已升高。
癌症治疗功效的其它量度包括总体存活时间间隔(即从诊断或从被评估的治疗开始测量到因任何原因导致死亡的时间)、无癌存活时间间隔(即，在完全反应后癌症保持不可检测的时长)和无进展存活时间间隔(即，在疾病稳定化或部分反应后恢复的肿瘤生长不可检测的时长)。
有两种关于肿瘤大小(肿瘤负荷)来评估实体癌治疗反应的标准方法，即WHO标准和RECIST标准。这些方法测量实体瘤，以将当前肿瘤与过去的测量结果进行比较，或者以将变化与未来的测量结果进行比较，并对治疗方案进行改变。在WHO方法中，测量实体肿瘤的长轴和短轴，然后计算这两个测量值的乘积；如果有多个实体瘤，则计算所有乘积的总和。在RECIST方法中，仅测量长轴。如果有多个实体瘤，则计算所有长轴测量值的总和。然而，对于淋巴结，测量的是短轴而不是长轴。
本公开提供了一种治疗眼部疾患的方法，所述方法包括向需要此类治疗的患者施用本文所公开的抗体。示例性眼部疾患包括年龄相关性黄斑变性(AMD)，例如湿性AMD或干性AMD；或黄斑水肿，例如糖尿病性黄斑水肿。在一些实施方式中，所述眼部疾患是视网膜疾患。
本发明还提供了治疗神经退行性疾病的方法，所述神经退行性疾病包括但不限于阿尔茨海默氏病、路易体病、帕金森氏病、多发性硬化、肌萎缩侧索硬化症、脑白质营养不良、进行性核上麻痹、神经炎症、炎性脱髓鞘疾病、痴呆或神经病。在一个实施方式中，神经退行性疾病是阿尔茨海默氏病。
提供以下实施例、序列表和附图来帮助理解本发明，本发明的真实范围在所附权利要求中阐述。应当理解，在不脱离本发明精神的情况下，可以对所述工序进行修改。
特定实施方式的列表
以下实施方式列表是关于本文阐述的宽度、组合和子组合、发明类别等的各种实施方式的说明，但并不旨在是本文中寻求支持的所有实施方式的详尽列举。
实施方式1.一种对CD47具有抗原结合特异性的重链可变(VHH)结构域。
实施方式2.根据实施方式1所述的VHH结构域，所述VHH结构域具有SEQ ID NO:2至SEQ ID NO:29或SEQ ID NO:223中的一者所示的氨基酸序列。
实施方式3.一种对PD-L1具有抗原结合特异性的重链可变(VHH)结构域。
实施方式4.根据实施方式3所述的VHH结构域，所述VHH结构域具有SEQ ID NO:31至SEQ ID NO:38中的一者所示的氨基酸序列。
实施方式5.一种对人血清白蛋白(HSA)具有抗原结合特异性的重链可变(VHH)结构域。
实施方式6.根据实施方式5所述的VHH结构域，所述VHH结构域具有SEQ ID NO:40至SEQ ID NO:48中的一者所示的氨基酸序列。
实施方式7.一种对CD33具有抗原结合特异性的重链可变(VHH)结构域。
实施方式8.根据实施方式7所述的VHH结构域，所述VHH结构域具有SEQ ID NO:50至SEQ ID NO:78中的一者所示的氨基酸序列。
实施方式9.一种对LAG3具有抗原结合特异性的重链可变(VHH)结构域。
实施方式10.根据实施方式9所述的VHH结构域，所述VHH结构域具有SEQ ID NO:80至SEQ ID NO:93中的一者所示的氨基酸序列。
实施方式11.一种对CD16具有抗原结合特异性的重链可变(VHH)结构域。
实施方式12.根据实施方式11所述的VHH结构域，所述VHH结构域具有SEQ ID NO:96至SEQ ID NO:99中的一者所示的氨基酸序列。
实施方式13.一种仅重链抗体(HCAb)，所述仅重链抗体包含根据实施方式1-12中任一项所述的VHH结构域。
实施方式14.一种抗体，所述抗体包含一个或多个恒定结构域和用于结合CD47、HSA、PD-L1、CD33、CD16或LAG3的手段。
实施方式15.一种多特异性抗体，所述多特异性抗体包含根据实施方式1-12所述的VHH结构域或用于结合CD47、HSA、PD-L1、CD33、CD16或LAG3的手段中的一者或多者。
实施方式16.根据实施方式15所述的多特异性抗体，所述多特异性抗体还包含一个或多个附加抗体结合结构域。
实施方式17.根据实施方式16所述的多特异性抗体，其中所述附加抗体结合结构域包含FC5(SEQ ID NO:222)。
实施方式18.根据实施方式16所述的多特异性抗体，其中所述附加抗体结合结构域包含Fv或Fab。
实施方式19.根据实施方式15-17中任一项所述的多特异性抗体，所述多特异性抗体为多特异性单链抗体(MVSCA)。
实施方式20.根据实施方式19所述的MVSCA，所述MVSCA包含2个、3个、4个、5个或6个抗体结合结构域。
实施方式21.根据实施方式20所述的MVSCA，所述MVSCA具有1种、2种、3种或4种抗体结合特异性。
实施方式22.根据实施方式19-21中任一项所述的MVSCA，所述MVSCA包含识别HSA、CD47和PD-L1的抗体结合结构域。
实施方式23.根据实施方式19-21中任一项所述的MVSCA，所述MVSCA包含识别HSA、CD47和CD33的抗体结合结构域。
实施方式24.根据实施方式19-21中任一项所述的MVSCA，所述MVSCA包含识别HSA、LAG3和PD-L1的抗体结合结构域。
实施方式25.根据实施方式19-21中任一项所述的MVSCA，所述MVSCA包含识别HSA、LAG3和CD33的抗体结合结构域。
实施方式26.根据实施方式19-21中任一项所述的MVSCA，所述MVSCA包含识别CD16、HSA和PD-L1的抗体结合结构域。
实施方式27.根据实施方式19-21中任一项所述的MVSCA，所述MVSCA包含识别CD16、HSA和CD33的抗体结合结构域。
实施方式28.根据实施方式19-21中任一项所述的MVSCA，所述MVSCA包含识别CD16、HSA、CD47和PD-L1的抗体结合结构域。
实施方式29.根据实施方式19-21中任一项所述的MVSCA，所述MVSCA包含识别CD16、HSA、CD47和CD33的抗体结合结构域。
实施方式30.根据实施方式14-21或26-29中任一项所述的MVSCA，其中所述识别CD16的抗体结合结构域优先识别CD16A。
实施方式31.根据实施方式19-30中任一项所述的MVSCA，所述MVSCA包含具有相同特异性的两个相邻抗体结合结构域。
实施方式32.根据实施方式31所述的MVSCA，其中所述具有相同特异性的两个相邻抗体结合结构域具有插置在它们之间的短刚性接头手段。
实施方式33.根据实施方式31所述的MVSCA，其中所述短刚性接头手段由氨基酸序列AAA(SEQ ID NO:102)组成。
实施方式34.根据实施方式31-33中任一项所述的MVSCA，其中所述两个相邻的抗体结合结构域结合CD33。
实施方式35.根据实施方式34所述的MVSCA，所述MVSCA还包含识别HSA的抗体结合结构域。
实施方式36.根据实施方式34或35所述的MVSCA，所述MVSCA还包含FC5。
实施方式37.根据实施方式31-33中任一项所述的MVSCA，其中所述两个相邻的抗体结合结构域结合PD-L1。
实施方式38.根据实施方式31-33中任一项所述的MVSCA，其中所述两个相邻的抗体结合结构域结合LAG3。
实施方式39.根据实施方式31-33中任一项所述的MVSCA，其中所述两个相邻的抗体结合结构域结合CD16。
实施方式40.根据实施方式31-33中任一项所述的MVSCA，其中所述两个相邻的抗体结合结构域结合CD47。
实施方式41.根据实施方式19-30中任一项所述的MVSCA，所述MVSCA包含相邻抗体结合结构域之间的接头。
实施方式42.根据实施方式4`所述的MVSCA，其中插置在不同抗原结合结构域之间的所述接头是L1(SEQ ID NO:100)、L2(SEQ ID NO:101)或L4(SEQ ID NO:103))。
实施方式43.根据实施方式19-30中任一项所述的MVSCA，所述MVSCA包含插置在不同抗原结合结构域之间的柔性、不可切割的接头手段。
实施方式44.根据实施方式19-30中任一项所述的MVSCA，所述MVSCA包含结合HSA的N末端或C末端定位的抗体结合结构域。
实施方式45.根据实施方式44所述的MVSCA，其中在结合HSA时，与所述结合HSA的抗体结合结构域相邻的抗体结合结构域被抑制与其抗原结合。
实施方式46.根据实施方式45所述的MVSCA，其中与所述结合HSA的抗体结合结构域相邻的抗体结合结构域识别CD47。
实施方式47.根据实施方式45或46所述的MVSCA，其中可切割的接头插置在所述结合HSA的抗体结合结构域与同其相邻的抗体结合结构域之间，其中所述可切割的接头是L11*3(SEQ ID NO:104)、L11*4(SEQ ID NO:105)、L11*5(SEQ ID NO:106)、L11*6(SEQ IDNO:107)、L11*7(SEQ ID NO:108)、L11*8(SEQ ID NO:109)、L11*9(SEQ ID NO:110)、L11*10(SEQ ID NO:111)、L11*11(SEQ ID NO:112)、L11*12(SEQ ID NO:113)、L11*13(SEQ ID NO:114)、L11*14(SEQ ID NO:115)、L11*15(SEQ ID NO:116)、L11*16(SEQ ID NO:117)、L11*17(SEQ ID NO:118)或L11*18(SEQ ID NO:119)。
实施方式48.根据实施方式45或46所述的MVSCA，其中可切割的接头手段插置在所述结合HSA的抗体结合结构域与同其相邻的抗体结合结构域之间。
实施方式49.根据实施方式19-48中任一项所述的MVSCA，其中所有的所述抗体结合结构域都是VHH结构域。
实施方式50.一种药物组合物，所述药物组合物包含根据实施方式1-49中任一项所述的VHH结构域或抗体。
实施方式51.一种药物组合物，所述药物组合物包含用于结合HSA的手段、用于延长多特异性抗体或MVSCA在体内的半衰期的手段、用于可逆地抑制相邻结合结构域的结合活性的手段。
实施方式52.一种药物组合物，所述药物组合物包含用于结合CD47的手段或用于降低对吞噬作用的抑制的手段。
实施方式53.一种药物组合物，所述药物组合物包含用于结合CD16或CD16A的手段或用于募集NK介导的ADCC的手段。
实施方式54.一种药物组合物，所述药物组合物包含用于结合PD-L1的手段、用于结合PD-L1肿瘤抗原的手段、用于PD-1阻断的手段或用于释放PD-1免疫检查点的手段。
实施方式55.一种药物组合物，所述药物组合物包含用于结合肿瘤抗原的手段、用于结合所述PD-L1肿瘤抗原的手段、或用于结合所述CD33肿瘤抗原的手段。
实施方式56.一种药物组合物，所述药物组合物包含用于结合LAG3的手段或用于释放所述LAG3免疫检查点的手段。
实施方式57.一种药物组合物，所述药物组合物包含用于释放免疫检查点的手段、用于释放所述PD-1免疫检查点的手段或用于释放所述LAG3免疫检查点的手段。
实施方式58.一种药物组合物，所述药物组合物包含用于结合CD33的手段、用于结合所述CD33肿瘤抗原的手段、用于促进β-淀粉样蛋白的清除的手段或用于清除不溶性沉积物的手段。
实施方式59.一种药物组合物，所述药物组合物包含用于促进表达PD-L1的肿瘤的吞噬作用的手段。
实施方式60.一种药物组合物，所述药物组合物包含用于将T效应细胞募集到表达PD-L1的肿瘤的手段。
实施方式61.一种药物组合物，所述药物组合物包含用于促进对表达PD-L1的肿瘤的吞噬作用和将NK介导的ADCC募集至所述表达PD-L1的肿瘤的手段。
实施方式61.一种药物组合物，所述药物组合物包含用于促进对表达PD-L1的肿瘤的吞噬作用和将NK介导的ADCC募集至所述表达PD-L1的肿瘤的手段。
实施方式62：一种药物组合物，所述药物组合物包含用于促进对表达CD33的肿瘤的吞噬作用和将NK介导的ADCC募集至所述表达CD33的肿瘤的手段。
实施方式63.一种治疗癌症的方法，所述方法包括向有需要的患者施用根据实施方式1-48中任一项所述的抗体或根据实施方式49-61中任一项所述的药物组合物。
实施方式64.一种治疗阿尔茨海默氏病或视网膜疾病的方法，所述方法包括向有需要的患者施用根据实施方式7-8、13-21、34-36或48-49中任一项所述的抗体或根据实施方式58所述的药物组合物，其中所述抗体包含CD33结合结构域。
实施方式65.根据实施方式64所述的方法，其中所述抗体不包含识别CD47、PD-L1、LAG3或CD16的抗体结合结构域。
实施方式66.根据实施方式64或65所述的方法，其中所述视网膜疾病是干性AMD。
对于实施方式63-66中的每一者，存在用于治疗的组合物、用于制造药物的组合物、组合物在治疗中的用途、以及组合物在药物制造中的用途的对应实施方式。
实施例
实施例1.抗CD47 HCAb抗体
从经免疫的美洲驼中分离抗CD47 HCAb抗体。
免疫接种.在Abcore Inc(Ramona,CA)按照其标准方案对两只美洲驼进行免疫。将重组人CD47(细胞外结构域19至139，SEQ ID NO:1)与完全弗氏佐剂(第0天)或不完全弗氏佐剂(免疫接种后)混合(Difco,BD Biosciences)。每只美洲驼以50μg/剂，以每两周一次的时间间隔执行六次皮下注射。在第45天，从用重组CD47蛋白免疫的美洲驼收集血清，以通过ELISA测定抗体抗hCD47的滴度。在ELISA中，用100ng/孔的hCD47包被96孔Maxisorp板(Nunc)。在封闭并加入稀释的血清样品后，使用辣根过氧化物酶(HRP)缀合的山羊抗骆驼IgG(H+L)抗体(Invitrogen)证明抗CD47抗体的存在。
SEQ ID NO:1人CD47的细胞外结构域(19-139，Q08722)
Figure BDA0003664798220000411
噬菌体文库的构建和选择.根据制造商的使用说明，使用Ficoll-Paque Plus(GEHealthcare)从来自用重组CD47蛋白免疫的美洲驼的第45天血液样品制备外周血单核细胞。使用RNeasy Midi试剂盒(Qiagen)，按照制造商的使用说明从外周血单核细胞中提取总RNA，并用作RT-PCR的起始材料以扩增编码VHH的基因片段。将这些片段克隆到噬菌粒载体中，从而允许在用辅助噬菌体感染后产生重组噬菌体粒子，所述重组噬菌体粒子在噬菌体粒子的表面上展示作为基因-lll融合蛋白的VHH。根据标准方法制备噬菌体，并在过滤灭菌后在4℃贮存以备后用。
为了选择结合CD47的噬菌体，将生物素化的CD47与噬菌体文库一起孵育，随后在链霉亲和素Dynabeads(Invitrogen)上捕获。充分洗涤后，用1mg/ml胰蛋白酶洗脱结合的噬菌体。将来自选择的输出拯救到大肠杆菌TG1细胞中。在BATJ,Inc.(San Diego,CA)挑取菌落并测序。
在Atum(Newark,CA)将编码结合CD47的VHH的cDNA合成为具有C末端His标签，并瞬时转染到HEK293细胞中，并通过IMAC层析纯化阳性VHH。
对来自经免疫的美洲驼噬菌体文库的结合CD47的噬菌体集落进行测序，并针对每个VHH确定下面(表2)列出的它们的氨基酸序列。将基于以下氨基酸序列的cDNA序列与人Fc融合，并在pJ607表达载体中合成。将表达质粒转染到HEK293细胞系中以产生重组抗CD47HCAb抗体。经表达的抗CD47 HCAb通过HiTrap蛋白A柱纯化。
A09-10VHH是基于IGHV3-23人类种系序列人源化的。
表2.美洲驼抗CD47 VHH序列
Figure BDA0003664798220000412
Figure BDA0003664798220000421
Figure BDA0003664798220000431
Figure BDA0003664798220000441
Figure BDA0003664798220000451
Figure BDA0003664798220000461
*Biv＝二价
表2的VHH构成了用于结合CD47的手段。
抗CD47 HCAb分子的
Figure BDA0003664798220000463
结合分析
使用生物层干涉测量法(Bio-Layer Interferometry,BLI)，一种无标记技术，来测量人CD47(R&D systems)与抗CD47 VHH的结合动力学。使用配备有抗Penta-His捕获(HIS1K)生物传感器尖端
Figure BDA0003664798220000464
的
Figure BDA0003664798220000465
QKe执行亲和力测量。在30℃，在1x PBS缓冲液((
Figure BDA0003664798220000466
PBS pH 7.2)中执行测定。将样品以1000rpm搅拌。在分析之前，将传感器加湿15min。用HIS1K传感器尖端测试纯化的抗CD47 VHH的结合能力。使用20g/ml的抗CD47 VHH装载所述尖端。装载进行300秒，导致捕获水平在1.8nm与2nm之间。通过在1x PBS中稀释至100nM、150nM、250nM、350nM浓度，制备用于结合分析的人CD47抗原。开始缔合并监测200秒，在此之后将尖端转移到1xPBS缓冲液(Gibco，PBS pH 7.2)中，以监测解离。在整个实验中收集传感器数据，处理，并使用
Figure BDA00036647982200004610
数据分析软件7
Figure BDA0003664798220000467
进行分析。
表3列出了抗CD47 HCAb的结合亲和力的
Figure BDA0003664798220000468
动力学分析。HCAb A09-04、A09-06、A09-08和A09-10表现出pM结合亲和力。
表3.抗CD47 HCAb的结合亲和力(KD)的
Figure BDA0003664798220000469
动力学分析
Figure BDA0003664798220000462
Figure BDA0003664798220000471
抗CD47 HCAb对过表达CD47的CHO细胞系的结合亲和力的流式细胞术分析。
将冰冷FACS缓冲液(PBS，1％BSA，0.1％NaN3)中的1×106个细胞/ml的过表达CD47的CHO细胞与浓度范围为100nM至0.00128nM的抗CD47HCAb或作为对照的B6H12抗CD47抗体一起孵育，并且在冰上孵育45min。根据制造商的使用说明，用FACS缓冲液洗涤细胞并加入山羊抗人IgG Fc、FITC缀合物抗体(ThermoFisher)，然后在4℃孵育30min。使用GuavaEasyCyte HT系统获取数据。
按照上述流式细胞术方法，抗CD47 HCAb的结合亲和力被测定为EC50，如图1所描绘的。
具有抗CD47结构域的多特异性分子的竞争性ELISA结合分析
执行竞争性ELISA结合测定以筛选结合CD47的多特异性分子1511(SEQ ID NO156；CD16F-L1-HSA-L1-CD47-L3-CD47-L1-PDL1-L3-PDL1)和3321(SEQ ID NO 159；CD16F-L1-HSA-L1-CD47-L1-CD33-L3-CD33)，两者都含有抗CD47 VHH A09-10，所述抗CD47 VHHA09-10竞争性阻断CD47抗原与其受体SIRPα的结合。多特异性抗体通过它们的结合结构域(即，CD47)和分隔结合结构域的接头(即，表15中标识的L1)来鉴定。将100纳克/孔的CD47-Fc(R&D systems)包被在96孔板中，将10nM生物素化的人SIRPα与不同浓度的多特异性分子1511和3321一起预孵育，然后加入HRP-缀合的链霉亲和素。多特异性分子1511和3321竞争性阻断CD47与其受体SIRPα以EC50结合，如图2所描绘的。
具有抗CD47结构域的多特异性分子的竞争性流式细胞术结合分析
执行竞争性流式细胞术结合测定，以确认多特异性分子1511和3321阻断CD47抗原与天然表达CD47的细胞表面上的其受体SIRPα结合。将冰冷FACS缓冲液(PBS，1％BSA，0.1％NaN3)中的1×106个细胞/ml的Jurkat细胞(ATCC)与浓度范围为100nM至0.00128nM的1511或3321一起孵育并在冰上孵育45min，然后加入25nM SIRPα-Fc(R&D systems)，并再孵育45min。根据制造商的使用说明，用FACS缓冲液洗涤细胞并加入山羊抗人VHH FITC缀合物抗体(Jackson Immuno Research)，然后在4℃孵育30min。使用Guava EasyCyte HT系统获取数据。多特异性分子1511和3321竞争性阻断CD47与在Jurkat细胞表面上的其受体SIRPα以EC50结合，如图3所描绘的。
具有抗CD47结构域的多特异性分子的人RBC凝集测定
由健康供体提供人类血液样品。将全血以3000rpm(1800rcf)离心5min，并去除血浆和血沉棕黄层。将红细胞重悬于体积为红细胞体积的约两倍的生理盐水(0.9％NaCl)中，并将试管倒置以混合。将红细胞进一步以2000rpm离心20min，并将RBC与生理盐水混合以获得6％(v/v)的细胞悬液。然后将RBC细胞加入到96孔圆底平板中，并与不同量的抗体(0ug/ml至100ug/ml)混合。将平板在37℃孵育2小时。与Hu5F9抗CD47对照抗体不同，多特异性分子1511和3321不诱导RBC凝集，如图4所描绘的。
执行流式细胞术结合测定以确认多特异性分子，含1511和3321的抗CD47VHH，其可选择性结合到天然表达CD47的肿瘤细胞表面，但不结合到RBC细胞表面CD47。将冰冷FACS缓冲液(PBS，1％BSA，0.1％NaN3)中1×106个细胞/ml的HL60细胞(ATCC)或10％经洗涤的人RBC细胞(Rockland Immunochemicals,Inc)与浓度范围为500nM至0.00128nM的1511或3321一起孵育并在冰上孵育45min。根据制造商的使用说明，用FACS缓冲液洗涤细胞并加入山羊抗人VHH FITC缀合物抗体(Jackson Immuno Research)，然后在4℃孵育30min。使用GuavaEasyCyte HT系统获取数据。多特异性分子1511和3321以EC50选择性结合到天然表达CD47的肿瘤细胞表面，但不结合RBC细胞表面CD47，如图4B所描绘的。
具有抗CD47结构域的多特异性分子的抗肿瘤活性
将1E6Raji-Luc细胞静脉内接种到NSG小鼠中。每天静脉注射10mg/kg的多特异性分子3321或PBS对照以处理小鼠。Raji肿瘤在处理开始时(第0天)、实验中期第3天和实验结束时(第7天)的代表性生物发光图像。多特异性分子3321保护异种移植小鼠免于患上人类白血病，如图5所描绘的。
实施例2.抗PD-L1 HCAb抗体
从经免疫的骆驼中分离抗PD-L1 HCAb抗体
在Abcore Inc.按照其标准方案对两只美洲驼进行免疫。将重组人PD-L1(细胞外结构域19至238，SEQ ID NO:30)与完全弗氏佐剂(第0天)或不完全弗氏佐剂(免疫接种后)混合。每只美洲驼以50μg/剂，以每两周一次的时间间隔执行六次皮下注射。在第45天，从用重组PD-L1蛋白免疫的美洲驼收集血清，以通过ELISA测定抗体抗PD-L1的滴度。在ELISA中，用100ng/孔的PD-L1包被96孔Maxisorp板。在封闭并加入稀释的血清样品后，使用HRP缀合的山羊抗骆驼IgG(H+L)抗体证明抗PD-L1抗体的存在。
SEQ ID NO:30人PD-L1的细胞外结构域(19-238，Q9NZQ7)
Figure BDA0003664798220000491
根据制造商的使用说明，使用Ficoll-Paque+从来自用重组PD-L1蛋白免疫的美洲驼的第45天血液样品制备外周血单核细胞。使用RNeasy Midi试剂盒，按照制造商的使用说明从外周血单核细胞中提取总RNA，并用作RT-PCR的起始材料以扩增编码VHH的基因片段。将这些片段克隆到噬菌粒载体中，从而允许在用辅助噬菌体感染后产生重组噬菌体粒子，所述重组噬菌体粒子在噬菌体粒子的表面上展示作为基因-lll融合蛋白的VHH。根据标准方法制备噬菌体，并在过滤灭菌后在4℃贮存以备后用。
为了选择结合PD-L1的VHH，将生物素化的PD-L1与噬菌体文库一起孵育，随后在链霉亲和素Dynabeads上捕获。充分洗涤后，用1mg/ml胰蛋白酶洗脱结合的噬菌体。将来自选择的输出拯救到大肠杆菌TG1细胞中。在BATJ,Inc.挑取菌落并测序。
将编码结合PD-L1的VHH的cDNA合成为具有C末端His标签，并瞬时转染到HEK293细胞中，并通过IMAC层析纯化阳性VHH。
对来自经免疫的美洲驼噬菌体文库的结合PD-L1的噬菌体集落进行测序。每个VHH的氨基酸序列在以下列出(表4)。基于以下氨基酸序列的cDNA序列与人Fc融合，并在pJ607表达载体中合成。将表达质粒转染到HEK293细胞系中以产生重组抗PD-L1 HCAb抗体。经表达的抗PD-L1 HCAb通过HiTrap蛋白A柱纯化。将美洲驼VHH、PL14和PL16中的两者基于IGHV3-23人类种系序列进行人源化。
表4.美洲驼抗PD-L1 VHH序列
Figure BDA0003664798220000501
Figure BDA0003664798220000511
表4的VHH构成了用于结合PD-L1的手段。
Figure BDA0003664798220000512
动力学结合分析
如实施例1中一样进行
Figure BDA0003664798220000513
动力学结合分析。简而言之，用HIS1K传感器尖端测试纯化的抗PD-L1 VHH的结合能力。使用20g/ml的抗PD-L1 VHH装载所述尖端。装载进行300秒，导致捕获水平在1.8nm与2nm之间。通过在1x PBS中稀释至100nM、150nM、250nM、350nM浓度，制备用于结合分析的人PD-L1抗原。开始缔合并监测200秒，在此之后将尖端转移到不含PD-L1蛋白的1xPBS缓冲液中，以监测解离。
表5呈现了抗CD47 HCAb的结合亲和力的
Figure BDA0003664798220000514
动力学分析。分析表明PL14、PL16和PL17表现出了pM结合亲和力。
表5.抗PD-L1 HCAb的结合动力学分析(KD)
VHH K<sub>on</sub>(1/Ms) K<sub>off</sub>(1/s) K<sub>D</sub>(M)
PL2 3.33E+04 2.10E-02 6.30E-07
PL11 2.75E+04 5.22E-04 1.90E-08
PL14 6.21E+04 1.10E-06 1.77E-011
PL16 1.10+05 2.98E-06 2.71E-011
PL17 8.70E+04 1.09E-06 1.14E-011
PL18 4.27E+04 1.14E-04 2.67E-09
抗PD-L1 HCAb的流式细胞术结合分析
将冰冷FACS缓冲液(PBS，1％BSA，0.1％NaN3)中的1×106个细胞/ml的过表达PD-L1的CHO细胞与浓度范围为100nM至0.00128nM的抗PD-L1HCAb一起孵育，并且在冰上孵育45min。用FACS缓冲液洗涤细胞并加入山羊抗人IgG Fc-FITC缀合物抗体(ThermoFisher)，然后在4℃孵育30min。使用Guava EasyCyte HT系统获取数据。抗PD-L1 HCAb对过表达PD-L1的CHO细胞上的PD-L1的结合亲和力被测定为EC50，图6所描绘的。
具有PD-L1结合结构域的多特异性分子的基于细胞的功能测定
将表达PD-L1的APC/CHO-K1细胞以100K/孔接种在96孔板中，并在37℃孵育16小时。接下来，以100nM开始，将多特异性分子1511和对照抗体阿特朱单抗以1:3进行连续稀释，以25μl/孔加入到细胞孔中。最后，加入PD-1效应细胞(PD-1和荧光素酶表达细胞)并在37℃孵育6小时。在6小时后，加入75μl的Bio-GloTM荧光素酶测定试剂，并使用VICTOR多标记酶标仪测量发光。用GraphPad Prism软件执行数据分析。
基于细胞的功能数据表明，多特异性分子1511和对照抗体阿特朱单抗完全阻断了PD-L1活性，具有相似的EC50，如图7所示。
具有PD-L1结合结构域的多特异性分子的抗肿瘤活性
将鼠结肠癌MC38-hPD-L1细胞(Biocytogen Co.,Ltd；5×105)皮下植入纯合的B-hPD-L1小鼠(雌性，6周龄，n＝6)中。当肿瘤体积达到约100mm3时，将小鼠分组，此时用将它们用多特异性分子1518(SEQ ID NO:157；CD16F-L1-HSA-L1-CD47-L3-CD47-L1-PDL1-L3-PDL1)以图8A所指示的剂量和方案处理。处理期间的体重变化在图8B中示出。如图8A所示，多特异性分子1518A1在控制B-hPD-L1小鼠中的肿瘤生长方面是有效的。数值以平均值±SEM表示。
实施例3.抗HSA HCAb抗体
抗HSA VHH抗体的分离
如实施例1中所述，在Abcore,Inc.用与完全弗氏佐剂(第0天)或不完全弗氏佐剂(免疫接种后)混合的重组人HSA(SEQ ID NO:39)对美洲驼进行免疫。
人血清白蛋白(SEQ ID NO:39)
Figure BDA0003664798220000521
Figure BDA0003664798220000531
为了选择抗HSA VHH，将生物素化的HSA与噬菌体文库一起孵育，随后在链霉亲和素Dynabeads(Invitrogen)上捕获。充分洗涤后，用1mg/ml胰蛋白酶洗脱结合的噬菌体。将来自选择的输出拯救到大肠杆菌TG1细胞中。在BATJ,Inc.(San Diego,California)挑取菌落并测序。
将编码HSA特异性VHH的cDNA合成为具有C末端His标签，并瞬时转染到HEK293细胞中，并通过IMAC层析纯化阳性VHH。
对来自美洲驼噬菌体文库的结合HSA的噬菌体克隆进行测序，每个VHH的氨基酸序列在以下列出(表6)。在pJ607表达载体中合成基于以下氨基酸序列的cDNA序列。将表达质粒转染入HEK293细胞系中以产生具有C末端his标签的重组单结构域抗体(sdAb)。将所表达的sdAb通过HisTrap HP柱纯化。
将美洲驼VHH、HS5和HS10中的两者基于IGHV3-23人类种系序列进行人源化。
表6.美洲驼抗HSA VHH序列
Figure BDA0003664798220000532
Figure BDA0003664798220000541
这些VHH构成了用于结合HSA的手段。
Figure BDA0003664798220000542
动力学结合分析
如实施例1中一样进行
Figure BDA0003664798220000552
动力学结合分析，并且结果呈现在表7和图9中。HS5、HS6、HS12和HS27克隆表现出对HSA的亲和力。跨物种活性得到证实，并在表8中列出。
表7.抗HSA VHH抗体的结合亲和力(KD)
sdAb K<sub>on</sub>(1/Ms) K<sub>off</sub>(1/s) K<sub>D</sub>(M)
HS2 1.72E+04 2.60E-02 1.51E-07
HS5 8.09E+05 7.65E-04 9.46E-10
HS6 1.67E+06 8.29E-04 4.980E-10
HS12 1.03E+06 5.83E-04 5.68E-10
HS22 1.73E+04 9.09E-05 5.25E-08
HS27 7.61E+05 8.65E-04 4.32E-08
HS5-41 4.22E+04 9.17E-05 1.14E-09
HS10 2.77E+04 8.01E-05 2.89E-09
表8.HS10和HS5VHH的跨物种结合亲和力
样品 人类(K<sub>D</sub>) 猴子(K<sub>D</sub>) 小鼠(K<sub>D</sub>)
hHS10 3.18E-09 8.08E-09 4.57E-09
hHS5 8.17E-10 1.16E-08 不适用
实施例4.抗CD33HCAb抗体
抗CD33 VHH抗体的分离
在Abcore,Inc.用与完全弗氏佐剂(第0天)或不完全弗氏佐剂(免疫接种后)和如实施例1中制备的噬菌体文库混合的重组人CD33(SEQ ID NO:49)对美洲驼进行免疫。
人CD33(SEQ ID NO:49，P20138|18-259)
Figure BDA0003664798220000551
Figure BDA0003664798220000561
为了选择抗CD33 VHH，将生物素化的CD33与噬菌体文库一起孵育，随后在链霉亲和素Dynabeads上捕获。充分洗涤后，用1mg/ml胰蛋白酶洗脱结合的噬菌体。将来自选择的输出拯救到大肠杆菌TG1细胞中。在BATJ,Inc.挑取菌落并测序。
将编码结合CD33的VHH的cDNA合成为具有C末端His标签，并瞬时转染到HEK293细胞中，并通过IMAC层析纯化阳性VHH。
对来自经免疫的美洲驼噬菌体文库的结合CD33的噬菌体集落进行测序，并且每个VHH的氨基酸序列在下面(表9)列出。将基于以下氨基酸序列的cDNA序列与人Fc融合，并在pJ607表达载体中合成。将表达质粒转染到HEK293细胞系中以产生重组抗CD33HCAb抗体。经表达的抗CD33HCAb通过HiTrap蛋白A柱纯化。
将美洲驼VHH、33-14中的一者基于IGHV3-23人类种系序列进行人源化。
表9.美洲驼抗CD33 VHH序列
Figure BDA0003664798220000562
Figure BDA0003664798220000571
Figure BDA0003664798220000581
Figure BDA0003664798220000591
Figure BDA0003664798220000601
表9中VHH构成了用于结合CD33的手段。
如实施例1中一样进行
Figure BDA0003664798220000602
动力学结合分析，并且KD结果呈现在图10和表10中。
表10.抗CD33 VHH抗体的结合亲和力
VHH K<sub>on</sub>(1/Ms) K<sub>off</sub>(1/s) K<sub>D</sub>(M)
33-1 8.0+05 8.10E-04 1.01E-09
33-2 8.0E+05 6.0E-04 7.53E-10
33-4 9.0E+05 9.0E-04 9.95E-10
33-8 1.1E+06 7.0E-04 5.11E-10
33-13 1.0E+06 5E-04 4.09E-10
33-14 8.0E+05 1.09E-04 1.36E-010
33-24 8.0E+05 9E-04 1.13E-010
实施例5.抗LAG3 VHH
抗LAG3 VHH抗体的分离
在Abcore Inc.按照其标准方案对美洲驼进行免疫。将重组人LAG3(细胞外结构域19至238，SEQ ID NO:79)与完全弗氏佐剂(第0天)或不完全弗氏佐剂(免疫接种后)混合。每只美洲驼以50μg/剂，以每两周一次的时间间隔执行六次皮下注射。在第45天，从用重组人LAG3蛋白免疫的美洲驼收集血清，以通过ELISA界定抗体抗人LAG3的滴度。在ELISA中，用100ng/孔的LAG3包被96孔Maxisorp板。在封闭并加入稀释的血清样品后，使用通过ELISA测定的抗血清的抗体滴度证明抗LAG3抗体的存在。用100ng/孔的hLAG3包被96孔Maxisorp板。在封闭并加入稀释的血清样品后，使用HRP缀合的山羊抗骆驼IgG(H+L)抗体证明抗LAG3抗体的存在。
人LAG3的细胞外结构域(SEQ ID NO:79，P18627，23-450)
Figure BDA0003664798220000611
如实施例1至4中所述制备噬菌体文库。将编码结合LAG3的VHH的cDNA合成为具有C末端His标签，并瞬时转染到HEK293细胞中，并通过IMAC层析纯化结合LAG3的VHH。
对来自经免疫的美洲驼噬菌体文库的结合LAG3的噬菌体集落进行测序，并且每个VHH的氨基酸序列在下面(表11)列出。将基于以下氨基酸序列的cDNA序列与人Fc融合，并在pJ607表达载体中合成。将表达质粒转染到HEK293细胞系中以产生重组抗LAG3HCAb抗体。经表达的抗LAG3HCAb通过HiTrap蛋白A柱纯化。
将美洲驼VHH、LG9中的一者基于IGHV3-23人类种系序列进行人源化。
表11.美洲驼抗LAG3 VHH序列
Figure BDA0003664798220000612
Figure BDA0003664798220000621
Figure BDA0003664798220000631
表11的VHH构成了用于结合LAG3的手段。
如实施例1至4中进行抗LAG3 VHH的
Figure BDA0003664798220000633
结合分析，并且结果表示在表12中。
表12.抗LAG3单结构域抗体的结合亲和力(KD)
Figure BDA0003664798220000632
Figure BDA0003664798220000641
实施例6.抗CD16 VHH
抗CD16 VHH抗体的分离
在Abcore Inc.按照其标准方案对美洲驼进行免疫。将重组人CD16A(SEQ ID NO:94)与完全弗氏佐剂(第0天)或不完全弗氏佐剂(免疫接种后)混合。每只美洲驼以50μg/剂，以每两周一次的时间间隔执行六次皮下注射。在第45天，从经免疫的美洲驼收集血清以通过ELISA确定抗体滴度。在ELISA中，用100ng/孔的抗原包被96孔Maxisorp板。在封闭并加入稀释的血清样品后，使用HRP缀合的山羊抗骆驼IgG(H+L)抗体证明特异性抗体的存在。
人CD16A(SEQ ID NO:94)
Figure BDA0003664798220000642
人CD16B(SEQ ID NO:95)
Figure BDA0003664798220000643
如实施例1中那样制备噬菌体文库。将编码结合CD16A的VHH的cDNA合成为具有C末端His标签，并瞬时转染到HEK293细胞中，并通过IMAC层析纯化结合CD16A的VHH。
对来自经免疫的美洲驼噬菌体文库的结合CD16A的的噬菌体集落进行测序，并且每个VHH的氨基酸序列在下面(表13)列出。将基于以下氨基酸序列的cDNA序列与人Fc融合，并在pJ607表达载体中合成。将表达质粒转染到HEK293细胞系中以产生重组抗CD16 HCAb抗体。经表达的抗CD16 HCAb通过HiTrap蛋白A柱纯化。
将美洲驼VHH、CD16F1中的一者基于IGHV3-23人类种系序列进行人源化。
表13.抗CD16 VHH序列
Figure BDA0003664798220000651
表13的VHH构成了用于结合CD16的手段。
如实施例1中进行抗CD16 VHH的
Figure BDA0003664798220000652
结合分析，并且结果表示在表14和图11中。
表14.抗CD16 VHH抗体的结合亲和力(KD)
sdAb K<sub>on</sub>(1/Ms) K<sub>off</sub>(1/s) K<sub>D</sub>(M)
CD16F1 2.33E+04 1.09E-04 4.68E-09
CD16E11 1.99E+04 6.00E-05 3.02E-09
CD16-F1对CD16A有选择性，而CD16-E11与CD16A和CD16B两者结合。
CD16F1和CD16E11都是激动剂抗CD16 VHH抗体，其在Jurkat-Lucia NFAT-CD16ADCC报道测定(Invivogen)中活化CD16A。
使用Jurkat-Lucia NFAT-CD16报道测定(Invivogen)进行多特异性分子1511、3321(含有抗CD16A VHH CD16F1)和对照抗CD47抗体B6H12IgG1和B6H12IgG4的功能性测定，并且结果表示在图12中。数据表明CD16F1是有效的CD16A激动剂。
实施例7.三特异性单链抗体(HSA/CD47/PD-L1或HSA/LAG3/PD-L1)
为了构建三特异性单链抗体，通过重组DNA技术，将抗HSA、抗CD47和抗PD-L1或抗CD33 VHH序列；或者抗HSA、抗LAG3和抗PD-L1或CD33VHH序列通过接头以六种不同的方式融合在一起(图13)。图13描绘了示例性三特异性分子抗HSA/CD47/PD-L1、抗HSA/CD47/CD33和抗HSA/LAG3/PD-L1、抗HSA/LAG37/CD33抗体的结构。示例性的不可切割和可切割的接头序列呈现在表15中。这些构成了接头手段或用于连接蛋白质结构域的手段。这些手段可以进一步表征为可切割或不可切割的。示例性三特异性分子的氨基酸序列呈现在表16中。表16和表17中的接头序列带有下划线。
表15.不可切割和可切割的接头序列
Figure BDA0003664798220000661
Figure BDA0003664798220000671
表16.三特异性分子
Figure BDA0003664798220000672
Figure BDA0003664798220000681
Figure BDA0003664798220000691
Figure BDA0003664798220000701
Figure BDA0003664798220000711
Figure BDA0003664798220000721
Figure BDA0003664798220000731
Figure BDA0003664798220000741
Figure BDA0003664798220000751
Figure BDA0003664798220000761
Figure BDA0003664798220000771
Figure BDA0003664798220000781
Figure BDA0003664798220000791
Figure BDA0003664798220000801
Figure BDA0003664798220000811
Figure BDA0003664798220000821
通过与HSA结合，抗HSA结构域可以延长MVSCA的体内半衰期。它还可能干扰其它结构域的活性，这在某些情况下对于分布于全身的MVSCA是期望的，但当MVSCA位于其预期作用位点(例如，肿瘤)时是非期望的。因此通过可切割的接头将抗HSA结构域与其它抗原结合结构域连接，该可切割的接头可优先在预期的作用位点被切割。以这种方式，MVSCA可以充当前药。在HSA·VHH与CD47·VHH或LAG3 VHH之间使用一种此类带有含有蛋白酶可切割序列的接头的MVSCA，并且使用不同的接头来连接CD47·VHH与PD-L1·VHH或连接LAG3 VHH与PD-L1，如图13和表9所示。图14B示出了对图14A的抗体进行蛋白酶消化后的SDS-page分析。
蛋白酶测定
(1)MMP-9活性测定。将重组人MMP-9(rhMMP-9，R&D Systems)在测定缓冲液(50mMTris，10mM CaCl2，150mM NaCl，0.05％Brij-35，pH 7.5)中稀释至100μg/ml。然后通过加入APMA(对氨基苯乙酸汞，Sigma)至1mM的终浓度并在37℃孵育24小时来活化rhMMP-9。用等体积的测定缓冲液中的20μM抗体滴定活化的rhMMP-9，并在室温下孵育1小时。通过SDS-PAGE分析所得经消化的底物。
(2)u-纤溶酶原活化剂(uPA、尿激酶)活性测定。将底物在测定缓冲液(50mM Tris，0.01％Tween 20，pH8.5)中稀释至200μM，并用等体积的测定缓冲液中的重组人u-纤溶酶原活化剂(rhuPA，R&D Systems)滴定。将反应混合物在室温下孵育1-2小时，并通过SDS-PAGE分析所得经消化的底物。
(3)马曲肽酶活性测定。将底物在测定缓冲液(50mM Tris，50mM NaCl，0.01％Tween 20)中稀释至200μM，并用等体积的测定缓冲液中的重组人基质酶(R&D Systems)滴定。将反应混合物在室温下孵育1-2小时，并通过SDS-PAGE分析所得经消化的底物。
聚丙烯酰胺凝胶电泳(SDS-PAGE)。根据Invitrogen
Figure BDA0003664798220000831
说明书执行变性SDS-PAGE。简言之，将7.5μL蛋白质样品(3μg蛋白质)与2.5μL的4X LDS样品上样缓冲液(Invitrogen)混合，并在70℃加热10min。然后将样品上样到预制的NuPAGE Novex 4-12％Bis-Tris 1.0mm微凝胶(Invitrogen)中。然后，在每次凝胶运行中上样5μL预染色的SDS-PAGE标准品(Bio-Rad)。在室温下，在NuPAGE MOPS SDS运行缓冲液(Invitrogen)的1X溶液中使用恒定电压(200V)执行电泳达约45min，直到染料前沿到达60mm凝胶的末端。将凝胶用SimplyBlue SafeStain(Invitrogen)染色。
图15描述了在10mg/ml HSA存在下，PD-L1/pro-CD47(HSA-CD47-PD-L1抗体)对比PD-L1/活性CD47(HSA结合结构域被切除的相同抗体)的实时动力学结合分析。PD-L1/pro-CD47没有或很少结合CD47，而PD-L1/活性CD47显示出与CD47的强结合。在该测定中，PD-L1结合没有差异或对PD-L1结合没有影响。
实施例8.含有CD16A/HSA/CD47/(PD-L1或CD33)的多特异性分子
为了构建多特异性分子，通过重组DNA技术，将抗CD16A、抗HSA、抗CD47和抗PD-L1或CD33 VHH序列通过接头以八种不同方式融合在一起。图16描绘了抗CD16A、抗HSA、抗CD47和抗PD-L1或CD33 VHH的示例性多特异性分子的结构。下面列出了示例性多特异性分子的氨基酸序列(表17)
图17A在HL60细胞上的流式细胞术结合测定中比较了VHH2与VHH3之间的接头G4SG3S(L1,SEQ ID NO:100)对比(G4S)3(L4,SEQ ID NO:103)的长度。HL60细胞表达CD47，但不表达PD-L1，因此1518-HS5(SEQ ID 173)和1518-HS5-GS15(SEQ ID 184)的结合表明这两种分子与HL60细胞表面上的CD47结合(图18)。较长的接头如(G4S)3(GS15代表15个氨基酸的接头)对比G4SG3S(9个氨基酸)提高了CD47结合，EC50为8.4nM对比26nM。
表17.多特异性分子
Figure BDA0003664798220000841
Figure BDA0003664798220000851
Figure BDA0003664798220000861
Figure BDA0003664798220000871
Figure BDA0003664798220000881
Figure BDA0003664798220000891
Figure BDA0003664798220000901
Figure BDA0003664798220000911
Figure BDA0003664798220000921
Figure BDA0003664798220000931
Figure BDA0003664798220000941
Figure BDA0003664798220000951
Figure BDA0003664798220000961
Figure BDA0003664798220000971
Figure BDA0003664798220000981
Figure BDA0003664798220000991
Figure BDA0003664798220001001
Figure BDA0003664798220001011
Figure BDA0003664798220001021
Figure BDA0003664798220001031
Figure BDA0003664798220001041
Figure BDA0003664798220001051
Figure BDA0003664798220001061
Figure BDA0003664798220001071
Figure BDA0003664798220001081
Figure BDA0003664798220001091
Figure BDA0003664798220001101
Figure BDA0003664798220001111
Figure BDA0003664798220001121
Figure BDA0003664798220001131
Figure BDA0003664798220001141
Figure BDA0003664798220001151
Figure BDA0003664798220001161
Figure BDA0003664798220001171
Figure BDA0003664798220001181
Figure BDA0003664798220001191
Figure BDA0003664798220001201
Figure BDA0003664798220001211
Figure BDA0003664798220001221
Figure BDA0003664798220001231
Figure BDA0003664798220001241
Figure BDA0003664798220001251
Figure BDA0003664798220001261
Figure BDA0003664798220001271
Figure BDA0003664798220001281
如实施例8中进行多特异性分子的
Figure BDA0003664798220001283
结合分析，并且结果表示在图17和图18中。
实施例9.用于治疗阿尔茨海默氏病和视网膜疾病的包含抗CD33结构域的MVSCA
表18.包含抗CD33 VHH*的MVSCA
Figure BDA0003664798220001282
Figure BDA0003664798220001291
Figure BDA0003664798220001301
*插置在VHH结构域之间的接头序列是加下划线的
**该序列显示为具有任选的C末端his标签
表18中的四种MVSCA中的每一种MVSCA都含有一对通过接头L3(序列AAA；SEQ IDNO:102)接合的抗CD33结构域。在表18中的第一个条目，hHS5-L1-H33-14-L3-H33-14，包含N末端抗HSA结构域以增加体内半衰期。表18中的第二个条目FC5-L1-H33-14-L3-H33-14包含N末端FC5纳米抗体结构域，以促进穿过血脑屏障。表18中的第三个条目，FC5-L1-H33-14-L3-H33-14-L1-hHS5，包含N-末端FC5纳米抗体结构域以促进穿过血脑屏障，并且包含C末端抗HSA结构域以增加体内半衰期。这三种形式通常适用于全身施用，例如静脉内或皮下注射或输注。表18中的第四个条目H33-14-L3-H3314是二价、单特异性的MVSCA，其仅对CD33具有特异性。其较小的大小使其更适合局部注射入大脑或眼睛。
FC5纳米抗体结构域的氨基酸序列是：
Figure BDA0003664798220001302
实施例10.多重序列比对
图21至图26呈现了针对每种特异性通过Clustal O(1.2.4)进行的本文所公开的VHH序列的多重序列比对，使得人们容易看到相同的、保守的和高度可变的位置。在比对中的每一个位置下面都有一个符号：星号表示同一性，冒号表示较高程度的保守性，句号表示较低程度的保守性，空格表示在比对的序列中普遍缺乏保守性。
除非另有说明，否则在说明书和权利要求中使用的表示成分的量、性质(例如分子量)、反应条件等的所有数字应理解为在所有情况下均由术语“约”修饰。如本文所用，术语“约”和“大致”是指在10％至15％之内，优选在5％至10％之内。因此，除非有相反的指示，否则在说明书和所附权利要求书中列出的数值参数是近似值，所述近似值可以根据本发明寻求获得的所需性质而变化。无论如何，并非试图限制权利要求书范围的等同物的原则的应用，每个数值参数应至少根据报告的有效位的数量并通过应用普通的舍入技术来解释。尽管阐述本发明广泛范围的数值范围和参数是近似值，但是具体实施例中列出的数值是尽可能精确报告的。然而，任何数值固有地含有必然由其各自相应的测试测量中存在的标准偏差引起的某些误差。
除非在此另外指明或者明显与上下文相矛盾，否则在描述本发明的上下文中(尤其是在以下权利要求的上下文中)使用的术语“一”、“一个”、“所述”以及类似的指示词应被解释为涵盖单数和复数两者。本文中对值范围的描述仅旨在用作为引用落入该范围的每个单独值的速记方法。除非本文另有说明，否则每个单独的值被并入说明书中，如同其在本文中被单独引用一样。除非本文另有说明或明显与上下文相矛盾，否则本文所述的所有方法均可以任何合适的顺序进行。本文提供的任何和所有示例、或例示性语言(例如“例如”)的使用仅旨在更好地说明本发明，而不是对要求保护的本发明的范围构成限制。说明书中的任何语言都不应被解释为表示任何不要求保护的要素对于本发明的实践为必不可少的。
本文公开的本发明的替代要素或实施方式的分组不应解释为限制。每个组成员可以单独地或与该组中的其他成员或本文中找到的其他要素任意组合地被提及和要求保护。预期组中的一个或多个成员可以出于方便和/或可专利性的原因而被包括在组中或从组中删除。当发生任何此类包括或删除时，本说明书被视为包含经修改的组，从而满足对所附权利要求书中使用的所有马库什组的书面描述。
本文描述了本发明的某些实施方式，包括本发明人已知的用于实现本发明的最佳方式。当然，对于本领域普通技术人员来说，在阅读前面的描述后，这些描述的实施方式的变型将变得显而易见。本发明人希望技术人员适当地采用此类变型，并且本发明人希望以不同于本文具体描述的方式实践本发明。因此，本发明包括适用法律所允许的本文所附权利要求中所述主题的所有修改和等同物。此外，除非本文另有说明或明显与上下文相矛盾，否则本发明涵盖上述要素的所有可能变型的任何组合。
本文公开的具体实施方式可以在权利要求中使用由......组成或基本上由……组成的语言来进一步限制。当在权利要求中使用时，无论是原始提交还是按照修正添加，过渡术语“由...组成”不包括权利要求中未指定的任何要素、步骤或成分。过渡术语“基本上由......组成”将权利要求的范围限制于指定的材料或步骤，以及不会对基本和新颖特征产生实质性影响的那些材料或步骤。如此要求保护的本发明的实施方式在本文中被固有地或明确地描述和实现。
此外，在整个说明书中，已经对专利和印刷出版物进行了大量引用。上面引用的参考文献和印刷出版物中的每一者的全部内容均以引用方式单独地并入本文。
最后，应理解，本文公开的本发明的实施方式是对本发明原理的说明。可以采用的其他修改在本发明的范围内。因此，举例来说而非限制，可以根据本文的教导使用本发明的替代配置。因此，本发明不被限制为如精确地所示和所描述的。
序列表
<110> 北京烁星生物医药科技有限公司 (Beijing StarMab BioMed TechnologyLtd.)
<120> 单特异性和多特异性抗体
<130> 1959708-00002
<150> US62/907,275
<151> 2019-09-27
<150> US62/989,327
<151> 2020-03-13
<160> 225
<170> PatentIn version 3.5
<210> 1
<211> 121
<212> PRT
<213> 智人 (Homo sapiens)
<400> 1
Gln Leu Leu Phe Asn Lys Thr Lys Ser Val Glu Phe Thr Phe Cys Asn
1 5 10 15
Asp Thr Val Val Ile Pro Cys Phe Val Thr Asn Met Glu Ala Gln Asn
20 25 30
Thr Thr Glu Val Tyr Val Lys Trp Lys Phe Lys Gly Arg Asp Ile Tyr
35 40 45
Thr Phe Asp Gly Ala Leu Asn Lys Ser Thr Val Pro Thr Asp Phe Ser
50 55 60
Ser Ala Lys Ile Glu Val Ser Gln Leu Leu Lys Gly Asp Ala Ser Leu
65 70 75 80
Lys Met Asp Lys Ser Asp Ala Val Ser His Thr Gly Asn Tyr Thr Cys
85 90 95
Glu Val Thr Glu Leu Thr Arg Glu Gly Glu Thr Ile Ile Glu Leu Lys
100 105 110
Tyr Arg Val Val Ser Trp Phe Ser Pro
115 120
<210> 2
<211> 127
<212> PRT
<213> 羊驼 (Lama glama)
<400> 2
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Ala Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Tyr Gly Val Asn Ser Tyr
20 25 30
Ala Leu Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val
35 40 45
Ala Ala Ile Ser Arg Ser Gly Gly Asn Ile Asn Tyr Ala Asp Ser Ala
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Phe Lys Asn Thr Thr Tyr
65 70 75 80
Leu Gln Met Ser Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Ala His Tyr Leu Leu Leu Pro Ser Tyr Ile Ser Thr Ser Thr Asn
100 105 110
Met Tyr Asn Tyr Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser
115 120 125
<210> 3
<211> 127
<212> PRT
<213> 羊驼 (Lama glama)
<400> 3
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Ala Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Tyr Gly Val Asn Ser Tyr
20 25 30
Ala Leu Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val
35 40 45
Ala Ala Ile Ser Arg Ser Gly Gly Asn Ile Asn Tyr Ala Asp Ser Ala
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Phe Lys Asn Thr Thr Tyr
65 70 75 80
Leu Gln Met Ser Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Ala His Tyr Leu Leu Leu Pro Ser Tyr Ile Ala Thr Ala Ile Lys
100 105 110
Met Tyr Asn Tyr Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser
115 120 125
<210> 4
<211> 127
<212> PRT
<213> 羊驼 (Lama glama)
<400> 4
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Ala Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Tyr Gly Val Asn Ser Tyr
20 25 30
Ala Leu Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val
35 40 45
Ala Ala Ile Ser Arg Ser Gly Gly Asn Ile Asn Tyr Ala Asp Ser Ala
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Phe Lys Asn Thr Thr Tyr
65 70 75 80
Leu Gln Met Ser Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Ala His Tyr Leu Leu Leu Pro Ser Tyr Ile Ser Phe Ala Ser Lys
100 105 110
Met Tyr Asn Tyr Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser
115 120 125
<210> 5
<211> 127
<212> PRT
<213> 羊驼 (Lama glama)
<400> 5
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Ala Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Gly Val Met Trp Ser Ser
20 25 30
Ala Leu Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val
35 40 45
Ala Ala Ile Ser Arg Ser Gly Gly Asn Ile Asn Tyr Ala Asp Ser Ala
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Phe Lys Asn Thr Thr Tyr
65 70 75 80
Leu Gln Met Ser Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Ala His Tyr Leu Leu Leu Pro Ser Tyr Ile Ser Thr Ser Thr Asn
100 105 110
Met Tyr Asn Tyr Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser
115 120 125
<210> 6
<211> 127
<212> PRT
<213> 羊驼 (Lama glama)
<400> 6
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Ala Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Ile Arg Phe Phe Gly Ser
20 25 30
Ala Leu Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val
35 40 45
Ala Ala Ile Ser Arg Ser Gly Gly Asn Ile Asn Tyr Ala Asp Ser Ala
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Phe Lys Asn Thr Thr Tyr
65 70 75 80
Leu Gln Met Ser Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Ala His Tyr Leu Leu Leu Pro Ser Tyr Ile Ser Thr Ser Thr Asn
100 105 110
Met Tyr Asn Tyr Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser
115 120 125
<210> 7
<211> 129
<212> PRT
<213> 羊驼 (Lama glama)
<400> 7
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Ala Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Gly Gly Arg Thr Phe Ser
20 25 30
Asn Tyr Ala Leu Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu
35 40 45
Phe Val Ala Ala Ile Ser Arg Ser Gly Gly Asn Ile Asn Tyr Ala Asp
50 55 60
Ser Ala Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Phe Lys Asn Thr
65 70 75 80
Thr Tyr Leu Gln Met Ser Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr
85 90 95
Tyr Cys Ala Ala His Tyr Leu Leu Leu Pro Ser Tyr Ile Ser Thr Ser
100 105 110
Thr Asn Met Tyr Asn Tyr Trp Gly Gln Gly Thr Gln Val Thr Val Ser
115 120 125
Ser
<210> 8
<211> 129
<212> PRT
<213> 人工序列 (Artificial Sequence)
<220>
<223> 人源化VHH A09-10
<400> 8
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Gly Gly Arg Thr Phe Ser
20 25 30
Asn Tyr Ala Leu Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu
35 40 45
Phe Val Ala Ala Ile Ser Arg Ser Gly Gly Asn Ile Asn Tyr Ala Asp
50 55 60
Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr
65 70 75 80
Val Tyr Leu Gln Met Ser Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr
85 90 95
Tyr Cys Ala Ala His Tyr Leu Leu Leu Pro Ser Tyr Ile Ser Thr Ser
100 105 110
Thr Asn Met Tyr Asn Tyr Trp Gly Gln Gly Thr Gln Val Thr Val Ser
115 120 125
Ser
<210> 9
<211> 129
<212> PRT
<213> 人工序列 (Artificial Sequence)
<220>
<223> 人源化hA09-10-1
<400> 9
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Gly Gly Arg Thr Phe Ser
20 25 30
Asn Tyr Ala Leu Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu
35 40 45
Phe Val Ala Ala Ile Ser Arg Ser Gly Gly Asn Ile Asn Tyr Ala Asp
50 55 60
Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr
65 70 75 80
Val Tyr Leu Gln Met Ser Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr
85 90 95
Tyr Cys Ala Ala His Tyr Leu Leu Leu Pro Ser Tyr Ile Ser Thr Ser
100 105 110
Thr Asn Met Tyr Asn Tyr Trp Gly Gln Gly Thr Gln Val Thr Val Ser
115 120 125
Ser
<210> 10
<211> 129
<212> PRT
<213> 人工序列 (Artificial Sequence)
<220>
<223> 人源化hA09-10-2
<400> 10
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Gly Gly Arg Thr Phe Ser
20 25 30
Asn Tyr Ala Leu Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu
35 40 45
Phe Val Ala Ala Ile Ser Arg Ser Gly Gly Asn Ile Asn Tyr Ala Asp
50 55 60
Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Phe Lys Asn Thr
65 70 75 80
Thr Tyr Leu Gln Met Ser Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr
85 90 95
Tyr Cys Ala Ala His Tyr Leu Leu Leu Pro Ser Tyr Ile Ser Thr Ser
100 105 110
Thr Asn Met Tyr Asn Tyr Trp Gly Gln Gly Thr Gln Val Thr Val Ser
115 120 125
Ser
<210> 11
<211> 129
<212> PRT
<213> 人工序列 (Artificial Sequence)
<220>
<223> 人源化hA09-10-3
<400> 11
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Gly Gly Arg Thr Phe Ser
20 25 30
Asn Tyr Ala Leu Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu
35 40 45
Phe Val Ala Ala Ile Ser Arg Ser Gly Gly Asn Ile Asn Tyr Ala Asp
50 55 60
Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Phe Lys Asn Thr
65 70 75 80
Val Tyr Leu Gln Met Ser Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr
85 90 95
Tyr Cys Ala Ala His Tyr Leu Leu Leu Pro Ser Tyr Ile Ser Thr Ser
100 105 110
Thr Asn Met Tyr Asn Tyr Trp Gly Gln Gly Thr Gln Val Thr Val Ser
115 120 125
Ser
<210> 12
<211> 129
<212> PRT
<213> 人工序列 (Artificial Sequence)
<220>
<223> 人源化hA09-10-04
<400> 12
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Gly Gly Arg Thr Phe Ser
20 25 30
Asn Tyr Ala Leu Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu
35 40 45
Phe Val Ala Ala Ile Ser Arg Ser Gly Gly Asn Ile Asn Tyr Ala Asp
50 55 60
Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr
65 70 75 80
Val Tyr Leu Gln Met Ser Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr
85 90 95
Tyr Cys Ala Ala His Tyr Leu Leu Leu Pro Ser Tyr Ile Ser Thr Ser
100 105 110
Thr Asn Met Tyr Asn Tyr Trp Gly Gln Gly Thr Gln Val Thr Val Ser
115 120 125
Ser
<210> 13
<211> 261
<212> PRT
<213> 人工序列 (Artificial Sequence)
<220>
<223> 二价人源化hA09-10-45
<400> 13
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Arg Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Gly Gly Arg Thr Phe Ser
20 25 30
Asn Tyr Ala Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu
35 40 45
Phe Val Ser Ala Ile Ser Arg Ser Gly Gly Asn Ile Tyr Tyr Ala Asp
50 55 60
Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Phe Lys Asn Thr
65 70 75 80
Val Tyr Leu Gln Met Ser Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr
85 90 95
Tyr Cys Ala Ala His Tyr Leu Leu Leu Pro Ser Tyr Ile Ser Thr Ser
100 105 110
Thr Asn Met Tyr Asn Tyr Trp Gly Gln Gly Thr Gln Val Thr Val Ser
115 120 125
Ser Ala Ala Ala Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val
130 135 140
Arg Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Gly Gly
145 150 155 160
Arg Thr Phe Ser Asn Tyr Ala Met Gly Trp Phe Arg Gln Ala Pro Gly
165 170 175
Lys Glu Arg Glu Phe Val Ser Ala Ile Ser Arg Ser Gly Gly Asn Ile
180 185 190
Tyr Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn
195 200 205
Ala Lys Asn Thr Val Tyr Leu Gln Met Ser Ser Leu Arg Ala Glu Asp
210 215 220
Thr Ala Val Tyr Tyr Cys Ala Ala His Tyr Leu Leu Leu Pro Ser Tyr
225 230 235 240
Ile Ser Thr Ser Thr Asn Met Tyr Asn Tyr Trp Gly Gln Gly Thr Gln
245 250 255
Val Thr Val Ser Ser
260
<210> 14
<211> 129
<212> PRT
<213> 人工序列 (Artificial Sequence)
<220>
<223> 人源化hA09-10-5
<400> 14
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Gly Gly Arg Thr Phe Ser
20 25 30
Asn Tyr Ala Leu Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu
35 40 45
Phe Val Ala Ala Ile Ser Arg Ser Gly Gly Asn Ile Asn Tyr Ala Asp
50 55 60
Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr
65 70 75 80
Leu Tyr Leu Gln Met Ser Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr
85 90 95
Tyr Cys Ala Ala His Tyr Leu Leu Leu Pro Ser Tyr Ile Ser Thr Ser
100 105 110
Thr Asn Met Tyr Asn Tyr Trp Gly Gln Gly Thr Gln Val Thr Val Ser
115 120 125
Ser
<210> 15
<211> 261
<212> PRT
<213> 人工序列 (Artificial Sequence)
<220>
<223> 二价人源化hA09-10-55
<400> 15
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Arg Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Gly Gly Arg Thr Phe Ser
20 25 30
Asn Tyr Ala Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu
35 40 45
Phe Val Ser Ala Ile Ser Arg Ser Gly Gly Asn Ile Tyr Tyr Ala Asp
50 55 60
Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr
65 70 75 80
Leu Tyr Leu Gln Met Ser Ser Leu Glu Pro Glu Asp Thr Ala Val Tyr
85 90 95
Tyr Cys Ala Ala His Tyr Leu Leu Leu Pro Ser Tyr Ile Ser Thr Ser
100 105 110
Thr Asn Met Tyr Asn Tyr Trp Gly Gln Gly Thr Gln Val Thr Val Ser
115 120 125
Ser Ala Ala Ala Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val
130 135 140
Arg Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Gly Gly
145 150 155 160
Arg Thr Phe Ser Asn Tyr Ala Met Gly Trp Phe Arg Gln Ala Pro Gly
165 170 175
Lys Glu Arg Glu Phe Val Ser Ala Ile Ser Arg Ser Gly Gly Asn Ile
180 185 190
Tyr Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn
195 200 205
Ser Lys Asn Thr Leu Tyr Leu Gln Met Ser Ser Leu Glu Pro Glu Asp
210 215 220
Thr Ala Val Tyr Tyr Cys Ala Ala His Tyr Leu Leu Leu Pro Ser Tyr
225 230 235 240
Ile Ser Thr Ser Thr Asn Met Tyr Asn Tyr Trp Gly Gln Gly Thr Gln
245 250 255
Val Thr Val Ser Ser
260
<210> 16
<211> 132
<212> PRT
<213> 人工序列 (Artificial Sequence)
<220>
<223> 人源化hA09-10-6
<400> 16
Ala Ala Ala Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln
1 5 10 15
Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Gly Gly Arg
20 25 30
Thr Phe Ser Asn Tyr Ala Leu Gly Trp Phe Arg Gln Ala Pro Gly Lys
35 40 45
Glu Arg Glu Phe Val Ser Ala Ile Ser Arg Ser Gly Gly Asn Ile Asp
50 55 60
Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala
65 70 75 80
Lys Asn Thr Val Tyr Leu Gln Met Ser Ser Leu Arg Ala Glu Asp Thr
85 90 95
Ala Val Tyr Tyr Cys Ala Ala His Tyr Leu Leu Leu Pro Ser Tyr Ile
100 105 110
Ser Thr Ser Thr Asn Met Tyr Asn Tyr Trp Gly Gln Gly Thr Gln Val
115 120 125
Thr Val Ser Ser
130
<210> 17
<211> 261
<212> PRT
<213> 人工序列 (Artificial Sequence)
<220>
<223> 二价人源化hA09-10-66
<400> 17
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Gly Gly Arg Thr Phe Ser
20 25 30
Asn Tyr Ala Leu Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu
35 40 45
Phe Val Ser Ala Ile Ser Arg Ser Gly Gly Asn Ile Asp Tyr Ala Asp
50 55 60
Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Phe Lys Asn Thr
65 70 75 80
Val Tyr Leu Gln Met Ser Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr
85 90 95
Tyr Cys Ala Ala His Tyr Leu Leu Leu Pro Ser Tyr Ile Ser Thr Ser
100 105 110
Thr Asn Met Tyr Asn Tyr Trp Gly Gln Gly Thr Gln Val Thr Val Ser
115 120 125
Ser Ala Ala Ala Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val
130 135 140
Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Gly Gly
145 150 155 160
Arg Thr Phe Ser Asn Tyr Ala Leu Gly Trp Phe Arg Gln Ala Pro Gly
165 170 175
Lys Glu Arg Glu Phe Val Ser Ala Ile Ser Arg Ser Gly Gly Asn Ile
180 185 190
Tyr Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn
195 200 205
Ala Lys Asn Thr Val Tyr Leu Gln Met Ser Ser Leu Arg Ala Glu Asp
210 215 220
Thr Ala Val Tyr Tyr Cys Ala Ala His Tyr Leu Leu Leu Pro Ser Tyr
225 230 235 240
Ile Ser Thr Ser Thr Asn Met Tyr Asn Tyr Trp Gly Gln Gly Thr Gln
245 250 255
Val Thr Val Ser Ser
260
<210> 18
<211> 129
<212> PRT
<213> 人工序列 (Artificial Sequence)
<220>
<223> 人源化hA09-10-7
<400> 18
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Gly Gly Arg Thr Phe Ser
20 25 30
Asn Tyr Ala Leu Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu
35 40 45
Phe Val Ser Ala Ile Ser Arg Ser Gly Gly Asn Ile Asp Tyr Ala Asp
50 55 60
Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr
65 70 75 80
Leu Tyr Leu Gln Met Ser Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr
85 90 95
Tyr Cys Ala Ala His Tyr Leu Leu Leu Pro Ser Tyr Ile Ser Thr Ser
100 105 110
Thr Asn Met Tyr Asn Tyr Trp Gly Gln Gly Thr Gln Val Thr Val Ser
115 120 125
Ser
<210> 19
<211> 261
<212> PRT
<213> 人工序列 (Artificial Sequence)
<220>
<223> 二价人源化hA09-10-77
<400> 19
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Gly Gly Arg Thr Phe Ser
20 25 30
Asn Tyr Ala Leu Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu
35 40 45
Phe Val Ser Ala Ile Ser Arg Ser Gly Gly Asn Ile Asp Tyr Ala Asp
50 55 60
Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr
65 70 75 80
Leu Tyr Leu Gln Met Ser Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr
85 90 95
Tyr Cys Ala Ala His Tyr Leu Leu Leu Pro Ser Tyr Ile Ser Thr Ser
100 105 110
Thr Asn Met Tyr Asn Tyr Trp Gly Gln Gly Thr Gln Val Thr Val Ser
115 120 125
Ser Ala Ala Ala Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val
130 135 140
Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Gly Gly
145 150 155 160
Arg Thr Phe Ser Asn Tyr Ala Leu Gly Trp Phe Arg Gln Ala Pro Gly
165 170 175
Lys Glu Arg Glu Phe Val Ser Ala Ile Ser Arg Ser Gly Gly Asn Ile
180 185 190
Asp Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn
195 200 205
Ser Lys Asn Thr Leu Tyr Leu Gln Met Ser Ser Leu Lys Pro Glu Asp
210 215 220
Thr Ala Val Tyr Tyr Cys Ala Ala His Tyr Leu Leu Leu Pro Ser Tyr
225 230 235 240
Ile Ser Thr Ser Thr Asn Met Tyr Asn Tyr Trp Gly Gln Gly Thr Gln
245 250 255
Val Thr Val Ser Ser
260
<210> 20
<211> 129
<212> PRT
<213> 人工序列 (Artificial Sequence)
<220>
<223> 人源化hA09-10-8
<400> 20
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Gly Gly Arg Thr Phe Ser
20 25 30
Asn Tyr Ala Leu Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu
35 40 45
Phe Val Ser Ala Ile Ser Arg Ser Gly Gly Asn Ile Tyr Tyr Ala Asp
50 55 60
Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr
65 70 75 80
Leu Tyr Leu Gln Met Ser Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr
85 90 95
Tyr Cys Ala Ala His Tyr Leu Leu Leu Pro Ser Tyr Ile Ser Thr Ser
100 105 110
Thr Asn Met Tyr Asn Tyr Trp Gly Gln Gly Thr Gln Val Thr Val Ser
115 120 125
Ser
<210> 21
<211> 261
<212> PRT
<213> 人工序列 (Artificial Sequence)
<220>
<223> 二价人源化hA09-10-88
<400> 21
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Gly Gly Arg Thr Phe Ser
20 25 30
Asn Tyr Ala Leu Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu
35 40 45
Phe Val Ser Ala Ile Ser Arg Ser Gly Gly Asn Ile Tyr Tyr Ala Asp
50 55 60
Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr
65 70 75 80
Leu Tyr Leu Gln Met Ser Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr
85 90 95
Tyr Cys Ala Ala His Tyr Leu Leu Leu Pro Ser Tyr Ile Ser Thr Ser
100 105 110
Thr Asn Met Tyr Asn Tyr Trp Gly Gln Gly Thr Gln Val Thr Val Ser
115 120 125
Ser Ala Ala Ala Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val
130 135 140
Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Gly Gly
145 150 155 160
Arg Thr Phe Ser Asn Tyr Ala Leu Gly Trp Phe Arg Gln Ala Pro Gly
165 170 175
Lys Glu Arg Glu Phe Val Ser Ala Ile Ser Arg Ser Gly Gly Asn Ile
180 185 190
Tyr Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn
195 200 205
Ser Lys Asn Thr Leu Tyr Leu Gln Met Ser Ser Leu Lys Pro Glu Asp
210 215 220
Thr Ala Val Tyr Tyr Cys Ala Ala His Tyr Leu Leu Leu Pro Ser Tyr
225 230 235 240
Ile Ser Thr Ser Thr Asn Met Tyr Asn Tyr Trp Gly Gln Gly Thr Gln
245 250 255
Val Thr Val Ser Ser
260
<210> 22
<211> 129
<212> PRT
<213> 人工序列 (Artificial Sequence)
<220>
<223> 人源化hA09-10-9
<400> 22
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Gly Gly Arg Thr Phe Ser
20 25 30
Asn Tyr Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Glu Arg Glu
35 40 45
Phe Val Ser Ala Ile Ser Arg Ser Gly Gly Asn Ile Tyr Tyr Ala Asp
50 55 60
Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr
65 70 75 80
Leu Tyr Leu Gln Met Ser Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr
85 90 95
Tyr Cys Ala Ala His Tyr Leu Leu Leu Pro Ser Tyr Ile Ser Thr Ser
100 105 110
Thr Asn Met Tyr Asn Tyr Trp Gly Gln Gly Thr Gln Val Thr Val Ser
115 120 125
Ser
<210> 23
<211> 261
<212> PRT
<213> 人工序列 (Artificial Sequence)
<220>
<223> 二价人源化hA09-10-99
<400> 23
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Gly Gly Arg Thr Phe Ser
20 25 30
Asn Tyr Ala Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu
35 40 45
Phe Val Ser Ala Ile Ser Arg Ser Gly Gly Asn Ile Tyr Tyr Ala Asp
50 55 60
Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr
65 70 75 80
Leu Tyr Leu Gln Met Ser Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr
85 90 95
Tyr Cys Ala Ala His Tyr Leu Leu Leu Pro Ser Tyr Ile Ser Thr Ser
100 105 110
Thr Asn Met Tyr Asn Tyr Trp Gly Gln Gly Thr Gln Val Thr Val Ser
115 120 125
Ser Ala Ala Ala Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val
130 135 140
Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Gly Gly
145 150 155 160
Arg Thr Phe Ser Asn Tyr Ala Met Gly Trp Phe Arg Gln Ala Pro Gly
165 170 175
Lys Glu Arg Glu Phe Val Ser Ala Ile Ser Arg Ser Gly Gly Asn Ile
180 185 190
Tyr Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn
195 200 205
Ser Lys Asn Thr Leu Tyr Leu Gln Met Ser Ser Leu Lys Pro Glu Asp
210 215 220
Thr Ala Val Tyr Tyr Cys Ala Ala His Tyr Leu Leu Leu Pro Ser Tyr
225 230 235 240
Ile Ser Thr Ser Thr Asn Met Tyr Asn Tyr Trp Gly Gln Gly Thr Gln
245 250 255
Val Thr Val Ser Ser
260
<210> 24
<211> 129
<212> PRT
<213> 人工序列 (Artificial Sequence)
<220>
<223> 人源化hA09-10-10
<400> 24
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Gly Gly Arg Thr Phe Ser
20 25 30
Asn Tyr Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Glu Arg Glu
35 40 45
Phe Val Ser Ala Ile Ser Arg Ser Gly Gly Asn Ile Tyr Tyr Ala Asp
50 55 60
Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr
65 70 75 80
Leu Tyr Leu Gln Met Ser Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr
85 90 95
Tyr Cys Ala Ala His Tyr Leu Leu Leu Pro Ser Tyr Ile Ser Thr Ser
100 105 110
Thr Asn Met Tyr Asn Tyr Trp Gly Gln Gly Thr Gln Val Thr Val Ser
115 120 125
Ser
<210> 25
<211> 261
<212> PRT
<213> 人工序列 (Artificial Sequence)
<220>
<223> 二价人源化hA09-10-100
<400> 25
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Gly Gly Arg Thr Phe Ser
20 25 30
Asn Tyr Ala Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu
35 40 45
Phe Val Ser Ala Ile Ser Arg Ser Gly Gly Asn Ile Tyr Tyr Ala Asp
50 55 60
Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr
65 70 75 80
Leu Tyr Leu Gln Met Ser Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr
85 90 95
Tyr Cys Ala Ala His Tyr Leu Leu Leu Pro Ser Tyr Ile Ser Thr Ser
100 105 110
Thr Asn Met Tyr Asn Tyr Trp Gly Gln Gly Thr Gln Val Thr Val Ser
115 120 125
Ser Ala Ala Ala Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val
130 135 140
Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Gly Gly
145 150 155 160
Arg Thr Phe Ser Asn Tyr Ala Met Gly Trp Phe Arg Gln Ala Pro Gly
165 170 175
Lys Glu Arg Glu Phe Val Ser Ala Ile Ser Arg Ser Gly Gly Asn Ile
180 185 190
Tyr Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn
195 200 205
Ser Lys Asn Thr Leu Tyr Leu Gln Met Ser Ser Leu Arg Ala Glu Asp
210 215 220
Thr Ala Val Tyr Tyr Cys Ala Ala His Tyr Leu Leu Leu Pro Ser Tyr
225 230 235 240
Ile Ser Thr Ser Thr Asn Met Tyr Asn Tyr Trp Gly Gln Gly Thr Gln
245 250 255
Val Thr Val Ser Ser
260
<210> 26
<211> 129
<212> PRT
<213> 人工序列 (Artificial Sequence)
<220>
<223> 人源化hA09-10-11
<400> 26
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Gly Gly Arg Thr Phe Ser
20 25 30
Asn Tyr Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Glu Arg Glu
35 40 45
Phe Val Ser Ala Ile Ser Arg Ser Gly Gly Asn Ile Tyr Tyr Ala Asp
50 55 60
Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr
65 70 75 80
Val Tyr Leu Gln Met Ser Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr
85 90 95
Tyr Cys Ala Ala His Tyr Leu Leu Leu Pro Ser Tyr Ile Ser Thr Ser
100 105 110
Thr Asn Met Tyr Asn Tyr Trp Gly Gln Gly Thr Gln Val Thr Val Ser
115 120 125
Ser
<210> 27
<211> 129
<212> PRT
<213> 人工序列 (Artificial Sequence)
<220>
<223> 人源化hA09-10-12
<400> 27
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Gly Gly Arg Thr Phe Ser
20 25 30
Asn Tyr Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Glu Arg Glu
35 40 45
Phe Val Ser Ala Ile Ser Arg Ser Gly Gly Asn Ile Tyr Tyr Ala Asp
50 55 60
Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr
65 70 75 80
Leu Tyr Leu Gln Met Ser Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr
85 90 95
Tyr Cys Ala Ala His Tyr Leu Leu Leu Pro Ser Tyr Ile Ser Thr Ser
100 105 110
Thr Asn Met Tyr Asn Tyr Trp Gly Gln Gly Thr Gln Val Thr Val Ser
115 120 125
Ser
<210> 28
<211> 129
<212> PRT
<213> 人工序列 (Artificial Sequence)
<220>
<223> 人源化hA09-10-13
<400> 28
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Gly Gly Arg Thr Phe Ser
20 25 30
Asn Tyr Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Glu Arg Glu
35 40 45
Phe Val Ser Ala Ile Ser Arg Ser Gly Gly Asn Ile Tyr Tyr Ala Asp
50 55 60
Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr
65 70 75 80
Val Tyr Leu Gln Met Ser Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr
85 90 95
Tyr Cys Ala Ala His Tyr Leu Leu Leu Pro Ser Tyr Ile Ser Thr Ser
100 105 110
Thr Asn Met Tyr Asn Tyr Trp Gly Gln Gly Thr Gln Val Thr Val Ser
115 120 125
Ser
<210> 29
<211> 129
<212> PRT
<213> 人工序列 (Artificial Sequence)
<220>
<223> 人源化hA09-10-14
<400> 29
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Gly Gly Arg Thr Phe Ser
20 25 30
Asn Tyr Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Glu Arg Glu
35 40 45
Phe Val Ser Ala Ile Ser Arg Ser Gly Gly Asn Ile Tyr Tyr Ala Asp
50 55 60
Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr
65 70 75 80
Leu Tyr Leu Gln Met Ser Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr
85 90 95
Tyr Cys Ala Ala His Tyr Leu Leu Leu Pro Ser Tyr Ile Ser Thr Ser
100 105 110
Thr Asn Met Tyr Asn Tyr Trp Gly Gln Gly Thr Gln Val Thr Val Ser
115 120 125
Ser
<210> 30
<211> 220
<212> PRT
<213> 智人 (Homo sapiens)
<400> 30
Phe Thr Val Thr Val Pro Lys Asp Leu Tyr Val Val Glu Tyr Gly Ser
1 5 10 15
Asn Met Thr Ile Glu Cys Lys Phe Pro Val Glu Lys Gln Leu Asp Leu
20 25 30
Ala Ala Leu Ile Val Tyr Trp Glu Met Glu Asp Lys Asn Ile Ile Gln
35 40 45
Phe Val His Gly Glu Glu Asp Leu Lys Val Gln His Ser Ser Tyr Arg
50 55 60
Gln Arg Ala Arg Leu Leu Lys Asp Gln Leu Ser Leu Gly Asn Ala Ala
65 70 75 80
Leu Gln Ile Thr Asp Val Lys Leu Gln Asp Ala Gly Val Tyr Arg Cys
85 90 95
Met Ile Ser Tyr Gly Gly Ala Asp Tyr Lys Arg Ile Thr Val Lys Val
100 105 110
Asn Ala Pro Tyr Asn Lys Ile Asn Gln Arg Ile Leu Val Val Asp Pro
115 120 125
Val Thr Ser Glu His Glu Leu Thr Cys Gln Ala Glu Gly Tyr Pro Lys
130 135 140
Ala Glu Val Ile Trp Thr Ser Ser Asp His Gln Val Leu Ser Gly Lys
145 150 155 160
Thr Thr Thr Thr Asn Ser Lys Arg Glu Glu Lys Leu Phe Asn Val Thr
165 170 175
Ser Thr Leu Arg Ile Asn Thr Thr Thr Asn Glu Ile Phe Tyr Cys Thr
180 185 190
Phe Arg Arg Leu Asp Pro Glu Glu Asn His Thr Ala Glu Leu Val Ile
195 200 205
Pro Glu Leu Pro Leu Ala His Pro Pro Asn Glu Arg
210 215 220
<210> 31
<211> 127
<212> PRT
<213> 羊驼 (Lama glama)
<400> 31
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Ala Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Val Ser Gly Leu Thr Leu Ser Arg Tyr
20 25 30
Thr Met Ala Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val
35 40 45
Ala Ala Ile Ile Arg Asn Ser Val Ser Thr Phe His Glu Glu Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Val Lys Asn Met Met Tyr
65 70 75 80
Leu Gln Met Asn Thr Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Thr Asn Val Gly Pro Thr Gly Gly Phe Ser Leu Gln Ser Val Gln
100 105 110
Arg Tyr Asp Ala Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser
115 120 125
<210> 32
<211> 123
<212> PRT
<213> 羊驼 (Lama glama)
<400> 32
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Ala Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Thr Phe Asn Thr Tyr
20 25 30
Asp Met Gly Trp Phe Arg Arg Ala Pro Gly Lys Glu Arg Glu Phe Val
35 40 45
Ala Gly Ile Asp Trp Tyr Thr Thr Asn Thr Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr
65 70 75 80
Leu Gln Met Arg Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Ala Gly Ile Arg Ser Thr Ala Thr Ile Thr Gly Gln Ala Asp Tyr
100 105 110
Trp Gly Gln Gly Ala Gln Val Thr Val Ser Ser
115 120
<210> 33
<211> 114
<212> PRT
<213> 羊驼 (Lama glama)
<400> 33
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Ala Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Ser Thr Ser Gly Ile Tyr
20 25 30
Asp Met Gly Trp Tyr Arg Gln Ala Pro Gly Lys Leu Arg Glu Val Val
35 40 45
Gly Ile Ile Thr Ser Gly Gly Thr Thr Asn Tyr Ala Asp Phe Ala Lys
50 55 60
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Met Met Tyr Leu
65 70 75 80
Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys Asn
85 90 95
Ile Arg Thr Arg Leu Ile Ile Trp Gly Gln Gly Thr Gln Val Thr Val
100 105 110
Ser Ser
<210> 34
<211> 124
<212> PRT
<213> 羊驼 (Lama glama)
<400> 34
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Ala Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Phe Ser Gly Gly Thr Phe Leu Thr Tyr
20 25 30
Ser Leu Gly Trp Phe Arg Gln Gly Pro Gly Lys Glu Arg Glu Phe Val
35 40 45
Ala Ser Ile Asn Trp Ser Gly Tyr Met Thr Ser Tyr Val Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Leu Tyr Tyr Cys
85 90 95
Ala Ala Ala Arg Thr Ala Ile Ala Ala Lys Arg Ser Ser Glu Phe Asp
100 105 110
Tyr Trp Gly Gln Gly Ala Gln Val Thr Val Ser Ser
115 120
<210> 35
<211> 123
<212> PRT
<213> 羊驼 (Lama glama)
<400> 35
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Ala Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Thr Phe Asn Thr Tyr
20 25 30
Asp Met Gly Trp Phe Arg Arg Thr Pro Gly Lys Glu Arg Glu Phe Val
35 40 45
Ala Gly Met Asp Trp Asn Thr Ile Asn Thr Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr
65 70 75 80
Leu Gln Met Arg Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Ala Gly Ile Arg Ser Thr Ala Ile Ile Thr Gly Gln Ala Asp Tyr
100 105 110
Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser
115 120
<210> 36
<211> 127
<212> PRT
<213> 羊驼 (Lama glama)
<400> 36
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Ala Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Thr Phe Asn Ile Tyr
20 25 30
Ser Met Ala Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val
35 40 45
Val Arg Ile Asn Trp Asn Arg Gly Thr Thr Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr
65 70 75 80
Leu Gln Met Ser Asn Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Ala Arg Gly Ser Pro Ser Thr Ile Gly Ala Phe Thr Ser Ala Ser
100 105 110
His Tyr Asp Tyr Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser
115 120 125
<210> 37
<211> 114
<212> PRT
<213> 人工序列 (Artificial Sequence)
<220>
<223> 人源化PL14
<400> 37
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Ser Thr Ser Gly Ile Tyr
20 25 30
Asp Met Gly Trp Tyr Arg Gln Ala Pro Gly Lys Leu Arg Glu Val Val
35 40 45
Ser Val Ile Thr Ser Gly Gly Thr Thr Tyr Tyr Ala Asp Ser Val Lys
50 55 60
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu
65 70 75 80
Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Asn
85 90 95
Ile Arg Thr Arg Leu Ile Ile Trp Gly Gln Gly Thr Leu Val Thr Val
100 105 110
Ser Ser
<210> 38
<211> 124
<212> PRT
<213> 人工序列 (Artificial Sequence)
<220>
<223> 人源化PL16
<400> 38
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Gly Thr Phe Leu Thr Tyr
20 25 30
Ser Met Ser Trp Val Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val
35 40 45
Ser Ser Ile Asn Trp Ser Gly Tyr Met Thr Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Ala Ala Arg Thr Ala Ile Ala Ala Lys Arg Ser Ser Glu Phe Asp
100 105 110
Tyr Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser
115 120
<210> 39
<211> 609
<212> PRT
<213> 智人 (Homo sapiens)
<400> 39
Met Lys Trp Val Thr Phe Ile Ser Leu Leu Phe Leu Phe Ser Ser Ala
1 5 10 15
Tyr Ser Arg Gly Val Phe Arg Arg Asp Ala His Lys Ser Glu Val Ala
20 25 30
His Arg Phe Lys Asp Leu Gly Glu Glu Asn Phe Lys Ala Leu Val Leu
35 40 45
Ile Ala Phe Ala Gln Tyr Leu Gln Gln Cys Pro Phe Glu Asp His Val
50 55 60
Lys Leu Val Asn Glu Val Thr Glu Phe Ala Lys Thr Cys Val Ala Asp
65 70 75 80
Glu Ser Ala Glu Asn Cys Asp Lys Ser Leu His Thr Leu Phe Gly Asp
85 90 95
Lys Leu Cys Thr Val Ala Thr Leu Arg Glu Thr Tyr Gly Glu Met Ala
100 105 110
Asp Cys Cys Ala Lys Gln Glu Pro Glu Arg Asn Glu Cys Phe Leu Gln
115 120 125
His Lys Asp Asp Asn Pro Asn Leu Pro Arg Leu Val Arg Pro Glu Val
130 135 140
Asp Val Met Cys Thr Ala Phe His Asp Asn Glu Glu Thr Phe Leu Lys
145 150 155 160
Lys Tyr Leu Tyr Glu Ile Ala Arg Arg His Pro Tyr Phe Tyr Ala Pro
165 170 175
Glu Leu Leu Phe Phe Ala Lys Arg Tyr Lys Ala Ala Phe Thr Glu Cys
180 185 190
Cys Gln Ala Ala Asp Lys Ala Ala Cys Leu Leu Pro Lys Leu Asp Glu
195 200 205
Leu Arg Asp Glu Gly Lys Ala Ser Ser Ala Lys Gln Arg Leu Lys Cys
210 215 220
Ala Ser Leu Gln Lys Phe Gly Glu Arg Ala Phe Lys Ala Trp Ala Val
225 230 235 240
Ala Arg Leu Ser Gln Arg Phe Pro Lys Ala Glu Phe Ala Glu Val Ser
245 250 255
Lys Leu Val Thr Asp Leu Thr Lys Val His Thr Glu Cys Cys His Gly
260 265 270
Asp Leu Leu Glu Cys Ala Asp Asp Arg Ala Asp Leu Ala Lys Tyr Ile
275 280 285
Cys Glu Asn Gln Asp Ser Ile Ser Ser Lys Leu Lys Glu Cys Cys Glu
290 295 300
Lys Pro Leu Leu Glu Lys Ser His Cys Ile Ala Glu Val Glu Asn Asp
305 310 315 320
Glu Met Pro Ala Asp Leu Pro Ser Leu Ala Ala Asp Phe Val Glu Ser
325 330 335
Lys Asp Val Cys Lys Asn Tyr Ala Glu Ala Lys Asp Val Phe Leu Gly
340 345 350
Met Phe Leu Tyr Glu Tyr Ala Arg Arg His Pro Asp Tyr Ser Val Val
355 360 365
Leu Leu Leu Arg Leu Ala Lys Thr Tyr Glu Thr Thr Leu Glu Lys Cys
370 375 380
Cys Ala Ala Ala Asp Pro His Glu Cys Tyr Ala Lys Val Phe Asp Glu
385 390 395 400
Phe Lys Pro Leu Val Glu Glu Pro Gln Asn Leu Ile Lys Gln Asn Cys
405 410 415
Glu Leu Phe Glu Gln Leu Gly Glu Tyr Lys Phe Gln Asn Ala Leu Leu
420 425 430
Val Arg Tyr Thr Lys Lys Val Pro Gln Val Ser Thr Pro Thr Leu Val
435 440 445
Glu Val Ser Arg Asn Leu Gly Lys Val Gly Ser Lys Cys Cys Lys His
450 455 460
Pro Glu Ala Lys Arg Met Pro Cys Ala Glu Asp Tyr Leu Ser Val Val
465 470 475 480
Leu Asn Gln Leu Cys Val Leu His Glu Lys Thr Pro Val Ser Asp Arg
485 490 495
Val Thr Lys Cys Cys Thr Glu Ser Leu Val Asn Arg Arg Pro Cys Phe
500 505 510
Ser Ala Leu Glu Val Asp Glu Thr Tyr Val Pro Lys Glu Phe Asn Ala
515 520 525
Glu Thr Phe Thr Phe His Ala Asp Ile Cys Thr Leu Ser Glu Lys Glu
530 535 540
Arg Gln Ile Lys Lys Gln Thr Ala Leu Val Glu Leu Val Lys His Lys
545 550 555 560
Pro Lys Ala Thr Lys Glu Gln Leu Lys Ala Val Met Asp Asp Phe Ala
565 570 575
Ala Phe Val Glu Lys Cys Cys Lys Ala Asp Asp Lys Glu Thr Cys Phe
580 585 590
Ala Glu Glu Gly Lys Lys Leu Val Ala Ala Ser Gln Ala Ala Leu Gly
595 600 605
Leu
<210> 40
<211> 122
<212> PRT
<213> 羊驼 (Lama glama)
<400> 40
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Ala Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Ala Phe Ser Ser Tyr
20 25 30
Ala Met Gly Trp Phe Arg Gln Ala Pro Arg Lys Glu Arg Glu Phe Val
35 40 45
Ala Thr Ile Ser Leu Ser Gly Gly Tyr Thr Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Ala Gly Glu Ser Ser Ser Arg Gln Asp Lys Trp Tyr Asp Tyr Trp
100 105 110
Gly Gln Gly Thr Gln Val Thr Val Ser Ser
115 120
<210> 41
<211> 123
<212> PRT
<213> 羊驼 (Lama glama)
<400> 41
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Ala Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Thr Phe Thr Thr His
20 25 30
Ala Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val
35 40 45
Ala Thr Ile Asn Trp Gly Gly Arg Thr Thr Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Ile Ile Ser Arg Asp Thr Gly Ala Asn Thr Val Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Ser Asn Leu Asp Thr Tyr Asn Val Arg Ala Gly Thr Thr Asn Ser
100 105 110
Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser
115 120
<210> 42
<211> 123
<212> PRT
<213> 羊驼 (Lama glama)
<400> 42
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Ala Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Ile Phe His Thr Tyr
20 25 30
Ala Val Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Ser Val
35 40 45
Val Ile Ile Asn Trp Ser Ser Asp His Thr Tyr Val Ala Gln Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Arg Ala Lys Asn Thr Phe Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Val Arg Arg Arg Leu Tyr Gly Leu Arg Glu Ser Asp Phe Asp Ser
100 105 110
Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser
115 120
<210> 43
<211> 124
<212> PRT
<213> 羊驼 (Lama glama)
<400> 43
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Ser Val Gln Ala Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Thr Phe Ile Ser Phe
20 25 30
Ser Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val
35 40 45
Ala Ser Ile Thr Asn Ser Gly Ser Gly Ile Leu Tyr Gly Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Met Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Ala Gly Thr Gly Ala Gly Arg Tyr Arg Tyr Ala Ser Met Phe Asp
100 105 110
Tyr Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser
115 120
<210> 44
<211> 128
<212> PRT
<213> 羊驼 (Lama glama)
<400> 44
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val His Ala Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Pro Thr Phe Ser Asn Tyr
20 25 30
Phe Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val
35 40 45
Ala Ala Val Lys Trp Ser Gly Tyr His Thr Tyr Tyr Ser Asp Ser Val
50 55 60
Lys Gly Gln Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Ala Gly Gly Thr Phe Ser Asn Trp Tyr Thr Arg Pro Arg Ser Gly
100 105 110
Asp Ser Tyr Asp His Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser
115 120 125
<210> 45
<211> 124
<212> PRT
<213> 羊驼 (Lama glama)
<400> 45
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Thr Phe Ser Pro Tyr
20 25 30
Thr Met Gly Trp Phe Arg Gln Ala Ser Gly Lys Glu Arg Glu Ser Val
35 40 45
Ala Ala Thr Thr Trp Thr Gly Ser Arg Ser Tyr Tyr Gly Glu Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Ser Thr Lys Asn Thr Met Ser
65 70 75 80
Leu Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Ala Ala Asp Gly Ala Gly Leu Tyr Thr Asn Arg Gly Gln Tyr Asp
100 105 110
Tyr Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser
115 120
<210> 46
<211> 123
<212> PRT
<213> 人工序列 (Artificial Sequence)
<220>
<223> 人源化hHS5
<400> 46
Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Thr Phe Thr Thr His
20 25 30
Ala Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val
35 40 45
Ser Ala Ile Asn Trp Gly Gly Arg Thr Thr Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Ile Ile Ser Arg Asp Thr Gly Ala Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Ser Asn Leu Asp Thr Tyr Asn Val Arg Ala Gly Thr Thr Asn Ser
100 105 110
Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser
115 120
<210> 47
<211> 125
<212> PRT
<213> 羊驼 (Lama glama)
<400> 47
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Ser Thr Asp Ser Ala Tyr
20 25 30
Arg Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val
35 40 45
Ser Ala Ile Asn Trp Ser Asp Gly Arg Thr Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Ala Asp Pro Asp Ser Arg Leu Tyr Tyr Thr Val Pro Gln Asn Tyr
100 105 110
Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
115 120 125
<210> 48
<211> 125
<212> PRT
<213> 人工序列 (Artificial Sequence)
<220>
<223> 人源化hHS10
<400> 48
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Ser Thr Asp Ser Ala Tyr
20 25 30
Arg Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val
35 40 45
Ser Ala Ile Asn Trp Ser Asp Gly Arg Thr Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Ala Asp Pro Asp Ser Arg Leu Tyr Tyr Thr Val Pro Gln Asn Tyr
100 105 110
Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
115 120 125
<210> 49
<211> 242
<212> PRT
<213> 智人 (Homo sapiens)
<400> 49
Asp Pro Asn Phe Trp Leu Gln Val Gln Glu Ser Val Thr Val Gln Glu
1 5 10 15
Gly Leu Cys Val Leu Val Pro Cys Thr Phe Phe His Pro Ile Pro Tyr
20 25 30
Tyr Asp Lys Asn Ser Pro Val His Gly Tyr Trp Phe Arg Glu Gly Ala
35 40 45
Ile Ile Ser Arg Asp Ser Pro Val Ala Thr Asn Lys Leu Asp Gln Glu
50 55 60
Val Gln Glu Glu Thr Gln Gly Arg Phe Arg Leu Leu Gly Asp Pro Ser
65 70 75 80
Arg Asn Asn Cys Ser Leu Ser Ile Val Asp Ala Arg Arg Arg Asp Asn
85 90 95
Gly Ser Tyr Phe Phe Arg Met Glu Arg Gly Ser Thr Lys Tyr Ser Tyr
100 105 110
Lys Ser Pro Gln Leu Ser Val His Val Thr Asp Leu Thr His Arg Pro
115 120 125
Lys Ile Leu Ile Pro Gly Thr Leu Glu Pro Gly His Ser Lys Asn Leu
130 135 140
Thr Cys Ser Val Ser Trp Ala Cys Glu Gln Gly Thr Pro Pro Ile Phe
145 150 155 160
Ser Trp Leu Ser Ala Ala Pro Thr Ser Leu Gly Pro Arg Thr Thr His
165 170 175
Ser Ser Val Leu Ile Ile Thr Pro Arg Pro Gln Asp His Gly Thr Asn
180 185 190
Leu Thr Cys Gln Val Lys Phe Ala Gly Ala Gly Val Thr Thr Glu Arg
195 200 205
Thr Ile Gln Leu Asn Val Thr Tyr Val Pro Gln Asn Pro Thr Thr Gly
210 215 220
Ile Phe Pro Gly Asp Gly Ser Gly Lys Gln Glu Thr Arg Ala Gly Val
225 230 235 240
Val His
<210> 50
<211> 123
<212> PRT
<213> 羊驼 (Lama glama)
<400> 50
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Thr Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Gly Thr Phe Thr Asn Tyr
20 25 30
Ala Met Gly Trp Phe Arg Glu Ala Pro Gly Lys Glu Arg Glu Phe Val
35 40 45
Ala Gly Ile Asn Asn Asn Gly Asp Thr Leu Tyr Asn Thr Asn Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr
65 70 75 80
Leu His Met Asn Ser Leu Lys Leu Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Ala Asn Leu Lys Gly Ala Ser Trp Tyr Ser Ala Asn Tyr Asp Tyr
100 105 110
Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser
115 120
<210> 51
<211> 111
<212> PRT
<213> 羊驼 (Lama glama)
<400> 51
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Ala Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Thr Ala Ser Ala Asn Ile Leu Arg Thr Ala
20 25 30
Pro Met Ala Trp Tyr Arg Gln Ala Pro Gly Lys Gln Arg Glu Phe Val
35 40 45
Ala Leu Ile Thr Ala Asp Gly Thr Thr Asp Tyr Gln Glu Ser Val Lys
50 55 60
Gly Arg Phe Thr Thr Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr Leu
65 70 75 80
Gln Met Asn Ser Leu Gln Ser Glu Asp Thr Ala Arg Tyr Phe Cys Lys
85 90 95
Val Tyr Ser Tyr Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser
100 105 110
<210> 52
<211> 118
<212> PRT
<213> 羊驼 (Lama glama)
<400> 52
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Ser Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Glu Ala Ser Gly Ser Ile Phe Ser Ile Ala
20 25 30
His Met Gly Trp Tyr Arg Gln Ala Pro Gly Lys Gln Arg Glu Leu Val
35 40 45
Ala Val Ile Ser Ser Gly Gly Arg Thr Asn Tyr Val Asp Ser Val Lys
50 55 60
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr Leu
65 70 75 80
Gln Met Asn Ser Leu Lys Ala Glu Asp Thr Ala Val Tyr Phe Cys Asn
85 90 95
Val Ala Val Val Gly Gly Pro Arg Phe Asp Tyr Trp Gly Gln Gly Thr
100 105 110
Gln Val Thr Val Ser Ser
115
<210> 53
<211> 119
<212> PRT
<213> 羊驼 (Lama glama)
<400> 53
Glu Val Gln Leu Met Glu Ser Gly Gly Gly Leu Val Gln Ala Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Thr Val Ser Thr Tyr
20 25 30
Val Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val
35 40 45
Ala Glu Ile Asn Arg Ile Gly Asp Thr Leu Tyr Asn Arg Thr Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Glu Pro Glu Asp Thr Ala Val Tyr Ser Cys
85 90 95
Ala Ala Arg Val Ile Gly Thr Ser Thr Tyr Asn Tyr Trp Gly Gln Gly
100 105 110
Thr Gln Val Thr Val Ser Ser
115
<210> 54
<211> 121
<212> PRT
<213> 羊驼 (Lama glama)
<400> 54
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Ala Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Ser Ile Ser Ser Ile Asn
20 25 30
Ser Met Asn Trp Tyr Arg Gln Ala Pro Gly Lys Gln Arg Glu Lys Val
35 40 45
Ala Gly Ile Asn Ser Ser Gly Asp Thr Asn Tyr Val Asp Ser Val Lys
50 55 60
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Glu Arg Thr Thr Tyr Leu
65 70 75 80
Gln Met Asn Asn Leu Lys Pro Glu Asp Thr Gly Leu Tyr Tyr Cys Asn
85 90 95
Ala Asp Pro Arg Pro Trp Pro Asn Asp Val Ala Phe Gly Ser Trp Gly
100 105 110
Gln Gly Thr Arg Val Thr Val Ser Ser
115 120
<210> 55
<211> 117
<212> PRT
<213> 羊驼 (Lama glama)
<400> 55
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Ala Gly Asp
1 5 10 15
Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Arg Thr Ser Leu Ile Leu
20 25 30
Ala Met Ala Trp Trp Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Ala
35 40 45
Gly Arg Ile Trp Trp Asn Asn Asp Met Thr Arg Tyr Ser Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Lys Asp Asn Thr Lys Asn Met Val Tyr
65 70 75 80
Leu Arg Met Asp Asn Leu Gly Pro Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Glu Ala Asp Leu Ile Gly Gly Ser Arg Gly Trp Gly Gln Gly Thr Gln
100 105 110
Val Thr Val Ser Ser
115
<210> 56
<211> 123
<212> PRT
<213> 羊驼 (Lama glama)
<400> 56
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Ala Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Leu Ala Ser Gly Arg Thr Ser Ser Asn Ser
20 25 30
Ala Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val
35 40 45
Gly Ala Ile Thr Trp Asn Gly Asp Thr Thr Leu Tyr Ala Tyr Tyr Val
50 55 60
Lys Asp Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Arg Met Val Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Ala Thr Asp Lys Phe Ala Ser Ser Gln Ala Asp Ser Tyr Thr Thr
100 105 110
Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser
115 120
<210> 57
<211> 123
<212> PRT
<213> 羊驼 (Lama glama)
<400> 57
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Thr Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Gly Thr Phe Thr Asn Tyr
20 25 30
Ala Met Gly Trp Phe Arg Glu Ala Pro Gly Lys Glu Arg Glu Phe Val
35 40 45
Ala Gly Ile Asn Asn Asn Gly Asp Thr Leu Tyr Asn Thr Asn Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr
65 70 75 80
Leu His Met Asn Ser Leu Lys Leu Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Ala Lys Phe Ser Gly Ala Ser Trp Tyr Ser Ala Gln Tyr His Ser
100 105 110
Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser
115 120
<210> 58
<211> 123
<212> PRT
<213> 羊驼 (Lama glama)
<400> 58
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Thr Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Gly Thr Phe Thr Asn Tyr
20 25 30
Ala Met Gly Trp Phe Arg Glu Ala Pro Gly Lys Glu Arg Glu Phe Val
35 40 45
Ala Gly Ile Asn Asn Asn Gly Asp Thr Leu Tyr Asn Thr Asn Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr
65 70 75 80
Leu His Met Asn Ser Leu Lys Leu Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Ala Asn Phe Asn Gly Ala Ser Trp Phe Ala Ala Asn Tyr His Phe
100 105 110
Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser
115 120
<210> 59
<211> 123
<212> PRT
<213> 羊驼 (Lama glama)
<400> 59
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Thr Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Gly Thr Phe Thr Asn Tyr
20 25 30
Ala Met Gly Trp Phe Arg Glu Ala Pro Gly Lys Glu Arg Glu Phe Val
35 40 45
Ala Gly Ile Asn Asn Asn Gly Asp Thr Leu Tyr Asn Thr Asn Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr
65 70 75 80
Leu His Met Asn Ser Leu Lys Leu Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Ala Lys Leu Lys Gly Ala Ser Trp Phe Ala Ser His Tyr Lys Ser
100 105 110
Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser
115 120
<210> 60
<211> 123
<212> PRT
<213> 羊驼 (Lama glama)
<400> 60
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Thr Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Gly Thr Phe Thr Asn Tyr
20 25 30
Ala Met Gly Trp Phe Arg Glu Ala Pro Gly Lys Glu Arg Glu Phe Val
35 40 45
Ala Gly Ile Asn Asn Asn Gly Asp Thr Leu Tyr Asn Thr Asn Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr
65 70 75 80
Leu His Met Asn Ser Leu Lys Leu Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Ala Asn Ile Asn Ala Ala Ser Trp Phe Ala Ala Lys Tyr Asp Ser
100 105 110
Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser
115 120
<210> 61
<211> 123
<212> PRT
<213> 羊驼 (Lama glama)
<400> 61
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Thr Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Gly Thr Phe Thr Asn Tyr
20 25 30
Ala Met Gly Trp Phe Arg Glu Ala Pro Gly Lys Glu Arg Glu Phe Val
35 40 45
Ala Gly Ile Asn Asn Asn Gly Asp Thr Leu Tyr Asn Thr Asn Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr
65 70 75 80
Leu His Met Asn Ser Leu Lys Leu Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Ala Asn Val Arg Gly Ser Ser Trp Phe Ser Ser His Tyr Asp Phe
100 105 110
Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser
115 120
<210> 62
<211> 123
<212> PRT
<213> 羊驼 (Lama glama)
<400> 62
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Thr Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Gly Thr Phe Thr Asn Tyr
20 25 30
Ala Met Gly Trp Phe Arg Glu Ala Pro Gly Lys Glu Arg Glu Phe Val
35 40 45
Ala Gly Ile Asn Asn Asn Gly Asp Thr Leu Tyr Asn Thr Asn Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr
65 70 75 80
Leu His Met Asn Ser Leu Lys Leu Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Ala Asn Leu Ser Gly Ala Ser Trp Phe Ala Ser Gln Tyr Glu Phe
100 105 110
Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser
115 120
<210> 63
<211> 123
<212> PRT
<213> 羊驼 (Lama glama)
<400> 63
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Thr Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Gly Thr Phe Thr Asn Tyr
20 25 30
Ala Met Gly Trp Phe Arg Glu Ala Pro Gly Lys Glu Arg Glu Phe Val
35 40 45
Ala Gly Ile Asn Asn Asn Gly Asp Thr Leu Tyr Asn Thr Asn Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr
65 70 75 80
Leu His Met Asn Ser Leu Lys Leu Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Ala Asn Val Lys Gly Ala Ser Trp Phe Ser Ala Asn Tyr Gln Ser
100 105 110
Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser
115 120
<210> 64
<211> 123
<212> PRT
<213> 羊驼 (Lama glama)
<400> 64
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Thr Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Val Ala Ser Gly Gly Thr Phe Thr Asn Tyr
20 25 30
Ala Met Gly Trp Phe Arg Glu Ala Pro Gly Lys Glu Arg Glu Phe Val
35 40 45
Ala Gly Ile Asn Asn Asn Gly Asp Thr Leu Tyr Asn Thr Asn Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr
65 70 75 80
Leu His Met Asn Ser Leu Lys Leu Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Ala Asn Phe Lys Gly Ala Ser Trp Phe Ala Ser His Tyr Gln Ser
100 105 110
Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser
115 120
<210> 65
<211> 123
<212> PRT
<213> 羊驼 (Lama glama)
<400> 65
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Thr Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Gly Thr Phe Thr Asn Tyr
20 25 30
Ala Met Gly Trp Phe Arg Glu Ala Pro Gly Lys Glu Arg Glu Phe Val
35 40 45
Ala Gly Ile Asn Asn Asn Gly Asp Thr Leu Tyr Asn Thr Asn Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr
65 70 75 80
Leu His Met Asn Ser Leu Lys Leu Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Ala Asn Phe Asn Gly Ala Ser Trp Phe Ser Ser Asn Tyr Glu Tyr
100 105 110
Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser
115 120
<210> 66
<211> 123
<212> PRT
<213> 羊驼 (Lama glama)
<400> 66
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Thr Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Gly Thr Phe Thr Asn Tyr
20 25 30
Ala Met Gly Trp Phe Arg Glu Ala Pro Gly Lys Glu Arg Glu Phe Val
35 40 45
Ala Gly Ile Asn Asn Asn Gly Asp Thr Leu Tyr Asn Thr Asn Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr
65 70 75 80
Leu His Met Asn Ser Leu Lys Leu Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Ala Asn Ile Arg Gly Ser Ser Trp Phe Ala Thr His Tyr Asp Ser
100 105 110
Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser
115 120
<210> 67
<211> 123
<212> PRT
<213> 羊驼 (Lama glama)
<400> 67
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Thr Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Gly Thr Phe Thr Asn Tyr
20 25 30
Ala Met Gly Trp Phe Arg Glu Ala Pro Gly Lys Glu Arg Glu Phe Val
35 40 45
Ala Gly Ile Asn Asn Asn Gly Asp Thr Leu Tyr Asn Thr Asn Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr
65 70 75 80
Leu His Met Asn Ser Leu Lys Leu Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Ala Asn Leu Arg Gly Ala Ser Trp Phe Ala Ala Asn Tyr Lys Tyr
100 105 110
Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser
115 120
<210> 68
<211> 123
<212> PRT
<213> 羊驼 (Lama glama)
<400> 68
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Thr Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Gly Thr Phe Thr Asn Tyr
20 25 30
Ala Met Gly Trp Phe Arg Glu Ala Pro Gly Lys Glu Arg Glu Phe Val
35 40 45
Ala Gly Ile Asn Asn Asn Gly Asp Thr Leu Tyr Asn Thr Asn Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr
65 70 75 80
Leu His Met Asn Ser Leu Lys Leu Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Ala Lys Leu Arg Gly Ala Ser Trp Phe Ala Ala Asn Tyr Asp Ser
100 105 110
Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser
115 120
<210> 69
<211> 123
<212> PRT
<213> 羊驼 (Lama glama)
<400> 69
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Thr Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Gly Thr Phe Thr Asn Tyr
20 25 30
Ala Met Gly Trp Phe Arg Glu Ala Pro Gly Lys Glu Arg Glu Phe Val
35 40 45
Ala Gly Ile Asn Asn Asn Gly Asp Thr Leu Tyr Asn Thr Asn Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr
65 70 75 80
Leu His Met Asn Ser Leu Lys Leu Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Ala Asn Ile Ser Ala Ala Ser Trp Tyr Ala Ser Gln Tyr Asp Phe
100 105 110
Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser
115 120
<210> 70
<211> 123
<212> PRT
<213> 羊驼 (Lama glama)
<400> 70
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Thr Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Gly Thr Phe Thr Asn Tyr
20 25 30
Ala Met Gly Trp Phe Arg Glu Ala Pro Gly Lys Glu Arg Glu Phe Val
35 40 45
Ala Gly Ile Asn Asn Asn Gly Asp Thr Leu Tyr Asn Thr Asn Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr
65 70 75 80
Leu His Met Asn Ser Leu Lys Leu Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Ala Asn Val Ser Gly Ala Ser Trp Tyr Ala Ser His Tyr Glu Phe
100 105 110
Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser
115 120
<210> 71
<211> 123
<212> PRT
<213> 羊驼 (Lama glama)
<400> 71
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Thr Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Gly Thr Phe Thr Asn Tyr
20 25 30
Ala Met Gly Trp Phe Arg Glu Ala Pro Gly Lys Glu Arg Glu Phe Val
35 40 45
Ala Gly Ile Asn Asn Asn Gly Asp Thr Leu Tyr Asn Thr Asn Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr
65 70 75 80
Leu His Met Asn Ser Leu Lys Leu Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Ala Asn Val Ser Glu Ala Ser Trp Phe Ala Ser Lys Tyr Asp Phe
100 105 110
Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser
115 120
<210> 72
<211> 123
<212> PRT
<213> 羊驼 (Lama glama)
<400> 72
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Thr Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Gly Thr Phe Thr Asn Tyr
20 25 30
Ala Met Gly Trp Phe Arg Glu Ala Pro Gly Lys Glu Arg Glu Phe Val
35 40 45
Ala Gly Ile Asn Asn Asn Gly Asp Thr Leu Tyr Asn Thr Asn Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr
65 70 75 80
Leu His Met Asn Ser Leu Lys Leu Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Ala Lys Ile Ser Gly Ala Ser Trp Phe Ala Ala His Tyr Lys Ser
100 105 110
Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser
115 120
<210> 73
<211> 123
<212> PRT
<213> 羊驼 (Lama glama)
<400> 73
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Thr Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Gly Thr Phe Thr Asn Tyr
20 25 30
Ala Met Gly Trp Phe Arg Glu Ala Pro Gly Lys Glu Arg Glu Phe Val
35 40 45
Ala Gly Ile Asn Asn Asn Gly Asp Thr Leu Tyr Asn Thr Asn Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr
65 70 75 80
Leu His Met Asn Ser Leu Lys Leu Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Ala Lys Phe Arg Gly Ala Ser Trp Phe Ser Ser His Tyr Asn Phe
100 105 110
Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser
115 120
<210> 74
<211> 123
<212> PRT
<213> 羊驼 (Lama glama)
<400> 74
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Thr Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Gly Thr Phe Thr Asn Tyr
20 25 30
Ala Met Gly Trp Phe Arg Glu Ala Pro Gly Lys Glu Arg Glu Phe Val
35 40 45
Ala Gly Ile Asn Asn Asn Gly Asp Thr Leu Tyr Asn Thr Asn Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr
65 70 75 80
Leu His Met Asn Ser Leu Lys Leu Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Ala Asn Val Lys Gly Ala Ser Trp Phe Ser Ser Asn Tyr Lys Tyr
100 105 110
Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser
115 120
<210> 75
<211> 123
<212> PRT
<213> 羊驼 (Lama glama)
<400> 75
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Thr Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Gly Thr Phe Thr Asn Tyr
20 25 30
Ala Met Gly Trp Phe Arg Glu Ala Pro Gly Lys Glu Arg Glu Phe Val
35 40 45
Ala Gly Ile Asn Asn Asn Gly Asp Thr Leu Tyr Asn Thr Asn Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr
65 70 75 80
Leu His Met Asn Ser Leu Lys Leu Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Ala Asn Ile Lys Ala Ser Ser Trp Tyr Ser Ser His Tyr Asn Tyr
100 105 110
Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser
115 120
<210> 76
<211> 123
<212> PRT
<213> 羊驼 (Lama glama)
<400> 76
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Thr Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Gly Thr Phe Thr Asn Tyr
20 25 30
Ala Met Gly Trp Phe Arg Glu Ala Pro Gly Lys Glu Arg Glu Phe Val
35 40 45
Ala Gly Ile Asn Asn Asn Gly Asp Thr Leu Tyr Asn Thr Asn Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr
65 70 75 80
Leu His Met Asn Ser Leu Lys Leu Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Ala Asn Val Arg Gly Ala Ser Trp Phe Ala Ala His Tyr Asn Ser
100 105 110
Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser
115 120
<210> 77
<211> 123
<212> PRT
<213> 羊驼 (Lama glama)
<400> 77
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Thr Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Gly Thr Phe Thr Asn Tyr
20 25 30
Ala Met Gly Trp Phe Arg Glu Ala Pro Gly Lys Glu Arg Glu Phe Val
35 40 45
Ala Gly Ile Asn Asn Asn Gly Asp Thr Leu Tyr Asn Thr Asn Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr
65 70 75 80
Leu His Met Asn Ser Leu Lys Leu Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Ala Lys Val Arg Ala Ala Ser Trp Phe Ala Ala Gln Tyr Lys Phe
100 105 110
Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser
115 120
<210> 78
<211> 117
<212> PRT
<213> 人工序列 (Artificial Sequence)
<220>
<223> 人源化h33-14
<400> 78
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Thr Ser Leu Ile Leu
20 25 30
Ala Met Ala Trp Trp Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Ala
35 40 45
Gly Arg Ile Trp Trp Asn Asn Asp Met Thr Arg Tyr Ser Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr
65 70 75 80
Leu Gln Met Ser Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Glu Ala Asp Leu Ile Gly Gly Ser Arg Gly Trp Gly Gln Gly Thr Gln
100 105 110
Val Thr Val Ser Ser
115
<210> 79
<211> 422
<212> PRT
<213> 智人 (Homo sapiens)
<400> 79
Val Pro Val Val Trp Ala Gln Glu Gly Ala Pro Ala Gln Leu Pro Cys
1 5 10 15
Ser Pro Thr Ile Pro Leu Gln Asp Leu Ser Leu Leu Arg Arg Ala Gly
20 25 30
Val Thr Trp Gln His Gln Pro Asp Ser Gly Pro Pro Ala Ala Ala Pro
35 40 45
Gly His Pro Leu Ala Pro Gly Pro His Pro Ala Ala Pro Ser Ser Trp
50 55 60
Gly Pro Arg Pro Arg Arg Tyr Thr Val Leu Ser Val Gly Pro Gly Gly
65 70 75 80
Leu Arg Ser Gly Arg Leu Pro Leu Gln Pro Arg Val Gln Leu Asp Glu
85 90 95
Arg Gly Arg Gln Arg Gly Asp Phe Ser Leu Trp Leu Arg Pro Ala Arg
100 105 110
Arg Ala Asp Ala Gly Glu Tyr Arg Ala Ala Val His Leu Arg Asp Arg
115 120 125
Ala Leu Ser Cys Arg Leu Arg Leu Arg Leu Gly Gln Ala Ser Met Thr
130 135 140
Ala Ser Pro Pro Gly Ser Leu Arg Ala Ser Asp Trp Val Ile Leu Asn
145 150 155 160
Cys Ser Phe Ser Arg Pro Asp Arg Pro Ala Ser Val His Trp Phe Arg
165 170 175
Asn Arg Gly Gln Gly Arg Val Pro Val Arg Glu Ser Pro His His His
180 185 190
Leu Ala Glu Ser Phe Leu Phe Leu Pro Gln Val Ser Pro Met Asp Ser
195 200 205
Gly Pro Trp Gly Cys Ile Leu Thr Tyr Arg Asp Gly Phe Asn Val Ser
210 215 220
Ile Met Tyr Asn Leu Thr Val Leu Gly Leu Glu Pro Pro Thr Pro Leu
225 230 235 240
Thr Val Tyr Ala Gly Ala Gly Ser Arg Val Gly Leu Pro Cys Arg Leu
245 250 255
Pro Ala Gly Val Gly Thr Arg Ser Phe Leu Thr Ala Lys Trp Thr Pro
260 265 270
Pro Gly Gly Gly Pro Asp Leu Leu Val Thr Gly Asp Asn Gly Asp Phe
275 280 285
Thr Leu Arg Leu Glu Asp Val Ser Gln Ala Gln Ala Gly Thr Tyr Thr
290 295 300
Cys His Ile His Leu Gln Glu Gln Gln Leu Asn Ala Thr Val Thr Leu
305 310 315 320
Ala Ile Ile Thr Val Thr Pro Lys Ser Phe Gly Ser Pro Gly Ser Leu
325 330 335
Gly Lys Leu Leu Cys Glu Val Thr Pro Val Ser Gly Gln Glu Arg Phe
340 345 350
Val Trp Ser Ser Leu Asp Thr Pro Ser Gln Arg Ser Phe Ser Gly Pro
355 360 365
Trp Leu Glu Ala Gln Glu Ala Gln Leu Leu Ser Gln Pro Trp Gln Cys
370 375 380
Gln Leu Tyr Gln Gly Glu Arg Leu Leu Gly Ala Ala Val Tyr Phe Thr
385 390 395 400
Glu Leu Ser Ser Pro Gly Ala Gln Arg Ser Gly Arg Ala Pro Gly Ala
405 410 415
Leu Pro Ala Gly His Leu
420
<210> 80
<211> 121
<212> PRT
<213> 羊驼 (Lama glama)
<400> 80
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Thr Ile Phe Ser Ile Asn
20 25 30
Ala Met Gly Trp Tyr Arg Gln Ala Pro Gly Lys Gln Arg Glu Leu Val
35 40 45
Ala Ile Val Thr Phe Gly Gly Ser Thr Asn Tyr Ala Asp Ser Val Lys
50 55 60
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr Leu
65 70 75 80
Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys Ser
85 90 95
Ala Arg Asn Val Gln Ser Pro Val Gln Tyr His Leu Ala Val Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 81
<211> 118
<212> PRT
<213> 羊驼 (Lama glama)
<400> 81
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Ala Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Val Ser Gly Ser Ile Phe Ser Ile Ser
20 25 30
Thr Met Gly Trp Tyr Arg Gln Ala Pro Gly Lys Gln Arg Glu Leu Val
35 40 45
Ala Ser Ile Thr Ala Arg Gly Ser Ala Asp Tyr Ala Asp Ser Val Lys
50 55 60
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr Leu
65 70 75 80
Gln Met Ser Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys Asn
85 90 95
Thr Asp Thr Arg Ser Thr Leu Tyr His Tyr Ser Trp Gly Gln Gly Thr
100 105 110
Gln Val Thr Val Ser Ser
115
<210> 82
<211> 128
<212> PRT
<213> 羊驼 (Lama glama)
<400> 82
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Ser Thr Ile Asp Asp Tyr
20 25 30
Pro Ile Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Gly Val
35 40 45
Ser Cys Ile Asp Asp Ser Asp Glu Ser Thr Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Ala Ile Phe Met Ile Asp Gly Val Asp Val Phe Leu Thr
100 105 110
Tyr Tyr Tyr Asp Ser Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser
115 120 125
<210> 83
<211> 128
<212> PRT
<213> 羊驼 (Lama glama)
<400> 83
Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Ser Thr Ile Asp Asp Tyr
20 25 30
Pro Met Ser Trp Phe Arg Gln Ala Pro Gly Lys Gly Arg Glu Gly Val
35 40 45
Ala Ala Ile Asp Asp Ser Asp Glu Ser Thr Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Ala Ile Phe Met Ile Asp Gly Val Asp Val Phe Leu Thr
100 105 110
Tyr Tyr Tyr Asp Ser Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
115 120 125
<210> 84
<211> 120
<212> PRT
<213> 羊驼 (Lama glama)
<400> 84
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Leu Asp Tyr Tyr
20 25 30
Ala Ile Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Gly Val
35 40 45
Ser Cys Ile Ser Ser Ser Asp Gly Ser Thr Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Ala Asp Arg Arg Gly Ser Cys Arg Gln Tyr Asp Tyr Trp Gly Gln
100 105 110
Gly Thr Gln Val Thr Val Ser Ser
115 120
<210> 85
<211> 121
<212> PRT
<213> 羊驼 (Lama glama)
<400> 85
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Leu Asp Tyr Tyr
20 25 30
Ala Ile Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Gly Val
35 40 45
Ser Cys Ile Ile Asn Ser Asp Gly Ser Thr Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Thr Asp Arg Tyr Ser Asp Cys Arg Gly Pro Tyr Asp Tyr Trp Gly
100 105 110
Gln Gly Thr Gln Val Thr Val Ser Ser
115 120
<210> 86
<211> 121
<212> PRT
<213> 羊驼 (Lama glama)
<400> 86
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Gly Lys Tyr
20 25 30
Ala Met Ser Trp Val Arg Gln Val Pro Asp Lys Gly Leu Glu Trp Val
35 40 45
Ser Ser Ile Ser Ser Ser Gly Arg Asp Thr Ser Tyr Ala Asp Ser Ala
50 55 60
Lys Gly Arg Phe Thr Ile Phe Arg Asn Asn Ala Ala Asn Thr Val Tyr
65 70 75 80
Leu Gln Met Asp Asn Leu Lys Leu Glu Asp Thr Gly Val Tyr Tyr Cys
85 90 95
Val Lys Cys Leu Glu Val Trp Ala Thr Arg Glu Tyr Asp Gly Trp Gly
100 105 110
Gln Gly Thr Gln Val Thr Val Ser Ser
115 120
<210> 87
<211> 128
<212> PRT
<213> 羊驼 (Lama glama)
<400> 87
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val His Pro Gly Gly
1 5 10 15
Ser Leu Asn Leu Ser Cys Val Ala His Gly Phe Ser Leu Asp Ser His
20 25 30
Asp Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Val Val
35 40 45
Ala Cys Ile Lys His Arg Asp Gly Arg Ile Tyr Ile Leu Glu Ala Val
50 55 60
Lys Asp Arg Phe Val Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr
65 70 75 80
Leu Glu Met Asn Asn Leu Ser Asp Glu Asp Thr Ala Val Tyr His Cys
85 90 95
Ala Thr Ala Ser Ser Cys Ser Asp Asn Trp Trp Leu Leu Ile Gly Asp
100 105 110
Ala Tyr Ala Gly Tyr Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser
115 120 125
<210> 88
<211> 115
<212> PRT
<213> 羊驼 (Lama glama)
<400> 88
Glu Val Gln Leu Ala Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Thr Ser Gly Phe Ala Phe Arg Ser Tyr
20 25 30
Val Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Thr Ile Asn Ser Asp Ser Arg Thr Ser Tyr Ala Asp Ser Val Lys
50 55 60
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr Leu
65 70 75 80
Gln Met Asn Ser Leu Lys Val Glu Asp Thr Ala Val Tyr Tyr Cys Ser
85 90 95
Lys Gln Ser Pro Gly Thr Ser Gln Arg Gly Gln Gly Thr Gln Val Thr
100 105 110
Val Ser Ser
115
<210> 89
<211> 129
<212> PRT
<213> 羊驼 (Lama glama)
<400> 89
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Val Ser Gly Phe Thr Ser Ala Thr Tyr
20 25 30
Ser Ile Ala Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Gly Val
35 40 45
Ser Cys Ile Ser Thr Gly Asp Gly Ser Thr Tyr Tyr Ala Pro Ala Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Ser Asp Asn Ala Lys Asn Thr Val Tyr
65 70 75 80
Leu Gln Met Asn Gly Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Lys Arg Ala Gly Tyr Gly Ser Ala Trp Phe Cys Pro Leu Asp Pro
100 105 110
Ser Leu Gln Tyr Asp Ser Trp Gly Gln Gly Thr Gln Val Thr Val Ser
115 120 125
Ser
<210> 90
<211> 128
<212> PRT
<213> 羊驼 (Lama glama)
<400> 90
Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Ser Thr Ile Asp Asp Tyr
20 25 30
Pro Met Ser Trp Phe Arg Gln Ala Pro Gly Lys Gly Arg Glu Gly Val
35 40 45
Ala Ala Ile Asp Asp Ser Asp Glu Ser Thr Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Ala Leu Phe Met Ile Asp Gly Val Asp Val Phe Leu Thr
100 105 110
Tyr Tyr Phe Glu Phe Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
115 120 125
<210> 91
<211> 126
<212> PRT
<213> 羊驼 (Lama glama)
<400> 91
Gln Val Gln Leu Val Glu Ser Gly Gly Arg Leu Val Gln Ala Gly Gly
1 5 10 15
Ser Leu Gly Leu Ser Cys Ala Ala Ser Gly Leu Ala Phe Arg Glu Tyr
20 25 30
Ser Met Gly Trp Phe Arg Arg Ala Pro Gly Lys Glu Arg Glu Phe Val
35 40 45
Ala Ala Val Asp Trp Thr Gly Ile Gln Tyr Tyr Ala Asp Ser Val Lys
50 55 60
Gly Arg Ala Thr Ile Ser Arg Asp Thr Ala Lys Ser Thr Val Phe Leu
65 70 75 80
Gln Met Asn Ser Leu Asn Pro Glu Asp Thr Ala Phe Tyr Tyr Cys Ala
85 90 95
Ala Gly Lys Lys Leu Thr Gly Ile Val Leu Leu Thr Arg Arg Thr Glu
100 105 110
Tyr Asp Tyr Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser
115 120 125
<210> 92
<211> 125
<212> PRT
<213> 羊驼 (Lama glama)
<400> 92
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala His Ser Gly Phe Thr Leu Asp Tyr Tyr
20 25 30
Ala Leu Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Ala Val
35 40 45
Ser Cys Ile Ser Ser Ser Asp Gly Ser Thr Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Ser Thr Arg Tyr Gly Ser Ser Cys Arg Gly Gly Gln Trp Asp Thr
100 105 110
Gly Ser Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser
115 120 125
<210> 93
<211> 125
<212> PRT
<213> 羊驼 (Lama glama)
<400> 93
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Ser Leu Asp Tyr Tyr
20 25 30
Thr Ile Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Ala Val
35 40 45
Ser Cys Ile Asn Arg Ser Asp Gly Ser Thr Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Ser Thr Thr Tyr Gly Thr Ser Cys Arg Gly Gly Gln Trp Asp Thr
100 105 110
Gly Ser Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser
115 120 125
<210> 94
<211> 254
<212> PRT
<213> 智人 (Homo sapiens)
<400> 94
Met Trp Gln Leu Leu Leu Pro Thr Ala Leu Leu Leu Leu Val Ser Ala
1 5 10 15
Gly Met Arg Thr Glu Asp Leu Pro Lys Ala Val Val Phe Leu Glu Pro
20 25 30
Gln Trp Tyr Arg Val Leu Glu Lys Asp Ser Val Thr Leu Lys Cys Gln
35 40 45
Gly Ala Tyr Ser Pro Glu Asp Asn Ser Thr Gln Trp Phe His Asn Glu
50 55 60
Ser Leu Ile Ser Ser Gln Ala Ser Ser Tyr Phe Ile Asp Ala Ala Thr
65 70 75 80
Val Asp Asp Ser Gly Glu Tyr Arg Cys Gln Thr Asn Leu Ser Thr Leu
85 90 95
Ser Asp Pro Val Gln Leu Glu Val His Ile Gly Trp Leu Leu Leu Gln
100 105 110
Ala Pro Arg Trp Val Phe Lys Glu Glu Asp Pro Ile His Leu Arg Cys
115 120 125
His Ser Trp Lys Asn Thr Ala Leu His Lys Val Thr Tyr Leu Gln Asn
130 135 140
Gly Lys Gly Arg Lys Tyr Phe His His Asn Ser Asp Phe Tyr Ile Pro
145 150 155 160
Lys Ala Thr Leu Lys Asp Ser Gly Ser Tyr Phe Cys Arg Gly Leu Phe
165 170 175
Gly Ser Lys Asn Val Ser Ser Glu Thr Val Asn Ile Thr Ile Thr Gln
180 185 190
Gly Leu Ala Val Ser Thr Ile Ser Ser Phe Phe Pro Pro Gly Tyr Gln
195 200 205
Val Ser Phe Cys Leu Val Met Val Leu Leu Phe Ala Val Asp Thr Gly
210 215 220
Leu Tyr Phe Ser Val Lys Thr Asn Ile Arg Ser Ser Thr Arg Asp Trp
225 230 235 240
Lys Asp His Lys Phe Lys Trp Arg Lys Asp Pro Gln Asp Lys
245 250
<210> 95
<211> 233
<212> PRT
<213> 智人 (Homo sapiens)
<400> 95
Met Trp Gln Leu Leu Leu Pro Thr Ala Leu Leu Leu Leu Val Ser Ala
1 5 10 15
Gly Met Arg Thr Glu Asp Leu Pro Lys Ala Val Val Phe Leu Glu Pro
20 25 30
Gln Trp Tyr Ser Val Leu Glu Lys Asp Ser Val Thr Leu Lys Cys Gln
35 40 45
Gly Ala Tyr Ser Pro Glu Asp Asn Ser Thr Gln Trp Phe His Asn Glu
50 55 60
Ser Leu Ile Ser Ser Gln Ala Ser Ser Tyr Phe Ile Asp Ala Ala Thr
65 70 75 80
Val Asn Asp Ser Gly Glu Tyr Arg Cys Gln Thr Asn Leu Ser Thr Leu
85 90 95
Ser Asp Pro Val Gln Leu Glu Val His Ile Gly Trp Leu Leu Leu Gln
100 105 110
Ala Pro Arg Trp Val Phe Lys Glu Glu Asp Pro Ile His Leu Arg Cys
115 120 125
His Ser Trp Lys Asn Thr Ala Leu His Lys Val Thr Tyr Leu Gln Asn
130 135 140
Gly Lys Asp Arg Lys Tyr Phe His His Asn Ser Asp Phe His Ile Pro
145 150 155 160
Lys Ala Thr Leu Lys Asp Ser Gly Ser Tyr Phe Cys Arg Gly Leu Val
165 170 175
Gly Ser Lys Asn Val Ser Ser Glu Thr Val Asn Ile Thr Ile Thr Gln
180 185 190
Gly Leu Ala Val Ser Thr Ile Ser Ser Phe Ser Pro Pro Gly Tyr Gln
195 200 205
Val Ser Phe Cys Leu Val Met Val Leu Leu Phe Ala Val Asp Thr Gly
210 215 220
Leu Tyr Phe Ser Val Lys Thr Asn Ile
225 230
<210> 96
<211> 116
<212> PRT
<213> 羊驼 (Lama glama)
<400> 96
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Val Ser Gly Ser Leu Phe Ser Ala Arg
20 25 30
Val Met Gly Trp Tyr Arg Gln Ala Pro Gly Lys Gln Arg Glu Leu Val
35 40 45
Ala Ala Ile Thr Ser Gly Val Arg Thr Asp Tyr Ala Asp Ser Val Lys
50 55 60
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Arg Ala Val Tyr Leu
65 70 75 80
Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys Asn
85 90 95
Val Asn Leu Tyr Asn Thr Gly Asn Tyr Trp Gly Gln Gly Thr Gln Val
100 105 110
Thr Val Ser Ser
115
<210> 97
<211> 116
<212> PRT
<213> 人工序列 (Artificial Sequence)
<220>
<223> 人源化hCD16F1-1
<400> 97
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Val Ser Gly Ser Leu Phe Ser Ala Arg
20 25 30
Val Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gln Arg Glu Leu Val
35 40 45
Ser Ala Ile Thr Ser Gly Val Arg Thr Tyr Tyr Ala Asp Ser Val Lys
50 55 60
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Arg Ala Val Tyr Leu
65 70 75 80
Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys Asn
85 90 95
Val Asn Leu Tyr Asn Thr Gly Asn Tyr Trp Gly Gln Gly Thr Gln Val
100 105 110
Thr Val Ser Ser
115
<210> 98
<211> 116
<212> PRT
<213> 人工序列 (Artificial Sequence)
<220>
<223> 人源化hCD16F1-2
<400> 98
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Val Ser Gly Ser Leu Phe Ser Ala Arg
20 25 30
Val Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gln Arg Glu Leu Val
35 40 45
Ser Ala Ile Thr Ser Gly Val Arg Thr Tyr Tyr Ala Asp Ser Val Lys
50 55 60
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Arg Ala Val Tyr Leu
65 70 75 80
Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Asn
85 90 95
Val Asn Leu Tyr Asn Thr Gly Asn Tyr Trp Gly Gln Gly Thr Gln Val
100 105 110
Thr Val Ser Ser
115
<210> 99
<211> 119
<212> PRT
<213> 羊驼 (Lama glama)
<400> 99
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Thr Leu Ser Cys Arg Ala Ser Gly Phe Thr Phe Ser Asn His
20 25 30
Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Glu Ile Ser Phe Asn Gly His Ala Thr Arg Tyr Ala Asp Ser Leu
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Thr Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Arg Lys Gly Trp Asn Ala Thr Pro Gln Ile Gly Glu Arg Gly Arg Gly
100 105 110
Thr Gln Val Thr Val Ser Ser
115
<210> 100
<211> 9
<212> PRT
<213> 人工序列 (Artificial Sequence)
<220>
<223> 接头 L1
<400> 100
Gly Gly Gly Gly Ser Gly Gly Gly Ser
1 5
<210> 101
<211> 9
<212> PRT
<213> 人工序列 (Artificial Sequence)
<220>
<223> 接头 L2
<220>
<221> REPEAT
<222> (1)..(5)
<223> 重复= 1-35
<220>
<221> REPEAT
<222> (5)..(9)
<223> 重复= 0-35
<400> 101
Gly Gly Gly Ser Ser Gly Gly Gly Ser
1 5
<210> 102
<211> 3
<212> PRT
<213> 人工序列 (Artificial Sequence)
<220>
<223> 接头 L3
<400> 102
Ala Ala Ala
1
<210> 103
<211> 5
<212> PRT
<213> 人工序列 (Artificial Sequence)
<220>
<223> 接头 L4
<220>
<221> REPEAT
<222> (1)..(5)
<223> 重复= 1-35
<400> 103
Gly Gly Gly Gly Ser
1 5
<210> 104
<211> 18
<212> PRT
<213> 人工序列 (Artificial Sequence)
<220>
<223> 接头 L11*3
<400> 104
Gly Gly Arg Gly Pro Leu Gly Leu Ala Gly Ser Arg Ser Ala Phe Gly
1 5 10 15
Gly Ser
<210> 105
<211> 9
<212> PRT
<213> 人工序列 (Artificial Sequence)
<220>
<223> 接头 L11*4
<400> 105
Gly Ser Pro Leu Gly Leu Ala Gly Ser
1 5
<210> 106
<211> 16
<212> PRT
<213> 人工序列 (Artificial Sequence)
<220>
<223> 接头 L11*5
<400> 106
Gly Gly Ser Gly Pro Leu Gly Leu Ala Gly Ser Arg Ser Ala Phe Gly
1 5 10 15
<210> 107
<211> 18
<212> PRT
<213> 人工序列 (Artificial Sequence)
<220>
<223> 接头 L11*6
<400> 107
Gly Pro Leu Gly Leu Ala Gly Ser Arg Ser Ala Gly Gly Ser Gln Val
1 5 10 15
Gln Leu
<210> 108
<211> 15
<212> PRT
<213> 人工序列 (Artificial Sequence)
<220>
<223> 接头 L11*7
<400> 108
Gly Ser Gly Pro Leu Gly Leu Ala Ala Arg Ser Ala Gly Gly Ser
1 5 10 15
<210> 109
<211> 16
<212> PRT
<213> 人工序列 (Artificial Sequence)
<220>
<223> 接头 L11*8
<400> 109
Gly Ser Gly Pro Leu Gly Leu Ala Ala Arg Ser Ala Phe Gly Gly Ser
1 5 10 15
<210> 110
<211> 21
<212> PRT
<213> 人工序列 (Artificial Sequence)
<220>
<223> 接头 L11*9
<400> 110
Gly Gly Ser Gly Arg Ser Ala Pro Leu Gly Leu Ala Arg Gln Ala Arg
1 5 10 15
Gln Val Gly Gly Ser
20
<210> 111
<211> 19
<212> PRT
<213> 人工序列 (Artificial Sequence)
<220>
<223> 接头 L11*10
<400> 111
Gly Gly Ser Gly Arg Ser Ala Pro Leu Gly Leu Gly Arg Gln Ala Arg
1 5 10 15
Gly Gly Ser
<210> 112
<211> 21
<212> PRT
<213> 人工序列 (Artificial Sequence)
<220>
<223> 接头 L11*11
<400> 112
Gly Gly Ser Pro Leu Gly Leu Ala Arg Gln Ala Arg Gly Ser Gly Arg
1 5 10 15
Ser Ala Gly Gly Ser
20
<210> 113
<211> 21
<212> PRT
<213> 人工序列 (Artificial Sequence)
<220>
<223> 接头 L11*12
<400> 113
Gly Gly Ser Gly Arg Ser Ala Pro Leu Gly Leu Ala Arg Gln Ala Arg
1 5 10 15
Val Val Gly Gly Ser
20
<210> 114
<211> 10
<212> PRT
<213> 人工序列 (Artificial Sequence)
<220>
<223> 接头 L11*13
<400> 114
Gly Ser Arg Gln Ala Arg Val Val Gly Ser
1 5 10
<210> 115
<211> 10
<212> PRT
<213> 人工序列 (Artificial Sequence)
<220>
<223> 接头 L11*14
<400> 115
Gly Ser Arg Gln Arg Arg Val Val Gly Ser
1 5 10
<210> 116
<211> 8
<212> PRT
<213> 人工序列 (Artificial Sequence)
<220>
<223> 接头 L11*15
<400> 116
Gly Ser Arg Gln Ala Arg Gly Ser
1 5
<210> 117
<211> 8
<212> PRT
<213> 人工序列 (Artificial Sequence)
<220>
<223> 接头 L11*16
<400> 117
Gly Ser Arg Gln Arg Arg Gly Ser
1 5
<210> 118
<211> 9
<212> PRT
<213> 人工序列 (Artificial Sequence)
<220>
<223> 接头 L11*17
<400> 118
Gly Ser Arg Gln Ala Arg Gly Gly Ser
1 5
<210> 119
<211> 9
<212> PRT
<213> 人工序列 (Artificial Sequence)
<220>
<223> 接头 L11*18
<400> 119
Gly Ser Arg Gln Arg Arg Gly Gly Ser
1 5
<210> 120
<211> 401
<212> PRT
<213> 人工序列 (Artificial Sequence)
<220>
<223> 三特异性抗体 hHS5-L11*3-hA09-10-2-L1-hPL16
<400> 120
Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Thr Phe Thr Thr His
20 25 30
Ala Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val
35 40 45
Ser Ala Ile Asn Trp Gly Gly Arg Thr Thr Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Ile Ile Ser Arg Asp Thr Gly Ala Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Ser Asn Leu Asp Thr Tyr Asn Val Arg Ala Gly Thr Thr Asn Ser
100 105 110
Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser Gly Gly Ser Pro Leu
115 120 125
Gly Leu Ala Gly Arg Ser Ala Phe Gly Gly Ser Glu Val Gln Leu Val
130 135 140
Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser
145 150 155 160
Cys Ala Ala Ser Gly Gly Gly Arg Thr Phe Ser Asn Tyr Ala Leu Gly
165 170 175
Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val Ala Ala Ile
180 185 190
Ser Arg Ser Gly Gly Asn Ile Asn Tyr Ala Asp Ser Val Lys Gly Arg
195 200 205
Phe Thr Ile Ser Arg Asp Asn Phe Lys Asn Thr Thr Tyr Leu Gln Met
210 215 220
Ser Ser Leu Glu Pro Glu Asp Thr Ala Val Tyr Tyr Cys Ala Ala His
225 230 235 240
Tyr Leu Leu Leu Pro Ser Tyr Ile Ser Thr Ser Thr Asn Met Tyr Asn
245 250 255
Tyr Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser Gly Gly Gly Gly
260 265 270
Ser Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu
275 280 285
Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Gly
290 295 300
Thr Phe Leu Thr Tyr Ser Met Ser Trp Val Arg Gln Ala Pro Gly Lys
305 310 315 320
Glu Arg Glu Phe Val Ser Ser Ile Asn Trp Ser Gly Tyr Met Thr Tyr
325 330 335
Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser
340 345 350
Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr
355 360 365
Ala Val Tyr Tyr Cys Ala Ala Ala Arg Thr Ala Ile Ala Ala Lys Arg
370 375 380
Ser Ser Glu Phe Asp Tyr Trp Gly Gln Gly Thr Gln Val Thr Val Ser
385 390 395 400
Ser
<210> 121
<211> 533
<212> PRT
<213> 人工序列 (Artificial Sequence)
<220>
<223> 三特异性抗体 hHS5-L11*3-hA09-10-2-L3-A09-10-L1-hPL16
<400> 121
Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Thr Phe Thr Thr His
20 25 30
Ala Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val
35 40 45
Ser Ala Ile Asn Trp Gly Gly Arg Thr Thr Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Ile Ile Ser Arg Asp Thr Gly Ala Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Ser Asn Leu Asp Thr Tyr Asn Val Arg Ala Gly Thr Thr Asn Ser
100 105 110
Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser Gly Gly Ser Pro Leu
115 120 125
Gly Leu Ala Gly Arg Ser Ala Phe Gly Gly Ser Glu Val Gln Leu Val
130 135 140
Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser
145 150 155 160
Cys Ala Ala Ser Gly Gly Gly Arg Thr Phe Ser Asn Tyr Ala Leu Gly
165 170 175
Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val Ala Ala Ile
180 185 190
Ser Arg Ser Gly Gly Asn Ile Asn Tyr Ala Asp Ser Val Lys Gly Arg
195 200 205
Phe Thr Ile Ser Arg Asp Asn Phe Lys Asn Thr Thr Tyr Leu Gln Met
210 215 220
Ser Ser Leu Glu Pro Glu Asp Thr Ala Val Tyr Tyr Cys Ala Ala His
225 230 235 240
Tyr Leu Leu Leu Pro Ser Tyr Ile Ser Thr Ser Thr Asn Met Tyr Asn
245 250 255
Tyr Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser Ala Ala Ala Gln
260 265 270
Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Ala Gly Gly Ser
275 280 285
Leu Arg Leu Ser Cys Ala Ala Ser Gly Gly Gly Arg Thr Phe Ser Asn
290 295 300
Tyr Ala Leu Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe
305 310 315 320
Val Ala Ala Ile Ser Arg Ser Gly Gly Asn Ile Asn Tyr Ala Asp Ser
325 330 335
Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Phe Lys Asn Thr Thr
340 345 350
Tyr Leu Gln Met Ser Ser Leu Glu Pro Glu Asp Thr Ala Val Tyr Tyr
355 360 365
Cys Ala Ala His Tyr Leu Leu Leu Pro Ser Tyr Ile Ser Thr Ser Thr
370 375 380
Asn Met Tyr Asn Tyr Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser
385 390 395 400
Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser
405 410 415
Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala
420 425 430
Ala Ser Gly Gly Thr Phe Leu Thr Tyr Ser Met Ser Trp Val Arg Gln
435 440 445
Ala Pro Gly Lys Glu Arg Glu Phe Val Ser Ser Ile Asn Trp Ser Gly
450 455 460
Tyr Met Thr Tyr Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser
465 470 475 480
Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg
485 490 495
Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Ala Ala Arg Thr Ala Ile
500 505 510
Ala Ala Lys Arg Ser Ser Glu Phe Asp Tyr Trp Gly Gln Gly Thr Gln
515 520 525
Val Thr Val Ser Ser
530
<210> 122
<211> 660
<212> PRT
<213> 人工序列 (Artificial Sequence)
<220>
<223> 三特异性抗体 hHS5-L11*3-
hA09-10-2-L3-A09-10-L1-hPL16-L3-hPL16
<400> 122
Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Thr Phe Thr Thr His
20 25 30
Ala Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val
35 40 45
Ser Ala Ile Asn Trp Gly Gly Arg Thr Thr Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Ile Ile Ser Arg Asp Thr Gly Ala Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Ser Asn Leu Asp Thr Tyr Asn Val Arg Ala Gly Thr Thr Asn Ser
100 105 110
Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser Gly Gly Ser Pro Leu
115 120 125
Gly Leu Ala Gly Arg Ser Ala Phe Gly Gly Ser Glu Val Gln Leu Val
130 135 140
Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser
145 150 155 160
Cys Ala Ala Ser Gly Gly Gly Arg Thr Phe Ser Asn Tyr Ala Leu Gly
165 170 175
Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val Ala Ala Ile
180 185 190
Ser Arg Ser Gly Gly Asn Ile Asn Tyr Ala Asp Ser Val Lys Gly Arg
195 200 205
Phe Thr Ile Ser Arg Asp Asn Phe Lys Asn Thr Thr Tyr Leu Gln Met
210 215 220
Ser Ser Leu Glu Pro Glu Asp Thr Ala Val Tyr Tyr Cys Ala Ala His
225 230 235 240
Tyr Leu Leu Leu Pro Ser Tyr Ile Ser Thr Ser Thr Asn Met Tyr Asn
245 250 255
Tyr Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser Ala Ala Ala Gln
260 265 270
Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Ala Gly Gly Ser
275 280 285
Leu Arg Leu Ser Cys Ala Ala Ser Gly Gly Gly Arg Thr Phe Ser Asn
290 295 300
Tyr Ala Leu Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe
305 310 315 320
Val Ala Ala Ile Ser Arg Ser Gly Gly Asn Ile Asn Tyr Ala Asp Ser
325 330 335
Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Phe Lys Asn Thr Thr
340 345 350
Tyr Leu Gln Met Ser Ser Leu Glu Pro Glu Asp Thr Ala Val Tyr Tyr
355 360 365
Cys Ala Ala His Tyr Leu Leu Leu Pro Ser Tyr Ile Ser Thr Ser Thr
370 375 380
Asn Met Tyr Asn Tyr Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser
385 390 395 400
Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser
405 410 415
Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala
420 425 430
Ala Ser Gly Gly Thr Phe Leu Thr Tyr Ser Met Ser Trp Val Arg Gln
435 440 445
Ala Pro Gly Lys Glu Arg Glu Phe Val Ser Ser Ile Asn Trp Ser Gly
450 455 460
Tyr Met Thr Tyr Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser
465 470 475 480
Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg
485 490 495
Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Ala Ala Arg Thr Ala Ile
500 505 510
Ala Ala Lys Arg Ser Ser Glu Phe Asp Tyr Trp Gly Gln Gly Thr Gln
515 520 525
Val Thr Val Ser Ser Ala Ala Ala Glu Val Gln Leu Val Glu Ser Gly
530 535 540
Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala
545 550 555 560
Ser Gly Gly Thr Phe Leu Thr Tyr Ser Met Ser Trp Val Arg Gln Ala
565 570 575
Pro Gly Lys Glu Arg Glu Phe Val Ser Ser Ile Asn Trp Ser Gly Tyr
580 585 590
Met Thr Tyr Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg
595 600 605
Asp Asn Ser Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala
610 615 620
Glu Asp Thr Ala Val Tyr Tyr Cys Ala Ala Ala Arg Thr Ala Ile Ala
625 630 635 640
Ala Lys Arg Ser Ser Glu Phe Asp Tyr Trp Gly Gln Gly Thr Gln Val
645 650 655
Thr Val Ser Ser
660
<210> 123
<211> 394
<212> PRT
<213> 人工序列 (Artificial Sequence)
<220>
<223> 三特异性抗体 hA09 -10-1-L1- hHS5-L1-hPL16
<400> 123
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Gly Gly Arg Thr Phe Ser
20 25 30
Asn Tyr Ala Leu Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu
35 40 45
Phe Val Ala Ala Ile Ser Arg Ser Gly Gly Asn Ile Asn Tyr Ala Asp
50 55 60
Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr
65 70 75 80
Val Tyr Leu Gln Met Ser Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr
85 90 95
Tyr Cys Ala Ala His Tyr Leu Leu Leu Pro Ser Tyr Ile Ser Thr Ser
100 105 110
Thr Asn Met Tyr Asn Tyr Trp Gly Gln Gly Thr Gln Val Thr Val Ser
115 120 125
Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu Val Gln Leu Leu Glu
130 135 140
Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys
145 150 155 160
Ala Ala Ser Gly Arg Thr Phe Thr Thr His Ala Met Gly Trp Phe Arg
165 170 175
Gln Ala Pro Gly Lys Glu Arg Glu Phe Val Ser Ala Ile Asn Trp Gly
180 185 190
Gly Arg Thr Thr Tyr Tyr Ala Asp Ser Val Lys Gly Arg Phe Ile Ile
195 200 205
Ser Arg Asp Thr Gly Ala Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu
210 215 220
Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Ser Asn Leu Asp Thr
225 230 235 240
Tyr Asn Val Arg Ala Gly Thr Thr Asn Ser Trp Gly Gln Gly Thr Gln
245 250 255
Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu Val
260 265 270
Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu
275 280 285
Arg Leu Ser Cys Ala Ala Ser Gly Gly Thr Phe Leu Thr Tyr Ser Met
290 295 300
Ser Trp Val Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val Ser Ser
305 310 315 320
Ile Asn Trp Ser Gly Tyr Met Thr Tyr Tyr Ala Asp Ser Val Lys Gly
325 330 335
Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu Gln
340 345 350
Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Ala
355 360 365
Ala Arg Thr Ala Ile Ala Ala Lys Arg Ser Ser Glu Phe Asp Tyr Trp
370 375 380
Gly Gln Gly Thr Gln Val Thr Val Ser Ser
385 390
<210> 124
<211> 526
<212> PRT
<213> 人工序列 (Artificial Sequence)
<220>
<223> 三特异性抗体 hA09-10-2-L3-A09-10-L1-hHS5-L1-hPL16
<400> 124
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Gly Gly Arg Thr Phe Ser
20 25 30
Asn Tyr Ala Leu Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu
35 40 45
Phe Val Ala Ala Ile Ser Arg Ser Gly Gly Asn Ile Asn Tyr Ala Asp
50 55 60
Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Phe Lys Asn Thr
65 70 75 80
Thr Tyr Leu Gln Met Ser Ser Leu Glu Pro Glu Asp Thr Ala Val Tyr
85 90 95
Tyr Cys Ala Ala His Tyr Leu Leu Leu Pro Ser Tyr Ile Ser Thr Ser
100 105 110
Thr Asn Met Tyr Asn Tyr Trp Gly Gln Gly Thr Gln Val Thr Val Ser
115 120 125
Ser Ala Ala Ala Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val
130 135 140
Gln Ala Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Gly Gly
145 150 155 160
Arg Thr Phe Ser Asn Tyr Ala Leu Gly Trp Phe Arg Gln Ala Pro Gly
165 170 175
Lys Glu Arg Glu Phe Val Ala Ala Ile Ser Arg Ser Gly Gly Asn Ile
180 185 190
Asn Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn
195 200 205
Phe Lys Asn Thr Thr Tyr Leu Gln Met Ser Ser Leu Glu Pro Glu Asp
210 215 220
Thr Ala Val Tyr Tyr Cys Ala Ala His Tyr Leu Leu Leu Pro Ser Tyr
225 230 235 240
Ile Ser Thr Ser Thr Asn Met Tyr Asn Tyr Trp Gly Gln Gly Thr Gln
245 250 255
Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu Val
260 265 270
Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu
275 280 285
Arg Leu Ser Cys Ala Ala Ser Gly Arg Thr Phe Thr Thr His Ala Met
290 295 300
Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val Ser Ala
305 310 315 320
Ile Asn Trp Gly Gly Arg Thr Thr Tyr Tyr Ala Asp Ser Val Lys Gly
325 330 335
Arg Phe Ile Ile Ser Arg Asp Thr Gly Ala Asn Thr Leu Tyr Leu Gln
340 345 350
Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Ser
355 360 365
Asn Leu Asp Thr Tyr Asn Val Arg Ala Gly Thr Thr Asn Ser Trp Gly
370 375 380
Gln Gly Thr Gln Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly
385 390 395 400
Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro
405 410 415
Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Gly Thr Phe Leu
420 425 430
Thr Tyr Ser Met Ser Trp Val Arg Gln Ala Pro Gly Lys Glu Arg Glu
435 440 445
Phe Val Ser Ser Ile Asn Trp Ser Gly Tyr Met Thr Tyr Tyr Ala Asp
450 455 460
Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr
465 470 475 480
Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr
485 490 495
Tyr Cys Ala Ala Ala Arg Thr Ala Ile Ala Ala Lys Arg Ser Ser Glu
500 505 510
Phe Asp Tyr Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser
515 520 525
<210> 125
<211> 653
<212> PRT
<213> 人工序列 (Artificial Sequence)
<220>
<223> 三特异性抗体
hA09-10-2-L3-A09-10-L1-hHS5-L1-hPL16-L3-hPL16
<400> 125
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Gly Gly Arg Thr Phe Ser
20 25 30
Asn Tyr Ala Leu Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu
35 40 45
Phe Val Ala Ala Ile Ser Arg Ser Gly Gly Asn Ile Asn Tyr Ala Asp
50 55 60
Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Phe Lys Asn Thr
65 70 75 80
Thr Tyr Leu Gln Met Ser Ser Leu Glu Pro Glu Asp Thr Ala Val Tyr
85 90 95
Tyr Cys Ala Ala His Tyr Leu Leu Leu Pro Ser Tyr Ile Ser Thr Ser
100 105 110
Thr Asn Met Tyr Asn Tyr Trp Gly Gln Gly Thr Gln Val Thr Val Ser
115 120 125
Ser Ala Ala Ala Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val
130 135 140
Gln Ala Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Gly Gly
145 150 155 160
Arg Thr Phe Ser Asn Tyr Ala Leu Gly Trp Phe Arg Gln Ala Pro Gly
165 170 175
Lys Glu Arg Glu Phe Val Ala Ala Ile Ser Arg Ser Gly Gly Asn Ile
180 185 190
Asn Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn
195 200 205
Phe Lys Asn Thr Thr Tyr Leu Gln Met Ser Ser Leu Glu Pro Glu Asp
210 215 220
Thr Ala Val Tyr Tyr Cys Ala Ala His Tyr Leu Leu Leu Pro Ser Tyr
225 230 235 240
Ile Ser Thr Ser Thr Asn Met Tyr Asn Tyr Trp Gly Gln Gly Thr Gln
245 250 255
Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu Val
260 265 270
Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu
275 280 285
Arg Leu Ser Cys Ala Ala Ser Gly Arg Thr Phe Thr Thr His Ala Met
290 295 300
Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val Ser Ala
305 310 315 320
Ile Asn Trp Gly Gly Arg Thr Thr Tyr Tyr Ala Asp Ser Val Lys Gly
325 330 335
Arg Phe Ile Ile Ser Arg Asp Thr Gly Ala Asn Thr Leu Tyr Leu Gln
340 345 350
Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Ser
355 360 365
Asn Leu Asp Thr Tyr Asn Val Arg Ala Gly Thr Thr Asn Ser Trp Gly
370 375 380
Gln Gly Thr Gln Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly
385 390 395 400
Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro
405 410 415
Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Gly Thr Phe Leu
420 425 430
Thr Tyr Ser Met Ser Trp Val Arg Gln Ala Pro Gly Lys Glu Arg Glu
435 440 445
Phe Val Ser Ser Ile Asn Trp Ser Gly Tyr Met Thr Tyr Tyr Ala Asp
450 455 460
Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr
465 470 475 480
Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr
485 490 495
Tyr Cys Ala Ala Ala Arg Thr Ala Ile Ala Ala Lys Arg Ser Ser Glu
500 505 510
Phe Asp Tyr Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser Ala Ala
515 520 525
Ala Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly
530 535 540
Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Gly Thr Phe Leu Thr
545 550 555 560
Tyr Ser Met Ser Trp Val Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe
565 570 575
Val Ser Ser Ile Asn Trp Ser Gly Tyr Met Thr Tyr Tyr Ala Asp Ser
580 585 590
Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu
595 600 605
Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr
610 615 620
Cys Ala Ala Ala Arg Thr Ala Ile Ala Ala Lys Arg Ser Ser Glu Phe
625 630 635 640
Asp Tyr Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser
645 650
<210> 126
<211> 521
<212> PRT
<213> 人工序列 (Artificial Sequence)
<220>
<223> 三特异性抗体 hA09-10-3-L1-hHS5-L1-hPL16-L3-hPL16
<400> 126
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Gly Gly Arg Thr Phe Ser
20 25 30
Asn Tyr Ala Leu Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu
35 40 45
Phe Val Ala Ala Ile Ser Arg Ser Gly Gly Asn Ile Asn Tyr Ala Asp
50 55 60
Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Phe Lys Asn Thr
65 70 75 80
Val Tyr Leu Gln Met Ser Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr
85 90 95
Tyr Cys Ala Ala His Tyr Leu Leu Leu Pro Ser Tyr Ile Ser Thr Ser
100 105 110
Thr Asn Met Tyr Asn Tyr Trp Gly Gln Gly Thr Gln Val Thr Val Ser
115 120 125
Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu Val Gln Leu Leu Glu
130 135 140
Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys
145 150 155 160
Ala Ala Ser Gly Arg Thr Phe Thr Thr His Ala Met Gly Trp Phe Arg
165 170 175
Gln Ala Pro Gly Lys Glu Arg Glu Phe Val Ser Ala Ile Asn Trp Gly
180 185 190
Gly Arg Thr Thr Tyr Tyr Ala Asp Ser Val Lys Gly Arg Phe Ile Ile
195 200 205
Ser Arg Asp Thr Gly Ala Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu
210 215 220
Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Ser Asn Leu Asp Thr
225 230 235 240
Tyr Asn Val Arg Ala Gly Thr Thr Asn Ser Trp Gly Gln Gly Thr Gln
245 250 255
Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu Val
260 265 270
Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu
275 280 285
Arg Leu Ser Cys Ala Ala Ser Gly Gly Thr Phe Leu Thr Tyr Ser Met
290 295 300
Ser Trp Val Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val Ser Ser
305 310 315 320
Ile Asn Trp Ser Gly Tyr Met Thr Tyr Tyr Ala Asp Ser Val Lys Gly
325 330 335
Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu Gln
340 345 350
Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Ala
355 360 365
Ala Arg Thr Ala Ile Ala Ala Lys Arg Ser Ser Glu Phe Asp Tyr Trp
370 375 380
Gly Gln Gly Thr Gln Val Thr Val Ser Ser Ala Ala Ala Glu Val Gln
385 390 395 400
Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg
405 410 415
Leu Ser Cys Ala Ala Ser Gly Gly Thr Phe Leu Thr Tyr Ser Met Ser
420 425 430
Trp Val Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val Ser Ser Ile
435 440 445
Asn Trp Ser Gly Tyr Met Thr Tyr Tyr Ala Asp Ser Val Lys Gly Arg
450 455 460
Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu Gln Met
465 470 475 480
Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Ala Ala
485 490 495
Arg Thr Ala Ile Ala Ala Lys Arg Ser Ser Glu Phe Asp Tyr Trp Gly
500 505 510
Gln Gly Thr Gln Val Thr Val Ser Ser
515 520
<210> 127
<211> 394
<212> PRT
<213> 人工序列 (Artificial Sequence)
<220>
<223> 三特异性抗体 hHS5-L11*3-hA09-10-3-L1-H33-14
<400> 127
Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Thr Phe Thr Thr His
20 25 30
Ala Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val
35 40 45
Ser Ala Ile Asn Trp Gly Gly Arg Thr Thr Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Ile Ile Ser Arg Asp Thr Gly Ala Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Ser Asn Leu Asp Thr Tyr Asn Val Arg Ala Gly Thr Thr Asn Ser
100 105 110
Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser Gly Gly Ser Pro Leu
115 120 125
Gly Leu Ala Gly Arg Ser Ala Phe Gly Gly Ser Glu Val Gln Leu Val
130 135 140
Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser
145 150 155 160
Cys Ala Ala Ser Gly Gly Gly Arg Thr Phe Ser Asn Tyr Ala Leu Gly
165 170 175
Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val Ala Ala Ile
180 185 190
Ser Arg Ser Gly Gly Asn Ile Asn Tyr Ala Asp Ser Val Lys Gly Arg
195 200 205
Phe Thr Ile Ser Arg Asp Asn Phe Lys Asn Thr Val Tyr Leu Gln Met
210 215 220
Ser Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Ala His
225 230 235 240
Tyr Leu Leu Leu Pro Ser Tyr Ile Ser Thr Ser Thr Asn Met Tyr Asn
245 250 255
Tyr Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser Gly Gly Gly Gly
260 265 270
Ser Gly Gly Gly Ser Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu
275 280 285
Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg
290 295 300
Thr Ser Leu Ile Leu Ala Met Ala Trp Trp Arg Gln Ala Pro Gly Lys
305 310 315 320
Glu Arg Glu Phe Ala Gly Arg Ile Trp Trp Asn Asn Asp Met Thr Arg
325 330 335
Tyr Ser Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala
340 345 350
Lys Asn Thr Val Tyr Leu Gln Met Ser Ser Leu Arg Ala Glu Asp Thr
355 360 365
Ala Val Tyr Tyr Cys Glu Ala Asp Leu Ile Gly Gly Ser Arg Gly Trp
370 375 380
Gly Gln Gly Thr Gln Val Thr Val Ser Ser
385 390
<210> 128
<211> 526
<212> PRT
<213> 人工序列 (Artificial Sequence)
<220>
<223> 三特异性抗体 hHS5-L11*3-hA09-10-2-L3-A09-10-L1-H33-14
<400> 128
Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Thr Phe Thr Thr His
20 25 30
Ala Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val
35 40 45
Ser Ala Ile Asn Trp Gly Gly Arg Thr Thr Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Ile Ile Ser Arg Asp Thr Gly Ala Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Ser Asn Leu Asp Thr Tyr Asn Val Arg Ala Gly Thr Thr Asn Ser
100 105 110
Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser Gly Gly Ser Pro Leu
115 120 125
Gly Leu Ala Gly Arg Ser Ala Phe Gly Gly Ser Glu Val Gln Leu Val
130 135 140
Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser
145 150 155 160
Cys Ala Ala Ser Gly Gly Gly Arg Thr Phe Ser Asn Tyr Ala Leu Gly
165 170 175
Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val Ala Ala Ile
180 185 190
Ser Arg Ser Gly Gly Asn Ile Asn Tyr Ala Asp Ser Val Lys Gly Arg
195 200 205
Phe Thr Ile Ser Arg Asp Asn Phe Lys Asn Thr Thr Tyr Leu Gln Met
210 215 220
Ser Ser Leu Glu Pro Glu Asp Thr Ala Val Tyr Tyr Cys Ala Ala His
225 230 235 240
Tyr Leu Leu Leu Pro Ser Tyr Ile Ser Thr Ser Thr Asn Met Tyr Asn
245 250 255
Tyr Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser Ala Ala Ala Gln
260 265 270
Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Ala Gly Gly Ser
275 280 285
Leu Arg Leu Ser Cys Ala Ala Ser Gly Gly Gly Arg Thr Phe Ser Asn
290 295 300
Tyr Ala Leu Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe
305 310 315 320
Val Ala Ala Ile Ser Arg Ser Gly Gly Asn Ile Asn Tyr Ala Asp Ser
325 330 335
Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Phe Lys Asn Thr Thr
340 345 350
Tyr Leu Gln Met Ser Ser Leu Glu Pro Glu Asp Thr Ala Val Tyr Tyr
355 360 365
Cys Ala Ala His Tyr Leu Leu Leu Pro Ser Tyr Ile Ser Thr Ser Thr
370 375 380
Asn Met Tyr Asn Tyr Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser
385 390 395 400
Gly Gly Gly Gly Ser Gly Gly Gly Ser Gln Val Gln Leu Val Glu Ser
405 410 415
Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala
420 425 430
Ala Ser Gly Arg Thr Ser Leu Ile Leu Ala Met Ala Trp Trp Arg Gln
435 440 445
Ala Pro Gly Lys Glu Arg Glu Phe Ala Gly Arg Ile Trp Trp Asn Asn
450 455 460
Asp Met Thr Arg Tyr Ser Asp Ser Val Lys Gly Arg Phe Thr Ile Ser
465 470 475 480
Arg Asp Asn Ala Lys Asn Thr Val Tyr Leu Gln Met Ser Ser Leu Arg
485 490 495
Ala Glu Asp Thr Ala Val Tyr Tyr Cys Glu Ala Asp Leu Ile Gly Gly
500 505 510
Ser Arg Gly Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser
515 520 525
<210> 129
<211> 639
<212> PRT
<213> 人工序列 (Artificial Sequence)
<220>
<223> 三特异性抗体
hHS5-L1-hA09-10-2-L3-A09-10-L1-H33-14-L3-H33-14
<400> 129
Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Thr Phe Thr Thr His
20 25 30
Ala Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val
35 40 45
Ser Ala Ile Asn Trp Gly Gly Arg Thr Thr Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Ile Ile Ser Arg Asp Thr Gly Ala Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Ser Asn Leu Asp Thr Tyr Asn Val Arg Ala Gly Thr Thr Asn Ser
100 105 110
Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser Gly Gly Gly Gly Ser
115 120 125
Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val
130 135 140
Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Gly Gly
145 150 155 160
Arg Thr Phe Ser Asn Tyr Ala Leu Gly Trp Phe Arg Gln Ala Pro Gly
165 170 175
Lys Glu Arg Glu Phe Val Ala Ala Ile Ser Arg Ser Gly Gly Asn Ile
180 185 190
Asn Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn
195 200 205
Phe Lys Asn Thr Thr Tyr Leu Gln Met Ser Ser Leu Glu Pro Glu Asp
210 215 220
Thr Ala Val Tyr Tyr Cys Ala Ala His Tyr Leu Leu Leu Pro Ser Tyr
225 230 235 240
Ile Ser Thr Ser Thr Asn Met Tyr Asn Tyr Trp Gly Gln Gly Thr Gln
245 250 255
Val Thr Val Ser Ser Ala Ala Ala Gln Val Gln Leu Val Glu Ser Gly
260 265 270
Gly Gly Leu Val Gln Ala Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala
275 280 285
Ser Gly Gly Gly Arg Thr Phe Ser Asn Tyr Ala Leu Gly Trp Phe Arg
290 295 300
Gln Ala Pro Gly Lys Glu Arg Glu Phe Val Ala Ala Ile Ser Arg Ser
305 310 315 320
Gly Gly Asn Ile Asn Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile
325 330 335
Ser Arg Asp Asn Phe Lys Asn Thr Thr Tyr Leu Gln Met Ser Ser Leu
340 345 350
Glu Pro Glu Asp Thr Ala Val Tyr Tyr Cys Ala Ala His Tyr Leu Leu
355 360 365
Leu Pro Ser Tyr Ile Ser Thr Ser Thr Asn Met Tyr Asn Tyr Trp Gly
370 375 380
Gln Gly Thr Gln Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly
385 390 395 400
Gly Ser Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro
405 410 415
Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Thr Ser Leu
420 425 430
Ile Leu Ala Met Ala Trp Trp Arg Gln Ala Pro Gly Lys Glu Arg Glu
435 440 445
Phe Ala Gly Arg Ile Trp Trp Asn Asn Asp Met Thr Arg Tyr Ser Asp
450 455 460
Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr
465 470 475 480
Val Tyr Leu Gln Met Ser Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr
485 490 495
Tyr Cys Glu Ala Asp Leu Ile Gly Gly Ser Arg Gly Trp Gly Gln Gly
500 505 510
Thr Gln Val Thr Val Ser Ser Ala Ala Ala Gln Val Gln Leu Val Glu
515 520 525
Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys
530 535 540
Ala Ala Ser Gly Arg Thr Ser Leu Ile Leu Ala Met Ala Trp Trp Arg
545 550 555 560
Gln Ala Pro Gly Lys Glu Arg Glu Phe Ala Gly Arg Ile Trp Trp Asn
565 570 575
Asn Asp Met Thr Arg Tyr Ser Asp Ser Val Lys Gly Arg Phe Thr Ile
580 585 590
Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr Leu Gln Met Ser Ser Leu
595 600 605
Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Glu Ala Asp Leu Ile Gly
610 615 620
Gly Ser Arg Gly Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser
625 630 635
<210> 130
<211> 646
<212> PRT
<213> 人工序列 (Artificial Sequence)
<220>
<223> 三特异性抗体
hHS5-L11*3-hA09-10-2-L3-A09-10-L1-H33-14-L3-H3-14
<400> 130
Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Thr Phe Thr Thr His
20 25 30
Ala Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val
35 40 45
Ser Ala Ile Asn Trp Gly Gly Arg Thr Thr Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Ile Ile Ser Arg Asp Thr Gly Ala Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Ser Asn Leu Asp Thr Tyr Asn Val Arg Ala Gly Thr Thr Asn Ser
100 105 110
Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser Gly Gly Ser Pro Leu
115 120 125
Gly Leu Ala Gly Arg Ser Ala Phe Gly Gly Ser Glu Val Gln Leu Val
130 135 140
Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser
145 150 155 160
Cys Ala Ala Ser Gly Gly Gly Arg Thr Phe Ser Asn Tyr Ala Leu Gly
165 170 175
Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val Ala Ala Ile
180 185 190
Ser Arg Ser Gly Gly Asn Ile Asn Tyr Ala Asp Ser Val Lys Gly Arg
195 200 205
Phe Thr Ile Ser Arg Asp Asn Phe Lys Asn Thr Thr Tyr Leu Gln Met
210 215 220
Ser Ser Leu Glu Pro Glu Asp Thr Ala Val Tyr Tyr Cys Ala Ala His
225 230 235 240
Tyr Leu Leu Leu Pro Ser Tyr Ile Ser Thr Ser Thr Asn Met Tyr Asn
245 250 255
Tyr Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser Ala Ala Ala Gln
260 265 270
Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Ala Gly Gly Ser
275 280 285
Leu Arg Leu Ser Cys Ala Ala Ser Gly Gly Gly Arg Thr Phe Ser Asn
290 295 300
Tyr Ala Leu Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe
305 310 315 320
Val Ala Ala Ile Ser Arg Ser Gly Gly Asn Ile Asn Tyr Ala Asp Ser
325 330 335
Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Phe Lys Asn Thr Thr
340 345 350
Tyr Leu Gln Met Ser Ser Leu Glu Pro Glu Asp Thr Ala Val Tyr Tyr
355 360 365
Cys Ala Ala His Tyr Leu Leu Leu Pro Ser Tyr Ile Ser Thr Ser Thr
370 375 380
Asn Met Tyr Asn Tyr Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser
385 390 395 400
Gly Gly Gly Gly Ser Gly Gly Gly Ser Gln Val Gln Leu Val Glu Ser
405 410 415
Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala
420 425 430
Ala Ser Gly Arg Thr Ser Leu Ile Leu Ala Met Ala Trp Trp Arg Gln
435 440 445
Ala Pro Gly Lys Glu Arg Glu Phe Ala Gly Arg Ile Trp Trp Asn Asn
450 455 460
Asp Met Thr Arg Tyr Ser Asp Ser Val Lys Gly Arg Phe Thr Ile Ser
465 470 475 480
Arg Asp Asn Ala Lys Asn Thr Val Tyr Leu Gln Met Ser Ser Leu Arg
485 490 495
Ala Glu Asp Thr Ala Val Tyr Tyr Cys Glu Ala Asp Leu Ile Gly Gly
500 505 510
Ser Arg Gly Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser Ala Ala
515 520 525
Ala Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly
530 535 540
Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Thr Ser Leu Ile
545 550 555 560
Leu Ala Met Ala Trp Trp Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe
565 570 575
Ala Gly Arg Ile Trp Trp Asn Asn Asp Met Thr Arg Tyr Ser Asp Ser
580 585 590
Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Val
595 600 605
Tyr Leu Gln Met Ser Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr
610 615 620
Cys Glu Ala Asp Leu Ile Gly Gly Ser Arg Gly Trp Gly Gln Gly Thr
625 630 635 640
Gln Val Thr Val Ser Ser
645
<210> 131
<211> 387
<212> PRT
<213> 人工序列 (Artificial Sequence)
<220>
<223> 三特异性抗体 hA09-10-3-L1-hHS5-L1-H33-14
<400> 131
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Gly Gly Arg Thr Phe Ser
20 25 30
Asn Tyr Ala Leu Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu
35 40 45
Phe Val Ala Ala Ile Ser Arg Ser Gly Gly Asn Ile Asn Tyr Ala Asp
50 55 60
Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Phe Lys Asn Thr
65 70 75 80
Val Tyr Leu Gln Met Ser Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr
85 90 95
Tyr Cys Ala Ala His Tyr Leu Leu Leu Pro Ser Tyr Ile Ser Thr Ser
100 105 110
Thr Asn Met Tyr Asn Tyr Trp Gly Gln Gly Thr Gln Val Thr Val Ser
115 120 125
Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu Val Gln Leu Leu Glu
130 135 140
Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys
145 150 155 160
Ala Ala Ser Gly Arg Thr Phe Thr Thr His Ala Met Gly Trp Phe Arg
165 170 175
Gln Ala Pro Gly Lys Glu Arg Glu Phe Val Ser Ala Ile Asn Trp Gly
180 185 190
Gly Arg Thr Thr Tyr Tyr Ala Asp Ser Val Lys Gly Arg Phe Ile Ile
195 200 205
Ser Arg Asp Thr Gly Ala Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu
210 215 220
Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Ser Asn Leu Asp Thr
225 230 235 240
Tyr Asn Val Arg Ala Gly Thr Thr Asn Ser Trp Gly Gln Gly Thr Gln
245 250 255
Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Gln Val
260 265 270
Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu
275 280 285
Arg Leu Ser Cys Ala Ala Ser Gly Arg Thr Ser Leu Ile Leu Ala Met
290 295 300
Ala Trp Trp Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Ala Gly Arg
305 310 315 320
Ile Trp Trp Asn Asn Asp Met Thr Arg Tyr Ser Asp Ser Val Lys Gly
325 330 335
Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr Leu Gln
340 345 350
Met Ser Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Glu Ala
355 360 365
Asp Leu Ile Gly Gly Ser Arg Gly Trp Gly Gln Gly Thr Gln Val Thr
370 375 380
Val Ser Ser
385
<210> 132
<211> 519
<212> PRT
<213> 人工序列 (Artificial Sequence)
<220>
<223> 三特异性抗体 hA09-10-2-L3-A09-10-L1-hHS5-L1-H33-14
<400> 132
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Gly Gly Arg Thr Phe Ser
20 25 30
Asn Tyr Ala Leu Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu
35 40 45
Phe Val Ala Ala Ile Ser Arg Ser Gly Gly Asn Ile Asn Tyr Ala Asp
50 55 60
Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Phe Lys Asn Thr
65 70 75 80
Thr Tyr Leu Gln Met Ser Ser Leu Glu Pro Glu Asp Thr Ala Val Tyr
85 90 95
Tyr Cys Ala Ala His Tyr Leu Leu Leu Pro Ser Tyr Ile Ser Thr Ser
100 105 110
Thr Asn Met Tyr Asn Tyr Trp Gly Gln Gly Thr Gln Val Thr Val Ser
115 120 125
Ser Ala Ala Ala Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val
130 135 140
Gln Ala Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Gly Gly
145 150 155 160
Arg Thr Phe Ser Asn Tyr Ala Leu Gly Trp Phe Arg Gln Ala Pro Gly
165 170 175
Lys Glu Arg Glu Phe Val Ala Ala Ile Ser Arg Ser Gly Gly Asn Ile
180 185 190
Asn Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn
195 200 205
Phe Lys Asn Thr Thr Tyr Leu Gln Met Ser Ser Leu Glu Pro Glu Asp
210 215 220
Thr Ala Val Tyr Tyr Cys Ala Ala His Tyr Leu Leu Leu Pro Ser Tyr
225 230 235 240
Ile Ser Thr Ser Thr Asn Met Tyr Asn Tyr Trp Gly Gln Gly Thr Gln
245 250 255
Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu Val
260 265 270
Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu
275 280 285
Arg Leu Ser Cys Ala Ala Ser Gly Arg Thr Phe Thr Thr His Ala Met
290 295 300
Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val Ser Ala
305 310 315 320
Ile Asn Trp Gly Gly Arg Thr Thr Tyr Tyr Ala Asp Ser Val Lys Gly
325 330 335
Arg Phe Ile Ile Ser Arg Asp Thr Gly Ala Asn Thr Leu Tyr Leu Gln
340 345 350
Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Ser
355 360 365
Asn Leu Asp Thr Tyr Asn Val Arg Ala Gly Thr Thr Asn Ser Trp Gly
370 375 380
Gln Gly Thr Gln Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly
385 390 395 400
Gly Ser Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro
405 410 415
Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Thr Ser Leu
420 425 430
Ile Leu Ala Met Ala Trp Trp Arg Gln Ala Pro Gly Lys Glu Arg Glu
435 440 445
Phe Ala Gly Arg Ile Trp Trp Asn Asn Asp Met Thr Arg Tyr Ser Asp
450 455 460
Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr
465 470 475 480
Val Tyr Leu Gln Met Ser Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr
485 490 495
Tyr Cys Glu Ala Asp Leu Ile Gly Gly Ser Arg Gly Trp Gly Gln Gly
500 505 510
Thr Gln Val Thr Val Ser Ser
515
<210> 133
<211> 507
<212> PRT
<213> 人工序列 (Artificial Sequence)
<220>
<223> 三特异性抗体 hA09-10-L1-hHS5-L1-H33-14-L3-H33-14
<400> 133
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Gly Gly Arg Thr Phe Ser
20 25 30
Asn Tyr Ala Leu Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu
35 40 45
Phe Val Ala Ala Ile Ser Arg Ser Gly Gly Asn Ile Asn Tyr Ala Asp
50 55 60
Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr
65 70 75 80
Val Tyr Leu Gln Met Ser Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr
85 90 95
Tyr Cys Ala Ala His Tyr Leu Leu Leu Pro Ser Tyr Ile Ser Thr Ser
100 105 110
Thr Asn Met Tyr Asn Tyr Trp Gly Gln Gly Thr Gln Val Thr Val Ser
115 120 125
Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu Val Gln Leu Leu Glu
130 135 140
Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys
145 150 155 160
Ala Ala Ser Gly Arg Thr Phe Thr Thr His Ala Met Gly Trp Phe Arg
165 170 175
Gln Ala Pro Gly Lys Glu Arg Glu Phe Val Ser Ala Ile Asn Trp Gly
180 185 190
Gly Arg Thr Thr Tyr Tyr Ala Asp Ser Val Lys Gly Arg Phe Ile Ile
195 200 205
Ser Arg Asp Thr Gly Ala Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu
210 215 220
Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Ser Asn Leu Asp Thr
225 230 235 240
Tyr Asn Val Arg Ala Gly Thr Thr Asn Ser Trp Gly Gln Gly Thr Gln
245 250 255
Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Gln Val
260 265 270
Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu
275 280 285
Arg Leu Ser Cys Ala Ala Ser Gly Arg Thr Ser Leu Ile Leu Ala Met
290 295 300
Ala Trp Trp Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Ala Gly Arg
305 310 315 320
Ile Trp Trp Asn Asn Asp Met Thr Arg Tyr Ser Asp Ser Val Lys Gly
325 330 335
Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr Leu Gln
340 345 350
Met Ser Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Glu Ala
355 360 365
Asp Leu Ile Gly Gly Ser Arg Gly Trp Gly Gln Gly Thr Gln Val Thr
370 375 380
Val Ser Ser Ala Ala Ala Gln Val Gln Leu Val Glu Ser Gly Gly Gly
385 390 395 400
Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly
405 410 415
Arg Thr Ser Leu Ile Leu Ala Met Ala Trp Trp Arg Gln Ala Pro Gly
420 425 430
Lys Glu Arg Glu Phe Ala Gly Arg Ile Trp Trp Asn Asn Asp Met Thr
435 440 445
Arg Tyr Ser Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn
450 455 460
Ala Lys Asn Thr Val Tyr Leu Gln Met Ser Ser Leu Arg Ala Glu Asp
465 470 475 480
Thr Ala Val Tyr Tyr Cys Glu Ala Asp Leu Ile Gly Gly Ser Arg Gly
485 490 495
Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser
500 505
<210> 134
<211> 639
<212> PRT
<213> 人工序列 (Artificial Sequence)
<220>
<223> 三特异性抗体
hA09-10-2-L3-A09-10-L1-hHS5-L1-H33-14-L3-H33-14
<400> 134
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Gly Gly Arg Thr Phe Ser
20 25 30
Asn Tyr Ala Leu Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu
35 40 45
Phe Val Ala Ala Ile Ser Arg Ser Gly Gly Asn Ile Asn Tyr Ala Asp
50 55 60
Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Phe Lys Asn Thr
65 70 75 80
Thr Tyr Leu Gln Met Ser Ser Leu Glu Pro Glu Asp Thr Ala Val Tyr
85 90 95
Tyr Cys Ala Ala His Tyr Leu Leu Leu Pro Ser Tyr Ile Ser Thr Ser
100 105 110
Thr Asn Met Tyr Asn Tyr Trp Gly Gln Gly Thr Gln Val Thr Val Ser
115 120 125
Ser Ala Ala Ala Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val
130 135 140
Gln Ala Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Gly Gly
145 150 155 160
Arg Thr Phe Ser Asn Tyr Ala Leu Gly Trp Phe Arg Gln Ala Pro Gly
165 170 175
Lys Glu Arg Glu Phe Val Ala Ala Ile Ser Arg Ser Gly Gly Asn Ile
180 185 190
Asn Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn
195 200 205
Phe Lys Asn Thr Thr Tyr Leu Gln Met Ser Ser Leu Glu Pro Glu Asp
210 215 220
Thr Ala Val Tyr Tyr Cys Ala Ala His Tyr Leu Leu Leu Pro Ser Tyr
225 230 235 240
Ile Ser Thr Ser Thr Asn Met Tyr Asn Tyr Trp Gly Gln Gly Thr Gln
245 250 255
Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu Val
260 265 270
Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu
275 280 285
Arg Leu Ser Cys Ala Ala Ser Gly Arg Thr Phe Thr Thr His Ala Met
290 295 300
Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val Ser Ala
305 310 315 320
Ile Asn Trp Gly Gly Arg Thr Thr Tyr Tyr Ala Asp Ser Val Lys Gly
325 330 335
Arg Phe Ile Ile Ser Arg Asp Thr Gly Ala Asn Thr Leu Tyr Leu Gln
340 345 350
Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Ser
355 360 365
Asn Leu Asp Thr Tyr Asn Val Arg Ala Gly Thr Thr Asn Ser Trp Gly
370 375 380
Gln Gly Thr Gln Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly
385 390 395 400
Gly Ser Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro
405 410 415
Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Thr Ser Leu
420 425 430
Ile Leu Ala Met Ala Trp Trp Arg Gln Ala Pro Gly Lys Glu Arg Glu
435 440 445
Phe Ala Gly Arg Ile Trp Trp Asn Asn Asp Met Thr Arg Tyr Ser Asp
450 455 460
Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr
465 470 475 480
Val Tyr Leu Gln Met Ser Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr
485 490 495
Tyr Cys Glu Ala Asp Leu Ile Gly Gly Ser Arg Gly Trp Gly Gln Gly
500 505 510
Thr Gln Val Thr Val Ser Ser Ala Ala Ala Gln Val Gln Leu Val Glu
515 520 525
Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys
530 535 540
Ala Ala Ser Gly Arg Thr Ser Leu Ile Leu Ala Met Ala Trp Trp Arg
545 550 555 560
Gln Ala Pro Gly Lys Glu Arg Glu Phe Ala Gly Arg Ile Trp Trp Asn
565 570 575
Asn Asp Met Thr Arg Tyr Ser Asp Ser Val Lys Gly Arg Phe Thr Ile
580 585 590
Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr Leu Gln Met Ser Ser Leu
595 600 605
Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Glu Ala Asp Leu Ile Gly
610 615 620
Gly Ser Arg Gly Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser
625 630 635
<210> 135
<211> 374
<212> PRT
<213> 人工序列 (Artificial Sequence)
<220>
<223> 三特异性抗体 H33-14-L1-hHS5-L1-CD16F1
<400> 135
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Thr Ser Leu Ile Leu
20 25 30
Ala Met Ala Trp Trp Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Ala
35 40 45
Gly Arg Ile Trp Trp Asn Asn Asp Met Thr Arg Tyr Ser Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr
65 70 75 80
Leu Gln Met Ser Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Glu Ala Asp Leu Ile Gly Gly Ser Arg Gly Trp Gly Gln Gly Thr Gln
100 105 110
Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu Val
115 120 125
Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu
130 135 140
Arg Leu Ser Cys Ala Ala Ser Gly Arg Thr Phe Thr Thr His Ala Met
145 150 155 160
Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val Ser Ala
165 170 175
Ile Asn Trp Gly Gly Arg Thr Thr Tyr Tyr Ala Asp Ser Val Lys Gly
180 185 190
Arg Phe Ile Ile Ser Arg Asp Thr Gly Ala Asn Thr Leu Tyr Leu Gln
195 200 205
Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Ser
210 215 220
Asn Leu Asp Thr Tyr Asn Val Arg Ala Gly Thr Thr Asn Ser Trp Gly
225 230 235 240
Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly
245 250 255
Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro
260 265 270
Gly Gly Ser Leu Arg Leu Ser Cys Ala Val Ser Gly Ser Leu Phe Ser
275 280 285
Ala Arg Val Met Gly Trp Tyr Arg Gln Ala Pro Gly Lys Gln Arg Glu
290 295 300
Leu Val Ala Ala Ile Thr Ser Gly Val Arg Thr Asp Tyr Ala Asp Ser
305 310 315 320
Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Arg Ala Val
325 330 335
Tyr Leu Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr
340 345 350
Cys Asn Val Asn Leu Tyr Asn Thr Gly Asn Tyr Trp Gly Gln Gly Thr
355 360 365
Gln Val Thr Val Ser Ser
370
<210> 136
<211> 493
<212> PRT
<213> 人工序列 (Artificial Sequence)
<220>
<223> 三特异性抗体 H33-14-L1-hHS5-L1-CD16F1-L3-CD16F1
<400> 136
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Thr Ser Leu Ile Leu
20 25 30
Ala Met Ala Trp Trp Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Ala
35 40 45
Gly Arg Ile Trp Trp Asn Asn Asp Met Thr Arg Tyr Ser Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr
65 70 75 80
Leu Gln Met Ser Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Glu Ala Asp Leu Ile Gly Gly Ser Arg Gly Trp Gly Gln Gly Thr Gln
100 105 110
Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu Val
115 120 125
Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu
130 135 140
Arg Leu Ser Cys Ala Ala Ser Gly Arg Thr Phe Thr Thr His Ala Met
145 150 155 160
Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val Ser Ala
165 170 175
Ile Asn Trp Gly Gly Arg Thr Thr Tyr Tyr Ala Asp Ser Val Lys Gly
180 185 190
Arg Phe Ile Ile Ser Arg Asp Thr Gly Ala Asn Thr Leu Tyr Leu Gln
195 200 205
Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Ser
210 215 220
Asn Leu Asp Thr Tyr Asn Val Arg Ala Gly Thr Thr Asn Ser Trp Gly
225 230 235 240
Gln Gly Thr Gln Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly
245 250 255
Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro
260 265 270
Gly Gly Ser Leu Arg Leu Ser Cys Ala Val Ser Gly Ser Leu Phe Ser
275 280 285
Ala Arg Val Met Gly Trp Tyr Arg Gln Ala Pro Gly Lys Gln Arg Glu
290 295 300
Leu Val Ala Ala Ile Thr Ser Gly Val Arg Thr Asp Tyr Ala Asp Ser
305 310 315 320
Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Arg Ala Val
325 330 335
Tyr Leu Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr
340 345 350
Cys Asn Val Asn Leu Tyr Asn Thr Gly Asn Tyr Trp Gly Gln Gly Thr
355 360 365
Gln Val Thr Val Ser Ser Ala Ala Ala Glu Val Gln Leu Val Glu Ser
370 375 380
Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala
385 390 395 400
Val Ser Gly Ser Leu Phe Ser Ala Arg Val Met Gly Trp Tyr Arg Gln
405 410 415
Ala Pro Gly Lys Gln Arg Glu Leu Val Ala Ala Ile Thr Ser Gly Val
420 425 430
Arg Thr Asp Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg
435 440 445
Asp Asn Ala Lys Arg Ala Val Tyr Leu Gln Met Asn Ser Leu Lys Pro
450 455 460
Glu Asp Thr Ala Val Tyr Tyr Cys Asn Val Asn Leu Tyr Asn Thr Gly
465 470 475 480
Asn Tyr Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser
485 490
<210> 137
<211> 494
<212> PRT
<213> 人工序列 (Artificial Sequence)
<220>
<223> 三特异性抗体 H33-14-L3-H33-14-L1-hHS5-L1-CD16F1
<400> 137
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Thr Ser Leu Ile Leu
20 25 30
Ala Met Ala Trp Trp Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Ala
35 40 45
Gly Arg Ile Trp Trp Asn Asn Asp Met Thr Arg Tyr Ser Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr
65 70 75 80
Leu Gln Met Ser Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Glu Ala Asp Leu Ile Gly Gly Ser Arg Gly Trp Gly Gln Gly Thr Gln
100 105 110
Val Thr Val Ser Ser Ala Ala Ala Gln Val Gln Leu Val Glu Ser Gly
115 120 125
Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala
130 135 140
Ser Gly Arg Thr Ser Leu Ile Leu Ala Met Ala Trp Trp Arg Gln Ala
145 150 155 160
Pro Gly Lys Glu Arg Glu Phe Ala Gly Arg Ile Trp Trp Asn Asn Asp
165 170 175
Met Thr Arg Tyr Ser Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg
180 185 190
Asp Asn Ala Lys Asn Thr Val Tyr Leu Gln Met Ser Ser Leu Arg Ala
195 200 205
Glu Asp Thr Ala Val Tyr Tyr Cys Glu Ala Asp Leu Ile Gly Gly Ser
210 215 220
Arg Gly Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser Gly Gly Gly
225 230 235 240
Gly Ser Gly Gly Gly Ser Glu Val Gln Leu Leu Glu Ser Gly Gly Gly
245 250 255
Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly
260 265 270
Arg Thr Phe Thr Thr His Ala Met Gly Trp Phe Arg Gln Ala Pro Gly
275 280 285
Lys Glu Arg Glu Phe Val Ser Ala Ile Asn Trp Gly Gly Arg Thr Thr
290 295 300
Tyr Tyr Ala Asp Ser Val Lys Gly Arg Phe Ile Ile Ser Arg Asp Thr
305 310 315 320
Gly Ala Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp
325 330 335
Thr Ala Val Tyr Tyr Cys Ala Ser Asn Leu Asp Thr Tyr Asn Val Arg
340 345 350
Ala Gly Thr Thr Asn Ser Trp Gly Gln Gly Thr Gln Val Thr Val Ser
355 360 365
Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu Val Gln Leu Val Glu
370 375 380
Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys
385 390 395 400
Ala Val Ser Gly Ser Leu Phe Ser Ala Arg Val Met Gly Trp Tyr Arg
405 410 415
Gln Ala Pro Gly Lys Gln Arg Glu Leu Val Ala Ala Ile Thr Ser Gly
420 425 430
Val Arg Thr Asp Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser
435 440 445
Arg Asp Asn Ala Lys Arg Ala Val Tyr Leu Gln Met Asn Ser Leu Lys
450 455 460
Pro Glu Asp Thr Ala Val Tyr Tyr Cys Asn Val Asn Leu Tyr Asn Thr
465 470 475 480
Gly Asn Tyr Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser
485 490
<210> 138
<211> 613
<212> PRT
<213> 人工序列 (Artificial Sequence)
<220>
<223> 三特异性抗体 H33-14-L3-H33-14-L1-hHS5-L1-CD16F1-L3-CD16F1
<400> 138
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Thr Ser Leu Ile Leu
20 25 30
Ala Met Ala Trp Trp Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Ala
35 40 45
Gly Arg Ile Trp Trp Asn Asn Asp Met Thr Arg Tyr Ser Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr
65 70 75 80
Leu Gln Met Ser Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Glu Ala Asp Leu Ile Gly Gly Ser Arg Gly Trp Gly Gln Gly Thr Gln
100 105 110
Val Thr Val Ser Ser Ala Ala Ala Gln Val Gln Leu Val Glu Ser Gly
115 120 125
Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala
130 135 140
Ser Gly Arg Thr Ser Leu Ile Leu Ala Met Ala Trp Trp Arg Gln Ala
145 150 155 160
Pro Gly Lys Glu Arg Glu Phe Ala Gly Arg Ile Trp Trp Asn Asn Asp
165 170 175
Met Thr Arg Tyr Ser Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg
180 185 190
Asp Asn Ala Lys Asn Thr Val Tyr Leu Gln Met Ser Ser Leu Arg Ala
195 200 205
Glu Asp Thr Ala Val Tyr Tyr Cys Glu Ala Asp Leu Ile Gly Gly Ser
210 215 220
Arg Gly Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser Gly Gly Gly
225 230 235 240
Gly Ser Gly Gly Gly Ser Glu Val Gln Leu Leu Glu Ser Gly Gly Gly
245 250 255
Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly
260 265 270
Arg Thr Phe Thr Thr His Ala Met Gly Trp Phe Arg Gln Ala Pro Gly
275 280 285
Lys Glu Arg Glu Phe Val Ser Ala Ile Asn Trp Gly Gly Arg Thr Thr
290 295 300
Tyr Tyr Ala Asp Ser Val Lys Gly Arg Phe Ile Ile Ser Arg Asp Thr
305 310 315 320
Gly Ala Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp
325 330 335
Thr Ala Val Tyr Tyr Cys Ala Ser Asn Leu Asp Thr Tyr Asn Val Arg
340 345 350
Ala Gly Thr Thr Asn Ser Trp Gly Gln Gly Thr Gln Val Thr Val Ser
355 360 365
Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu Val Gln Leu Val Glu
370 375 380
Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys
385 390 395 400
Ala Val Ser Gly Ser Leu Phe Ser Ala Arg Val Met Gly Trp Tyr Arg
405 410 415
Gln Ala Pro Gly Lys Gln Arg Glu Leu Val Ala Ala Ile Thr Ser Gly
420 425 430
Val Arg Thr Asp Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser
435 440 445
Arg Asp Asn Ala Lys Arg Ala Val Tyr Leu Gln Met Asn Ser Leu Lys
450 455 460
Pro Glu Asp Thr Ala Val Tyr Tyr Cys Asn Val Asn Leu Tyr Asn Thr
465 470 475 480
Gly Asn Tyr Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser Ala Ala
485 490 495
Ala Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly
500 505 510
Gly Ser Leu Arg Leu Ser Cys Ala Val Ser Gly Ser Leu Phe Ser Ala
515 520 525
Arg Val Met Gly Trp Tyr Arg Gln Ala Pro Gly Lys Gln Arg Glu Leu
530 535 540
Val Ala Ala Ile Thr Ser Gly Val Arg Thr Asp Tyr Ala Asp Ser Val
545 550 555 560
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Arg Ala Val Tyr
565 570 575
Leu Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys
580 585 590
Asn Val Asn Leu Tyr Asn Thr Gly Asn Tyr Trp Gly Gln Gly Thr Gln
595 600 605
Val Thr Val Ser Ser
610
<210> 139
<211> 381
<212> PRT
<213> 人工序列 (Artificial Sequence)
<220>
<223> 三特异性抗体 hPL16-L1-hHS5-L1-CD16F1
<400> 139
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Gly Thr Phe Leu Thr Tyr
20 25 30
Ser Met Ser Trp Val Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val
35 40 45
Ser Ser Ile Asn Trp Ser Gly Tyr Met Thr Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Ala Ala Arg Thr Ala Ile Ala Ala Lys Arg Ser Ser Glu Phe Asp
100 105 110
Tyr Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser Gly Gly Gly Gly
115 120 125
Ser Gly Gly Gly Ser Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu
130 135 140
Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg
145 150 155 160
Thr Phe Thr Thr His Ala Met Gly Trp Phe Arg Gln Ala Pro Gly Lys
165 170 175
Glu Arg Glu Phe Val Ser Ala Ile Asn Trp Gly Gly Arg Thr Thr Tyr
180 185 190
Tyr Ala Asp Ser Val Lys Gly Arg Phe Ile Ile Ser Arg Asp Thr Gly
195 200 205
Ala Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr
210 215 220
Ala Val Tyr Tyr Cys Ala Ser Asn Leu Asp Thr Tyr Asn Val Arg Ala
225 230 235 240
Gly Thr Thr Asn Ser Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser
245 250 255
Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser
260 265 270
Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala
275 280 285
Val Ser Gly Ser Leu Phe Ser Ala Arg Val Met Gly Trp Tyr Arg Gln
290 295 300
Ala Pro Gly Lys Gln Arg Glu Leu Val Ala Ala Ile Thr Ser Gly Val
305 310 315 320
Arg Thr Asp Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg
325 330 335
Asp Asn Ala Lys Arg Ala Val Tyr Leu Gln Met Asn Ser Leu Lys Pro
340 345 350
Glu Asp Thr Ala Val Tyr Tyr Cys Asn Val Asn Leu Tyr Asn Thr Gly
355 360 365
Asn Tyr Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser
370 375 380
<210> 140
<211> 508
<212> PRT
<213> 人工序列 (Artificial Sequence)
<220>
<223> 三特异性抗体 hPL16-L3-hPL16-L1-hHS5-L1-CD16F1
<400> 140
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Gly Thr Phe Leu Thr Tyr
20 25 30
Ser Met Ser Trp Val Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val
35 40 45
Ser Ser Ile Asn Trp Ser Gly Tyr Met Thr Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Ala Ala Arg Thr Ala Ile Ala Ala Lys Arg Ser Ser Glu Phe Asp
100 105 110
Tyr Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser Ala Ala Ala Glu
115 120 125
Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser
130 135 140
Leu Arg Leu Ser Cys Ala Ala Ser Gly Gly Thr Phe Leu Thr Tyr Ser
145 150 155 160
Met Ser Trp Val Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val Ser
165 170 175
Ser Ile Asn Trp Ser Gly Tyr Met Thr Tyr Tyr Ala Asp Ser Val Lys
180 185 190
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu
195 200 205
Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala
210 215 220
Ala Ala Arg Thr Ala Ile Ala Ala Lys Arg Ser Ser Glu Phe Asp Tyr
225 230 235 240
Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser Gly Gly Gly Gly Ser
245 250 255
Gly Gly Gly Ser Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val
260 265 270
Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Thr
275 280 285
Phe Thr Thr His Ala Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu
290 295 300
Arg Glu Phe Val Ser Ala Ile Asn Trp Gly Gly Arg Thr Thr Tyr Tyr
305 310 315 320
Ala Asp Ser Val Lys Gly Arg Phe Ile Ile Ser Arg Asp Thr Gly Ala
325 330 335
Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala
340 345 350
Val Tyr Tyr Cys Ala Ser Asn Leu Asp Thr Tyr Asn Val Arg Ala Gly
355 360 365
Thr Thr Asn Ser Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser Gly
370 375 380
Gly Gly Gly Ser Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly
385 390 395 400
Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Val
405 410 415
Ser Gly Ser Leu Phe Ser Ala Arg Val Met Gly Trp Tyr Arg Gln Ala
420 425 430
Pro Gly Lys Gln Arg Glu Leu Val Ala Ala Ile Thr Ser Gly Val Arg
435 440 445
Thr Asp Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp
450 455 460
Asn Ala Lys Arg Ala Val Tyr Leu Gln Met Asn Ser Leu Lys Pro Glu
465 470 475 480
Asp Thr Ala Val Tyr Tyr Cys Asn Val Asn Leu Tyr Asn Thr Gly Asn
485 490 495
Tyr Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser
500 505
<210> 141
<211> 500
<212> PRT
<213> 人工序列 (Artificial Sequence)
<220>
<223> 三特异性抗体 hPL16-L1-hHS5-L1-CD16F1-L3-CD16F1
<400> 141
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Gly Thr Phe Leu Thr Tyr
20 25 30
Ser Met Ser Trp Val Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val
35 40 45
Ser Ser Ile Asn Trp Ser Gly Tyr Met Thr Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Ala Ala Arg Thr Ala Ile Ala Ala Lys Arg Ser Ser Glu Phe Asp
100 105 110
Tyr Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser Gly Gly Gly Gly
115 120 125
Ser Gly Gly Gly Ser Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu
130 135 140
Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg
145 150 155 160
Thr Phe Thr Thr His Ala Met Gly Trp Phe Arg Gln Ala Pro Gly Lys
165 170 175
Glu Arg Glu Phe Val Ser Ala Ile Asn Trp Gly Gly Arg Thr Thr Tyr
180 185 190
Tyr Ala Asp Ser Val Lys Gly Arg Phe Ile Ile Ser Arg Asp Thr Gly
195 200 205
Ala Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr
210 215 220
Ala Val Tyr Tyr Cys Ala Ser Asn Leu Asp Thr Tyr Asn Val Arg Ala
225 230 235 240
Gly Thr Thr Asn Ser Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser
245 250 255
Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser
260 265 270
Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala
275 280 285
Val Ser Gly Ser Leu Phe Ser Ala Arg Val Met Gly Trp Tyr Arg Gln
290 295 300
Ala Pro Gly Lys Gln Arg Glu Leu Val Ala Ala Ile Thr Ser Gly Val
305 310 315 320
Arg Thr Asp Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg
325 330 335
Asp Asn Ala Lys Arg Ala Val Tyr Leu Gln Met Asn Ser Leu Lys Pro
340 345 350
Glu Asp Thr Ala Val Tyr Tyr Cys Asn Val Asn Leu Tyr Asn Thr Gly
355 360 365
Asn Tyr Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser Ala Ala Ala
370 375 380
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
385 390 395 400
Ser Leu Arg Leu Ser Cys Ala Val Ser Gly Ser Leu Phe Ser Ala Arg
405 410 415
Val Met Gly Trp Tyr Arg Gln Ala Pro Gly Lys Gln Arg Glu Leu Val
420 425 430
Ala Ala Ile Thr Ser Gly Val Arg Thr Asp Tyr Ala Asp Ser Val Lys
435 440 445
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Arg Ala Val Tyr Leu
450 455 460
Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys Asn
465 470 475 480
Val Asn Leu Tyr Asn Thr Gly Asn Tyr Trp Gly Gln Gly Thr Gln Val
485 490 495
Thr Val Ser Ser
500
<210> 142
<211> 627
<212> PRT
<213> 人工序列 (Artificial Sequence)
<220>
<223> 三特异性抗体 hPL16-L3-hPL16-L1-hHS5-L1-CD16F1-L3-CD16F1
<400> 142
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Gly Thr Phe Leu Thr Tyr
20 25 30
Ser Met Ser Trp Val Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val
35 40 45
Ser Ser Ile Asn Trp Ser Gly Tyr Met Thr Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Ala Ala Arg Thr Ala Ile Ala Ala Lys Arg Ser Ser Glu Phe Asp
100 105 110
Tyr Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser Ala Ala Ala Glu
115 120 125
Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser
130 135 140
Leu Arg Leu Ser Cys Ala Ala Ser Gly Gly Thr Phe Leu Thr Tyr Ser
145 150 155 160
Met Ser Trp Val Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val Ser
165 170 175
Ser Ile Asn Trp Ser Gly Tyr Met Thr Tyr Tyr Ala Asp Ser Val Lys
180 185 190
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu
195 200 205
Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala
210 215 220
Ala Ala Arg Thr Ala Ile Ala Ala Lys Arg Ser Ser Glu Phe Asp Tyr
225 230 235 240
Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser Gly Gly Gly Gly Ser
245 250 255
Gly Gly Gly Ser Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val
260 265 270
Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Thr
275 280 285
Phe Thr Thr His Ala Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu
290 295 300
Arg Glu Phe Val Ser Ala Ile Asn Trp Gly Gly Arg Thr Thr Tyr Tyr
305 310 315 320
Ala Asp Ser Val Lys Gly Arg Phe Ile Ile Ser Arg Asp Thr Gly Ala
325 330 335
Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala
340 345 350
Val Tyr Tyr Cys Ala Ser Asn Leu Asp Thr Tyr Asn Val Arg Ala Gly
355 360 365
Thr Thr Asn Ser Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser Gly
370 375 380
Gly Gly Gly Ser Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly
385 390 395 400
Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Val
405 410 415
Ser Gly Ser Leu Phe Ser Ala Arg Val Met Gly Trp Tyr Arg Gln Ala
420 425 430
Pro Gly Lys Gln Arg Glu Leu Val Ala Ala Ile Thr Ser Gly Val Arg
435 440 445
Thr Asp Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp
450 455 460
Asn Ala Lys Arg Ala Val Tyr Leu Gln Met Asn Ser Leu Lys Pro Glu
465 470 475 480
Asp Thr Ala Val Tyr Tyr Cys Asn Val Asn Leu Tyr Asn Thr Gly Asn
485 490 495
Tyr Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser Ala Ala Ala Glu
500 505 510
Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser
515 520 525
Leu Arg Leu Ser Cys Ala Val Ser Gly Ser Leu Phe Ser Ala Arg Val
530 535 540
Met Gly Trp Tyr Arg Gln Ala Pro Gly Lys Gln Arg Glu Leu Val Ala
545 550 555 560
Ala Ile Thr Ser Gly Val Arg Thr Asp Tyr Ala Asp Ser Val Lys Gly
565 570 575
Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Arg Ala Val Tyr Leu Gln
580 585 590
Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys Asn Val
595 600 605
Asn Leu Tyr Asn Thr Gly Asn Tyr Trp Gly Gln Gly Thr Gln Val Thr
610 615 620
Val Ser Ser
625
<210> 143
<211> 393
<212> PRT
<213> 人工序列 (Artificial Sequence)
<220>
<223> 三特异性抗体 hLG9-L1-hHS5-L1-hPL16 (005R)
<400> 143
Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Ser Thr Ile Asp Asp Tyr
20 25 30
Pro Met Ser Trp Phe Arg Gln Ala Pro Gly Lys Gly Arg Glu Gly Val
35 40 45
Ala Ala Ile Asp Asp Ser Asp Glu Ser Thr Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Ala Ile Phe Met Ile Asp Gly Val Asp Val Phe Leu Thr
100 105 110
Tyr Tyr Tyr Asp Ser Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
115 120 125
Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu Val Gln Leu Leu Glu Ser
130 135 140
Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala
145 150 155 160
Ala Ser Gly Arg Thr Phe Thr Thr His Ala Met Gly Trp Phe Arg Gln
165 170 175
Ala Pro Gly Lys Glu Arg Glu Phe Val Ser Ala Ile Asn Trp Gly Gly
180 185 190
Arg Thr Thr Tyr Tyr Ala Asp Ser Val Lys Gly Arg Phe Ile Ile Ser
195 200 205
Arg Asp Thr Gly Ala Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg
210 215 220
Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Ser Asn Leu Asp Thr Tyr
225 230 235 240
Asn Val Arg Ala Gly Thr Thr Asn Ser Trp Gly Gln Gly Thr Gln Val
245 250 255
Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu Val Gln
260 265 270
Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg
275 280 285
Leu Ser Cys Ala Ala Ser Gly Gly Thr Phe Leu Thr Tyr Ser Met Ser
290 295 300
Trp Val Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val Ser Ser Ile
305 310 315 320
Asn Trp Ser Gly Tyr Met Thr Tyr Tyr Ala Asp Ser Val Lys Gly Arg
325 330 335
Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu Gln Met
340 345 350
Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Ala Ala
355 360 365
Arg Thr Ala Ile Ala Ala Lys Arg Ser Ser Glu Phe Asp Tyr Trp Gly
370 375 380
Gln Gly Thr Gln Val Thr Val Ser Ser
385 390
<210> 144
<211> 524
<212> PRT
<213> 人工序列 (Artificial Sequence)
<220>
<223> 三特异性抗体 hLG9-L3-hLG9-L1-hHS5-L1-hPL16
<400> 144
Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Ser Thr Ile Asp Asp Tyr
20 25 30
Pro Met Ser Trp Phe Arg Gln Ala Pro Gly Lys Gly Arg Glu Gly Val
35 40 45
Ala Ala Ile Asp Asp Ser Asp Glu Ser Thr Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Ala Ile Phe Met Ile Asp Gly Val Asp Val Phe Leu Thr
100 105 110
Tyr Tyr Tyr Asp Ser Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
115 120 125
Ala Ala Ala Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln
130 135 140
Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Ser Thr Ile
145 150 155 160
Asp Asp Tyr Pro Met Ser Trp Phe Arg Gln Ala Pro Gly Lys Gly Arg
165 170 175
Glu Gly Val Ala Ala Ile Asp Asp Ser Asp Glu Ser Thr Tyr Tyr Ala
180 185 190
Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn
195 200 205
Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val
210 215 220
Tyr Tyr Cys Ala Arg Gly Ala Ile Phe Met Ile Asp Gly Val Asp Val
225 230 235 240
Phe Leu Thr Tyr Tyr Tyr Asp Ser Trp Gly Gln Gly Thr Leu Val Thr
245 250 255
Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu Val Gln Leu
260 265 270
Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu
275 280 285
Ser Cys Ala Ala Ser Gly Arg Thr Phe Thr Thr His Ala Met Gly Trp
290 295 300
Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val Ser Ala Ile Asn
305 310 315 320
Trp Gly Gly Arg Thr Thr Tyr Tyr Ala Asp Ser Val Lys Gly Arg Phe
325 330 335
Ile Ile Ser Arg Asp Thr Gly Ala Asn Thr Leu Tyr Leu Gln Met Asn
340 345 350
Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Ser Asn Leu
355 360 365
Asp Thr Tyr Asn Val Arg Ala Gly Thr Thr Asn Ser Trp Gly Gln Gly
370 375 380
Thr Gln Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser
385 390 395 400
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
405 410 415
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Gly Thr Phe Leu Thr Tyr
420 425 430
Ser Met Ser Trp Val Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val
435 440 445
Ser Ser Ile Asn Trp Ser Gly Tyr Met Thr Tyr Tyr Ala Asp Ser Val
450 455 460
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
465 470 475 480
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
485 490 495
Ala Ala Ala Arg Thr Ala Ile Ala Ala Lys Arg Ser Ser Glu Phe Asp
500 505 510
Tyr Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser
515 520
<210> 145
<211> 520
<212> PRT
<213> 人工序列 (Artificial Sequence)
<220>
<223> 三特异性抗体 hLG9-L1-hHS5-L1-hPL16-L3-hPL16
<400> 145
Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Ser Thr Ile Asp Asp Tyr
20 25 30
Pro Met Ser Trp Phe Arg Gln Ala Pro Gly Lys Gly Arg Glu Gly Val
35 40 45
Ala Ala Ile Asp Asp Ser Asp Glu Ser Thr Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Ala Ile Phe Met Ile Asp Gly Val Asp Val Phe Leu Thr
100 105 110
Tyr Tyr Tyr Asp Ser Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
115 120 125
Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu Val Gln Leu Leu Glu Ser
130 135 140
Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala
145 150 155 160
Ala Ser Gly Arg Thr Phe Thr Thr His Ala Met Gly Trp Phe Arg Gln
165 170 175
Ala Pro Gly Lys Glu Arg Glu Phe Val Ser Ala Ile Asn Trp Gly Gly
180 185 190
Arg Thr Thr Tyr Tyr Ala Asp Ser Val Lys Gly Arg Phe Ile Ile Ser
195 200 205
Arg Asp Thr Gly Ala Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg
210 215 220
Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Ser Asn Leu Asp Thr Tyr
225 230 235 240
Asn Val Arg Ala Gly Thr Thr Asn Ser Trp Gly Gln Gly Thr Gln Val
245 250 255
Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu Val Gln
260 265 270
Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg
275 280 285
Leu Ser Cys Ala Ala Ser Gly Gly Thr Phe Leu Thr Tyr Ser Met Ser
290 295 300
Trp Val Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val Ser Ser Ile
305 310 315 320
Asn Trp Ser Gly Tyr Met Thr Tyr Tyr Ala Asp Ser Val Lys Gly Arg
325 330 335
Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu Gln Met
340 345 350
Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Ala Ala
355 360 365
Arg Thr Ala Ile Ala Ala Lys Arg Ser Ser Glu Phe Asp Tyr Trp Gly
370 375 380
Gln Gly Thr Gln Val Thr Val Ser Ser Ala Ala Ala Glu Val Gln Leu
385 390 395 400
Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu
405 410 415
Ser Cys Ala Ala Ser Gly Gly Thr Phe Leu Thr Tyr Ser Met Ser Trp
420 425 430
Val Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val Ser Ser Ile Asn
435 440 445
Trp Ser Gly Tyr Met Thr Tyr Tyr Ala Asp Ser Val Lys Gly Arg Phe
450 455 460
Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu Gln Met Asn
465 470 475 480
Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Ala Ala Arg
485 490 495
Thr Ala Ile Ala Ala Lys Arg Ser Ser Glu Phe Asp Tyr Trp Gly Gln
500 505 510
Gly Thr Gln Val Thr Val Ser Ser
515 520
<210> 146
<211> 651
<212> PRT
<213> 人工序列 (Artificial Sequence)
<220>
<223> 三特异性抗体 hLG9-L3-hLG9-L1-hHS5-L1-hPL16-L3-hPL16
<400> 146
Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Ser Thr Ile Asp Asp Tyr
20 25 30
Pro Met Ser Trp Phe Arg Gln Ala Pro Gly Lys Gly Arg Glu Gly Val
35 40 45
Ala Ala Ile Asp Asp Ser Asp Glu Ser Thr Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Ala Ile Phe Met Ile Asp Gly Val Asp Val Phe Leu Thr
100 105 110
Tyr Tyr Tyr Asp Ser Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
115 120 125
Ala Ala Ala Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln
130 135 140
Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Ser Thr Ile
145 150 155 160
Asp Asp Tyr Pro Met Ser Trp Phe Arg Gln Ala Pro Gly Lys Gly Arg
165 170 175
Glu Gly Val Ala Ala Ile Asp Asp Ser Asp Glu Ser Thr Tyr Tyr Ala
180 185 190
Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn
195 200 205
Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val
210 215 220
Tyr Tyr Cys Ala Arg Gly Ala Ile Phe Met Ile Asp Gly Val Asp Val
225 230 235 240
Phe Leu Thr Tyr Tyr Tyr Asp Ser Trp Gly Gln Gly Thr Leu Val Thr
245 250 255
Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu Val Gln Leu
260 265 270
Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu
275 280 285
Ser Cys Ala Ala Ser Gly Arg Thr Phe Thr Thr His Ala Met Gly Trp
290 295 300
Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val Ser Ala Ile Asn
305 310 315 320
Trp Gly Gly Arg Thr Thr Tyr Tyr Ala Asp Ser Val Lys Gly Arg Phe
325 330 335
Ile Ile Ser Arg Asp Thr Gly Ala Asn Thr Leu Tyr Leu Gln Met Asn
340 345 350
Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Ser Asn Leu
355 360 365
Asp Thr Tyr Asn Val Arg Ala Gly Thr Thr Asn Ser Trp Gly Gln Gly
370 375 380
Thr Gln Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser
385 390 395 400
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
405 410 415
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Gly Thr Phe Leu Thr Tyr
420 425 430
Ser Met Ser Trp Val Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val
435 440 445
Ser Ser Ile Asn Trp Ser Gly Tyr Met Thr Tyr Tyr Ala Asp Ser Val
450 455 460
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
465 470 475 480
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
485 490 495
Ala Ala Ala Arg Thr Ala Ile Ala Ala Lys Arg Ser Ser Glu Phe Asp
500 505 510
Tyr Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser Ala Ala Ala Glu
515 520 525
Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser
530 535 540
Leu Arg Leu Ser Cys Ala Ala Ser Gly Gly Thr Phe Leu Thr Tyr Ser
545 550 555 560
Met Ser Trp Val Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val Ser
565 570 575
Ser Ile Asn Trp Ser Gly Tyr Met Thr Tyr Tyr Ala Asp Ser Val Lys
580 585 590
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu
595 600 605
Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala
610 615 620
Ala Ala Arg Thr Ala Ile Ala Ala Lys Arg Ser Ser Glu Phe Asp Tyr
625 630 635 640
Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser
645 650
<210> 147
<211> 393
<212> PRT
<213> 人工序列 (Artificial Sequence)
<220>
<223> 三特异性抗体 hPL16-L1-hHS5-L1-hLG9
<400> 147
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Gly Thr Phe Leu Thr Tyr
20 25 30
Ser Met Ser Trp Val Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val
35 40 45
Ser Ser Ile Asn Trp Ser Gly Tyr Met Thr Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Ala Ala Arg Thr Ala Ile Ala Ala Lys Arg Ser Ser Glu Phe Asp
100 105 110
Tyr Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser Gly Gly Gly Gly
115 120 125
Ser Gly Gly Gly Ser Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu
130 135 140
Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg
145 150 155 160
Thr Phe Thr Thr His Ala Met Gly Trp Phe Arg Gln Ala Pro Gly Lys
165 170 175
Glu Arg Glu Phe Val Ser Ala Ile Asn Trp Gly Gly Arg Thr Thr Tyr
180 185 190
Tyr Ala Asp Ser Val Lys Gly Arg Phe Ile Ile Ser Arg Asp Thr Gly
195 200 205
Ala Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr
210 215 220
Ala Val Tyr Tyr Cys Ala Ser Asn Leu Asp Thr Tyr Asn Val Arg Ala
225 230 235 240
Gly Thr Thr Asn Ser Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser
245 250 255
Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu Val Gln Leu Leu Glu Ser
260 265 270
Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala
275 280 285
Ala Ser Gly Ser Thr Ile Asp Asp Tyr Pro Met Ser Trp Phe Arg Gln
290 295 300
Ala Pro Gly Lys Gly Arg Glu Gly Val Ala Ala Ile Asp Asp Ser Asp
305 310 315 320
Glu Ser Thr Tyr Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser
325 330 335
Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg
340 345 350
Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Gly Ala Ile Phe Met
355 360 365
Ile Asp Gly Val Asp Val Phe Leu Thr Tyr Tyr Tyr Asp Ser Trp Gly
370 375 380
Gln Gly Thr Leu Val Thr Val Ser Ser
385 390
<210> 148
<211> 524
<212> PRT
<213> 人工序列 (Artificial Sequence)
<220>
<223> 三特异性抗体 hPL16-L1-hHS5-L1-hLG9-L3-hLG9
<400> 148
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Gly Thr Phe Leu Thr Tyr
20 25 30
Ser Met Ser Trp Val Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val
35 40 45
Ser Ser Ile Asn Trp Ser Gly Tyr Met Thr Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Ala Ala Arg Thr Ala Ile Ala Ala Lys Arg Ser Ser Glu Phe Asp
100 105 110
Tyr Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser Gly Gly Gly Gly
115 120 125
Ser Gly Gly Gly Ser Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu
130 135 140
Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg
145 150 155 160
Thr Phe Thr Thr His Ala Met Gly Trp Phe Arg Gln Ala Pro Gly Lys
165 170 175
Glu Arg Glu Phe Val Ser Ala Ile Asn Trp Gly Gly Arg Thr Thr Tyr
180 185 190
Tyr Ala Asp Ser Val Lys Gly Arg Phe Ile Ile Ser Arg Asp Thr Gly
195 200 205
Ala Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr
210 215 220
Ala Val Tyr Tyr Cys Ala Ser Asn Leu Asp Thr Tyr Asn Val Arg Ala
225 230 235 240
Gly Thr Thr Asn Ser Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser
245 250 255
Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu Val Gln Leu Leu Glu Ser
260 265 270
Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala
275 280 285
Ala Ser Gly Ser Thr Ile Asp Asp Tyr Pro Met Ser Trp Phe Arg Gln
290 295 300
Ala Pro Gly Lys Gly Arg Glu Gly Val Ala Ala Ile Asp Asp Ser Asp
305 310 315 320
Glu Ser Thr Tyr Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser
325 330 335
Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg
340 345 350
Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Gly Ala Ile Phe Met
355 360 365
Ile Asp Gly Val Asp Val Phe Leu Thr Tyr Tyr Tyr Asp Ser Trp Gly
370 375 380
Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ala Ala Glu Val Gln Leu
385 390 395 400
Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu
405 410 415
Ser Cys Ala Ala Ser Gly Ser Thr Ile Asp Asp Tyr Pro Met Ser Trp
420 425 430
Phe Arg Gln Ala Pro Gly Lys Gly Arg Glu Gly Val Ala Ala Ile Asp
435 440 445
Asp Ser Asp Glu Ser Thr Tyr Tyr Ala Asp Ser Val Lys Gly Arg Phe
450 455 460
Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu Gln Met Asn
465 470 475 480
Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Gly Ala
485 490 495
Ile Phe Met Ile Asp Gly Val Asp Val Phe Leu Thr Tyr Tyr Tyr Asp
500 505 510
Ser Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
515 520
<210> 149
<211> 520
<212> PRT
<213> 人工序列 (Artificial Sequence)
<220>
<223> 三特异性抗体 hPL16-L3-hPL16-L1-hHS5-L1-hLG9
<400> 149
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Gly Thr Phe Leu Thr Tyr
20 25 30
Ser Met Ser Trp Val Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val
35 40 45
Ser Ser Ile Asn Trp Ser Gly Tyr Met Thr Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Ala Ala Arg Thr Ala Ile Ala Ala Lys Arg Ser Ser Glu Phe Asp
100 105 110
Tyr Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser Ala Ala Ala Glu
115 120 125
Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser
130 135 140
Leu Arg Leu Ser Cys Ala Ala Ser Gly Gly Thr Phe Leu Thr Tyr Ser
145 150 155 160
Met Ser Trp Val Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val Ser
165 170 175
Ser Ile Asn Trp Ser Gly Tyr Met Thr Tyr Tyr Ala Asp Ser Val Lys
180 185 190
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu
195 200 205
Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala
210 215 220
Ala Ala Arg Thr Ala Ile Ala Ala Lys Arg Ser Ser Glu Phe Asp Tyr
225 230 235 240
Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser Gly Gly Gly Gly Ser
245 250 255
Gly Gly Gly Ser Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val
260 265 270
Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Thr
275 280 285
Phe Thr Thr His Ala Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu
290 295 300
Arg Glu Phe Val Ser Ala Ile Asn Trp Gly Gly Arg Thr Thr Tyr Tyr
305 310 315 320
Ala Asp Ser Val Lys Gly Arg Phe Ile Ile Ser Arg Asp Thr Gly Ala
325 330 335
Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala
340 345 350
Val Tyr Tyr Cys Ala Ser Asn Leu Asp Thr Tyr Asn Val Arg Ala Gly
355 360 365
Thr Thr Asn Ser Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser Gly
370 375 380
Gly Gly Gly Ser Gly Gly Gly Ser Glu Val Gln Leu Leu Glu Ser Gly
385 390 395 400
Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala
405 410 415
Ser Gly Ser Thr Ile Asp Asp Tyr Pro Met Ser Trp Phe Arg Gln Ala
420 425 430
Pro Gly Lys Gly Arg Glu Gly Val Ala Ala Ile Asp Asp Ser Asp Glu
435 440 445
Ser Thr Tyr Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg
450 455 460
Asp Asn Ser Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala
465 470 475 480
Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Gly Ala Ile Phe Met Ile
485 490 495
Asp Gly Val Asp Val Phe Leu Thr Tyr Tyr Tyr Asp Ser Trp Gly Gln
500 505 510
Gly Thr Leu Val Thr Val Ser Ser
515 520
<210> 150
<211> 651
<212> PRT
<213> 人工序列 (Artificial Sequence)
<220>
<223> 三特异性抗体 hPL16-L3-hPL16-L1-hHS5-L1-hLG9-L3-hLG9
<400> 150
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Gly Thr Phe Leu Thr Tyr
20 25 30
Ser Met Ser Trp Val Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val
35 40 45
Ser Ser Ile Asn Trp Ser Gly Tyr Met Thr Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Ala Ala Arg Thr Ala Ile Ala Ala Lys Arg Ser Ser Glu Phe Asp
100 105 110
Tyr Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser Ala Ala Ala Glu
115 120 125
Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser
130 135 140
Leu Arg Leu Ser Cys Ala Ala Ser Gly Gly Thr Phe Leu Thr Tyr Ser
145 150 155 160
Met Ser Trp Val Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val Ser
165 170 175
Ser Ile Asn Trp Ser Gly Tyr Met Thr Tyr Tyr Ala Asp Ser Val Lys
180 185 190
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu
195 200 205
Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala
210 215 220
Ala Ala Arg Thr Ala Ile Ala Ala Lys Arg Ser Ser Glu Phe Asp Tyr
225 230 235 240
Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser Gly Gly Gly Gly Ser
245 250 255
Gly Gly Gly Ser Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val
260 265 270
Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Thr
275 280 285
Phe Thr Thr His Ala Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu
290 295 300
Arg Glu Phe Val Ser Ala Ile Asn Trp Gly Gly Arg Thr Thr Tyr Tyr
305 310 315 320
Ala Asp Ser Val Lys Gly Arg Phe Ile Ile Ser Arg Asp Thr Gly Ala
325 330 335
Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala
340 345 350
Val Tyr Tyr Cys Ala Ser Asn Leu Asp Thr Tyr Asn Val Arg Ala Gly
355 360 365
Thr Thr Asn Ser Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser Gly
370 375 380
Gly Gly Gly Ser Gly Gly Gly Ser Glu Val Gln Leu Leu Glu Ser Gly
385 390 395 400
Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala
405 410 415
Ser Gly Ser Thr Ile Asp Asp Tyr Pro Met Ser Trp Phe Arg Gln Ala
420 425 430
Pro Gly Lys Gly Arg Glu Gly Val Ala Ala Ile Asp Asp Ser Asp Glu
435 440 445
Ser Thr Tyr Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg
450 455 460
Asp Asn Ser Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala
465 470 475 480
Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Gly Ala Ile Phe Met Ile
485 490 495
Asp Gly Val Asp Val Phe Leu Thr Tyr Tyr Tyr Asp Ser Trp Gly Gln
500 505 510
Gly Thr Leu Val Thr Val Ser Ser Ala Ala Ala Glu Val Gln Leu Leu
515 520 525
Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser
530 535 540
Cys Ala Ala Ser Gly Ser Thr Ile Asp Asp Tyr Pro Met Ser Trp Phe
545 550 555 560
Arg Gln Ala Pro Gly Lys Gly Arg Glu Gly Val Ala Ala Ile Asp Asp
565 570 575
Ser Asp Glu Ser Thr Tyr Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr
580 585 590
Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser
595 600 605
Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Gly Ala Ile
610 615 620
Phe Met Ile Asp Gly Val Asp Val Phe Leu Thr Tyr Tyr Tyr Asp Ser
625 630 635 640
Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
645 650
<210> 151
<211> 381
<212> PRT
<213> 人工序列 (Artificial Sequence)
<220>
<223> 多特异性抗体 hPL16-L1-hHS5-L1-CD16F1
<400> 151
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Gly Thr Phe Leu Thr Tyr
20 25 30
Ser Met Ser Trp Val Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val
35 40 45
Ser Ser Ile Asn Trp Ser Gly Tyr Met Thr Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Ala Ala Arg Thr Ala Ile Ala Ala Lys Arg Ser Ser Glu Phe Asp
100 105 110
Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly
115 120 125
Ser Gly Gly Gly Ser Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu
130 135 140
Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg
145 150 155 160
Thr Phe Thr Thr His Ala Met Gly Trp Phe Arg Gln Ala Pro Gly Lys
165 170 175
Glu Arg Glu Phe Val Ser Ala Ile Asn Trp Gly Gly Arg Thr Thr Tyr
180 185 190
Tyr Ala Asp Ser Val Lys Gly Arg Phe Ile Ile Ser Arg Asp Thr Gly
195 200 205
Ala Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr
210 215 220
Ala Val Tyr Tyr Cys Ala Ser Asn Leu Asp Thr Tyr Asn Val Arg Ala
225 230 235 240
Gly Thr Thr Asn Ser Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser
245 250 255
Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser
260 265 270
Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala
275 280 285
Val Ser Gly Ser Leu Phe Ser Ala Arg Val Met Gly Trp Tyr Arg Gln
290 295 300
Ala Pro Gly Lys Gln Arg Glu Leu Val Ala Ala Ile Thr Ser Gly Val
305 310 315 320
Arg Thr Asp Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg
325 330 335
Asp Asn Ala Lys Arg Ala Val Tyr Leu Gln Met Asn Ser Leu Lys Pro
340 345 350
Glu Asp Thr Ala Val Tyr Tyr Cys Asn Val Asn Leu Tyr Asn Thr Gly
355 360 365
Asn Tyr Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser
370 375 380
<210> 152
<211> 654
<212> PRT
<213> 人工序列 (Artificial Sequence)
<220>
<223> 多特异性抗体 CD16F1-L1-hHS10-L1-
hA09-10-2-L3-A09-10-L1-hPL16 (015-3)
<400> 152
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Val Ser Gly Ser Leu Phe Ser Ala Arg
20 25 30
Val Met Gly Trp Tyr Arg Gln Ala Pro Gly Lys Gln Arg Glu Leu Val
35 40 45
Ala Ala Ile Thr Ser Gly Val Arg Thr Asp Tyr Ala Asp Ser Val Lys
50 55 60
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Arg Ala Val Tyr Leu
65 70 75 80
Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys Asn
85 90 95
Val Asn Leu Tyr Asn Thr Gly Asn Tyr Trp Gly Gln Gly Thr Gln Val
100 105 110
Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu Val Gln
115 120 125
Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg
130 135 140
Leu Ser Cys Ala Ala Ser Gly Ser Thr Asp Ser Ala Tyr Arg Met Gly
145 150 155 160
Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val Ser Ala Ile
165 170 175
Asn Trp Ser Asp Gly Arg Thr Tyr Tyr Ala Asp Ser Val Lys Gly Arg
180 185 190
Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu Gln Met
195 200 205
Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Ala Asp
210 215 220
Pro Asp Ser Arg Leu Tyr Tyr Thr Val Pro Gln Asn Tyr Asp Tyr Trp
225 230 235 240
Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly
245 250 255
Gly Gly Ser Glu Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val
260 265 270
Gln Ala Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Gly Gly
275 280 285
Arg Thr Phe Ser Asn Tyr Ala Leu Gly Trp Phe Arg Gln Ala Pro Gly
290 295 300
Lys Glu Arg Glu Phe Val Ala Ala Ile Ser Arg Ser Gly Gly Asn Ile
305 310 315 320
Asn Tyr Ala Asp Ser Ala Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn
325 330 335
Phe Lys Asn Thr Thr Tyr Leu Gln Met Ser Ser Leu Lys Pro Glu Asp
340 345 350
Thr Ala Val Tyr Tyr Cys Ala Ala His Tyr Leu Leu Leu Pro Ser Tyr
355 360 365
Ile Ser Thr Ser Thr Asn Met Tyr Asn Tyr Trp Gly Gln Gly Thr Gln
370 375 380
Val Thr Val Ser Ser Ala Ala Ala Gln Val Gln Leu Val Glu Ser Gly
385 390 395 400
Gly Gly Leu Val Gln Ala Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala
405 410 415
Ser Gly Gly Gly Arg Thr Phe Ser Asn Tyr Ala Leu Gly Trp Phe Arg
420 425 430
Gln Ala Pro Gly Lys Glu Arg Glu Phe Val Ala Ala Ile Ser Arg Ser
435 440 445
Gly Gly Asn Ile Asn Tyr Ala Asp Ser Ala Lys Gly Arg Phe Thr Ile
450 455 460
Ser Arg Asp Asn Phe Lys Asn Thr Thr Tyr Leu Gln Met Ser Ser Leu
465 470 475 480
Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys Ala Ala His Tyr Leu Leu
485 490 495
Leu Pro Ser Tyr Ile Ser Thr Ser Thr Asn Met Tyr Asn Tyr Trp Gly
500 505 510
Gln Gly Thr Gln Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly
515 520 525
Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro
530 535 540
Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Gly Thr Phe Leu
545 550 555 560
Thr Tyr Ser Met Ser Trp Val Arg Gln Ala Pro Gly Lys Glu Arg Glu
565 570 575
Phe Val Ser Ser Ile Asn Trp Ser Gly Tyr Met Thr Tyr Tyr Ala Asp
580 585 590
Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr
595 600 605
Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr
610 615 620
Tyr Cys Ala Ala Ala Arg Thr Ala Ile Ala Ala Lys Arg Ser Ser Glu
625 630 635 640
Phe Asp Tyr Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser
645 650
<210> 153
<211> 665
<212> PRT
<213> 人工序列 (Artificial Sequence)
<220>
<223> 多特异性抗体
hHS10-L11*12-CD16F1-L1-hA09-10-2-L3-A09-10-L1-hPL16
<400> 153
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Ser Thr Asp Ser Ala Tyr
20 25 30
Arg Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val
35 40 45
Ser Ala Ile Asn Trp Ser Asp Gly Arg Thr Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Ala Asp Pro Asp Ser Arg Leu Tyr Tyr Thr Val Pro Gln Asn Tyr
100 105 110
Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Ser
115 120 125
Gly Arg Ser Ala Pro Leu Gly Leu Ala Arg Gln Ala Arg Gln Val Gly
130 135 140
Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro
145 150 155 160
Gly Gly Ser Leu Arg Leu Ser Cys Ala Val Ser Gly Ser Leu Phe Ser
165 170 175
Ala Arg Val Met Gly Trp Tyr Arg Gln Ala Pro Gly Lys Gln Arg Glu
180 185 190
Leu Val Ala Ala Ile Thr Ser Gly Val Arg Thr Asp Tyr Ala Asp Ser
195 200 205
Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Arg Ala Val
210 215 220
Tyr Leu Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr
225 230 235 240
Cys Asn Val Asn Leu Tyr Asn Thr Gly Asn Tyr Trp Gly Gln Gly Thr
245 250 255
Gln Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu
260 265 270
Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser
275 280 285
Leu Arg Leu Ser Cys Ala Ala Ser Gly Gly Gly Arg Thr Phe Ser Asn
290 295 300
Tyr Ala Leu Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe
305 310 315 320
Val Ala Ala Ile Ser Arg Ser Gly Gly Asn Ile Asn Tyr Ala Asp Ser
325 330 335
Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Phe Lys Asn Thr Thr
340 345 350
Tyr Leu Gln Met Ser Ser Leu Glu Pro Glu Asp Thr Ala Val Tyr Tyr
355 360 365
Cys Ala Ala His Tyr Leu Leu Leu Pro Ser Tyr Ile Ser Thr Ser Thr
370 375 380
Asn Met Tyr Asn Tyr Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser
385 390 395 400
Ala Ala Ala Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln
405 410 415
Ala Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Gly Gly Arg
420 425 430
Thr Phe Ser Asn Tyr Ala Leu Gly Trp Phe Arg Gln Ala Pro Gly Lys
435 440 445
Glu Arg Glu Phe Val Ala Ala Ile Ser Arg Ser Gly Gly Asn Ile Asn
450 455 460
Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Phe
465 470 475 480
Lys Asn Thr Thr Tyr Leu Gln Met Ser Ser Leu Glu Pro Glu Asp Thr
485 490 495
Ala Val Tyr Tyr Cys Ala Ala His Tyr Leu Leu Leu Pro Ser Tyr Ile
500 505 510
Ser Thr Ser Thr Asn Met Tyr Asn Tyr Trp Gly Gln Gly Thr Gln Val
515 520 525
Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu Val Gln
530 535 540
Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg
545 550 555 560
Leu Ser Cys Ala Ala Ser Gly Gly Thr Phe Leu Thr Tyr Ser Met Ser
565 570 575
Trp Val Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val Ser Ser Ile
580 585 590
Asn Trp Ser Gly Tyr Met Thr Tyr Tyr Ala Asp Ser Val Lys Gly Arg
595 600 605
Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu Gln Met
610 615 620
Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Ala Ala
625 630 635 640
Arg Thr Ala Ile Ala Ala Lys Arg Ser Ser Glu Phe Asp Tyr Trp Gly
645 650 655
Gln Gly Thr Gln Val Thr Val Ser Ser
660 665
<210> 154
<211> 521
<212> PRT
<213> 人工序列 (Artificial Sequence)
<220>
<223> 多特异性抗体 CD16F1-L1-hHS10-L1- A09-10-L1-hPL16
(015-2)
<400> 154
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Val Ser Gly Ser Leu Phe Ser Ala Arg
20 25 30
Val Met Gly Trp Tyr Arg Gln Ala Pro Gly Lys Gln Arg Glu Leu Val
35 40 45
Ala Ala Ile Thr Ser Gly Val Arg Thr Asp Tyr Ala Asp Ser Val Lys
50 55 60
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Arg Ala Val Tyr Leu
65 70 75 80
Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys Asn
85 90 95
Val Asn Leu Tyr Asn Thr Gly Asn Tyr Trp Gly Gln Gly Thr Gln Val
100 105 110
Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu Val Gln
115 120 125
Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg
130 135 140
Leu Ser Cys Ala Ala Ser Gly Ser Thr Asp Ser Ala Tyr Arg Met Gly
145 150 155 160
Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val Ser Ala Ile
165 170 175
Asn Trp Ser Asp Gly Arg Thr Tyr Tyr Ala Asp Ser Val Lys Gly Arg
180 185 190
Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu Gln Met
195 200 205
Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Ala Asp
210 215 220
Pro Asp Ser Arg Leu Tyr Tyr Thr Val Pro Gln Asn Tyr Asp Tyr Trp
225 230 235 240
Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly
245 250 255
Gly Gly Ser Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln
260 265 270
Ala Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Gly Gly Arg
275 280 285
Thr Phe Ser Asn Tyr Ala Leu Gly Trp Phe Arg Gln Ala Pro Gly Lys
290 295 300
Glu Arg Glu Phe Val Ala Ala Ile Ser Arg Ser Gly Gly Asn Ile Asn
305 310 315 320
Tyr Ala Asp Ser Ala Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Phe
325 330 335
Lys Asn Thr Thr Tyr Leu Gln Met Ser Ser Leu Lys Pro Glu Asp Thr
340 345 350
Ala Val Tyr Tyr Cys Ala Ala His Tyr Leu Leu Leu Pro Ser Tyr Ile
355 360 365
Ser Thr Ser Thr Asn Met Tyr Asn Tyr Trp Gly Gln Gly Thr Gln Val
370 375 380
Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu Val Gln
385 390 395 400
Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg
405 410 415
Leu Ser Cys Ala Ala Ser Gly Gly Thr Phe Leu Thr Tyr Ser Met Ser
420 425 430
Trp Val Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val Ser Ser Ile
435 440 445
Asn Trp Ser Gly Tyr Met Thr Tyr Tyr Ala Asp Ser Val Lys Gly Arg
450 455 460
Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu Gln Met
465 470 475 480
Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Ala Ala
485 490 495
Arg Thr Ala Ile Ala Ala Lys Arg Ser Ser Glu Phe Asp Tyr Trp Gly
500 505 510
Gln Gly Thr Gln Val Thr Val Ser Ser
515 520
<210> 155
<211> 792
<212> PRT
<213> 人工序列 (Artificial Sequence)
<220>
<223> 多特异性抗体
hHS10-L11*12-CD16F1-L1-hA09-10-2-L3-A09-10-L1-hPL16-L3-hPL16
<400> 155
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Ser Thr Asp Ser Ala Tyr
20 25 30
Arg Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val
35 40 45
Ser Ala Ile Asn Trp Ser Asp Gly Arg Thr Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Ala Asp Pro Asp Ser Arg Leu Tyr Tyr Thr Val Pro Gln Asn Tyr
100 105 110
Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Ser
115 120 125
Gly Arg Ser Ala Pro Leu Gly Leu Ala Arg Gln Ala Arg Gln Val Gly
130 135 140
Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro
145 150 155 160
Gly Gly Ser Leu Arg Leu Ser Cys Ala Val Ser Gly Ser Leu Phe Ser
165 170 175
Ala Arg Val Met Gly Trp Tyr Arg Gln Ala Pro Gly Lys Gln Arg Glu
180 185 190
Leu Val Ala Ala Ile Thr Ser Gly Val Arg Thr Asp Tyr Ala Asp Ser
195 200 205
Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Arg Ala Val
210 215 220
Tyr Leu Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr
225 230 235 240
Cys Asn Val Asn Leu Tyr Asn Thr Gly Asn Tyr Trp Gly Gln Gly Thr
245 250 255
Gln Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu
260 265 270
Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser
275 280 285
Leu Arg Leu Ser Cys Ala Ala Ser Gly Gly Gly Arg Thr Phe Ser Asn
290 295 300
Tyr Ala Leu Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe
305 310 315 320
Val Ala Ala Ile Ser Arg Ser Gly Gly Asn Ile Asn Tyr Ala Asp Ser
325 330 335
Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Phe Lys Asn Thr Thr
340 345 350
Tyr Leu Gln Met Ser Ser Leu Glu Pro Glu Asp Thr Ala Val Tyr Tyr
355 360 365
Cys Ala Ala His Tyr Leu Leu Leu Pro Ser Tyr Ile Ser Thr Ser Thr
370 375 380
Asn Met Tyr Asn Tyr Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser
385 390 395 400
Ala Ala Ala Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln
405 410 415
Ala Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Gly Gly Arg
420 425 430
Thr Phe Ser Asn Tyr Ala Leu Gly Trp Phe Arg Gln Ala Pro Gly Lys
435 440 445
Glu Arg Glu Phe Val Ala Ala Ile Ser Arg Ser Gly Gly Asn Ile Asn
450 455 460
Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Phe
465 470 475 480
Lys Asn Thr Thr Tyr Leu Gln Met Ser Ser Leu Glu Pro Glu Asp Thr
485 490 495
Ala Val Tyr Tyr Cys Ala Ala His Tyr Leu Leu Leu Pro Ser Tyr Ile
500 505 510
Ser Thr Ser Thr Asn Met Tyr Asn Tyr Trp Gly Gln Gly Thr Gln Val
515 520 525
Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu Val Gln
530 535 540
Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg
545 550 555 560
Leu Ser Cys Ala Ala Ser Gly Gly Thr Phe Leu Thr Tyr Ser Met Ser
565 570 575
Trp Val Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val Ser Ser Ile
580 585 590
Asn Trp Ser Gly Tyr Met Thr Tyr Tyr Ala Asp Ser Val Lys Gly Arg
595 600 605
Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu Gln Met
610 615 620
Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Ala Ala
625 630 635 640
Arg Thr Ala Ile Ala Ala Lys Arg Ser Ser Glu Phe Asp Tyr Trp Gly
645 650 655
Gln Gly Thr Gln Val Thr Val Ser Ser Ala Ala Ala Glu Val Gln Leu
660 665 670
Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu
675 680 685
Ser Cys Ala Ala Ser Gly Gly Thr Phe Leu Thr Tyr Ser Met Ser Trp
690 695 700
Val Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val Ser Ser Ile Asn
705 710 715 720
Trp Ser Gly Tyr Met Thr Tyr Tyr Ala Asp Ser Val Lys Gly Arg Phe
725 730 735
Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu Gln Met Asn
740 745 750
Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Ala Ala Arg
755 760 765
Thr Ala Ile Ala Ala Lys Arg Ser Ser Glu Phe Asp Tyr Trp Gly Gln
770 775 780
Gly Thr Gln Val Thr Val Ser Ser
785 790
<210> 156
<211> 780
<212> PRT
<213> 人工序列 (Artificial Sequence)
<220>
<223> 多特异性抗体
CD16F1-L1-hHS10-L1-hA09-10-2-L3-A09-10-L1-hPL16-L3-hPL16 (1511)
<400> 156
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Val Ser Gly Ser Leu Phe Ser Ala Arg
20 25 30
Val Met Gly Trp Tyr Arg Gln Ala Pro Gly Lys Gln Arg Glu Leu Val
35 40 45
Ala Ala Ile Thr Ser Gly Val Arg Thr Asp Tyr Ala Asp Ser Val Lys
50 55 60
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Arg Ala Val Tyr Leu
65 70 75 80
Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys Asn
85 90 95
Val Asn Leu Tyr Asn Thr Gly Asn Tyr Trp Gly Gln Gly Thr Gln Val
100 105 110
Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu Val Gln
115 120 125
Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg
130 135 140
Leu Ser Cys Ala Ala Ser Gly Ser Thr Asp Ser Ala Tyr Arg Met Gly
145 150 155 160
Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val Ser Ala Ile
165 170 175
Asn Trp Ser Asp Gly Arg Thr Tyr Tyr Ala Asp Ser Val Lys Gly Arg
180 185 190
Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu Gln Met
195 200 205
Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Ala Asp
210 215 220
Pro Asp Ser Arg Leu Tyr Tyr Thr Val Pro Gln Asn Tyr Asp Tyr Trp
225 230 235 240
Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly
245 250 255
Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln
260 265 270
Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Gly Gly Arg
275 280 285
Thr Phe Ser Asn Tyr Ala Leu Gly Trp Phe Arg Gln Ala Pro Gly Lys
290 295 300
Glu Arg Glu Phe Val Ala Ala Ile Ser Arg Ser Gly Gly Asn Ile Asn
305 310 315 320
Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Phe
325 330 335
Lys Asn Thr Thr Tyr Leu Gln Met Ser Ser Leu Glu Pro Glu Asp Thr
340 345 350
Ala Val Tyr Tyr Cys Ala Ala His Tyr Leu Leu Leu Pro Ser Tyr Ile
355 360 365
Ser Thr Ser Thr Asn Met Tyr Asn Tyr Trp Gly Gln Gly Thr Gln Val
370 375 380
Thr Val Ser Ser Ala Ala Ala Gln Val Gln Leu Val Glu Ser Gly Gly
385 390 395 400
Gly Leu Val Gln Ala Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser
405 410 415
Gly Gly Gly Arg Thr Phe Ser Asn Tyr Ala Leu Gly Trp Phe Arg Gln
420 425 430
Ala Pro Gly Lys Glu Arg Glu Phe Val Ala Ala Ile Ser Arg Ser Gly
435 440 445
Gly Asn Ile Asn Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser
450 455 460
Arg Asp Asn Phe Lys Asn Thr Thr Tyr Leu Gln Met Ser Ser Leu Glu
465 470 475 480
Pro Glu Asp Thr Ala Val Tyr Tyr Cys Ala Ala His Tyr Leu Leu Leu
485 490 495
Pro Ser Tyr Ile Ser Thr Ser Thr Asn Met Tyr Asn Tyr Trp Gly Gln
500 505 510
Gly Thr Gln Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly
515 520 525
Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly
530 535 540
Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Gly Thr Phe Leu Thr
545 550 555 560
Tyr Ser Met Ser Trp Val Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe
565 570 575
Val Ser Ser Ile Asn Trp Ser Gly Tyr Met Thr Tyr Tyr Ala Asp Ser
580 585 590
Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu
595 600 605
Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr
610 615 620
Cys Ala Ala Ala Arg Thr Ala Ile Ala Ala Lys Arg Ser Ser Glu Phe
625 630 635 640
Asp Tyr Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser Ala Ala Ala
645 650 655
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
660 665 670
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Gly Thr Phe Leu Thr Tyr
675 680 685
Ser Met Ser Trp Val Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val
690 695 700
Ser Ser Ile Asn Trp Ser Gly Tyr Met Thr Tyr Tyr Ala Asp Ser Val
705 710 715 720
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
725 730 735
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
740 745 750
Ala Ala Ala Arg Thr Ala Ile Ala Ala Lys Arg Ser Ser Glu Phe Asp
755 760 765
Tyr Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser
770 775 780
<210> 157
<211> 780
<212> PRT
<213> 人工序列 (Artificial Sequence)
<220>
<223> 多特异性抗体
CD16F1-L1-hHS10-L1-hA09-10-3-L3-hA09-10-4-L1-hPL16-L3-hPL16
(1518)
<400> 157
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Val Ser Gly Ser Leu Phe Ser Ala Arg
20 25 30
Val Met Gly Trp Tyr Arg Gln Ala Pro Gly Lys Gln Arg Glu Leu Val
35 40 45
Ala Ala Ile Thr Ser Gly Val Arg Thr Asp Tyr Ala Asp Ser Val Lys
50 55 60
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Arg Ala Val Tyr Leu
65 70 75 80
Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys Asn
85 90 95
Val Asn Leu Tyr Asn Thr Gly Asn Tyr Trp Gly Gln Gly Thr Gln Val
100 105 110
Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu Val Gln
115 120 125
Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg
130 135 140
Leu Ser Cys Ala Ala Ser Gly Ser Thr Asp Ser Ala Tyr Arg Met Gly
145 150 155 160
Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val Ser Ala Ile
165 170 175
Asn Trp Ser Asp Gly Arg Thr Tyr Tyr Ala Asp Ser Val Lys Gly Arg
180 185 190
Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu Gln Met
195 200 205
Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Ala Asp
210 215 220
Pro Asp Ser Arg Leu Tyr Tyr Thr Val Pro Gln Asn Tyr Asp Tyr Trp
225 230 235 240
Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly
245 250 255
Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln
260 265 270
Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Gly Gly Arg
275 280 285
Thr Phe Ser Asn Tyr Ala Leu Gly Trp Phe Arg Gln Ala Pro Gly Lys
290 295 300
Glu Arg Glu Phe Val Ala Ala Ile Ser Arg Ser Gly Gly Asn Ile Asn
305 310 315 320
Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Phe
325 330 335
Lys Asn Thr Val Tyr Leu Gln Met Ser Ser Leu Arg Ala Glu Asp Thr
340 345 350
Ala Val Tyr Tyr Cys Ala Ala His Tyr Leu Leu Leu Pro Ser Tyr Ile
355 360 365
Ser Thr Ser Thr Asn Met Tyr Asn Tyr Trp Gly Gln Gly Thr Gln Val
370 375 380
Thr Val Ser Ser Ala Ala Ala Gln Val Gln Leu Val Glu Ser Gly Gly
385 390 395 400
Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser
405 410 415
Gly Gly Gly Arg Thr Phe Ser Asn Tyr Ala Leu Gly Trp Phe Arg Gln
420 425 430
Ala Pro Gly Lys Glu Arg Glu Phe Val Ala Ala Ile Ser Arg Ser Gly
435 440 445
Gly Asn Ile Asn Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser
450 455 460
Arg Asp Asn Ala Lys Asn Thr Val Tyr Leu Gln Met Ser Ser Leu Arg
465 470 475 480
Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Ala His Tyr Leu Leu Leu
485 490 495
Pro Ser Tyr Ile Ser Thr Ser Thr Asn Met Tyr Asn Tyr Trp Gly Gln
500 505 510
Gly Thr Gln Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly
515 520 525
Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly
530 535 540
Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Gly Thr Phe Leu Thr
545 550 555 560
Tyr Ser Met Ser Trp Val Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe
565 570 575
Val Ser Ser Ile Asn Trp Ser Gly Tyr Met Thr Tyr Tyr Ala Asp Ser
580 585 590
Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu
595 600 605
Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr
610 615 620
Cys Ala Ala Ala Arg Thr Ala Ile Ala Ala Lys Arg Ser Ser Glu Phe
625 630 635 640
Asp Tyr Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser Ala Ala Ala
645 650 655
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
660 665 670
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Gly Thr Phe Leu Thr Tyr
675 680 685
Ser Met Ser Trp Val Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val
690 695 700
Ser Ser Ile Asn Trp Ser Gly Tyr Met Thr Tyr Tyr Ala Asp Ser Val
705 710 715 720
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
725 730 735
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
740 745 750
Ala Ala Ala Arg Thr Ala Ile Ala Ala Lys Arg Ser Ser Glu Phe Asp
755 760 765
Tyr Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser
770 775 780
<210> 158
<211> 778
<212> PRT
<213> 人工序列 (Artificial Sequence)
<220>
<223> 多特异性抗体 hHS10-L11*9-CD16F1-
L1-hA09-10-2-L3-A09-10-L1- H33-14-L3-H33-14
<400> 158
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Ser Thr Asp Ser Ala Tyr
20 25 30
Arg Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val
35 40 45
Ser Ala Ile Asn Trp Ser Asp Gly Arg Thr Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Ala Asp Pro Asp Ser Arg Leu Tyr Tyr Thr Val Pro Gln Asn Tyr
100 105 110
Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Ser
115 120 125
Gly Arg Ser Ala Pro Leu Gly Leu Ala Arg Gln Ala Arg Gln Val Gly
130 135 140
Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro
145 150 155 160
Gly Gly Ser Leu Arg Leu Ser Cys Ala Val Ser Gly Ser Leu Phe Ser
165 170 175
Ala Arg Val Met Gly Trp Tyr Arg Gln Ala Pro Gly Lys Gln Arg Glu
180 185 190
Leu Val Ala Ala Ile Thr Ser Gly Val Arg Thr Asp Tyr Ala Asp Ser
195 200 205
Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Arg Ala Val
210 215 220
Tyr Leu Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr
225 230 235 240
Cys Asn Val Asn Leu Tyr Asn Thr Gly Asn Tyr Trp Gly Gln Gly Thr
245 250 255
Gln Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu
260 265 270
Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser
275 280 285
Leu Arg Leu Ser Cys Ala Ala Ser Gly Gly Gly Arg Thr Phe Ser Asn
290 295 300
Tyr Ala Leu Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe
305 310 315 320
Val Ala Ala Ile Ser Arg Ser Gly Gly Asn Ile Asn Tyr Ala Asp Ser
325 330 335
Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Phe Lys Asn Thr Thr
340 345 350
Tyr Leu Gln Met Ser Ser Leu Glu Pro Glu Asp Thr Ala Val Tyr Tyr
355 360 365
Cys Ala Ala His Tyr Leu Leu Leu Pro Ser Tyr Ile Ser Thr Ser Thr
370 375 380
Asn Met Tyr Asn Tyr Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser
385 390 395 400
Ala Ala Ala Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln
405 410 415
Ala Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Gly Gly Arg
420 425 430
Thr Phe Ser Asn Tyr Ala Leu Gly Trp Phe Arg Gln Ala Pro Gly Lys
435 440 445
Glu Arg Glu Phe Val Ala Ala Ile Ser Arg Ser Gly Gly Asn Ile Asn
450 455 460
Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Phe
465 470 475 480
Lys Asn Thr Thr Tyr Leu Gln Met Ser Ser Leu Glu Pro Glu Asp Thr
485 490 495
Ala Val Tyr Tyr Cys Ala Ala His Tyr Leu Leu Leu Pro Ser Tyr Ile
500 505 510
Ser Thr Ser Thr Asn Met Tyr Asn Tyr Trp Gly Gln Gly Thr Gln Val
515 520 525
Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Gln Val Gln
530 535 540
Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg
545 550 555 560
Leu Ser Cys Ala Ala Ser Gly Arg Thr Ser Leu Ile Leu Ala Met Ala
565 570 575
Trp Trp Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Ala Gly Arg Ile
580 585 590
Trp Trp Asn Asn Asp Met Thr Arg Tyr Ser Asp Ser Val Lys Gly Arg
595 600 605
Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr Leu Gln Met
610 615 620
Ser Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Glu Ala Asp
625 630 635 640
Leu Ile Gly Gly Ser Arg Gly Trp Gly Gln Gly Thr Leu Val Thr Val
645 650 655
Ser Ser Ala Ala Ala Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu
660 665 670
Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg
675 680 685
Thr Ser Leu Ile Leu Ala Met Ala Trp Trp Arg Gln Ala Pro Gly Lys
690 695 700
Glu Arg Glu Phe Ala Gly Arg Ile Trp Trp Asn Asn Asp Met Thr Arg
705 710 715 720
Tyr Ser Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala
725 730 735
Lys Asn Thr Val Tyr Leu Gln Met Ser Ser Leu Arg Ala Glu Asp Thr
740 745 750
Ala Val Tyr Tyr Cys Glu Ala Asp Leu Ile Gly Gly Ser Arg Gly Trp
755 760 765
Gly Gln Gly Thr Leu Val Thr Val Ser Ser
770 775
<210> 159
<211> 766
<212> PRT
<213> 人工序列 (Artificial Sequence)
<220>
<223> 多特异性抗体
CD16F1-L1-hHS10-L1-hA09-10-3-L3-hA09-10-4-L1-H33-14-L3-H33-14
(3321)
<400> 159
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Val Ser Gly Ser Leu Phe Ser Ala Arg
20 25 30
Val Met Gly Trp Tyr Arg Gln Ala Pro Gly Lys Gln Arg Glu Leu Val
35 40 45
Ala Ala Ile Thr Ser Gly Val Arg Thr Asp Tyr Ala Asp Ser Val Lys
50 55 60
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Arg Ala Val Tyr Leu
65 70 75 80
Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys Asn
85 90 95
Val Asn Leu Tyr Asn Thr Gly Asn Tyr Trp Gly Gln Gly Thr Gln Val
100 105 110
Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu Val Gln
115 120 125
Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg
130 135 140
Leu Ser Cys Ala Ala Ser Gly Ser Thr Asp Ser Ala Tyr Arg Met Gly
145 150 155 160
Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val Ser Ala Ile
165 170 175
Asn Trp Ser Asp Gly Arg Thr Tyr Tyr Ala Asp Ser Val Lys Gly Arg
180 185 190
Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu Gln Met
195 200 205
Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Ala Asp
210 215 220
Pro Asp Ser Arg Leu Tyr Tyr Thr Val Pro Gln Asn Tyr Asp Tyr Trp
225 230 235 240
Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly
245 250 255
Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln
260 265 270
Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Gly Gly Arg
275 280 285
Thr Phe Ser Asn Tyr Ala Leu Gly Trp Phe Arg Gln Ala Pro Gly Lys
290 295 300
Glu Arg Glu Phe Val Ala Ala Ile Ser Arg Ser Gly Gly Asn Ile Asn
305 310 315 320
Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Phe
325 330 335
Lys Asn Thr Val Tyr Leu Gln Met Ser Ser Leu Arg Ala Glu Asp Thr
340 345 350
Ala Val Tyr Tyr Cys Ala Ala His Tyr Leu Leu Leu Pro Ser Tyr Ile
355 360 365
Ser Thr Ser Thr Asn Met Tyr Asn Tyr Trp Gly Gln Gly Thr Gln Val
370 375 380
Thr Val Ser Ser Ala Ala Ala Gln Val Gln Leu Val Glu Ser Gly Gly
385 390 395 400
Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser
405 410 415
Gly Gly Gly Arg Thr Phe Ser Asn Tyr Ala Leu Gly Trp Phe Arg Gln
420 425 430
Ala Pro Gly Lys Glu Arg Glu Phe Val Ala Ala Ile Ser Arg Ser Gly
435 440 445
Gly Asn Ile Asn Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser
450 455 460
Arg Asp Asn Ala Lys Asn Thr Val Tyr Leu Gln Met Ser Ser Leu Arg
465 470 475 480
Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Ala His Tyr Leu Leu Leu
485 490 495
Pro Ser Tyr Ile Ser Thr Ser Thr Asn Met Tyr Asn Tyr Trp Gly Gln
500 505 510
Gly Thr Gln Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly
515 520 525
Ser Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly
530 535 540
Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Thr Ser Leu Ile
545 550 555 560
Leu Ala Met Ala Trp Trp Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe
565 570 575
Ala Gly Arg Ile Trp Trp Asn Asn Asp Met Thr Arg Tyr Ser Asp Ser
580 585 590
Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Val
595 600 605
Tyr Leu Gln Met Ser Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr
610 615 620
Cys Glu Ala Asp Leu Ile Gly Gly Ser Arg Gly Trp Gly Gln Gly Thr
625 630 635 640
Leu Val Thr Val Ser Ser Ala Ala Ala Gln Val Gln Leu Val Glu Ser
645 650 655
Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala
660 665 670
Ala Ser Gly Arg Thr Ser Leu Ile Leu Ala Met Ala Trp Trp Arg Gln
675 680 685
Ala Pro Gly Lys Glu Arg Glu Phe Ala Gly Arg Ile Trp Trp Asn Asn
690 695 700
Asp Met Thr Arg Tyr Ser Asp Ser Val Lys Gly Arg Phe Thr Ile Ser
705 710 715 720
Arg Asp Asn Ala Lys Asn Thr Val Tyr Leu Gln Met Ser Ser Leu Arg
725 730 735
Ala Glu Asp Thr Ala Val Tyr Tyr Cys Glu Ala Asp Leu Ile Gly Gly
740 745 750
Ser Arg Gly Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
755 760 765
<210> 160
<211> 917
<212> PRT
<213> 人工序列 (Artificial Sequence)
<220>
<223> 多特异性抗体 hHS10-L11*9-CD16F1-L1-CD16F1-L1-
hA09-10-2-L3-A09-10-L1- hPL-16-L3-hPL-16
<400> 160
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Ser Thr Asp Ser Ala Tyr
20 25 30
Arg Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val
35 40 45
Ser Ala Ile Asn Trp Ser Asp Gly Arg Thr Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Ala Asp Pro Asp Ser Arg Leu Tyr Tyr Thr Val Pro Gln Asn Tyr
100 105 110
Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Ser
115 120 125
Gly Arg Ser Ala Pro Leu Gly Leu Ala Arg Gln Ala Arg Gln Val Gly
130 135 140
Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro
145 150 155 160
Gly Gly Ser Leu Arg Leu Ser Cys Ala Val Ser Gly Ser Leu Phe Ser
165 170 175
Ala Arg Val Met Gly Trp Tyr Arg Gln Ala Pro Gly Lys Gln Arg Glu
180 185 190
Leu Val Ala Ala Ile Thr Ser Gly Val Arg Thr Asp Tyr Ala Asp Ser
195 200 205
Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Arg Ala Val
210 215 220
Tyr Leu Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr
225 230 235 240
Cys Asn Val Asn Leu Tyr Asn Thr Gly Asn Tyr Trp Gly Gln Gly Thr
245 250 255
Gln Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu
260 265 270
Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser
275 280 285
Leu Arg Leu Ser Cys Ala Val Ser Gly Ser Leu Phe Ser Ala Arg Val
290 295 300
Met Gly Trp Tyr Arg Gln Ala Pro Gly Lys Gln Arg Glu Leu Val Ala
305 310 315 320
Ala Ile Thr Ser Gly Val Arg Thr Asp Tyr Ala Asp Ser Val Lys Gly
325 330 335
Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Arg Ala Val Tyr Leu Gln
340 345 350
Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys Asn Val
355 360 365
Asn Leu Tyr Asn Thr Gly Asn Tyr Trp Gly Gln Gly Thr Gln Val Thr
370 375 380
Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu Val Gln Leu
385 390 395 400
Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu
405 410 415
Ser Cys Ala Ala Ser Gly Gly Gly Arg Thr Phe Ser Asn Tyr Ala Leu
420 425 430
Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val Ala Ala
435 440 445
Ile Ser Arg Ser Gly Gly Asn Ile Asn Tyr Ala Asp Ser Val Lys Gly
450 455 460
Arg Phe Thr Ile Ser Arg Asp Asn Phe Lys Asn Thr Thr Tyr Leu Gln
465 470 475 480
Met Ser Ser Leu Glu Pro Glu Asp Thr Ala Val Tyr Tyr Cys Ala Ala
485 490 495
His Tyr Leu Leu Leu Pro Ser Tyr Ile Ser Thr Ser Thr Asn Met Tyr
500 505 510
Asn Tyr Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser Ala Ala Ala
515 520 525
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Ala Gly Gly
530 535 540
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Gly Gly Arg Thr Phe Ser
545 550 555 560
Asn Tyr Ala Leu Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu
565 570 575
Phe Val Ala Ala Ile Ser Arg Ser Gly Gly Asn Ile Asn Tyr Ala Asp
580 585 590
Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Phe Lys Asn Thr
595 600 605
Thr Tyr Leu Gln Met Ser Ser Leu Glu Pro Glu Asp Thr Ala Val Tyr
610 615 620
Tyr Cys Ala Ala His Tyr Leu Leu Leu Pro Ser Tyr Ile Ser Thr Ser
625 630 635 640
Thr Asn Met Tyr Asn Tyr Trp Gly Gln Gly Thr Gln Val Thr Val Ser
645 650 655
Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu Val Gln Leu Val Glu
660 665 670
Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys
675 680 685
Ala Ala Ser Gly Gly Thr Phe Leu Thr Tyr Ser Met Ser Trp Val Arg
690 695 700
Gln Ala Pro Gly Lys Glu Arg Glu Phe Val Ser Ser Ile Asn Trp Ser
705 710 715 720
Gly Tyr Met Thr Tyr Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile
725 730 735
Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu
740 745 750
Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Ala Ala Arg Thr Ala
755 760 765
Ile Ala Ala Lys Arg Ser Ser Glu Phe Asp Tyr Trp Gly Gln Gly Thr
770 775 780
Gln Val Thr Val Ser Ser Ala Ala Ala Glu Val Gln Leu Val Glu Ser
785 790 795 800
Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala
805 810 815
Ala Ser Gly Gly Thr Phe Leu Thr Tyr Ser Met Ser Trp Val Arg Gln
820 825 830
Ala Pro Gly Lys Glu Arg Glu Phe Val Ser Ser Ile Asn Trp Ser Gly
835 840 845
Tyr Met Thr Tyr Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser
850 855 860
Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg
865 870 875 880
Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Ala Ala Arg Thr Ala Ile
885 890 895
Ala Ala Lys Arg Ser Ser Glu Phe Asp Tyr Trp Gly Gln Gly Thr Gln
900 905 910
Val Thr Val Ser Ser
915
<210> 161
<211> 885
<212> PRT
<213> 人工序列 (Artificial Sequence)
<220>
<223> 多特异性抗体
CD16F1-L3-CD16F1-L1-hHS10-L1-hA09-10-2-L3-A09-10-L1-H33-14-L3-H33
-14
<400> 161
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Val Ser Gly Ser Leu Phe Ser Ala Arg
20 25 30
Val Met Gly Trp Tyr Arg Gln Ala Pro Gly Lys Gln Arg Glu Leu Val
35 40 45
Ala Ala Ile Thr Ser Gly Val Arg Thr Asp Tyr Ala Asp Ser Val Lys
50 55 60
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Arg Ala Val Tyr Leu
65 70 75 80
Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys Asn
85 90 95
Val Asn Leu Tyr Asn Thr Gly Asn Tyr Trp Gly Gln Gly Thr Gln Val
100 105 110
Thr Val Ser Ser Ala Ala Ala Glu Val Gln Leu Val Glu Ser Gly Gly
115 120 125
Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Val Ser
130 135 140
Gly Ser Leu Phe Ser Ala Arg Val Met Gly Trp Tyr Arg Gln Ala Pro
145 150 155 160
Gly Lys Gln Arg Glu Leu Val Ala Ala Ile Thr Ser Gly Val Arg Thr
165 170 175
Asp Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn
180 185 190
Ala Lys Arg Ala Val Tyr Leu Gln Met Asn Ser Leu Lys Pro Glu Asp
195 200 205
Thr Ala Val Tyr Tyr Cys Asn Val Asn Leu Tyr Asn Thr Gly Asn Tyr
210 215 220
Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser Gly Gly Gly Gly Ser
225 230 235 240
Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val
245 250 255
Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Ser Thr
260 265 270
Asp Ser Ala Tyr Arg Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu
275 280 285
Arg Glu Phe Val Ser Ala Ile Asn Trp Ser Asp Gly Arg Thr Tyr Tyr
290 295 300
Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys
305 310 315 320
Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala
325 330 335
Val Tyr Tyr Cys Ala Ala Asp Pro Asp Ser Arg Leu Tyr Tyr Thr Val
340 345 350
Pro Gln Asn Tyr Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser
355 360 365
Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu Val Gln Leu Val Glu
370 375 380
Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys
385 390 395 400
Ala Ala Ser Gly Gly Gly Arg Thr Phe Ser Asn Tyr Ala Leu Gly Trp
405 410 415
Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val Ala Ala Ile Ser
420 425 430
Arg Ser Gly Gly Asn Ile Asn Tyr Ala Asp Ser Val Lys Gly Arg Phe
435 440 445
Thr Ile Ser Arg Asp Asn Phe Lys Asn Thr Thr Tyr Leu Gln Met Ser
450 455 460
Ser Leu Glu Pro Glu Asp Thr Ala Val Tyr Tyr Cys Ala Ala His Tyr
465 470 475 480
Leu Leu Leu Pro Ser Tyr Ile Ser Thr Ser Thr Asn Met Tyr Asn Tyr
485 490 495
Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser Ala Ala Ala Gln Val
500 505 510
Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Ala Gly Gly Ser Leu
515 520 525
Arg Leu Ser Cys Ala Ala Ser Gly Gly Gly Arg Thr Phe Ser Asn Tyr
530 535 540
Ala Leu Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val
545 550 555 560
Ala Ala Ile Ser Arg Ser Gly Gly Asn Ile Asn Tyr Ala Asp Ser Val
565 570 575
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Phe Lys Asn Thr Thr Tyr
580 585 590
Leu Gln Met Ser Ser Leu Glu Pro Glu Asp Thr Ala Val Tyr Tyr Cys
595 600 605
Ala Ala His Tyr Leu Leu Leu Pro Ser Tyr Ile Ser Thr Ser Thr Asn
610 615 620
Met Tyr Asn Tyr Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser Gly
625 630 635 640
Gly Gly Gly Ser Gly Gly Gly Ser Gln Val Gln Leu Val Glu Ser Gly
645 650 655
Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala
660 665 670
Ser Gly Arg Thr Ser Leu Ile Leu Ala Met Ala Trp Trp Arg Gln Ala
675 680 685
Pro Gly Lys Glu Arg Glu Phe Ala Gly Arg Ile Trp Trp Asn Asn Asp
690 695 700
Met Thr Arg Tyr Ser Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg
705 710 715 720
Asp Asn Ala Lys Asn Thr Val Tyr Leu Gln Met Ser Ser Leu Arg Ala
725 730 735
Glu Asp Thr Ala Val Tyr Tyr Cys Glu Ala Asp Leu Ile Gly Gly Ser
740 745 750
Arg Gly Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ala Ala
755 760 765
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
770 775 780
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Thr Ser Leu Ile Leu
785 790 795 800
Ala Met Ala Trp Trp Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Ala
805 810 815
Gly Arg Ile Trp Trp Asn Asn Asp Met Thr Arg Tyr Ser Asp Ser Val
820 825 830
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr
835 840 845
Leu Gln Met Ser Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
850 855 860
Glu Ala Asp Leu Ile Gly Gly Ser Arg Gly Trp Gly Gln Gly Thr Leu
865 870 875 880
Val Thr Val Ser Ser
885
<210> 162
<211> 897
<212> PRT
<213> 人工序列 (Artificial Sequence)
<220>
<223> 多特异性抗体 hHS10-L11*12-CD16F1-L3-CD16F1-L1-
hA09-10-2-L3-A09-10-L1-H33-14-L3-H33-14
<400> 162
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Ser Thr Asp Ser Ala Tyr
20 25 30
Arg Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val
35 40 45
Ser Ala Ile Asn Trp Ser Asp Gly Arg Thr Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Ala Asp Pro Asp Ser Arg Leu Tyr Tyr Thr Val Pro Gln Asn Tyr
100 105 110
Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Ser
115 120 125
Gly Arg Ser Ala Pro Leu Gly Leu Ala Arg Gln Ala Arg Gln Val Gly
130 135 140
Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro
145 150 155 160
Gly Gly Ser Leu Arg Leu Ser Cys Ala Val Ser Gly Ser Leu Phe Ser
165 170 175
Ala Arg Val Met Gly Trp Tyr Arg Gln Ala Pro Gly Lys Gln Arg Glu
180 185 190
Leu Val Ala Ala Ile Thr Ser Gly Val Arg Thr Asp Tyr Ala Asp Ser
195 200 205
Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Arg Ala Val
210 215 220
Tyr Leu Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr
225 230 235 240
Cys Asn Val Asn Leu Tyr Asn Thr Gly Asn Tyr Trp Gly Gln Gly Thr
245 250 255
Gln Val Thr Val Ser Ser Ala Ala Ala Glu Val Gln Leu Val Glu Ser
260 265 270
Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala
275 280 285
Val Ser Gly Ser Leu Phe Ser Ala Arg Val Met Gly Trp Tyr Arg Gln
290 295 300
Ala Pro Gly Lys Gln Arg Glu Leu Val Ala Ala Ile Thr Ser Gly Val
305 310 315 320
Arg Thr Asp Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg
325 330 335
Asp Asn Ala Lys Arg Ala Val Tyr Leu Gln Met Asn Ser Leu Lys Pro
340 345 350
Glu Asp Thr Ala Val Tyr Tyr Cys Asn Val Asn Leu Tyr Asn Thr Gly
355 360 365
Asn Tyr Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser Gly Gly Gly
370 375 380
Gly Ser Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly
385 390 395 400
Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly
405 410 415
Gly Gly Arg Thr Phe Ser Asn Tyr Ala Leu Gly Trp Phe Arg Gln Ala
420 425 430
Pro Gly Lys Glu Arg Glu Phe Val Ala Ala Ile Ser Arg Ser Gly Gly
435 440 445
Asn Ile Asn Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg
450 455 460
Asp Asn Phe Lys Asn Thr Thr Tyr Leu Gln Met Ser Ser Leu Glu Pro
465 470 475 480
Glu Asp Thr Ala Val Tyr Tyr Cys Ala Ala His Tyr Leu Leu Leu Pro
485 490 495
Ser Tyr Ile Ser Thr Ser Thr Asn Met Tyr Asn Tyr Trp Gly Gln Gly
500 505 510
Thr Gln Val Thr Val Ser Ser Ala Ala Ala Gln Val Gln Leu Val Glu
515 520 525
Ser Gly Gly Gly Leu Val Gln Ala Gly Gly Ser Leu Arg Leu Ser Cys
530 535 540
Ala Ala Ser Gly Gly Gly Arg Thr Phe Ser Asn Tyr Ala Leu Gly Trp
545 550 555 560
Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val Ala Ala Ile Ser
565 570 575
Arg Ser Gly Gly Asn Ile Asn Tyr Ala Asp Ser Val Lys Gly Arg Phe
580 585 590
Thr Ile Ser Arg Asp Asn Phe Lys Asn Thr Thr Tyr Leu Gln Met Ser
595 600 605
Ser Leu Glu Pro Glu Asp Thr Ala Val Tyr Tyr Cys Ala Ala His Tyr
610 615 620
Leu Leu Leu Pro Ser Tyr Ile Ser Thr Ser Thr Asn Met Tyr Asn Tyr
625 630 635 640
Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser Gly Gly Gly Gly Ser
645 650 655
Gly Gly Gly Ser Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val
660 665 670
Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Thr
675 680 685
Ser Leu Ile Leu Ala Met Ala Trp Trp Arg Gln Ala Pro Gly Lys Glu
690 695 700
Arg Glu Phe Ala Gly Arg Ile Trp Trp Asn Asn Asp Met Thr Arg Tyr
705 710 715 720
Ser Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys
725 730 735
Asn Thr Val Tyr Leu Gln Met Ser Ser Leu Arg Ala Glu Asp Thr Ala
740 745 750
Val Tyr Tyr Cys Glu Ala Asp Leu Ile Gly Gly Ser Arg Gly Trp Gly
755 760 765
Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ala Ala Gln Val Gln Leu
770 775 780
Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu
785 790 795 800
Ser Cys Ala Ala Ser Gly Arg Thr Ser Leu Ile Leu Ala Met Ala Trp
805 810 815
Trp Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Ala Gly Arg Ile Trp
820 825 830
Trp Asn Asn Asp Met Thr Arg Tyr Ser Asp Ser Val Lys Gly Arg Phe
835 840 845
Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr Leu Gln Met Ser
850 855 860
Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Glu Ala Asp Leu
865 870 875 880
Ile Gly Gly Ser Arg Gly Trp Gly Gln Gly Thr Leu Val Thr Val Ser
885 890 895
Ser
<210> 163
<211> 751
<212> PRT
<213> 人工序列 (Artificial Sequence)
<220>
<223> 多特异性抗体 CD16F1-L3-CD16F1-L1-
hA09-10-2-L3-A09-10-L1-H33-14-L3-H33-14
<400> 163
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Val Ser Gly Ser Leu Phe Ser Ala Arg
20 25 30
Val Met Gly Trp Tyr Arg Gln Ala Pro Gly Lys Gln Arg Glu Leu Val
35 40 45
Ala Ala Ile Thr Ser Gly Val Arg Thr Asp Tyr Ala Asp Ser Val Lys
50 55 60
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Arg Ala Val Tyr Leu
65 70 75 80
Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys Asn
85 90 95
Val Asn Leu Tyr Asn Thr Gly Asn Tyr Trp Gly Gln Gly Thr Gln Val
100 105 110
Thr Val Ser Ser Ala Ala Ala Glu Val Gln Leu Val Glu Ser Gly Gly
115 120 125
Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Val Ser
130 135 140
Gly Ser Leu Phe Ser Ala Arg Val Met Gly Trp Tyr Arg Gln Ala Pro
145 150 155 160
Gly Lys Gln Arg Glu Leu Val Ala Ala Ile Thr Ser Gly Val Arg Thr
165 170 175
Asp Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn
180 185 190
Ala Lys Arg Ala Val Tyr Leu Gln Met Asn Ser Leu Lys Pro Glu Asp
195 200 205
Thr Ala Val Tyr Tyr Cys Asn Val Asn Leu Tyr Asn Thr Gly Asn Tyr
210 215 220
Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser Gly Gly Gly Gly Ser
225 230 235 240
Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val
245 250 255
Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Gly Gly
260 265 270
Arg Thr Phe Ser Asn Tyr Ala Leu Gly Trp Phe Arg Gln Ala Pro Gly
275 280 285
Lys Glu Arg Glu Phe Val Ala Ala Ile Ser Arg Ser Gly Gly Asn Ile
290 295 300
Asn Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn
305 310 315 320
Phe Lys Asn Thr Thr Tyr Leu Gln Met Ser Ser Leu Glu Pro Glu Asp
325 330 335
Thr Ala Val Tyr Tyr Cys Ala Ala His Tyr Leu Leu Leu Pro Ser Tyr
340 345 350
Ile Ser Thr Ser Thr Asn Met Tyr Asn Tyr Trp Gly Gln Gly Thr Gln
355 360 365
Val Thr Val Ser Ser Ala Ala Ala Gln Val Gln Leu Val Glu Ser Gly
370 375 380
Gly Gly Leu Val Gln Ala Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala
385 390 395 400
Ser Gly Gly Gly Arg Thr Phe Ser Asn Tyr Ala Leu Gly Trp Phe Arg
405 410 415
Gln Ala Pro Gly Lys Glu Arg Glu Phe Val Ala Ala Ile Ser Arg Ser
420 425 430
Gly Gly Asn Ile Asn Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile
435 440 445
Ser Arg Asp Asn Phe Lys Asn Thr Thr Tyr Leu Gln Met Ser Ser Leu
450 455 460
Glu Pro Glu Asp Thr Ala Val Tyr Tyr Cys Ala Ala His Tyr Leu Leu
465 470 475 480
Leu Pro Ser Tyr Ile Ser Thr Ser Thr Asn Met Tyr Asn Tyr Trp Gly
485 490 495
Gln Gly Thr Gln Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly
500 505 510
Gly Ser Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro
515 520 525
Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Thr Ser Leu
530 535 540
Ile Leu Ala Met Ala Trp Trp Arg Gln Ala Pro Gly Lys Glu Arg Glu
545 550 555 560
Phe Ala Gly Arg Ile Trp Trp Asn Asn Asp Met Thr Arg Tyr Ser Asp
565 570 575
Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr
580 585 590
Val Tyr Leu Gln Met Ser Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr
595 600 605
Tyr Cys Glu Ala Asp Leu Ile Gly Gly Ser Arg Gly Trp Gly Gln Gly
610 615 620
Thr Leu Val Thr Val Ser Ser Ala Ala Ala Gln Val Gln Leu Val Glu
625 630 635 640
Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys
645 650 655
Ala Ala Ser Gly Arg Thr Ser Leu Ile Leu Ala Met Ala Trp Trp Arg
660 665 670
Gln Ala Pro Gly Lys Glu Arg Glu Phe Ala Gly Arg Ile Trp Trp Asn
675 680 685
Asn Asp Met Thr Arg Tyr Ser Asp Ser Val Lys Gly Arg Phe Thr Ile
690 695 700
Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr Leu Gln Met Ser Ser Leu
705 710 715 720
Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Glu Ala Asp Leu Ile Gly
725 730 735
Gly Ser Arg Gly Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
740 745 750
<210> 164
<211> 766
<212> PRT
<213> 人工序列 (Artificial Sequence)
<220>
<223> 多特异性抗体 H33-14-L3-H33-14-L1-
hA09-10-2-L3-A09-10-L1-hHS10-L1-CD16F1
<400> 164
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Thr Ser Leu Ile Leu
20 25 30
Ala Met Ala Trp Trp Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Ala
35 40 45
Gly Arg Ile Trp Trp Asn Asn Asp Met Thr Arg Tyr Ser Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr
65 70 75 80
Leu Gln Met Ser Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Glu Ala Asp Leu Ile Gly Gly Ser Arg Gly Trp Gly Gln Gly Thr Leu
100 105 110
Val Thr Val Ser Ser Ala Ala Ala Gln Val Gln Leu Val Glu Ser Gly
115 120 125
Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala
130 135 140
Ser Gly Arg Thr Ser Leu Ile Leu Ala Met Ala Trp Trp Arg Gln Ala
145 150 155 160
Pro Gly Lys Glu Arg Glu Phe Ala Gly Arg Ile Trp Trp Asn Asn Asp
165 170 175
Met Thr Arg Tyr Ser Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg
180 185 190
Asp Asn Ala Lys Asn Thr Val Tyr Leu Gln Met Ser Ser Leu Arg Ala
195 200 205
Glu Asp Thr Ala Val Tyr Tyr Cys Glu Ala Asp Leu Ile Gly Gly Ser
210 215 220
Arg Gly Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly
225 230 235 240
Gly Ser Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly
245 250 255
Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly
260 265 270
Gly Gly Arg Thr Phe Ser Asn Tyr Ala Leu Gly Trp Phe Arg Gln Ala
275 280 285
Pro Gly Lys Glu Arg Glu Phe Val Ala Ala Ile Ser Arg Ser Gly Gly
290 295 300
Asn Ile Asn Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg
305 310 315 320
Asp Asn Phe Lys Asn Thr Thr Tyr Leu Gln Met Ser Ser Leu Glu Pro
325 330 335
Glu Asp Thr Ala Val Tyr Tyr Cys Ala Ala His Tyr Leu Leu Leu Pro
340 345 350
Ser Tyr Ile Ser Thr Ser Thr Asn Met Tyr Asn Tyr Trp Gly Gln Gly
355 360 365
Thr Gln Val Thr Val Ser Ser Ala Ala Ala Gln Val Gln Leu Val Glu
370 375 380
Ser Gly Gly Gly Leu Val Gln Ala Gly Gly Ser Leu Arg Leu Ser Cys
385 390 395 400
Ala Ala Ser Gly Gly Gly Arg Thr Phe Ser Asn Tyr Ala Leu Gly Trp
405 410 415
Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val Ala Ala Ile Ser
420 425 430
Arg Ser Gly Gly Asn Ile Asn Tyr Ala Asp Ser Val Lys Gly Arg Phe
435 440 445
Thr Ile Ser Arg Asp Asn Phe Lys Asn Thr Thr Tyr Leu Gln Met Ser
450 455 460
Ser Leu Glu Pro Glu Asp Thr Ala Val Tyr Tyr Cys Ala Ala His Tyr
465 470 475 480
Leu Leu Leu Pro Ser Tyr Ile Ser Thr Ser Thr Asn Met Tyr Asn Tyr
485 490 495
Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser Gly Gly Gly Gly Ser
500 505 510
Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val
515 520 525
Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Ser Thr
530 535 540
Asp Ser Ala Tyr Arg Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu
545 550 555 560
Arg Glu Phe Val Ser Ala Ile Asn Trp Ser Asp Gly Arg Thr Tyr Tyr
565 570 575
Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys
580 585 590
Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala
595 600 605
Val Tyr Tyr Cys Ala Ala Asp Pro Asp Ser Arg Leu Tyr Tyr Thr Val
610 615 620
Pro Gln Asn Tyr Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser
625 630 635 640
Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu Val Gln Leu Val Glu
645 650 655
Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys
660 665 670
Ala Val Ser Gly Ser Leu Phe Ser Ala Arg Val Met Gly Trp Tyr Arg
675 680 685
Gln Ala Pro Gly Lys Gln Arg Glu Leu Val Ala Ala Ile Thr Ser Gly
690 695 700
Val Arg Thr Asp Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser
705 710 715 720
Arg Asp Asn Ala Lys Arg Ala Val Tyr Leu Gln Met Asn Ser Leu Lys
725 730 735
Pro Glu Asp Thr Ala Val Tyr Tyr Cys Asn Val Asn Leu Tyr Asn Thr
740 745 750
Gly Asn Tyr Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser
755 760 765
<210> 165
<211> 885
<212> PRT
<213> 人工序列 (Artificial Sequence)
<220>
<223> 多特异性抗体 H33-14-L3-H33-14-L1-
hA09-10-2-L3-A09-10-L1-hHS10-L1-CD16F1-L3-CD16F1
<400> 165
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Thr Ser Leu Ile Leu
20 25 30
Ala Met Ala Trp Trp Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Ala
35 40 45
Gly Arg Ile Trp Trp Asn Asn Asp Met Thr Arg Tyr Ser Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr
65 70 75 80
Leu Gln Met Ser Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Glu Ala Asp Leu Ile Gly Gly Ser Arg Gly Trp Gly Gln Gly Thr Leu
100 105 110
Val Thr Val Ser Ser Ala Ala Ala Gln Val Gln Leu Val Glu Ser Gly
115 120 125
Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala
130 135 140
Ser Gly Arg Thr Ser Leu Ile Leu Ala Met Ala Trp Trp Arg Gln Ala
145 150 155 160
Pro Gly Lys Glu Arg Glu Phe Ala Gly Arg Ile Trp Trp Asn Asn Asp
165 170 175
Met Thr Arg Tyr Ser Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg
180 185 190
Asp Asn Ala Lys Asn Thr Val Tyr Leu Gln Met Ser Ser Leu Arg Ala
195 200 205
Glu Asp Thr Ala Val Tyr Tyr Cys Glu Ala Asp Leu Ile Gly Gly Ser
210 215 220
Arg Gly Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly
225 230 235 240
Gly Ser Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly
245 250 255
Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly
260 265 270
Gly Gly Arg Thr Phe Ser Asn Tyr Ala Leu Gly Trp Phe Arg Gln Ala
275 280 285
Pro Gly Lys Glu Arg Glu Phe Val Ala Ala Ile Ser Arg Ser Gly Gly
290 295 300
Asn Ile Asn Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg
305 310 315 320
Asp Asn Phe Lys Asn Thr Thr Tyr Leu Gln Met Ser Ser Leu Glu Pro
325 330 335
Glu Asp Thr Ala Val Tyr Tyr Cys Ala Ala His Tyr Leu Leu Leu Pro
340 345 350
Ser Tyr Ile Ser Thr Ser Thr Asn Met Tyr Asn Tyr Trp Gly Gln Gly
355 360 365
Thr Gln Val Thr Val Ser Ser Ala Ala Ala Gln Val Gln Leu Val Glu
370 375 380
Ser Gly Gly Gly Leu Val Gln Ala Gly Gly Ser Leu Arg Leu Ser Cys
385 390 395 400
Ala Ala Ser Gly Gly Gly Arg Thr Phe Ser Asn Tyr Ala Leu Gly Trp
405 410 415
Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val Ala Ala Ile Ser
420 425 430
Arg Ser Gly Gly Asn Ile Asn Tyr Ala Asp Ser Val Lys Gly Arg Phe
435 440 445
Thr Ile Ser Arg Asp Asn Phe Lys Asn Thr Thr Tyr Leu Gln Met Ser
450 455 460
Ser Leu Glu Pro Glu Asp Thr Ala Val Tyr Tyr Cys Ala Ala His Tyr
465 470 475 480
Leu Leu Leu Pro Ser Tyr Ile Ser Thr Ser Thr Asn Met Tyr Asn Tyr
485 490 495
Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser Gly Gly Gly Gly Ser
500 505 510
Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val
515 520 525
Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Ser Thr
530 535 540
Asp Ser Ala Tyr Arg Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu
545 550 555 560
Arg Glu Phe Val Ser Ala Ile Asn Trp Ser Asp Gly Arg Thr Tyr Tyr
565 570 575
Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys
580 585 590
Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala
595 600 605
Val Tyr Tyr Cys Ala Ala Asp Pro Asp Ser Arg Leu Tyr Tyr Thr Val
610 615 620
Pro Gln Asn Tyr Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser
625 630 635 640
Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu Val Gln Leu Val Glu
645 650 655
Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys
660 665 670
Ala Val Ser Gly Ser Leu Phe Ser Ala Arg Val Met Gly Trp Tyr Arg
675 680 685
Gln Ala Pro Gly Lys Gln Arg Glu Leu Val Ala Ala Ile Thr Ser Gly
690 695 700
Val Arg Thr Asp Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser
705 710 715 720
Arg Asp Asn Ala Lys Arg Ala Val Tyr Leu Gln Met Asn Ser Leu Lys
725 730 735
Pro Glu Asp Thr Ala Val Tyr Tyr Cys Asn Val Asn Leu Tyr Asn Thr
740 745 750
Gly Asn Tyr Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser Ala Ala
755 760 765
Ala Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly
770 775 780
Gly Ser Leu Arg Leu Ser Cys Ala Val Ser Gly Ser Leu Phe Ser Ala
785 790 795 800
Arg Val Met Gly Trp Tyr Arg Gln Ala Pro Gly Lys Gln Arg Glu Leu
805 810 815
Val Ala Ala Ile Thr Ser Gly Val Arg Thr Asp Tyr Ala Asp Ser Val
820 825 830
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Arg Ala Val Tyr
835 840 845
Leu Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys
850 855 860
Asn Val Asn Leu Tyr Asn Thr Gly Asn Tyr Trp Gly Gln Gly Thr Gln
865 870 875 880
Val Thr Val Ser Ser
885
<210> 166
<211> 778
<212> PRT
<213> 人工序列 (Artificial Sequence)
<220>
<223> 多特异性抗体 H33-14-L3-H33-14-L1-
hA09-10-2-L3-A09-10-L1-CD16F1-L11*9-hHS10
<400> 166
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Thr Ser Leu Ile Leu
20 25 30
Ala Met Ala Trp Trp Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Ala
35 40 45
Gly Arg Ile Trp Trp Asn Asn Asp Met Thr Arg Tyr Ser Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr
65 70 75 80
Leu Gln Met Ser Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Glu Ala Asp Leu Ile Gly Gly Ser Arg Gly Trp Gly Gln Gly Thr Leu
100 105 110
Val Thr Val Ser Ser Ala Ala Ala Gln Val Gln Leu Val Glu Ser Gly
115 120 125
Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala
130 135 140
Ser Gly Arg Thr Ser Leu Ile Leu Ala Met Ala Trp Trp Arg Gln Ala
145 150 155 160
Pro Gly Lys Glu Arg Glu Phe Ala Gly Arg Ile Trp Trp Asn Asn Asp
165 170 175
Met Thr Arg Tyr Ser Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg
180 185 190
Asp Asn Ala Lys Asn Thr Val Tyr Leu Gln Met Ser Ser Leu Arg Ala
195 200 205
Glu Asp Thr Ala Val Tyr Tyr Cys Glu Ala Asp Leu Ile Gly Gly Ser
210 215 220
Arg Gly Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly
225 230 235 240
Gly Ser Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly
245 250 255
Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly
260 265 270
Gly Gly Arg Thr Phe Ser Asn Tyr Ala Leu Gly Trp Phe Arg Gln Ala
275 280 285
Pro Gly Lys Glu Arg Glu Phe Val Ala Ala Ile Ser Arg Ser Gly Gly
290 295 300
Asn Ile Asn Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg
305 310 315 320
Asp Asn Phe Lys Asn Thr Thr Tyr Leu Gln Met Ser Ser Leu Glu Pro
325 330 335
Glu Asp Thr Ala Val Tyr Tyr Cys Ala Ala His Tyr Leu Leu Leu Pro
340 345 350
Ser Tyr Ile Ser Thr Ser Thr Asn Met Tyr Asn Tyr Trp Gly Gln Gly
355 360 365
Thr Gln Val Thr Val Ser Ser Ala Ala Ala Gln Val Gln Leu Val Glu
370 375 380
Ser Gly Gly Gly Leu Val Gln Ala Gly Gly Ser Leu Arg Leu Ser Cys
385 390 395 400
Ala Ala Ser Gly Gly Gly Arg Thr Phe Ser Asn Tyr Ala Leu Gly Trp
405 410 415
Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val Ala Ala Ile Ser
420 425 430
Arg Ser Gly Gly Asn Ile Asn Tyr Ala Asp Ser Val Lys Gly Arg Phe
435 440 445
Thr Ile Ser Arg Asp Asn Phe Lys Asn Thr Thr Tyr Leu Gln Met Ser
450 455 460
Ser Leu Glu Pro Glu Asp Thr Ala Val Tyr Tyr Cys Ala Ala His Tyr
465 470 475 480
Leu Leu Leu Pro Ser Tyr Ile Ser Thr Ser Thr Asn Met Tyr Asn Tyr
485 490 495
Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser Gly Gly Gly Gly Ser
500 505 510
Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val
515 520 525
Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Val Ser Gly Ser Leu
530 535 540
Phe Ser Ala Arg Val Met Gly Trp Tyr Arg Gln Ala Pro Gly Lys Gln
545 550 555 560
Arg Glu Leu Val Ala Ala Ile Thr Ser Gly Val Arg Thr Asp Tyr Ala
565 570 575
Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Arg
580 585 590
Ala Val Tyr Leu Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Val
595 600 605
Tyr Tyr Cys Asn Val Asn Leu Tyr Asn Thr Gly Asn Tyr Trp Gly Gln
610 615 620
Gly Thr Gln Val Thr Val Ser Ser Gly Gly Ser Gly Arg Ser Ala Pro
625 630 635 640
Leu Gly Leu Ala Arg Gln Ala Arg Gln Val Gly Gly Ser Glu Val Gln
645 650 655
Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg
660 665 670
Leu Ser Cys Ala Ala Ser Gly Ser Thr Asp Ser Ala Tyr Arg Met Gly
675 680 685
Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val Ser Ala Ile
690 695 700
Asn Trp Ser Asp Gly Arg Thr Tyr Tyr Ala Asp Ser Val Lys Gly Arg
705 710 715 720
Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu Gln Met
725 730 735
Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Ala Asp
740 745 750
Pro Asp Ser Arg Leu Tyr Tyr Thr Val Pro Gln Asn Tyr Asp Tyr Trp
755 760 765
Gly Gln Gly Thr Leu Val Thr Val Ser Ser
770 775
<210> 167
<211> 897
<212> PRT
<213> 人工序列 (Artificial Sequence)
<220>
<223> 多特异性抗体
H33-14-L3-H33-14-L1-hA09-10-2-L3-A09-10-L1-CD16-F1-L3-CD16F1-L11*
9-hHS10
<400> 167
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Thr Ser Leu Ile Leu
20 25 30
Ala Met Ala Trp Trp Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Ala
35 40 45
Gly Arg Ile Trp Trp Asn Asn Asp Met Thr Arg Tyr Ser Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr
65 70 75 80
Leu Gln Met Ser Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Glu Ala Asp Leu Ile Gly Gly Ser Arg Gly Trp Gly Gln Gly Thr Leu
100 105 110
Val Thr Val Ser Ser Ala Ala Ala Gln Val Gln Leu Val Glu Ser Gly
115 120 125
Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala
130 135 140
Ser Gly Arg Thr Ser Leu Ile Leu Ala Met Ala Trp Trp Arg Gln Ala
145 150 155 160
Pro Gly Lys Glu Arg Glu Phe Ala Gly Arg Ile Trp Trp Asn Asn Asp
165 170 175
Met Thr Arg Tyr Ser Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg
180 185 190
Asp Asn Ala Lys Asn Thr Val Tyr Leu Gln Met Ser Ser Leu Arg Ala
195 200 205
Glu Asp Thr Ala Val Tyr Tyr Cys Glu Ala Asp Leu Ile Gly Gly Ser
210 215 220
Arg Gly Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly
225 230 235 240
Gly Ser Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly
245 250 255
Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly
260 265 270
Gly Gly Arg Thr Phe Ser Asn Tyr Ala Leu Gly Trp Phe Arg Gln Ala
275 280 285
Pro Gly Lys Glu Arg Glu Phe Val Ala Ala Ile Ser Arg Ser Gly Gly
290 295 300
Asn Ile Asn Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg
305 310 315 320
Asp Asn Phe Lys Asn Thr Thr Tyr Leu Gln Met Ser Ser Leu Glu Pro
325 330 335
Glu Asp Thr Ala Val Tyr Tyr Cys Ala Ala His Tyr Leu Leu Leu Pro
340 345 350
Ser Tyr Ile Ser Thr Ser Thr Asn Met Tyr Asn Tyr Trp Gly Gln Gly
355 360 365
Thr Gln Val Thr Val Ser Ser Ala Ala Ala Gln Val Gln Leu Val Glu
370 375 380
Ser Gly Gly Gly Leu Val Gln Ala Gly Gly Ser Leu Arg Leu Ser Cys
385 390 395 400
Ala Ala Ser Gly Gly Gly Arg Thr Phe Ser Asn Tyr Ala Leu Gly Trp
405 410 415
Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val Ala Ala Ile Ser
420 425 430
Arg Ser Gly Gly Asn Ile Asn Tyr Ala Asp Ser Val Lys Gly Arg Phe
435 440 445
Thr Ile Ser Arg Asp Asn Phe Lys Asn Thr Thr Tyr Leu Gln Met Ser
450 455 460
Ser Leu Glu Pro Glu Asp Thr Ala Val Tyr Tyr Cys Ala Ala His Tyr
465 470 475 480
Leu Leu Leu Pro Ser Tyr Ile Ser Thr Ser Thr Asn Met Tyr Asn Tyr
485 490 495
Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser Gly Gly Gly Gly Ser
500 505 510
Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val
515 520 525
Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Val Ser Gly Ser Leu
530 535 540
Phe Ser Ala Arg Val Met Gly Trp Tyr Arg Gln Ala Pro Gly Lys Gln
545 550 555 560
Arg Glu Leu Val Ala Ala Ile Thr Ser Gly Val Arg Thr Asp Tyr Ala
565 570 575
Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Arg
580 585 590
Ala Val Tyr Leu Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Val
595 600 605
Tyr Tyr Cys Asn Val Asn Leu Tyr Asn Thr Gly Asn Tyr Trp Gly Gln
610 615 620
Gly Thr Gln Val Thr Val Ser Ser Ala Ala Ala Glu Val Gln Leu Val
625 630 635 640
Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser
645 650 655
Cys Ala Val Ser Gly Ser Leu Phe Ser Ala Arg Val Met Gly Trp Tyr
660 665 670
Arg Gln Ala Pro Gly Lys Gln Arg Glu Leu Val Ala Ala Ile Thr Ser
675 680 685
Gly Val Arg Thr Asp Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile
690 695 700
Ser Arg Asp Asn Ala Lys Arg Ala Val Tyr Leu Gln Met Asn Ser Leu
705 710 715 720
Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys Asn Val Asn Leu Tyr Asn
725 730 735
Thr Gly Asn Tyr Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser Gly
740 745 750
Gly Ser Gly Arg Ser Ala Pro Leu Gly Leu Ala Arg Gln Ala Arg Gln
755 760 765
Val Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val
770 775 780
Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Ser Thr
785 790 795 800
Asp Ser Ala Tyr Arg Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu
805 810 815
Arg Glu Phe Val Ser Ala Ile Asn Trp Ser Asp Gly Arg Thr Tyr Tyr
820 825 830
Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys
835 840 845
Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala
850 855 860
Val Tyr Tyr Cys Ala Ala Asp Pro Asp Ser Arg Leu Tyr Tyr Thr Val
865 870 875 880
Pro Gln Asn Tyr Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser
885 890 895
Ser
<210> 168
<211> 651
<212> PRT
<213> 人工序列 (Artificial Sequence)
<220>
<223> 多特异性抗体 CD16F1-L1-hHS5-L1-
hA09-10-2-L3-A09-10-L1-hPL16 (015-3-HS5)
<400> 168
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Val Ser Gly Ser Leu Phe Ser Ala Arg
20 25 30
Val Met Gly Trp Tyr Arg Gln Ala Pro Gly Lys Gln Arg Glu Leu Val
35 40 45
Ala Ala Ile Thr Ser Gly Val Arg Thr Asp Tyr Ala Asp Ser Val Lys
50 55 60
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Arg Ala Val Tyr Leu
65 70 75 80
Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys Asn
85 90 95
Val Asn Leu Tyr Asn Thr Gly Asn Tyr Trp Gly Gln Gly Thr Gln Val
100 105 110
Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu Val Gln
115 120 125
Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg
130 135 140
Leu Ser Cys Ala Ala Ser Gly Arg Thr Phe Thr Thr His Ala Met Gly
145 150 155 160
Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val Ser Ala Ile
165 170 175
Asn Trp Gly Gly Arg Thr Thr Tyr Tyr Ala Asp Ser Val Lys Gly Arg
180 185 190
Phe Ile Ile Ser Arg Asp Thr Gly Ala Asn Thr Leu Tyr Leu Gln Met
195 200 205
Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Ser Asn
210 215 220
Leu Asp Thr Tyr Asn Val Arg Ala Gly Thr Thr Asn Ser Trp Gly Gln
225 230 235 240
Gly Thr Gln Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly
245 250 255
Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly
260 265 270
Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Gly Gly Arg Thr Phe
275 280 285
Ser Asn Tyr Ala Leu Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg
290 295 300
Glu Phe Val Ala Ala Ile Ser Arg Ser Gly Gly Asn Ile Asn Tyr Ala
305 310 315 320
Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Phe Lys Asn
325 330 335
Thr Thr Tyr Leu Gln Met Ser Ser Leu Glu Pro Glu Asp Thr Ala Val
340 345 350
Tyr Tyr Cys Ala Ala His Tyr Leu Leu Leu Pro Ser Tyr Ile Ser Thr
355 360 365
Ser Thr Asn Met Tyr Asn Tyr Trp Gly Gln Gly Thr Gln Val Thr Val
370 375 380
Ser Ser Ala Ala Ala Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu
385 390 395 400
Val Gln Ala Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Gly
405 410 415
Gly Arg Thr Phe Ser Asn Tyr Ala Leu Gly Trp Phe Arg Gln Ala Pro
420 425 430
Gly Lys Glu Arg Glu Phe Val Ala Ala Ile Ser Arg Ser Gly Gly Asn
435 440 445
Ile Asn Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp
450 455 460
Asn Phe Lys Asn Thr Thr Tyr Leu Gln Met Ser Ser Leu Glu Pro Glu
465 470 475 480
Asp Thr Ala Val Tyr Tyr Cys Ala Ala His Tyr Leu Leu Leu Pro Ser
485 490 495
Tyr Ile Ser Thr Ser Thr Asn Met Tyr Asn Tyr Trp Gly Gln Gly Thr
500 505 510
Gln Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu
515 520 525
Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser
530 535 540
Leu Arg Leu Ser Cys Ala Ala Ser Gly Gly Thr Phe Leu Thr Tyr Ser
545 550 555 560
Met Ser Trp Val Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val Ser
565 570 575
Ser Ile Asn Trp Ser Gly Tyr Met Thr Tyr Tyr Ala Asp Ser Val Lys
580 585 590
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu
595 600 605
Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala
610 615 620
Ala Ala Arg Thr Ala Ile Ala Ala Lys Arg Ser Ser Glu Phe Asp Tyr
625 630 635 640
Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser
645 650
<210> 169
<211> 663
<212> PRT
<213> 人工序列 (Artificial Sequence)
<220>
<223> 多特异性抗体 hHS5-L11*9-CD16F1-L1-
hA09-10-2-L3-A09-10-L1-hPL16
<400> 169
Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Thr Phe Thr Thr His
20 25 30
Ala Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val
35 40 45
Ser Ala Ile Asn Trp Gly Gly Arg Thr Thr Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Ile Ile Ser Arg Asp Thr Gly Ala Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Ser Asn Leu Asp Thr Tyr Asn Val Arg Ala Gly Thr Thr Asn Ser
100 105 110
Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser Gly Gly Ser Gly Arg
115 120 125
Ser Ala Pro Leu Gly Leu Ala Arg Gln Ala Arg Gln Val Gly Gly Ser
130 135 140
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
145 150 155 160
Ser Leu Arg Leu Ser Cys Ala Val Ser Gly Ser Leu Phe Ser Ala Arg
165 170 175
Val Met Gly Trp Tyr Arg Gln Ala Pro Gly Lys Gln Arg Glu Leu Val
180 185 190
Ala Ala Ile Thr Ser Gly Val Arg Thr Asp Tyr Ala Asp Ser Val Lys
195 200 205
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Arg Ala Val Tyr Leu
210 215 220
Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys Asn
225 230 235 240
Val Asn Leu Tyr Asn Thr Gly Asn Tyr Trp Gly Gln Gly Thr Gln Val
245 250 255
Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu Val Gln
260 265 270
Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg
275 280 285
Leu Ser Cys Ala Ala Ser Gly Gly Gly Arg Thr Phe Ser Asn Tyr Ala
290 295 300
Leu Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val Ala
305 310 315 320
Ala Ile Ser Arg Ser Gly Gly Asn Ile Asn Tyr Ala Asp Ser Val Lys
325 330 335
Gly Arg Phe Thr Ile Ser Arg Asp Asn Phe Lys Asn Thr Thr Tyr Leu
340 345 350
Gln Met Ser Ser Leu Glu Pro Glu Asp Thr Ala Val Tyr Tyr Cys Ala
355 360 365
Ala His Tyr Leu Leu Leu Pro Ser Tyr Ile Ser Thr Ser Thr Asn Met
370 375 380
Tyr Asn Tyr Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser Ala Ala
385 390 395 400
Ala Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Ala Gly
405 410 415
Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Gly Gly Arg Thr Phe
420 425 430
Ser Asn Tyr Ala Leu Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg
435 440 445
Glu Phe Val Ala Ala Ile Ser Arg Ser Gly Gly Asn Ile Asn Tyr Ala
450 455 460
Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Phe Lys Asn
465 470 475 480
Thr Thr Tyr Leu Gln Met Ser Ser Leu Glu Pro Glu Asp Thr Ala Val
485 490 495
Tyr Tyr Cys Ala Ala His Tyr Leu Leu Leu Pro Ser Tyr Ile Ser Thr
500 505 510
Ser Thr Asn Met Tyr Asn Tyr Trp Gly Gln Gly Thr Gln Val Thr Val
515 520 525
Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu Val Gln Leu Val
530 535 540
Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser
545 550 555 560
Cys Ala Ala Ser Gly Gly Thr Phe Leu Thr Tyr Ser Met Ser Trp Val
565 570 575
Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val Ser Ser Ile Asn Trp
580 585 590
Ser Gly Tyr Met Thr Tyr Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr
595 600 605
Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser
610 615 620
Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Ala Ala Arg Thr
625 630 635 640
Ala Ile Ala Ala Lys Arg Ser Ser Glu Phe Asp Tyr Trp Gly Gln Gly
645 650 655
Thr Gln Val Thr Val Ser Ser
660
<210> 170
<211> 526
<212> PRT
<213> 人工序列 (Artificial Sequence)
<220>
<223> 多特异性抗体 CD16F1-L1-hHS5-L1- A09-10-L1 -hPL16
(015-2-HS5)
<400> 170
Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Thr Phe Thr Thr His
20 25 30
Ala Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val
35 40 45
Ser Ala Ile Asn Trp Gly Gly Arg Thr Thr Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Ile Ile Ser Arg Asp Thr Gly Ala Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Ser Asn Leu Asp Thr Tyr Asn Val Arg Ala Gly Thr Thr Asn Ser
100 105 110
Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser Gly Gly Gly Gly Ser
115 120 125
Gly Gly Gly Ser Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val
130 135 140
Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Thr
145 150 155 160
Phe Thr Thr His Ala Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu
165 170 175
Arg Glu Phe Val Ser Ala Ile Asn Trp Gly Gly Arg Thr Thr Tyr Tyr
180 185 190
Ala Asp Ser Val Lys Gly Arg Phe Ile Ile Ser Arg Asp Thr Gly Ala
195 200 205
Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala
210 215 220
Val Tyr Tyr Cys Ala Ser Asn Leu Asp Thr Tyr Asn Val Arg Ala Gly
225 230 235 240
Thr Thr Asn Ser Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser Gly
245 250 255
Gly Gly Gly Ser Gly Gly Gly Ser Gln Val Gln Leu Val Glu Ser Gly
260 265 270
Gly Gly Leu Val Gln Ala Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala
275 280 285
Ser Gly Gly Gly Arg Thr Phe Ser Asn Tyr Ala Leu Gly Trp Phe Arg
290 295 300
Gln Ala Pro Gly Lys Glu Arg Glu Phe Val Ala Ala Ile Ser Arg Ser
305 310 315 320
Gly Gly Asn Ile Asn Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile
325 330 335
Ser Arg Asp Asn Phe Lys Asn Thr Thr Tyr Leu Gln Met Ser Ser Leu
340 345 350
Glu Pro Glu Asp Thr Ala Val Tyr Tyr Cys Ala Ala His Tyr Leu Leu
355 360 365
Leu Pro Ser Tyr Ile Ser Thr Ser Thr Asn Met Tyr Asn Tyr Trp Gly
370 375 380
Gln Gly Thr Gln Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly
385 390 395 400
Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro
405 410 415
Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Gly Thr Phe Leu
420 425 430
Thr Tyr Ser Met Ser Trp Val Arg Gln Ala Pro Gly Lys Glu Arg Glu
435 440 445
Phe Val Ser Ser Ile Asn Trp Ser Gly Tyr Met Thr Tyr Tyr Ala Asp
450 455 460
Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr
465 470 475 480
Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr
485 490 495
Tyr Cys Ala Ala Ala Arg Thr Ala Ile Ala Ala Lys Arg Ser Ser Glu
500 505 510
Phe Asp Tyr Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser
515 520 525
<210> 171
<211> 796
<212> PRT
<213> 人工序列 (Artificial Sequence)
<220>
<223> 多特异性抗体 hHS5-L11*9-CD16F1-
L1-A09-10-L3-A0910-L1-hPL16-L3-hPL16
<400> 171
Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Thr Phe Thr Thr His
20 25 30
Ala Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val
35 40 45
Ser Ala Ile Asn Trp Gly Gly Arg Thr Thr Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Ile Ile Ser Arg Asp Thr Gly Ala Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Ser Asn Leu Asp Thr Tyr Asn Val Arg Ala Gly Thr Thr Asn Ser
100 105 110
Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser Gly Gly Ser Gly Arg
115 120 125
Ser Ala Pro Leu Gly Leu Ala Arg Gln Ala Arg Gln Val Gly Gly Ser
130 135 140
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
145 150 155 160
Ser Leu Arg Leu Ser Cys Ala Val Ser Gly Ser Leu Phe Ser Ala Arg
165 170 175
Val Met Gly Trp Tyr Arg Gln Ala Pro Gly Lys Gln Arg Glu Leu Val
180 185 190
Ala Ala Ile Thr Ser Gly Val Arg Thr Asp Tyr Ala Asp Ser Val Lys
195 200 205
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Arg Ala Val Tyr Leu
210 215 220
Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys Asn
225 230 235 240
Val Asn Leu Tyr Asn Thr Gly Asn Tyr Trp Gly Gln Gly Thr Gln Val
245 250 255
Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu Val Gln
260 265 270
Leu Val Glu Ser Gly Gly Gly Leu Val Gln Ala Gly Gly Ser Leu Arg
275 280 285
Leu Ser Cys Ala Ala Ser Gly Gly Gly Arg Thr Phe Ser Asn Tyr Ala
290 295 300
Leu Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val Ala
305 310 315 320
Ala Ile Ser Arg Ser Gly Gly Asn Ile Asn Tyr Ala Asp Ser Ala Lys
325 330 335
Gly Arg Phe Thr Ile Ser Arg Asp Asn Phe Lys Asn Thr Thr Tyr Leu
340 345 350
Gln Met Ser Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys Ala
355 360 365
Ala His Tyr Leu Leu Leu Pro Ser Tyr Ile Ser Thr Ser Thr Asn Met
370 375 380
Tyr Asn Tyr Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser Ala Ala
385 390 395 400
Ala Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Ala Gly
405 410 415
Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Gly Gly Arg Thr Phe
420 425 430
Ser Asn Tyr Ala Leu Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg
435 440 445
Glu Phe Val Ala Ala Ile Ser Arg Ser Gly Gly Asn Ile Asn Tyr Ala
450 455 460
Asp Ser Ala Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Phe Lys Asn
465 470 475 480
Thr Thr Tyr Leu Gln Met Ser Ser Leu Lys Pro Glu Asp Thr Ala Val
485 490 495
Tyr Tyr Cys Ala Ala His Tyr Leu Leu Leu Pro Ser Tyr Ile Ser Thr
500 505 510
Ser Thr Asn Met Tyr Asn Tyr Trp Gly Gln Gly Thr Gln Val Thr Val
515 520 525
Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu Val Gln Leu Val
530 535 540
Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser
545 550 555 560
Cys Ala Ala Ser Gly Gly Thr Phe Leu Thr Tyr Ser Met Ser Trp Val
565 570 575
Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val Ser Ser Ile Asn Trp
580 585 590
Ser Gly Tyr Met Thr Tyr Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr
595 600 605
Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser
610 615 620
Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Ala Ala Arg Thr
625 630 635 640
Ala Ile Ala Ala Lys Arg Ser Ser Glu Phe Asp Tyr Trp Gly Gln Gly
645 650 655
Thr Gln Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser
660 665 670
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
675 680 685
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Gly Thr Phe Leu Thr Tyr
690 695 700
Ser Met Ser Trp Val Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val
705 710 715 720
Ser Ser Ile Asn Trp Ser Gly Tyr Met Thr Tyr Tyr Ala Asp Ser Val
725 730 735
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
740 745 750
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
755 760 765
Ala Ala Ala Arg Thr Ala Ile Ala Ala Lys Arg Ser Ser Glu Phe Asp
770 775 780
Tyr Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser
785 790 795
<210> 172
<211> 778
<212> PRT
<213> 人工序列 (Artificial Sequence)
<220>
<223> 多特异性抗体
CD16F1-L1-hHS5-L1-A09-10-L3-A09-10-L1-hPL16-L3-hPL16
(1511-HS5)
<400> 172
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Val Ser Gly Ser Leu Phe Ser Ala Arg
20 25 30
Val Met Gly Trp Tyr Arg Gln Ala Pro Gly Lys Gln Arg Glu Leu Val
35 40 45
Ala Ala Ile Thr Ser Gly Val Arg Thr Asp Tyr Ala Asp Ser Val Lys
50 55 60
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Arg Ala Val Tyr Leu
65 70 75 80
Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys Asn
85 90 95
Val Asn Leu Tyr Asn Thr Gly Asn Tyr Trp Gly Gln Gly Thr Gln Val
100 105 110
Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu Val Gln
115 120 125
Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg
130 135 140
Leu Ser Cys Ala Ala Ser Gly Arg Thr Phe Thr Thr His Ala Met Gly
145 150 155 160
Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val Ser Ala Ile
165 170 175
Asn Trp Gly Gly Arg Thr Thr Tyr Tyr Ala Asp Ser Val Lys Gly Arg
180 185 190
Phe Ile Ile Ser Arg Asp Thr Gly Ala Asn Thr Leu Tyr Leu Gln Met
195 200 205
Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Ser Asn
210 215 220
Leu Asp Thr Tyr Asn Val Arg Ala Gly Thr Thr Asn Ser Trp Gly Gln
225 230 235 240
Gly Thr Gln Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly
245 250 255
Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Ala Gly
260 265 270
Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Gly Gly Arg Thr Phe
275 280 285
Ser Asn Tyr Ala Leu Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg
290 295 300
Glu Phe Val Ala Ala Ile Ser Arg Ser Gly Gly Asn Ile Asn Tyr Ala
305 310 315 320
Asp Ser Ala Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Phe Lys Asn
325 330 335
Thr Thr Tyr Leu Gln Met Ser Ser Leu Lys Pro Glu Asp Thr Ala Val
340 345 350
Tyr Tyr Cys Ala Ala His Tyr Leu Leu Leu Pro Ser Tyr Ile Ser Thr
355 360 365
Ser Thr Asn Met Tyr Asn Tyr Trp Gly Gln Gly Thr Gln Val Thr Val
370 375 380
Ser Ser Ala Ala Ala Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu
385 390 395 400
Val Gln Ala Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Gly
405 410 415
Gly Arg Thr Phe Ser Asn Tyr Ala Leu Gly Trp Phe Arg Gln Ala Pro
420 425 430
Gly Lys Glu Arg Glu Phe Val Ala Ala Ile Ser Arg Ser Gly Gly Asn
435 440 445
Ile Asn Tyr Ala Asp Ser Ala Lys Gly Arg Phe Thr Ile Ser Arg Asp
450 455 460
Asn Phe Lys Asn Thr Thr Tyr Leu Gln Met Ser Ser Leu Lys Pro Glu
465 470 475 480
Asp Thr Ala Val Tyr Tyr Cys Ala Ala His Tyr Leu Leu Leu Pro Ser
485 490 495
Tyr Ile Ser Thr Ser Thr Asn Met Tyr Asn Tyr Trp Gly Gln Gly Thr
500 505 510
Gln Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu
515 520 525
Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser
530 535 540
Leu Arg Leu Ser Cys Ala Ala Ser Gly Gly Thr Phe Leu Thr Tyr Ser
545 550 555 560
Met Ser Trp Val Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val Ser
565 570 575
Ser Ile Asn Trp Ser Gly Tyr Met Thr Tyr Tyr Ala Asp Ser Val Lys
580 585 590
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu
595 600 605
Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala
610 615 620
Ala Ala Arg Thr Ala Ile Ala Ala Lys Arg Ser Ser Glu Phe Asp Tyr
625 630 635 640
Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser Ala Ala Ala Glu Val
645 650 655
Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu
660 665 670
Arg Leu Ser Cys Ala Ala Ser Gly Gly Thr Phe Leu Thr Tyr Ser Met
675 680 685
Ser Trp Val Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val Ser Ser
690 695 700
Ile Asn Trp Ser Gly Tyr Met Thr Tyr Tyr Ala Asp Ser Val Lys Gly
705 710 715 720
Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu Gln
725 730 735
Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Ala
740 745 750
Ala Arg Thr Ala Ile Ala Ala Lys Arg Ser Ser Glu Phe Asp Tyr Trp
755 760 765
Gly Gln Gly Thr Gln Val Thr Val Ser Ser
770 775
<210> 173
<211> 778
<212> PRT
<213> 人工序列 (Artificial Sequence)
<220>
<223> 多特异性抗体
CD16F1-L1-hHS5-L1-hA09-10-3-L3-hA09-10-4-L1-hPL16-L3-hPL16
(1518-HS5)
<400> 173
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Val Ser Gly Ser Leu Phe Ser Ala Arg
20 25 30
Val Met Gly Trp Tyr Arg Gln Ala Pro Gly Lys Gln Arg Glu Leu Val
35 40 45
Ala Ala Ile Thr Ser Gly Val Arg Thr Asp Tyr Ala Asp Ser Val Lys
50 55 60
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Arg Ala Val Tyr Leu
65 70 75 80
Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys Asn
85 90 95
Val Asn Leu Tyr Asn Thr Gly Asn Tyr Trp Gly Gln Gly Thr Gln Val
100 105 110
Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu Val Gln
115 120 125
Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg
130 135 140
Leu Ser Cys Ala Ala Ser Gly Arg Thr Phe Thr Thr His Ala Met Gly
145 150 155 160
Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val Ser Ala Ile
165 170 175
Asn Trp Gly Gly Arg Thr Thr Tyr Tyr Ala Asp Ser Val Lys Gly Arg
180 185 190
Phe Ile Ile Ser Arg Asp Thr Gly Ala Asn Thr Leu Tyr Leu Gln Met
195 200 205
Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Ser Asn
210 215 220
Leu Asp Thr Tyr Asn Val Arg Ala Gly Thr Thr Asn Ser Trp Gly Gln
225 230 235 240
Gly Thr Gln Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly
245 250 255
Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly
260 265 270
Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Gly Gly Arg Thr Phe
275 280 285
Ser Asn Tyr Ala Leu Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg
290 295 300
Glu Phe Val Ala Ala Ile Ser Arg Ser Gly Gly Asn Ile Asn Tyr Ala
305 310 315 320
Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Phe Lys Asn
325 330 335
Thr Val Tyr Leu Gln Met Ser Ser Leu Arg Ala Glu Asp Thr Ala Val
340 345 350
Tyr Tyr Cys Ala Ala His Tyr Leu Leu Leu Pro Ser Tyr Ile Ser Thr
355 360 365
Ser Thr Asn Met Tyr Asn Tyr Trp Gly Gln Gly Thr Gln Val Thr Val
370 375 380
Ser Ser Ala Ala Ala Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu
385 390 395 400
Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Gly
405 410 415
Gly Arg Thr Phe Ser Asn Tyr Ala Leu Gly Trp Phe Arg Gln Ala Pro
420 425 430
Gly Lys Glu Arg Glu Phe Val Ala Ala Ile Ser Arg Ser Gly Gly Asn
435 440 445
Ile Asn Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp
450 455 460
Asn Ala Lys Asn Thr Val Tyr Leu Gln Met Ser Ser Leu Arg Ala Glu
465 470 475 480
Asp Thr Ala Val Tyr Tyr Cys Ala Ala His Tyr Leu Leu Leu Pro Ser
485 490 495
Tyr Ile Ser Thr Ser Thr Asn Met Tyr Asn Tyr Trp Gly Gln Gly Thr
500 505 510
Gln Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu
515 520 525
Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser
530 535 540
Leu Arg Leu Ser Cys Ala Ala Ser Gly Gly Thr Phe Leu Thr Tyr Ser
545 550 555 560
Met Ser Trp Val Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val Ser
565 570 575
Ser Ile Asn Trp Ser Gly Tyr Met Thr Tyr Tyr Ala Asp Ser Val Lys
580 585 590
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu
595 600 605
Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala
610 615 620
Ala Ala Arg Thr Ala Ile Ala Ala Lys Arg Ser Ser Glu Phe Asp Tyr
625 630 635 640
Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser Ala Ala Ala Glu Val
645 650 655
Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu
660 665 670
Arg Leu Ser Cys Ala Ala Ser Gly Gly Thr Phe Leu Thr Tyr Ser Met
675 680 685
Ser Trp Val Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val Ser Ser
690 695 700
Ile Asn Trp Ser Gly Tyr Met Thr Tyr Tyr Ala Asp Ser Val Lys Gly
705 710 715 720
Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu Gln
725 730 735
Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Ala
740 745 750
Ala Arg Thr Ala Ile Ala Ala Lys Arg Ser Ser Glu Phe Asp Tyr Trp
755 760 765
Gly Gln Gly Thr Gln Val Thr Val Ser Ser
770 775
<210> 174
<211> 776
<212> PRT
<213> 人工序列 (Artificial Sequence)
<220>
<223> 多特异性抗体 hHS5-L11*9-CD16F1-
L1-hA09-10-2-L3-A09-10-L1- H33-14-L3-H33-14
<400> 174
Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Thr Phe Thr Thr His
20 25 30
Ala Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val
35 40 45
Ser Ala Ile Asn Trp Gly Gly Arg Thr Thr Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Ile Ile Ser Arg Asp Thr Gly Ala Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Ser Asn Leu Asp Thr Tyr Asn Val Arg Ala Gly Thr Thr Asn Ser
100 105 110
Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser Gly Gly Ser Gly Arg
115 120 125
Ser Ala Pro Leu Gly Leu Ala Arg Gln Ala Arg Gln Val Gly Gly Ser
130 135 140
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
145 150 155 160
Ser Leu Arg Leu Ser Cys Ala Val Ser Gly Ser Leu Phe Ser Ala Arg
165 170 175
Val Met Gly Trp Tyr Arg Gln Ala Pro Gly Lys Gln Arg Glu Leu Val
180 185 190
Ala Ala Ile Thr Ser Gly Val Arg Thr Asp Tyr Ala Asp Ser Val Lys
195 200 205
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Arg Ala Val Tyr Leu
210 215 220
Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys Asn
225 230 235 240
Val Asn Leu Tyr Asn Thr Gly Asn Tyr Trp Gly Gln Gly Thr Gln Val
245 250 255
Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu Val Gln
260 265 270
Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg
275 280 285
Leu Ser Cys Ala Ala Ser Gly Gly Gly Arg Thr Phe Ser Asn Tyr Ala
290 295 300
Leu Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val Ala
305 310 315 320
Ala Ile Ser Arg Ser Gly Gly Asn Ile Asn Tyr Ala Asp Ser Val Lys
325 330 335
Gly Arg Phe Thr Ile Ser Arg Asp Asn Phe Lys Asn Thr Thr Tyr Leu
340 345 350
Gln Met Ser Ser Leu Glu Pro Glu Asp Thr Ala Val Tyr Tyr Cys Ala
355 360 365
Ala His Tyr Leu Leu Leu Pro Ser Tyr Ile Ser Thr Ser Thr Asn Met
370 375 380
Tyr Asn Tyr Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser Ala Ala
385 390 395 400
Ala Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Ala Gly
405 410 415
Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Gly Gly Arg Thr Phe
420 425 430
Ser Asn Tyr Ala Leu Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg
435 440 445
Glu Phe Val Ala Ala Ile Ser Arg Ser Gly Gly Asn Ile Asn Tyr Ala
450 455 460
Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Phe Lys Asn
465 470 475 480
Thr Thr Tyr Leu Gln Met Ser Ser Leu Glu Pro Glu Asp Thr Ala Val
485 490 495
Tyr Tyr Cys Ala Ala His Tyr Leu Leu Leu Pro Ser Tyr Ile Ser Thr
500 505 510
Ser Thr Asn Met Tyr Asn Tyr Trp Gly Gln Gly Thr Gln Val Thr Val
515 520 525
Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Gln Val Gln Leu Val
530 535 540
Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser
545 550 555 560
Cys Ala Ala Ser Gly Arg Thr Ser Leu Ile Leu Ala Met Ala Trp Trp
565 570 575
Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Ala Gly Arg Ile Trp Trp
580 585 590
Asn Asn Asp Met Thr Arg Tyr Ser Asp Ser Val Lys Gly Arg Phe Thr
595 600 605
Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr Leu Gln Met Ser Ser
610 615 620
Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Glu Ala Asp Leu Ile
625 630 635 640
Gly Gly Ser Arg Gly Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
645 650 655
Ala Ala Ala Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln
660 665 670
Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Thr Ser
675 680 685
Leu Ile Leu Ala Met Ala Trp Trp Arg Gln Ala Pro Gly Lys Glu Arg
690 695 700
Glu Phe Ala Gly Arg Ile Trp Trp Asn Asn Asp Met Thr Arg Tyr Ser
705 710 715 720
Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn
725 730 735
Thr Val Tyr Leu Gln Met Ser Ser Leu Arg Ala Glu Asp Thr Ala Val
740 745 750
Tyr Tyr Cys Glu Ala Asp Leu Ile Gly Gly Ser Arg Gly Trp Gly Gln
755 760 765
Gly Thr Leu Val Thr Val Ser Ser
770 775
<210> 175
<211> 764
<212> PRT
<213> 人工序列 (Artificial Sequence)
<220>
<223> 多特异性抗体
CD16F1-L1-hHS5-L1-hA09-10-3-L3-hA09-10-4-L1-H33-14-L3-H33-14
(3211-HS5)
<400> 175
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Val Ser Gly Ser Leu Phe Ser Ala Arg
20 25 30
Val Met Gly Trp Tyr Arg Gln Ala Pro Gly Lys Gln Arg Glu Leu Val
35 40 45
Ala Ala Ile Thr Ser Gly Val Arg Thr Asp Tyr Ala Asp Ser Val Lys
50 55 60
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Arg Ala Val Tyr Leu
65 70 75 80
Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys Asn
85 90 95
Val Asn Leu Tyr Asn Thr Gly Asn Tyr Trp Gly Gln Gly Thr Gln Val
100 105 110
Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu Val Gln
115 120 125
Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg
130 135 140
Leu Ser Cys Ala Ala Ser Gly Arg Thr Phe Thr Thr His Ala Met Gly
145 150 155 160
Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val Ser Ala Ile
165 170 175
Asn Trp Gly Gly Arg Thr Thr Tyr Tyr Ala Asp Ser Val Lys Gly Arg
180 185 190
Phe Ile Ile Ser Arg Asp Thr Gly Ala Asn Thr Leu Tyr Leu Gln Met
195 200 205
Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Ser Asn
210 215 220
Leu Asp Thr Tyr Asn Val Arg Ala Gly Thr Thr Asn Ser Trp Gly Gln
225 230 235 240
Gly Thr Gln Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly
245 250 255
Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly
260 265 270
Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Gly Gly Arg Thr Phe
275 280 285
Ser Asn Tyr Ala Leu Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg
290 295 300
Glu Phe Val Ala Ala Ile Ser Arg Ser Gly Gly Asn Ile Asn Tyr Ala
305 310 315 320
Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Phe Lys Asn
325 330 335
Thr Val Tyr Leu Gln Met Ser Ser Leu Arg Ala Glu Asp Thr Ala Val
340 345 350
Tyr Tyr Cys Ala Ala His Tyr Leu Leu Leu Pro Ser Tyr Ile Ser Thr
355 360 365
Ser Thr Asn Met Tyr Asn Tyr Trp Gly Gln Gly Thr Gln Val Thr Val
370 375 380
Ser Ser Ala Ala Ala Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu
385 390 395 400
Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Gly
405 410 415
Gly Arg Thr Phe Ser Asn Tyr Ala Leu Gly Trp Phe Arg Gln Ala Pro
420 425 430
Gly Lys Glu Arg Glu Phe Val Ala Ala Ile Ser Arg Ser Gly Gly Asn
435 440 445
Ile Asn Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp
450 455 460
Asn Ala Lys Asn Thr Val Tyr Leu Gln Met Ser Ser Leu Arg Ala Glu
465 470 475 480
Asp Thr Ala Val Tyr Tyr Cys Ala Ala His Tyr Leu Leu Leu Pro Ser
485 490 495
Tyr Ile Ser Thr Ser Thr Asn Met Tyr Asn Tyr Trp Gly Gln Gly Thr
500 505 510
Gln Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Gln
515 520 525
Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser
530 535 540
Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Thr Ser Leu Ile Leu Ala
545 550 555 560
Met Ala Trp Trp Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Ala Gly
565 570 575
Arg Ile Trp Trp Asn Asn Asp Met Thr Arg Tyr Ser Asp Ser Val Lys
580 585 590
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr Leu
595 600 605
Gln Met Ser Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Glu
610 615 620
Ala Asp Leu Ile Gly Gly Ser Arg Gly Trp Gly Gln Gly Thr Leu Val
625 630 635 640
Thr Val Ser Ser Ala Ala Ala Gln Val Gln Leu Val Glu Ser Gly Gly
645 650 655
Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser
660 665 670
Gly Arg Thr Ser Leu Ile Leu Ala Met Ala Trp Trp Arg Gln Ala Pro
675 680 685
Gly Lys Glu Arg Glu Phe Ala Gly Arg Ile Trp Trp Asn Asn Asp Met
690 695 700
Thr Arg Tyr Ser Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp
705 710 715 720
Asn Ala Lys Asn Thr Val Tyr Leu Gln Met Ser Ser Leu Arg Ala Glu
725 730 735
Asp Thr Ala Val Tyr Tyr Cys Glu Ala Asp Leu Ile Gly Gly Ser Arg
740 745 750
Gly Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
755 760
<210> 176
<211> 909
<212> PRT
<213> 人工序列 (Artificial Sequence)
<220>
<223> 多特异性抗体
hHS5-L11*9-CD16F1-L3-CD16F1-L1-hA09-10-2-L3-A09-10-L1-hPL-16-L3-h
PL-16
<400> 176
Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Thr Phe Thr Thr His
20 25 30
Ala Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val
35 40 45
Ser Ala Ile Asn Trp Gly Gly Arg Thr Thr Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Ile Ile Ser Arg Asp Thr Gly Ala Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Ser Asn Leu Asp Thr Tyr Asn Val Arg Ala Gly Thr Thr Asn Ser
100 105 110
Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser Gly Gly Ser Gly Arg
115 120 125
Ser Ala Pro Leu Gly Leu Ala Arg Gln Ala Arg Gln Val Gly Gly Ser
130 135 140
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
145 150 155 160
Ser Leu Arg Leu Ser Cys Ala Val Ser Gly Ser Leu Phe Ser Ala Arg
165 170 175
Val Met Gly Trp Tyr Arg Gln Ala Pro Gly Lys Gln Arg Glu Leu Val
180 185 190
Ala Ala Ile Thr Ser Gly Val Arg Thr Asp Tyr Ala Asp Ser Val Lys
195 200 205
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Arg Ala Val Tyr Leu
210 215 220
Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys Asn
225 230 235 240
Val Asn Leu Tyr Asn Thr Gly Asn Tyr Trp Gly Gln Gly Thr Gln Val
245 250 255
Thr Val Ser Ser Ala Ala Ala Glu Val Gln Leu Val Glu Ser Gly Gly
260 265 270
Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Val Ser
275 280 285
Gly Ser Leu Phe Ser Ala Arg Val Met Gly Trp Tyr Arg Gln Ala Pro
290 295 300
Gly Lys Gln Arg Glu Leu Val Ala Ala Ile Thr Ser Gly Val Arg Thr
305 310 315 320
Asp Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn
325 330 335
Ala Lys Arg Ala Val Tyr Leu Gln Met Asn Ser Leu Lys Pro Glu Asp
340 345 350
Thr Ala Val Tyr Tyr Cys Asn Val Asn Leu Tyr Asn Thr Gly Asn Tyr
355 360 365
Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser Gly Gly Gly Gly Ser
370 375 380
Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val
385 390 395 400
Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Gly Gly
405 410 415
Arg Thr Phe Ser Asn Tyr Ala Leu Gly Trp Phe Arg Gln Ala Pro Gly
420 425 430
Lys Glu Arg Glu Phe Val Ala Ala Ile Ser Arg Ser Gly Gly Asn Ile
435 440 445
Asn Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn
450 455 460
Phe Lys Asn Thr Thr Tyr Leu Gln Met Ser Ser Leu Glu Pro Glu Asp
465 470 475 480
Thr Ala Val Tyr Tyr Cys Ala Ala His Tyr Leu Leu Leu Pro Ser Tyr
485 490 495
Ile Ser Thr Ser Thr Asn Met Tyr Asn Tyr Trp Gly Gln Gly Thr Gln
500 505 510
Val Thr Val Ser Ser Ala Ala Ala Gln Val Gln Leu Val Glu Ser Gly
515 520 525
Gly Gly Leu Val Gln Ala Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala
530 535 540
Ser Gly Gly Gly Arg Thr Phe Ser Asn Tyr Ala Leu Gly Trp Phe Arg
545 550 555 560
Gln Ala Pro Gly Lys Glu Arg Glu Phe Val Ala Ala Ile Ser Arg Ser
565 570 575
Gly Gly Asn Ile Asn Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile
580 585 590
Ser Arg Asp Asn Phe Lys Asn Thr Thr Tyr Leu Gln Met Ser Ser Leu
595 600 605
Glu Pro Glu Asp Thr Ala Val Tyr Tyr Cys Ala Ala His Tyr Leu Leu
610 615 620
Leu Pro Ser Tyr Ile Ser Thr Ser Thr Asn Met Tyr Asn Tyr Trp Gly
625 630 635 640
Gln Gly Thr Gln Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly
645 650 655
Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro
660 665 670
Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Gly Thr Phe Leu
675 680 685
Thr Tyr Ser Met Ser Trp Val Arg Gln Ala Pro Gly Lys Glu Arg Glu
690 695 700
Phe Val Ser Ser Ile Asn Trp Ser Gly Tyr Met Thr Tyr Tyr Ala Asp
705 710 715 720
Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr
725 730 735
Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr
740 745 750
Tyr Cys Ala Ala Ala Arg Thr Ala Ile Ala Ala Lys Arg Ser Ser Glu
755 760 765
Phe Asp Tyr Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser Ala Ala
770 775 780
Ala Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly
785 790 795 800
Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Gly Thr Phe Leu Thr
805 810 815
Tyr Ser Met Ser Trp Val Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe
820 825 830
Val Ser Ser Ile Asn Trp Ser Gly Tyr Met Thr Tyr Tyr Ala Asp Ser
835 840 845
Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu
850 855 860
Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr
865 870 875 880
Cys Ala Ala Ala Arg Thr Ala Ile Ala Ala Lys Arg Ser Ser Glu Phe
885 890 895
Asp Tyr Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser
900 905
<210> 177
<211> 883
<212> PRT
<213> 人工序列 (Artificial Sequence)
<220>
<223> 多特异性抗体 CD16F1-L3-CD16F1-L1-hHS5-L1-
hA09-10-2-L3-A09-10-L1-H33-14-L3-H33-14
<400> 177
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Val Ser Gly Ser Leu Phe Ser Ala Arg
20 25 30
Val Met Gly Trp Tyr Arg Gln Ala Pro Gly Lys Gln Arg Glu Leu Val
35 40 45
Ala Ala Ile Thr Ser Gly Val Arg Thr Asp Tyr Ala Asp Ser Val Lys
50 55 60
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Arg Ala Val Tyr Leu
65 70 75 80
Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys Asn
85 90 95
Val Asn Leu Tyr Asn Thr Gly Asn Tyr Trp Gly Gln Gly Thr Gln Val
100 105 110
Thr Val Ser Ser Ala Ala Ala Glu Val Gln Leu Val Glu Ser Gly Gly
115 120 125
Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Val Ser
130 135 140
Gly Ser Leu Phe Ser Ala Arg Val Met Gly Trp Tyr Arg Gln Ala Pro
145 150 155 160
Gly Lys Gln Arg Glu Leu Val Ala Ala Ile Thr Ser Gly Val Arg Thr
165 170 175
Asp Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn
180 185 190
Ala Lys Arg Ala Val Tyr Leu Gln Met Asn Ser Leu Lys Pro Glu Asp
195 200 205
Thr Ala Val Tyr Tyr Cys Asn Val Asn Leu Tyr Asn Thr Gly Asn Tyr
210 215 220
Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser Gly Gly Gly Gly Ser
225 230 235 240
Gly Gly Gly Ser Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val
245 250 255
Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Thr
260 265 270
Phe Thr Thr His Ala Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu
275 280 285
Arg Glu Phe Val Ser Ala Ile Asn Trp Gly Gly Arg Thr Thr Tyr Tyr
290 295 300
Ala Asp Ser Val Lys Gly Arg Phe Ile Ile Ser Arg Asp Thr Gly Ala
305 310 315 320
Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala
325 330 335
Val Tyr Tyr Cys Ala Ser Asn Leu Asp Thr Tyr Asn Val Arg Ala Gly
340 345 350
Thr Thr Asn Ser Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser Gly
355 360 365
Gly Gly Gly Ser Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly
370 375 380
Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala
385 390 395 400
Ser Gly Gly Gly Arg Thr Phe Ser Asn Tyr Ala Leu Gly Trp Phe Arg
405 410 415
Gln Ala Pro Gly Lys Glu Arg Glu Phe Val Ala Ala Ile Ser Arg Ser
420 425 430
Gly Gly Asn Ile Asn Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile
435 440 445
Ser Arg Asp Asn Phe Lys Asn Thr Thr Tyr Leu Gln Met Ser Ser Leu
450 455 460
Glu Pro Glu Asp Thr Ala Val Tyr Tyr Cys Ala Ala His Tyr Leu Leu
465 470 475 480
Leu Pro Ser Tyr Ile Ser Thr Ser Thr Asn Met Tyr Asn Tyr Trp Gly
485 490 495
Gln Gly Thr Gln Val Thr Val Ser Ser Ala Ala Ala Gln Val Gln Leu
500 505 510
Val Glu Ser Gly Gly Gly Leu Val Gln Ala Gly Gly Ser Leu Arg Leu
515 520 525
Ser Cys Ala Ala Ser Gly Gly Gly Arg Thr Phe Ser Asn Tyr Ala Leu
530 535 540
Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val Ala Ala
545 550 555 560
Ile Ser Arg Ser Gly Gly Asn Ile Asn Tyr Ala Asp Ser Val Lys Gly
565 570 575
Arg Phe Thr Ile Ser Arg Asp Asn Phe Lys Asn Thr Thr Tyr Leu Gln
580 585 590
Met Ser Ser Leu Glu Pro Glu Asp Thr Ala Val Tyr Tyr Cys Ala Ala
595 600 605
His Tyr Leu Leu Leu Pro Ser Tyr Ile Ser Thr Ser Thr Asn Met Tyr
610 615 620
Asn Tyr Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser Gly Gly Gly
625 630 635 640
Gly Ser Gly Gly Gly Ser Gln Val Gln Leu Val Glu Ser Gly Gly Gly
645 650 655
Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly
660 665 670
Arg Thr Ser Leu Ile Leu Ala Met Ala Trp Trp Arg Gln Ala Pro Gly
675 680 685
Lys Glu Arg Glu Phe Ala Gly Arg Ile Trp Trp Asn Asn Asp Met Thr
690 695 700
Arg Tyr Ser Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn
705 710 715 720
Ala Lys Asn Thr Val Tyr Leu Gln Met Ser Ser Leu Arg Ala Glu Asp
725 730 735
Thr Ala Val Tyr Tyr Cys Glu Ala Asp Leu Ile Gly Gly Ser Arg Gly
740 745 750
Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ala Ala Gln Val
755 760 765
Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu
770 775 780
Arg Leu Ser Cys Ala Ala Ser Gly Arg Thr Ser Leu Ile Leu Ala Met
785 790 795 800
Ala Trp Trp Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Ala Gly Arg
805 810 815
Ile Trp Trp Asn Asn Asp Met Thr Arg Tyr Ser Asp Ser Val Lys Gly
820 825 830
Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr Leu Gln
835 840 845
Met Ser Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Glu Ala
850 855 860
Asp Leu Ile Gly Gly Ser Arg Gly Trp Gly Gln Gly Thr Leu Val Thr
865 870 875 880
Val Ser Ser
<210> 178
<211> 895
<212> PRT
<213> 人工序列 (Artificial Sequence)
<220>
<223> 多特异性抗体 hHS5-L11*9-CD16F1-L3-CD16F1-L1-
hA09-10-2-L3-A09-10-L1-H33-14-L3-H33-14
<400> 178
Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Thr Phe Thr Thr His
20 25 30
Ala Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val
35 40 45
Ser Ala Ile Asn Trp Gly Gly Arg Thr Thr Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Ile Ile Ser Arg Asp Thr Gly Ala Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Ser Asn Leu Asp Thr Tyr Asn Val Arg Ala Gly Thr Thr Asn Ser
100 105 110
Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser Gly Gly Ser Gly Arg
115 120 125
Ser Ala Pro Leu Gly Leu Ala Arg Gln Ala Arg Gln Val Gly Gly Ser
130 135 140
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
145 150 155 160
Ser Leu Arg Leu Ser Cys Ala Val Ser Gly Ser Leu Phe Ser Ala Arg
165 170 175
Val Met Gly Trp Tyr Arg Gln Ala Pro Gly Lys Gln Arg Glu Leu Val
180 185 190
Ala Ala Ile Thr Ser Gly Val Arg Thr Asp Tyr Ala Asp Ser Val Lys
195 200 205
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Arg Ala Val Tyr Leu
210 215 220
Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys Asn
225 230 235 240
Val Asn Leu Tyr Asn Thr Gly Asn Tyr Trp Gly Gln Gly Thr Gln Val
245 250 255
Thr Val Ser Ser Ala Ala Ala Glu Val Gln Leu Val Glu Ser Gly Gly
260 265 270
Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Val Ser
275 280 285
Gly Ser Leu Phe Ser Ala Arg Val Met Gly Trp Tyr Arg Gln Ala Pro
290 295 300
Gly Lys Gln Arg Glu Leu Val Ala Ala Ile Thr Ser Gly Val Arg Thr
305 310 315 320
Asp Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn
325 330 335
Ala Lys Arg Ala Val Tyr Leu Gln Met Asn Ser Leu Lys Pro Glu Asp
340 345 350
Thr Ala Val Tyr Tyr Cys Asn Val Asn Leu Tyr Asn Thr Gly Asn Tyr
355 360 365
Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser Gly Gly Gly Gly Ser
370 375 380
Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val
385 390 395 400
Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Gly Gly
405 410 415
Arg Thr Phe Ser Asn Tyr Ala Leu Gly Trp Phe Arg Gln Ala Pro Gly
420 425 430
Lys Glu Arg Glu Phe Val Ala Ala Ile Ser Arg Ser Gly Gly Asn Ile
435 440 445
Asn Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn
450 455 460
Phe Lys Asn Thr Thr Tyr Leu Gln Met Ser Ser Leu Glu Pro Glu Asp
465 470 475 480
Thr Ala Val Tyr Tyr Cys Ala Ala His Tyr Leu Leu Leu Pro Ser Tyr
485 490 495
Ile Ser Thr Ser Thr Asn Met Tyr Asn Tyr Trp Gly Gln Gly Thr Gln
500 505 510
Val Thr Val Ser Ser Ala Ala Ala Gln Val Gln Leu Val Glu Ser Gly
515 520 525
Gly Gly Leu Val Gln Ala Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala
530 535 540
Ser Gly Gly Gly Arg Thr Phe Ser Asn Tyr Ala Leu Gly Trp Phe Arg
545 550 555 560
Gln Ala Pro Gly Lys Glu Arg Glu Phe Val Ala Ala Ile Ser Arg Ser
565 570 575
Gly Gly Asn Ile Asn Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile
580 585 590
Ser Arg Asp Asn Phe Lys Asn Thr Thr Tyr Leu Gln Met Ser Ser Leu
595 600 605
Glu Pro Glu Asp Thr Ala Val Tyr Tyr Cys Ala Ala His Tyr Leu Leu
610 615 620
Leu Pro Ser Tyr Ile Ser Thr Ser Thr Asn Met Tyr Asn Tyr Trp Gly
625 630 635 640
Gln Gly Thr Gln Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly
645 650 655
Gly Ser Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro
660 665 670
Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Thr Ser Leu
675 680 685
Ile Leu Ala Met Ala Trp Trp Arg Gln Ala Pro Gly Lys Glu Arg Glu
690 695 700
Phe Ala Gly Arg Ile Trp Trp Asn Asn Asp Met Thr Arg Tyr Ser Asp
705 710 715 720
Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr
725 730 735
Val Tyr Leu Gln Met Ser Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr
740 745 750
Tyr Cys Glu Ala Asp Leu Ile Gly Gly Ser Arg Gly Trp Gly Gln Gly
755 760 765
Thr Leu Val Thr Val Ser Ser Ala Ala Ala Gln Val Gln Leu Val Glu
770 775 780
Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys
785 790 795 800
Ala Ala Ser Gly Arg Thr Ser Leu Ile Leu Ala Met Ala Trp Trp Arg
805 810 815
Gln Ala Pro Gly Lys Glu Arg Glu Phe Ala Gly Arg Ile Trp Trp Asn
820 825 830
Asn Asp Met Thr Arg Tyr Ser Asp Ser Val Lys Gly Arg Phe Thr Ile
835 840 845
Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr Leu Gln Met Ser Ser Leu
850 855 860
Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Glu Ala Asp Leu Ile Gly
865 870 875 880
Gly Ser Arg Gly Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
885 890 895
<210> 179
<211> 764
<212> PRT
<213> 人工序列 (Artificial Sequence)
<220>
<223> 多特异性抗体 H33-14-L3-H33-14-L1-
hA09-10-2-L3-A09-10-L1-hHS5-L1-CD16F1
<400> 179
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Thr Ser Leu Ile Leu
20 25 30
Ala Met Ala Trp Trp Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Ala
35 40 45
Gly Arg Ile Trp Trp Asn Asn Asp Met Thr Arg Tyr Ser Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr
65 70 75 80
Leu Gln Met Ser Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Glu Ala Asp Leu Ile Gly Gly Ser Arg Gly Trp Gly Gln Gly Thr Leu
100 105 110
Val Thr Val Ser Ser Ala Ala Ala Gln Val Gln Leu Val Glu Ser Gly
115 120 125
Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala
130 135 140
Ser Gly Arg Thr Ser Leu Ile Leu Ala Met Ala Trp Trp Arg Gln Ala
145 150 155 160
Pro Gly Lys Glu Arg Glu Phe Ala Gly Arg Ile Trp Trp Asn Asn Asp
165 170 175
Met Thr Arg Tyr Ser Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg
180 185 190
Asp Asn Ala Lys Asn Thr Val Tyr Leu Gln Met Ser Ser Leu Arg Ala
195 200 205
Glu Asp Thr Ala Val Tyr Tyr Cys Glu Ala Asp Leu Ile Gly Gly Ser
210 215 220
Arg Gly Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly
225 230 235 240
Gly Ser Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly
245 250 255
Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly
260 265 270
Gly Gly Arg Thr Phe Ser Asn Tyr Ala Leu Gly Trp Phe Arg Gln Ala
275 280 285
Pro Gly Lys Glu Arg Glu Phe Val Ala Ala Ile Ser Arg Ser Gly Gly
290 295 300
Asn Ile Asn Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg
305 310 315 320
Asp Asn Phe Lys Asn Thr Thr Tyr Leu Gln Met Ser Ser Leu Glu Pro
325 330 335
Glu Asp Thr Ala Val Tyr Tyr Cys Ala Ala His Tyr Leu Leu Leu Pro
340 345 350
Ser Tyr Ile Ser Thr Ser Thr Asn Met Tyr Asn Tyr Trp Gly Gln Gly
355 360 365
Thr Gln Val Thr Val Ser Ser Ala Ala Ala Gln Val Gln Leu Val Glu
370 375 380
Ser Gly Gly Gly Leu Val Gln Ala Gly Gly Ser Leu Arg Leu Ser Cys
385 390 395 400
Ala Ala Ser Gly Gly Gly Arg Thr Phe Ser Asn Tyr Ala Leu Gly Trp
405 410 415
Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val Ala Ala Ile Ser
420 425 430
Arg Ser Gly Gly Asn Ile Asn Tyr Ala Asp Ser Val Lys Gly Arg Phe
435 440 445
Thr Ile Ser Arg Asp Asn Phe Lys Asn Thr Thr Tyr Leu Gln Met Ser
450 455 460
Ser Leu Glu Pro Glu Asp Thr Ala Val Tyr Tyr Cys Ala Ala His Tyr
465 470 475 480
Leu Leu Leu Pro Ser Tyr Ile Ser Thr Ser Thr Asn Met Tyr Asn Tyr
485 490 495
Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser Gly Gly Gly Gly Ser
500 505 510
Gly Gly Gly Ser Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val
515 520 525
Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Thr
530 535 540
Phe Thr Thr His Ala Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu
545 550 555 560
Arg Glu Phe Val Ser Ala Ile Asn Trp Gly Gly Arg Thr Thr Tyr Tyr
565 570 575
Ala Asp Ser Val Lys Gly Arg Phe Ile Ile Ser Arg Asp Thr Gly Ala
580 585 590
Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala
595 600 605
Val Tyr Tyr Cys Ala Ser Asn Leu Asp Thr Tyr Asn Val Arg Ala Gly
610 615 620
Thr Thr Asn Ser Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser Gly
625 630 635 640
Gly Gly Gly Ser Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly
645 650 655
Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Val
660 665 670
Ser Gly Ser Leu Phe Ser Ala Arg Val Met Gly Trp Tyr Arg Gln Ala
675 680 685
Pro Gly Lys Gln Arg Glu Leu Val Ala Ala Ile Thr Ser Gly Val Arg
690 695 700
Thr Asp Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp
705 710 715 720
Asn Ala Lys Arg Ala Val Tyr Leu Gln Met Asn Ser Leu Lys Pro Glu
725 730 735
Asp Thr Ala Val Tyr Tyr Cys Asn Val Asn Leu Tyr Asn Thr Gly Asn
740 745 750
Tyr Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser
755 760
<210> 180
<211> 883
<212> PRT
<213> 人工序列 (Artificial Sequence)
<220>
<223> 多特异性抗体 H33-14-L3-H33-14-L1-
hA09-10-2-L3-A09-10-L1-hHS5-L1-CD16F1-L3-CD16F1
<400> 180
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Thr Ser Leu Ile Leu
20 25 30
Ala Met Ala Trp Trp Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Ala
35 40 45
Gly Arg Ile Trp Trp Asn Asn Asp Met Thr Arg Tyr Ser Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr
65 70 75 80
Leu Gln Met Ser Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Glu Ala Asp Leu Ile Gly Gly Ser Arg Gly Trp Gly Gln Gly Thr Leu
100 105 110
Val Thr Val Ser Ser Ala Ala Ala Gln Val Gln Leu Val Glu Ser Gly
115 120 125
Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala
130 135 140
Ser Gly Arg Thr Ser Leu Ile Leu Ala Met Ala Trp Trp Arg Gln Ala
145 150 155 160
Pro Gly Lys Glu Arg Glu Phe Ala Gly Arg Ile Trp Trp Asn Asn Asp
165 170 175
Met Thr Arg Tyr Ser Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg
180 185 190
Asp Asn Ala Lys Asn Thr Val Tyr Leu Gln Met Ser Ser Leu Arg Ala
195 200 205
Glu Asp Thr Ala Val Tyr Tyr Cys Glu Ala Asp Leu Ile Gly Gly Ser
210 215 220
Arg Gly Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly
225 230 235 240
Gly Ser Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly
245 250 255
Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly
260 265 270
Gly Gly Arg Thr Phe Ser Asn Tyr Ala Leu Gly Trp Phe Arg Gln Ala
275 280 285
Pro Gly Lys Glu Arg Glu Phe Val Ala Ala Ile Ser Arg Ser Gly Gly
290 295 300
Asn Ile Asn Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg
305 310 315 320
Asp Asn Phe Lys Asn Thr Thr Tyr Leu Gln Met Ser Ser Leu Glu Pro
325 330 335
Glu Asp Thr Ala Val Tyr Tyr Cys Ala Ala His Tyr Leu Leu Leu Pro
340 345 350
Ser Tyr Ile Ser Thr Ser Thr Asn Met Tyr Asn Tyr Trp Gly Gln Gly
355 360 365
Thr Gln Val Thr Val Ser Ser Ala Ala Ala Gln Val Gln Leu Val Glu
370 375 380
Ser Gly Gly Gly Leu Val Gln Ala Gly Gly Ser Leu Arg Leu Ser Cys
385 390 395 400
Ala Ala Ser Gly Gly Gly Arg Thr Phe Ser Asn Tyr Ala Leu Gly Trp
405 410 415
Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val Ala Ala Ile Ser
420 425 430
Arg Ser Gly Gly Asn Ile Asn Tyr Ala Asp Ser Val Lys Gly Arg Phe
435 440 445
Thr Ile Ser Arg Asp Asn Phe Lys Asn Thr Thr Tyr Leu Gln Met Ser
450 455 460
Ser Leu Glu Pro Glu Asp Thr Ala Val Tyr Tyr Cys Ala Ala His Tyr
465 470 475 480
Leu Leu Leu Pro Ser Tyr Ile Ser Thr Ser Thr Asn Met Tyr Asn Tyr
485 490 495
Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser Gly Gly Gly Gly Ser
500 505 510
Gly Gly Gly Ser Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val
515 520 525
Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Thr
530 535 540
Phe Thr Thr His Ala Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu
545 550 555 560
Arg Glu Phe Val Ser Ala Ile Asn Trp Gly Gly Arg Thr Thr Tyr Tyr
565 570 575
Ala Asp Ser Val Lys Gly Arg Phe Ile Ile Ser Arg Asp Thr Gly Ala
580 585 590
Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala
595 600 605
Val Tyr Tyr Cys Ala Ser Asn Leu Asp Thr Tyr Asn Val Arg Ala Gly
610 615 620
Thr Thr Asn Ser Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser Gly
625 630 635 640
Gly Gly Gly Ser Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly
645 650 655
Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Val
660 665 670
Ser Gly Ser Leu Phe Ser Ala Arg Val Met Gly Trp Tyr Arg Gln Ala
675 680 685
Pro Gly Lys Gln Arg Glu Leu Val Ala Ala Ile Thr Ser Gly Val Arg
690 695 700
Thr Asp Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp
705 710 715 720
Asn Ala Lys Arg Ala Val Tyr Leu Gln Met Asn Ser Leu Lys Pro Glu
725 730 735
Asp Thr Ala Val Tyr Tyr Cys Asn Val Asn Leu Tyr Asn Thr Gly Asn
740 745 750
Tyr Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser Ala Ala Ala Glu
755 760 765
Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser
770 775 780
Leu Arg Leu Ser Cys Ala Val Ser Gly Ser Leu Phe Ser Ala Arg Val
785 790 795 800
Met Gly Trp Tyr Arg Gln Ala Pro Gly Lys Gln Arg Glu Leu Val Ala
805 810 815
Ala Ile Thr Ser Gly Val Arg Thr Asp Tyr Ala Asp Ser Val Lys Gly
820 825 830
Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Arg Ala Val Tyr Leu Gln
835 840 845
Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys Asn Val
850 855 860
Asn Leu Tyr Asn Thr Gly Asn Tyr Trp Gly Gln Gly Thr Gln Val Thr
865 870 875 880
Val Ser Ser
<210> 181
<211> 776
<212> PRT
<213> 人工序列 (Artificial Sequence)
<220>
<223> 多特异性抗体 H33-14-L3-H33-14-L1-
hA09-10-2-L3-A09-10-L1-CD16F1-L11*9-hHS5
<400> 181
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Thr Ser Leu Ile Leu
20 25 30
Ala Met Ala Trp Trp Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Ala
35 40 45
Gly Arg Ile Trp Trp Asn Asn Asp Met Thr Arg Tyr Ser Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr
65 70 75 80
Leu Gln Met Ser Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Glu Ala Asp Leu Ile Gly Gly Ser Arg Gly Trp Gly Gln Gly Thr Leu
100 105 110
Val Thr Val Ser Ser Ala Ala Ala Gln Val Gln Leu Val Glu Ser Gly
115 120 125
Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala
130 135 140
Ser Gly Arg Thr Ser Leu Ile Leu Ala Met Ala Trp Trp Arg Gln Ala
145 150 155 160
Pro Gly Lys Glu Arg Glu Phe Ala Gly Arg Ile Trp Trp Asn Asn Asp
165 170 175
Met Thr Arg Tyr Ser Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg
180 185 190
Asp Asn Ala Lys Asn Thr Val Tyr Leu Gln Met Ser Ser Leu Arg Ala
195 200 205
Glu Asp Thr Ala Val Tyr Tyr Cys Glu Ala Asp Leu Ile Gly Gly Ser
210 215 220
Arg Gly Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly
225 230 235 240
Gly Ser Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly
245 250 255
Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly
260 265 270
Gly Gly Arg Thr Phe Ser Asn Tyr Ala Leu Gly Trp Phe Arg Gln Ala
275 280 285
Pro Gly Lys Glu Arg Glu Phe Val Ala Ala Ile Ser Arg Ser Gly Gly
290 295 300
Asn Ile Asn Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg
305 310 315 320
Asp Asn Phe Lys Asn Thr Thr Tyr Leu Gln Met Ser Ser Leu Glu Pro
325 330 335
Glu Asp Thr Ala Val Tyr Tyr Cys Ala Ala His Tyr Leu Leu Leu Pro
340 345 350
Ser Tyr Ile Ser Thr Ser Thr Asn Met Tyr Asn Tyr Trp Gly Gln Gly
355 360 365
Thr Gln Val Thr Val Ser Ser Ala Ala Ala Gln Val Gln Leu Val Glu
370 375 380
Ser Gly Gly Gly Leu Val Gln Ala Gly Gly Ser Leu Arg Leu Ser Cys
385 390 395 400
Ala Ala Ser Gly Gly Gly Arg Thr Phe Ser Asn Tyr Ala Leu Gly Trp
405 410 415
Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val Ala Ala Ile Ser
420 425 430
Arg Ser Gly Gly Asn Ile Asn Tyr Ala Asp Ser Val Lys Gly Arg Phe
435 440 445
Thr Ile Ser Arg Asp Asn Phe Lys Asn Thr Thr Tyr Leu Gln Met Ser
450 455 460
Ser Leu Glu Pro Glu Asp Thr Ala Val Tyr Tyr Cys Ala Ala His Tyr
465 470 475 480
Leu Leu Leu Pro Ser Tyr Ile Ser Thr Ser Thr Asn Met Tyr Asn Tyr
485 490 495
Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser Gly Gly Gly Gly Ser
500 505 510
Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val
515 520 525
Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Val Ser Gly Ser Leu
530 535 540
Phe Ser Ala Arg Val Met Gly Trp Tyr Arg Gln Ala Pro Gly Lys Gln
545 550 555 560
Arg Glu Leu Val Ala Ala Ile Thr Ser Gly Val Arg Thr Asp Tyr Ala
565 570 575
Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Arg
580 585 590
Ala Val Tyr Leu Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Val
595 600 605
Tyr Tyr Cys Asn Val Asn Leu Tyr Asn Thr Gly Asn Tyr Trp Gly Gln
610 615 620
Gly Thr Gln Val Thr Val Ser Ser Gly Gly Ser Gly Arg Ser Ala Pro
625 630 635 640
Leu Gly Leu Ala Arg Gln Ala Arg Gln Val Gly Gly Ser Glu Val Gln
645 650 655
Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg
660 665 670
Leu Ser Cys Ala Ala Ser Gly Arg Thr Phe Thr Thr His Ala Met Gly
675 680 685
Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val Ser Ala Ile
690 695 700
Asn Trp Gly Gly Arg Thr Thr Tyr Tyr Ala Asp Ser Val Lys Gly Arg
705 710 715 720
Phe Ile Ile Ser Arg Asp Thr Gly Ala Asn Thr Leu Tyr Leu Gln Met
725 730 735
Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Ser Asn
740 745 750
Leu Asp Thr Tyr Asn Val Arg Ala Gly Thr Thr Asn Ser Trp Gly Gln
755 760 765
Gly Thr Gln Val Thr Val Ser Ser
770 775
<210> 182
<211> 895
<212> PRT
<213> 人工序列 (Artificial Sequence)
<220>
<223> 多特异性抗体 H33-14-L3-H33-14-
L1-hA09-10-2-L3-A09-10-L1-CD16-F1-L3-CD16F1-L11*9-hHS5
<400> 182
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Thr Ser Leu Ile Leu
20 25 30
Ala Met Ala Trp Trp Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Ala
35 40 45
Gly Arg Ile Trp Trp Asn Asn Asp Met Thr Arg Tyr Ser Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr
65 70 75 80
Leu Gln Met Ser Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Glu Ala Asp Leu Ile Gly Gly Ser Arg Gly Trp Gly Gln Gly Thr Leu
100 105 110
Val Thr Val Ser Ser Ala Ala Ala Gln Val Gln Leu Val Glu Ser Gly
115 120 125
Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala
130 135 140
Ser Gly Arg Thr Ser Leu Ile Leu Ala Met Ala Trp Trp Arg Gln Ala
145 150 155 160
Pro Gly Lys Glu Arg Glu Phe Ala Gly Arg Ile Trp Trp Asn Asn Asp
165 170 175
Met Thr Arg Tyr Ser Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg
180 185 190
Asp Asn Ala Lys Asn Thr Val Tyr Leu Gln Met Ser Ser Leu Arg Ala
195 200 205
Glu Asp Thr Ala Val Tyr Tyr Cys Glu Ala Asp Leu Ile Gly Gly Ser
210 215 220
Arg Gly Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly
225 230 235 240
Gly Ser Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly
245 250 255
Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly
260 265 270
Gly Gly Arg Thr Phe Ser Asn Tyr Ala Leu Gly Trp Phe Arg Gln Ala
275 280 285
Pro Gly Lys Glu Arg Glu Phe Val Ala Ala Ile Ser Arg Ser Gly Gly
290 295 300
Asn Ile Asn Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg
305 310 315 320
Asp Asn Phe Lys Asn Thr Thr Tyr Leu Gln Met Ser Ser Leu Glu Pro
325 330 335
Glu Asp Thr Ala Val Tyr Tyr Cys Ala Ala His Tyr Leu Leu Leu Pro
340 345 350
Ser Tyr Ile Ser Thr Ser Thr Asn Met Tyr Asn Tyr Trp Gly Gln Gly
355 360 365
Thr Gln Val Thr Val Ser Ser Ala Ala Ala Gln Val Gln Leu Val Glu
370 375 380
Ser Gly Gly Gly Leu Val Gln Ala Gly Gly Ser Leu Arg Leu Ser Cys
385 390 395 400
Ala Ala Ser Gly Gly Gly Arg Thr Phe Ser Asn Tyr Ala Leu Gly Trp
405 410 415
Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val Ala Ala Ile Ser
420 425 430
Arg Ser Gly Gly Asn Ile Asn Tyr Ala Asp Ser Val Lys Gly Arg Phe
435 440 445
Thr Ile Ser Arg Asp Asn Phe Lys Asn Thr Thr Tyr Leu Gln Met Ser
450 455 460
Ser Leu Glu Pro Glu Asp Thr Ala Val Tyr Tyr Cys Ala Ala His Tyr
465 470 475 480
Leu Leu Leu Pro Ser Tyr Ile Ser Thr Ser Thr Asn Met Tyr Asn Tyr
485 490 495
Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser Gly Gly Gly Gly Ser
500 505 510
Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val
515 520 525
Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Val Ser Gly Ser Leu
530 535 540
Phe Ser Ala Arg Val Met Gly Trp Tyr Arg Gln Ala Pro Gly Lys Gln
545 550 555 560
Arg Glu Leu Val Ala Ala Ile Thr Ser Gly Val Arg Thr Asp Tyr Ala
565 570 575
Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Arg
580 585 590
Ala Val Tyr Leu Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Val
595 600 605
Tyr Tyr Cys Asn Val Asn Leu Tyr Asn Thr Gly Asn Tyr Trp Gly Gln
610 615 620
Gly Thr Gln Val Thr Val Ser Ser Ala Ala Ala Glu Val Gln Leu Val
625 630 635 640
Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser
645 650 655
Cys Ala Val Ser Gly Ser Leu Phe Ser Ala Arg Val Met Gly Trp Tyr
660 665 670
Arg Gln Ala Pro Gly Lys Gln Arg Glu Leu Val Ala Ala Ile Thr Ser
675 680 685
Gly Val Arg Thr Asp Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile
690 695 700
Ser Arg Asp Asn Ala Lys Arg Ala Val Tyr Leu Gln Met Asn Ser Leu
705 710 715 720
Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys Asn Val Asn Leu Tyr Asn
725 730 735
Thr Gly Asn Tyr Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser Gly
740 745 750
Gly Ser Gly Arg Ser Ala Pro Leu Gly Leu Ala Arg Gln Ala Arg Gln
755 760 765
Val Gly Gly Ser Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val
770 775 780
Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Thr
785 790 795 800
Phe Thr Thr His Ala Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu
805 810 815
Arg Glu Phe Val Ser Ala Ile Asn Trp Gly Gly Arg Thr Thr Tyr Tyr
820 825 830
Ala Asp Ser Val Lys Gly Arg Phe Ile Ile Ser Arg Asp Thr Gly Ala
835 840 845
Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala
850 855 860
Val Tyr Tyr Cys Ala Ser Asn Leu Asp Thr Tyr Asn Val Arg Ala Gly
865 870 875 880
Thr Thr Asn Ser Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser
885 890 895
<210> 183
<211> 770
<212> PRT
<213> 人工序列 (Artificial Sequence)
<220>
<223> 多特异性抗体
CD16F1-L1-hHS5-L4-hA09-10-3-L3-hA09-10-4-L1-H33-14-L3-H33-14
(3321-HS5-GS15)
<400> 183
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Val Ser Gly Ser Leu Phe Ser Ala Arg
20 25 30
Val Met Gly Trp Tyr Arg Gln Ala Pro Gly Lys Gln Arg Glu Leu Val
35 40 45
Ala Ala Ile Thr Ser Gly Val Arg Thr Asp Tyr Ala Asp Ser Val Lys
50 55 60
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Arg Ala Val Tyr Leu
65 70 75 80
Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys Asn
85 90 95
Val Asn Leu Tyr Asn Thr Gly Asn Tyr Trp Gly Gln Gly Thr Gln Val
100 105 110
Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu Val Gln
115 120 125
Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg
130 135 140
Leu Ser Cys Ala Ala Ser Gly Arg Thr Phe Thr Thr His Ala Met Gly
145 150 155 160
Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val Ser Ala Ile
165 170 175
Asn Trp Gly Gly Arg Thr Thr Tyr Tyr Ala Asp Ser Val Lys Gly Arg
180 185 190
Phe Ile Ile Ser Arg Asp Thr Gly Ala Asn Thr Leu Tyr Leu Gln Met
195 200 205
Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Ser Asn
210 215 220
Leu Asp Thr Tyr Asn Val Arg Ala Gly Thr Thr Asn Ser Trp Gly Gln
225 230 235 240
Gly Thr Gln Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly
245 250 255
Gly Ser Gly Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly
260 265 270
Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser
275 280 285
Gly Gly Gly Arg Thr Phe Ser Asn Tyr Ala Leu Gly Trp Phe Arg Gln
290 295 300
Ala Pro Gly Lys Glu Arg Glu Phe Val Ala Ala Ile Ser Arg Ser Gly
305 310 315 320
Gly Asn Ile Asn Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser
325 330 335
Arg Asp Asn Phe Lys Asn Thr Val Tyr Leu Gln Met Ser Ser Leu Arg
340 345 350
Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Ala His Tyr Leu Leu Leu
355 360 365
Pro Ser Tyr Ile Ser Thr Ser Thr Asn Met Tyr Asn Tyr Trp Gly Gln
370 375 380
Gly Thr Gln Val Thr Val Ser Ser Ala Ala Ala Gln Val Gln Leu Val
385 390 395 400
Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser
405 410 415
Cys Ala Ala Ser Gly Gly Gly Arg Thr Phe Ser Asn Tyr Ala Leu Gly
420 425 430
Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val Ala Ala Ile
435 440 445
Ser Arg Ser Gly Gly Asn Ile Asn Tyr Ala Asp Ser Val Lys Gly Arg
450 455 460
Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr Leu Gln Met
465 470 475 480
Ser Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Ala His
485 490 495
Tyr Leu Leu Leu Pro Ser Tyr Ile Ser Thr Ser Thr Asn Met Tyr Asn
500 505 510
Tyr Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser Gly Gly Gly Gly
515 520 525
Ser Gly Gly Gly Ser Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu
530 535 540
Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg
545 550 555 560
Thr Ser Leu Ile Leu Ala Met Ala Trp Trp Arg Gln Ala Pro Gly Lys
565 570 575
Glu Arg Glu Phe Ala Gly Arg Ile Trp Trp Asn Asn Asp Met Thr Arg
580 585 590
Tyr Ser Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala
595 600 605
Lys Asn Thr Val Tyr Leu Gln Met Ser Ser Leu Arg Ala Glu Asp Thr
610 615 620
Ala Val Tyr Tyr Cys Glu Ala Asp Leu Ile Gly Gly Ser Arg Gly Trp
625 630 635 640
Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ala Ala Gln Val Gln
645 650 655
Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg
660 665 670
Leu Ser Cys Ala Ala Ser Gly Arg Thr Ser Leu Ile Leu Ala Met Ala
675 680 685
Trp Trp Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Ala Gly Arg Ile
690 695 700
Trp Trp Asn Asn Asp Met Thr Arg Tyr Ser Asp Ser Val Lys Gly Arg
705 710 715 720
Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr Leu Gln Met
725 730 735
Ser Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Glu Ala Asp
740 745 750
Leu Ile Gly Gly Ser Arg Gly Trp Gly Gln Gly Thr Leu Val Thr Val
755 760 765
Ser Ser
770
<210> 184
<211> 784
<212> PRT
<213> 人工序列 (Artificial Sequence)
<220>
<223> 多特异性抗体
CD16F1-L1-hHS5-L1-hA09-10-3-L3-hA09-10-4-L1-hPL16-L3-hPL16
(1518-HS5-GS15)
<400> 184
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Val Ser Gly Ser Leu Phe Ser Ala Arg
20 25 30
Val Met Gly Trp Tyr Arg Gln Ala Pro Gly Lys Gln Arg Glu Leu Val
35 40 45
Ala Ala Ile Thr Ser Gly Val Arg Thr Asp Tyr Ala Asp Ser Val Lys
50 55 60
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Arg Ala Val Tyr Leu
65 70 75 80
Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys Asn
85 90 95
Val Asn Leu Tyr Asn Thr Gly Asn Tyr Trp Gly Gln Gly Thr Gln Val
100 105 110
Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu Val Gln
115 120 125
Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg
130 135 140
Leu Ser Cys Ala Ala Ser Gly Arg Thr Phe Thr Thr His Ala Met Gly
145 150 155 160
Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val Ser Ala Ile
165 170 175
Asn Trp Gly Gly Arg Thr Thr Tyr Tyr Ala Asp Ser Val Lys Gly Arg
180 185 190
Phe Ile Ile Ser Arg Asp Thr Gly Ala Asn Thr Leu Tyr Leu Gln Met
195 200 205
Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Ser Asn
210 215 220
Leu Asp Thr Tyr Asn Val Arg Ala Gly Thr Thr Asn Ser Trp Gly Gln
225 230 235 240
Gly Thr Gln Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly
245 250 255
Gly Ser Gly Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly
260 265 270
Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser
275 280 285
Gly Gly Gly Arg Thr Phe Ser Asn Tyr Ala Leu Gly Trp Phe Arg Gln
290 295 300
Ala Pro Gly Lys Glu Arg Glu Phe Val Ala Ala Ile Ser Arg Ser Gly
305 310 315 320
Gly Asn Ile Asn Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser
325 330 335
Arg Asp Asn Phe Lys Asn Thr Val Tyr Leu Gln Met Ser Ser Leu Arg
340 345 350
Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Ala His Tyr Leu Leu Leu
355 360 365
Pro Ser Tyr Ile Ser Thr Ser Thr Asn Met Tyr Asn Tyr Trp Gly Gln
370 375 380
Gly Thr Gln Val Thr Val Ser Ser Ala Ala Ala Gln Val Gln Leu Val
385 390 395 400
Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser
405 410 415
Cys Ala Ala Ser Gly Gly Gly Arg Thr Phe Ser Asn Tyr Ala Leu Gly
420 425 430
Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val Ala Ala Ile
435 440 445
Ser Arg Ser Gly Gly Asn Ile Asn Tyr Ala Asp Ser Val Lys Gly Arg
450 455 460
Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr Leu Gln Met
465 470 475 480
Ser Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Ala His
485 490 495
Tyr Leu Leu Leu Pro Ser Tyr Ile Ser Thr Ser Thr Asn Met Tyr Asn
500 505 510
Tyr Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser Gly Gly Gly Gly
515 520 525
Ser Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu
530 535 540
Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Gly
545 550 555 560
Thr Phe Leu Thr Tyr Ser Met Ser Trp Val Arg Gln Ala Pro Gly Lys
565 570 575
Glu Arg Glu Phe Val Ser Ser Ile Asn Trp Ser Gly Tyr Met Thr Tyr
580 585 590
Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser
595 600 605
Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr
610 615 620
Ala Val Tyr Tyr Cys Ala Ala Ala Arg Thr Ala Ile Ala Ala Lys Arg
625 630 635 640
Ser Ser Glu Phe Asp Tyr Trp Gly Gln Gly Thr Gln Val Thr Val Ser
645 650 655
Ser Ala Ala Ala Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val
660 665 670
Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Gly Thr
675 680 685
Phe Leu Thr Tyr Ser Met Ser Trp Val Arg Gln Ala Pro Gly Lys Glu
690 695 700
Arg Glu Phe Val Ser Ser Ile Asn Trp Ser Gly Tyr Met Thr Tyr Tyr
705 710 715 720
Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys
725 730 735
Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala
740 745 750
Val Tyr Tyr Cys Ala Ala Ala Arg Thr Ala Ile Ala Ala Lys Arg Ser
755 760 765
Ser Glu Phe Asp Tyr Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser
770 775 780
<210> 185
<211> 784
<212> PRT
<213> 人工序列 (Artificial Sequence)
<220>
<223> 多特异性抗体 hCD16F1-1-L1-hHS5-L4-hA09-10-45-
L1-hPL16-L3-hPL-16
<400> 185
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Ser Leu Phe Ser Ala Arg
20 25 30
Val Met Gly Trp Tyr Arg Gln Ala Pro Gly Lys Gln Arg Glu Leu Val
35 40 45
Ser Ala Ile Thr Ser Gly Val Arg Thr Tyr Tyr Ala Asp Ser Val Lys
50 55 60
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Arg Ala Val Tyr Leu
65 70 75 80
Gln Met Ser Ser Leu Glu Pro Glu Asp Thr Ala Val Tyr Tyr Cys Asn
85 90 95
Val Asn Leu Tyr Asn Thr Gly Asn Tyr Trp Gly Gln Gly Thr Gln Val
100 105 110
Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu Val Gln
115 120 125
Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg
130 135 140
Leu Ser Cys Ala Ala Ser Gly Arg Thr Phe Thr Thr His Ala Met Gly
145 150 155 160
Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val Ser Ala Ile
165 170 175
Asn Trp Gly Gly Arg Thr Thr Tyr Tyr Ala Asp Ser Val Lys Gly Arg
180 185 190
Phe Ile Ile Ser Arg Asp Thr Gly Ala Asn Thr Leu Tyr Leu Gln Met
195 200 205
Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Ser Asn
210 215 220
Leu Asp Thr Tyr Asn Val Arg Ala Gly Thr Thr Asn Ser Trp Gly Gln
225 230 235 240
Gly Thr Gln Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly
245 250 255
Gly Ser Gly Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly
260 265 270
Gly Val Val Arg Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser
275 280 285
Gly Gly Gly Arg Thr Phe Ser Asn Tyr Ala Met Gly Trp Phe Arg Gln
290 295 300
Ala Pro Gly Lys Glu Arg Glu Phe Val Ser Ala Ile Ser Arg Ser Gly
305 310 315 320
Gly Asn Ile Tyr Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser
325 330 335
Arg Asp Asn Phe Lys Asn Thr Val Tyr Leu Gln Met Ser Ser Leu Arg
340 345 350
Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Ala His Tyr Leu Leu Leu
355 360 365
Pro Ser Tyr Ile Ser Thr Ser Thr Asn Met Tyr Asn Tyr Trp Gly Gln
370 375 380
Gly Thr Gln Val Thr Val Ser Ser Ala Ala Ala Gln Val Gln Leu Val
385 390 395 400
Glu Ser Gly Gly Gly Val Val Arg Pro Gly Gly Ser Leu Arg Leu Ser
405 410 415
Cys Ala Ala Ser Gly Gly Gly Arg Thr Phe Ser Asn Tyr Ala Met Gly
420 425 430
Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val Ser Ala Ile
435 440 445
Ser Arg Ser Gly Gly Asn Ile Tyr Tyr Ala Asp Ser Val Lys Gly Arg
450 455 460
Phe Thr Ile Ser Arg Asp Asn Phe Lys Asn Thr Thr Tyr Leu Gln Met
465 470 475 480
Ser Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Ala His
485 490 495
Tyr Leu Leu Leu Pro Ser Tyr Ile Ser Thr Ser Thr Asn Met Tyr Asn
500 505 510
Tyr Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser Gly Gly Gly Gly
515 520 525
Ser Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu
530 535 540
Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Gly
545 550 555 560
Thr Phe Leu Thr Tyr Ser Met Ser Trp Val Arg Gln Ala Pro Gly Lys
565 570 575
Glu Arg Glu Phe Val Ser Ser Ile Asn Trp Ser Gly Tyr Met Thr Tyr
580 585 590
Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser
595 600 605
Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr
610 615 620
Ala Val Tyr Tyr Cys Ala Ala Ala Arg Thr Ala Ile Ala Ala Lys Arg
625 630 635 640
Ser Ser Glu Phe Asp Tyr Trp Gly Gln Gly Thr Gln Val Thr Val Ser
645 650 655
Ser Ala Ala Ala Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val
660 665 670
Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Gly Thr
675 680 685
Phe Leu Thr Tyr Ser Met Ser Trp Val Arg Gln Ala Pro Gly Lys Glu
690 695 700
Arg Glu Phe Val Ser Ser Ile Asn Trp Ser Gly Tyr Met Thr Tyr Tyr
705 710 715 720
Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys
725 730 735
Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala
740 745 750
Val Tyr Tyr Cys Ala Ala Ala Arg Thr Ala Ile Ala Ala Lys Arg Ser
755 760 765
Ser Glu Phe Asp Tyr Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser
770 775 780
<210> 186
<211> 784
<212> PRT
<213> 人工序列 (Artificial Sequence)
<220>
<223> 多特异性抗体 hCD16F1-2-L1-hHS5-L4-hA09-10-45-
L1-hPL16-L3-hPL-16
<400> 186
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Ser Leu Phe Ser Ala Arg
20 25 30
Val Met Gly Trp Tyr Arg Gln Ala Pro Gly Lys Gln Arg Glu Leu Val
35 40 45
Ser Ala Ile Thr Ser Gly Val Arg Thr Tyr Tyr Ala Asp Ser Val Lys
50 55 60
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Arg Ala Val Tyr Leu
65 70 75 80
Gln Met Ser Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Asn
85 90 95
Val Asn Leu Tyr Asn Thr Gly Asn Tyr Trp Gly Gln Gly Thr Gln Val
100 105 110
Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu Val Gln
115 120 125
Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg
130 135 140
Leu Ser Cys Ala Ala Ser Gly Arg Thr Phe Thr Thr His Ala Met Gly
145 150 155 160
Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val Ser Ala Ile
165 170 175
Asn Trp Gly Gly Arg Thr Thr Tyr Tyr Ala Asp Ser Val Lys Gly Arg
180 185 190
Phe Ile Ile Ser Arg Asp Thr Gly Ala Asn Thr Leu Tyr Leu Gln Met
195 200 205
Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Ser Asn
210 215 220
Leu Asp Thr Tyr Asn Val Arg Ala Gly Thr Thr Asn Ser Trp Gly Gln
225 230 235 240
Gly Thr Gln Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly
245 250 255
Gly Ser Gly Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly
260 265 270
Gly Val Val Arg Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser
275 280 285
Gly Gly Gly Arg Thr Phe Ser Asn Tyr Ala Met Gly Trp Phe Arg Gln
290 295 300
Ala Pro Gly Lys Glu Arg Glu Phe Val Ser Ala Ile Ser Arg Ser Gly
305 310 315 320
Gly Asn Ile Tyr Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser
325 330 335
Arg Asp Asn Phe Lys Asn Thr Val Tyr Leu Gln Met Ser Ser Leu Arg
340 345 350
Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Ala His Tyr Leu Leu Leu
355 360 365
Pro Ser Tyr Ile Ser Thr Ser Thr Asn Met Tyr Asn Tyr Trp Gly Gln
370 375 380
Gly Thr Gln Val Thr Val Ser Ser Ala Ala Ala Gln Val Gln Leu Val
385 390 395 400
Glu Ser Gly Gly Gly Val Val Arg Pro Gly Gly Ser Leu Arg Leu Ser
405 410 415
Cys Ala Ala Ser Gly Gly Gly Arg Thr Phe Ser Asn Tyr Ala Met Gly
420 425 430
Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val Ser Ala Ile
435 440 445
Ser Arg Ser Gly Gly Asn Ile Tyr Tyr Ala Asp Ser Val Lys Gly Arg
450 455 460
Phe Thr Ile Ser Arg Asp Asn Phe Lys Asn Thr Thr Tyr Leu Gln Met
465 470 475 480
Ser Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Ala His
485 490 495
Tyr Leu Leu Leu Pro Ser Tyr Ile Ser Thr Ser Thr Asn Met Tyr Asn
500 505 510
Tyr Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser Gly Gly Gly Gly
515 520 525
Ser Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu
530 535 540
Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Gly
545 550 555 560
Thr Phe Leu Thr Tyr Ser Met Ser Trp Val Arg Gln Ala Pro Gly Lys
565 570 575
Glu Arg Glu Phe Val Ser Ser Ile Asn Trp Ser Gly Tyr Met Thr Tyr
580 585 590
Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser
595 600 605
Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr
610 615 620
Ala Val Tyr Tyr Cys Ala Ala Ala Arg Thr Ala Ile Ala Ala Lys Arg
625 630 635 640
Ser Ser Glu Phe Asp Tyr Trp Gly Gln Gly Thr Gln Val Thr Val Ser
645 650 655
Ser Ala Ala Ala Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val
660 665 670
Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Gly Thr
675 680 685
Phe Leu Thr Tyr Ser Met Ser Trp Val Arg Gln Ala Pro Gly Lys Glu
690 695 700
Arg Glu Phe Val Ser Ser Ile Asn Trp Ser Gly Tyr Met Thr Tyr Tyr
705 710 715 720
Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys
725 730 735
Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala
740 745 750
Val Tyr Tyr Cys Ala Ala Ala Arg Thr Ala Ile Ala Ala Lys Arg Ser
755 760 765
Ser Glu Phe Asp Tyr Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser
770 775 780
<210> 187
<211> 784
<212> PRT
<213> 人工序列 (Artificial Sequence)
<220>
<223> 多特异性抗体
hCD16F1-1-L1-hHS5-L4-hA09-10-55-L1-hPL16-L3-hPL16
<400> 187
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Val Ser Gly Ser Leu Phe Ser Ala Arg
20 25 30
Val Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gln Arg Glu Leu Val
35 40 45
Ser Ala Ile Thr Ser Gly Val Arg Thr Tyr Tyr Ala Asp Ser Val Lys
50 55 60
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Arg Ala Val Tyr Leu
65 70 75 80
Gln Met Ser Ser Leu Glu Pro Glu Asp Thr Ala Val Tyr Tyr Cys Asn
85 90 95
Val Asn Leu Tyr Asn Thr Gly Asn Tyr Trp Gly Gln Gly Thr Gln Val
100 105 110
Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu Val Gln
115 120 125
Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg
130 135 140
Leu Ser Cys Ala Ala Ser Gly Arg Thr Phe Thr Thr His Ala Met Gly
145 150 155 160
Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val Ser Ala Ile
165 170 175
Asn Trp Gly Gly Arg Thr Thr Tyr Tyr Ala Asp Ser Val Lys Gly Arg
180 185 190
Phe Ile Ile Ser Arg Asp Thr Gly Ala Asn Thr Leu Tyr Leu Gln Met
195 200 205
Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Ser Asn
210 215 220
Leu Asp Thr Tyr Asn Val Arg Ala Gly Thr Thr Asn Ser Trp Gly Gln
225 230 235 240
Gly Thr Gln Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly
245 250 255
Gly Ser Gly Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly
260 265 270
Gly Val Val Arg Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser
275 280 285
Gly Gly Gly Arg Thr Phe Ser Asn Tyr Ala Met Gly Trp Phe Arg Gln
290 295 300
Ala Pro Gly Lys Glu Arg Glu Phe Val Ser Ala Ile Ser Arg Ser Gly
305 310 315 320
Gly Asn Ile Tyr Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser
325 330 335
Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu Gln Met Ser Ser Leu Glu
340 345 350
Pro Glu Asp Thr Ala Val Tyr Tyr Cys Ala Ala His Tyr Leu Leu Leu
355 360 365
Pro Ser Tyr Ile Ser Thr Ser Thr Asn Met Tyr Asn Tyr Trp Gly Gln
370 375 380
Gly Thr Gln Val Thr Val Ser Ser Ala Ala Ala Gln Val Gln Leu Val
385 390 395 400
Glu Ser Gly Gly Gly Val Val Arg Pro Gly Gly Ser Leu Arg Leu Ser
405 410 415
Cys Ala Ala Ser Gly Gly Gly Arg Thr Phe Ser Asn Tyr Ala Met Gly
420 425 430
Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val Ser Ala Ile
435 440 445
Ser Arg Ser Gly Gly Asn Ile Tyr Tyr Ala Asp Ser Val Lys Gly Arg
450 455 460
Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu Gln Met
465 470 475 480
Ser Ser Leu Glu Pro Glu Asp Thr Ala Val Tyr Tyr Cys Ala Ala His
485 490 495
Tyr Leu Leu Leu Pro Ser Tyr Ile Ser Thr Ser Thr Asn Met Tyr Asn
500 505 510
Tyr Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser Gly Gly Gly Gly
515 520 525
Ser Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu
530 535 540
Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Gly
545 550 555 560
Thr Phe Leu Thr Tyr Ser Met Ser Trp Val Arg Gln Ala Pro Gly Lys
565 570 575
Glu Arg Glu Phe Val Ser Ser Ile Asn Trp Ser Gly Tyr Met Thr Tyr
580 585 590
Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser
595 600 605
Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr
610 615 620
Ala Val Tyr Tyr Cys Ala Ala Ala Arg Thr Ala Ile Ala Ala Lys Arg
625 630 635 640
Ser Ser Glu Phe Asp Tyr Trp Gly Gln Gly Thr Gln Val Thr Val Ser
645 650 655
Ser Ala Ala Ala Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val
660 665 670
Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Gly Thr
675 680 685
Phe Leu Thr Tyr Ser Met Ser Trp Val Arg Gln Ala Pro Gly Lys Glu
690 695 700
Arg Glu Phe Val Ser Ser Ile Asn Trp Ser Gly Tyr Met Thr Tyr Tyr
705 710 715 720
Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys
725 730 735
Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala
740 745 750
Val Tyr Tyr Cys Ala Ala Ala Arg Thr Ala Ile Ala Ala Lys Arg Ser
755 760 765
Ser Glu Phe Asp Tyr Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser
770 775 780
<210> 188
<211> 784
<212> PRT
<213> 人工序列 (Artificial Sequence)
<220>
<223> 多特异性抗体
hCD16F1-2-L1-hHS5-L4-hA09-10-55-L1-hPL16-L3-hPl-16
<400> 188
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Val Ser Gly Ser Leu Phe Ser Ala Arg
20 25 30
Val Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gln Arg Glu Leu Val
35 40 45
Ser Ala Ile Thr Ser Gly Val Arg Thr Tyr Tyr Ala Asp Ser Val Lys
50 55 60
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Arg Ala Val Tyr Leu
65 70 75 80
Gln Met Ser Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Asn
85 90 95
Val Asn Leu Tyr Asn Thr Gly Asn Tyr Trp Gly Gln Gly Thr Gln Val
100 105 110
Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu Val Gln
115 120 125
Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg
130 135 140
Leu Ser Cys Ala Ala Ser Gly Arg Thr Phe Thr Thr His Ala Met Gly
145 150 155 160
Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val Ser Ala Ile
165 170 175
Asn Trp Gly Gly Arg Thr Thr Tyr Tyr Ala Asp Ser Val Lys Gly Arg
180 185 190
Phe Ile Ile Ser Arg Asp Thr Gly Ala Asn Thr Leu Tyr Leu Gln Met
195 200 205
Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Ser Asn
210 215 220
Leu Asp Thr Tyr Asn Val Arg Ala Gly Thr Thr Asn Ser Trp Gly Gln
225 230 235 240
Gly Thr Gln Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly
245 250 255
Gly Ser Gly Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly
260 265 270
Gly Val Val Arg Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser
275 280 285
Gly Gly Gly Arg Thr Phe Ser Asn Tyr Ala Met Gly Trp Phe Arg Gln
290 295 300
Ala Pro Gly Lys Glu Arg Glu Phe Val Ser Ala Ile Ser Arg Ser Gly
305 310 315 320
Gly Asn Ile Tyr Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser
325 330 335
Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu Gln Met Ser Ser Leu Glu
340 345 350
Pro Glu Asp Thr Ala Val Tyr Tyr Cys Ala Ala His Tyr Leu Leu Leu
355 360 365
Pro Ser Tyr Ile Ser Thr Ser Thr Asn Met Tyr Asn Tyr Trp Gly Gln
370 375 380
Gly Thr Gln Val Thr Val Ser Ser Ala Ala Ala Gln Val Gln Leu Val
385 390 395 400
Glu Ser Gly Gly Gly Val Val Arg Pro Gly Gly Ser Leu Arg Leu Ser
405 410 415
Cys Ala Ala Ser Gly Gly Gly Arg Thr Phe Ser Asn Tyr Ala Met Gly
420 425 430
Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val Ser Ala Ile
435 440 445
Ser Arg Ser Gly Gly Asn Ile Tyr Tyr Ala Asp Ser Val Lys Gly Arg
450 455 460
Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu Gln Met
465 470 475 480
Ser Ser Leu Glu Pro Glu Asp Thr Ala Val Tyr Tyr Cys Ala Ala His
485 490 495
Tyr Leu Leu Leu Pro Ser Tyr Ile Ser Thr Ser Thr Asn Met Tyr Asn
500 505 510
Tyr Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser Gly Gly Gly Gly
515 520 525
Ser Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu
530 535 540
Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Gly
545 550 555 560
Thr Phe Leu Thr Tyr Ser Met Ser Trp Val Arg Gln Ala Pro Gly Lys
565 570 575
Glu Arg Glu Phe Val Ser Ser Ile Asn Trp Ser Gly Tyr Met Thr Tyr
580 585 590
Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser
595 600 605
Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr
610 615 620
Ala Val Tyr Tyr Cys Ala Ala Ala Arg Thr Ala Ile Ala Ala Lys Arg
625 630 635 640
Ser Ser Glu Phe Asp Tyr Trp Gly Gln Gly Thr Gln Val Thr Val Ser
645 650 655
Ser Ala Ala Ala Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val
660 665 670
Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Gly Thr
675 680 685
Phe Leu Thr Tyr Ser Met Ser Trp Val Arg Gln Ala Pro Gly Lys Glu
690 695 700
Arg Glu Phe Val Ser Ser Ile Asn Trp Ser Gly Tyr Met Thr Tyr Tyr
705 710 715 720
Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys
725 730 735
Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala
740 745 750
Val Tyr Tyr Cys Ala Ala Ala Arg Thr Ala Ile Ala Ala Lys Arg Ser
755 760 765
Ser Glu Phe Asp Tyr Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser
770 775 780
<210> 189
<211> 784
<212> PRT
<213> 人工序列 (Artificial Sequence)
<220>
<223> 多特异性抗体 hCD16F1-1-L1-hHS5-L4-hA09-10-66-
L1-hPL16-L3-hPL-16
<400> 189
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Val Ser Gly Ser Leu Phe Ser Ala Arg
20 25 30
Val Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gln Arg Glu Leu Val
35 40 45
Ser Ala Ile Thr Ser Gly Val Arg Thr Tyr Tyr Ala Asp Ser Val Lys
50 55 60
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Arg Ala Val Tyr Leu
65 70 75 80
Gln Met Ser Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys Asn
85 90 95
Val Asn Leu Tyr Asn Thr Gly Asn Tyr Trp Gly Gln Gly Thr Gln Val
100 105 110
Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu Val Gln
115 120 125
Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg
130 135 140
Leu Ser Cys Ala Ala Ser Gly Arg Thr Phe Thr Thr His Ala Met Gly
145 150 155 160
Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val Ser Ala Ile
165 170 175
Asn Trp Gly Gly Arg Thr Thr Tyr Tyr Ala Asp Ser Val Lys Gly Arg
180 185 190
Phe Ile Ile Ser Arg Asp Thr Gly Ala Asn Thr Leu Tyr Leu Gln Met
195 200 205
Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Ser Asn
210 215 220
Leu Asp Thr Tyr Asn Val Arg Ala Gly Thr Thr Asn Ser Trp Gly Gln
225 230 235 240
Gly Thr Gln Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly
245 250 255
Gly Ser Gly Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly
260 265 270
Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser
275 280 285
Gly Gly Gly Arg Thr Phe Ser Asn Tyr Ala Leu Gly Trp Phe Arg Gln
290 295 300
Ala Pro Gly Lys Glu Arg Glu Phe Val Ser Ala Ile Ser Arg Ser Gly
305 310 315 320
Gly Asn Ile Asp Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser
325 330 335
Arg Asp Asn Phe Lys Asn Thr Val Tyr Leu Gln Met Ser Ser Leu Arg
340 345 350
Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Ala His Tyr Leu Leu Leu
355 360 365
Pro Ser Tyr Ile Ser Thr Ser Thr Asn Met Tyr Asn Tyr Trp Gly Gln
370 375 380
Gly Thr Gln Val Thr Val Ser Ser Ala Ala Ala Gln Val Gln Leu Val
385 390 395 400
Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser
405 410 415
Cys Ala Ala Ser Gly Gly Gly Arg Thr Phe Ser Asn Tyr Ala Leu Gly
420 425 430
Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val Ser Ala Ile
435 440 445
Ser Arg Ser Gly Gly Asn Ile Tyr Tyr Ala Asp Ser Val Lys Gly Arg
450 455 460
Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr Leu Gln Met
465 470 475 480
Ser Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Ala His
485 490 495
Tyr Leu Leu Leu Pro Ser Tyr Ile Ser Thr Ser Thr Asn Met Tyr Asn
500 505 510
Tyr Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser Gly Gly Gly Gly
515 520 525
Ser Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu
530 535 540
Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Gly
545 550 555 560
Thr Phe Leu Thr Tyr Ser Met Ser Trp Val Arg Gln Ala Pro Gly Lys
565 570 575
Glu Arg Glu Phe Val Ser Ser Ile Asn Trp Ser Gly Tyr Met Thr Tyr
580 585 590
Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser
595 600 605
Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr
610 615 620
Ala Val Tyr Tyr Cys Ala Ala Ala Arg Thr Ala Ile Ala Ala Lys Arg
625 630 635 640
Ser Ser Glu Phe Asp Tyr Trp Gly Gln Gly Thr Gln Val Thr Val Ser
645 650 655
Ser Ala Ala Ala Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val
660 665 670
Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Gly Thr
675 680 685
Phe Leu Thr Tyr Ser Met Ser Trp Val Arg Gln Ala Pro Gly Lys Glu
690 695 700
Arg Glu Phe Val Ser Ser Ile Asn Trp Ser Gly Tyr Met Thr Tyr Tyr
705 710 715 720
Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys
725 730 735
Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala
740 745 750
Val Tyr Tyr Cys Ala Ala Ala Arg Thr Ala Ile Ala Ala Lys Arg Ser
755 760 765
Ser Glu Phe Asp Tyr Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser
770 775 780
<210> 190
<211> 784
<212> PRT
<213> 人工序列 (Artificial Sequence)
<220>
<223> 多特异性抗体 hCD16F1-2-L1-hHS5-L4-hA09-10-66-
L1-hPL16-L3-hPL-16
<400> 190
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Val Ser Gly Ser Leu Phe Ser Ala Arg
20 25 30
Val Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gln Arg Glu Leu Val
35 40 45
Ser Ala Ile Thr Ser Gly Val Arg Thr Tyr Tyr Ala Asp Ser Val Lys
50 55 60
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Arg Ala Val Tyr Leu
65 70 75 80
Gln Met Ser Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Asn
85 90 95
Val Asn Leu Tyr Asn Thr Gly Asn Tyr Trp Gly Gln Gly Thr Gln Val
100 105 110
Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu Val Gln
115 120 125
Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg
130 135 140
Leu Ser Cys Ala Ala Ser Gly Arg Thr Phe Thr Thr His Ala Met Gly
145 150 155 160
Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val Ser Ala Ile
165 170 175
Asn Trp Gly Gly Arg Thr Thr Tyr Tyr Ala Asp Ser Val Lys Gly Arg
180 185 190
Phe Ile Ile Ser Arg Asp Thr Gly Ala Asn Thr Leu Tyr Leu Gln Met
195 200 205
Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Ser Asn
210 215 220
Leu Asp Thr Tyr Asn Val Arg Ala Gly Thr Thr Asn Ser Trp Gly Gln
225 230 235 240
Gly Thr Gln Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly
245 250 255
Gly Ser Gly Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly
260 265 270
Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser
275 280 285
Gly Gly Gly Arg Thr Phe Ser Asn Tyr Ala Leu Gly Trp Phe Arg Gln
290 295 300
Ala Pro Gly Lys Glu Arg Glu Phe Val Ser Ala Ile Ser Arg Ser Gly
305 310 315 320
Gly Asn Ile Asp Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser
325 330 335
Arg Asp Asn Phe Lys Asn Thr Val Tyr Leu Gln Met Ser Ser Leu Arg
340 345 350
Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Ala His Tyr Leu Leu Leu
355 360 365
Pro Ser Tyr Ile Ser Thr Ser Thr Asn Met Tyr Asn Tyr Trp Gly Gln
370 375 380
Gly Thr Gln Val Thr Val Ser Ser Ala Ala Ala Gln Val Gln Leu Val
385 390 395 400
Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser
405 410 415
Cys Ala Ala Ser Gly Gly Gly Arg Thr Phe Ser Asn Tyr Ala Leu Gly
420 425 430
Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val Ser Ala Ile
435 440 445
Ser Arg Ser Gly Gly Asn Ile Tyr Tyr Ala Asp Ser Val Lys Gly Arg
450 455 460
Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr Leu Gln Met
465 470 475 480
Ser Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Ala His
485 490 495
Tyr Leu Leu Leu Pro Ser Tyr Ile Ser Thr Ser Thr Asn Met Tyr Asn
500 505 510
Tyr Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser Gly Gly Gly Gly
515 520 525
Ser Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu
530 535 540
Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Gly
545 550 555 560
Thr Phe Leu Thr Tyr Ser Met Ser Trp Val Arg Gln Ala Pro Gly Lys
565 570 575
Glu Arg Glu Phe Val Ser Ser Ile Asn Trp Ser Gly Tyr Met Thr Tyr
580 585 590
Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser
595 600 605
Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr
610 615 620
Ala Val Tyr Tyr Cys Ala Ala Ala Arg Thr Ala Ile Ala Ala Lys Arg
625 630 635 640
Ser Ser Glu Phe Asp Tyr Trp Gly Gln Gly Thr Gln Val Thr Val Ser
645 650 655
Ser Ala Ala Ala Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val
660 665 670
Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Gly Thr
675 680 685
Phe Leu Thr Tyr Ser Met Ser Trp Val Arg Gln Ala Pro Gly Lys Glu
690 695 700
Arg Glu Phe Val Ser Ser Ile Asn Trp Ser Gly Tyr Met Thr Tyr Tyr
705 710 715 720
Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys
725 730 735
Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala
740 745 750
Val Tyr Tyr Cys Ala Ala Ala Arg Thr Ala Ile Ala Ala Lys Arg Ser
755 760 765
Ser Glu Phe Asp Tyr Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser
770 775 780
<210> 191
<211> 784
<212> PRT
<213> 人工序列 (Artificial Sequence)
<220>
<223> 多特异性抗体 hCD16F1-1-L1-hHS5-L4-hA09-10-77-
L1-hPL16-L3-hPL-16
<400> 191
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Val Ser Gly Ser Leu Phe Ser Ala Arg
20 25 30
Val Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gln Arg Glu Leu Val
35 40 45
Ser Ala Ile Thr Ser Gly Val Arg Thr Tyr Tyr Ala Asp Ser Val Lys
50 55 60
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Arg Ala Val Tyr Leu
65 70 75 80
Gln Met Ser Ser Leu Glu Pro Glu Asp Thr Ala Val Tyr Tyr Cys Asn
85 90 95
Val Asn Leu Tyr Asn Thr Gly Asn Tyr Trp Gly Gln Gly Thr Gln Val
100 105 110
Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu Val Gln
115 120 125
Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg
130 135 140
Leu Ser Cys Ala Ala Ser Gly Arg Thr Phe Thr Thr His Ala Met Gly
145 150 155 160
Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val Ser Ala Ile
165 170 175
Asn Trp Gly Gly Arg Thr Thr Tyr Tyr Ala Asp Ser Val Lys Gly Arg
180 185 190
Phe Ile Ile Ser Arg Asp Thr Gly Ala Asn Thr Leu Tyr Leu Gln Met
195 200 205
Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Ser Asn
210 215 220
Leu Asp Thr Tyr Asn Val Arg Ala Gly Thr Thr Asn Ser Trp Gly Gln
225 230 235 240
Gly Thr Gln Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly
245 250 255
Gly Ser Gly Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly
260 265 270
Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser
275 280 285
Gly Gly Gly Arg Thr Phe Ser Asn Tyr Ala Leu Gly Trp Phe Arg Gln
290 295 300
Ala Pro Gly Lys Glu Arg Glu Phe Val Ser Ala Ile Ser Arg Ser Gly
305 310 315 320
Gly Asn Ile Asp Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser
325 330 335
Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu Gln Met Ser Ser Leu Lys
340 345 350
Pro Glu Asp Thr Ala Val Tyr Tyr Cys Ala Ala His Tyr Leu Leu Leu
355 360 365
Pro Ser Tyr Ile Ser Thr Ser Thr Asn Met Tyr Asn Tyr Trp Gly Gln
370 375 380
Gly Thr Gln Val Thr Val Ser Ser Ala Ala Ala Gln Val Gln Leu Val
385 390 395 400
Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser
405 410 415
Cys Ala Ala Ser Gly Gly Gly Arg Thr Phe Ser Asn Tyr Ala Leu Gly
420 425 430
Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val Ser Ala Ile
435 440 445
Ser Arg Ser Gly Gly Asn Ile Asp Tyr Ala Asp Ser Val Lys Gly Arg
450 455 460
Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu Gln Met
465 470 475 480
Ser Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys Ala Ala His
485 490 495
Tyr Leu Leu Leu Pro Ser Tyr Ile Ser Thr Ser Thr Asn Met Tyr Asn
500 505 510
Tyr Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser Gly Gly Gly Gly
515 520 525
Ser Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu
530 535 540
Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Gly
545 550 555 560
Thr Phe Leu Thr Tyr Ser Met Ser Trp Val Arg Gln Ala Pro Gly Lys
565 570 575
Glu Arg Glu Phe Val Ser Ser Ile Asn Trp Ser Gly Tyr Met Thr Tyr
580 585 590
Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser
595 600 605
Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr
610 615 620
Ala Val Tyr Tyr Cys Ala Ala Ala Arg Thr Ala Ile Ala Ala Lys Arg
625 630 635 640
Ser Ser Glu Phe Asp Tyr Trp Gly Gln Gly Thr Gln Val Thr Val Ser
645 650 655
Ser Ala Ala Ala Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val
660 665 670
Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Gly Thr
675 680 685
Phe Leu Thr Tyr Ser Met Ser Trp Val Arg Gln Ala Pro Gly Lys Glu
690 695 700
Arg Glu Phe Val Ser Ser Ile Asn Trp Ser Gly Tyr Met Thr Tyr Tyr
705 710 715 720
Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys
725 730 735
Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala
740 745 750
Val Tyr Tyr Cys Ala Ala Ala Arg Thr Ala Ile Ala Ala Lys Arg Ser
755 760 765
Ser Glu Phe Asp Tyr Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser
770 775 780
<210> 192
<211> 784
<212> PRT
<213> 人工序列 (Artificial Sequence)
<220>
<223> 多特异性抗体 hCD16F1-2-L1-hHS5-L4-hA09-10-77-
L1-hPL16-L3-hPL-16
<400> 192
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Val Ser Gly Ser Leu Phe Ser Ala Arg
20 25 30
Val Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gln Arg Glu Leu Val
35 40 45
Ser Ala Ile Thr Ser Gly Val Arg Thr Tyr Tyr Ala Asp Ser Val Lys
50 55 60
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Arg Ala Val Tyr Leu
65 70 75 80
Gln Met Ser Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Asn
85 90 95
Val Asn Leu Tyr Asn Thr Gly Asn Tyr Trp Gly Gln Gly Thr Gln Val
100 105 110
Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu Val Gln
115 120 125
Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg
130 135 140
Leu Ser Cys Ala Ala Ser Gly Arg Thr Phe Thr Thr His Ala Met Gly
145 150 155 160
Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val Ser Ala Ile
165 170 175
Asn Trp Gly Gly Arg Thr Thr Tyr Tyr Ala Asp Ser Val Lys Gly Arg
180 185 190
Phe Ile Ile Ser Arg Asp Thr Gly Ala Asn Thr Leu Tyr Leu Gln Met
195 200 205
Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Ser Asn
210 215 220
Leu Asp Thr Tyr Asn Val Arg Ala Gly Thr Thr Asn Ser Trp Gly Gln
225 230 235 240
Gly Thr Gln Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly
245 250 255
Gly Ser Gly Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly
260 265 270
Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser
275 280 285
Gly Gly Gly Arg Thr Phe Ser Asn Tyr Ala Leu Gly Trp Phe Arg Gln
290 295 300
Ala Pro Gly Lys Glu Arg Glu Phe Val Ser Ala Ile Ser Arg Ser Gly
305 310 315 320
Gly Asn Ile Asp Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser
325 330 335
Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu Gln Met Ser Ser Leu Lys
340 345 350
Pro Glu Asp Thr Ala Val Tyr Tyr Cys Ala Ala His Tyr Leu Leu Leu
355 360 365
Pro Ser Tyr Ile Ser Thr Ser Thr Asn Met Tyr Asn Tyr Trp Gly Gln
370 375 380
Gly Thr Gln Val Thr Val Ser Ser Ala Ala Ala Gln Val Gln Leu Val
385 390 395 400
Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser
405 410 415
Cys Ala Ala Ser Gly Gly Gly Arg Thr Phe Ser Asn Tyr Ala Leu Gly
420 425 430
Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val Ser Ala Ile
435 440 445
Ser Arg Ser Gly Gly Asn Ile Asp Tyr Ala Asp Ser Val Lys Gly Arg
450 455 460
Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu Gln Met
465 470 475 480
Ser Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys Ala Ala His
485 490 495
Tyr Leu Leu Leu Pro Ser Tyr Ile Ser Thr Ser Thr Asn Met Tyr Asn
500 505 510
Tyr Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser Gly Gly Gly Gly
515 520 525
Ser Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu
530 535 540
Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Gly
545 550 555 560
Thr Phe Leu Thr Tyr Ser Met Ser Trp Val Arg Gln Ala Pro Gly Lys
565 570 575
Glu Arg Glu Phe Val Ser Ser Ile Asn Trp Ser Gly Tyr Met Thr Tyr
580 585 590
Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser
595 600 605
Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr
610 615 620
Ala Val Tyr Tyr Cys Ala Ala Ala Arg Thr Ala Ile Ala Ala Lys Arg
625 630 635 640
Ser Ser Glu Phe Asp Tyr Trp Gly Gln Gly Thr Gln Val Thr Val Ser
645 650 655
Ser Ala Ala Ala Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val
660 665 670
Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Gly Thr
675 680 685
Phe Leu Thr Tyr Ser Met Ser Trp Val Arg Gln Ala Pro Gly Lys Glu
690 695 700
Arg Glu Phe Val Ser Ser Ile Asn Trp Ser Gly Tyr Met Thr Tyr Tyr
705 710 715 720
Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys
725 730 735
Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala
740 745 750
Val Tyr Tyr Cys Ala Ala Ala Arg Thr Ala Ile Ala Ala Lys Arg Ser
755 760 765
Ser Glu Phe Asp Tyr Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser
770 775 780
<210> 193
<211> 784
<212> PRT
<213> 人工序列 (Artificial Sequence)
<220>
<223> 多特异性抗体 hCD16F1-1-L1-hHS5-L4-hA09-10-88-
L1-hPL16-L3-hPL-16
<400> 193
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Val Ser Gly Ser Leu Phe Ser Ala Arg
20 25 30
Val Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gln Arg Glu Leu Val
35 40 45
Ser Ala Ile Thr Ser Gly Val Arg Thr Tyr Tyr Ala Asp Ser Val Lys
50 55 60
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Arg Ala Val Tyr Leu
65 70 75 80
Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys Asn
85 90 95
Val Asn Leu Tyr Asn Thr Gly Asn Tyr Trp Gly Gln Gly Thr Gln Val
100 105 110
Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu Val Gln
115 120 125
Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg
130 135 140
Leu Ser Cys Ala Ala Ser Gly Arg Thr Phe Thr Thr His Ala Met Gly
145 150 155 160
Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val Ser Ala Ile
165 170 175
Asn Trp Gly Gly Arg Thr Thr Tyr Tyr Ala Asp Ser Val Lys Gly Arg
180 185 190
Phe Ile Ile Ser Arg Asp Thr Gly Ala Asn Thr Leu Tyr Leu Gln Met
195 200 205
Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Ser Asn
210 215 220
Leu Asp Thr Tyr Asn Val Arg Ala Gly Thr Thr Asn Ser Trp Gly Gln
225 230 235 240
Gly Thr Gln Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly
245 250 255
Gly Ser Gly Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly
260 265 270
Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser
275 280 285
Gly Gly Gly Arg Thr Phe Ser Asn Tyr Ala Leu Gly Trp Phe Arg Gln
290 295 300
Ala Pro Gly Lys Glu Arg Glu Phe Val Ser Ala Ile Ser Arg Ser Gly
305 310 315 320
Gly Asn Ile Tyr Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser
325 330 335
Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu Gln Met Ser Ser Leu Lys
340 345 350
Pro Glu Asp Thr Ala Val Tyr Tyr Cys Ala Ala His Tyr Leu Leu Leu
355 360 365
Pro Ser Tyr Ile Ser Thr Ser Thr Asn Met Tyr Asn Tyr Trp Gly Gln
370 375 380
Gly Thr Gln Val Thr Val Ser Ser Ala Ala Ala Gln Val Gln Leu Val
385 390 395 400
Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser
405 410 415
Cys Ala Ala Ser Gly Gly Gly Arg Thr Phe Ser Asn Tyr Ala Leu Gly
420 425 430
Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val Ser Ala Ile
435 440 445
Ser Arg Ser Gly Gly Asn Ile Tyr Tyr Ala Asp Ser Val Lys Gly Arg
450 455 460
Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu Gln Met
465 470 475 480
Ser Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys Ala Ala His
485 490 495
Tyr Leu Leu Leu Pro Ser Tyr Ile Ser Thr Ser Thr Asn Met Tyr Asn
500 505 510
Tyr Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser Gly Gly Gly Gly
515 520 525
Ser Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu
530 535 540
Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Gly
545 550 555 560
Thr Phe Leu Thr Tyr Ser Met Ser Trp Val Arg Gln Ala Pro Gly Lys
565 570 575
Glu Arg Glu Phe Val Ser Ser Ile Asn Trp Ser Gly Tyr Met Thr Tyr
580 585 590
Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser
595 600 605
Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr
610 615 620
Ala Val Tyr Tyr Cys Ala Ala Ala Arg Thr Ala Ile Ala Ala Lys Arg
625 630 635 640
Ser Ser Glu Phe Asp Tyr Trp Gly Gln Gly Thr Gln Val Thr Val Ser
645 650 655
Ser Ala Ala Ala Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val
660 665 670
Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Gly Thr
675 680 685
Phe Leu Thr Tyr Ser Met Ser Trp Val Arg Gln Ala Pro Gly Lys Glu
690 695 700
Arg Glu Phe Val Ser Ser Ile Asn Trp Ser Gly Tyr Met Thr Tyr Tyr
705 710 715 720
Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys
725 730 735
Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala
740 745 750
Val Tyr Tyr Cys Ala Ala Ala Arg Thr Ala Ile Ala Ala Lys Arg Ser
755 760 765
Ser Glu Phe Asp Tyr Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser
770 775 780
<210> 194
<211> 784
<212> PRT
<213> 人工序列 (Artificial Sequence)
<220>
<223> 多特异性抗体 hCD16F1-2-L1-hHS5-L4-hA09-10-88-
L1-hPL16-L3-hPL-16
<400> 194
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Val Ser Gly Ser Leu Phe Ser Ala Arg
20 25 30
Val Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gln Arg Glu Leu Val
35 40 45
Ser Ala Ile Thr Ser Gly Val Arg Thr Tyr Tyr Ala Asp Ser Val Lys
50 55 60
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Arg Ala Val Tyr Leu
65 70 75 80
Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Asn
85 90 95
Val Asn Leu Tyr Asn Thr Gly Asn Tyr Trp Gly Gln Gly Thr Gln Val
100 105 110
Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu Val Gln
115 120 125
Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg
130 135 140
Leu Ser Cys Ala Ala Ser Gly Arg Thr Phe Thr Thr His Ala Met Gly
145 150 155 160
Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val Ser Ala Ile
165 170 175
Asn Trp Gly Gly Arg Thr Thr Tyr Tyr Ala Asp Ser Val Lys Gly Arg
180 185 190
Phe Ile Ile Ser Arg Asp Thr Gly Ala Asn Thr Leu Tyr Leu Gln Met
195 200 205
Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Ser Asn
210 215 220
Leu Asp Thr Tyr Asn Val Arg Ala Gly Thr Thr Asn Ser Trp Gly Gln
225 230 235 240
Gly Thr Gln Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly
245 250 255
Gly Ser Gly Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly
260 265 270
Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser
275 280 285
Gly Gly Gly Arg Thr Phe Ser Asn Tyr Ala Leu Gly Trp Phe Arg Gln
290 295 300
Ala Pro Gly Lys Glu Arg Glu Phe Val Ser Ala Ile Ser Arg Ser Gly
305 310 315 320
Gly Asn Ile Tyr Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser
325 330 335
Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu Gln Met Ser Ser Leu Lys
340 345 350
Pro Glu Asp Thr Ala Val Tyr Tyr Cys Ala Ala His Tyr Leu Leu Leu
355 360 365
Pro Ser Tyr Ile Ser Thr Ser Thr Asn Met Tyr Asn Tyr Trp Gly Gln
370 375 380
Gly Thr Gln Val Thr Val Ser Ser Ala Ala Ala Gln Val Gln Leu Val
385 390 395 400
Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser
405 410 415
Cys Ala Ala Ser Gly Gly Gly Arg Thr Phe Ser Asn Tyr Ala Leu Gly
420 425 430
Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val Ser Ala Ile
435 440 445
Ser Arg Ser Gly Gly Asn Ile Tyr Tyr Ala Asp Ser Val Lys Gly Arg
450 455 460
Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu Gln Met
465 470 475 480
Ser Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys Ala Ala His
485 490 495
Tyr Leu Leu Leu Pro Ser Tyr Ile Ser Thr Ser Thr Asn Met Tyr Asn
500 505 510
Tyr Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser Gly Gly Gly Gly
515 520 525
Ser Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu
530 535 540
Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Gly
545 550 555 560
Thr Phe Leu Thr Tyr Ser Met Ser Trp Val Arg Gln Ala Pro Gly Lys
565 570 575
Glu Arg Glu Phe Val Ser Ser Ile Asn Trp Ser Gly Tyr Met Thr Tyr
580 585 590
Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser
595 600 605
Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr
610 615 620
Ala Val Tyr Tyr Cys Ala Ala Ala Arg Thr Ala Ile Ala Ala Lys Arg
625 630 635 640
Ser Ser Glu Phe Asp Tyr Trp Gly Gln Gly Thr Gln Val Thr Val Ser
645 650 655
Ser Ala Ala Ala Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val
660 665 670
Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Gly Thr
675 680 685
Phe Leu Thr Tyr Ser Met Ser Trp Val Arg Gln Ala Pro Gly Lys Glu
690 695 700
Arg Glu Phe Val Ser Ser Ile Asn Trp Ser Gly Tyr Met Thr Tyr Tyr
705 710 715 720
Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys
725 730 735
Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala
740 745 750
Val Tyr Tyr Cys Ala Ala Ala Arg Thr Ala Ile Ala Ala Lys Arg Ser
755 760 765
Ser Glu Phe Asp Tyr Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser
770 775 780
<210> 195
<211> 784
<212> PRT
<213> 人工序列 (Artificial Sequence)
<220>
<223> 多特异性抗体 hCD16F1-1-L1-hHS5-L4-hA09-10-99-
L1-hPL16-L3-hPL-16
<400> 195
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Val Ser Gly Ser Leu Phe Ser Ala Arg
20 25 30
Val Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gln Arg Glu Leu Val
35 40 45
Ser Ala Ile Thr Ser Gly Val Arg Thr Tyr Tyr Ala Asp Ser Val Lys
50 55 60
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Arg Ala Val Tyr Leu
65 70 75 80
Gln Met Asn Ser Leu Glu Pro Glu Asp Thr Ala Val Tyr Tyr Cys Asn
85 90 95
Val Asn Leu Tyr Asn Thr Gly Asn Tyr Trp Gly Gln Gly Thr Gln Val
100 105 110
Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu Val Gln
115 120 125
Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg
130 135 140
Leu Ser Cys Ala Ala Ser Gly Arg Thr Phe Thr Thr His Ala Met Gly
145 150 155 160
Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val Ser Ala Ile
165 170 175
Asn Trp Gly Gly Arg Thr Thr Tyr Tyr Ala Asp Ser Val Lys Gly Arg
180 185 190
Phe Ile Ile Ser Arg Asp Thr Gly Ala Asn Thr Leu Tyr Leu Gln Met
195 200 205
Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Ser Asn
210 215 220
Leu Asp Thr Tyr Asn Val Arg Ala Gly Thr Thr Asn Ser Trp Gly Gln
225 230 235 240
Gly Thr Gln Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly
245 250 255
Gly Ser Gly Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly
260 265 270
Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser
275 280 285
Gly Gly Gly Arg Thr Phe Ser Asn Tyr Ala Met Gly Trp Phe Arg Gln
290 295 300
Ala Pro Gly Lys Glu Arg Glu Phe Val Ser Ala Ile Ser Arg Ser Gly
305 310 315 320
Gly Asn Ile Tyr Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser
325 330 335
Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu Gln Met Ser Ser Leu Lys
340 345 350
Pro Glu Asp Thr Ala Val Tyr Tyr Cys Ala Ala His Tyr Leu Leu Leu
355 360 365
Pro Ser Tyr Ile Ser Thr Ser Thr Asn Met Tyr Asn Tyr Trp Gly Gln
370 375 380
Gly Thr Gln Val Thr Val Ser Ser Ala Ala Ala Gln Val Gln Leu Val
385 390 395 400
Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser
405 410 415
Cys Ala Ala Ser Gly Gly Gly Arg Thr Phe Ser Asn Tyr Ala Met Gly
420 425 430
Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val Ser Ala Ile
435 440 445
Ser Arg Ser Gly Gly Asn Ile Tyr Tyr Ala Asp Ser Val Lys Gly Arg
450 455 460
Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu Gln Met
465 470 475 480
Ser Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys Ala Ala His
485 490 495
Tyr Leu Leu Leu Pro Ser Tyr Ile Ser Thr Ser Thr Asn Met Tyr Asn
500 505 510
Tyr Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser Gly Gly Gly Gly
515 520 525
Ser Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu
530 535 540
Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Gly
545 550 555 560
Thr Phe Leu Thr Tyr Ser Met Ser Trp Val Arg Gln Ala Pro Gly Lys
565 570 575
Glu Arg Glu Phe Val Ser Ser Ile Asn Trp Ser Gly Tyr Met Thr Tyr
580 585 590
Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser
595 600 605
Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr
610 615 620
Ala Val Tyr Tyr Cys Ala Ala Ala Arg Thr Ala Ile Ala Ala Lys Arg
625 630 635 640
Ser Ser Glu Phe Asp Tyr Trp Gly Gln Gly Thr Gln Val Thr Val Ser
645 650 655
Ser Ala Ala Ala Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val
660 665 670
Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Gly Thr
675 680 685
Phe Leu Thr Tyr Ser Met Ser Trp Val Arg Gln Ala Pro Gly Lys Glu
690 695 700
Arg Glu Phe Val Ser Ser Ile Asn Trp Ser Gly Tyr Met Thr Tyr Tyr
705 710 715 720
Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys
725 730 735
Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala
740 745 750
Val Tyr Tyr Cys Ala Ala Ala Arg Thr Ala Ile Ala Ala Lys Arg Ser
755 760 765
Ser Glu Phe Asp Tyr Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser
770 775 780
<210> 196
<211> 784
<212> PRT
<213> 人工序列 (Artificial Sequence)
<220>
<223> 多特异性抗体 hCD16F1-2-L1-hHS5-L4-hA09-10-99-
L1-hPL16-L3-hPL-16
<400> 196
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Val Ser Gly Ser Leu Phe Ser Ala Arg
20 25 30
Val Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gln Arg Glu Leu Val
35 40 45
Ser Ala Ile Thr Ser Gly Val Arg Thr Tyr Tyr Ala Asp Ser Val Lys
50 55 60
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Arg Ala Val Tyr Leu
65 70 75 80
Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Asn
85 90 95
Val Asn Leu Tyr Asn Thr Gly Asn Tyr Trp Gly Gln Gly Thr Gln Val
100 105 110
Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu Val Gln
115 120 125
Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg
130 135 140
Leu Ser Cys Ala Ala Ser Gly Arg Thr Phe Thr Thr His Ala Met Gly
145 150 155 160
Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val Ser Ala Ile
165 170 175
Asn Trp Gly Gly Arg Thr Thr Tyr Tyr Ala Asp Ser Val Lys Gly Arg
180 185 190
Phe Ile Ile Ser Arg Asp Thr Gly Ala Asn Thr Leu Tyr Leu Gln Met
195 200 205
Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Ser Asn
210 215 220
Leu Asp Thr Tyr Asn Val Arg Ala Gly Thr Thr Asn Ser Trp Gly Gln
225 230 235 240
Gly Thr Gln Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly
245 250 255
Gly Ser Gly Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly
260 265 270
Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser
275 280 285
Gly Gly Gly Arg Thr Phe Ser Asn Tyr Ala Met Gly Trp Phe Arg Gln
290 295 300
Ala Pro Gly Lys Glu Arg Glu Phe Val Ser Ala Ile Ser Arg Ser Gly
305 310 315 320
Gly Asn Ile Tyr Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser
325 330 335
Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu Gln Met Ser Ser Leu Lys
340 345 350
Pro Glu Asp Thr Ala Val Tyr Tyr Cys Ala Ala His Tyr Leu Leu Leu
355 360 365
Pro Ser Tyr Ile Ser Thr Ser Thr Asn Met Tyr Asn Tyr Trp Gly Gln
370 375 380
Gly Thr Gln Val Thr Val Ser Ser Ala Ala Ala Gln Val Gln Leu Val
385 390 395 400
Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser
405 410 415
Cys Ala Ala Ser Gly Gly Gly Arg Thr Phe Ser Asn Tyr Ala Met Gly
420 425 430
Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val Ser Ala Ile
435 440 445
Ser Arg Ser Gly Gly Asn Ile Tyr Tyr Ala Asp Ser Val Lys Gly Arg
450 455 460
Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu Gln Met
465 470 475 480
Ser Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys Ala Ala His
485 490 495
Tyr Leu Leu Leu Pro Ser Tyr Ile Ser Thr Ser Thr Asn Met Tyr Asn
500 505 510
Tyr Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser Gly Gly Gly Gly
515 520 525
Ser Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu
530 535 540
Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Gly
545 550 555 560
Thr Phe Leu Thr Tyr Ser Met Ser Trp Val Arg Gln Ala Pro Gly Lys
565 570 575
Glu Arg Glu Phe Val Ser Ser Ile Asn Trp Ser Gly Tyr Met Thr Tyr
580 585 590
Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser
595 600 605
Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr
610 615 620
Ala Val Tyr Tyr Cys Ala Ala Ala Arg Thr Ala Ile Ala Ala Lys Arg
625 630 635 640
Ser Ser Glu Phe Asp Tyr Trp Gly Gln Gly Thr Gln Val Thr Val Ser
645 650 655
Ser Ala Ala Ala Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val
660 665 670
Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Gly Thr
675 680 685
Phe Leu Thr Tyr Ser Met Ser Trp Val Arg Gln Ala Pro Gly Lys Glu
690 695 700
Arg Glu Phe Val Ser Ser Ile Asn Trp Ser Gly Tyr Met Thr Tyr Tyr
705 710 715 720
Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys
725 730 735
Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala
740 745 750
Val Tyr Tyr Cys Ala Ala Ala Arg Thr Ala Ile Ala Ala Lys Arg Ser
755 760 765
Ser Glu Phe Asp Tyr Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser
770 775 780
<210> 197
<211> 784
<212> PRT
<213> 人工序列 (Artificial Sequence)
<220>
<223> 多特异性抗体 hCD16F1-1-L1-hHS5-L4-hA09-10-100-
L1-hPL16-L3-hPL-16
<400> 197
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Val Ser Gly Ser Leu Phe Ser Ala Arg
20 25 30
Val Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gln Arg Glu Leu Val
35 40 45
Ser Ala Ile Thr Ser Gly Val Arg Thr Tyr Tyr Ala Asp Ser Val Lys
50 55 60
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Arg Ala Val Tyr Leu
65 70 75 80
Gln Met Asn Ser Leu Glu Pro Glu Asp Thr Ala Val Tyr Tyr Cys Asn
85 90 95
Val Asn Leu Tyr Asn Thr Gly Asn Tyr Trp Gly Gln Gly Thr Gln Val
100 105 110
Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu Val Gln
115 120 125
Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg
130 135 140
Leu Ser Cys Ala Ala Ser Gly Arg Thr Phe Thr Thr His Ala Met Gly
145 150 155 160
Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val Ser Ala Ile
165 170 175
Asn Trp Gly Gly Arg Thr Thr Tyr Tyr Ala Asp Ser Val Lys Gly Arg
180 185 190
Phe Ile Ile Ser Arg Asp Thr Gly Ala Asn Thr Leu Tyr Leu Gln Met
195 200 205
Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Ser Asn
210 215 220
Leu Asp Thr Tyr Asn Val Arg Ala Gly Thr Thr Asn Ser Trp Gly Gln
225 230 235 240
Gly Thr Gln Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly
245 250 255
Gly Ser Gly Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly
260 265 270
Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser
275 280 285
Gly Gly Gly Arg Thr Phe Ser Asn Tyr Ala Met Gly Trp Phe Arg Gln
290 295 300
Ala Pro Gly Lys Glu Arg Glu Phe Val Ser Ala Ile Ser Arg Ser Gly
305 310 315 320
Gly Asn Ile Tyr Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser
325 330 335
Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu Gln Met Ser Ser Leu Arg
340 345 350
Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Ala His Tyr Leu Leu Leu
355 360 365
Pro Ser Tyr Ile Ser Thr Ser Thr Asn Met Tyr Asn Tyr Trp Gly Gln
370 375 380
Gly Thr Gln Val Thr Val Ser Ser Ala Ala Ala Gln Val Gln Leu Val
385 390 395 400
Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser
405 410 415
Cys Ala Ala Ser Gly Gly Gly Arg Thr Phe Ser Asn Tyr Ala Met Gly
420 425 430
Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val Ser Ala Ile
435 440 445
Ser Arg Ser Gly Gly Asn Ile Tyr Tyr Ala Asp Ser Val Lys Gly Arg
450 455 460
Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu Gln Met
465 470 475 480
Ser Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Ala His
485 490 495
Tyr Leu Leu Leu Pro Ser Tyr Ile Ser Thr Ser Thr Asn Met Tyr Asn
500 505 510
Tyr Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser Gly Gly Gly Gly
515 520 525
Ser Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu
530 535 540
Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Gly
545 550 555 560
Thr Phe Leu Thr Tyr Ser Met Ser Trp Val Arg Gln Ala Pro Gly Lys
565 570 575
Glu Arg Glu Phe Val Ser Ser Ile Asn Trp Ser Gly Tyr Met Thr Tyr
580 585 590
Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser
595 600 605
Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr
610 615 620
Ala Val Tyr Tyr Cys Ala Ala Ala Arg Thr Ala Ile Ala Ala Lys Arg
625 630 635 640
Ser Ser Glu Phe Asp Tyr Trp Gly Gln Gly Thr Gln Val Thr Val Ser
645 650 655
Ser Ala Ala Ala Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val
660 665 670
Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Gly Thr
675 680 685
Phe Leu Thr Tyr Ser Met Ser Trp Val Arg Gln Ala Pro Gly Lys Glu
690 695 700
Arg Glu Phe Val Ser Ser Ile Asn Trp Ser Gly Tyr Met Thr Tyr Tyr
705 710 715 720
Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys
725 730 735
Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala
740 745 750
Val Tyr Tyr Cys Ala Ala Ala Arg Thr Ala Ile Ala Ala Lys Arg Ser
755 760 765
Ser Glu Phe Asp Tyr Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser
770 775 780
<210> 198
<211> 784
<212> PRT
<213> 人工序列 (Artificial Sequence)
<220>
<223> 多特异性抗体
hCD16F1-2-L1-hHS5-L4-hA09-10-100-L1-hPL16-L3-hPL-16
<400> 198
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Val Ser Gly Ser Leu Phe Ser Ala Arg
20 25 30
Val Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gln Arg Glu Leu Val
35 40 45
Ser Ala Ile Thr Ser Gly Val Arg Thr Tyr Tyr Ala Asp Ser Val Lys
50 55 60
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Arg Ala Val Tyr Leu
65 70 75 80
Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Asn
85 90 95
Val Asn Leu Tyr Asn Thr Gly Asn Tyr Trp Gly Gln Gly Thr Gln Val
100 105 110
Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu Val Gln
115 120 125
Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg
130 135 140
Leu Ser Cys Ala Ala Ser Gly Arg Thr Phe Thr Thr His Ala Met Gly
145 150 155 160
Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val Ser Ala Ile
165 170 175
Asn Trp Gly Gly Arg Thr Thr Tyr Tyr Ala Asp Ser Val Lys Gly Arg
180 185 190
Phe Ile Ile Ser Arg Asp Thr Gly Ala Asn Thr Leu Tyr Leu Gln Met
195 200 205
Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Ser Asn
210 215 220
Leu Asp Thr Tyr Asn Val Arg Ala Gly Thr Thr Asn Ser Trp Gly Gln
225 230 235 240
Gly Thr Gln Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly
245 250 255
Gly Ser Gly Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly
260 265 270
Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser
275 280 285
Gly Gly Gly Arg Thr Phe Ser Asn Tyr Ala Met Gly Trp Phe Arg Gln
290 295 300
Ala Pro Gly Lys Glu Arg Glu Phe Val Ser Ala Ile Ser Arg Ser Gly
305 310 315 320
Gly Asn Ile Tyr Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser
325 330 335
Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu Gln Met Ser Ser Leu Arg
340 345 350
Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Ala His Tyr Leu Leu Leu
355 360 365
Pro Ser Tyr Ile Ser Thr Ser Thr Asn Met Tyr Asn Tyr Trp Gly Gln
370 375 380
Gly Thr Gln Val Thr Val Ser Ser Ala Ala Ala Gln Val Gln Leu Val
385 390 395 400
Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser
405 410 415
Cys Ala Ala Ser Gly Gly Gly Arg Thr Phe Ser Asn Tyr Ala Met Gly
420 425 430
Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val Ser Ala Ile
435 440 445
Ser Arg Ser Gly Gly Asn Ile Tyr Tyr Ala Asp Ser Val Lys Gly Arg
450 455 460
Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu Gln Met
465 470 475 480
Ser Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Ala His
485 490 495
Tyr Leu Leu Leu Pro Ser Tyr Ile Ser Thr Ser Thr Asn Met Tyr Asn
500 505 510
Tyr Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser Gly Gly Gly Gly
515 520 525
Ser Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu
530 535 540
Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Gly
545 550 555 560
Thr Phe Leu Thr Tyr Ser Met Ser Trp Val Arg Gln Ala Pro Gly Lys
565 570 575
Glu Arg Glu Phe Val Ser Ser Ile Asn Trp Ser Gly Tyr Met Thr Tyr
580 585 590
Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser
595 600 605
Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr
610 615 620
Ala Val Tyr Tyr Cys Ala Ala Ala Arg Thr Ala Ile Ala Ala Lys Arg
625 630 635 640
Ser Ser Glu Phe Asp Tyr Trp Gly Gln Gly Thr Gln Val Thr Val Ser
645 650 655
Ser Ala Ala Ala Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val
660 665 670
Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Gly Thr
675 680 685
Phe Leu Thr Tyr Ser Met Ser Trp Val Arg Gln Ala Pro Gly Lys Glu
690 695 700
Arg Glu Phe Val Ser Ser Ile Asn Trp Ser Gly Tyr Met Thr Tyr Tyr
705 710 715 720
Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys
725 730 735
Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala
740 745 750
Val Tyr Tyr Cys Ala Ala Ala Arg Thr Ala Ile Ala Ala Lys Arg Ser
755 760 765
Ser Glu Phe Asp Tyr Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser
770 775 780
<210> 199
<211> 770
<212> PRT
<213> 人工序列 (Artificial Sequence)
<220>
<223> 多特异性抗体
CD16F1-L1-hHS5-L4-hA09-10-L3-hA09-10-L1-H33-14-L3-H33-14
(3321-HS5-GS15)
<400> 199
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Val Ser Gly Ser Leu Phe Ser Ala Arg
20 25 30
Val Met Gly Trp Tyr Arg Gln Ala Pro Gly Lys Gln Arg Glu Leu Val
35 40 45
Ala Ala Ile Thr Ser Gly Val Arg Thr Asp Tyr Ala Asp Ser Val Lys
50 55 60
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Arg Ala Val Tyr Leu
65 70 75 80
Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys Asn
85 90 95
Val Asn Leu Tyr Asn Thr Gly Asn Tyr Trp Gly Gln Gly Thr Gln Val
100 105 110
Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu Val Gln
115 120 125
Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg
130 135 140
Leu Ser Cys Ala Ala Ser Gly Arg Thr Phe Thr Thr His Ala Met Gly
145 150 155 160
Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val Ser Ala Ile
165 170 175
Asn Trp Gly Gly Arg Thr Thr Tyr Tyr Ala Asp Ser Val Lys Gly Arg
180 185 190
Phe Ile Ile Ser Arg Asp Thr Gly Ala Asn Thr Leu Tyr Leu Gln Met
195 200 205
Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Ser Asn
210 215 220
Leu Asp Thr Tyr Asn Val Arg Ala Gly Thr Thr Asn Ser Trp Gly Gln
225 230 235 240
Gly Thr Gln Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly
245 250 255
Gly Ser Gly Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly
260 265 270
Gly Val Val Arg Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser
275 280 285
Gly Gly Gly Arg Thr Phe Ser Asn Tyr Ala Leu Gly Trp Phe Arg Gln
290 295 300
Ala Pro Gly Lys Glu Arg Glu Phe Val Ala Ala Ile Ser Arg Ser Gly
305 310 315 320
Gly Asn Ile Asn Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser
325 330 335
Arg Asp Asn Phe Lys Asn Thr Val Tyr Leu Gln Met Ser Ser Leu Arg
340 345 350
Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Ala His Tyr Leu Leu Leu
355 360 365
Pro Ser Tyr Ile Ser Thr Ser Thr Asn Met Tyr Asn Tyr Trp Gly Gln
370 375 380
Gly Thr Gln Val Thr Val Ser Ser Ala Ala Ala Gln Val Gln Leu Val
385 390 395 400
Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser
405 410 415
Cys Ala Ala Ser Gly Gly Gly Arg Thr Phe Ser Asn Tyr Ala Leu Gly
420 425 430
Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val Ala Ala Ile
435 440 445
Ser Arg Ser Gly Gly Asn Ile Asn Tyr Ala Asp Ser Val Lys Gly Arg
450 455 460
Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr Leu Gln Met
465 470 475 480
Ser Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Ala His
485 490 495
Tyr Leu Leu Leu Pro Ser Tyr Ile Ser Thr Ser Thr Asn Met Tyr Asn
500 505 510
Tyr Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser Gly Gly Gly Gly
515 520 525
Ser Gly Gly Gly Ser Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu
530 535 540
Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg
545 550 555 560
Thr Ser Leu Ile Leu Ala Met Ala Trp Trp Arg Gln Ala Pro Gly Lys
565 570 575
Glu Arg Glu Phe Ala Gly Arg Ile Trp Trp Asn Asn Asp Met Thr Arg
580 585 590
Tyr Ser Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala
595 600 605
Lys Asn Thr Val Tyr Leu Gln Met Ser Ser Leu Arg Ala Glu Asp Thr
610 615 620
Ala Val Tyr Tyr Cys Glu Ala Asp Leu Ile Gly Gly Ser Arg Gly Trp
625 630 635 640
Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ala Ala Gln Val Gln
645 650 655
Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg
660 665 670
Leu Ser Cys Ala Ala Ser Gly Arg Thr Ser Leu Ile Leu Ala Met Ala
675 680 685
Trp Trp Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Ala Gly Arg Ile
690 695 700
Trp Trp Asn Asn Asp Met Thr Arg Tyr Ser Asp Ser Val Lys Gly Arg
705 710 715 720
Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr Leu Gln Met
725 730 735
Ser Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Glu Ala Asp
740 745 750
Leu Ile Gly Gly Ser Arg Gly Trp Gly Gln Gly Thr Leu Val Thr Val
755 760 765
Ser Ser
770
<210> 200
<211> 770
<212> PRT
<213> 人工序列 (Artificial Sequence)
<220>
<223> 多特异性抗体
hCD16F1-1-L1-hHS5-L4-hA09-10-3-L3-hA09-10-4-L1-H33-14-L3-H33-14
<400> 200
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Val Ser Gly Ser Leu Phe Ser Ala Arg
20 25 30
Val Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gln Arg Glu Leu Val
35 40 45
Ser Ala Ile Thr Ser Gly Val Arg Thr Tyr Tyr Ala Asp Ser Val Lys
50 55 60
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Arg Ala Val Tyr Leu
65 70 75 80
Gln Met Ser Ser Leu Glu Pro Glu Asp Thr Ala Val Tyr Tyr Cys Asn
85 90 95
Val Asn Leu Tyr Asn Thr Gly Asn Tyr Trp Gly Gln Gly Thr Gln Val
100 105 110
Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu Val Gln
115 120 125
Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg
130 135 140
Leu Ser Cys Ala Ala Ser Gly Arg Thr Phe Thr Thr His Ala Met Gly
145 150 155 160
Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val Ser Ala Ile
165 170 175
Asn Trp Gly Gly Arg Thr Thr Tyr Tyr Ala Asp Ser Val Lys Gly Arg
180 185 190
Phe Ile Ile Ser Arg Asp Thr Gly Ala Asn Thr Leu Tyr Leu Gln Met
195 200 205
Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Ser Asn
210 215 220
Leu Asp Thr Tyr Asn Val Arg Ala Gly Thr Thr Asn Ser Trp Gly Gln
225 230 235 240
Gly Thr Gln Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly
245 250 255
Gly Ser Gly Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly
260 265 270
Gly Val Val Arg Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser
275 280 285
Gly Gly Gly Arg Thr Phe Ser Asn Tyr Ala Leu Gly Trp Phe Arg Gln
290 295 300
Ala Pro Gly Lys Glu Arg Glu Phe Val Ala Ala Ile Ser Arg Ser Gly
305 310 315 320
Gly Asn Ile Asn Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser
325 330 335
Arg Asp Asn Phe Lys Asn Thr Val Tyr Leu Gln Met Ser Ser Leu Arg
340 345 350
Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Ala His Tyr Leu Leu Leu
355 360 365
Pro Ser Tyr Ile Ser Thr Ser Thr Asn Met Tyr Asn Tyr Trp Gly Gln
370 375 380
Gly Thr Gln Val Thr Val Ser Ser Ala Ala Ala Gln Val Gln Leu Val
385 390 395 400
Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser
405 410 415
Cys Ala Ala Ser Gly Gly Gly Arg Thr Phe Ser Asn Tyr Ala Leu Gly
420 425 430
Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val Ala Ala Ile
435 440 445
Ser Arg Ser Gly Gly Asn Ile Asn Tyr Ala Asp Ser Val Lys Gly Arg
450 455 460
Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr Leu Gln Met
465 470 475 480
Ser Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Ala His
485 490 495
Tyr Leu Leu Leu Pro Ser Tyr Ile Ser Thr Ser Thr Asn Met Tyr Asn
500 505 510
Tyr Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser Gly Gly Gly Gly
515 520 525
Ser Gly Gly Gly Ser Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu
530 535 540
Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg
545 550 555 560
Thr Ser Leu Ile Leu Ala Met Ala Trp Trp Arg Gln Ala Pro Gly Lys
565 570 575
Glu Arg Glu Phe Ala Gly Arg Ile Trp Trp Asn Asn Asp Met Thr Arg
580 585 590
Tyr Ser Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala
595 600 605
Lys Asn Thr Val Tyr Leu Gln Met Ser Ser Leu Arg Ala Glu Asp Thr
610 615 620
Ala Val Tyr Tyr Cys Glu Ala Asp Leu Ile Gly Gly Ser Arg Gly Trp
625 630 635 640
Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ala Ala Gln Val Gln
645 650 655
Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg
660 665 670
Leu Ser Cys Ala Ala Ser Gly Arg Thr Ser Leu Ile Leu Ala Met Ala
675 680 685
Trp Trp Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Ala Gly Arg Ile
690 695 700
Trp Trp Asn Asn Asp Met Thr Arg Tyr Ser Asp Ser Val Lys Gly Arg
705 710 715 720
Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr Leu Gln Met
725 730 735
Ser Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Glu Ala Asp
740 745 750
Leu Ile Gly Gly Ser Arg Gly Trp Gly Gln Gly Thr Leu Val Thr Val
755 760 765
Ser Ser
770
<210> 201
<211> 770
<212> PRT
<213> 人工序列 (Artificial Sequence)
<220>
<223> 多特异性抗体
hCD16F1-2-L1-hHS5-L4-hA09-10-3-L3-hA09-10-4-L1-H33-14-L3-H33-14
<400> 201
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Val Ser Gly Ser Leu Phe Ser Ala Arg
20 25 30
Val Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gln Arg Glu Leu Val
35 40 45
Ser Ala Ile Thr Ser Gly Val Arg Thr Tyr Tyr Ala Asp Ser Val Lys
50 55 60
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Arg Ala Val Tyr Leu
65 70 75 80
Gln Met Ser Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Asn
85 90 95
Val Asn Leu Tyr Asn Thr Gly Asn Tyr Trp Gly Gln Gly Thr Gln Val
100 105 110
Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu Val Gln
115 120 125
Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg
130 135 140
Leu Ser Cys Ala Ala Ser Gly Arg Thr Phe Thr Thr His Ala Met Gly
145 150 155 160
Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val Ser Ala Ile
165 170 175
Asn Trp Gly Gly Arg Thr Thr Tyr Tyr Ala Asp Ser Val Lys Gly Arg
180 185 190
Phe Ile Ile Ser Arg Asp Thr Gly Ala Asn Thr Leu Tyr Leu Gln Met
195 200 205
Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Ser Asn
210 215 220
Leu Asp Thr Tyr Asn Val Arg Ala Gly Thr Thr Asn Ser Trp Gly Gln
225 230 235 240
Gly Thr Gln Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly
245 250 255
Gly Ser Gly Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly
260 265 270
Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser
275 280 285
Gly Gly Gly Arg Thr Phe Ser Asn Tyr Ala Leu Gly Trp Phe Arg Gln
290 295 300
Ala Pro Gly Lys Glu Arg Glu Phe Val Ala Ala Ile Ser Arg Ser Gly
305 310 315 320
Gly Asn Ile Asn Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser
325 330 335
Arg Asp Asn Phe Lys Asn Thr Val Tyr Leu Gln Met Ser Ser Leu Arg
340 345 350
Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Ala His Tyr Leu Leu Leu
355 360 365
Pro Ser Tyr Ile Ser Thr Ser Thr Asn Met Tyr Asn Tyr Trp Gly Gln
370 375 380
Gly Thr Gln Val Thr Val Ser Ser Ala Ala Ala Gln Val Gln Leu Val
385 390 395 400
Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser
405 410 415
Cys Ala Ala Ser Gly Gly Gly Arg Thr Phe Ser Asn Tyr Ala Leu Gly
420 425 430
Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val Ala Ala Ile
435 440 445
Ser Arg Ser Gly Gly Asn Ile Asn Tyr Ala Asp Ser Val Lys Gly Arg
450 455 460
Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr Leu Gln Met
465 470 475 480
Ser Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Ala His
485 490 495
Tyr Leu Leu Leu Pro Ser Tyr Ile Ser Thr Ser Thr Asn Met Tyr Asn
500 505 510
Tyr Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser Gly Gly Gly Gly
515 520 525
Ser Gly Gly Gly Ser Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu
530 535 540
Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg
545 550 555 560
Thr Ser Leu Ile Leu Ala Met Ala Trp Trp Arg Gln Ala Pro Gly Lys
565 570 575
Glu Arg Glu Phe Ala Gly Arg Ile Trp Trp Asn Asn Asp Met Thr Arg
580 585 590
Tyr Ser Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala
595 600 605
Lys Asn Thr Val Tyr Leu Gln Met Ser Ser Leu Arg Ala Glu Asp Thr
610 615 620
Ala Val Tyr Tyr Cys Glu Ala Asp Leu Ile Gly Gly Ser Arg Gly Trp
625 630 635 640
Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ala Ala Gln Val Gln
645 650 655
Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg
660 665 670
Leu Ser Cys Ala Ala Ser Gly Arg Thr Ser Leu Ile Leu Ala Met Ala
675 680 685
Trp Trp Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Ala Gly Arg Ile
690 695 700
Trp Trp Asn Asn Asp Met Thr Arg Tyr Ser Asp Ser Val Lys Gly Arg
705 710 715 720
Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr Leu Gln Met
725 730 735
Ser Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Glu Ala Asp
740 745 750
Leu Ile Gly Gly Ser Arg Gly Trp Gly Gln Gly Thr Leu Val Thr Val
755 760 765
Ser Ser
770
<210> 202
<211> 770
<212> PRT
<213> 人工序列 (Artificial Sequence)
<220>
<223> 多特异性抗体 hCD16F1-1-L1-hHS5-L4-hA09-10-45-
L1-H33-14-L3-H33-14
<400> 202
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Val Ser Gly Ser Leu Phe Ser Ala Arg
20 25 30
Val Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gln Arg Glu Leu Val
35 40 45
Ser Ala Ile Thr Ser Gly Val Arg Thr Tyr Tyr Ala Asp Ser Val Lys
50 55 60
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Arg Ala Val Tyr Leu
65 70 75 80
Gln Met Ser Ser Leu Glu Pro Glu Asp Thr Ala Val Tyr Tyr Cys Asn
85 90 95
Val Asn Leu Tyr Asn Thr Gly Asn Tyr Trp Gly Gln Gly Thr Gln Val
100 105 110
Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu Val Gln
115 120 125
Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg
130 135 140
Leu Ser Cys Ala Ala Ser Gly Arg Thr Phe Thr Thr His Ala Met Gly
145 150 155 160
Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val Ser Ala Ile
165 170 175
Asn Trp Gly Gly Arg Thr Thr Tyr Tyr Ala Asp Ser Val Lys Gly Arg
180 185 190
Phe Ile Ile Ser Arg Asp Thr Gly Ala Asn Thr Leu Tyr Leu Gln Met
195 200 205
Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Ser Asn
210 215 220
Leu Asp Thr Tyr Asn Val Arg Ala Gly Thr Thr Asn Ser Trp Gly Gln
225 230 235 240
Gly Thr Gln Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly
245 250 255
Gly Ser Gly Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly
260 265 270
Gly Val Val Arg Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser
275 280 285
Gly Gly Gly Arg Thr Phe Ser Asn Tyr Ala Met Gly Trp Phe Arg Gln
290 295 300
Ala Pro Gly Lys Glu Arg Glu Phe Val Ser Ala Ile Ser Arg Ser Gly
305 310 315 320
Gly Asn Ile Tyr Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser
325 330 335
Arg Asp Asn Phe Lys Asn Thr Val Tyr Leu Gln Met Ser Ser Leu Arg
340 345 350
Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Ala His Tyr Leu Leu Leu
355 360 365
Pro Ser Tyr Ile Ser Thr Ser Thr Asn Met Tyr Asn Tyr Trp Gly Gln
370 375 380
Gly Thr Gln Val Thr Val Ser Ser Ala Ala Ala Gln Val Gln Leu Val
385 390 395 400
Glu Ser Gly Gly Gly Val Val Arg Pro Gly Gly Ser Leu Arg Leu Ser
405 410 415
Cys Ala Ala Ser Gly Gly Gly Arg Thr Phe Ser Asn Tyr Ala Met Gly
420 425 430
Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val Ser Ala Ile
435 440 445
Ser Arg Ser Gly Gly Asn Ile Tyr Tyr Ala Asp Ser Val Lys Gly Arg
450 455 460
Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr Leu Gln Met
465 470 475 480
Ser Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Ala His
485 490 495
Tyr Leu Leu Leu Pro Ser Tyr Ile Ser Thr Ser Thr Asn Met Tyr Asn
500 505 510
Tyr Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser Gly Gly Gly Gly
515 520 525
Ser Gly Gly Gly Ser Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu
530 535 540
Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg
545 550 555 560
Thr Ser Leu Ile Leu Ala Met Ala Trp Trp Arg Gln Ala Pro Gly Lys
565 570 575
Glu Arg Glu Phe Ala Gly Arg Ile Trp Trp Asn Asn Asp Met Thr Arg
580 585 590
Tyr Ser Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala
595 600 605
Lys Asn Thr Val Tyr Leu Gln Met Ser Ser Leu Arg Ala Glu Asp Thr
610 615 620
Ala Val Tyr Tyr Cys Glu Ala Asp Leu Ile Gly Gly Ser Arg Gly Trp
625 630 635 640
Gly Gln Gly Thr Gln Val Thr Val Ser Ser Ala Ala Ala Gln Val Gln
645 650 655
Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg
660 665 670
Leu Ser Cys Ala Ala Ser Gly Arg Thr Ser Leu Ile Leu Ala Met Ala
675 680 685
Trp Trp Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Ala Gly Arg Ile
690 695 700
Trp Trp Asn Asn Asp Met Thr Arg Tyr Ser Asp Ser Val Lys Gly Arg
705 710 715 720
Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr Leu Gln Met
725 730 735
Ser Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Glu Ala Asp
740 745 750
Leu Ile Gly Gly Ser Arg Gly Trp Gly Gln Gly Thr Gln Val Thr Val
755 760 765
Ser Ser
770
<210> 203
<211> 770
<212> PRT
<213> 人工序列 (Artificial Sequence)
<220>
<223> 多特异性抗体 hCD16F1-2-L1-hHS5-L4-hA09-10-45-
L1-H33-14-L3-H33-14
<400> 203
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Val Ser Gly Ser Leu Phe Ser Ala Arg
20 25 30
Val Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gln Arg Glu Leu Val
35 40 45
Ser Ala Ile Thr Ser Gly Val Arg Thr Tyr Tyr Ala Asp Ser Val Lys
50 55 60
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Arg Ala Val Tyr Leu
65 70 75 80
Gln Met Ser Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Asn
85 90 95
Val Asn Leu Tyr Asn Thr Gly Asn Tyr Trp Gly Gln Gly Thr Gln Val
100 105 110
Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu Val Gln
115 120 125
Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg
130 135 140
Leu Ser Cys Ala Ala Ser Gly Arg Thr Phe Thr Thr His Ala Met Gly
145 150 155 160
Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val Ser Ala Ile
165 170 175
Asn Trp Gly Gly Arg Thr Thr Tyr Tyr Ala Asp Ser Val Lys Gly Arg
180 185 190
Phe Ile Ile Ser Arg Asp Thr Gly Ala Asn Thr Leu Tyr Leu Gln Met
195 200 205
Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Ser Asn
210 215 220
Leu Asp Thr Tyr Asn Val Arg Ala Gly Thr Thr Asn Ser Trp Gly Gln
225 230 235 240
Gly Thr Gln Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly
245 250 255
Gly Ser Gly Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly
260 265 270
Gly Val Val Arg Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser
275 280 285
Gly Gly Gly Arg Thr Phe Ser Asn Tyr Ala Met Gly Trp Phe Arg Gln
290 295 300
Ala Pro Gly Lys Glu Arg Glu Phe Val Ser Ala Ile Ser Arg Ser Gly
305 310 315 320
Gly Asn Ile Tyr Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser
325 330 335
Arg Asp Asn Phe Lys Asn Thr Val Tyr Leu Gln Met Ser Ser Leu Arg
340 345 350
Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Ala His Tyr Leu Leu Leu
355 360 365
Pro Ser Tyr Ile Ser Thr Ser Thr Asn Met Tyr Asn Tyr Trp Gly Gln
370 375 380
Gly Thr Gln Val Thr Val Ser Ser Ala Ala Ala Gln Val Gln Leu Val
385 390 395 400
Glu Ser Gly Gly Gly Val Val Arg Pro Gly Gly Ser Leu Arg Leu Ser
405 410 415
Cys Ala Ala Ser Gly Gly Gly Arg Thr Phe Ser Asn Tyr Ala Met Gly
420 425 430
Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val Ser Ala Ile
435 440 445
Ser Arg Ser Gly Gly Asn Ile Tyr Tyr Ala Asp Ser Val Lys Gly Arg
450 455 460
Phe Thr Ile Ser Arg Asp Asn Phe Lys Asn Thr Thr Tyr Leu Gln Met
465 470 475 480
Ser Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Ala His
485 490 495
Tyr Leu Leu Leu Pro Ser Tyr Ile Ser Thr Ser Thr Asn Met Tyr Asn
500 505 510
Tyr Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser Gly Gly Gly Gly
515 520 525
Ser Gly Gly Gly Ser Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu
530 535 540
Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg
545 550 555 560
Thr Ser Leu Ile Leu Ala Met Ala Trp Trp Arg Gln Ala Pro Gly Lys
565 570 575
Glu Arg Glu Phe Ala Gly Arg Ile Trp Trp Asn Asn Asp Met Thr Arg
580 585 590
Tyr Ser Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala
595 600 605
Lys Asn Thr Val Tyr Leu Gln Met Ser Ser Leu Arg Ala Glu Asp Thr
610 615 620
Ala Val Tyr Tyr Cys Glu Ala Asp Leu Ile Gly Gly Ser Arg Gly Trp
625 630 635 640
Gly Gln Gly Thr Gln Val Thr Val Ser Ser Ala Ala Ala Gln Val Gln
645 650 655
Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg
660 665 670
Leu Ser Cys Ala Ala Ser Gly Arg Thr Ser Leu Ile Leu Ala Met Ala
675 680 685
Trp Trp Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Ala Gly Arg Ile
690 695 700
Trp Trp Asn Asn Asp Met Thr Arg Tyr Ser Asp Ser Val Lys Gly Arg
705 710 715 720
Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr Leu Gln Met
725 730 735
Ser Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Glu Ala Asp
740 745 750
Leu Ile Gly Gly Ser Arg Gly Trp Gly Gln Gly Thr Gln Val Thr Val
755 760 765
Ser Ser
770
<210> 204
<211> 770
<212> PRT
<213> 人工序列 (Artificial Sequence)
<220>
<223> 多特异性抗体
hCD16F1-1-L1-hHS5-L4-hA09-10-55-L1-H33-14-L3-H33-14
<400> 204
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Val Ser Gly Ser Leu Phe Ser Ala Arg
20 25 30
Val Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gln Arg Glu Leu Val
35 40 45
Ser Ala Ile Thr Ser Gly Val Arg Thr Tyr Tyr Ala Asp Ser Val Lys
50 55 60
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Arg Ala Val Tyr Leu
65 70 75 80
Gln Met Ser Ser Leu Glu Pro Glu Asp Thr Ala Val Tyr Tyr Cys Asn
85 90 95
Val Asn Leu Tyr Asn Thr Gly Asn Tyr Trp Gly Gln Gly Thr Gln Val
100 105 110
Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu Val Gln
115 120 125
Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg
130 135 140
Leu Ser Cys Ala Ala Ser Gly Arg Thr Phe Thr Thr His Ala Met Gly
145 150 155 160
Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val Ser Ala Ile
165 170 175
Asn Trp Gly Gly Arg Thr Thr Tyr Tyr Ala Asp Ser Val Lys Gly Arg
180 185 190
Phe Ile Ile Ser Arg Asp Thr Gly Ala Asn Thr Leu Tyr Leu Gln Met
195 200 205
Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Ser Asn
210 215 220
Leu Asp Thr Tyr Asn Val Arg Ala Gly Thr Thr Asn Ser Trp Gly Gln
225 230 235 240
Gly Thr Gln Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly
245 250 255
Gly Ser Gly Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly
260 265 270
Gly Val Val Arg Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser
275 280 285
Gly Gly Gly Arg Thr Phe Ser Asn Tyr Ala Met Gly Trp Phe Arg Gln
290 295 300
Ala Pro Gly Lys Glu Arg Glu Phe Val Ser Ala Ile Ser Arg Ser Gly
305 310 315 320
Gly Asn Ile Tyr Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser
325 330 335
Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu Gln Met Ser Ser Leu Glu
340 345 350
Pro Glu Asp Thr Ala Val Tyr Tyr Cys Ala Ala His Tyr Leu Leu Leu
355 360 365
Pro Ser Tyr Ile Ser Thr Ser Thr Asn Met Tyr Asn Tyr Trp Gly Gln
370 375 380
Gly Thr Gln Val Thr Val Ser Ser Ala Ala Ala Gln Val Gln Leu Val
385 390 395 400
Glu Ser Gly Gly Gly Val Val Arg Pro Gly Gly Ser Leu Arg Leu Ser
405 410 415
Cys Ala Ala Ser Gly Gly Gly Arg Thr Phe Ser Asn Tyr Ala Met Gly
420 425 430
Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val Ser Ala Ile
435 440 445
Ser Arg Ser Gly Gly Asn Ile Tyr Tyr Ala Asp Ser Val Lys Gly Arg
450 455 460
Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu Gln Met
465 470 475 480
Ser Ser Leu Glu Pro Glu Asp Thr Ala Val Tyr Tyr Cys Ala Ala His
485 490 495
Tyr Leu Leu Leu Pro Ser Tyr Ile Ser Thr Ser Thr Asn Met Tyr Asn
500 505 510
Tyr Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser Gly Gly Gly Gly
515 520 525
Ser Gly Gly Gly Ser Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu
530 535 540
Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg
545 550 555 560
Thr Ser Leu Ile Leu Ala Met Ala Trp Trp Arg Gln Ala Pro Gly Lys
565 570 575
Glu Arg Glu Phe Ala Gly Arg Ile Trp Trp Asn Asn Asp Met Thr Arg
580 585 590
Tyr Ser Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala
595 600 605
Lys Asn Thr Val Tyr Leu Gln Met Ser Ser Leu Arg Ala Glu Asp Thr
610 615 620
Ala Val Tyr Tyr Cys Glu Ala Asp Leu Ile Gly Gly Ser Arg Gly Trp
625 630 635 640
Gly Gln Gly Thr Gln Val Thr Val Ser Ser Ala Ala Ala Gln Val Gln
645 650 655
Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg
660 665 670
Leu Ser Cys Ala Ala Ser Gly Arg Thr Ser Leu Ile Leu Ala Met Ala
675 680 685
Trp Trp Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Ala Gly Arg Ile
690 695 700
Trp Trp Asn Asn Asp Met Thr Arg Tyr Ser Asp Ser Val Lys Gly Arg
705 710 715 720
Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr Leu Gln Met
725 730 735
Ser Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Glu Ala Asp
740 745 750
Leu Ile Gly Gly Ser Arg Gly Trp Gly Gln Gly Thr Gln Val Thr Val
755 760 765
Ser Ser
770
<210> 205
<211> 770
<212> PRT
<213> 人工序列 (Artificial Sequence)
<220>
<223> 多特异性抗体 hCD16F1-2-L1-hHS5-L4-hA09-10-55-
L1-H33-14-L3-H33-14
<400> 205
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Val Ser Gly Ser Leu Phe Ser Ala Arg
20 25 30
Val Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gln Arg Glu Leu Val
35 40 45
Ser Ala Ile Thr Ser Gly Val Arg Thr Tyr Tyr Ala Asp Ser Val Lys
50 55 60
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Arg Ala Val Tyr Leu
65 70 75 80
Gln Met Ser Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Asn
85 90 95
Val Asn Leu Tyr Asn Thr Gly Asn Tyr Trp Gly Gln Gly Thr Gln Val
100 105 110
Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu Val Gln
115 120 125
Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg
130 135 140
Leu Ser Cys Ala Ala Ser Gly Arg Thr Phe Thr Thr His Ala Met Gly
145 150 155 160
Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val Ser Ala Ile
165 170 175
Asn Trp Gly Gly Arg Thr Thr Tyr Tyr Ala Asp Ser Val Lys Gly Arg
180 185 190
Phe Ile Ile Ser Arg Asp Thr Gly Ala Asn Thr Leu Tyr Leu Gln Met
195 200 205
Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Ser Asn
210 215 220
Leu Asp Thr Tyr Asn Val Arg Ala Gly Thr Thr Asn Ser Trp Gly Gln
225 230 235 240
Gly Thr Gln Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly
245 250 255
Gly Ser Gly Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly
260 265 270
Gly Val Val Arg Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser
275 280 285
Gly Gly Gly Arg Thr Phe Ser Asn Tyr Ala Met Gly Trp Phe Arg Gln
290 295 300
Ala Pro Gly Lys Glu Arg Glu Phe Val Ser Ala Ile Ser Arg Ser Gly
305 310 315 320
Gly Asn Ile Tyr Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser
325 330 335
Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu Gln Met Ser Ser Leu Glu
340 345 350
Pro Glu Asp Thr Ala Val Tyr Tyr Cys Ala Ala His Tyr Leu Leu Leu
355 360 365
Pro Ser Tyr Ile Ser Thr Ser Thr Asn Met Tyr Asn Tyr Trp Gly Gln
370 375 380
Gly Thr Gln Val Thr Val Ser Ser Ala Ala Ala Gln Val Gln Leu Val
385 390 395 400
Glu Ser Gly Gly Gly Val Val Arg Pro Gly Gly Ser Leu Arg Leu Ser
405 410 415
Cys Ala Ala Ser Gly Gly Gly Arg Thr Phe Ser Asn Tyr Ala Met Gly
420 425 430
Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val Ser Ala Ile
435 440 445
Ser Arg Ser Gly Gly Asn Ile Tyr Tyr Ala Asp Ser Val Lys Gly Arg
450 455 460
Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu Gln Met
465 470 475 480
Ser Ser Leu Glu Pro Glu Asp Thr Ala Val Tyr Tyr Cys Ala Ala His
485 490 495
Tyr Leu Leu Leu Pro Ser Tyr Ile Ser Thr Ser Thr Asn Met Tyr Asn
500 505 510
Tyr Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser Gly Gly Gly Gly
515 520 525
Ser Gly Gly Gly Ser Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu
530 535 540
Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg
545 550 555 560
Thr Ser Leu Ile Leu Ala Met Ala Trp Trp Arg Gln Ala Pro Gly Lys
565 570 575
Glu Arg Glu Phe Ala Gly Arg Ile Trp Trp Asn Asn Asp Met Thr Arg
580 585 590
Tyr Ser Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala
595 600 605
Lys Asn Thr Val Tyr Leu Gln Met Ser Ser Leu Arg Ala Glu Asp Thr
610 615 620
Ala Val Tyr Tyr Cys Glu Ala Asp Leu Ile Gly Gly Ser Arg Gly Trp
625 630 635 640
Gly Gln Gly Thr Gln Val Thr Val Ser Ser Ala Ala Ala Gln Val Gln
645 650 655
Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg
660 665 670
Leu Ser Cys Ala Ala Ser Gly Arg Thr Ser Leu Ile Leu Ala Met Ala
675 680 685
Trp Trp Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Ala Gly Arg Ile
690 695 700
Trp Trp Asn Asn Asp Met Thr Arg Tyr Ser Asp Ser Val Lys Gly Arg
705 710 715 720
Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr Leu Gln Met
725 730 735
Ser Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Glu Ala Asp
740 745 750
Leu Ile Gly Gly Ser Arg Gly Trp Gly Gln Gly Thr Gln Val Thr Val
755 760 765
Ser Ser
770
<210> 206
<211> 770
<212> PRT
<213> 人工序列 (Artificial Sequence)
<220>
<223> 多特异性抗体 hCD16F1-1-L1-hHS5-L4-hA09-10-77-
L1-H33-14-L3-H33-14
<400> 206
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Val Ser Gly Ser Leu Phe Ser Ala Arg
20 25 30
Val Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gln Arg Glu Leu Val
35 40 45
Ser Ala Ile Thr Ser Gly Val Arg Thr Tyr Tyr Ala Asp Ser Val Lys
50 55 60
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Arg Ala Val Tyr Leu
65 70 75 80
Gln Met Ser Ser Leu Glu Pro Glu Asp Thr Ala Val Tyr Tyr Cys Asn
85 90 95
Val Asn Leu Tyr Asn Thr Gly Asn Tyr Trp Gly Gln Gly Thr Gln Val
100 105 110
Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu Val Gln
115 120 125
Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg
130 135 140
Leu Ser Cys Ala Ala Ser Gly Arg Thr Phe Thr Thr His Ala Met Gly
145 150 155 160
Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val Ser Ala Ile
165 170 175
Asn Trp Gly Gly Arg Thr Thr Tyr Tyr Ala Asp Ser Val Lys Gly Arg
180 185 190
Phe Ile Ile Ser Arg Asp Thr Gly Ala Asn Thr Leu Tyr Leu Gln Met
195 200 205
Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Ser Asn
210 215 220
Leu Asp Thr Tyr Asn Val Arg Ala Gly Thr Thr Asn Ser Trp Gly Gln
225 230 235 240
Gly Thr Gln Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly
245 250 255
Gly Ser Gly Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly
260 265 270
Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser
275 280 285
Gly Gly Gly Arg Thr Phe Ser Asn Tyr Ala Leu Gly Trp Phe Arg Gln
290 295 300
Ala Pro Gly Lys Glu Arg Glu Phe Val Ser Ala Ile Ser Arg Ser Gly
305 310 315 320
Gly Asn Ile Asp Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser
325 330 335
Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu Gln Met Ser Ser Leu Lys
340 345 350
Pro Glu Asp Thr Ala Val Tyr Tyr Cys Ala Ala His Tyr Leu Leu Leu
355 360 365
Pro Ser Tyr Ile Ser Thr Ser Thr Asn Met Tyr Asn Tyr Trp Gly Gln
370 375 380
Gly Thr Gln Val Thr Val Ser Ser Ala Ala Ala Gln Val Gln Leu Val
385 390 395 400
Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser
405 410 415
Cys Ala Ala Ser Gly Gly Gly Arg Thr Phe Ser Asn Tyr Ala Leu Gly
420 425 430
Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val Ser Ala Ile
435 440 445
Ser Arg Ser Gly Gly Asn Ile Asp Tyr Ala Asp Ser Val Lys Gly Arg
450 455 460
Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu Gln Met
465 470 475 480
Ser Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys Ala Ala His
485 490 495
Tyr Leu Leu Leu Pro Ser Tyr Ile Ser Thr Ser Thr Asn Met Tyr Asn
500 505 510
Tyr Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser Gly Gly Gly Gly
515 520 525
Ser Gly Gly Gly Ser Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu
530 535 540
Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg
545 550 555 560
Thr Ser Leu Ile Leu Ala Met Ala Trp Trp Arg Gln Ala Pro Gly Lys
565 570 575
Glu Arg Glu Phe Ala Gly Arg Ile Trp Trp Asn Asn Asp Met Thr Arg
580 585 590
Tyr Ser Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala
595 600 605
Lys Asn Thr Val Tyr Leu Gln Met Ser Ser Leu Arg Ala Glu Asp Thr
610 615 620
Ala Val Tyr Tyr Cys Glu Ala Asp Leu Ile Gly Gly Ser Arg Gly Trp
625 630 635 640
Gly Gln Gly Thr Gln Val Thr Val Ser Ser Ala Ala Ala Gln Val Gln
645 650 655
Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg
660 665 670
Leu Ser Cys Ala Ala Ser Gly Arg Thr Ser Leu Ile Leu Ala Met Ala
675 680 685
Trp Trp Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Ala Gly Arg Ile
690 695 700
Trp Trp Asn Asn Asp Met Thr Arg Tyr Ser Asp Ser Val Lys Gly Arg
705 710 715 720
Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr Leu Gln Met
725 730 735
Ser Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Glu Ala Asp
740 745 750
Leu Ile Gly Gly Ser Arg Gly Trp Gly Gln Gly Thr Gln Val Thr Val
755 760 765
Ser Ser
770
<210> 207
<211> 770
<212> PRT
<213> 人工序列 (Artificial Sequence)
<220>
<223> 多特异性抗体 hCD16F1-2-L1-hHS5-L4-hA09-10-77-
L1-H33-14-L3-H33-14
<400> 207
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Val Ser Gly Ser Leu Phe Ser Ala Arg
20 25 30
Val Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gln Arg Glu Leu Val
35 40 45
Ser Ala Ile Thr Ser Gly Val Arg Thr Tyr Tyr Ala Asp Ser Val Lys
50 55 60
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Arg Ala Val Tyr Leu
65 70 75 80
Gln Met Ser Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Asn
85 90 95
Val Asn Leu Tyr Asn Thr Gly Asn Tyr Trp Gly Gln Gly Thr Gln Val
100 105 110
Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu Val Gln
115 120 125
Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg
130 135 140
Leu Ser Cys Ala Ala Ser Gly Arg Thr Phe Thr Thr His Ala Met Gly
145 150 155 160
Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val Ser Ala Ile
165 170 175
Asn Trp Gly Gly Arg Thr Thr Tyr Tyr Ala Asp Ser Val Lys Gly Arg
180 185 190
Phe Ile Ile Ser Arg Asp Thr Gly Ala Asn Thr Leu Tyr Leu Gln Met
195 200 205
Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Ser Asn
210 215 220
Leu Asp Thr Tyr Asn Val Arg Ala Gly Thr Thr Asn Ser Trp Gly Gln
225 230 235 240
Gly Thr Gln Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly
245 250 255
Gly Ser Gly Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly
260 265 270
Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser
275 280 285
Gly Gly Gly Arg Thr Phe Ser Asn Tyr Ala Leu Gly Trp Phe Arg Gln
290 295 300
Ala Pro Gly Lys Glu Arg Glu Phe Val Ser Ala Ile Ser Arg Ser Gly
305 310 315 320
Gly Asn Ile Asp Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser
325 330 335
Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu Gln Met Ser Ser Leu Lys
340 345 350
Pro Glu Asp Thr Ala Val Tyr Tyr Cys Ala Ala His Tyr Leu Leu Leu
355 360 365
Pro Ser Tyr Ile Ser Thr Ser Thr Asn Met Tyr Asn Tyr Trp Gly Gln
370 375 380
Gly Thr Gln Val Thr Val Ser Ser Ala Ala Ala Gln Val Gln Leu Val
385 390 395 400
Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser
405 410 415
Cys Ala Ala Ser Gly Gly Gly Arg Thr Phe Ser Asn Tyr Ala Leu Gly
420 425 430
Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val Ser Ala Ile
435 440 445
Ser Arg Ser Gly Gly Asn Ile Asp Tyr Ala Asp Ser Val Lys Gly Arg
450 455 460
Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu Gln Met
465 470 475 480
Ser Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys Ala Ala His
485 490 495
Tyr Leu Leu Leu Pro Ser Tyr Ile Ser Thr Ser Thr Asn Met Tyr Asn
500 505 510
Tyr Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser Gly Gly Gly Gly
515 520 525
Ser Gly Gly Gly Ser Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu
530 535 540
Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg
545 550 555 560
Thr Ser Leu Ile Leu Ala Met Ala Trp Trp Arg Gln Ala Pro Gly Lys
565 570 575
Glu Arg Glu Phe Ala Gly Arg Ile Trp Trp Asn Asn Asp Met Thr Arg
580 585 590
Tyr Ser Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala
595 600 605
Lys Asn Thr Val Tyr Leu Gln Met Ser Ser Leu Arg Ala Glu Asp Thr
610 615 620
Ala Val Tyr Tyr Cys Glu Ala Asp Leu Ile Gly Gly Ser Arg Gly Trp
625 630 635 640
Gly Gln Gly Thr Gln Val Thr Val Ser Ser Ala Ala Ala Gln Val Gln
645 650 655
Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg
660 665 670
Leu Ser Cys Ala Ala Ser Gly Arg Thr Ser Leu Ile Leu Ala Met Ala
675 680 685
Trp Trp Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Ala Gly Arg Ile
690 695 700
Trp Trp Asn Asn Asp Met Thr Arg Tyr Ser Asp Ser Val Lys Gly Arg
705 710 715 720
Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr Leu Gln Met
725 730 735
Ser Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Glu Ala Asp
740 745 750
Leu Ile Gly Gly Ser Arg Gly Trp Gly Gln Gly Thr Gln Val Thr Val
755 760 765
Ser Ser
770
<210> 208
<211> 770
<212> PRT
<213> 人工序列 (Artificial Sequence)
<220>
<223> 多特异性抗体 hCD16F1-1-L1-hHS5-L1-hA09-10-66-L1
-H33-14-L3-H33-14
<400> 208
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Val Ser Gly Ser Leu Phe Ser Ala Arg
20 25 30
Val Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gln Arg Glu Leu Val
35 40 45
Ser Ala Ile Thr Ser Gly Val Arg Thr Tyr Tyr Ala Asp Ser Val Lys
50 55 60
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Arg Ala Val Tyr Leu
65 70 75 80
Gln Met Ser Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys Asn
85 90 95
Val Asn Leu Tyr Asn Thr Gly Asn Tyr Trp Gly Gln Gly Thr Gln Val
100 105 110
Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu Val Gln
115 120 125
Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg
130 135 140
Leu Ser Cys Ala Ala Ser Gly Arg Thr Phe Thr Thr His Ala Met Gly
145 150 155 160
Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val Ser Ala Ile
165 170 175
Asn Trp Gly Gly Arg Thr Thr Tyr Tyr Ala Asp Ser Val Lys Gly Arg
180 185 190
Phe Ile Ile Ser Arg Asp Thr Gly Ala Asn Thr Leu Tyr Leu Gln Met
195 200 205
Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Ser Asn
210 215 220
Leu Asp Thr Tyr Asn Val Arg Ala Gly Thr Thr Asn Ser Trp Gly Gln
225 230 235 240
Gly Thr Gln Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly
245 250 255
Gly Ser Gly Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly
260 265 270
Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser
275 280 285
Gly Gly Gly Arg Thr Phe Ser Asn Tyr Ala Leu Gly Trp Phe Arg Gln
290 295 300
Ala Pro Gly Lys Glu Arg Glu Phe Val Ser Ala Ile Ser Arg Ser Gly
305 310 315 320
Gly Asn Ile Asp Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser
325 330 335
Arg Asp Asn Phe Lys Asn Thr Val Tyr Leu Gln Met Ser Ser Leu Arg
340 345 350
Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Ala His Tyr Leu Leu Leu
355 360 365
Pro Ser Tyr Ile Ser Thr Ser Thr Asn Met Tyr Asn Tyr Trp Gly Gln
370 375 380
Gly Thr Gln Val Thr Val Ser Ser Ala Ala Ala Gln Val Gln Leu Val
385 390 395 400
Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser
405 410 415
Cys Ala Ala Ser Gly Gly Gly Arg Thr Phe Ser Asn Tyr Ala Leu Gly
420 425 430
Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val Ser Ala Ile
435 440 445
Ser Arg Ser Gly Gly Asn Ile Tyr Tyr Ala Asp Ser Val Lys Gly Arg
450 455 460
Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr Leu Gln Met
465 470 475 480
Ser Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Ala His
485 490 495
Tyr Leu Leu Leu Pro Ser Tyr Ile Ser Thr Ser Thr Asn Met Tyr Asn
500 505 510
Tyr Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser Gly Gly Gly Gly
515 520 525
Ser Gly Gly Gly Ser Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu
530 535 540
Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg
545 550 555 560
Thr Ser Leu Ile Leu Ala Met Ala Trp Trp Arg Gln Ala Pro Gly Lys
565 570 575
Glu Arg Glu Phe Ala Gly Arg Ile Trp Trp Asn Asn Asp Met Thr Arg
580 585 590
Tyr Ser Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala
595 600 605
Lys Asn Thr Val Tyr Leu Gln Met Ser Ser Leu Arg Ala Glu Asp Thr
610 615 620
Ala Val Tyr Tyr Cys Glu Ala Asp Leu Ile Gly Gly Ser Arg Gly Trp
625 630 635 640
Gly Gln Gly Thr Gln Val Thr Val Ser Ser Ala Ala Ala Gln Val Gln
645 650 655
Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg
660 665 670
Leu Ser Cys Ala Ala Ser Gly Arg Thr Ser Leu Ile Leu Ala Met Ala
675 680 685
Trp Trp Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Ala Gly Arg Ile
690 695 700
Trp Trp Asn Asn Asp Met Thr Arg Tyr Ser Asp Ser Val Lys Gly Arg
705 710 715 720
Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr Leu Gln Met
725 730 735
Ser Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Glu Ala Asp
740 745 750
Leu Ile Gly Gly Ser Arg Gly Trp Gly Gln Gly Thr Gln Val Thr Val
755 760 765
Ser Ser
770
<210> 209
<211> 770
<212> PRT
<213> 人工序列 (Artificial Sequence)
<220>
<223> 多特异性抗体
hCD16F1-2-L1-hHS5-L4-hA09-10-66-L1-H33-14-L3-H33-14
<400> 209
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Val Ser Gly Ser Leu Phe Ser Ala Arg
20 25 30
Val Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gln Arg Glu Leu Val
35 40 45
Ser Ala Ile Thr Ser Gly Val Arg Thr Tyr Tyr Ala Asp Ser Val Lys
50 55 60
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Arg Ala Val Tyr Leu
65 70 75 80
Gln Met Ser Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Asn
85 90 95
Val Asn Leu Tyr Asn Thr Gly Asn Tyr Trp Gly Gln Gly Thr Gln Val
100 105 110
Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu Val Gln
115 120 125
Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg
130 135 140
Leu Ser Cys Ala Ala Ser Gly Arg Thr Phe Thr Thr His Ala Met Gly
145 150 155 160
Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val Ser Ala Ile
165 170 175
Asn Trp Gly Gly Arg Thr Thr Tyr Tyr Ala Asp Ser Val Lys Gly Arg
180 185 190
Phe Ile Ile Ser Arg Asp Thr Gly Ala Asn Thr Leu Tyr Leu Gln Met
195 200 205
Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Ser Asn
210 215 220
Leu Asp Thr Tyr Asn Val Arg Ala Gly Thr Thr Asn Ser Trp Gly Gln
225 230 235 240
Gly Thr Gln Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly
245 250 255
Gly Ser Gly Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly
260 265 270
Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser
275 280 285
Gly Gly Gly Arg Thr Phe Ser Asn Tyr Ala Leu Gly Trp Phe Arg Gln
290 295 300
Ala Pro Gly Lys Glu Arg Glu Phe Val Ser Ala Ile Ser Arg Ser Gly
305 310 315 320
Gly Asn Ile Asp Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser
325 330 335
Arg Asp Asn Phe Lys Asn Thr Val Tyr Leu Gln Met Ser Ser Leu Arg
340 345 350
Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Ala His Tyr Leu Leu Leu
355 360 365
Pro Ser Tyr Ile Ser Thr Ser Thr Asn Met Tyr Asn Tyr Trp Gly Gln
370 375 380
Gly Thr Gln Val Thr Val Ser Ser Ala Ala Ala Gln Val Gln Leu Val
385 390 395 400
Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser
405 410 415
Cys Ala Ala Ser Gly Gly Gly Arg Thr Phe Ser Asn Tyr Ala Leu Gly
420 425 430
Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val Ser Ala Ile
435 440 445
Ser Arg Ser Gly Gly Asn Ile Tyr Tyr Ala Asp Ser Val Lys Gly Arg
450 455 460
Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr Leu Gln Met
465 470 475 480
Ser Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Ala His
485 490 495
Tyr Leu Leu Leu Pro Ser Tyr Ile Ser Thr Ser Thr Asn Met Tyr Asn
500 505 510
Tyr Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser Gly Gly Gly Gly
515 520 525
Ser Gly Gly Gly Ser Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu
530 535 540
Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg
545 550 555 560
Thr Ser Leu Ile Leu Ala Met Ala Trp Trp Arg Gln Ala Pro Gly Lys
565 570 575
Glu Arg Glu Phe Ala Gly Arg Ile Trp Trp Asn Asn Asp Met Thr Arg
580 585 590
Tyr Ser Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala
595 600 605
Lys Asn Thr Val Tyr Leu Gln Met Ser Ser Leu Arg Ala Glu Asp Thr
610 615 620
Ala Val Tyr Tyr Cys Glu Ala Asp Leu Ile Gly Gly Ser Arg Gly Trp
625 630 635 640
Gly Gln Gly Thr Gln Val Thr Val Ser Ser Ala Ala Ala Gln Val Gln
645 650 655
Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg
660 665 670
Leu Ser Cys Ala Ala Ser Gly Arg Thr Ser Leu Ile Leu Ala Met Ala
675 680 685
Trp Trp Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Ala Gly Arg Ile
690 695 700
Trp Trp Asn Asn Asp Met Thr Arg Tyr Ser Asp Ser Val Lys Gly Arg
705 710 715 720
Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr Leu Gln Met
725 730 735
Ser Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Glu Ala Asp
740 745 750
Leu Ile Gly Gly Ser Arg Gly Trp Gly Gln Gly Thr Gln Val Thr Val
755 760 765
Ser Ser
770
<210> 210
<211> 770
<212> PRT
<213> 人工序列 (Artificial Sequence)
<220>
<223> 多特异性抗体
hCD16F1-1-L1-hHS5-L4-hA09-10-88-L1-H33-14-L3-H33-14
<400> 210
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Val Ser Gly Ser Leu Phe Ser Ala Arg
20 25 30
Val Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gln Arg Glu Leu Val
35 40 45
Ser Ala Ile Thr Ser Gly Val Arg Thr Tyr Tyr Ala Asp Ser Val Lys
50 55 60
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Arg Ala Val Tyr Leu
65 70 75 80
Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys Asn
85 90 95
Val Asn Leu Tyr Asn Thr Gly Asn Tyr Trp Gly Gln Gly Thr Gln Val
100 105 110
Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu Val Gln
115 120 125
Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg
130 135 140
Leu Ser Cys Ala Ala Ser Gly Arg Thr Phe Thr Thr His Ala Met Gly
145 150 155 160
Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val Ser Ala Ile
165 170 175
Asn Trp Gly Gly Arg Thr Thr Tyr Tyr Ala Asp Ser Val Lys Gly Arg
180 185 190
Phe Ile Ile Ser Arg Asp Thr Gly Ala Asn Thr Leu Tyr Leu Gln Met
195 200 205
Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Ser Asn
210 215 220
Leu Asp Thr Tyr Asn Val Arg Ala Gly Thr Thr Asn Ser Trp Gly Gln
225 230 235 240
Gly Thr Gln Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly
245 250 255
Gly Ser Gly Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly
260 265 270
Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser
275 280 285
Gly Gly Gly Arg Thr Phe Ser Asn Tyr Ala Leu Gly Trp Phe Arg Gln
290 295 300
Ala Pro Gly Lys Glu Arg Glu Phe Val Ser Ala Ile Ser Arg Ser Gly
305 310 315 320
Gly Asn Ile Tyr Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser
325 330 335
Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu Gln Met Ser Ser Leu Lys
340 345 350
Pro Glu Asp Thr Ala Val Tyr Tyr Cys Ala Ala His Tyr Leu Leu Leu
355 360 365
Pro Ser Tyr Ile Ser Thr Ser Thr Asn Met Tyr Asn Tyr Trp Gly Gln
370 375 380
Gly Thr Gln Val Thr Val Ser Ser Ala Ala Ala Gln Val Gln Leu Val
385 390 395 400
Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser
405 410 415
Cys Ala Ala Ser Gly Gly Gly Arg Thr Phe Ser Asn Tyr Ala Leu Gly
420 425 430
Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val Ser Ala Ile
435 440 445
Ser Arg Ser Gly Gly Asn Ile Tyr Tyr Ala Asp Ser Val Lys Gly Arg
450 455 460
Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu Gln Met
465 470 475 480
Ser Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys Ala Ala His
485 490 495
Tyr Leu Leu Leu Pro Ser Tyr Ile Ser Thr Ser Thr Asn Met Tyr Asn
500 505 510
Tyr Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser Gly Gly Gly Gly
515 520 525
Ser Gly Gly Gly Ser Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu
530 535 540
Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg
545 550 555 560
Thr Ser Leu Ile Leu Ala Met Ala Trp Trp Arg Gln Ala Pro Gly Lys
565 570 575
Glu Arg Glu Phe Ala Gly Arg Ile Trp Trp Asn Asn Asp Met Thr Arg
580 585 590
Tyr Ser Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala
595 600 605
Lys Asn Thr Val Tyr Leu Gln Met Ser Ser Leu Arg Ala Glu Asp Thr
610 615 620
Ala Val Tyr Tyr Cys Glu Ala Asp Leu Ile Gly Gly Ser Arg Gly Trp
625 630 635 640
Gly Gln Gly Thr Gln Val Thr Val Ser Ser Ala Ala Ala Gln Val Gln
645 650 655
Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg
660 665 670
Leu Ser Cys Ala Ala Ser Gly Arg Thr Ser Leu Ile Leu Ala Met Ala
675 680 685
Trp Trp Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Ala Gly Arg Ile
690 695 700
Trp Trp Asn Asn Asp Met Thr Arg Tyr Ser Asp Ser Val Lys Gly Arg
705 710 715 720
Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr Leu Gln Met
725 730 735
Ser Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Glu Ala Asp
740 745 750
Leu Ile Gly Gly Ser Arg Gly Trp Gly Gln Gly Thr Gln Val Thr Val
755 760 765
Ser Ser
770
<210> 211
<211> 770
<212> PRT
<213> 人工序列 (Artificial Sequence)
<220>
<223> 多特异性抗体
hCD16F1-2-L1-hHS5-L4-hA09-10-88-L1-H33-14-L3-H33-14
<400> 211
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Val Ser Gly Ser Leu Phe Ser Ala Arg
20 25 30
Val Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gln Arg Glu Leu Val
35 40 45
Ser Ala Ile Thr Ser Gly Val Arg Thr Tyr Tyr Ala Asp Ser Val Lys
50 55 60
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Arg Ala Val Tyr Leu
65 70 75 80
Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Asn
85 90 95
Val Asn Leu Tyr Asn Thr Gly Asn Tyr Trp Gly Gln Gly Thr Gln Val
100 105 110
Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu Val Gln
115 120 125
Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg
130 135 140
Leu Ser Cys Ala Ala Ser Gly Arg Thr Phe Thr Thr His Ala Met Gly
145 150 155 160
Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val Ser Ala Ile
165 170 175
Asn Trp Gly Gly Arg Thr Thr Tyr Tyr Ala Asp Ser Val Lys Gly Arg
180 185 190
Phe Ile Ile Ser Arg Asp Thr Gly Ala Asn Thr Leu Tyr Leu Gln Met
195 200 205
Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Ser Asn
210 215 220
Leu Asp Thr Tyr Asn Val Arg Ala Gly Thr Thr Asn Ser Trp Gly Gln
225 230 235 240
Gly Thr Gln Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly
245 250 255
Gly Ser Gly Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly
260 265 270
Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser
275 280 285
Gly Gly Gly Arg Thr Phe Ser Asn Tyr Ala Leu Gly Trp Phe Arg Gln
290 295 300
Ala Pro Gly Lys Glu Arg Glu Phe Val Ser Ala Ile Ser Arg Ser Gly
305 310 315 320
Gly Asn Ile Tyr Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser
325 330 335
Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu Gln Met Ser Ser Leu Lys
340 345 350
Pro Glu Asp Thr Ala Val Tyr Tyr Cys Ala Ala His Tyr Leu Leu Leu
355 360 365
Pro Ser Tyr Ile Ser Thr Ser Thr Asn Met Tyr Asn Tyr Trp Gly Gln
370 375 380
Gly Thr Gln Val Thr Val Ser Ser Ala Ala Ala Gln Val Gln Leu Val
385 390 395 400
Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser
405 410 415
Cys Ala Ala Ser Gly Gly Gly Arg Thr Phe Ser Asn Tyr Ala Leu Gly
420 425 430
Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val Ser Ala Ile
435 440 445
Ser Arg Ser Gly Gly Asn Ile Tyr Tyr Ala Asp Ser Val Lys Gly Arg
450 455 460
Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu Gln Met
465 470 475 480
Ser Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys Ala Ala His
485 490 495
Tyr Leu Leu Leu Pro Ser Tyr Ile Ser Thr Ser Thr Asn Met Tyr Asn
500 505 510
Tyr Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser Gly Gly Gly Gly
515 520 525
Ser Gly Gly Gly Ser Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu
530 535 540
Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg
545 550 555 560
Thr Ser Leu Ile Leu Ala Met Ala Trp Trp Arg Gln Ala Pro Gly Lys
565 570 575
Glu Arg Glu Phe Ala Gly Arg Ile Trp Trp Asn Asn Asp Met Thr Arg
580 585 590
Tyr Ser Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala
595 600 605
Lys Asn Thr Val Tyr Leu Gln Met Ser Ser Leu Arg Ala Glu Asp Thr
610 615 620
Ala Val Tyr Tyr Cys Glu Ala Asp Leu Ile Gly Gly Ser Arg Gly Trp
625 630 635 640
Gly Gln Gly Thr Gln Val Thr Val Ser Ser Ala Ala Ala Gln Val Gln
645 650 655
Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg
660 665 670
Leu Ser Cys Ala Ala Ser Gly Arg Thr Ser Leu Ile Leu Ala Met Ala
675 680 685
Trp Trp Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Ala Gly Arg Ile
690 695 700
Trp Trp Asn Asn Asp Met Thr Arg Tyr Ser Asp Ser Val Lys Gly Arg
705 710 715 720
Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr Leu Gln Met
725 730 735
Ser Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Glu Ala Asp
740 745 750
Leu Ile Gly Gly Ser Arg Gly Trp Gly Gln Gly Thr Gln Val Thr Val
755 760 765
Ser Ser
770
<210> 212
<211> 770
<212> PRT
<213> 人工序列 (Artificial Sequence)
<220>
<223> 多特异性抗体
hCD16F1-1-L1-hHS5-L4-hA09-10-99-L1-H33-14-L3-H33-14
<400> 212
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Val Ser Gly Ser Leu Phe Ser Ala Arg
20 25 30
Val Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gln Arg Glu Leu Val
35 40 45
Ser Ala Ile Thr Ser Gly Val Arg Thr Tyr Tyr Ala Asp Ser Val Lys
50 55 60
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Arg Ala Val Tyr Leu
65 70 75 80
Gln Met Asn Ser Leu Glu Pro Glu Asp Thr Ala Val Tyr Tyr Cys Asn
85 90 95
Val Asn Leu Tyr Asn Thr Gly Asn Tyr Trp Gly Gln Gly Thr Gln Val
100 105 110
Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu Val Gln
115 120 125
Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg
130 135 140
Leu Ser Cys Ala Ala Ser Gly Arg Thr Phe Thr Thr His Ala Met Gly
145 150 155 160
Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val Ser Ala Ile
165 170 175
Asn Trp Gly Gly Arg Thr Thr Tyr Tyr Ala Asp Ser Val Lys Gly Arg
180 185 190
Phe Ile Ile Ser Arg Asp Thr Gly Ala Asn Thr Leu Tyr Leu Gln Met
195 200 205
Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Ser Asn
210 215 220
Leu Asp Thr Tyr Asn Val Arg Ala Gly Thr Thr Asn Ser Trp Gly Gln
225 230 235 240
Gly Thr Gln Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly
245 250 255
Gly Ser Gly Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly
260 265 270
Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser
275 280 285
Gly Gly Gly Arg Thr Phe Ser Asn Tyr Ala Met Gly Trp Phe Arg Gln
290 295 300
Ala Pro Gly Lys Glu Arg Glu Phe Val Ser Ala Ile Ser Arg Ser Gly
305 310 315 320
Gly Asn Ile Tyr Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser
325 330 335
Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu Gln Met Ser Ser Leu Lys
340 345 350
Pro Glu Asp Thr Ala Val Tyr Tyr Cys Ala Ala His Tyr Leu Leu Leu
355 360 365
Pro Ser Tyr Ile Ser Thr Ser Thr Asn Met Tyr Asn Tyr Trp Gly Gln
370 375 380
Gly Thr Gln Val Thr Val Ser Ser Ala Ala Ala Gln Val Gln Leu Val
385 390 395 400
Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser
405 410 415
Cys Ala Ala Ser Gly Gly Gly Arg Thr Phe Ser Asn Tyr Ala Met Gly
420 425 430
Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val Ser Ala Ile
435 440 445
Ser Arg Ser Gly Gly Asn Ile Tyr Tyr Ala Asp Ser Val Lys Gly Arg
450 455 460
Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu Gln Met
465 470 475 480
Ser Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys Ala Ala His
485 490 495
Tyr Leu Leu Leu Pro Ser Tyr Ile Ser Thr Ser Thr Asn Met Tyr Asn
500 505 510
Tyr Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser Gly Gly Gly Gly
515 520 525
Ser Gly Gly Gly Ser Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu
530 535 540
Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg
545 550 555 560
Thr Ser Leu Ile Leu Ala Met Ala Trp Trp Arg Gln Ala Pro Gly Lys
565 570 575
Glu Arg Glu Phe Ala Gly Arg Ile Trp Trp Asn Asn Asp Met Thr Arg
580 585 590
Tyr Ser Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala
595 600 605
Lys Asn Thr Val Tyr Leu Gln Met Ser Ser Leu Arg Ala Glu Asp Thr
610 615 620
Ala Val Tyr Tyr Cys Glu Ala Asp Leu Ile Gly Gly Ser Arg Gly Trp
625 630 635 640
Gly Gln Gly Thr Gln Val Thr Val Ser Ser Ala Ala Ala Gln Val Gln
645 650 655
Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg
660 665 670
Leu Ser Cys Ala Ala Ser Gly Arg Thr Ser Leu Ile Leu Ala Met Ala
675 680 685
Trp Trp Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Ala Gly Arg Ile
690 695 700
Trp Trp Asn Asn Asp Met Thr Arg Tyr Ser Asp Ser Val Lys Gly Arg
705 710 715 720
Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr Leu Gln Met
725 730 735
Ser Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Glu Ala Asp
740 745 750
Leu Ile Gly Gly Ser Arg Gly Trp Gly Gln Gly Thr Gln Val Thr Val
755 760 765
Ser Ser
770
<210> 213
<211> 770
<212> PRT
<213> 人工序列 (Artificial Sequence)
<220>
<223> 多特异性抗体
hCD16F1-2-L1-hHS5-L4-hA09-10-99-L1-H33-14-L3-H33-14
<400> 213
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Val Ser Gly Ser Leu Phe Ser Ala Arg
20 25 30
Val Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gln Arg Glu Leu Val
35 40 45
Ser Ala Ile Thr Ser Gly Val Arg Thr Tyr Tyr Ala Asp Ser Val Lys
50 55 60
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Arg Ala Val Tyr Leu
65 70 75 80
Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Asn
85 90 95
Val Asn Leu Tyr Asn Thr Gly Asn Tyr Trp Gly Gln Gly Thr Gln Val
100 105 110
Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu Val Gln
115 120 125
Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg
130 135 140
Leu Ser Cys Ala Ala Ser Gly Arg Thr Phe Thr Thr His Ala Met Gly
145 150 155 160
Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val Ser Ala Ile
165 170 175
Asn Trp Gly Gly Arg Thr Thr Tyr Tyr Ala Asp Ser Val Lys Gly Arg
180 185 190
Phe Ile Ile Ser Arg Asp Thr Gly Ala Asn Thr Leu Tyr Leu Gln Met
195 200 205
Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Ser Asn
210 215 220
Leu Asp Thr Tyr Asn Val Arg Ala Gly Thr Thr Asn Ser Trp Gly Gln
225 230 235 240
Gly Thr Gln Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly
245 250 255
Gly Ser Gly Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly
260 265 270
Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser
275 280 285
Gly Gly Gly Arg Thr Phe Ser Asn Tyr Ala Met Gly Trp Phe Arg Gln
290 295 300
Ala Pro Gly Lys Glu Arg Glu Phe Val Ser Ala Ile Ser Arg Ser Gly
305 310 315 320
Gly Asn Ile Tyr Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser
325 330 335
Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu Gln Met Ser Ser Leu Lys
340 345 350
Pro Glu Asp Thr Ala Val Tyr Tyr Cys Ala Ala His Tyr Leu Leu Leu
355 360 365
Pro Ser Tyr Ile Ser Thr Ser Thr Asn Met Tyr Asn Tyr Trp Gly Gln
370 375 380
Gly Thr Gln Val Thr Val Ser Ser Ala Ala Ala Gln Val Gln Leu Val
385 390 395 400
Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser
405 410 415
Cys Ala Ala Ser Gly Gly Gly Arg Thr Phe Ser Asn Tyr Ala Met Gly
420 425 430
Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val Ser Ala Ile
435 440 445
Ser Arg Ser Gly Gly Asn Ile Tyr Tyr Ala Asp Ser Val Lys Gly Arg
450 455 460
Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu Gln Met
465 470 475 480
Ser Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys Ala Ala His
485 490 495
Tyr Leu Leu Leu Pro Ser Tyr Ile Ser Thr Ser Thr Asn Met Tyr Asn
500 505 510
Tyr Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser Gly Gly Gly Gly
515 520 525
Ser Gly Gly Gly Ser Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu
530 535 540
Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg
545 550 555 560
Thr Ser Leu Ile Leu Ala Met Ala Trp Trp Arg Gln Ala Pro Gly Lys
565 570 575
Glu Arg Glu Phe Ala Gly Arg Ile Trp Trp Asn Asn Asp Met Thr Arg
580 585 590
Tyr Ser Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala
595 600 605
Lys Asn Thr Val Tyr Leu Gln Met Ser Ser Leu Arg Ala Glu Asp Thr
610 615 620
Ala Val Tyr Tyr Cys Glu Ala Asp Leu Ile Gly Gly Ser Arg Gly Trp
625 630 635 640
Gly Gln Gly Thr Gln Val Thr Val Ser Ser Ala Ala Ala Gln Val Gln
645 650 655
Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg
660 665 670
Leu Ser Cys Ala Ala Ser Gly Arg Thr Ser Leu Ile Leu Ala Met Ala
675 680 685
Trp Trp Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Ala Gly Arg Ile
690 695 700
Trp Trp Asn Asn Asp Met Thr Arg Tyr Ser Asp Ser Val Lys Gly Arg
705 710 715 720
Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr Leu Gln Met
725 730 735
Ser Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Glu Ala Asp
740 745 750
Leu Ile Gly Gly Ser Arg Gly Trp Gly Gln Gly Thr Gln Val Thr Val
755 760 765
Ser Ser
770
<210> 214
<211> 770
<212> PRT
<213> 人工序列 (Artificial Sequence)
<220>
<223> 多特异性抗体
hCD16F1-1-L1-hHS5-L4-hA09-10-100-L1-H33-14-L3-H33-14
<400> 214
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Val Ser Gly Ser Leu Phe Ser Ala Arg
20 25 30
Val Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gln Arg Glu Leu Val
35 40 45
Ser Ala Ile Thr Ser Gly Val Arg Thr Tyr Tyr Ala Asp Ser Val Lys
50 55 60
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Arg Ala Val Tyr Leu
65 70 75 80
Gln Met Asn Ser Leu Glu Pro Glu Asp Thr Ala Val Tyr Tyr Cys Asn
85 90 95
Val Asn Leu Tyr Asn Thr Gly Asn Tyr Trp Gly Gln Gly Thr Gln Val
100 105 110
Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu Val Gln
115 120 125
Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg
130 135 140
Leu Ser Cys Ala Ala Ser Gly Arg Thr Phe Thr Thr His Ala Met Gly
145 150 155 160
Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val Ser Ala Ile
165 170 175
Asn Trp Gly Gly Arg Thr Thr Tyr Tyr Ala Asp Ser Val Lys Gly Arg
180 185 190
Phe Ile Ile Ser Arg Asp Thr Gly Ala Asn Thr Leu Tyr Leu Gln Met
195 200 205
Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Ser Asn
210 215 220
Leu Asp Thr Tyr Asn Val Arg Ala Gly Thr Thr Asn Ser Trp Gly Gln
225 230 235 240
Gly Thr Gln Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly
245 250 255
Gly Ser Gly Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly
260 265 270
Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser
275 280 285
Gly Gly Gly Arg Thr Phe Ser Asn Tyr Ala Met Gly Trp Phe Arg Gln
290 295 300
Ala Pro Gly Lys Glu Arg Glu Phe Val Ser Ala Ile Ser Arg Ser Gly
305 310 315 320
Gly Asn Ile Tyr Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser
325 330 335
Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu Gln Met Ser Ser Leu Arg
340 345 350
Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Ala His Tyr Leu Leu Leu
355 360 365
Pro Ser Tyr Ile Ser Thr Ser Thr Asn Met Tyr Asn Tyr Trp Gly Gln
370 375 380
Gly Thr Gln Val Thr Val Ser Ser Ala Ala Ala Gln Val Gln Leu Val
385 390 395 400
Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser
405 410 415
Cys Ala Ala Ser Gly Gly Gly Arg Thr Phe Ser Asn Tyr Ala Met Gly
420 425 430
Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val Ser Ala Ile
435 440 445
Ser Arg Ser Gly Gly Asn Ile Tyr Tyr Ala Asp Ser Val Lys Gly Arg
450 455 460
Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu Gln Met
465 470 475 480
Ser Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Ala His
485 490 495
Tyr Leu Leu Leu Pro Ser Tyr Ile Ser Thr Ser Thr Asn Met Tyr Asn
500 505 510
Tyr Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser Gly Gly Gly Gly
515 520 525
Ser Gly Gly Gly Ser Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu
530 535 540
Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg
545 550 555 560
Thr Ser Leu Ile Leu Ala Met Ala Trp Trp Arg Gln Ala Pro Gly Lys
565 570 575
Glu Arg Glu Phe Ala Gly Arg Ile Trp Trp Asn Asn Asp Met Thr Arg
580 585 590
Tyr Ser Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala
595 600 605
Lys Asn Thr Val Tyr Leu Gln Met Ser Ser Leu Arg Ala Glu Asp Thr
610 615 620
Ala Val Tyr Tyr Cys Glu Ala Asp Leu Ile Gly Gly Ser Arg Gly Trp
625 630 635 640
Gly Gln Gly Thr Gln Val Thr Val Ser Ser Ala Ala Ala Gln Val Gln
645 650 655
Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg
660 665 670
Leu Ser Cys Ala Ala Ser Gly Arg Thr Ser Leu Ile Leu Ala Met Ala
675 680 685
Trp Trp Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Ala Gly Arg Ile
690 695 700
Trp Trp Asn Asn Asp Met Thr Arg Tyr Ser Asp Ser Val Lys Gly Arg
705 710 715 720
Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr Leu Gln Met
725 730 735
Ser Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Glu Ala Asp
740 745 750
Leu Ile Gly Gly Ser Arg Gly Trp Gly Gln Gly Thr Gln Val Thr Val
755 760 765
Ser Ser
770
<210> 215
<211> 770
<212> PRT
<213> 人工序列 (Artificial Sequence)
<220>
<223> 多特异性抗体
hCD16F1-2-L1-hHS5-L4-hA09-10-100-L1-H33-14-L3-H33-14
<400> 215
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Val Ser Gly Ser Leu Phe Ser Ala Arg
20 25 30
Val Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gln Arg Glu Leu Val
35 40 45
Ser Ala Ile Thr Ser Gly Val Arg Thr Tyr Tyr Ala Asp Ser Val Lys
50 55 60
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Arg Ala Val Tyr Leu
65 70 75 80
Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Asn
85 90 95
Val Asn Leu Tyr Asn Thr Gly Asn Tyr Trp Gly Gln Gly Thr Gln Val
100 105 110
Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu Val Gln
115 120 125
Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg
130 135 140
Leu Ser Cys Ala Ala Ser Gly Arg Thr Phe Thr Thr His Ala Met Gly
145 150 155 160
Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val Ser Ala Ile
165 170 175
Asn Trp Gly Gly Arg Thr Thr Tyr Tyr Ala Asp Ser Val Lys Gly Arg
180 185 190
Phe Ile Ile Ser Arg Asp Thr Gly Ala Asn Thr Leu Tyr Leu Gln Met
195 200 205
Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Ser Asn
210 215 220
Leu Asp Thr Tyr Asn Val Arg Ala Gly Thr Thr Asn Ser Trp Gly Gln
225 230 235 240
Gly Thr Gln Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly
245 250 255
Gly Ser Gly Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly
260 265 270
Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser
275 280 285
Gly Gly Gly Arg Thr Phe Ser Asn Tyr Ala Met Gly Trp Phe Arg Gln
290 295 300
Ala Pro Gly Lys Glu Arg Glu Phe Val Ser Ala Ile Ser Arg Ser Gly
305 310 315 320
Gly Asn Ile Tyr Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser
325 330 335
Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu Gln Met Ser Ser Leu Arg
340 345 350
Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Ala His Tyr Leu Leu Leu
355 360 365
Pro Ser Tyr Ile Ser Thr Ser Thr Asn Met Tyr Asn Tyr Trp Gly Gln
370 375 380
Gly Thr Gln Val Thr Val Ser Ser Ala Ala Ala Gln Val Gln Leu Val
385 390 395 400
Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser
405 410 415
Cys Ala Ala Ser Gly Gly Gly Arg Thr Phe Ser Asn Tyr Ala Met Gly
420 425 430
Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val Ser Ala Ile
435 440 445
Ser Arg Ser Gly Gly Asn Ile Tyr Tyr Ala Asp Ser Val Lys Gly Arg
450 455 460
Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu Gln Met
465 470 475 480
Ser Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Ala His
485 490 495
Tyr Leu Leu Leu Pro Ser Tyr Ile Ser Thr Ser Thr Asn Met Tyr Asn
500 505 510
Tyr Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser Gly Gly Gly Gly
515 520 525
Ser Gly Gly Gly Ser Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu
530 535 540
Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg
545 550 555 560
Thr Ser Leu Ile Leu Ala Met Ala Trp Trp Arg Gln Ala Pro Gly Lys
565 570 575
Glu Arg Glu Phe Ala Gly Arg Ile Trp Trp Asn Asn Asp Met Thr Arg
580 585 590
Tyr Ser Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala
595 600 605
Lys Asn Thr Val Tyr Leu Gln Met Ser Ser Leu Arg Ala Glu Asp Thr
610 615 620
Ala Val Tyr Tyr Cys Glu Ala Asp Leu Ile Gly Gly Ser Arg Gly Trp
625 630 635 640
Gly Gln Gly Thr Gln Val Thr Val Ser Ser Ala Ala Ala Gln Val Gln
645 650 655
Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg
660 665 670
Leu Ser Cys Ala Ala Ser Gly Arg Thr Ser Leu Ile Leu Ala Met Ala
675 680 685
Trp Trp Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Ala Gly Arg Ile
690 695 700
Trp Trp Asn Asn Asp Met Thr Arg Tyr Ser Asp Ser Val Lys Gly Arg
705 710 715 720
Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr Leu Gln Met
725 730 735
Ser Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Glu Ala Asp
740 745 750
Leu Ile Gly Gly Ser Arg Gly Trp Gly Gln Gly Thr Gln Val Thr Val
755 760 765
Ser Ser
770
<210> 216
<211> 772
<212> PRT
<213> 人工序列 (Artificial Sequence)
<220>
<223> 多特异性抗体
CD16F1-L1-hHS10-L4-hA09-10-3-L3-hA09-10-4-L1-H33-14-L3-H33-14
(3321-GS15)
<400> 216
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Val Ser Gly Ser Leu Phe Ser Ala Arg
20 25 30
Val Met Gly Trp Tyr Arg Gln Ala Pro Gly Lys Gln Arg Glu Leu Val
35 40 45
Ala Ala Ile Thr Ser Gly Val Arg Thr Asp Tyr Ala Asp Ser Val Lys
50 55 60
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Arg Ala Val Tyr Leu
65 70 75 80
Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys Asn
85 90 95
Val Asn Leu Tyr Asn Thr Gly Asn Tyr Trp Gly Gln Gly Thr Gln Val
100 105 110
Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu Val Gln
115 120 125
Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg
130 135 140
Leu Ser Cys Ala Ala Ser Gly Ser Thr Asp Ser Ala Tyr Arg Met Gly
145 150 155 160
Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val Ser Ala Ile
165 170 175
Asn Trp Ser Asp Gly Arg Thr Tyr Tyr Ala Asp Ser Val Lys Gly Arg
180 185 190
Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu Gln Met
195 200 205
Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Ala Asp
210 215 220
Pro Asp Ser Arg Leu Tyr Tyr Thr Val Pro Gln Asn Tyr Asp Tyr Trp
225 230 235 240
Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly
245 250 255
Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser
260 265 270
Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala
275 280 285
Ala Ser Gly Gly Gly Arg Thr Phe Ser Asn Tyr Ala Leu Gly Trp Phe
290 295 300
Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val Ala Ala Ile Ser Arg
305 310 315 320
Ser Gly Gly Asn Ile Asn Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr
325 330 335
Ile Ser Arg Asp Asn Phe Lys Asn Thr Val Tyr Leu Gln Met Ser Ser
340 345 350
Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Ala His Tyr Leu
355 360 365
Leu Leu Pro Ser Tyr Ile Ser Thr Ser Thr Asn Met Tyr Asn Tyr Trp
370 375 380
Gly Gln Gly Thr Gln Val Thr Val Ser Ser Ala Ala Ala Gln Val Gln
385 390 395 400
Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg
405 410 415
Leu Ser Cys Ala Ala Ser Gly Gly Gly Arg Thr Phe Ser Asn Tyr Ala
420 425 430
Leu Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val Ala
435 440 445
Ala Ile Ser Arg Ser Gly Gly Asn Ile Asn Tyr Ala Asp Ser Val Lys
450 455 460
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr Leu
465 470 475 480
Gln Met Ser Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala
485 490 495
Ala His Tyr Leu Leu Leu Pro Ser Tyr Ile Ser Thr Ser Thr Asn Met
500 505 510
Tyr Asn Tyr Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser Gly Gly
515 520 525
Gly Gly Ser Gly Gly Gly Ser Gln Val Gln Leu Val Glu Ser Gly Gly
530 535 540
Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser
545 550 555 560
Gly Arg Thr Ser Leu Ile Leu Ala Met Ala Trp Trp Arg Gln Ala Pro
565 570 575
Gly Lys Glu Arg Glu Phe Ala Gly Arg Ile Trp Trp Asn Asn Asp Met
580 585 590
Thr Arg Tyr Ser Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp
595 600 605
Asn Ala Lys Asn Thr Val Tyr Leu Gln Met Ser Ser Leu Arg Ala Glu
610 615 620
Asp Thr Ala Val Tyr Tyr Cys Glu Ala Asp Leu Ile Gly Gly Ser Arg
625 630 635 640
Gly Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ala Ala Gln
645 650 655
Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser
660 665 670
Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Thr Ser Leu Ile Leu Ala
675 680 685
Met Ala Trp Trp Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Ala Gly
690 695 700
Arg Ile Trp Trp Asn Asn Asp Met Thr Arg Tyr Ser Asp Ser Val Lys
705 710 715 720
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr Leu
725 730 735
Gln Met Ser Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Glu
740 745 750
Ala Asp Leu Ile Gly Gly Ser Arg Gly Trp Gly Gln Gly Thr Leu Val
755 760 765
Thr Val Ser Ser
770
<210> 217
<211> 786
<212> PRT
<213> 人工序列 (Artificial Sequence)
<220>
<223> 多特异性抗体
CD16F1-L1-hHS10-L4-hA09-10-3-L3-hA09-10-4-L1-hPL16-L3-hPL16
(1518-GS15)
<400> 217
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Val Ser Gly Ser Leu Phe Ser Ala Arg
20 25 30
Val Met Gly Trp Tyr Arg Gln Ala Pro Gly Lys Gln Arg Glu Leu Val
35 40 45
Ala Ala Ile Thr Ser Gly Val Arg Thr Asp Tyr Ala Asp Ser Val Lys
50 55 60
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Arg Ala Val Tyr Leu
65 70 75 80
Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys Asn
85 90 95
Val Asn Leu Tyr Asn Thr Gly Asn Tyr Trp Gly Gln Gly Thr Gln Val
100 105 110
Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu Val Gln
115 120 125
Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg
130 135 140
Leu Ser Cys Ala Ala Ser Gly Ser Thr Asp Ser Ala Tyr Arg Met Gly
145 150 155 160
Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val Ser Ala Ile
165 170 175
Asn Trp Ser Asp Gly Arg Thr Tyr Tyr Ala Asp Ser Val Lys Gly Arg
180 185 190
Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu Gln Met
195 200 205
Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Ala Asp
210 215 220
Pro Asp Ser Arg Leu Tyr Tyr Thr Val Pro Gln Asn Tyr Asp Tyr Trp
225 230 235 240
Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly
245 250 255
Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser
260 265 270
Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala
275 280 285
Ala Ser Gly Gly Gly Arg Thr Phe Ser Asn Tyr Ala Leu Gly Trp Phe
290 295 300
Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val Ala Ala Ile Ser Arg
305 310 315 320
Ser Gly Gly Asn Ile Asn Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr
325 330 335
Ile Ser Arg Asp Asn Phe Lys Asn Thr Val Tyr Leu Gln Met Ser Ser
340 345 350
Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Ala His Tyr Leu
355 360 365
Leu Leu Pro Ser Tyr Ile Ser Thr Ser Thr Asn Met Tyr Asn Tyr Trp
370 375 380
Gly Gln Gly Thr Gln Val Thr Val Ser Ser Ala Ala Ala Gln Val Gln
385 390 395 400
Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg
405 410 415
Leu Ser Cys Ala Ala Ser Gly Gly Gly Arg Thr Phe Ser Asn Tyr Ala
420 425 430
Leu Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val Ala
435 440 445
Ala Ile Ser Arg Ser Gly Gly Asn Ile Asn Tyr Ala Asp Ser Val Lys
450 455 460
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr Leu
465 470 475 480
Gln Met Ser Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala
485 490 495
Ala His Tyr Leu Leu Leu Pro Ser Tyr Ile Ser Thr Ser Thr Asn Met
500 505 510
Tyr Asn Tyr Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser Gly Gly
515 520 525
Gly Gly Ser Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly
530 535 540
Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser
545 550 555 560
Gly Gly Thr Phe Leu Thr Tyr Ser Met Ser Trp Val Arg Gln Ala Pro
565 570 575
Gly Lys Glu Arg Glu Phe Val Ser Ser Ile Asn Trp Ser Gly Tyr Met
580 585 590
Thr Tyr Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp
595 600 605
Asn Ser Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu
610 615 620
Asp Thr Ala Val Tyr Tyr Cys Ala Ala Ala Arg Thr Ala Ile Ala Ala
625 630 635 640
Lys Arg Ser Ser Glu Phe Asp Tyr Trp Gly Gln Gly Thr Gln Val Thr
645 650 655
Val Ser Ser Ala Ala Ala Glu Val Gln Leu Val Glu Ser Gly Gly Gly
660 665 670
Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly
675 680 685
Gly Thr Phe Leu Thr Tyr Ser Met Ser Trp Val Arg Gln Ala Pro Gly
690 695 700
Lys Glu Arg Glu Phe Val Ser Ser Ile Asn Trp Ser Gly Tyr Met Thr
705 710 715 720
Tyr Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn
725 730 735
Ser Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp
740 745 750
Thr Ala Val Tyr Tyr Cys Ala Ala Ala Arg Thr Ala Ile Ala Ala Lys
755 760 765
Arg Ser Ser Glu Phe Asp Tyr Trp Gly Gln Gly Thr Gln Val Thr Val
770 775 780
Ser Ser
785
<210> 218
<211> 375
<212> PRT
<213> 人工序列 (Artificial Sequence)
<220>
<223> 多特异性抗体 hHS5-L1-H33-14-L3-H33-14**
<400> 218
Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Thr Phe Thr Thr His
20 25 30
Ala Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val
35 40 45
Ser Ala Ile Asn Trp Gly Gly Arg Thr Thr Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Ile Ile Ser Arg Asp Thr Gly Ala Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Ser Asn Leu Asp Thr Tyr Asn Val Arg Ala Gly Thr Thr Asn Ser
100 105 110
Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser Gly Gly Gly Gly Ser
115 120 125
Gly Gly Gly Ser Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val
130 135 140
Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Thr
145 150 155 160
Ser Leu Ile Leu Ala Met Ala Trp Trp Arg Gln Ala Pro Gly Lys Glu
165 170 175
Arg Glu Phe Ala Gly Arg Ile Trp Trp Asn Asn Asp Met Thr Arg Tyr
180 185 190
Ser Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys
195 200 205
Asn Thr Val Tyr Leu Gln Met Ser Ser Leu Arg Ala Glu Asp Thr Ala
210 215 220
Val Tyr Tyr Cys Glu Ala Asp Leu Ile Gly Gly Ser Arg Gly Trp Gly
225 230 235 240
Gln Gly Thr Gln Val Thr Val Ser Ser Ala Ala Ala Gln Val Gln Leu
245 250 255
Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu
260 265 270
Ser Cys Ala Ala Ser Gly Arg Thr Ser Leu Ile Leu Ala Met Ala Trp
275 280 285
Trp Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Ala Gly Arg Ile Trp
290 295 300
Trp Asn Asn Asp Met Thr Arg Tyr Ser Asp Ser Val Lys Gly Arg Phe
305 310 315 320
Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr Leu Gln Met Ser
325 330 335
Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Glu Ala Asp Leu
340 345 350
Ile Gly Gly Ser Arg Gly Trp Gly Gln Gly Thr Gln Val Thr Val Ser
355 360 365
Ser His His His His His His
370 375
<210> 219
<211> 368
<212> PRT
<213> 人工序列 (Artificial Sequence)
<220>
<223> 多特异性抗体 FC5-L1-H33-14-L3-H33-14
<400> 219
Glu Val Gln Leu Gln Ala Ser Gly Gly Gly Leu Val Gln Ala Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Lys Ile Thr His Tyr
20 25 30
Thr Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val
35 40 45
Ser Arg Ile Thr Trp Gly Gly Asp Asn Thr Phe Tyr Ser Asn Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Asp Tyr Tyr Cys
85 90 95
Ala Ala Gly Ser Thr Ser Thr Ala Thr Pro Leu Arg Val Asp Tyr Trp
100 105 110
Gly Lys Gly Thr Gln Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly
115 120 125
Gly Gly Ser Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln
130 135 140
Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Thr Ser
145 150 155 160
Leu Ile Leu Ala Met Ala Trp Trp Arg Gln Ala Pro Gly Lys Glu Arg
165 170 175
Glu Phe Ala Gly Arg Ile Trp Trp Asn Asn Asp Met Thr Arg Tyr Ser
180 185 190
Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn
195 200 205
Thr Val Tyr Leu Gln Met Ser Ser Leu Arg Ala Glu Asp Thr Ala Val
210 215 220
Tyr Tyr Cys Glu Ala Asp Leu Ile Gly Gly Ser Arg Gly Trp Gly Gln
225 230 235 240
Gly Thr Gln Val Thr Val Ser Ser Ala Ala Ala Gln Val Gln Leu Val
245 250 255
Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser
260 265 270
Cys Ala Ala Ser Gly Arg Thr Ser Leu Ile Leu Ala Met Ala Trp Trp
275 280 285
Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Ala Gly Arg Ile Trp Trp
290 295 300
Asn Asn Asp Met Thr Arg Tyr Ser Asp Ser Val Lys Gly Arg Phe Thr
305 310 315 320
Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr Leu Gln Met Ser Ser
325 330 335
Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Glu Ala Asp Leu Ile
340 345 350
Gly Gly Ser Arg Gly Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser
355 360 365
<210> 220
<211> 500
<212> PRT
<213> 人工序列 (Artificial Sequence)
<220>
<223> 多特异性抗体 FC5-L1-H33-14-L3-H33-14-L1-hHS5
<400> 220
Glu Val Gln Leu Gln Ala Ser Gly Gly Gly Leu Val Gln Ala Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Lys Ile Thr His Tyr
20 25 30
Thr Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val
35 40 45
Ser Arg Ile Thr Trp Gly Gly Asp Asn Thr Phe Tyr Ser Asn Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Asp Tyr Tyr Cys
85 90 95
Ala Ala Gly Ser Thr Ser Thr Ala Thr Pro Leu Arg Val Asp Tyr Trp
100 105 110
Gly Lys Gly Thr Gln Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly
115 120 125
Gly Gly Ser Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln
130 135 140
Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Thr Ser
145 150 155 160
Leu Ile Leu Ala Met Ala Trp Trp Arg Gln Ala Pro Gly Lys Glu Arg
165 170 175
Glu Phe Ala Gly Arg Ile Trp Trp Asn Asn Asp Met Thr Arg Tyr Ser
180 185 190
Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn
195 200 205
Thr Val Tyr Leu Gln Met Ser Ser Leu Arg Ala Glu Asp Thr Ala Val
210 215 220
Tyr Tyr Cys Glu Ala Asp Leu Ile Gly Gly Ser Arg Gly Trp Gly Gln
225 230 235 240
Gly Thr Gln Val Thr Val Ser Ser Ala Ala Ala Gln Val Gln Leu Val
245 250 255
Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser
260 265 270
Cys Ala Ala Ser Gly Arg Thr Ser Leu Ile Leu Ala Met Ala Trp Trp
275 280 285
Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Ala Gly Arg Ile Trp Trp
290 295 300
Asn Asn Asp Met Thr Arg Tyr Ser Asp Ser Val Lys Gly Arg Phe Thr
305 310 315 320
Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr Leu Gln Met Ser Ser
325 330 335
Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Glu Ala Asp Leu Ile
340 345 350
Gly Gly Ser Arg Gly Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser
355 360 365
Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu Val Gln Leu Leu Glu Ser
370 375 380
Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala
385 390 395 400
Ala Ser Gly Arg Thr Phe Thr Thr His Ala Met Gly Trp Phe Arg Gln
405 410 415
Ala Pro Gly Lys Glu Arg Glu Phe Val Ser Ala Ile Asn Trp Gly Gly
420 425 430
Arg Thr Thr Tyr Tyr Ala Asp Ser Val Lys Gly Arg Phe Ile Ile Ser
435 440 445
Arg Asp Thr Gly Ala Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg
450 455 460
Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Ser Asn Leu Asp Thr Tyr
465 470 475 480
Asn Val Arg Ala Gly Thr Thr Asn Ser Trp Gly Gln Gly Thr Gln Val
485 490 495
Thr Val Ser Ser
500
<210> 221
<211> 237
<212> PRT
<213> 人工序列 (Artificial Sequence)
<220>
<223> 多特异性抗体 H33-14-L3-H33-14
<400> 221
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Thr Ser Leu Ile Leu
20 25 30
Ala Met Ala Trp Trp Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Ala
35 40 45
Gly Arg Ile Trp Trp Asn Asn Asp Met Thr Arg Tyr Ser Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr
65 70 75 80
Leu Gln Met Ser Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Glu Ala Asp Leu Ile Gly Gly Ser Arg Gly Trp Gly Gln Gly Thr Gln
100 105 110
Val Thr Val Ser Ser Ala Ala Ala Gln Val Gln Leu Val Glu Ser Gly
115 120 125
Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala
130 135 140
Ser Gly Arg Thr Ser Leu Ile Leu Ala Met Ala Trp Trp Arg Gln Ala
145 150 155 160
Pro Gly Lys Glu Arg Glu Phe Ala Gly Arg Ile Trp Trp Asn Asn Asp
165 170 175
Met Thr Arg Tyr Ser Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg
180 185 190
Asp Asn Ala Lys Asn Thr Val Tyr Leu Gln Met Ser Ser Leu Arg Ala
195 200 205
Glu Asp Thr Ala Val Tyr Tyr Cys Glu Ala Asp Leu Ile Gly Gly Ser
210 215 220
Arg Gly Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser
225 230 235
<210> 222
<211> 122
<212> PRT
<213> 人工序列 (Artificial Sequence)
<220>
<223> FC5 纳米抗体
<400> 222
Glu Val Gln Leu Gln Ala Ser Gly Gly Gly Leu Val Gln Ala Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Lys Ile Thr His Tyr
20 25 30
Thr Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val
35 40 45
Ser Arg Ile Thr Trp Gly Gly Asp Asn Thr Phe Tyr Ser Asn Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Asp Tyr Tyr Cys
85 90 95
Ala Ala Gly Ser Thr Ser Thr Ala Thr Pro Leu Arg Val Asp Tyr Trp
100 105 110
Gly Lys Gly Thr Gln Val Thr Val Ser Ser
115 120
<210> 223
<211> 129
<212> PRT
<213> 人工序列 (Artificial Sequence)
<220>
<223> 人源化hA09-10-30
<400> 223
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Gly Gly Arg Thr Phe Ser
20 25 30
Asn Tyr Ala Leu Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu
35 40 45
Phe Val Ala Ala Ile Ser Arg Ser Gly Gly Asn Ile Asn Tyr Ala Asp
50 55 60
Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr
65 70 75 80
Val Tyr Leu Gln Met Ser Ser Leu Glu Pro Glu Asp Thr Ala Val Tyr
85 90 95
Tyr Cys Ala Ala His Tyr Leu Leu Leu Pro Ser Tyr Ile Ser Thr Ser
100 105 110
Thr Asn Met Tyr Asn Tyr Trp Gly Gln Gly Thr Gln Val Thr Val Ser
115 120 125
Ser
<210> 224
<211> 6
<212> PRT
<213> 人工序列 (Artificial Sequence)
<220>
<223> 接头
<400> 224
Glu Pro Lys Ser Cys Asp
1 5
<210> 225
<211> 6
<212> PRT
<213> 人工序列 (Artificial Sequence)
<220>
<223> 接头
<400> 225
Ala Ser Thr Lys Gly Pro
1 5

Claims (28)

1.一种对以下中的一者具有抗原结合特异性的重链可变(VHH)结构域：
(a)CD47，其中所述VHH结构域具有SEQ ID NO:2至SEQ ID NO:29或SEQ ID NO:223中的一者所示的氨基酸序列；
(b)PD-L1，其中所述VHH区具有SEQ ID NO:31至SEQ ID NO:38中的一者所示的氨基酸序列；
(c)人血清白蛋白(HSA)，其中所述VHH结构域具有SEQ ID NO:40至SEQ ID NO:48中的一者所示的氨基酸序列；
(d)CD33，其中所述VHH结构域具有SEQ ID NO:50至SEQ ID NO:78中的一者所示的氨基酸序列；
(e)LAG3，其中所述VHH结构域具有SEQ ID NO:80至SEQ ID NO:93中的一者所示的氨基酸序列；或者
(f)CD16，其中所述VHH结构域具有SEQ ID NO:96至SEQ ID NO:99中的一者所示的氨基酸序列。
2.一种仅重链抗体(HCAb)，所述仅重链抗体包含权利要求1所述的VHH结构域。
3.一种多特异性抗体，所述多特异性抗体包含具有第一结合特异性的抗体结合结构域和具有与所述第一结合特异性不同的第二结合特异性的第二抗体结合结构域，其中所述第一结合特异性对CD47、PD-L1、HSA、CD33、LAG3或CD16是特异性的；其中
(a)所述CD47结合特异性由SEQ ID NO:2至SEQ ID NO:29或SEQ ID NO:223中的一者所示的氨基酸序列表示；
(b)所述PD-L1结合特异性由SEQ ID NO:31至SEQ ID NO:38中的一者所示的氨基酸序列表示；
(c)所述HSA结合特异性由SEQ ID NO:40至SEQ ID NO:48中的一者所示的氨基酸序列表示；
(d)所述CD33结合特异性由SEQ ID NO:50至SEQ ID NO:78中的一者所示的氨基酸序列表示；
(e)所述LAG3结合特异性由SEQ ID NO:80至SEQ ID NO:93中的一者所示的氨基酸序列表示；并且
(f)所述CD16结合特异性由SEQ ID NO:96至SEQ ID NO:99中的一者所示的氨基酸序列表示。
4.根据权利要求3所述的多特异性抗体，其中所述第二抗体结合结构域对CD47、PD-L1、HSA、CD33、LAG3或CD16是特异的；其中
(a)所述CD47结合特异性由SEQ ID NO:2至SEQ ID NO:29或SEQ ID NO:223中的一者所示的氨基酸序列表示；
(b)所述PD-L1结合特异性由SEQ ID NO:31至SEQ ID NO:38中的一者所示的氨基酸序列表示；
(c)所述HSA结合特异性由SEQ ID NO:40至SEQ ID NO:48中的一者所示的氨基酸序列表示；
(d)所述CD33结合特异性由SEQ ID NO:50至SEQ ID NO:78中的一者所示的氨基酸序列表示；
(e)所述LAG3结合特异性由SEQ ID NO:80至SEQ ID NO:93中的一者所示的氨基酸序列表示；并且
(f)所述CD16结合特异性由SEQ ID NO:96至SEQ ID NO:99中的一者所示的氨基酸序列表示。
5.根据权利要求3所述的多特异性抗体，所述多特异性抗体进一步包含1至5个附加抗体结合结构域，其中每个附加抗体结合结构域单独地对CD47、PD-L1、HSA、CD33、LAG3或CD16是特异的；其中
(a)所述CD47结合特异性由SEQ ID NO:2至SEQ ID NO:29或SEQ ID NO:223中的一者所示的氨基酸序列表示；
(b)所述PD-L1结合特异性由SEQ ID NO:31至SEQ ID NO:38中的一者所示的氨基酸序列表示；
(c)所述HSA结合特异性由SEQ ID NO:40至SEQ ID NO:48中的一者所示的氨基酸序列表示；
(d)所述CD33结合特异性由SEQ ID NO:50至SEQ ID NO:78中的一者所示的氨基酸序列表示；
(e)所述LAG3结合特异性由SEQ ID NO:80至SEQ ID NO:93中的一者所示的氨基酸序列表示；并且
(f)所述CD16结合特异性由SEQ ID NO:96至SEQ ID NO:99中的一者所示的氨基酸序列表示。
6.根据权利要求4所述的多特异性抗体，所述多特异性抗体进一步包含1至4个附加抗体结合结构域，其中每个附加抗体结合结构域对CD47、PD-L1、HSA、CD33、LAG3或CD16是特异的；其中
(a)所述CD47结合特异性由SEQ ID NO:2至SEQ ID NO:29或SEQ ID NO:223中的一者所示的氨基酸序列表示；
(b)所述PD-L1结合特异性由SEQ ID NO:31至SEQ ID NO:38中的一者所示的氨基酸序列表示；
(c)所述HSA结合特异性由SEQ ID NO:40至SEQ ID NO:48中的一者所示的氨基酸序列表示；
(d)所述CD33结合特异性由SEQ ID NO:50至SEQ ID NO:78中的一者所示的氨基酸序列表示；
(e)所述LAG3结合特异性由SEQ ID NO:80至SEQ ID NO:93中的一者所示的氨基酸序列表示；并且
(f)所述CD16结合特异性由SEQ ID NO:96至SEQ ID NO:99中的一者所示的氨基酸序列表示。
7.根据权利要求3-6中任一项所述的多特异性抗体，其中所述抗体是多特异性单链抗体(MVSCA)。
8.根据权利要求3-7中任一项所述的多特异性抗体，其中接头L1(SEQ ID NO:100)、L2(SEQ ID NO:101)或L4(SEQ ID NO:103)插置在一对或多对不同的抗体结合结构域之间。
9.根据权利要求3-8中任一项所述的多特异性抗体，所述多特异性抗体包含至少一对具有相同特异性的抗体结合结构域。
10.根据权利要求9所述的多特异性抗体，其中所述至少一对具有相同特异性的抗体结合结构域彼此相邻，并且在它们之间插置有接头L3(SEQ ID NO:102)。
11.根据权利要求3-10中任一项所述的多特异性抗体，所述多特异性抗体包含N末端或C末端定位的HSA特异性抗体结合结构域，在所述抗体结合结构域与同其相邻的抗体结合结构域之间插置有可切割接头。
12.根据权利要求11所述的多特异性抗体，其中所述可切割接头是L11*3(SEQ ID NO:104)、L11*4(SEQ ID NO:105)、L11*5(SEQ ID NO:106)、L11*6(SEQ ID NO:107)、L11*7(SEQID NO:108)、L11*8(SEQ ID NO:109)、L11*9(SEQ ID NO:110)、L11*10(SEQ ID NO:111)、L11*11(SEQ ID NO:112)、L11*12(SEQ ID NO:113)、L11*13(SEQ ID NO:114)、L11*14(SEQID NO:115)、L11*15(SEQ ID NO:116)、L11*16(SEQ ID NO:117)、L11*17(SEQ ID NO:118)或L11*18(SEQ ID NO:119)。
13.根据权利要求3-12中任一项所述的多特异性抗体，其中所有的所述抗体结合结构域都是VHH结构域。
14.根据权利要求3-13中任一项所述的多特异性抗体，所述多特异性抗体包含识别HSA、CD47和PD-L1的抗体结合结构域。
15.根据权利要求3-13中任一项所述的多特异性抗体，所述多特异性抗体包含识别HSA、CD47和CD33的抗体结合结构域。
16.根据权利要求3-13中任一项所述的多特异性抗体，所述多特异性抗体包含识别HSA、LAG3和PD-L1的抗体结合域。
17.根据权利要求3-13中任一项所述的多特异性抗体，所述多特异性抗体包含识别HSA、LAG3和CD33的抗体结合结构域。
18.根据权利要求3-13中任一项所述的多特异性抗体，所述多特异性抗体包含识别CD16、HSA和PD-L1的抗体结合域。
19.根据权利要求3-13中任一项所述的多特异性抗体，所述多特异性抗体包含识别CD16、HSA和CD33的抗体结合域。
20.根据权利要求3-13中任一项所述的多特异性抗体，CD16、HSA、CD47和PD-L1。
21.根据权利要求3-13中任一项所述的多特异性抗体，所述多特异性抗体包含识别CD16、HSA、CD47和CD33的抗体结合结构域。
22.一种多特异性抗体，所述多特异性抗体包含一对具有CD33特异性的抗体结合结构域。
23.根据权利要求22所述的多特异性抗体，所述多特异性抗体进一步包含对HSA、FC5纳米抗体(SEQ ID NO:222)或两者具有特异性的抗体结合结构域。
24.一种药物组合物，所述药物组合物包含根据权利要求1所述的VHH结构域、根据权利要求2所述的HCAb、或根据权利要求3-21中任一项所述的多特异性抗体。
25.一种治疗癌症的方法，所述方法包括向有需要的患者施用根据权利要求24所述的药物组合物。
26.一种药物组合物，所述药物组合物包含根据权利要求22-23中任一项所述的多特异性抗体。
27.一种治疗阿尔茨海默氏病或视网膜疾病的方法，所述方法包括向有需要的患者施用根据权利要求24所述的药物组合物。
28.根据权利要求27所述的方法，其中所述视网膜疾病是干性年龄相关性黄斑变性。
CN202080082179.3A 2019-09-27 2020-09-28 单特异性和多特异性抗体 Pending CN115052884A (zh)

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