CN108367004B - Cd3结合多肽 - Google Patents

Cd3结合多肽 Download PDF

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CN108367004B
CN108367004B CN201680054840.3A CN201680054840A CN108367004B CN 108367004 B CN108367004 B CN 108367004B CN 201680054840 A CN201680054840 A CN 201680054840A CN 108367004 B CN108367004 B CN 108367004B
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J·W·布兰肯什普
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Abstract

本公开涉及特异性结合至CD3的蛋白质分子，其可具有至少一个人源化CD3结合结构域。此类分子可用于治疗癌症。结合至CD3的所述蛋白质分子可具有结合至另一靶标的第二结合结构域。在一个实施方案中，多特异性多肽分子结合肿瘤抗原表达细胞和T细胞上的T细胞受体复合物的CD3亚基以诱导靶标‑依赖性T细胞细胞毒性、活化和增殖。本公开还提供了包含所述CD3结合多肽分子的药物组合物、编码这些多肽的核酸分子及制备这些分子的方法。

Description

CD3结合多肽
本申请要求于2015年9月21日提交的美国临时专利申请第 62/221,190号的优先权和权益。本申请的内容通过引用整体并入本文。
以电子方式提交的文本文件的描述
与此一起以电子方式提交的文本文件的内容通过引用整体并入本文：序列表的计算机可读格式副本(文件名： APVO_052_01WO_SeqList_ST25.txt，记录日期：2016年9月21日，文件大小544千字节)。
公开领域
本公开涉及特异性结合至CD3的分子，其可具有至少一个人源化CD3结合结构域。结合至CD3的蛋白质治疗剂可为单特异性蛋白质治疗剂或多特异性蛋白质治疗剂。多特异性蛋白质治疗剂可结合肿瘤抗原和T细胞上的T细胞受体复合物的CD3亚基以诱导靶标-依赖性T细胞细胞毒性、活化和增殖。
公共背景
已经提出用抗CD3抗体靶向人T细胞上的T细胞受体复合物 (TCR)来治疗自身免疫疾病和相关病症，例如用于治疗器官同种异体移植物排斥。除了靶向CD3的单特异性治疗剂外，选择性结合至T- 细胞和肿瘤细胞两者的多特异性多肽可提供将T细胞细胞毒性重导向至肿瘤细胞的机制。此类多特异性多肽可用于治疗癌症。
一些抗CD3抗体的临床使用已受到严重副作用的阻碍。例如， OKT3，对人类CD3有特异性的小鼠单克隆抗体，在体外诱导T细胞增殖和细胞因子产生并导致体内细胞因子的大规模释放(Hirsch等人 (1989)J.Immunol 142:737-43)。细胞因子释放(也称为“细胞因子风暴”) 转而导致“流感样”综合征，其特征在于发热、寒战、头痛、恶心、呕吐、腹泻、呼吸窘迫、感染性脑膜炎和低血压(Chatenoud(2003)Nature Reviews 3:123-132)。
需要具有提高的热稳定性及良好的可制造性和减少的不利影响的CD3结合分子。
公开概述
本公开涵盖具有有利的可制造性的CD3结合结构域和多肽。包含本文公开的CD3结合结构域的多肽可以是热稳定的。在一些情况下，与另一种CD3结合多肽相比，多肽具有提高的热稳定性。本文公开的CD3结合结构域和多肽可具有减少的副作用(例如，当施用于受试者时可导致低水平的细胞因子释放)。
在某些实施方案中，本公开涉及特异性结合至人CD3并且包含免疫球蛋白轻链可变区和免疫球蛋白重链可变区的CD3结合结构域；其中所述免疫球蛋白轻链可变区包含(a)与SEQ ID NO:88中的氨基酸序列至少约93％同一、至少约95％同一、至少约97％同一、至少约 98％同一或至少约99％同一；或(b)与SEQ ID NO:89中的氨基酸序列至少约94％同一、至少约95％同一、至少约97％同一、至少约98％同一或至少约99％同一的氨基酸序列；并且其中所述免疫球蛋白重链可变区包含与SEQ ID NO:86中的氨基酸序列至少约82％同一、至少约85％同一、至少约87％同一、至少约90％同一、至少约92％同一、至少约95％同一、至少约97％同一、至少约98％同一或至少约99％同一的氨基酸序列。CD3结合结构域可包含与SEQ ID NO:83或SEQ ID NO:84中的氨基酸序列至少约87％同一、至少约90％同一、至少约92％同一、至少约95％同一、至少约97％同一、至少约98％同一或至少约99％同一的氨基酸序列。CD3结合结构域可包含SEQ ID NO:83或SEQ ID NO:84。
在一个实施方案中，CD3结合结构域包含免疫球蛋白轻链可变区，所述免疫球蛋白轻链可变区包含SEQ ID NO:94的LCDR1氨基酸序列、SEQ ID NO:95的LCDR2氨基酸序列和SEQ ID NO:96的 LCDR3氨基酸序列，和免疫球蛋白重链可变区，所述免疫球蛋白重链可变区包含SEQ ID NO:91的HCDR1氨基酸序列、SEQ ID NO:92 的HCDR2氨基酸序列和SEQ IDNO:93的HCDR3氨基酸序列。在另一个实施方案中，CD3结合结构域包含免疫球蛋白轻链可变区，所述免疫球蛋白轻链可变区包含SEQ ID NO:202的LCDR1氨基酸序列、SEQ ID NO:203的LCDR2氨基酸序列和SEQ ID NO:204的 LCDR3氨基酸序列，和免疫球蛋白重链可变区，所述免疫球蛋白重链可变区包含SEQ ID NO:199的HCDR1氨基酸序列、SEQ ID NO:200 的HCDR2氨基酸序列和SEQ ID NO:201的HCDR3氨基酸序列。
在某些方面，CD3结合结构域可包含含有框架区的免疫球蛋白轻链可变区和免疫球蛋白重链可变区，并且所述免疫球蛋白轻链可变区和所述免疫球蛋白重链可变区中的至少一个可经人源化。在一个实施方案中，免疫球蛋白轻链可变区包含基于人IGKV3D-20*1种系氨基酸序列的框架区。在另一个实施方案中，免疫球蛋白重链可变区包含基于人IGHV1-69*02种系氨基酸序列的框架区。
在一些实施方案中，CD3结合结构域的免疫球蛋白轻链可变区的根据IMGT编号系统的位置52处的氨基酸残基为精氨酸和/或CD3 结合结构域的免疫球蛋白轻链可变区的根据IMGT编号系统的位置 53处的氨基酸残基为色氨酸。CD3结合结构域的免疫球蛋白重链可变区的根据IMGT编号系统的位置27处的氨基酸残基可为酪氨酸。在一些实施方案中，CD3结合结构域包含以下一种或多种：(a)免疫球蛋白重链可变区的根据IMGT编号系统的位置9处的氨基酸残基为脯氨酸；(b)免疫球蛋白重链可变区的根据IMGT编号系统的位置53 处的氨基酸残基为异亮氨酸；并且(c)免疫球蛋白轻链可变区的根据 IMGT编号系统的位置21处的氨基酸残基为甲硫氨酸。CD3结合结构域的免疫球蛋白重链可变区的根据IMGT编号系统的位置87处的氨基酸残基可为酪氨酸。CD3结合结构域的免疫球蛋白重链可变区的根据IMGT编号系统的位置86处的氨基酸残基可为天冬氨酸。在一个实施方案中，CD3结合结构域的免疫球蛋白重链可变区的根据 IMGT编号系统的位置86处的氨基酸残基为天冬氨酸，并且CD3结合结构域的免疫球蛋白重链可变区的根据IMGT编号系统的位置87 处的氨基酸残基为酪氨酸。
本公开涵盖为单链可变片段(scFv)的CD3结合结构域。在一些方面，scFv可包含介于重链可变区和轻链可变区之间的接头。在一个实施方案中，介于重链可变区和轻链可变区之间的接头包含氨基酸序列 QRHNNSSLNTGTQMAGHSPNS(SEQ ID NO:148)。在一些实施方案中，scFv的重链可变区为scFv的轻链可变区的氨基端。在其它实施方案中，scFv的轻链可变区为scFv的重链可变区的氨基端。
本公开涵盖与包含含有SEQ ID NO:90的轻链可变区和含有SEQ ID NO:87的重链可变区的CD3结合结构域的热稳定性相比时具有增加至少约10％的热稳定性的CD3结合结构域。与包含含有SEQ ID NO:90的轻链可变区和含有SEQ ID NO:87的重链可变区的CD3结合结构域的Tm相比时，CD3结合结构域的热转变中点(Tm)可增加至少约3℃、至少约4℃、至少约5℃或至少约6℃且多达约20℃。CD3 结合结构域的热转变中点可为至少约54℃、至少约55℃、至少约 56℃或至少约57℃并且高达约72℃。CD3结合结构域的热稳定性或热转变中点可通过差示扫描量热法或差示扫描荧光测定法来测量。
与包含含有SEQ ID NO:90的轻链可变区和含有SEQ ID NO:87 的重链可变区的CD3结合结构域的储存稳定性相比时，本文公开的 CD3结合结构域可具有增加至少约5％、至少约10％、至少约20％、至少约30％、至少约40％、至少约50％、至少约60％、至少约70％、至少约80％、至少约90％和多达约100％的储存稳定性。将CD3结合结构域储存在约25℃的PBS中后，可测量储存稳定性。在一个实施方案中，CD3结合结构域在约25℃的PBS中稳定储存至少约6天、至少约10天或至少约13天且多达约90天。
在一些方面，与包含含有SEQ ID NO:90的轻链可变区和含有 SEQ ID NO:87的重链可变区的CD3结合结构域在重组表达期间产生的高分子量聚集物水平相比，本文公开的CD3结合结构域具有降低至少约5％、至少约10％、至少约20％、至少约30％且降低多达约50％的在重组表达期间产生的高分子量聚集物水平。
本公开还涉及以约10nM或更低的EC50结合至人CD3的CD3 结合结构域。在一些实施方案中，本公开的CD3结合结构域也可特异性结合至食蟹猴CD3。例如，CD3结合结构域可以约30nM或更低的EC50结合至食蟹猴CD3。
本公开涵盖特异性结合至人CD3且包含免疫球蛋白轻链可变区和免疫球蛋白重链可变区的CD3结合结构域，其中(a)所述免疫球蛋白轻链可变区包含SEQ ID NO:94的LCDR1氨基酸序列、SEQ ID NO:95的LCDR2氨基酸序列和SEQ ID NO:96的LCDR3氨基酸序列，并且其中所述免疫球蛋白重链可变区包含SEQ ID NO:91的HCDR1 氨基酸序列、SEQ ID NO:92的HCDR2氨基酸序列和SEQ ID NO:93 的HCDR3氨基酸序列；或(b)所述免疫球蛋白轻链可变区包含SEQ ID NO:202的LCDR1氨基酸序列，SEQ ID NO:203的LCDR2氨基酸序列和SEQ ID NO:204的LCDR3氨基酸序列，并且其中所述免疫球蛋白重链可变区包含SEQ ID NO:199的HCDR1氨基酸序列，SEQ ID NO:200的HCDR2氨基酸序列和SEQ ID NO:201的HCDR3氨基酸序列；并且其中所述CD3结合结构域具有本文描述的任何一种或多种特性。例如，(i)所述CD3结合结构域(或包含所述CD3结合结构域的蛋白质)的热转变中点为至少约54℃、至少约55℃、至少约56℃或至少约57℃并且高达约72℃；(ii)所述CD3结合结构域(或包含所述CD3结合结构域的蛋白质)在约25℃的PBS中稳定储存至少约6 天、至少约10天或至少约13天并且多达约90天；(iii)所述CD3结合结构域(或包含所述CD3结合结构域的蛋白质)以约10nM或更低的EC50结合至人CD3；及(iv)所述CD3结合结构域(或包含所述CD3 结合结构域的蛋白质)以约30nM或更低的EC50结合至食蟹猴CD3。
本公开还涉及包含本文描述的任何CD3结合结构域的CD3结合多肽。在一些变型中，CD3结合多肽可包含免疫球蛋白恒定区。这种免疫球蛋白恒定区可包含IgG1、IgG2、IgG3、IgG4、IgA1、IgA2或 IgD的免疫球蛋白CH2和CH3结构域。在一些实施方案中，免疫球蛋白恒定区包含含有根据EU编号系统的取代L234A、L235A、G237A 和K322A的人IgG1CH2结构域。在某些实施方案中，免疫球蛋白恒定区包含含有根据EU编号系统的取代L234A、L235A、G237A和 K322A中的一个或多个的人IgG1CH2结构域。在一些实施方案中， CD3结合多肽与T细胞上的CD3蛋白结合时不诱导或诱导来自所述 T细胞的最低限度可检测细胞因子释放。在某些方面，与向患者施用抗CD3抗体OKT3时释放的细胞因子相比，CD3结合蛋白或多肽在患者中表现出减少的细胞因子释放。在一些情况下，CD3结合多肽可诱导T细胞活化或T细胞增殖。
在某些方面，CD3结合多肽还包含第二结合结构域。第二结合结构域可为单链可变片段(scFv)。在一些实施方案中，第二结合结构域与肿瘤相关抗原(例如PSMA、CD19、CD20、CD37、CD38、CD123、 Her2、ROR1、RON、糖蛋白A33抗原(gpA33)或CEA)结合或相互作用。
本公开还涵盖一种CD3结合多肽，其包含：(i)CD3结合结构域和(ii)第二结合结构域。在一些实施方案中，CD3结合多肽按照从氨基端至羧基端的顺序或按照从羧基端至氨基端的顺序包含(i)CD3结合结构域，(ii)铰链区和(iii)免疫球蛋白恒定区。在一些实施方案中， CD3结合多肽按照从氨基端至羧基端的顺序包含(i)第二结合结构域， (ii)铰链区，(iii)免疫球蛋白恒定区，(iv)羧基端接头，和(v)CD3结合结构域。在其它实施方案中，CD3结合多肽按照从羧基端至氨基端的顺序包含(i)第二结合结构域，(ii)铰链区，(iii)免疫球蛋白恒定区，(iv) 氨基端接头，和(v)CD3结合结构域。在某些变型中，第一和/或第二结合结构域为scFv。羧基端和氨基端接头的非限制性实例包括包含甘氨酸-丝氨酸(例如，(Gly4Ser))重复序列的柔性接头和源自(i)II型C凝集素的茎区或(ii)免疫球蛋白铰链区的接头。在某些方面，羧基端接头(或氨基端接头)包含SEQ ID NO:196或由SEQ ID NO:196组成。在一些方面，本公开涉及一种CD3结合多肽(例如，多特异性的)，其中 (i)所述CD3结合结构域包含(a)含有LCDR1、LCDR2和LCDR3的免疫球蛋白轻链可变区，和(b)含有HCDR1、HCDR2和HCDR3的免疫球蛋白重链可变区；并且(ii)所述第二结合结构域包含(a)含有LCDR1、LCDR2和LCDR3的免疫球蛋白轻链可变区，和(b)含有 HCDR1、HCDR2和HCDR3的免疫球蛋白重链可变区。
本公开涵盖诱导重导向T细胞细胞毒性(RTCC)的CD3结合多肽。例如，CD3结合多肽可以约30pM或更低的EC50诱导RTCC。在一些实施方案中，CD3结合多肽未表现出或表现出最小的抗体依赖性细胞介导的细胞毒性(ADCC)活性和/或补体依赖性细胞毒性(CDC) 活性。在某些方面，无效ADCC和/或CDC活性通过铰链区和Ig恒定区(例如Fc)中的突变实现。
CD3结合多肽还可包含免疫球蛋白异二聚化结构域。在一些实施方案中，免疫球蛋白异二聚化结构域包含免疫球蛋白CH1结构域或免疫球蛋白CL结构域。在一些方面，CD3结合多肽为异二聚体CD3 结合蛋白，其包含(i)第一多肽链，所述第一多肽链按照从氨基端至羧基端或从羧基端至氨基端的顺序包含(a)特异性结合人CD3的CD3结合结构域，(b)第一铰链区，(c)第一免疫球蛋白恒定区，和(d)第一免疫球蛋白异二聚化结构域；和(ii)第二多肽链，所述第二多肽链按照从氨基端至羧基端或从羧基端至氨基端的顺序包含(a')第二铰链区， (b')第二免疫球蛋白恒定区和(c')与所述第一单链多肽的所述第一免疫球蛋白异二聚化结构域不同的第二免疫球蛋白异二聚化结构域，其中所述第一和第二免疫球蛋白异二聚化结构域彼此缔合形成异二聚体。在一个实施方案中，所述第一免疫球蛋白异源二聚化结构域包含免疫球蛋白CH1结构域并且所述第二免疫球蛋白异源二聚化结构域包含免疫球蛋白CL结构域，或其中所述第一免疫球蛋白异源二聚化结构域包含免疫球蛋白CL结构域并且所述第二免疫球蛋白异源二聚化结构域包含免疫球蛋白CH1结构域。第一和第二免疫球蛋白恒定区中的至少一个可包含IgG1、IgG2、IgG3、IgG4、IgA1、IgA2、IgD或其任何组合的免疫球蛋白CH2和CH3结构域；IgG1、IgG2、IgG3、 IgG4、IgA1、IgA2、IgD、IgE、IgM或其任何组合的免疫球蛋白CH3 结构域；或IgE、IgM或其组合的免疫球蛋白CH3和CH4结构域。在一些方面，异二聚体CD3结合蛋白的第二多肽链还可包含第二结合结构域。在某些实施方案中，第二结合结构域可为第二铰链区的氨基端或羧基端。
在一些变型中，CD3结合多肽可为包含CD3结合结构域和第二结合结构域的双特异性单链抗体分子，其中所述结合结构域按照VH CD3-VL CD3-VH第二结合结构域-VL第二结合结构域或VL CD3-VH CD3-VH第二结合结构域-VL第二结合结构域或VH第二结合结构域-VL第二结合结构域-VH CD3-VL CD3或VH第二结合结构域-VL第二结合结构域-VL CD3-VHCD3的顺序排列。
本公开还涉及编码本文描述的CD3结合结构域或CD3结合多肽或所述CD3结合结构域或多肽的一部分的分离的核酸分子。在一些方面，本公开涵盖包含编码本文描述的CD3结合结构域或CD3结合多肽的核酸区段的表达载体，其中使所述核酸区段可操作地连接至适于在宿主细胞中表达所述核酸区段的调控序列。包含表达载体的重组宿主细胞包括在本公开中。
本公开涵盖包含第一和第二表达单元的表达载体，其中所述第一和第二表达单元分别包含编码异二聚体CD3结合多肽的第一和第二多肽链的第一和第二核酸区段，并且其中使所述第一和第二核酸区段可操作地连接至适于在宿主细胞中表达所述核酸区段的调控序列。包含含有第一和第二表达单元的表达载体的重组宿主细胞是本公开的一部分。
本公开还涉及用于产生CD3结合多肽的方法，所述方法包括：在借此表达所述核酸区段的条件下培养包含本文描述的表达载体的重组宿主细胞，从而产生所述CD3结合多肽。在一些实施方案中，用于产生异二聚体CD3结合蛋白的方法包括：培养包含第一和第二表达单元的重组宿主细胞，其中所述第一和第二表达单元分别包含编码异二聚体CD3结合蛋白的第一和第二多肽链的第一和第二核酸区段，其中使所述第一和第二核酸区段可操作地连接至适合于在宿主细胞中表达所述核酸区段的调控序列，并且其中所述培养是在借此表达第一和第二核酸区段并且所述编码的多肽链作为异二聚体CD3结合蛋白产生的条件下进行的。这些方法还可包括回收CD3结合多肽或异二聚体CD3结合蛋白。
本公开涵盖包含本文公开的CD3结合多肽和药学上可接受的载体、稀释剂或赋形剂的药物组合物。本公开还涉及一种用于诱导针对表达肿瘤相关抗原的细胞的重导向T细胞细胞毒性(RTCC)的方法，所述方法包括：使所述肿瘤相关抗原表达细胞与CD3结合多肽接触，其中所述接触是在借此诱导针对所述肿瘤相关抗原表达细胞的RTCC 的条件下进行的。本公开的一个方面包括用于在有需要的受试者中抑制肿瘤生长的方法，其包括向受试者施用治疗有效量的本文描述的 CD3结合多肽或药物组合物。本公开涵盖用于在有需要的受试者中治疗癌症或自身免疫病症的方法，其包括向受试者施用治疗有效量的本文描述的CD3结合多肽或组合物。可通过本文描述的方法和CD3结合多肽治疗的癌症的非限制性实例包括前列腺癌、结直肠癌、肾细胞癌、膀胱癌、唾液腺癌、胰腺癌、卵巢癌、非小细胞肺癌、乳腺癌(例如三阴性乳腺癌)、黑素瘤、肾上腺癌、套细胞淋巴瘤、急性淋巴母细胞性白血病、慢性淋巴细胞性白血病、非霍奇金氏淋巴瘤 (Non-Hodgkin’s lymphoma)、急性髓细胞性白血病(AML)、B淋巴样白血病、母细胞性浆细胞样树突细胞肿瘤(BPDCN)和毛细胞白血病。
本公开涵盖特异性结合至人CD3并且包含SEQ ID NO:4、6、8、 10、12、14、16、18、20、22、24、26、28、30、32、34、36、38、 40、42、44、46、48、50、52、54、56、58或60的CD3结合结构域。
本公开还涉及是两个同一多肽的二聚体的CD3结合蛋白，其中每个多肽均为本文公开的任何CD3结合多肽。
参考本公开的以下详细描述和附图，本公开的这些和其它实施方案和/或其它方面将变得明显。
附图简述
图1(上图)是显示测量CD3结合结构域构建体与Jurkat T细胞结合的流式细胞术研究结果的曲线图。y轴上显示活细胞上结合分子的平均荧光强度(MFI)。x轴上显示CD3结合结构域构建体的浓度(nM)。表(下图)显示了由曲线图中的数据获得的EC50值。
图2(上图)是显示测量CD3结合结构域构建体与具有更高CD3 表达水平的JurkatT细胞系亚克隆的结合的流式细胞术研究结果的曲线图。y轴上显示活细胞上结合分子的平均荧光强度(MFI)。x轴上显示CD3结合结构域构建体的浓度(nM)。表(下图)显示了由曲线图中的数据获得的EC50值。
图3是显示用CD3结合结构域构建体进行的差示扫描荧光测定法研究结果的曲线图。该图还显示了由曲线图中的数据获得的热转变中点(Tm)值。
图4是显示测量CD3结合结构域构建体与具有更高CD3表达水平的Jurkat T细胞系亚克隆的结合的流式细胞术研究结果的曲线图。 y轴上显示活细胞上结合分子的平均荧光强度(MFI)。x轴上显示CD3 结合结构域构建体的浓度(nM)。
图5是显示测量CD3结合结构域构建体与具有更高CD3表达水平的Jurkat T细胞系亚克隆的结合的流式细胞术研究结果的曲线图。 y轴上显示活细胞上结合分子的平均荧光强度(MFI)。x轴上显示CD3 结合结构域构建体的浓度(nM)。
图6(上图)是显示铬-51释放测定法结果的曲线图，该测定法测量 4小时内与人PBMC诱导对C4-2B细胞的靶标-依赖性T细胞细胞毒性时双特异性抗PSMA和抗CD3构建体的有效性。y轴上显示相对于总裂解对照的特异性裂解百分比。x轴上显示CD3结合结构域构建体的浓度(pM)。表(下图)显示了由曲线图中的数据获得的EC50值。
图7A和图7B是显示测量CD3结合结构域构建体与食蟹猴T细胞结合的流式细胞术研究结果的曲线图。每张曲线图的y轴上显示活细胞上结合分子的平均荧光强度(MFI)。每张曲线图的x轴上显示 CD3结合结构域构建体的浓度(nM)。
图8A和图8B是显示铬-51释放测定法结果的曲线图，该测定法测量4小时内与食蟹猴PBMC诱导对C4-2B细胞的靶标-依赖性T细胞细胞毒性时CD3结合结构域构建体的有效性。每张曲线图的y轴上显示相对于总裂解对照的特异性裂解百分比。每张曲线图的x轴上显示CD3结合结构域构建体的浓度(pM)。
图9是显示测量双特异性抗CD37和抗CD3构建体与食蟹猴T- 细胞的结合的流式细胞术研究结果的曲线图。y轴上显示活细胞上结合分子的平均荧光强度(MFI)。x轴上显示CD3结合结构域构建体的浓度(nM)。TSC394DY是指包括E86D和F87Y取代的TSC394构建体。
图10(上图)是显示铬-51释放测定法结果的曲线图，该测定法测量4小时内与食蟹猴PBMC诱导对Ramos细胞的靶标-依赖性T细胞细胞毒性时双特异性抗CD37和抗CD3构建体的有效性。每张曲线图的y轴上显示相对于总裂解对照的特异性裂解百分比。每张曲线图的x轴上显示CD3结合结构域构建体的浓度(pM)。表(下图)显示了由曲线图中的数据获得的EC50值。TSC394DY是指包括E86D和F87Y 取代的TSC394构建体。
图11是显示测量CD3结合结构域构建体在25℃下在x轴上指定的天数内的储存稳定性的研究结果的曲线图。CAS105是包含 DRA222CD3结合结构域的对照构建体。
图12是显示测量抗ROR1x抗CD3双特异性分子在x轴上指定的天数内在人血清中的血清稳定性的研究结果的曲线图。
图13显示了DRA222scFv(SEQ ID NO:85)、TSC455scFv(SEQ ID NO:83)和TSC456scFv(SEQ ID NO:84)的氨基酸序列的比对。表 14中也显示了这些构建体的序列。
图14是显示测量BALB/c小鼠中随时间变化抗PSMA X抗CD3 双特异性结合分子的血清浓度的研究结果的曲线图。结果表示为每个治疗组随时间推移的平均血清浓度(μg/mL)。每个点显示单个动物的平均值(+标准偏差)。
图15是显示BALB/c小鼠中抗PSMA X抗CD3双特异性结合分子的药代动力学参数的比较的表。
图16是显示测量NSG小鼠中随时间变化抗ROR1X抗CD3双特异性结合分子的血清浓度的研究结果的曲线图。结果表示为每个治疗组随时间推移的平均血清浓度(μg/mL)。
图17A和图17B是显示NSG小鼠中抗ROR1X抗CD3双特异性结合分子的药代动力学参数的比较的表。图17A显示了对于每个治疗组IV给药及稀释取样和均匀加权，使用NCA计算的药代动力学参数估计值。图17B显示了对于每个治疗组使用2室IV模型和1/Y 加权确定的药代动力学参数估计值。
图18是显示分析抗ROR1X抗CD3双特异性结合分子对 MDA-MB-231异种移植肿瘤生长的影响的研究结果的曲线图。
图19是显示分析抗ROR1X抗CD3双特异性结合分子对 Kasumi-2异种移植肿瘤生长的影响的研究结果的曲线图。显示了人T 细胞供体#336的结果。
公开详述
本公开提供了特异性结合至CD3(分化群3)的结合结构域和特异性结合至CD3的结合分子(例如多肽和蛋白质)。这些结合分子可特异性结合至CD3和至少一个其它靶标。在一些实施方案中，本文描述的CD3结合分子具有良好的可制造性，具有下文描述的一种或多种特性。在某些实施方案中，来自Cris7抗CD3抗体的CDR已经用于工程改造具有改良和新颖特性的CD3结合分子。因此，本公开涉及与其它抗CD3结合结构域和蛋白质相比具有改良特性(例如，热稳定性、储存稳定性、血清半衰期、高分子量聚集物形成减少)的人源化抗CD3结合结构域和蛋白质。在本公开的一些方面，CD3结合分子是热稳定的。例如，与另一种CD3结合分子(例如，DRA222)相比，所述分子可具有提高的热稳定性。CD3结合分子可具有高产量及长的血清半衰期和长的储存半衰期。此外，本文描述的CD3结合分子在施用给受试者时可具有较低的不良副作用风险。例如，CD3结合分子可导致低水平的细胞因子释放。
在本说明书中，除非另有说明，否则任何浓度范围、百分比范围、比率范围或整数范围应被理解为包括所列范围内的任何整数值，并且在适当的情况下，包括其分数值(例如整数的十分之一和百分之一)。应该理解，除非另有说明，否则如本文所用的术语“一”和“一种(个)”是指所列举组分中的“一种(个)或多种(个)”。替代方案(例如“或”)的使用应理解为意指替代方案中的一个、两者或其任何组合。如本文所用，术语“包括”和“包含”可作为同义词使用。另外，应当理解的是，包含组分(例如，结构域或区)和本文描述的取代基的各种组合的多肽通过本申请公开的程度如同单独阐述每个多肽一样。因此，单个多肽的特定组分的选择在本公开的范围内。
本文引用的所有文件或部分文件(包括但不限于专利、专利申请、文章、书籍和论文)均据此明确地通过引用整体并入用于任何目的。如果一个或多个并入的文件或部分文件定义的术语与该术语在本申请中的定义相矛盾，则以本申请中出现的定义为准。然而，本文引用的任何参考文献、文章、出版物、专利、专利出版物和专利申请的提及不得且不应被视为承认或以任何形式表明，它们构成有效的现有技术或形成世界上任何国家公知常识的一部分。
如本文所用，术语“结合结构域”或“结合区”是指蛋白质、多肽、寡肽或肽或抗体的结构域、区域、部分或位点或源自具有特异性识别和结合靶分子，如抗原、配体、受体、底物或抑制剂(例如，CD3)的能力的抗体的结合结构域。示例性结合结构域包括单链抗体可变区(例如，结构域抗体、sFv、scFv、scFab)、受体胞外域和配体(例如，细胞因子、趋化因子)。在某些实施方案中，结合结构域包含抗原结合位点或由其组成(例如，包含可变重链序列和可变轻链序列或三个轻链互补决定区(CDR)和来自抗体的置于可选框架区(FR)内的三个重链CDR(例如，任选包含一个或多个氨基酸取代的人FR)。已知用于鉴定特异性结合特定靶标的本公开的结合结构域的各种测定法，包括 Western印迹、ELISA、噬菌体展示库筛选和
Figure BDA0001603367540000141
相互作用分析。如本文所用，CD3结合多肽可具有“第一结合结构域”和任选地，“第二结合结构域”。在某些实施方案中，“第一结合结构域”为CD3 结合结构域，并且该形式为抗体或抗体样蛋白质或结构域。在包含第一和第二结合结构域的某些实施方案中，第二结合结构域为肿瘤抗原结合结构域。在其它实施方案中，第二结合结构域为第二CD3结合结构域。在其它实施方案中，第二结合结构域是除肿瘤抗原结合结构域之外的结合结构域。
结合结构域或蛋白质如果以等于或大于105M-1,的亲和力或Ka (即，单位为1/M的特定结合相互作用的平衡缔合常数)结合靶标，而未显著结合试样中存在的其它组分，则“特异性结合”靶标。结合结构域可以分类为“高亲和力”结合结构域和“低亲和力”结合结构域。“高亲和力”结合结构域是指Ka为至少107M-1、至少108M-1、至少109 M-1、至少1010M-1、至少1011M-1、至少1012M-1或至少1013M-1的那些结合结构域。“低亲和力”结合结构域是指Ka高达107M-1、高达106M-1、高达105M-1的那些结合结构域。可选地，可将亲和力定义为单位为M(例如，10-5M至10-13M)的特定结合相互作用的平衡解离常数(Kd)。使用常规技术可容易地测定根据本公开的结合结构域多肽和单链多肽的亲和力(参见例如，Scatchard等人(1949)Ann.N.Y.Ac ad.Sci.51:660；和美国专利第5,283,173、5,468,614号或等同专利)。
“CD3”在本领域中被称为六条链的多蛋白复合物(参见例如， Abbas和Lichtman，2003；Janeway等人，第172和178页，1999)，其是T细胞受体复合物的亚基。在哺乳动物中，T细胞受体复合物的 CD3亚基是CD3γ链、CD3δ链、两条CD3ε链和CD3ζ链的同型二聚体。CD3γ、CD3δ和CD3ε链是含有单个免疫球蛋白结构域的免疫球蛋白超家族的高度相关细胞表面蛋白。CD3γ、CD3δ和CD3ε链的跨膜区带负电荷，这是允许这些链与带正电荷的T细胞受体链缔合的特征。CD3γ、CD3δ和CD3ε链的细胞内尾部均含有单个保守基序，称为基于免疫受体酪氨酸的活化基序或ITAM，而每条CD3ζ链具有三个。据信ITAM对于TCR复合物的信号容量是重要的。如本公开中使用的CD3可以来自各种动物物种，包括人、猴、小鼠、大鼠或其它哺乳动物。
如本文所用，“保守性取代”在本领域中被认为是用一个氨基酸取代具有相似性质的另一个氨基酸。示例性的保守取代在本领域中是公知的(参见例如，WO 97/09433，第10页，1997年3月13日公开； Lehninger，Biochemistry，第二版；Worth Publishers,Inc.NY:NY(1975)，第71-77页；Lewin,Genes IV,Oxford University Press,NY and Cell Press,Cambridge,MA(1990)，第8页)。在某些实施方案中，保守性取代包括亮氨酸至丝氨酸取代。
如本文所用，术语“衍生物”是指通过化学或生物学手段，用或不用酶，例如通过糖基化、烷基化、酰化、酯形成或酰胺形成对肽的一个或多个氨基酸残基的修饰。
如本文所用，“源自”指定多肽或蛋白质的多肽或氨基酸序列是指多肽的来源。在某些实施方案中，源自特定序列(有时称为“起始”或“亲本”或“亲本”序列)的多肽或氨基酸序列具有与起始序列或其一部分基本上同一的氨基酸序列，其中所述部分由至少10-20个氨基酸，至少 20-30个氨基酸，或至少30-50个氨基酸，或至少50-150个氨基酸组成，或其可由本领域的普通技术人员以其它方法鉴定为起源于所述起始序列。例如，结合结构域可源自抗体，例如Fab、F(ab')2、Fab'、scFv、单结构域抗体(sdAb)等。
源自另一多肽的多肽相对于起始多肽可具有一个或多个突变，例如，一个或多个氨基酸残基已被另一个氨基酸残基取代或有一个或多个氨基酸残基插入或缺失。多肽可包含非天然存在的氨基酸序列。此类变异必须与起始多肽具有小于100％的序列同一性或相似性。在一个实施方案中，变体将具有与起始多肽的氨基酸序列具有约60％至小于100％的氨基酸序列同一性或相似性的氨基酸序列。在另一个实施方案中，所述变体将具有与起始多肽的氨基酸序列具有约75％至小于 100％、约80％至小于100％、约85％至小于100％、约90％至小于100％、约95％至小于100％的氨基酸序列同一性或相似性的氨基酸序列。
如本文所用，除非另外提供，否则使用IMGT标准对免疫球蛋白分子的可变区中的氨基酸残基的位置进行编号(Brochet,X等人， Nucl.Acids Res.(2008)36，W503-508)，并且根据EU命名法对免疫球蛋白分子的恒定区中的氨基酸残基的位置进行编号(Ward等人，，1995 Therap.Immunol.2:77-94)。Kabat编号规定(Kabat,Sequences of Proteins ofImmunological Interest，第5版.Bethesda,MD:Public Health Service, NationalInstitutes of Health(1991))是用于指免疫球蛋白分子可变区中氨基酸残基的位置的替代系统。
如本文所用，术语“二聚体”是指由通过一种或多种形式的分子内力，包括共价键(例如，二硫键)和其它相互作用(例如，静电相互作用、盐桥、氢键键合和疏水性相互作用)，相互缔合的两个亚基组成，并且在适当条件下(例如，在生理条件下，在适于表达、纯化和/或储存重组蛋白的水溶液中，或在用于非变性和/或非还原电泳的条件下)稳定的生物实体。如本文所用，“异二聚体”或“异二聚体蛋白质”是指由两个不同多肽形成的二聚体。异二聚体不包括由四个多肽(，即，两条轻链和两条重链)形成的抗体。如本文所用，“同型二聚体”或“同型二聚体蛋白质”是指由两个相同多肽形成的二聚体。
在一些实施方案中，CD3结合多肽按照从氨基端至羧基端的顺序或按照从羧基端至氨基端的顺序包含(i)第二结合结构域，(ii)铰链区， (iii)免疫球蛋白恒定区，(iv)羧基端接头(或氨基端接头)和(v)CD3结合结构域。如本文所用且根据上下文，“铰链区”或“铰链”是指介于结合结构域(例如，CD3结合结构域或第二结合结构域)与免疫球蛋白恒定区之间的多肽区。如本文所用并且根据上下文，“接头”可以指(1)单链 Fv(scFv)中介于VH和VL区之间的多肽区或(2)包含两个结合结构域的 CD3结合多肽中介于免疫球蛋白恒定区和第二结合结构域之间的多肽区。包含两个结合结构域的CD3结合多肽中介于免疫球蛋白恒定区和CD3结合结构域之间的多肽区也可称为“羧基端接头”或“氨基端接头”。羧基端和氨基端接头的非限制性实例包括包含甘氨酸-丝氨酸重复序列的柔性接头，及源自(a)跨膜蛋白(例如，I型跨膜蛋白)的域间区域；(b)II型C凝集素的茎区；或(c)免疫球蛋白铰链的接头。表1 和2中提供了铰链和接头的非限制性实例。在一些实施方案中，“接头”提供与两个亚结合结构域的相互作用相容的间隔区功能，使得所得多肽保留对与包含相同轻链和重链可变区的抗体相同的靶分子的特异性结合亲和力。在某些实施方案中，接头包含5至约35个氨基酸，例如约15至约25个氨基酸。
“野生型免疫球蛋白铰链区”是指在抗体重链中发现的插入CH1 和CH2结构域之间并连接CH1和CH2结构域(对于IgG、IgA和IgD 而言)或插入CH1和CH3结构域之间并连接CH1和CH3结构域(对于IgE和IgM而言)的天然存在的上部和中间铰链氨基酸序列。在某些实施方案中，野生型免疫球蛋白铰链区序列是人的，并且可包含人 IgG铰链区。
“改变的野生型免疫球蛋白铰链区”或“改变的免疫球蛋白铰链区”是指(a)具有高达30％的氨基酸变化(例如，高达25％、20％、15％、 10％或5％的氨基酸取代或缺失)的野生型免疫球蛋白铰链区，或(b) 长度为约5个氨基酸(例如，约5、6、7、8、9、10、11、12、13、14、15、16、17、18、19或20个氨基酸)至约120个氨基酸(例如，长度为约10至约40个氨基酸或约15至约30个氨基酸或约15至约20个氨基酸或约20至约25个氨基酸)，具有高达约30％的氨基酸变化(例如，高达约25％、20％、15％、10％、5％、4％、3％、2％或1％的氨基酸取代或缺失或其组合)，并且具有如US 2013/0129723和US 2013/0095097中公开的IgG核心铰链区的野生型免疫球蛋白铰链区的一部分。
如本文所用，术语“人源化”是指使用基因工程技术，制备源自非人物种(例如，小鼠或大鼠)，对人免疫原性较低，同时仍保留原始抗体的抗原结合特性的抗体或免疫球蛋白结合蛋白和多肽的方法。在一些实施方案中，抗体或免疫球蛋白结合蛋白和多肽(例如，轻链和重链可变区、Fab、scFv)的结合结构域经人源化。可使用称为CDR移植的技术(Jones等人，Nature 321:522(1986))及其变型使非人结合结构域人源化，所述变型包括“重构(reshaping)”(Verhoeyen等人，1988 Science 239:1534-1536；Riechmann等人，1988Nature 332:323-337； Tempest等人，Bio/Technol 1991 9:266-271)、“高度嵌合(hyperchimerization)”(Queen等人，1989Proc Natl Acad Sci USA 86:10029-10033；Co等人，1991Proc Natl Acad Sci USA 88:2869-2873； Co等人，1992J Immunol 148:1149-1154)和“饰面(veneering)”(Mark等人，"Derivation of therapeutically activehumanized and veneered anti-CD18antibodies.”In:Metcalf BW,Dalton BJ编辑，Cellular adhesion:molecular definition to therapeutic potential.New York:Plenum Press,1994:291-312)。如果源自非人来源，则抗体或免疫球蛋白结合蛋白和多肽的其它区域如铰链区和恒定区结构域也可人源化。
如本文所用，“免疫球蛋白二聚化结构域”或“免疫球蛋白异二聚化结构域”是指优先与第二多肽链的不同免疫球蛋白结构域相互作用或缔合的多肽链的免疫球蛋白结构域，其中不同免疫球蛋白异二聚化结构域的相互作用基本上有助于或有效促进第一和第二多肽链的异二聚化(即，两条不同多肽链之间的二聚体(也称为异二聚体)的形成)。如果在不存在第一多肽链的免疫球蛋白异源二聚化结构域和/或第二多肽链的免疫球蛋白异源二聚化结构域的情况下第一和第二多肽链之间的二聚化在统计学上显著减少，则免疫球蛋白异二聚化结构域之间的相互作用“基本上有助于或有效促进”第一和第二多肽链的异二聚化。在某些实施方案中，当第一和第二多肽链共表达时，至少60％、至少约60％至约70％、至少约70％至约80％、至少80％至约90％、 91％、92％、93％、94％、95％、96％、97％、98％或99％的第一和第二多肽链彼此形成异二聚体。代表性免疫球蛋白异二聚化结构域包括免疫球蛋白CH1结构域、免疫球蛋白CL结构域(例如，Cκ或Cλ同种型)或其衍生物，包括如其中所提供的野生型免疫球蛋白CH1和CL 结构域和改变(或突变)的免疫球蛋白CH1和CL结构域。
“免疫球蛋白恒定区”或“恒定区”是本文定义的术语，是指对应或源自一个或多个恒定区结构域的一部分或全部的肽或多肽序列。在某些实施方案中，免疫球蛋白恒定区对应或源自一个或多个恒定区结构域的一部分或全部，但不是源抗体的全部恒定区结构域。在某些实施方案中，恒定区包含IgG CH2和CH3结构域，例如IgG1CH2和CH3 结构域。在某些实施方案中，恒定区不包含CH1结构域。在某些实施方案中，构成恒定区的恒定区结构域是人类的。在一些实施方案中 (例如，在CD3结合多肽或蛋白质的某些变型中)，本公开的融合蛋白的恒定区结构域缺乏或具有抗体依赖性细胞介导的细胞毒性(ADCC) 及补体活化和补体依赖性细胞毒性(CDC)的最小效应功能，同时保持结合一些FC受体(如FCRn，新生儿Fc受体)的能力并且在体内保持相对较长的半衰期。在其它变型中，本公开的融合蛋白包括保持ADCC 和CDC之一或两者的这种效应功能的恒定结构域。在某些实施方案中，本公开的结合结构域与人IgG1恒定区融合，其中IgG1恒定区有以下一个或多个氨基酸突变：位置234处的亮氨酸(L234)，位置235 处的亮氨酸(L235)，位置237处的甘氨酸(G237)，位置318处的谷氨酸(E318)，位置320处的赖氨酸(K320)，位置322处的赖氨酸位(K322) 或其任何组合(根据EU编号)。例如，这些氨基酸中的任何一个或多个可变成丙氨酸。再一个实施方案中，IgG1Fc结构域的L234、L235、 G237、E318、K320和K322(根据EU编号)各自突变为丙氨酸(即，分别为L234A、L235A、G237A、E318A、K320A和K322A)，并且任选地也具有N297A突变(即，基本上消除了CH2结构域的糖基化)。
“Fc区”或“Fc结构域”是指对应或源自源抗体负责结合细胞上的抗体受体和补体的C1q组分的部分的多肽序列。Fc代表“片段结晶”，即将容易形成蛋白质晶体的抗体片段。最初通过蛋白水解消化描述的不同蛋白质片段可以限定免疫球蛋白的整体一般结构。如文献中最初定义的，Fc片段由二硫键连接的重链铰链区、CH2和CH3结构域组成。然而，最近已将该术语应用于由CH3、CH2和至少一部分铰链组成的单链，其足以与第二条这样的链形成二硫键连接的二聚体。对于免疫球蛋白结构和功能的综述，参见Putnam，The PlasmaProteins，第V卷(Academic Press,Inc.,1987)，第49-140页；和Padlan，Mol. Immunol.31:169-217,1994。如本文所用，术语Fc包括天然存在的序列的变体。
在一些实施方案中，CD3结合蛋白包含于例如美国专利申请公开第2003/0133939、2003/0118592和2005/0136049号中总体公开的蛋白支架。CD3结合蛋白按照从氨基端至羧基端的顺序可包含第一结合结构域、铰链区和免疫球蛋白恒定区。在其它实施方案中，CD3结合蛋白包含于例如美国专利申请公开第2009/0148447号中总体公开的蛋白支架。CD3结合蛋白按照从羧基端至氨基端的顺序可包含免疫球蛋白恒定区、铰链区和第一结合结构域。
本文公开的CD3结合多肽和蛋白可并入多特异性结合蛋白支架。例如，在各自通过引用整体并入本文的PCT申请公开WO 2007/146968号、美国专利申请公开2006/0051844号、PCT申请公开 WO 2010/040105号、PCT申请公开WO 2010/003108号、美国专利 7,166,707号和美国专利8,409,577号中公开了使用支架的多特异性结合蛋白和多肽。CD3结合蛋白可包含两个结合结构域(该结构域可设计为特异性结合相同或不同靶标)、两个铰链区和一个免疫球蛋白恒定区。CD3结合蛋白可以是包含两个相同的二硫键键合多肽的同型二聚体蛋白。
如本文所用，II型C凝集素的茎区是指II型C凝集素位于C型凝集素样结构域(CTLD；例如，与自然杀伤细胞受体的CTLD类似) 和跨膜结构域之间的胞外结构域部分。例如，在人CD94分子中 (GenBank登录号AAC50291.1，PRI 1995年11月30日)，胞外结构域对应氨基酸残基34-179，而CTLD对应氨基酸残基61-176。因此，人CD94分子的茎区包括在膜和CTLD之间发现的氨基酸残基 34-60(参见Boyington等人，Immunity 10:75,1999；对于其它茎区的描述，也参见Beavil等人，Proc.Nat’l.Acad.Sci.USA 89:753,1992；和 Figdor等人，Nature Rev.Immunol.2:77,2002)。这些II型C凝集素在茎区和跨膜区或CTLD之间还可具有6至10个接点氨基酸。在另一个实例中，233个氨基酸的人NKG2A蛋白(GenBank登录号P26715.1， PRI 2010年6月15日)具有范围为氨基酸71-93的跨膜结构域和范围为氨基酸94-233的胞外结构域。CTLD包含氨基酸119-231，并且茎区包含氨基酸99-116，其侧接有5个和2个氨基酸的接点。其它II 型C凝集素及其胞外配体结合结构域、域间区域或茎区和CTLD是本领域已知的(对于人CD23、CD69、CD72、NKG2A和NKG2D的序列及其描述，分别参见例如，GenBank登录号NP_001993.2； AAH07037.1,PRI 2006年7月15日；NP_001773.1,PRI 1010年6月 20日；AAL65234.1,PRI 2002年1月17日和CAA04925.1,PRI 2006 年11月14日)。
如本文所用，跨膜蛋白(例如，I型跨膜蛋白)的“域间区域”是指跨膜蛋白位于两个相邻结构域之间的胞外结构域的一部分。域间区域的实例包括连接免疫球蛋白超家族成员的相邻Ig结构域的区域(例如，来自IgG、IgA、IgD或IgE的免疫球蛋白铰链区；连接CD2的IgV和IgC2结构域的区域；连接CD80或CD86的IgV和IgC结构域的区域)。域间区域的另一个实例是连接CD22的非Ig和IgC2结构域的区域，CD22是I型唾液酸结合Ig样凝集素。
“源自”II型C凝集素的茎区或“源自”跨膜蛋白域间区域(例如，免疫球蛋白铰链区)的多肽区是指约5至约150个氨基酸的序列，约5 至约100个氨基酸的序列，约5至约50个氨基酸的序列，约5至约 40个氨基酸的序列，约5至约30个氨基酸的序列，约5至约25个氨基酸的序列，约5至约20个氨基酸的序列，约10至约25个氨基酸的序列，约10至约20个氨基酸的序列，约8至约20个氨基酸的序列，约9至约20个氨基酸的序列，约10个约20个氨基酸的序列，约11至约20个氨基酸的序列，约12至约20个氨基酸的序列，约 13至约20个氨基酸的序列，约14至约20个氨基酸的序列，约15 至约20个氨基酸的序列或约5、6、7、8、9、10、11、12、13、14、 15、16、17、18、19或20个氨基酸的序列，其中全部或至少一部分包含(i)野生型茎区或域间区域序列；(ii)野生型茎区或域间区域序列的片段；(iii)与(i)或(ii)具有至少80％、85％、90％或95％氨基酸序列同一性的多肽；或(iv)其中一个、两个、三个、四个或五个氨基酸具有缺失、插入、取代或其任何组合的(i)或(ii)，例如，所述一个或多个变化是取代或所述一个或多个突变仅包含一个缺失。在一些实施方案中，与野生型茎区序列相比，例如源自NKG2A、NKG2D、CD23、 CD64、CD72或CD94的约8至约20个氨基酸的那些，茎区的衍生物对蛋白水解裂解更具抗性。
如本文所用，术语“接点氨基酸”或“接点氨基酸残基”是指多肽的两个相邻区域或结构域之间，例如铰链与相邻免疫球蛋白恒定区或铰链与相邻结合结构域之间或肽接头与相邻免疫球蛋白可变结构域或相邻免疫球蛋白恒定区之间的一个或多个(例如，约2-10个)氨基酸残基。接点氨基酸可由多肽的构建体设计产生(例如，在构建编码多肽的核酸分子期间使用限制酶位点产生的氨基酸残基)。
如本文所用，短语“CH3和CH1或CL之间的接头”是指CH3结构域(例如，野生型CH3或突变CH3)的C端和CH1结构域或CL结构域(例如，Ck)的N端之间的一个或多个(例如，约2-12个、约2-10 个、约4-10个、约5-10个、约6-10个、约7-10个、约8-10个、约 9-10个、约8-12个、约9-12个或约10-12个)氨基酸残基。
如本文所用，术语“有需要的患者”或“有需要的受试者”是指处于易于用本文提供的CD3结合蛋白或多肽或其组合物治疗或改善的疾病、病症或病状风险中或患有所述疾病、病症或病状的患者或受试者。
如本文所用，术语“药学上可接受的”是指使用本领域公知的途径施用时通常不产生过敏性或其它严重不良反应的分子实体和组合物。经联邦或国家政府的管理机构批准或列入美国药典或其它公认药典中用于动物，且更特别是用于人的分子实体和组合物被认为是“药学上可接受的”。
如本文所用，术语“启动子”是指参与结合RNA聚合酶以启动转录的DNA区域。
如本文所用，术语“核酸”、“核酸分子”或“多核苷酸”是指单链或双链形式的脱氧核糖核苷酸或核糖核苷酸及其聚合物。除非特别限制，否则这些术语涵盖含有天然核苷酸类似物的核酸，其具有与参考核酸相似的结合特性并且以类似于天然存在的核苷酸的方式代谢。除非另有说明，否则特定核酸序列还隐含地涵盖其经保守性修饰的变体 (例如，简并密码子取代)和互补序列以及明确指出的序列。具体而言，简并密码子取代可以通过产生其中一个或多个选定(或全部)密码子的第三个位置经混合碱基和/或脱氧肌苷残基取代的序列来实现(Batzer 等人，(1991)Nucleic Acid Res.19:5081；Ohtsuka等人(1985)J.Biol.Chem.260:2605-2608；Cassol等人(1992)；Rossolini等人 (1994)Mol.Cell.Probes8:91-98)。术语核酸可与基因、cDNA和基因编码的mRNA互换使用。如本文所用，术语“核酸”、“核酸分子”或“多核苷酸”旨在包括DNA分子(例如，cDNA或基因组DNA)、RNA分子(例如，mRNA)、使用核苷酸类似物产生的DNA或RNA类似物及其衍生物、片段和同源物。
术语“表达”是指由核酸编码的产物的生物合成。例如，在编码目标多肽的核酸区段的情况下，表达涉及核酸区段转录成mRNA和 mRNA翻译成一个或多个多肽。
术语“表达单元”和“表达盒”在本文中可互换使用，并且表示编码目标多肽并且能够在宿主细胞中提供核酸区段表达的核酸区段。表达单元通常包含转录启动子，编码目标多肽的开放阅读框和转录终止子，其全部呈可操作构型。除转录启动子和终止子外，表达单元还可包括其它核酸区段，例如，增强子或多聚腺苷酸化信号。
如本文所用，术语“表达载体”是指包含一个或多个表达单位的线性或环状核酸分子。除一个或多个表达单元外，表达载体还可包括附加核酸区段，例如一个或多个复制起点或一个或多个选择标记。表达载体通常源自质粒或病毒DNA，或可含两者的元件。
如本文所用，术语“序列同一性”是指两个或更多个多核苷酸序列之间或两个或更多个多肽序列之间的关系。当一个序列中的位置被比较序列相应位置上的相同核酸碱基或氨基酸残基占据时，称该序列在该位置是“同一的”。通过确定两个序列中出现相同核酸碱基或氨基酸残基的位置数量以得到“同一”位置的数量来计算百分比“序列同一性”。然后将“同一”位置的数量除以比较窗口中的位置总数并乘以100 得到“序列同一性”的百分比。通过在比较窗口上比较两个最佳比对序列来确定“序列同一性”的百分比。核酸序列的比较窗口长度可为，例如，至少20、30、40、50、60、70、80、90、100、110、120、130、 140、150、160、170、180、190、200、300、400、500、600、700、 800、900或1000个或更多个核酸。多肽序列的比较窗口长度可为，例如，至少20、30、40、50、60、70、80、90、100、110、120、130、 140、150、160、170、180、190、200、300个或更多个氨基酸。为了最佳地比对序列以进行比较，比较窗口中的多核苷酸或多肽序列部分可包含称为空位的添加或缺失，而参考序列保持不变。最佳比对是即使有空位也能在参考序列和比较序列之间产生尽可能多的“同一”位置的比对。两个序列之间的百分比“序列同一性”可以使用自2004 年9月1日起可从国家生物技术信息中心获得的程序“BLAST 2 Sequences”版本测定，该程序并入了程序BLASTN(用于核苷酸序列比较)和BLASTP(用于多肽序列比较)，该程序基于Karlin和Altschul算法(Proc.Natl.Acad.Sci.USA 90(12):5873-5877,1993)。当利用“BLAST 2 Sequences”时，对于字长(3)、开放空位罚分(11)、扩展空位罚分(1)、空位丢失(50)、期望值(10)和任何其它所需参数，包括但不限于矩阵选项，可以使用自2004年9月1日起为默认参数的参数。如果两个序列相对于彼此具有至少80％、至少85％、至少90％、至少95％、至少96％、至少97％、至少98％或至少99％序列同一性，则认为两个核苷酸或氨基酸序列具有“实质上相似的序列同一性”或“实质性序列同一性”。
如本文所用，“多肽”或“多肽链”是共价连接的氨基酸的单一、线性和连续排列。不包括以非线性方式，例如通过链间二硫键连接在一起的两条多肽链(例如，其中轻链通过二硫键与重链连接的半免疫球蛋白分子)。多肽可具有或形成一个或多个链内二硫键。关于如本文所描述的多肽，提及与SEQ ID NO指定的那些相对应的氨基酸残基包括此类残基的翻译后修饰。
如本文所用，“CD3结合蛋白”可与“CD3结合多肽”互换使用。此类分子与分化群3蛋白(CD3)(例如，人CD3)特异性结合。
“蛋白质”是包含一条或多条多肽链的大分子。蛋白质还可包含非肽组分，例如碳水化合物类。碳水化合物和其它非肽取代基可以通过其中产生蛋白质的细胞添加到蛋白质中，并且会随着细胞类型而变化。本文根据蛋白质的氨基酸框架结构来定义蛋白质；取代基例如碳水化合物类通常未指定，但仍可存在。蛋白质可以是抗体或抗体的抗原结合片段。在一些实施方案中，蛋白质还可以是scFv-Fc-scFv分子、 scFv-scFv二聚体或双链抗体。
术语“氨基端”和“羧基端”在本文中用于表示多肽中的位置。在上下文允许的情况下，这些术语关于多肽的特定序列或部分用于表示邻近或相对位置。例如，多肽内位于参考序列的羧基端的某一序列位于参考序列的羧基端附近，但不一定位于完整多肽的羧基端。
“T细胞受体”(TCR)是在T细胞表面发现的分子，与CD3一起，通常负责识别与主要组织相容性复合体(MHC)分子结合的抗原。在大多数T细胞中由二硫键连接的高度可变的α和β链的异二聚体组成。在其它T细胞中，表达由可变γ和δ链构成的替代受体。TCR的每条链都是免疫球蛋白超家族的成员，并且具有一个N端免疫球蛋白可变结构域、一个免疫球蛋白恒定结构域、一个跨膜区和C末端的一个短细胞质尾(参见Abbas和Lichtman，Cellular andMolecular Immunology(第5版),Editor:Saunders,Philadelphia,2003；Janeway等人，Immunobiology:The Immune System in Health and Disease，第4版， Current BiologyPublications，第148、149和172页，1999)。如本公开中所用的TCR可以来自各种动物物种，包括人、小鼠、大鼠或其它哺乳动物。
如本文所用，“TCR复合物”是指由CD3链与其它TCR链缔合形成的复合物。例如，TCR复合物可由CD3γ链、CD3δ链、两条CD3ε链、CD3ζ链的同型二聚体、TCRα链和TCRβ链组成。可选地，TCR 复合物可由CD3γ链、CD3δ链、两条CD3ε链、CD3ζ链的同型二聚体、TCRγ链和TCRδ链组成。
如本文所用，“TCR复合物的组分”是指TCR链(即，TCRα、TCRβ、 TCRγ或TCRδ)、CD3链(即，CD3γ、CD3δ、CD3ε或CD3ζ)或由两条或更多条TCR链或CD3链形成的复合物(例如，TCRα和TCRβ的复合物、TCRγ和TCRδ复合物、CD3ε和CD3δ的复合物、CD3γ和 CD3ε的复合物或TCRα、TCRβ、CD3γ、CD3δ和两条CD3ε链的亚 TCR复合物)。
如本文所用的“抗体依赖性细胞介导的细胞毒性”和“ADCC”是指细胞介导的过程，其中表达FcγRs的非特异性细胞毒性细胞(例如，单核细胞如天然杀伤(NK)细胞和巨噬细胞)识别靶细胞上结合的抗体 (或能够结合FcγRs的其它蛋白质)并随后导致靶细胞的裂解。原则上，具有活化FcγR的任何效应细胞均可被触发以介导ADCC。介导ADCC 的原代细胞是仅表达FcγRIII的NK细胞，而单核细胞，根据其活化、定位或分化状态，可表达FcγRI、FcγRII和FcγRIII。关于造血细胞上 FcγR表达的综述，参见例如，Ravetch等人，1991,Annu.Rev.Immunol., 9:457-92。
如本文关于多肽或蛋白质所用的术语“具有ADCC活性”意指多肽或蛋白质(例如，包含免疫球蛋白铰链区和具有CH2和CH3结构域的免疫球蛋白恒定区，例如源自IgG(例如，IgG1)的多肽或蛋白质) 能够通过结合表达Fc受体的细胞溶解性免疫效应细胞(例如，NK细胞)上的细胞溶解性Fc受体(例如，FcγRIII)介导抗体依赖性细胞介导的细胞毒性(ADCC)。
如本文所用，“补体依赖性细胞毒性”和“CDC”是指其中正常血清中的组分(“补体”)连同与靶抗原结合的抗体或其它C1q-补体结合蛋白一起表现出表达靶抗原的靶细胞裂解。补体由一类血清蛋白组成，它们协调有序地起作用以发挥其作用。
如本文所用的术语“经典补体途径”和“经典补体系统”同义并且是指用于补体活化的特定途径。经典途径需要用于引发的抗原-抗体复合物，并且涉及以有序方式活化称为C1至C9的九种主要蛋白质组分。对于活化过程中的几个步骤，产物是催化后续步骤的酶。这种级联通过相对较小的初始信号提供大量补体的扩增和活化。
如本文关于多肽或蛋白质所用的术语“具有CDC活性”意指多肽或蛋白质(例如，包含免疫球蛋白铰链区和具有CH2和CH3结构域的免疫球蛋白恒定区，例如源自IgG(例如，IgG1)的多肽或蛋白质)能够通过结合C1q补体蛋白和活化经典补体系统来介导补体依赖性细胞毒性(CDC)。
如本文所用，“重导向T细胞细胞毒性”和“RTCC”是指T细胞介导的过程，其中使用能够特异性结合细胞毒性T细胞和靶细胞两者的多特异性蛋白使细胞毒性T细胞募集至靶细胞，并且由此引发针对靶细胞的靶标-依赖性细胞毒性T细胞反应。包含如本文所公开的CD3 结合结构域和肿瘤抗原结合结构域的多肽和蛋白质能够具有RTCC。
如本文所用，术语“治疗”或“改善”是指治疗性治疗或防治性/预防性治疗。如果接受治疗的个体中的疾病的至少一种症状改善或治疗可延迟个体中的进行性疾病恶化或预防另外的相关疾病的发作，则治疗是治疗性的。
如本文所用，术语特定结合分子或化合物的“治疗有效量(或剂量)”或“有效量(或剂量)”是指足以引起所治疾病的一种或多种症状以统计上显著的方式改善或器官功能上统计学显著的改善的化合物的量。当提及单独施用的单一活性成分时，治疗有效剂量是指单独的该成分。当提及组合时，治疗有效剂量是指产生治疗效果的活性成分的组合量，无论是连续或同时施用(在同一制剂中或在单独制剂中同时施用)。
如本文所用，术语“转化”、“转染”和“转导”是指将核酸(即，核苷酸聚合物)转移到细胞中。如本文所用，术语“遗传转化”是指将 DNA(特别是重组DNA)转移和并入细胞中。转移的核酸可通过表达载体引入细胞。
如本文所用，术语“变体”是指与参考核酸或多肽不同，但保持其基本特性的核酸或多肽。通常，变体与参考核酸或多肽总体上非常相似，并且在许多区域同一。例如，变体与活性部分或全长参考核酸或多肽相比可表现出至少约70％、至少约80％、至少约90％、至少约 95％、至少约96％、至少约97％、至少约98％或在至少约99％的序列同一性。
术语“轻链可变区”(也称为“轻链可变结构域”或“VL”或VL)和“重链可变区”(也称为“重链可变结构域”或“VH”或VH)分别指来自抗体轻链和重链的可变结合区。可变结合区由离散的、定义明确的称为“互补决定区”(CDR)和“框架区”(FR)的亚区组成，通常从氨基端至羧基端按顺序包含FR1-CDR1-FR2-CDR2-FR3-CDR3-FR4。在一个实施方案中，FR经人源化。术语“CL”是指“免疫球蛋白轻链恒定区”或“轻链恒定区”，即来自抗体轻链的恒定区。术语“CH”是指“免疫球蛋白重链恒定区”或“重链恒定区”，根据抗体同种型，可进一步分为CH1、CH2 和CH3(IgA、IgD、IgG)或CH1、CH2、CH3和CH4结构域(IgE、IgM)。“Fab”(抗原结合片段)是与抗原结合的抗体部分，并且包括通过链间二硫键与轻链连接的重链可变区和CH1结构域。
本公开描述了特异性结合CD3(例如，人CD3)的结合结构域，以及包含这些结合结构域的多肽和蛋白质。在一些实施方案中，CD3 结合蛋白和多肽包含可与肿瘤抗原(例如，PSMA、CD19、CD20、 CD37、CD38、CD123、Her2、ROR1、RON、糖蛋白A33抗原(gpA33) 或CEA)结合的第二结合结构域。包含本公开的结合结构域的多肽和蛋白质还可包含免疫球蛋白恒定区、接头肽、铰链区、免疫球蛋白二聚化/异二聚化结构域、接合氨基酸、标签等。下文更详细地描述了所公开的多肽和蛋白质的这些组分。
另外，本文公开的CD3结合多肽和蛋白可以呈各种不同形式中任一种的抗体或融合蛋白的形式(例如，融合蛋白可以呈结合CD3的双特异性或多特异性分子的形式)。双特异性分子的非限制性实例包括scFv-Fc-scFv分子。一些双特异性分子通常包含与抗CD3scFv连接的抗肿瘤抗原scFv或由其组成，并且通常不包括其它序列，例如免疫球蛋白恒定区。在其它实施方案中，CD3结合蛋白为双链抗体。
根据本公开的CD3结合蛋白通常包括至少一条CD3结合多肽链，该链包含(a)如本文所阐述的CD3结合结构域。在某些变型中， CD3结合多肽还包括(b)CD3结合结构域羧基端的铰链区和(c)免疫球蛋白恒定区。在其它变型中，ROR1结合多肽还包括(d)免疫球蛋白恒定区羧基端的羧基端接头，和(e)羧基端接头羧基端的第二结合结构域。
在其它变型中，CD3结合多肽包含(b)CD3结合结构域氨基端的铰链区和(c)铰链区氨基端的免疫球蛋白亚区。在一些变型中，CD3 结合多肽包含(b)CD3结合结构域羧基端的铰链区，和(c)铰链区羧基端的免疫球蛋白亚区。
在一些实施方案中，CD3结合多肽能够同型二聚化，通常是通过二硫键键合，经由免疫球蛋白恒定区和/或铰链区(例如，经由包含IgG CH2和CH3结构域的免疫球蛋白恒定区和IgG铰链区)进行。因此，在本公开的某些实施方案中，两个同一的单链CD3结合多肽同型二聚化形成二聚体CD3结合蛋白。
在其它实施方案中，CD3结合多肽包括能够与第二条不同一的多肽链中的不同异二聚化结构域异二聚化的异二聚化结构域。在某些变型中，用于异二聚化的第二多肽链包括第二结合结构域。因此，在本公开的某些实施方案中，两条不同一的多肽链(一条包含CD3结合结构域且第二条任选包含第二结合结构域的)二聚化形成异二聚体CD3 结合蛋白。异二聚体类型的实例包括US 2013/0095097和US 2013/0129723中描述的那些。
在一些实施方案中，使CD3结合结构域、蛋白或多肽缀合至药物或毒性部分。
下文进一步描述了本公开中使用的CD3结合多肽、蛋白及其各种组分。
如上所述，本公开涉及特异性结合CD3(例如，人CD3)的结合结构域。CD3结合结构域可包含表14中所示的氨基酸序列。在一些实施方案中，CD3结合多肽或蛋白包含信号序列。本公开还涵盖包含表 14中所示的任何序列(不包括为这些序列的一部分的信号序列)或由这些序列编码的CD3结合结构域和蛋白。表15汇总了CD3结合结构域和多肽、其内部名称及其序列。在一些情况下，本公开的CD3 结合结构域含有氨基酸取代。例如，TSC370具有TSC342的氨基酸序列，根据IMGT编号系统在位置27处的甘氨酸残基经酪氨酸取代。
在某些实施方案中，本公开涉及特异性结合至人CD3并且包含免疫球蛋白轻链可变区和免疫球蛋白重链可变区的CD3结合结构域；其中所述免疫球蛋白轻链可变区包含(a)与SEQ ID NO:88中的氨基酸序列至少约93％同一、至少约95％同一、至少约97％同一、至少约 98％同一或至少约99％同一；或(b)与SEQ ID NO:89中的氨基酸序列至少约94％同一、至少约95％同一、至少约97％同一、至少约98％同一或至少约99％同一的氨基酸序列；并且其中所述免疫球蛋白重链可变区包含与SEQ ID NO:86中的氨基酸序列至少约82％同一、至少约85％同一、至少约87％同一、至少约90％同一、至少约92％同一、至少约95％同一、至少约97％同一、至少约98％同一或至少约99％同一的氨基酸序列。CD3结合结构域可包含与SEQ ID NO:83或SEQ ID NO:84中的氨基酸序列至少约87％同一、至少约90％同一、至少约92％同一、至少约95％同一、至少约97％同一、至少约98％同一或至少约99％同一的氨基酸序列。CD3结合结构域可包含SEQ ID NO:83或SEQ ID NO:84或由其组成。在一些实施方案中，CD3结合结构域包含与SEQ ID NO:4、6、8、10、12、14、16、18、20、22、 24、26、28、30、32、34、36、38、40、42、44、46、48、50、52、 54、56、58或60中的氨基酸序列至少约87％同一、至少约90％同一、至少约92％同一、至少约95％同一、至少约97％同一、至少约98％同一、至少约99％同一或100％同一的氨基酸序列。
在一些实施方案中，CD3结合结构域可包含免疫球蛋白轻链可变区，其包含与SEQID NO:94相差至少一个氨基酸取代的LCDR1氨基酸序列，与SEQ ID NO:95相差至少一个氨基酸取代的LCDR2氨基酸序列和与SEQ ID NO:96相差至少一个氨基酸取代的LCDR3氨基酸序列，和免疫球蛋白重链可变区，其包含与SEQ ID NO:91相差至少一个氨基酸取代的HCDR1氨基酸序列，与SEQ ID NO:92相差至少一个氨基酸取代的HCDR2氨基酸序列和与SEQ IDNO:93相差至少一个氨基酸取代的HCDR3氨基酸序列。在其它实施方案中，CD3 结合结构域可包含免疫球蛋白轻链可变区，其包含与SEQ ID NO:202 相差至少一个氨基酸取代的LCDR1氨基酸序列，与SEQ ID NO:203 相差至少一个氨基酸取代的LCDR2氨基酸序列和与SEQ ID NO:204 相差至少一个氨基酸取代的LCDR3氨基酸序列，和免疫球蛋白重链可变区，其包含与SEQ ID NO:199相差至少一个氨基酸取代的 HCDR1氨基酸序列，与SEQ ID NO:200相差至少一个氨基酸取代的 HCDR2氨基酸序列和与SEQ ID NO:201相差至少一个氨基酸取代的 HCDR3氨基酸序列。CD3结合结构域的CDR氨基酸序列可与所列序列相差至少一个氨基酸取代。所述至少一个氨基酸取代可为保守或非保守性氨基酸取代。在一些实施方案中，LCDR1、LCDR2、LCDR3、 HCDR1、HCDR2和/或HCDR3与以上所列CDR序列有1、2、3、4、 5、6、7、8、9或10个氨基酸不同。在某些实施方案中，与已知单克隆抗体的CDR序列比较时，本公开的CDR含有约一个或多个(例如，约2、3、4、5、6、7、8、9、10个)插入、约一个或多个(例如，，约2、3、4、5、6、7、8、9、10个)缺失、约一个或多个(例如，约约 2、3、4、5、6、7、8、9、10个)氨基酸取代(例如，保守性氨基酸取代或非保守性氨基酸取代)或上述变化的组合。
在本公开中描述氨基酸取代时，通常使用IMGT标准对免疫球蛋白分子可变区中的氨基酸残基的位置进行编号(Brochet,X,et al, Nucl.Acids Res.(2008)36,W503-508)。在一些实施方案中，CD3结合结构域的免疫球蛋白轻链可变区的位置52处的氨基酸残基为精氨酸和/或CD3结合结构域的免疫球蛋白轻链可变区的位置53处的氨基酸残基为色氨酸。CD3结合结构域的免疫球蛋白重链可变区的位置27 处的氨基酸残基可为酪氨酸。在一些实施方案中，CD3结合结构域包含以下一种或多种：(a)免疫球蛋白重链可变区的位置9处的氨基酸残基为脯氨酸；(b)免疫球蛋白重链可变区的位置53处的氨基酸残基为异亮氨酸；并且(c)免疫球蛋白轻链可变区的位置21处的氨基酸残基为甲硫氨酸。CD3结合结构域的免疫球蛋白重链可变区的位置87 处的氨基酸残基可为酪氨酸。CD3结合结构域的免疫球蛋白重链可变区的位置86处的氨基酸残基可为天冬氨酸。在一个实施方案中，CD3 结合结构域的免疫球蛋白重链可变区的位置86处的氨基酸残基为天冬氨酸并且CD3结合结构域的免疫球蛋白重链可变区的位置87处的氨基酸残基为酪氨酸。
在某些实施方案中，CD3结合结构域包含人源化免疫球蛋白VL 和/或VH区。人源化免疫球蛋白VL和VH区的技术是本领域已知的并且例如在美国专利申请公开第2006/0153837号中有讨论。在某些方面，CD3结合结构域可包含含有框架区的免疫球蛋白轻链可变区和免疫球蛋白重链可变区，并且所述免疫球蛋白轻链可变区和所述免疫球蛋白重链可变区中的至少一个可经人源化。在一个实施方案中，免疫球蛋白轻链可变区包含基于人IGKV3D-20*1种系氨基酸序列的框架区。在另一个实施方案中，免疫球蛋白重链可变区包含基于人 IGHV1-69*02种系氨基酸序列的框架区。在一些方面，免疫球蛋白重链可变区包含基于人IGHV1-2*02(H7)、IGHV1-46*02(H8)、 IGHV1-3*01(H9)或IGHV1-69*02(H10)种系氨基酸序列的框架区。免疫球蛋白轻链可变区可包含基于人IGKV3-11*01(L4)、IGKV1-33*01(L5)、IGKV1-39*01(L7)或IGKV3D-20*1(L8)种系氨基酸序列的框架区。
本公开涉及与DRA222CD3结合结构域相比具有改善的特性的 CD3结合结构域。DRA222具有包含SEQ ID NO:90的轻链可变区和包含SEQ ID NO:87的重链可变区。WO2013/158856中描述了 DRA222。在本公开中DRA222有时被称为TSC311或TSC312。Fc DRA222具有SEQ ID NO:2的氨基酸序列。本公开涵盖与包含含有 SEQ ID NO:90的轻链可变区和含有SEQ ID NO:87的重链可变区的 CD3结合结构域的热稳定性相比时具有增加至少约10％的热稳定性的CD3结合结构域(或包含所述结构域的蛋白)。与包含含有SEQ ID NO:90的轻链可变区和含有SEQ ID NO:87的重链可变区的CD3结合结构域的Tm相比时，CD3结合结构域(或包含所述结构域的蛋白)的热转变中点(Tm)可增加至少约3℃、至少约4℃、至少约5℃或至少约6℃且增加多达约20℃。CD3结合结构域(或包含所述结构域的蛋白)的热转变中点可为至少约54℃、至少约55℃、至少约56℃或至少约57℃并且高达约72℃。CD3结合结构域(或包含所述结构域的蛋白)的热稳定性或热转变中点可通过差示扫描量热法或差示扫描荧光测定法来测量。
与包含含有SEQ ID NO:90的轻链可变区和含有SEQ ID NO:87 的重链可变区的CD3结合结构域的储存稳定性相比时，如本文所公开的CD3结合结构域(或包含所述结构域的蛋白)可具有增加至少约 5％、至少约10％、至少约20％、至少约30％、至少约40％、至少约 50％、至少约60％、至少约70％、至少约80％、至少约90％和多达约 100％的储存稳定性。将CD3结合结构域(或包含所述结构域的蛋白) 储存在约25℃的PBS中后，可测量储存稳定性。在一个实施方案中， CD3结合结构域(或包含所述结构域的蛋白)在约25℃的PBS中稳定储存至少约6天、至少约10天或至少约13天且多达约90天。
在一些方面，与包含含有SEQ ID NO:90的轻链可变区和含有 SEQ ID NO:87的重链可变区的CD3结合结构域在重组表达期间产生的高分子量聚集物水平相比，如本文所公开的CD3结合结构域(或包含所述结构域的蛋白)具有降低至少约5％、至少约10％、至少约20％、至少约30％且降低多达约50％的在重组表达期间产生的高分子量聚集物水平。
本公开还涉及以约10nM或更低的EC50结合至人CD3的CD3 结合结构域。本公开的CD3结合结构域可特异性结合至人CD3和食蟹猴CD3。例如，CD3结合结构域可以约30nM或更低的EC50结合至食蟹猴CD3。结合至食蟹猴CD3允许在非人灵长类动物中测试抗 CD3治疗剂。
本公开涵盖特异性结合至人CD3并且包含免疫球蛋白轻链可变区和免疫球蛋白重链可变区的CD3结合结构域，其中所述免疫球蛋白轻链可变区包含SEQ ID NO:94的LCDR1氨基酸序列、SEQ ID NO:95的LCDR2氨基酸序列和SEQ ID NO:96的LCDR3氨基酸序列，并且其中所述免疫球蛋白重链可变区包含SEQ ID NO:91的HCDR1 氨基酸序列、SEQ ID NO:92的HCDR2氨基酸序列和SEQ ID NO:93 的HCDR3氨基酸序列，并且其中所述CD3结合结构域具有本文描述的任何一种或多种特性。例如，(i)所述CD3结合结构域(或包含所述 CD3结合结构域的蛋白质)的热转变中点为至少约54℃、至少约55℃、至少约56℃或至少约57℃并且高达约72℃；(ii)所述CD3结合结构域(或包含所述CD3结合结构域的蛋白质)在约25℃的PBS中稳定储存至少约6天、至少约10天或至少约13天并且多达约90天；(iii)所述CD3结合结构域(或包含所述CD3结合结构域的蛋白质)以约10nM 或更低的EC50结合至人CD3；及(iv)所述CD3结合结构域(或包含所述CD3结合结构域的蛋白质)以约30nM或更低的EC50结合至食蟹猴CD3。
在一些实施方案中，CD3结合多肽与T细胞上的CD3蛋白结合时不诱导或诱导来自所述T细胞的最低限度可检测细胞因子释放。在某些方面，与向患者施用抗CD3抗体OKT3时释放的细胞因子相比， CD3结合蛋白或多肽在患者中表现出减少的细胞因子释放。CD3结合多肽可诱导T细胞活化或T细胞增殖。
在某些实施方案中，CD3结合蛋白可包含结合除CD3以外的靶标的一个或多个附加结合结构域(例如，第二结合结构域)。这些其它结合结构域可包含，例如特定细胞因子或使结合结构域多肽靶向特定细胞类型、毒素、另外的细胞受体、抗体等的分子。
在某些实施方案中，本文描述的方法和组合物中使用的CD3结合多肽是包含CD3结合结构域和第二结合结构域的双特异性单链分子。在一些实施方案中，CD3和/或第二结合结构域源自抗体并且包含可变重链(VH)和可变轻链(VL)。这些结合结构域和可变链可以按照仍然保持与靶标的一些结合的任何顺序排列。例如，可变结构域可以按照诸如VH SBD-VLSBD-VH CD3-VL CD3；VL SBD-VH SBD-VH CD3-VL CD3；VH SBD-VL SBD-VL CD3-VH CD3；VLSBD-VH SBD-VL CD3-VH CD3；VH CD3-VL CD3-VH SBD-VL SBD；VL CD3-VH CD3-VL SBD-VHSBD；VH CD3-VL CD3-VL SBD-VH SBD；或VL CD3-VH CD3-VH SBD-VL SBD的顺序排列(其中SBD 指“第二结合结构域”)。在某些方面，结合至CD3的结合结构域中的成对VH区和VL区呈单链抗体(scFv)的形式。VH和VL区可按照 VH-VL或VL-VH的顺序排列。在某些实施方案中，scFv可以在 VL-VH方向上比在VH-VL方向上更有效地结合CD3，或反之亦然。 VH区可位于接头序列的N端。VL区可位于接头序列的C端。双特异性单链分子的CD3结合结构域中的结构域排列可为VH-VL，所述 CD3结合结构域位于第二结合结构域的C端。在一些情况下，双特异性分子可包含结合至第二结合结构域的scFv，其与结合至CD3的 scFv连接。这些scFv可经短肽连接。在一些实施方案中，双特异性单链分子不包含铰链区或恒定区(参见例如，US2013/0295121、US 2013/0129730、US 2011/0293619、US 7,635,472、WO 2010/037836、 WO2004/106381和WO 2011/121110；各自通过引用整体并入本文)。
在一些实施方案中，结合结构域是包含对目标靶标有特异性的 VH和VL区的单链Fv片段(scFv)。在某些实施方案中，VH和VL区是人类的或经人源化。在一些变型中，结合结构域是包含通过肽接头连接的免疫球蛋白VL和VH区的单链Fv(scFv)。使用肽接头连接VL和 VH区在本领域中是公知的，并且该特定领域中存在大量出版物。接头可包含氨基酸序列QRHNNSSLNTGTQMAGHSPNS(SEQ ID NO:148)。在一些实施方案中，肽接头是由Gly-Gly-Gly-Gly-Ser氨基酸序列((Gly4Ser)3)(SEQ ID NO：193)的三个重复序列组成的15mer。已使用其它接头，并且噬菌体展示技术以及选择性感染噬菌体技术已用于多样化和选择适当接头序列(Tang等人，J.Biol.Chem.271, 15682-15686,1996；Hennecke等人，Protein Eng.11,405-410,1998)。在某些实施方案中，VL和VH区域通过具有包含式(Gly4Ser)n(其中 n＝1-5(SEQ ID NO：194))的氨基酸序列的肽接头连接。在一些实施方案中，Gly4Ser序列可以重复6至10次。其它合适的接头可通过随机诱变优化简单接头(例如，(Gly4Ser)n(SEQ ID NO：194))来获得。在一些实施方案中，scFv的重链可变区为scFv的轻链可变区的氨基端。在其它实施方案中，scFv的轻链可变区为scFv的重链可变区的氨基端。
在一些实施方案中，CD3结合多肽按照从氨基端至羧基端的顺序 (或按照从羧基端至氨基端的顺序)包含(i)第二结合结构域，(ii)铰链区，(iii)免疫球蛋白恒定区，(iv)羧基端接头(或氨基端接头)，和(v)CD3 结合结构域。如本文在包含第一结合结构域和第二结合结构域的多肽构建体的上下文中使用的，“铰链区”或“铰链”是指第一结合结构域和Fc区之间的多肽区。“羧基端接头“或”氨基端接头“是指Fc区和第二结合结构域之间的多肽区。在一些实施方案中，羧基端接头(或氨基端接头)包含SEQ ID NO:196或由SEQ ID NO:196组成。在某些实施方案中，铰链为野生型人免疫球蛋白铰链区。在某些其它实施方案中，可以在野生型免疫球蛋白铰链区的氨基或羧基端添加一个或多个氨基酸残基作为融合蛋白构建体设计的一部分。例如，铰链氨基端的附加接点氨基酸残基可为“RT”、“RSS”、“TG”或“T”，或铰链羧基端的可为“SG”，或铰链缺失可与添加组合，例如ΔP在羧基端添加“SG”。
在某些实施方案中，铰链、羧基端接头或氨基端接头是改变的免疫球蛋白铰链，其中野生型免疫球蛋白铰链区中的一个或多个半胱氨酸残基被一个或多个其它氨基酸残基(例如，丝氨酸或丙氨酸)取代。
示例性的改变的免疫球蛋白铰链、羧基端接头和氨基端接头包括在野生型人IgG1铰链中发现的1、2或3个半胱氨酸残基被1、2或 3个不同的氨基酸残基(例如，丝氨酸或丙氨酸)取代的免疫球蛋白人 IgG1铰链区。改变的免疫球蛋白铰链可另有脯氨酸被另一氨基酸(例如，丝氨酸或丙氨酸)取代。例如，上述改变的人IgG1铰链可另有位于野生型人IgG1铰链区的三个半胱氨酸的羧基端的脯氨酸被另一氨基酸残基(例如，丝氨酸、丙氨酸)取代。在一个实施方案中，核心铰链区的脯氨酸未取代。
在某些实施方案中，铰链、羧基端接头或氨基端接头多肽包含或者是与野生型免疫球蛋白铰链区例如野生型人IgG1铰链、野生型人 IgG2铰链或野生型人IgG4铰链至少80％、至少81％、至少82％、至少83％、至少84％、至少85％、至少86％、至少87％、至少88％、至少89％、至少90％、至少91％、至少92％、至少93％、至少94％、至少95％、至少96％、至少97％、至少98％或至少99％同一的序列。
在其它实施方案中，CD3结合多肽中存在的铰链、羧基端接头或氨基端接头可以是不基于或源自免疫球蛋白铰链的铰链(即，非野生型免疫球蛋白铰链或改变的免疫球蛋白铰链)。此类铰链和羧基端接头的实例包括源自跨膜蛋白域间区域或II型C凝集素茎区的约5至约150个氨基酸的肽，例如约8至25个氨基酸的肽和约7至18个氨基酸的肽。
在某些实施方案中，域间区域或茎区铰链、羧基端接头和氨基端接头具有7至18个氨基酸并且可形成α-螺旋卷曲螺旋结构。在某些实施方案中，域间区域或茎区铰链、羧基端接头或氨基端接头含有0、 1、2、3或4个半胱氨酸。示例性域间区域或茎区铰链、羧基端接头和氨基端接头是域间区域或茎区的片段，例如来自CD69、CD72、 CD94、NKG2A和NKG2D茎区的10至150个氨基酸的片段。铰链、羧基端接头或氨基端接头也可以是包含(Gly4Ser)重复序列的柔性接头序列。在一些实施方案中，铰链是由Gly-Gly-Gly-Gly-Ser氨基酸序列((Gly4Ser)3)(SEQ ID NO:193)的三个重复序列组成的15mer。在某些实施方案中，铰链具有包含式(Gly4Ser)n的氨基酸序列，其中 n＝1-5(SEQ ID NO:194)。在一些实施方案中，Gly4Ser序列可以重复6 至10次。其它合适的铰链可通过随机诱变优化简单接头(例如，(Gly4Ser)n(SEQ ID NO:194))来获得。
在某些实施方案中，铰链、羧基端接头和氨基端接头序列具有约 5至150个氨基酸、5至10个氨基酸、10至20个氨基酸、20至30 个氨基酸、30至40个氨基酸、40至50个氨基酸、50至60个氨基酸、5至60个氨基酸、5至40个氨基酸、8至20个氨基酸或10至 15个氨基酸。铰链或接头可以主要是柔性的，但也可以提供更加刚性的特征，或者可以主要包含具有最小β-折叠结构的α-螺旋结构。铰链和接头的长度或序列可以影响与铰链直接或间接(通过另一个区域或结构域，例如异二聚化结构域)连接的结合结构域的结合亲和力以及与铰链或接头直接或间接连接的Fc区部分的一种或多种活性。
在某些实施方案中，铰链、羧基端接头和氨基端接头序列在血浆和血清中稳定并且对蛋白水解裂解有抗性。IgG1上部铰链区中的第一个赖氨酸可以突变以使蛋白水解裂解最小化，例如，赖氨酸可以被甲硫氨酸、苏氨酸、丙氨酸或甘氨酸取代，或缺失。
在本公开的一些实施方案中，CD3结合多肽能够与第二多肽链形成异二聚体并且包含铰链区，所述铰链区(a)紧靠免疫球蛋白恒定区的氨基端(例如，CH2结构域的氨基端，其中免疫球蛋白恒定区包括CH2 和CH3结构域，或CH3结构域的氨基端，其中免疫球蛋白亚区包括 CH3和CH4结构域)，(b)插入结合结构域(例如，scFv)和免疫球蛋白异二聚化结构域之间并连接二者，(c)插入免疫球蛋白异二聚化结构域和免疫球蛋白恒定区之间并连接二者(例如，其中免疫球蛋白恒定区包括CH2和CH3结构域或CH3和CH4结构域)，(d)插入免疫球蛋白恒定区和结合结构域之间并连接二者，(e)在多肽链的氨基端，或(f) 在多肽链的羧基端。如本文所述的包含铰链区的多肽链将能够与不同多肽链缔合以形成本文提供的异二聚体蛋白，并且所形成的异二聚体将含有保持其靶特异性或其特异性靶结合亲和力的结合结构域。
在某些实施方案中，与另一多肽链形成异二聚体的多肽中存在的铰链可以是免疫球蛋白铰链，例如野生型免疫球蛋白铰链区或其改变的免疫球蛋白铰链区。在某些实施方案中，异二聚体蛋白的一条多肽链的铰链与异二聚体的另一条多肽链的对应铰链同一。在某些其它实施方案中，一条链的铰链不同于另一条链的铰链(在其长度或序列上)。不同链中的不同铰链允许对与铰链连接的结合结构域的结合亲和力进行不同的操纵，使得异二聚体能够与一个结合结构域的靶标优先于另一个结合结构域的靶标结合。例如，在某些实施方案中，异二聚体蛋白在一条链中具有CD3结合结构域而在另一条链中具有第二结合结构域。所述两条链中具有两个不同的铰链可允许异二聚体首先与第二靶标结合，然后与CD3组分结合。因此，异二聚体使将CD3+T细胞募集至第二靶标表达细胞(例如，肿瘤或癌细胞)，其可转而损害或破坏第二靶标表达细胞。
下面表1和2中显示了适合根据本公开使用的一些示例性铰链、羧基端接头和氨基端接头序列。另外的示例性铰链和接头区在US 2013/0129723的SEQ ID NO:241-244、601、78、763-791、228、379-434、 618-749中列出(所述序列通过引用并入本文)。
表1.示例性铰链和接头
Figure BDA0001603367540000411
Figure BDA0001603367540000421
表2.示例性铰链和接头(源自H7铰链、II型C凝集素的茎区或 I型跨膜蛋白的域间区域)
Figure BDA0001603367540000422
Figure BDA0001603367540000431
在某些实施方案中，本公开的CD3结合多肽或蛋白可包含“免疫球蛋白二聚化结构域”或“免疫球蛋白异二聚化结构域”。
如本文所用，“免疫球蛋白二聚化结构域”或“免疫球蛋白异二聚化结构域”是指优先与另一多肽链的不同免疫球蛋白结构域相互作用或缔合的多肽链的免疫球蛋白结构域，其中不同免疫球蛋白异二聚化结构域的相互作用基本上有助于或有效促进第一和第二多肽链的异二聚化(即，两条不同多肽链之间的二聚体(也称为“异二聚体”或“异二聚体蛋白”)的形成)。如果在不存在第一多肽链的免疫球蛋白异源二聚化结构域和/或第二多肽链的免疫球蛋白异源二聚化结构域的情况下第一和第二多肽链之间的二聚化在统计学上显著减少，则免疫球蛋白异二聚化结构域之间的相互作用“基本上有助于或有效促进”第一和第二多肽链的异二聚化。在某些实施方案中，当第一和第二多肽链共表达时，至少60％、至少约60％至约70％、至少约70％至约80％、至少80％至约90％、91％、92％、93％、94％、95％、96％、97％、98％或99％的第一和第二多肽链彼此形成异二聚体。代表性免疫球蛋白异二聚化结构域包括免疫球蛋白CH1结构域、免疫球蛋白CL1结构域 (例如，Cκ或Cλ同种型)或其衍生物，包括野生型免疫球蛋白CH1 和CL结构域和例如本文提供的改变的(或突变的)免疫球蛋白CH1和 CL结构域。
希望由两条不同一的多肽链形成异二聚体，其中一条或两条多肽链包含结合结构域时，可以使用二聚化/异二聚化结构域。在某些实施方案中，本文描述的某些异二聚体的一个多肽链成员不含结合结构域。如上所述，本公开的异二聚体蛋白在每条多肽链中包含免疫球蛋白异二聚化结构域。异二聚体的多肽链中的免疫球蛋白异二聚化结构域彼此不同，因此可经差异性修饰以利于两条链异二聚化并且使任一条链的同型二聚化减到最少。本文提供的免疫球蛋白异二聚化结构域允许不同多肽之间的有效异二聚化并且利于所得异二聚体蛋白的纯化。
如本文所提供的，根据本公开用于促进两个不同单链多肽(例如，一短一长)的异二聚化的免疫球蛋白异二聚化结构域包括免疫球蛋白 CH1和CL结构域，例如人CH1和CL结构域。在某些实施方案中，免疫球蛋白异二聚化结构域为野生型CH1结构域，例如野生型IgG1、 IgG2、IgG3、IgG4、IgA1、IgA2、IgD、IgE或IgM CH1结构域。在其它实施方案中，免疫球蛋白异二聚化结构域是分别如US 2013/0129723的SEQ ID NO:114、186-192和194所示的野生型人 IgG1、IgG2、IgG3、IgG4、IgA1、IgA2、IgD、IgE或IgM CH1结构域(所述序列通过引用并入本文)。在某些实施方案中，免疫球蛋白异二聚化结构域是如US 2013/0129723的SEQID NO:114中所示的野生型人IgG1CH1结构域(所述序列通过引用并入本文)。
在其它实施方案中，免疫球蛋白异二聚化结构域是改变的免疫球蛋白CH1结构域，如改变的IgG1、IgG2、IgG3、IgG4、IgA1、IgA2、 IgD、IgE或IgM CH1结构域。在某些实施方案中，免疫球蛋白异二聚化结构域是改变的人IgG1、IgG2、IgG3、IgG4、IgA1、IgA2、IgD、 IgE或IgM CH1结构域。在其它实施方案中，涉及与野生型免疫球蛋白CL结构域(例如，人CL)形成二硫键的野生型CH1结构域(例如，人CH1)的半胱氨酸残基在改变的免疫球蛋白CH1结构域中缺失或被取代，使得在改变的CH1结构域和野生型CL结构域之间不形成二硫键。
在某些实施方案中，免疫球蛋白异二聚化结构域是野生型CL结构域，如野生型Cκ结构域或野生型Cλ结构域。在某些实施方案中，免疫球蛋白异二聚化结构域是分别如US2013/0129723的SEQ ID NO:112和113中所示的野生型人Cκ或人Cλ结构域(所述序列通过引用并入本文)。在其它实施方案中，免疫球蛋白异二聚化结构域是改变的免疫球蛋白CL结构域，例如改变的Cκ或Cλ结构域，例如改变的人Cκ或人Cλ结构域。
在某些实施方案中，涉及与野生型免疫球蛋白CH1结构域(例如，人CH1)形成二硫键的野生型CL结构域(例如，人CL)的半胱氨酸残基在改变的免疫球蛋白CL结构域中缺失或被取代。此类改变的CL 结构域在其氨基端还可包含氨基酸缺失。示例性Cκ结构域在US2013/0129723的SEQ ID NO:141中示出(所述序列通过引用并入本文)，其中野生型人Ck结构域的第一个精氨酸和最后一个半胱氨酸均缺失。在某些实施方案中，野生型人Ck结构域仅最后一个半胱氨酸在改变的Ck结构域中缺失，因为从野生型人Ck结构域缺失的第一个精氨酸可以由其羧基端具有精氨酸的接头提供并且将改变的Ck结构域的氨基端与另一个结构域(例如，免疫球蛋白亚区，如包含免疫球蛋白CH2和CH3结构域的亚区)连接。示例性Cλ结构域在US 2013/0129723的SEQIDNO:140中示出(所述序列通过引用并入本文)，其中野生型人Cλ结构域的第一个精氨酸缺失并且涉及与CH1结构域中的半胱氨酸形成二硫键的半胱氨酸被丝氨酸取代。
在其它实施方案中，免疫球蛋白异二聚化结构域是改变的Cκ结构域，其与野生型Cκ结构域相比，在可能涉及形成Cκ-Cκ界面处的链间氢键网络的位置处含有一个或多个氨基酸取代。例如，在某些实施方案中，免疫球蛋白异二聚化结构域是在位置N29、N30、Q52、V55、T56、S68或T70处有一个或多个氨基酸被不同氨基酸取代的改变的人Cκ结构域。氨基酸的编号基于其在改变的人Cκ序列中的位置，如US 2013/0129723的SEQ ID NO:141中所示(所述序列通过引用并入本文)。在某些实施方案中，免疫球蛋白异二聚化结构域是在位置N29、N30、V55或T70处有1、2、3或4个氨基酸取代的改变的人Cκ结构域。用作上述位置的取代物的氨基酸可为丙氨酸，或具有大侧链部分的氨基酸残基，例如精氨酸、色氨酸、酪氨酸、谷氨酸、谷氨酰胺或赖氨酸。可用于取代野生型人Ck序列在上述位置的氨基酸残基的其它氨基酸残基(例如，N30)包括天冬氨酸、甲硫氨酸、丝氨酸和苯丙氨酸。示例性的改变的人Cκ结构域在US 2013/0129723 的SEQ ID NO:142-178中示出(所述序列通过引用并入本文)。改变的人Cκ结构域是那些利于与CH1结构域异二聚化，但使与另一Cκ结构域的同型二聚化减到最少的结构域。代表性的改变的人Cκ结构域在US 2013/0129723的SEQ ID NO:160(N29WV55A T70A)、161 (N29Y V55A T70A)、202(T70E N29A N30A V55A)、167(N30R V55A T70A)、168(N30K V55A T70A)、170(N30E V55A T70A)、172(V55R N29A N30A)、175(N29W N30YV55A T70E)、176(N29Y N30Y V55A T70E)、177(N30E V55A T70E)、178(N30Y V55A T70E)、838(N30D V55A T70E)、839(N30M V55A T70E)、840(N30S V55A T70E)和841 (N30F V55AT70E)中示出(所述序列通过引用并入本文)。
在某些实施方案中，除本文描述的Cκ结构域中的突变外或作为其替代，多肽异二聚体的免疫球蛋白异二聚化结构域(即，免疫球蛋白CH1和CL结构域)都具有突变，使得所得免疫球蛋白异二聚化结构域在突变位点处的氨基酸残基之间形成盐桥(即，离子相互作用)。例如，多肽异二聚体的免疫球蛋白异二聚化结构域可以是与突变Ck 结构域组合的突变CH1结构域。在突变CH1结构域中，野生型人 CH1结构域的位置68处的缬氨酸(V68)被具有负电荷的氨基酸残基 (例如，天冬氨酸或谷氨酸)取代，而其中第一个精氨酸和最后一个半胱氨酸已经缺失的突变人Ck结构域的位置29处的亮氨酸(L29)被具有正电荷的氨基酸残基(例如，赖氨酸、精氨酸或组氨酸)取代。所得突变CH1结构域的具有负电荷的氨基酸残基与所得突变Ck结构域的具有正电荷的氨基酸残基之间的电荷-电荷相互作用形成盐桥，其稳定了突变CH1和Ck结构域之间的异二聚界面。可选地，野生型CH1 的V68可被具有正电荷的氨基酸残基取代，而其中第一个精氨酸和最后一个半胱氨酸已缺失的突变人Ck结构域的L29可被具有负电荷的氨基酸残基取代。其中V68被具有负电荷或正电荷的氨基酸取代的示例性突变CH1序列在US 2013/0129723的SEQ ID NO:844和845 中示出(所述序列通过引用并入本文)。其中L29被具有负电荷或正电荷的氨基酸取代的示例性突变Ck序列在US 2013/0129723的SEQ ID NO:842和843中示出(所述序列通过引用并入本文)。
除人CH1结构域的V68和人Ck结构域的L29以外的位置可以被具有相反电荷的氨基酸取代，以在CH1结构域的V68和Ck结构域的L29中的突变之外或作为其替代，在氨基酸之间产生离子相互作用。此类位置可以通过任何合适的方法鉴定，包括随机诱变，分析 CH1-Ck对的晶体结构以鉴定CH1-Ck界面处的氨基酸残基，并使用一套标准(例如，参与离子相互作用的倾向，与潜在伴侣残基的接近度等)进一步鉴定CH1-Ck界面处氨基酸残基中的合适位置。
在某些实施方案中，本公开的多肽异二聚体仅含一对免疫球蛋白异二聚化结构域。例如，多肽异二聚体的第一条链可包含作为免疫球蛋白异二聚化结构域的CH1结构域，而第二条链可包含作为免疫球蛋白异二聚化结构域的CL结构域(例如，Cκ或Cλ)。可选地，第一条链可包含作为免疫球蛋白异二聚化结构域的CL结构域(例如，Cκ或Cλ)，而第二条链可包含作为免疫球蛋白异二聚化结构域的CH1 结构域。如本文所述，第一和第二条链的免疫球蛋白异二聚化结构域能够缔合形成本公开内容的异二聚体蛋白。
在某些其它实施方案中，本公开的异二聚体蛋白可具有两对免疫球蛋白异二聚化结构域。例如，异二聚体的第一条链可包含两个CH1 结构域，而第二条链可具有两个CL结构域，其与第一条链中的两个 CH1结构域缔合。可选地，第一条链可包含两个CL结构域，而第二条链可具有两个CH1结构域，其与第一条链中的两个CL结构域缔合。在某些实施方案中，第一条多肽链包含CH1结构域和CL结构域，而第二条多肽链包含分别与第一条多肽链的CH1结构域和CL结构域缔合的CL结构域和CH1结构域。
在其中异二聚体蛋白仅包含一个异二聚化对(即，即每条链中有一个免疫球蛋白异二聚化结构域)的实施方案中，每条链的免疫球蛋白异二聚化结构域可位于该链的免疫球蛋白恒定区的氨基端。可选地，每条链中的免疫球蛋白异二聚化结构域可位于该链的免疫球蛋白恒定区的羧基端。
在其中异二聚体蛋白包含两个异二聚化对(即，每条链中有两个免疫球蛋白异二聚化结构域)的实施方案中，每条链中的两个免疫球蛋白异二聚化结构域可位于该链的免疫球蛋白恒定区的氨基端。可选地，每条链中的两个免疫球蛋白异二聚化结构域可位于该链的免疫球蛋白恒定区的羧基端。在其它实施方案中，每条链中的一个免疫球蛋白异二聚化结构域可位于该链的免疫球蛋白恒定区的氨基端，而每条链的另一个免疫球蛋白异二聚化结构域可位于该链的免疫球蛋白恒定区的羧基端。换言之，在那些实施方案中，免疫球蛋白恒定区插入每条链的两个免疫球蛋白异二聚化结构域之间。
如本文所示，在某些实施方案中，本公开的CD3结合多肽在多肽链中包含免疫球蛋白恒定区(也称为恒定区)。包含免疫球蛋白恒定区减缓了向受试者施用后由两条CD3结合多肽链形成的同型二聚体和异二聚体蛋白从循环中的清除率。通过突变或其它改变，免疫球蛋白恒定区进一步使得能够相对容易地调节二聚体多肽效应功能(例如，ADCC、ADCP、CDC、补体固定和与Fc受体的结合)，其如本领域已知并在本文中描述的那样，根据受治疾病可以增加或降低。在某些实施方案中，本公开的多肽同型二聚体和异二聚体的一条或两条多肽链的免疫球蛋白恒定区将能够介导这些效应功能中的一种或多种。在其它实施方案中，与相应的野生型免疫球蛋白恒定区相比，在本公开的多肽同型二聚体和异二聚体的一条或两条多肽链的免疫球蛋白恒定区中这些效应功能中的一种或多种降低或缺乏。例如，对于设计为例如通过包含第二结合结构域而引发RTCC的二聚体CD3结合多肽，免疫球蛋白恒定区可具有相对于相应的野生型免疫球蛋白恒定区降低的效应功能或无效应功能。
本公开的CD3结合多肽中存在的免疫球蛋白恒定区可包含或源自以下的部分或全部：CH2结构域、CH3结构域、CH4结构域或其任何组合。例如，免疫球蛋白恒定区可包含CH2结构域、CH3结构域、CH2和CH3结构域两者、CH3和CH4结构域两者、两个CH3 结构域、CH4结构域、两个CH4结构域和CH2结构域和部分CH3 结构域。
可以形成本公开的CD3结合多肽的免疫球蛋白恒定区的CH2结构域可以是来自某些免疫球蛋白类或亚类(例如，IgG1、IgG2、IgG3、 IgG4、IgA1、IgA2或IgD)和来自不同物种(包括人、小鼠、大鼠和其它哺乳动物)的野生型免疫球蛋白CH2结构域或其改变的免疫球蛋白 CH2结构域。
在某些实施方案中，CH2结构域为野生型人免疫球蛋白CH2结构域，例如分别如US2013/0129723的SEQ ID NO:115、199-201和 195-197中所示的人IgG1、IgG2、IgG3、IgG4、IgA1、IgA2或IgD 的野生型CH2结构域(所述序列通过引用并入本文)。在某些实施方案中，CH2结构域是如US 2013/0129723的SEQ ID NO:115中所示的野生型人IgG1CH2结构域(所述序列通过引用并入本文)。
在某些实施方案中，CH2结构域是在位置297的天冬酰胺处包含氨基酸取代(例如，天冬酰胺取代为丙氨酸)的改变的免疫球蛋白CH2 区(例如，改变的人IgG1CH2结构域)。此类氨基酸取代减少或消除了该位点的糖基化，并且消除了Fc与FcγR和C1q的有效结合。在US 2013/0129723的SEQ ID NO:324中示出了位置297位Asn取代为 Ala的改变的人IgG1CH2结构域的序列(所述序列通过引用并入本文)。
在某些实施方案中，CH2结构域是在位置234-238处包含至少一个取代或缺失的改变的免疫球蛋白CH2区(例如，改变的人IgG1CH2 结构域)。例如，免疫球蛋白CH2区可包含位置234、235、236、237 或238，位置234和235，位置234和236，位置234和237，位置 234和238，位置234-236，位置234、235和237，位置234、236和 238，位置234、235、237和238，位置236-238处，或位置234-238 的2、3、4或5个氨基酸的任何其它组合的取代。另外或可选地，改变的CH2区可以在位置234-238处，例如在位置236或位置237中的一处包含一个或多个(例如，2、3、4或5个)氨基酸缺失，而另一个位置被取代。上述突变降低或消除了包含改变的CH2结构域的多肽异二聚体的抗体依赖性细胞介导的细胞毒性(ADCC)活性或Fc受体结合能力。在某些实施方案中，位置234-238中的一处或多处的氨基酸残基已被一个或多个丙氨酸残基置换。在其它实施方案中，位置 234-238的仅一个氨基酸残基已缺失，而位置234-238的其余氨基酸中的一个或多个可被另一氨基酸(例如，丙氨酸或丝氨酸)取代。
在某些其它实施方案中，CH2结构域是在位置253、310、318、320、322和331处包含一个或多个氨基酸取代的改变的免疫球蛋白 CH2区(例如，改变的人IgG1CH2结构域)。例如，免疫球蛋白CH2 区可包含位置253、310、318、320、322或331，位置318和320，位置318和322，位置318、320和322，或位置253、310、318、320、 322和331处2、3、4、5或6个氨基酸的任何其它组合的取代。上述突变降低或消除了包含改变的CH2结构域的多肽异二聚体的补体依赖性细胞毒性(CDC)。
在某些其它实施方案中，除位置297处的氨基酸取代外，改变的 CH2区(例如，改变的人IgG1CH2结构域)还可在位置234-238处包含一个或多个(例如，2、3、4或5个)的附加取代。例如，免疫球蛋白CH2区可包含位置234和297，位置234、235和297，位置234、 236和297，位置234-236和297，位置234、235、237和297，位置 234、236、238和297，位置234、235、237、238和297，位置236-238 和297处，或位置234-238(除位置297以外)的2、3、4或5个氨基酸的任何组合的取代。另外或可选地，改变的CH2区可以在位置 234-238处，例如在位置236或位置237处包含一个或多个(例如，2、 3、4或5个)氨基酸缺失。所述附加突变降低或消除了包含改变的CH2 结构域的多肽异二聚体的抗体依赖性细胞介导的细胞毒性(ADCC)活性或Fc受体结合能力。在某些实施方案中，位置234-238中的一处或多处的氨基酸残基已被一个或多个丙氨酸残基置换。在其它实施方案中，位置234-238的仅一个氨基酸残基已缺失，而位置234-238的其余氨基酸中的一个或多个可被另一氨基酸(例如，丙氨酸或丝氨酸) 取代。
在某些实施方案中，除位置234-238处的一个或多个(例如，2、3、 4或5个)氨基酸取代之外，本公开融合蛋白中的突变CH2区(例如，改变的人IgG1CH2结构域)可以在涉及补体固定的一个或多个位置 (例如，在位置I253、H310、E318、K320、K322或P331)含有一个或多个(例如，2、3、4、5或6个)附加氨基酸取代(例如，经丙氨酸取代)。突变免疫球蛋白CH2区的实例包括在位置234、235、237(如果存在)、318、320和322处具有丙氨酸取代的人IgG1、IgG2、IgG4 和小鼠IgG2a CH2区。示例性突变免疫球蛋白CH2区是在L234、 L235、G237、E318、K320和K322处具有丙氨酸取代的小鼠IGHG2c CH2区。
在其它实施方案中，除了位置297的氨基酸取代和位置234-238 的附加缺失或取代之外，改变的CH2区(例如，改变的人IgG1CH2 结构域)在位置253、310、318、320、322和331处还可包含一个或多个(例如，2、3、4、5或6个)附加取代。例如，免疫球蛋白CH2 区可包含(1)位置297处的取代，(2)位置234-238处的一个或多个取代或缺失或其组合，及位置I253、H310、E318、K320、K322和P331 处的一个或多个(例如，2、3、4、5或6个)氨基酸取代，例如位置 E318、K320和K322处的1、2、3个取代。上述位置的氨基酸可以被丙氨酸或丝氨酸取代。
在某些实施方案中，免疫球蛋白CH2区多肽包含：(i)位置297 的天冬酰胺处的氨基酸取代和位置234、235、236或237处的一个氨基酸取代；(ii)位置297的天冬酰胺处的氨基酸取代和位置234-237中两处的氨基酸取代；(iii)位置297的天冬酰胺处的氨基酸取代和位置 234-237中三处的氨基酸取代；(iv)位置297的天冬酰胺处的氨基酸取代，位置234、235和237处的氨基酸取代以及位置236处的氨基酸缺失；(v)位置234-237中三处的氨基酸取代和位置318、320和322 处的氨基酸取代；或(vi)位置234-237中三处的氨基酸取代，位置236 处的氨基酸缺失和位置318、320和322处的氨基酸取代。
在位置297的天冬酰胺处具有氨基酸取代的示例性改变的免疫球蛋白CH2区包括：在L234、L235、G237和N297处具有丙氨酸取代和G236处具有缺失的人IgG1CH2区(US 2013/0129723的SEQ ID NO:325，所述序列通过引用并入本文)，在V234、G236和N297处具有丙氨酸取代的人IgG2CH2区(US 2013/0129723的SEQ ID NO:326，所述序列通过引用并入本文)，在F234、L235、G237和N297 处具有丙氨酸取代和G236缺失的人IgG4CH2区(US 2013/0129723 的SEQ ID NO:322，所述序列通过引用并入本文)，在F234和N297 处具有丙氨酸取代的人IgG4CH2区(US 2013/0129723的SEQ ID NO:343，所述序列通过引用并入本文)，在L235和N297处具有丙氨酸取代的人IgG4CH2区(US 2013/0129723的SEQ ID NO:344，所述序列通过引用并入本文)，在G236和N297处具有丙氨酸取代的人 IgG4CH2区(US 2013/0129723的SEQ ID NO:345，所述序列通过引用并入本文)和在G237和N297处具有丙氨酸取代的人IgG4 CH2区 (US 2013/0129723的SEQ ID NO:346，所述序列通过引用并入本文)。
在某些实施方案中，除上面描述的氨基酸取代之外，改变的CH2 区(例如，改变的人IgG1CH2结构域)可以在除了上述位置外的一个或多个位置处含有一个或多个附加氨基酸取代。此类氨基酸取代可以是保守或非保守性氨基酸取代。例如，在某些实施方案中，在改变的 IgG2 CH2区中P233可以变为E233(参见例如，US 2013/0129723的 SEQ ID NO:326，所述序列通过引用并入本文)。另外或可选地，在某些实施方案中，改变的CH2区可含一个或多个氨基酸插入、缺失或两者。插入、缺失或取代可以是免疫球蛋白CH2区中的任何位置，例如由CH2区与另一个区(例如，结合结构域或免疫球蛋白异二聚化结构域)经由铰链连接产生的野生型免疫球蛋白CH2区的N端或C 端。
在某些实施方案中，本公开多肽中改变的CH2区包含或是与野生型免疫球蛋白CH2区，例如野生型人IgG1、IgG2或IgG4或小鼠 IgG2a(例如，IGHG2c)的CH2区至少90％、至少91％、至少92％、至少93％、至少94％、至少95％、至少96％、至少97％、至少98％、至少99％同一的序列。
本公开的CD3结合多肽中改变的免疫球蛋白CH2区可源自不同物种(包括人、小鼠、大鼠和其它哺乳动物)的各种免疫球蛋白同种型例如IgG1、IgG2、IgG3、IgG4、IgA1、IgA2和IgD的CH2区。在某些实施方案中，本公开融合蛋白中改变的免疫球蛋白CH2区可源自人IgG1、IgG2或IgG4或小鼠IgG2a(例如，IGHG2c)的CH2区，其序列在US 2013/0129723的SEQID NO:115、199、201和320中示出(所述序列通过引用并入本文)。
在某些实施方案中，改变的CH2结构域是在位置235、318、320 和322处具有丙氨酸取代(即，具有L235A、E318A、K320A和K322A 取代的人IgG1CH2结构域)(US 2013/0129723的SEQ ID NO:595，所述序列通过引用并入本文)且任选具有N297突变(例如，突变为丙氨酸)的人IgG1CH2结构域。在某些其它实施方案中，改变的CH2结构域是在位置234、235、237、318、320和322处具有丙氨酸取代(即，具有L234A、L235A、G237A、E318A、K320A和K322A取代的人 IgG1CH2结构域)(US 2013/0129723的SEQ ID NO:596，所述序列通过引用并入本文)且任选具有N297突变(例如，突变为丙氨酸)的人 IgG1CH2结构域。
在某些实施方案中，改变的CH2结构域是改变的人IgG1 CH2 结构域，其具有本领域已知的增强免疫活性如ADCC、ADCP、CDC、补体固定、Fc受体结合或其任何组合的突变。
可以形成本公开的CD3结合多肽的免疫球蛋白恒定区的CH3结构域可以是来自某些免疫球蛋白类或亚类(例如，IgG1、IgG2、IgG3、 IgG4、IgA1、IgA2、IgD、IgE、IgM)和来自不同物种(包括人、小鼠、大鼠和其它哺乳动物)的野生型免疫球蛋白CH3结构域或其改变的免疫球蛋白CH3结构域。在某些实施方案中，CH3结构域为野生型人免疫球蛋白CH3结构域，例如分别如US 2013/0129723的SEQ ID NO:116、208-210、204-207和212中所示的人IgG1、IgG2、IgG3、 IgG4、IgA1、IgA2、IgD、IgE或IgM的野生型CH3结构域(所述序列通过引用并入本文)。在某些实施方案中，CH3结构域是如US 2013/0129723的SEQ ID NO:116中所示的野生型人IgG1 CH3结构域 (所述序列通过引用并入本文)。在某些实施方案中，CH3结构域是改变的人免疫球蛋白CH3结构域，例如基于或源自人IgG1、IgG2、IgG3、 IgG4、IgA1、IgA2、IgD、IgE或IgM抗体的野生型CH3结构域的改变的CH3结构域。例如，改变的CH3结构域可以是在位置H433和 N434处具有一个或两个突变的人IgG1CH3结构域(位置根据EU编号进行编号)。此类位置的突变可涉及补体固定。在某些其它实施方案中，改变的CH3结构域可以是人IgG1CH3结构域，但在位置F405 或Y407处具有一个或两个氨基酸取代。此类位置的氨基酸涉及与另一个CH3结构域相互作用。在某些实施方案中，改变的CH3结构域可以是改变的人IgG1CH3结构域，其最后一个赖氨酸缺失。这种改变的CH3结构域的序列在US 2013/0129723的SEQ ID NO:761中示出(所述序列通过引用并入本文)。
在某些实施方案中，形成多肽异二聚体的CD3结合多肽包含CH3 对，其包含所谓的“钮入孔(knobs-into-holes)”突变(参见，Marvin和Zhu, Acta Pharmacologica Sinica26:649-58,2005；Ridgway等人，Protein Engineering 9:617-21,1966)。更具体地说，可向每条多肽链的两个CH3 结构域中的每一个引突变入，使得CH3/CH3缔合所需的空间互补性迫使这两个CH3结构域彼此配对。例如，多肽异二聚体的一条单链多肽中的CH3结构域可含T366W突变(“钮”突变，其用较大氨基酸取代小氨基酸)，而多肽异二聚体另一条单链多肽中的CH3结构域可含 Y407A突变(“孔”突变，其用较小氨基酸取代大氨基酸)。其它示例性钮入孔突变包括(1)一个CH3结构域中的T366Y突变和另一个CH3 结构域中的Y407T，以及(2)一个CH3结构域中的T366W突变和另一个CH3结构域中的T366S、L368A和Y407V突变。
可以形成本公开CD3结合多肽的免疫球蛋白恒定区的CH4结构域可以是来自IgE或IgM分子的野生型免疫球蛋白CH4结构域或其改变的免疫球蛋白CH4结构域。在某些实施方案中，CH4结构域为野生型人免疫球蛋白CH4结构域，例如分别如US 2013/0129723的 SEQID NO:213和214所示的人IgE和IgM分子的野生型CH4结构域(所述序列通过引用并入本文)。在某些实施方案中，CH4结构域是改变的人免疫球蛋白CH4结构域，例如基于或源自人IgE或IgM分子的CH4结构域的改变的CH4结构域，其具有增加或降低已知与IgE 或IgM Fc区相关的免疫活性的突变。
在某些实施方案中，本公开的CD3结合多肽的免疫球蛋白恒定区包含CH2、CH3或CH4结构域的组合(即，多于一个选自CH2、 CH3和CH4的恒定区结构域)。例如，免疫球蛋白恒定区可包含CH2 和CH3结构域或CH3和CH4结构域。在某些其它实施方案中，免疫球蛋白恒定区可包含两个CH3结构域而不包含CH2或CH4结构域 (即，仅两个或更多个CH3)。形成免疫球蛋白恒定区的多个恒定区结构域可基于或源自相同的免疫球蛋白分子或相同类别或亚类的免疫球蛋白分子。在某些实施方案中，免疫球蛋白恒定区为IgG CH2CH3 (例如，IgG1CH2CH3、IgG2 CH2CH3和IgG4 CH2CH3)并且可为人(例如，人IgG1、IgG2和IgG4)CH2CH3。例如，在某些实施方案中，免疫球蛋白恒定区包含(1)野生型人IgG1CH2和CH3结构域，(2)具有N297A取代的人IgG1CH2(即，CH2(N297A))和野生型人IgG1 CH3，或(3)人IgG1 CH2(N297A)和最后一个赖氨酸缺失的改变的人IgG1 CH3。
可选地，多个恒定区结构域可基于或源自不同的免疫球蛋白分子，或不同类别或亚类的免疫球蛋白分子。例如，在某些实施方案中，免疫球蛋白恒定区包含人IgM CH3结构域和人IgG1CH3结构域两者。形成免疫球蛋白恒定区的多个恒定区结构域可直接连接在一起或者可经由一个或多个(例如，约2-10个)氨基酸彼此连接。
示例性免疫球蛋白恒定区在US 2013/0129723的SEQ ID NO:305-309、321、323、341、342和762中示出(所述序列通过引用并入本文)。
在某些实施方案中，多肽同型二聚体或异二聚体的CD3结合多肽的免疫球蛋白恒定区彼此同一。在某些其它实施方案中，异二聚体蛋白的一条多肽链的免疫球蛋白恒定区与异二聚体的另一条多肽链的免疫球蛋白恒定区不同。例如，异二聚体蛋白的一个免疫球蛋白恒定区可含有具有“钮”突变的CH3结构域，而异二聚体蛋白的另一个免疫球蛋白恒定区可含有具有“孔”突变的CH3结构域。
本公开涉及可包含表14所示的任何序列的CD3结合蛋白和多肽。多肽构建体的氨基酸序列可以包括或不包括信号序列。CD3结合蛋白可包含上面描述的任何CD3结合结构域。在一些方面，CD3结合蛋白包含人源化VH或VL氨基酸序列，或两者。
表12和13中提供了双特异性CD3结合多肽的实例。此类实例包括抗PSMAx抗CD3结合分子(SEQ ID NO:62、64、66和68)、抗 CD37x抗CD3结合分子(SEQ ID NO:72、74、76、78、80和82)、抗 ROR1x抗CD3结合分子(SEQ ID NO:100、104、108、112、116和 120)和抗CD123x抗CD3结合分子(SEQ ID NO:197和198)。
如各自通过引用整体并入本的US 2013/0129723和US 2013/0095097中总体上公开的，可以使用支架来制备CD3结合分子。 CD3结合蛋白可包含两条不同一的多肽链，每条多肽链均包含免疫球蛋白异二聚化结构域。界面免疫球蛋白异二聚化结构域不同。在一个实施方案中，免疫球蛋白异二聚化结构域包含CH1结构域或其衍生物。在另一个实施方案中，免疫球蛋白异二聚化结构域包含CL结构域或其衍生物。在一个实施方案中，CL结构域为Cκ或Cλ同种型或其衍生物。
本公开还包括编码本文描述的CD3结合结构域、蛋白和多肽或本文所描述的同型二聚体或异二聚体CD3结合蛋白的一条或多条多肽链的核酸(例如，DNA或RNA)。本公开的核酸包括具有与下文表 14中列出的多核苷酸基本上同一的区域的核酸。在某些实施方案中，根据本公开的核酸与表14中列出的编码多肽的多核苷酸具有至少 80％，通常至少约90％，并且更通常至少约95％或至少约98％的同一性。本公开的核酸还包括互补核酸。在一些情况下，比对时序列将完全互补(无错配)。在其它情况下，序列中可存在高达约20％的错配。在本公开的一些实施方案中，提供了编码本公开的异二聚体CD3结合蛋白的第一和第二多肽链的核酸。本文提供的核酸序列可以使用密码子优化、简并序列、沉默突变和其它DNA技术以优化在特定宿主中的表达，并且本公开涵盖此类序列修饰。
本公开涉及编码本文描述的CD3结合结构域、蛋白和多肽(或其部分)的分离的核酸分子，其中所述核酸分子包含SEQ ID NO:3、5、 7、9、11、13、15、17、19、21、23、25、27、29、31、33、35、37、 39、41、43、45、47、49、51、53、55、57或59中列出的核苷酸序列。
包含所需多核苷酸序列的多核苷酸分子通过将所述分子置于载体中来增殖。使用病毒和非病毒载体，包括质粒。质粒的选择将取决于需要增殖的细胞类型和增殖目的。某些载体可用于扩增和制备大量所需的DNA序列。其它载体适于在培养细胞中表达。还有其它载体适于在整个动物或人的细胞中转移和表达。适当载体的选择完全在本领域的技术范围内。许多此类载体可商购。通常通过将DNA连接酶附连至载体中的裂解限制酶位点，将部分或全长多核苷酸插入载体中。可选地，可以通过体内同源重组插入所需的核苷酸序列。通常这是通过将同源性区域附连至载体中所需核苷酸序列的侧翼上来实现。例如，通过连接寡核苷酸或通过使用包含同源性区域和部分所需核苷酸序列的引物的聚合酶链式反应添加同源性区域。
为了表达，可采用表达盒或系统。为了表达编码本文公开的多肽的核酸，将编码所述多肽的可操作地连接至控制表达载体中的转录表达的调控序列的核酸分子引入宿主细胞。除了转录调控序列如启动子和增强子外，表达载体还可包括翻译调控序列和适于选择携带表达载体的细胞的标记基因。由本公开的多核苷酸编码的基因产物在任何便利的表达系统中表达，包括例如细菌、酵母、昆虫、两栖动物和哺乳动物系统。在表达载体中，编码多肽的多核苷酸视情况与调控序列连接以获得所需的表达特性。这些可以包括启动子、增强子、终止子、操纵子、阻遏因子和诱导因子。启动子可以调节(例如，来自类固醇诱导型pIND载体(Invitrogen)的启动子)或为组成型(例如，来自CMV、 SV40、延伸因子或LTR序列的启动子)。使用上述用于与载体连接的技术将这些与所需核苷酸序列连接。可以使用本领域已知的任何技术。因此，表达载体通常会提供转录和翻译起始区，其可为诱导型或组成型，其中使编码区在转录起始区可操作地连接至转录和翻译终止区的转录控制下。
可将表达盒(“表达单元”)引入多种载体，例如质粒、BAC、YAC、噬菌体(例如λ、P1、M13等)、植物或动物病毒载体(例如，基于逆转录病毒的载体、腺病毒载体)等，其中所述载体通常特征在于提供选择包含表达载体的细胞的能力。载体可以提供染色体外维持，特别是作为质粒或病毒，或用于整合到宿主染色体中。在需要染色体外维持的情况下，提供用于质粒复制的起始序列，其可为低拷贝数或高拷贝数。各种各样的标记可用于选择，特别是那些防御毒素，更特别是防御抗生素的标记。所选择的特定标记是根据宿主的性质选定的，其中在一些情况下，互补作用可以与营养缺陷型宿主一起使用。DNA构建体的引入可以使用任何便利的方法，包括例如，偶联、细菌转化、钙沉淀DNA、电穿孔、融合、转染、病毒载体感染、基因枪(biolistics) 等。本公开涉及包含核酸区段的表达载体，其中所述核酸区段可包含SEQ ID NO:3、5、7、9、11、13、15、17、19、21、23、25、27、29、 31、33、35、37、39、41、43、45、47、49、51、53、55、57或59 中示出的核苷酸序列。
因此，可以根据常规技术在经基因工程改造的宿主细胞中产生用于本公开的蛋白质。合适的宿主细胞是那些可用外源DNA转化或转染并在培养物中生长的细胞类型，并且包括细菌、真菌细胞和培养的高等真核细胞(包括培养的多细胞生物细胞)，特别是培养的哺乳动物细胞。Sambrook和Russell,Molecular Cloning:A Laboratory Manual (第3版，Cold Spring Harbor Laboratory Press,Cold Spring Harbor,NY, 2001)和Ausubel等人,Short Protocols in Molecular Biology(第4版， John Wiley&Sons,1999)公开了操纵克隆DNA分子和向各种宿主细胞引入外源DNA的技术。
例如，为重组表达包含两个如本文所描述的同一CD3结合多肽的同型二聚体CD3结合蛋白，表达载体通常将包括编码CD3结合多肽，与启动子可操作地连接的核酸区段。为了重组表达包含不同的第一和第二多肽链的异二聚体CD3结合蛋白，第一和第二多肽链可由宿主细胞中的单独载体共表达，以表达整个异二聚体蛋白。可选地，为了表达异二聚体CD3结合蛋白，第一和第二多肽链由宿主细胞中同一载体中的单独表达单元共表达，以表达整个异二聚体蛋白。通过常规技术将表达载体转移至宿主细胞，然后通过常规技术培养转染细胞以产生编码的多肽以产生相应的CD3结合蛋白。
为了将重组蛋白导入宿主细胞的分泌途径，在表达载体中提供分泌信号序列(也称为前导序列)。分泌信号序列可以是天然形式的重组蛋白的分泌信号序列，或者可源自另一种分泌蛋白或从头合成。使分泌信号序列可操作地连接至编码多肽的DNA序列，即，两个序列以正确的阅读框连接并且定位以将新合成的多肽导入宿主细胞的分泌途径。分泌信号序列通常位于编码目标多肽的DNA序列的5'，尽管某些信号序列可位于目标DNA序列中的其它位置(参见例如，Welch 等人，美国专利第5,037,743号；Holland等人，美国专利第5,143,830 号)。在某些变型中，根据本公开使用的分泌信号序列具有氨基酸序列MEAPAQLLFLLLLWLPDTTG(SEQ ID NO:195)。
培养的哺乳动物细胞是用于产生用于本公开的重组蛋白的合适宿主。用于将外源DNA引入哺乳动物宿主细胞的方法包括磷酸钙介导转染(Wigler等人，Cell 14:725,1978；Corsaro和Pearson，Somatic Cell Genetics7:603,1981:Graham和Van der Eb,Virology52:456,1973)、电穿孔(Neumann等人，EMBO J.1:841-845,1982)、DEAE-葡聚糖介导转染(Ausubel等人，同上)和脂质体介导转染(Hawley-Nelson等人， Focus 15:73,1993；Ciccarone等人，Focus 15:80,1993)。例如，Levinson 等人，美国专利第4,713,339号；Hagen等人，美国专利第4,784,950 号；Palmiter等人，美国专利第4,579,821号；和Ringold，美国专利第4,656,134号公开了在培养的哺乳动物细胞中用于产生重组多肽。合适的哺乳动物宿主细胞的实例包括非洲绿猴肾细胞(Vero；ATCC CRL 1587)、人胚肾细胞(293-HEK；ATCC CRL 1573)、幼仓鼠肾细胞 (BHK-21、BHK-570；ATCC CRL 8544、ATCC CRL10314)、犬肾细胞(MDCK；ATCC CCL 34)、中国仓鼠卵巢细胞(CHO-K1；ATCC CCL61；CHODG44；CHO DXB11(Hyclone,Logan,UT)；还参见，例如Chasin等人，Som.Cell.Molec.Genet.12:555,1986))、大鼠垂体细胞(GH1；ATCC CCL82)，、HeLa S3细胞(ATCC CCL2.2)、大鼠肝癌细胞(H-4-II-E；ATCC CRL 1548)、SV40转化的猴肾细胞(COS-1；ATCC CRL 1650)和鼠胚胎细胞(NIH-3T3；ATCC CRL 1658)。其它合适的细胞系在本领域中是已知的并且可以从公共保藏机构获得，例如 American Type Culture Collection,Manassas,Virginia。可以使用强转录启动子，例如来自SV-40或巨细胞病毒的启动子。参见例如，美国专利第4,956,288号。其它合适的启动子包括来自金属硫蛋白基因的启动子(美国专利第4,579,821和4,601,978号)和腺病毒主要晚期启动子。
通常使用药物选择来选择已向其中插入外源DNA的培养的哺乳动物细胞。此类细胞通常称为“转染子”。已经在选择剂的存在下培养并且能够将目标基因传递给其后代的细胞称为“稳定转染子”。示例性选择标记包括编码抗生素新霉素抗性的基因，其允许在新霉素型药物如G-418等的存在下进行选择；黄嘌呤-鸟嘌呤磷酸核糖转移酶的gpt 基因，其容许宿主细胞在霉酚酸/黄嘌呤的存在下生长；和提供吉欧霉素(zeocin)、博莱霉素(bleomycin)、杀稻瘟菌素(blastocidin)和潮霉素(hygromycin)抗性的标记(参见例如，Gatignol等人， Mol.Gen.Genet.207:342,1987；Drocourt等人，Nucl.Acids Res.18:4009,1990)。选择系统也可用于增加目标基因的表达水平，这一过程称为“扩增”。扩增通过在低水平选择剂的存在下培养转染子，然后增加选择剂的量以选择产生高水平的引入基因产物的细胞来进行。示例性的可扩增选择标记为二氢叶酸还原酶，其赋予对甲氨蝶呤的抗性。也可以使用其它药物抗性基因(例如，潮霉素抗性、多重抗药性、嘌呤霉素乙酰转移酶)。
其它高等真核细胞也可用作宿主，包括昆虫细胞、植物细胞和禽类细胞。发根土壤杆菌(Agrobacterium rhizogenes)作为用于在植物细胞中表达基因的载体的用途已经由Sinkar等人进行了综述，J. Biosci.(Bangalore)11:47-58,1987。Guarino等人，US 5,162,222和WO 94/06463公开了昆虫细胞的转化及其中外源多肽的产生。
可用通常源自苜蓿银纹夜蛾(Autographa californica)核型多角体病毒(AcNPV)的重组杆状病毒感染昆虫细胞。参见King和Possee，T he Baculovirus ExpressionSystem:A Laboratory Guide(Chapman &Hall,London)；O’Reilly等人，BaculovirusExpression Vectors:A Laboratory Manual(Oxford University Press.,New York1994)；和 Baculovirus Expression Protocols.Methods in Molecular Biology(Richardson编辑，Humana Press,Totowa,NJ,1995)。重组杆状病毒也可以通过使用由Luckow等人描述的基于转座子的系统产生(J.Virol.67: 4566-4579,1993)。利用转移载体的这种系统，可以呈试剂盒形式商购(BAC-TO-BAC试剂盒；Life Technologies,Gaithersburg,MD)。转移载体(例如，PFASTBAC1；Life Technologies)含有Tn7转座子，以将编码目标蛋白的DNA移入保持在大肠杆菌(E.coli)中作为称为“杆粒”的大质粒的杆状病毒基因组中。参见Hill-Perkins和Possee，J.G en.Virol.71:971-976,1990；Bonning等人，J.Gen.Virol.75:1551-1556, 1994；及Chazenbalk和Rapoport，J.Biol.Chem.270:1543-1549,1995。另外，转移载体可包括与编码以上公开的多肽延伸或亲和标签的DN A的框内融合物。使用本领域已知的技术，将含有编码蛋白质的DN A序列的转移载体转化至大肠杆菌宿主细胞中，筛选细胞中含有指示重组杆状病毒的断裂lacZ基因的杆粒。使用常用技术分离含有重组杆状病毒基因组的杆粒DNA，并用于转染草地贪夜蛾(Spodoptera fr ugiperda)细胞，如Sf9细胞。随后产生表达目标蛋白质的重组病毒。通过本领域常用的方法制备重组病毒原液。
对于蛋白质生产，重组病毒用于感染宿主细胞，通常是来自秋粘虫、草地贪夜蛾(例如，Sf9或Sf21细胞)或粉纹夜蛾(Trichoplusia ni) 的细胞系(例如，HIGH FIVE细胞；Invitrogen,Carlsbad,CA)。通常参见Glick和Pasternak，Molecular Biotechnology,Principles& Applications of Recombinant DNA(ASM Press,Washington,D.C., 1994)。还参见美国专利第5,300,435号。无血清培养基用于使所述细胞生长和维持。合适的培养基制剂是本领域已知的并且可以从商业供应商处获得。细胞从大约2-5x105个细胞的接种密度生长至1-2x106个细胞的密度，此时以0.1至10，更通常接近3的感染复数(MOI)添加重组病毒原液。使用的程序通常在可用实验室手册中有描述(参见例如，King和Possee，同上；O’Reilly等人，同上；Richardson，同上)。
真菌细胞，包括酵母细胞，也可用于本公开中。这方面的酵母种类包括例如酿酒酵母(Saccharomyces cerevisiae)、巴斯德毕赤酵母 (Pichia pastoris)和甲醇毕赤酵母(Pichia methanolica)。用外源DNA转化酿酒酵母细胞并由其产生重组多肽的方法，由例如Kawasaki，美国专利第4,599,311号；Kawasaki等人，美国专利第4,931,373号； Brake，美国专利第4,870,008号；Welch等人，美国专利第5,037,743 号；和Murray等人，美国专利第4,845,075号公开。通过选择标记确定的表型来选择转化细胞，所述表型通常是抗药性或在缺乏特定营养素(例如，亮氨酸)的情况下生长的能力。用于酿酒酵母的示例性载体系统是由Kawasaki等人公开的POT1载体系统(美国专利第4,931,373 号)，其允许通过在含葡萄糖的培养基中的生长来选择转化细胞。用于酵母的合适启动子和终止子包括来自糖酵解酶基因(参见例如， Kawasaki，美国专利第4,599,311号；Kingsman等人，美国专利第 4,615,974号；和Bitter，美国专利第4,977,092号)和醇脱氢酶基因的那些。还可参见美国专利第4,990,446；5,063,154；5,139,936；和 4,661,454号。用于其它酵母，包括多形汉逊酵母(Hansenula polymorpha)、粟酒裂殖酵母(Schizosaccharomyces pombe)、乳酸克鲁维酵母(Kluyveromyces lactis)、脆壁克鲁维酵母(Kluyveromyces fragilis)、玉蜀黍黑粉菌(Ustilago maydis)、巴斯德毕赤酵母、甲醇毕赤酵母、季也蒙毕赤酵母(Pichiaguillermondii)和麦芽糖假丝酵母 (Candida maltosa)的转化系统是本领域已知的。参见例如，Gleeson等人，J.Gen.Microbiol.132:3459-3465,1986；Cregg，美国专利第 4,882,279号；和Raymond等人，Yeast 14:11-23,1998。根据McKnight 等人，美国专利第4,935,349号的方法可以利用曲霉菌(Aspergillus)细胞。Sumino等人，美国专利第5,162,228号中公开了转化产黄支顶孢 (Acremonium chrysogenum)的方法。Lambowitz，美国专利第4,486,533 号公开了用于转化脉孢菌(Neurospora)的方法。在美国专利第 5,716,808、5,736,383、5,854,039和5,888,768号中公开了甲醇毕赤酵母中重组蛋白的产生。
原核宿主细胞，包括细菌大肠杆菌(Escherichia coli)、芽孢杆菌 (Bacillus)和其它属的菌株也是本公开中有用的宿主细胞。用于转化这些宿主并表达在其中克隆的外源DNA序列的技术在本领域中是公知的(参见例如，Sambrook和Russell，同上)。在细菌如大肠杆菌中表达重组蛋白时，蛋白质可保留在细胞质中，通常作为不溶性颗粒，或者可以通过细菌分泌序列导入周质空间。在前一种情况下，裂解细胞，并且回收颗粒并使用例如异硫氰酸胍或尿素使其变性。然后可通过稀释变性剂，例如通过用尿素及还原和氧化谷胱甘肽的组合的溶液透析，然后用缓冲盐水溶液透析来使变性蛋白重新折叠并二聚化。在替代方案中，蛋白质可呈可溶性形式从细胞质中回收，并且分离无需使用变性剂。在例如磷酸盐缓冲盐水中蛋白质作为水性提取物从细胞中回收。为了捕获目标蛋白质，将提取物直接施加至色谱介质，例如固定抗体或肝素-琼脂糖凝胶柱。分泌蛋白通过下述方式呈可溶性和功能性形式从周质空间回收：破坏细胞(通过例如超声处理或渗透压休克)以释放周质空间的内容物并回收蛋白质，从而避免了变性和重新折叠的需要。根据已知方法，可在细菌宿主细胞中产生抗体，包括单链抗体。参见例如，Bird等人，Science 242:423-426,1988；Huston 等人，Proc.Natl.Acad.Sci.USA 85:5879-5883,1988；和Pantoliano等人， Biochem.30:10117-10125,1991。
经转化或转染的宿主细胞根据常规程序在含有营养素和所选宿主细胞生长所需的其它组分的培养基中培养。各种合适的培养基，包括规定的培养基和复合培养基，在本领域中是已知的，并且通常包括碳源、氮源、必需氨基酸、维生素和矿物质。根据需要，培养基还可含诸如生长因子或血清等组分。生长培养基通常通过例如药物选择或必需营养素的缺乏来选择含有外源添加的DNA的细胞，所述必需营养素通过表达载体上携带的选择标记补充或共转染至宿主细胞中。
可通过常规蛋白质纯化方法，通常通过色谱技术的组合纯化CD3 结合蛋白。通常参见Affinity Chromatography:Principles&Methods (Pharmacia LKB Biotechnology,Uppsala,Sweden,1988)； Scopes,Protein Purification:Principles and Practice(Springer-Verlag, New York 1994)。包含免疫球蛋白Fc区的蛋白质可以通过在固定蛋白A或蛋白G上进行亲和色谱法来纯化。可以使用附加纯化步骤，例如凝胶过滤来获得所需纯度水平或提供脱盐、缓冲液交换等。
本文公开的CD3结合分子可用于治疗受试者(例如人或非人灵长类动物)或生产用于治疗受试者的药剂的方法中。通常，此类方法包括向需要此类治疗的受试者施用如本文所描述的CD3结合蛋白。
本文公开的CD3结合分子可用于治疗受试者(例如人或非人灵长类动物)或生产用于治疗受试者的药剂的方法中。通常，此类方法包括向需要此类治疗的受试者施用如本文所描述的CD3结合蛋白。在一些实施方案中，CD3结合蛋白包含选自抗体依赖性细胞介导的细胞毒性(ADCC)和补体依赖性细胞毒性(CDC)的至少一种效应功能，使得 CD3结合蛋白在受试者中诱导针对CD3表达细胞的ADCC和/或 CDC。
在一些方面，本公开提供了用于治疗患有特征在于CD3过表达的病症的受试者的方法。在一种情况下，向患有自身免疫疾病(例如，类风湿性关节炎)的患者施用单特异性CD3结合多肽。在某些变型中，本文提供的CD3结合蛋白可用于调节T细胞功能和命运，从而提供 T细胞介导的疾病，包括其中T细胞是重要组成部分的自身免疫或炎性疾病的治疗性治疗。因为本公开的一些CD3结合蛋白未活化T细胞和/或未诱导细胞因子释放，所以它们比针对TCR复合物的其它分子(例如，抗CD3抗体)有优势，无副作用或副作用例如细胞因子释放综合征和急性毒性减少。在另一种情况下，向将要接受器官移植的受试者施用CD3结合多肽。
另一方面，本公开提供了用于治疗特征在于肿瘤抗原过表达的病症(例如癌症)的方法。双特异性CD3结合蛋白可识别的肿瘤抗原的实例包括PSMA、CD19、CD20、CD37、CD38、CD123、Her2、ROR1、 RON、糖蛋白A33抗原(gpA33)和CEA。通常，此类方法包括向需要此类治疗的受试者施用治疗有效量的包含如本文所描述的结合肿瘤抗原的第二结合结构域的CD3结合蛋白。在一些实施方案中，CD3 结合蛋白诱导受试者中针对肿瘤抗原表达细胞的重导向T细胞细胞毒性(RTCC)。易于根据本公开治疗的示例性癌症包括例如前列腺癌、结直肠癌、肾细胞癌、膀胱癌、唾液腺癌、胰腺癌、卵巢癌、非小细胞肺癌、黑素瘤、乳腺癌(例如三阴性乳腺癌)、肾上腺癌、套细胞淋巴瘤、急性淋巴母细胞性白血病、慢性淋巴细胞性白血病、非霍奇金氏淋巴瘤、急性髓细胞性白血病(AML)、B淋巴样白血病、母细胞性浆细胞样树突细胞肿瘤(BPDCN)和毛细胞白血病。
本公开还提供了用于治疗癌症或自身免疫病症的方法，其包括向有需要的患者施用治疗有效量的本文描述的组合物或CD3结合多肽。
在一些实施方案中，本公开提供了治疗癌症患者的方法，所述方法包括向患者施用CD3结合多肽，所述CD3结合多肽包含特异性结合至人CD3并且包含免疫球蛋白轻链可变区和免疫球蛋白重链可变区的CD3结合结构域；其中所述免疫球蛋白轻链可变区包含(a)与SEQ ID NO:88中的氨基酸序列至少约93％同一、至少约95％同一、至少约97％同一、至少约98％同一或至少约99％同一；或(b)与SEQ ID NO:89中的氨基酸序列至少约94％同一、至少约95％同一、至少约 97％同一、至少约98％同一或至少约99％同一的氨基酸序列；并且其中所述免疫球蛋白重链可变区包含与SEQ ID NO:86中的氨基酸序列至少约82％同一、至少约85％同一、至少约87％同一、至少约90％同一、至少约92％同一、至少约95％同一、至少约97％同一、至少约98％同一或至少约99％同一的氨基酸序列。
在一些实施方案中，对于本文描述的治疗方法和用途，以与寻求治疗的疾病或病症的管理相关的常规方法一致的方式递送CD3结合蛋白。根据本文的公开内容，在足以预防或治疗疾病或病症的条件下向需要此类治疗的受试者施用治疗有效量的CD3结合蛋白一段时间。
施用如本文所描述的CD3结合蛋白的受试者包括处于发展特定病症的高风险中的患者以及呈现存在此类病症的患者。通常，受试者已诊断为患有寻求治疗的病症。进一步地，可以在治疗过程中监测受试者病症的任何变化(例如，病症临床症状的增加或减少)。同样，在一些变型中，受试者未患需要涉及靶向CD3表达细胞的治疗的另一种病症。
在预防性应用中，按足以消除或降低病症风险或延迟病症发作的量向易患特定病症或以其它方式处于特定病症风险中的患者施用药物组合物或药剂。在治疗性应用中，按足以治愈或至少部分阻止病症及其并发症的症状的量向怀疑或已经患有此类病症的患者施用组合物或药剂。将足以实现这一点的量称为治疗有效剂量或量。在预防和治疗方案中，通常分几个剂量施用试剂，直至实现足够的反应。通常，监测反应并且如果所需反应开始减弱，则给予重复剂量。
为了根据本公开的方法鉴定受试患者进行治疗，可采用公认的筛选方法来确定与特定病症相关的风险因素或确定受试者中鉴定的现有病症的状态。例如，此类方法可包括确定个体是否有已经诊断为患有特定病症的亲属。筛选方法还可包括例如常规检查以确定已知有可遗传组分的特定病症的家族状况。例如，也已知各种癌症具有某些可遗传组分。癌症的可遗传组分包括例如正在转化的多个基因(例如，R as、Raf、EGFR、cMet等)中的突变，某些HLA和杀伤细胞抑制受体 (KIR)分子的存在或不存在，或癌细胞能够直接或间接调节细胞如N K细胞和T细胞的免疫抑制的机制(参见例如，Ljunggren和Malmber g,NatureRev.Immunol.7:329-339,2007；Boyton和Altmann,Clin.Exp. Immunol.149:1-8,2007)。为此，可以常规使用核苷酸探针来鉴定携带与特定目标病症相关的遗传标记的个体。另外，本领域已知各种免疫学方法可用于鉴定特定病症的标志物。例如，各种ELISA免疫测定法可用并且是本领域公知的，其采用单克隆抗体探针来检测与特定肿瘤相关的抗原。如已知的患者症状学、年龄因素、相关风险因素等所示，可以实施筛选。这些方法允许临床医生常规地选择需要本文描述的方法进行治疗的患者。根据这些方法，靶向病理性肿瘤抗原表达细胞可作为独立的治疗程序或作为其它治疗的后续、辅助或协调治疗方案来执行。
对于施用，可以将CD3结合蛋白配制成药物组合物。药物组合物可包含：(i)CD3结合多肽；和(ii)药学上可接受的载体、稀释剂或赋形剂。可以根据已知方法配制包含CD3结合蛋白的药物组合物以制备药学上有用的组合物，由此将治疗性分子与药学上可接受的载体、稀释剂或赋形剂组合成混合物。如果载体的施用能够为受体患者所耐受，则称载体为“药学上可接受的载体”。无菌磷酸盐缓冲盐水是药学上可接受的载体的一个实例。其它合适的载体、稀释剂或赋形剂是本领域技术人员公知的。(参见例如，Gennaro(编辑),Remington's Pharmaceutical Sciences(Mack Publishing Company，1995年第19版)。)制剂还可包括一种或多种赋形剂、防腐剂、增溶剂、缓冲剂、防止小瓶表面上的蛋白质损失的白蛋白等。
药物组合物可配制成选自以下的剂型：口服单位剂型、静脉内单位剂型、鼻内单位剂型、栓剂单位剂型、皮内单位剂型、肌肉内单位剂型、腹膜内单位剂型、皮下单位剂型、硬膜外单位剂型、舌下单位剂型和脑内单位剂型。口服单位剂型可选自：片剂、丸剂、小丸、胶囊、粉剂、锭剂、粒剂、溶液、混悬剂、乳剂、糖浆、酏剂、缓释制剂、气溶胶和喷雾剂。
包含CD3结合蛋白治疗剂的药物组合物可按治疗有效量向受试者施用。根据本公开的方法，CD3结合蛋白可通过多种施用模式向受试者施用，包括例如肌肉内、皮下、静脉内、心房内、关节内、肠胃外、鼻内、肺内、透皮、胸膜内、鞘内和口服施用途径。为了预防和治疗目的，可以单次推注递送，通过长期持续递送(例如，持续透皮递送)或按重复施用方案(例如，每小时、每天、每周或每月)向受试者施用拮抗剂。
在这种情况下有效剂量的确定通常基于动物模型研究和随后的人类临床试验，并且通过确定显著降低模型受试者中受试者病症的发生或严重性的有效剂量和施用方案来指导。本公开组合物的有效剂量根据许多不同因素变化，包括施用方式，目标部位，患者的生理状态，患者是人还是动物、施用的其它药剂，治疗是预防性的还是治疗性的，以及组合物本身的比活性及其在个体中引起所需反应的能力。通常，患者为人，但在某些疾病中，患者可为非人哺乳类动物。通常，调整剂量方案以提供最佳治疗反应，即优化安全性和功效。因此，治疗有效量也是其中施用如本文所描述的CD3结合蛋白的有益作用超过任何不良间接作用的量。对于CD3结合蛋白的施用，剂量范围可为约 0.1μg至100mg/kg或1μg/kg至约50mg/kg，并且更通常为10μg至 5mg/kg受试者体重。在更具体的实施方案中，所述试剂的有效量为约1μg/kg至约20mg/kg，约10μg/kg至约10mg/kg或约0.1mg/kg至约5mg/kg。在这个范围内的剂量可通过单次或多次施用来实现，包括例如，每天多次施用或每天、每周、每两周或每月施用一次。例如，在某些变型中，方案由初次施用和接着以每周或每两周的间隔进行的多次后续施用组成。另一种方案由初次施用和接着以每月或每两月的间隔进行的多次后续施用组成。可选地，如通过监测病症的临床症状所指示的，施用可以是不定期的。
主治临床医生可以改变药物组合物的剂量，以维持目标部位的所需浓度。例如，如果选择静脉内递送模式，则根据受试者的状态和预计测量反应，靶组织血流中试剂的局部浓度可为每升约0.01-50纳摩尔组合物，有时为每升约1.0纳摩尔至每升10、15或25纳摩尔。可以基于递送模式，例如经表皮递送与至粘膜表面的递送来选择更高或更低的浓度。还应基于所施用的制剂，例如鼻喷雾剂与粉剂、缓释口服或注射颗粒、透皮制剂等的释放速率，调整剂量。为了达到相同的血清浓度水平，例如，(在标准条件下)释放速率为5纳摩尔的缓释颗粒将以释放速率为10纳摩尔的颗粒约两倍的剂量施用。
抗CD3治疗剂(例如，CD3结合蛋白)也可按约0.001至约10毫克(mg)/千克(mpk)体重的日剂量施用，优选作为单一日剂量给予或以分剂量每天分约2-6次给予。对于向成人患者的施用，治疗有效量可以按每剂0.2mg至800mg范围的剂量施用，包括但不限于每剂0.2mg、每剂0.5mg、每剂1mg、每剂5mg、每剂10mg、每剂25mg、每剂100mg、每剂200mg和每剂400mg，并且可以在治疗过程中施用多个、通常连续的日剂量。抗CD3治疗剂可在一天的不同时间施用。在一个实施方案中，最佳治疗剂量可在晚间施用。在一个实施方案中，最佳治疗剂量可在晨间施用。因此抗CD3治疗剂的总日剂量在一个实施方案中范围可为约1mg至约2g，并且经常范围为约100mg至约1.5g，并且最经常范围为约200mg至约1200mg。在典型的70kg成人的情况下，抗CD3治疗剂的总日剂量范围可为约2mg至约1200mg，并且如上所述经常范围将为约0.2mg至约800mg。
特别是关于实体瘤的治疗，用于评估终点和抗肿瘤活性的方案是本领域公知的。虽然每个方案可以不同地定义肿瘤反应评估，但是 RECIST标准(实体瘤治疗疗效评价标准)目前被认为是国家癌症研究所推荐用于评估肿瘤反应的指南(参见Therasse等人，J.Natl.Cancer Inst.92:205-216,2000)。根据RECIST标准，肿瘤反应意指所有可测病变或转移的减少或消除。如果疾病包括在至少一个维度上可用常规技术准确测量为≥20mm或用螺旋CT扫描以清晰边缘，通过医学摄影或 X-射线、计算机化轴向断层摄影术(CT)、磁共振成象(MRI)或临床检查准确测量为≥10mm的病变(如果病变是表面的)，则通常将疾病视为可测量。不可测量的疾病意指该疾病包含用常规技术测量<20mm或用螺旋CT扫描测量<10mm的病变，及真正不可测量的病变(太小而不能准确测量)。不可测量的疾病包括胸腔积液、腹水和间接证据证明的疾病。
评估实体瘤反应的方案需要客观状态标准。代表性标准包括以下内容：(1)完全反应(CR)，定义为所有可测量疾病完全消失；无新病变；无疾病相关症状；无不可测量的疾病的证据；(2)局部反应(PR)，定义为目标病变最长直径总和减小30％；(3)进行性疾病(PD)，定义为目标病变最长直径总和增加20％或任何新病变的出现；(4)稳定或无反应，定义为不符合CR、PR或进行性疾病。(参见Therasse等人，同上。)
在肿瘤学领域公认的其它终点包括总生存期(OS)、无病生存期 (DFS)、客观反应率(ORR)、进展时间(TTP)和无进展生存期(PFS)(参见Guidance for Industry:ClinicalTrial Endpoints for the Approval of Cancer Drugs and Biologics，2005年4月，Center for Drug Evaluation and Research,FDA,Rockville,MD.)。
药物组合物可作为包含容器的试剂盒供应，所述容器包含如本文所描述的药物组合物。药物组合物可以例如呈用于单剂量或多剂量的可注射溶液的形式提供，或作为将在注射前复水的无菌粉末提供。可选地，此类试剂盒可包括用于施用药物组合物的干粉分散器、液体气溶胶发生器或喷雾器。此类试剂盒还可包含关于药物组合物的适应症和用法的书面信息。
将通过以下实施例进一步阐明本公开，以下实施例旨在为本公开的单纯性示例而绝非限制。
实施例
实施例1.稳定化CD3结合分子的产生
为了提高CD3结合分子DRA222(人源化Cris7抗体的工程化变体)的热稳定性，使用替代人种系框架序列将Cris7可变结构域重新人源化。DRA222可变重链结构域为SEQ IDNO:87，并且DRA222可变轻链结构域为SEQ ID NO:90。Fc DRA222有时称为TSC311或TSC312(氨基酸序列为SEQ ID NO:2；核酸序列为SEQ ID NO:1)。对亲本Cris7抗体的描述，参见Reinherz,E.L.等人(编辑)，Leukocyte typing II.,Springer Verlag,New York,(1986)。还进行了其它改变以提高亲和力和热稳定性。
方法
使用以下方法获得该实施例中显示的结果：
差示扫描量热法(DSC)。在配备有自动取样器的GE VP-毛细管 DSC仪器上获得通过标准纯化技术纯化的重组蛋白的热谱图。将大约550μL于PBS中的每种样品(通常为0.5mg/mL)注入样品毛细管中，在第二毛细管中使用PBS作为对照。在25℃至130℃的温度下进行分析，加热速率为每分钟1℃。反馈设置为低，并且使用8ms的取样时间。使用Origin进行数据分析。通过减去使用制剂媒介物的先前的缓冲液/缓冲液扫描校正样品热谱图的缓冲液的热容量，并基于样品浓度和校正的基线进行归一化。
差示扫描量荧光测定法(DSF)。在高通量形式下，通过在实时PCR 仪(Bio-RadiCycler iQ5)上运行的DSF测定也获得了通过标准纯化技术纯化的重组蛋白的热谱图。将大约40μL于PBS中浓度为0.8 mg/mL的每种样品与5μL预先稀释的SYPRO橙色染料(目录号S-6650，Life Technologies)混合。熔融曲线方案设定为温度从25℃斜升至90℃，每步0.2℃。通过TexasRed荧光染料滤光片组(TexasRed Fluorescent Dye filter set)，即575/30X激发滤光片和620/30M发射滤光片收集荧光信号。将收集的荧光强度数据输出到数据分析软件 Prism 6(GraphPad Software,Inc.)。计算蛋白质热Tm值作为荧光强度对温度的二阶导数-d(RUF)/dT2＝0时的温度。
人Jurkat T细胞的流式细胞术。使用CD3+Jurkat T细胞系通过基于标准流式细胞术的染色程序进行结合研究。所有的标记和洗涤在 U形底96孔板中含有3％BSA和2mM EDTA的盐水缓冲液中进行。按每孔200,000个细胞接种Jurkat细胞并且将其与0.1nM至200nM 浓度范围内的测试分子以50μL体积/孔在冰上孵育30分钟。洗涤细胞三次，然后再在冰上用荧光标记的最小交叉反应性二级多克隆抗体、F(ab’)2山羊抗人IgG(JacksonImmunoResearch Laboratories)和活力染料7-AAD孵育30分钟。然后将细胞洗涤两次，并在BD LSRII 流式细胞仪中获取样品。使用FlowJo软件分析样品文件；对活细胞门控(正向对比侧向散射，然后是7-AAD-细胞)后，计算每个孔中 Jurkat活细胞群体的平均荧光强度(MFI)。
同源建模、空间聚集倾向分析。使用注释抗体序列 (AnnotateAntibodySequence)、识别框架模板(Identify Framework Templates)、模型抗体框架(ModelAntibody Framework)和模型抗体环方案(Model Antibody loops protocols)，在Accelrys Discovery Studio 4.0 中为可变结构域构建同源性模型。使用计算聚集评分方案(Calculate Aggregation Scores protocol)在Accelrys Discovery Studio 4.0中进行空间聚集倾向分析(Spatial Aggregation Propensity analysis)。
用人T细胞进行铬释放测定。根据所提供的方案培养所有靶标阳性肿瘤细胞系(MDA-MB-231、Kasumi-2、C4-2B和Ramos细胞系)。使用标准聚蔗糖(ficoll)梯度从人血液中分离外周血单核细胞 (PBMC)。将分离的细胞在盐水缓冲液中洗涤。使用制造商的方案，使用Pan T细胞分离试剂盒(Pan T-cell Isolation Kit)(目录号 130-096-535,MiltenyiBiotec,Bergisch Gladbach,Germany)另外分离T 细胞。将分离的T细胞等分并长期储存在液氮中。将预先制备的T 细胞在测定前一天解冻到含有10％人血清的温热RPMI培养基中。在测定过程中，将最终浓度范围为200pM至0.01pM的双特异性分子浓缩物添加到预先制备的T细胞中(每孔大约100,000个)。通过包括 0.04％NP-40作为处理剂产生总体裂解对照。
用0.125mCi的51Cr处理大约2.5×106个靶细胞，并在37℃、5％ CO2加湿孵育箱中孵育90分钟。孵育后，用稀释的测定培养基(含有 1％人血清的RPMI)洗涤细胞4次，并重新悬浮于12.5mL完全测定培养基(含有10％人血清的RPMI)中。从该悬浮液中，向U形底96 孔板每孔分配50μL(每孔大约10,000个细胞)，使总体积达到每孔 200mL，并且使T细胞与靶细胞比率达到10:1。仅靶细胞产生零裂解对照，省略了T细胞。
将板在37℃、5％CO2下在加湿孵育箱中孵育4小时(并且有时也孵育24小时)，之后将它们以1000rpm离心3分钟，并且从每孔将 25μL上清液转移到96孔Luma样品板的相应孔中。使样品板在化学安全罩中风干18小时，然后使用标准方案在TopCount微孔板闪烁计数器(PerkinElmer)上读取放射性。
使用下式计算特异性裂解百分比：((药物处理样品中的信号-来自仅具有靶细胞的样品的本底信号)/(总裂解孔中的信号-来自仅具有靶细胞的样品的本底信号))×100。
食蟹猴T细胞的流式细胞术。在肝素管中收集的食蟹猕猴外周血连夜从供应商(Charles River laboratories)处运输。接收时，使用密度分离管(CPT管，BecktonDickinson)分离外周血细胞(PBMC)。在转移到CPT管中之前，将血液在盐水缓冲液中稀释1至1.5。将CPT管离心并收集分离的PBMC群体并用含有0.2％BSA和5nM EDTA的盐水缓冲液洗涤。使用铵-氯化物-钾红色血液裂解缓冲液裂解制剂中剩余的红细胞。再次洗涤细胞以去除剩余的血小板。
PBMC标记和洗涤步骤在U形底96孔板中含有0.2％BSA和 2mM EDTA的盐水缓冲液中进行。按每孔200,000个细胞涂铺PBMC 并且在测试分子0.1nM至300nM浓度范围内以50μL体积/孔在冰上孵育30分钟。洗涤细胞三次，然后在冰上用非人灵长类动物CD2 和CD16的荧光标记的抗体(Biolegend)、抗PSMA或抗CD37结合结构域的抗独特型抗体和存活力染料7-AAD再孵育30分钟。洗涤样品两次，在冰上用1％甲醛溶液在盐水中固定20分钟，再次洗涤，并在 BD LSRII流式细胞仪中获得。使用FlowJo软件分析样品文件；对活 T细胞门控(正向对比侧向散射，7-AAD-，CD2+CD16-细胞)后，计算每个孔中T细胞上测试分子结合的平均荧光强度(MFI)。
用食蟹猴PBMC进行铬释放测定。C4-2B和Ramos细胞系均根据所提供的方案培养。使用具有肝素钠的BD
Figure BDA0001603367540000751
CPTTM细胞制备管(目录号362753)从食蟹猕猴外周血分离外周血单核细胞 (PBMC)。将分离的细胞在盐水缓冲液中洗涤。将最终浓度范围为10000pM至0.0128pM的双特异性分子浓缩物添加到分离的PBMC 中(大约100,000个)。通过包括0.04％NP-40作为处理剂产生总体裂解对照。
用0.25mCi的51Cr处理大约5x106个靶C4-2B或Ramos细胞并将其在37℃下孵育75分钟。孵育后，用细胞培养基(含10％FBS、 1％NEAA、1％丙酮酸钠、谷氨酰胺钠和20mM HEPES的RPMI)洗涤细胞4次，并将其重新悬浮于25mL培养基中。从该悬浮液中，向 U形底96孔板每孔分配50μL(大约10,000个细胞/孔)以使T细胞与靶细胞比率达到10:1。
将板在37℃、5％CO2下在加湿孵育箱中孵育4小时，之后将它们以225x G离心3分钟，并且从每孔将25μL上清液转移到96孔 Luma样品板的相应孔中。使样品板在化学安全罩中风干18小时，然后使用标准方案在Topcount闪烁计数器上读取放射性。
结果
步骤1：初始人源化CD3结合构建体的产生
使用4条人可变重链种系序列(IGHV1-2*02(H7)、IGHV1-46*02 (H8)、IGHV1-3*01(H9)和IGHV1-69*02(H10))和2条人可变轻链种系序列(IGKV3-11*01(L4)和IGKV1-33*01(L5))基于序列同源性重新人源化Cris7可变结构域。使用H75接头(QRHNNSSLNTGTQMAGHSPNS；SEQ ID NO:148)(表3)产生呈Fc抗CD3scFv形式的总共 12个单链可变片段(scFv)构建体。表14中提供了12个构建体和对照分子Fc DRA222(TSC311或TSC312)的序列。
表3.初始构建体的可变结构域组成
Figure BDA0001603367540000761
12个构建体全部在HEK293细胞中瞬时表达，纯化并测试其与 Jurkat T细胞的结合并评价其热稳定性。含L4轻链或H9重链的构建体具有较低水平的蛋白质表达(见表4中的最终产量栏)和/或较高水平的高分子量聚集物(参见表4中的分析SEC栏)并且在后续优化步骤中消除。虽然如使用差示扫描量热法(DSC)(表5)通过热变性中点(Tm) 测量，大多数其它构建体相对于原始人源化结构域(TSC312)在scFv 的热稳定性上有一些提高，但在Jurkat T细胞上观察到的结合饱和度水平降低不同水平(图1)。与原始人源化构建体(TSC312，也称为 DRA222)相比时，最稳定的构建体TSC324在饱和时观察到的中值荧光强度降低近50％，并且结合的EC50增加两倍(3.6nM)。
表4.瞬时表达材料的表达和纯度
Figure BDA0001603367540000771
表5.如通过差示扫描量热法测量的热稳定性
Figure BDA0001603367540000772
Figure BDA0001603367540000781
步骤2：初始优化以恢复与CD3的结合
下一步的目标是提高与CD3的结合，同时保持比DRA222更高的热稳定性。在这个步骤中引入了三条附加轻链序列。第一条轻链基于L5序列，该序列在位置52和53处含有两个恢复为亲本鼠类残基的氨基酸(LL恢复为RW)，并且该轻链被命名为L6。还使用了两条附加种系轻链(IGKV1-39*01(L7)和IGKV3D-20*1(L8)，其含有两个相同的在位置52和53处恢复的氨基酸。将3条新的轻链(L6、L7和L8) 与3条重链(H7、H8和H10)(呈Fc抗CD3scFv形式)组合以产生以下 scFv组合(表6)：
表6.第二轮构建体的可变结构域组成
Figure BDA0001603367540000782
使这9个构建体在HEK293细胞中瞬时表达并检测蛋白质质量、表达、结合和热稳定性。这9个构建体的序列见表14。H10系列分子(TSC340、TSC341、TSC342)具有所有新构建体的最佳结合(图2)，并且在Jurkat T细胞上达到与TSC312相当的结合饱和度水平。然而，测得的结合EC50仍比原始分子TSC312高两倍。如使用差示扫描量热法(DSF)(图3)，通过相对于TSC312的Tm增加测量，H10系列分子在热稳定性上也具有显著提高。在这三种分子中，由于其热稳定性提高，挑选TSC342作为前导分子以进一步优化。
然后检查亲本鼠类序列的突变的潜在热点以改善结合。选择三个残基进行恢复并进行独立的回复突变：G27Y(TSC370)、M53I(TSC371) 和I21M(TSC372)。这三个构建体在Jurkat T细胞上的结合研究揭示，重链上的G27Y突变使得与CD3的结合恢复到与原始构建体TSC312 相当的水平(图4)。还通过DSC评价这三个构建体的稳定性。虽然 G27Y突变未提高Tm，但令人惊讶的是，剩余两个突变，即重链上的M53I和轻链上的I21M独立地使Tm提高3-4℃(表7)。
表7.经设计以改善结合的突变体的热稳定性
Figure BDA0001603367540000791
步骤3：提高热稳定性的最终优化步骤
使用空间聚集倾向(Spatial Aggregation Propensity)来检查TSC370 同源性模型以鉴定潜在聚集热点。鉴定重链上的一个突变A9P，以减少同源性模型中的潜在聚集热点。将该突变引入到TSC370主链中以产生TSC390。单独的这种突变对提高Tm有轻度影响(0.25℃)。将 A9P突变与上面描述的M53I和I21M突变组合以产生以下Fc抗CD3 构建体(表8)：
表8.第四轮构建体突变组背后的基本原理
Figure BDA0001603367540000792
Figure BDA0001603367540000801
表9.通过DSC评估的第四轮构建体的热稳定性
Figure BDA0001603367540000802
正如从DSC分析看Tm大幅增长所示，组合这些突变中的两个或多个似乎对热稳定性具有有益影响(表9)。令人惊讶的是，A9P突变也与其它突变协同作用，与不以A9P突变为特征的匹配构建体相比，稳定性增加1至2.6C不等。更重要的是，稳定化突变不影响与 CD3的结合(图5)。
还使用这些新的抗CD3scFv分子构建了靶向PSMA和CD3的双特异性分子以研究抗CD3scFv的变化对重导向T细胞细胞毒性 (RTCC)活性的影响(如果有的话)。原始人源化构建体(DRA222)在重导向T细胞细胞毒性方面是高效的(参见例如，US 2014/0161800)。测试新构建体显示相似活性的能力。使用TSC391、TSC392、TSC393和 TSC394制备四个不同的抗PSMA x抗CD3构建体，并将这些分别命名为TSC408、TSC409、TSC410和TSC411。所有四个构建体与用亲本DRA222scFv(TSC249)(图6)构建的分子具有相似的RTCC活性，证实细胞毒性活性以及结合与人T细胞相当。
步骤4：恢复食蟹猴交叉反应性和活性的优化步骤
先前证实原始人源化构建体(DRA222)也结合食蟹猴T细胞，并且当以双特异性形式使用时将其细胞毒活性重导向至靶细胞。用食蟹猴T细胞评价所有的TSC408、TSC409、TSC410和TSC411的结合和细胞毒活性。出乎意料的是，与含DRA222的抗PSMA x抗CD3 双特异性分子相比时，TSC408、TSC409、TSC410和TSC411与食蟹猴T细胞的结合全部减少(图7A和7B)并且RTCC活性显著降低(使用食蟹猴T细胞作为效应细胞)(图8A和8B)。这是没有预料到的，因为与人T细胞的结合和活性可与含DRA222的构建体直接相当。
使用两种方法尝试恢复与食蟹猴CD3的结合。一种方法是将来自TSC394的轻链与来自DRA222的重链组合或者将来自TSC394的重链与来自DRA222的轻链组合，以发现对一个框架具有特异性的框架残基是否有助于结合。第二种方法是使TSC394轻链上位置86和 87处的残基回复突变。使这两个位置处的残基与可影响与食蟹猴CD3 结合的轻链CDR相互作用。将这些变体掺入到抗CD37x抗CD3双特异性分子中(表10)。正如在饱和浓度下的较高结合水平所示(图9)，一些变体，特别是TSC455、TSC456和TSC452与抗CD37x TSC394(TSC445)相比显示出与食蟹猴T细胞的结合改善。还进行食蟹猴RTCC测定，其显示TSC456和TSC452具有与CAS105相当的活性(图10)。另外，正如通过DSC分析时更高的Tm1所示，这些分子与CAS105相比具有优良的热稳定性(表11)。图13显示了DRA222 scFv、TSC455scFv和TSC456scFv的比对。
表10.第五轮优化构建体
Figure BDA0001603367540000811
Figure BDA0001603367540000821
表11.双特异性构建体的稳定性
Figure BDA0001603367540000822
实施例2.热稳定性提高对储存稳定性的影响
原则上，热力学稳定性提高的蛋白质在储存时也应该更耐聚集，并且与不太稳定的蛋白质相比应该具有更强的储存稳定性。为了确定在Tm上看到的增加是否与储存稳定性提高相关，评价表10所列蛋白质在两周内在25℃的PBS中的储存稳定性。
使用制备尺寸排阻色谱法将每种蛋白质缓冲液交换到PBS中，并将蛋白质浓度调整至1mg/mL。对于每种待评估的蛋白质，准备四个各装有大约120μL的小瓶。在每个稳定时间点使用一个小瓶。通过在PBS中平衡的分析尺寸排阻HPLC柱上分析25μL(或25μg)并测量280nm下的吸光度来测定纯度。在每个时间点对每个构建体进行一式三份注射。SEC方法完成后，使用Agilent ChemStation软件整合色谱。通过完整分子的峰面积除以总峰面积，然后乘以100来计算每种蛋白质的纯度百分比。
(完整分子的峰面积)/(总峰面积)x 100＝纯度％
报告的纯度是从同一小瓶三次注射得到的平均值。通常在T＝0、 3、7和14天时测定纯度。将纯度值作为时间的函数绘制在图上，并进行线性回归分析。回归线的斜率表示对于每种蛋白质而言纯度降低的速率。纯度下降速率用于估计会导致纯度降低2％的储存天数。通过按估计会导致下降2％的最高至最低天数进行排序，比较不同变种的稳定性。为了减少测定间可变性，在不同实验中不比较储存稳定性值，仅对相同实验组内的构建体相互排序。
与CAS105相比，所有新分子在25℃的PBS中表现出优良的溶液稳定性(图11)。还计算了每种构建体形成聚集物的时间(表12)。
表12.25℃下的相对储存稳定性
Figure BDA0001603367540000831
该数据显示，与含原始抗CD3scFv(DRA222)的构建体相比，几乎所有构建体在25℃时的储存稳定性增加两倍或更多。
实施例3.热稳定性提高对血清稳定性的影响
与储存稳定性类似，具有较高热力学稳定性的分子也常常更耐蛋白质水解，这可以提高在人血清中的稳定性。这可以转而改善治疗剂的总体血清药代动力学和总体暴露。
为了测试热力学稳定性的提高是否影响总体血清稳定性，在抗 ROR1x抗CD3双特异性分子(ROR193)的情况下评价稳定化的抗CD3 scFv分子之一(TSC394F463Y)的血清稳定性。同时还评价了类似双特异性分子，其含有原始抗CD3scFv，DRA222(ROR133)。例如，在美国专利申请公开第2013/0251642号和Yang等人，PLoS ONE 6(6): e21018(2011)中描述了用于产生ROR1结合结构域的亲本兔抗ROR1 抗体R11。
将随机健康供体捐献的人血清收集在Red/Grey Vacutanor(BD# 367988)中，并根据供应商建议的方案制备。在无菌PCR管中将供试品以1μM的浓度加标至50μL血清中，并在37℃加湿组织培养孵育箱中孵育长达21天。具体时间点为21、14、7、3和0天。以“测定第21天”开始按相反时间顺序孵育样品，并且按照以上实施例1中所列的方案，在“实验第0天”孵育结束时使用铬释放RTCC测定同时评估所有样品。由每个时间点用样品进行的滴定曲线拟合EC50值，并将EC50值针对第0天测量的每个构建体的EC50值归一化。
绘制随时间推移的EC50值显示观察到的ROR133相对于 ROR193的血清稳定性的显著差异(图12)，其中对于ROR133而言在 21天内观察到的EC50损失2.5倍，但对于ROR193而言EC50仅有最小变化。这证明热力学稳定性的适度变化可对血清稳定性具有明显影响。
实施例4.热力学稳定性提高对蛋白质表达和质量的影响
先前，还已证实正如通过蛋白质产生期间高分子量聚集物的产量所测量的，热力学稳定性的提高可引起蛋白质表达和总体蛋白质质量的提高。
为了测试新的抗CD3scFv区的热力学稳定性提高是否转化为蛋白质表达或蛋白质质量提高，在五对不同的抗ROR1x抗CD3双特异性分子的情况下，将抗CD3结构域之一(TSC394DY)与DRA222进行比较，每对双特异性分子以相同的抗ROR1scFv为特征(表13)。
表13.相对表达和蛋白质质量
Figure BDA0001603367540000851
对于每个分子对而言，看到总体蛋白质表达的较高滴度-高31％至93％-其中构建体以稳定化的抗CD3scFv(TSC394DY)为特征。同样，在每个分子对中，在蛋白A纯化后，以稳定化的抗CD3scFv为特征的构建体具有较低水平的高分子量聚集物(聚集物水平降低20％至50％不等)。这证实与原始抗CD3scFv相比时，包含稳定化的抗 CD3scFv可引起蛋白质表达提高和蛋白质质量提高。
实施例5.稳定化的抗CD3结合结构域对抗PSMA X抗CD3结合分子的稳定性和药代动力学的影响
为了测试稳定化的抗CD3scFv对双特异性结合分子的稳定性和药代动力学的影响，利用TSC456抗CD3scFv将TSC266(包含 DRA222CD3结合结构域的抗PSMA X抗CD3双特异性分子)的 PSMA结合结构域转移至双特异性分子中。这种新的双特异性分子称为TSC471。BALB/c小鼠以TSC266和TSC471按大约10mg/kg静脉内给药。将TSC266稀释到PBS中，同时将TSC471稀释到用于所有稀释液的制剂缓冲液(5mM琥珀酸盐、6.5％蔗糖、0.02％吐温 80(Tween80)，pH 4.8)中。在10个时间点从3只动物收集血清(总计 n＝30)。时间点是施用双特异性分子后15分钟和2、6、24、48、72、 96、168、336和504小时。使用末端出血收集更大的体积。使用捕获抗PSMA结合结构域和检测抗CD3结合结构域的ELISA方法来测定血清浓度。使用随时间推移的血清浓度通过非房室分析(NCA)和房室分析来测定药代动力学(PK)参数估计值。还使用标准桥式ELISA，用各双特异性分子+/-生物素测试来自晚期时间点的血清样品的抗药抗体。
更具体地，使用以下ELISA方法。使用涂有小鼠单克隆抗体(mAb 1H5)的96孔板以捕获每种构建体的抗PSMA部分来测定抗PSMA X 抗CD3双特异性物的浓度。使用靶向抗CD3结合结构域的生物素缀合的小鼠单克隆抗体(mAb 5H5)检测构建体的另一末端，所以用这种 ELISA方法将仅测量完整蛋白。为了量化来自血清样品和测定对照的结合免疫复合物，使用聚合的辣根过氧化物酶(聚HRP)和荧光过氧化物酶底物，在荧光读板仪上测量结果。用于计算血清浓度的标准曲线由加标至ELISA稀释剂中的各种已知浓度的适当PSMA双特异性构建体组成。
Figure BDA0001603367540000861
Pro软件用于使用4参数逻辑方程计算血清浓度，以及标准品和测试样品的精确度和准确度。
图14和15中显示了这些研究的结果。通过使用Phoenix-64 WinNonLin软件的非房室分析(NCA)，与TSC266相比，TSC471的半衰期提高约2倍，清除率参数减小3-4倍。TSC471的Fc维持TSC266 的功能特征(无ADCC或CDC活性，同等的FcRn结合)，且稳定性提高。TSC471的Fc包含稳定性提高形式的CH2结构域。在分子的‘234-236’区域中突变与TSC266Fc中相同，但是TSC471Fc在CDC 区中的突变数量减少，仅保持K322A突变，而不是在无效Fc CH2 中发现的全部三个。TSC471的抗CD3scFv保持对人和食蟹猴T细胞的结合和活性。TSC471中使用的接头对CHO蛋白酶和其它PTM 的抗性增强，并且不含N连接的糖基化位点。
实施例6.稳定化的抗CD3结合结构域对抗ROR1X抗CD3结合分子药代动力学的影响
比较含不太稳定的DRA222CD3结合结构域或更稳定的TSC456 CD3结合结构域的抗-ROR1x抗CD3双特异性分子的药代动力学。评价以下构建体。表14中提供了构建体的序列。
Figure BDA0001603367540000871
向NSG小鼠以抗ROR1X抗CD3双特异性物按大约10mg/kg 静脉内给药。将所有双特异性物稀释到PBS中。在施用后的10个时间点(对于每种构建体而言n＝30)以及在给药前的一个时间点从3只动物收集血清。时间点是施用双特异性分子后15分钟和2、6、24、48、 72、96、168、336和504小时。使用末端出血收集更大的体积。使用ELISA方法测定血清浓度以检测完整分子。使用随时间推移的血清浓度通过非房室分析(NCA)和房室分析来测定PK参数估计值。
更具体地，使用以下ELISA方法。使用涂有ROR1 ECD-AFH (ROR177)的96孔板以捕获每种构建体的抗ROR1部分来测定抗 ROR1X抗CD3双特异性物的浓度。使用靶向抗CD3结合结构域的生物素缀合的小鼠单克隆抗体(mAb 5H5)检测ROR构建体的另一末端，所以用这种ELISA方法将仅测量完整蛋白。为了量化来自血清样品和测定对照的结合免疫复合物，使用聚合的辣根过氧化物酶(聚 HRP)和荧光过氧化物酶底物，在荧光读板仪上测量结果。用于计算血清浓度的标准曲线由加标至ELISA稀释剂中各种已知浓度的适当 ROR构建体组成。
Figure BDA0001603367540000872
Pro软件用于使用4参数逻辑方程计算血清浓度，以及标准品和试验样品的精确度和准确度。
图16、17A和17B中显示了这些研究的结果。通过NCA和房室分析，ROR209a具有最长的半衰期。通过两种分析方法，ROR207a 具有最低的清除率和体积估计值。具有DRA222CD3结合结构域的两种抗ROR1双特异性物具有较短的半衰期和较快的清除率参数。值得注意的是，具有改进的抗CD3结合结构域(TSC456)的构建体比具有不太稳定的抗CD3结合结构域(DRA222)的构建体具有更佳的药代动力学。
实施例7.稳定化的抗CD3结合结构域对抗ROR1X抗CD3结合分子体内功效的影响
在研究的第0天将MDA-MB-231细胞与供体T细胞和基质胶 (matrigel)共同混合并植入NOD/SCID小鼠的胁腹。每个组含N＝5只动物，T细胞来自一个供体。图18显示了示例图，其显示了T细胞对供体T细胞肿瘤生长的最小影响。用PBS或30μg或3μg的 ROR208(DRA222抗CD3结合结构域)或ROR209(TSC456抗CD3结合结构域)处理动物。剂量在第0、4和8天施用。随研究时间推移用卡尺测量肿瘤生长。
用两种ROR双特异性物处理后看到肿瘤生长的显著抑制。与仅有肿瘤相比，来自供体的T细胞没有看到肿瘤生长的显著差异(图18)。在任何剂量水平下，与ROR209相比，用ROR208处理的动物无显著差异，表明稳定性改善的抗CD3结合结构域具有与非稳定性抗CD3结合结构域相同的效力。
实施例8.稳定化的抗CD3结合结构域对抗ROR1X抗CD3结合分子体内功效的影响
在研究的第0天将Kasumi-2细胞与供体T细胞和基质胶共同混合并植入NOD/SCID小鼠的胁腹。每组含N＝10只动物，T细胞来自一个供体。如图19所示，用PBS或30μg、3μg或0.3μg的 ROR243(TSC456抗CD3结合结构域)处理动物。剂量在第0、4和8 天施用。施用途径为静脉内(IV)，一组除外，其中剂量经皮下(SC)施用。图19显示了测定的结果。随研究时间推移用卡尺测量肿瘤生长。
在T细胞的存在下在ROR243不存在的情况下或在T细胞不存在的情况下用ROR243处理，没有看到对肿瘤生长的抑制。在每剂 0.3μg时看到对肿瘤生长的显著抑制，具有剂量依赖性滴定。没有看到施用途径上的差异。
表14.结合结构域及多肽序列和组分
Fc DRA222(TSC311或TSC312)的DNA序列：
Figure BDA0001603367540000891
信号序列为残基1至60。Fc区为残基61–753。接头为754至816。抗CD3scFv为817至1560。
Fc DRA222(TSC311或TSC312)的成熟蛋白序列
Figure BDA0001603367540000892
Figure BDA0001603367540000901
Fc H7L1(TSC313)的DNA序列：
Figure BDA0001603367540000902
信号序列为残基1至60。Fc区为残基61–753。接头为754至816。抗CD3scFv为817至1569。
Fc H7L1(TSC313)的成熟蛋白序列：
Figure BDA0001603367540000903
Fc H7L4(TSC314)的DNA序列：
Figure BDA0001603367540000911
信号序列为残基1至60
Fc H7L4(TSC314)的成熟蛋白序列：
Figure BDA0001603367540000912
Fc H7L5(TSC315)的DNA序列：
Figure BDA0001603367540000921
信号序列为残基1至60
Fc H7L5(TSC315)的成熟蛋白序列：
Figure BDA0001603367540000922
Fc H8L1(TSC316)的DNA序列：
Figure BDA0001603367540000931
信号序列为残基1至60
Fc H8L1(TSC316)的成熟蛋白序列：
Figure BDA0001603367540000932
Fc H8L4(TSC317)的DNA序列：
Figure BDA0001603367540000941
信号序列为残基1至60
Fc H8L4(TSC317)的成熟蛋白序列：
Figure BDA0001603367540000942
Fc H8L5(TSC318)的DNA序列：
Figure BDA0001603367540000943
Figure BDA0001603367540000951
信号序列为残基1至60
Fc H8L5(TSC318)的成熟蛋白序列：
Figure BDA0001603367540000952
Fc H9L1(TSC319)的DNA序列：
Figure BDA0001603367540000953
信号序列为残基1至60
Fc H9L1(TSC319)的成熟蛋白序列：
Figure BDA0001603367540000961
Fc H9L4(TSC320)的DNA序列：
Figure BDA0001603367540000962
信号序列为残基1至60
Fc H9L4(TSC320)的成熟蛋白序列：
Figure BDA0001603367540000963
Fc H9L5(TSC321)的DNA序列：
Figure BDA0001603367540000971
信号序列为残基1至60
Fc H9L5(TSC321)的成熟蛋白序列：
Figure BDA0001603367540000972
Fc H10L1(TSC322)的DNA序列：
Figure BDA0001603367540000981
信号序列为残基1至60
FC H10L1(TSC322)的成熟蛋白序列：
Figure BDA0001603367540000982
Fc H10L4(TSC323)的DNA序列：
Figure BDA0001603367540000991
信号序列为残基1至60
Fc H10L4(TSC323)的成熟蛋白序列：
Figure BDA0001603367540000992
Fc H10L5(TSC324)的DNA序列：
Figure BDA0001603367540001001
信号序列为残基1至60
Fc H10L5(TSC324)的成熟蛋白序列：
Figure BDA0001603367540001002
Fc H7L6(TSC334)的DNA序列：
Figure BDA0001603367540001003
Figure BDA0001603367540001011
信号序列为残基1至60
Fc H7L6(TSC334)的成熟蛋白序列：
Figure BDA0001603367540001012
Fc H7L7(TSC335)的DNA序列：
Figure BDA0001603367540001021
信号序列为残基1至60
Fc H7L7(TSC335)的成熟蛋白序列：
Figure BDA0001603367540001022
Fc H7L8(TSC336)的DNA序列：
Figure BDA0001603367540001031
信号序列为残基1至60
Fc H7L8(TSC336)的成熟蛋白序列：
Figure BDA0001603367540001032
Fc H8L6(TSC337)的DNA序列：
Figure BDA0001603367540001041
信号序列为残基1至60
Fc H8L6(TSC337)的成熟蛋白序列：
Figure BDA0001603367540001042
Fc H8L7(TSC338)的DNA序列：
Figure BDA0001603367540001043
Figure BDA0001603367540001051
信号序列为残基1至60
Fc H8L7(TSC338)的成熟蛋白序列：
Figure BDA0001603367540001052
Fc H8L8(TSC339)的DNA序列：
Figure BDA0001603367540001053
Figure BDA0001603367540001061
信号序列为残基1至60
Fc H8L8(TSC339)的成熟蛋白序列：
Figure BDA0001603367540001062
Fc H10L6(TSC340)的DNA序列：
Figure BDA0001603367540001063
信号序列为残基1至60
Fc H10L6(TSC340)的成熟蛋白序列：
Figure BDA0001603367540001071
Fc H10L7(TSC341)的DNA序列：
Figure BDA0001603367540001072
信号序列为残基1至60
Fc H10L7(TSC341)的成熟蛋白序列：
Figure BDA0001603367540001073
Fc H10L8(TSC342)的DNA序列：
Figure BDA0001603367540001081
信号序列为残基1至60
Fc H10L8(TSC342)的成熟蛋白序列：
Figure BDA0001603367540001082
TSC370的DNA序列：
Figure BDA0001603367540001091
信号序列为残基1至60
TSC370的成熟蛋白序列：
Figure BDA0001603367540001092
TSC371的DNA序列：
Figure BDA0001603367540001101
信号序列为残基1至60
TSC371的成熟蛋白序列：
Figure BDA0001603367540001102
TSC372的DNA序列：
Figure BDA0001603367540001111
信号序列为残基1至60
TSC372的成熟蛋白序列：
Figure BDA0001603367540001112
TSC390的DNA序列：
Figure BDA0001603367540001113
Figure BDA0001603367540001121
信号序列为残基1至60
TSC390的成熟蛋白序列：
Figure BDA0001603367540001122
TSC391的DNA序列：
Figure BDA0001603367540001123
信号序列为残基1至60
TSC391的成熟蛋白序列：
Figure BDA0001603367540001131
TSC392的DNA序列：
Figure BDA0001603367540001132
信号序列为残基1至60
TSC392的成熟蛋白序列：
Figure BDA0001603367540001141
TSC393的DNA序列：
Figure BDA0001603367540001142
信号序列为残基1至60
TSC393的成熟蛋白序列：
Figure BDA0001603367540001143
TSC394的DNA序列：
Figure BDA0001603367540001151
信号序列为残基1至60
TSC394的成熟蛋白序列：
Figure BDA0001603367540001152
TSC408的DNA序列：
Figure BDA0001603367540001161
信号序列为残基1至60
TSC408的成熟蛋白序列：
Figure BDA0001603367540001162
TSC409的DNA序列：
Figure BDA0001603367540001171
信号序列为残基1至60
TSC409的成熟蛋白序列：
Figure BDA0001603367540001181
TSC410的DNA序列：
Figure BDA0001603367540001182
信号序列为残基1至60
TSC410的成熟蛋白序列：
Figure BDA0001603367540001191
TSC411的DNA序列：
Figure BDA0001603367540001192
信号序列为残基1至60
TSC411的成熟蛋白序列：
Figure BDA0001603367540001201
CAS105的DNA序列：
Figure BDA0001603367540001202
Figure BDA0001603367540001211
信号序列为残基1至60
CAS105的成熟蛋白序列：
Figure BDA0001603367540001212
抗CD37X TSC445的DNA序列：
Figure BDA0001603367540001213
Figure BDA0001603367540001221
信号序列为残基1至60
抗CD37X TSC445的成熟蛋白序列：
Figure BDA0001603367540001222
抗CD37X TSC452的DNA序列：
Figure BDA0001603367540001223
Figure BDA0001603367540001231
信号序列为残基1至60
抗CD37X TSC452的成熟蛋白序列：
Figure BDA0001603367540001232
抗CD37X TSC453的DNA序列：
Figure BDA0001603367540001233
Figure BDA0001603367540001241
信号序列为残基1至60
抗CD37X TSC453的成熟蛋白序列：
Figure BDA0001603367540001242
抗CD37X TSC454的DNA序列：
Figure BDA0001603367540001243
Figure BDA0001603367540001251
信号序列为残基1至60
抗CD37X TSC454的成熟蛋白序列：
Figure BDA0001603367540001252
抗CD37X TSC455的DNA序列：
Figure BDA0001603367540001253
Figure BDA0001603367540001261
信号序列为残基1至60
抗CD37X TSC455的成熟蛋白序列：
Figure BDA0001603367540001262
抗CD37X TSC456的DNA序列：
Figure BDA0001603367540001263
信号序列为残基1至60
抗CD37X TSC456的成熟蛋白序列：
Figure BDA0001603367540001271
(SEQ ID NO：82)
TSC455抗CD3scFv的蛋白质序列
QVQLVQSGPEVKKPGSSVKVSCKASGYTFSRSTMHWVRQAPGQGLEWIGYINPSSAYTNYNQKFKDRVTITADK STSTAYMELSSLRSEDTAVYYCARPQVHYDYNGFPYWGQGTLVTVSSGGGGSGGGGSGGGGSGGGGSDIQMTQS PSTLSASVGDRVTMTCSASSSVSYMNWYQQKPGKAPKRWIYDSSKLASGVPSRFSGSGSGTEYTLTISSLQPDD FATYYCQQWSRNPPTFGGGTKVEIKRSSS
(SEQ ID NO：83)
TSC456抗CD3scFv的蛋白质序列
QVQLVQSGPEVKKPGSSVKVSCKASGYTFSRSTMHWVRQAPGQGLEWIGYINPSSAYTNYNQKFKDRVTITADK STSTAYMELSSLRSEDTAVYYCARPQVHYDYNGFPYWGQGTLVIVSSGGGGSGGGGSGGGGSGGGGSDIQMTQS PSTLSASVGDRVTMTCSASSSVSYMNWYQQKPGKAPKRWIYDSSKLASGVPSRFSGSGSGTDYTLTISSLQPDD FATYYCQQWSRNPPTFGGGTKVEIKRSSS
(SEQ ID NO:84)
DRA222抗CD3scFv的蛋白质序列
QVQLVESGGGVVQPGRSLRLSCKASGYTFTRSTMHWVRQAPGQGLEWIGYINPSSAYTNYNQKFKDRFTISADK SKSTAFLQMDSLRPEDTGVYFCARPQVHYDYNGFPYWGQGTPVTVSSGGGGSGGGGSGGGGSAQDIQMTQSPSS LSASVGDRVTMTCSASSSVSYMNWYQQKPGKAPKRWIYDSSKLASGVPARFSGSGSGTDYTLTISSLQPEDFAT YYCQQWSRNPPTFGGGTKLQITSSS
(SEQ ID NO:85)
TSC455和TSC456可变重链结构域的蛋白质序列
QVQLVQSGPEVKKPGSSVKVSCKASGYTFSRSTMHWVRQAPGQGLEWIGYINPSSAYTNYNQKFKDRVTITADK STSTAYMELSSLRSEDTAVYYCARPQVHYDYNGFPYWGQGTLVTVSS
(SEQ ID NO：86)
DRA222可变重链结构域的蛋白质序列
QVQLVESGGGVVQPGRSLRLSCKASASGYTFTRSTMHWVRQAPGQGLEWIGYINPSSAYTNYNQKFKDRFTISADK SKSTAFLQMDSLRPEDTGVYFCARPQVHYDYNGFPYWGQGTPVTVSS
(SEQ ID NO:87)
TSC455可变轻链结构域的蛋白质序列
DIQMTQSPSTLSASVGDRVTMTCSASSSVSYMNWYQQKPGKAPKRWIYDSSKLASGVPSRFSGSGSGTEYTLTI SSLQPDDFATYYCQQWSRNPPTFGGGTKVEIKRS
(SEQ ID NO:88)
TSC456可变轻链结构域的蛋白质序列
DIQMTQSPSTLSASVGDRVTMTCSASSSVSYMNWYQQKPGKAPKRWIYDSSKLASGVPSRFSGSGSGTDYTLTI SSLQPDDFATYYCQQWSRNPPTFGGGTKVEIKRS
(SEQ ID NO:89)
DRA222可变轻链结构域的蛋白质序列
DIQMTQSPSSLSASVGDRVTMTCSASSSVSYMNWYQQKPGKAPKRWIYDSSKLASGVPARFSGSGSGTDYTLTI SSLQPEDFATYYCQQWSRNPPTFGGGTKLQITS
(SEQ ID NO：90)
Cris7和DRA222VHCDR1(Kabat)RSTMH(SEQ IDNO：91)
Cris7和DRA222VHCDR2(Kabat)YINPSSAYTNYNQKFK(SEQ ID NO：92)
Cris7和DRA222VHCDR3(Kabat)QVHYDYNGFPY(SEQ ID NO：93)
Cris7和DRA222VLCDR1(Kabat)SASSSVSYMN(SEQ ID NO：94)
Cris7和DRA222VL CDR2(Kabat)DSSKLAS(SEQ ID NO：95)
Cris7和DRA222VL CD R3(Kabat)QQWSRNPPT(SEQ ID NO：96)
Cris7和DRA222 VH CDR1(IMGT)GYTFTRST(SEQ ID NO：199)
Cris7和DRA222 VH CDR2 (IMGT)INPSSAYT(SEQ ID NO：200)
Cris7和DRA222 VH CDR3 (IMGT) QQWSRNPPT (SEQ ID NO:201)
Cris7和DRA222 VL CDR1(IMGT)ASSSVSY(SEQ ID NO：202)
Cris7和DRA222 VL CDR2(IMGT)DSS(SEQ ID NO：203)
Cris7和DRA222 VL CDR3(IMGT)QQWSRNPPT(SEQ ID NO：204)
ROR133的DNA序列：
atggaagcaccagcgcagcttctcttcctcctgctactctggctcccagataccaccggtgacatccagatgacccagtccccctcctccctg tccgcctccgtgggcgaccgggtgaccatcaactgccaggcctcccagtccatcgactccaacctggcctggttccagcagaagcccggc aagccccccaagctgctgatctaccgggcctccaacctggcctccggcgtgccctcccggttctccggctccggctccggcaccgacttca ccctgaccatctcctccctgcagcccgaggacgtggccacctactactgcctgggcggcgtgggcgccgtgtcctaccggacctccttcg gcggcggcaccaaggtggagatcaagggtggaggcggttcaggcggaggtggatccggcggtggcggctccggtggcggcggatct gaggtgcagctggtggagtccggcggcggcctggtgcagcccggccggtccctgcggctgtcctgcaccgcctccggctccgacatca acgactaccccatctcctgggtgcggcaggcccccggcaagggcctggagtggatcggcttcatcaactccggcggctccacctggtac gcctcctgggtgaagggccggttcaccatctcccgggacgactccaagtccatcgcctacctgcagatgaactccctgaagaccgaggac accgccgtgtactattgcgcccggggctactccacctactacggcgacttcaacatctggggccagggcaccctggtgaccgtgtcctcga gtgagcccaaatcttctgacaaaactcacacatgcccaccgtgcccagcacctgaagccgcgggtgcaccgtcagtcttcctcttcccccca aaacccaaggacaccctcatgatctcccggacccctgaggtcacatgcgtggtggtggacgtgagccacgaagaccctgaggtcaagttc aactggtacgtggacggcgtggaggtgcataatgccaagacaaagccgcgggaggagcagtacaacagcacgtaccgtgtggtcagcg tcctcaccgtcctgcaccaggactggctgaatggcaaggaatacaagtgcgcggtctccaacaaagccctcccagcccccatcgagaaaa ccatctccaaagccaaagggcagccccgagaaccacaggtgtacaccctgcccccatcccgggatgagctgaccaagaaccaggtcag
cctgacctgcctggtcaaaggcttctatccaagcgacatcgccgtggagtgggagagcaatgggcagccggagaacaactacaagacca cgcctcccgtgctggactccgacggctccttcttcctctacagcaagctcaccgtggacaagagcaggtggcagcaggggaacgtcttctc atgctccgtgatgcatgaggctctgcacaaccactacacgcagaagagcctctccctgtctccgggttctggtggaggcggttcaggcgga ggtggctccggcggtggcggatcgccgggctctcaggtccagctggtggagtctgggggcggagtggtgcagcctgggcggtcactga ggctgtcctgcaaggcttctggctacacctttactagatctacgatgcactgggtaaggcaggcccctggacaaggtctggaatggattgga tacattaatcctagcagtgcttatactaattacaatcagaaattcaaggacaggttcacaatcagcgcagacaaatccaagagcacagccttc ctgcagatggacagcctgaggcccgaggacaccggcgtctatttctgtgcacggccccaagtccactatgattacaacgggtttccttactg gggccaagggactcccgtcactgtctctagcggtggcggagggtctgggggtggcggatccggaggtggtggctctgcacaagacatcc agatgacccagtctccaagcagcctgtctgcaagcgtgggggacagggtcaccatgacctgcagtgccagctcaagtgtaagttacatga actggtaccagcagaagccgggcaaggcccccaaaagatggatttatgactcatccaaactggcttctggagtccctgctcgcttcagtgg cagtgggtctgggaccgactataccctcacaatcagcagcctgcagcccgaagatttcgccacttattactgccagcagtggagtcgtaacc cacccacgttcggaggggggaccaagctacaaattacatcctccagctaa
(SEQ ID NO:97)
ROR133的成熟蛋白序列：
diqmtqspsslsasvgdrvtincqasqsidsnlawfqqkpgkppklliyrasnlasgvpsrfsgsgsgtdftltisslqpedvatyyclggv gavsyrtsfgggtkveikggggsggggsggggsggggsevqlvesggglvqpgrslrlsctasgsdindypiswvrqapgkglewigf insggstwyaswvkgrftisrddsksiaylqmnslktedtavyycargystyygdfniwgqgtlvtvsssepkssdkthtcppcpapea agapsvflfppkpkdtlmisrtpevtcvvvdvshedpevkfnwyvdgvevhnaktkpreeqynstyrvvsvltvlhqdwlngkeyk cavsnkalpapiektiskakgqprepqvytlppsrdeltknqvsltclvkgfypsdiavewesngqpennykttppvldsdgsfflyskltvdksrwqqgnvfscsvmhealhnhytqkslslspgsggggsggggsggggspgsqvqlvesgggvvqpgrslrlsckasgytftrst mhwvrqapgqglewigyinpssaytnynqkfkdrftisadkskstaflqmdslrpedtgvyfcarpqvhydyngfpywgqgtpvtv ssggggsggggsggggsaqdiqmtqspsslsasvgdrvtmtcsasssvsymnwyqqkpgkapkrwiydssklasgvparfsgsgs gtdytltisslqpedfatyycqqwsrnpptfgggtklqitsss
(SEQ ID NO:98)
ROR193的DNA序列：
atggaagcaccagcgcagcttctcttcctcctgctactctggctcccagataccaccggtgacatccagatgacccagtccccctcctccctg tccgcctccgtgggcgaccgggtgaccatcaactgccaggcctcccagtccatcgactccaacctggcctggttccagcagaagcccggc aagccccccaagctgctgatctaccgggcctccaacctggcctccggcgtgccctcccggttctccggctccggctccggcaccgacttca ccctgaccatctcctccctgcagcccgaggacgtggccacctactactgcctgggcggcgtgggcgccgtgtcctaccggacctccttcg gcggcggcaccaaggtggagatcaagggtggaggcggttcaggcggaggtggatccggcggtggcggctccggtggcggcggatct gaggtgcagctggtggagtccggcggcggcctggtgcagcccggccggtccctgcggctgtcctgcaccgcctccggctccgacatca acgactaccccatctcctgggtgcggcaggcccccggcaagggcctggagtggatcggcttcatcaactccggcggctccacctggtac gcctcctgggtgaagggccggttcaccatctcccgggacgactccaagtccatcgcctacctgcagatgaactccctgaagaccgaggac accgccgtgtactattgcgcccggggctactccacctactacggcgacttcaacatctggggccagggcaccctggtgaccgtgtcctcga gtgagcccaaatcttctgacaaaactcacacatgcccaccgtgcccagcacctgaagccgcgggtgcaccgtcagtcttcctcttcccccca aaacccaaggacaccctcatgatctcccggacccctgaggtcacatgcgtggtggtggacgtgagccacgaagaccctgaggtcaagtc aactggtacgtggacggcgtggaggtgcataatgccaagacaaagccgcgggaggagcagtacaacagcacgtaccgtgtggtcagcg tcctcaccgtcctgcaccaggactggctgaatggcaaggaatacaagtgcgcggtctccaacaaagccctcccagcccccatcgagaaaa ccatctccaaagccaaagggcagccccgagaaccacaggtgtacaccctgcccccatcccgggatgagctgaccaagaaccaggtcag cctgacctgcctggtcaaaggcttctatccaagcgacatcgccgtggagtgggagagcaatgggcagccggagaacaactacaagacca cgcctcccgtgctggactccgacggctccttcttcctctacagcaagctcaccgtggacaagagcaggtggcagcaggggaacgtcttctc
atgctccgtgatgcatgaggctctgcacaaccactacacgcagaagagcctctccctgtctccgggttctggtggaggcggttcaggcgga ggtggctccggcggtggcggatcgccgggctctcaggtccagctggtgcaatctgggcctgaggtgaagaagcctgggtcctcggtgaa ggtctcctgcaaggcttctggatataccttcagcagatctacgatgcactgggtgcgacaggcccctggacaagggcttgagtggataggat acattaatcctagcagtgcttatactaattacaatcagaaattcaaggacagagtcacgattaccgcggacaaatccacgagcacagcctaca tggagctgagcagcctgagatctgaggacacggccgtgtattactgtgcgagaccccaagtccactatgattacaacgggtttccttactgg ggccaaggaaccctggtcaccgtctcctcaggtggaggcggttcaggcggaggtggatccggcggtggcggatcgggtggcggcggat ctgacatccagatgacccagtctccttccaccctgtctgcatctgtaggagacagagtcaccatgacttgcagtgccagctcaagtgtaagtt acatgaactggtatcagcagaaaccagggaaagcccctaagagatggatttatgactcatccaaactggcttctggggtcccatcaaggttc agcggcagtggatctgggacagagtatactctcaccatcagcagcctgcagcctgatgattttgcaacttattactgccaacagtggagtcgt aacccacccactttcggcggagggaccaaggtggagatcaaacggtcctccagctaa
(SEQ ID NO:99)
ROR193的成熟蛋白序列：
Diqmtqspsslsasvgdrvtincqasqsidsnlawfqqkpgkppklliyrasnlasgvpsffsgsgsgtdftltisslqpedvatyyclgg vgavsyrtsfgggtkveikggggsggggsggggsggggsevqlvesggglvqpgrslrlsctasgsdindypiswvrqapgkglewi gfinsggstwyaswvkgrftisrddsksiaylqmnslktedtavyycargystyygdfniwgqgtlvtvsssepkssdkthtcppcpap eaagapsvflfppkpkdtlmisrtpevtcvvvdvshedpevkfnwyvdgvevhnaktkpreeqynstyrvvsvltvlhqdwlngke ykcavsnkalpapiektiskakgqprepqvytlppsrdeltknqvsltclvkgfypsdiavewesngqpennykttppvldsdgsffly skltvdksrwqqgnvfscsvmhealhnhytqkslslspgsggggsggggsggggspgsqvqlvqsgpevkkpgssvkvsckasgy tfsrstmhwvrqapgqglewigyinpssaytnynqkfkdrvtitadkststaymelsslrsedtavyycarpqvhydyngfpywgqgt lvtvssggggsggggsggggsggggsdiqmtqspstlsasvgdrvtmtcsasssvsymnwyqqkpgkapkrwiydssklasgvps rfsgsgsgteytltisslqpddfatyycqqwsrnpptfgggtkveikrsss
(SEQ ID NO:100)
ROR134的DNA序列：
atggaagcaccagcgcagcttctcttcctcctgctactctggctcccagataccaccggtgacatccagatgacccagtccccctcctccctg tccgcctccgtgggcgaccgggtgaccatcaactgccaggcctcccagtccatcgactccaacctggcctggttccagcagaagcccggc aagccccccaagctgctgatctaccgggcctccaacctggcctccggcgtgccctcccggttctccggctccggctccggcaccgacttca ccctgaccatctcctccctgcagcccgaggacgtggccacctactactgcctgggcggcgtgggcgccgtgtcctaccggacctccttcg gcggcggcaccaaggtggagatcaagggtggaggcggttcaggcgggaggtggatccggcggtggcggctccggtggcggcggatct gaggtgcagctggtggagtccggcggcggcctggtgcagcccggcggctccctgcggctgtcctgcaccgcctccggctccgacatca acgactaccccatctcctgggtgcggcaggcccccggcaagggcctggagtggatcggcttcatcaactccggcggctccacctggtac gccgactcggtgaagggccggttcaccatctcccggcactcctccaagaacaccctgtacctgcagatgaactccctgcgggccgaggac accgccgtgtacttctgcgcccggggctactccacctactacggcgacttcaacatctggggccagggcaccctggtgaccgtgtcctcga gtgagcccaaatcttctgacaaaactcacacatgcccaccgtgcccagcacctgaagccgcgggtgcaccgtcagtcttcctcttcccccca aaacccaaggacaccctcatgatctcccggacccctgaggtcacatgcgtggtggtggacgtgagccacgaagaccctgaggtcaagttc aactggtacgtggacggcgtggaggtgcataatgccaagacaaagccgcgggaggagcagtacaacagcacgtaccgtgtggtcagcg tcctcaccgtcctgcaccaggactggctgaatggcaaggaatacaagtgcgcggtctccaacaaagccctcccagcccccatcgagaaaa ccatctccaaagccaaagggcagccccgagaaccacaggtgtacaccctgcccccatcccgggatgagctgaccaagaaccaggtcag cctgacctgcctggtcaaaggcttctatccaagcgacatcgccgtggagtgggagagcaatgggcagccggagaacaactacaagaccacgcctcccgtgctggactccgacggctccttcttcctctacagcaagctcaccgtggacaagagcaggtggcagcaggggaacgtcttctc atgctccgtgatgcatgaggctctgcacaaccactacacgcagaagagcctctccctgtctccgggttctggtggagggcggttcaggcgga ggtggctccggcggtggcggatcgccgggctctcaggtccagctggtggagtctgggggcggagtggtgcagcctgggcggtcactga ggctgtcctgcaaggcttctggctacacctttactagatctacgatgcactgggtaaggcaggcccctggacaaggtctggaatggattgga tacattaatcctagcagtgcttatactaattacaatcagaaattcaaggacaggttcacaatcagcgcagacaaatccaagagcacagccttc ctgcagatggacagcctgaggcccgaggacaccggcgtctatttctgtgcacggccccaagtccactatgattacaacgggtttccttactg
gggccaagggactcccgtcactgtctctagcggtggcggagggtctgggggtggcggatccggaggtggtggctctgcacaagacatcc agatgacccagtctccaagcagcctgtctgcaagcgtgggggacagggtcaccatgacctgcagtgccagctcaagtgtaagttacatga actggtaccagcagaagccgggcaaggcccccaaaagatggatttatgactcatccaaactggcttctggagtccctgctcgcttcagtgg cagtgggtctgggaccgactataccctcacaatcagcagcctgcagcccgaagatttcgccacttattactgccagcagtggagtcgtaacc cacccacgttcggaggggggaccaagctacaaattacatcctccagctaa
(SEQ ID NO：101)
ROR134的成熟蛋白序列：
Diqmtqspsslsasvgdrvtincqasqsidsnlawfqqkpgkppklliyrasnlasgvpsrfsgsgsgtdftltisslqpedvatyyclgg vgavsyrtsfgggtkveikggggsggggsggggsggggsevqlvesggglvqpggslrlsctasgsdindypiswvrqapgkglewi gfinsggstwyadsvkgrftisrhsskntlylqmnslraedtavyfcargystyygdfniwgqgtlvtvsssepkssdkthtcppcpape aagapsvflfppkpkdtlmisrtpevtcvvvdvshedpevkfnwyvdgvevhnaktkpreeqynstyrvvsvltvlhqdwlngkey kcavsnkalpapiektiskakgqprepqvytlppsrdeltknqvsltclvkgfypsdiavewesngqpennykttppvldsdgsfflyskltvdksrwqqgnvfscsvmhealhnhytqkslslspgsggggsggggsggggspgsqvqlvesgggvvqpgrslrlsckasgytft rstmhwvrqapgqglewigyinpssaytnynqkfkdrftisadkskstaflqmdslrpedtgvyfcarpqvhydyngfpywgqgtp vtvssggggsggggsggggsaqdiqmtqspsslsasvgdrvtmtcsasssvsymnwyqqkpgkapkrwiydssklasgvparfsg sgsgtdytltisslqpedfatyycqqwsrnpptfgggtklqitsss
(SEQ ID NO:102)
ROR189的DNA序列：
atggaagcaccagcgcagcttctcttcctcctgctactctggctcccagataccaccggtgacatccagatgacccagtccccctcctccctg tccgcctccgtgggcgaccgggtgaccatcaactgccaggcctcccagtccatcgactccaacctggcctggttccagcagaagcccggc aagccccccaagctgctgatctaccgggcctccaacctggcctccggcgtgccctcccggttctccggctccggctccggcaccgacttca ccctgaccatctcctccctgcagcccgaggacgtggccacctactactgcctgggcggcgtgggcgccgtgtcctaccggacctccttcg gcggcggcaccaaggtggagatcaagggtggaggcggttcaggcggaggtggatccggcggtggcggctccggtggcggcggatct gaggtgcagctggtggagtccggcggcggcctggtgcagcccggcggctccctgcggctgtcctgcaccgcctccggctccgacatca acgactaccccatctcctgggtgcggcaggcccccggcaagggcctggagtggatcggcttcatcaactccggcggctccacctggtac gccgactcggtgaagggccggttcaccatctcccggcactcctccaagaacaccctgtacctgcagatgaactccctgcgggccgaggac accgccgtgtacttctgcgcccggggctactccacctactacggcgacttcaacatctggggccagggcaccctggtgaccgtgtcctcga gtgagcccaaatcttctgacaaaactcacacatgcccaccgtgcccagcacctgaagccgcgggtgcaccgtcagtcttcctcttcccccca aaacccaaggacaccctcatgatctcccggacccctgaggtcacatgcgtggtggtggacgtgagccacgaagaccctgaggtcaagttc aactggtacgtggacggcgtggaggtgcataatgccaagacaaagccgcgggaggagcagtacaacagcacgtaccgtgtggtcagcg tcctcaccgtcctgcaccaggactggctgaatggcaaggaatacaagtgcgcggtctccaacaaagccctcccagcccccatcgagaaaa ccatctccaaagccaaagggcagccccgagaaccacaggtgtacaccctgcccccatcccgggatgagctgaccaagaaccaggtcag cctgacctgcctggtcaaaggcttctatccaagcgacatcgccgtggagtgggagagcaatgggcagccggagaacaactacaagaccacgcctcccgtgctggactccgacggctccttcttcctctacagcaagctcaccgtggacaagagcaggtggcagcaggggaacgtcttctc atgctccgtgatgcatgaggctctgcacaaccactacacgcagaagagcctctccctgtctccgggttctggtggaggcggttcaggcgga ggtggctccggcggtggcgggatcgccgggctctcaggtccagctggtgcaatctgggcctgaggtgaagaagcctgggtcctcggtgaa ggtctcctgcaaggcttctggatataccttcagcagatctacgatgcactgggtgcgacaggcccctggacaagggcttcagtggataggat acattaatcctagcagtgcttatactaattacaatcagaaattcaaggacagagtcacgattaccgcggacaaatccacgagcacagcctaca tggagctgagcagcctgagatctgaggacacggccgtgtattactgtgcgagaccccaagtccactatgattacaacgggtttccttactgg ggccaaggaaccctggtcaccgtctcctcaggtggaggcggttcaggcggaggtggatccggcggtggcggatcgggtggcggcggat
ctgacatccagatgacccagtctccttccaccctgtctgcatctgtaggagacagagtcaccatgacttgcagtgccagctcaagtgtaagtt acatgaactggtatcagcagaaaccagggaaagcccctaagagatggatttatgactcatccaaactggcttctggggtcccatcaaggttc agcggcagtggatctgggacagattatactctcaccatcagcagcctgcagcctgatgattttgcaacttattactgccaacagtggagtcgt aacccacccactttcggcggagggaccaaggtggagatcaaacggtcctccagctaa
(SEQ ID NO:103)
ROR189的成熟蛋白序列：
diqmtqspsslsasvgdrvtincqasqsidsnlawfqqkpgkppklliyrasnlasgvpsffsgsgsgtdftltisslqpedvatyyclggv gavsyrtsfgggtkveikggggsggggsggggsggggsevqlvesggglvqpggslrlsctasgsdindypiswvrqapgkglewig finsggstwyadsvkgrftisrhsskntlylqmnslraedtavyfcargystyygdfniwgqgtlvtvsssepkssdkthtcppcpapea agapsvflfppkpkdtlmisrtpevtcvvvdvshedpevkfnwyvdgvevhnaktkpreeqynstyrvvsvltvlhqdwlngkeyk cavsnkalpapiektiskakgqprepqvytlppsrdeltknqvsltclvkgfypsdiavewesngqpennykttppvldsdgsfflyskltvdksrwqqgnvfscsvmhealhnhytqkslslspgsggggsggggsggggspgsqvqlvqsgpevkkpgssvkvsckasgytfs rstmhwvrqapgqglewigyinpssaytnynqkfkdrvtitadkststaymelsslrsedtavyycarpqvhydyngfpywgqgtlv tvssggggsggggsggggsggggsdiqmtqspstlsasvgdrvtmtcsasssvsymnwyqqkpgkapkrwiydssklasgvpsrf sgsgsgtdytltisslqpddfatyycqqwsrnpptfgggtkveikrsss
(SEQ ID NO:104)
ROR154的DNA序列：
atggaagcaccagcgcagcttctcttcctcctgctactctggctcccagataccaccggtgacatccagatgacccagtccccctcctccctg tccgcctccgtgggcgaccgggtgaccatcaactgccaggcctcccagtccatcgactccaacctggcctggttccagcagaagcccggc aagccccccaagctgctgatctaccgggcctccaacctggcctccggcgtgccctcccggttctccggctccggctccggcaccgacttca ccctgaccatctcctccctgcagcccgaggacgtggccacctactactgcctgggcggcgtgggcgccgtgtcctaccggacctccttcg gcggcggcaccaaggtggagatcaagggtggaggcggttcaggcggaggtggatccggcggtggcggctccggtggcggcggatct gaggtgcagctggtggagtccggcggcggcctggtgcagcccggccggtccctgcggctgtcctgcaccgcctccggctccgacatca acgactaccccatcacctgggtgcggcaggcccccggcaagggcctggagtggatcggcttcatcaactccggcggctccacctggtac gcctcctgggtgaagggccggttcaccatctcccgggacgactccaagtccatcgcctacctgcagatgaactccctgaagaccgaggac accgccgtgtactattgcgcccggggctactccacctactaccgggacttcaacatctggggccagggcaccctggtgaccgtgtcctcga gtgagcccaaatcttctgacaaaactcacacatgcccaccgtgcccagcacctgaagccgcgggtgcaccgtcagtcttcctcttcccccca aaacccaaggacaccctcatgatctcccggacccctgaggtcacatgcgtggtggtggacgtgagccacgaagaccctgaggtcaagttc aactggtacgtggacggcgtggaggtgcataatgccaagacaaagccgcgggaggagcagtacaacagcacgtaccgtgtggtcagcg tcctcaccgtcctgcaccaggactggctgaatggcaaggaatacaagtgcgcggtctccaacaaagccctcccagcccccatcgagaaaa ccatctccaaagccaaagggcagccccgagaaccacaggtgtacaccctgcccccatcccgggatgagctgaccaagaaccaggtcag cctgacctgcctggtcaaaggcttctatccaagcgacatcgccgtggagtgggagagcaatgggcagccggagaacaactacaagaccacgcctcccgtgctggactccgacggctccttcttcctctacagcaagctcaccgtggacaagagcaggtggcagcaggggaacgtcttctc atgctccgtgatgcatgaggctctgcacaaccactacacgcagaagagcctctccctgtctccgggttctggtggaggcggttcaggcgga ggtggctccggcggtggcggatcgccgggctctcaggtccagctggtggagtctgggggcgggagtggtgcagcctgggcggtcactga ggctgtcctgcaaggcttctggctacacctttactagatctacgatgcactgggtaaggcaggcccctggacaaggtctggaatggattgga tacattaatcctagcagtgcttatactaattacaatcagaaattcaaggacaggttcacaatcagcgcagacaaatccaagagcacagccttc ctgcagatggacagcctgaggcccgaggacaccggcgtctatttctgtgcacggccccaagtccactatgattacaacgggtttccttactg gggccaagggactcccgtcactgtctctagcggtggcggagggtctgggggtggcggatccggaggtggtggctctgcacaagacatcc agatgacccagtctccaagcagcctgtctgcaagcgtgggggacagggtcaccatgacctgcagtgccagctcaagtgtaagttacatga actggtaccagcagaagccgggcaaggcccccaaaagatggatttatgactcatccaaactggcttctggagtccctgctcgcttcagtgg cagtgggtctgggaccgactataccctcacaatcagcagcctgcagcccgaagatttcgccacttattactgccagcagtggagtcgtaacc cacccacgttcggaggggggaccaagctacaaattacatcctccagctaa
(SEQ ID NO：105)
ROR154的成熟蛋白序列：
diqmtqspsslsasvgdrvtincqasqsidsnlawfqqkpgkppklliyrasnlasgvpsrfsgsgsgtdftltisslqpedvatyyclggv gavsyrtsfgggtkveikggggsggggsggggsggggsevqlvesggglvqpgrslrlsctasgsdindypitwvrqapgkglewigf insggstwyaswvkgrftisrddsksiaylqmnslktedtavyycargystyyrdfniwgqgtlvtvsssepkssdkthtcppcpapea agapsvflfppkpkdtlmisrtpevtcvvvdvshedpevkfnwyvdgvevhnaktkpreeqynstyrvvsvltvlhqdwlngkeyk cavsnkalpapiektiskakgqprepqvytlppsrdeltknqvsltclvkgfypsdiavewesngqpennykttppvldsdgsfflyskltvdksrwqqgnvfscsvmhealhnhytqkslslspgsggggsggggsggggspgsqvqlvesgggvvqpgrslrlsckasgytftrst mhwvrqapgqglewigyinpssaytnynqkfkdrftisadkskstaflqmdslrpedtgvyfcarpqvhydyngfpywgqgtpvtv ssggggsggggsggggsaqdiqmtqspsslsasvgdrvtmtcsasssvsymnwyqqkpgkapkrwiydssklasgvparfsgsgs gtdytltisslqpedfatyycqqwsrnpptfgggtklqitsss
(SEQ ID NO:106)
ROR185的DNA序列：
atggaagcaccagcgcagcttctcttcctcctgctactctggctcccagataccaccggtgacatccagatgacccagtccccctcctccctg tccgcctccgtgggcgaccgggtgaccatcaactgccaggcctcccagtccatcgactccaacctggcctggttccagcagaagcccggc aagccccccaagctgctgatctaccgggcctccaacctggcctccggcgtgccctcccggttctccggctccggctccggcaccgacttca ccctgaccatctcctccctgcagcccgaggacgtggccacctactactgcctgggcggcgtgggcgccgtgtcctaccggacctccttcg gcggcggcaccaaggtggagatcaagggtggaggcggttcaggcggaggtggatccggcggtggcggctccggtggcggcggatct gaggtgcagctggtggagtccggcggcggcctggtgcagcccggccggtccctgcggctgtcctgcaccgcctccggctccgacatca acgactaccccatcacctgggtgcggcaggcccccggcaagggcctggagtggatcggcttcatcaactccggcggctccacctggtac gcctcctgggtgaagggccggttcaccatctcccgggacgactccaagtccatcgcctacctgcagatgaactccctgaagaccgaggac accgccgtgtactattgcgcccggggctactccacctactaccgggacttcaacatctggggccagggcaccctggtgaccgtgtcctcga gtgagcccaaatcttctgacaaaactcacacatgcccaccgtgcccagcacctgaagccgcgggtgcaccgtcagtcttcctcttcccccca aaacccaagggacaccctcatgatctcccggacccctgaggtcacatgcgtggtggtggacgtgagccacgaagaccctgaggtcaagttc aactggtacgtggacggcgtggaggtgcataatgccaagacaaagccgcgggaggagcagtacaacagcacgtaccgtgtggtcagcg tcctcaccgtcctgcaccaggactggctgaatggcaaggaatacaagtgcgcggtctccaacaaagccctcccagcccccatcgagaaaa ccatctccaaagccaaagggcagccccgagaaccacaggtgtacaccctgcccccatcccgggatgagctgaccaagaaccaggtcag cctgacctgcctggtcaaaggcttctatccaagcgacatcgccgtggagtgggagagcaatgggcagccggagaacaactacaagaccacgcctcccgtgctggactccgacggctccttcttcctctacagcaagctcaccgtggacaagagcaggtggcagcaggggaacgtcttctc atgctccgtgatgcatgaggctctgcacaaccactacacgcagaagagcctctccctgtctccgggttctggtggaggcggttcaggcgga ggtggctccgggcggtggcggatcgccgggctctcaggtccagctggtgcaatctgggcctgaggtgaagaagcctgggtcctcggtgaa ggtctcctgcaaggcttctggatataccttcagcagatctacgatgcactgggtgcgacaggcccctggacaagggcttgagtggataggat acattaatcctagcagtgcttatactaattacaatcagaaattcaaggacagagtcacgattaccgcggacaaatccacgagcacagcctaca tggagctgagcagcctgagatctgaggacacggccgtgtattactgtgcgagaccccaagtccactatgattacaacgggtttccttactgg ggccaaggaaccctggtcaccgtctcctcaggtggaggcggttcaggcggaggtggatccggcggtggcggatcgggtggcggcggat ctgacatccagatgacccagtctccttccaccctgtctgcatctgtaggagacagagtcaccatgacttgcagtgccagctcaagtgtaagtt acatgaactggtatcagcagaaaccagggaaagcccctaagagatggatttatgactcatccaaactggcttctggggtcccatcaaggttc agcggcagtggatctgggacagattatactctcaccatcagcagcctgcagcctgatgattttgcaacttattactgccaacagtggagtcgt aacccacccactttcggcggagggaccaaggtggagatcaaacggtcctccagctaa
(SEQ ID NO:107)
ROR185的成熟蛋白序列：
diqmtqspsslsasvgdrvtincqasqsidsnlawfqqkpgkppklliyrasnlasgvpsrfsgsgsgtdftltisslqpedvatyyclggv gavsyrtsfgggtkveikggggsggggsggggsggggsevqlvesggglvqpgrslrlsctasgsdindypitwvrqapgkglewigf insggstwyaswvkgrftisrddsksiaylqmnslktedtavyycargystyyrdfniwgqgtlvtvsssepkssdkthtcppcpapea agapsvflfppkpkdtlmisrtpevtcvvvdvshedpevkfnwyvdgvevhnaktkpreeqynstyrvvsvltvlhqdwlngkeyk cavsnkalpapiektiskakgqprepqvytlppsrdeltknqvsltclvkgfypsdiavewesngqpennykttppvldsdgsfflyskltvdksrwqqgnvfscsvmhealhnhytqkslslspgsggggsggggsggggspgsqvqlvqsgpevkkpgssvkvsckasgytfs rstmhwvrqapgqglewigyinpssaytnynqkfkdrvtitadkststaymelsslrsedtavyycarpqvhydyngfpywgqgtlv tvssggggsggggsggggsggggsdiqmtqspstlsasvgdrvtmtcsasssvsymnwyqqkpgkapkrwiydssklasgvpsff sgsgsgtdytltisslqpddfatyycqqwsrnppffgggtkveikrsss
(SEQ ID NO：108)
ROR179的DNA序列：
atggaagcaccagcgcagcttctcttcctcctgctactctggctcccagataccaccggtgacatccagatgacccagtccccctcctccctg tccgcctccgtgggcgaccgggtgaccatcaactgccaggcctcccagtccatcgactccaacctggcctggttccagcagaagcccggc aagccccccaagctgctgatctaccgggcctccaacctggcctccggcgtgccctcccggttctccggctccggctccggcaccgacttca ccctgaccatctcctccctgcagcccgaggacgtggccacctactactgcctgggcggcgtgggcgccgtgtcctactgggacctccttcgg cggcggcaccaaggtggagatcaagggtggaggcggttcaggcggaggtggatccggcggtggcggctccggtggcggcggatctg aggtgcagctggtggagtccggcgggcggcctggtgcagcccggccggtccctgcggctgtcctgcaccgcctccggctccgacatcaac gactaccccatcacctgggtgcggcaggcccccggcaagggcctggagtggatcggcttcatcaactccggcggctccacctggtacgc ctcctgggtgaagggccggttcaccatctcccgggacgactccaagtccatcgcctacctgcagatgaactccctgaagaccgaggacac cgccgtgtactattgcgcccggggctactccacctactaccgggacttcaacatctggggccagggcaccctggtgaccgtgtcctcgagt gagcccaaatcttctgacaaaactcacacatgcccaccgtgcccagcacctgaagccgcgggtgcaccgtcagtcttcctcttccccccaa aacccaaggacaccctcatgatctcccggacccctgaggtcacatgcgtggtggtggacgtgagccacgaagaccctgaggtcaagttca actggtacgtggacggcgtggaggtgcataatgccaagacaaagccgcggggaggagcagtacaacagcacgtaccgtgtggtcagcgt cctcaccgtcctgcaccaggactggctgaatggcaaggaatacaagtgcgcggtctccaacaaagccctcccagcccccatcgagaaaa ccatctccaaagccaaagggcagccccgagaaccacaggtgtacaccctgcccccatcccgggatgagctgaccaagaaccaggtcag cctgacctgcctggtcaaaggcttctatccaagcgacatcgccgtggagtgggagagcaatgggcagccggagaacaactacaagacca cgcctcccgtgctggactccgacggctccttcttcctctacagcaagctcaccgtggacaagagcaggtggcagcaggggaacgtcttctc atgctccgtgatgcatgaggctctgcacaaccactacacgcagaagagcctctccctgtctccgggttctggtggaggcggttcaggcgga ggtggctccgggcggtggcggatcgccgggctctcaggtccagctggtggagtctggggggcggagtggtgcagcctgggcggtcactga ggctgtcctgcaaggcttctggctacacctttactagatctacgatgcactgggtaaggcaggcccctggacaaggtctggaatggattgga tacattaatcctagcagtgcttatactaattacaatcagaaattcaaggacaggttcacaatcagcgcagacaaatccaagagcacagccttc ctgcagatggacagcctgaggcccgaggacaccggcgtctatttctgtgcacggccccaagtccactatgattacaacgggtttccttactg gggccaagggactcccgtcactgtctctagcggtggcggagggtctgggggtggcggatccggaggtggtggctctgcacaagacatcc agatgacccagtctccaagcagcctgtctgcaagcgtgggggacagggtcaccatgacctgcagtgccagctcaagtgtaagttacatga actggtaccagcagaagccgggcaaggcccccaaaagatggatttatgactcatccaaactggcttctggagtccctgctcgcttcagtgg cagtgggtctgggaccgactataccctcacaatcagcagcctgcagcccgaagatttcgccacttattactgccagcagtggagtcgtaacc cacccacgttcggaggggggaccaagctacaaattacatcctccagctaa
(SEQ ID NO:109)
ROR179的成熟蛋白序列：
diqmtqspsslsasvgdrvtincqasqsidsnlawfqqkpgkppklliyrasnlasgvpsrfsgsgsgtdftltisslqpedvatyyclggv gavsywtsfgggtkveikggggsggggsggggsggggsevqlvesggglvqpgrslrlsctasgsdindypitwvrqapgkglewig finsggstwyaswvkgrftisrddsksiaylqmnslktedtavyycargystyyrdfniwgqgtlvtvsssepkssdkthtcppcpape aagapsvflfppkpkdtlmisrtpevtcvvvdvshedpevkfnwyvdgvevhnaktkpreeqynstyrvvsvltvlhqdwlngkey kcavsnkalpapiektiskakgqprepqvytlppsrdeltknqvsltclvkgfypsdiavewesngqpennykttppvldsdgsfflyskltvdksrwqqgnvfscsvmhealhnhytqkslslspgsggggsggggsggggspgsqvqlvesgggvvqpgrslrlsckasgytft rstmhwvrqapgqglewigyinpssaytnynqkfkdrftisadkskstaflqmdslrpedtgvyfcarpqvhydyngfpywgqgtp vtvssggggsggggsggggsaqdiqmtqspsslsasvgdrvtmtcsasssvsymnwyqqkpgkapkrwiydssklasgvparfsg sgsgtdytltisslqpedfatyycqqwsrnppffgggtklqitsss
(SEQ ID NO:110)
ROR186的DNA序列：
atggaagcaccagcgcagcttctcttcctcctgctactctggctcccagataccaccggtgacatccagatgacccagtccccctcctccctg tccgcctccgtggggcgaccggggtgaccatcaactgccaggcctcccagtccatcgactccaacctggcctggttccagcagaagcccggc aagccccccaagctgctgatctaccgggcctccaacctggcctccggcgtgccctcccggttctccggctccggctccggcaccgacttca ccctgaccatctcctccctgcagcccgaggacgtggccacctactactgcctgggcggcgtgggcgccgtgtcctactggacctccttcgg cggcggcaccaaggtggagatcaagggtggaggcggttcaggcggaggtggatccggcggtggcggctccggtggcggcggatctg aggtgcagctggtggagtccggcggcgggcctggtgcagcccggccggtccctgcggctgtcctgcaccgcctccggctccgacatcaac gactaccccatcacctgggtgcggcaggcccccggcaagggcctggagtggatcggcttcatcaactccggcggctccacctggtacgc ctcctgggtgaagggccggttcaccatctcccgggacgactccaagtccatcgcctacctgcagatgaactccctgaagaccgaggacac cgccgtgtactattgcgcccggggctactccacctactaccgggacttcaacatctggggccagggcaccctggtgaccgtgtcctcggagt gagcccaaatcttctgacaaaactcacacatgcccaccgtgcccagcacctgaagccgcgggtgcaccgtcagtcttcctcttccccccaa aacccaaggacaccctcatgatctcccggacccctgaggtcacatgcgtggtggtggacgtgagccacgaagaccctgaggtcaagttca actggtacgtggacggcgtggaggtgcataatgccaagacaaagccgcgggaggagcagtacaacagcacgtaccgtgtggtcagcgt cctcaccgtcctgcaccaggactggctgaatggcaaggaatacaagtgcgcggtctccaacaaagccctcccagcccccatcgagaaaa ccatctccaaagccaaagggcagccccgagaaccacaggtgtacaccctgcccccatcccgggatgagctgaccaagaaccaggtcag cctgacctgcctggtcaaaggcttctatccaagcgacatcgccgtggagtgggagagcaatgggcagccggagaacaactacaagacca cgcctcccgtgctggactccgacggctccttcttcctctacagcaagctcaccgtggacaagagcaggtggcagcaggggaacgtcttctc atgctccgtgatgcatgaggctctgcacaaccactacacgcagaagagcctctccctgtctccgggttctggtggaggcggttcaggcgga ggtggctccggcggtggcggatcgccgggctctcaggtccagctggtgcaatctgggcctgaggtgaagaagcctgggtcctcggtgaa ggtctcctgcaaggcttctggatataccttcagcagatctacgatgcactgggtgcgacaggcccctggacaagggcttgagtggataggat acattaatcctagcagtgcttatactaattacaatcagaaattcaaggacagagtcacgattaccgcggacaaatccacgagcacagcctaca tggagctgagcagcctgagatctggaggacacggccgtgtattactgtgcgagaccccaagtccactatgattacaacgggtttccttactgg ggccaaggaaccctggtcaccgtctcctcaggtggaggcggttcaggcggaggtggatccggcggtggcggatcgggtggcggcggat ctgacatccagatgacccagtctccttccaccctgtctgcatctgtaggagacagagtcaccatgacttgcagtgccagctcaagtgtaagtt acatgaactggtatcagcagaaaccagggaaagcccctaagagatggatttatgactcatccaaactggcttctggggtcccatcaaggttc agcggcagtggatctgggacagattatactctcaccatcagcagcctgcagcctgatgattttgcaacttattactgccaacagtggagtcgt aacccacccacttcggcggagggaccaaggtggagatcaaacggtcctccagctaa
(SEQ ID NO:111)
ROR186的成熟蛋白序列：
diqmtqspsslsasvgdrvtincqasqsidsnlawfqqkpgkppklliyrasnlasgvpsrfsgsgsgtdftltisslqpedvatyyclggv gavsywtsfgggtkveikgggggsggggsggggsggggsevqlvesggglvqpgrslrlsctasgsdindypitwvrqapgkglewig finsggstwyaswvkgrftisrddsksiaylqmnslktedtavyycargystyyrdfniwgqgtlvtvsssepkssdkthtcppcpape aagapsvflfppkpkdtlmisrtpevtcvvvdvshedpevkfnwyvdgvevhnaktkpreeqynstyrvvsvltvlhqdwlngkey kcavsnkalpapiektiskakgqprepqvytltlppsrdeltknqvsltclvkgfypsdiavewesngqpennykttppvldsdgsfflys kltvdksrwqqgnvfscsvmhealhnhytqkslslspgsggggsggggsggggspgsqvqlvqsgpevkkpgssvkvsckasgyt fsrstmhwvrqapgqglewigyinpssaytnynqkfkdrvtitadkststaymelsslrsedtavyycarpqvhydyngfpywgqgtl vtvssggggsggggsggggsggggsdiqmtqspstlsasvgdrvtmtcsasssvsymnwyqqkpgkapkrwiydssklasgvpsr fsgsgsgtdytltisslqpddfatyycqqwsrnpptfgggtkveikrsss
(SEQ ID NO:112)
ROR181的DNA序列：
atggaagcaccagcgcagcttctcttcctcctgctactctggctcccagataccaccggtgacatccagatgacccagtccccctcctccctg tccgcctccgtgggcgaccgggtgaccatcaactgccaggcctcccagtccatcgactccaacctggcctggttccagcagaagcccggc aagccccccaagctgctgatctaccgggcctccaacctggcctccggcgtgccctcccggttctccggctccggctccggcaccgacttca ccctgaccatctcctccctgcagcccgaggacgtggccacctactactgcctgggcggcgtgggcgccgtgtcctaccggacctccttcg gcggcggcaccaaggtggagatcaagggtggaggcggttcaggcggaggtggatccggcggtggcggctccggtggcggcggatct gaggtgcagctggtggagtccggcggcggcctggtgcagcccggcggctccctgcggctgtcctgcaccgtgtccggcaccgacatca acgactaccccatctcctgggtgcggcaggcccccggcaagggcctggagtggatcggcttcatcaactccggcggctccacctggtac gccgactcggtgaagggccggttcaccatctcccggcactcctccaagaacaccctggtacctgcagatgaactccctgcgggccgaggac accgccgtgtacttctgcgcccggggctactccacctactaccgggacttcaacatctggggccagggcaccctggtgaccgtgtcctcga gtgagcccaaatcttctgacaaaactcacacatgcccaccgtgcccagcacctgaagccgcgggtgcaccgtcagtcttcctcttcccccca aaacccaaggacaccctcatgatctcccggacccctgaggtcacatgcgtggtggtggacgtgagccacgaagaccctgaggtcaagttc aactggtacgtggacggcgtggaggtgcataatgccaagacaaagccgcgggaggagcagtacaacagcacgtaccgtgtggtcagcg tcctcaccgtcctgcaccaggactggctgaatggcaaggaatacaagtgcgcggtctccaacaaagccctcccagcccccatcgagaaaa ccatctccaaagccaaagggcagccccgagaaccacaggtgtacaccctgcccccatcccgggatgagctgaccaagaaccaggtcag cctgacctgcctggtcaaaggcttctatccaagcgacatcgccgtggagtgggagagcaatgggcagccggagaacaactacaagaccacgcctcccgtgctggactccgacggctccttcttcctctacagcaagctcaccgtggacaagagcaggtggcagcaggggaacgtcttctc atgctccgtgatgcatgaggctctgcacaaccactacacgcagaagagcctctccctgtctccgggttctggtggagggcggttcaggcgga ggtggctccggcggtggcggatcgccgggctctcaggtccagctggtggagtctggggggcggagtggtgcagcctgggcggtcactga ggctgtcctgcaaggcttctggctacacctttactagatctacgatgcactgggtaaggcaggcccctggacaaggtctggaatggattgga tacattaatcctagcagtgcttatactaattacaatcagaaattcaaggacaggttcacaatcagcgcagacaaatccaagagcacagccttc ctgcagatggacagcctgaggcccgaggacaccggcgtctatttctgtgcacggccccaagtccactatgattacaacgggtttccttactg gggccaagggactcccgtcactgtctctagcggtggcggagggtctgggggtggcggatccggaggtggtggctctgcacaagacatcc agatgacccagtctccaagcagcctgtctgcaagcgtgggggacagggtcaccatgacctgcagtgccagctcaagtgtaagttacatga actggtaccagcagaagccgggcaaggcccccaaaagatggatttatgactcatccaaactggcttctggagtccctgctcgcttcagtgg cagtgggtctgggaccgactataccctcacaatcagcagcctgcagcccgaagatttcgccacttattactgccagcagtggagtcgtaacc cacccacgttcggaggggggaccaagctacaaattacatcctccagctaa
(SEQ ID NO:113)
ROR181的成熟蛋白序列：
diqmtqspsslsasvgdrvtincqasqsidsnlawfqqkpgkppklliyrasnlasgvpsrfsgsgsgtdftltisslqpedvatyyclggv gavsyrtsfgggtkveikggggsggggsggggsggggsevqlvesggglvqpggslrlsctvsgtdindypiswvrqapgkglewig finsggstwyadsvkgrftisrhsskntlylqmnslraedtavyfcargystyyrdfniwgqgtlvtvsssepkssdkthtcppcpapeaa gapsvflfppkpkdtlmisrtpevtcvvvdvshedpevkfnwyvdgvevhnaktkpreeqynstyrvvsvltvlhqdwlngkeykc avsnkalpapiektiskakgqprepqvytlppsrdeltknqvsltclvkgfypsdiavewesngqpennykttppvldsdgsf～lysklt vdksrwqqgnvfscsvmhealhnhytqkslslspgsggggsggggsggggspgsqvqlvesgggvvclpgrslrlsckasgytftrst mhwvrqapgqglewigyinpssaytnynqkfkdrftisadkskstaflqmdslrpedtgvyfcarpqvhydyngfpywgqgtpvtv ssggggsggggsggggsaqdiqmtqspsslsasvgdrvtmtcsasssvsymnwyqqqqkpgkapkrwiydssklasgvparfsgsgs gtdytltisslqpedfatyycqqwsrnpptfgggtklqitsss
(SEQ ID NO:114)
ROR191的DNA序列：
atggaagcaccagcgcagcttctcttcctcctgctactctggctcccagataccaccggtgacatccagatgacccagtccccctcctccctg tccgcctccgtgggcgaccgggtgaccatcaactgccaggcctcccagtccatcgactccaacctggcctggttccagcagaagcccggc aagccccccaagctgctgatctaccgggcctccaacctggcctccggcgtgccctcccggttctccggctccggctccggcaccgacttca ccctgaccatctcctccctgcagcccgaggacgtggccacctactactgcctgggcggcgtgggcgccgtgtcctaccggacctccttcg gcggcggcaccaaggtggagatcaagggtggaggcggttcaggcggaggtggatccggcggtggcggctccggtggcggcggatct gaggtgcagctggtggagtccggcggcggcctggtgcagcccggcggctccctgcggctgtcctgcaccgtgtccggcaccgacatca acgactaccccatctcctgggtgcggcaggcccccggcaagggcctggagtggatcggcttcatcaactccggcggctccacctggtac gccgactcggtgaagggccggttcaccatctcccggcactcctccaagaacaccctgtacctgcagatgaactccctgcgggccgaggac accgccgtgtacttctgcgcccggggctactccacctactaccgggacttcaacatctggggccagggcaccctggtgaccgtgtcctcga gtgagcccaaatcttctgacaaaactcacacatgcccaccgtgcccagcacctgaagccgcgggtgcaccgtcagtcttcctcttcccccca aaacccaaggacaccctcatgatctcccggacccctgaggtcacatgcgtggtggtggacgtgagccacgaagaccctgaggtcaagttc aactggtacgtggacggcgtggaggtgcataatgccaagacaaagccgcgggaggagcagtacaacagcacgtaccgtgtggtcagcg tcctcaccgtcctgcaccaggactggctgaatggcaaggaatacaagtgcgcggtctccaacaaagccctcccagcccccatcgagaaaa ccatctccaaagccaaagggcagccccgagaaccacaggtgtacaccctgcccccatcccgggatgagctgaccaagaaccaggtcag cctgacctgcctggtcaaaggcttctatccaagcgacatcgccgtggagtgggagagcaatgggcagccggagaacaactacaagaccacgcctcccgtgctggactccgacggctccttcttcctctacagcaagctcaccgtggacaagagcaggtggcagcaggggaacgtcttctc atgctccgtgatgcatgaggctctgcacaaccactacacgcagaagagcctctccctgtctccgggttctggtggaggcggttcaggcgga ggtggctccggcggtggcggatcgccgggctctcaggtccagctggtgcaatctgggcctgaggtgaagaagcctgggtcctcggtgaa ggtctcctgcaaggcttctggatataccttcagcagatctacgatgcactgggtgcgacaggcccctggacaagggcttgagtggataggat acattaatcctagcagtgcttatactaattacaatcagaaattcaaggacagagtcacgattaccgcggacaaatccacgagcacagcctaca tggagctgagcagcctgagatctgaggacacggccgtgtattactgtgcgagaccccaagtccactatgattacaacgggtttccttactgg ggccaaggaaccctggtcaccgtctcctcaggtggaggcggttcaggcggaggtggatccggcggtggcggatcgggtggcggcggat ctgacatccagatgacccagtctccttccaccctgtctgcatctgtaggagacagagtcaccatgacttgcagtgccagctcaagtgtaagtt acatgaactggtatcagcagaaaccagggaaagcccctaagagatggatttatgactcatccaaactggcttctggggtcccatcaaggttc agcggcagtggatctgggacagattatactctcaccatcagcagcctgcagcctgatgattttgcaacttattactgccaacagtggagtcgt aacccacccactttcggcggagggaccaaggtggagatcaaacggtcctccagctaa
(SEQ ID NO:115)
ROR191的成熟蛋白序列：
diqmtqspsslsasvgdrvtincqasqsidsnlawfqqkpgkppklliyrasnlasgvpsrfsgsgsgtdftltisslqpedvatyyclggv gaysyrtsfgggtkveikggggsggggsggggsggggsevqlvesggglvqpggslrlsctvsgtdindypiswvrqapgkglewig finsggstwyadsvkgrftisrhsskntlylqmnslraedtavyfcargystyyrdfniwgqgtlvtvsssepkssdkthtcppcpapeaa gapsvflfppkpkdtlmisrtpevtcvvvdvshedpevkfnwyvdgvevhnaktkpreeqynstyrvvsvltvlhqdwlngkeykc avsnkalpapiektiskakgqprepqvytlppsrdeltknqvsltclvkgfypsdiavewesngqpennykttppvldsdgsfflysklt vdksrwqqgnvfscsvmhealhnhytqkslslspgsggggsggggsggggspgsqvqlvqsgpevkkpgssvkvsckasgytfsr stmhwvrqapgqglewigyinpssaytnynqkfkdrvtitadkststaymelsslrsedtavyycarpqvhydyngfpywgqgtlvt vssggggsggggsggggsggggsdiqmtqspstlsasvgdrvtmtcsasssvsymnwyqqkpgkapkrwiydssklasgvpsrfs gsgsgtdytltisslqpddfatyycqqwsrnpptfgggtkveikrsss
(SEQ ID NO:116)
ROR182的DNA序列：
atggaagcaccagcgcagcttctcttcctcctgctactctggctcccagataccaccggtgacatccagatgacccagtccccctcctccctg tccgcctccgtgggcgaccggggtgaccatcaactgccaggcctcccagtccatcgactccaacctggcctggttccagcagaagcccggc cagccccccaagctgctgatctaccgggcctccaacctggcctccggcgtgcccgaccggttctccggctccggctccggcaccgacttc accctgaccatctcctccctggaggccgaggacgtggccacctactactgcctgggcggcgtgggcgccgtgtcctaccggacctccttc ggcggcggcaccaaggtggagatcaagggtggaggcggttcaggcggaggtggatccggcggtggcggctccggtggcggcggatc tgaggtgcagctggtgggagtccggcggcggcctggtgcagcccggccggtccctgcggctgtcctgcaccgcctccggctccgacatca acgactaccccatcacctgggtgcggcaggcccccggccagggcctggagtggatcggcttcatcaactccggcggctccacctggtac gcctcctgggtgaagggccggttcaccatctcccgggacgactccaagtccatcgcctacctgcagatgaactccctgaagaccgaggac accgccgtgtactattgcgcccggggctactccacctactaccgggacttcaacatctggggccagggcaccctggtgaccgtgtcctcga gtgagcccaaatcttctgacaaaactcacacatgcccaccgtgcccagcacctgaagccgcgggtgcaccgtcagtcttcctcttcccccca aaacccaaggacaccctcatgatctcccggacccctgaggtcacatgcgtggtggtggacgtgagccacgaagaccctgaggtcaagttc aactggtacgtggacggcgtggaggtgcataatgccaagacaaagccgcgggaggagcagtacaacagcacgtaccgtgtggtcagcg tcctcaccgtcctgcaccaggactggctgaatggcaaggaatacaagtgcgcggtctccaacaaagccctcccagcccccatcgagaaaa ccatctccaaagccaaagggcagccccgagaaccacaggtgtacaccctgcccccatcccgggatgagctgaccaagaaccaggtcag cctgacctgcctggtcaaaggcttctatccaagcgacatcgccgtggagtgggagagcaatgggcagccggagaacaactacaagaccacgcctcccgtgctggactccgacggctccttcttcctctacagcaagctcaccgtggacaagagcaggtggcagcaggggaacgtcttctc atgctccgtgatgcatgaggctctgcacaaccactacacgcagaagagcctctccctgtctccgggttctggtggagggcggttcaggcgga ggtggctccggcggtggcggatcgccgggctctcaggtccagctggtggagtctgggggcggagtggtgcagcctgggcggtcactga ggctgtcctgcaaggcttctggctacacctttactagatctacgatgcactgggtaaggcaggcccctggacaaggtctggaatggattgga tacattaatcctagcagtgcttatactaattacaatcagaaattcaaggacaggttcacaatcagcgcagacaaatccaagagcacagccttc ctgcagatggacagcctgaggcccgaggacaccggcgtctatttctgtgcacggccccaagtccactatgattacaacgggtttccttactg gggccaagggactcccgtcactgtctctagcggtggcggagggtctgggggtggcggatccggaggtggtggctctgcacaagacatcc agatgacccagtctccaagcagcctgtctgcaagcgtgggggacagggtcaccatgacctgcagtgccagctcaagtgtaagttacatga actggtaccagcagaagccgggcaaggcccccaaaagatggatttatgactcatccaaactggcttctggagtccctgctcgcttcagtgg cagtgggtctgggaccgactataccctcacaatcagcagcctgcagcccgaagatttcgccacttattactgccagcagtggagtcgtaacc cacccacgttcggaggggggaccaagctacaaattacatcctccagctaa
(SEQ ID NO:117)
ROR182的成熟蛋白序列：
diqmtqspsslsasvgdrvtincqasqsidsnlawfqqkpgqppklliyrasnlasgvpdrfsgsgsgtdftltissleaedvatyyclggv gaysyrtsfgggtkveikggggsggggsggggsggggsevqlvesggglvqpgrslrlsctasgsdindypitwvrqapgqglewigf insggstwyaswvkgrftisrddsksiaylqmnslktedtavyycargystyyrdfniwgqgtlvtvsssepkssdkthtcppcpapea agapsvflfppkpkdtlmisrtpevtcvvvdvshedpevkfnwyvdgvevhnaktkpreeqynstyrvvsvltvlhqdwlngkeyk cavsnkalpapiektiskakgqprepqvytlppsrdeltknqvsltclvkgfypsdiavewesngqpennykttppvldsdgsfflyskltvdksrwqqgnvfscsvmhealhnhytqkslslspgsggggsggggsggggspgsqvqlvesgggvvqpgrslrlsckasgytftrst mhwvrqapgqglewigyinpssaytnynqkfkdrftisadkskstaflqmdslrpedtgvyfcarpqvhydyngfpywgqgtpvtv ssggggsggggsggggsaqdiqmtqspsslsasvgdrvtmtcsasssvsymnwyqqkpgkapkrwiydssklasgvpartsgsgs gtdytltisslqpedfatyycqqwsrnpptfgggtklqitsss
(SEQ ID NO:118)
ROR192的DNA序列： atggaagcaccagcgcagcttctcttcctcctgctactctggctcccagataccaccggtgacatccagatgacccagtccccctcctccctg tccgcctccgtgggcgaccgggtgaccatcaactgccaggcctcccagtccatcgactccaacctggcctggttccagcagaagcccggc cagccccccaagctgctgatctaccgggcctccaacctggcctccggcgtgcccgaccggttctccggctccggctccggcaccgacttc accctgaccatctcctccctggaggccgaggacgtggccacctactactgcctgggcggcgtgggcgccgtgtcctaccggacctccttc ggcggcggcaccaaggtggagatcaagggtggaggcggttcaggcggaggtggatccggcggtggcggctccggtggcggcggatc tgaggtgcagctggtggagtccggcggcggcctggtgcagcccggccggtccctgcggctgtcctgcaccgcctccggctccgacatca acgactaccccatcacctgggtgcggcaggcccccggccagggcctggagtggatcggcttcatcaactccggcggctccacctggtac gcctcctgggtgaagggccggttcaccatctcccgggacgactccaagtccatcgcctacctgcagatgaactccctgaagaccgaggac accgccgtgtactattgcgcccggggctactccacctactaccgggacttcaacatctggggccagggcaccctggtgaccgtgtcctcga gtgagcccaaatcttctgacaaaactcacacatgcccaccggtggcccaggcacctgaagccgcgggtgcaccgtcagtcttcctcttcccccca aaacccaaggacaccctcatgatctcccggacccctgaggtcacatgcgtggtggtggacgtgagccacgaagaccctgaggtcaagttc aactggtacgtggacggcgtggaggtgcataatgccaagacaaagccgcgggaggagcagtacaacagcacgtaccgtggtcagcg tcctcaccgtcctgcaccaggactggctgaatggcaaggaatacaagtgcgcggtctccaacaaagccctcccagcccccatcgagaaaa ccatctccaaagccaaagggcagccccgagaaccacaggtgtacaccctgcccccatcccgggatgagctgaccaagaaccaggtcag cctgacctgcctggtcaaaggcttctatccaagcgacatcgccgtggagtgggagagcaatgggcagccggagaacaactacagacca cgcctcccgtgctggactccgacggctccttcttcctctacagcaagctcaccgtggacaagagcaggtggcagcaggggaacgtcttctc atgctccgtgatgcatgaggctctgcacaaccactacacgcagaagagcctctccctgtctccgggttctggtggaggcggttcaggcgga ggtggctccggcggtggcggatcgccgggctctcaggtccagctggtgcaatctgggcctgaggtgaagaagcctgggtcctcggtgaa ggtctcctgcaaggcttctggatataccttcagcagatctacgatgcactgggtgcgacaggcccctggacaagggcttgagtggataggat acattaatcctagcagtgcttatactaattacaatcaggaaattcaaggacagagtcacggattaccgcggacaaatccacgagcacacctsca tggagctgagcagcctgagatctgsggacacggccgtgtattactgtgcgagaccccaagtccactatgattacaacgggtttccttactgg ggccaaggaaccctggtcaccgtctcctcaggtggaggcggttcaggcggaggtggatccggcggtggcggatcgggtggcggcggat 6tgacatccagatgacccagtctccttccaccctgtctgcatctgtaggagacagagtcaccatgacttgcagtgccagctcaagtgtaagtt acatgactggtatcagcagaaaccagggaaagcccctaagagatggatttatgactcatccaaactggcttctgggtcccatcaaggttc agcggcagtggatctgggacagattatactctcaccatcagcagcctgcagcctgatgattttgcaacttattactgccaacagtggagtcgt aacccacccactttcggcggagggaccaaggtggagatcaaacggtcctccagctaa
(SEQ ID NO:119)
ROR192的成熟蛋白序列：
diqmtqspsslsasvgdrvtincqasqsidsnlawfqqkpgqppklliyrasnlasgvpdrfsgsgsgtdftltissleaedvatyyclggv gavsyrtsfgggtkveikggggsggggsggggsggggsevqlvesggglvqpgrslrlsctasgsdindypitwvrqapgqglewigf msggstwyaswvkgrftisrddsksiaylqmnslktedtavyycargystyyrdfniwgqgtlvtvsssepkssdkthtcppcpapea agapsvflfppkpkdtlmisrtpevtcvvvdvshedpevkfnwyvdgvevhnaktkpreeqynstyrvvsvltvlhqdwlngkeyk cavsnkalpapiektiskakgqpepqytipsrdeltknqvsltclvkgfypsdiavewesngqpennykttppvldsdgsfflyskl tvdksrwqqgnvfscsvmhealhnhytqkslslspgsggggsggggsggggspgsqvqlvqsgPevkkpgssvkvsckasgytfs rstmhwvrqapgqglewigyinpssaytnynqkfkdrvtitadkststaymelsslrsedtavyycarpqvhdyngfpywgqgtlv tvssggggsggggsggggsggggsdiqmtqspstlsasvgdrvtmtcsasssvsymnwyqqkpgkapkrwiydssklasgvpsrf sgsgsgtdytltisslqpddfatyycqqwsmpptfgggtkveikrsss
(SEQ ID NO：120)
嵌合双特异性抗CD123(VLVH)x抗CD3(TSC456) scFv-Fc-scFv
Dimmsqspsslavsvgekftmtckssqslffgstqknylawyqqkpgqspklliywastresgvpdrftgsgsgtdftlaissvmped lavyycqqyynypwtfgggtkleikggggsggggsggggsggggsvqlqesgpglvkpsqslsltcsvtdysitsgyywnwirqfp gnklewmgyisydgsnnynpslknrisitrdtsknqfflklssvttedtatyycsrgegfyfdswgqgttltvsssepkssdkthtcppcp apeaagapsvflfppkpkdtlmisrtpevtcvvvdvshedpevkfnwyvdgvevhnaktkpreeqynstyrvsvltvlhqdwlng keykcavsnkalpapiektiskakgqprepqvytlppsrdeltknqvsltclvkgfypsdiavewesngqpennykttppvldsdgsff lyskltvdksrwqqgnvfscsvmhealhnhytqkslslspgsggggsggggsggggspgsqvqlvqsgpevkkpgssvkvsckas gytfsrstmhwvrqapgqglewigyinpssaytnynqkfkdrvtitadkststaymelsslrsedtavyycarpqvhydyngfpywg qgtlvtvssggggsggggsggggsggggsdiqmtqspstlsasvgdrvtmtcsasssvsymnwyqqkpgkapkrwiydssklasg vpsrfsgsgsgtdytltisslqpddfatyycqqwsrnpptfgggtkveikrsss(SEQ ID NO:197)
嵌合双特异性抗CD123(VHVL)x抗CD3(TSC456) scFv-Fc-scFv
Vqlqesgpglvkpsqslsltcsvtdysitsgyywnwirqfpgnklewmgyisydgsnnynpslknrisitrdtsknqfflklssvttedt atyycsrgegfyfdswgqgttltvssggggsggggsggggsggggsdimmsqspsslavsvgekftmtckssqslffgstqknylaw yqqkpgqspklliywastresgvpdrftgsgsgtdftlaissvmpedlavyycqqyynypwtfgggtkleiksssepkssdkthtcppc papeaagapsvflfppkpkdtlmisrtpevtcvvvdvshedpevkfnwyvdgvevhnaktkpreeqynstyrvvsvltvlhqdwln gkeykcavsnkalpapiektiskakgqprepqvytlppsrdeltknqvsltclvkgfypsdiavewesngqpennykttppvldsdgs fflyskltvdksrwqqgnvfscsvmhealhnhytqkslslspgsgggggsggggsggggspgsqvqlvqsgpevkkpgssvkvscka sgytfsrstmhwvrqapgqglewigyinpssaytnynqkfkdrvtitadkststaymelsslrsedtavyycarpqvhydyngfpyw gqgtlvtvssggggsggggsggggsggggsdiqmtqspstlsasvgdrvtmtcsasssvsymnwyqqkpgkapkrwiydssklas gvpsrffsgsgsgtdytltisslqpddfatyycqqwsrnpptfgggtkveikrsss(SEQ ID NO:198)
TSC471的DNA序列：
atggaagcaccagcgcagcttctcttcctcctgctactctggctcccagataccaccggtgatatccagatgacccagtctccatccgccatg tctgcatctgtaggagacagagtcaccatcacttgccgggcgagtaagagcattagcaaatatttagcctggtttcagcagaaaccagggaa agttcctaagctccgcatccattctggatctactttgcaatcaggggtcccatctcggttcagtggcagtggatctgggacagaatttactctca ccatcagcagcctgcagcctgaagattttgcaacttattactgtcaacagcatattgaatacccgtggacgttcggccaagggaccaaggtg gaaatcaaacgaggtggcggagggtctgggggtggcggatccggaggtggtggctctcaggtccagctggtacagtctggggctgaggt gaagaagcctggggcttcagtgaaggtctcctgcaaggcttctggatacacattcactgactactacatgcactgggtgcgacaggcccctg gacaagggcttgagtggatgggatattttaatccttataatgattatactagatacgcacagaagttccagggcagagtcaccatgaccaggg acacgtctatcagcacagcctacatggagctgagcagcctgagatctgacgacacggccgtgtattactgtgcaagatcggatggttactac gatgctatggactactggggtcaaggaaccacagtcaccgtctcctcgagtgagcccaaatcttctgacaaaactcacacatgcccaccgtg cccagcacctgaagccgcgggtgcaccgtcagtcttcctcttccccccaaaacccaaggacaccctcatgatctcccggacccctgaggtc acatgcgtggtggtggacgtgagccacgaagaccctgaggtcaagttcaactggtacgtggacggcgtggagggtgcataatgccaagac aaagccgcgggaggagcagtacaacagcacgtaccgtgtggtcagcgtcctcaccgtcctgcaccaggactggctgaatggcaaggaat acaagtgcgcggtctccaacaaagccctcccagcccccatcgagaaaaccatctccaaagccaaagggcagccccgagaaccacaggt gtacaccctgcccccatcccgggatgagctgaccaagaccaggtcagcctgacctgcctggtcaaaggcttctatccaagcgacatcgc cgtggagtgggagagcaatgggcagccggagaacaactacaagaccacgcctcccgtgctggactccgacggctccttcttcctctacag caagctcaccgtggacaagagcaggtggcagcagggggaacgtcttctcatgctccgtgatgcatgaggctctgcacaaccactacacgca gaagagcctctccctgtctccgggttccggaggtggcggttcgggaggtggcgggtcaggaggtgggggctctccttcacaggtgcagct ggtgcagtctggtcctgaggtgaaaaagcctggctccagcgtgaaggtgtcctgcaaggccagcggatacacctttagccgggtccaccat gcattgggtgaggcaggctcctggacagggcctggagtggatcggctacatcaaccccagcagcgcttataccaactacaatcagaagttt aaggaccgggtgaccatcaccgccgataagtccaccagcaccgcctacatggagctgtccagcctgaggagcgaggataccgccgtgta ctattgcgcccggccccaggtccattacgactacaacggcttcccctattggggccagggaaccctggtgaccgtgtccagcggtggcggt ggcagcggcggcggcggctctggcggaggtggcagcggcggagggggctccgacattcagatgacccagtccccctccaccctgtcc gctagcgtgggcgatcgggtgaccatgacctgcagcgccagcagctccgtgtcctacatgaactggtaccagcagaagcccggcaaggc tcccaagaggtggatttacgactccagcaagctggcctctggtgtccccagcaggttctctggtagcggcagcggcacagactacaccctg accatctcctccctgcagcccgacgatttcgccacctactattgccagcagtggtcccggaatccccctacctttggcggcggcaccaaggt ggagatcaagaggagctaa(SEQ ID NO:205)
TSC471的成熟蛋白序列：
Diqmtqspsamsasvgdrvtitcrasksiskylawfqqkpgkvpklrihsgstlqsgvpsrfsgsgsgteftltisslqpedfatyycqqh ieypwtfgqgtkveikrggggsggggsggggsqvqlvqsgaevkkpgasvkvsckasgytftdyymhwvrqapgqglewmgyf npyndytryaqkfqgrvtmtrdtsistaymelsslrsddtavyycarsdgyydamdywgqgttvtvsssepkssdkthtcppcpapea agapsvflfppkpkdtlmisrtpevtcvvvdvshedpevkfnwyvdgvevhnaktkpreeqynstyrvvsvltvlhqdwlngkeyk cavsnkalpapiektiskakgqprepqvytlppsrdeltknqvsltclvkgfypsdiavewesngqpennykttppvldsdgsfflyskl tvdksrwqqgnvfscsvmhealhnhytqkslslspgsggggsggggsggggspsqvqlvqsgpevkkpgssvkvsckasgytfsrs tmhwvrqapgqglewigyinpssaytnynqkfkdrvtitadkststaymelsslrsedtavyycarpqvhydyngfpywgqgtlvtv ssggggsggggsggggsggggsdiqrntqspstlsasvgdrvtmtcsasssvsymnwyqqkpgkapkrwiydssklasgvpsrfsg sgsgtdytltisslqpddfatyycqqwsrnpptfgggtkveikrs(SEQ ID NO：206)
ROR243的DNA序列：
atggaggctcccgctcagctgctgttcctcctgctgctctggctgcccgacaccacaggcgacatccagatgacccagtccccttcctccct gtccgctagcgtgggcgatagggtgaccatcaactgccaggcctcccagtccattgactccaatctggcctggttccagcagaagcccgg acagccccccaagctgctgatttacagggcctccaacctggcttccggcgtgcctgacaggttctccggatccggcagcggcaccgacttc accctgaccatctcctccctggaggccgaggatgtcgccacctactactgtctgggcggcgtgggcgctgtgagctatcggacctccttcg gcggcggcaccaaggtggagatcaagggcggcggcggcagcggcggcggcggcagcggcggcggaggctccggcggcggcggc agcgaggtgcagctggtggaaagcggaggaggcctggtgcagcctggaaggtccctgaggctgtcctgcacagccagcggctccgac atcaacgactaccccatcacctgggtgaggcaggctcctggccagggcctgggaatggatcggctttatcaacagcggcggcagcacctg gtatgcttcctgggtgaagggccggttcaccattagcagggacgactccaagtccattgcctacctgcagatgaactccctgaagaccgag gacaccgccgtgtactactgcgccaggggctacagcacctattaccgggactttaacatctggggccagggcacactggtcaccgtgtcct cgagtgagcccaaatcttctgacaaaactcacacatgcccaccgtgcccagcacctgaagccgcgggtgcaccgtcagtcttcctcttccc cccaaaacccaaggacaccctcatgatctcccggacccctgaggtcacatgcgtggtggtggacgtgagccacgaagaccctgaggtca agttcaactggtacgtggacggcgtggaggtgcataatgccaagacaaagccgcgggaggagcagtacaacagcacgtaccgtgtggtc agcgtcctcaccgtcctgcaccaggactggctgaatggcaaggaatacaagtgcgcggtctccaacaaagccctcccagcccccatcga gaaaaccatctccaaagccaaagggcagccccgagaaccacaggtgtacaccctgcccccatcccgggatgagctgaccaagaaccag gtcagcctgacctgcctggtcaaaggcttctatccaagcgacatcgccgtggagtgggagagcaatgggcagccggagaacaactacaa gaccacgcctcccgtgctggactccgacggctccttcttcctctacagcaagctcaccgtggacaagagcaggtggcagcaggggaacgt cttctcatgctccgtgatgcatgaggctctgcacaaccactacacgcagaagagcctctccctgtctccgggttccggaggagggggttcag gtgggggaggttctggcggcgggggaagcccttcacaggtgcaactggtgcagagtggacccgaggttaaaaaaccagggtcctccgtt aaggttagctgcaaagcctctggctacacattttccaggagtacaatgcactgggtgaggcaggctcctggacagggactcgagtggatcg ggtatatcaacccatctagcgcctataccaattacaaccaaaagtttaaggaccgagttaccattaccgctgacaaatccaccagtacagcttatatggagctgtcatctcttaggtccgaggacactgctgtttattactgcgctcgtcctcaggttcactatgactataatggttttccctactggggt cagggaaccctggtgactgtctcttctggcggtggaggcagcggtgggggtgggtctggaggcggtggcagtggcggcggaggctctg atattcagatgactcagtctcctagcactctcagcgccagcgtgggggatcgtgtgacaatgacttgctccgctagcagtagtgtgtcttacat gaattggtatcagcagaagcccgggaaagcacctaagcgctggatctatgactcttccaagctggcaagtggtgtcccctcacggttctctg gctcaggttctggtactgactatactttgactatctcctccctccagcccgatgatttcgctacctattattgtcagcagtggagccgtaacccac ccactttcggaggcggtaccaaagtggagatcaagaggtcatga(SEQ ID NO:207)
ROR243的成熟蛋白序列：
Diqmtqspsslsasvgdrvtincqasqsidsnlawfqqkpgqppklliyrasnlasgvpdrfsgsgsgtdftltissleaedvatyyclgg vgavsyrtsfgggtkveikggggsggggsggggsggggsevqlvesggglvqpgrslrlsctasgsdindypitwvrqapgqglewi gfinsggstwyaswvkgrftisrddsksiaylqmnslktedtavyycargystyyrdfniwgqgtlvtvsssepkssdkthtcppcpap eaagapsvflfppkpkdtlmisrtpevtcvvvdvshedpevkfnwyvdgvevhnaktkpreeqynstyrvvsvltvlhqdwlngke ykcavsnkalpapiektiskakgqprepqvytlppsrdeltknqvsltclvkgfypsdiavewesngqpennykttppvldsdgsffly skltvdksrwqqgnvfscsvmhealhnhytqkslslspgsggggsggggsggggspsqvqlvqsgpevkkpgssvkvsckasgyt
fsrstmhwvrqapgqglewigyinpssaytnynqkfkdrvtitadkststaymelsslrsedtavyycarpqvhydyngfpywgqgtl vtvssggggsggggsggggsggggsdiqmtqspstlsasvgdrvtmtcsasssvsymnwyqqkpgkapkrwiydssklasgvpsr fsgsgsgtdytltisslqpddfatycqqwsrnpptfgggtkveikrs(SEQ ID NO:208)
TSC266的DNA序列：
atggaagcaccagcgcagcttctcttcctcctgctactctggctcccagataccaccggtgatatccagatgacccagtctccatccgccatg tctgcatctgtaggagacagagtcaccatcacttgccgggcgagtaagagcattagcaaatatttagcctggtttcagcagaaaccagggaa agttcctaagctccgcatccattctggatctactttgcaatcaggggtcccatctcggttcagtggcagtggatctgggacagaatttactctca ccatcagcagcctgcagcctgaagattttgcaacttattactgtcaacagcatattgaatacccgtggacgttcggccaagggaccaaggtg gaaatcaaacgaggtggcggagggtctgggggtggcggatccggaggtggtggctctcaggtccagctggtacagtctggggctgaggt gaagaagcctggggcttcagtgaaggtctcctgcaaggcttctggatacacattcactgactactacatgcactgggtgcgacaggcccctg gacaagggcttgagtggatgggatattttaatccttataatgattatactagatacgcacagaagttccagggcagagtcaccatgaccaggg acacgtctatcagcacagcctacatggagctgagcagcctgagatctgacgacacggccgtgtattactgtgcaagatcggatggttactac gatgctatggactactggggtcaaggaaccacagtcaccgtctcctcgagtgagcccaaatcttctgacaaaactcacacatgcccaccgtg cccagcacctgaagccgcgggtgcaccgtcagtcttcctcttccccccaaaacccaaggacaccctcatgatctcccggacccctgaggtc acatgcgtggtggtggacgtgagccacgaagaccctgaggtcaagttcaactggtacgtggacggcgtggaggtgcataatgccaagac aaagccgcgggaggagcagtacaacagcacgtaccgtgtggtcagcgtcctcaccgtcctgcaccaggactggctgaatggcaaggcgt acgcgtgcgcggtctccaacaaagccctcccagcccccatcgagaaaaccatctccaaagccaaagggcagccccgagaaccacaggt gtacaccctgcccccatcccgggatgagctgaccaagaaccaggtcagcctgacctgcctggtcaaaggcttctatccaagcgacatcgc cgtggagtgggagagcaatgggcagccggagaacaactacaagaccacgcctcccgtgctggactccgacggctccttcttcctctacag caagctcaccgtggacaagagcaggtggcagcaggggaacgtcttctcatgctccgtgatgcatgaggctctgcacaaccactacacgca gaagagcctctccctgtctccgggtcagaggcacaacaattcttccctgaatacaggaactcagatggcaggtcattctccgaattctcaggt ccagctggtggagtctgggggcggagtggtgcagcctgggcggtcactgaggctgtcctgcaaggcttctggctacacctttactagatct acgatgcactgggtaaggcaggcccctggacaaggtctggaatggattggatacattaatcctagcagtgcttatactaattacaatcagaaa ttcaaggacaggttcacaatcagcgcagacaaatccaagagcacagccttcctgcagatggacagcctgaggcccgaggacaccggcgt ctatttctgtgcacggccccaagtccactatgattacaacgggtttccttactggggccaagggactcccgtcactgtctctagcggtggcgg agggtctggggggtggcggatccggaggtggtggctctgcacaagacatccagatgacccagtctccaagcagcctgtctgcaagcgtgg gggacagggtcaccatgacctgcagtgccagctcaagtgtaagttacatgaactggtaccagcagaagccgggcaaggcccccaaaaga tggatttatgactcatccaaactggcttctggagtccctgctcgcttcagtggcagtgggtctgggaccgactataccctcacaatcagcagc ctgcagcccgaagatttcgccacttattactgccagcagtggagtcgtaacccacccacgttcggaggggggaccaagctacaaattacat cctccagctaa(SEQ IDNO:209)
TSC266的蛋白质序列：
Diqmtqspsamsasvgdrvtitcrasksiskylawfqqkpgkvpklrihsgstlqsgvpsrfsgsgsgteftltisslqpedfatycqqh ieypwtfgqgtkveikrggggsggggsggggsqvqlvqsgaevkkpgasvkvsckasgytftdyymhwvrqapgqglewmgyf npyndytryaqkfqgrvtmtrdtsistaymelsslrsddtavyycarsdgyydamdywgqgttvtvsssepkssdkthtcppcpapea agapsvflfppkpkdtlmisrtpevtcvvvdvshedpevkfnwyvdgvevhnaktkpreeqynstyrvvsvltvlhqdwlngkaya cavsnkalpapiektiskakgqprepqvytlppsrdeltknqvsltclvkgfypsdiavewesngqpennykttppvldsdgsfflyskl tvdksrwqqgnvfscsvmhealhnhytqkslslspgqrhnnsslntgtqmaghspnsqvqlvesgggvvqpgrslrlsckasgytftr stmhwvrqapgqglewigyinpssaytnynqkfkdrftisadkskstaflqmdslrpedtgvyfcarpqvhydyngfpywgqgtpv tvssggggsggggsggggsaqdiqmtqspsslsasvgdrvtmtcsasssvsymnwyqqkpgkapkrwiydssklasgvparfsgs gsgtdytltisslqpedfatyycqqwsrnpptfgggtklqitsss(SEQIDNO:210)
ROR206的DNA序列：
atggaagcaccagcgcagcttctcttcctcctgctactctggctcccagataccaccggtgacatccagatgacccagtccccctcctccctg tccgcctccgtgggcgaccgggtgaccatcaactgccaggcctcccagtccatcgactccaacctggcctggttccagcagaagcccggc aagccccccaagctgctgatctaccgggcctccaacctggcctccggcgtgccctcccggttctccggctccggctccggcaccgacttca ccctgaccatctcctccctgcagcccgaggacgtggccacctactactgcctgggcggcgtgggcgccgtgtcctaccggacctccttcg gcggcggcaccaaggtggagatcaagggtggaggcggttcaggcggaggtggatccggcggtggcggctccggtggcggcggatct gaggtgcagctggtggagtccggcggcggcctggtgcagcccggccggtccctgcggctgtcctgcaccgcctccggctccgacatca acgactaccccatcacctgggtgcggcaggcccccggcaagggcctggagtggatcggcttcatcaactccggcggctccacctggtac gcctcctgggtgaagggccggttcaccatctcccgggacgactccaagtccatcgcctacctgcagatgaactccctgaagaccgaggac accgccgtgtactattgcgcccggggctactccacctactaccgggacttcaacatctggggccagggcaccctggtgaccgtgtcctcga gtgagcccaaatcttctgacaaaactcacacatgcccaccgtgcccagcacctgaagccgcgggtgcaccgtcagtcttcctcttcccccca aaacccaaggacaccctcatgatctcccggacccctgaggtcacatgcgtggtggtggacgtgagccacgaagaccctgaggtcaagttc aactggtacgtggacggcgtggaggtgcataatgccaagacaaagccgcgggaggagcagtacaacagcacgtaccgtgtggtcagcg tcctcaccgtcctgcaccaggactggctgaatggcaaggaatacaagtgcgcggtctccaacaaagccctcccagcccccatcgagaaaa ccatctccaaagccaaagggcagccccgagaaccacaggtgtacaccctgcccccatcccgggatgagctgaccaagaaccaggtcag cctgacctgcctggtcaaaggcttctatccaagcgacatcgccgtggagtgggagagcaatgggcagccggagaacaactacaagaccacgcctcccgtgctggactccgacggctccttcttcctctacagcaagctcaccgtggacaagagcaggtggcagcaggggaacgtcttctc atgctccgtgatgcatgaggctctgcacaaccactacacgcagaagagcctctccctgtctccgggttctggtggaggcggttcaggcgga ggtggctccggcggtggcggatcgccgggctctcaggtccagctggtggagtctgggggcggagtggtgcagcctgggcggtcactga ggctgtcctgcaaggcttctggctacacctttactagatctacgatgcactgggtaaggcaggcccctggacaaggtctggaatggattgga tacattaatcctagcagtgcttatactaattacaatcagaaattcaaggacaggttcacaatcagcgcagacaaatccaagagcacagccttc ctgcagatggacagcctgaggcccgaggacaccggcgtctatttctgtgcacggccccaagtccactatgattacaacgggtttccttactg gggccaagggactcccgtcactgtctctagcggtggcggagggtctgggggtggcggatccggaggtggtggctctgcacaagacatcc agatgacccagtctccaagcagcctgtctgcaagcgtgggggacagggtcaccatgacctgcagtgccagctcaagtgtaagttacatga actggtaccagcagaagccgggcaaggcccccaaaagatggatttatgactcatccaaactggcttctggagtccctgctcgcttcagtgg cagtgggtctgggaccgactataccctcacaatcagcagcctgcagcccgaagatttcgccacttattactgccagcagtggagtcgtaacc cacccacgttcggaggggggaccaagctacaaattacatcctccagc(SEQ ID NO:211)
ROR206的蛋白质序列：
MEAPAQLLFLLLLWLPDTTGDIQMTQSPSSLSASVGDRVTINCQASQSIDSNLAWFQQKP GKPPKLLIYRASNLASGVPSRFSGSGSGTDFTLTISSLQPEDVATYYCLGGVGAVSYRTSF GGGTKVEIKGGGGSGGGGSGGGGSGGGGSEVQLVESGGGLVQPGRSLRLSCTASGSDI NDYPITWVRQAPGKGLEWIGFINSGGSTWYASWVKGRFTISRDDSKSIAYLQMNSLKTE DTAVYYCARGYSTYYRDFNIWGQGTLVTVSSSEPKSSDKTHTCPPCPAPEAAGAPSVFL FPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTY RVVSVLTVLHQDWLNGKEYKCAVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELT KNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQ QGNVFSCSVMHEALHNHYTQKSLSLSPGSGGGGSGGGGGSGGGGSPGSQVQLVESGGGV VQPGRSLRLSCKASGYTFTRSTMHWYRQAPGQGLEWIGYINPSSAYTNYNQKFKDRFTISADKSKSTAFLQMDSLRPEDTGVYFCARPQVHYDYNGFPYWGQGTPVTVSSGGGGSG GGGSGGGGSAQDIQMTQSPSSLSASVGDRVTMTCSASSSVSYMNWYQQKPGKAPKRWI YDSSKLASGVPARFSGSGSGTDYTLTISSLQPEDFATYYCQQWSRNPPTFGGGTKLQITS SS(SEQ ID NO:212)
ROR207的DNA序列：
atggaagcaccagcgcagcttctcttcctcctgctactctggctcccagataccaccggtgacatccagatgacccagtccccctcctccctg tccgcctccgtgggcgaccgggtgaccatcaactgccaggcctcccagtccatcgactccaacctggcctggttccagcagaagcccggc aagccccccaagctgctgatctaccgggcctccaacctggcctccggcgtgccctcccggttctccggctccggctccggcaccgacttca ccctgaccatctcctccctgcagcccgaggacgtggccacctactactgcctgggcggcgtgggcgccgtgtcctaccggacctccttcg gcggcggcaccaaggtggagatcaagggtggaggcggttcaggcggaggtggatccggcggtggcggctccggtggcggcggatct gaggtgcagctggtggagtccggcggcggcctggtgcagcccggccggtccctgcggctgtcctgcaccgcctccggctccgacatca acgactaccccatcacctgggtgcggcaggcccccggcaagggcctggagtggatcggcttcatcaactccggcggctccacctggtac gcctcctgggtgaagggccggttcaccatctcccgggacgactccaagtccatcgcctacctgcagatgaactccctgaagaccgaggac accgccgtgtactattgcgcccggggctactccacctactaccgggacttcaacatctggggccagggcaccctggtgaccgtgtcctcga gtgagcccaaatcttctgacaaaactcacacatgcccaccgtgcccagcacctgaagccgcgggtgcaccgtcagtcttcctcttcccccca aaacccaaggacaccctcatgatctcccggacccctgaggtcacatgcgtggtggtggacgtgagccacgaagaccctgaggtcaagttc aactggtacgtggacggcgtggaggtgcataatgccaagacaaagccgcgggaggagcagtacaacagcacgtaccgtgtggtcagcg tcctcaccgtcctgcaccaggactggctgaatggcaaggaatacaagtgcgcggtctccaacaaagccctcccagcccccatcgagaaaa ccatctccaaagccaaagggcagccccgagaaccacaggtgtacaccctgcccccatcccgggatgagctgaccaagaaccaggtcag cctgacctgcctggtcaaaggcttctatccaagcgacatcgccgtggagtgggagagcaatgggcagccggagaacaactacaagaccacgcctcccgtgctggactccgacggctccttcttcctctacagcaagctcaccgtggacaagagcaggtggcagcaggggaacgtcttctc atgctccgtgatgcatgaggctctgcacaaccactacacgcagaagagcctctccctgtctccgggttctggtggaggcggttcaggcgga ggtggctccggcggtggcggatcgccgggctctcaggtccagctggtgcaatctgggcctgaggtgaagaagcctgggtcctcggtgaa ggtctcctgcaaggcttctggatataccttcagcagatctacgatgcactgggtgcgacaggcccctggacaagggcttgagtggataggat acattaatcctagcagtgcttatactaattacaatcagaaattcaaggacagagtcacgattaccgcggacaaatccacgagcacagcctaca tggagctgagcagcctgagatctgaggacacggccgtgtattactgtgcgagaccccaagtccactatgattacaacgggtttccttactgg ggccaaggaaccctggtcaccgtctcctcaggtgggaggcggttcaggcggaggtggatccggcggtggcggatcgggtggcggcggat ctgacatccagatgacccagtctccttccaccctgtctgcatctgtaggagacagagtcaccatgacttgcagtgccagctcaagtgtaagtt acatgaactggtatcagcagaaaccagggaaagcccctaagagatggatttatgactcatccaaactggcttctggggtcccatcaaggttc agcggcagtggatctgggacagattatactctcaccatcagcagcctgcagcctgatgattttgcaacttattactgccaacagtggagtcgt aacccacccactttcggcggagggaccaaggtggagatcaaacggtcctccagc(SEQ IDNO:213)
ROR207的蛋白质序列：
MEAPAQLLFLLLLWLPDTTGDIQMTQSPSSLSASVGDRVTINCQASQSIDSNLAWFQQKP GKPPKLLIYRASNLASGVPSRFSGSGSGTDFTLTISSLQPEDVATYYCLGGVGAVSYRTSF GGGTKVEIKGGGGSGGGGSGGGGSGGGGSEVQLVESGGGLVQPGRSLRLSCTASGSDI NDYPITWVRQAPGKGLEWIGFINSGGSTWYASWVKGRFTISRDDSKSIA YLQMNSLKTE DTAVYYCARGYSTYYRDFNIWGQGTLVTVSSSEPKSSDKTHTCPPCPAPEAAGAPSVFL FPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTY RVVSVLTVLHQDWLNGKEYKCAVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDEkT KNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTIPPVLDSDGSFFLYSKLTVDKSRWQ QGNVFSCSVMHEALHNHYTQKSLSLSPGSGGGGSGGGGSGGGGSPGSQVQLVQSGPEV KKPGSSVKVSCKASGYIFSRSTMHWVRQAPGQGLEWIGYINPSSAYTNYNQKFKDRVTTTADKSTSTAYMELSSLRSEDTAVYYCARPQVHYDYNGFPYWGQGTLVTVSSGGGGSG GGGSGGGGSGGGGSDIQMTQSPSTLSASVGDRVTMTCSASSSVSYMNWYQQKPGKAP KRWIYDSSKLASGVPSRFSGSGSGTDYTLTISSLQPDDFATYYCQQWSRNPPTFGGGTKV EIKRSSS(SEQ ID NO：214)
ROR208的DNA序列：
atggaagcaccagcgcagcttctcttcctcctgctactctggctcccagataccaccggtgacatccagatgacccagtccccctcctccctg tccgcctccgtgggcgaccgggtgaccatcaactgccaggcctcccagtccatcgactccaacctggcctggttccagcagaagcccggc cagccccccaagctgctgatctaccgggcctccaacctggcctccggcgtgcccgaccggttctccggctccggctccggcaccgacttc accctgaccatctcctccctggaggccgaggacgtggccacctactactgcctgggcggcgtgggcgccgtgtcctaccggacctccttc ggcggcggcaccaaggtggagatcaagggtggaggcggttcaggcggaggtggatccggcggtggcggctccggtggcggcggatc tgaggtgcagctggtggagtccggcggcggcctggtgcagcccggccggtccctgcggctgtcctgcaccgcctccggctccgacatca acgactaccccatcacctgggtgcggcaggcccccggccagggcctggagtggatcggcttcatcaactccggcggctccacctggtac gcctcctgggtgaagggccggttcaccatctcccgggacgactccaagtccatcgcctacctgcagatgaactccctgaagaccgaggac accgccgtgtactattgcgcccggggctactccacctactaccgggacttcaacatctggggccagggcaccctggtgaccgtgtcctcga gtgagcccaaatcttctgacaaaactcacacatgcccaccgtgcccagcacctgaagccgcgggtgcaccgtcagtcttcctcttcccccca aaacccaaggacaccctcatgatctcccggacccctgaggtcacatgcgtggtggtggacgtgagccacgaagaccctgaggtcaagttc aactggtacgtggacggcgtggaggtgcataatgccaagacaaagccgcgggaggagcagtacaacagcacgtaccgtgtggtcagcg tcctcaccgtcctgcaccaggactggctgaatggcaaggaatacaagtgcgcggtctccaacaaagccctcccagcccccatcgagaaaa ccatctccaaagccaaagggcagccccgagaaccacaggtgtacaccctgcccccatcccgggatgagctgaccaagaaccaggtcag cctgacctgcctggtcaaaggcttctatccaagcgacatcgccgtggagtgggagagcaatgggcagccggagaacaactacaagaccacgcctcccgtgctggactccgacggctccttcttcctctacagcaagctcaccgtggacaagagcaggtggcagcaggggaacgtcttctc atgctccgtgatgcatgaggctctgcacaaccactacacgcagaagagcctctccctgtctccgggttctggtggaggcggttcaggcgga ggtggctccggcggtggcggatcgccgggctctcaggtccagctggtggagtctgggggcggagtggtgcagcctgggcggtcactga ggctgtcctgcaaggcttctggctacacctttactagatctacgatgcactgggtaaggcaggcccctggacaaggtctggaatggattgga tacattaatcctagcagtgcttatactaattacaatcagaaattcaaggacaggttcacaatcagcgcagacaaatccaagagcacagccttc ctgcagatggacagcctgaggcccgaggacaccggcgtctatttctgtgcacggccccaagtccactatgattacaacgggtttccttactg gggccaagggactcccgtcactgtctctagcggtggcggagggtctgggggtggcggatccggaggtggtggctctgcacaagacatcc agatgacccagtctccaagcagcctgtctgcaagcgtgggggacagggtcaccatgacctgcagtgccagctcaagtgtaagttacatga actggtaccagcagaagccgggcaaggcccccaaaagatggatttatgactcatccaaactggcttctggagtccctgctcgcttcagtgg cagtgggtctgggaccgactataccctcacaatcagcagcctgcagcccgaagatttcgccacttattactgccagcagtggagtcgtaacc cacccacgttcggaggggggaccaagctacaaattacatcctccagc(SEQ ID NO:215)
ROR208的蛋白质序列：
MEAPAQLLFLLLLWLPDTTGDIQMTQSPSSLSASVGDRVTINCQASQSIDSNLAWFQQKP GQPPKLLIYRASNLASGVPDRFSGSGSGTDFTLTISSLEAEDVATYYCLGGVGAVSYRTS FGGGTKVEIKGGGGSGGGGSGGGGSGGGGSEVQLVESGGGLVQPGRSLRLSCTASGSDI NDYPITWVRQAPGQGLEWIGFINSGGSTWYASWVKGRFTISRDDSKSIAYLQMNSLKTE DTAVYYCARGYSTYYRDFNIWGQGTLVTVSSSEPKSSDKTHTCPPCPAPEAAGAPSVFL FPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTY RVVSVLTVLHQDWLNGKEYKCAVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELT KNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQ QGNVFSCSVMHEALHNHYTQKSLSLSPGSGGGGSGGGGSGGGGSPGSQVQLVESGGGV VQPGRSLRLSCKASGYTFTRSTMHWVRQAPGQGLEWIGYINPSSAYTNYNQKFKDRFTISADKSKSTAFLQMDSLRPEDTGVYFCARPQVHYDYNGFPYWGQGTPVTVSSGGGGSG GGGSGGGGSAQDIQMTQSPSSLSASVGDRVTMTCSASSSVSYMNWYQQKPGKAPKRWI YDSSKLASGVPARFSGSGSGTDYTLTISSLQPEDFATYYCQQWSRNPPTFGGGTKLQITS SS(SEQ IDNO:216)
ROR209的DNA序列：
atggaagcaccagcgcagcttctcttcctcctgctactctggctcccagataccaccggtgacatccagatgacccagtccccctcctccctg tccgcctccgtgggcgaccgggtgaccatcaactgccaggcctcccagtccatcgactccaacctggcctggttccagcagaagcccggc cagccccccaagctgctgatctaccgggcctccaacctggcctccggcgtgcccgaccggttctccggctccggctccggcaccgacttc accctgaccatctcctccctggaggccgaggacgtggccacctactactgcctgggcggcgtgggcgccgtgtcctaccggacctccttc ggcggcggcaccaaggtggagatcaagggtggaggcggttcaggcggaggtggatccggcggtggcggctccggtggcggcggatc tgaggtgcagctggtggagtccggcggcggcctggtgcagcccggccggtccctgcggctgtcctgcaccgcctccggctccgacatca acgactaccccatcacctgggtgcggcaggcccccggccagggcctggagtggatcggcttcatcaactccggcggctccacctggtac gcctcctgggtgaagggccggttcaccatctcccgggacgactccaagtccatcgcctacctgcagatgaactccctgaagaccgaggac accgccgtgtactattgcgcccggggctactccacctactaccgggacttcaacatctggggccagggcaccctggtgaccgtgtcctcga gtgagcccaaatcttctgacaaaactcacacatgcccaccgtgcccagcacctgaagccgcgggtgcaccgtcagtcttcctcttcccccca aaacccaaggacaccctcatgatctcccggacccctgaggtcacatgcgtggtggtggacgtgagccacgaagaccctgaggtcaagttc aactggtacgtggacggcgtggaggtgcataatgccaagacaaagccgcgggaggagcagtacaacagcacgtaccgtgtggtcagcg tcctcaccgtcctgcaccaggactggctgaatggcaaggaatacaagtgcgcggtctccaacaaagccctcccagcccccatcgagaaaa ccatctccaaagccaaagggcagccccgagaaccacaggtgtacaccctgcccccatcccgggatgagctgaccaagaaccaggtcag cctgacctgcctggtcaaaggcttctatccaagcgacatcgccgtggagtgggagagcaatgggcagccggagaacaactacaagaccacgcctcccgtgctggactccgacggctccttcttcctctacagcaagctcaccgtggacaagagcaggtggcagcaggggaacgtcttctc atgctccgtgatgcatgaggctctgcacaaccactacacgcagaagagcctctccctgtctccgggttctggtggaggcggttcaggcgga ggtggctccggcggtggcggatcgccgggctctcaggtccagctggtgcaatctgggcctgaggtgaagaagcctgggtcctcggtgaa ggtctcctgcaaggcttctggatataccttcagcagatctacgatgcactgggtgcgacaggcccctggacaagggcttgagtggataggat acattaatcctagcagtgcttatactaattacaatcagaaattcaaggacagagtcacgattaccgcggacaaatccacgagcacagcctaca tggagctgagcagcctgagatctgaggacacggccgtgtattactgtgcgagaccccaagtccactatgattacaacgggtttccttactgg ggccaaggaaccctggtcaccgtctcctcaggtggaggcggttcaggcggaggtggatccggcggtggcggatcgggtggcggcggat ctgacatccagatgacccagtctccttccaccctgtctgcatctgtaggagacagagtcaccatgacttgcagtgccagctcaagtgtaagtt acatgaactggtatcagcagaaaccagggaaagcccctaagagatggatttatgactcatccaaactggcttctggggtcccatcaaggttc agcggcagtggatctgggacagattatactctcaccatcagcagcctgcagcctgatgattttgcaacttattactgccaacagtggagtcgt aacccacccactttcggcggagggaccaaggtggagatcaaacggtcctccagc(SEQ ID NO:217)
ROR209的蛋白质序列：
MEAPAQLLFLLLLWLPDTTGDIQMTQSPSSLSASVGDRVTINCQASQSIDSNLAWFQQKP GQPPKLLIYRASNLASGVPDRFSGSGSGTDFTLTISSLEAEDVATYYCLGGVGAVSYRTS FGGGTKVEIKGGGGSGGGGSGGGGSGGGGSEVQLVESGGGLVQPGRSLRLSCTASGSDI NDYPITWVRQAPGQGLEWIGFINSGGSTWYASWVKGRFTISRDDSKSIAYLQMNSLKTE DTAVYYCARGYSTYYRDFNIWGQGTLVTVSSSEPKSSDKTHTCPPCPAPEAAGAPSVFL FPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTY RVVSVLTVLHQDWLNGKEYKCAVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELT KNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQ QGNVFSCSVMHEALHNHYTQKSLSLSPGSGGGGSGGGGSGGGGSPGSQVQLVQSGPEV KKPGSSVKVSCKASGYTFSRSTMHWVRQAPGQGLEWIGYINPSSAYTNYNQKFKDRVT ITADKSTSTAYMELSSLSSEDTAVYYCARPQVHYDYNGFPYWGQGTLVTVSSGGGGSG GGGSGGGGSGGGGSDIQMTQSPSTLSASVGDRVTMTCSASSSVSYMNWYQQKPGKAP KRWIYDSSKLASGVPSRFSGSGSGTDYTLTISSLQPDDFATYYCQQWSRNPPTFGGGTKV EIKRSSS(SEQ ID NO:218)
ROR231的DNA序列：
atggaggcacccgcccagctgctgttcttgttgctgctgtggctccctgataccaccggagacatccagatgacccaatccccttctagtctct ccgctagcgtcggagaccgcgtgaccatcaattgtcaagcatctcagagtattgacagcaatctcgcctggtttcagcagaagccaggaaa gccacccaagctcctgatttatagggctagcaacctggcttctggtgtccctagtaggttcagcggctctgggagtggcacagacttcaccct gaccattagtagtctgcagcccgaagatgtcgctacctattactgcctcggaggagtgggtgccgtttcttatcgcacctcatttggaggtggc accaaagtggagatcaaaggtggtggcggctccgggggtggcgggtcaggggggggagggtctggaggcggcggatcagaagttca gctggtggaatctggaggaggtctggtgcagccagggcaggtccctccggctgagctgcactgcatccggctctgacattaatgactaccct atcacctgggtgaggcaggcccccggtaaaggcctggagtggatcgggttcatcaattctggtggatctacttggtacgcaagctgggtga aaggacgcttcacaattagtagagacgactctaagtctatcgcatatctgcagatgaatagcttgaagacagaggacaccgccgtgtactatt gtgcaagaggatactccacttactaccgcgatttcaatatctggggccagggaaccctggtgacagtgtcctcgagtgagcccaaatcttctg acaaaactcacacatgcccaccgtgcccagcacctgaagccgcgggtgcaccgtcagtcttcctcttccccccaaaacccaaggacaccc tcatgatctcccggacccctgaggtcacatgcgtggtggtggacgtgagccacgaagaccctgaggtcaagttcaactggtacgtggacg gcgtggaggtgcataatgccaagacaaagccgcgggaggagcagtacaacagcacgtaccgtgtggtcagcgtcctcaccgtcctgcac caggactggctgaatggcaagggaatacaagtgcgcggtctccaacaaagccctcccagcccccatcgagaaaaccatctccaaagccaa agggcagccccgagaaccacaggtgtacaccctgcccccatcccgggatgagctgaccaagaaccaggtcagcctgacctgcctggtc aaaggcttctatccaagcgacatcgccgtggagtgggagagcaatgggcagccggagaacaactacaagaccacgcctcccgtgctgg actccgacggctccttcttcctctacagcaagctcaccgtggacaagagcaggtggcagcaggggaacgtcttctcatgctccgtgatgcat gaggctctgcacaaccactacacgcagaagagcctctccctgtctccgggttccggaggcggcggctccggcggcggcggcagcggc ggcggcggcagccccggatcccaggtgcagctggtgcagtctggtcctgaggtgaaaaagcctggctccagcgtgaaggtgtcctgcaa ggccagcggatacacctttagccggtccaccatgcattgggtgaggcaggctcctggacagggcctggagtggatcggctacatcaaccc cagcagcgcttataccaactacaatcagaagtttaaggaccgggtgaccatcaccgccgataagtccaccagcaccgcctacatggagct gtccagcctgaggagcgaggataccgccgtgtactattgcgcccggccccaggtccattacgactacaacggcttcccctattggggcca gggaaccctggtgaccgtgtccagcggaggcggcggcagcggcggcggcggcagcggcggaggaggcagcggcggaggaggctc cgacattcagatgacccagtccccctccaccctgtccgctagcgtgggcgatcgggtgaccatgacctgcagcgccagcagctccgtgtc ctacatgaactggtaccagcagaagcccggcaaggctcccaagaggtggatttacgactccagcaagctggcctctggtgtccccagcag gttctctggtagcggcagcggcacagactacaccctgaccatctcctccctgcagcccgacgatttcgccacctactattgccagcagtggt cccggaatccccctacctttggcggcggcaccaaggtggagatcaagaggagctccagc(SEQ IDNO:219)
ROR231的蛋白质序列：
MEAPAQLLFLLLLWLPDTTGDIQMTQSPSSLSASVGDRVTINCQASQSIDSNLAWFQQKP GKPPKLLIYRASNLASGVPSRFSGSGSGTDFTLTISSLQPEDVATYYCLGGVGAVSYRTSF GGGTKVEIKGGGGSGGGGSGGGGSGGGGSEVQLVESGGGLVQVQPGRSLRLSCTASGSDI NDYPITWVRQAPGKGLEWIGFINSGGSTWYASWVKGRFTISRDDSKSIAYLQMNSLKTE DTAVYYCARGYSTYYRDFNIWGQGTLVVTVSSSEPKSSDKTHTCPPCPAPEAAGAPSVFL FPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTY RVVSVLTVLHQDWLNGKEYKCAVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELT KNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQ QGNVFSCSVMHEALHNHYTQKSLSLSPGSGGGGSGGGGSGGGGSPGSQVQLVQSGPEV KKPGSSVKVSCKASGYTFSRSTMHWVRQAPGQGLEWIGYINPSSAYTNYNQKFKDRVTITADKSTSTAYMELSSLRSEDTAVYYCARPQVHYDYNGFPYWGQGTLVTVSSGGGGSG GGGSGGGGSGGGGSDIQMTQSPSTLSASVGDRVTMTCSASSSVSYMNWYQQKPGKAP KRWIYDSSKLASGVPSRFSGSGSGTDYTLTISSLQPDDFATYYCQQWSRNPPTFGGGTKV EIKRSSS(SEQ ID NO:220)
ROR233的DNA序列：
atggaggctcccgctcagctgctgttcctcctgctgctctggctgcccgacaccacaggcgacatccagatgacccagtccccttcctccct gtccgctagcgtggggcgatagggtgaccatcaactgccaggcctcccagtccattgactccaatctggcctggttccagcagaagcccgg acagccccccaagctgctgatttacagggcctccaacctggcttccggcgtgcctgacaggttctccggatccggcagcggcaccgacttc accctgaccatctcctccctggaggccgaggatgtcgccacctactactgtctgggcggcgtgggcgctgtgagctatcggacctccttcg gcggcggcaccaaggtggagatcaagggcggcggcggcagcggcggcggcggcagcggcggcggaggctccggcggcggcggc agcgaggtgcagctggtggaaagcggaggaggcctggtgcagcctggaaggtccctgaggctgtcctgcacagccagcggctccgac atcaacgactaccccatcacctgggtgaggcaggctcctggccagggcctggaatggatcggctttatcaacagcggcggcagcacctg gtatgcttcctgggtgaagggccggttcaccattagcagggacgactccaagtccattgcctacctgcagatgaactccctgaagaccgag gacaccgccgtgtactactgcgccaggggctacagcacctattaccgggactttaacatctggggccagggcacactggtcaccgtgtcct cgagtgagcccaaatcttctgacaaaactcacacatgcccaccgtgcccagcacctgaagccgcgggtgcaccgtcagtcttcctcttccc cccaaaacccaaggacaccctcatgatctcccggacccctgaggtcacatgcgtggtggtggacgtgagccacgaagaccctgaggtca agttcaactggtacgtggacggcgtggaggtgcataatgccaagacaaagccgcgggaggagcagtacaacagcacgtaccgtgtggtc agcgtcctcaccgtcctgcaccaggactggctgaatggcaaggaatacaagtgcgcggtctccaacaaagccctcccagcccccatcga gaaaaccatctccaaagccaaagggcagccccgagaaccacaggtgtacaccctgcccccatcccgggatgagctgaccaagaaccag gtcagcctgacctgcctggtcaaaggcttctatccaagcgacatcgccgtggagtgggagagcaatgggcagccggagaacaactacaa gaccacgcctcccgtgctggactccgacggctccttcttcctctacagcaagctcaccgtggacaagagcaggtggcagcaggggaacgt cttctcatgctccgtgatgcatgaggctctgcacaaccactacacgcagaagagcctctccctgtctccgggttccggaggcggcggctcc ggcggcggcggcagcggcggcggcggcagccccggatcccaggtgcagctggtgcagtctggtcctgaggtgaaaaagcctggctcc agcgtgaaggtgtcctgcaaggccagcggatacacctttagccggtccaccatgcattgggtgaggcaggctcctggacagggcctgga gtggatcggctacatcaaccccagcagcgcttataccaactacaatcagaagtttaaggaccgggtgaccatcaccgccgataagtccacc agcaccgcctacatggagctgtccagcctgaggagcgaggataccgccgtgtactattgcgcccggccccaggtccattacgactacaac ggcttcccctattggggccagggaaccctggtgaccgtgtccagcggaggcggcggcagcggcggcggcggcagcggcggaggagg cagcggcggaggaggctccgacattcagatgacccagtccccctccaccctgtccgctagcgtgggcgatcgggtgaccatgacctgca gcgccagcagctccgtgtcctacatgaactggtaccagcagaagcccggcaaggctcccaagaggtggatttacgactccagcaagctg gcctctggtgtccccagcaggttctctggtagcggcagcggcacagactacaccctgaccatctcctccctgcagcccgacgatttcgcca cctactattgccagcagtggtcccggaatccccctacctttggcggcggcaccaaggtggagatcaagaggagctccagc(SEQ IDNO:221)
ROR233的蛋白质序列：
MEAPAQLLFLLLLWLPDTTGDIQMTQSPSSLSASVGDRVTINCQASQSIDSNLAWFQQKP GQPPKLLIYRASNLASGVPDRFSGSGSGTDFTLTISSLEAEDVATYYCLGGVGAVSYRTS FGGGTKVEIKGGGGSGGGGSGGGGSGGGGSEVQLVESGGGLVQPGRSLRLSCTASGSDI NDYPITWVRQAPGQGLEWIGFINSGGSTWYASWVKGRFTISRDDSKSIAYLQMNSLKTE DTAVYYCARGYSTYYRDFNIWGQGTLVTVSSSEPKSSDKTHTCPPCPAPEAAGAPSVFL FPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTY RVVSVLTVLHQDWLNGKEYKCAVSNKALPAPIEKTISK AKGQPREPQVYTLPPSRDELT KNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQ QGNVFSC SVMHEALHNHYTQKSLSLSPGSGGGGSGGGGSGGGGSPGSQVQLVQSGPEV KKPGSSVKVSCKASGYTFSRSTMHWVRQAPGQGLEWIGYINPSSAYTNYNQKFKDRVTITADKSTSTAYMELSSLRSEDTAVYYCARPQVHYDYNGFPYWGQGTLVTVSSGGGGSG GGGSGGGGSGGGGSDIQMTQSPSTLSASVGDRVTMTCSASSSVSYMNWYQQKPGKAP KRWIYDSSKLASGVPSRFSGSGSGTDYTLTTSSLQPDDFATYYCQQWSRNPPTFGGGTKV EIKRSSS(SEQ ID NO:222)
表15.SEQ ID NO汇总
Figure BDA0001603367540001491
Figure BDA0001603367540001501
Figure BDA0001603367540001511
Figure BDA0001603367540001521
序列表
<110> APTEVO RESEARCH AND DEVELOPMENT LLC
Tan, Philip
Blankenship, John W.
<120> CD3结合多肽
<130> APVO-052/01WO
<150> US 62/221,190
<151> 2015-09-21
<160> 222
<170> PatentIn 3.5版
<210> 1
<211> 1560
<212> DNA
<213> 人工序列
<220>
<223> Fc DRA222 (TSC311或TSC312) CD3结合结构域
<400> 1
atggaagcac cagcgcagct tctcttcctc ctgctactct ggctcccaga taccaccggt 60
gagcccaaat cttctgacaa aactcacaca tgcccaccgt gcccagcacc tgaagccgcg 120
ggtgcaccgt cagtcttcct cttcccccca aaacccaagg acaccctcat gatctcccgg 180
acccctgagg tcacatgcgt ggtggtggac gtgagccacg aagaccctga ggtcaagttc 240
aactggtacg tggacggcgt ggaggtgcat aatgccaaga caaagccgcg ggaggagcag 300
tacaacagca cgtaccgtgt ggtcagcgtc ctcaccgtcc tgcaccagga ctggctgaat 360
ggcaaggcat acgcgtgcgc ggtctccaac aaagccctcc cagcccccat cgagaaaacc 420
atctccaaag ccaaagggca gccccgagaa ccacaggtgt acaccctgcc cccatcccgg 480
gatgagctga ccaagaacca ggtcagcctg acctgcctgg tcaaaggctt ctatccaagc 540
gacatcgccg tggagtggga gagcaatggg cagccggaga acaactacaa gaccacgcct 600
cccgtgctgg actccgacgg ctccttcttc ctctacagca agctcaccgt ggacaagagc 660
aggtggcagc aggggaacgt cttctcatgc tccgtgatgc atgaggctct gcacaaccac 720
tacacgcaga agagcctctc cctgtctccg ggtcagaggc acaacaattc ttccctgaat 780
acaggaactc agatggcagg tcattctccg aattctcagg tccagctggt ggagtctggg 840
ggcggagtgg tgcagcctgg gcggtcactg aggctgtcct gcaaggcttc tggctacacc 900
tttactagat ctacgatgca ctgggtaagg caggcccctg gacaaggtct ggaatggatt 960
ggatacatta atcctagcag tgcttatact aattacaatc agaaattcaa ggacaggttc 1020
acaatcagcg cagacaaatc caagagcaca gccttcctgc agatggacag cctgaggccc 1080
gaggacaccg gcgtctattt ctgtgcacgg ccccaagtcc actatgatta caacgggttt 1140
ccttactggg gccaagggac tcccgtcact gtctctagcg gtggcggagg gtctgggggt 1200
ggcggatccg gaggtggtgg ctctgcacaa gacatccaga tgacccagtc tccaagcagc 1260
ctgtctgcaa gcgtggggga cagggtcacc atgacctgca gtgccagctc aagtgtaagt 1320
tacatgaact ggtaccagca gaagccgggc aaggccccca aaagatggat ttatgactca 1380
tccaaactgg cttctggagt ccctgctcgc ttcagtggca gtgggtctgg gaccgactat 1440
accctcacaa tcagcagcct gcagcccgaa gatttcgcca cttattactg ccagcagtgg 1500
agtcgtaacc cacccacgtt cggagggggg accaagctac aaattacatc ctccagctaa 1560
<210> 2
<211> 499
<212> PRT
<213> 人工序列
<220>
<223> Fc DRA222 (TSC311或TSC312) CD3结合结构域
<400> 2
Glu Pro Lys Ser Ser Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala
1 5 10 15
Pro Glu Ala Ala Gly Ala Pro Ser Val Phe Leu Phe Pro Pro Lys Pro
20 25 30
Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val
35 40 45
Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val
50 55 60
Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln
65 70 75 80
Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln
85 90 95
Asp Trp Leu Asn Gly Lys Ala Tyr Ala Cys Ala Val Ser Asn Lys Ala
100 105 110
Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro
115 120 125
Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr
130 135 140
Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser
145 150 155 160
Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr
165 170 175
Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr
180 185 190
Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe
195 200 205
Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys
210 215 220
Ser Leu Ser Leu Ser Pro Gly Gln Arg His Asn Asn Ser Ser Leu Asn
225 230 235 240
Thr Gly Thr Gln Met Ala Gly His Ser Pro Asn Ser Gln Val Gln Leu
245 250 255
Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg Ser Leu Arg Leu
260 265 270
Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Arg Ser Thr Met His Trp
275 280 285
Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Ile Gly Tyr Ile Asn
290 295 300
Pro Ser Ser Ala Tyr Thr Asn Tyr Asn Gln Lys Phe Lys Asp Arg Phe
305 310 315 320
Thr Ile Ser Ala Asp Lys Ser Lys Ser Thr Ala Phe Leu Gln Met Asp
325 330 335
Ser Leu Arg Pro Glu Asp Thr Gly Val Tyr Phe Cys Ala Arg Pro Gln
340 345 350
Val His Tyr Asp Tyr Asn Gly Phe Pro Tyr Trp Gly Gln Gly Thr Pro
355 360 365
Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly
370 375 380
Gly Gly Gly Ser Ala Gln Asp Ile Gln Met Thr Gln Ser Pro Ser Ser
385 390 395 400
Leu Ser Ala Ser Val Gly Asp Arg Val Thr Met Thr Cys Ser Ala Ser
405 410 415
Ser Ser Val Ser Tyr Met Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala
420 425 430
Pro Lys Arg Trp Ile Tyr Asp Ser Ser Lys Leu Ala Ser Gly Val Pro
435 440 445
Ala Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Tyr Thr Leu Thr Ile
450 455 460
Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Trp
465 470 475 480
Ser Arg Asn Pro Pro Thr Phe Gly Gly Gly Thr Lys Leu Gln Ile Thr
485 490 495
Ser Ser Ser
<210> 3
<211> 1569
<212> DNA
<213> 人工序列
<220>
<223> Fc H7L1 (TSC313) CD3结合结构域
<400> 3
atggaagcac cagcgcagct tctcttcctc ctgctactct ggctcccaga taccaccggt 60
gagcccaaat cttctgacaa aactcacaca tgcccaccgt gcccagcacc tgaagccgcg 120
ggtgcaccgt cagtcttcct cttcccccca aaacccaagg acaccctcat gatctcccgg 180
acccctgagg tcacatgcgt ggtggtggac gtgagccacg aagaccctga ggtcaagttc 240
aactggtacg tggacggcgt ggaggtgcat aatgccaaga caaagccgcg ggaggagcag 300
tacaacagca cgtaccgtgt ggtcagcgtc ctcaccgtcc tgcaccagga ctggctgaat 360
ggcaaggcat acgcgtgcgc ggtctccaac aaagccctcc cagcccccat cgagaaaacc 420
atctccaaag ccaaagggca gccccgagaa ccacaggtgt acaccctgcc cccatcccgg 480
gatgagctga ccaagaacca ggtcagcctg acctgcctgg tcaaaggctt ctatccaagc 540
gacatcgccg tggagtggga gagcaatggg cagccggaga acaactacaa gaccacgcct 600
cccgtgctgg actccgacgg ctccttcttc ctctacagca agctcaccgt ggacaagagc 660
aggtggcagc aggggaacgt cttctcatgc tccgtgatgc atgaggctct gcacaaccac 720
tacacgcaga agagcctctc cctgtctccg ggtcagaggc acaacaattc ttccctgaat 780
acaggaactc agatggcagg tcattctccg aattctcagg tgcagctggt gcagtctggg 840
gctgaggtga agaagcctgg ggcctcagtg aaggtctcct gcaaggcttc tggatacacc 900
ttcaccagat ctacgatgca ctgggtgcga caggcccctg gacaagggct tgagtggatg 960
ggatacatta atcctagcag tgcttatact aattacaatc agaaattcaa ggacagggtc 1020
accatgacca gggacacgtc catcagcaca gcctacatgg agctgagcag gctgagatct 1080
gacgacacgg ccgtgtatta ctgtgcgaga ccccaagtcc actatgatta caacgggttt 1140
ccttactggg gccaaggaac cctggtcacc gtctcctcag gtggaggcgg ttcaggcgga 1200
ggtggatccg gcggtggcgg atcgggtggc ggcggatctg acatccagat gacccagtct 1260
ccaagcagcc tgtctgcaag cgtgggggac agggtcacca tgacctgcag tgccagctca 1320
agtgtaagtt acatgaactg gtaccagcag aagccgggca aggcccccaa aagatggatt 1380
tatgactcat ccaaactggc ttctggagtc cctgctcgct tcagtggcag tgggtctggg 1440
accgactata ccctcacaat cagcagcctg cagcccgaag atttcgccac ttattactgc 1500
cagcagtgga gtcgtaaccc acccacgttc ggagggggga ccaagctaca aattacatcc 1560
tccagctaa 1569
<210> 4
<211> 502
<212> PRT
<213> 人工序列
<220>
<223> Fc H7L1 (TSC313) CD3结合结构域
<400> 4
Glu Pro Lys Ser Ser Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala
1 5 10 15
Pro Glu Ala Ala Gly Ala Pro Ser Val Phe Leu Phe Pro Pro Lys Pro
20 25 30
Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val
35 40 45
Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val
50 55 60
Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln
65 70 75 80
Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln
85 90 95
Asp Trp Leu Asn Gly Lys Ala Tyr Ala Cys Ala Val Ser Asn Lys Ala
100 105 110
Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro
115 120 125
Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr
130 135 140
Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser
145 150 155 160
Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr
165 170 175
Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr
180 185 190
Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe
195 200 205
Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys
210 215 220
Ser Leu Ser Leu Ser Pro Gly Gln Arg His Asn Asn Ser Ser Leu Asn
225 230 235 240
Thr Gly Thr Gln Met Ala Gly His Ser Pro Asn Ser Gln Val Gln Leu
245 250 255
Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala Ser Val Lys Val
260 265 270
Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Arg Ser Thr Met His Trp
275 280 285
Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met Gly Tyr Ile Asn
290 295 300
Pro Ser Ser Ala Tyr Thr Asn Tyr Asn Gln Lys Phe Lys Asp Arg Val
305 310 315 320
Thr Met Thr Arg Asp Thr Ser Ile Ser Thr Ala Tyr Met Glu Leu Ser
325 330 335
Arg Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys Ala Arg Pro Gln
340 345 350
Val His Tyr Asp Tyr Asn Gly Phe Pro Tyr Trp Gly Gln Gly Thr Leu
355 360 365
Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly
370 375 380
Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Gln Met Thr Gln Ser
385 390 395 400
Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Met Thr Cys
405 410 415
Ser Ala Ser Ser Ser Val Ser Tyr Met Asn Trp Tyr Gln Gln Lys Pro
420 425 430
Gly Lys Ala Pro Lys Arg Trp Ile Tyr Asp Ser Ser Lys Leu Ala Ser
435 440 445
Gly Val Pro Ala Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Tyr Thr
450 455 460
Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys
465 470 475 480
Gln Gln Trp Ser Arg Asn Pro Pro Thr Phe Gly Gly Gly Thr Lys Leu
485 490 495
Gln Ile Thr Ser Ser Ser
500
<210> 5
<211> 1572
<212> DNA
<213> 人工序列
<220>
<223> H7L4 (TSC314) CD3结合结构域
<400> 5
atggaagcac cagcgcagct tctcttcctc ctgctactct ggctcccaga taccaccggt 60
gagcccaaat cttctgacaa aactcacaca tgcccaccgt gcccagcacc tgaagccgcg 120
ggtgcaccgt cagtcttcct cttcccccca aaacccaagg acaccctcat gatctcccgg 180
acccctgagg tcacatgcgt ggtggtggac gtgagccacg aagaccctga ggtcaagttc 240
aactggtacg tggacggcgt ggaggtgcat aatgccaaga caaagccgcg ggaggagcag 300
tacaacagca cgtaccgtgt ggtcagcgtc ctcaccgtcc tgcaccagga ctggctgaat 360
ggcaaggcat acgcgtgcgc ggtctccaac aaagccctcc cagcccccat cgagaaaacc 420
atctccaaag ccaaagggca gccccgagaa ccacaggtgt acaccctgcc cccatcccgg 480
gatgagctga ccaagaacca ggtcagcctg acctgcctgg tcaaaggctt ctatccaagc 540
gacatcgccg tggagtggga gagcaatggg cagccggaga acaactacaa gaccacgcct 600
cccgtgctgg actccgacgg ctccttcttc ctctacagca agctcaccgt ggacaagagc 660
aggtggcagc aggggaacgt cttctcatgc tccgtgatgc atgaggctct gcacaaccac 720
tacacgcaga agagcctctc cctgtctccg ggtcagaggc acaacaattc ttccctgaat 780
acaggaactc agatggcagg tcattctccg aattctcagg tgcagctggt gcagtctggg 840
gctgaggtga agaagcctgg ggcctcagtg aaggtctcct gcaaggcttc tggatacacc 900
ttcaccagat ctacgatgca ctgggtgcga caggcccctg gacaagggct tgagtggatg 960
ggatacatta atcctagcag tgcttatact aattacaatc agaaattcaa ggacagggtc 1020
accatgacca gggacacgtc catcagcaca gcctacatgg agctgagcag gctgagatct 1080
gacgacacgg ccgtgtatta ctgtgcgaga ccccaagtcc actatgatta caacgggttt 1140
ccttactggg gccaaggaac cctggtcacc gtctcctcag gtggaggcgg ttcaggcgga 1200
ggtggatccg gcggtggcgg atcgggtggc ggcggatctg aaattgtgtt gacacagtct 1260
ccagccaccc tgtctttgtc tccaggggaa agagccaccc tctcctgcag tgccagctca 1320
agtgtaagtt acatgaactg gtaccaacag aaacctggcc aggctcccag gctcctcatc 1380
tatgactcat ccaaactggc ttctggcatc ccagccaggt tcagtggcag tgggtctggg 1440
acagacttca ctctcaccat cagcagccta gagcctgaag attttgcagt ttattactgt 1500
cagcagtgga gtcgtaaccc acccactttc ggcggaggga ccaaggtgga gatcaaacgg 1560
tcctccagct aa 1572
<210> 6
<211> 503
<212> PRT
<213> 人工序列
<220>
<223> Fc H7L4 (TSC314) CD3结合结构域
<400> 6
Glu Pro Lys Ser Ser Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala
1 5 10 15
Pro Glu Ala Ala Gly Ala Pro Ser Val Phe Leu Phe Pro Pro Lys Pro
20 25 30
Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val
35 40 45
Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val
50 55 60
Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln
65 70 75 80
Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln
85 90 95
Asp Trp Leu Asn Gly Lys Ala Tyr Ala Cys Ala Val Ser Asn Lys Ala
100 105 110
Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro
115 120 125
Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr
130 135 140
Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser
145 150 155 160
Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr
165 170 175
Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr
180 185 190
Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe
195 200 205
Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys
210 215 220
Ser Leu Ser Leu Ser Pro Gly Gln Arg His Asn Asn Ser Ser Leu Asn
225 230 235 240
Thr Gly Thr Gln Met Ala Gly His Ser Pro Asn Ser Gln Val Gln Leu
245 250 255
Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala Ser Val Lys Val
260 265 270
Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Arg Ser Thr Met His Trp
275 280 285
Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met Gly Tyr Ile Asn
290 295 300
Pro Ser Ser Ala Tyr Thr Asn Tyr Asn Gln Lys Phe Lys Asp Arg Val
305 310 315 320
Thr Met Thr Arg Asp Thr Ser Ile Ser Thr Ala Tyr Met Glu Leu Ser
325 330 335
Arg Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys Ala Arg Pro Gln
340 345 350
Val His Tyr Asp Tyr Asn Gly Phe Pro Tyr Trp Gly Gln Gly Thr Leu
355 360 365
Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly
370 375 380
Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Ile Val Leu Thr Gln Ser
385 390 395 400
Pro Ala Thr Leu Ser Leu Ser Pro Gly Glu Arg Ala Thr Leu Ser Cys
405 410 415
Ser Ala Ser Ser Ser Val Ser Tyr Met Asn Trp Tyr Gln Gln Lys Pro
420 425 430
Gly Gln Ala Pro Arg Leu Leu Ile Tyr Asp Ser Ser Lys Leu Ala Ser
435 440 445
Gly Ile Pro Ala Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr
450 455 460
Leu Thr Ile Ser Ser Leu Glu Pro Glu Asp Phe Ala Val Tyr Tyr Cys
465 470 475 480
Gln Gln Trp Ser Arg Asn Pro Pro Thr Phe Gly Gly Gly Thr Lys Val
485 490 495
Glu Ile Lys Arg Ser Ser Ser
500
<210> 7
<211> 1572
<212> DNA
<213> 人工序列
<220>
<223> Fc H7L5 (TSC315) CD3结合结构域
<400> 7
atggaagcac cagcgcagct tctcttcctc ctgctactct ggctcccaga taccaccggt 60
gagcccaaat cttctgacaa aactcacaca tgcccaccgt gcccagcacc tgaagccgcg 120
ggtgcaccgt cagtcttcct cttcccccca aaacccaagg acaccctcat gatctcccgg 180
acccctgagg tcacatgcgt ggtggtggac gtgagccacg aagaccctga ggtcaagttc 240
aactggtacg tggacggcgt ggaggtgcat aatgccaaga caaagccgcg ggaggagcag 300
tacaacagca cgtaccgtgt ggtcagcgtc ctcaccgtcc tgcaccagga ctggctgaat 360
ggcaaggcat acgcgtgcgc ggtctccaac aaagccctcc cagcccccat cgagaaaacc 420
atctccaaag ccaaagggca gccccgagaa ccacaggtgt acaccctgcc cccatcccgg 480
gatgagctga ccaagaacca ggtcagcctg acctgcctgg tcaaaggctt ctatccaagc 540
gacatcgccg tggagtggga gagcaatggg cagccggaga acaactacaa gaccacgcct 600
cccgtgctgg actccgacgg ctccttcttc ctctacagca agctcaccgt ggacaagagc 660
aggtggcagc aggggaacgt cttctcatgc tccgtgatgc atgaggctct gcacaaccac 720
tacacgcaga agagcctctc cctgtctccg ggtcagaggc acaacaattc ttccctgaat 780
acaggaactc agatggcagg tcattctccg aattctcagg tgcagctggt gcagtctggg 840
gctgaggtga agaagcctgg ggcctcagtg aaggtctcct gcaaggcttc tggatacacc 900
ttcaccagat ctacgatgca ctgggtgcga caggcccctg gacaagggct tgagtggatg 960
ggatacatta atcctagcag tgcttatact aattacaatc agaaattcaa ggacagggtc 1020
accatgacca gggacacgtc catcagcaca gcctacatgg agctgagcag gctgagatct 1080
gacgacacgg ccgtgtatta ctgtgcgaga ccccaagtcc actatgatta caacgggttt 1140
ccttactggg gccaaggaac cctggtcacc gtctcctcag gtggaggcgg ttcaggcgga 1200
ggtggatccg gcggtggcgg atcgggtggc ggcggatctg acatccagat gacccagtct 1260
ccatcctccc tgtctgcatc tgtaggagac agagtcacca tcacttgcag tgccagctca 1320
agtgtaagtt acatgaactg gtatcagcag aaaccaggga aagcccctaa gctcctgatc 1380
tatgactcat ccaaactggc ttctggggtc ccatcaaggt tcagtggcag tggatctggg 1440
acagatttca ctctcaccat cagcagtctg caacctgaag attttgcaac ttactactgt 1500
caacagtgga gtcgtaaccc acccactttc ggcggaggga ccaaggtgga gatcaaacgg 1560
tcctccagct aa 1572
<210> 8
<211> 503
<212> PRT
<213> 人工序列
<220>
<223> Fc H7L5 (TSC315) CD3结合结构域
<400> 8
Glu Pro Lys Ser Ser Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala
1 5 10 15
Pro Glu Ala Ala Gly Ala Pro Ser Val Phe Leu Phe Pro Pro Lys Pro
20 25 30
Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val
35 40 45
Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val
50 55 60
Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln
65 70 75 80
Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln
85 90 95
Asp Trp Leu Asn Gly Lys Ala Tyr Ala Cys Ala Val Ser Asn Lys Ala
100 105 110
Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro
115 120 125
Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr
130 135 140
Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser
145 150 155 160
Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr
165 170 175
Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr
180 185 190
Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe
195 200 205
Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys
210 215 220
Ser Leu Ser Leu Ser Pro Gly Gln Arg His Asn Asn Ser Ser Leu Asn
225 230 235 240
Thr Gly Thr Gln Met Ala Gly His Ser Pro Asn Ser Gln Val Gln Leu
245 250 255
Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala Ser Val Lys Val
260 265 270
Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Arg Ser Thr Met His Trp
275 280 285
Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met Gly Tyr Ile Asn
290 295 300
Pro Ser Ser Ala Tyr Thr Asn Tyr Asn Gln Lys Phe Lys Asp Arg Val
305 310 315 320
Thr Met Thr Arg Asp Thr Ser Ile Ser Thr Ala Tyr Met Glu Leu Ser
325 330 335
Arg Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys Ala Arg Pro Gln
340 345 350
Val His Tyr Asp Tyr Asn Gly Phe Pro Tyr Trp Gly Gln Gly Thr Leu
355 360 365
Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly
370 375 380
Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Gln Met Thr Gln Ser
385 390 395 400
Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys
405 410 415
Ser Ala Ser Ser Ser Val Ser Tyr Met Asn Trp Tyr Gln Gln Lys Pro
420 425 430
Gly Lys Ala Pro Lys Leu Leu Ile Tyr Asp Ser Ser Lys Leu Ala Ser
435 440 445
Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr
450 455 460
Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys
465 470 475 480
Gln Gln Trp Ser Arg Asn Pro Pro Thr Phe Gly Gly Gly Thr Lys Val
485 490 495
Glu Ile Lys Arg Ser Ser Ser
500
<210> 9
<211> 1569
<212> DNA
<213> 人工序列
<220>
<223> Fc H8L1 (TSC316) CD3结合结构域
<400> 9
atggaagcac cagcgcagct tctcttcctc ctgctactct ggctcccaga taccaccggt 60
gagcccaaat cttctgacaa aactcacaca tgcccaccgt gcccagcacc tgaagccgcg 120
ggtgcaccgt cagtcttcct cttcccccca aaacccaagg acaccctcat gatctcccgg 180
acccctgagg tcacatgcgt ggtggtggac gtgagccacg aagaccctga ggtcaagttc 240
aactggtacg tggacggcgt ggaggtgcat aatgccaaga caaagccgcg ggaggagcag 300
tacaacagca cgtaccgtgt ggtcagcgtc ctcaccgtcc tgcaccagga ctggctgaat 360
ggcaaggcat acgcgtgcgc ggtctccaac aaagccctcc cagcccccat cgagaaaacc 420
atctccaaag ccaaagggca gccccgagaa ccacaggtgt acaccctgcc cccatcccgg 480
gatgagctga ccaagaacca ggtcagcctg acctgcctgg tcaaaggctt ctatccaagc 540
gacatcgccg tggagtggga gagcaatggg cagccggaga acaactacaa gaccacgcct 600
cccgtgctgg actccgacgg ctccttcttc ctctacagca agctcaccgt ggacaagagc 660
aggtggcagc aggggaacgt cttctcatgc tccgtgatgc atgaggctct gcacaaccac 720
tacacgcaga agagcctctc cctgtctccg ggtcagaggc acaacaattc ttccctgaat 780
acaggaactc agatggcagg tcattctccg aattctcagg tgcagctggt gcagtctggg 840
gctgaggtga agaagcctgg ggcctcagtg aaggtttcct gcaaggcatc tggatacacc 900
ttcaccagat ctacgatgca ctgggtgcga caggcccctg gacaagggct tgagtggatg 960
ggatacatta atcctagcag tgcttatact aattacaatc agaaattcaa ggacagagtc 1020
accatgacca gggacacgtc cacgagcaca gtctacatgg agctgagcag cctgagatct 1080
gaggacacgg ccgtgtatta ctgtgctaga ccccaagtcc actatgatta caacgggttt 1140
ccttactggg gccaaggaac cctggtcacc gtctcctcag gtggaggcgg ttcaggcgga 1200
ggtggatccg gcggtggcgg atcgggtggc ggcggatctg acatccagat gacccagtct 1260
ccaagcagcc tgtctgcaag cgtgggggac agggtcacca tgacctgcag tgccagctca 1320
agtgtaagtt acatgaactg gtaccagcag aagccgggca aggcccccaa aagatggatt 1380
tatgactcat ccaaactggc ttctggagtc cctgctcgct tcagtggcag tgggtctggg 1440
accgactata ccctcacaat cagcagcctg cagcccgaag atttcgccac ttattactgc 1500
cagcagtgga gtcgtaaccc acccacgttc ggagggggga ccaagctaca aattacatcc 1560
tccagctaa 1569
<210> 10
<211> 502
<212> PRT
<213> 人工序列
<220>
<223> Fc H8L1 (TSC316) CD3结合结构域
<400> 10
Glu Pro Lys Ser Ser Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala
1 5 10 15
Pro Glu Ala Ala Gly Ala Pro Ser Val Phe Leu Phe Pro Pro Lys Pro
20 25 30
Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val
35 40 45
Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val
50 55 60
Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln
65 70 75 80
Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln
85 90 95
Asp Trp Leu Asn Gly Lys Ala Tyr Ala Cys Ala Val Ser Asn Lys Ala
100 105 110
Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro
115 120 125
Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr
130 135 140
Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser
145 150 155 160
Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr
165 170 175
Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr
180 185 190
Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe
195 200 205
Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys
210 215 220
Ser Leu Ser Leu Ser Pro Gly Gln Arg His Asn Asn Ser Ser Leu Asn
225 230 235 240
Thr Gly Thr Gln Met Ala Gly His Ser Pro Asn Ser Gln Val Gln Leu
245 250 255
Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala Ser Val Lys Val
260 265 270
Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Arg Ser Thr Met His Trp
275 280 285
Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met Gly Tyr Ile Asn
290 295 300
Pro Ser Ser Ala Tyr Thr Asn Tyr Asn Gln Lys Phe Lys Asp Arg Val
305 310 315 320
Thr Met Thr Arg Asp Thr Ser Thr Ser Thr Val Tyr Met Glu Leu Ser
325 330 335
Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Pro Gln
340 345 350
Val His Tyr Asp Tyr Asn Gly Phe Pro Tyr Trp Gly Gln Gly Thr Leu
355 360 365
Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly
370 375 380
Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Gln Met Thr Gln Ser
385 390 395 400
Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Met Thr Cys
405 410 415
Ser Ala Ser Ser Ser Val Ser Tyr Met Asn Trp Tyr Gln Gln Lys Pro
420 425 430
Gly Lys Ala Pro Lys Arg Trp Ile Tyr Asp Ser Ser Lys Leu Ala Ser
435 440 445
Gly Val Pro Ala Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Tyr Thr
450 455 460
Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys
465 470 475 480
Gln Gln Trp Ser Arg Asn Pro Pro Thr Phe Gly Gly Gly Thr Lys Leu
485 490 495
Gln Ile Thr Ser Ser Ser
500
<210> 11
<211> 1572
<212> DNA
<213> 人工序列
<220>
<223> Fc H8L4 (TSC317) CD3结合结构域
<400> 11
atggaagcac cagcgcagct tctcttcctc ctgctactct ggctcccaga taccaccggt 60
gagcccaaat cttctgacaa aactcacaca tgcccaccgt gcccagcacc tgaagccgcg 120
ggtgcaccgt cagtcttcct cttcccccca aaacccaagg acaccctcat gatctcccgg 180
acccctgagg tcacatgcgt ggtggtggac gtgagccacg aagaccctga ggtcaagttc 240
aactggtacg tggacggcgt ggaggtgcat aatgccaaga caaagccgcg ggaggagcag 300
tacaacagca cgtaccgtgt ggtcagcgtc ctcaccgtcc tgcaccagga ctggctgaat 360
ggcaaggcat acgcgtgcgc ggtctccaac aaagccctcc cagcccccat cgagaaaacc 420
atctccaaag ccaaagggca gccccgagaa ccacaggtgt acaccctgcc cccatcccgg 480
gatgagctga ccaagaacca ggtcagcctg acctgcctgg tcaaaggctt ctatccaagc 540
gacatcgccg tggagtggga gagcaatggg cagccggaga acaactacaa gaccacgcct 600
cccgtgctgg actccgacgg ctccttcttc ctctacagca agctcaccgt ggacaagagc 660
aggtggcagc aggggaacgt cttctcatgc tccgtgatgc atgaggctct gcacaaccac 720
tacacgcaga agagcctctc cctgtctccg ggtcagaggc acaacaattc ttccctgaat 780
acaggaactc agatggcagg tcattctccg aattctcagg tgcagctggt gcagtctggg 840
gctgaggtga agaagcctgg ggcctcagtg aaggtttcct gcaaggcatc tggatacacc 900
ttcaccagat ctacgatgca ctgggtgcga caggcccctg gacaagggct tgagtggatg 960
ggatacatta atcctagcag tgcttatact aattacaatc agaaattcaa ggacagagtc 1020
accatgacca gggacacgtc cacgagcaca gtctacatgg agctgagcag cctgagatct 1080
gaggacacgg ccgtgtatta ctgtgctaga ccccaagtcc actatgatta caacgggttt 1140
ccttactggg gccaaggaac cctggtcacc gtctcctcag gtggaggcgg ttcaggcgga 1200
ggtggatccg gcggtggcgg atcgggtggc ggcggatctg aaattgtgtt gacacagtct 1260
ccagccaccc tgtctttgtc tccaggggaa agagccaccc tctcctgcag tgccagctca 1320
agtgtaagtt acatgaactg gtaccaacag aaacctggcc aggctcccag gctcctcatc 1380
tatgactcat ccaaactggc ttctggcatc ccagccaggt tcagtggcag tgggtctggg 1440
acagacttca ctctcaccat cagcagccta gagcctgaag attttgcagt ttattactgt 1500
cagcagtgga gtcgtaaccc acccactttc ggcggaggga ccaaggtgga gatcaaacgg 1560
tcctccagct aa 1572
<210> 12
<211> 503
<212> PRT
<213> 人工序列
<220>
<223> Fc H8L4 (TSC317) CD3结合结构域
<400> 12
Glu Pro Lys Ser Ser Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala
1 5 10 15
Pro Glu Ala Ala Gly Ala Pro Ser Val Phe Leu Phe Pro Pro Lys Pro
20 25 30
Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val
35 40 45
Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val
50 55 60
Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln
65 70 75 80
Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln
85 90 95
Asp Trp Leu Asn Gly Lys Ala Tyr Ala Cys Ala Val Ser Asn Lys Ala
100 105 110
Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro
115 120 125
Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr
130 135 140
Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser
145 150 155 160
Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr
165 170 175
Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr
180 185 190
Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe
195 200 205
Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys
210 215 220
Ser Leu Ser Leu Ser Pro Gly Gln Arg His Asn Asn Ser Ser Leu Asn
225 230 235 240
Thr Gly Thr Gln Met Ala Gly His Ser Pro Asn Ser Gln Val Gln Leu
245 250 255
Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala Ser Val Lys Val
260 265 270
Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Arg Ser Thr Met His Trp
275 280 285
Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met Gly Tyr Ile Asn
290 295 300
Pro Ser Ser Ala Tyr Thr Asn Tyr Asn Gln Lys Phe Lys Asp Arg Val
305 310 315 320
Thr Met Thr Arg Asp Thr Ser Thr Ser Thr Val Tyr Met Glu Leu Ser
325 330 335
Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Pro Gln
340 345 350
Val His Tyr Asp Tyr Asn Gly Phe Pro Tyr Trp Gly Gln Gly Thr Leu
355 360 365
Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly
370 375 380
Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Ile Val Leu Thr Gln Ser
385 390 395 400
Pro Ala Thr Leu Ser Leu Ser Pro Gly Glu Arg Ala Thr Leu Ser Cys
405 410 415
Ser Ala Ser Ser Ser Val Ser Tyr Met Asn Trp Tyr Gln Gln Lys Pro
420 425 430
Gly Gln Ala Pro Arg Leu Leu Ile Tyr Asp Ser Ser Lys Leu Ala Ser
435 440 445
Gly Ile Pro Ala Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr
450 455 460
Leu Thr Ile Ser Ser Leu Glu Pro Glu Asp Phe Ala Val Tyr Tyr Cys
465 470 475 480
Gln Gln Trp Ser Arg Asn Pro Pro Thr Phe Gly Gly Gly Thr Lys Val
485 490 495
Glu Ile Lys Arg Ser Ser Ser
500
<210> 13
<211> 1572
<212> DNA
<213> 人工序列
<220>
<223> Fc H8L5 (TSC318) CD3结合结构域
<400> 13
atggaagcac cagcgcagct tctcttcctc ctgctactct ggctcccaga taccaccggt 60
gagcccaaat cttctgacaa aactcacaca tgcccaccgt gcccagcacc tgaagccgcg 120
ggtgcaccgt cagtcttcct cttcccccca aaacccaagg acaccctcat gatctcccgg 180
acccctgagg tcacatgcgt ggtggtggac gtgagccacg aagaccctga ggtcaagttc 240
aactggtacg tggacggcgt ggaggtgcat aatgccaaga caaagccgcg ggaggagcag 300
tacaacagca cgtaccgtgt ggtcagcgtc ctcaccgtcc tgcaccagga ctggctgaat 360
ggcaaggcat acgcgtgcgc ggtctccaac aaagccctcc cagcccccat cgagaaaacc 420
atctccaaag ccaaagggca gccccgagaa ccacaggtgt acaccctgcc cccatcccgg 480
gatgagctga ccaagaacca ggtcagcctg acctgcctgg tcaaaggctt ctatccaagc 540
gacatcgccg tggagtggga gagcaatggg cagccggaga acaactacaa gaccacgcct 600
cccgtgctgg actccgacgg ctccttcttc ctctacagca agctcaccgt ggacaagagc 660
aggtggcagc aggggaacgt cttctcatgc tccgtgatgc atgaggctct gcacaaccac 720
tacacgcaga agagcctctc cctgtctccg ggtcagaggc acaacaattc ttccctgaat 780
acaggaactc agatggcagg tcattctccg aattctcagg tgcagctggt gcagtctggg 840
gctgaggtga agaagcctgg ggcctcagtg aaggtttcct gcaaggcatc tggatacacc 900
ttcaccagat ctacgatgca ctgggtgcga caggcccctg gacaagggct tgagtggatg 960
ggatacatta atcctagcag tgcttatact aattacaatc agaaattcaa ggacagagtc 1020
accatgacca gggacacgtc cacgagcaca gtctacatgg agctgagcag cctgagatct 1080
gaggacacgg ccgtgtatta ctgtgctaga ccccaagtcc actatgatta caacgggttt 1140
ccttactggg gccaaggaac cctggtcacc gtctcctcag gtggaggcgg ttcaggcgga 1200
ggtggatccg gcggtggcgg atcgggtggc ggcggatctg acatccagat gacccagtct 1260
ccatcctccc tgtctgcatc tgtaggagac agagtcacca tcacttgcag tgccagctca 1320
agtgtaagtt acatgaactg gtatcagcag aaaccaggga aagcccctaa gctcctgatc 1380
tatgactcat ccaaactggc ttctggggtc ccatcaaggt tcagtggcag tggatctggg 1440
acagatttca ctctcaccat cagcagtctg caacctgaag attttgcaac ttactactgt 1500
caacagtgga gtcgtaaccc acccactttc ggcggaggga ccaaggtgga gatcaaacgg 1560
tcctccagct aa 1572
<210> 14
<211> 503
<212> PRT
<213> 人工序列
<220>
<223> Fc H8L5 (TSC318) CD3结合结构域
<400> 14
Glu Pro Lys Ser Ser Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala
1 5 10 15
Pro Glu Ala Ala Gly Ala Pro Ser Val Phe Leu Phe Pro Pro Lys Pro
20 25 30
Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val
35 40 45
Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val
50 55 60
Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln
65 70 75 80
Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln
85 90 95
Asp Trp Leu Asn Gly Lys Ala Tyr Ala Cys Ala Val Ser Asn Lys Ala
100 105 110
Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro
115 120 125
Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr
130 135 140
Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser
145 150 155 160
Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr
165 170 175
Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr
180 185 190
Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe
195 200 205
Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys
210 215 220
Ser Leu Ser Leu Ser Pro Gly Gln Arg His Asn Asn Ser Ser Leu Asn
225 230 235 240
Thr Gly Thr Gln Met Ala Gly His Ser Pro Asn Ser Gln Val Gln Leu
245 250 255
Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala Ser Val Lys Val
260 265 270
Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Arg Ser Thr Met His Trp
275 280 285
Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met Gly Tyr Ile Asn
290 295 300
Pro Ser Ser Ala Tyr Thr Asn Tyr Asn Gln Lys Phe Lys Asp Arg Val
305 310 315 320
Thr Met Thr Arg Asp Thr Ser Thr Ser Thr Val Tyr Met Glu Leu Ser
325 330 335
Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Pro Gln
340 345 350
Val His Tyr Asp Tyr Asn Gly Phe Pro Tyr Trp Gly Gln Gly Thr Leu
355 360 365
Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly
370 375 380
Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Gln Met Thr Gln Ser
385 390 395 400
Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys
405 410 415
Ser Ala Ser Ser Ser Val Ser Tyr Met Asn Trp Tyr Gln Gln Lys Pro
420 425 430
Gly Lys Ala Pro Lys Leu Leu Ile Tyr Asp Ser Ser Lys Leu Ala Ser
435 440 445
Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr
450 455 460
Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys
465 470 475 480
Gln Gln Trp Ser Arg Asn Pro Pro Thr Phe Gly Gly Gly Thr Lys Val
485 490 495
Glu Ile Lys Arg Ser Ser Ser
500
<210> 15
<211> 1569
<212> DNA
<213> 人工序列
<220>
<223> Fc H9L1 (TSC319) CD3结合结构域
<400> 15
atggaagcac cagcgcagct tctcttcctc ctgctactct ggctcccaga taccaccggt 60
gagcccaaat cttctgacaa aactcacaca tgcccaccgt gcccagcacc tgaagccgcg 120
ggtgcaccgt cagtcttcct cttcccccca aaacccaagg acaccctcat gatctcccgg 180
acccctgagg tcacatgcgt ggtggtggac gtgagccacg aagaccctga ggtcaagttc 240
aactggtacg tggacggcgt ggaggtgcat aatgccaaga caaagccgcg ggaggagcag 300
tacaacagca cgtaccgtgt ggtcagcgtc ctcaccgtcc tgcaccagga ctggctgaat 360
ggcaaggcat acgcgtgcgc ggtctccaac aaagccctcc cagcccccat cgagaaaacc 420
atctccaaag ccaaagggca gccccgagaa ccacaggtgt acaccctgcc cccatcccgg 480
gatgagctga ccaagaacca ggtcagcctg acctgcctgg tcaaaggctt ctatccaagc 540
gacatcgccg tggagtggga gagcaatggg cagccggaga acaactacaa gaccacgcct 600
cccgtgctgg actccgacgg ctccttcttc ctctacagca agctcaccgt ggacaagagc 660
aggtggcagc aggggaacgt cttctcatgc tccgtgatgc atgaggctct gcacaaccac 720
tacacgcaga agagcctctc cctgtctccg ggtcagaggc acaacaattc ttccctgaat 780
acaggaactc agatggcagg tcattctccg aattctcagg tccagcttgt gcagtctggg 840
gctgaggtga agaagcctgg ggcctcagtg aaggtttcct gcaaggcttc tggctacacc 900
tttactagat ctacgatgca ttgggtgcgc caggcccccg gacaaaggct tgagtggatg 960
ggatacatta atcctagcag tgcttatact aattacaatc agaaattcaa ggacagggtc 1020
accattacca gggacacatc cgcgagcaca gcctacatgg agctgagcag cctgagatct 1080
gaagacacgg ctgtgtatta ctgtgcgaga ccccaagtcc actatgatta caacgggttt 1140
ccttactggg gccaaggaac cctggtcacc gtctcctcag gtggaggcgg ttcaggcgga 1200
ggtggatccg gcggtggcgg atcgggtggc ggcggatctg acatccagat gacccagtct 1260
ccaagcagcc tgtctgcaag cgtgggggac agggtcacca tgacctgcag tgccagctca 1320
agtgtaagtt acatgaactg gtaccagcag aagccgggca aggcccccaa aagatggatt 1380
tatgactcat ccaaactggc ttctggagtc cctgctcgct tcagtggcag tgggtctggg 1440
accgactata ccctcacaat cagcagcctg cagcccgaag atttcgccac ttattactgc 1500
cagcagtgga gtcgtaaccc acccacgttc ggagggggga ccaagctaca aattacatcc 1560
tccagctaa 1569
<210> 16
<211> 502
<212> PRT
<213> 人工序列
<220>
<223> Fc H9L1 (TSC319) CD3结合结构域
<400> 16
Glu Pro Lys Ser Ser Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala
1 5 10 15
Pro Glu Ala Ala Gly Ala Pro Ser Val Phe Leu Phe Pro Pro Lys Pro
20 25 30
Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val
35 40 45
Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val
50 55 60
Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln
65 70 75 80
Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln
85 90 95
Asp Trp Leu Asn Gly Lys Ala Tyr Ala Cys Ala Val Ser Asn Lys Ala
100 105 110
Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro
115 120 125
Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr
130 135 140
Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser
145 150 155 160
Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr
165 170 175
Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr
180 185 190
Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe
195 200 205
Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys
210 215 220
Ser Leu Ser Leu Ser Pro Gly Gln Arg His Asn Asn Ser Ser Leu Asn
225 230 235 240
Thr Gly Thr Gln Met Ala Gly His Ser Pro Asn Ser Gln Val Gln Leu
245 250 255
Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala Ser Val Lys Val
260 265 270
Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Arg Ser Thr Met His Trp
275 280 285
Val Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp Met Gly Tyr Ile Asn
290 295 300
Pro Ser Ser Ala Tyr Thr Asn Tyr Asn Gln Lys Phe Lys Asp Arg Val
305 310 315 320
Thr Ile Thr Arg Asp Thr Ser Ala Ser Thr Ala Tyr Met Glu Leu Ser
325 330 335
Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Pro Gln
340 345 350
Val His Tyr Asp Tyr Asn Gly Phe Pro Tyr Trp Gly Gln Gly Thr Leu
355 360 365
Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly
370 375 380
Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Gln Met Thr Gln Ser
385 390 395 400
Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Met Thr Cys
405 410 415
Ser Ala Ser Ser Ser Val Ser Tyr Met Asn Trp Tyr Gln Gln Lys Pro
420 425 430
Gly Lys Ala Pro Lys Arg Trp Ile Tyr Asp Ser Ser Lys Leu Ala Ser
435 440 445
Gly Val Pro Ala Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Tyr Thr
450 455 460
Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys
465 470 475 480
Gln Gln Trp Ser Arg Asn Pro Pro Thr Phe Gly Gly Gly Thr Lys Leu
485 490 495
Gln Ile Thr Ser Ser Ser
500
<210> 17
<211> 1572
<212> DNA
<213> 人工序列
<220>
<223> Fc H9L4 (TSC320) CD3结合结构域
<400> 17
atggaagcac cagcgcagct tctcttcctc ctgctactct ggctcccaga taccaccggt 60
gagcccaaat cttctgacaa aactcacaca tgcccaccgt gcccagcacc tgaagccgcg 120
ggtgcaccgt cagtcttcct cttcccccca aaacccaagg acaccctcat gatctcccgg 180
acccctgagg tcacatgcgt ggtggtggac gtgagccacg aagaccctga ggtcaagttc 240
aactggtacg tggacggcgt ggaggtgcat aatgccaaga caaagccgcg ggaggagcag 300
tacaacagca cgtaccgtgt ggtcagcgtc ctcaccgtcc tgcaccagga ctggctgaat 360
ggcaaggcat acgcgtgcgc ggtctccaac aaagccctcc cagcccccat cgagaaaacc 420
atctccaaag ccaaagggca gccccgagaa ccacaggtgt acaccctgcc cccatcccgg 480
gatgagctga ccaagaacca ggtcagcctg acctgcctgg tcaaaggctt ctatccaagc 540
gacatcgccg tggagtggga gagcaatggg cagccggaga acaactacaa gaccacgcct 600
cccgtgctgg actccgacgg ctccttcttc ctctacagca agctcaccgt ggacaagagc 660
aggtggcagc aggggaacgt cttctcatgc tccgtgatgc atgaggctct gcacaaccac 720
tacacgcaga agagcctctc cctgtctccg ggtcagaggc acaacaattc ttccctgaat 780
acaggaactc agatggcagg tcattctccg aattctcagg tccagcttgt gcagtctggg 840
gctgaggtga agaagcctgg ggcctcagtg aaggtttcct gcaaggcttc tggctacacc 900
tttactagat ctacgatgca ttgggtgcgc caggcccccg gacaaaggct tgagtggatg 960
ggatacatta atcctagcag tgcttatact aattacaatc agaaattcaa ggacagggtc 1020
accattacca gggacacatc cgcgagcaca gcctacatgg agctgagcag cctgagatct 1080
gaagacacgg ctgtgtatta ctgtgcgaga ccccaagtcc actatgatta caacgggttt 1140
ccttactggg gccaaggaac cctggtcacc gtctcctcag gtggaggcgg ttcaggcgga 1200
ggtggatccg gcggtggcgg atcgggtggc ggcggatctg aaattgtgtt gacacagtct 1260
ccagccaccc tgtctttgtc tccaggggaa agagccaccc tctcctgcag tgccagctca 1320
agtgtaagtt acatgaactg gtaccaacag aaacctggcc aggctcccag gctcctcatc 1380
tatgactcat ccaaactggc ttctggcatc ccagccaggt tcagtggcag tgggtctggg 1440
acagacttca ctctcaccat cagcagccta gagcctgaag attttgcagt ttattactgt 1500
cagcagtgga gtcgtaaccc acccactttc ggcggaggga ccaaggtgga gatcaaacgg 1560
tcctccagct aa 1572
<210> 18
<211> 503
<212> PRT
<213> 人工序列
<220>
<223> Fc H9L4 (TSC320) CD3结合结构域
<400> 18
Glu Pro Lys Ser Ser Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala
1 5 10 15
Pro Glu Ala Ala Gly Ala Pro Ser Val Phe Leu Phe Pro Pro Lys Pro
20 25 30
Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val
35 40 45
Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val
50 55 60
Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln
65 70 75 80
Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln
85 90 95
Asp Trp Leu Asn Gly Lys Ala Tyr Ala Cys Ala Val Ser Asn Lys Ala
100 105 110
Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro
115 120 125
Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr
130 135 140
Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser
145 150 155 160
Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr
165 170 175
Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr
180 185 190
Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe
195 200 205
Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys
210 215 220
Ser Leu Ser Leu Ser Pro Gly Gln Arg His Asn Asn Ser Ser Leu Asn
225 230 235 240
Thr Gly Thr Gln Met Ala Gly His Ser Pro Asn Ser Gln Val Gln Leu
245 250 255
Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala Ser Val Lys Val
260 265 270
Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Arg Ser Thr Met His Trp
275 280 285
Val Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp Met Gly Tyr Ile Asn
290 295 300
Pro Ser Ser Ala Tyr Thr Asn Tyr Asn Gln Lys Phe Lys Asp Arg Val
305 310 315 320
Thr Ile Thr Arg Asp Thr Ser Ala Ser Thr Ala Tyr Met Glu Leu Ser
325 330 335
Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Pro Gln
340 345 350
Val His Tyr Asp Tyr Asn Gly Phe Pro Tyr Trp Gly Gln Gly Thr Leu
355 360 365
Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly
370 375 380
Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Ile Val Leu Thr Gln Ser
385 390 395 400
Pro Ala Thr Leu Ser Leu Ser Pro Gly Glu Arg Ala Thr Leu Ser Cys
405 410 415
Ser Ala Ser Ser Ser Val Ser Tyr Met Asn Trp Tyr Gln Gln Lys Pro
420 425 430
Gly Gln Ala Pro Arg Leu Leu Ile Tyr Asp Ser Ser Lys Leu Ala Ser
435 440 445
Gly Ile Pro Ala Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr
450 455 460
Leu Thr Ile Ser Ser Leu Glu Pro Glu Asp Phe Ala Val Tyr Tyr Cys
465 470 475 480
Gln Gln Trp Ser Arg Asn Pro Pro Thr Phe Gly Gly Gly Thr Lys Val
485 490 495
Glu Ile Lys Arg Ser Ser Ser
500
<210> 19
<211> 1572
<212> DNA
<213> 人工序列
<220>
<223> Fc H9L5 (TSC321) CD3结合结构域
<400> 19
atggaagcac cagcgcagct tctcttcctc ctgctactct ggctcccaga taccaccggt 60
gagcccaaat cttctgacaa aactcacaca tgcccaccgt gcccagcacc tgaagccgcg 120
ggtgcaccgt cagtcttcct cttcccccca aaacccaagg acaccctcat gatctcccgg 180
acccctgagg tcacatgcgt ggtggtggac gtgagccacg aagaccctga ggtcaagttc 240
aactggtacg tggacggcgt ggaggtgcat aatgccaaga caaagccgcg ggaggagcag 300
tacaacagca cgtaccgtgt ggtcagcgtc ctcaccgtcc tgcaccagga ctggctgaat 360
ggcaaggcat acgcgtgcgc ggtctccaac aaagccctcc cagcccccat cgagaaaacc 420
atctccaaag ccaaagggca gccccgagaa ccacaggtgt acaccctgcc cccatcccgg 480
gatgagctga ccaagaacca ggtcagcctg acctgcctgg tcaaaggctt ctatccaagc 540
gacatcgccg tggagtggga gagcaatggg cagccggaga acaactacaa gaccacgcct 600
cccgtgctgg actccgacgg ctccttcttc ctctacagca agctcaccgt ggacaagagc 660
aggtggcagc aggggaacgt cttctcatgc tccgtgatgc atgaggctct gcacaaccac 720
tacacgcaga agagcctctc cctgtctccg ggtcagaggc acaacaattc ttccctgaat 780
acaggaactc agatggcagg tcattctccg aattctcagg tccagcttgt gcagtctggg 840
gctgaggtga agaagcctgg ggcctcagtg aaggtttcct gcaaggcttc tggctacacc 900
tttactagat ctacgatgca ttgggtgcgc caggcccccg gacaaaggct tgagtggatg 960
ggatacatta atcctagcag tgcttatact aattacaatc agaaattcaa ggacagggtc 1020
accattacca gggacacatc cgcgagcaca gcctacatgg agctgagcag cctgagatct 1080
gaagacacgg ctgtgtatta ctgtgcgaga ccccaagtcc actatgatta caacgggttt 1140
ccttactggg gccaaggaac cctggtcacc gtctcctcag gtggaggcgg ttcaggcgga 1200
ggtggatccg gcggtggcgg atcgggtggc ggcggatctg acatccagat gacccagtct 1260
ccatcctccc tgtctgcatc tgtaggagac agagtcacca tcacttgcag tgccagctca 1320
agtgtaagtt acatgaactg gtatcagcag aaaccaggga aagcccctaa gctcctgatc 1380
tatgactcat ccaaactggc ttctggggtc ccatcaaggt tcagtggcag tggatctggg 1440
acagatttca ctctcaccat cagcagtctg caacctgaag attttgcaac ttactactgt 1500
caacagtgga gtcgtaaccc acccactttc ggcggaggga ccaaggtgga gatcaaacgg 1560
tcctccagct aa 1572
<210> 20
<211> 503
<212> PRT
<213> 人工序列
<220>
<223> Fc H9L5 (TSC321) CD3结合结构域
<400> 20
Glu Pro Lys Ser Ser Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala
1 5 10 15
Pro Glu Ala Ala Gly Ala Pro Ser Val Phe Leu Phe Pro Pro Lys Pro
20 25 30
Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val
35 40 45
Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val
50 55 60
Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln
65 70 75 80
Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln
85 90 95
Asp Trp Leu Asn Gly Lys Ala Tyr Ala Cys Ala Val Ser Asn Lys Ala
100 105 110
Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro
115 120 125
Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr
130 135 140
Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser
145 150 155 160
Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr
165 170 175
Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr
180 185 190
Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe
195 200 205
Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys
210 215 220
Ser Leu Ser Leu Ser Pro Gly Gln Arg His Asn Asn Ser Ser Leu Asn
225 230 235 240
Thr Gly Thr Gln Met Ala Gly His Ser Pro Asn Ser Gln Val Gln Leu
245 250 255
Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala Ser Val Lys Val
260 265 270
Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Arg Ser Thr Met His Trp
275 280 285
Val Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp Met Gly Tyr Ile Asn
290 295 300
Pro Ser Ser Ala Tyr Thr Asn Tyr Asn Gln Lys Phe Lys Asp Arg Val
305 310 315 320
Thr Ile Thr Arg Asp Thr Ser Ala Ser Thr Ala Tyr Met Glu Leu Ser
325 330 335
Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Pro Gln
340 345 350
Val His Tyr Asp Tyr Asn Gly Phe Pro Tyr Trp Gly Gln Gly Thr Leu
355 360 365
Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly
370 375 380
Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Gln Met Thr Gln Ser
385 390 395 400
Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys
405 410 415
Ser Ala Ser Ser Ser Val Ser Tyr Met Asn Trp Tyr Gln Gln Lys Pro
420 425 430
Gly Lys Ala Pro Lys Leu Leu Ile Tyr Asp Ser Ser Lys Leu Ala Ser
435 440 445
Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr
450 455 460
Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys
465 470 475 480
Gln Gln Trp Ser Arg Asn Pro Pro Thr Phe Gly Gly Gly Thr Lys Val
485 490 495
Glu Ile Lys Arg Ser Ser Ser
500
<210> 21
<211> 1569
<212> DNA
<213> 人工序列
<220>
<223> Fc H10L1 (TSC322) CD3结合结构域
<400> 21
atggaagcac cagcgcagct tctcttcctc ctgctactct ggctcccaga taccaccggt 60
gagcccaaat cttctgacaa aactcacaca tgcccaccgt gcccagcacc tgaagccgcg 120
ggtgcaccgt cagtcttcct cttcccccca aaacccaagg acaccctcat gatctcccgg 180
acccctgagg tcacatgcgt ggtggtggac gtgagccacg aagaccctga ggtcaagttc 240
aactggtacg tggacggcgt ggaggtgcat aatgccaaga caaagccgcg ggaggagcag 300
tacaacagca cgtaccgtgt ggtcagcgtc ctcaccgtcc tgcaccagga ctggctgaat 360
ggcaaggcat acgcgtgcgc ggtctccaac aaagccctcc cagcccccat cgagaaaacc 420
atctccaaag ccaaagggca gccccgagaa ccacaggtgt acaccctgcc cccatcccgg 480
gatgagctga ccaagaacca ggtcagcctg acctgcctgg tcaaaggctt ctatccaagc 540
gacatcgccg tggagtggga gagcaatggg cagccggaga acaactacaa gaccacgcct 600
cccgtgctgg actccgacgg ctccttcttc ctctacagca agctcaccgt ggacaagagc 660
aggtggcagc aggggaacgt cttctcatgc tccgtgatgc atgaggctct gcacaaccac 720
tacacgcaga agagcctctc cctgtctccg ggtcagaggc acaacaattc ttccctgaat 780
acaggaactc agatggcagg tcattctccg aattctcagg tccagctggt gcaatctggg 840
gctgaggtga agaagcctgg gtcctcggtg aaggtctcct gcaaggcttc tggaggcacc 900
ttcagcagat ctacgatgca ctgggtgcga caggcccctg gacaagggct tgagtggatg 960
ggatacatta atcctagcag tgcttatact aattacaatc agaaattcaa ggacagagtc 1020
acgattaccg cggacaaatc cacgagcaca gcctacatgg agctgagcag cctgagatct 1080
gaggacacgg ccgtgtatta ctgtgcgaga ccccaagtcc actatgatta caacgggttt 1140
ccttactggg gccaaggaac cctggtcacc gtctcctcag gtggaggcgg ttcaggcgga 1200
ggtggatccg gcggtggcgg atcgggtggc ggcggatctg acatccagat gacccagtct 1260
ccaagcagcc tgtctgcaag cgtgggggac agggtcacca tgacctgcag tgccagctca 1320
agtgtaagtt acatgaactg gtaccagcag aagccgggca aggcccccaa aagatggatt 1380
tatgactcat ccaaactggc ttctggagtc cctgctcgct tcagtggcag tgggtctggg 1440
accgactata ccctcacaat cagcagcctg cagcccgaag atttcgccac ttattactgc 1500
cagcagtgga gtcgtaaccc acccacgttc ggagggggga ccaagctaca aattacatcc 1560
tccagctaa 1569
<210> 22
<211> 502
<212> PRT
<213> 人工序列
<220>
<223> Fc H10L1 (TSC322) CD3结合结构域
<400> 22
Glu Pro Lys Ser Ser Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala
1 5 10 15
Pro Glu Ala Ala Gly Ala Pro Ser Val Phe Leu Phe Pro Pro Lys Pro
20 25 30
Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val
35 40 45
Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val
50 55 60
Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln
65 70 75 80
Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln
85 90 95
Asp Trp Leu Asn Gly Lys Ala Tyr Ala Cys Ala Val Ser Asn Lys Ala
100 105 110
Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro
115 120 125
Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr
130 135 140
Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser
145 150 155 160
Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr
165 170 175
Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr
180 185 190
Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe
195 200 205
Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys
210 215 220
Ser Leu Ser Leu Ser Pro Gly Gln Arg His Asn Asn Ser Ser Leu Asn
225 230 235 240
Thr Gly Thr Gln Met Ala Gly His Ser Pro Asn Ser Gln Val Gln Leu
245 250 255
Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser Ser Val Lys Val
260 265 270
Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Arg Ser Thr Met His Trp
275 280 285
Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met Gly Tyr Ile Asn
290 295 300
Pro Ser Ser Ala Tyr Thr Asn Tyr Asn Gln Lys Phe Lys Asp Arg Val
305 310 315 320
Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr Met Glu Leu Ser
325 330 335
Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Pro Gln
340 345 350
Val His Tyr Asp Tyr Asn Gly Phe Pro Tyr Trp Gly Gln Gly Thr Leu
355 360 365
Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly
370 375 380
Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Gln Met Thr Gln Ser
385 390 395 400
Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Met Thr Cys
405 410 415
Ser Ala Ser Ser Ser Val Ser Tyr Met Asn Trp Tyr Gln Gln Lys Pro
420 425 430
Gly Lys Ala Pro Lys Arg Trp Ile Tyr Asp Ser Ser Lys Leu Ala Ser
435 440 445
Gly Val Pro Ala Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Tyr Thr
450 455 460
Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys
465 470 475 480
Gln Gln Trp Ser Arg Asn Pro Pro Thr Phe Gly Gly Gly Thr Lys Leu
485 490 495
Gln Ile Thr Ser Ser Ser
500
<210> 23
<211> 1572
<212> DNA
<213> 人工序列
<220>
<223> Fc H10L4 (TSC323) CD3结合结构域
<400> 23
atggaagcac cagcgcagct tctcttcctc ctgctactct ggctcccaga taccaccggt 60
gagcccaaat cttctgacaa aactcacaca tgcccaccgt gcccagcacc tgaagccgcg 120
ggtgcaccgt cagtcttcct cttcccccca aaacccaagg acaccctcat gatctcccgg 180
acccctgagg tcacatgcgt ggtggtggac gtgagccacg aagaccctga ggtcaagttc 240
aactggtacg tggacggcgt ggaggtgcat aatgccaaga caaagccgcg ggaggagcag 300
tacaacagca cgtaccgtgt ggtcagcgtc ctcaccgtcc tgcaccagga ctggctgaat 360
ggcaaggcat acgcgtgcgc ggtctccaac aaagccctcc cagcccccat cgagaaaacc 420
atctccaaag ccaaagggca gccccgagaa ccacaggtgt acaccctgcc cccatcccgg 480
gatgagctga ccaagaacca ggtcagcctg acctgcctgg tcaaaggctt ctatccaagc 540
gacatcgccg tggagtggga gagcaatggg cagccggaga acaactacaa gaccacgcct 600
cccgtgctgg actccgacgg ctccttcttc ctctacagca agctcaccgt ggacaagagc 660
aggtggcagc aggggaacgt cttctcatgc tccgtgatgc atgaggctct gcacaaccac 720
tacacgcaga agagcctctc cctgtctccg ggtcagaggc acaacaattc ttccctgaat 780
acaggaactc agatggcagg tcattctccg aattctcagg tccagctggt gcaatctggg 840
gctgaggtga agaagcctgg gtcctcggtg aaggtctcct gcaaggcttc tggaggcacc 900
ttcagcagat ctacgatgca ctgggtgcga caggcccctg gacaagggct tgagtggatg 960
ggatacatta atcctagcag tgcttatact aattacaatc agaaattcaa ggacagagtc 1020
acgattaccg cggacaaatc cacgagcaca gcctacatgg agctgagcag cctgagatct 1080
gaggacacgg ccgtgtatta ctgtgcgaga ccccaagtcc actatgatta caacgggttt 1140
ccttactggg gccaaggaac cctggtcacc gtctcctcag gtggaggcgg ttcaggcgga 1200
ggtggatccg gcggtggcgg atcgggtggc ggcggatctg aaattgtgtt gacacagtct 1260
ccagccaccc tgtctttgtc tccaggggaa agagccaccc tctcctgcag tgccagctca 1320
agtgtaagtt acatgaactg gtaccaacag aaacctggcc aggctcccag gctcctcatc 1380
tatgactcat ccaaactggc ttctggcatc ccagccaggt tcagtggcag tgggtctggg 1440
acagacttca ctctcaccat cagcagccta gagcctgaag attttgcagt ttattactgt 1500
cagcagtgga gtcgtaaccc acccactttc ggcggaggga ccaaggtgga gatcaaacgg 1560
tcctccagct aa 1572
<210> 24
<211> 503
<212> PRT
<213> 人工序列
<220>
<223> Fc H10L4 (TSC323) CD3结合结构域
<400> 24
Glu Pro Lys Ser Ser Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala
1 5 10 15
Pro Glu Ala Ala Gly Ala Pro Ser Val Phe Leu Phe Pro Pro Lys Pro
20 25 30
Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val
35 40 45
Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val
50 55 60
Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln
65 70 75 80
Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln
85 90 95
Asp Trp Leu Asn Gly Lys Ala Tyr Ala Cys Ala Val Ser Asn Lys Ala
100 105 110
Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro
115 120 125
Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr
130 135 140
Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser
145 150 155 160
Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr
165 170 175
Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr
180 185 190
Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe
195 200 205
Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys
210 215 220
Ser Leu Ser Leu Ser Pro Gly Gln Arg His Asn Asn Ser Ser Leu Asn
225 230 235 240
Thr Gly Thr Gln Met Ala Gly His Ser Pro Asn Ser Gln Val Gln Leu
245 250 255
Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser Ser Val Lys Val
260 265 270
Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Arg Ser Thr Met His Trp
275 280 285
Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met Gly Tyr Ile Asn
290 295 300
Pro Ser Ser Ala Tyr Thr Asn Tyr Asn Gln Lys Phe Lys Asp Arg Val
305 310 315 320
Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr Met Glu Leu Ser
325 330 335
Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Pro Gln
340 345 350
Val His Tyr Asp Tyr Asn Gly Phe Pro Tyr Trp Gly Gln Gly Thr Leu
355 360 365
Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly
370 375 380
Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Ile Val Leu Thr Gln Ser
385 390 395 400
Pro Ala Thr Leu Ser Leu Ser Pro Gly Glu Arg Ala Thr Leu Ser Cys
405 410 415
Ser Ala Ser Ser Ser Val Ser Tyr Met Asn Trp Tyr Gln Gln Lys Pro
420 425 430
Gly Gln Ala Pro Arg Leu Leu Ile Tyr Asp Ser Ser Lys Leu Ala Ser
435 440 445
Gly Ile Pro Ala Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr
450 455 460
Leu Thr Ile Ser Ser Leu Glu Pro Glu Asp Phe Ala Val Tyr Tyr Cys
465 470 475 480
Gln Gln Trp Ser Arg Asn Pro Pro Thr Phe Gly Gly Gly Thr Lys Val
485 490 495
Glu Ile Lys Arg Ser Ser Ser
500
<210> 25
<211> 1572
<212> DNA
<213> 人工序列
<220>
<223> Fc H10L5 (TSC324) CD3结合结构域
<400> 25
atggaagcac cagcgcagct tctcttcctc ctgctactct ggctcccaga taccaccggt 60
gagcccaaat cttctgacaa aactcacaca tgcccaccgt gcccagcacc tgaagccgcg 120
ggtgcaccgt cagtcttcct cttcccccca aaacccaagg acaccctcat gatctcccgg 180
acccctgagg tcacatgcgt ggtggtggac gtgagccacg aagaccctga ggtcaagttc 240
aactggtacg tggacggcgt ggaggtgcat aatgccaaga caaagccgcg ggaggagcag 300
tacaacagca cgtaccgtgt ggtcagcgtc ctcaccgtcc tgcaccagga ctggctgaat 360
ggcaaggcat acgcgtgcgc ggtctccaac aaagccctcc cagcccccat cgagaaaacc 420
atctccaaag ccaaagggca gccccgagaa ccacaggtgt acaccctgcc cccatcccgg 480
gatgagctga ccaagaacca ggtcagcctg acctgcctgg tcaaaggctt ctatccaagc 540
gacatcgccg tggagtggga gagcaatggg cagccggaga acaactacaa gaccacgcct 600
cccgtgctgg actccgacgg ctccttcttc ctctacagca agctcaccgt ggacaagagc 660
aggtggcagc aggggaacgt cttctcatgc tccgtgatgc atgaggctct gcacaaccac 720
tacacgcaga agagcctctc cctgtctccg ggtcagaggc acaacaattc ttccctgaat 780
acaggaactc agatggcagg tcattctccg aattctcagg tccagctggt gcaatctggg 840
gctgaggtga agaagcctgg gtcctcggtg aaggtctcct gcaaggcttc tggaggcacc 900
ttcagcagat ctacgatgca ctgggtgcga caggcccctg gacaagggct tgagtggatg 960
ggatacatta atcctagcag tgcttatact aattacaatc agaaattcaa ggacagagtc 1020
acgattaccg cggacaaatc cacgagcaca gcctacatgg agctgagcag cctgagatct 1080
gaggacacgg ccgtgtatta ctgtgcgaga ccccaagtcc actatgatta caacgggttt 1140
ccttactggg gccaaggaac cctggtcacc gtctcctcag gtggaggcgg ttcaggcgga 1200
ggtggatccg gcggtggcgg atcgggtggc ggcggatctg acatccagat gacccagtct 1260
ccatcctccc tgtctgcatc tgtaggagac agagtcacca tcacttgcag tgccagctca 1320
agtgtaagtt acatgaactg gtatcagcag aaaccaggga aagcccctaa gctcctgatc 1380
tatgactcat ccaaactggc ttctggggtc ccatcaaggt tcagtggcag tggatctggg 1440
acagatttca ctctcaccat cagcagtctg caacctgaag attttgcaac ttactactgt 1500
caacagtgga gtcgtaaccc acccactttc ggcggaggga ccaaggtgga gatcaaacgg 1560
tcctccagct aa 1572
<210> 26
<211> 503
<212> PRT
<213> 人工序列
<220>
<223> Fc H10L5 (TSC324) CD3结合结构域
<400> 26
Glu Pro Lys Ser Ser Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala
1 5 10 15
Pro Glu Ala Ala Gly Ala Pro Ser Val Phe Leu Phe Pro Pro Lys Pro
20 25 30
Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val
35 40 45
Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val
50 55 60
Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln
65 70 75 80
Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln
85 90 95
Asp Trp Leu Asn Gly Lys Ala Tyr Ala Cys Ala Val Ser Asn Lys Ala
100 105 110
Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro
115 120 125
Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr
130 135 140
Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser
145 150 155 160
Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr
165 170 175
Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr
180 185 190
Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe
195 200 205
Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys
210 215 220
Ser Leu Ser Leu Ser Pro Gly Gln Arg His Asn Asn Ser Ser Leu Asn
225 230 235 240
Thr Gly Thr Gln Met Ala Gly His Ser Pro Asn Ser Gln Val Gln Leu
245 250 255
Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser Ser Val Lys Val
260 265 270
Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Arg Ser Thr Met His Trp
275 280 285
Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met Gly Tyr Ile Asn
290 295 300
Pro Ser Ser Ala Tyr Thr Asn Tyr Asn Gln Lys Phe Lys Asp Arg Val
305 310 315 320
Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr Met Glu Leu Ser
325 330 335
Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Pro Gln
340 345 350
Val His Tyr Asp Tyr Asn Gly Phe Pro Tyr Trp Gly Gln Gly Thr Leu
355 360 365
Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly
370 375 380
Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Gln Met Thr Gln Ser
385 390 395 400
Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys
405 410 415
Ser Ala Ser Ser Ser Val Ser Tyr Met Asn Trp Tyr Gln Gln Lys Pro
420 425 430
Gly Lys Ala Pro Lys Leu Leu Ile Tyr Asp Ser Ser Lys Leu Ala Ser
435 440 445
Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr
450 455 460
Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys
465 470 475 480
Gln Gln Trp Ser Arg Asn Pro Pro Thr Phe Gly Gly Gly Thr Lys Val
485 490 495
Glu Ile Lys Arg Ser Ser Ser
500
<210> 27
<211> 1572
<212> DNA
<213> 人工序列
<220>
<223> Fc H7L6 (TSC334) CD3结合结构域
<400> 27
atggaagcac cagcgcagct tctcttcctc ctgctactct ggctcccaga taccaccggt 60
gagcccaaat cttctgacaa aactcacaca tgcccaccgt gcccagcacc tgaagccgcg 120
ggtgcaccgt cagtcttcct cttcccccca aaacccaagg acaccctcat gatctcccgg 180
acccctgagg tcacatgcgt ggtggtggac gtgagccacg aagaccctga ggtcaagttc 240
aactggtacg tggacggcgt ggaggtgcat aatgccaaga caaagccgcg ggaggagcag 300
tacaacagca cgtaccgtgt ggtcagcgtc ctcaccgtcc tgcaccagga ctggctgaat 360
ggcaaggcat acgcatgcgc ggtctccaac aaagccctcc cagcccccat cgagaaaacc 420
atctccaaag ccaaagggca gccccgagaa ccacaggtgt acaccctgcc cccatcccgg 480
gatgagctga ccaagaacca ggtcagcctg acctgcctgg tcaaaggctt ctatccaagc 540
gacatcgccg tggagtggga gagcaatggg cagccggaga acaactacaa gaccacgcct 600
cccgtgctgg actccgacgg ctccttcttc ctctacagca agctcaccgt ggacaagagc 660
aggtggcagc aggggaacgt cttctcatgc tccgtgatgc atgaggctct gcacaaccac 720
tacacgcaga agagcctctc cctgtctccg ggtcagaggc acaacaattc ttccctgaat 780
acaggaactc agatggcagg tcattctccg aattctcagg tgcagctggt gcagtctggg 840
gctgaggtga agaagcctgg ggcctcagtg aaggtctcct gcaaggcttc tggatacacc 900
ttcaccagat ctacgatgca ctgggtgcga caggcccctg gacaagggct tgagtggatg 960
ggatacatta atcctagcag tgcttatact aattacaatc agaaattcaa ggacagggtc 1020
accatgacca gggacacgtc catcagcaca gcctacatgg agctgagcag gctgagatct 1080
gacgacacgg ccgtgtatta ctgtgcgaga ccccaagtcc actatgatta caacgggttt 1140
ccttactggg gccaaggaac cctggtcacc gtctcctcag gtggaggcgg ttcaggcgga 1200
ggtggatccg gcggtggcgg atcgggtggc ggcggatctg acatccagat gacccagtct 1260
ccatcctccc tgtctgcatc tgtaggagac agagtcacca tcacttgcag tgccagctca 1320
agtgtaagtt acatgaactg gtatcagcag aaaccaggga aagcccctaa gagatggatt 1380
tatgactcat ccaaactggc ttctggggtc ccatcaaggt tcagtggcag tggatctggg 1440
acagatttca ctctcaccat cagcagtctg caacctgaag attttgcaac ttactactgt 1500
caacagtgga gtcgtaaccc acccactttc ggcggaggga ccaaggtgga gatcaaacgg 1560
tcctccagct aa 1572
<210> 28
<211> 503
<212> PRT
<213> 人工序列
<220>
<223> Fc H7L6 (TSC334) CD3结合结构域
<400> 28
Glu Pro Lys Ser Ser Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala
1 5 10 15
Pro Glu Ala Ala Gly Ala Pro Ser Val Phe Leu Phe Pro Pro Lys Pro
20 25 30
Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val
35 40 45
Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val
50 55 60
Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln
65 70 75 80
Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln
85 90 95
Asp Trp Leu Asn Gly Lys Ala Tyr Ala Cys Ala Val Ser Asn Lys Ala
100 105 110
Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro
115 120 125
Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr
130 135 140
Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser
145 150 155 160
Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr
165 170 175
Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr
180 185 190
Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe
195 200 205
Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys
210 215 220
Ser Leu Ser Leu Ser Pro Gly Gln Arg His Asn Asn Ser Ser Leu Asn
225 230 235 240
Thr Gly Thr Gln Met Ala Gly His Ser Pro Asn Ser Gln Val Gln Leu
245 250 255
Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala Ser Val Lys Val
260 265 270
Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Arg Ser Thr Met His Trp
275 280 285
Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met Gly Tyr Ile Asn
290 295 300
Pro Ser Ser Ala Tyr Thr Asn Tyr Asn Gln Lys Phe Lys Asp Arg Val
305 310 315 320
Thr Met Thr Arg Asp Thr Ser Ile Ser Thr Ala Tyr Met Glu Leu Ser
325 330 335
Arg Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys Ala Arg Pro Gln
340 345 350
Val His Tyr Asp Tyr Asn Gly Phe Pro Tyr Trp Gly Gln Gly Thr Leu
355 360 365
Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly
370 375 380
Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Gln Met Thr Gln Ser
385 390 395 400
Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys
405 410 415
Ser Ala Ser Ser Ser Val Ser Tyr Met Asn Trp Tyr Gln Gln Lys Pro
420 425 430
Gly Lys Ala Pro Lys Arg Trp Ile Tyr Asp Ser Ser Lys Leu Ala Ser
435 440 445
Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr
450 455 460
Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys
465 470 475 480
Gln Gln Trp Ser Arg Asn Pro Pro Thr Phe Gly Gly Gly Thr Lys Val
485 490 495
Glu Ile Lys Arg Ser Ser Ser
500
<210> 29
<211> 1572
<212> DNA
<213> 人工序列
<220>
<223> Fc H7L7 (TSC335) CD3结合结构域
<400> 29
atggaagcac cagcgcagct tctcttcctc ctgctactct ggctcccaga taccaccggt 60
gagcccaaat cttctgacaa aactcacaca tgcccaccgt gcccagcacc tgaagccgcg 120
ggtgcaccgt cagtcttcct cttcccccca aaacccaagg acaccctcat gatctcccgg 180
acccctgagg tcacatgcgt ggtggtggac gtgagccacg aagaccctga ggtcaagttc 240
aactggtacg tggacggcgt ggaggtgcat aatgccaaga caaagccgcg ggaggagcag 300
tacaacagca cgtaccgtgt ggtcagcgtc ctcaccgtcc tgcaccagga ctggctgaat 360
ggcaaggcat acgcatgcgc ggtctccaac aaagccctcc cagcccccat cgagaaaacc 420
atctccaaag ccaaagggca gccccgagaa ccacaggtgt acaccctgcc cccatcccgg 480
gatgagctga ccaagaacca ggtcagcctg acctgcctgg tcaaaggctt ctatccaagc 540
gacatcgccg tggagtggga gagcaatggg cagccggaga acaactacaa gaccacgcct 600
cccgtgctgg actccgacgg ctccttcttc ctctacagca agctcaccgt ggacaagagc 660
aggtggcagc aggggaacgt cttctcatgc tccgtgatgc atgaggctct gcacaaccac 720
tacacgcaga agagcctctc cctgtctccg ggtcagaggc acaacaattc ttccctgaat 780
acaggaactc agatggcagg tcattctccg aattctcagg tgcagctggt gcagtctggg 840
gctgaggtga agaagcctgg ggcctcagtg aaggtctcct gcaaggcttc tggatacacc 900
ttcaccagat ctacgatgca ctgggtgcga caggcccctg gacaagggct tgagtggatg 960
ggatacatta atcctagcag tgcttatact aattacaatc agaaattcaa ggacagggtc 1020
accatgacca gggacacgtc catcagcaca gcctacatgg agctgagcag gctgagatct 1080
gacgacacgg ccgtgtatta ctgtgcgaga ccccaagtcc actatgatta caacgggttt 1140
ccttactggg gccaaggaac cctggtcacc gtctcctcag gtggaggcgg ttcaggcgga 1200
ggtggatccg gcggtggcgg atcgggtggc ggcggatctg aaattgtgtt gacgcagtct 1260
ccagccaccc tgtctttgtc tccaggggaa agagccaccc tctcctgcag tgccagctca 1320
agtgtaagtt acatgaactg gtaccagcag aaacctggcc tggcgcccag gagatggatt 1380
tatgactcat ccaaactggc ttctggcatc ccagacaggt tcagtggcag tgggtctggg 1440
acagacttca ctctcaccat cagcagactg gagcctgaag attttgcagt gtattactgt 1500
cagcagtgga gtcgtaaccc acccactttc ggcggaggga ccaaggtgga gatcaaacgg 1560
tcctccagct aa 1572
<210> 30
<211> 503
<212> PRT
<213> 人工序列
<220>
<223> Fc H7L7 (TSC335) CD3结合结构域
<400> 30
Glu Pro Lys Ser Ser Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala
1 5 10 15
Pro Glu Ala Ala Gly Ala Pro Ser Val Phe Leu Phe Pro Pro Lys Pro
20 25 30
Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val
35 40 45
Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val
50 55 60
Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln
65 70 75 80
Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln
85 90 95
Asp Trp Leu Asn Gly Lys Ala Tyr Ala Cys Ala Val Ser Asn Lys Ala
100 105 110
Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro
115 120 125
Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr
130 135 140
Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser
145 150 155 160
Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr
165 170 175
Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr
180 185 190
Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe
195 200 205
Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys
210 215 220
Ser Leu Ser Leu Ser Pro Gly Gln Arg His Asn Asn Ser Ser Leu Asn
225 230 235 240
Thr Gly Thr Gln Met Ala Gly His Ser Pro Asn Ser Gln Val Gln Leu
245 250 255
Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala Ser Val Lys Val
260 265 270
Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Arg Ser Thr Met His Trp
275 280 285
Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met Gly Tyr Ile Asn
290 295 300
Pro Ser Ser Ala Tyr Thr Asn Tyr Asn Gln Lys Phe Lys Asp Arg Val
305 310 315 320
Thr Met Thr Arg Asp Thr Ser Ile Ser Thr Ala Tyr Met Glu Leu Ser
325 330 335
Arg Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys Ala Arg Pro Gln
340 345 350
Val His Tyr Asp Tyr Asn Gly Phe Pro Tyr Trp Gly Gln Gly Thr Leu
355 360 365
Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly
370 375 380
Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Ile Val Leu Thr Gln Ser
385 390 395 400
Pro Ala Thr Leu Ser Leu Ser Pro Gly Glu Arg Ala Thr Leu Ser Cys
405 410 415
Ser Ala Ser Ser Ser Val Ser Tyr Met Asn Trp Tyr Gln Gln Lys Pro
420 425 430
Gly Leu Ala Pro Arg Arg Trp Ile Tyr Asp Ser Ser Lys Leu Ala Ser
435 440 445
Gly Ile Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr
450 455 460
Leu Thr Ile Ser Arg Leu Glu Pro Glu Asp Phe Ala Val Tyr Tyr Cys
465 470 475 480
Gln Gln Trp Ser Arg Asn Pro Pro Thr Phe Gly Gly Gly Thr Lys Val
485 490 495
Glu Ile Lys Arg Ser Ser Ser
500
<210> 31
<211> 1572
<212> DNA
<213> 人工序列
<220>
<223> Fc H7L8 (TSC336) CD3结合结构域
<400> 31
atggaagcac cagcgcagct tctcttcctc ctgctactct ggctcccaga taccaccggt 60
gagcccaaat cttctgacaa aactcacaca tgcccaccgt gcccagcacc tgaagccgcg 120
ggtgcaccgt cagtcttcct cttcccccca aaacccaagg acaccctcat gatctcccgg 180
acccctgagg tcacatgcgt ggtggtggac gtgagccacg aagaccctga ggtcaagttc 240
aactggtacg tggacggcgt ggaggtgcat aatgccaaga caaagccgcg ggaggagcag 300
tacaacagca cgtaccgtgt ggtcagcgtc ctcaccgtcc tgcaccagga ctggctgaat 360
ggcaaggcat acgcatgcgc ggtctccaac aaagccctcc cagcccccat cgagaaaacc 420
atctccaaag ccaaagggca gccccgagaa ccacaggtgt acaccctgcc cccatcccgg 480
gatgagctga ccaagaacca ggtcagcctg acctgcctgg tcaaaggctt ctatccaagc 540
gacatcgccg tggagtggga gagcaatggg cagccggaga acaactacaa gaccacgcct 600
cccgtgctgg actccgacgg ctccttcttc ctctacagca agctcaccgt ggacaagagc 660
aggtggcagc aggggaacgt cttctcatgc tccgtgatgc atgaggctct gcacaaccac 720
tacacgcaga agagcctctc cctgtctccg ggtcagaggc acaacaattc ttccctgaat 780
acaggaactc agatggcagg tcattctccg aattctcagg tgcagctggt gcagtctggg 840
gctgaggtga agaagcctgg ggcctcagtg aaggtctcct gcaaggcttc tggatacacc 900
ttcaccagat ctacgatgca ctgggtgcga caggcccctg gacaagggct tgagtggatg 960
ggatacatta atcctagcag tgcttatact aattacaatc agaaattcaa ggacagggtc 1020
accatgacca gggacacgtc catcagcaca gcctacatgg agctgagcag gctgagatct 1080
gacgacacgg ccgtgtatta ctgtgcgaga ccccaagtcc actatgatta caacgggttt 1140
ccttactggg gccaaggaac cctggtcacc gtctcctcag gtggaggcgg ttcaggcgga 1200
ggtggatccg gcggtggcgg atcgggtggc ggcggatctg acatccagat gacccagtct 1260
ccttccaccc tgtctgcatc tgtaggagac agagtcacca tcacttgcag tgccagctca 1320
agtgtaagtt acatgaactg gtatcagcag aaaccaggga aagcccctaa gagatggatt 1380
tatgactcat ccaaactggc ttctggggtc ccatcaaggt tcagcggcag tggatctggg 1440
acagaattca ctctcaccat cagcagcctg cagcctgatg attttgcaac ttattactgc 1500
caacagtgga gtcgtaaccc acccactttc ggcggaggga ccaaggtgga gatcaaacgg 1560
tcctccagct aa 1572
<210> 32
<211> 503
<212> PRT
<213> 人工序列
<220>
<223> Fc H7L8 (TSC336) CD3结合结构域
<400> 32
Glu Pro Lys Ser Ser Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala
1 5 10 15
Pro Glu Ala Ala Gly Ala Pro Ser Val Phe Leu Phe Pro Pro Lys Pro
20 25 30
Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val
35 40 45
Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val
50 55 60
Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln
65 70 75 80
Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln
85 90 95
Asp Trp Leu Asn Gly Lys Ala Tyr Ala Cys Ala Val Ser Asn Lys Ala
100 105 110
Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro
115 120 125
Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr
130 135 140
Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser
145 150 155 160
Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr
165 170 175
Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr
180 185 190
Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe
195 200 205
Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys
210 215 220
Ser Leu Ser Leu Ser Pro Gly Gln Arg His Asn Asn Ser Ser Leu Asn
225 230 235 240
Thr Gly Thr Gln Met Ala Gly His Ser Pro Asn Ser Gln Val Gln Leu
245 250 255
Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala Ser Val Lys Val
260 265 270
Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Arg Ser Thr Met His Trp
275 280 285
Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met Gly Tyr Ile Asn
290 295 300
Pro Ser Ser Ala Tyr Thr Asn Tyr Asn Gln Lys Phe Lys Asp Arg Val
305 310 315 320
Thr Met Thr Arg Asp Thr Ser Ile Ser Thr Ala Tyr Met Glu Leu Ser
325 330 335
Arg Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys Ala Arg Pro Gln
340 345 350
Val His Tyr Asp Tyr Asn Gly Phe Pro Tyr Trp Gly Gln Gly Thr Leu
355 360 365
Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly
370 375 380
Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Gln Met Thr Gln Ser
385 390 395 400
Pro Ser Thr Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys
405 410 415
Ser Ala Ser Ser Ser Val Ser Tyr Met Asn Trp Tyr Gln Gln Lys Pro
420 425 430
Gly Lys Ala Pro Lys Arg Trp Ile Tyr Asp Ser Ser Lys Leu Ala Ser
435 440 445
Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Glu Phe Thr
450 455 460
Leu Thr Ile Ser Ser Leu Gln Pro Asp Asp Phe Ala Thr Tyr Tyr Cys
465 470 475 480
Gln Gln Trp Ser Arg Asn Pro Pro Thr Phe Gly Gly Gly Thr Lys Val
485 490 495
Glu Ile Lys Arg Ser Ser Ser
500
<210> 33
<211> 1572
<212> DNA
<213> 人工序列
<220>
<223> Fc H8L6 (TSC337) CD3结合结构域
<400> 33
atggaagcac cagcgcagct tctcttcctc ctgctactct ggctcccaga taccaccggt 60
gagcccaaat cttctgacaa aactcacaca tgcccaccgt gcccagcacc tgaagccgcg 120
ggtgcaccgt cagtcttcct cttcccccca aaacccaagg acaccctcat gatctcccgg 180
acccctgagg tcacatgcgt ggtggtggac gtgagccacg aagaccctga ggtcaagttc 240
aactggtacg tggacggcgt ggaggtgcat aatgccaaga caaagccgcg ggaggagcag 300
tacaacagca cgtaccgtgt ggtcagcgtc ctcaccgtcc tgcaccagga ctggctgaat 360
ggcaaggcat acgcatgcgc ggtctccaac aaagccctcc cagcccccat cgagaaaacc 420
atctccaaag ccaaagggca gccccgagaa ccacaggtgt acaccctgcc cccatcccgg 480
gatgagctga ccaagaacca ggtcagcctg acctgcctgg tcaaaggctt ctatccaagc 540
gacatcgccg tggagtggga gagcaatggg cagccggaga acaactacaa gaccacgcct 600
cccgtgctgg actccgacgg ctccttcttc ctctacagca agctcaccgt ggacaagagc 660
aggtggcagc aggggaacgt cttctcatgc tccgtgatgc atgaggctct gcacaaccac 720
tacacgcaga agagcctctc cctgtctccg ggtcagaggc acaacaattc ttccctgaat 780
acaggaactc agatggcagg tcattctccg aattctcagg tgcagctggt gcagtctggg 840
gctgaggtga agaagcctgg ggcctcagtg aaggtttcct gcaaggcatc tggatacacc 900
ttcaccagat ctacgatgca ctgggtgcga caggcccctg gacaagggct tgagtggatg 960
ggatacatta atcctagcag tgcttatact aattacaatc agaaattcaa ggacagagtc 1020
accatgacca gggacacgtc cacgagcaca gtctacatgg agctgagcag cctgagatct 1080
gaggacacgg ccgtgtatta ctgtgctaga ccccaagtcc actatgatta caacgggttt 1140
ccttactggg gccaaggaac cctggtcacc gtctcctcag gtggaggcgg ttcaggcgga 1200
ggtggatccg gcggtggcgg atcgggtggc ggcggatctg acatccagat gacccagtct 1260
ccatcctccc tgtctgcatc tgtaggagac agagtcacca tcacttgcag tgccagctca 1320
agtgtaagtt acatgaactg gtatcagcag aaaccaggga aagcccctaa gagatggatt 1380
tatgactcat ccaaactggc ttctggggtc ccatcaaggt tcagtggcag tggatctggg 1440
acagatttca ctctcaccat cagcagtctg caacctgaag attttgcaac ttactactgt 1500
caacagtgga gtcgtaaccc acccactttc ggcggaggga ccaaggtgga gatcaaacgg 1560
tcctccagct aa 1572
<210> 34
<211> 503
<212> PRT
<213> 人工序列
<220>
<223> Fc H8L6 (TSC337) CD3结合结构域
<400> 34
Glu Pro Lys Ser Ser Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala
1 5 10 15
Pro Glu Ala Ala Gly Ala Pro Ser Val Phe Leu Phe Pro Pro Lys Pro
20 25 30
Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val
35 40 45
Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val
50 55 60
Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln
65 70 75 80
Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln
85 90 95
Asp Trp Leu Asn Gly Lys Ala Tyr Ala Cys Ala Val Ser Asn Lys Ala
100 105 110
Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro
115 120 125
Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr
130 135 140
Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser
145 150 155 160
Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr
165 170 175
Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr
180 185 190
Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe
195 200 205
Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys
210 215 220
Ser Leu Ser Leu Ser Pro Gly Gln Arg His Asn Asn Ser Ser Leu Asn
225 230 235 240
Thr Gly Thr Gln Met Ala Gly His Ser Pro Asn Ser Gln Val Gln Leu
245 250 255
Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala Ser Val Lys Val
260 265 270
Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Arg Ser Thr Met His Trp
275 280 285
Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met Gly Tyr Ile Asn
290 295 300
Pro Ser Ser Ala Tyr Thr Asn Tyr Asn Gln Lys Phe Lys Asp Arg Val
305 310 315 320
Thr Met Thr Arg Asp Thr Ser Thr Ser Thr Val Tyr Met Glu Leu Ser
325 330 335
Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Pro Gln
340 345 350
Val His Tyr Asp Tyr Asn Gly Phe Pro Tyr Trp Gly Gln Gly Thr Leu
355 360 365
Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly
370 375 380
Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Gln Met Thr Gln Ser
385 390 395 400
Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys
405 410 415
Ser Ala Ser Ser Ser Val Ser Tyr Met Asn Trp Tyr Gln Gln Lys Pro
420 425 430
Gly Lys Ala Pro Lys Arg Trp Ile Tyr Asp Ser Ser Lys Leu Ala Ser
435 440 445
Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr
450 455 460
Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys
465 470 475 480
Gln Gln Trp Ser Arg Asn Pro Pro Thr Phe Gly Gly Gly Thr Lys Val
485 490 495
Glu Ile Lys Arg Ser Ser Ser
500
<210> 35
<211> 1572
<212> DNA
<213> 人工序列
<220>
<223> Fc H8L7 (TSC338) CD3结合结构域
<400> 35
atggaagcac cagcgcagct tctcttcctc ctgctactct ggctcccaga taccaccggt 60
gagcccaaat cttctgacaa aactcacaca tgcccaccgt gcccagcacc tgaagccgcg 120
ggtgcaccgt cagtcttcct cttcccccca aaacccaagg acaccctcat gatctcccgg 180
acccctgagg tcacatgcgt ggtggtggac gtgagccacg aagaccctga ggtcaagttc 240
aactggtacg tggacggcgt ggaggtgcat aatgccaaga caaagccgcg ggaggagcag 300
tacaacagca cgtaccgtgt ggtcagcgtc ctcaccgtcc tgcaccagga ctggctgaat 360
ggcaaggcat acgcatgcgc ggtctccaac aaagccctcc cagcccccat cgagaaaacc 420
atctccaaag ccaaagggca gccccgagaa ccacaggtgt acaccctgcc cccatcccgg 480
gatgagctga ccaagaacca ggtcagcctg acctgcctgg tcaaaggctt ctatccaagc 540
gacatcgccg tggagtggga gagcaatggg cagccggaga acaactacaa gaccacgcct 600
cccgtgctgg actccgacgg ctccttcttc ctctacagca agctcaccgt ggacaagagc 660
aggtggcagc aggggaacgt cttctcatgc tccgtgatgc atgaggctct gcacaaccac 720
tacacgcaga agagcctctc cctgtctccg ggtcagaggc acaacaattc ttccctgaat 780
acaggaactc agatggcagg tcattctccg aattctcagg tgcagctggt gcagtctggg 840
gctgaggtga agaagcctgg ggcctcagtg aaggtttcct gcaaggcatc tggatacacc 900
ttcaccagat ctacgatgca ctgggtgcga caggcccctg gacaagggct tgagtggatg 960
ggatacatta atcctagcag tgcttatact aattacaatc agaaattcaa ggacagagtc 1020
accatgacca gggacacgtc cacgagcaca gtctacatgg agctgagcag cctgagatct 1080
gaggacacgg ccgtgtatta ctgtgctaga ccccaagtcc actatgatta caacgggttt 1140
ccttactggg gccaaggaac cctggtcacc gtctcctcag gtggaggcgg ttcaggcgga 1200
ggtggatccg gcggtggcgg atcgggtggc ggcggatctg aaattgtgtt gacgcagtct 1260
ccagccaccc tgtctttgtc tccaggggaa agagccaccc tctcctgcag tgccagctca 1320
agtgtaagtt acatgaactg gtaccagcag aaacctggcc tggcgcccag gagatggatt 1380
tatgactcat ccaaactggc ttctggcatc ccagacaggt tcagtggcag tgggtctggg 1440
acagacttca ctctcaccat cagcagactg gagcctgaag attttgcagt gtattactgt 1500
cagcagtgga gtcgtaaccc acccactttc ggcggaggga ccaaggtgga gatcaaacgg 1560
tcctccagct aa 1572
<210> 36
<211> 503
<212> PRT
<213> 人工序列
<220>
<223> Fc H8L7 (TSC338) CD3结合结构域
<400> 36
Glu Pro Lys Ser Ser Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala
1 5 10 15
Pro Glu Ala Ala Gly Ala Pro Ser Val Phe Leu Phe Pro Pro Lys Pro
20 25 30
Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val
35 40 45
Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val
50 55 60
Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln
65 70 75 80
Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln
85 90 95
Asp Trp Leu Asn Gly Lys Ala Tyr Ala Cys Ala Val Ser Asn Lys Ala
100 105 110
Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro
115 120 125
Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr
130 135 140
Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser
145 150 155 160
Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr
165 170 175
Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr
180 185 190
Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe
195 200 205
Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys
210 215 220
Ser Leu Ser Leu Ser Pro Gly Gln Arg His Asn Asn Ser Ser Leu Asn
225 230 235 240
Thr Gly Thr Gln Met Ala Gly His Ser Pro Asn Ser Gln Val Gln Leu
245 250 255
Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala Ser Val Lys Val
260 265 270
Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Arg Ser Thr Met His Trp
275 280 285
Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met Gly Tyr Ile Asn
290 295 300
Pro Ser Ser Ala Tyr Thr Asn Tyr Asn Gln Lys Phe Lys Asp Arg Val
305 310 315 320
Thr Met Thr Arg Asp Thr Ser Thr Ser Thr Val Tyr Met Glu Leu Ser
325 330 335
Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Pro Gln
340 345 350
Val His Tyr Asp Tyr Asn Gly Phe Pro Tyr Trp Gly Gln Gly Thr Leu
355 360 365
Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly
370 375 380
Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Ile Val Leu Thr Gln Ser
385 390 395 400
Pro Ala Thr Leu Ser Leu Ser Pro Gly Glu Arg Ala Thr Leu Ser Cys
405 410 415
Ser Ala Ser Ser Ser Val Ser Tyr Met Asn Trp Tyr Gln Gln Lys Pro
420 425 430
Gly Leu Ala Pro Arg Arg Trp Ile Tyr Asp Ser Ser Lys Leu Ala Ser
435 440 445
Gly Ile Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr
450 455 460
Leu Thr Ile Ser Arg Leu Glu Pro Glu Asp Phe Ala Val Tyr Tyr Cys
465 470 475 480
Gln Gln Trp Ser Arg Asn Pro Pro Thr Phe Gly Gly Gly Thr Lys Val
485 490 495
Glu Ile Lys Arg Ser Ser Ser
500
<210> 37
<211> 1572
<212> DNA
<213> 人工序列
<220>
<223> Fc H8L8 (TSC339) CD3结合结构域
<400> 37
atggaagcac cagcgcagct tctcttcctc ctgctactct ggctcccaga taccaccggt 60
gagcccaaat cttctgacaa aactcacaca tgcccaccgt gcccagcacc tgaagccgcg 120
ggtgcaccgt cagtcttcct cttcccccca aaacccaagg acaccctcat gatctcccgg 180
acccctgagg tcacatgcgt ggtggtggac gtgagccacg aagaccctga ggtcaagttc 240
aactggtacg tggacggcgt ggaggtgcat aatgccaaga caaagccgcg ggaggagcag 300
tacaacagca cgtaccgtgt ggtcagcgtc ctcaccgtcc tgcaccagga ctggctgaat 360
ggcaaggcat acgcatgcgc ggtctccaac aaagccctcc cagcccccat cgagaaaacc 420
atctccaaag ccaaagggca gccccgagaa ccacaggtgt acaccctgcc cccatcccgg 480
gatgagctga ccaagaacca ggtcagcctg acctgcctgg tcaaaggctt ctatccaagc 540
gacatcgccg tggagtggga gagcaatggg cagccggaga acaactacaa gaccacgcct 600
cccgtgctgg actccgacgg ctccttcttc ctctacagca agctcaccgt ggacaagagc 660
aggtggcagc aggggaacgt cttctcatgc tccgtgatgc atgaggctct gcacaaccac 720
tacacgcaga agagcctctc cctgtctccg ggtcagaggc acaacaattc ttccctgaat 780
acaggaactc agatggcagg tcattctccg aattctcagg tgcagctggt gcagtctggg 840
gctgaggtga agaagcctgg ggcctcagtg aaggtttcct gcaaggcatc tggatacacc 900
ttcaccagat ctacgatgca ctgggtgcga caggcccctg gacaagggct tgagtggatg 960
ggatacatta atcctagcag tgcttatact aattacaatc agaaattcaa ggacagagtc 1020
accatgacca gggacacgtc cacgagcaca gtctacatgg agctgagcag cctgagatct 1080
gaggacacgg ccgtgtatta ctgtgctaga ccccaagtcc actatgatta caacgggttt 1140
ccttactggg gccaaggaac cctggtcacc gtctcctcag gtggaggcgg ttcaggcgga 1200
ggtggatccg gcggtggcgg atcgggtggc ggcggatctg acatccagat gacccagtct 1260
ccttccaccc tgtctgcatc tgtaggagac agagtcacca tcacttgcag tgccagctca 1320
agtgtaagtt acatgaactg gtatcagcag aaaccaggga aagcccctaa gagatggatt 1380
tatgactcat ccaaactggc ttctggggtc ccatcaaggt tcagcggcag tggatctggg 1440
acagaattca ctctcaccat cagcagcctg cagcctgatg attttgcaac ttattactgc 1500
caacagtgga gtcgtaaccc acccactttc ggcggaggga ccaaggtgga gatcaaacgg 1560
tcctccagct aa 1572
<210> 38
<211> 503
<212> PRT
<213> 人工序列
<220>
<223> Fc H8L8 (TSC339) CD3结合结构域
<400> 38
Glu Pro Lys Ser Ser Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala
1 5 10 15
Pro Glu Ala Ala Gly Ala Pro Ser Val Phe Leu Phe Pro Pro Lys Pro
20 25 30
Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val
35 40 45
Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val
50 55 60
Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln
65 70 75 80
Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln
85 90 95
Asp Trp Leu Asn Gly Lys Ala Tyr Ala Cys Ala Val Ser Asn Lys Ala
100 105 110
Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro
115 120 125
Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr
130 135 140
Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser
145 150 155 160
Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr
165 170 175
Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr
180 185 190
Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe
195 200 205
Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys
210 215 220
Ser Leu Ser Leu Ser Pro Gly Gln Arg His Asn Asn Ser Ser Leu Asn
225 230 235 240
Thr Gly Thr Gln Met Ala Gly His Ser Pro Asn Ser Gln Val Gln Leu
245 250 255
Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala Ser Val Lys Val
260 265 270
Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Arg Ser Thr Met His Trp
275 280 285
Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met Gly Tyr Ile Asn
290 295 300
Pro Ser Ser Ala Tyr Thr Asn Tyr Asn Gln Lys Phe Lys Asp Arg Val
305 310 315 320
Thr Met Thr Arg Asp Thr Ser Thr Ser Thr Val Tyr Met Glu Leu Ser
325 330 335
Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Pro Gln
340 345 350
Val His Tyr Asp Tyr Asn Gly Phe Pro Tyr Trp Gly Gln Gly Thr Leu
355 360 365
Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly
370 375 380
Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Gln Met Thr Gln Ser
385 390 395 400
Pro Ser Thr Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys
405 410 415
Ser Ala Ser Ser Ser Val Ser Tyr Met Asn Trp Tyr Gln Gln Lys Pro
420 425 430
Gly Lys Ala Pro Lys Arg Trp Ile Tyr Asp Ser Ser Lys Leu Ala Ser
435 440 445
Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Glu Phe Thr
450 455 460
Leu Thr Ile Ser Ser Leu Gln Pro Asp Asp Phe Ala Thr Tyr Tyr Cys
465 470 475 480
Gln Gln Trp Ser Arg Asn Pro Pro Thr Phe Gly Gly Gly Thr Lys Val
485 490 495
Glu Ile Lys Arg Ser Ser Ser
500
<210> 39
<211> 1572
<212> DNA
<213> 人工序列
<220>
<223> Fc H10L6 (TSC340) CD3结合结构域
<400> 39
atggaagcac cagcgcagct tctcttcctc ctgctactct ggctcccaga taccaccggt 60
gagcccaaat cttctgacaa aactcacaca tgcccaccgt gcccagcacc tgaagccgcg 120
ggtgcaccgt cagtcttcct cttcccccca aaacccaagg acaccctcat gatctcccgg 180
acccctgagg tcacatgcgt ggtggtggac gtgagccacg aagaccctga ggtcaagttc 240
aactggtacg tggacggcgt ggaggtgcat aatgccaaga caaagccgcg ggaggagcag 300
tacaacagca cgtaccgtgt ggtcagcgtc ctcaccgtcc tgcaccagga ctggctgaat 360
ggcaaggcat acgcatgcgc ggtctccaac aaagccctcc cagcccccat cgagaaaacc 420
atctccaaag ccaaagggca gccccgagaa ccacaggtgt acaccctgcc cccatcccgg 480
gatgagctga ccaagaacca ggtcagcctg acctgcctgg tcaaaggctt ctatccaagc 540
gacatcgccg tggagtggga gagcaatggg cagccggaga acaactacaa gaccacgcct 600
cccgtgctgg actccgacgg ctccttcttc ctctacagca agctcaccgt ggacaagagc 660
aggtggcagc aggggaacgt cttctcatgc tccgtgatgc atgaggctct gcacaaccac 720
tacacgcaga agagcctctc cctgtctccg ggtcagaggc acaacaattc ttccctgaat 780
acaggaactc agatggcagg tcattctccg aattctcagg tccagctggt gcaatctggg 840
gctgaggtga agaagcctgg gtcctcggtg aaggtctcct gcaaggcttc tggaggcacc 900
ttcagcagat ctacgatgca ctgggtgcga caggcccctg gacaagggct tgagtggatg 960
ggatacatta atcctagcag tgcttatact aattacaatc agaaattcaa ggacagagtc 1020
acgattaccg cggacaaatc cacgagcaca gcctacatgg agctgagcag cctgagatct 1080
gaggacacgg ccgtgtatta ctgtgcgaga ccccaagtcc actatgatta caacgggttt 1140
ccttactggg gccaaggaac cctggtcacc gtctcctcag gtggaggcgg ttcaggcgga 1200
ggtggatccg gcggtggcgg atcgggtggc ggcggatctg acatccagat gacccagtct 1260
ccatcctccc tgtctgcatc tgtaggagac agagtcacca tcacttgcag tgccagctca 1320
agtgtaagtt acatgaactg gtatcagcag aaaccaggga aagcccctaa gagatggatt 1380
tatgactcat ccaaactggc ttctggggtc ccatcaaggt tcagtggcag tggatctggg 1440
acagatttca ctctcaccat cagcagtctg caacctgaag attttgcaac ttactactgt 1500
caacagtgga gtcgtaaccc acccactttc ggcggaggga ccaaggtgga gatcaaacgg 1560
tcctccagct aa 1572
<210> 40
<211> 503
<212> PRT
<213> 人工序列
<220>
<223> Fc H10L6 (TSC340) CD3结合结构域
<400> 40
Glu Pro Lys Ser Ser Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala
1 5 10 15
Pro Glu Ala Ala Gly Ala Pro Ser Val Phe Leu Phe Pro Pro Lys Pro
20 25 30
Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val
35 40 45
Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val
50 55 60
Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln
65 70 75 80
Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln
85 90 95
Asp Trp Leu Asn Gly Lys Ala Tyr Ala Cys Ala Val Ser Asn Lys Ala
100 105 110
Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro
115 120 125
Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr
130 135 140
Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser
145 150 155 160
Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr
165 170 175
Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr
180 185 190
Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe
195 200 205
Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys
210 215 220
Ser Leu Ser Leu Ser Pro Gly Gln Arg His Asn Asn Ser Ser Leu Asn
225 230 235 240
Thr Gly Thr Gln Met Ala Gly His Ser Pro Asn Ser Gln Val Gln Leu
245 250 255
Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser Ser Val Lys Val
260 265 270
Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Arg Ser Thr Met His Trp
275 280 285
Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met Gly Tyr Ile Asn
290 295 300
Pro Ser Ser Ala Tyr Thr Asn Tyr Asn Gln Lys Phe Lys Asp Arg Val
305 310 315 320
Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr Met Glu Leu Ser
325 330 335
Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Pro Gln
340 345 350
Val His Tyr Asp Tyr Asn Gly Phe Pro Tyr Trp Gly Gln Gly Thr Leu
355 360 365
Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly
370 375 380
Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Gln Met Thr Gln Ser
385 390 395 400
Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys
405 410 415
Ser Ala Ser Ser Ser Val Ser Tyr Met Asn Trp Tyr Gln Gln Lys Pro
420 425 430
Gly Lys Ala Pro Lys Arg Trp Ile Tyr Asp Ser Ser Lys Leu Ala Ser
435 440 445
Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr
450 455 460
Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys
465 470 475 480
Gln Gln Trp Ser Arg Asn Pro Pro Thr Phe Gly Gly Gly Thr Lys Val
485 490 495
Glu Ile Lys Arg Ser Ser Ser
500
<210> 41
<211> 1572
<212> DNA
<213> 人工序列
<220>
<223> Fc H10L7 (TSC341) CD3结合结构域
<400> 41
atggaagcac cagcgcagct tctcttcctc ctgctactct ggctcccaga taccaccggt 60
gagcccaaat cttctgacaa aactcacaca tgcccaccgt gcccagcacc tgaagccgcg 120
ggtgcaccgt cagtcttcct cttcccccca aaacccaagg acaccctcat gatctcccgg 180
acccctgagg tcacatgcgt ggtggtggac gtgagccacg aagaccctga ggtcaagttc 240
aactggtacg tggacggcgt ggaggtgcat aatgccaaga caaagccgcg ggaggagcag 300
tacaacagca cgtaccgtgt ggtcagcgtc ctcaccgtcc tgcaccagga ctggctgaat 360
ggcaaggcat acgcatgcgc ggtctccaac aaagccctcc cagcccccat cgagaaaacc 420
atctccaaag ccaaagggca gccccgagaa ccacaggtgt acaccctgcc cccatcccgg 480
gatgagctga ccaagaacca ggtcagcctg acctgcctgg tcaaaggctt ctatccaagc 540
gacatcgccg tggagtggga gagcaatggg cagccggaga acaactacaa gaccacgcct 600
cccgtgctgg actccgacgg ctccttcttc ctctacagca agctcaccgt ggacaagagc 660
aggtggcagc aggggaacgt cttctcatgc tccgtgatgc atgaggctct gcacaaccac 720
tacacgcaga agagcctctc cctgtctccg ggtcagaggc acaacaattc ttccctgaat 780
acaggaactc agatggcagg tcattctccg aattctcagg tccagctggt gcaatctggg 840
gctgaggtga agaagcctgg gtcctcggtg aaggtctcct gcaaggcttc tggaggcacc 900
ttcagcagat ctacgatgca ctgggtgcga caggcccctg gacaagggct tgagtggatg 960
ggatacatta atcctagcag tgcttatact aattacaatc agaaattcaa ggacagagtc 1020
acgattaccg cggacaaatc cacgagcaca gcctacatgg agctgagcag cctgagatct 1080
gaggacacgg ccgtgtatta ctgtgcgaga ccccaagtcc actatgatta caacgggttt 1140
ccttactggg gccaaggaac cctggtcacc gtctcctcag gtggaggcgg ttcaggcgga 1200
ggtggatccg gcggtggcgg atcgggtggc ggcggatctg aaattgtgtt gacgcagtct 1260
ccagccaccc tgtctttgtc tccaggggaa agagccaccc tctcctgcag tgccagctca 1320
agtgtaagtt acatgaactg gtaccagcag aaacctggcc tggcgcccag gagatggatt 1380
tatgactcat ccaaactggc ttctggcatc ccagacaggt tcagtggcag tgggtctggg 1440
acagacttca ctctcaccat cagcagactg gagcctgaag attttgcagt gtattactgt 1500
cagcagtgga gtcgtaaccc acccactttc ggcggaggga ccaaggtgga gatcaaacgg 1560
tcctccagct aa 1572
<210> 42
<211> 503
<212> PRT
<213> 人工序列
<220>
<223> Fc H10L7 (TSC341) CD3结合结构域
<400> 42
Glu Pro Lys Ser Ser Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala
1 5 10 15
Pro Glu Ala Ala Gly Ala Pro Ser Val Phe Leu Phe Pro Pro Lys Pro
20 25 30
Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val
35 40 45
Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val
50 55 60
Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln
65 70 75 80
Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln
85 90 95
Asp Trp Leu Asn Gly Lys Ala Tyr Ala Cys Ala Val Ser Asn Lys Ala
100 105 110
Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro
115 120 125
Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr
130 135 140
Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser
145 150 155 160
Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr
165 170 175
Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr
180 185 190
Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe
195 200 205
Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys
210 215 220
Ser Leu Ser Leu Ser Pro Gly Gln Arg His Asn Asn Ser Ser Leu Asn
225 230 235 240
Thr Gly Thr Gln Met Ala Gly His Ser Pro Asn Ser Gln Val Gln Leu
245 250 255
Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser Ser Val Lys Val
260 265 270
Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Arg Ser Thr Met His Trp
275 280 285
Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met Gly Tyr Ile Asn
290 295 300
Pro Ser Ser Ala Tyr Thr Asn Tyr Asn Gln Lys Phe Lys Asp Arg Val
305 310 315 320
Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr Met Glu Leu Ser
325 330 335
Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Pro Gln
340 345 350
Val His Tyr Asp Tyr Asn Gly Phe Pro Tyr Trp Gly Gln Gly Thr Leu
355 360 365
Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly
370 375 380
Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Ile Val Leu Thr Gln Ser
385 390 395 400
Pro Ala Thr Leu Ser Leu Ser Pro Gly Glu Arg Ala Thr Leu Ser Cys
405 410 415
Ser Ala Ser Ser Ser Val Ser Tyr Met Asn Trp Tyr Gln Gln Lys Pro
420 425 430
Gly Leu Ala Pro Arg Arg Trp Ile Tyr Asp Ser Ser Lys Leu Ala Ser
435 440 445
Gly Ile Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr
450 455 460
Leu Thr Ile Ser Arg Leu Glu Pro Glu Asp Phe Ala Val Tyr Tyr Cys
465 470 475 480
Gln Gln Trp Ser Arg Asn Pro Pro Thr Phe Gly Gly Gly Thr Lys Val
485 490 495
Glu Ile Lys Arg Ser Ser Ser
500
<210> 43
<211> 1572
<212> DNA
<213> 人工序列
<220>
<223> Fc H10L8 (TSC342) CD3结合结构域
<400> 43
atggaagcac cagcgcagct tctcttcctc ctgctactct ggctcccaga taccaccggt 60
gagcccaaat cttctgacaa aactcacaca tgcccaccgt gcccagcacc tgaagccgcg 120
ggtgcaccgt cagtcttcct cttcccccca aaacccaagg acaccctcat gatctcccgg 180
acccctgagg tcacatgcgt ggtggtggac gtgagccacg aagaccctga ggtcaagttc 240
aactggtacg tggacggcgt ggaggtgcat aatgccaaga caaagccgcg ggaggagcag 300
tacaacagca cgtaccgtgt ggtcagcgtc ctcaccgtcc tgcaccagga ctggctgaat 360
ggcaaggcat acgcatgcgc ggtctccaac aaagccctcc cagcccccat cgagaaaacc 420
atctccaaag ccaaagggca gccccgagaa ccacaggtgt acaccctgcc cccatcccgg 480
gatgagctga ccaagaacca ggtcagcctg acctgcctgg tcaaaggctt ctatccaagc 540
gacatcgccg tggagtggga gagcaatggg cagccggaga acaactacaa gaccacgcct 600
cccgtgctgg actccgacgg ctccttcttc ctctacagca agctcaccgt ggacaagagc 660
aggtggcagc aggggaacgt cttctcatgc tccgtgatgc atgaggctct gcacaaccac 720
tacacgcaga agagcctctc cctgtctccg ggtcagaggc acaacaattc ttccctgaat 780
acaggaactc agatggcagg tcattctccg aattctcagg tccagctggt gcaatctggg 840
gctgaggtga agaagcctgg gtcctcggtg aaggtctcct gcaaggcttc tggaggcacc 900
ttcagcagat ctacgatgca ctgggtgcga caggcccctg gacaagggct tgagtggatg 960
ggatacatta atcctagcag tgcttatact aattacaatc agaaattcaa ggacagagtc 1020
acgattaccg cggacaaatc cacgagcaca gcctacatgg agctgagcag cctgagatct 1080
gaggacacgg ccgtgtatta ctgtgcgaga ccccaagtcc actatgatta caacgggttt 1140
ccttactggg gccaaggaac cctggtcacc gtctcctcag gtggaggcgg ttcaggcgga 1200
ggtggatccg gcggtggcgg atcgggtggc ggcggatctg acatccagat gacccagtct 1260
ccttccaccc tgtctgcatc tgtaggagac agagtcacca tcacttgcag tgccagctca 1320
agtgtaagtt acatgaactg gtatcagcag aaaccaggga aagcccctaa gagatggatt 1380
tatgactcat ccaaactggc ttctggggtc ccatcaaggt tcagcggcag tggatctggg 1440
acagaattca ctctcaccat cagcagcctg cagcctgatg attttgcaac ttattactgc 1500
caacagtgga gtcgtaaccc acccactttc ggcggaggga ccaaggtgga gatcaaacgg 1560
tcctccagct aa 1572
<210> 44
<211> 503
<212> PRT
<213> 人工序列
<220>
<223> Fc H10L8 (TSC342) CD3结合结构域
<400> 44
Glu Pro Lys Ser Ser Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala
1 5 10 15
Pro Glu Ala Ala Gly Ala Pro Ser Val Phe Leu Phe Pro Pro Lys Pro
20 25 30
Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val
35 40 45
Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val
50 55 60
Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln
65 70 75 80
Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln
85 90 95
Asp Trp Leu Asn Gly Lys Ala Tyr Ala Cys Ala Val Ser Asn Lys Ala
100 105 110
Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro
115 120 125
Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr
130 135 140
Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser
145 150 155 160
Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr
165 170 175
Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr
180 185 190
Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe
195 200 205
Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys
210 215 220
Ser Leu Ser Leu Ser Pro Gly Gln Arg His Asn Asn Ser Ser Leu Asn
225 230 235 240
Thr Gly Thr Gln Met Ala Gly His Ser Pro Asn Ser Gln Val Gln Leu
245 250 255
Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser Ser Val Lys Val
260 265 270
Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Arg Ser Thr Met His Trp
275 280 285
Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met Gly Tyr Ile Asn
290 295 300
Pro Ser Ser Ala Tyr Thr Asn Tyr Asn Gln Lys Phe Lys Asp Arg Val
305 310 315 320
Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr Met Glu Leu Ser
325 330 335
Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Pro Gln
340 345 350
Val His Tyr Asp Tyr Asn Gly Phe Pro Tyr Trp Gly Gln Gly Thr Leu
355 360 365
Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly
370 375 380
Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Gln Met Thr Gln Ser
385 390 395 400
Pro Ser Thr Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys
405 410 415
Ser Ala Ser Ser Ser Val Ser Tyr Met Asn Trp Tyr Gln Gln Lys Pro
420 425 430
Gly Lys Ala Pro Lys Arg Trp Ile Tyr Asp Ser Ser Lys Leu Ala Ser
435 440 445
Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Glu Phe Thr
450 455 460
Leu Thr Ile Ser Ser Leu Gln Pro Asp Asp Phe Ala Thr Tyr Tyr Cys
465 470 475 480
Gln Gln Trp Ser Arg Asn Pro Pro Thr Phe Gly Gly Gly Thr Lys Val
485 490 495
Glu Ile Lys Arg Ser Ser Ser
500
<210> 45
<211> 1572
<212> DNA
<213> 人工序列
<220>
<223> TSC370 CD3结合结构域
<400> 45
atggaagcac cagcgcagct tctcttcctc ctgctactct ggctcccaga taccaccggt 60
gagcccaaat cttctgacaa aactcacaca tgcccaccgt gcccagcacc tgaagccgcg 120
ggtgcaccgt cagtcttcct cttcccccca aaacccaagg acaccctcat gatctcccgg 180
acccctgagg tcacatgcgt ggtggtggac gtgagccacg aagaccctga ggtcaagttc 240
aactggtacg tggacggcgt ggaggtgcat aatgccaaga caaagccgcg ggaggagcag 300
tacaacagca cgtaccgtgt ggtcagcgtc ctcaccgtcc tgcaccagga ctggctgaat 360
ggcaaggcat acgcatgcgc ggtctccaac aaagccctcc cagcccccat cgagaaaacc 420
atctccaaag ccaaagggca gccccgagaa ccacaggtgt acaccctgcc cccatcccgg 480
gatgagctga ccaagaacca ggtcagcctg acctgcctgg tcaaaggctt ctatccaagc 540
gacatcgccg tggagtggga gagcaatggg cagccggaga acaactacaa gaccacgcct 600
cccgtgctgg actccgacgg ctccttcttc ctctacagca agctcaccgt ggacaagagc 660
aggtggcagc aggggaacgt cttctcatgc tccgtgatgc atgaggctct gcacaaccac 720
tacacgcaga agagcctctc cctgtctccg ggtcagaggc acaacaattc ttccctgaat 780
acaggaactc agatggcagg tcattctccg aattctcagg tccagctggt gcaatctggg 840
gctgaggtga agaagcctgg gtcctcggtg aaggtctcct gcaaggcttc tggatatacc 900
ttcagcagat ctacgatgca ctgggtgcga caggcccctg gacaagggct tgagtggatg 960
ggatacatta atcctagcag tgcttatact aattacaatc agaaattcaa ggacagagtc 1020
acgattaccg cggacaaatc cacgagcaca gcctacatgg agctgagcag cctgagatct 1080
gaggacacgg ccgtgtatta ctgtgcgaga ccccaagtcc actatgatta caacgggttt 1140
ccttactggg gccaaggaac cctggtcacc gtctcctcag gtggaggcgg ttcaggcgga 1200
ggtggatccg gcggtggcgg atcgggtggc ggcggatctg acatccagat gacccagtct 1260
ccttccaccc tgtctgcatc tgtaggagac agagtcacca tcacttgcag tgccagctca 1320
agtgtaagtt acatgaactg gtatcagcag aaaccaggga aagcccctaa gagatggatt 1380
tatgactcat ccaaactggc ttctggggtc ccatcaaggt tcagcggcag tggatctggg 1440
acagaattca ctctcaccat cagcagcctg cagcctgatg attttgcaac ttattactgc 1500
caacagtgga gtcgtaaccc acccactttc ggcggaggga ccaaggtgga gatcaaacgg 1560
tcctccagct aa 1572
<210> 46
<211> 503
<212> PRT
<213> 人工序列
<220>
<223> TSC370 CD3结合结构域
<400> 46
Glu Pro Lys Ser Ser Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala
1 5 10 15
Pro Glu Ala Ala Gly Ala Pro Ser Val Phe Leu Phe Pro Pro Lys Pro
20 25 30
Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val
35 40 45
Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val
50 55 60
Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln
65 70 75 80
Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln
85 90 95
Asp Trp Leu Asn Gly Lys Ala Tyr Ala Cys Ala Val Ser Asn Lys Ala
100 105 110
Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro
115 120 125
Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr
130 135 140
Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser
145 150 155 160
Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr
165 170 175
Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr
180 185 190
Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe
195 200 205
Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys
210 215 220
Ser Leu Ser Leu Ser Pro Gly Gln Arg His Asn Asn Ser Ser Leu Asn
225 230 235 240
Thr Gly Thr Gln Met Ala Gly His Ser Pro Asn Ser Gln Val Gln Leu
245 250 255
Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser Ser Val Lys Val
260 265 270
Ser Cys Lys Ala Ser Gly Tyr Thr Phe Ser Arg Ser Thr Met His Trp
275 280 285
Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met Gly Tyr Ile Asn
290 295 300
Pro Ser Ser Ala Tyr Thr Asn Tyr Asn Gln Lys Phe Lys Asp Arg Val
305 310 315 320
Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr Met Glu Leu Ser
325 330 335
Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Pro Gln
340 345 350
Val His Tyr Asp Tyr Asn Gly Phe Pro Tyr Trp Gly Gln Gly Thr Leu
355 360 365
Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly
370 375 380
Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Gln Met Thr Gln Ser
385 390 395 400
Pro Ser Thr Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys
405 410 415
Ser Ala Ser Ser Ser Val Ser Tyr Met Asn Trp Tyr Gln Gln Lys Pro
420 425 430
Gly Lys Ala Pro Lys Arg Trp Ile Tyr Asp Ser Ser Lys Leu Ala Ser
435 440 445
Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Glu Phe Thr
450 455 460
Leu Thr Ile Ser Ser Leu Gln Pro Asp Asp Phe Ala Thr Tyr Tyr Cys
465 470 475 480
Gln Gln Trp Ser Arg Asn Pro Pro Thr Phe Gly Gly Gly Thr Lys Val
485 490 495
Glu Ile Lys Arg Ser Ser Ser
500
<210> 47
<211> 1572
<212> DNA
<213> 人工序列
<220>
<223> TSC371 CD3结合结构域
<400> 47
atggaagcac cagcgcagct tctcttcctc ctgctactct ggctcccaga taccaccggt 60
gagcccaaat cttctgacaa aactcacaca tgcccaccgt gcccagcacc tgaagccgcg 120
ggtgcaccgt cagtcttcct cttcccccca aaacccaagg acaccctcat gatctcccgg 180
acccctgagg tcacatgcgt ggtggtggac gtgagccacg aagaccctga ggtcaagttc 240
aactggtacg tggacggcgt ggaggtgcat aatgccaaga caaagccgcg ggaggagcag 300
tacaacagca cgtaccgtgt ggtcagcgtc ctcaccgtcc tgcaccagga ctggctgaat 360
ggcaaggcat acgcatgcgc ggtctccaac aaagccctcc cagcccccat cgagaaaacc 420
atctccaaag ccaaagggca gccccgagaa ccacaggtgt acaccctgcc cccatcccgg 480
gatgagctga ccaagaacca ggtcagcctg acctgcctgg tcaaaggctt ctatccaagc 540
gacatcgccg tggagtggga gagcaatggg cagccggaga acaactacaa gaccacgcct 600
cccgtgctgg actccgacgg ctccttcttc ctctacagca agctcaccgt ggacaagagc 660
aggtggcagc aggggaacgt cttctcatgc tccgtgatgc atgaggctct gcacaaccac 720
tacacgcaga agagcctctc cctgtctccg ggtcagaggc acaacaattc ttccctgaat 780
acaggaactc agatggcagg tcattctccg aattctcagg tccagctggt gcaatctggg 840
gctgaggtga agaagcctgg gtcctcggtg aaggtctcct gcaaggcttc tggaggcacc 900
ttcagcagat ctacgatgca ctgggtgcga caggcccctg gacaagggct tgagtggata 960
ggatacatta atcctagcag tgcttatact aattacaatc agaaattcaa ggacagagtc 1020
acgattaccg cggacaaatc cacgagcaca gcctacatgg agctgagcag cctgagatct 1080
gaggacacgg ccgtgtatta ctgtgcgaga ccccaagtcc actatgatta caacgggttt 1140
ccttactggg gccaaggaac cctggtcacc gtctcctcag gtggaggcgg ttcaggcgga 1200
ggtggatccg gcggtggcgg atcgggtggc ggcggatctg acatccagat gacccagtct 1260
ccttccaccc tgtctgcatc tgtaggagac agagtcacca tcacttgcag tgccagctca 1320
agtgtaagtt acatgaactg gtatcagcag aaaccaggga aagcccctaa gagatggatt 1380
tatgactcat ccaaactggc ttctggggtc ccatcaaggt tcagcggcag tggatctggg 1440
acagaattca ctctcaccat cagcagcctg cagcctgatg attttgcaac ttattactgc 1500
caacagtgga gtcgtaaccc acccactttc ggcggaggga ccaaggtgga gatcaaacgg 1560
tcctccagct aa 1572
<210> 48
<211> 503
<212> PRT
<213> 人工序列
<220>
<223> TSC371 CD3结合结构域
<400> 48
Glu Pro Lys Ser Ser Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala
1 5 10 15
Pro Glu Ala Ala Gly Ala Pro Ser Val Phe Leu Phe Pro Pro Lys Pro
20 25 30
Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val
35 40 45
Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val
50 55 60
Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln
65 70 75 80
Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln
85 90 95
Asp Trp Leu Asn Gly Lys Ala Tyr Ala Cys Ala Val Ser Asn Lys Ala
100 105 110
Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro
115 120 125
Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr
130 135 140
Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser
145 150 155 160
Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr
165 170 175
Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr
180 185 190
Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe
195 200 205
Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys
210 215 220
Ser Leu Ser Leu Ser Pro Gly Gln Arg His Asn Asn Ser Ser Leu Asn
225 230 235 240
Thr Gly Thr Gln Met Ala Gly His Ser Pro Asn Ser Gln Val Gln Leu
245 250 255
Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser Ser Val Lys Val
260 265 270
Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Arg Ser Thr Met His Trp
275 280 285
Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Ile Gly Tyr Ile Asn
290 295 300
Pro Ser Ser Ala Tyr Thr Asn Tyr Asn Gln Lys Phe Lys Asp Arg Val
305 310 315 320
Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr Met Glu Leu Ser
325 330 335
Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Pro Gln
340 345 350
Val His Tyr Asp Tyr Asn Gly Phe Pro Tyr Trp Gly Gln Gly Thr Leu
355 360 365
Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly
370 375 380
Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Gln Met Thr Gln Ser
385 390 395 400
Pro Ser Thr Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys
405 410 415
Ser Ala Ser Ser Ser Val Ser Tyr Met Asn Trp Tyr Gln Gln Lys Pro
420 425 430
Gly Lys Ala Pro Lys Arg Trp Ile Tyr Asp Ser Ser Lys Leu Ala Ser
435 440 445
Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Glu Phe Thr
450 455 460
Leu Thr Ile Ser Ser Leu Gln Pro Asp Asp Phe Ala Thr Tyr Tyr Cys
465 470 475 480
Gln Gln Trp Ser Arg Asn Pro Pro Thr Phe Gly Gly Gly Thr Lys Val
485 490 495
Glu Ile Lys Arg Ser Ser Ser
500
<210> 49
<211> 1572
<212> DNA
<213> 人工序列
<220>
<223> TSC372 CD3结合结构域
<400> 49
atggaagcac cagcgcagct tctcttcctc ctgctactct ggctcccaga taccaccggt 60
gagcccaaat cttctgacaa aactcacaca tgcccaccgt gcccagcacc tgaagccgcg 120
ggtgcaccgt cagtcttcct cttcccccca aaacccaagg acaccctcat gatctcccgg 180
acccctgagg tcacatgcgt ggtggtggac gtgagccacg aagaccctga ggtcaagttc 240
aactggtacg tggacggcgt ggaggtgcat aatgccaaga caaagccgcg ggaggagcag 300
tacaacagca cgtaccgtgt ggtcagcgtc ctcaccgtcc tgcaccagga ctggctgaat 360
ggcaaggcat acgcatgcgc ggtctccaac aaagccctcc cagcccccat cgagaaaacc 420
atctccaaag ccaaagggca gccccgagaa ccacaggtgt acaccctgcc cccatcccgg 480
gatgagctga ccaagaacca ggtcagcctg acctgcctgg tcaaaggctt ctatccaagc 540
gacatcgccg tggagtggga gagcaatggg cagccggaga acaactacaa gaccacgcct 600
cccgtgctgg actccgacgg ctccttcttc ctctacagca agctcaccgt ggacaagagc 660
aggtggcagc aggggaacgt cttctcatgc tccgtgatgc atgaggctct gcacaaccac 720
tacacgcaga agagcctctc cctgtctccg ggtcagaggc acaacaattc ttccctgaat 780
acaggaactc agatggcagg tcattctccg aattctcagg tccagctggt gcaatctggg 840
gctgaggtga agaagcctgg gtcctcggtg aaggtctcct gcaaggcttc tggaggcacc 900
ttcagcagat ctacgatgca ctgggtgcga caggcccctg gacaagggct tgagtggatg 960
ggatacatta atcctagcag tgcttatact aattacaatc agaaattcaa ggacagagtc 1020
acgattaccg cggacaaatc cacgagcaca gcctacatgg agctgagcag cctgagatct 1080
gaggacacgg ccgtgtatta ctgtgcgaga ccccaagtcc actatgatta caacgggttt 1140
ccttactggg gccaaggaac cctggtcacc gtctcctcag gtggaggcgg ttcaggcgga 1200
ggtggatccg gcggtggcgg atcgggtggc ggcggatctg acatccagat gacccagtct 1260
ccttccaccc tgtctgcatc tgtaggagac agagtcacca tgacttgcag tgccagctca 1320
agtgtaagtt acatgaactg gtatcagcag aaaccaggga aagcccctaa gagatggatt 1380
tatgactcat ccaaactggc ttctggggtc ccatcaaggt tcagcggcag tggatctggg 1440
acagaattca ctctcaccat cagcagcctg cagcctgatg attttgcaac ttattactgc 1500
caacagtgga gtcgtaaccc acccactttc ggcggaggga ccaaggtgga gatcaaacgg 1560
tcctccagct aa 1572
<210> 50
<211> 503
<212> PRT
<213> 人工序列
<220>
<223> TSC372 CD3结合结构域
<400> 50
Glu Pro Lys Ser Ser Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala
1 5 10 15
Pro Glu Ala Ala Gly Ala Pro Ser Val Phe Leu Phe Pro Pro Lys Pro
20 25 30
Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val
35 40 45
Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val
50 55 60
Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln
65 70 75 80
Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln
85 90 95
Asp Trp Leu Asn Gly Lys Ala Tyr Ala Cys Ala Val Ser Asn Lys Ala
100 105 110
Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro
115 120 125
Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr
130 135 140
Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser
145 150 155 160
Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr
165 170 175
Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr
180 185 190
Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe
195 200 205
Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys
210 215 220
Ser Leu Ser Leu Ser Pro Gly Gln Arg His Asn Asn Ser Ser Leu Asn
225 230 235 240
Thr Gly Thr Gln Met Ala Gly His Ser Pro Asn Ser Gln Val Gln Leu
245 250 255
Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser Ser Val Lys Val
260 265 270
Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Arg Ser Thr Met His Trp
275 280 285
Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met Gly Tyr Ile Asn
290 295 300
Pro Ser Ser Ala Tyr Thr Asn Tyr Asn Gln Lys Phe Lys Asp Arg Val
305 310 315 320
Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr Met Glu Leu Ser
325 330 335
Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Pro Gln
340 345 350
Val His Tyr Asp Tyr Asn Gly Phe Pro Tyr Trp Gly Gln Gly Thr Leu
355 360 365
Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly
370 375 380
Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Gln Met Thr Gln Ser
385 390 395 400
Pro Ser Thr Leu Ser Ala Ser Val Gly Asp Arg Val Thr Met Thr Cys
405 410 415
Ser Ala Ser Ser Ser Val Ser Tyr Met Asn Trp Tyr Gln Gln Lys Pro
420 425 430
Gly Lys Ala Pro Lys Arg Trp Ile Tyr Asp Ser Ser Lys Leu Ala Ser
435 440 445
Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Glu Phe Thr
450 455 460
Leu Thr Ile Ser Ser Leu Gln Pro Asp Asp Phe Ala Thr Tyr Tyr Cys
465 470 475 480
Gln Gln Trp Ser Arg Asn Pro Pro Thr Phe Gly Gly Gly Thr Lys Val
485 490 495
Glu Ile Lys Arg Ser Ser Ser
500
<210> 51
<211> 1572
<212> DNA
<213> 人工序列
<220>
<223> TSC390 CD3结合结构域
<400> 51
atggaagcac cagcgcagct tctcttcctc ctgctactct ggctcccaga taccaccggt 60
gagcccaaat cttctgacaa aactcacaca tgcccaccgt gcccagcacc tgaagccgcg 120
ggtgcaccgt cagtcttcct cttcccccca aaacccaagg acaccctcat gatctcccgg 180
acccctgagg tcacatgcgt ggtggtggac gtgagccacg aagaccctga ggtcaagttc 240
aactggtacg tggacggcgt ggaggtgcat aatgccaaga caaagccgcg ggaggagcag 300
tacaacagca cgtaccgtgt ggtcagcgtc ctcaccgtcc tgcaccagga ctggctgaat 360
ggcaaggcat acgcatgcgc ggtctccaac aaagccctcc cagcccccat cgagaaaacc 420
atctccaaag ccaaagggca gccccgagaa ccacaggtgt acaccctgcc cccatcccgg 480
gatgagctga ccaagaacca ggtcagcctg acctgcctgg tcaaaggctt ctatccaagc 540
gacatcgccg tggagtggga gagcaatggg cagccggaga acaactacaa gaccacgcct 600
cccgtgctgg actccgacgg ctccttcttc ctctacagca agctcaccgt ggacaagagc 660
aggtggcagc aggggaacgt cttctcatgc tccgtgatgc atgaggctct gcacaaccac 720
tacacgcaga agagcctctc cctgtctccg ggtcagaggc acaacaattc ttccctgaat 780
acaggaactc agatggcagg tcattctccg aattctcagg tccagctggt gcaatctggg 840
cctgaggtga agaagcctgg gtcctcggtg aaggtctcct gcaaggcttc tggatatacc 900
ttcagcagat ctacgatgca ctgggtgcga caggcccctg gacaagggct tgagtggatg 960
ggatacatta atcctagcag tgcttatact aattacaatc agaaattcaa ggacagagtc 1020
acgattaccg cggacaaatc cacgagcaca gcctacatgg agctgagcag cctgagatct 1080
gaggacacgg ccgtgtatta ctgtgcgaga ccccaagtcc actatgatta caacgggttt 1140
ccttactggg gccaaggaac cctggtcacc gtctcctcag gtggaggcgg ttcaggcgga 1200
ggtggatccg gcggtggcgg atcgggtggc ggcggatctg acatccagat gacccagtct 1260
ccttccaccc tgtctgcatc tgtaggagac agagtcacca tcacttgcag tgccagctca 1320
agtgtaagtt acatgaactg gtatcagcag aaaccaggga aagcccctaa gagatggatt 1380
tatgactcat ccaaactggc ttctggggtc ccatcaaggt tcagcggcag tggatctggg 1440
acagagttca ctctcaccat cagcagcctg cagcctgatg attttgcaac ttattactgc 1500
caacagtgga gtcgtaaccc acccactttc ggcggaggga ccaaggtgga gatcaaacgg 1560
tcctccagct aa 1572
<210> 52
<211> 503
<212> PRT
<213> 人工序列
<220>
<223> TSC390 CD3结合结构域
<400> 52
Glu Pro Lys Ser Ser Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala
1 5 10 15
Pro Glu Ala Ala Gly Ala Pro Ser Val Phe Leu Phe Pro Pro Lys Pro
20 25 30
Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val
35 40 45
Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val
50 55 60
Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln
65 70 75 80
Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln
85 90 95
Asp Trp Leu Asn Gly Lys Ala Tyr Ala Cys Ala Val Ser Asn Lys Ala
100 105 110
Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro
115 120 125
Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr
130 135 140
Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser
145 150 155 160
Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr
165 170 175
Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr
180 185 190
Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe
195 200 205
Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys
210 215 220
Ser Leu Ser Leu Ser Pro Gly Gln Arg His Asn Asn Ser Ser Leu Asn
225 230 235 240
Thr Gly Thr Gln Met Ala Gly His Ser Pro Asn Ser Gln Val Gln Leu
245 250 255
Val Gln Ser Gly Pro Glu Val Lys Lys Pro Gly Ser Ser Val Lys Val
260 265 270
Ser Cys Lys Ala Ser Gly Tyr Thr Phe Ser Arg Ser Thr Met His Trp
275 280 285
Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met Gly Tyr Ile Asn
290 295 300
Pro Ser Ser Ala Tyr Thr Asn Tyr Asn Gln Lys Phe Lys Asp Arg Val
305 310 315 320
Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr Met Glu Leu Ser
325 330 335
Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Pro Gln
340 345 350
Val His Tyr Asp Tyr Asn Gly Phe Pro Tyr Trp Gly Gln Gly Thr Leu
355 360 365
Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly
370 375 380
Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Gln Met Thr Gln Ser
385 390 395 400
Pro Ser Thr Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys
405 410 415
Ser Ala Ser Ser Ser Val Ser Tyr Met Asn Trp Tyr Gln Gln Lys Pro
420 425 430
Gly Lys Ala Pro Lys Arg Trp Ile Tyr Asp Ser Ser Lys Leu Ala Ser
435 440 445
Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Glu Phe Thr
450 455 460
Leu Thr Ile Ser Ser Leu Gln Pro Asp Asp Phe Ala Thr Tyr Tyr Cys
465 470 475 480
Gln Gln Trp Ser Arg Asn Pro Pro Thr Phe Gly Gly Gly Thr Lys Val
485 490 495
Glu Ile Lys Arg Ser Ser Ser
500
<210> 53
<211> 1572
<212> DNA
<213> 人工序列
<220>
<223> TSC391 CD3结合结构域
<400> 53
atggaagcac cagcgcagct tctcttcctc ctgctactct ggctcccaga taccaccggt 60
gagcccaaat cttctgacaa aactcacaca tgcccaccgt gcccagcacc tgaagccgcg 120
ggtgcaccgt cagtcttcct cttcccccca aaacccaagg acaccctcat gatctcccgg 180
acccctgagg tcacatgcgt ggtggtggac gtgagccacg aagaccctga ggtcaagttc 240
aactggtacg tggacggcgt ggaggtgcat aatgccaaga caaagccgcg ggaggagcag 300
tacaacagca cgtaccgtgt ggtcagcgtc ctcaccgtcc tgcaccagga ctggctgaat 360
ggcaaggcat acgcatgcgc ggtctccaac aaagccctcc cagcccccat cgagaaaacc 420
atctccaaag ccaaagggca gccccgagaa ccacaggtgt acaccctgcc cccatcccgg 480
gatgagctga ccaagaacca ggtcagcctg acctgcctgg tcaaaggctt ctatccaagc 540
gacatcgccg tggagtggga gagcaatggg cagccggaga acaactacaa gaccacgcct 600
cccgtgctgg actccgacgg ctccttcttc ctctacagca agctcaccgt ggacaagagc 660
aggtggcagc aggggaacgt cttctcatgc tccgtgatgc atgaggctct gcacaaccac 720
tacacgcaga agagcctctc cctgtctccg ggtcagaggc acaacaattc ttccctgaat 780
acaggaactc agatggcagg tcattctccg aattctcagg tccagctggt gcaatctggg 840
cctgaggtga agaagcctgg gtcctcggtg aaggtctcct gcaaggcttc tggatatacc 900
ttcagcagat ctacgatgca ctgggtgcga caggcccctg gacaagggct tgagtggata 960
ggatacatta atcctagcag tgcttatact aattacaatc agaaattcaa ggacagagtc 1020
acgattaccg cggacaaatc cacgagcaca gcctacatgg agctgagcag cctgagatct 1080
gaggacacgg ccgtgtatta ctgtgcgaga ccccaagtcc actatgatta caacgggttt 1140
ccttactggg gccaaggaac cctggtcacc gtctcctcag gtggaggcgg ttcaggcgga 1200
ggtggatccg gcggtggcgg atcgggtggc ggcggatctg acatccagat gacccagtct 1260
ccttccaccc tgtctgcatc tgtaggagac agagtcacca tcacttgcag tgccagctca 1320
agtgtaagtt acatgaactg gtatcagcag aaaccaggga aagcccctaa gagatggatt 1380
tatgactcat ccaaactggc ttctggggtc ccatcaaggt tcagcggcag tggatctggg 1440
acagagttca ctctcaccat cagcagcctg cagcctgatg attttgcaac ttattactgc 1500
caacagtgga gtcgtaaccc acccactttc ggcggaggga ccaaggtgga gatcaaacgg 1560
tcctccagct aa 1572
<210> 54
<211> 503
<212> PRT
<213> 人工序列
<220>
<223> TSC391 CD3结合结构域
<400> 54
Glu Pro Lys Ser Ser Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala
1 5 10 15
Pro Glu Ala Ala Gly Ala Pro Ser Val Phe Leu Phe Pro Pro Lys Pro
20 25 30
Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val
35 40 45
Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val
50 55 60
Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln
65 70 75 80
Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln
85 90 95
Asp Trp Leu Asn Gly Lys Ala Tyr Ala Cys Ala Val Ser Asn Lys Ala
100 105 110
Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro
115 120 125
Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr
130 135 140
Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser
145 150 155 160
Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr
165 170 175
Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr
180 185 190
Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe
195 200 205
Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys
210 215 220
Ser Leu Ser Leu Ser Pro Gly Gln Arg His Asn Asn Ser Ser Leu Asn
225 230 235 240
Thr Gly Thr Gln Met Ala Gly His Ser Pro Asn Ser Gln Val Gln Leu
245 250 255
Val Gln Ser Gly Pro Glu Val Lys Lys Pro Gly Ser Ser Val Lys Val
260 265 270
Ser Cys Lys Ala Ser Gly Tyr Thr Phe Ser Arg Ser Thr Met His Trp
275 280 285
Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Ile Gly Tyr Ile Asn
290 295 300
Pro Ser Ser Ala Tyr Thr Asn Tyr Asn Gln Lys Phe Lys Asp Arg Val
305 310 315 320
Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr Met Glu Leu Ser
325 330 335
Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Pro Gln
340 345 350
Val His Tyr Asp Tyr Asn Gly Phe Pro Tyr Trp Gly Gln Gly Thr Leu
355 360 365
Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly
370 375 380
Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Gln Met Thr Gln Ser
385 390 395 400
Pro Ser Thr Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys
405 410 415
Ser Ala Ser Ser Ser Val Ser Tyr Met Asn Trp Tyr Gln Gln Lys Pro
420 425 430
Gly Lys Ala Pro Lys Arg Trp Ile Tyr Asp Ser Ser Lys Leu Ala Ser
435 440 445
Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Glu Phe Thr
450 455 460
Leu Thr Ile Ser Ser Leu Gln Pro Asp Asp Phe Ala Thr Tyr Tyr Cys
465 470 475 480
Gln Gln Trp Ser Arg Asn Pro Pro Thr Phe Gly Gly Gly Thr Lys Val
485 490 495
Glu Ile Lys Arg Ser Ser Ser
500
<210> 55
<211> 1572
<212> DNA
<213> 人工序列
<220>
<223> TSC392 CD3结合结构域
<400> 55
atggaagcac cagcgcagct tctcttcctc ctgctactct ggctcccaga taccaccggt 60
gagcccaaat cttctgacaa aactcacaca tgcccaccgt gcccagcacc tgaagccgcg 120
ggtgcaccgt cagtcttcct cttcccccca aaacccaagg acaccctcat gatctcccgg 180
acccctgagg tcacatgcgt ggtggtggac gtgagccacg aagaccctga ggtcaagttc 240
aactggtacg tggacggcgt ggaggtgcat aatgccaaga caaagccgcg ggaggagcag 300
tacaacagca cgtaccgtgt ggtcagcgtc ctcaccgtcc tgcaccagga ctggctgaat 360
ggcaaggcat acgcatgcgc ggtctccaac aaagccctcc cagcccccat cgagaaaacc 420
atctccaaag ccaaagggca gccccgagaa ccacaggtgt acaccctgcc cccatcccgg 480
gatgagctga ccaagaacca ggtcagcctg acctgcctgg tcaaaggctt ctatccaagc 540
gacatcgccg tggagtggga gagcaatggg cagccggaga acaactacaa gaccacgcct 600
cccgtgctgg actccgacgg ctccttcttc ctctacagca agctcaccgt ggacaagagc 660
aggtggcagc aggggaacgt cttctcatgc tccgtgatgc atgaggctct gcacaaccac 720
tacacgcaga agagcctctc cctgtctccg ggtcagaggc acaacaattc ttccctgaat 780
acaggaactc agatggcagg tcattctccg aattctcagg tccagctggt gcaatctggg 840
cctgaggtga agaagcctgg gtcctcggtg aaggtctcct gcaaggcttc tggatatacc 900
ttcagcagat ctacgatgca ctgggtgcga caggcccctg gacaagggct tgagtggatg 960
ggatacatta atcctagcag tgcttatact aattacaatc agaaattcaa ggacagagtc 1020
acgattaccg cggacaaatc cacgagcaca gcctacatgg agctgagcag cctgagatct 1080
gaggacacgg ccgtgtatta ctgtgcgaga ccccaagtcc actatgatta caacgggttt 1140
ccttactggg gccaaggaac cctggtcacc gtctcctcag gtggaggcgg ttcaggcgga 1200
ggtggatccg gcggtggcgg atcgggtggc ggcggatctg acatccagat gacccagtct 1260
ccttccaccc tgtctgcatc tgtaggagac agagtcacca tgacttgcag tgccagctca 1320
agtgtaagtt acatgaactg gtatcagcag aaaccaggga aagcccctaa gagatggatt 1380
tatgactcat ccaaactggc ttctggggtc ccatcaaggt tcagcggcag tggatctggg 1440
acagagttca ctctcaccat cagcagcctg cagcctgatg attttgcaac ttattactgc 1500
caacagtgga gtcgtaaccc acccactttc ggcggaggga ccaaggtgga gatcaaacgg 1560
tcctccagct aa 1572
<210> 56
<211> 503
<212> PRT
<213> 人工序列
<220>
<223> TSC392 CD3结合结构域
<400> 56
Glu Pro Lys Ser Ser Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala
1 5 10 15
Pro Glu Ala Ala Gly Ala Pro Ser Val Phe Leu Phe Pro Pro Lys Pro
20 25 30
Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val
35 40 45
Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val
50 55 60
Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln
65 70 75 80
Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln
85 90 95
Asp Trp Leu Asn Gly Lys Ala Tyr Ala Cys Ala Val Ser Asn Lys Ala
100 105 110
Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro
115 120 125
Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr
130 135 140
Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser
145 150 155 160
Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr
165 170 175
Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr
180 185 190
Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe
195 200 205
Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys
210 215 220
Ser Leu Ser Leu Ser Pro Gly Gln Arg His Asn Asn Ser Ser Leu Asn
225 230 235 240
Thr Gly Thr Gln Met Ala Gly His Ser Pro Asn Ser Gln Val Gln Leu
245 250 255
Val Gln Ser Gly Pro Glu Val Lys Lys Pro Gly Ser Ser Val Lys Val
260 265 270
Ser Cys Lys Ala Ser Gly Tyr Thr Phe Ser Arg Ser Thr Met His Trp
275 280 285
Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met Gly Tyr Ile Asn
290 295 300
Pro Ser Ser Ala Tyr Thr Asn Tyr Asn Gln Lys Phe Lys Asp Arg Val
305 310 315 320
Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr Met Glu Leu Ser
325 330 335
Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Pro Gln
340 345 350
Val His Tyr Asp Tyr Asn Gly Phe Pro Tyr Trp Gly Gln Gly Thr Leu
355 360 365
Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly
370 375 380
Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Gln Met Thr Gln Ser
385 390 395 400
Pro Ser Thr Leu Ser Ala Ser Val Gly Asp Arg Val Thr Met Thr Cys
405 410 415
Ser Ala Ser Ser Ser Val Ser Tyr Met Asn Trp Tyr Gln Gln Lys Pro
420 425 430
Gly Lys Ala Pro Lys Arg Trp Ile Tyr Asp Ser Ser Lys Leu Ala Ser
435 440 445
Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Glu Phe Thr
450 455 460
Leu Thr Ile Ser Ser Leu Gln Pro Asp Asp Phe Ala Thr Tyr Tyr Cys
465 470 475 480
Gln Gln Trp Ser Arg Asn Pro Pro Thr Phe Gly Gly Gly Thr Lys Val
485 490 495
Glu Ile Lys Arg Ser Ser Ser
500
<210> 57
<211> 1572
<212> DNA
<213> 人工序列
<220>
<223> TSC393 CD3结合结构域
<400> 57
atggaagcac cagcgcagct tctcttcctc ctgctactct ggctcccaga taccaccggt 60
gagcccaaat cttctgacaa aactcacaca tgcccaccgt gcccagcacc tgaagccgcg 120
ggtgcaccgt cagtcttcct cttcccccca aaacccaagg acaccctcat gatctcccgg 180
acccctgagg tcacatgcgt ggtggtggac gtgagccacg aagaccctga ggtcaagttc 240
aactggtacg tggacggcgt ggaggtgcat aatgccaaga caaagccgcg ggaggagcag 300
tacaacagca cgtaccgtgt ggtcagcgtc ctcaccgtcc tgcaccagga ctggctgaat 360
ggcaaggcat acgcatgcgc ggtctccaac aaagccctcc cagcccccat cgagaaaacc 420
atctccaaag ccaaagggca gccccgagaa ccacaggtgt acaccctgcc cccatcccgg 480
gatgagctga ccaagaacca ggtcagcctg acctgcctgg tcaaaggctt ctatccaagc 540
gacatcgccg tggagtggga gagcaatggg cagccggaga acaactacaa gaccacgcct 600
cccgtgctgg actccgacgg ctccttcttc ctctacagca agctcaccgt ggacaagagc 660
aggtggcagc aggggaacgt cttctcatgc tccgtgatgc atgaggctct gcacaaccac 720
tacacgcaga agagcctctc cctgtctccg ggtcagaggc acaacaattc ttccctgaat 780
acaggaactc agatggcagg tcattctccg aattctcagg tccagctggt gcaatctggg 840
gctgaggtga agaagcctgg gtcctcggtg aaggtctcct gcaaggcttc tggatatacc 900
ttcagcagat ctacgatgca ctgggtgcga caggcccctg gacaagggct tgagtggata 960
ggatacatta atcctagcag tgcttatact aattacaatc agaaattcaa ggacagagtc 1020
acgattaccg cggacaaatc cacgagcaca gcctacatgg agctgagcag cctgagatct 1080
gaggacacgg ccgtgtatta ctgtgcgaga ccccaagtcc actatgatta caacgggttt 1140
ccttactggg gccaaggaac cctggtcacc gtctcctcag gtggaggcgg ttcaggcgga 1200
ggtggatccg gcggtggcgg atcgggtggc ggcggatctg acatccagat gacccagtct 1260
ccttccaccc tgtctgcatc tgtaggagac agagtcacca tgacttgcag tgccagctca 1320
agtgtaagtt acatgaactg gtatcagcag aaaccaggga aagcccctaa gagatggatt 1380
tatgactcat ccaaactggc ttctggggtc ccatcaaggt tcagcggcag tggatctggg 1440
acagagttca ctctcaccat cagcagcctg cagcctgatg attttgcaac ttattactgc 1500
caacagtgga gtcgtaaccc acccactttc ggcggaggga ccaaggtgga gatcaaacgg 1560
tcctccagct aa 1572
<210> 58
<211> 503
<212> PRT
<213> 人工序列
<220>
<223> TSC393 CD3结合结构域
<400> 58
Glu Pro Lys Ser Ser Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala
1 5 10 15
Pro Glu Ala Ala Gly Ala Pro Ser Val Phe Leu Phe Pro Pro Lys Pro
20 25 30
Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val
35 40 45
Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val
50 55 60
Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln
65 70 75 80
Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln
85 90 95
Asp Trp Leu Asn Gly Lys Ala Tyr Ala Cys Ala Val Ser Asn Lys Ala
100 105 110
Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro
115 120 125
Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr
130 135 140
Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser
145 150 155 160
Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr
165 170 175
Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr
180 185 190
Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe
195 200 205
Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys
210 215 220
Ser Leu Ser Leu Ser Pro Gly Gln Arg His Asn Asn Ser Ser Leu Asn
225 230 235 240
Thr Gly Thr Gln Met Ala Gly His Ser Pro Asn Ser Gln Val Gln Leu
245 250 255
Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser Ser Val Lys Val
260 265 270
Ser Cys Lys Ala Ser Gly Tyr Thr Phe Ser Arg Ser Thr Met His Trp
275 280 285
Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Ile Gly Tyr Ile Asn
290 295 300
Pro Ser Ser Ala Tyr Thr Asn Tyr Asn Gln Lys Phe Lys Asp Arg Val
305 310 315 320
Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr Met Glu Leu Ser
325 330 335
Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Pro Gln
340 345 350
Val His Tyr Asp Tyr Asn Gly Phe Pro Tyr Trp Gly Gln Gly Thr Leu
355 360 365
Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly
370 375 380
Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Gln Met Thr Gln Ser
385 390 395 400
Pro Ser Thr Leu Ser Ala Ser Val Gly Asp Arg Val Thr Met Thr Cys
405 410 415
Ser Ala Ser Ser Ser Val Ser Tyr Met Asn Trp Tyr Gln Gln Lys Pro
420 425 430
Gly Lys Ala Pro Lys Arg Trp Ile Tyr Asp Ser Ser Lys Leu Ala Ser
435 440 445
Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Glu Phe Thr
450 455 460
Leu Thr Ile Ser Ser Leu Gln Pro Asp Asp Phe Ala Thr Tyr Tyr Cys
465 470 475 480
Gln Gln Trp Ser Arg Asn Pro Pro Thr Phe Gly Gly Gly Thr Lys Val
485 490 495
Glu Ile Lys Arg Ser Ser Ser
500
<210> 59
<211> 1572
<212> DNA
<213> 人工序列
<220>
<223> TSC394 CD3结合结构域
<400> 59
atggaagcac cagcgcagct tctcttcctc ctgctactct ggctcccaga taccaccggt 60
gagcccaaat cttctgacaa aactcacaca tgcccaccgt gcccagcacc tgaagccgcg 120
ggtgcaccgt cagtcttcct cttcccccca aaacccaagg acaccctcat gatctcccgg 180
acccctgagg tcacatgcgt ggtggtggac gtgagccacg aagaccctga ggtcaagttc 240
aactggtacg tggacggcgt ggaggtgcat aatgccaaga caaagccgcg ggaggagcag 300
tacaacagca cgtaccgtgt ggtcagcgtc ctcaccgtcc tgcaccagga ctggctgaat 360
ggcaaggcat acgcatgcgc ggtctccaac aaagccctcc cagcccccat cgagaaaacc 420
atctccaaag ccaaagggca gccccgagaa ccacaggtgt acaccctgcc cccatcccgg 480
gatgagctga ccaagaacca ggtcagcctg acctgcctgg tcaaaggctt ctatccaagc 540
gacatcgccg tggagtggga gagcaatggg cagccggaga acaactacaa gaccacgcct 600
cccgtgctgg actccgacgg ctccttcttc ctctacagca agctcaccgt ggacaagagc 660
aggtggcagc aggggaacgt cttctcatgc tccgtgatgc atgaggctct gcacaaccac 720
tacacgcaga agagcctctc cctgtctccg ggtcagaggc acaacaattc ttccctgaat 780
acaggaactc agatggcagg tcattctccg aattctcagg tccagctggt gcaatctggg 840
cctgaggtga agaagcctgg gtcctcggtg aaggtctcct gcaaggcttc tggatatacc 900
ttcagcagat ctacgatgca ctgggtgcga caggcccctg gacaagggct tgagtggata 960
ggatacatta atcctagcag tgcttatact aattacaatc agaaattcaa ggacagagtc 1020
acgattaccg cggacaaatc cacgagcaca gcctacatgg agctgagcag cctgagatct 1080
gaggacacgg ccgtgtatta ctgtgcgaga ccccaagtcc actatgatta caacgggttt 1140
ccttactggg gccaaggaac cctggtcacc gtctcctcag gtggaggcgg ttcaggcgga 1200
ggtggatccg gcggtggcgg atcgggtggc ggcggatctg acatccagat gacccagtct 1260
ccttccaccc tgtctgcatc tgtaggagac agagtcacca tgacttgcag tgccagctca 1320
agtgtaagtt acatgaactg gtatcagcag aaaccaggga aagcccctaa gagatggatt 1380
tatgactcat ccaaactggc ttctggggtc ccatcaaggt tcagcggcag tggatctggg 1440
acagagttca ctctcaccat cagcagcctg cagcctgatg attttgcaac ttattactgc 1500
caacagtgga gtcgtaaccc acccactttc ggcggaggga ccaaggtgga gatcaaacgg 1560
tcctccagct aa 1572
<210> 60
<211> 503
<212> PRT
<213> 人工序列
<220>
<223> TSC394 CD3结合结构域
<400> 60
Glu Pro Lys Ser Ser Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala
1 5 10 15
Pro Glu Ala Ala Gly Ala Pro Ser Val Phe Leu Phe Pro Pro Lys Pro
20 25 30
Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val
35 40 45
Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val
50 55 60
Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln
65 70 75 80
Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln
85 90 95
Asp Trp Leu Asn Gly Lys Ala Tyr Ala Cys Ala Val Ser Asn Lys Ala
100 105 110
Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro
115 120 125
Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr
130 135 140
Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser
145 150 155 160
Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr
165 170 175
Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr
180 185 190
Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe
195 200 205
Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys
210 215 220
Ser Leu Ser Leu Ser Pro Gly Gln Arg His Asn Asn Ser Ser Leu Asn
225 230 235 240
Thr Gly Thr Gln Met Ala Gly His Ser Pro Asn Ser Gln Val Gln Leu
245 250 255
Val Gln Ser Gly Pro Glu Val Lys Lys Pro Gly Ser Ser Val Lys Val
260 265 270
Ser Cys Lys Ala Ser Gly Tyr Thr Phe Ser Arg Ser Thr Met His Trp
275 280 285
Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Ile Gly Tyr Ile Asn
290 295 300
Pro Ser Ser Ala Tyr Thr Asn Tyr Asn Gln Lys Phe Lys Asp Arg Val
305 310 315 320
Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr Met Glu Leu Ser
325 330 335
Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Pro Gln
340 345 350
Val His Tyr Asp Tyr Asn Gly Phe Pro Tyr Trp Gly Gln Gly Thr Leu
355 360 365
Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly
370 375 380
Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Gln Met Thr Gln Ser
385 390 395 400
Pro Ser Thr Leu Ser Ala Ser Val Gly Asp Arg Val Thr Met Thr Cys
405 410 415
Ser Ala Ser Ser Ser Val Ser Tyr Met Asn Trp Tyr Gln Gln Lys Pro
420 425 430
Gly Lys Ala Pro Lys Arg Trp Ile Tyr Asp Ser Ser Lys Leu Ala Ser
435 440 445
Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Glu Phe Thr
450 455 460
Leu Thr Ile Ser Ser Leu Gln Pro Asp Asp Phe Ala Thr Tyr Tyr Cys
465 470 475 480
Gln Gln Trp Ser Arg Asn Pro Pro Thr Phe Gly Gly Gly Thr Lys Val
485 490 495
Glu Ile Lys Arg Ser Ser Ser
500
<210> 61
<211> 2301
<212> DNA
<213> 人工序列
<220>
<223> TSC408 抗PSMA X 抗CD3双特异性分子
<400> 61
atggaagcac cagcgcagct tctcttcctc ctgctactct ggctcccaga taccaccggt 60
gatatccaga tgacccagtc tccatccgcc atgtctgcat ctgtaggaga cagagtcacc 120
atcacttgcc gggcgagtaa gagcattagc aaatatttag cctggtttca gcagaaacca 180
gggaaagttc ctaagctccg catccattct ggatctactt tgcaatcagg ggtcccatct 240
cggttcagtg gcagtggatc tgggacagaa tttactctca ccatcagcag cctgcagcct 300
gaagattttg caacttatta ctgtcaacag catattgaat acccgtggac gttcggccaa 360
gggaccaagg tggaaatcaa acgaggtggc ggagggtctg ggggtggcgg atccggaggt 420
ggtggctctc aggtccagct ggtacagtct ggggctgagg tgaagaagcc tggggcttca 480
gtgaaggtct cctgcaaggc ttctggatac acattcactg actactacat gcactgggtg 540
cgacaggccc ctggacaagg gcttgagtgg atgggatatt ttaatcctta taatgattat 600
actagatacg cacagaagtt ccagggcaga gtcaccatga ccagggacac gtctatcagc 660
acagcctaca tggagctgag cagcctgaga tctgacgaca cggccgtgta ttactgtgca 720
agatcggatg gttactacga tgctatggac tactggggtc aaggaaccac agtcaccgtc 780
tcctcgagtg agcccaaatc ttctgacaaa actcacacat gcccaccgtg cccagcacct 840
gaagccgcgg gtgcaccgtc agtcttcctc ttccccccaa aacccaagga caccctcatg 900
atctcccgga cccctgaggt cacatgcgtg gtggtggacg tgagccacga agaccctgag 960
gtcaagttca actggtacgt ggacggcgtg gaggtgcata atgccaagac aaagccgcgg 1020
gaggagcagt acaacagcac gtaccgtgtg gtcagcgtcc tcaccgtcct gcaccaggac 1080
tggctgaatg gcaaggcgta cgcgtgcgcg gtctccaaca aagccctccc agcccccatc 1140
gagaaaacca tctccaaagc caaagggcag ccccgagaac cacaggtgta caccctgccc 1200
ccatcccggg atgagctgac caagaaccag gtcagcctga cctgcctggt caaaggcttc 1260
tatccaagcg acatcgccgt ggagtgggag agcaatgggc agccggagaa caactacaag 1320
accacgcctc ccgtgctgga ctccgacggc tccttcttcc tctacagcaa gctcaccgtg 1380
gacaagagca ggtggcagca ggggaacgtc ttctcatgct ccgtgatgca tgaggctctg 1440
cacaaccact acacgcagaa gagcctctcc ctgtctccgg gtcagaggca caacaattct 1500
tccctgaata caggaactca gatggcaggt cattctccga attctcaggt ccagctggtg 1560
caatctgggc ctgaggtgaa gaagcctggg tcctcggtga aggtctcctg caaggcttct 1620
ggatatacct tcagcagatc tacgatgcac tgggtgcgac aggcccctgg acaagggctt 1680
gagtggatag gatacattaa tcctagcagt gcttatacta attacaatca gaaattcaag 1740
gacagagtca cgattaccgc ggacaaatcc acgagcacag cctacatgga gctgagcagc 1800
ctgagatctg aggacacggc cgtgtattac tgtgcgagac cccaagtcca ctatgattac 1860
aacgggtttc cttactgggg ccaaggaacc ctggtcaccg tctcctcagg tggaggcggt 1920
tcaggcggag gtggatccgg cggtggcgga tcgggtggcg gcggatctga catccagatg 1980
acccagtctc cttccaccct gtctgcatct gtaggagaca gagtcaccat cacttgcagt 2040
gccagctcaa gtgtaagtta catgaactgg tatcagcaga aaccagggaa agcccctaag 2100
agatggattt atgactcatc caaactggct tctggggtcc catcaaggtt cagcggcagt 2160
ggatctggga cagagttcac tctcaccatc agcagcctgc agcctgatga ttttgcaact 2220
tattactgcc aacagtggag tcgtaaccca cccactttcg gcggagggac caaggtggag 2280
atcaaacggt cctccagcta a 2301
<210> 62
<211> 746
<212> PRT
<213> 人工序列
<220>
<223> TSC408 抗PSMA X 抗CD3双特异性分子
<400> 62
Asp Ile Gln Met Thr Gln Ser Pro Ser Ala Met Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Lys Ser Ile Ser Lys Tyr
20 25 30
Leu Ala Trp Phe Gln Gln Lys Pro Gly Lys Val Pro Lys Leu Arg Ile
35 40 45
His Ser Gly Ser Thr Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln His Ile Glu Tyr Pro Trp
85 90 95
Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Gly Gly Gly Gly
100 105 110
Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gln Val Gln Leu Val
115 120 125
Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala Ser Val Lys Val Ser
130 135 140
Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Tyr Tyr Met His Trp Val
145 150 155 160
Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met Gly Tyr Phe Asn Pro
165 170 175
Tyr Asn Asp Tyr Thr Arg Tyr Ala Gln Lys Phe Gln Gly Arg Val Thr
180 185 190
Met Thr Arg Asp Thr Ser Ile Ser Thr Ala Tyr Met Glu Leu Ser Ser
195 200 205
Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys Ala Arg Ser Asp Gly
210 215 220
Tyr Tyr Asp Ala Met Asp Tyr Trp Gly Gln Gly Thr Thr Val Thr Val
225 230 235 240
Ser Ser Ser Glu Pro Lys Ser Ser Asp Lys Thr His Thr Cys Pro Pro
245 250 255
Cys Pro Ala Pro Glu Ala Ala Gly Ala Pro Ser Val Phe Leu Phe Pro
260 265 270
Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr
275 280 285
Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn
290 295 300
Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg
305 310 315 320
Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val
325 330 335
Leu His Gln Asp Trp Leu Asn Gly Lys Ala Tyr Ala Cys Ala Val Ser
340 345 350
Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys
355 360 365
Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp
370 375 380
Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe
385 390 395 400
Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu
405 410 415
Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe
420 425 430
Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly
435 440 445
Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr
450 455 460
Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Gln Arg His Asn Asn Ser
465 470 475 480
Ser Leu Asn Thr Gly Thr Gln Met Ala Gly His Ser Pro Asn Ser Gln
485 490 495
Val Gln Leu Val Gln Ser Gly Pro Glu Val Lys Lys Pro Gly Ser Ser
500 505 510
Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Ser Arg Ser Thr
515 520 525
Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Ile Gly
530 535 540
Tyr Ile Asn Pro Ser Ser Ala Tyr Thr Asn Tyr Asn Gln Lys Phe Lys
545 550 555 560
Asp Arg Val Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr Met
565 570 575
Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys Ala
580 585 590
Arg Pro Gln Val His Tyr Asp Tyr Asn Gly Phe Pro Tyr Trp Gly Gln
595 600 605
Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly
610 615 620
Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Gln Met
625 630 635 640
Thr Gln Ser Pro Ser Thr Leu Ser Ala Ser Val Gly Asp Arg Val Thr
645 650 655
Ile Thr Cys Ser Ala Ser Ser Ser Val Ser Tyr Met Asn Trp Tyr Gln
660 665 670
Gln Lys Pro Gly Lys Ala Pro Lys Arg Trp Ile Tyr Asp Ser Ser Lys
675 680 685
Leu Ala Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr
690 695 700
Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Asp Asp Phe Ala Thr
705 710 715 720
Tyr Tyr Cys Gln Gln Trp Ser Arg Asn Pro Pro Thr Phe Gly Gly Gly
725 730 735
Thr Lys Val Glu Ile Lys Arg Ser Ser Ser
740 745
<210> 63
<211> 2301
<212> DNA
<213> 人工序列
<220>
<223> TSC409 抗PSMA X 抗CD3双特异性分子
<400> 63
atggaagcac cagcgcagct tctcttcctc ctgctactct ggctcccaga taccaccggt 60
gatatccaga tgacccagtc tccatccgcc atgtctgcat ctgtaggaga cagagtcacc 120
atcacttgcc gggcgagtaa gagcattagc aaatatttag cctggtttca gcagaaacca 180
gggaaagttc ctaagctccg catccattct ggatctactt tgcaatcagg ggtcccatct 240
cggttcagtg gcagtggatc tgggacagaa tttactctca ccatcagcag cctgcagcct 300
gaagattttg caacttatta ctgtcaacag catattgaat acccgtggac gttcggccaa 360
gggaccaagg tggaaatcaa acgaggtggc ggagggtctg ggggtggcgg atccggaggt 420
ggtggctctc aggtccagct ggtacagtct ggggctgagg tgaagaagcc tggggcttca 480
gtgaaggtct cctgcaaggc ttctggatac acattcactg actactacat gcactgggtg 540
cgacaggccc ctggacaagg gcttgagtgg atgggatatt ttaatcctta taatgattat 600
actagatacg cacagaagtt ccagggcaga gtcaccatga ccagggacac gtctatcagc 660
acagcctaca tggagctgag cagcctgaga tctgacgaca cggccgtgta ttactgtgca 720
agatcggatg gttactacga tgctatggac tactggggtc aaggaaccac agtcaccgtc 780
tcctcgagtg agcccaaatc ttctgacaaa actcacacat gcccaccgtg cccagcacct 840
gaagccgcgg gtgcaccgtc agtcttcctc ttccccccaa aacccaagga caccctcatg 900
atctcccgga cccctgaggt cacatgcgtg gtggtggacg tgagccacga agaccctgag 960
gtcaagttca actggtacgt ggacggcgtg gaggtgcata atgccaagac aaagccgcgg 1020
gaggagcagt acaacagcac gtaccgtgtg gtcagcgtcc tcaccgtcct gcaccaggac 1080
tggctgaatg gcaaggcgta cgcgtgcgcg gtctccaaca aagccctccc agcccccatc 1140
gagaaaacca tctccaaagc caaagggcag ccccgagaac cacaggtgta caccctgccc 1200
ccatcccggg atgagctgac caagaaccag gtcagcctga cctgcctggt caaaggcttc 1260
tatccaagcg acatcgccgt ggagtgggag agcaatgggc agccggagaa caactacaag 1320
accacgcctc ccgtgctgga ctccgacggc tccttcttcc tctacagcaa gctcaccgtg 1380
gacaagagca ggtggcagca ggggaacgtc ttctcatgct ccgtgatgca tgaggctctg 1440
cacaaccact acacgcagaa gagcctctcc ctgtctccgg gtcagaggca caacaattct 1500
tccctgaata caggaactca gatggcaggt cattctccga attctcaggt ccagctggtg 1560
caatctgggc ctgaggtgaa gaagcctggg tcctcggtga aggtctcctg caaggcttct 1620
ggatatacct tcagcagatc tacgatgcac tgggtgcgac aggcccctgg acaagggctt 1680
gagtggatgg gatacattaa tcctagcagt gcttatacta attacaatca gaaattcaag 1740
gacagagtca cgattaccgc ggacaaatcc acgagcacag cctacatgga gctgagcagc 1800
ctgagatctg aggacacggc cgtgtattac tgtgcgagac cccaagtcca ctatgattac 1860
aacgggtttc cttactgggg ccaaggaacc ctggtcaccg tctcctcagg tggaggcggt 1920
tcaggcggag gtggatccgg cggtggcgga tcgggtggcg gcggatctga catccagatg 1980
acccagtctc cttccaccct gtctgcatct gtaggagaca gagtcaccat gacttgcagt 2040
gccagctcaa gtgtaagtta catgaactgg tatcagcaga aaccagggaa agcccctaag 2100
agatggattt atgactcatc caaactggct tctggggtcc catcaaggtt cagcggcagt 2160
ggatctggga cagagttcac tctcaccatc agcagcctgc agcctgatga ttttgcaact 2220
tattactgcc aacagtggag tcgtaaccca cccactttcg gcggagggac caaggtggag 2280
atcaaacggt cctccagcta a 2301
<210> 64
<211> 746
<212> PRT
<213> 人工序列
<220>
<223> TSC409 抗PSMA X 抗CD3双特异性分子
<400> 64
Asp Ile Gln Met Thr Gln Ser Pro Ser Ala Met Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Lys Ser Ile Ser Lys Tyr
20 25 30
Leu Ala Trp Phe Gln Gln Lys Pro Gly Lys Val Pro Lys Leu Arg Ile
35 40 45
His Ser Gly Ser Thr Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln His Ile Glu Tyr Pro Trp
85 90 95
Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Gly Gly Gly Gly
100 105 110
Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gln Val Gln Leu Val
115 120 125
Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala Ser Val Lys Val Ser
130 135 140
Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Tyr Tyr Met His Trp Val
145 150 155 160
Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met Gly Tyr Phe Asn Pro
165 170 175
Tyr Asn Asp Tyr Thr Arg Tyr Ala Gln Lys Phe Gln Gly Arg Val Thr
180 185 190
Met Thr Arg Asp Thr Ser Ile Ser Thr Ala Tyr Met Glu Leu Ser Ser
195 200 205
Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys Ala Arg Ser Asp Gly
210 215 220
Tyr Tyr Asp Ala Met Asp Tyr Trp Gly Gln Gly Thr Thr Val Thr Val
225 230 235 240
Ser Ser Ser Glu Pro Lys Ser Ser Asp Lys Thr His Thr Cys Pro Pro
245 250 255
Cys Pro Ala Pro Glu Ala Ala Gly Ala Pro Ser Val Phe Leu Phe Pro
260 265 270
Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr
275 280 285
Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn
290 295 300
Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg
305 310 315 320
Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val
325 330 335
Leu His Gln Asp Trp Leu Asn Gly Lys Ala Tyr Ala Cys Ala Val Ser
340 345 350
Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys
355 360 365
Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp
370 375 380
Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe
385 390 395 400
Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu
405 410 415
Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe
420 425 430
Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly
435 440 445
Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr
450 455 460
Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Gln Arg His Asn Asn Ser
465 470 475 480
Ser Leu Asn Thr Gly Thr Gln Met Ala Gly His Ser Pro Asn Ser Gln
485 490 495
Val Gln Leu Val Gln Ser Gly Pro Glu Val Lys Lys Pro Gly Ser Ser
500 505 510
Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Ser Arg Ser Thr
515 520 525
Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met Gly
530 535 540
Tyr Ile Asn Pro Ser Ser Ala Tyr Thr Asn Tyr Asn Gln Lys Phe Lys
545 550 555 560
Asp Arg Val Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr Met
565 570 575
Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys Ala
580 585 590
Arg Pro Gln Val His Tyr Asp Tyr Asn Gly Phe Pro Tyr Trp Gly Gln
595 600 605
Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly
610 615 620
Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Gln Met
625 630 635 640
Thr Gln Ser Pro Ser Thr Leu Ser Ala Ser Val Gly Asp Arg Val Thr
645 650 655
Met Thr Cys Ser Ala Ser Ser Ser Val Ser Tyr Met Asn Trp Tyr Gln
660 665 670
Gln Lys Pro Gly Lys Ala Pro Lys Arg Trp Ile Tyr Asp Ser Ser Lys
675 680 685
Leu Ala Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr
690 695 700
Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Asp Asp Phe Ala Thr
705 710 715 720
Tyr Tyr Cys Gln Gln Trp Ser Arg Asn Pro Pro Thr Phe Gly Gly Gly
725 730 735
Thr Lys Val Glu Ile Lys Arg Ser Ser Ser
740 745
<210> 65
<211> 2301
<212> DNA
<213> 人工序列
<220>
<223> TSC410 抗PSMA X 抗CD3双特异性分子
<400> 65
atggaagcac cagcgcagct tctcttcctc ctgctactct ggctcccaga taccaccggt 60
gatatccaga tgacccagtc tccatccgcc atgtctgcat ctgtaggaga cagagtcacc 120
atcacttgcc gggcgagtaa gagcattagc aaatatttag cctggtttca gcagaaacca 180
gggaaagttc ctaagctccg catccattct ggatctactt tgcaatcagg ggtcccatct 240
cggttcagtg gcagtggatc tgggacagaa tttactctca ccatcagcag cctgcagcct 300
gaagattttg caacttatta ctgtcaacag catattgaat acccgtggac gttcggccaa 360
gggaccaagg tggaaatcaa acgaggtggc ggagggtctg ggggtggcgg atccggaggt 420
ggtggctctc aggtccagct ggtacagtct ggggctgagg tgaagaagcc tggggcttca 480
gtgaaggtct cctgcaaggc ttctggatac acattcactg actactacat gcactgggtg 540
cgacaggccc ctggacaagg gcttgagtgg atgggatatt ttaatcctta taatgattat 600
actagatacg cacagaagtt ccagggcaga gtcaccatga ccagggacac gtctatcagc 660
acagcctaca tggagctgag cagcctgaga tctgacgaca cggccgtgta ttactgtgca 720
agatcggatg gttactacga tgctatggac tactggggtc aaggaaccac agtcaccgtc 780
tcctcgagtg agcccaaatc ttctgacaaa actcacacat gcccaccgtg cccagcacct 840
gaagccgcgg gtgcaccgtc agtcttcctc ttccccccaa aacccaagga caccctcatg 900
atctcccgga cccctgaggt cacatgcgtg gtggtggacg tgagccacga agaccctgag 960
gtcaagttca actggtacgt ggacggcgtg gaggtgcata atgccaagac aaagccgcgg 1020
gaggagcagt acaacagcac gtaccgtgtg gtcagcgtcc tcaccgtcct gcaccaggac 1080
tggctgaatg gcaaggcgta cgcgtgcgcg gtctccaaca aagccctccc agcccccatc 1140
gagaaaacca tctccaaagc caaagggcag ccccgagaac cacaggtgta caccctgccc 1200
ccatcccggg atgagctgac caagaaccag gtcagcctga cctgcctggt caaaggcttc 1260
tatccaagcg acatcgccgt ggagtgggag agcaatgggc agccggagaa caactacaag 1320
accacgcctc ccgtgctgga ctccgacggc tccttcttcc tctacagcaa gctcaccgtg 1380
gacaagagca ggtggcagca ggggaacgtc ttctcatgct ccgtgatgca tgaggctctg 1440
cacaaccact acacgcagaa gagcctctcc ctgtctccgg gtcagaggca caacaattct 1500
tccctgaata caggaactca gatggcaggt cattctccga attctcaggt ccagctggtg 1560
caatctgggg ctgaggtgaa gaagcctggg tcctcggtga aggtctcctg caaggcttct 1620
ggatatacct tcagcagatc tacgatgcac tgggtgcgac aggcccctgg acaagggctt 1680
gagtggatag gatacattaa tcctagcagt gcttatacta attacaatca gaaattcaag 1740
gacagagtca cgattaccgc ggacaaatcc acgagcacag cctacatgga gctgagcagc 1800
ctgagatctg aggacacggc cgtgtattac tgtgcgagac cccaagtcca ctatgattac 1860
aacgggtttc cttactgggg ccaaggaacc ctggtcaccg tctcctcagg tggaggcggt 1920
tcaggcggag gtggatccgg cggtggcgga tcgggtggcg gcggatctga catccagatg 1980
acccagtctc cttccaccct gtctgcatct gtaggagaca gagtcaccat gacttgcagt 2040
gccagctcaa gtgtaagtta catgaactgg tatcagcaga aaccagggaa agcccctaag 2100
agatggattt atgactcatc caaactggct tctggggtcc catcaaggtt cagcggcagt 2160
ggatctggga cagagttcac tctcaccatc agcagcctgc agcctgatga ttttgcaact 2220
tattactgcc aacagtggag tcgtaaccca cccactttcg gcggagggac caaggtggag 2280
atcaaacggt cctccagcta a 2301
<210> 66
<211> 746
<212> PRT
<213> 人工序列
<220>
<223> TSC410 抗PSMA X 抗CD3双特异性分子
<400> 66
Asp Ile Gln Met Thr Gln Ser Pro Ser Ala Met Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Lys Ser Ile Ser Lys Tyr
20 25 30
Leu Ala Trp Phe Gln Gln Lys Pro Gly Lys Val Pro Lys Leu Arg Ile
35 40 45
His Ser Gly Ser Thr Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln His Ile Glu Tyr Pro Trp
85 90 95
Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Gly Gly Gly Gly
100 105 110
Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gln Val Gln Leu Val
115 120 125
Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala Ser Val Lys Val Ser
130 135 140
Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Tyr Tyr Met His Trp Val
145 150 155 160
Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met Gly Tyr Phe Asn Pro
165 170 175
Tyr Asn Asp Tyr Thr Arg Tyr Ala Gln Lys Phe Gln Gly Arg Val Thr
180 185 190
Met Thr Arg Asp Thr Ser Ile Ser Thr Ala Tyr Met Glu Leu Ser Ser
195 200 205
Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys Ala Arg Ser Asp Gly
210 215 220
Tyr Tyr Asp Ala Met Asp Tyr Trp Gly Gln Gly Thr Thr Val Thr Val
225 230 235 240
Ser Ser Ser Glu Pro Lys Ser Ser Asp Lys Thr His Thr Cys Pro Pro
245 250 255
Cys Pro Ala Pro Glu Ala Ala Gly Ala Pro Ser Val Phe Leu Phe Pro
260 265 270
Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr
275 280 285
Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn
290 295 300
Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg
305 310 315 320
Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val
325 330 335
Leu His Gln Asp Trp Leu Asn Gly Lys Ala Tyr Ala Cys Ala Val Ser
340 345 350
Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys
355 360 365
Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp
370 375 380
Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe
385 390 395 400
Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu
405 410 415
Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe
420 425 430
Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly
435 440 445
Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr
450 455 460
Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Gln Arg His Asn Asn Ser
465 470 475 480
Ser Leu Asn Thr Gly Thr Gln Met Ala Gly His Ser Pro Asn Ser Gln
485 490 495
Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser Ser
500 505 510
Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Ser Arg Ser Thr
515 520 525
Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Ile Gly
530 535 540
Tyr Ile Asn Pro Ser Ser Ala Tyr Thr Asn Tyr Asn Gln Lys Phe Lys
545 550 555 560
Asp Arg Val Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr Met
565 570 575
Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys Ala
580 585 590
Arg Pro Gln Val His Tyr Asp Tyr Asn Gly Phe Pro Tyr Trp Gly Gln
595 600 605
Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly
610 615 620
Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Gln Met
625 630 635 640
Thr Gln Ser Pro Ser Thr Leu Ser Ala Ser Val Gly Asp Arg Val Thr
645 650 655
Met Thr Cys Ser Ala Ser Ser Ser Val Ser Tyr Met Asn Trp Tyr Gln
660 665 670
Gln Lys Pro Gly Lys Ala Pro Lys Arg Trp Ile Tyr Asp Ser Ser Lys
675 680 685
Leu Ala Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr
690 695 700
Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Asp Asp Phe Ala Thr
705 710 715 720
Tyr Tyr Cys Gln Gln Trp Ser Arg Asn Pro Pro Thr Phe Gly Gly Gly
725 730 735
Thr Lys Val Glu Ile Lys Arg Ser Ser Ser
740 745
<210> 67
<211> 2301
<212> DNA
<213> 人工序列
<220>
<223> TSC411 抗PSMA X 抗CD3双特异性分子
<400> 67
atggaagcac cagcgcagct tctcttcctc ctgctactct ggctcccaga taccaccggt 60
gatatccaga tgacccagtc tccatccgcc atgtctgcat ctgtaggaga cagagtcacc 120
atcacttgcc gggcgagtaa gagcattagc aaatatttag cctggtttca gcagaaacca 180
gggaaagttc ctaagctccg catccattct ggatctactt tgcaatcagg ggtcccatct 240
cggttcagtg gcagtggatc tgggacagaa tttactctca ccatcagcag cctgcagcct 300
gaagattttg caacttatta ctgtcaacag catattgaat acccgtggac gttcggccaa 360
gggaccaagg tggaaatcaa acgaggtggc ggagggtctg ggggtggcgg atccggaggt 420
ggtggctctc aggtccagct ggtacagtct ggggctgagg tgaagaagcc tggggcttca 480
gtgaaggtct cctgcaaggc ttctggatac acattcactg actactacat gcactgggtg 540
cgacaggccc ctggacaagg gcttgagtgg atgggatatt ttaatcctta taatgattat 600
actagatacg cacagaagtt ccagggcaga gtcaccatga ccagggacac gtctatcagc 660
acagcctaca tggagctgag cagcctgaga tctgacgaca cggccgtgta ttactgtgca 720
agatcggatg gttactacga tgctatggac tactggggtc aaggaaccac agtcaccgtc 780
tcctcgagtg agcccaaatc ttctgacaaa actcacacat gcccaccgtg cccagcacct 840
gaagccgcgg gtgcaccgtc agtcttcctc ttccccccaa aacccaagga caccctcatg 900
atctcccgga cccctgaggt cacatgcgtg gtggtggacg tgagccacga agaccctgag 960
gtcaagttca actggtacgt ggacggcgtg gaggtgcata atgccaagac aaagccgcgg 1020
gaggagcagt acaacagcac gtaccgtgtg gtcagcgtcc tcaccgtcct gcaccaggac 1080
tggctgaatg gcaaggcgta cgcgtgcgcg gtctccaaca aagccctccc agcccccatc 1140
gagaaaacca tctccaaagc caaagggcag ccccgagaac cacaggtgta caccctgccc 1200
ccatcccggg atgagctgac caagaaccag gtcagcctga cctgcctggt caaaggcttc 1260
tatccaagcg acatcgccgt ggagtgggag agcaatgggc agccggagaa caactacaag 1320
accacgcctc ccgtgctgga ctccgacggc tccttcttcc tctacagcaa gctcaccgtg 1380
gacaagagca ggtggcagca ggggaacgtc ttctcatgct ccgtgatgca tgaggctctg 1440
cacaaccact acacgcagaa gagcctctcc ctgtctccgg gtcagaggca caacaattct 1500
tccctgaata caggaactca gatggcaggt cattctccga attctcaggt ccagctggtg 1560
caatctgggc ctgaggtgaa gaagcctggg tcctcggtga aggtctcctg caaggcttct 1620
ggatatacct tcagcagatc tacgatgcac tgggtgcgac aggcccctgg acaagggctt 1680
gagtggatag gatacattaa tcctagcagt gcttatacta attacaatca gaaattcaag 1740
gacagagtca cgattaccgc ggacaaatcc acgagcacag cctacatgga gctgagcagc 1800
ctgagatctg aggacacggc cgtgtattac tgtgcgagac cccaagtcca ctatgattac 1860
aacgggtttc cttactgggg ccaaggaacc ctggtcaccg tctcctcagg tggaggcggt 1920
tcaggcggag gtggatccgg cggtggcgga tcgggtggcg gcggatctga catccagatg 1980
acccagtctc cttccaccct gtctgcatct gtaggagaca gagtcaccat gacttgcagt 2040
gccagctcaa gtgtaagtta catgaactgg tatcagcaga aaccagggaa agcccctaag 2100
agatggattt atgactcatc caaactggct tctggggtcc catcaaggtt cagcggcagt 2160
ggatctggga cagagttcac tctcaccatc agcagcctgc agcctgatga ttttgcaact 2220
tattactgcc aacagtggag tcgtaaccca cccactttcg gcggagggac caaggtggag 2280
atcaaacggt cctccagcta a 2301
<210> 68
<211> 746
<212> PRT
<213> 人工序列
<220>
<223> TSC411 抗PSMA X 抗CD3双特异性分子
<400> 68
Asp Ile Gln Met Thr Gln Ser Pro Ser Ala Met Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Lys Ser Ile Ser Lys Tyr
20 25 30
Leu Ala Trp Phe Gln Gln Lys Pro Gly Lys Val Pro Lys Leu Arg Ile
35 40 45
His Ser Gly Ser Thr Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln His Ile Glu Tyr Pro Trp
85 90 95
Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Gly Gly Gly Gly
100 105 110
Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gln Val Gln Leu Val
115 120 125
Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala Ser Val Lys Val Ser
130 135 140
Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Tyr Tyr Met His Trp Val
145 150 155 160
Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met Gly Tyr Phe Asn Pro
165 170 175
Tyr Asn Asp Tyr Thr Arg Tyr Ala Gln Lys Phe Gln Gly Arg Val Thr
180 185 190
Met Thr Arg Asp Thr Ser Ile Ser Thr Ala Tyr Met Glu Leu Ser Ser
195 200 205
Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys Ala Arg Ser Asp Gly
210 215 220
Tyr Tyr Asp Ala Met Asp Tyr Trp Gly Gln Gly Thr Thr Val Thr Val
225 230 235 240
Ser Ser Ser Glu Pro Lys Ser Ser Asp Lys Thr His Thr Cys Pro Pro
245 250 255
Cys Pro Ala Pro Glu Ala Ala Gly Ala Pro Ser Val Phe Leu Phe Pro
260 265 270
Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr
275 280 285
Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn
290 295 300
Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg
305 310 315 320
Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val
325 330 335
Leu His Gln Asp Trp Leu Asn Gly Lys Ala Tyr Ala Cys Ala Val Ser
340 345 350
Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys
355 360 365
Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp
370 375 380
Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe
385 390 395 400
Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu
405 410 415
Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe
420 425 430
Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly
435 440 445
Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr
450 455 460
Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Gln Arg His Asn Asn Ser
465 470 475 480
Ser Leu Asn Thr Gly Thr Gln Met Ala Gly His Ser Pro Asn Ser Gln
485 490 495
Val Gln Leu Val Gln Ser Gly Pro Glu Val Lys Lys Pro Gly Ser Ser
500 505 510
Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Ser Arg Ser Thr
515 520 525
Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Ile Gly
530 535 540
Tyr Ile Asn Pro Ser Ser Ala Tyr Thr Asn Tyr Asn Gln Lys Phe Lys
545 550 555 560
Asp Arg Val Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr Met
565 570 575
Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys Ala
580 585 590
Arg Pro Gln Val His Tyr Asp Tyr Asn Gly Phe Pro Tyr Trp Gly Gln
595 600 605
Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly
610 615 620
Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Gln Met
625 630 635 640
Thr Gln Ser Pro Ser Thr Leu Ser Ala Ser Val Gly Asp Arg Val Thr
645 650 655
Met Thr Cys Ser Ala Ser Ser Ser Val Ser Tyr Met Asn Trp Tyr Gln
660 665 670
Gln Lys Pro Gly Lys Ala Pro Lys Arg Trp Ile Tyr Asp Ser Ser Lys
675 680 685
Leu Ala Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr
690 695 700
Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Asp Asp Phe Ala Thr
705 710 715 720
Tyr Tyr Cys Gln Gln Trp Ser Arg Asn Pro Pro Thr Phe Gly Gly Gly
725 730 735
Thr Lys Val Glu Ile Lys Arg Ser Ser Ser
740 745
<210> 69
<211> 2313
<212> DNA
<213> 人工序列
<220>
<223> CAS105 抗CD37 X 抗CD3双特异性分子
<400> 69
atggaagcac cagcgcagct tctcttcctc ctgctactct ggctcccaga taccaccggt 60
gaggtgcagc tggtgcagtc tggagcagag gtgaaaaagc ccggagagtc tctgaagatt 120
tcctgtaagg gctccggtta ctcattcact ggctacaata tgaactgggt gcgccagatg 180
cccgggaaag gcctggagtg gatgggcaat attgatcctt attatggtgg tactacctac 240
aaccggaagt tcaagggcca ggtcactatc tccgccgaca agtccatcag caccgcctac 300
ctgcaatgga gcagcctgaa ggcctcggac accgccatgt attactgtgc acgctcagtc 360
ggccctttcg actcctgggg ccagggcacc ctggtcactg tctcctctgg gggtggaggc 420
tctggtggcg gtggctctgg cggaggtgga tccggtggcg gcggatctgg cgggggtggc 480
tctgaaattg tgttgacaca gtctccagcc accctgtctt tgtctccagg cgaaagagcc 540
accctctcct gccgagcaag tgaaaatgtt tacagctact tagcctggta ccaacagaaa 600
cctggccagg ctcctaggct cctcatctat tttgcaaaaa ccttagcaga aggtattcca 660
gccaggttca gtggcagtgg ctccgggaca gacttcactc tcaccatcag cagcctagag 720
cctgaagatt ttgcagttta ttactgtcaa catcattccg ataatccgtg gacattcggc 780
caagggacca aggtggaaat caaatcctcg agtgagccca aatcttctga caaaactcac 840
acatgcccac cgtgcccagc acctgaagcc gcgggtgcac cgtcagtctt cctcttcccc 900
ccaaaaccca aggacaccct catgatctcc cggacccctg aggtcacatg cgtggtggtg 960
gacgtgagcc acgaagaccc tgaggtcaag ttcaactggt acgtggacgg cgtggaggtg 1020
cataatgcca agacaaagcc gcgggaggag cagtacaaca gcacgtaccg tgtggtcagc 1080
gtcctcaccg tcctgcacca ggactggctg aatggcaagg catacgcgtg cgcggtctcc 1140
aacaaagccc tcccagcccc catcgagaaa accatctcca aagccaaagg gcagccccga 1200
gaaccacagg tgtacaccct gcccccatcc cgggatgagc tgaccaagaa ccaggtcagc 1260
ctgacctgcc tggtcaaagg cttctatcca agcgacatcg ccgtggagtg ggagagcaat 1320
gggcagccgg agaacaacta caagaccacg cctcccgtgc tggactccga cggctccttc 1380
ttcctctaca gcaagctcac cgtggacaag agcaggtggc agcaggggaa cgtcttctca 1440
tgctccgtga tgcatgaggc tctgcacaac cactacacgc agaagagcct ctccctgtct 1500
ccgggtcaga ggcacaacaa ttcttccctg aatacaggaa ctcagatggc aggtcattct 1560
ccgaattctc aggtccagct ggtggagtct gggggcggag tggtgcagcc tgggcggtca 1620
ctgaggctgt cctgcaaggc ttctggctac acctttacta gatctacgat gcactgggta 1680
aggcaggccc ctggacaagg tctggaatgg attggataca ttaatcctag cagtgcttat 1740
actaattaca atcagaaatt caaggacagg ttcacaatca gcgcagacaa atccaagagc 1800
acagccttcc tgcagatgga cagcctgagg cccgaggaca ccggcgtcta tttctgtgca 1860
cggccccaag tccactatga ttacaacggg tttccttact ggggccaagg gactcccgtc 1920
actgtctcta gcggtggcgg agggtctggg ggtggcggat ccggaggtgg tggctctgca 1980
caagacatcc agatgaccca gtctccaagc agcctgtctg caagcgtggg ggacagggtc 2040
accatgacct gcagtgccag ctcaagtgta agttacatga actggtacca gcagaagccg 2100
ggcaaggccc ccaaaagatg gatttatgac tcatccaaac tggcttctgg agtccctgct 2160
cgcttcagtg gcagtgggtc tgggaccgac tataccctca caatcagcag cctgcagccc 2220
gaagatttcg ccacttatta ctgccagcag tggagtcgta acccacccac gttcggaggg 2280
gggaccaagc tacaaattac atcctccagc taa 2313
<210> 70
<211> 750
<212> PRT
<213> 人工序列
<220>
<223> CAS105 抗CD37 X 抗CD3双特异性分子
<400> 70
Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Glu
1 5 10 15
Ser Leu Lys Ile Ser Cys Lys Gly Ser Gly Tyr Ser Phe Thr Gly Tyr
20 25 30
Asn Met Asn Trp Val Arg Gln Met Pro Gly Lys Gly Leu Glu Trp Met
35 40 45
Gly Asn Ile Asp Pro Tyr Tyr Gly Gly Thr Thr Tyr Asn Arg Lys Phe
50 55 60
Lys Gly Gln Val Thr Ile Ser Ala Asp Lys Ser Ile Ser Thr Ala Tyr
65 70 75 80
Leu Gln Trp Ser Ser Leu Lys Ala Ser Asp Thr Ala Met Tyr Tyr Cys
85 90 95
Ala Arg Ser Val Gly Pro Phe Asp Ser Trp Gly Gln Gly Thr Leu Val
100 105 110
Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
115 120 125
Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Ile Val
130 135 140
Leu Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly Glu Arg Ala
145 150 155 160
Thr Leu Ser Cys Arg Ala Ser Glu Asn Val Tyr Ser Tyr Leu Ala Trp
165 170 175
Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile Tyr Phe Ala
180 185 190
Lys Thr Leu Ala Glu Gly Ile Pro Ala Arg Phe Ser Gly Ser Gly Ser
195 200 205
Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Glu Pro Glu Asp Phe
210 215 220
Ala Val Tyr Tyr Cys Gln His His Ser Asp Asn Pro Trp Thr Phe Gly
225 230 235 240
Gln Gly Thr Lys Val Glu Ile Lys Ser Ser Ser Glu Pro Lys Ser Ser
245 250 255
Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly
260 265 270
Ala Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
275 280 285
Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His
290 295 300
Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val
305 310 315 320
His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr
325 330 335
Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly
340 345 350
Lys Ala Tyr Ala Cys Ala Val Ser Asn Lys Ala Leu Pro Ala Pro Ile
355 360 365
Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val
370 375 380
Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser
385 390 395 400
Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu
405 410 415
Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro
420 425 430
Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val
435 440 445
Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met
450 455 460
His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser
465 470 475 480
Pro Gly Gln Arg His Asn Asn Ser Ser Leu Asn Thr Gly Thr Gln Met
485 490 495
Ala Gly His Ser Pro Asn Ser Gln Val Gln Leu Val Glu Ser Gly Gly
500 505 510
Gly Val Val Gln Pro Gly Arg Ser Leu Arg Leu Ser Cys Lys Ala Ser
515 520 525
Gly Tyr Thr Phe Thr Arg Ser Thr Met His Trp Val Arg Gln Ala Pro
530 535 540
Gly Gln Gly Leu Glu Trp Ile Gly Tyr Ile Asn Pro Ser Ser Ala Tyr
545 550 555 560
Thr Asn Tyr Asn Gln Lys Phe Lys Asp Arg Phe Thr Ile Ser Ala Asp
565 570 575
Lys Ser Lys Ser Thr Ala Phe Leu Gln Met Asp Ser Leu Arg Pro Glu
580 585 590
Asp Thr Gly Val Tyr Phe Cys Ala Arg Pro Gln Val His Tyr Asp Tyr
595 600 605
Asn Gly Phe Pro Tyr Trp Gly Gln Gly Thr Pro Val Thr Val Ser Ser
610 615 620
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Ala
625 630 635 640
Gln Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val
645 650 655
Gly Asp Arg Val Thr Met Thr Cys Ser Ala Ser Ser Ser Val Ser Tyr
660 665 670
Met Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Arg Trp Ile
675 680 685
Tyr Asp Ser Ser Lys Leu Ala Ser Gly Val Pro Ala Arg Phe Ser Gly
690 695 700
Ser Gly Ser Gly Thr Asp Tyr Thr Leu Thr Ile Ser Ser Leu Gln Pro
705 710 715 720
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Trp Ser Arg Asn Pro Pro
725 730 735
Thr Phe Gly Gly Gly Thr Lys Leu Gln Ile Thr Ser Ser Ser
740 745 750
<210> 71
<211> 2325
<212> DNA
<213> 人工序列
<220>
<223> 抗CD37 X TSC445抗CD3双特异性分子
<400> 71
atggaagcac cagcgcagct tctcttcctc ctgctactct ggctcccaga taccaccggt 60
gaggtgcagc tggtgcagtc tggagcagag gtgaaaaagc ccggagagtc tctgaagatt 120
tcctgtaagg gctccggtta ctcattcact ggctacaata tgaactgggt gcgccagatg 180
cccgggaaag gcctggagtg gatgggcaat attgatcctt attatggtgg tactacctac 240
aaccggaagt tcaagggcca ggtcactatc tccgccgaca agtccatcag caccgcctac 300
ctgcaatgga gcagcctgaa ggcctcggac accgccatgt attactgtgc acgctcagtc 360
ggccctttcg actcctgggg ccagggcacc ctggtcactg tctcctctgg gggtggaggc 420
tctggtggcg gtggctctgg cggaggtgga tccggtggcg gcggatctgg cgggggtggc 480
tctgaaattg tgttgacaca gtctccagcc accctgtctt tgtctccagg cgaaagagcc 540
accctctcct gccgagcaag tgaaaatgtt tacagctact tagcctggta ccaacagaaa 600
cctggccagg ctcctaggct cctcatctat tttgcaaaaa ccttagcaga aggtattcca 660
gccaggttca gtggcagtgg ctccgggaca gacttcactc tcaccatcag cagcctagag 720
cctgaagatt ttgcagttta ttactgtcaa catcattccg ataatccgtg gacattcggc 780
caagggacca aggtggaaat caaatcctcg agtgagccca aatcttctga caaaactcac 840
acatgcccac cgtgcccagc acctgaagcc gcgggtgcac cgtcagtctt cctcttcccc 900
ccaaaaccca aggacaccct catgatctcc cggacccctg aggtcacatg cgtggtggtg 960
gacgtgagcc acgaagaccc tgaggtcaag ttcaactggt acgtggacgg cgtggaggtg 1020
cataatgcca agacaaagcc gcgggaggag cagtacaaca gcacgtaccg tgtggtcagc 1080
gtcctcaccg tcctgcacca ggactggctg aatggcaagg catacgcgtg cgcggtctcc 1140
aacaaagccc tcccagcccc catcgagaaa accatctcca aagccaaagg gcagccccga 1200
gaaccacagg tgtacaccct gcccccatcc cgggatgagc tgaccaagaa ccaggtcagc 1260
ctgacctgcc tggtcaaagg cttctatcca agcgacatcg ccgtggagtg ggagagcaat 1320
gggcagccgg agaacaacta caagaccacg cctcccgtgc tggactccga cggctccttc 1380
ttcctctaca gcaagctcac cgtggacaag agcaggtggc agcaggggaa cgtcttctca 1440
tgctccgtga tgcatgaggc tctgcacaac cactacacgc agaagagcct ctccctgtct 1500
ccgggtcaga ggcacaacaa ttcttccctg aatacaggaa ctcagatggc aggtcattct 1560
ccgaattctc aggtccagct ggtgcaatct gggcctgagg tgaagaagcc tgggtcctcg 1620
gtgaaggtct cctgcaaggc ttctggatat accttcagca gatctacgat gcactgggtg 1680
cgacaggccc ctggacaagg gcttgagtgg ataggataca ttaatcctag cagtgcttat 1740
actaattaca atcagaaatt caaggacaga gtcacgatta ccgcggacaa atccacgagc 1800
acagcctaca tggagctgag cagcctgaga tctgaggaca cggccgtgta ttactgtgcg 1860
agaccccaag tccactatga ttacaacggg tttccttact ggggccaagg aaccctggtc 1920
accgtctcct caggtggagg cggttcaggc ggaggtggat ccggcggtgg cggatcgggt 1980
ggcggcggat ctgacatcca gatgacccag tctccttcca ccctgtctgc atctgtagga 2040
gacagagtca ccatgacttg cagtgccagc tcaagtgtaa gttacatgaa ctggtatcag 2100
cagaaaccag ggaaagcccc taagagatgg atttatgact catccaaact ggcttctggg 2160
gtcccatcaa ggttcagcgg cagtggatct gggacagagt tcactctcac catcagcagc 2220
ctgcagcctg atgattttgc aacttattac tgccaacagt ggagtcgtaa cccacccact 2280
ttcggcggag ggaccaaggt ggagatcaaa cggtcctcca gctaa 2325
<210> 72
<211> 754
<212> PRT
<213> 人工序列
<220>
<223> 抗CD37 X TSC445抗CD3双特异性分子
<400> 72
Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Glu
1 5 10 15
Ser Leu Lys Ile Ser Cys Lys Gly Ser Gly Tyr Ser Phe Thr Gly Tyr
20 25 30
Asn Met Asn Trp Val Arg Gln Met Pro Gly Lys Gly Leu Glu Trp Met
35 40 45
Gly Asn Ile Asp Pro Tyr Tyr Gly Gly Thr Thr Tyr Asn Arg Lys Phe
50 55 60
Lys Gly Gln Val Thr Ile Ser Ala Asp Lys Ser Ile Ser Thr Ala Tyr
65 70 75 80
Leu Gln Trp Ser Ser Leu Lys Ala Ser Asp Thr Ala Met Tyr Tyr Cys
85 90 95
Ala Arg Ser Val Gly Pro Phe Asp Ser Trp Gly Gln Gly Thr Leu Val
100 105 110
Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
115 120 125
Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Ile Val
130 135 140
Leu Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly Glu Arg Ala
145 150 155 160
Thr Leu Ser Cys Arg Ala Ser Glu Asn Val Tyr Ser Tyr Leu Ala Trp
165 170 175
Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile Tyr Phe Ala
180 185 190
Lys Thr Leu Ala Glu Gly Ile Pro Ala Arg Phe Ser Gly Ser Gly Ser
195 200 205
Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Glu Pro Glu Asp Phe
210 215 220
Ala Val Tyr Tyr Cys Gln His His Ser Asp Asn Pro Trp Thr Phe Gly
225 230 235 240
Gln Gly Thr Lys Val Glu Ile Lys Ser Ser Ser Glu Pro Lys Ser Ser
245 250 255
Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly
260 265 270
Ala Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
275 280 285
Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His
290 295 300
Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val
305 310 315 320
His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr
325 330 335
Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly
340 345 350
Lys Ala Tyr Ala Cys Ala Val Ser Asn Lys Ala Leu Pro Ala Pro Ile
355 360 365
Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val
370 375 380
Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser
385 390 395 400
Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu
405 410 415
Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro
420 425 430
Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val
435 440 445
Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met
450 455 460
His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser
465 470 475 480
Pro Gly Gln Arg His Asn Asn Ser Ser Leu Asn Thr Gly Thr Gln Met
485 490 495
Ala Gly His Ser Pro Asn Ser Gln Val Gln Leu Val Gln Ser Gly Pro
500 505 510
Glu Val Lys Lys Pro Gly Ser Ser Val Lys Val Ser Cys Lys Ala Ser
515 520 525
Gly Tyr Thr Phe Ser Arg Ser Thr Met His Trp Val Arg Gln Ala Pro
530 535 540
Gly Gln Gly Leu Glu Trp Ile Gly Tyr Ile Asn Pro Ser Ser Ala Tyr
545 550 555 560
Thr Asn Tyr Asn Gln Lys Phe Lys Asp Arg Val Thr Ile Thr Ala Asp
565 570 575
Lys Ser Thr Ser Thr Ala Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu
580 585 590
Asp Thr Ala Val Tyr Tyr Cys Ala Arg Pro Gln Val His Tyr Asp Tyr
595 600 605
Asn Gly Phe Pro Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
610 615 620
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly
625 630 635 640
Gly Gly Gly Ser Asp Ile Gln Met Thr Gln Ser Pro Ser Thr Leu Ser
645 650 655
Ala Ser Val Gly Asp Arg Val Thr Met Thr Cys Ser Ala Ser Ser Ser
660 665 670
Val Ser Tyr Met Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys
675 680 685
Arg Trp Ile Tyr Asp Ser Ser Lys Leu Ala Ser Gly Val Pro Ser Arg
690 695 700
Phe Ser Gly Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser
705 710 715 720
Leu Gln Pro Asp Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Trp Ser Arg
725 730 735
Asn Pro Pro Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg Ser
740 745 750
Ser Ser
<210> 73
<211> 2325
<212> DNA
<213> 人工序列
<220>
<223> 抗CD37 X TSC452 抗CD3双特异性分子
<400> 73
atggaagcac cagcgcagct tctcttcctc ctgctactct ggctcccaga taccaccggt 60
gaggtgcagc tggtgcagtc tggagcagag gtgaaaaagc ccggagagtc tctgaagatt 120
tcctgtaagg gctccggtta ctcattcact ggctacaata tgaactgggt gcgccagatg 180
cccgggaaag gcctggagtg gatgggcaat attgatcctt attatggtgg tactacctac 240
aaccggaagt tcaagggcca ggtcactatc tccgccgaca agtccatcag caccgcctac 300
ctgcaatgga gcagcctgaa ggcctcggac accgccatgt attactgtgc acgctcagtc 360
ggccctttcg actcctgggg ccagggcacc ctggtcactg tctcctctgg gggtggaggc 420
tctggtggcg gtggctctgg cggaggtgga tccggtggcg gcggatctgg cgggggtggc 480
tctgaaattg tgttgacaca gtctccagcc accctgtctt tgtctccagg cgaaagagcc 540
accctctcct gccgagcaag tgaaaatgtt tacagctact tagcctggta ccaacagaaa 600
cctggccagg ctcctaggct cctcatctat tttgcaaaaa ccttagcaga aggtattcca 660
gccaggttca gtggcagtgg ctccgggaca gacttcactc tcaccatcag cagcctagag 720
cctgaagatt ttgcagttta ttactgtcaa catcattccg ataatccgtg gacattcggc 780
caagggacca aggtggaaat caaatcctcg agtgagccca aatcttctga caaaactcac 840
acatgcccac cgtgcccagc acctgaagcc gcgggtgcac cgtcagtctt cctcttcccc 900
ccaaaaccca aggacaccct catgatctcc cggacccctg aggtcacatg cgtggtggtg 960
gacgtgagcc acgaagaccc tgaggtcaag ttcaactggt acgtggacgg cgtggaggtg 1020
cataatgcca agacaaagcc gcgggaggag cagtacaaca gcacgtaccg tgtggtcagc 1080
gtcctcaccg tcctgcacca ggactggctg aatggcaagg catacgcgtg cgcggtctcc 1140
aacaaagccc tcccagcccc catcgagaaa accatctcca aagccaaagg gcagccccga 1200
gaaccacagg tgtacaccct gcccccatcc cgggatgagc tgaccaagaa ccaggtcagc 1260
ctgacctgcc tggtcaaagg cttctatcca agcgacatcg ccgtggagtg ggagagcaat 1320
gggcagccgg agaacaacta caagaccacg cctcccgtgc tggactccga cggctccttc 1380
ttcctctaca gcaagctcac cgtggacaag agcaggtggc agcaggggaa cgtcttctca 1440
tgctccgtga tgcatgaggc tctgcacaac cactacacgc agaagagcct ctccctgtct 1500
ccgggtcaga ggcacaacaa ttcttccctg aatacaggaa ctcagatggc aggtcattct 1560
ccgaattctc aggtccagct ggtggagtct gggggcggag tggtgcagcc tgggcggtca 1620
ctgaggctgt cctgcaaggc ttctggctac acctttacta gatctacgat gcactgggta 1680
aggcaggccc ctggacaagg tctggaatgg attggataca ttaatcctag cagtgcttat 1740
actaattaca atcagaaatt caaggacagg ttcacaatca gcgcagacaa atccaagagc 1800
acagccttcc tgcagatgga cagcctgagg cccgaggaca ccggcgtcta tttctgtgca 1860
cggccccaag tccactatga ttacaacggg tttccttact ggggccaagg gactcccgtc 1920
actgtctcta gcggtggcgg agggtctggg ggtggcggat ccggcggtgg cggatcgggt 1980
ggcggcggat ctgacatcca gatgacccag tctccttcca ccctgtctgc atctgtagga 2040
gacagagtca ccatgacttg cagtgccagc tcaagtgtaa gttacatgaa ctggtatcag 2100
cagaaaccag ggaaagcccc taagagatgg atttatgact catccaaact ggcttctggg 2160
gtcccatcaa ggttcagcgg cagtggatct gggacagagt tcactctcac catcagcagc 2220
ctgcagcctg atgattttgc aacttattac tgccaacagt ggagtcgtaa cccacccact 2280
ttcggcggag ggaccaaggt ggagatcaaa cggtcctcca gctaa 2325
<210> 74
<211> 754
<212> PRT
<213> 人工序列
<220>
<223> 抗CD37 X TSC452 抗CD3双特异性分子
<400> 74
Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Glu
1 5 10 15
Ser Leu Lys Ile Ser Cys Lys Gly Ser Gly Tyr Ser Phe Thr Gly Tyr
20 25 30
Asn Met Asn Trp Val Arg Gln Met Pro Gly Lys Gly Leu Glu Trp Met
35 40 45
Gly Asn Ile Asp Pro Tyr Tyr Gly Gly Thr Thr Tyr Asn Arg Lys Phe
50 55 60
Lys Gly Gln Val Thr Ile Ser Ala Asp Lys Ser Ile Ser Thr Ala Tyr
65 70 75 80
Leu Gln Trp Ser Ser Leu Lys Ala Ser Asp Thr Ala Met Tyr Tyr Cys
85 90 95
Ala Arg Ser Val Gly Pro Phe Asp Ser Trp Gly Gln Gly Thr Leu Val
100 105 110
Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
115 120 125
Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Ile Val
130 135 140
Leu Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly Glu Arg Ala
145 150 155 160
Thr Leu Ser Cys Arg Ala Ser Glu Asn Val Tyr Ser Tyr Leu Ala Trp
165 170 175
Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile Tyr Phe Ala
180 185 190
Lys Thr Leu Ala Glu Gly Ile Pro Ala Arg Phe Ser Gly Ser Gly Ser
195 200 205
Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Glu Pro Glu Asp Phe
210 215 220
Ala Val Tyr Tyr Cys Gln His His Ser Asp Asn Pro Trp Thr Phe Gly
225 230 235 240
Gln Gly Thr Lys Val Glu Ile Lys Ser Ser Ser Glu Pro Lys Ser Ser
245 250 255
Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly
260 265 270
Ala Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
275 280 285
Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His
290 295 300
Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val
305 310 315 320
His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr
325 330 335
Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly
340 345 350
Lys Ala Tyr Ala Cys Ala Val Ser Asn Lys Ala Leu Pro Ala Pro Ile
355 360 365
Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val
370 375 380
Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser
385 390 395 400
Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu
405 410 415
Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro
420 425 430
Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val
435 440 445
Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met
450 455 460
His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser
465 470 475 480
Pro Gly Gln Arg His Asn Asn Ser Ser Leu Asn Thr Gly Thr Gln Met
485 490 495
Ala Gly His Ser Pro Asn Ser Gln Val Gln Leu Val Glu Ser Gly Gly
500 505 510
Gly Val Val Gln Pro Gly Arg Ser Leu Arg Leu Ser Cys Lys Ala Ser
515 520 525
Gly Tyr Thr Phe Thr Arg Ser Thr Met His Trp Val Arg Gln Ala Pro
530 535 540
Gly Gln Gly Leu Glu Trp Ile Gly Tyr Ile Asn Pro Ser Ser Ala Tyr
545 550 555 560
Thr Asn Tyr Asn Gln Lys Phe Lys Asp Arg Phe Thr Ile Ser Ala Asp
565 570 575
Lys Ser Lys Ser Thr Ala Phe Leu Gln Met Asp Ser Leu Arg Pro Glu
580 585 590
Asp Thr Gly Val Tyr Phe Cys Ala Arg Pro Gln Val His Tyr Asp Tyr
595 600 605
Asn Gly Phe Pro Tyr Trp Gly Gln Gly Thr Pro Val Thr Val Ser Ser
610 615 620
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly
625 630 635 640
Gly Gly Gly Ser Asp Ile Gln Met Thr Gln Ser Pro Ser Thr Leu Ser
645 650 655
Ala Ser Val Gly Asp Arg Val Thr Met Thr Cys Ser Ala Ser Ser Ser
660 665 670
Val Ser Tyr Met Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys
675 680 685
Arg Trp Ile Tyr Asp Ser Ser Lys Leu Ala Ser Gly Val Pro Ser Arg
690 695 700
Phe Ser Gly Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser
705 710 715 720
Leu Gln Pro Asp Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Trp Ser Arg
725 730 735
Asn Pro Pro Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg Ser
740 745 750
Ser Ser
<210> 75
<211> 2322
<212> DNA
<213> 人工序列
<220>
<223> 抗CD37 X TSC453 抗CD3双特异性分子
<400> 75
atggaagcac cagcgcagct tctcttcctc ctgctactct ggctcccaga taccaccggt 60
gaggtgcagc tggtgcagtc tggagcagag gtgaaaaagc ccggagagtc tctgaagatt 120
tcctgtaagg gctccggtta ctcattcact ggctacaata tgaactgggt gcgccagatg 180
cccgggaaag gcctggagtg gatgggcaat attgatcctt attatggtgg tactacctac 240
aaccggaagt tcaagggcca ggtcactatc tccgccgaca agtccatcag caccgcctac 300
ctgcaatgga gcagcctgaa ggcctcggac accgccatgt attactgtgc acgctcagtc 360
ggccctttcg actcctgggg ccagggcacc ctggtcactg tctcctctgg gggtggaggc 420
tctggtggcg gtggctctgg cggaggtgga tccggtggcg gcggatctgg cgggggtggc 480
tctgaaattg tgttgacaca gtctccagcc accctgtctt tgtctccagg cgaaagagcc 540
accctctcct gccgagcaag tgaaaatgtt tacagctact tagcctggta ccaacagaaa 600
cctggccagg ctcctaggct cctcatctat tttgcaaaaa ccttagcaga aggtattcca 660
gccaggttca gtggcagtgg ctccgggaca gacttcactc tcaccatcag cagcctagag 720
cctgaagatt ttgcagttta ttactgtcaa catcattccg ataatccgtg gacattcggc 780
caagggacca aggtggaaat caaatcctcg agtgagccca aatcttctga caaaactcac 840
acatgcccac cgtgcccagc acctgaagcc gcgggtgcac cgtcagtctt cctcttcccc 900
ccaaaaccca aggacaccct catgatctcc cggacccctg aggtcacatg cgtggtggtg 960
gacgtgagcc acgaagaccc tgaggtcaag ttcaactggt acgtggacgg cgtggaggtg 1020
cataatgcca agacaaagcc gcgggaggag cagtacaaca gcacgtaccg tgtggtcagc 1080
gtcctcaccg tcctgcacca ggactggctg aatggcaagg catacgcgtg cgcggtctcc 1140
aacaaagccc tcccagcccc catcgagaaa accatctcca aagccaaagg gcagccccga 1200
gaaccacagg tgtacaccct gcccccatcc cgggatgagc tgaccaagaa ccaggtcagc 1260
ctgacctgcc tggtcaaagg cttctatcca agcgacatcg ccgtggagtg ggagagcaat 1320
gggcagccgg agaacaacta caagaccacg cctcccgtgc tggactccga cggctccttc 1380
ttcctctaca gcaagctcac cgtggacaag agcaggtggc agcaggggaa cgtcttctca 1440
tgctccgtga tgcatgaggc tctgcacaac cactacacgc agaagagcct ctccctgtct 1500
ccgggtcaga ggcacaacaa ttcttccctg aatacaggaa ctcagatggc aggtcattct 1560
ccgaattctc aggtccagct ggtgcaatct gggcctgagg tgaagaagcc tgggtcctcg 1620
gtgaaggtct cctgcaaggc ttctggatat accttcagca gatctacgat gcactgggtg 1680
cgacaggccc ctggacaagg gcttgagtgg ataggataca ttaatcctag cagtgcttat 1740
actaattaca atcagaaatt caaggacaga gtcacgatta ccgcggacaa atccacgagc 1800
acagcctaca tggagctgag cagcctgaga tctgaggaca cggccgtgta ttactgtgcg 1860
agaccccaag tccactatga ttacaacggg tttccttact ggggccaagg aaccctggtc 1920
accgtctcct caggtggagg cggttcaggc ggaggtggat ccggaggtgg tggctctggt 1980
ggcggcggat ctgacatcca gatgacccag tctccaagca gcctgtctgc aagcgtgggg 2040
gacagggtca ccatgacctg cagtgccagc tcaagtgtaa gttacatgaa ctggtaccag 2100
cagaagccgg gcaaggcccc caaaagatgg atttatgact catccaaact ggcttctgga 2160
gtccctgctc gcttcagtgg cagtgggtct gggaccgact ataccctcac aatcagcagc 2220
ctgcagcccg aagatttcgc cacttattac tgccagcagt ggagtcgtaa cccacccacg 2280
ttcggagggg ggaccaagct acaaattaca tcctccagct aa 2322
<210> 76
<211> 753
<212> PRT
<213> 人工序列
<220>
<223> 抗CD37 X TSC453 抗CD3双特异性分子
<400> 76
Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Glu
1 5 10 15
Ser Leu Lys Ile Ser Cys Lys Gly Ser Gly Tyr Ser Phe Thr Gly Tyr
20 25 30
Asn Met Asn Trp Val Arg Gln Met Pro Gly Lys Gly Leu Glu Trp Met
35 40 45
Gly Asn Ile Asp Pro Tyr Tyr Gly Gly Thr Thr Tyr Asn Arg Lys Phe
50 55 60
Lys Gly Gln Val Thr Ile Ser Ala Asp Lys Ser Ile Ser Thr Ala Tyr
65 70 75 80
Leu Gln Trp Ser Ser Leu Lys Ala Ser Asp Thr Ala Met Tyr Tyr Cys
85 90 95
Ala Arg Ser Val Gly Pro Phe Asp Ser Trp Gly Gln Gly Thr Leu Val
100 105 110
Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
115 120 125
Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Ile Val
130 135 140
Leu Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly Glu Arg Ala
145 150 155 160
Thr Leu Ser Cys Arg Ala Ser Glu Asn Val Tyr Ser Tyr Leu Ala Trp
165 170 175
Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile Tyr Phe Ala
180 185 190
Lys Thr Leu Ala Glu Gly Ile Pro Ala Arg Phe Ser Gly Ser Gly Ser
195 200 205
Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Glu Pro Glu Asp Phe
210 215 220
Ala Val Tyr Tyr Cys Gln His His Ser Asp Asn Pro Trp Thr Phe Gly
225 230 235 240
Gln Gly Thr Lys Val Glu Ile Lys Ser Ser Ser Glu Pro Lys Ser Ser
245 250 255
Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly
260 265 270
Ala Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
275 280 285
Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His
290 295 300
Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val
305 310 315 320
His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr
325 330 335
Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly
340 345 350
Lys Ala Tyr Ala Cys Ala Val Ser Asn Lys Ala Leu Pro Ala Pro Ile
355 360 365
Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val
370 375 380
Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser
385 390 395 400
Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu
405 410 415
Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro
420 425 430
Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val
435 440 445
Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met
450 455 460
His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser
465 470 475 480
Pro Gly Gln Arg His Asn Asn Ser Ser Leu Asn Thr Gly Thr Gln Met
485 490 495
Ala Gly His Ser Pro Asn Ser Gln Val Gln Leu Val Gln Ser Gly Pro
500 505 510
Glu Val Lys Lys Pro Gly Ser Ser Val Lys Val Ser Cys Lys Ala Ser
515 520 525
Gly Tyr Thr Phe Ser Arg Ser Thr Met His Trp Val Arg Gln Ala Pro
530 535 540
Gly Gln Gly Leu Glu Trp Ile Gly Tyr Ile Asn Pro Ser Ser Ala Tyr
545 550 555 560
Thr Asn Tyr Asn Gln Lys Phe Lys Asp Arg Val Thr Ile Thr Ala Asp
565 570 575
Lys Ser Thr Ser Thr Ala Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu
580 585 590
Asp Thr Ala Val Tyr Tyr Cys Ala Arg Pro Gln Val His Tyr Asp Tyr
595 600 605
Asn Gly Phe Pro Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
610 615 620
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly
625 630 635 640
Gly Gly Gly Ser Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser
645 650 655
Ala Ser Val Gly Asp Arg Val Thr Met Thr Cys Ser Ala Ser Ser Ser
660 665 670
Val Ser Tyr Met Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys
675 680 685
Arg Trp Ile Tyr Asp Ser Ser Lys Leu Ala Ser Gly Val Pro Ala Arg
690 695 700
Phe Ser Gly Ser Gly Ser Gly Thr Asp Tyr Thr Leu Thr Ile Ser Ser
705 710 715 720
Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Trp Ser Arg
725 730 735
Asn Pro Pro Thr Phe Gly Gly Gly Thr Lys Leu Gln Ile Thr Ser Ser
740 745 750
Ser
<210> 77
<211> 2325
<212> DNA
<213> 人工序列
<220>
<223> 抗CD37 X TSC454 抗CD3双特异性分子
<400> 77
atggaagcac cagcgcagct tctcttcctc ctgctactct ggctcccaga taccaccggt 60
gaggtgcagc tggtgcagtc tggagcagag gtgaaaaagc ccggagagtc tctgaagatt 120
tcctgtaagg gctccggtta ctcattcact ggctacaata tgaactgggt gcgccagatg 180
cccgggaaag gcctggagtg gatgggcaat attgatcctt attatggtgg tactacctac 240
aaccggaagt tcaagggcca ggtcactatc tccgccgaca agtccatcag caccgcctac 300
ctgcaatgga gcagcctgaa ggcctcggac accgccatgt attactgtgc acgctcagtc 360
ggccctttcg actcctgggg ccagggcacc ctggtcactg tctcctctgg gggtggaggc 420
tctggtggcg gtggctctgg cggaggtgga tccggtggcg gcggatctgg cgggggtggc 480
tctgaaattg tgttgacaca gtctccagcc accctgtctt tgtctccagg cgaaagagcc 540
accctctcct gccgagcaag tgaaaatgtt tacagctact tagcctggta ccaacagaaa 600
cctggccagg ctcctaggct cctcatctat tttgcaaaaa ccttagcaga aggtattcca 660
gccaggttca gtggcagtgg ctccgggaca gacttcactc tcaccatcag cagcctagag 720
cctgaagatt ttgcagttta ttactgtcaa catcattccg ataatccgtg gacattcggc 780
caagggacca aggtggaaat caaatcctcg agtgagccca aatcttctga caaaactcac 840
acatgcccac cgtgcccagc acctgaagcc gcgggtgcac cgtcagtctt cctcttcccc 900
ccaaaaccca aggacaccct catgatctcc cggacccctg aggtcacatg cgtggtggtg 960
gacgtgagcc acgaagaccc tgaggtcaag ttcaactggt acgtggacgg cgtggaggtg 1020
cataatgcca agacaaagcc gcgggaggag cagtacaaca gcacgtaccg tgtggtcagc 1080
gtcctcaccg tcctgcacca ggactggctg aatggcaagg catacgcgtg cgcggtctcc 1140
aacaaagccc tcccagcccc catcgagaaa accatctcca aagccaaagg gcagccccga 1200
gaaccacagg tgtacaccct gcccccatcc cgggatgagc tgaccaagaa ccaggtcagc 1260
ctgacctgcc tggtcaaagg cttctatcca agcgacatcg ccgtggagtg ggagagcaat 1320
gggcagccgg agaacaacta caagaccacg cctcccgtgc tggactccga cggctccttc 1380
ttcctctaca gcaagctcac cgtggacaag agcaggtggc agcaggggaa cgtcttctca 1440
tgctccgtga tgcatgaggc tctgcacaac cactacacgc agaagagcct ctccctgtct 1500
ccgggtcaga ggcacaacaa ttcttccctg aatacaggaa ctcagatggc aggtcattct 1560
ccgaattctc aggtccagct ggtgcaatct gggcctgagg tgaagaagcc tgggtcctcg 1620
gtgaaggtct cctgcaaggc ttctggatat accttcagca gatctacgat gcactgggtg 1680
cgacaggccc ctggacaagg gcttgagtgg ataggataca ttaatcctag cagtgcttat 1740
actaattaca atcagaaatt caaggacaga gtcacgatta ccgcggacaa atccacgagc 1800
acagcctaca tggagctgag cagcctgaga tctgaggaca cggccgtgta ttactgtgcg 1860
agaccccaag tccactatga ttacaacggg tttccttact ggggccaagg aaccctggtc 1920
accgtctcct caggtggagg cggttcaggc ggaggtggat ccggcggtgg cggatcgggt 1980
ggcggcggat ctgacatcca gatgacccag tctccttcca ccctgtctgc atctgtagga 2040
gacagagtca ccatgacttg cagtgccagc tcaagtgtaa gttacatgaa ctggtatcag 2100
cagaaaccag ggaaagcccc taagagatgg atttatgact catccaaact ggcttctggg 2160
gtcccatcaa ggttcagcgg cagtggatct gggacagatt tcactctcac catcagcagc 2220
ctgcagcctg atgattttgc aacttattac tgccaacagt ggagtcgtaa cccacccact 2280
ttcggcggag ggaccaaggt ggagatcaaa cggtcctcca gctaa 2325
<210> 78
<211> 754
<212> PRT
<213> 人工序列
<220>
<223> 抗CD37 X TSC454 抗CD3双特异性分子
<400> 78
Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Glu
1 5 10 15
Ser Leu Lys Ile Ser Cys Lys Gly Ser Gly Tyr Ser Phe Thr Gly Tyr
20 25 30
Asn Met Asn Trp Val Arg Gln Met Pro Gly Lys Gly Leu Glu Trp Met
35 40 45
Gly Asn Ile Asp Pro Tyr Tyr Gly Gly Thr Thr Tyr Asn Arg Lys Phe
50 55 60
Lys Gly Gln Val Thr Ile Ser Ala Asp Lys Ser Ile Ser Thr Ala Tyr
65 70 75 80
Leu Gln Trp Ser Ser Leu Lys Ala Ser Asp Thr Ala Met Tyr Tyr Cys
85 90 95
Ala Arg Ser Val Gly Pro Phe Asp Ser Trp Gly Gln Gly Thr Leu Val
100 105 110
Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
115 120 125
Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Ile Val
130 135 140
Leu Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly Glu Arg Ala
145 150 155 160
Thr Leu Ser Cys Arg Ala Ser Glu Asn Val Tyr Ser Tyr Leu Ala Trp
165 170 175
Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile Tyr Phe Ala
180 185 190
Lys Thr Leu Ala Glu Gly Ile Pro Ala Arg Phe Ser Gly Ser Gly Ser
195 200 205
Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Glu Pro Glu Asp Phe
210 215 220
Ala Val Tyr Tyr Cys Gln His His Ser Asp Asn Pro Trp Thr Phe Gly
225 230 235 240
Gln Gly Thr Lys Val Glu Ile Lys Ser Ser Ser Glu Pro Lys Ser Ser
245 250 255
Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly
260 265 270
Ala Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
275 280 285
Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His
290 295 300
Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val
305 310 315 320
His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr
325 330 335
Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly
340 345 350
Lys Ala Tyr Ala Cys Ala Val Ser Asn Lys Ala Leu Pro Ala Pro Ile
355 360 365
Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val
370 375 380
Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser
385 390 395 400
Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu
405 410 415
Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro
420 425 430
Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val
435 440 445
Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met
450 455 460
His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser
465 470 475 480
Pro Gly Gln Arg His Asn Asn Ser Ser Leu Asn Thr Gly Thr Gln Met
485 490 495
Ala Gly His Ser Pro Asn Ser Gln Val Gln Leu Val Gln Ser Gly Pro
500 505 510
Glu Val Lys Lys Pro Gly Ser Ser Val Lys Val Ser Cys Lys Ala Ser
515 520 525
Gly Tyr Thr Phe Ser Arg Ser Thr Met His Trp Val Arg Gln Ala Pro
530 535 540
Gly Gln Gly Leu Glu Trp Ile Gly Tyr Ile Asn Pro Ser Ser Ala Tyr
545 550 555 560
Thr Asn Tyr Asn Gln Lys Phe Lys Asp Arg Val Thr Ile Thr Ala Asp
565 570 575
Lys Ser Thr Ser Thr Ala Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu
580 585 590
Asp Thr Ala Val Tyr Tyr Cys Ala Arg Pro Gln Val His Tyr Asp Tyr
595 600 605
Asn Gly Phe Pro Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
610 615 620
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly
625 630 635 640
Gly Gly Gly Ser Asp Ile Gln Met Thr Gln Ser Pro Ser Thr Leu Ser
645 650 655
Ala Ser Val Gly Asp Arg Val Thr Met Thr Cys Ser Ala Ser Ser Ser
660 665 670
Val Ser Tyr Met Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys
675 680 685
Arg Trp Ile Tyr Asp Ser Ser Lys Leu Ala Ser Gly Val Pro Ser Arg
690 695 700
Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser
705 710 715 720
Leu Gln Pro Asp Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Trp Ser Arg
725 730 735
Asn Pro Pro Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg Ser
740 745 750
Ser Ser
<210> 79
<211> 2325
<212> DNA
<213> 人工序列
<220>
<223> 抗CD37 X TSC455抗CD3双特异性分子
<400> 79
atggaagcac cagcgcagct tctcttcctc ctgctactct ggctcccaga taccaccggt 60
gaggtgcagc tggtgcagtc tggagcagag gtgaaaaagc ccggagagtc tctgaagatt 120
tcctgtaagg gctccggtta ctcattcact ggctacaata tgaactgggt gcgccagatg 180
cccgggaaag gcctggagtg gatgggcaat attgatcctt attatggtgg tactacctac 240
aaccggaagt tcaagggcca ggtcactatc tccgccgaca agtccatcag caccgcctac 300
ctgcaatgga gcagcctgaa ggcctcggac accgccatgt attactgtgc acgctcagtc 360
ggccctttcg actcctgggg ccagggcacc ctggtcactg tctcctctgg gggtggaggc 420
tctggtggcg gtggctctgg cggaggtgga tccggtggcg gcggatctgg cgggggtggc 480
tctgaaattg tgttgacaca gtctccagcc accctgtctt tgtctccagg cgaaagagcc 540
accctctcct gccgagcaag tgaaaatgtt tacagctact tagcctggta ccaacagaaa 600
cctggccagg ctcctaggct cctcatctat tttgcaaaaa ccttagcaga aggtattcca 660
gccaggttca gtggcagtgg ctccgggaca gacttcactc tcaccatcag cagcctagag 720
cctgaagatt ttgcagttta ttactgtcaa catcattccg ataatccgtg gacattcggc 780
caagggacca aggtggaaat caaatcctcg agtgagccca aatcttctga caaaactcac 840
acatgcccac cgtgcccagc acctgaagcc gcgggtgcac cgtcagtctt cctcttcccc 900
ccaaaaccca aggacaccct catgatctcc cggacccctg aggtcacatg cgtggtggtg 960
gacgtgagcc acgaagaccc tgaggtcaag ttcaactggt acgtggacgg cgtggaggtg 1020
cataatgcca agacaaagcc gcgggaggag cagtacaaca gcacgtaccg tgtggtcagc 1080
gtcctcaccg tcctgcacca ggactggctg aatggcaagg catacgcgtg cgcggtctcc 1140
aacaaagccc tcccagcccc catcgagaaa accatctcca aagccaaagg gcagccccga 1200
gaaccacagg tgtacaccct gcccccatcc cgggatgagc tgaccaagaa ccaggtcagc 1260
ctgacctgcc tggtcaaagg cttctatcca agcgacatcg ccgtggagtg ggagagcaat 1320
gggcagccgg agaacaacta caagaccacg cctcccgtgc tggactccga cggctccttc 1380
ttcctctaca gcaagctcac cgtggacaag agcaggtggc agcaggggaa cgtcttctca 1440
tgctccgtga tgcatgaggc tctgcacaac cactacacgc agaagagcct ctccctgtct 1500
ccgggtcaga ggcacaacaa ttcttccctg aatacaggaa ctcagatggc aggtcattct 1560
ccgaattctc aggtccagct ggtgcaatct gggcctgagg tgaagaagcc tgggtcctcg 1620
gtgaaggtct cctgcaaggc ttctggatat accttcagca gatctacgat gcactgggtg 1680
cgacaggccc ctggacaagg gcttgagtgg ataggataca ttaatcctag cagtgcttat 1740
actaattaca atcagaaatt caaggacaga gtcacgatta ccgcggacaa atccacgagc 1800
acagcctaca tggagctgag cagcctgaga tctgaggaca cggccgtgta ttactgtgcg 1860
agaccccaag tccactatga ttacaacggg tttccttact ggggccaagg aaccctggtc 1920
accgtctcct caggtggagg cggttcaggc ggaggtggat ccggcggtgg cggatcgggt 1980
ggcggcggat ctgacatcca gatgacccag tctccttcca ccctgtctgc atctgtagga 2040
gacagagtca ccatgacttg cagtgccagc tcaagtgtaa gttacatgaa ctggtatcag 2100
cagaaaccag ggaaagcccc taagagatgg atttatgact catccaaact ggcttctggg 2160
gtcccatcaa ggttcagcgg cagtggatct gggacagagt atactctcac catcagcagc 2220
ctgcagcctg atgattttgc aacttattac tgccaacagt ggagtcgtaa cccacccact 2280
ttcggcggag ggaccaaggt ggagatcaaa cggtcctcca gctaa 2325
<210> 80
<211> 754
<212> PRT
<213> 人工序列
<220>
<223> 抗CD37 X TSC455抗CD3双特异性分子
<400> 80
Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Glu
1 5 10 15
Ser Leu Lys Ile Ser Cys Lys Gly Ser Gly Tyr Ser Phe Thr Gly Tyr
20 25 30
Asn Met Asn Trp Val Arg Gln Met Pro Gly Lys Gly Leu Glu Trp Met
35 40 45
Gly Asn Ile Asp Pro Tyr Tyr Gly Gly Thr Thr Tyr Asn Arg Lys Phe
50 55 60
Lys Gly Gln Val Thr Ile Ser Ala Asp Lys Ser Ile Ser Thr Ala Tyr
65 70 75 80
Leu Gln Trp Ser Ser Leu Lys Ala Ser Asp Thr Ala Met Tyr Tyr Cys
85 90 95
Ala Arg Ser Val Gly Pro Phe Asp Ser Trp Gly Gln Gly Thr Leu Val
100 105 110
Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
115 120 125
Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Ile Val
130 135 140
Leu Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly Glu Arg Ala
145 150 155 160
Thr Leu Ser Cys Arg Ala Ser Glu Asn Val Tyr Ser Tyr Leu Ala Trp
165 170 175
Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile Tyr Phe Ala
180 185 190
Lys Thr Leu Ala Glu Gly Ile Pro Ala Arg Phe Ser Gly Ser Gly Ser
195 200 205
Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Glu Pro Glu Asp Phe
210 215 220
Ala Val Tyr Tyr Cys Gln His His Ser Asp Asn Pro Trp Thr Phe Gly
225 230 235 240
Gln Gly Thr Lys Val Glu Ile Lys Ser Ser Ser Glu Pro Lys Ser Ser
245 250 255
Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly
260 265 270
Ala Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
275 280 285
Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His
290 295 300
Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val
305 310 315 320
His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr
325 330 335
Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly
340 345 350
Lys Ala Tyr Ala Cys Ala Val Ser Asn Lys Ala Leu Pro Ala Pro Ile
355 360 365
Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val
370 375 380
Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser
385 390 395 400
Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu
405 410 415
Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro
420 425 430
Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val
435 440 445
Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met
450 455 460
His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser
465 470 475 480
Pro Gly Gln Arg His Asn Asn Ser Ser Leu Asn Thr Gly Thr Gln Met
485 490 495
Ala Gly His Ser Pro Asn Ser Gln Val Gln Leu Val Gln Ser Gly Pro
500 505 510
Glu Val Lys Lys Pro Gly Ser Ser Val Lys Val Ser Cys Lys Ala Ser
515 520 525
Gly Tyr Thr Phe Ser Arg Ser Thr Met His Trp Val Arg Gln Ala Pro
530 535 540
Gly Gln Gly Leu Glu Trp Ile Gly Tyr Ile Asn Pro Ser Ser Ala Tyr
545 550 555 560
Thr Asn Tyr Asn Gln Lys Phe Lys Asp Arg Val Thr Ile Thr Ala Asp
565 570 575
Lys Ser Thr Ser Thr Ala Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu
580 585 590
Asp Thr Ala Val Tyr Tyr Cys Ala Arg Pro Gln Val His Tyr Asp Tyr
595 600 605
Asn Gly Phe Pro Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
610 615 620
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly
625 630 635 640
Gly Gly Gly Ser Asp Ile Gln Met Thr Gln Ser Pro Ser Thr Leu Ser
645 650 655
Ala Ser Val Gly Asp Arg Val Thr Met Thr Cys Ser Ala Ser Ser Ser
660 665 670
Val Ser Tyr Met Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys
675 680 685
Arg Trp Ile Tyr Asp Ser Ser Lys Leu Ala Ser Gly Val Pro Ser Arg
690 695 700
Phe Ser Gly Ser Gly Ser Gly Thr Glu Tyr Thr Leu Thr Ile Ser Ser
705 710 715 720
Leu Gln Pro Asp Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Trp Ser Arg
725 730 735
Asn Pro Pro Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg Ser
740 745 750
Ser Ser
<210> 81
<211> 2325
<212> DNA
<213> 人工序列
<220>
<223> 抗CD37 X TSC456抗CD3双特异性分子
<400> 81
atggaagcac cagcgcagct tctcttcctc ctgctactct ggctcccaga taccaccggt 60
gaggtgcagc tggtgcagtc tggagcagag gtgaaaaagc ccggagagtc tctgaagatt 120
tcctgtaagg gctccggtta ctcattcact ggctacaata tgaactgggt gcgccagatg 180
cccgggaaag gcctggagtg gatgggcaat attgatcctt attatggtgg tactacctac 240
aaccggaagt tcaagggcca ggtcactatc tccgccgaca agtccatcag caccgcctac 300
ctgcaatgga gcagcctgaa ggcctcggac accgccatgt attactgtgc acgctcagtc 360
ggccctttcg actcctgggg ccagggcacc ctggtcactg tctcctctgg gggtggaggc 420
tctggtggcg gtggctctgg cggaggtgga tccggtggcg gcggatctgg cgggggtggc 480
tctgaaattg tgttgacaca gtctccagcc accctgtctt tgtctccagg cgaaagagcc 540
accctctcct gccgagcaag tgaaaatgtt tacagctact tagcctggta ccaacagaaa 600
cctggccagg ctcctaggct cctcatctat tttgcaaaaa ccttagcaga aggtattcca 660
gccaggttca gtggcagtgg ctccgggaca gacttcactc tcaccatcag cagcctagag 720
cctgaagatt ttgcagttta ttactgtcaa catcattccg ataatccgtg gacattcggc 780
caagggacca aggtggaaat caaatcctcg agtgagccca aatcttctga caaaactcac 840
acatgcccac cgtgcccagc acctgaagcc gcgggtgcac cgtcagtctt cctcttcccc 900
ccaaaaccca aggacaccct catgatctcc cggacccctg aggtcacatg cgtggtggtg 960
gacgtgagcc acgaagaccc tgaggtcaag ttcaactggt acgtggacgg cgtggaggtg 1020
cataatgcca agacaaagcc gcgggaggag cagtacaaca gcacgtaccg tgtggtcagc 1080
gtcctcaccg tcctgcacca ggactggctg aatggcaagg catacgcgtg cgcggtctcc 1140
aacaaagccc tcccagcccc catcgagaaa accatctcca aagccaaagg gcagccccga 1200
gaaccacagg tgtacaccct gcccccatcc cgggatgagc tgaccaagaa ccaggtcagc 1260
ctgacctgcc tggtcaaagg cttctatcca agcgacatcg ccgtggagtg ggagagcaat 1320
gggcagccgg agaacaacta caagaccacg cctcccgtgc tggactccga cggctccttc 1380
ttcctctaca gcaagctcac cgtggacaag agcaggtggc agcaggggaa cgtcttctca 1440
tgctccgtga tgcatgaggc tctgcacaac cactacacgc agaagagcct ctccctgtct 1500
ccgggtcaga ggcacaacaa ttcttccctg aatacaggaa ctcagatggc aggtcattct 1560
ccgaattctc aggtccagct ggtgcaatct gggcctgagg tgaagaagcc tgggtcctcg 1620
gtgaaggtct cctgcaaggc ttctggatat accttcagca gatctacgat gcactgggtg 1680
cgacaggccc ctggacaagg gcttgagtgg ataggataca ttaatcctag cagtgcttat 1740
actaattaca atcagaaatt caaggacaga gtcacgatta ccgcggacaa atccacgagc 1800
acagcctaca tggagctgag cagcctgaga tctgaggaca cggccgtgta ttactgtgcg 1860
agaccccaag tccactatga ttacaacggg tttccttact ggggccaagg aaccctggtc 1920
accgtctcct caggtggagg cggttcaggc ggaggtggat ccggcggtgg cggatcgggt 1980
ggcggcggat ctgacatcca gatgacccag tctccttcca ccctgtctgc atctgtagga 2040
gacagagtca ccatgacttg cagtgccagc tcaagtgtaa gttacatgaa ctggtatcag 2100
cagaaaccag ggaaagcccc taagagatgg atttatgact catccaaact ggcttctggg 2160
gtcccatcaa ggttcagcgg cagtggatct gggacagatt atactctcac catcagcagc 2220
ctgcagcctg atgattttgc aacttattac tgccaacagt ggagtcgtaa cccacccact 2280
ttcggcggag ggaccaaggt ggagatcaaa cggtcctcca gctaa 2325
<210> 82
<211> 754
<212> PRT
<213> 人工序列
<220>
<223> 抗CD37 X TSC456抗CD3双特异性分子
<400> 82
Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Glu
1 5 10 15
Ser Leu Lys Ile Ser Cys Lys Gly Ser Gly Tyr Ser Phe Thr Gly Tyr
20 25 30
Asn Met Asn Trp Val Arg Gln Met Pro Gly Lys Gly Leu Glu Trp Met
35 40 45
Gly Asn Ile Asp Pro Tyr Tyr Gly Gly Thr Thr Tyr Asn Arg Lys Phe
50 55 60
Lys Gly Gln Val Thr Ile Ser Ala Asp Lys Ser Ile Ser Thr Ala Tyr
65 70 75 80
Leu Gln Trp Ser Ser Leu Lys Ala Ser Asp Thr Ala Met Tyr Tyr Cys
85 90 95
Ala Arg Ser Val Gly Pro Phe Asp Ser Trp Gly Gln Gly Thr Leu Val
100 105 110
Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
115 120 125
Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Ile Val
130 135 140
Leu Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly Glu Arg Ala
145 150 155 160
Thr Leu Ser Cys Arg Ala Ser Glu Asn Val Tyr Ser Tyr Leu Ala Trp
165 170 175
Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile Tyr Phe Ala
180 185 190
Lys Thr Leu Ala Glu Gly Ile Pro Ala Arg Phe Ser Gly Ser Gly Ser
195 200 205
Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Glu Pro Glu Asp Phe
210 215 220
Ala Val Tyr Tyr Cys Gln His His Ser Asp Asn Pro Trp Thr Phe Gly
225 230 235 240
Gln Gly Thr Lys Val Glu Ile Lys Ser Ser Ser Glu Pro Lys Ser Ser
245 250 255
Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly
260 265 270
Ala Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
275 280 285
Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His
290 295 300
Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val
305 310 315 320
His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr
325 330 335
Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly
340 345 350
Lys Ala Tyr Ala Cys Ala Val Ser Asn Lys Ala Leu Pro Ala Pro Ile
355 360 365
Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val
370 375 380
Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser
385 390 395 400
Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu
405 410 415
Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro
420 425 430
Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val
435 440 445
Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met
450 455 460
His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser
465 470 475 480
Pro Gly Gln Arg His Asn Asn Ser Ser Leu Asn Thr Gly Thr Gln Met
485 490 495
Ala Gly His Ser Pro Asn Ser Gln Val Gln Leu Val Gln Ser Gly Pro
500 505 510
Glu Val Lys Lys Pro Gly Ser Ser Val Lys Val Ser Cys Lys Ala Ser
515 520 525
Gly Tyr Thr Phe Ser Arg Ser Thr Met His Trp Val Arg Gln Ala Pro
530 535 540
Gly Gln Gly Leu Glu Trp Ile Gly Tyr Ile Asn Pro Ser Ser Ala Tyr
545 550 555 560
Thr Asn Tyr Asn Gln Lys Phe Lys Asp Arg Val Thr Ile Thr Ala Asp
565 570 575
Lys Ser Thr Ser Thr Ala Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu
580 585 590
Asp Thr Ala Val Tyr Tyr Cys Ala Arg Pro Gln Val His Tyr Asp Tyr
595 600 605
Asn Gly Phe Pro Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
610 615 620
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly
625 630 635 640
Gly Gly Gly Ser Asp Ile Gln Met Thr Gln Ser Pro Ser Thr Leu Ser
645 650 655
Ala Ser Val Gly Asp Arg Val Thr Met Thr Cys Ser Ala Ser Ser Ser
660 665 670
Val Ser Tyr Met Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys
675 680 685
Arg Trp Ile Tyr Asp Ser Ser Lys Leu Ala Ser Gly Val Pro Ser Arg
690 695 700
Phe Ser Gly Ser Gly Ser Gly Thr Asp Tyr Thr Leu Thr Ile Ser Ser
705 710 715 720
Leu Gln Pro Asp Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Trp Ser Arg
725 730 735
Asn Pro Pro Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg Ser
740 745 750
Ser Ser
<210> 83
<211> 251
<212> PRT
<213> 人工序列
<220>
<223> TSC455 CD3 scFv CD3结合结构域
<400> 83
Gln Val Gln Leu Val Gln Ser Gly Pro Glu Val Lys Lys Pro Gly Ser
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Ser Arg Ser
20 25 30
Thr Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Tyr Ile Asn Pro Ser Ser Ala Tyr Thr Asn Tyr Asn Gln Lys Phe
50 55 60
Lys Asp Arg Val Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Pro Gln Val His Tyr Asp Tyr Asn Gly Phe Pro Tyr Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly
115 120 125
Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Gln
130 135 140
Met Thr Gln Ser Pro Ser Thr Leu Ser Ala Ser Val Gly Asp Arg Val
145 150 155 160
Thr Met Thr Cys Ser Ala Ser Ser Ser Val Ser Tyr Met Asn Trp Tyr
165 170 175
Gln Gln Lys Pro Gly Lys Ala Pro Lys Arg Trp Ile Tyr Asp Ser Ser
180 185 190
Lys Leu Ala Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly
195 200 205
Thr Glu Tyr Thr Leu Thr Ile Ser Ser Leu Gln Pro Asp Asp Phe Ala
210 215 220
Thr Tyr Tyr Cys Gln Gln Trp Ser Arg Asn Pro Pro Thr Phe Gly Gly
225 230 235 240
Gly Thr Lys Val Glu Ile Lys Arg Ser Ser Ser
245 250
<210> 84
<211> 251
<212> PRT
<213> 人工序列
<220>
<223> TSC456 CD3 scFv CD3结合结构域
<400> 84
Gln Val Gln Leu Val Gln Ser Gly Pro Glu Val Lys Lys Pro Gly Ser
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Ser Arg Ser
20 25 30
Thr Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Tyr Ile Asn Pro Ser Ser Ala Tyr Thr Asn Tyr Asn Gln Lys Phe
50 55 60
Lys Asp Arg Val Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Pro Gln Val His Tyr Asp Tyr Asn Gly Phe Pro Tyr Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly
115 120 125
Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Gln
130 135 140
Met Thr Gln Ser Pro Ser Thr Leu Ser Ala Ser Val Gly Asp Arg Val
145 150 155 160
Thr Met Thr Cys Ser Ala Ser Ser Ser Val Ser Tyr Met Asn Trp Tyr
165 170 175
Gln Gln Lys Pro Gly Lys Ala Pro Lys Arg Trp Ile Tyr Asp Ser Ser
180 185 190
Lys Leu Ala Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly
195 200 205
Thr Asp Tyr Thr Leu Thr Ile Ser Ser Leu Gln Pro Asp Asp Phe Ala
210 215 220
Thr Tyr Tyr Cys Gln Gln Trp Ser Arg Asn Pro Pro Thr Phe Gly Gly
225 230 235 240
Gly Thr Lys Val Glu Ile Lys Arg Ser Ser Ser
245 250
<210> 85
<211> 247
<212> PRT
<213> 人工序列
<220>
<223> DRA222 CD3 scFv CD3结合结构域
<400> 85
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg
1 5 10 15
Ser Leu Arg Leu Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Arg Ser
20 25 30
Thr Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Tyr Ile Asn Pro Ser Ser Ala Tyr Thr Asn Tyr Asn Gln Lys Phe
50 55 60
Lys Asp Arg Phe Thr Ile Ser Ala Asp Lys Ser Lys Ser Thr Ala Phe
65 70 75 80
Leu Gln Met Asp Ser Leu Arg Pro Glu Asp Thr Gly Val Tyr Phe Cys
85 90 95
Ala Arg Pro Gln Val His Tyr Asp Tyr Asn Gly Phe Pro Tyr Trp Gly
100 105 110
Gln Gly Thr Pro Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly
115 120 125
Gly Gly Ser Gly Gly Gly Gly Ser Ala Gln Asp Ile Gln Met Thr Gln
130 135 140
Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Met Thr
145 150 155 160
Cys Ser Ala Ser Ser Ser Val Ser Tyr Met Asn Trp Tyr Gln Gln Lys
165 170 175
Pro Gly Lys Ala Pro Lys Arg Trp Ile Tyr Asp Ser Ser Lys Leu Ala
180 185 190
Ser Gly Val Pro Ala Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Tyr
195 200 205
Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr
210 215 220
Cys Gln Gln Trp Ser Arg Asn Pro Pro Thr Phe Gly Gly Gly Thr Lys
225 230 235 240
Leu Gln Ile Thr Ser Ser Ser
245
<210> 86
<211> 121
<212> PRT
<213> 人工序列
<220>
<223> TSC455和TSC456可变重链结构域CD3结合结构域
<400> 86
Gln Val Gln Leu Val Gln Ser Gly Pro Glu Val Lys Lys Pro Gly Ser
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Ser Arg Ser
20 25 30
Thr Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Tyr Ile Asn Pro Ser Ser Ala Tyr Thr Asn Tyr Asn Gln Lys Phe
50 55 60
Lys Asp Arg Val Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Pro Gln Val His Tyr Asp Tyr Asn Gly Phe Pro Tyr Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 87
<211> 121
<212> PRT
<213> 人工序列
<220>
<223> DRA222可变重链结构域CD3结合结构域
<400> 87
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg
1 5 10 15
Ser Leu Arg Leu Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Arg Ser
20 25 30
Thr Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Tyr Ile Asn Pro Ser Ser Ala Tyr Thr Asn Tyr Asn Gln Lys Phe
50 55 60
Lys Asp Arg Phe Thr Ile Ser Ala Asp Lys Ser Lys Ser Thr Ala Phe
65 70 75 80
Leu Gln Met Asp Ser Leu Arg Pro Glu Asp Thr Gly Val Tyr Phe Cys
85 90 95
Ala Arg Pro Gln Val His Tyr Asp Tyr Asn Gly Phe Pro Tyr Trp Gly
100 105 110
Gln Gly Thr Pro Val Thr Val Ser Ser
115 120
<210> 88
<211> 108
<212> PRT
<213> 人工序列
<220>
<223> TSC455可变轻链结构域CD3结合结构域
<400> 88
Asp Ile Gln Met Thr Gln Ser Pro Ser Thr Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Met Thr Cys Ser Ala Ser Ser Ser Val Ser Tyr Met
20 25 30
Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Arg Trp Ile Tyr
35 40 45
Asp Ser Ser Lys Leu Ala Ser Gly Val Pro Ser Arg Phe Ser Gly Ser
50 55 60
Gly Ser Gly Thr Glu Tyr Thr Leu Thr Ile Ser Ser Leu Gln Pro Asp
65 70 75 80
Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Trp Ser Arg Asn Pro Pro Thr
85 90 95
Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg Ser
100 105
<210> 89
<211> 108
<212> PRT
<213> 人工序列
<220>
<223> TSC456可变轻链结构域CD3结合结构域
<400> 89
Asp Ile Gln Met Thr Gln Ser Pro Ser Thr Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Met Thr Cys Ser Ala Ser Ser Ser Val Ser Tyr Met
20 25 30
Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Arg Trp Ile Tyr
35 40 45
Asp Ser Ser Lys Leu Ala Ser Gly Val Pro Ser Arg Phe Ser Gly Ser
50 55 60
Gly Ser Gly Thr Asp Tyr Thr Leu Thr Ile Ser Ser Leu Gln Pro Asp
65 70 75 80
Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Trp Ser Arg Asn Pro Pro Thr
85 90 95
Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg Ser
100 105
<210> 90
<211> 107
<212> PRT
<213> 人工序列
<220>
<223> DRA222可变轻链结构域CD3结合结构域
<400> 90
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Met Thr Cys Ser Ala Ser Ser Ser Val Ser Tyr Met
20 25 30
Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Arg Trp Ile Tyr
35 40 45
Asp Ser Ser Lys Leu Ala Ser Gly Val Pro Ala Arg Phe Ser Gly Ser
50 55 60
Gly Ser Gly Thr Asp Tyr Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu
65 70 75 80
Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Trp Ser Arg Asn Pro Pro Thr
85 90 95
Phe Gly Gly Gly Thr Lys Leu Gln Ile Thr Ser
100 105
<210> 91
<211> 5
<212> PRT
<213> 人工序列
<220>
<223> Cris7和DRA222 VH CDR1 (Kabat) CD3结合结构域
<400> 91
Arg Ser Thr Met His
1 5
<210> 92
<211> 16
<212> PRT
<213> 人工序列
<220>
<223> Cris7和DRA222 VH CDR2 (Kabat) CD3结合结构域
<400> 92
Tyr Ile Asn Pro Ser Ser Ala Tyr Thr Asn Tyr Asn Gln Lys Phe Lys
1 5 10 15
<210> 93
<211> 11
<212> PRT
<213> 人工序列
<220>
<223> Cris7和DRA222 VH CDR3 (Kabat) CD3结合结构域
<400> 93
Gln Val His Tyr Asp Tyr Asn Gly Phe Pro Tyr
1 5 10
<210> 94
<211> 10
<212> PRT
<213> 人工序列
<220>
<223> Cris7和DRA222 VL CDR1 (Kabat) CD3结合结构域
<400> 94
Ser Ala Ser Ser Ser Val Ser Tyr Met Asn
1 5 10
<210> 95
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> Cris7和DRA222 VL CDR2 (Kabat) CD3结合结构域
<400> 95
Asp Ser Ser Lys Leu Ala Ser
1 5
<210> 96
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> Cris7和DRA222 VL CDR3 (Kabat) CD3结合结构域
<400> 96
Gln Gln Trp Ser Arg Asn Pro Pro Thr
1 5
<210> 97
<211> 2304
<212> DNA
<213> 人工序列
<220>
<223> ROR133 抗ROR1 X 抗CD3双特异性分子
<400> 97
atggaagcac cagcgcagct tctcttcctc ctgctactct ggctcccaga taccaccggt 60
gacatccaga tgacccagtc cccctcctcc ctgtccgcct ccgtgggcga ccgggtgacc 120
atcaactgcc aggcctccca gtccatcgac tccaacctgg cctggttcca gcagaagccc 180
ggcaagcccc ccaagctgct gatctaccgg gcctccaacc tggcctccgg cgtgccctcc 240
cggttctccg gctccggctc cggcaccgac ttcaccctga ccatctcctc cctgcagccc 300
gaggacgtgg ccacctacta ctgcctgggc ggcgtgggcg ccgtgtccta ccggacctcc 360
ttcggcggcg gcaccaaggt ggagatcaag ggtggaggcg gttcaggcgg aggtggatcc 420
ggcggtggcg gctccggtgg cggcggatct gaggtgcagc tggtggagtc cggcggcggc 480
ctggtgcagc ccggccggtc cctgcggctg tcctgcaccg cctccggctc cgacatcaac 540
gactacccca tctcctgggt gcggcaggcc cccggcaagg gcctggagtg gatcggcttc 600
atcaactccg gcggctccac ctggtacgcc tcctgggtga agggccggtt caccatctcc 660
cgggacgact ccaagtccat cgcctacctg cagatgaact ccctgaagac cgaggacacc 720
gccgtgtact attgcgcccg gggctactcc acctactacg gcgacttcaa catctggggc 780
cagggcaccc tggtgaccgt gtcctcgagt gagcccaaat cttctgacaa aactcacaca 840
tgcccaccgt gcccagcacc tgaagccgcg ggtgcaccgt cagtcttcct cttcccccca 900
aaacccaagg acaccctcat gatctcccgg acccctgagg tcacatgcgt ggtggtggac 960
gtgagccacg aagaccctga ggtcaagttc aactggtacg tggacggcgt ggaggtgcat 1020
aatgccaaga caaagccgcg ggaggagcag tacaacagca cgtaccgtgt ggtcagcgtc 1080
ctcaccgtcc tgcaccagga ctggctgaat ggcaaggaat acaagtgcgc ggtctccaac 1140
aaagccctcc cagcccccat cgagaaaacc atctccaaag ccaaagggca gccccgagaa 1200
ccacaggtgt acaccctgcc cccatcccgg gatgagctga ccaagaacca ggtcagcctg 1260
acctgcctgg tcaaaggctt ctatccaagc gacatcgccg tggagtggga gagcaatggg 1320
cagccggaga acaactacaa gaccacgcct cccgtgctgg actccgacgg ctccttcttc 1380
ctctacagca agctcaccgt ggacaagagc aggtggcagc aggggaacgt cttctcatgc 1440
tccgtgatgc atgaggctct gcacaaccac tacacgcaga agagcctctc cctgtctccg 1500
ggttctggtg gaggcggttc aggcggaggt ggctccggcg gtggcggatc gccgggctct 1560
caggtccagc tggtggagtc tgggggcgga gtggtgcagc ctgggcggtc actgaggctg 1620
tcctgcaagg cttctggcta cacctttact agatctacga tgcactgggt aaggcaggcc 1680
cctggacaag gtctggaatg gattggatac attaatccta gcagtgctta tactaattac 1740
aatcagaaat tcaaggacag gttcacaatc agcgcagaca aatccaagag cacagccttc 1800
ctgcagatgg acagcctgag gcccgaggac accggcgtct atttctgtgc acggccccaa 1860
gtccactatg attacaacgg gtttccttac tggggccaag ggactcccgt cactgtctct 1920
agcggtggcg gagggtctgg gggtggcgga tccggaggtg gtggctctgc acaagacatc 1980
cagatgaccc agtctccaag cagcctgtct gcaagcgtgg gggacagggt caccatgacc 2040
tgcagtgcca gctcaagtgt aagttacatg aactggtacc agcagaagcc gggcaaggcc 2100
cccaaaagat ggatttatga ctcatccaaa ctggcttctg gagtccctgc tcgcttcagt 2160
ggcagtgggt ctgggaccga ctataccctc acaatcagca gcctgcagcc cgaagatttc 2220
gccacttatt actgccagca gtggagtcgt aacccaccca cgttcggagg ggggaccaag 2280
ctacaaatta catcctccag ctaa 2304
<210> 98
<211> 747
<212> PRT
<213> 人工序列
<220>
<223> ROR133 抗ROR1 X 抗CD3双特异性分子
<400> 98
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Asn Cys Gln Ala Ser Gln Ser Ile Asp Ser Asn
20 25 30
Leu Ala Trp Phe Gln Gln Lys Pro Gly Lys Pro Pro Lys Leu Leu Ile
35 40 45
Tyr Arg Ala Ser Asn Leu Ala Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Val Ala Thr Tyr Tyr Cys Leu Gly Gly Val Gly Ala Val Ser
85 90 95
Tyr Arg Thr Ser Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Gly Gly
100 105 110
Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly
115 120 125
Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro
130 135 140
Gly Arg Ser Leu Arg Leu Ser Cys Thr Ala Ser Gly Ser Asp Ile Asn
145 150 155 160
Asp Tyr Pro Ile Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu
165 170 175
Trp Ile Gly Phe Ile Asn Ser Gly Gly Ser Thr Trp Tyr Ala Ser Trp
180 185 190
Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Ser Ile Ala
195 200 205
Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu Asp Thr Ala Val Tyr Tyr
210 215 220
Cys Ala Arg Gly Tyr Ser Thr Tyr Tyr Gly Asp Phe Asn Ile Trp Gly
225 230 235 240
Gln Gly Thr Leu Val Thr Val Ser Ser Ser Glu Pro Lys Ser Ser Asp
245 250 255
Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Ala
260 265 270
Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile
275 280 285
Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu
290 295 300
Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His
305 310 315 320
Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg
325 330 335
Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys
340 345 350
Glu Tyr Lys Cys Ala Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu
355 360 365
Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr
370 375 380
Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu
385 390 395 400
Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp
405 410 415
Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val
420 425 430
Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp
435 440 445
Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His
450 455 460
Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro
465 470 475 480
Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
485 490 495
Ser Pro Gly Ser Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val
500 505 510
Gln Pro Gly Arg Ser Leu Arg Leu Ser Cys Lys Ala Ser Gly Tyr Thr
515 520 525
Phe Thr Arg Ser Thr Met His Trp Val Arg Gln Ala Pro Gly Gln Gly
530 535 540
Leu Glu Trp Ile Gly Tyr Ile Asn Pro Ser Ser Ala Tyr Thr Asn Tyr
545 550 555 560
Asn Gln Lys Phe Lys Asp Arg Phe Thr Ile Ser Ala Asp Lys Ser Lys
565 570 575
Ser Thr Ala Phe Leu Gln Met Asp Ser Leu Arg Pro Glu Asp Thr Gly
580 585 590
Val Tyr Phe Cys Ala Arg Pro Gln Val His Tyr Asp Tyr Asn Gly Phe
595 600 605
Pro Tyr Trp Gly Gln Gly Thr Pro Val Thr Val Ser Ser Gly Gly Gly
610 615 620
Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Ala Gln Asp Ile
625 630 635 640
Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg
645 650 655
Val Thr Met Thr Cys Ser Ala Ser Ser Ser Val Ser Tyr Met Asn Trp
660 665 670
Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Arg Trp Ile Tyr Asp Ser
675 680 685
Ser Lys Leu Ala Ser Gly Val Pro Ala Arg Phe Ser Gly Ser Gly Ser
690 695 700
Gly Thr Asp Tyr Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe
705 710 715 720
Ala Thr Tyr Tyr Cys Gln Gln Trp Ser Arg Asn Pro Pro Thr Phe Gly
725 730 735
Gly Gly Thr Lys Leu Gln Ile Thr Ser Ser Ser
740 745
<210> 99
<211> 2316
<212> DNA
<213> 人工序列
<220>
<223> ROR193 抗ROR1 X 抗CD3双特异性分子
<400> 99
atggaagcac cagcgcagct tctcttcctc ctgctactct ggctcccaga taccaccggt 60
gacatccaga tgacccagtc cccctcctcc ctgtccgcct ccgtgggcga ccgggtgacc 120
atcaactgcc aggcctccca gtccatcgac tccaacctgg cctggttcca gcagaagccc 180
ggcaagcccc ccaagctgct gatctaccgg gcctccaacc tggcctccgg cgtgccctcc 240
cggttctccg gctccggctc cggcaccgac ttcaccctga ccatctcctc cctgcagccc 300
gaggacgtgg ccacctacta ctgcctgggc ggcgtgggcg ccgtgtccta ccggacctcc 360
ttcggcggcg gcaccaaggt ggagatcaag ggtggaggcg gttcaggcgg aggtggatcc 420
ggcggtggcg gctccggtgg cggcggatct gaggtgcagc tggtggagtc cggcggcggc 480
ctggtgcagc ccggccggtc cctgcggctg tcctgcaccg cctccggctc cgacatcaac 540
gactacccca tctcctgggt gcggcaggcc cccggcaagg gcctggagtg gatcggcttc 600
atcaactccg gcggctccac ctggtacgcc tcctgggtga agggccggtt caccatctcc 660
cgggacgact ccaagtccat cgcctacctg cagatgaact ccctgaagac cgaggacacc 720
gccgtgtact attgcgcccg gggctactcc acctactacg gcgacttcaa catctggggc 780
cagggcaccc tggtgaccgt gtcctcgagt gagcccaaat cttctgacaa aactcacaca 840
tgcccaccgt gcccagcacc tgaagccgcg ggtgcaccgt cagtcttcct cttcccccca 900
aaacccaagg acaccctcat gatctcccgg acccctgagg tcacatgcgt ggtggtggac 960
gtgagccacg aagaccctga ggtcaagttc aactggtacg tggacggcgt ggaggtgcat 1020
aatgccaaga caaagccgcg ggaggagcag tacaacagca cgtaccgtgt ggtcagcgtc 1080
ctcaccgtcc tgcaccagga ctggctgaat ggcaaggaat acaagtgcgc ggtctccaac 1140
aaagccctcc cagcccccat cgagaaaacc atctccaaag ccaaagggca gccccgagaa 1200
ccacaggtgt acaccctgcc cccatcccgg gatgagctga ccaagaacca ggtcagcctg 1260
acctgcctgg tcaaaggctt ctatccaagc gacatcgccg tggagtggga gagcaatggg 1320
cagccggaga acaactacaa gaccacgcct cccgtgctgg actccgacgg ctccttcttc 1380
ctctacagca agctcaccgt ggacaagagc aggtggcagc aggggaacgt cttctcatgc 1440
tccgtgatgc atgaggctct gcacaaccac tacacgcaga agagcctctc cctgtctccg 1500
ggttctggtg gaggcggttc aggcggaggt ggctccggcg gtggcggatc gccgggctct 1560
caggtccagc tggtgcaatc tgggcctgag gtgaagaagc ctgggtcctc ggtgaaggtc 1620
tcctgcaagg cttctggata taccttcagc agatctacga tgcactgggt gcgacaggcc 1680
cctggacaag ggcttgagtg gataggatac attaatccta gcagtgctta tactaattac 1740
aatcagaaat tcaaggacag agtcacgatt accgcggaca aatccacgag cacagcctac 1800
atggagctga gcagcctgag atctgaggac acggccgtgt attactgtgc gagaccccaa 1860
gtccactatg attacaacgg gtttccttac tggggccaag gaaccctggt caccgtctcc 1920
tcaggtggag gcggttcagg cggaggtgga tccggcggtg gcggatcggg tggcggcgga 1980
tctgacatcc agatgaccca gtctccttcc accctgtctg catctgtagg agacagagtc 2040
accatgactt gcagtgccag ctcaagtgta agttacatga actggtatca gcagaaacca 2100
gggaaagccc ctaagagatg gatttatgac tcatccaaac tggcttctgg ggtcccatca 2160
aggttcagcg gcagtggatc tgggacagag tatactctca ccatcagcag cctgcagcct 2220
gatgattttg caacttatta ctgccaacag tggagtcgta acccacccac tttcggcgga 2280
gggaccaagg tggagatcaa acggtcctcc agctaa 2316
<210> 100
<211> 751
<212> PRT
<213> 人工序列
<220>
<223> ROR193 抗ROR1 X 抗CD3双特异性分子
<400> 100
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Asn Cys Gln Ala Ser Gln Ser Ile Asp Ser Asn
20 25 30
Leu Ala Trp Phe Gln Gln Lys Pro Gly Lys Pro Pro Lys Leu Leu Ile
35 40 45
Tyr Arg Ala Ser Asn Leu Ala Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Val Ala Thr Tyr Tyr Cys Leu Gly Gly Val Gly Ala Val Ser
85 90 95
Tyr Arg Thr Ser Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Gly Gly
100 105 110
Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly
115 120 125
Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro
130 135 140
Gly Arg Ser Leu Arg Leu Ser Cys Thr Ala Ser Gly Ser Asp Ile Asn
145 150 155 160
Asp Tyr Pro Ile Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu
165 170 175
Trp Ile Gly Phe Ile Asn Ser Gly Gly Ser Thr Trp Tyr Ala Ser Trp
180 185 190
Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Ser Ile Ala
195 200 205
Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu Asp Thr Ala Val Tyr Tyr
210 215 220
Cys Ala Arg Gly Tyr Ser Thr Tyr Tyr Gly Asp Phe Asn Ile Trp Gly
225 230 235 240
Gln Gly Thr Leu Val Thr Val Ser Ser Ser Glu Pro Lys Ser Ser Asp
245 250 255
Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Ala
260 265 270
Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile
275 280 285
Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu
290 295 300
Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His
305 310 315 320
Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg
325 330 335
Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys
340 345 350
Glu Tyr Lys Cys Ala Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu
355 360 365
Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr
370 375 380
Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu
385 390 395 400
Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp
405 410 415
Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val
420 425 430
Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp
435 440 445
Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His
450 455 460
Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro
465 470 475 480
Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
485 490 495
Ser Pro Gly Ser Gln Val Gln Leu Val Gln Ser Gly Pro Glu Val Lys
500 505 510
Lys Pro Gly Ser Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr
515 520 525
Phe Ser Arg Ser Thr Met His Trp Val Arg Gln Ala Pro Gly Gln Gly
530 535 540
Leu Glu Trp Ile Gly Tyr Ile Asn Pro Ser Ser Ala Tyr Thr Asn Tyr
545 550 555 560
Asn Gln Lys Phe Lys Asp Arg Val Thr Ile Thr Ala Asp Lys Ser Thr
565 570 575
Ser Thr Ala Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala
580 585 590
Val Tyr Tyr Cys Ala Arg Pro Gln Val His Tyr Asp Tyr Asn Gly Phe
595 600 605
Pro Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly
610 615 620
Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
625 630 635 640
Ser Asp Ile Gln Met Thr Gln Ser Pro Ser Thr Leu Ser Ala Ser Val
645 650 655
Gly Asp Arg Val Thr Met Thr Cys Ser Ala Ser Ser Ser Val Ser Tyr
660 665 670
Met Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Arg Trp Ile
675 680 685
Tyr Asp Ser Ser Lys Leu Ala Ser Gly Val Pro Ser Arg Phe Ser Gly
690 695 700
Ser Gly Ser Gly Thr Glu Tyr Thr Leu Thr Ile Ser Ser Leu Gln Pro
705 710 715 720
Asp Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Trp Ser Arg Asn Pro Pro
725 730 735
Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg Ser Ser Ser
740 745 750
<210> 101
<211> 2304
<212> DNA
<213> 人工序列
<220>
<223> ROR134 抗ROR1 X 抗CD3双特异性分子
<400> 101
atggaagcac cagcgcagct tctcttcctc ctgctactct ggctcccaga taccaccggt 60
gacatccaga tgacccagtc cccctcctcc ctgtccgcct ccgtgggcga ccgggtgacc 120
atcaactgcc aggcctccca gtccatcgac tccaacctgg cctggttcca gcagaagccc 180
ggcaagcccc ccaagctgct gatctaccgg gcctccaacc tggcctccgg cgtgccctcc 240
cggttctccg gctccggctc cggcaccgac ttcaccctga ccatctcctc cctgcagccc 300
gaggacgtgg ccacctacta ctgcctgggc ggcgtgggcg ccgtgtccta ccggacctcc 360
ttcggcggcg gcaccaaggt ggagatcaag ggtggaggcg gttcaggcgg aggtggatcc 420
ggcggtggcg gctccggtgg cggcggatct gaggtgcagc tggtggagtc cggcggcggc 480
ctggtgcagc ccggcggctc cctgcggctg tcctgcaccg cctccggctc cgacatcaac 540
gactacccca tctcctgggt gcggcaggcc cccggcaagg gcctggagtg gatcggcttc 600
atcaactccg gcggctccac ctggtacgcc gactcggtga agggccggtt caccatctcc 660
cggcactcct ccaagaacac cctgtacctg cagatgaact ccctgcgggc cgaggacacc 720
gccgtgtact tctgcgcccg gggctactcc acctactacg gcgacttcaa catctggggc 780
cagggcaccc tggtgaccgt gtcctcgagt gagcccaaat cttctgacaa aactcacaca 840
tgcccaccgt gcccagcacc tgaagccgcg ggtgcaccgt cagtcttcct cttcccccca 900
aaacccaagg acaccctcat gatctcccgg acccctgagg tcacatgcgt ggtggtggac 960
gtgagccacg aagaccctga ggtcaagttc aactggtacg tggacggcgt ggaggtgcat 1020
aatgccaaga caaagccgcg ggaggagcag tacaacagca cgtaccgtgt ggtcagcgtc 1080
ctcaccgtcc tgcaccagga ctggctgaat ggcaaggaat acaagtgcgc ggtctccaac 1140
aaagccctcc cagcccccat cgagaaaacc atctccaaag ccaaagggca gccccgagaa 1200
ccacaggtgt acaccctgcc cccatcccgg gatgagctga ccaagaacca ggtcagcctg 1260
acctgcctgg tcaaaggctt ctatccaagc gacatcgccg tggagtggga gagcaatggg 1320
cagccggaga acaactacaa gaccacgcct cccgtgctgg actccgacgg ctccttcttc 1380
ctctacagca agctcaccgt ggacaagagc aggtggcagc aggggaacgt cttctcatgc 1440
tccgtgatgc atgaggctct gcacaaccac tacacgcaga agagcctctc cctgtctccg 1500
ggttctggtg gaggcggttc aggcggaggt ggctccggcg gtggcggatc gccgggctct 1560
caggtccagc tggtggagtc tgggggcgga gtggtgcagc ctgggcggtc actgaggctg 1620
tcctgcaagg cttctggcta cacctttact agatctacga tgcactgggt aaggcaggcc 1680
cctggacaag gtctggaatg gattggatac attaatccta gcagtgctta tactaattac 1740
aatcagaaat tcaaggacag gttcacaatc agcgcagaca aatccaagag cacagccttc 1800
ctgcagatgg acagcctgag gcccgaggac accggcgtct atttctgtgc acggccccaa 1860
gtccactatg attacaacgg gtttccttac tggggccaag ggactcccgt cactgtctct 1920
agcggtggcg gagggtctgg gggtggcgga tccggaggtg gtggctctgc acaagacatc 1980
cagatgaccc agtctccaag cagcctgtct gcaagcgtgg gggacagggt caccatgacc 2040
tgcagtgcca gctcaagtgt aagttacatg aactggtacc agcagaagcc gggcaaggcc 2100
cccaaaagat ggatttatga ctcatccaaa ctggcttctg gagtccctgc tcgcttcagt 2160
ggcagtgggt ctgggaccga ctataccctc acaatcagca gcctgcagcc cgaagatttc 2220
gccacttatt actgccagca gtggagtcgt aacccaccca cgttcggagg ggggaccaag 2280
ctacaaatta catcctccag ctaa 2304
<210> 102
<211> 747
<212> PRT
<213> 人工序列
<220>
<223> ROR134 抗ROR1 X 抗CD3双特异性分子
<400> 102
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Asn Cys Gln Ala Ser Gln Ser Ile Asp Ser Asn
20 25 30
Leu Ala Trp Phe Gln Gln Lys Pro Gly Lys Pro Pro Lys Leu Leu Ile
35 40 45
Tyr Arg Ala Ser Asn Leu Ala Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Val Ala Thr Tyr Tyr Cys Leu Gly Gly Val Gly Ala Val Ser
85 90 95
Tyr Arg Thr Ser Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Gly Gly
100 105 110
Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly
115 120 125
Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro
130 135 140
Gly Gly Ser Leu Arg Leu Ser Cys Thr Ala Ser Gly Ser Asp Ile Asn
145 150 155 160
Asp Tyr Pro Ile Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu
165 170 175
Trp Ile Gly Phe Ile Asn Ser Gly Gly Ser Thr Trp Tyr Ala Asp Ser
180 185 190
Val Lys Gly Arg Phe Thr Ile Ser Arg His Ser Ser Lys Asn Thr Leu
195 200 205
Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Phe
210 215 220
Cys Ala Arg Gly Tyr Ser Thr Tyr Tyr Gly Asp Phe Asn Ile Trp Gly
225 230 235 240
Gln Gly Thr Leu Val Thr Val Ser Ser Ser Glu Pro Lys Ser Ser Asp
245 250 255
Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Ala
260 265 270
Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile
275 280 285
Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu
290 295 300
Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His
305 310 315 320
Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg
325 330 335
Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys
340 345 350
Glu Tyr Lys Cys Ala Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu
355 360 365
Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr
370 375 380
Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu
385 390 395 400
Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp
405 410 415
Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val
420 425 430
Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp
435 440 445
Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His
450 455 460
Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro
465 470 475 480
Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
485 490 495
Ser Pro Gly Ser Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val
500 505 510
Gln Pro Gly Arg Ser Leu Arg Leu Ser Cys Lys Ala Ser Gly Tyr Thr
515 520 525
Phe Thr Arg Ser Thr Met His Trp Val Arg Gln Ala Pro Gly Gln Gly
530 535 540
Leu Glu Trp Ile Gly Tyr Ile Asn Pro Ser Ser Ala Tyr Thr Asn Tyr
545 550 555 560
Asn Gln Lys Phe Lys Asp Arg Phe Thr Ile Ser Ala Asp Lys Ser Lys
565 570 575
Ser Thr Ala Phe Leu Gln Met Asp Ser Leu Arg Pro Glu Asp Thr Gly
580 585 590
Val Tyr Phe Cys Ala Arg Pro Gln Val His Tyr Asp Tyr Asn Gly Phe
595 600 605
Pro Tyr Trp Gly Gln Gly Thr Pro Val Thr Val Ser Ser Gly Gly Gly
610 615 620
Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Ala Gln Asp Ile
625 630 635 640
Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg
645 650 655
Val Thr Met Thr Cys Ser Ala Ser Ser Ser Val Ser Tyr Met Asn Trp
660 665 670
Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Arg Trp Ile Tyr Asp Ser
675 680 685
Ser Lys Leu Ala Ser Gly Val Pro Ala Arg Phe Ser Gly Ser Gly Ser
690 695 700
Gly Thr Asp Tyr Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe
705 710 715 720
Ala Thr Tyr Tyr Cys Gln Gln Trp Ser Arg Asn Pro Pro Thr Phe Gly
725 730 735
Gly Gly Thr Lys Leu Gln Ile Thr Ser Ser Ser
740 745
<210> 103
<211> 2316
<212> DNA
<213> 人工序列
<220>
<223> ROR189 抗ROR1 X 抗CD3双特异性分子
<400> 103
atggaagcac cagcgcagct tctcttcctc ctgctactct ggctcccaga taccaccggt 60
gacatccaga tgacccagtc cccctcctcc ctgtccgcct ccgtgggcga ccgggtgacc 120
atcaactgcc aggcctccca gtccatcgac tccaacctgg cctggttcca gcagaagccc 180
ggcaagcccc ccaagctgct gatctaccgg gcctccaacc tggcctccgg cgtgccctcc 240
cggttctccg gctccggctc cggcaccgac ttcaccctga ccatctcctc cctgcagccc 300
gaggacgtgg ccacctacta ctgcctgggc ggcgtgggcg ccgtgtccta ccggacctcc 360
ttcggcggcg gcaccaaggt ggagatcaag ggtggaggcg gttcaggcgg aggtggatcc 420
ggcggtggcg gctccggtgg cggcggatct gaggtgcagc tggtggagtc cggcggcggc 480
ctggtgcagc ccggcggctc cctgcggctg tcctgcaccg cctccggctc cgacatcaac 540
gactacccca tctcctgggt gcggcaggcc cccggcaagg gcctggagtg gatcggcttc 600
atcaactccg gcggctccac ctggtacgcc gactcggtga agggccggtt caccatctcc 660
cggcactcct ccaagaacac cctgtacctg cagatgaact ccctgcgggc cgaggacacc 720
gccgtgtact tctgcgcccg gggctactcc acctactacg gcgacttcaa catctggggc 780
cagggcaccc tggtgaccgt gtcctcgagt gagcccaaat cttctgacaa aactcacaca 840
tgcccaccgt gcccagcacc tgaagccgcg ggtgcaccgt cagtcttcct cttcccccca 900
aaacccaagg acaccctcat gatctcccgg acccctgagg tcacatgcgt ggtggtggac 960
gtgagccacg aagaccctga ggtcaagttc aactggtacg tggacggcgt ggaggtgcat 1020
aatgccaaga caaagccgcg ggaggagcag tacaacagca cgtaccgtgt ggtcagcgtc 1080
ctcaccgtcc tgcaccagga ctggctgaat ggcaaggaat acaagtgcgc ggtctccaac 1140
aaagccctcc cagcccccat cgagaaaacc atctccaaag ccaaagggca gccccgagaa 1200
ccacaggtgt acaccctgcc cccatcccgg gatgagctga ccaagaacca ggtcagcctg 1260
acctgcctgg tcaaaggctt ctatccaagc gacatcgccg tggagtggga gagcaatggg 1320
cagccggaga acaactacaa gaccacgcct cccgtgctgg actccgacgg ctccttcttc 1380
ctctacagca agctcaccgt ggacaagagc aggtggcagc aggggaacgt cttctcatgc 1440
tccgtgatgc atgaggctct gcacaaccac tacacgcaga agagcctctc cctgtctccg 1500
ggttctggtg gaggcggttc aggcggaggt ggctccggcg gtggcggatc gccgggctct 1560
caggtccagc tggtgcaatc tgggcctgag gtgaagaagc ctgggtcctc ggtgaaggtc 1620
tcctgcaagg cttctggata taccttcagc agatctacga tgcactgggt gcgacaggcc 1680
cctggacaag ggcttgagtg gataggatac attaatccta gcagtgctta tactaattac 1740
aatcagaaat tcaaggacag agtcacgatt accgcggaca aatccacgag cacagcctac 1800
atggagctga gcagcctgag atctgaggac acggccgtgt attactgtgc gagaccccaa 1860
gtccactatg attacaacgg gtttccttac tggggccaag gaaccctggt caccgtctcc 1920
tcaggtggag gcggttcagg cggaggtgga tccggcggtg gcggatcggg tggcggcgga 1980
tctgacatcc agatgaccca gtctccttcc accctgtctg catctgtagg agacagagtc 2040
accatgactt gcagtgccag ctcaagtgta agttacatga actggtatca gcagaaacca 2100
gggaaagccc ctaagagatg gatttatgac tcatccaaac tggcttctgg ggtcccatca 2160
aggttcagcg gcagtggatc tgggacagat tatactctca ccatcagcag cctgcagcct 2220
gatgattttg caacttatta ctgccaacag tggagtcgta acccacccac tttcggcgga 2280
gggaccaagg tggagatcaa acggtcctcc agctaa 2316
<210> 104
<211> 751
<212> PRT
<213> 人工序列
<220>
<223> ROR189 抗ROR1 X 抗CD3双特异性分子
<400> 104
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Asn Cys Gln Ala Ser Gln Ser Ile Asp Ser Asn
20 25 30
Leu Ala Trp Phe Gln Gln Lys Pro Gly Lys Pro Pro Lys Leu Leu Ile
35 40 45
Tyr Arg Ala Ser Asn Leu Ala Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Val Ala Thr Tyr Tyr Cys Leu Gly Gly Val Gly Ala Val Ser
85 90 95
Tyr Arg Thr Ser Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Gly Gly
100 105 110
Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly
115 120 125
Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro
130 135 140
Gly Gly Ser Leu Arg Leu Ser Cys Thr Ala Ser Gly Ser Asp Ile Asn
145 150 155 160
Asp Tyr Pro Ile Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu
165 170 175
Trp Ile Gly Phe Ile Asn Ser Gly Gly Ser Thr Trp Tyr Ala Asp Ser
180 185 190
Val Lys Gly Arg Phe Thr Ile Ser Arg His Ser Ser Lys Asn Thr Leu
195 200 205
Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Phe
210 215 220
Cys Ala Arg Gly Tyr Ser Thr Tyr Tyr Gly Asp Phe Asn Ile Trp Gly
225 230 235 240
Gln Gly Thr Leu Val Thr Val Ser Ser Ser Glu Pro Lys Ser Ser Asp
245 250 255
Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Ala
260 265 270
Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile
275 280 285
Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu
290 295 300
Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His
305 310 315 320
Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg
325 330 335
Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys
340 345 350
Glu Tyr Lys Cys Ala Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu
355 360 365
Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr
370 375 380
Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu
385 390 395 400
Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp
405 410 415
Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val
420 425 430
Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp
435 440 445
Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His
450 455 460
Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro
465 470 475 480
Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
485 490 495
Ser Pro Gly Ser Gln Val Gln Leu Val Gln Ser Gly Pro Glu Val Lys
500 505 510
Lys Pro Gly Ser Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr
515 520 525
Phe Ser Arg Ser Thr Met His Trp Val Arg Gln Ala Pro Gly Gln Gly
530 535 540
Leu Glu Trp Ile Gly Tyr Ile Asn Pro Ser Ser Ala Tyr Thr Asn Tyr
545 550 555 560
Asn Gln Lys Phe Lys Asp Arg Val Thr Ile Thr Ala Asp Lys Ser Thr
565 570 575
Ser Thr Ala Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala
580 585 590
Val Tyr Tyr Cys Ala Arg Pro Gln Val His Tyr Asp Tyr Asn Gly Phe
595 600 605
Pro Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly
610 615 620
Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
625 630 635 640
Ser Asp Ile Gln Met Thr Gln Ser Pro Ser Thr Leu Ser Ala Ser Val
645 650 655
Gly Asp Arg Val Thr Met Thr Cys Ser Ala Ser Ser Ser Val Ser Tyr
660 665 670
Met Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Arg Trp Ile
675 680 685
Tyr Asp Ser Ser Lys Leu Ala Ser Gly Val Pro Ser Arg Phe Ser Gly
690 695 700
Ser Gly Ser Gly Thr Asp Tyr Thr Leu Thr Ile Ser Ser Leu Gln Pro
705 710 715 720
Asp Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Trp Ser Arg Asn Pro Pro
725 730 735
Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg Ser Ser Ser
740 745 750
<210> 105
<211> 2304
<212> DNA
<213> 人工序列
<220>
<223> ROR154 抗ROR1 X 抗CD3双特异性分子
<400> 105
atggaagcac cagcgcagct tctcttcctc ctgctactct ggctcccaga taccaccggt 60
gacatccaga tgacccagtc cccctcctcc ctgtccgcct ccgtgggcga ccgggtgacc 120
atcaactgcc aggcctccca gtccatcgac tccaacctgg cctggttcca gcagaagccc 180
ggcaagcccc ccaagctgct gatctaccgg gcctccaacc tggcctccgg cgtgccctcc 240
cggttctccg gctccggctc cggcaccgac ttcaccctga ccatctcctc cctgcagccc 300
gaggacgtgg ccacctacta ctgcctgggc ggcgtgggcg ccgtgtccta ccggacctcc 360
ttcggcggcg gcaccaaggt ggagatcaag ggtggaggcg gttcaggcgg aggtggatcc 420
ggcggtggcg gctccggtgg cggcggatct gaggtgcagc tggtggagtc cggcggcggc 480
ctggtgcagc ccggccggtc cctgcggctg tcctgcaccg cctccggctc cgacatcaac 540
gactacccca tcacctgggt gcggcaggcc cccggcaagg gcctggagtg gatcggcttc 600
atcaactccg gcggctccac ctggtacgcc tcctgggtga agggccggtt caccatctcc 660
cgggacgact ccaagtccat cgcctacctg cagatgaact ccctgaagac cgaggacacc 720
gccgtgtact attgcgcccg gggctactcc acctactacc gggacttcaa catctggggc 780
cagggcaccc tggtgaccgt gtcctcgagt gagcccaaat cttctgacaa aactcacaca 840
tgcccaccgt gcccagcacc tgaagccgcg ggtgcaccgt cagtcttcct cttcccccca 900
aaacccaagg acaccctcat gatctcccgg acccctgagg tcacatgcgt ggtggtggac 960
gtgagccacg aagaccctga ggtcaagttc aactggtacg tggacggcgt ggaggtgcat 1020
aatgccaaga caaagccgcg ggaggagcag tacaacagca cgtaccgtgt ggtcagcgtc 1080
ctcaccgtcc tgcaccagga ctggctgaat ggcaaggaat acaagtgcgc ggtctccaac 1140
aaagccctcc cagcccccat cgagaaaacc atctccaaag ccaaagggca gccccgagaa 1200
ccacaggtgt acaccctgcc cccatcccgg gatgagctga ccaagaacca ggtcagcctg 1260
acctgcctgg tcaaaggctt ctatccaagc gacatcgccg tggagtggga gagcaatggg 1320
cagccggaga acaactacaa gaccacgcct cccgtgctgg actccgacgg ctccttcttc 1380
ctctacagca agctcaccgt ggacaagagc aggtggcagc aggggaacgt cttctcatgc 1440
tccgtgatgc atgaggctct gcacaaccac tacacgcaga agagcctctc cctgtctccg 1500
ggttctggtg gaggcggttc aggcggaggt ggctccggcg gtggcggatc gccgggctct 1560
caggtccagc tggtggagtc tgggggcgga gtggtgcagc ctgggcggtc actgaggctg 1620
tcctgcaagg cttctggcta cacctttact agatctacga tgcactgggt aaggcaggcc 1680
cctggacaag gtctggaatg gattggatac attaatccta gcagtgctta tactaattac 1740
aatcagaaat tcaaggacag gttcacaatc agcgcagaca aatccaagag cacagccttc 1800
ctgcagatgg acagcctgag gcccgaggac accggcgtct atttctgtgc acggccccaa 1860
gtccactatg attacaacgg gtttccttac tggggccaag ggactcccgt cactgtctct 1920
agcggtggcg gagggtctgg gggtggcgga tccggaggtg gtggctctgc acaagacatc 1980
cagatgaccc agtctccaag cagcctgtct gcaagcgtgg gggacagggt caccatgacc 2040
tgcagtgcca gctcaagtgt aagttacatg aactggtacc agcagaagcc gggcaaggcc 2100
cccaaaagat ggatttatga ctcatccaaa ctggcttctg gagtccctgc tcgcttcagt 2160
ggcagtgggt ctgggaccga ctataccctc acaatcagca gcctgcagcc cgaagatttc 2220
gccacttatt actgccagca gtggagtcgt aacccaccca cgttcggagg ggggaccaag 2280
ctacaaatta catcctccag ctaa 2304
<210> 106
<211> 747
<212> PRT
<213> 人工序列
<220>
<223> ROR154 抗ROR1 X 抗CD3双特异性分子
<400> 106
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Asn Cys Gln Ala Ser Gln Ser Ile Asp Ser Asn
20 25 30
Leu Ala Trp Phe Gln Gln Lys Pro Gly Lys Pro Pro Lys Leu Leu Ile
35 40 45
Tyr Arg Ala Ser Asn Leu Ala Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Val Ala Thr Tyr Tyr Cys Leu Gly Gly Val Gly Ala Val Ser
85 90 95
Tyr Arg Thr Ser Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Gly Gly
100 105 110
Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly
115 120 125
Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro
130 135 140
Gly Arg Ser Leu Arg Leu Ser Cys Thr Ala Ser Gly Ser Asp Ile Asn
145 150 155 160
Asp Tyr Pro Ile Thr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu
165 170 175
Trp Ile Gly Phe Ile Asn Ser Gly Gly Ser Thr Trp Tyr Ala Ser Trp
180 185 190
Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Ser Ile Ala
195 200 205
Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu Asp Thr Ala Val Tyr Tyr
210 215 220
Cys Ala Arg Gly Tyr Ser Thr Tyr Tyr Arg Asp Phe Asn Ile Trp Gly
225 230 235 240
Gln Gly Thr Leu Val Thr Val Ser Ser Ser Glu Pro Lys Ser Ser Asp
245 250 255
Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Ala
260 265 270
Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile
275 280 285
Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu
290 295 300
Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His
305 310 315 320
Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg
325 330 335
Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys
340 345 350
Glu Tyr Lys Cys Ala Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu
355 360 365
Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr
370 375 380
Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu
385 390 395 400
Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp
405 410 415
Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val
420 425 430
Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp
435 440 445
Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His
450 455 460
Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro
465 470 475 480
Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
485 490 495
Ser Pro Gly Ser Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val
500 505 510
Gln Pro Gly Arg Ser Leu Arg Leu Ser Cys Lys Ala Ser Gly Tyr Thr
515 520 525
Phe Thr Arg Ser Thr Met His Trp Val Arg Gln Ala Pro Gly Gln Gly
530 535 540
Leu Glu Trp Ile Gly Tyr Ile Asn Pro Ser Ser Ala Tyr Thr Asn Tyr
545 550 555 560
Asn Gln Lys Phe Lys Asp Arg Phe Thr Ile Ser Ala Asp Lys Ser Lys
565 570 575
Ser Thr Ala Phe Leu Gln Met Asp Ser Leu Arg Pro Glu Asp Thr Gly
580 585 590
Val Tyr Phe Cys Ala Arg Pro Gln Val His Tyr Asp Tyr Asn Gly Phe
595 600 605
Pro Tyr Trp Gly Gln Gly Thr Pro Val Thr Val Ser Ser Gly Gly Gly
610 615 620
Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Ala Gln Asp Ile
625 630 635 640
Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg
645 650 655
Val Thr Met Thr Cys Ser Ala Ser Ser Ser Val Ser Tyr Met Asn Trp
660 665 670
Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Arg Trp Ile Tyr Asp Ser
675 680 685
Ser Lys Leu Ala Ser Gly Val Pro Ala Arg Phe Ser Gly Ser Gly Ser
690 695 700
Gly Thr Asp Tyr Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe
705 710 715 720
Ala Thr Tyr Tyr Cys Gln Gln Trp Ser Arg Asn Pro Pro Thr Phe Gly
725 730 735
Gly Gly Thr Lys Leu Gln Ile Thr Ser Ser Ser
740 745
<210> 107
<211> 2316
<212> DNA
<213> 人工序列
<220>
<223> ROR185 抗ROR1 X 抗CD3双特异性分子
<400> 107
atggaagcac cagcgcagct tctcttcctc ctgctactct ggctcccaga taccaccggt 60
gacatccaga tgacccagtc cccctcctcc ctgtccgcct ccgtgggcga ccgggtgacc 120
atcaactgcc aggcctccca gtccatcgac tccaacctgg cctggttcca gcagaagccc 180
ggcaagcccc ccaagctgct gatctaccgg gcctccaacc tggcctccgg cgtgccctcc 240
cggttctccg gctccggctc cggcaccgac ttcaccctga ccatctcctc cctgcagccc 300
gaggacgtgg ccacctacta ctgcctgggc ggcgtgggcg ccgtgtccta ccggacctcc 360
ttcggcggcg gcaccaaggt ggagatcaag ggtggaggcg gttcaggcgg aggtggatcc 420
ggcggtggcg gctccggtgg cggcggatct gaggtgcagc tggtggagtc cggcggcggc 480
ctggtgcagc ccggccggtc cctgcggctg tcctgcaccg cctccggctc cgacatcaac 540
gactacccca tcacctgggt gcggcaggcc cccggcaagg gcctggagtg gatcggcttc 600
atcaactccg gcggctccac ctggtacgcc tcctgggtga agggccggtt caccatctcc 660
cgggacgact ccaagtccat cgcctacctg cagatgaact ccctgaagac cgaggacacc 720
gccgtgtact attgcgcccg gggctactcc acctactacc gggacttcaa catctggggc 780
cagggcaccc tggtgaccgt gtcctcgagt gagcccaaat cttctgacaa aactcacaca 840
tgcccaccgt gcccagcacc tgaagccgcg ggtgcaccgt cagtcttcct cttcccccca 900
aaacccaagg acaccctcat gatctcccgg acccctgagg tcacatgcgt ggtggtggac 960
gtgagccacg aagaccctga ggtcaagttc aactggtacg tggacggcgt ggaggtgcat 1020
aatgccaaga caaagccgcg ggaggagcag tacaacagca cgtaccgtgt ggtcagcgtc 1080
ctcaccgtcc tgcaccagga ctggctgaat ggcaaggaat acaagtgcgc ggtctccaac 1140
aaagccctcc cagcccccat cgagaaaacc atctccaaag ccaaagggca gccccgagaa 1200
ccacaggtgt acaccctgcc cccatcccgg gatgagctga ccaagaacca ggtcagcctg 1260
acctgcctgg tcaaaggctt ctatccaagc gacatcgccg tggagtggga gagcaatggg 1320
cagccggaga acaactacaa gaccacgcct cccgtgctgg actccgacgg ctccttcttc 1380
ctctacagca agctcaccgt ggacaagagc aggtggcagc aggggaacgt cttctcatgc 1440
tccgtgatgc atgaggctct gcacaaccac tacacgcaga agagcctctc cctgtctccg 1500
ggttctggtg gaggcggttc aggcggaggt ggctccggcg gtggcggatc gccgggctct 1560
caggtccagc tggtgcaatc tgggcctgag gtgaagaagc ctgggtcctc ggtgaaggtc 1620
tcctgcaagg cttctggata taccttcagc agatctacga tgcactgggt gcgacaggcc 1680
cctggacaag ggcttgagtg gataggatac attaatccta gcagtgctta tactaattac 1740
aatcagaaat tcaaggacag agtcacgatt accgcggaca aatccacgag cacagcctac 1800
atggagctga gcagcctgag atctgaggac acggccgtgt attactgtgc gagaccccaa 1860
gtccactatg attacaacgg gtttccttac tggggccaag gaaccctggt caccgtctcc 1920
tcaggtggag gcggttcagg cggaggtgga tccggcggtg gcggatcggg tggcggcgga 1980
tctgacatcc agatgaccca gtctccttcc accctgtctg catctgtagg agacagagtc 2040
accatgactt gcagtgccag ctcaagtgta agttacatga actggtatca gcagaaacca 2100
gggaaagccc ctaagagatg gatttatgac tcatccaaac tggcttctgg ggtcccatca 2160
aggttcagcg gcagtggatc tgggacagat tatactctca ccatcagcag cctgcagcct 2220
gatgattttg caacttatta ctgccaacag tggagtcgta acccacccac tttcggcgga 2280
gggaccaagg tggagatcaa acggtcctcc agctaa 2316
<210> 108
<211> 751
<212> PRT
<213> 人工序列
<220>
<223> ROR185 抗ROR1 X 抗CD3双特异性分子
<400> 108
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Asn Cys Gln Ala Ser Gln Ser Ile Asp Ser Asn
20 25 30
Leu Ala Trp Phe Gln Gln Lys Pro Gly Lys Pro Pro Lys Leu Leu Ile
35 40 45
Tyr Arg Ala Ser Asn Leu Ala Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Val Ala Thr Tyr Tyr Cys Leu Gly Gly Val Gly Ala Val Ser
85 90 95
Tyr Arg Thr Ser Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Gly Gly
100 105 110
Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly
115 120 125
Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro
130 135 140
Gly Arg Ser Leu Arg Leu Ser Cys Thr Ala Ser Gly Ser Asp Ile Asn
145 150 155 160
Asp Tyr Pro Ile Thr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu
165 170 175
Trp Ile Gly Phe Ile Asn Ser Gly Gly Ser Thr Trp Tyr Ala Ser Trp
180 185 190
Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Ser Ile Ala
195 200 205
Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu Asp Thr Ala Val Tyr Tyr
210 215 220
Cys Ala Arg Gly Tyr Ser Thr Tyr Tyr Arg Asp Phe Asn Ile Trp Gly
225 230 235 240
Gln Gly Thr Leu Val Thr Val Ser Ser Ser Glu Pro Lys Ser Ser Asp
245 250 255
Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Ala
260 265 270
Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile
275 280 285
Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu
290 295 300
Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His
305 310 315 320
Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg
325 330 335
Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys
340 345 350
Glu Tyr Lys Cys Ala Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu
355 360 365
Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr
370 375 380
Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu
385 390 395 400
Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp
405 410 415
Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val
420 425 430
Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp
435 440 445
Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His
450 455 460
Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro
465 470 475 480
Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
485 490 495
Ser Pro Gly Ser Gln Val Gln Leu Val Gln Ser Gly Pro Glu Val Lys
500 505 510
Lys Pro Gly Ser Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr
515 520 525
Phe Ser Arg Ser Thr Met His Trp Val Arg Gln Ala Pro Gly Gln Gly
530 535 540
Leu Glu Trp Ile Gly Tyr Ile Asn Pro Ser Ser Ala Tyr Thr Asn Tyr
545 550 555 560
Asn Gln Lys Phe Lys Asp Arg Val Thr Ile Thr Ala Asp Lys Ser Thr
565 570 575
Ser Thr Ala Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala
580 585 590
Val Tyr Tyr Cys Ala Arg Pro Gln Val His Tyr Asp Tyr Asn Gly Phe
595 600 605
Pro Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly
610 615 620
Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
625 630 635 640
Ser Asp Ile Gln Met Thr Gln Ser Pro Ser Thr Leu Ser Ala Ser Val
645 650 655
Gly Asp Arg Val Thr Met Thr Cys Ser Ala Ser Ser Ser Val Ser Tyr
660 665 670
Met Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Arg Trp Ile
675 680 685
Tyr Asp Ser Ser Lys Leu Ala Ser Gly Val Pro Ser Arg Phe Ser Gly
690 695 700
Ser Gly Ser Gly Thr Asp Tyr Thr Leu Thr Ile Ser Ser Leu Gln Pro
705 710 715 720
Asp Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Trp Ser Arg Asn Pro Pro
725 730 735
Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg Ser Ser Ser
740 745 750
<210> 109
<211> 2304
<212> DNA
<213> 人工序列
<220>
<223> ROR179 抗ROR1 X 抗CD3双特异性分子
<400> 109
atggaagcac cagcgcagct tctcttcctc ctgctactct ggctcccaga taccaccggt 60
gacatccaga tgacccagtc cccctcctcc ctgtccgcct ccgtgggcga ccgggtgacc 120
atcaactgcc aggcctccca gtccatcgac tccaacctgg cctggttcca gcagaagccc 180
ggcaagcccc ccaagctgct gatctaccgg gcctccaacc tggcctccgg cgtgccctcc 240
cggttctccg gctccggctc cggcaccgac ttcaccctga ccatctcctc cctgcagccc 300
gaggacgtgg ccacctacta ctgcctgggc ggcgtgggcg ccgtgtccta ctggacctcc 360
ttcggcggcg gcaccaaggt ggagatcaag ggtggaggcg gttcaggcgg aggtggatcc 420
ggcggtggcg gctccggtgg cggcggatct gaggtgcagc tggtggagtc cggcggcggc 480
ctggtgcagc ccggccggtc cctgcggctg tcctgcaccg cctccggctc cgacatcaac 540
gactacccca tcacctgggt gcggcaggcc cccggcaagg gcctggagtg gatcggcttc 600
atcaactccg gcggctccac ctggtacgcc tcctgggtga agggccggtt caccatctcc 660
cgggacgact ccaagtccat cgcctacctg cagatgaact ccctgaagac cgaggacacc 720
gccgtgtact attgcgcccg gggctactcc acctactacc gggacttcaa catctggggc 780
cagggcaccc tggtgaccgt gtcctcgagt gagcccaaat cttctgacaa aactcacaca 840
tgcccaccgt gcccagcacc tgaagccgcg ggtgcaccgt cagtcttcct cttcccccca 900
aaacccaagg acaccctcat gatctcccgg acccctgagg tcacatgcgt ggtggtggac 960
gtgagccacg aagaccctga ggtcaagttc aactggtacg tggacggcgt ggaggtgcat 1020
aatgccaaga caaagccgcg ggaggagcag tacaacagca cgtaccgtgt ggtcagcgtc 1080
ctcaccgtcc tgcaccagga ctggctgaat ggcaaggaat acaagtgcgc ggtctccaac 1140
aaagccctcc cagcccccat cgagaaaacc atctccaaag ccaaagggca gccccgagaa 1200
ccacaggtgt acaccctgcc cccatcccgg gatgagctga ccaagaacca ggtcagcctg 1260
acctgcctgg tcaaaggctt ctatccaagc gacatcgccg tggagtggga gagcaatggg 1320
cagccggaga acaactacaa gaccacgcct cccgtgctgg actccgacgg ctccttcttc 1380
ctctacagca agctcaccgt ggacaagagc aggtggcagc aggggaacgt cttctcatgc 1440
tccgtgatgc atgaggctct gcacaaccac tacacgcaga agagcctctc cctgtctccg 1500
ggttctggtg gaggcggttc aggcggaggt ggctccggcg gtggcggatc gccgggctct 1560
caggtccagc tggtggagtc tgggggcgga gtggtgcagc ctgggcggtc actgaggctg 1620
tcctgcaagg cttctggcta cacctttact agatctacga tgcactgggt aaggcaggcc 1680
cctggacaag gtctggaatg gattggatac attaatccta gcagtgctta tactaattac 1740
aatcagaaat tcaaggacag gttcacaatc agcgcagaca aatccaagag cacagccttc 1800
ctgcagatgg acagcctgag gcccgaggac accggcgtct atttctgtgc acggccccaa 1860
gtccactatg attacaacgg gtttccttac tggggccaag ggactcccgt cactgtctct 1920
agcggtggcg gagggtctgg gggtggcgga tccggaggtg gtggctctgc acaagacatc 1980
cagatgaccc agtctccaag cagcctgtct gcaagcgtgg gggacagggt caccatgacc 2040
tgcagtgcca gctcaagtgt aagttacatg aactggtacc agcagaagcc gggcaaggcc 2100
cccaaaagat ggatttatga ctcatccaaa ctggcttctg gagtccctgc tcgcttcagt 2160
ggcagtgggt ctgggaccga ctataccctc acaatcagca gcctgcagcc cgaagatttc 2220
gccacttatt actgccagca gtggagtcgt aacccaccca cgttcggagg ggggaccaag 2280
ctacaaatta catcctccag ctaa 2304
<210> 110
<211> 747
<212> PRT
<213> 人工序列
<220>
<223> ROR179 抗ROR1 X 抗CD3双特异性分子
<400> 110
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Asn Cys Gln Ala Ser Gln Ser Ile Asp Ser Asn
20 25 30
Leu Ala Trp Phe Gln Gln Lys Pro Gly Lys Pro Pro Lys Leu Leu Ile
35 40 45
Tyr Arg Ala Ser Asn Leu Ala Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Val Ala Thr Tyr Tyr Cys Leu Gly Gly Val Gly Ala Val Ser
85 90 95
Tyr Trp Thr Ser Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Gly Gly
100 105 110
Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly
115 120 125
Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro
130 135 140
Gly Arg Ser Leu Arg Leu Ser Cys Thr Ala Ser Gly Ser Asp Ile Asn
145 150 155 160
Asp Tyr Pro Ile Thr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu
165 170 175
Trp Ile Gly Phe Ile Asn Ser Gly Gly Ser Thr Trp Tyr Ala Ser Trp
180 185 190
Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Ser Ile Ala
195 200 205
Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu Asp Thr Ala Val Tyr Tyr
210 215 220
Cys Ala Arg Gly Tyr Ser Thr Tyr Tyr Arg Asp Phe Asn Ile Trp Gly
225 230 235 240
Gln Gly Thr Leu Val Thr Val Ser Ser Ser Glu Pro Lys Ser Ser Asp
245 250 255
Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Ala
260 265 270
Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile
275 280 285
Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu
290 295 300
Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His
305 310 315 320
Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg
325 330 335
Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys
340 345 350
Glu Tyr Lys Cys Ala Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu
355 360 365
Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr
370 375 380
Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu
385 390 395 400
Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp
405 410 415
Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val
420 425 430
Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp
435 440 445
Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His
450 455 460
Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro
465 470 475 480
Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
485 490 495
Ser Pro Gly Ser Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val
500 505 510
Gln Pro Gly Arg Ser Leu Arg Leu Ser Cys Lys Ala Ser Gly Tyr Thr
515 520 525
Phe Thr Arg Ser Thr Met His Trp Val Arg Gln Ala Pro Gly Gln Gly
530 535 540
Leu Glu Trp Ile Gly Tyr Ile Asn Pro Ser Ser Ala Tyr Thr Asn Tyr
545 550 555 560
Asn Gln Lys Phe Lys Asp Arg Phe Thr Ile Ser Ala Asp Lys Ser Lys
565 570 575
Ser Thr Ala Phe Leu Gln Met Asp Ser Leu Arg Pro Glu Asp Thr Gly
580 585 590
Val Tyr Phe Cys Ala Arg Pro Gln Val His Tyr Asp Tyr Asn Gly Phe
595 600 605
Pro Tyr Trp Gly Gln Gly Thr Pro Val Thr Val Ser Ser Gly Gly Gly
610 615 620
Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Ala Gln Asp Ile
625 630 635 640
Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg
645 650 655
Val Thr Met Thr Cys Ser Ala Ser Ser Ser Val Ser Tyr Met Asn Trp
660 665 670
Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Arg Trp Ile Tyr Asp Ser
675 680 685
Ser Lys Leu Ala Ser Gly Val Pro Ala Arg Phe Ser Gly Ser Gly Ser
690 695 700
Gly Thr Asp Tyr Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe
705 710 715 720
Ala Thr Tyr Tyr Cys Gln Gln Trp Ser Arg Asn Pro Pro Thr Phe Gly
725 730 735
Gly Gly Thr Lys Leu Gln Ile Thr Ser Ser Ser
740 745
<210> 111
<211> 2316
<212> DNA
<213> 人工序列
<220>
<223> ROR186 抗ROR1 X 抗CD3双特异性分子
<400> 111
atggaagcac cagcgcagct tctcttcctc ctgctactct ggctcccaga taccaccggt 60
gacatccaga tgacccagtc cccctcctcc ctgtccgcct ccgtgggcga ccgggtgacc 120
atcaactgcc aggcctccca gtccatcgac tccaacctgg cctggttcca gcagaagccc 180
ggcaagcccc ccaagctgct gatctaccgg gcctccaacc tggcctccgg cgtgccctcc 240
cggttctccg gctccggctc cggcaccgac ttcaccctga ccatctcctc cctgcagccc 300
gaggacgtgg ccacctacta ctgcctgggc ggcgtgggcg ccgtgtccta ctggacctcc 360
ttcggcggcg gcaccaaggt ggagatcaag ggtggaggcg gttcaggcgg aggtggatcc 420
ggcggtggcg gctccggtgg cggcggatct gaggtgcagc tggtggagtc cggcggcggc 480
ctggtgcagc ccggccggtc cctgcggctg tcctgcaccg cctccggctc cgacatcaac 540
gactacccca tcacctgggt gcggcaggcc cccggcaagg gcctggagtg gatcggcttc 600
atcaactccg gcggctccac ctggtacgcc tcctgggtga agggccggtt caccatctcc 660
cgggacgact ccaagtccat cgcctacctg cagatgaact ccctgaagac cgaggacacc 720
gccgtgtact attgcgcccg gggctactcc acctactacc gggacttcaa catctggggc 780
cagggcaccc tggtgaccgt gtcctcgagt gagcccaaat cttctgacaa aactcacaca 840
tgcccaccgt gcccagcacc tgaagccgcg ggtgcaccgt cagtcttcct cttcccccca 900
aaacccaagg acaccctcat gatctcccgg acccctgagg tcacatgcgt ggtggtggac 960
gtgagccacg aagaccctga ggtcaagttc aactggtacg tggacggcgt ggaggtgcat 1020
aatgccaaga caaagccgcg ggaggagcag tacaacagca cgtaccgtgt ggtcagcgtc 1080
ctcaccgtcc tgcaccagga ctggctgaat ggcaaggaat acaagtgcgc ggtctccaac 1140
aaagccctcc cagcccccat cgagaaaacc atctccaaag ccaaagggca gccccgagaa 1200
ccacaggtgt acaccctgcc cccatcccgg gatgagctga ccaagaacca ggtcagcctg 1260
acctgcctgg tcaaaggctt ctatccaagc gacatcgccg tggagtggga gagcaatggg 1320
cagccggaga acaactacaa gaccacgcct cccgtgctgg actccgacgg ctccttcttc 1380
ctctacagca agctcaccgt ggacaagagc aggtggcagc aggggaacgt cttctcatgc 1440
tccgtgatgc atgaggctct gcacaaccac tacacgcaga agagcctctc cctgtctccg 1500
ggttctggtg gaggcggttc aggcggaggt ggctccggcg gtggcggatc gccgggctct 1560
caggtccagc tggtgcaatc tgggcctgag gtgaagaagc ctgggtcctc ggtgaaggtc 1620
tcctgcaagg cttctggata taccttcagc agatctacga tgcactgggt gcgacaggcc 1680
cctggacaag ggcttgagtg gataggatac attaatccta gcagtgctta tactaattac 1740
aatcagaaat tcaaggacag agtcacgatt accgcggaca aatccacgag cacagcctac 1800
atggagctga gcagcctgag atctgaggac acggccgtgt attactgtgc gagaccccaa 1860
gtccactatg attacaacgg gtttccttac tggggccaag gaaccctggt caccgtctcc 1920
tcaggtggag gcggttcagg cggaggtgga tccggcggtg gcggatcggg tggcggcgga 1980
tctgacatcc agatgaccca gtctccttcc accctgtctg catctgtagg agacagagtc 2040
accatgactt gcagtgccag ctcaagtgta agttacatga actggtatca gcagaaacca 2100
gggaaagccc ctaagagatg gatttatgac tcatccaaac tggcttctgg ggtcccatca 2160
aggttcagcg gcagtggatc tgggacagat tatactctca ccatcagcag cctgcagcct 2220
gatgattttg caacttatta ctgccaacag tggagtcgta acccacccac tttcggcgga 2280
gggaccaagg tggagatcaa acggtcctcc agctaa 2316
<210> 112
<211> 751
<212> PRT
<213> 人工序列
<220>
<223> ROR186 抗ROR1 X 抗CD3双特异性分子
<400> 112
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Asn Cys Gln Ala Ser Gln Ser Ile Asp Ser Asn
20 25 30
Leu Ala Trp Phe Gln Gln Lys Pro Gly Lys Pro Pro Lys Leu Leu Ile
35 40 45
Tyr Arg Ala Ser Asn Leu Ala Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Val Ala Thr Tyr Tyr Cys Leu Gly Gly Val Gly Ala Val Ser
85 90 95
Tyr Trp Thr Ser Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Gly Gly
100 105 110
Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly
115 120 125
Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro
130 135 140
Gly Arg Ser Leu Arg Leu Ser Cys Thr Ala Ser Gly Ser Asp Ile Asn
145 150 155 160
Asp Tyr Pro Ile Thr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu
165 170 175
Trp Ile Gly Phe Ile Asn Ser Gly Gly Ser Thr Trp Tyr Ala Ser Trp
180 185 190
Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Ser Ile Ala
195 200 205
Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu Asp Thr Ala Val Tyr Tyr
210 215 220
Cys Ala Arg Gly Tyr Ser Thr Tyr Tyr Arg Asp Phe Asn Ile Trp Gly
225 230 235 240
Gln Gly Thr Leu Val Thr Val Ser Ser Ser Glu Pro Lys Ser Ser Asp
245 250 255
Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Ala
260 265 270
Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile
275 280 285
Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu
290 295 300
Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His
305 310 315 320
Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg
325 330 335
Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys
340 345 350
Glu Tyr Lys Cys Ala Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu
355 360 365
Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr
370 375 380
Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu
385 390 395 400
Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp
405 410 415
Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val
420 425 430
Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp
435 440 445
Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His
450 455 460
Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro
465 470 475 480
Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
485 490 495
Ser Pro Gly Ser Gln Val Gln Leu Val Gln Ser Gly Pro Glu Val Lys
500 505 510
Lys Pro Gly Ser Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr
515 520 525
Phe Ser Arg Ser Thr Met His Trp Val Arg Gln Ala Pro Gly Gln Gly
530 535 540
Leu Glu Trp Ile Gly Tyr Ile Asn Pro Ser Ser Ala Tyr Thr Asn Tyr
545 550 555 560
Asn Gln Lys Phe Lys Asp Arg Val Thr Ile Thr Ala Asp Lys Ser Thr
565 570 575
Ser Thr Ala Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala
580 585 590
Val Tyr Tyr Cys Ala Arg Pro Gln Val His Tyr Asp Tyr Asn Gly Phe
595 600 605
Pro Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly
610 615 620
Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
625 630 635 640
Ser Asp Ile Gln Met Thr Gln Ser Pro Ser Thr Leu Ser Ala Ser Val
645 650 655
Gly Asp Arg Val Thr Met Thr Cys Ser Ala Ser Ser Ser Val Ser Tyr
660 665 670
Met Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Arg Trp Ile
675 680 685
Tyr Asp Ser Ser Lys Leu Ala Ser Gly Val Pro Ser Arg Phe Ser Gly
690 695 700
Ser Gly Ser Gly Thr Asp Tyr Thr Leu Thr Ile Ser Ser Leu Gln Pro
705 710 715 720
Asp Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Trp Ser Arg Asn Pro Pro
725 730 735
Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg Ser Ser Ser
740 745 750
<210> 113
<211> 2304
<212> DNA
<213> 人工序列
<220>
<223> ROR181 抗ROR1 X 抗CD3双特异性分子
<400> 113
atggaagcac cagcgcagct tctcttcctc ctgctactct ggctcccaga taccaccggt 60
gacatccaga tgacccagtc cccctcctcc ctgtccgcct ccgtgggcga ccgggtgacc 120
atcaactgcc aggcctccca gtccatcgac tccaacctgg cctggttcca gcagaagccc 180
ggcaagcccc ccaagctgct gatctaccgg gcctccaacc tggcctccgg cgtgccctcc 240
cggttctccg gctccggctc cggcaccgac ttcaccctga ccatctcctc cctgcagccc 300
gaggacgtgg ccacctacta ctgcctgggc ggcgtgggcg ccgtgtccta ccggacctcc 360
ttcggcggcg gcaccaaggt ggagatcaag ggtggaggcg gttcaggcgg aggtggatcc 420
ggcggtggcg gctccggtgg cggcggatct gaggtgcagc tggtggagtc cggcggcggc 480
ctggtgcagc ccggcggctc cctgcggctg tcctgcaccg tgtccggcac cgacatcaac 540
gactacccca tctcctgggt gcggcaggcc cccggcaagg gcctggagtg gatcggcttc 600
atcaactccg gcggctccac ctggtacgcc gactcggtga agggccggtt caccatctcc 660
cggcactcct ccaagaacac cctgtacctg cagatgaact ccctgcgggc cgaggacacc 720
gccgtgtact tctgcgcccg gggctactcc acctactacc gggacttcaa catctggggc 780
cagggcaccc tggtgaccgt gtcctcgagt gagcccaaat cttctgacaa aactcacaca 840
tgcccaccgt gcccagcacc tgaagccgcg ggtgcaccgt cagtcttcct cttcccccca 900
aaacccaagg acaccctcat gatctcccgg acccctgagg tcacatgcgt ggtggtggac 960
gtgagccacg aagaccctga ggtcaagttc aactggtacg tggacggcgt ggaggtgcat 1020
aatgccaaga caaagccgcg ggaggagcag tacaacagca cgtaccgtgt ggtcagcgtc 1080
ctcaccgtcc tgcaccagga ctggctgaat ggcaaggaat acaagtgcgc ggtctccaac 1140
aaagccctcc cagcccccat cgagaaaacc atctccaaag ccaaagggca gccccgagaa 1200
ccacaggtgt acaccctgcc cccatcccgg gatgagctga ccaagaacca ggtcagcctg 1260
acctgcctgg tcaaaggctt ctatccaagc gacatcgccg tggagtggga gagcaatggg 1320
cagccggaga acaactacaa gaccacgcct cccgtgctgg actccgacgg ctccttcttc 1380
ctctacagca agctcaccgt ggacaagagc aggtggcagc aggggaacgt cttctcatgc 1440
tccgtgatgc atgaggctct gcacaaccac tacacgcaga agagcctctc cctgtctccg 1500
ggttctggtg gaggcggttc aggcggaggt ggctccggcg gtggcggatc gccgggctct 1560
caggtccagc tggtggagtc tgggggcgga gtggtgcagc ctgggcggtc actgaggctg 1620
tcctgcaagg cttctggcta cacctttact agatctacga tgcactgggt aaggcaggcc 1680
cctggacaag gtctggaatg gattggatac attaatccta gcagtgctta tactaattac 1740
aatcagaaat tcaaggacag gttcacaatc agcgcagaca aatccaagag cacagccttc 1800
ctgcagatgg acagcctgag gcccgaggac accggcgtct atttctgtgc acggccccaa 1860
gtccactatg attacaacgg gtttccttac tggggccaag ggactcccgt cactgtctct 1920
agcggtggcg gagggtctgg gggtggcgga tccggaggtg gtggctctgc acaagacatc 1980
cagatgaccc agtctccaag cagcctgtct gcaagcgtgg gggacagggt caccatgacc 2040
tgcagtgcca gctcaagtgt aagttacatg aactggtacc agcagaagcc gggcaaggcc 2100
cccaaaagat ggatttatga ctcatccaaa ctggcttctg gagtccctgc tcgcttcagt 2160
ggcagtgggt ctgggaccga ctataccctc acaatcagca gcctgcagcc cgaagatttc 2220
gccacttatt actgccagca gtggagtcgt aacccaccca cgttcggagg ggggaccaag 2280
ctacaaatta catcctccag ctaa 2304
<210> 114
<211> 747
<212> PRT
<213> 人工序列
<220>
<223> ROR181 抗ROR1 X 抗CD3双特异性分子
<400> 114
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Asn Cys Gln Ala Ser Gln Ser Ile Asp Ser Asn
20 25 30
Leu Ala Trp Phe Gln Gln Lys Pro Gly Lys Pro Pro Lys Leu Leu Ile
35 40 45
Tyr Arg Ala Ser Asn Leu Ala Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Val Ala Thr Tyr Tyr Cys Leu Gly Gly Val Gly Ala Val Ser
85 90 95
Tyr Arg Thr Ser Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Gly Gly
100 105 110
Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly
115 120 125
Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro
130 135 140
Gly Gly Ser Leu Arg Leu Ser Cys Thr Val Ser Gly Thr Asp Ile Asn
145 150 155 160
Asp Tyr Pro Ile Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu
165 170 175
Trp Ile Gly Phe Ile Asn Ser Gly Gly Ser Thr Trp Tyr Ala Asp Ser
180 185 190
Val Lys Gly Arg Phe Thr Ile Ser Arg His Ser Ser Lys Asn Thr Leu
195 200 205
Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Phe
210 215 220
Cys Ala Arg Gly Tyr Ser Thr Tyr Tyr Arg Asp Phe Asn Ile Trp Gly
225 230 235 240
Gln Gly Thr Leu Val Thr Val Ser Ser Ser Glu Pro Lys Ser Ser Asp
245 250 255
Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Ala
260 265 270
Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile
275 280 285
Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu
290 295 300
Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His
305 310 315 320
Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg
325 330 335
Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys
340 345 350
Glu Tyr Lys Cys Ala Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu
355 360 365
Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr
370 375 380
Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu
385 390 395 400
Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp
405 410 415
Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val
420 425 430
Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp
435 440 445
Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His
450 455 460
Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro
465 470 475 480
Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
485 490 495
Ser Pro Gly Ser Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val
500 505 510
Gln Pro Gly Arg Ser Leu Arg Leu Ser Cys Lys Ala Ser Gly Tyr Thr
515 520 525
Phe Thr Arg Ser Thr Met His Trp Val Arg Gln Ala Pro Gly Gln Gly
530 535 540
Leu Glu Trp Ile Gly Tyr Ile Asn Pro Ser Ser Ala Tyr Thr Asn Tyr
545 550 555 560
Asn Gln Lys Phe Lys Asp Arg Phe Thr Ile Ser Ala Asp Lys Ser Lys
565 570 575
Ser Thr Ala Phe Leu Gln Met Asp Ser Leu Arg Pro Glu Asp Thr Gly
580 585 590
Val Tyr Phe Cys Ala Arg Pro Gln Val His Tyr Asp Tyr Asn Gly Phe
595 600 605
Pro Tyr Trp Gly Gln Gly Thr Pro Val Thr Val Ser Ser Gly Gly Gly
610 615 620
Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Ala Gln Asp Ile
625 630 635 640
Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg
645 650 655
Val Thr Met Thr Cys Ser Ala Ser Ser Ser Val Ser Tyr Met Asn Trp
660 665 670
Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Arg Trp Ile Tyr Asp Ser
675 680 685
Ser Lys Leu Ala Ser Gly Val Pro Ala Arg Phe Ser Gly Ser Gly Ser
690 695 700
Gly Thr Asp Tyr Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe
705 710 715 720
Ala Thr Tyr Tyr Cys Gln Gln Trp Ser Arg Asn Pro Pro Thr Phe Gly
725 730 735
Gly Gly Thr Lys Leu Gln Ile Thr Ser Ser Ser
740 745
<210> 115
<211> 2316
<212> DNA
<213> 人工序列
<220>
<223> ROR191 抗ROR1 X 抗CD3双特异性分子
<400> 115
atggaagcac cagcgcagct tctcttcctc ctgctactct ggctcccaga taccaccggt 60
gacatccaga tgacccagtc cccctcctcc ctgtccgcct ccgtgggcga ccgggtgacc 120
atcaactgcc aggcctccca gtccatcgac tccaacctgg cctggttcca gcagaagccc 180
ggcaagcccc ccaagctgct gatctaccgg gcctccaacc tggcctccgg cgtgccctcc 240
cggttctccg gctccggctc cggcaccgac ttcaccctga ccatctcctc cctgcagccc 300
gaggacgtgg ccacctacta ctgcctgggc ggcgtgggcg ccgtgtccta ccggacctcc 360
ttcggcggcg gcaccaaggt ggagatcaag ggtggaggcg gttcaggcgg aggtggatcc 420
ggcggtggcg gctccggtgg cggcggatct gaggtgcagc tggtggagtc cggcggcggc 480
ctggtgcagc ccggcggctc cctgcggctg tcctgcaccg tgtccggcac cgacatcaac 540
gactacccca tctcctgggt gcggcaggcc cccggcaagg gcctggagtg gatcggcttc 600
atcaactccg gcggctccac ctggtacgcc gactcggtga agggccggtt caccatctcc 660
cggcactcct ccaagaacac cctgtacctg cagatgaact ccctgcgggc cgaggacacc 720
gccgtgtact tctgcgcccg gggctactcc acctactacc gggacttcaa catctggggc 780
cagggcaccc tggtgaccgt gtcctcgagt gagcccaaat cttctgacaa aactcacaca 840
tgcccaccgt gcccagcacc tgaagccgcg ggtgcaccgt cagtcttcct cttcccccca 900
aaacccaagg acaccctcat gatctcccgg acccctgagg tcacatgcgt ggtggtggac 960
gtgagccacg aagaccctga ggtcaagttc aactggtacg tggacggcgt ggaggtgcat 1020
aatgccaaga caaagccgcg ggaggagcag tacaacagca cgtaccgtgt ggtcagcgtc 1080
ctcaccgtcc tgcaccagga ctggctgaat ggcaaggaat acaagtgcgc ggtctccaac 1140
aaagccctcc cagcccccat cgagaaaacc atctccaaag ccaaagggca gccccgagaa 1200
ccacaggtgt acaccctgcc cccatcccgg gatgagctga ccaagaacca ggtcagcctg 1260
acctgcctgg tcaaaggctt ctatccaagc gacatcgccg tggagtggga gagcaatggg 1320
cagccggaga acaactacaa gaccacgcct cccgtgctgg actccgacgg ctccttcttc 1380
ctctacagca agctcaccgt ggacaagagc aggtggcagc aggggaacgt cttctcatgc 1440
tccgtgatgc atgaggctct gcacaaccac tacacgcaga agagcctctc cctgtctccg 1500
ggttctggtg gaggcggttc aggcggaggt ggctccggcg gtggcggatc gccgggctct 1560
caggtccagc tggtgcaatc tgggcctgag gtgaagaagc ctgggtcctc ggtgaaggtc 1620
tcctgcaagg cttctggata taccttcagc agatctacga tgcactgggt gcgacaggcc 1680
cctggacaag ggcttgagtg gataggatac attaatccta gcagtgctta tactaattac 1740
aatcagaaat tcaaggacag agtcacgatt accgcggaca aatccacgag cacagcctac 1800
atggagctga gcagcctgag atctgaggac acggccgtgt attactgtgc gagaccccaa 1860
gtccactatg attacaacgg gtttccttac tggggccaag gaaccctggt caccgtctcc 1920
tcaggtggag gcggttcagg cggaggtgga tccggcggtg gcggatcggg tggcggcgga 1980
tctgacatcc agatgaccca gtctccttcc accctgtctg catctgtagg agacagagtc 2040
accatgactt gcagtgccag ctcaagtgta agttacatga actggtatca gcagaaacca 2100
gggaaagccc ctaagagatg gatttatgac tcatccaaac tggcttctgg ggtcccatca 2160
aggttcagcg gcagtggatc tgggacagat tatactctca ccatcagcag cctgcagcct 2220
gatgattttg caacttatta ctgccaacag tggagtcgta acccacccac tttcggcgga 2280
gggaccaagg tggagatcaa acggtcctcc agctaa 2316
<210> 116
<211> 751
<212> PRT
<213> 人工序列
<220>
<223> ROR191 抗ROR1 X 抗CD3双特异性分子
<400> 116
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Asn Cys Gln Ala Ser Gln Ser Ile Asp Ser Asn
20 25 30
Leu Ala Trp Phe Gln Gln Lys Pro Gly Lys Pro Pro Lys Leu Leu Ile
35 40 45
Tyr Arg Ala Ser Asn Leu Ala Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Val Ala Thr Tyr Tyr Cys Leu Gly Gly Val Gly Ala Val Ser
85 90 95
Tyr Arg Thr Ser Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Gly Gly
100 105 110
Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly
115 120 125
Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro
130 135 140
Gly Gly Ser Leu Arg Leu Ser Cys Thr Val Ser Gly Thr Asp Ile Asn
145 150 155 160
Asp Tyr Pro Ile Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu
165 170 175
Trp Ile Gly Phe Ile Asn Ser Gly Gly Ser Thr Trp Tyr Ala Asp Ser
180 185 190
Val Lys Gly Arg Phe Thr Ile Ser Arg His Ser Ser Lys Asn Thr Leu
195 200 205
Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Phe
210 215 220
Cys Ala Arg Gly Tyr Ser Thr Tyr Tyr Arg Asp Phe Asn Ile Trp Gly
225 230 235 240
Gln Gly Thr Leu Val Thr Val Ser Ser Ser Glu Pro Lys Ser Ser Asp
245 250 255
Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Ala
260 265 270
Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile
275 280 285
Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu
290 295 300
Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His
305 310 315 320
Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg
325 330 335
Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys
340 345 350
Glu Tyr Lys Cys Ala Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu
355 360 365
Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr
370 375 380
Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu
385 390 395 400
Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp
405 410 415
Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val
420 425 430
Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp
435 440 445
Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His
450 455 460
Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro
465 470 475 480
Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
485 490 495
Ser Pro Gly Ser Gln Val Gln Leu Val Gln Ser Gly Pro Glu Val Lys
500 505 510
Lys Pro Gly Ser Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr
515 520 525
Phe Ser Arg Ser Thr Met His Trp Val Arg Gln Ala Pro Gly Gln Gly
530 535 540
Leu Glu Trp Ile Gly Tyr Ile Asn Pro Ser Ser Ala Tyr Thr Asn Tyr
545 550 555 560
Asn Gln Lys Phe Lys Asp Arg Val Thr Ile Thr Ala Asp Lys Ser Thr
565 570 575
Ser Thr Ala Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala
580 585 590
Val Tyr Tyr Cys Ala Arg Pro Gln Val His Tyr Asp Tyr Asn Gly Phe
595 600 605
Pro Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly
610 615 620
Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
625 630 635 640
Ser Asp Ile Gln Met Thr Gln Ser Pro Ser Thr Leu Ser Ala Ser Val
645 650 655
Gly Asp Arg Val Thr Met Thr Cys Ser Ala Ser Ser Ser Val Ser Tyr
660 665 670
Met Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Arg Trp Ile
675 680 685
Tyr Asp Ser Ser Lys Leu Ala Ser Gly Val Pro Ser Arg Phe Ser Gly
690 695 700
Ser Gly Ser Gly Thr Asp Tyr Thr Leu Thr Ile Ser Ser Leu Gln Pro
705 710 715 720
Asp Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Trp Ser Arg Asn Pro Pro
725 730 735
Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg Ser Ser Ser
740 745 750
<210> 117
<211> 2304
<212> DNA
<213> 人工序列
<220>
<223> ROR182 抗ROR1 X 抗CD3双特异性分子
<400> 117
atggaagcac cagcgcagct tctcttcctc ctgctactct ggctcccaga taccaccggt 60
gacatccaga tgacccagtc cccctcctcc ctgtccgcct ccgtgggcga ccgggtgacc 120
atcaactgcc aggcctccca gtccatcgac tccaacctgg cctggttcca gcagaagccc 180
ggccagcccc ccaagctgct gatctaccgg gcctccaacc tggcctccgg cgtgcccgac 240
cggttctccg gctccggctc cggcaccgac ttcaccctga ccatctcctc cctggaggcc 300
gaggacgtgg ccacctacta ctgcctgggc ggcgtgggcg ccgtgtccta ccggacctcc 360
ttcggcggcg gcaccaaggt ggagatcaag ggtggaggcg gttcaggcgg aggtggatcc 420
ggcggtggcg gctccggtgg cggcggatct gaggtgcagc tggtggagtc cggcggcggc 480
ctggtgcagc ccggccggtc cctgcggctg tcctgcaccg cctccggctc cgacatcaac 540
gactacccca tcacctgggt gcggcaggcc cccggccagg gcctggagtg gatcggcttc 600
atcaactccg gcggctccac ctggtacgcc tcctgggtga agggccggtt caccatctcc 660
cgggacgact ccaagtccat cgcctacctg cagatgaact ccctgaagac cgaggacacc 720
gccgtgtact attgcgcccg gggctactcc acctactacc gggacttcaa catctggggc 780
cagggcaccc tggtgaccgt gtcctcgagt gagcccaaat cttctgacaa aactcacaca 840
tgcccaccgt gcccagcacc tgaagccgcg ggtgcaccgt cagtcttcct cttcccccca 900
aaacccaagg acaccctcat gatctcccgg acccctgagg tcacatgcgt ggtggtggac 960
gtgagccacg aagaccctga ggtcaagttc aactggtacg tggacggcgt ggaggtgcat 1020
aatgccaaga caaagccgcg ggaggagcag tacaacagca cgtaccgtgt ggtcagcgtc 1080
ctcaccgtcc tgcaccagga ctggctgaat ggcaaggaat acaagtgcgc ggtctccaac 1140
aaagccctcc cagcccccat cgagaaaacc atctccaaag ccaaagggca gccccgagaa 1200
ccacaggtgt acaccctgcc cccatcccgg gatgagctga ccaagaacca ggtcagcctg 1260
acctgcctgg tcaaaggctt ctatccaagc gacatcgccg tggagtggga gagcaatggg 1320
cagccggaga acaactacaa gaccacgcct cccgtgctgg actccgacgg ctccttcttc 1380
ctctacagca agctcaccgt ggacaagagc aggtggcagc aggggaacgt cttctcatgc 1440
tccgtgatgc atgaggctct gcacaaccac tacacgcaga agagcctctc cctgtctccg 1500
ggttctggtg gaggcggttc aggcggaggt ggctccggcg gtggcggatc gccgggctct 1560
caggtccagc tggtggagtc tgggggcgga gtggtgcagc ctgggcggtc actgaggctg 1620
tcctgcaagg cttctggcta cacctttact agatctacga tgcactgggt aaggcaggcc 1680
cctggacaag gtctggaatg gattggatac attaatccta gcagtgctta tactaattac 1740
aatcagaaat tcaaggacag gttcacaatc agcgcagaca aatccaagag cacagccttc 1800
ctgcagatgg acagcctgag gcccgaggac accggcgtct atttctgtgc acggccccaa 1860
gtccactatg attacaacgg gtttccttac tggggccaag ggactcccgt cactgtctct 1920
agcggtggcg gagggtctgg gggtggcgga tccggaggtg gtggctctgc acaagacatc 1980
cagatgaccc agtctccaag cagcctgtct gcaagcgtgg gggacagggt caccatgacc 2040
tgcagtgcca gctcaagtgt aagttacatg aactggtacc agcagaagcc gggcaaggcc 2100
cccaaaagat ggatttatga ctcatccaaa ctggcttctg gagtccctgc tcgcttcagt 2160
ggcagtgggt ctgggaccga ctataccctc acaatcagca gcctgcagcc cgaagatttc 2220
gccacttatt actgccagca gtggagtcgt aacccaccca cgttcggagg ggggaccaag 2280
ctacaaatta catcctccag ctaa 2304
<210> 118
<211> 747
<212> PRT
<213> 人工序列
<220>
<223> ROR182 抗ROR1 X 抗CD3双特异性分子
<400> 118
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Asn Cys Gln Ala Ser Gln Ser Ile Asp Ser Asn
20 25 30
Leu Ala Trp Phe Gln Gln Lys Pro Gly Gln Pro Pro Lys Leu Leu Ile
35 40 45
Tyr Arg Ala Ser Asn Leu Ala Ser Gly Val Pro Asp Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Glu Ala
65 70 75 80
Glu Asp Val Ala Thr Tyr Tyr Cys Leu Gly Gly Val Gly Ala Val Ser
85 90 95
Tyr Arg Thr Ser Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Gly Gly
100 105 110
Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly
115 120 125
Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro
130 135 140
Gly Arg Ser Leu Arg Leu Ser Cys Thr Ala Ser Gly Ser Asp Ile Asn
145 150 155 160
Asp Tyr Pro Ile Thr Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu
165 170 175
Trp Ile Gly Phe Ile Asn Ser Gly Gly Ser Thr Trp Tyr Ala Ser Trp
180 185 190
Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Ser Ile Ala
195 200 205
Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu Asp Thr Ala Val Tyr Tyr
210 215 220
Cys Ala Arg Gly Tyr Ser Thr Tyr Tyr Arg Asp Phe Asn Ile Trp Gly
225 230 235 240
Gln Gly Thr Leu Val Thr Val Ser Ser Ser Glu Pro Lys Ser Ser Asp
245 250 255
Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Ala
260 265 270
Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile
275 280 285
Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu
290 295 300
Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His
305 310 315 320
Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg
325 330 335
Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys
340 345 350
Glu Tyr Lys Cys Ala Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu
355 360 365
Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr
370 375 380
Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu
385 390 395 400
Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp
405 410 415
Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val
420 425 430
Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp
435 440 445
Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His
450 455 460
Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro
465 470 475 480
Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
485 490 495
Ser Pro Gly Ser Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val
500 505 510
Gln Pro Gly Arg Ser Leu Arg Leu Ser Cys Lys Ala Ser Gly Tyr Thr
515 520 525
Phe Thr Arg Ser Thr Met His Trp Val Arg Gln Ala Pro Gly Gln Gly
530 535 540
Leu Glu Trp Ile Gly Tyr Ile Asn Pro Ser Ser Ala Tyr Thr Asn Tyr
545 550 555 560
Asn Gln Lys Phe Lys Asp Arg Phe Thr Ile Ser Ala Asp Lys Ser Lys
565 570 575
Ser Thr Ala Phe Leu Gln Met Asp Ser Leu Arg Pro Glu Asp Thr Gly
580 585 590
Val Tyr Phe Cys Ala Arg Pro Gln Val His Tyr Asp Tyr Asn Gly Phe
595 600 605
Pro Tyr Trp Gly Gln Gly Thr Pro Val Thr Val Ser Ser Gly Gly Gly
610 615 620
Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Ala Gln Asp Ile
625 630 635 640
Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg
645 650 655
Val Thr Met Thr Cys Ser Ala Ser Ser Ser Val Ser Tyr Met Asn Trp
660 665 670
Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Arg Trp Ile Tyr Asp Ser
675 680 685
Ser Lys Leu Ala Ser Gly Val Pro Ala Arg Phe Ser Gly Ser Gly Ser
690 695 700
Gly Thr Asp Tyr Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe
705 710 715 720
Ala Thr Tyr Tyr Cys Gln Gln Trp Ser Arg Asn Pro Pro Thr Phe Gly
725 730 735
Gly Gly Thr Lys Leu Gln Ile Thr Ser Ser Ser
740 745
<210> 119
<211> 2316
<212> DNA
<213> 人工序列
<220>
<223> ROR192 抗ROR1 X 抗CD3双特异性分子
<400> 119
atggaagcac cagcgcagct tctcttcctc ctgctactct ggctcccaga taccaccggt 60
gacatccaga tgacccagtc cccctcctcc ctgtccgcct ccgtgggcga ccgggtgacc 120
atcaactgcc aggcctccca gtccatcgac tccaacctgg cctggttcca gcagaagccc 180
ggccagcccc ccaagctgct gatctaccgg gcctccaacc tggcctccgg cgtgcccgac 240
cggttctccg gctccggctc cggcaccgac ttcaccctga ccatctcctc cctggaggcc 300
gaggacgtgg ccacctacta ctgcctgggc ggcgtgggcg ccgtgtccta ccggacctcc 360
ttcggcggcg gcaccaaggt ggagatcaag ggtggaggcg gttcaggcgg aggtggatcc 420
ggcggtggcg gctccggtgg cggcggatct gaggtgcagc tggtggagtc cggcggcggc 480
ctggtgcagc ccggccggtc cctgcggctg tcctgcaccg cctccggctc cgacatcaac 540
gactacccca tcacctgggt gcggcaggcc cccggccagg gcctggagtg gatcggcttc 600
atcaactccg gcggctccac ctggtacgcc tcctgggtga agggccggtt caccatctcc 660
cgggacgact ccaagtccat cgcctacctg cagatgaact ccctgaagac cgaggacacc 720
gccgtgtact attgcgcccg gggctactcc acctactacc gggacttcaa catctggggc 780
cagggcaccc tggtgaccgt gtcctcgagt gagcccaaat cttctgacaa aactcacaca 840
tgcccaccgt gcccagcacc tgaagccgcg ggtgcaccgt cagtcttcct cttcccccca 900
aaacccaagg acaccctcat gatctcccgg acccctgagg tcacatgcgt ggtggtggac 960
gtgagccacg aagaccctga ggtcaagttc aactggtacg tggacggcgt ggaggtgcat 1020
aatgccaaga caaagccgcg ggaggagcag tacaacagca cgtaccgtgt ggtcagcgtc 1080
ctcaccgtcc tgcaccagga ctggctgaat ggcaaggaat acaagtgcgc ggtctccaac 1140
aaagccctcc cagcccccat cgagaaaacc atctccaaag ccaaagggca gccccgagaa 1200
ccacaggtgt acaccctgcc cccatcccgg gatgagctga ccaagaacca ggtcagcctg 1260
acctgcctgg tcaaaggctt ctatccaagc gacatcgccg tggagtggga gagcaatggg 1320
cagccggaga acaactacaa gaccacgcct cccgtgctgg actccgacgg ctccttcttc 1380
ctctacagca agctcaccgt ggacaagagc aggtggcagc aggggaacgt cttctcatgc 1440
tccgtgatgc atgaggctct gcacaaccac tacacgcaga agagcctctc cctgtctccg 1500
ggttctggtg gaggcggttc aggcggaggt ggctccggcg gtggcggatc gccgggctct 1560
caggtccagc tggtgcaatc tgggcctgag gtgaagaagc ctgggtcctc ggtgaaggtc 1620
tcctgcaagg cttctggata taccttcagc agatctacga tgcactgggt gcgacaggcc 1680
cctggacaag ggcttgagtg gataggatac attaatccta gcagtgctta tactaattac 1740
aatcagaaat tcaaggacag agtcacgatt accgcggaca aatccacgag cacagcctac 1800
atggagctga gcagcctgag atctgaggac acggccgtgt attactgtgc gagaccccaa 1860
gtccactatg attacaacgg gtttccttac tggggccaag gaaccctggt caccgtctcc 1920
tcaggtggag gcggttcagg cggaggtgga tccggcggtg gcggatcggg tggcggcgga 1980
tctgacatcc agatgaccca gtctccttcc accctgtctg catctgtagg agacagagtc 2040
accatgactt gcagtgccag ctcaagtgta agttacatga actggtatca gcagaaacca 2100
gggaaagccc ctaagagatg gatttatgac tcatccaaac tggcttctgg ggtcccatca 2160
aggttcagcg gcagtggatc tgggacagat tatactctca ccatcagcag cctgcagcct 2220
gatgattttg caacttatta ctgccaacag tggagtcgta acccacccac tttcggcgga 2280
gggaccaagg tggagatcaa acggtcctcc agctaa 2316
<210> 120
<211> 751
<212> PRT
<213> 人工序列
<220>
<223> ROR192 抗ROR1 X 抗CD3双特异性分子
<400> 120
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Asn Cys Gln Ala Ser Gln Ser Ile Asp Ser Asn
20 25 30
Leu Ala Trp Phe Gln Gln Lys Pro Gly Gln Pro Pro Lys Leu Leu Ile
35 40 45
Tyr Arg Ala Ser Asn Leu Ala Ser Gly Val Pro Asp Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Glu Ala
65 70 75 80
Glu Asp Val Ala Thr Tyr Tyr Cys Leu Gly Gly Val Gly Ala Val Ser
85 90 95
Tyr Arg Thr Ser Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Gly Gly
100 105 110
Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly
115 120 125
Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro
130 135 140
Gly Arg Ser Leu Arg Leu Ser Cys Thr Ala Ser Gly Ser Asp Ile Asn
145 150 155 160
Asp Tyr Pro Ile Thr Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu
165 170 175
Trp Ile Gly Phe Ile Asn Ser Gly Gly Ser Thr Trp Tyr Ala Ser Trp
180 185 190
Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Ser Ile Ala
195 200 205
Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu Asp Thr Ala Val Tyr Tyr
210 215 220
Cys Ala Arg Gly Tyr Ser Thr Tyr Tyr Arg Asp Phe Asn Ile Trp Gly
225 230 235 240
Gln Gly Thr Leu Val Thr Val Ser Ser Ser Glu Pro Lys Ser Ser Asp
245 250 255
Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Ala
260 265 270
Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile
275 280 285
Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu
290 295 300
Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His
305 310 315 320
Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg
325 330 335
Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys
340 345 350
Glu Tyr Lys Cys Ala Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu
355 360 365
Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr
370 375 380
Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu
385 390 395 400
Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp
405 410 415
Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val
420 425 430
Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp
435 440 445
Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His
450 455 460
Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro
465 470 475 480
Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
485 490 495
Ser Pro Gly Ser Gln Val Gln Leu Val Gln Ser Gly Pro Glu Val Lys
500 505 510
Lys Pro Gly Ser Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr
515 520 525
Phe Ser Arg Ser Thr Met His Trp Val Arg Gln Ala Pro Gly Gln Gly
530 535 540
Leu Glu Trp Ile Gly Tyr Ile Asn Pro Ser Ser Ala Tyr Thr Asn Tyr
545 550 555 560
Asn Gln Lys Phe Lys Asp Arg Val Thr Ile Thr Ala Asp Lys Ser Thr
565 570 575
Ser Thr Ala Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala
580 585 590
Val Tyr Tyr Cys Ala Arg Pro Gln Val His Tyr Asp Tyr Asn Gly Phe
595 600 605
Pro Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly
610 615 620
Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
625 630 635 640
Ser Asp Ile Gln Met Thr Gln Ser Pro Ser Thr Leu Ser Ala Ser Val
645 650 655
Gly Asp Arg Val Thr Met Thr Cys Ser Ala Ser Ser Ser Val Ser Tyr
660 665 670
Met Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Arg Trp Ile
675 680 685
Tyr Asp Ser Ser Lys Leu Ala Ser Gly Val Pro Ser Arg Phe Ser Gly
690 695 700
Ser Gly Ser Gly Thr Asp Tyr Thr Leu Thr Ile Ser Ser Leu Gln Pro
705 710 715 720
Asp Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Trp Ser Arg Asn Pro Pro
725 730 735
Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg Ser Ser Ser
740 745 750
<210> 121
<211> 15
<212> PRT
<213> 人工序列
<220>
<223> sss(s)-hIgG1铰链
<400> 121
Glu Pro Lys Ser Ser Asp Lys Thr His Thr Ser Pro Pro Ser Ser
1 5 10 15
<210> 122
<211> 15
<212> PRT
<213> 人工序列
<220>
<223> csc(s)-hIgG1铰链
<400> 122
Glu Pro Lys Ser Cys Asp Lys Thr His Thr Ser Pro Pro Cys Ser
1 5 10 15
<210> 123
<211> 15
<212> PRT
<213> 人工序列
<220>
<223> ssc(s)-hIgG1铰链
<400> 123
Glu Pro Lys Ser Ser Asp Lys Thr His Thr Ser Pro Pro Cys Ser
1 5 10 15
<210> 124
<211> 15
<212> PRT
<213> 人工序列
<220>
<223> scc(s)-hIgG1铰链
<400> 124
Glu Pro Lys Ser Ser Asp Lys Thr His Thr Cys Pro Pro Cys Ser
1 5 10 15
<210> 125
<211> 15
<212> PRT
<213> 人工序列
<220>
<223> css(s)-hIgG1铰链
<400> 125
Glu Pro Lys Ser Cys Asp Lys Thr His Thr Ser Pro Pro Ser Ser
1 5 10 15
<210> 126
<211> 15
<212> PRT
<213> 人工序列
<220>
<223> scs(s)-hIgG1铰链
<400> 126
Glu Pro Lys Ser Ser Asp Lys Thr His Thr Cys Pro Pro Ser Ser
1 5 10 15
<210> 127
<211> 15
<212> PRT
<213> 人工序列
<220>
<223> ccc(s)-hIgG1铰链
<400> 127
Glu Pro Lys Ser Cys Asp Lys Thr His Thr Ser Pro Pro Cys Ser
1 5 10 15
<210> 128
<211> 15
<212> PRT
<213> 人工序列
<220>
<223> ccc(p)-hIgG1铰链
<400> 128
Glu Pro Lys Ser Cys Asp Lys Thr His Thr Ser Pro Pro Cys Pro
1 5 10 15
<210> 129
<211> 15
<212> PRT
<213> 人工序列
<220>
<223> sss(p)-hIgG1铰链
<400> 129
Glu Pro Lys Ser Ser Asp Lys Thr His Thr Ser Pro Pro Ser Pro
1 5 10 15
<210> 130
<211> 15
<212> PRT
<213> 人工序列
<220>
<223> csc(p)-hIgG1铰链
<400> 130
Glu Pro Lys Ser Cys Asp Lys Thr His Thr Ser Pro Pro Cys Pro
1 5 10 15
<210> 131
<211> 15
<212> PRT
<213> 人工序列
<220>
<223> ssc(p)-hIgG1铰链
<400> 131
Glu Pro Lys Ser Ser Asp Lys Thr His Thr Ser Pro Pro Cys Pro
1 5 10 15
<210> 132
<211> 15
<212> PRT
<213> 人工序列
<220>
<223> scc(p)-hIgG1铰链
<400> 132
Glu Pro Lys Ser Ser Asp Lys Thr His Thr Cys Pro Pro Cys Pro
1 5 10 15
<210> 133
<211> 15
<212> PRT
<213> 人工序列
<220>
<223> css(p)-hIgG1铰链
<400> 133
Glu Pro Lys Ser Cys Asp Lys Thr His Thr Ser Pro Pro Ser Pro
1 5 10 15
<210> 134
<211> 15
<212> PRT
<213> 人工序列
<220>
<223> scs(p)-hIgG1铰链
<400> 134
Glu Pro Lys Ser Ser Asp Lys Thr His Thr Cys Pro Pro Ser Pro
1 5 10 15
<210> 135
<211> 6
<212> PRT
<213> 人工序列
<220>
<223> Scppcp接头
<400> 135
Ser Cys Pro Pro Cys Pro
1 5
<210> 136
<211> 20
<212> PRT
<213> 人工序列
<220>
<223> STD1接头
<400> 136
Asn Tyr Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
1 5 10 15
Ser Gly Asn Ser
20
<210> 137
<211> 38
<212> PRT
<213> 人工序列
<220>
<223> STD2接头
<400> 137
Asn Tyr Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
1 5 10 15
Ser Gly Asn Tyr Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
20 25 30
Gly Gly Ser Gly Asn Ser
35
<210> 138
<211> 2
<212> PRT
<213> 人工序列
<220>
<223> H1接头
<400> 138
Asn Ser
1
<210> 139
<211> 8
<212> PRT
<213> 人工序列
<220>
<223> H2接头
<400> 139
Gly Gly Gly Gly Ser Gly Asn Ser
1 5
<210> 140
<211> 10
<212> PRT
<213> 人工序列
<220>
<223> H3接头
<400> 140
Asn Tyr Gly Gly Gly Gly Ser Gly Asn Ser
1 5 10
<210> 141
<211> 13
<212> PRT
<213> 人工序列
<220>
<223> H4接头
<400> 141
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Asn Ser
1 5 10
<210> 142
<211> 15
<212> PRT
<213> 人工序列
<220>
<223> H5接头
<400> 142
Asn Tyr Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Asn Ser
1 5 10 15
<210> 143
<211> 18
<212> PRT
<213> 人工序列
<220>
<223> H6接头
<400> 143
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly
1 5 10 15
Asn Ser
<210> 144
<211> 8
<212> PRT
<213> 人工序列
<220>
<223> H7接头
<400> 144
Gly Cys Pro Pro Cys Pro Asn Ser
1 5
<210> 145
<211> 15
<212> PRT
<213> 人工序列
<220>
<223> (G4S)3接头
<400> 145
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
1 5 10 15
<210> 146
<211> 16
<212> PRT
<213> 人工序列
<220>
<223> H105接头
<400> 146
Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
1 5 10 15
<210> 147
<211> 20
<212> PRT
<213> 人工序列
<220>
<223> (G4S)4接头
<400> 147
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly
1 5 10 15
Gly Gly Gly Ser
20
<210> 148
<211> 21
<212> PRT
<213> 人工序列
<220>
<223> H75 (NKG2A四倍突变体)接头
<400> 148
Gln Arg His Asn Asn Ser Ser Leu Asn Thr Gly Thr Gln Met Ala Gly
1 5 10 15
His Ser Pro Asn Ser
20
<210> 149
<211> 16
<212> PRT
<213> 人工序列
<220>
<223> H83 (NKG2A来源的)接头
<400> 149
Ser Ser Leu Asn Thr Gly Thr Gln Met Ala Gly His Ser Pro Asn Ser
1 5 10 15
<210> 150
<211> 18
<212> PRT
<213> 人工序列
<220>
<223> H106 (NKG2A来源的)接头
<400> 150
Gln Arg His Asn Asn Ser Ser Leu Asn Thr Gly Thr Gln Met Ala Gly
1 5 10 15
His Ser
<210> 151
<211> 14
<212> PRT
<213> 人工序列
<220>
<223> H81 (NKG2D来源的)接头
<400> 151
Glu Val Gln Ile Pro Leu Thr Glu Ser Tyr Ser Pro Asn Ser
1 5 10
<210> 152
<211> 20
<212> PRT
<213> 人工序列
<220>
<223> H91 (NKG2D来源的)接头
<400> 152
Asn Ser Leu Ala Asn Gln Glu Val Gln Ile Pro Leu Thr Glu Ser Tyr
1 5 10 15
Ser Pro Asn Ser
20
<210> 153
<211> 19
<212> PRT
<213> 人工序列
<220>
<223> H94接头
<400> 153
Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
1 5 10 15
Pro Asn Ser
<210> 154
<211> 15
<212> PRT
<213> 人工序列
<220>
<223> H16铰链
<400> 154
Leu Ser Val Lys Ala Asp Phe Leu Thr Pro Ser Ile Gly Asn Ser
1 5 10 15
<210> 155
<211> 20
<212> PRT
<213> 人工序列
<220>
<223> H17铰链
<400> 155
Leu Ser Val Lys Ala Asp Phe Leu Thr Pro Ser Ile Ser Cys Pro Pro
1 5 10 15
Cys Pro Asn Ser
20
<210> 156
<211> 15
<212> PRT
<213> 人工序列
<220>
<223> H18铰链
<400> 156
Leu Ser Val Leu Ala Asn Phe Ser Gln Pro Glu Ile Gly Asn Ser
1 5 10 15
<210> 157
<211> 20
<212> PRT
<213> 人工序列
<220>
<223> H19铰链
<400> 157
Leu Ser Val Leu Ala Asn Phe Ser Gln Pro Glu Ile Ser Cys Pro Pro
1 5 10 15
Cys Pro Asn Ser
20
<210> 158
<211> 15
<212> PRT
<213> 人工序列
<220>
<223> H20铰链
<400> 158
Leu Lys Ile Gln Glu Arg Val Ser Lys Pro Lys Ile Ser Asn Ser
1 5 10 15
<210> 159
<211> 20
<212> PRT
<213> 人工序列
<220>
<223> H21铰链
<400> 159
Leu Lys Ile Gln Glu Arg Val Ser Lys Pro Lys Ile Ser Cys Pro Pro
1 5 10 15
Cys Pro Asn Ser
20
<210> 160
<211> 15
<212> PRT
<213> 人工序列
<220>
<223> H22铰链
<400> 160
Leu Asn Val Ser Glu Arg Pro Phe Pro Pro His Ile Gln Asn Ser
1 5 10 15
<210> 161
<211> 21
<212> PRT
<213> 人工序列
<220>
<223> H23铰链
<400> 161
Leu Asp Val Ser Glu Arg Pro Phe Pro Pro His Ile Gln Ser Cys Pro
1 5 10 15
Pro Cys Pro Asn Ser
20
<210> 162
<211> 15
<212> PRT
<213> 人工序列
<220>
<223> H24铰链
<400> 162
Arg Glu Gln Leu Ala Glu Val Thr Leu Ser Leu Lys Ala Asn Ser
1 5 10 15
<210> 163
<211> 20
<212> PRT
<213> 人工序列
<220>
<223> H25铰链
<400> 163
Arg Glu Gln Leu Ala Glu Val Thr Leu Ser Leu Lys Ala Cys Pro Pro
1 5 10 15
Cys Pro Asn Ser
20
<210> 164
<211> 15
<212> PRT
<213> 人工序列
<220>
<223> H26铰链
<400> 164
Arg Ile His Gln Met Asn Ser Glu Leu Ser Val Leu Ala Asn Ser
1 5 10 15
<210> 165
<211> 20
<212> PRT
<213> 人工序列
<220>
<223> H27铰链
<400> 165
Arg Ile His Gln Met Asn Ser Glu Leu Ser Val Leu Ala Cys Pro Pro
1 5 10 15
Cys Pro Asn Ser
20
<210> 166
<211> 15
<212> PRT
<213> 人工序列
<220>
<223> H28铰链
<400> 166
Asp Thr Lys Gly Lys Asn Val Leu Glu Lys Ile Phe Ser Asn Ser
1 5 10 15
<210> 167
<211> 15
<212> PRT
<213> 人工序列
<220>
<223> H30铰链
<400> 167
Leu Pro Pro Glu Thr Gln Glu Ser Gln Glu Val Thr Leu Asn Ser
1 5 10 15
<210> 168
<211> 15
<212> PRT
<213> 人工序列
<220>
<223> H32铰链
<400> 168
Arg Ile His Leu Asn Val Ser Glu Arg Pro Phe Pro Pro Asn Ser
1 5 10 15
<210> 169
<211> 20
<212> PRT
<213> 人工序列
<220>
<223> H33铰链
<400> 169
Arg Ile His Leu Asn Val Ser Glu Arg Pro Phe Pro Pro Cys Pro Pro
1 5 10 15
Cys Pro Asn Ser
20
<210> 170
<211> 13
<212> PRT
<213> 人工序列
<220>
<223> H36铰链
<400> 170
Gly Cys Pro Pro Cys Pro Gly Gly Gly Gly Ser Asn Ser
1 5 10
<210> 171
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> H40铰链
<400> 171
Gly Cys Pro Pro Cys Pro Ala Asn Ser
1 5
<210> 172
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> H41铰链
<400> 172
Gly Cys Pro Pro Cys Pro Ala Asn Ser
1 5
<210> 173
<211> 8
<212> PRT
<213> 人工序列
<220>
<223> H42铰链
<400> 173
Gly Cys Pro Pro Cys Pro Asn Ser
1 5
<210> 174
<211> 13
<212> PRT
<213> 人工序列
<220>
<223> H44铰链
<400> 174
Gly Gly Gly Ala Ser Cys Pro Pro Cys Pro Gly Asn Ser
1 5 10
<210> 175
<211> 13
<212> PRT
<213> 人工序列
<220>
<223> H45铰链
<400> 175
Gly Gly Gly Ala Ser Cys Pro Pro Cys Ala Gly Asn Ser
1 5 10
<210> 176
<211> 12
<212> PRT
<213> 人工序列
<220>
<223> H46铰链
<400> 176
Gly Gly Gly Ala Ser Cys Pro Pro Cys Ala Asn Ser
1 5 10
<210> 177
<211> 15
<212> PRT
<213> 人工序列
<220>
<223> H47铰链
<400> 177
Leu Ser Val Lys Ala Asp Phe Leu Thr Pro Ser Ile Gly Asn Ser
1 5 10 15
<210> 178
<211> 11
<212> PRT
<213> 人工序列
<220>
<223> H48铰链
<400> 178
Ala Asp Phe Leu Thr Pro Ser Ile Gly Asn Ser
1 5 10
<210> 179
<211> 15
<212> PRT
<213> 人工序列
<220>
<223> H50铰链
<400> 179
Leu Ser Val Leu Ala Asn Phe Ser Gln Pro Glu Ile Gly Asn Ser
1 5 10 15
<210> 180
<211> 15
<212> PRT
<213> 人工序列
<220>
<223> H51铰链
<400> 180
Leu Ser Val Leu Ala Asn Phe Ser Gln Pro Glu Ile Gly Asn Ser
1 5 10 15
<210> 181
<211> 11
<212> PRT
<213> 人工序列
<220>
<223> H52铰链
<400> 181
Ser Gln Pro Glu Ile Val Pro Ile Ser Asn Ser
1 5 10
<210> 182
<211> 16
<212> PRT
<213> 人工序列
<220>
<223> H53铰链
<400> 182
Ser Gln Pro Glu Ile Val Pro Ile Ser Cys Pro Pro Cys Pro Asn Ser
1 5 10 15
<210> 183
<211> 19
<212> PRT
<213> 人工序列
<220>
<223> H54铰链
<400> 183
Ser Val Leu Ala Asn Phe Ser Gln Pro Glu Ile Ser Cys Pro Pro Cys
1 5 10 15
Pro Asn Ser
<210> 184
<211> 15
<212> PRT
<213> 人工序列
<220>
<223> H55铰链
<400> 184
Arg Ile His Gln Met Asn Ser Glu Leu Ser Val Leu Ala Asn Ser
1 5 10 15
<210> 185
<211> 12
<212> PRT
<213> 人工序列
<220>
<223> H56铰链
<400> 185
Gln Met Asn Ser Glu Leu Ser Val Leu Ala Asn Ser
1 5 10
<210> 186
<211> 10
<212> PRT
<213> 人工序列
<220>
<223> H57铰链
<400> 186
Val Ser Glu Arg Pro Phe Pro Pro Asn Ser
1 5 10
<210> 187
<211> 15
<212> PRT
<213> 人工序列
<220>
<223> H58铰链
<400> 187
Lys Pro Phe Phe Thr Cys Gly Ser Ala Asp Thr Cys Pro Asn Ser
1 5 10 15
<210> 188
<211> 15
<212> PRT
<213> 人工序列
<220>
<223> H59铰链
<400> 188
Lys Pro Phe Phe Thr Cys Gly Ser Ala Asp Thr Cys Pro Asn Ser
1 5 10 15
<210> 189
<211> 15
<212> PRT
<213> 人工序列
<220>
<223> H60铰链
<400> 189
Gln Tyr Asn Cys Pro Gly Gln Tyr Thr Phe Ser Met Pro Asn Ser
1 5 10 15
<210> 190
<211> 21
<212> PRT
<213> 人工序列
<220>
<223> H61铰链
<400> 190
Glu Pro Ala Phe Thr Pro Gly Pro Asn Ile Glu Leu Gln Lys Asp Ser
1 5 10 15
Asp Cys Pro Asn Ser
20
<210> 191
<211> 21
<212> PRT
<213> 人工序列
<220>
<223> H62铰链
<400> 191
Gln Arg His Asn Asn Ser Ser Leu Asn Thr Arg Thr Gln Lys Ala Arg
1 5 10 15
His Cys Pro Asn Ser
20
<210> 192
<211> 20
<212> PRT
<213> 人工序列
<220>
<223> H63铰链
<400> 192
Asn Ser Leu Phe Asn Gln Glu Val Gln Ile Pro Leu Thr Glu Ser Tyr
1 5 10 15
Cys Pro Asn Ser
20
<210> 193
<211> 15
<212> PRT
<213> 人工序列
<220>
<223> ((Gly4Ser)3)接头
<400> 193
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
1 5 10 15
<210> 194
<211> 25
<212> PRT
<213> 人工序列
<220>
<223> (Gly4Ser)n接头
<220>
<221> MISC_FEATURE
<222> (6)..(25)
<223> 氨基酸残基可以不存在
<400> 194
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly
1 5 10 15
Gly Gly Gly Ser Gly Gly Gly Gly Ser
20 25
<210> 195
<211> 20
<212> PRT
<213> 人工序列
<220>
<223> 分泌信号序列
<400> 195
Met Glu Ala Pro Ala Gln Leu Leu Phe Leu Leu Leu Leu Trp Leu Pro
1 5 10 15
Asp Thr Thr Gly
20
<210> 196
<211> 19
<212> PRT
<213> 人工序列
<220>
<223> H111接头
<400> 196
Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
1 5 10 15
Pro Gly Ser
<210> 197
<211> 751
<212> PRT
<213> 人工序列
<220>
<223> 嵌合双特异性抗CD123 (VLVH) x 抗CD3 (TSC456) scFv-Fc-scFv CD3结合结构域
<400> 197
Asp Ile Met Met Ser Gln Ser Pro Ser Ser Leu Ala Val Ser Val Gly
1 5 10 15
Glu Lys Phe Thr Met Thr Cys Lys Ser Ser Gln Ser Leu Phe Phe Gly
20 25 30
Ser Thr Gln Lys Asn Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln
35 40 45
Ser Pro Lys Leu Leu Ile Tyr Trp Ala Ser Thr Arg Glu Ser Gly Val
50 55 60
Pro Asp Arg Phe Thr Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Ala
65 70 75 80
Ile Ser Ser Val Met Pro Glu Asp Leu Ala Val Tyr Tyr Cys Gln Gln
85 90 95
Tyr Tyr Asn Tyr Pro Trp Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile
100 105 110
Lys Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
115 120 125
Gly Gly Gly Gly Ser Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val
130 135 140
Lys Pro Ser Gln Ser Leu Ser Leu Thr Cys Ser Val Thr Asp Tyr Ser
145 150 155 160
Ile Thr Ser Gly Tyr Tyr Trp Asn Trp Ile Arg Gln Phe Pro Gly Asn
165 170 175
Lys Leu Glu Trp Met Gly Tyr Ile Ser Tyr Asp Gly Ser Asn Asn Tyr
180 185 190
Asn Pro Ser Leu Lys Asn Arg Ile Ser Ile Thr Arg Asp Thr Ser Lys
195 200 205
Asn Gln Phe Phe Leu Lys Leu Ser Ser Val Thr Thr Glu Asp Thr Ala
210 215 220
Thr Tyr Tyr Cys Ser Arg Gly Glu Gly Phe Tyr Phe Asp Ser Trp Gly
225 230 235 240
Gln Gly Thr Thr Leu Thr Val Ser Ser Ser Glu Pro Lys Ser Ser Asp
245 250 255
Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Ala
260 265 270
Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile
275 280 285
Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu
290 295 300
Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His
305 310 315 320
Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg
325 330 335
Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys
340 345 350
Glu Tyr Lys Cys Ala Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu
355 360 365
Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr
370 375 380
Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu
385 390 395 400
Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp
405 410 415
Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val
420 425 430
Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp
435 440 445
Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His
450 455 460
Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro
465 470 475 480
Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
485 490 495
Ser Pro Gly Ser Gln Val Gln Leu Val Gln Ser Gly Pro Glu Val Lys
500 505 510
Lys Pro Gly Ser Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr
515 520 525
Phe Ser Arg Ser Thr Met His Trp Val Arg Gln Ala Pro Gly Gln Gly
530 535 540
Leu Glu Trp Ile Gly Tyr Ile Asn Pro Ser Ser Ala Tyr Thr Asn Tyr
545 550 555 560
Asn Gln Lys Phe Lys Asp Arg Val Thr Ile Thr Ala Asp Lys Ser Thr
565 570 575
Ser Thr Ala Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala
580 585 590
Val Tyr Tyr Cys Ala Arg Pro Gln Val His Tyr Asp Tyr Asn Gly Phe
595 600 605
Pro Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly
610 615 620
Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
625 630 635 640
Ser Asp Ile Gln Met Thr Gln Ser Pro Ser Thr Leu Ser Ala Ser Val
645 650 655
Gly Asp Arg Val Thr Met Thr Cys Ser Ala Ser Ser Ser Val Ser Tyr
660 665 670
Met Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Arg Trp Ile
675 680 685
Tyr Asp Ser Ser Lys Leu Ala Ser Gly Val Pro Ser Arg Phe Ser Gly
690 695 700
Ser Gly Ser Gly Thr Asp Tyr Thr Leu Thr Ile Ser Ser Leu Gln Pro
705 710 715 720
Asp Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Trp Ser Arg Asn Pro Pro
725 730 735
Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg Ser Ser Ser
740 745 750
<210> 198
<211> 753
<212> PRT
<213> 人工序列
<220>
<223> 嵌合双特异性抗CD123 (VHVL) x 抗CD3 (TSC456) scFv-Fc-scFv CD3结合结构域
<400> 198
Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gln Ser
1 5 10 15
Leu Ser Leu Thr Cys Ser Val Thr Asp Tyr Ser Ile Thr Ser Gly Tyr
20 25 30
Tyr Trp Asn Trp Ile Arg Gln Phe Pro Gly Asn Lys Leu Glu Trp Met
35 40 45
Gly Tyr Ile Ser Tyr Asp Gly Ser Asn Asn Tyr Asn Pro Ser Leu Lys
50 55 60
Asn Arg Ile Ser Ile Thr Arg Asp Thr Ser Lys Asn Gln Phe Phe Leu
65 70 75 80
Lys Leu Ser Ser Val Thr Thr Glu Asp Thr Ala Thr Tyr Tyr Cys Ser
85 90 95
Arg Gly Glu Gly Phe Tyr Phe Asp Ser Trp Gly Gln Gly Thr Thr Leu
100 105 110
Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
115 120 125
Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Met Met Ser Gln Ser Pro
130 135 140
Ser Ser Leu Ala Val Ser Val Gly Glu Lys Phe Thr Met Thr Cys Lys
145 150 155 160
Ser Ser Gln Ser Leu Phe Phe Gly Ser Thr Gln Lys Asn Tyr Leu Ala
165 170 175
Trp Tyr Gln Gln Lys Pro Gly Gln Ser Pro Lys Leu Leu Ile Tyr Trp
180 185 190
Ala Ser Thr Arg Glu Ser Gly Val Pro Asp Arg Phe Thr Gly Ser Gly
195 200 205
Ser Gly Thr Asp Phe Thr Leu Ala Ile Ser Ser Val Met Pro Glu Asp
210 215 220
Leu Ala Val Tyr Tyr Cys Gln Gln Tyr Tyr Asn Tyr Pro Trp Thr Phe
225 230 235 240
Gly Gly Gly Thr Lys Leu Glu Ile Lys Ser Ser Ser Glu Pro Lys Ser
245 250 255
Ser Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala
260 265 270
Gly Ala Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu
275 280 285
Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser
290 295 300
His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu
305 310 315 320
Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr
325 330 335
Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn
340 345 350
Gly Lys Glu Tyr Lys Cys Ala Val Ser Asn Lys Ala Leu Pro Ala Pro
355 360 365
Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln
370 375 380
Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val
385 390 395 400
Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val
405 410 415
Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro
420 425 430
Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr
435 440 445
Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val
450 455 460
Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu
465 470 475 480
Ser Pro Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
485 490 495
Gly Gly Ser Pro Gly Ser Gln Val Gln Leu Val Gln Ser Gly Pro Glu
500 505 510
Val Lys Lys Pro Gly Ser Ser Val Lys Val Ser Cys Lys Ala Ser Gly
515 520 525
Tyr Thr Phe Ser Arg Ser Thr Met His Trp Val Arg Gln Ala Pro Gly
530 535 540
Gln Gly Leu Glu Trp Ile Gly Tyr Ile Asn Pro Ser Ser Ala Tyr Thr
545 550 555 560
Asn Tyr Asn Gln Lys Phe Lys Asp Arg Val Thr Ile Thr Ala Asp Lys
565 570 575
Ser Thr Ser Thr Ala Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp
580 585 590
Thr Ala Val Tyr Tyr Cys Ala Arg Pro Gln Val His Tyr Asp Tyr Asn
595 600 605
Gly Phe Pro Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly
610 615 620
Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
625 630 635 640
Gly Gly Ser Asp Ile Gln Met Thr Gln Ser Pro Ser Thr Leu Ser Ala
645 650 655
Ser Val Gly Asp Arg Val Thr Met Thr Cys Ser Ala Ser Ser Ser Val
660 665 670
Ser Tyr Met Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Arg
675 680 685
Trp Ile Tyr Asp Ser Ser Lys Leu Ala Ser Gly Val Pro Ser Arg Phe
690 695 700
Ser Gly Ser Gly Ser Gly Thr Asp Tyr Thr Leu Thr Ile Ser Ser Leu
705 710 715 720
Gln Pro Asp Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Trp Ser Arg Asn
725 730 735
Pro Pro Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg Ser Ser
740 745 750
Ser
<210> 199
<211> 8
<212> PRT
<213> 人工序列
<220>
<223> Cris7和DRA222 VH CDR1 (IMGT) CD3结合结构域
<400> 199
Gly Tyr Thr Phe Thr Arg Ser Thr
1 5
<210> 200
<211> 8
<212> PRT
<213> 人工序列
<220>
<223> Cris7和DRA222 VH CDR2 (IMGT) CD3结合结构域
<400> 200
Ile Asn Pro Ser Ser Ala Tyr Thr
1 5
<210> 201
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> Cris7和DRA222 VH CDR3 (IMGT) CD3结合结构域
<400> 201
Gln Gln Trp Ser Arg Asn Pro Pro Thr
1 5
<210> 202
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> Cris7和DRA222 VL CDR1 (IMGT) CD3结合结构域
<400> 202
Ala Ser Ser Ser Val Ser Tyr
1 5
<210> 203
<211> 3
<212> PRT
<213> 人工序列
<220>
<223> Cris7和DRA222 VL CDR2 (IMGT) CD3结合结构域
<400> 203
Asp Ser Ser
1
<210> 204
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> Cris7和DRA222 VL CDR3 (IMGT) CD3结合结构域
<400> 204
Gln Gln Trp Ser Arg Asn Pro Pro Thr
1 5
<210> 205
<211> 2286
<212> DNA
<213> 人工序列
<220>
<223> TSC471抗PSMA X 抗CD3双特异性分子
<400> 205
atggaagcac cagcgcagct tctcttcctc ctgctactct ggctcccaga taccaccggt 60
gatatccaga tgacccagtc tccatccgcc atgtctgcat ctgtaggaga cagagtcacc 120
atcacttgcc gggcgagtaa gagcattagc aaatatttag cctggtttca gcagaaacca 180
gggaaagttc ctaagctccg catccattct ggatctactt tgcaatcagg ggtcccatct 240
cggttcagtg gcagtggatc tgggacagaa tttactctca ccatcagcag cctgcagcct 300
gaagattttg caacttatta ctgtcaacag catattgaat acccgtggac gttcggccaa 360
gggaccaagg tggaaatcaa acgaggtggc ggagggtctg ggggtggcgg atccggaggt 420
ggtggctctc aggtccagct ggtacagtct ggggctgagg tgaagaagcc tggggcttca 480
gtgaaggtct cctgcaaggc ttctggatac acattcactg actactacat gcactgggtg 540
cgacaggccc ctggacaagg gcttgagtgg atgggatatt ttaatcctta taatgattat 600
actagatacg cacagaagtt ccagggcaga gtcaccatga ccagggacac gtctatcagc 660
acagcctaca tggagctgag cagcctgaga tctgacgaca cggccgtgta ttactgtgca 720
agatcggatg gttactacga tgctatggac tactggggtc aaggaaccac agtcaccgtc 780
tcctcgagtg agcccaaatc ttctgacaaa actcacacat gcccaccgtg cccagcacct 840
gaagccgcgg gtgcaccgtc agtcttcctc ttccccccaa aacccaagga caccctcatg 900
atctcccgga cccctgaggt cacatgcgtg gtggtggacg tgagccacga agaccctgag 960
gtcaagttca actggtacgt ggacggcgtg gaggtgcata atgccaagac aaagccgcgg 1020
gaggagcagt acaacagcac gtaccgtgtg gtcagcgtcc tcaccgtcct gcaccaggac 1080
tggctgaatg gcaaggaata caagtgcgcg gtctccaaca aagccctccc agcccccatc 1140
gagaaaacca tctccaaagc caaagggcag ccccgagaac cacaggtgta caccctgccc 1200
ccatcccggg atgagctgac caagaaccag gtcagcctga cctgcctggt caaaggcttc 1260
tatccaagcg acatcgccgt ggagtgggag agcaatgggc agccggagaa caactacaag 1320
accacgcctc ccgtgctgga ctccgacggc tccttcttcc tctacagcaa gctcaccgtg 1380
gacaagagca ggtggcagca ggggaacgtc ttctcatgct ccgtgatgca tgaggctctg 1440
cacaaccact acacgcagaa gagcctctcc ctgtctccgg gttccggagg tggcggttcg 1500
ggaggtggcg ggtcaggagg tgggggctct ccttcacagg tgcagctggt gcagtctggt 1560
cctgaggtga aaaagcctgg ctccagcgtg aaggtgtcct gcaaggccag cggatacacc 1620
tttagccggt ccaccatgca ttgggtgagg caggctcctg gacagggcct ggagtggatc 1680
ggctacatca accccagcag cgcttatacc aactacaatc agaagtttaa ggaccgggtg 1740
accatcaccg ccgataagtc caccagcacc gcctacatgg agctgtccag cctgaggagc 1800
gaggataccg ccgtgtacta ttgcgcccgg ccccaggtcc attacgacta caacggcttc 1860
ccctattggg gccagggaac cctggtgacc gtgtccagcg gtggcggtgg cagcggcggc 1920
ggcggctctg gcggaggtgg cagcggcgga gggggctccg acattcagat gacccagtcc 1980
ccctccaccc tgtccgctag cgtgggcgat cgggtgacca tgacctgcag cgccagcagc 2040
tccgtgtcct acatgaactg gtaccagcag aagcccggca aggctcccaa gaggtggatt 2100
tacgactcca gcaagctggc ctctggtgtc cccagcaggt tctctggtag cggcagcggc 2160
acagactaca ccctgaccat ctcctccctg cagcccgacg atttcgccac ctactattgc 2220
cagcagtggt cccggaatcc ccctaccttt ggcggcggca ccaaggtgga gatcaagagg 2280
agctaa 2286
<210> 206
<211> 741
<212> PRT
<213> 人工序列
<220>
<223> TSC471抗PSMA X 抗CD3双特异性分子
<400> 206
Asp Ile Gln Met Thr Gln Ser Pro Ser Ala Met Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Lys Ser Ile Ser Lys Tyr
20 25 30
Leu Ala Trp Phe Gln Gln Lys Pro Gly Lys Val Pro Lys Leu Arg Ile
35 40 45
His Ser Gly Ser Thr Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln His Ile Glu Tyr Pro Trp
85 90 95
Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Gly Gly Gly Gly
100 105 110
Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gln Val Gln Leu Val
115 120 125
Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala Ser Val Lys Val Ser
130 135 140
Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Tyr Tyr Met His Trp Val
145 150 155 160
Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met Gly Tyr Phe Asn Pro
165 170 175
Tyr Asn Asp Tyr Thr Arg Tyr Ala Gln Lys Phe Gln Gly Arg Val Thr
180 185 190
Met Thr Arg Asp Thr Ser Ile Ser Thr Ala Tyr Met Glu Leu Ser Ser
195 200 205
Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys Ala Arg Ser Asp Gly
210 215 220
Tyr Tyr Asp Ala Met Asp Tyr Trp Gly Gln Gly Thr Thr Val Thr Val
225 230 235 240
Ser Ser Ser Glu Pro Lys Ser Ser Asp Lys Thr His Thr Cys Pro Pro
245 250 255
Cys Pro Ala Pro Glu Ala Ala Gly Ala Pro Ser Val Phe Leu Phe Pro
260 265 270
Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr
275 280 285
Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn
290 295 300
Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg
305 310 315 320
Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val
325 330 335
Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Ala Val Ser
340 345 350
Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys
355 360 365
Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp
370 375 380
Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe
385 390 395 400
Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu
405 410 415
Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe
420 425 430
Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly
435 440 445
Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr
450 455 460
Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Ser Gly Gly Gly Gly Ser
465 470 475 480
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Pro Ser Gln Val Gln Leu
485 490 495
Val Gln Ser Gly Pro Glu Val Lys Lys Pro Gly Ser Ser Val Lys Val
500 505 510
Ser Cys Lys Ala Ser Gly Tyr Thr Phe Ser Arg Ser Thr Met His Trp
515 520 525
Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Ile Gly Tyr Ile Asn
530 535 540
Pro Ser Ser Ala Tyr Thr Asn Tyr Asn Gln Lys Phe Lys Asp Arg Val
545 550 555 560
Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr Met Glu Leu Ser
565 570 575
Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Pro Gln
580 585 590
Val His Tyr Asp Tyr Asn Gly Phe Pro Tyr Trp Gly Gln Gly Thr Leu
595 600 605
Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly
610 615 620
Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Gln Met Thr Gln Ser
625 630 635 640
Pro Ser Thr Leu Ser Ala Ser Val Gly Asp Arg Val Thr Met Thr Cys
645 650 655
Ser Ala Ser Ser Ser Val Ser Tyr Met Asn Trp Tyr Gln Gln Lys Pro
660 665 670
Gly Lys Ala Pro Lys Arg Trp Ile Tyr Asp Ser Ser Lys Leu Ala Ser
675 680 685
Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Tyr Thr
690 695 700
Leu Thr Ile Ser Ser Leu Gln Pro Asp Asp Phe Ala Thr Tyr Tyr Cys
705 710 715 720
Gln Gln Trp Ser Arg Asn Pro Pro Thr Phe Gly Gly Gly Thr Lys Val
725 730 735
Glu Ile Lys Arg Ser
740
<210> 207
<211> 2307
<212> DNA
<213> 人工序列
<220>
<223> ROR243抗ROR1 X 抗CD3双特异性分子
<400> 207
atggaggctc ccgctcagct gctgttcctc ctgctgctct ggctgcccga caccacaggc 60
gacatccaga tgacccagtc cccttcctcc ctgtccgcta gcgtgggcga tagggtgacc 120
atcaactgcc aggcctccca gtccattgac tccaatctgg cctggttcca gcagaagccc 180
ggacagcccc ccaagctgct gatttacagg gcctccaacc tggcttccgg cgtgcctgac 240
aggttctccg gatccggcag cggcaccgac ttcaccctga ccatctcctc cctggaggcc 300
gaggatgtcg ccacctacta ctgtctgggc ggcgtgggcg ctgtgagcta tcggacctcc 360
ttcggcggcg gcaccaaggt ggagatcaag ggcggcggcg gcagcggcgg cggcggcagc 420
ggcggcggag gctccggcgg cggcggcagc gaggtgcagc tggtggaaag cggaggaggc 480
ctggtgcagc ctggaaggtc cctgaggctg tcctgcacag ccagcggctc cgacatcaac 540
gactacccca tcacctgggt gaggcaggct cctggccagg gcctggaatg gatcggcttt 600
atcaacagcg gcggcagcac ctggtatgct tcctgggtga agggccggtt caccattagc 660
agggacgact ccaagtccat tgcctacctg cagatgaact ccctgaagac cgaggacacc 720
gccgtgtact actgcgccag gggctacagc acctattacc gggactttaa catctggggc 780
cagggcacac tggtcaccgt gtcctcgagt gagcccaaat cttctgacaa aactcacaca 840
tgcccaccgt gcccagcacc tgaagccgcg ggtgcaccgt cagtcttcct cttcccccca 900
aaacccaagg acaccctcat gatctcccgg acccctgagg tcacatgcgt ggtggtggac 960
gtgagccacg aagaccctga ggtcaagttc aactggtacg tggacggcgt ggaggtgcat 1020
aatgccaaga caaagccgcg ggaggagcag tacaacagca cgtaccgtgt ggtcagcgtc 1080
ctcaccgtcc tgcaccagga ctggctgaat ggcaaggaat acaagtgcgc ggtctccaac 1140
aaagccctcc cagcccccat cgagaaaacc atctccaaag ccaaagggca gccccgagaa 1200
ccacaggtgt acaccctgcc cccatcccgg gatgagctga ccaagaacca ggtcagcctg 1260
acctgcctgg tcaaaggctt ctatccaagc gacatcgccg tggagtggga gagcaatggg 1320
cagccggaga acaactacaa gaccacgcct cccgtgctgg actccgacgg ctccttcttc 1380
ctctacagca agctcaccgt ggacaagagc aggtggcagc aggggaacgt cttctcatgc 1440
tccgtgatgc atgaggctct gcacaaccac tacacgcaga agagcctctc cctgtctccg 1500
ggttccggag gagggggttc aggtggggga ggttctggcg gcgggggaag cccttcacag 1560
gtgcaactgg tgcagagtgg acccgaggtt aaaaaaccag ggtcctccgt taaggttagc 1620
tgcaaagcct ctggctacac attttccagg agtacaatgc actgggtgag gcaggctcct 1680
ggacagggac tcgagtggat cgggtatatc aacccatcta gcgcctatac caattacaac 1740
caaaagttta aggaccgagt taccattacc gctgacaaat ccaccagtac agcttatatg 1800
gagctgtcat ctcttaggtc cgaggacact gctgtttatt actgcgctcg tcctcaggtt 1860
cactatgact ataatggttt tccctactgg ggtcagggaa ccctggtgac tgtctcttct 1920
ggcggtggag gcagcggtgg gggtgggtct ggaggcggtg gcagtggcgg cggaggctct 1980
gatattcaga tgactcagtc tcctagcact ctcagcgcca gcgtggggga tcgtgtgaca 2040
atgacttgct ccgctagcag tagtgtgtct tacatgaatt ggtatcagca gaagcccggg 2100
aaagcaccta agcgctggat ctatgactct tccaagctgg caagtggtgt cccctcacgg 2160
ttctctggct caggttctgg tactgactat actttgacta tctcctccct ccagcccgat 2220
gatttcgcta cctattattg tcagcagtgg agccgtaacc cacccacttt cggaggcggt 2280
accaaagtgg agatcaagag gtcatga 2307
<210> 208
<211> 748
<212> PRT
<213> 人工序列
<220>
<223> ROR243抗ROR1 X 抗CD3双特异性分子
<400> 208
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Asn Cys Gln Ala Ser Gln Ser Ile Asp Ser Asn
20 25 30
Leu Ala Trp Phe Gln Gln Lys Pro Gly Gln Pro Pro Lys Leu Leu Ile
35 40 45
Tyr Arg Ala Ser Asn Leu Ala Ser Gly Val Pro Asp Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Glu Ala
65 70 75 80
Glu Asp Val Ala Thr Tyr Tyr Cys Leu Gly Gly Val Gly Ala Val Ser
85 90 95
Tyr Arg Thr Ser Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Gly Gly
100 105 110
Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly
115 120 125
Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro
130 135 140
Gly Arg Ser Leu Arg Leu Ser Cys Thr Ala Ser Gly Ser Asp Ile Asn
145 150 155 160
Asp Tyr Pro Ile Thr Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu
165 170 175
Trp Ile Gly Phe Ile Asn Ser Gly Gly Ser Thr Trp Tyr Ala Ser Trp
180 185 190
Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Ser Ile Ala
195 200 205
Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu Asp Thr Ala Val Tyr Tyr
210 215 220
Cys Ala Arg Gly Tyr Ser Thr Tyr Tyr Arg Asp Phe Asn Ile Trp Gly
225 230 235 240
Gln Gly Thr Leu Val Thr Val Ser Ser Ser Glu Pro Lys Ser Ser Asp
245 250 255
Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Ala
260 265 270
Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile
275 280 285
Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu
290 295 300
Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His
305 310 315 320
Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg
325 330 335
Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys
340 345 350
Glu Tyr Lys Cys Ala Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu
355 360 365
Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr
370 375 380
Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu
385 390 395 400
Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp
405 410 415
Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val
420 425 430
Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp
435 440 445
Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His
450 455 460
Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro
465 470 475 480
Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
485 490 495
Ser Pro Ser Gln Val Gln Leu Val Gln Ser Gly Pro Glu Val Lys Lys
500 505 510
Pro Gly Ser Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe
515 520 525
Ser Arg Ser Thr Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu
530 535 540
Glu Trp Ile Gly Tyr Ile Asn Pro Ser Ser Ala Tyr Thr Asn Tyr Asn
545 550 555 560
Gln Lys Phe Lys Asp Arg Val Thr Ile Thr Ala Asp Lys Ser Thr Ser
565 570 575
Thr Ala Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val
580 585 590
Tyr Tyr Cys Ala Arg Pro Gln Val His Tyr Asp Tyr Asn Gly Phe Pro
595 600 605
Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly
610 615 620
Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
625 630 635 640
Asp Ile Gln Met Thr Gln Ser Pro Ser Thr Leu Ser Ala Ser Val Gly
645 650 655
Asp Arg Val Thr Met Thr Cys Ser Ala Ser Ser Ser Val Ser Tyr Met
660 665 670
Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Arg Trp Ile Tyr
675 680 685
Asp Ser Ser Lys Leu Ala Ser Gly Val Pro Ser Arg Phe Ser Gly Ser
690 695 700
Gly Ser Gly Thr Asp Tyr Thr Leu Thr Ile Ser Ser Leu Gln Pro Asp
705 710 715 720
Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Trp Ser Arg Asn Pro Pro Thr
725 730 735
Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg Ser
740 745
<210> 209
<211> 2289
<212> DNA
<213> 人工序列
<220>
<223> TSC266抗PSMA X 抗CD3双特异性分子
<400> 209
atggaagcac cagcgcagct tctcttcctc ctgctactct ggctcccaga taccaccggt 60
gatatccaga tgacccagtc tccatccgcc atgtctgcat ctgtaggaga cagagtcacc 120
atcacttgcc gggcgagtaa gagcattagc aaatatttag cctggtttca gcagaaacca 180
gggaaagttc ctaagctccg catccattct ggatctactt tgcaatcagg ggtcccatct 240
cggttcagtg gcagtggatc tgggacagaa tttactctca ccatcagcag cctgcagcct 300
gaagattttg caacttatta ctgtcaacag catattgaat acccgtggac gttcggccaa 360
gggaccaagg tggaaatcaa acgaggtggc ggagggtctg ggggtggcgg atccggaggt 420
ggtggctctc aggtccagct ggtacagtct ggggctgagg tgaagaagcc tggggcttca 480
gtgaaggtct cctgcaaggc ttctggatac acattcactg actactacat gcactgggtg 540
cgacaggccc ctggacaagg gcttgagtgg atgggatatt ttaatcctta taatgattat 600
actagatacg cacagaagtt ccagggcaga gtcaccatga ccagggacac gtctatcagc 660
acagcctaca tggagctgag cagcctgaga tctgacgaca cggccgtgta ttactgtgca 720
agatcggatg gttactacga tgctatggac tactggggtc aaggaaccac agtcaccgtc 780
tcctcgagtg agcccaaatc ttctgacaaa actcacacat gcccaccgtg cccagcacct 840
gaagccgcgg gtgcaccgtc agtcttcctc ttccccccaa aacccaagga caccctcatg 900
atctcccgga cccctgaggt cacatgcgtg gtggtggacg tgagccacga agaccctgag 960
gtcaagttca actggtacgt ggacggcgtg gaggtgcata atgccaagac aaagccgcgg 1020
gaggagcagt acaacagcac gtaccgtgtg gtcagcgtcc tcaccgtcct gcaccaggac 1080
tggctgaatg gcaaggcgta cgcgtgcgcg gtctccaaca aagccctccc agcccccatc 1140
gagaaaacca tctccaaagc caaagggcag ccccgagaac cacaggtgta caccctgccc 1200
ccatcccggg atgagctgac caagaaccag gtcagcctga cctgcctggt caaaggcttc 1260
tatccaagcg acatcgccgt ggagtgggag agcaatgggc agccggagaa caactacaag 1320
accacgcctc ccgtgctgga ctccgacggc tccttcttcc tctacagcaa gctcaccgtg 1380
gacaagagca ggtggcagca ggggaacgtc ttctcatgct ccgtgatgca tgaggctctg 1440
cacaaccact acacgcagaa gagcctctcc ctgtctccgg gtcagaggca caacaattct 1500
tccctgaata caggaactca gatggcaggt cattctccga attctcaggt ccagctggtg 1560
gagtctgggg gcggagtggt gcagcctggg cggtcactga ggctgtcctg caaggcttct 1620
ggctacacct ttactagatc tacgatgcac tgggtaaggc aggcccctgg acaaggtctg 1680
gaatggattg gatacattaa tcctagcagt gcttatacta attacaatca gaaattcaag 1740
gacaggttca caatcagcgc agacaaatcc aagagcacag ccttcctgca gatggacagc 1800
ctgaggcccg aggacaccgg cgtctatttc tgtgcacggc cccaagtcca ctatgattac 1860
aacgggtttc cttactgggg ccaagggact cccgtcactg tctctagcgg tggcggaggg 1920
tctgggggtg gcggatccgg aggtggtggc tctgcacaag acatccagat gacccagtct 1980
ccaagcagcc tgtctgcaag cgtgggggac agggtcacca tgacctgcag tgccagctca 2040
agtgtaagtt acatgaactg gtaccagcag aagccgggca aggcccccaa aagatggatt 2100
tatgactcat ccaaactggc ttctggagtc cctgctcgct tcagtggcag tgggtctggg 2160
accgactata ccctcacaat cagcagcctg cagcccgaag atttcgccac ttattactgc 2220
cagcagtgga gtcgtaaccc acccacgttc ggagggggga ccaagctaca aattacatcc 2280
tccagctaa 2289
<210> 210
<211> 742
<212> PRT
<213> 人工序列
<220>
<223> TSC266抗PSMA X 抗CD3双特异性分子
<400> 210
Asp Ile Gln Met Thr Gln Ser Pro Ser Ala Met Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Lys Ser Ile Ser Lys Tyr
20 25 30
Leu Ala Trp Phe Gln Gln Lys Pro Gly Lys Val Pro Lys Leu Arg Ile
35 40 45
His Ser Gly Ser Thr Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln His Ile Glu Tyr Pro Trp
85 90 95
Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Gly Gly Gly Gly
100 105 110
Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gln Val Gln Leu Val
115 120 125
Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala Ser Val Lys Val Ser
130 135 140
Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Tyr Tyr Met His Trp Val
145 150 155 160
Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met Gly Tyr Phe Asn Pro
165 170 175
Tyr Asn Asp Tyr Thr Arg Tyr Ala Gln Lys Phe Gln Gly Arg Val Thr
180 185 190
Met Thr Arg Asp Thr Ser Ile Ser Thr Ala Tyr Met Glu Leu Ser Ser
195 200 205
Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys Ala Arg Ser Asp Gly
210 215 220
Tyr Tyr Asp Ala Met Asp Tyr Trp Gly Gln Gly Thr Thr Val Thr Val
225 230 235 240
Ser Ser Ser Glu Pro Lys Ser Ser Asp Lys Thr His Thr Cys Pro Pro
245 250 255
Cys Pro Ala Pro Glu Ala Ala Gly Ala Pro Ser Val Phe Leu Phe Pro
260 265 270
Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr
275 280 285
Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn
290 295 300
Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg
305 310 315 320
Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val
325 330 335
Leu His Gln Asp Trp Leu Asn Gly Lys Ala Tyr Ala Cys Ala Val Ser
340 345 350
Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys
355 360 365
Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp
370 375 380
Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe
385 390 395 400
Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu
405 410 415
Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe
420 425 430
Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly
435 440 445
Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr
450 455 460
Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Gln Arg His Asn Asn Ser
465 470 475 480
Ser Leu Asn Thr Gly Thr Gln Met Ala Gly His Ser Pro Asn Ser Gln
485 490 495
Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg Ser
500 505 510
Leu Arg Leu Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Arg Ser Thr
515 520 525
Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Ile Gly
530 535 540
Tyr Ile Asn Pro Ser Ser Ala Tyr Thr Asn Tyr Asn Gln Lys Phe Lys
545 550 555 560
Asp Arg Phe Thr Ile Ser Ala Asp Lys Ser Lys Ser Thr Ala Phe Leu
565 570 575
Gln Met Asp Ser Leu Arg Pro Glu Asp Thr Gly Val Tyr Phe Cys Ala
580 585 590
Arg Pro Gln Val His Tyr Asp Tyr Asn Gly Phe Pro Tyr Trp Gly Gln
595 600 605
Gly Thr Pro Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly
610 615 620
Gly Ser Gly Gly Gly Gly Ser Ala Gln Asp Ile Gln Met Thr Gln Ser
625 630 635 640
Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Met Thr Cys
645 650 655
Ser Ala Ser Ser Ser Val Ser Tyr Met Asn Trp Tyr Gln Gln Lys Pro
660 665 670
Gly Lys Ala Pro Lys Arg Trp Ile Tyr Asp Ser Ser Lys Leu Ala Ser
675 680 685
Gly Val Pro Ala Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Tyr Thr
690 695 700
Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys
705 710 715 720
Gln Gln Trp Ser Arg Asn Pro Pro Thr Phe Gly Gly Gly Thr Lys Leu
725 730 735
Gln Ile Thr Ser Ser Ser
740
<210> 211
<211> 2301
<212> DNA
<213> 人工序列
<220>
<223> ROR206抗ROR1 X 抗CD3双特异性分子
<400> 211
atggaagcac cagcgcagct tctcttcctc ctgctactct ggctcccaga taccaccggt 60
gacatccaga tgacccagtc cccctcctcc ctgtccgcct ccgtgggcga ccgggtgacc 120
atcaactgcc aggcctccca gtccatcgac tccaacctgg cctggttcca gcagaagccc 180
ggcaagcccc ccaagctgct gatctaccgg gcctccaacc tggcctccgg cgtgccctcc 240
cggttctccg gctccggctc cggcaccgac ttcaccctga ccatctcctc cctgcagccc 300
gaggacgtgg ccacctacta ctgcctgggc ggcgtgggcg ccgtgtccta ccggacctcc 360
ttcggcggcg gcaccaaggt ggagatcaag ggtggaggcg gttcaggcgg aggtggatcc 420
ggcggtggcg gctccggtgg cggcggatct gaggtgcagc tggtggagtc cggcggcggc 480
ctggtgcagc ccggccggtc cctgcggctg tcctgcaccg cctccggctc cgacatcaac 540
gactacccca tcacctgggt gcggcaggcc cccggcaagg gcctggagtg gatcggcttc 600
atcaactccg gcggctccac ctggtacgcc tcctgggtga agggccggtt caccatctcc 660
cgggacgact ccaagtccat cgcctacctg cagatgaact ccctgaagac cgaggacacc 720
gccgtgtact attgcgcccg gggctactcc acctactacc gggacttcaa catctggggc 780
cagggcaccc tggtgaccgt gtcctcgagt gagcccaaat cttctgacaa aactcacaca 840
tgcccaccgt gcccagcacc tgaagccgcg ggtgcaccgt cagtcttcct cttcccccca 900
aaacccaagg acaccctcat gatctcccgg acccctgagg tcacatgcgt ggtggtggac 960
gtgagccacg aagaccctga ggtcaagttc aactggtacg tggacggcgt ggaggtgcat 1020
aatgccaaga caaagccgcg ggaggagcag tacaacagca cgtaccgtgt ggtcagcgtc 1080
ctcaccgtcc tgcaccagga ctggctgaat ggcaaggaat acaagtgcgc ggtctccaac 1140
aaagccctcc cagcccccat cgagaaaacc atctccaaag ccaaagggca gccccgagaa 1200
ccacaggtgt acaccctgcc cccatcccgg gatgagctga ccaagaacca ggtcagcctg 1260
acctgcctgg tcaaaggctt ctatccaagc gacatcgccg tggagtggga gagcaatggg 1320
cagccggaga acaactacaa gaccacgcct cccgtgctgg actccgacgg ctccttcttc 1380
ctctacagca agctcaccgt ggacaagagc aggtggcagc aggggaacgt cttctcatgc 1440
tccgtgatgc atgaggctct gcacaaccac tacacgcaga agagcctctc cctgtctccg 1500
ggttctggtg gaggcggttc aggcggaggt ggctccggcg gtggcggatc gccgggctct 1560
caggtccagc tggtggagtc tgggggcgga gtggtgcagc ctgggcggtc actgaggctg 1620
tcctgcaagg cttctggcta cacctttact agatctacga tgcactgggt aaggcaggcc 1680
cctggacaag gtctggaatg gattggatac attaatccta gcagtgctta tactaattac 1740
aatcagaaat tcaaggacag gttcacaatc agcgcagaca aatccaagag cacagccttc 1800
ctgcagatgg acagcctgag gcccgaggac accggcgtct atttctgtgc acggccccaa 1860
gtccactatg attacaacgg gtttccttac tggggccaag ggactcccgt cactgtctct 1920
agcggtggcg gagggtctgg gggtggcgga tccggaggtg gtggctctgc acaagacatc 1980
cagatgaccc agtctccaag cagcctgtct gcaagcgtgg gggacagggt caccatgacc 2040
tgcagtgcca gctcaagtgt aagttacatg aactggtacc agcagaagcc gggcaaggcc 2100
cccaaaagat ggatttatga ctcatccaaa ctggcttctg gagtccctgc tcgcttcagt 2160
ggcagtgggt ctgggaccga ctataccctc acaatcagca gcctgcagcc cgaagatttc 2220
gccacttatt actgccagca gtggagtcgt aacccaccca cgttcggagg ggggaccaag 2280
ctacaaatta catcctccag c 2301
<210> 212
<211> 767
<212> PRT
<213> 人工序列
<220>
<223> ROR206抗ROR1 X 抗CD3双特异性分子
<400> 212
Met Glu Ala Pro Ala Gln Leu Leu Phe Leu Leu Leu Leu Trp Leu Pro
1 5 10 15
Asp Thr Thr Gly Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser
20 25 30
Ala Ser Val Gly Asp Arg Val Thr Ile Asn Cys Gln Ala Ser Gln Ser
35 40 45
Ile Asp Ser Asn Leu Ala Trp Phe Gln Gln Lys Pro Gly Lys Pro Pro
50 55 60
Lys Leu Leu Ile Tyr Arg Ala Ser Asn Leu Ala Ser Gly Val Pro Ser
65 70 75 80
Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser
85 90 95
Ser Leu Gln Pro Glu Asp Val Ala Thr Tyr Tyr Cys Leu Gly Gly Val
100 105 110
Gly Ala Val Ser Tyr Arg Thr Ser Phe Gly Gly Gly Thr Lys Val Glu
115 120 125
Ile Lys Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
130 135 140
Ser Gly Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly
145 150 155 160
Leu Val Gln Pro Gly Arg Ser Leu Arg Leu Ser Cys Thr Ala Ser Gly
165 170 175
Ser Asp Ile Asn Asp Tyr Pro Ile Thr Trp Val Arg Gln Ala Pro Gly
180 185 190
Lys Gly Leu Glu Trp Ile Gly Phe Ile Asn Ser Gly Gly Ser Thr Trp
195 200 205
Tyr Ala Ser Trp Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asp Ser
210 215 220
Lys Ser Ile Ala Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu Asp Thr
225 230 235 240
Ala Val Tyr Tyr Cys Ala Arg Gly Tyr Ser Thr Tyr Tyr Arg Asp Phe
245 250 255
Asn Ile Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ser Glu Pro
260 265 270
Lys Ser Ser Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu
275 280 285
Ala Ala Gly Ala Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp
290 295 300
Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp
305 310 315 320
Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly
325 330 335
Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn
340 345 350
Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp
355 360 365
Leu Asn Gly Lys Glu Tyr Lys Cys Ala Val Ser Asn Lys Ala Leu Pro
370 375 380
Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu
385 390 395 400
Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn
405 410 415
Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile
420 425 430
Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr
435 440 445
Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys
450 455 460
Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys
465 470 475 480
Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu
485 490 495
Ser Leu Ser Pro Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
500 505 510
Gly Gly Gly Gly Ser Pro Gly Ser Gln Val Gln Leu Val Glu Ser Gly
515 520 525
Gly Gly Val Val Gln Pro Gly Arg Ser Leu Arg Leu Ser Cys Lys Ala
530 535 540
Ser Gly Tyr Thr Phe Thr Arg Ser Thr Met His Trp Val Arg Gln Ala
545 550 555 560
Pro Gly Gln Gly Leu Glu Trp Ile Gly Tyr Ile Asn Pro Ser Ser Ala
565 570 575
Tyr Thr Asn Tyr Asn Gln Lys Phe Lys Asp Arg Phe Thr Ile Ser Ala
580 585 590
Asp Lys Ser Lys Ser Thr Ala Phe Leu Gln Met Asp Ser Leu Arg Pro
595 600 605
Glu Asp Thr Gly Val Tyr Phe Cys Ala Arg Pro Gln Val His Tyr Asp
610 615 620
Tyr Asn Gly Phe Pro Tyr Trp Gly Gln Gly Thr Pro Val Thr Val Ser
625 630 635 640
Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
645 650 655
Ala Gln Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser
660 665 670
Val Gly Asp Arg Val Thr Met Thr Cys Ser Ala Ser Ser Ser Val Ser
675 680 685
Tyr Met Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Arg Trp
690 695 700
Ile Tyr Asp Ser Ser Lys Leu Ala Ser Gly Val Pro Ala Arg Phe Ser
705 710 715 720
Gly Ser Gly Ser Gly Thr Asp Tyr Thr Leu Thr Ile Ser Ser Leu Gln
725 730 735
Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Trp Ser Arg Asn Pro
740 745 750
Pro Thr Phe Gly Gly Gly Thr Lys Leu Gln Ile Thr Ser Ser Ser
755 760 765
<210> 213
<211> 2313
<212> DNA
<213> 人工序列
<220>
<223> ROR207抗ROR1 X 抗CD3双特异性分子
<400> 213
atggaagcac cagcgcagct tctcttcctc ctgctactct ggctcccaga taccaccggt 60
gacatccaga tgacccagtc cccctcctcc ctgtccgcct ccgtgggcga ccgggtgacc 120
atcaactgcc aggcctccca gtccatcgac tccaacctgg cctggttcca gcagaagccc 180
ggcaagcccc ccaagctgct gatctaccgg gcctccaacc tggcctccgg cgtgccctcc 240
cggttctccg gctccggctc cggcaccgac ttcaccctga ccatctcctc cctgcagccc 300
gaggacgtgg ccacctacta ctgcctgggc ggcgtgggcg ccgtgtccta ccggacctcc 360
ttcggcggcg gcaccaaggt ggagatcaag ggtggaggcg gttcaggcgg aggtggatcc 420
ggcggtggcg gctccggtgg cggcggatct gaggtgcagc tggtggagtc cggcggcggc 480
ctggtgcagc ccggccggtc cctgcggctg tcctgcaccg cctccggctc cgacatcaac 540
gactacccca tcacctgggt gcggcaggcc cccggcaagg gcctggagtg gatcggcttc 600
atcaactccg gcggctccac ctggtacgcc tcctgggtga agggccggtt caccatctcc 660
cgggacgact ccaagtccat cgcctacctg cagatgaact ccctgaagac cgaggacacc 720
gccgtgtact attgcgcccg gggctactcc acctactacc gggacttcaa catctggggc 780
cagggcaccc tggtgaccgt gtcctcgagt gagcccaaat cttctgacaa aactcacaca 840
tgcccaccgt gcccagcacc tgaagccgcg ggtgcaccgt cagtcttcct cttcccccca 900
aaacccaagg acaccctcat gatctcccgg acccctgagg tcacatgcgt ggtggtggac 960
gtgagccacg aagaccctga ggtcaagttc aactggtacg tggacggcgt ggaggtgcat 1020
aatgccaaga caaagccgcg ggaggagcag tacaacagca cgtaccgtgt ggtcagcgtc 1080
ctcaccgtcc tgcaccagga ctggctgaat ggcaaggaat acaagtgcgc ggtctccaac 1140
aaagccctcc cagcccccat cgagaaaacc atctccaaag ccaaagggca gccccgagaa 1200
ccacaggtgt acaccctgcc cccatcccgg gatgagctga ccaagaacca ggtcagcctg 1260
acctgcctgg tcaaaggctt ctatccaagc gacatcgccg tggagtggga gagcaatggg 1320
cagccggaga acaactacaa gaccacgcct cccgtgctgg actccgacgg ctccttcttc 1380
ctctacagca agctcaccgt ggacaagagc aggtggcagc aggggaacgt cttctcatgc 1440
tccgtgatgc atgaggctct gcacaaccac tacacgcaga agagcctctc cctgtctccg 1500
ggttctggtg gaggcggttc aggcggaggt ggctccggcg gtggcggatc gccgggctct 1560
caggtccagc tggtgcaatc tgggcctgag gtgaagaagc ctgggtcctc ggtgaaggtc 1620
tcctgcaagg cttctggata taccttcagc agatctacga tgcactgggt gcgacaggcc 1680
cctggacaag ggcttgagtg gataggatac attaatccta gcagtgctta tactaattac 1740
aatcagaaat tcaaggacag agtcacgatt accgcggaca aatccacgag cacagcctac 1800
atggagctga gcagcctgag atctgaggac acggccgtgt attactgtgc gagaccccaa 1860
gtccactatg attacaacgg gtttccttac tggggccaag gaaccctggt caccgtctcc 1920
tcaggtggag gcggttcagg cggaggtgga tccggcggtg gcggatcggg tggcggcgga 1980
tctgacatcc agatgaccca gtctccttcc accctgtctg catctgtagg agacagagtc 2040
accatgactt gcagtgccag ctcaagtgta agttacatga actggtatca gcagaaacca 2100
gggaaagccc ctaagagatg gatttatgac tcatccaaac tggcttctgg ggtcccatca 2160
aggttcagcg gcagtggatc tgggacagat tatactctca ccatcagcag cctgcagcct 2220
gatgattttg caacttatta ctgccaacag tggagtcgta acccacccac tttcggcgga 2280
gggaccaagg tggagatcaa acggtcctcc agc 2313
<210> 214
<211> 771
<212> PRT
<213> 人工序列
<220>
<223> ROR207抗ROR1 X 抗CD3双特异性分子
<400> 214
Met Glu Ala Pro Ala Gln Leu Leu Phe Leu Leu Leu Leu Trp Leu Pro
1 5 10 15
Asp Thr Thr Gly Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser
20 25 30
Ala Ser Val Gly Asp Arg Val Thr Ile Asn Cys Gln Ala Ser Gln Ser
35 40 45
Ile Asp Ser Asn Leu Ala Trp Phe Gln Gln Lys Pro Gly Lys Pro Pro
50 55 60
Lys Leu Leu Ile Tyr Arg Ala Ser Asn Leu Ala Ser Gly Val Pro Ser
65 70 75 80
Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser
85 90 95
Ser Leu Gln Pro Glu Asp Val Ala Thr Tyr Tyr Cys Leu Gly Gly Val
100 105 110
Gly Ala Val Ser Tyr Arg Thr Ser Phe Gly Gly Gly Thr Lys Val Glu
115 120 125
Ile Lys Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
130 135 140
Ser Gly Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly
145 150 155 160
Leu Val Gln Pro Gly Arg Ser Leu Arg Leu Ser Cys Thr Ala Ser Gly
165 170 175
Ser Asp Ile Asn Asp Tyr Pro Ile Thr Trp Val Arg Gln Ala Pro Gly
180 185 190
Lys Gly Leu Glu Trp Ile Gly Phe Ile Asn Ser Gly Gly Ser Thr Trp
195 200 205
Tyr Ala Ser Trp Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asp Ser
210 215 220
Lys Ser Ile Ala Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu Asp Thr
225 230 235 240
Ala Val Tyr Tyr Cys Ala Arg Gly Tyr Ser Thr Tyr Tyr Arg Asp Phe
245 250 255
Asn Ile Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ser Glu Pro
260 265 270
Lys Ser Ser Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu
275 280 285
Ala Ala Gly Ala Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp
290 295 300
Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp
305 310 315 320
Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly
325 330 335
Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn
340 345 350
Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp
355 360 365
Leu Asn Gly Lys Glu Tyr Lys Cys Ala Val Ser Asn Lys Ala Leu Pro
370 375 380
Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu
385 390 395 400
Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn
405 410 415
Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile
420 425 430
Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr
435 440 445
Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys
450 455 460
Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys
465 470 475 480
Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu
485 490 495
Ser Leu Ser Pro Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
500 505 510
Gly Gly Gly Gly Ser Pro Gly Ser Gln Val Gln Leu Val Gln Ser Gly
515 520 525
Pro Glu Val Lys Lys Pro Gly Ser Ser Val Lys Val Ser Cys Lys Ala
530 535 540
Ser Gly Tyr Thr Phe Ser Arg Ser Thr Met His Trp Val Arg Gln Ala
545 550 555 560
Pro Gly Gln Gly Leu Glu Trp Ile Gly Tyr Ile Asn Pro Ser Ser Ala
565 570 575
Tyr Thr Asn Tyr Asn Gln Lys Phe Lys Asp Arg Val Thr Ile Thr Ala
580 585 590
Asp Lys Ser Thr Ser Thr Ala Tyr Met Glu Leu Ser Ser Leu Arg Ser
595 600 605
Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Pro Gln Val His Tyr Asp
610 615 620
Tyr Asn Gly Phe Pro Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser
625 630 635 640
Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
645 650 655
Gly Gly Gly Gly Ser Asp Ile Gln Met Thr Gln Ser Pro Ser Thr Leu
660 665 670
Ser Ala Ser Val Gly Asp Arg Val Thr Met Thr Cys Ser Ala Ser Ser
675 680 685
Ser Val Ser Tyr Met Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro
690 695 700
Lys Arg Trp Ile Tyr Asp Ser Ser Lys Leu Ala Ser Gly Val Pro Ser
705 710 715 720
Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Tyr Thr Leu Thr Ile Ser
725 730 735
Ser Leu Gln Pro Asp Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Trp Ser
740 745 750
Arg Asn Pro Pro Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg
755 760 765
Ser Ser Ser
770
<210> 215
<211> 2301
<212> DNA
<213> 人工序列
<220>
<223> ROR208抗ROR1 X 抗CD3双特异性分子
<400> 215
atggaagcac cagcgcagct tctcttcctc ctgctactct ggctcccaga taccaccggt 60
gacatccaga tgacccagtc cccctcctcc ctgtccgcct ccgtgggcga ccgggtgacc 120
atcaactgcc aggcctccca gtccatcgac tccaacctgg cctggttcca gcagaagccc 180
ggccagcccc ccaagctgct gatctaccgg gcctccaacc tggcctccgg cgtgcccgac 240
cggttctccg gctccggctc cggcaccgac ttcaccctga ccatctcctc cctggaggcc 300
gaggacgtgg ccacctacta ctgcctgggc ggcgtgggcg ccgtgtccta ccggacctcc 360
ttcggcggcg gcaccaaggt ggagatcaag ggtggaggcg gttcaggcgg aggtggatcc 420
ggcggtggcg gctccggtgg cggcggatct gaggtgcagc tggtggagtc cggcggcggc 480
ctggtgcagc ccggccggtc cctgcggctg tcctgcaccg cctccggctc cgacatcaac 540
gactacccca tcacctgggt gcggcaggcc cccggccagg gcctggagtg gatcggcttc 600
atcaactccg gcggctccac ctggtacgcc tcctgggtga agggccggtt caccatctcc 660
cgggacgact ccaagtccat cgcctacctg cagatgaact ccctgaagac cgaggacacc 720
gccgtgtact attgcgcccg gggctactcc acctactacc gggacttcaa catctggggc 780
cagggcaccc tggtgaccgt gtcctcgagt gagcccaaat cttctgacaa aactcacaca 840
tgcccaccgt gcccagcacc tgaagccgcg ggtgcaccgt cagtcttcct cttcccccca 900
aaacccaagg acaccctcat gatctcccgg acccctgagg tcacatgcgt ggtggtggac 960
gtgagccacg aagaccctga ggtcaagttc aactggtacg tggacggcgt ggaggtgcat 1020
aatgccaaga caaagccgcg ggaggagcag tacaacagca cgtaccgtgt ggtcagcgtc 1080
ctcaccgtcc tgcaccagga ctggctgaat ggcaaggaat acaagtgcgc ggtctccaac 1140
aaagccctcc cagcccccat cgagaaaacc atctccaaag ccaaagggca gccccgagaa 1200
ccacaggtgt acaccctgcc cccatcccgg gatgagctga ccaagaacca ggtcagcctg 1260
acctgcctgg tcaaaggctt ctatccaagc gacatcgccg tggagtggga gagcaatggg 1320
cagccggaga acaactacaa gaccacgcct cccgtgctgg actccgacgg ctccttcttc 1380
ctctacagca agctcaccgt ggacaagagc aggtggcagc aggggaacgt cttctcatgc 1440
tccgtgatgc atgaggctct gcacaaccac tacacgcaga agagcctctc cctgtctccg 1500
ggttctggtg gaggcggttc aggcggaggt ggctccggcg gtggcggatc gccgggctct 1560
caggtccagc tggtggagtc tgggggcgga gtggtgcagc ctgggcggtc actgaggctg 1620
tcctgcaagg cttctggcta cacctttact agatctacga tgcactgggt aaggcaggcc 1680
cctggacaag gtctggaatg gattggatac attaatccta gcagtgctta tactaattac 1740
aatcagaaat tcaaggacag gttcacaatc agcgcagaca aatccaagag cacagccttc 1800
ctgcagatgg acagcctgag gcccgaggac accggcgtct atttctgtgc acggccccaa 1860
gtccactatg attacaacgg gtttccttac tggggccaag ggactcccgt cactgtctct 1920
agcggtggcg gagggtctgg gggtggcgga tccggaggtg gtggctctgc acaagacatc 1980
cagatgaccc agtctccaag cagcctgtct gcaagcgtgg gggacagggt caccatgacc 2040
tgcagtgcca gctcaagtgt aagttacatg aactggtacc agcagaagcc gggcaaggcc 2100
cccaaaagat ggatttatga ctcatccaaa ctggcttctg gagtccctgc tcgcttcagt 2160
ggcagtgggt ctgggaccga ctataccctc acaatcagca gcctgcagcc cgaagatttc 2220
gccacttatt actgccagca gtggagtcgt aacccaccca cgttcggagg ggggaccaag 2280
ctacaaatta catcctccag c 2301
<210> 216
<211> 767
<212> PRT
<213> 人工序列
<220>
<223> ROR208抗ROR1 X 抗CD3双特异性分子
<400> 216
Met Glu Ala Pro Ala Gln Leu Leu Phe Leu Leu Leu Leu Trp Leu Pro
1 5 10 15
Asp Thr Thr Gly Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser
20 25 30
Ala Ser Val Gly Asp Arg Val Thr Ile Asn Cys Gln Ala Ser Gln Ser
35 40 45
Ile Asp Ser Asn Leu Ala Trp Phe Gln Gln Lys Pro Gly Gln Pro Pro
50 55 60
Lys Leu Leu Ile Tyr Arg Ala Ser Asn Leu Ala Ser Gly Val Pro Asp
65 70 75 80
Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser
85 90 95
Ser Leu Glu Ala Glu Asp Val Ala Thr Tyr Tyr Cys Leu Gly Gly Val
100 105 110
Gly Ala Val Ser Tyr Arg Thr Ser Phe Gly Gly Gly Thr Lys Val Glu
115 120 125
Ile Lys Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
130 135 140
Ser Gly Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly
145 150 155 160
Leu Val Gln Pro Gly Arg Ser Leu Arg Leu Ser Cys Thr Ala Ser Gly
165 170 175
Ser Asp Ile Asn Asp Tyr Pro Ile Thr Trp Val Arg Gln Ala Pro Gly
180 185 190
Gln Gly Leu Glu Trp Ile Gly Phe Ile Asn Ser Gly Gly Ser Thr Trp
195 200 205
Tyr Ala Ser Trp Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asp Ser
210 215 220
Lys Ser Ile Ala Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu Asp Thr
225 230 235 240
Ala Val Tyr Tyr Cys Ala Arg Gly Tyr Ser Thr Tyr Tyr Arg Asp Phe
245 250 255
Asn Ile Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ser Glu Pro
260 265 270
Lys Ser Ser Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu
275 280 285
Ala Ala Gly Ala Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp
290 295 300
Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp
305 310 315 320
Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly
325 330 335
Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn
340 345 350
Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp
355 360 365
Leu Asn Gly Lys Glu Tyr Lys Cys Ala Val Ser Asn Lys Ala Leu Pro
370 375 380
Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu
385 390 395 400
Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn
405 410 415
Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile
420 425 430
Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr
435 440 445
Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys
450 455 460
Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys
465 470 475 480
Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu
485 490 495
Ser Leu Ser Pro Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
500 505 510
Gly Gly Gly Gly Ser Pro Gly Ser Gln Val Gln Leu Val Glu Ser Gly
515 520 525
Gly Gly Val Val Gln Pro Gly Arg Ser Leu Arg Leu Ser Cys Lys Ala
530 535 540
Ser Gly Tyr Thr Phe Thr Arg Ser Thr Met His Trp Val Arg Gln Ala
545 550 555 560
Pro Gly Gln Gly Leu Glu Trp Ile Gly Tyr Ile Asn Pro Ser Ser Ala
565 570 575
Tyr Thr Asn Tyr Asn Gln Lys Phe Lys Asp Arg Phe Thr Ile Ser Ala
580 585 590
Asp Lys Ser Lys Ser Thr Ala Phe Leu Gln Met Asp Ser Leu Arg Pro
595 600 605
Glu Asp Thr Gly Val Tyr Phe Cys Ala Arg Pro Gln Val His Tyr Asp
610 615 620
Tyr Asn Gly Phe Pro Tyr Trp Gly Gln Gly Thr Pro Val Thr Val Ser
625 630 635 640
Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
645 650 655
Ala Gln Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser
660 665 670
Val Gly Asp Arg Val Thr Met Thr Cys Ser Ala Ser Ser Ser Val Ser
675 680 685
Tyr Met Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Arg Trp
690 695 700
Ile Tyr Asp Ser Ser Lys Leu Ala Ser Gly Val Pro Ala Arg Phe Ser
705 710 715 720
Gly Ser Gly Ser Gly Thr Asp Tyr Thr Leu Thr Ile Ser Ser Leu Gln
725 730 735
Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Trp Ser Arg Asn Pro
740 745 750
Pro Thr Phe Gly Gly Gly Thr Lys Leu Gln Ile Thr Ser Ser Ser
755 760 765
<210> 217
<211> 2313
<212> DNA
<213> 人工序列
<220>
<223> ROR209抗ROR1 X 抗CD3双特异性分子
<400> 217
atggaagcac cagcgcagct tctcttcctc ctgctactct ggctcccaga taccaccggt 60
gacatccaga tgacccagtc cccctcctcc ctgtccgcct ccgtgggcga ccgggtgacc 120
atcaactgcc aggcctccca gtccatcgac tccaacctgg cctggttcca gcagaagccc 180
ggccagcccc ccaagctgct gatctaccgg gcctccaacc tggcctccgg cgtgcccgac 240
cggttctccg gctccggctc cggcaccgac ttcaccctga ccatctcctc cctggaggcc 300
gaggacgtgg ccacctacta ctgcctgggc ggcgtgggcg ccgtgtccta ccggacctcc 360
ttcggcggcg gcaccaaggt ggagatcaag ggtggaggcg gttcaggcgg aggtggatcc 420
ggcggtggcg gctccggtgg cggcggatct gaggtgcagc tggtggagtc cggcggcggc 480
ctggtgcagc ccggccggtc cctgcggctg tcctgcaccg cctccggctc cgacatcaac 540
gactacccca tcacctgggt gcggcaggcc cccggccagg gcctggagtg gatcggcttc 600
atcaactccg gcggctccac ctggtacgcc tcctgggtga agggccggtt caccatctcc 660
cgggacgact ccaagtccat cgcctacctg cagatgaact ccctgaagac cgaggacacc 720
gccgtgtact attgcgcccg gggctactcc acctactacc gggacttcaa catctggggc 780
cagggcaccc tggtgaccgt gtcctcgagt gagcccaaat cttctgacaa aactcacaca 840
tgcccaccgt gcccagcacc tgaagccgcg ggtgcaccgt cagtcttcct cttcccccca 900
aaacccaagg acaccctcat gatctcccgg acccctgagg tcacatgcgt ggtggtggac 960
gtgagccacg aagaccctga ggtcaagttc aactggtacg tggacggcgt ggaggtgcat 1020
aatgccaaga caaagccgcg ggaggagcag tacaacagca cgtaccgtgt ggtcagcgtc 1080
ctcaccgtcc tgcaccagga ctggctgaat ggcaaggaat acaagtgcgc ggtctccaac 1140
aaagccctcc cagcccccat cgagaaaacc atctccaaag ccaaagggca gccccgagaa 1200
ccacaggtgt acaccctgcc cccatcccgg gatgagctga ccaagaacca ggtcagcctg 1260
acctgcctgg tcaaaggctt ctatccaagc gacatcgccg tggagtggga gagcaatggg 1320
cagccggaga acaactacaa gaccacgcct cccgtgctgg actccgacgg ctccttcttc 1380
ctctacagca agctcaccgt ggacaagagc aggtggcagc aggggaacgt cttctcatgc 1440
tccgtgatgc atgaggctct gcacaaccac tacacgcaga agagcctctc cctgtctccg 1500
ggttctggtg gaggcggttc aggcggaggt ggctccggcg gtggcggatc gccgggctct 1560
caggtccagc tggtgcaatc tgggcctgag gtgaagaagc ctgggtcctc ggtgaaggtc 1620
tcctgcaagg cttctggata taccttcagc agatctacga tgcactgggt gcgacaggcc 1680
cctggacaag ggcttgagtg gataggatac attaatccta gcagtgctta tactaattac 1740
aatcagaaat tcaaggacag agtcacgatt accgcggaca aatccacgag cacagcctac 1800
atggagctga gcagcctgag atctgaggac acggccgtgt attactgtgc gagaccccaa 1860
gtccactatg attacaacgg gtttccttac tggggccaag gaaccctggt caccgtctcc 1920
tcaggtggag gcggttcagg cggaggtgga tccggcggtg gcggatcggg tggcggcgga 1980
tctgacatcc agatgaccca gtctccttcc accctgtctg catctgtagg agacagagtc 2040
accatgactt gcagtgccag ctcaagtgta agttacatga actggtatca gcagaaacca 2100
gggaaagccc ctaagagatg gatttatgac tcatccaaac tggcttctgg ggtcccatca 2160
aggttcagcg gcagtggatc tgggacagat tatactctca ccatcagcag cctgcagcct 2220
gatgattttg caacttatta ctgccaacag tggagtcgta acccacccac tttcggcgga 2280
gggaccaagg tggagatcaa acggtcctcc agc 2313
<210> 218
<211> 771
<212> PRT
<213> 人工序列
<220>
<223> ROR209抗ROR1 X 抗CD3双特异性分子
<400> 218
Met Glu Ala Pro Ala Gln Leu Leu Phe Leu Leu Leu Leu Trp Leu Pro
1 5 10 15
Asp Thr Thr Gly Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser
20 25 30
Ala Ser Val Gly Asp Arg Val Thr Ile Asn Cys Gln Ala Ser Gln Ser
35 40 45
Ile Asp Ser Asn Leu Ala Trp Phe Gln Gln Lys Pro Gly Gln Pro Pro
50 55 60
Lys Leu Leu Ile Tyr Arg Ala Ser Asn Leu Ala Ser Gly Val Pro Asp
65 70 75 80
Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser
85 90 95
Ser Leu Glu Ala Glu Asp Val Ala Thr Tyr Tyr Cys Leu Gly Gly Val
100 105 110
Gly Ala Val Ser Tyr Arg Thr Ser Phe Gly Gly Gly Thr Lys Val Glu
115 120 125
Ile Lys Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
130 135 140
Ser Gly Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly
145 150 155 160
Leu Val Gln Pro Gly Arg Ser Leu Arg Leu Ser Cys Thr Ala Ser Gly
165 170 175
Ser Asp Ile Asn Asp Tyr Pro Ile Thr Trp Val Arg Gln Ala Pro Gly
180 185 190
Gln Gly Leu Glu Trp Ile Gly Phe Ile Asn Ser Gly Gly Ser Thr Trp
195 200 205
Tyr Ala Ser Trp Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asp Ser
210 215 220
Lys Ser Ile Ala Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu Asp Thr
225 230 235 240
Ala Val Tyr Tyr Cys Ala Arg Gly Tyr Ser Thr Tyr Tyr Arg Asp Phe
245 250 255
Asn Ile Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ser Glu Pro
260 265 270
Lys Ser Ser Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu
275 280 285
Ala Ala Gly Ala Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp
290 295 300
Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp
305 310 315 320
Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly
325 330 335
Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn
340 345 350
Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp
355 360 365
Leu Asn Gly Lys Glu Tyr Lys Cys Ala Val Ser Asn Lys Ala Leu Pro
370 375 380
Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu
385 390 395 400
Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn
405 410 415
Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile
420 425 430
Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr
435 440 445
Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys
450 455 460
Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys
465 470 475 480
Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu
485 490 495
Ser Leu Ser Pro Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
500 505 510
Gly Gly Gly Gly Ser Pro Gly Ser Gln Val Gln Leu Val Gln Ser Gly
515 520 525
Pro Glu Val Lys Lys Pro Gly Ser Ser Val Lys Val Ser Cys Lys Ala
530 535 540
Ser Gly Tyr Thr Phe Ser Arg Ser Thr Met His Trp Val Arg Gln Ala
545 550 555 560
Pro Gly Gln Gly Leu Glu Trp Ile Gly Tyr Ile Asn Pro Ser Ser Ala
565 570 575
Tyr Thr Asn Tyr Asn Gln Lys Phe Lys Asp Arg Val Thr Ile Thr Ala
580 585 590
Asp Lys Ser Thr Ser Thr Ala Tyr Met Glu Leu Ser Ser Leu Arg Ser
595 600 605
Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Pro Gln Val His Tyr Asp
610 615 620
Tyr Asn Gly Phe Pro Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser
625 630 635 640
Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
645 650 655
Gly Gly Gly Gly Ser Asp Ile Gln Met Thr Gln Ser Pro Ser Thr Leu
660 665 670
Ser Ala Ser Val Gly Asp Arg Val Thr Met Thr Cys Ser Ala Ser Ser
675 680 685
Ser Val Ser Tyr Met Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro
690 695 700
Lys Arg Trp Ile Tyr Asp Ser Ser Lys Leu Ala Ser Gly Val Pro Ser
705 710 715 720
Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Tyr Thr Leu Thr Ile Ser
725 730 735
Ser Leu Gln Pro Asp Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Trp Ser
740 745 750
Arg Asn Pro Pro Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg
755 760 765
Ser Ser Ser
770
<210> 219
<211> 2313
<212> DNA
<213> 人工序列
<220>
<223> ROR231抗ROR1 X 抗CD3双特异性分子
<400> 219
atggaggcac ccgcccagct gctgttcttg ttgctgctgt ggctccctga taccaccgga 60
gacatccaga tgacccaatc cccttctagt ctctccgcta gcgtcggaga ccgcgtgacc 120
atcaattgtc aagcatctca gagtattgac agcaatctcg cctggtttca gcagaagcca 180
ggaaagccac ccaagctcct gatttatagg gctagcaacc tggcttctgg tgtccctagt 240
aggttcagcg gctctgggag tggcacagac ttcaccctga ccattagtag tctgcagccc 300
gaagatgtcg ctacctatta ctgcctcgga ggagtgggtg ccgtttctta tcgcacctca 360
tttggaggtg gcaccaaagt ggagatcaaa ggtggtggcg gctccggggg tggcgggtca 420
ggggggggag ggtctggagg cggcggatca gaagttcagc tggtggaatc tggaggaggt 480
ctggtgcagc caggcaggtc cctccggctg agctgcactg catccggctc tgacattaat 540
gactacccta tcacctgggt gaggcaggcc cccggtaaag gcctggagtg gatcgggttc 600
atcaattctg gtggatctac ttggtacgca agctgggtga aaggacgctt cacaattagt 660
agagacgact ctaagtctat cgcatatctg cagatgaata gcttgaagac agaggacacc 720
gccgtgtact attgtgcaag aggatactcc acttactacc gcgatttcaa tatctggggc 780
cagggaaccc tggtgacagt gtcctcgagt gagcccaaat cttctgacaa aactcacaca 840
tgcccaccgt gcccagcacc tgaagccgcg ggtgcaccgt cagtcttcct cttcccccca 900
aaacccaagg acaccctcat gatctcccgg acccctgagg tcacatgcgt ggtggtggac 960
gtgagccacg aagaccctga ggtcaagttc aactggtacg tggacggcgt ggaggtgcat 1020
aatgccaaga caaagccgcg ggaggagcag tacaacagca cgtaccgtgt ggtcagcgtc 1080
ctcaccgtcc tgcaccagga ctggctgaat ggcaaggaat acaagtgcgc ggtctccaac 1140
aaagccctcc cagcccccat cgagaaaacc atctccaaag ccaaagggca gccccgagaa 1200
ccacaggtgt acaccctgcc cccatcccgg gatgagctga ccaagaacca ggtcagcctg 1260
acctgcctgg tcaaaggctt ctatccaagc gacatcgccg tggagtggga gagcaatggg 1320
cagccggaga acaactacaa gaccacgcct cccgtgctgg actccgacgg ctccttcttc 1380
ctctacagca agctcaccgt ggacaagagc aggtggcagc aggggaacgt cttctcatgc 1440
tccgtgatgc atgaggctct gcacaaccac tacacgcaga agagcctctc cctgtctccg 1500
ggttccggag gcggcggctc cggcggcggc ggcagcggcg gcggcggcag ccccggatcc 1560
caggtgcagc tggtgcagtc tggtcctgag gtgaaaaagc ctggctccag cgtgaaggtg 1620
tcctgcaagg ccagcggata cacctttagc cggtccacca tgcattgggt gaggcaggct 1680
cctggacagg gcctggagtg gatcggctac atcaacccca gcagcgctta taccaactac 1740
aatcagaagt ttaaggaccg ggtgaccatc accgccgata agtccaccag caccgcctac 1800
atggagctgt ccagcctgag gagcgaggat accgccgtgt actattgcgc ccggccccag 1860
gtccattacg actacaacgg cttcccctat tggggccagg gaaccctggt gaccgtgtcc 1920
agcggaggcg gcggcagcgg cggcggcggc agcggcggag gaggcagcgg cggaggaggc 1980
tccgacattc agatgaccca gtccccctcc accctgtccg ctagcgtggg cgatcgggtg 2040
accatgacct gcagcgccag cagctccgtg tcctacatga actggtacca gcagaagccc 2100
ggcaaggctc ccaagaggtg gatttacgac tccagcaagc tggcctctgg tgtccccagc 2160
aggttctctg gtagcggcag cggcacagac tacaccctga ccatctcctc cctgcagccc 2220
gacgatttcg ccacctacta ttgccagcag tggtcccgga atccccctac ctttggcggc 2280
ggcaccaagg tggagatcaa gaggagctcc agc 2313
<210> 220
<211> 771
<212> PRT
<213> 人工序列
<220>
<223> ROR231抗ROR1 X 抗CD3双特异性分子
<400> 220
Met Glu Ala Pro Ala Gln Leu Leu Phe Leu Leu Leu Leu Trp Leu Pro
1 5 10 15
Asp Thr Thr Gly Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser
20 25 30
Ala Ser Val Gly Asp Arg Val Thr Ile Asn Cys Gln Ala Ser Gln Ser
35 40 45
Ile Asp Ser Asn Leu Ala Trp Phe Gln Gln Lys Pro Gly Lys Pro Pro
50 55 60
Lys Leu Leu Ile Tyr Arg Ala Ser Asn Leu Ala Ser Gly Val Pro Ser
65 70 75 80
Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser
85 90 95
Ser Leu Gln Pro Glu Asp Val Ala Thr Tyr Tyr Cys Leu Gly Gly Val
100 105 110
Gly Ala Val Ser Tyr Arg Thr Ser Phe Gly Gly Gly Thr Lys Val Glu
115 120 125
Ile Lys Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
130 135 140
Ser Gly Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly
145 150 155 160
Leu Val Gln Pro Gly Arg Ser Leu Arg Leu Ser Cys Thr Ala Ser Gly
165 170 175
Ser Asp Ile Asn Asp Tyr Pro Ile Thr Trp Val Arg Gln Ala Pro Gly
180 185 190
Lys Gly Leu Glu Trp Ile Gly Phe Ile Asn Ser Gly Gly Ser Thr Trp
195 200 205
Tyr Ala Ser Trp Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asp Ser
210 215 220
Lys Ser Ile Ala Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu Asp Thr
225 230 235 240
Ala Val Tyr Tyr Cys Ala Arg Gly Tyr Ser Thr Tyr Tyr Arg Asp Phe
245 250 255
Asn Ile Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ser Glu Pro
260 265 270
Lys Ser Ser Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu
275 280 285
Ala Ala Gly Ala Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp
290 295 300
Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp
305 310 315 320
Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly
325 330 335
Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn
340 345 350
Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp
355 360 365
Leu Asn Gly Lys Glu Tyr Lys Cys Ala Val Ser Asn Lys Ala Leu Pro
370 375 380
Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu
385 390 395 400
Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn
405 410 415
Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile
420 425 430
Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr
435 440 445
Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys
450 455 460
Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys
465 470 475 480
Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu
485 490 495
Ser Leu Ser Pro Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
500 505 510
Gly Gly Gly Gly Ser Pro Gly Ser Gln Val Gln Leu Val Gln Ser Gly
515 520 525
Pro Glu Val Lys Lys Pro Gly Ser Ser Val Lys Val Ser Cys Lys Ala
530 535 540
Ser Gly Tyr Thr Phe Ser Arg Ser Thr Met His Trp Val Arg Gln Ala
545 550 555 560
Pro Gly Gln Gly Leu Glu Trp Ile Gly Tyr Ile Asn Pro Ser Ser Ala
565 570 575
Tyr Thr Asn Tyr Asn Gln Lys Phe Lys Asp Arg Val Thr Ile Thr Ala
580 585 590
Asp Lys Ser Thr Ser Thr Ala Tyr Met Glu Leu Ser Ser Leu Arg Ser
595 600 605
Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Pro Gln Val His Tyr Asp
610 615 620
Tyr Asn Gly Phe Pro Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser
625 630 635 640
Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
645 650 655
Gly Gly Gly Gly Ser Asp Ile Gln Met Thr Gln Ser Pro Ser Thr Leu
660 665 670
Ser Ala Ser Val Gly Asp Arg Val Thr Met Thr Cys Ser Ala Ser Ser
675 680 685
Ser Val Ser Tyr Met Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro
690 695 700
Lys Arg Trp Ile Tyr Asp Ser Ser Lys Leu Ala Ser Gly Val Pro Ser
705 710 715 720
Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Tyr Thr Leu Thr Ile Ser
725 730 735
Ser Leu Gln Pro Asp Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Trp Ser
740 745 750
Arg Asn Pro Pro Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg
755 760 765
Ser Ser Ser
770
<210> 221
<211> 2313
<212> DNA
<213> 人工序列
<220>
<223> ROR233抗ROR1 X 抗CD3双特异性分子
<400> 221
atggaggctc ccgctcagct gctgttcctc ctgctgctct ggctgcccga caccacaggc 60
gacatccaga tgacccagtc cccttcctcc ctgtccgcta gcgtgggcga tagggtgacc 120
atcaactgcc aggcctccca gtccattgac tccaatctgg cctggttcca gcagaagccc 180
ggacagcccc ccaagctgct gatttacagg gcctccaacc tggcttccgg cgtgcctgac 240
aggttctccg gatccggcag cggcaccgac ttcaccctga ccatctcctc cctggaggcc 300
gaggatgtcg ccacctacta ctgtctgggc ggcgtgggcg ctgtgagcta tcggacctcc 360
ttcggcggcg gcaccaaggt ggagatcaag ggcggcggcg gcagcggcgg cggcggcagc 420
ggcggcggag gctccggcgg cggcggcagc gaggtgcagc tggtggaaag cggaggaggc 480
ctggtgcagc ctggaaggtc cctgaggctg tcctgcacag ccagcggctc cgacatcaac 540
gactacccca tcacctgggt gaggcaggct cctggccagg gcctggaatg gatcggcttt 600
atcaacagcg gcggcagcac ctggtatgct tcctgggtga agggccggtt caccattagc 660
agggacgact ccaagtccat tgcctacctg cagatgaact ccctgaagac cgaggacacc 720
gccgtgtact actgcgccag gggctacagc acctattacc gggactttaa catctggggc 780
cagggcacac tggtcaccgt gtcctcgagt gagcccaaat cttctgacaa aactcacaca 840
tgcccaccgt gcccagcacc tgaagccgcg ggtgcaccgt cagtcttcct cttcccccca 900
aaacccaagg acaccctcat gatctcccgg acccctgagg tcacatgcgt ggtggtggac 960
gtgagccacg aagaccctga ggtcaagttc aactggtacg tggacggcgt ggaggtgcat 1020
aatgccaaga caaagccgcg ggaggagcag tacaacagca cgtaccgtgt ggtcagcgtc 1080
ctcaccgtcc tgcaccagga ctggctgaat ggcaaggaat acaagtgcgc ggtctccaac 1140
aaagccctcc cagcccccat cgagaaaacc atctccaaag ccaaagggca gccccgagaa 1200
ccacaggtgt acaccctgcc cccatcccgg gatgagctga ccaagaacca ggtcagcctg 1260
acctgcctgg tcaaaggctt ctatccaagc gacatcgccg tggagtggga gagcaatggg 1320
cagccggaga acaactacaa gaccacgcct cccgtgctgg actccgacgg ctccttcttc 1380
ctctacagca agctcaccgt ggacaagagc aggtggcagc aggggaacgt cttctcatgc 1440
tccgtgatgc atgaggctct gcacaaccac tacacgcaga agagcctctc cctgtctccg 1500
ggttccggag gcggcggctc cggcggcggc ggcagcggcg gcggcggcag ccccggatcc 1560
caggtgcagc tggtgcagtc tggtcctgag gtgaaaaagc ctggctccag cgtgaaggtg 1620
tcctgcaagg ccagcggata cacctttagc cggtccacca tgcattgggt gaggcaggct 1680
cctggacagg gcctggagtg gatcggctac atcaacccca gcagcgctta taccaactac 1740
aatcagaagt ttaaggaccg ggtgaccatc accgccgata agtccaccag caccgcctac 1800
atggagctgt ccagcctgag gagcgaggat accgccgtgt actattgcgc ccggccccag 1860
gtccattacg actacaacgg cttcccctat tggggccagg gaaccctggt gaccgtgtcc 1920
agcggaggcg gcggcagcgg cggcggcggc agcggcggag gaggcagcgg cggaggaggc 1980
tccgacattc agatgaccca gtccccctcc accctgtccg ctagcgtggg cgatcgggtg 2040
accatgacct gcagcgccag cagctccgtg tcctacatga actggtacca gcagaagccc 2100
ggcaaggctc ccaagaggtg gatttacgac tccagcaagc tggcctctgg tgtccccagc 2160
aggttctctg gtagcggcag cggcacagac tacaccctga ccatctcctc cctgcagccc 2220
gacgatttcg ccacctacta ttgccagcag tggtcccgga atccccctac ctttggcggc 2280
ggcaccaagg tggagatcaa gaggagctcc agc 2313
<210> 222
<211> 771
<212> PRT
<213> 人工序列
<220>
<223> ROR233抗ROR1 X 抗CD3双特异性分子
<400> 222
Met Glu Ala Pro Ala Gln Leu Leu Phe Leu Leu Leu Leu Trp Leu Pro
1 5 10 15
Asp Thr Thr Gly Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser
20 25 30
Ala Ser Val Gly Asp Arg Val Thr Ile Asn Cys Gln Ala Ser Gln Ser
35 40 45
Ile Asp Ser Asn Leu Ala Trp Phe Gln Gln Lys Pro Gly Gln Pro Pro
50 55 60
Lys Leu Leu Ile Tyr Arg Ala Ser Asn Leu Ala Ser Gly Val Pro Asp
65 70 75 80
Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser
85 90 95
Ser Leu Glu Ala Glu Asp Val Ala Thr Tyr Tyr Cys Leu Gly Gly Val
100 105 110
Gly Ala Val Ser Tyr Arg Thr Ser Phe Gly Gly Gly Thr Lys Val Glu
115 120 125
Ile Lys Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
130 135 140
Ser Gly Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly
145 150 155 160
Leu Val Gln Pro Gly Arg Ser Leu Arg Leu Ser Cys Thr Ala Ser Gly
165 170 175
Ser Asp Ile Asn Asp Tyr Pro Ile Thr Trp Val Arg Gln Ala Pro Gly
180 185 190
Gln Gly Leu Glu Trp Ile Gly Phe Ile Asn Ser Gly Gly Ser Thr Trp
195 200 205
Tyr Ala Ser Trp Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asp Ser
210 215 220
Lys Ser Ile Ala Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu Asp Thr
225 230 235 240
Ala Val Tyr Tyr Cys Ala Arg Gly Tyr Ser Thr Tyr Tyr Arg Asp Phe
245 250 255
Asn Ile Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ser Glu Pro
260 265 270
Lys Ser Ser Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu
275 280 285
Ala Ala Gly Ala Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp
290 295 300
Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp
305 310 315 320
Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly
325 330 335
Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn
340 345 350
Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp
355 360 365
Leu Asn Gly Lys Glu Tyr Lys Cys Ala Val Ser Asn Lys Ala Leu Pro
370 375 380
Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu
385 390 395 400
Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn
405 410 415
Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile
420 425 430
Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr
435 440 445
Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys
450 455 460
Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys
465 470 475 480
Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu
485 490 495
Ser Leu Ser Pro Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
500 505 510
Gly Gly Gly Gly Ser Pro Gly Ser Gln Val Gln Leu Val Gln Ser Gly
515 520 525
Pro Glu Val Lys Lys Pro Gly Ser Ser Val Lys Val Ser Cys Lys Ala
530 535 540
Ser Gly Tyr Thr Phe Ser Arg Ser Thr Met His Trp Val Arg Gln Ala
545 550 555 560
Pro Gly Gln Gly Leu Glu Trp Ile Gly Tyr Ile Asn Pro Ser Ser Ala
565 570 575
Tyr Thr Asn Tyr Asn Gln Lys Phe Lys Asp Arg Val Thr Ile Thr Ala
580 585 590
Asp Lys Ser Thr Ser Thr Ala Tyr Met Glu Leu Ser Ser Leu Arg Ser
595 600 605
Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Pro Gln Val His Tyr Asp
610 615 620
Tyr Asn Gly Phe Pro Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser
625 630 635 640
Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
645 650 655
Gly Gly Gly Gly Ser Asp Ile Gln Met Thr Gln Ser Pro Ser Thr Leu
660 665 670
Ser Ala Ser Val Gly Asp Arg Val Thr Met Thr Cys Ser Ala Ser Ser
675 680 685
Ser Val Ser Tyr Met Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro
690 695 700
Lys Arg Trp Ile Tyr Asp Ser Ser Lys Leu Ala Ser Gly Val Pro Ser
705 710 715 720
Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Tyr Thr Leu Thr Ile Ser
725 730 735
Ser Leu Gln Pro Asp Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Trp Ser
740 745 750
Arg Asn Pro Pro Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg
755 760 765
Ser Ser Ser
770

Claims (33)

1.一种CD3结合多肽，其包括特异性结合至人CD3且包含免疫球蛋白轻链可变区和免疫球蛋白重链可变区的CD3结合结构域；
其中所述免疫球蛋白轻链可变区包含SEQ ID NO:88或SEQ ID NO:89；并且其中所述免疫球蛋白重链可变区包含SEQ ID NO:86。
2.权利要求1所述的CD3结合多肽，其中所述CD3结合结构域包含SEQ ID NO:83或SEQID NO:84。
3.权利要求1所述的CD3结合多肽，其中所述CD3结合结构域为单链可变片段(scFv)。
4.权利要求3所述的CD3结合多肽，其中所述scFv包含介于所述scFv的重链可变区和轻链可变区之间的接头并且其中所述接头包含氨基酸序列QRHNNSSLNTGTQMAGHSPNS (SEQ IDNO:148)。
5.权利要求3所述的CD3结合多肽，其中所述scFv的重链可变区位于所述scFv的轻链可变区的氨基端。
6.权利要求1所述的CD3结合多肽，其中所述CD3结合多肽包含免疫球蛋白恒定区。
7.权利要求6所述的CD3结合多肽，其还包含第二结合结构域。
8.权利要求7所述的CD3结合多肽，其中所述CD3结合多肽按照从氨基端至羧基端的顺序包含(i)所述第二结合结构域、(ii)铰链区、(iii)免疫球蛋白恒定区、(iv)羧基端接头和(v)所述CD3结合结构域。
9.权利要求8所述的CD3结合多肽，其中
(i) 所述CD3结合结构域包含(a)含有LCDR1、LCDR2和LCDR3的免疫球蛋白轻链可变区，和(b)含有HCDR1、HCDR2和HCDR3的免疫球蛋白重链可变区；并且
(ii) 所述第二结合结构域包含(a)含有LCDR1、LCDR2和LCDR3的免疫球蛋白轻链可变区，和(b)含有HCDR1、HCDR2和HCDR3的免疫球蛋白重链可变区。
10.权利要求8所述的CD3结合多肽，其中所述铰链区源自免疫球蛋白铰链区。
11.权利要求8所述的CD3结合多肽，其中所述羧基端接头包含SEQ ID NO:196或由SEQID NO:196组成。
12.权利要求7所述的CD3结合多肽，其中所述免疫球蛋白恒定区包含IgG1、IgG2、IgG3、IgG4、IgA1、IgA2或IgD的免疫球蛋白CH2和CH3结构域。
13.权利要求12所述的CD3结合多肽，其中所述免疫球蛋白恒定区包含含有根据EU编号系统的取代L234A、L235A、G237A和K322A的人IgG1 CH2结构域。
14.权利要求7所述的CD3结合多肽，其中所述CD3结合多肽诱导重导向T细胞细胞毒性(RTCC)。
15.权利要求14所述的CD3结合多肽，其中所述CD3结合多肽以30 pM或更低的EC50诱导RTCC。
16.权利要求7所述的CD3结合多肽，其中所述第二结合结构域为单链可变片段(scFv)。
17.权利要求7所述的CD3结合多肽，其中所述第二结合结构域与肿瘤相关抗原结合或相互作用。
18.权利要求17所述的CD3结合多肽，其中所述CD3结合多肽诱导表达所述肿瘤相关抗原的细胞的T细胞依赖性裂解。
19.权利要求17所述的CD3结合多肽，其中所述肿瘤相关抗原选自由以下组成的组：PSMA、CD19、CD20、CD37、CD38、CD123、Her2、ROR1、RON、gpA33和CEA。
20.一种异二聚体CD3结合蛋白，其包含(i)第一多肽链，所述第一多肽链按照从氨基端至羧基端或从羧基端至氨基端的顺序包含(a)权利要求1-5中任一项所述的CD3结合多肽，(b)第一铰链区，(c)第一免疫球蛋白恒定区，和(d)第一免疫球蛋白异二聚化结构域；和(ii)第二多肽链，所述第二多肽链按照从氨基端至羧基端或从羧基端至氨基端的顺序包含(a')第二铰链区，(b')第二免疫球蛋白恒定区和(c')与所述第一多肽链的第一免疫球蛋白异二聚化结构域不同的第二免疫球蛋白异二聚化结构域，其中所述第一和第二免疫球蛋白异二聚化结构域彼此缔合形成异二聚体。
21.一种分离的核酸分子，其编码权利要求1-19中任一项所述的CD3结合多肽。
22.一种表达载体，其包含编码权利要求1-19中任一项所述的CD3结合多肽的核酸区段，其中使所述核酸区段可操作地连接至适于在宿主细胞中表达所述核酸区段的调控序列。
23.一种重组宿主细胞，其包含权利要求22所述的表达载体。
24.一种用于产生CD3结合多肽的方法，所述方法包括：
在表达编码权利要求1-19中任一项所述的CD3结合多肽的核酸区段的条件下培养包含权利要求22所述的表达载体的重组宿主细胞，由此产生所述CD3结合多肽。
25.权利要求24所述的方法，其还包括回收所述CD3结合多肽。
26.一种药物组合物，其包含权利要求1-19中任一项所述的CD3结合多肽或权利要求20所述的异二聚体CD3结合蛋白和药学上可接受的载体、稀释剂或赋形剂。
27.权利要求17-19中任一项所述的CD3结合多肽在制造用于诱导针对表达肿瘤相关抗原的细胞的重导向T细胞细胞毒性(RTCC)的药物中的用途，所述用途包括：使所述肿瘤相关抗原表达细胞与权利要求17-19中任一项所述的CD3结合多肽接触，其中所述接触是在诱导针对所述肿瘤相关抗原表达细胞的RTCC的条件下进行的，并且其中所述第二结合结构域结合肿瘤相关抗原。
28.治疗有效量的权利要求17-19中任一项所述的CD3结合多肽或权利要求26所述的药物组合物在制造用于抑制有需要的受试者中的肿瘤生长的药物中的用途，其中所述免疫球蛋白轻链可变区包含SEQ ID NO:89并且所述免疫球蛋白重链可变区包含SEQ ID NO:86，并且其中所述药物组合物包括权利要求17-19中任一项所述的CD3结合多肽和药学上可接受的载体、稀释剂或赋形剂。
29.治疗有效量的权利要求17-19中任一项所述的CD3结合多肽或权利要求26所述的药物组合物在制造用于治疗有需要的受试者中的癌症的药物中的用途，其中所述免疫球蛋白轻链可变区包含SEQ ID NO:89并且所述免疫球蛋白重链可变区包含SEQ ID NO:86，并且其中所述药物组合物包含权利要求17-19中任一项所述的CD3结合多肽和药学上可接受的载体、稀释剂或赋形剂。
30.权利要求29所述的用途，其中所述癌症是前列腺癌、结直肠癌、肾细胞癌、膀胱癌、唾液腺癌、胰腺癌、卵巢癌、非小细胞肺癌、乳腺癌、黑素瘤、肾上腺癌、套细胞淋巴瘤、急性淋巴母细胞性白血病、慢性淋巴细胞性白血病、非霍奇金氏淋巴瘤、急性髓细胞性白血病(AML)、B淋巴样白血病、母细胞性浆细胞样树突细胞肿瘤(BPDCN)或毛细胞白血病。
31.权利要求29所述的用途，其中所述癌症是三阴性乳腺癌。
32.一种CD3结合蛋白，其为两个同一多肽的二聚体，其中每个多肽均为权利要求1-19中任一项所述的CD3结合多肽。
33.权利要求1-19中任一项所述的CD3结合多肽，其中所述CD3结合多肽未表现出或表现出最小的抗体依赖性细胞介导的细胞毒性(ADCC)活性和/或补体依赖性细胞毒性(CDC)活性。
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Families Citing this family (23)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2017072361A1 (en) 2015-10-30 2017-05-04 Nbe-Therapeutics Ag Anti-ror1 antibodies
CA3011815A1 (en) 2016-01-20 2017-07-27 The Scripps Research Institute Ror1 antibody compositions and related methods
MX2019003225A (es) * 2016-09-21 2019-06-10 Aptevo Res & Development Llc Proteínas de unión a cd123 y composiciones y métodos relacionados.
KR102696143B1 (ko) * 2017-04-07 2024-08-21 아이쥐엠 바이오사이언스 인코포레이티드 보체-의존성 세포용해 효과기 기능의 조정을 위한 변형된 인간 IgM 불변 영역
EP3409322A1 (en) 2017-06-01 2018-12-05 F. Hoffmann-La Roche AG Treatment method
IL272103B1 (en) 2017-07-20 2024-06-01 Aptevo Res & Development Llc Antigen-binding proteins that bind to 5T4 and 4-1BB, as well as compositions and methods for treating cancer related to them
EP3655435A1 (en) * 2017-07-20 2020-05-27 NBE-Therapeutics AG Multispecific antibody product that binds to different ror1 epitopes
KR20230008269A (ko) 2017-08-07 2023-01-13 엔비이-테라퓨틱스 아게 생체 내 내성이 높은 항체 약물 결합체
BR112020005675A2 (pt) * 2017-09-22 2020-10-20 WuXi Biologics Ireland Limited novos complexos de polipeptideo cd3/cd19 biespecíficos
EA202090812A1 (ru) 2017-09-22 2020-08-07 Уси Байолоджикс Аэлэнд Лимитед Новые биспецифические полипептидные комплексы
US11685781B2 (en) 2018-02-15 2023-06-27 Macrogenics, Inc. Variant CD3-binding domains and their use in combination therapies for the treatment of disease
SG11202010235QA (en) 2018-04-18 2020-11-27 Exelixis Inc Anti-ror antibody constructs
KR102353568B1 (ko) * 2018-11-14 2022-01-20 주식회사 헬릭스미스 안정성이 향상된 항 c-Met 항체 또는 그의 항원 결합 단편
US20230151102A1 (en) * 2020-01-13 2023-05-18 Aptevo Research And Development Llc Methods and compositions for preventing adsorption of therapeutic proteins to drug delivery system components
BR112022013725A2 (pt) 2020-01-13 2022-10-11 Aptevo Res & Development Llc Formulações para agentes terapêuticos proteicos
JP2023538945A (ja) * 2020-08-24 2023-09-12 エピムアブ、バイオセラピューティクス、（ホンコン）、リミテッド 抗ｒｏｒ１抗体及び関連の二重特異性結合タンパク質
MX2023006426A (es) * 2020-12-01 2023-07-17 Aptevo Res & Development Llc Antígenos asociados a tumores y proteínas de unión a cd3 y composiciones y métodos relacionados.
AU2022276523A1 (en) 2021-05-21 2024-01-18 Aptevo Research And Development Llc Dosing regimens for protein therapeutics
WO2023288191A1 (en) * 2021-07-13 2023-01-19 University Of Washington Multiple de novo designed protein binding proteins
EP4416182A1 (en) * 2021-10-12 2024-08-21 Concept to Medicine Biotech Co., Ltd. Anti-cd3 antibodies with cross-reactivity to human and cynomolgus proteins
WO2023169419A1 (en) * 2022-03-09 2023-09-14 Antengene (Hangzhou) Biologics Co., Ltd. Novel anti-cd3 antibodies and uses thereof
WO2024088987A1 (en) 2022-10-26 2024-05-02 F. Hoffmann-La Roche Ag Combination therapy for the treatment of cancer
WO2024148328A2 (en) 2023-01-06 2024-07-11 Aptevo Research And Development Llc Bispecific pd-l1 and cd40 binding molecules and uses thereof

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011090762A1 (en) * 2009-12-29 2011-07-28 Emergent Product Development Seattle, Llc Heterodimer binding proteins and uses thereof
WO2012162067A2 (en) * 2011-05-21 2012-11-29 Macrogenics, Inc. Cd3-binding molecules capable of binding to human and non-human cd3
CN104487587A (zh) * 2012-04-20 2015-04-01 新兴产品开发西雅图有限公司 Cd3结合多肽

Family Cites Families (483)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3927193A (en) 1973-05-18 1975-12-16 Hoffmann La Roche Localization of tumors by radiolabelled antibodies
US4179337A (en) 1973-07-20 1979-12-18 Davis Frank F Non-immunogenic polypeptides
JPS6023084B2 (ja) 1979-07-11 1985-06-05 味の素株式会社 代用血液
US4460559A (en) 1980-03-03 1984-07-17 Goldenberg Milton David Tumor localization and therapy with labeled antibodies specific to intracellular tumor-associated markers
US4331647A (en) 1980-03-03 1982-05-25 Goldenberg Milton David Tumor localization and therapy with labeled antibody fragments specific to tumor-associated markers
US4361544A (en) 1980-03-03 1982-11-30 Goldenberg Milton David Tumor localization and therapy with labeled antibodies specific to intracellular tumor-associated markers
US4348376A (en) 1980-03-03 1982-09-07 Goldenberg Milton David Tumor localization and therapy with labeled anti-CEA antibody
US4444744A (en) 1980-03-03 1984-04-24 Goldenberg Milton David Tumor localization and therapy with labeled antibodies to cell surface antigens
US4460561A (en) 1980-03-03 1984-07-17 Goldenberg M David Tumor localization and therapy with labeled antibodies specific to intracellular tumor-associated markers
US4468457A (en) 1981-06-01 1984-08-28 David M. Goldenberg Method for producing a CSAp tryptic peptide and anti-CSAp antibodies
US4640835A (en) 1981-10-30 1987-02-03 Nippon Chemiphar Company, Ltd. Plasminogen activator derivatives
US4769330A (en) 1981-12-24 1988-09-06 Health Research, Incorporated Modified vaccinia virus and methods for making and using the same
US4818709A (en) 1983-01-21 1989-04-04 Primus Frederick J CEA-family antigens, Anti-CEA antibodies and CEA immunoassay
US4460459A (en) 1983-02-16 1984-07-17 Anschutz Mining Corporation Sequential flotation of sulfide ores
US4816567A (en) 1983-04-08 1989-03-28 Genentech, Inc. Recombinant immunoglobin preparations
US4624846A (en) 1983-07-29 1986-11-25 Immunomedics, Inc. Method for enhancing target specificity of antibody localization and clearance of non-target diagnostic and therapeutic principles
US4496689A (en) 1983-12-27 1985-01-29 Miles Laboratories, Inc. Covalently attached complex of alpha-1-proteinase inhibitor with a water soluble polymer
US4782840A (en) 1984-03-02 1988-11-08 Neoprobe Corporation Method for locating, differentiating, and removing neoplasms
US4906562A (en) 1984-12-21 1990-03-06 Oncogen Monocolonal antibodies and antigen for human non-small cell lung carcinomas
US4935495A (en) 1984-12-21 1990-06-19 Oncogen Monoclonal antibodies to the L6 glycolipid antigenic determinant found on human non-small cell lung carcinomas
GB8508845D0 (en) 1985-04-04 1985-05-09 Hoffmann La Roche Vaccinia dna
DE3675588D1 (de) 1985-06-19 1990-12-20 Ajinomoto Kk Haemoglobin, das an ein poly(alkenylenoxid) gebunden ist.
US5656266A (en) 1985-11-19 1997-08-12 Schering Corporation Method of using interleukin-4
US5225539A (en) 1986-03-27 1993-07-06 Medical Research Council Recombinant altered antibodies and methods of making altered antibodies
US4791192A (en) 1986-06-26 1988-12-13 Takeda Chemical Industries, Ltd. Chemically modified protein with polyethyleneglycol
US4946778A (en) 1987-09-21 1990-08-07 Genex Corporation Single polypeptide chain binding molecules
US5260203A (en) 1986-09-02 1993-11-09 Enzon, Inc. Single polypeptide chain binding molecules
US4704692A (en) 1986-09-02 1987-11-03 Ladner Robert C Computer based system and method for determining and displaying possible chemical structures for converting double- or multiple-chain polypeptides to single-chain polypeptides
US5869620A (en) 1986-09-02 1999-02-09 Enzon, Inc. Multivalent antigen-binding proteins
US5075109A (en) 1986-10-24 1991-12-24 Southern Research Institute Method of potentiating an immune response
US6893625B1 (en) 1986-10-27 2005-05-17 Royalty Pharma Finance Trust Chimeric antibody with specificity to human B cell surface antigen
US4932412A (en) 1986-12-18 1990-06-12 Immunomedics, Inc. Intraoperative and endoscopic tumor detection and therapy
IL85035A0 (en) 1987-01-08 1988-06-30 Int Genetic Eng Polynucleotide molecule,a chimeric antibody with specificity for human b cell surface antigen,a process for the preparation and methods utilizing the same
US5892019A (en) 1987-07-15 1999-04-06 The United States Of America, As Represented By The Department Of Health And Human Services Production of a single-gene-encoded immunoglobulin
US4897268A (en) 1987-08-03 1990-01-30 Southern Research Institute Drug delivery system and method of making the same
WO1989001973A2 (en) 1987-09-02 1989-03-09 Applied Biotechnology, Inc. Recombinant pox virus for immunization against tumor-associated antigens
GB8720833D0 (en) 1987-09-04 1987-10-14 Celltech Ltd Recombinant dna product
US5677425A (en) 1987-09-04 1997-10-14 Celltech Therapeutics Limited Recombinant antibody
JP3095168B2 (ja) 1988-02-05 2000-10-03 エル． モリソン，シェリー ドメイン‐変性不変部を有する抗体
HUT53672A (en) 1988-02-25 1990-11-28 Gen Hospital Corp Quick immunoselective cloning process
US5506126A (en) 1988-02-25 1996-04-09 The General Hospital Corporation Rapid immunoselection cloning method
US4861579A (en) 1988-03-17 1989-08-29 American Cyanamid Company Suppression of B-lymphocytes in mammals by administration of anti-B-lymphocyte antibodies
US5601819A (en) 1988-08-11 1997-02-11 The General Hospital Corporation Bispecific antibodies for selective immune regulation and for selective immune cell binding
US6352694B1 (en) 1994-06-03 2002-03-05 Genetics Institute, Inc. Methods for inducing a population of T cells to proliferate using agents which recognize TCR/CD3 and ligands which stimulate an accessory molecule on the surface of the T cells
US5217713A (en) 1988-12-27 1993-06-08 Takeda Chemical Industries, Ltd. Cytotoxic bispecific monoclonal antibody, its production and use
CA2006408A1 (en) 1988-12-27 1990-06-27 Susumu Iwasa Bispecific monoclonal antibody, its production and use
US5530101A (en) 1988-12-28 1996-06-25 Protein Design Labs, Inc. Humanized immunoglobulins
JP2752788B2 (ja) 1989-01-23 1998-05-18 カイロン コーポレイション 感染および過剰増殖障害の為の組換え療法
US5225538A (en) 1989-02-23 1993-07-06 Genentech, Inc. Lymphocyte homing receptor/immunoglobulin fusion proteins
US5098833A (en) 1989-02-23 1992-03-24 Genentech, Inc. DNA sequence encoding a functional domain of a lymphocyte homing receptor
DE3920358A1 (de) 1989-06-22 1991-01-17 Behringwerke Ag Bispezifische und oligospezifische, mono- und oligovalente antikoerperkonstrukte, ihre herstellung und verwendung
WO1991000360A1 (en) 1989-06-29 1991-01-10 Medarex, Inc. Bispecific reagents for aids therapy
US5897861A (en) 1989-06-29 1999-04-27 Medarex, Inc. Bispecific reagents for AIDS therapy
US5980896A (en) 1989-06-30 1999-11-09 Bristol-Myers Squibb Company Antibodies reactive with human carcinomas
US6020145A (en) 1989-06-30 2000-02-01 Bristol-Myers Squibb Company Methods for determining the presence of carcinoma using the antigen binding region of monoclonal antibody BR96
EP0845537A1 (en) 1989-08-18 1998-06-03 Chiron Corporation Recombinant retroviruses delivering vector constructs to target cells
US5605690A (en) 1989-09-05 1997-02-25 Immunex Corporation Methods of lowering active TNF-α levels in mammals using tumor necrosis factor receptor
DK0493418T3 (da) 1989-09-20 1997-11-03 Abbott Lab Fremgangsmåde til fremstilling af fusionsproteiner
US6018031A (en) 1989-10-20 2000-01-25 Trustees Of Dartmouth College Binding agents specific for IgA receptor
GB8928874D0 (en) 1989-12-21 1990-02-28 Celltech Ltd Humanised antibodies
US6150584A (en) 1990-01-12 2000-11-21 Abgenix, Inc. Human antibodies derived from immunized xenomice
US5314995A (en) 1990-01-22 1994-05-24 Oncogen Therapeutic interleukin-2-antibody based fusion proteins
DE69126607T2 (de) 1990-01-23 1998-01-15 Tanox Biosystems, Inc., Houston, Tex. Extrazelluläre teilstücke humaner ige-immunoglobulin-ankerpeptide und dafür spezifische antikörper
CA2077348A1 (en) 1990-03-02 1991-09-03 Stephen D. Gillies Antibody constructs with enhanced binding affinity
US20030219446A1 (en) 1990-03-26 2003-11-27 Bristol-Myers Squibb Company Ligand for CD28 receptor on B cells and methods
US5521288A (en) 1990-03-26 1996-05-28 Bristol-Myers Squibb Company CD28IG fusion protein
GB9009106D0 (en) 1990-04-23 1990-06-20 3I Res Expl Ltd Processes and intermediates for synthetic antibody derivatives
CA2086325C (en) 1990-07-02 2010-10-05 Peter S. Linsley Ligand for cd28 receptor on b cells and methods
EP0557300B1 (en) 1990-10-29 1997-11-19 Chiron Corporation Bispecific antibodies, method of production, and uses thereof
US5709859A (en) 1991-01-24 1998-01-20 Bristol-Myers Squibb Company Mixed specificity fusion proteins
JPH06506358A (ja) 1991-03-28 1994-07-21 ザ・リージェンツ・オブ・ザ・ユニバーシティ・オブ・ミネソタ ナチュラルキラー細胞に特異的なｄｎａおよびアミノ酸配列
AU651228B2 (en) 1991-05-31 1994-07-14 Genentech Inc. Treatment of HIV-associated immune thrombocytopenic purpura
DE4118120A1 (de) 1991-06-03 1992-12-10 Behringwerke Ag Tetravalente bispezifische rezeptoren, ihre herstellung und verwendung
US6090914A (en) 1991-06-27 2000-07-18 Bristol-Myers Squibb Company CTLA4/CD28Ig hybrid fusion proteins and uses thereof
US5770197A (en) 1991-06-27 1998-06-23 Bristol-Myers Squibb Company Methods for regulating the immune response using B7 binding molecules and IL4-binding molecules
CA2580812A1 (en) 1991-06-27 1993-01-07 Bristol-Myers Squibb Company Ctla4 receptor, fusion proteins containing it and uses thereof
US5844095A (en) 1991-06-27 1998-12-01 Bristol-Myers Squibb Company CTLA4 Ig fusion proteins
US5637481A (en) 1993-02-01 1997-06-10 Bristol-Myers Squibb Company Expression vectors encoding bispecific fusion proteins and methods of producing biologically active bispecific fusion proteins in a mammalian cell
CA2115364A1 (en) 1991-08-16 1993-03-04 Philip L. Felgner Composition and method for treating cystic fibrosis
US5962406A (en) 1991-10-25 1999-10-05 Immunex Corporation Recombinant soluble CD40 ligand polypeptide and pharmaceutical composition containing the same
EP1136556B1 (en) 1991-11-25 2005-06-08 Enzon, Inc. Method of producing multivalent antigen-binding proteins
US6025165A (en) 1991-11-25 2000-02-15 Enzon, Inc. Methods for producing multivalent antigen-binding proteins
US5932448A (en) 1991-11-29 1999-08-03 Protein Design Labs., Inc. Bispecific antibody heterodimers
ATE408012T1 (de) 1991-12-02 2008-09-15 Medical Res Council Herstellung von autoantikörpern auf phagenoberflächen ausgehend von antikörpersegmentbibliotheken
CA2089229C (en) 1992-02-14 2010-04-13 Alejandro A. Aruffo Cd40cr receptor and ligands therefor
US6472510B1 (en) 1992-02-14 2002-10-29 Bristol-Myers Squibb Company CD40 receptor ligands
US7381803B1 (en) 1992-03-27 2008-06-03 Pdl Biopharma, Inc. Humanized antibodies against CD3
US6129914A (en) 1992-03-27 2000-10-10 Protein Design Labs, Inc. Bispecific antibody effective to treat B-cell lymphoma and cell line
EP0650370A4 (en) 1992-06-08 1995-11-22 Univ California METHODS AND COMPOSITIONS TARGETED ON SPECIFIC TISSUES.
EP0644946A4 (en) 1992-06-10 1997-03-12 Us Health VECTOR PARTICLES RESISTANT TO HUMAN SERUM INACTIVATION.
GB2269175A (en) 1992-07-31 1994-02-02 Imperial College Retroviral vectors
ES2144440T3 (es) 1992-08-18 2000-06-16 Centro Inmunologia Molecular Anticuerpos monoclonales que reconocen el receptor del factor de crecimiento epidermico, celulas y metodos para su produccion y compuestos que los contienen.
EP1621554B2 (en) 1992-08-21 2012-08-29 Vrije Universiteit Brussel Immunoglobulins devoid of light chains
ZA936260B (en) 1992-09-09 1994-03-18 Smithkline Beecham Corp Novel antibodies for conferring passive immunity against infection by a pathogen in man
US6066718A (en) 1992-09-25 2000-05-23 Novartis Corporation Reshaped monoclonal antibodies against an immunoglobulin isotype
EP0668875A4 (en) 1992-10-12 1999-05-26 Agen Ltd ANTI-COAGULAR AGENT ON BLOOD CLOTH, METHOD FOR PRODUCING THE SAME AND ITS USE.
US5736137A (en) 1992-11-13 1998-04-07 Idec Pharmaceuticals Corporation Therapeutic application of chimeric and radiolabeled antibodies to human B lymphocyte restricted differentiation antigen for treatment of B cell lymphoma
NZ258392A (en) 1992-11-13 1997-09-22 Idec Pharma Corp Chimeric and radiolabelled antibodies to the b lymphocyte cellsurface antigen bp35 (cd-20) and their use in the treatment of b cell lymphona
GB9225453D0 (en) 1992-12-04 1993-01-27 Medical Res Council Binding proteins
ATE199392T1 (de) 1992-12-04 2001-03-15 Medical Res Council Multivalente und multispezifische bindungsproteine, deren herstellung und verwendung
US5773253A (en) 1993-01-22 1998-06-30 Bristol-Myers Squibb Company MYPPPY variants of CTL A4 and uses thereof
US6482919B2 (en) 1993-02-01 2002-11-19 Bristol-Myers Squibb Company Expression vectors encoding bispecific fusion proteins and methods of producing biologically active bispecific fusion proteins in a mammalian cell
US5597707A (en) 1993-04-15 1997-01-28 Bristol-Myers Squibb Company Tumor associated antigen recognized by the murine monoclonal antibody L6, its oligonucleotide sequence and methods for their use
US6838254B1 (en) 1993-04-29 2005-01-04 Conopco, Inc. Production of antibodies or (functionalized) fragments thereof derived from heavy chain immunoglobulins of camelidae
US5795572A (en) 1993-05-25 1998-08-18 Bristol-Myers Squibb Company Monoclonal antibodies and FV specific for CD2 antigen
US5885573A (en) 1993-06-01 1999-03-23 Arch Development Corporation Methods and materials for modulation of the immunosuppressive activity and toxicity of monoclonal antibodies
US20030108548A1 (en) 1993-06-01 2003-06-12 Bluestone Jeffrey A. Methods and materials for modulation of the immunosuppressive activity and toxicity of monoclonal antibodies
US5747654A (en) 1993-06-14 1998-05-05 The United States Of America As Represented By The Department Of Health And Human Services Recombinant disulfide-stabilized polypeptide fragments having binding specificity
US6476198B1 (en) 1993-07-13 2002-11-05 The Scripps Research Institute Multispecific and multivalent antigen-binding polypeptide molecules
US5417972A (en) 1993-08-02 1995-05-23 The Board Of Trustees Of The Leland Stanford Junior University Method of killing B-cells in a complement independent and an ADCC independent manner using antibodies which specifically bind CDIM
US5869049A (en) 1993-09-02 1999-02-09 Trustees Of Dartmouth College Methods of inducing T cell unresponsiveness to bone marrow with gp39 antagonists
CN100341896C (zh) 1993-09-02 2007-10-10 达特茅斯学院理事 抗gp39抗体及其应用
US5595721A (en) 1993-09-16 1997-01-21 Coulter Pharmaceutical, Inc. Radioimmunotherapy of lymphoma using anti-CD20
ATE173740T1 (de) 1993-09-22 1998-12-15 Medical Res Council Antikoerper mit geaenderter zielrichtung
GB9412166D0 (en) 1993-09-22 1994-08-10 Medical Res Council Retargetting antibodies
WO1995009917A1 (en) 1993-10-07 1995-04-13 The Regents Of The University Of California Genetically engineered bispecific tetravalent antibodies
CA2180954C (en) 1994-01-11 2007-03-20 William Markland Inhibitors of human plasmin derived from the kunitz domains
US6380369B1 (en) 1994-01-27 2002-04-30 Human Genome Sciences, Inc. Human DNA mismatch repair proteins
AU689214B2 (en) 1994-02-01 1998-03-26 United States Of America, Represented By The Secretary, Department Of Health And Human Services, The Fusion proteins that include antibody and nonantibody portions
EP0749325B1 (en) 1994-03-07 2002-06-12 Medarex, Inc. Bispecific molecules having clinical utilities
EP0699237B1 (en) 1994-03-17 2003-02-19 MERCK PATENT GmbH Anti-egfr single-chain fvs and anti-egfr antibodies
DE69528894T2 (de) 1994-05-02 2003-03-27 Bernd Groner Bifunktionelles protein, herstellung und verwendung
US5945273A (en) 1997-06-03 1999-08-31 Human Genome Sciences, Inc. Human oxalyl-coa decarboxylase
US5888773A (en) 1994-08-17 1999-03-30 The United States Of America As Represented By The Department Of Health And Human Services Method of producing single-chain Fv molecules
AU690336B2 (en) 1994-08-26 1998-04-23 Hoechst Aktiengesellschaft Genetic therapy of diseases caused by the immune system, said therapy using a cell-specific active substance regulated by the cell cycle
US6380169B1 (en) 1994-08-31 2002-04-30 Isis Pharmaceuticals, Inc. Metal complex containing oligonucleoside cleavage compounds and therapies
US5736524A (en) 1994-11-14 1998-04-07 Merck & Co.,. Inc. Polynucleotide tuberculosis vaccine
US6383814B1 (en) 1994-12-09 2002-05-07 Genzyme Corporation Cationic amphiphiles for intracellular delivery of therapeutic molecules
US5876950A (en) 1995-01-26 1999-03-02 Bristol-Myers Squibb Company Monoclonal antibodies specific for different epitopes of human GP39 and methods for their use in diagnosis and therapy
US5731168A (en) 1995-03-01 1998-03-24 Genentech, Inc. Method for making heteromultimeric polypeptides
EP0739981A1 (en) 1995-04-25 1996-10-30 Vrije Universiteit Brussel Variable fragments of immunoglobulins - use for therapeutic or veterinary purposes
US6410690B1 (en) 1995-06-07 2002-06-25 Medarex, Inc. Therapeutic compounds comprised of anti-Fc receptor antibodies
US6696248B1 (en) 1995-08-18 2004-02-24 Morphosys Ag Protein/(poly)peptide libraries
GB9518220D0 (en) 1995-09-06 1995-11-08 Medical Res Council Checkpoint gene
US5866330A (en) 1995-09-12 1999-02-02 The Johns Hopkins University School Of Medicine Method for serial analysis of gene expression
CA2234666A1 (en) 1995-10-13 1997-04-17 The Government Of The United States Of America, Represented By The Secre Tary, Department Of Health And Human Services Immunotoxin containing a disulfide-stabilized antibody fragment
US6440418B1 (en) 1995-11-07 2002-08-27 Idec Pharmaceuticals Corporation Methods of treating autoimmune diseases with gp39-specific antibodies
US6379966B2 (en) 1999-02-26 2002-04-30 Mirus Corporation Intravascular delivery of non-viral nucleic acid
US6750334B1 (en) 1996-02-02 2004-06-15 Repligen Corporation CTLA4-immunoglobulin fusion proteins having modified effector functions and uses therefor
GB2310894A (en) 1996-03-06 1997-09-10 Clive William Efford Multi-engine drive unit
ATE219376T1 (de) 1996-03-20 2002-07-15 Bristol Myers Squibb Co Verfahren zur inhibierung der immunreaktion durch blockierung der gp39/cd40 und ctla4/cd28/b7 routen und zusammensetzung zu deren verwendung
EP1186300A1 (en) 1996-03-20 2002-03-13 Bristol-Myers Squibb Company Pharmaceutical compositions useful for inhibiting an immune response by blocking the GP39/CD40 and CTLA4/CD28/B7 pathways
US6962981B1 (en) 1996-03-25 2005-11-08 Medarex, Inc. Monoclonal antibodies specific for the extracellular domain of prostate-specific membrane antigen
WO1997035616A1 (en) 1996-03-25 1997-10-02 Pacific Northwest Cancer Foundation Monoclonal antibodies specific for the extracellular domain of prostate specific membrane antigen
US7381407B1 (en) 1996-03-25 2008-06-03 Medarex, Inc. Monoclonal antibodies specific for the extracellular domain of prostate-specific membrane antigen
US6150508A (en) 1996-03-25 2000-11-21 Northwest Biotherapeutics, Inc. Monoclonal antibodies specific for the extracellular domain of prostate-specific membrane antigen
DE19613691A1 (de) 1996-04-05 1997-10-09 Boehringer Ingelheim Int Arzneimittel für die Behandlung von Tumorerkrankungen
US5834597A (en) 1996-05-20 1998-11-10 Protein Design Labs, Inc. Mutated nonactivating IgG2 domains and anti CD3 antibodies incorporating the same
US5922845A (en) 1996-07-11 1999-07-13 Medarex, Inc. Therapeutic multispecific compounds comprised of anti-Fcα receptor antibodies
EP0938556B1 (en) 1996-07-12 2005-03-09 Genentech, Inc. Gamma-heregulin
DE69726003T2 (de) 1996-07-16 2004-08-26 Andreas Plückthun Immunglobulin-superfamilie domainen und fragmente mit erhöhter löslichkeit
CA2260752A1 (en) 1996-07-23 1998-01-29 Tanox Pharma B.V. Induction of t cell tolerance using a soluble molecule that can simultaneously block two costimulatory pathways
US5846948A (en) 1996-08-30 1998-12-08 Arch Development Corporation Herpes simplex virus ORF P is a repressor of viral protein synthesis
EP0826696B1 (de) 1996-09-03 2002-05-29 GSF-Forschungszentrum für Umwelt und Gesundheit GmbH Verwendung bi-und trispezifischer Antikörper zur Induktion einer Tumorimmunität
GB9618477D0 (en) 1996-09-04 1996-10-16 Univ Leeds Gene therapy
US5972361A (en) 1996-10-25 1999-10-26 The Procter & Gamble Company Cleansing products
DE19651443A1 (de) 1996-12-11 1998-06-18 Hoechst Ag Selbstverstärkende, pharmakologisch kontrollierbare Expressionssysteme
EP0860445A1 (en) 1997-02-18 1998-08-26 Hoechst Aktiengesellschaft New nucleotide sequences for the cell cycle regulated expression of structural genes
US6133426A (en) 1997-02-21 2000-10-17 Genentech, Inc. Humanized anti-IL-8 monoclonal antibodies
WO1998040088A1 (en) 1997-03-11 1998-09-17 Les Laboratoires Aeterna Inc. Compositions for treating tumors containing shark cartilage extracts and anti-neoplastic agents
AU751956B2 (en) 1997-03-20 2002-09-05 University Of Washington Solvent for biopolymer synthesis, solvent microdroplets and methods of use
US6306393B1 (en) 1997-03-24 2001-10-23 Immunomedics, Inc. Immunotherapy of B-cell malignancies using anti-CD22 antibodies
US6384203B1 (en) 1999-05-12 2002-05-07 Immunex Corporation Family of immunoregulators designated leukocyte immunoglobulin-like receptors (LIR)
US6217900B1 (en) 1997-04-30 2001-04-17 American Home Products Corporation Vesicular complexes and methods of making and using the same
US20020062010A1 (en) 1997-05-02 2002-05-23 Genentech, Inc. Method for making multispecific antibodies having heteromultimeric and common components
US6171586B1 (en) 1997-06-13 2001-01-09 Genentech, Inc. Antibody formulation
AU740284B2 (en) 1997-06-13 2001-11-01 Genentech Inc. Stabilized antibody formulation
CA2293829C (en) 1997-06-24 2011-06-14 Genentech, Inc. Methods and compositions for galactosylated glycoproteins
US5994511A (en) 1997-07-02 1999-11-30 Genentech, Inc. Anti-IgE antibodies and methods of improving polypeptides
US6368596B1 (en) 1997-07-08 2002-04-09 Board Of Regents, The University Of Texas System Compositions and methods for homoconjugates of antibodies which induce growth arrest or apoptosis of tumor cells
US6165476A (en) 1997-07-10 2000-12-26 Beth Israel Deaconess Medical Center Fusion proteins with an immunoglobulin hinge region linker
US6207805B1 (en) 1997-07-18 2001-03-27 University Of Iowa Research Foundation Prostate cell surface antigen-specific antibodies
US6342220B1 (en) 1997-08-25 2002-01-29 Genentech, Inc. Agonist antibodies
US6383746B1 (en) 1997-10-23 2002-05-07 The United States Of America As Represented By The Department Of Health And Human Services Functional promoter for CCR5
EP1028751B1 (en) 1997-10-31 2008-12-31 Genentech, Inc. Methods and compositions comprising glycoprotein glycoforms
US6383811B2 (en) 1997-12-30 2002-05-07 Mirus Corporation Polyampholytes for delivering polyions to a cell
DE69922159T2 (de) 1998-01-23 2005-12-01 Vlaams Interuniversitair Instituut Voor Biotechnologie Mehrzweck-antikörperderivate
ID26964A (id) 1998-02-19 2001-02-22 Xcyte Therapies Inc Komposisi dan metode untuk pengaturan pengaktifan limfosit
CZ20003099A3 (cs) 1998-02-25 2002-04-17 Lexigen Pharmaceuticals Corporation Zvýąení doby poloviční ľivotnosti cirkulujících fúzních proteinů odvozených od protilátek
AUPP221098A0 (en) 1998-03-06 1998-04-02 Diatech Pty Ltd V-like domain binding molecules
US6383481B1 (en) 1998-03-30 2002-05-07 Japan Immunoresearch Laboratories Co., Ltd. Method for transplantation of hemopoietic stem cells
US6528624B1 (en) 1998-04-02 2003-03-04 Genentech, Inc. Polypeptide variants
JP2002510481A (ja) 1998-04-02 2002-04-09 ジェネンテック・インコーポレーテッド 抗体変異体及びその断片
US6242195B1 (en) 1998-04-02 2001-06-05 Genentech, Inc. Methods for determining binding of an analyte to a receptor
US6194551B1 (en) 1998-04-02 2001-02-27 Genentech, Inc. Polypeptide variants
US6284536B1 (en) 1998-04-20 2001-09-04 The Regents Of The University Of California Modified immunoglobin molecules and methods for use thereof
IL139040A0 (en) 1998-04-22 2001-11-25 Genvec Inc Efficient purification of adenovirus
GB9809280D0 (en) 1998-04-30 1998-07-01 Rpms Technology Ltd Immunosupression
DE19819846B4 (de) 1998-05-05 2016-11-24 Deutsches Krebsforschungszentrum Stiftung des öffentlichen Rechts Multivalente Antikörper-Konstrukte
AU5203199A (en) 1998-05-26 1999-12-13 Procter & Gamble Company, The Chimeric molecules comprising an extracellular ligand binding domain of a receptor and an ige fc or constant region, and their use in an assay system
US7052872B1 (en) 1999-06-22 2006-05-30 Immunomedics, Inc. Bi-specific antibodies for pre-targeting diagnosis and therapy
US7405320B2 (en) 1998-06-22 2008-07-29 Immunomedics, Inc. Therapeutic and diagnostic conjugates for use with multispecific antibodies
US7833528B2 (en) 1998-06-22 2010-11-16 Immunomedics, Inc. Use of multispecific, non-covalent complexes for targeted delivery of therapeutics
ATE460946T1 (de) 1998-06-22 2010-04-15 Immunomedics Inc Gebrauch von bispezifischen antikörpern in diagnose und therapie
US6818213B1 (en) 1998-07-13 2004-11-16 Board Of Regents, The University Of Texas System Cancer treatment compositions comprising therapeutic conjugates that bind to aminophospholipids
DE69904831T2 (de) 1998-07-13 2003-11-06 Univ Texas Krebsbehandlung mit aminophospholipide bindenden, therapeutischen konjugaten
WO2000006605A2 (en) 1998-07-28 2000-02-10 Micromet Ag Heterominibodies
CN1320044A (zh) 1998-08-11 2001-10-31 Idec药物公司 包括施用抗－cd20抗体的b－细胞淋巴瘤联合疗法
AU5689699A (en) 1998-08-24 2000-03-14 Uab Research Foundation Methods of producing high titer recombinant adeno-associated virus
US6472179B2 (en) 1998-09-25 2002-10-29 Regeneron Pharmaceuticals, Inc. Receptor based antagonists and methods of making and using
US6224866B1 (en) 1998-10-07 2001-05-01 Biocrystal Ltd. Immunotherapy of B cell involvement in progression of solid, nonlymphoid tumors
WO2000023573A2 (en) 1998-10-20 2000-04-27 City Of Hope Cd20-specific redirected t cells and their use in cellular immunotherapy of cd20+ malignancies
US6660843B1 (en) 1998-10-23 2003-12-09 Amgen Inc. Modified peptides as therapeutic agents
US6197294B1 (en) 1998-10-26 2001-03-06 Neurotech S.A. Cell surface molecule-induced macrophage activation
WO2000027885A1 (fr) 1998-11-05 2000-05-18 Kyowa Hakko Kogyo Co., Ltd. Nouveau popypeptide chimerique
MY155913A (en) 1998-11-09 2015-12-15 Biogen Inc Chimeric anti-cd20 antibody treatment of patients receiving bmt or pbsc transpants
ES2543819T3 (es) 1998-11-09 2015-08-24 Biogen Inc. Tratamiento de neoplasias hematológicas asociadas con células tumorales circulantes utilizando anticuerpo quimérico dirigido contra CD20
US6380371B1 (en) 1998-12-10 2002-04-30 The Regents Of The University Of California Endoglycan: a novel protein having selectin ligand and chemokine presentation activity
PL209786B1 (pl) 1999-01-15 2011-10-31 Genentech Inc Przeciwciało zawierające wariant regionu Fc ludzkiej IgG1, przeciwciało wiążące czynnik wzrostu śródbłonka naczyń oraz immunoadhezyna
US6897044B1 (en) 1999-01-28 2005-05-24 Biogen Idec, Inc. Production of tetravalent antibodies
WO2000044777A1 (en) 1999-01-29 2000-08-03 Imclone Systems Incorporated Antibodies specific to kdr and uses thereof
US6383276B1 (en) 1999-03-12 2002-05-07 Fuji Photo Film Co., Ltd. Azomethine compound and oily magenta ink
US6383753B1 (en) 1999-03-31 2002-05-07 Regents Of The University Of Michigan Yeast mammalian regulators of cell proliferation
WO2000064954A1 (en) 1999-04-22 2000-11-02 Vanderbilt University Polymeric encapsulation system promoting angiogenesis
GB9909925D0 (en) 1999-04-29 1999-06-30 Pharmacia & Upjohn Spa Combined preparations comprising anthracycline derivatives
EP1642596A3 (en) 1999-05-07 2006-04-12 Genentech, Inc. Treatment of autoimmune diseases with antagonists which bind to B cell surface markers
AU777963B2 (en) 1999-05-19 2004-11-04 Merck Patent Gmbh Expression and export of interferon-alpha proteins as Fc fusion proteins
DE60042785D1 (de) 1999-06-09 2009-10-01 Immunomedics Inc Immuntherapie von autoimmunerkrankungen durch die verwendung von b-zell spezifischen antikörpern
ITMI991299A1 (it) 1999-06-11 2000-12-11 Consiglio Nazionale Ricerche Uso di anticorpi contro antigeni di superficie per il trattamento della malattia trapianto contro ospite
US6380382B1 (en) 1999-06-30 2002-04-30 Millennium Pharmaceuticals, Inc. Gene encoding a protein having diagnostic, preventive, therapeutic, and other uses
DE19930748C2 (de) 1999-07-02 2001-05-17 Infineon Technologies Ag Verfahren zur Herstellung von EEPROM- und DRAM-Grabenspeicherzellbereichen auf einem Chip
PL201086B1 (pl) 1999-07-12 2009-03-31 Genentech Inc Zastosowanie przeciwciał wiążących się z antygenem CD20
WO2001009192A1 (en) 1999-07-29 2001-02-08 Medarex, Inc. Human monoclonal antibodies to prostate specific membrane antigen
DE60037896D1 (de) 1999-07-29 2008-03-13 Medarex Inc Menschliche antikörper gegen her2/neu
CA2381565A1 (en) 1999-07-30 2001-02-08 Medarex, Inc. Therapeutic compounds comprised of anti-fc receptor binding agents
AU784971B2 (en) 1999-08-11 2006-08-10 Biogen Inc. Treatment of patients having non-Hodgkins lymphoma with bone marrow involvement with anti-CD20 antibodies
US6451284B1 (en) 1999-08-11 2002-09-17 Idec Pharmaceuticals Corporation Clinical parameters for determining hematologic toxicity prior to radioimmunotheraphy
US8557244B1 (en) 1999-08-11 2013-10-15 Biogen Idec Inc. Treatment of aggressive non-Hodgkins lymphoma with anti-CD20 antibody
AU6929100A (en) 1999-08-23 2001-03-19 Biocrystal Limited Methods and compositions for immunotherapy of b cell involvement in promotion ofa disease condition comprising multiple sclerosis
IL149500A0 (en) 1999-11-08 2002-11-10 Idec Pharma Corp Treatment of b cell malignancies using anti-cd40l antibodies in combination with anti-cd20 antibodies and/or chemotherapeutics and radiotherapy
US20020006404A1 (en) 1999-11-08 2002-01-17 Idec Pharmaceuticals Corporation Treatment of cell malignancies using combination of B cell depleting antibody and immune modulating antibody related applications
AU2001264612C1 (en) 1999-11-08 2007-11-22 Biogen Idec Inc. Treatment of B cell malignancies using combination of B cell depleting antibody and immune modulating antibody related applications
US6380362B1 (en) 1999-12-23 2002-04-30 Genesis Research & Development Corporation Ltd. Polynucleotides, polypeptides expressed by the polynucleotides and methods for their use
CA2397742A1 (en) 2000-02-25 2001-08-30 Health Research, Inc. Method for transdermal sampling of analytes
JP2003528155A (ja) 2000-03-24 2003-09-24 カイロン コーポレイション Ｃｄ２０に対する抗体とインターロイキン−２との組み合わせを用いる非ホジキンリンパ腫の治療方法
WO2001074388A1 (en) 2000-03-31 2001-10-11 Idec Pharmaceuticals Corporation Combined use of anti-cytokine antibodies or antagonists and anti-cd20 for the treatment of b cell lymphoma
KR20020093029A (ko) 2000-04-11 2002-12-12 제넨테크, 인크. 다가 항체 및 그의 용도
EP1278748B1 (en) 2000-04-25 2011-03-23 ICOS Corporation Inhibitors of human phosphatidyl-inositol 3-kinase delta
AU5914201A (en) 2000-04-25 2001-11-07 Idec Pharma Corp Intrathecal administration of rituximab for treatment of central nervous system lymphomas
US6667300B2 (en) 2000-04-25 2003-12-23 Icos Corporation Inhibitors of human phosphatidylinositol 3-kinase delta
US7560534B2 (en) 2000-05-08 2009-07-14 Celldex Research Corporation Molecular conjugates comprising human monoclonal antibodies to dendritic cells
NZ534864A (en) 2000-05-08 2006-04-28 Celldex Therapeutics Inc Human monoclonal antibodies to dentritic cells
JP2004511430A (ja) 2000-05-24 2004-04-15 イムクローン　システムズ　インコーポレイティド 二重特異性免疫グロブリン様抗原結合蛋白および製造方法
EP1299128A2 (en) 2000-06-20 2003-04-09 Idec Pharmaceuticals Corporation Cold anti-cd20 antibody/radiolabeled anti-cd22 antibody combination
PT1296714E (pt) 2000-06-22 2009-10-15 Coley Pharm Gmbh Combinação de cpg e anticorpos dirigidos contra cd19, cd20, cd22 ou cd40 para o tratamento ou prevenção do cancro
SK1152003A3 (en) 2000-06-29 2003-07-01 Abbott Lab Dual specificity antibodies and methods of making and using
US20040220388A1 (en) 2000-06-30 2004-11-04 Nico Mertens Novel heterodimeric fusion proteins
IL152940A0 (en) 2000-07-19 2003-06-24 Orbotech Ltd Apparatus and method for electrical testing of electrical circuits
US20020025317A1 (en) 2000-07-20 2002-02-28 Schering Ag Bispecific monoclonal antibodies to IL-12 and IL-18
US20050054000A1 (en) 2000-08-11 2005-03-10 Stefan Dubel Fv constructs with an influenceable affinity for a substance that is to be linked
DE10043437A1 (de) 2000-09-04 2002-03-28 Horst Lindhofer Verwendung von trifunktionellen bispezifischen und trispezifischen Antikörpern zur Behandlung von malignem Aszites
US6946292B2 (en) 2000-10-06 2005-09-20 Kyowa Hakko Kogyo Co., Ltd. Cells producing antibody compositions with increased antibody dependent cytotoxic activity
US20020128448A1 (en) 2000-10-20 2002-09-12 Idec Pharmaceuticals Corporation Variant IgG3 Rituxan and therapeutic use thereof
US7521054B2 (en) 2000-11-17 2009-04-21 The United States Of America As Represented By The Department Of Health And Human Services Reduction of the nonspecific animal toxicity of immunotoxins by mutating the framework regions of the Fv to lower the isoelectric point
RU2179862C1 (ru) 2000-12-26 2002-02-27 Общество с ограниченной ответственностью Научно-производственный центр "МедБиоСпектр" Лекарственное средство для предотвращения отторжения трансплантата, моноклональное антитело к cd3-антигену т-лимфоцитов человека, гибридома и способ лечения больных, имеющих реакцию острого отторжения трансплантата после пересадки почки
US7829084B2 (en) 2001-01-17 2010-11-09 Trubion Pharmaceuticals, Inc. Binding constructs and methods for use thereof
RU2420537C2 (ru) 2001-01-17 2011-06-10 Трабьон Фармасьютикалз Инк. Слитые белки связывающий домен-иммуноглобулин
US20030133939A1 (en) 2001-01-17 2003-07-17 Genecraft, Inc. Binding domain-immunoglobulin fusion proteins
US7754208B2 (en) 2001-01-17 2010-07-13 Trubion Pharmaceuticals, Inc. Binding domain-immunoglobulin fusion proteins
MXPA03006771A (es) 2001-01-29 2004-05-05 Idec Pharma Corp Anticuerpos modificados y metodos de uso.
AU2002327164A1 (en) 2001-01-29 2002-12-09 Idec Pharmaceuticals Corporation Engineered tetravalent antibodies and methods of use
EP1370588A2 (en) 2001-02-12 2003-12-17 Medarex, Inc. Human monoclonal antibodies to fc alpha receptor (cd89)
AU2002248571B2 (en) 2001-03-07 2007-01-18 Merck Patent Gmbh Expression technology for proteins containing a hybrid isotype antibody moiety
US20050118164A1 (en) 2001-03-09 2005-06-02 William Herman Targeted ligands
EP2359849A1 (en) 2001-04-02 2011-08-24 Genentech, Inc. Combination therapy
WO2002079255A1 (en) 2001-04-02 2002-10-10 Idec Pharmaceuticals Corporation RECOMBINANT ANTIBODIES COEXPRESSED WITH GnTIII
US20040058445A1 (en) 2001-04-26 2004-03-25 Ledbetter Jeffrey Alan Activation of tumor-reactive lymphocytes via antibodies or genes recognizing CD3 or 4-1BB
US7666414B2 (en) 2001-06-01 2010-02-23 Cornell Research Foundation, Inc. Methods for treating prostate cancer using modified antibodies to prostate-specific membrane antigen
IL158969A0 (en) 2001-06-01 2004-05-12 Cornell Res Foundation Inc Modified antibodies to prostate-specific membrane antigen and uses thereof
US7514078B2 (en) 2001-06-01 2009-04-07 Cornell Research Foundation, Inc. Methods of treating prostate cancer with anti-prostate specific membrane antigen antibodies
CA2450285C (en) 2001-06-13 2016-08-02 Genmab A/S Human monoclonal antibodies to epidermal growth factor receptor (egfr)
EP1404366A4 (en) 2001-06-14 2006-06-07 Intermune Inc COMBINED THERAPY USING INTERFERON GAMMA AND SPECIFIC B-CELL ANTIBODIES
EP2298809A3 (en) 2001-07-12 2012-02-15 FOOTE, Jefferson Super humanized antibodies
US20030026780A1 (en) 2001-07-18 2003-02-06 Hood Leroy E. Innate immunity mediated methods of treating pathological conditions
WO2003020906A2 (en) 2001-08-31 2003-03-13 Abmaxis, Inc. Multivalent protein conjugate with multiple ligand-binding domains of receptors
ES2276735T3 (es) 2001-09-14 2007-07-01 Affimed Therapeutics Ag Anticuerpos fv multimericos de cadena sencilla en tandem.
US20040044182A1 (en) 2001-09-17 2004-03-04 Hunt Joan S Expression, preparation,uses, and sequence of recombinantly-derived soluble hla-g
JP2005510470A (ja) 2001-09-28 2005-04-21 エリューシス セラピューティクス，インコーポレーテッド 二重特異性分子を用いた癌の予防、診断、および治療の方法ならびに組成物
EP1439857B1 (en) 2001-10-12 2009-02-25 Schering Corporation USE OF BISPECIFIC ANTIBODIES BINDING TO THE ACTIVATING RECEPTOR FcEpsilonRI AND TO THE INHIBITING RECEPTOR OX2Ra (CD200Ra) TO REGULATE IMMUNE RESPONSES
US20050215472A1 (en) 2001-10-23 2005-09-29 Psma Development Company, Llc PSMA formulations and uses thereof
EP1448588A4 (en) 2001-10-23 2006-10-25 Psma Dev Company L L C ANTIBODIES AND MULTIMERS OF PSMA PROTEINS
DE10156482A1 (de) 2001-11-12 2003-05-28 Gundram Jung Bispezifisches Antikörper-Molekül
ATE356149T1 (de) 2001-11-14 2007-03-15 Affimed Therapeutics Ag Bispezifische antikörper gegen cd19 und cd16 und deren verwendung
CN1189483C (zh) 2001-11-23 2005-02-16 上海中信国健药业有限公司 人源化抗cd3单克隆抗体
KR20040091616A (ko) 2001-12-26 2004-10-28 이뮤노메딕스, 인코오포레이티드 Ｖｈ 및 ｖｌ 도메인으로부터 멀티특이성, 다원자가제제를 제조하는 방법
US7638326B2 (en) 2002-01-03 2009-12-29 The Trustees Of The University Of Pennsylvania Activation and expansion of T-cells using an engineered multivalent signaling platform
AU2003224604B2 (en) 2002-01-28 2007-06-14 Medarex, Inc. Human monoclonal antibodies to prostate specific membrane antigen (PSMA)
CN101914158A (zh) 2002-02-14 2010-12-15 免疫医疗公司 抗cd 20抗体及其融合蛋白和使用方法
KR20040088572A (ko) 2002-03-01 2004-10-16 이뮤노메딕스, 인코오포레이티드 제거율 증강을 위한 양특이성 항체 점 돌연변이들
US7317091B2 (en) 2002-03-01 2008-01-08 Xencor, Inc. Optimized Fc variants
US20030219436A1 (en) 2002-03-15 2003-11-27 Ledbetter Jeffrey A. Compositions and methods to regulate an immune response using CD83 gene expressed in tumors and using soluble CD83-Ig fusion protein
US7332585B2 (en) 2002-04-05 2008-02-19 The Regents Of The California University Bispecific single chain Fv antibody molecules and methods of use thereof
US7332580B2 (en) 2002-04-05 2008-02-19 The Regents Of The University Of California Bispecific single chain Fv antibody molecules and methods of use thereof
CA2379586A1 (en) 2002-04-10 2003-10-10 William Herman Fluid targeted ligands
ATE428778T1 (de) 2002-04-26 2009-05-15 Chugai Pharmaceutical Co Ltd Verfahren zum screening auf agonistische antikörper
US7026330B2 (en) 2002-05-30 2006-04-11 The Children's Hospital Of Philadelphia Methods for treatment of acute lymphocytic leukemia
US8034904B2 (en) 2002-06-14 2011-10-11 Immunogen Inc. Anti-IGF-I receptor antibody
CN1678634A (zh) 2002-06-28 2005-10-05 多曼蒂斯有限公司 免疫球蛋白单个变体抗原结合区及其特异性构建体
ATE536188T1 (de) 2002-08-14 2011-12-15 Macrogenics Inc Fcgammariib-spezifische antikörper und verfahren zur verwendung davon
US20040091503A1 (en) 2002-08-20 2004-05-13 Genitrix, Llc Lectin compositions and methods for modulating an immune response to an antigen
ES2562177T3 (es) 2002-09-27 2016-03-02 Xencor Inc. Variantes de Fc optimizadas y métodos para su generación
CN101972478B (zh) 2002-10-08 2012-10-31 免疫医疗公司 抗体治疗
RU2349340C2 (ru) 2002-10-10 2009-03-20 Мерк Патент Гмбх Биспецифические антитела к erb-b и их применение для лечения опухолей
US7820166B2 (en) 2002-10-11 2010-10-26 Micromet Ag Potent T cell modulating molecules
RS20050300A (en) 2002-10-16 2007-08-03 Euro-Celtique S.A., Antibodies that bind cell-associated ca 125/0772p and methods of use thereof
CN101928344B (zh) 2002-10-17 2014-08-13 根马布股份公司 抗cd20的人单克隆抗体
CA2511013A1 (en) 2002-12-20 2004-07-15 Biogen Idec Ma Inc. Multivalent lymphotoxin beta receptor agonists and therapeutic uses thereof
AU2003299778A1 (en) 2002-12-20 2004-07-22 Protein Design Labs, Inc. Antibodies against gpr64 and uses thereof
US7332303B2 (en) 2002-12-23 2008-02-19 Bristol-Myers Squibb Company Product quality enhancement in mammalian cell culture processes for protein production
CA2414148A1 (en) 2002-12-30 2004-06-30 William Herman Targeted ligands
US7534427B2 (en) 2002-12-31 2009-05-19 Immunomedics, Inc. Immunotherapy of B cell malignancies and autoimmune diseases using unconjugated antibodies and conjugated antibodies and antibody combinations and fusion proteins
ES2897506T3 (es) 2003-01-09 2022-03-01 Macrogenics Inc Identificación y modificación de anticuerpos con regiones Fc variantes y métodos de utilización de los mismos
DK1587837T3 (da) 2003-01-28 2012-09-24 Proscan Rx Pharma Inc Epitopsekvenser til diagnose og behandling af prostatacancer
JP3803790B2 (ja) 2003-02-17 2006-08-02 株式会社東北テクノアーチ 新規なダイアボディ型二重特異性抗体
PT1599504E (pt) 2003-02-25 2015-03-02 Vaccibody As Anticorpo modificado
AU2004242846A1 (en) 2003-05-31 2004-12-09 Micromet Ag Pharmaceutical compositions comprising bispecific anti-CD3, anti-CD19 antibody constructs for the treatment of B-cell related disorders
AU2004242845B2 (en) 2003-05-31 2011-06-02 Amgen Research (Munich) Gmbh Human-anti-human CD3 binding molecules
US20050008649A1 (en) 2003-06-02 2005-01-13 University Of Miami Chimeric molecules and methods of use
CN1279056C (zh) 2003-06-06 2006-10-11 马菁 肿瘤相关抗原sm5－1的特异性抗体及其应用
EP1633773A4 (en) 2003-06-13 2010-10-20 Immunomedics Inc PEPTIDES OF AMINO ACIDS D
NZ544924A (en) 2003-06-27 2009-03-31 Biogen Idec Inc Modified binding molecules comprising connecting peptides
KR20060041205A (ko) 2003-07-01 2006-05-11 이뮤노메딕스, 인코오포레이티드 양특이성 항체들의 다가 담체들
US7754209B2 (en) 2003-07-26 2010-07-13 Trubion Pharmaceuticals Binding constructs and methods for use thereof
FR2858235B1 (fr) 2003-07-31 2006-02-17 Lab Francais Du Fractionnement Utilisation d'anticorps optimises en adcc pour traiter les patients faibles repondeurs
WO2005014618A2 (en) 2003-08-08 2005-02-17 Immunomedics, Inc. Bispecific antibodies for inducing apoptosis of tumor and diseased cells
US20080241884A1 (en) 2003-10-08 2008-10-02 Kenya Shitara Fused Protein Composition
KR101229731B1 (ko) 2003-10-16 2013-03-07 암젠 리서치 (뮌헨) 게엠베하 다중특이적 탈면역화된 ｃｄ3-바인더
EP1682584B1 (en) 2003-11-13 2013-04-17 Hanmi Science Co., Ltd. A pharmaceutical composition comprising an immunoglobulin fc region as a carrier
CA2544532C (en) 2003-11-28 2015-06-16 Micromet Ag Compositions comprising polypeptides
NZ547438A (en) 2003-12-19 2010-01-29 Genentech Inc Monovalent antibody fragments useful as therapeutics
US7235641B2 (en) 2003-12-22 2007-06-26 Micromet Ag Bispecific antibodies
US20050249723A1 (en) 2003-12-22 2005-11-10 Xencor, Inc. Fc polypeptides with novel Fc ligand binding sites
WO2005070456A2 (en) 2004-01-09 2005-08-04 Millennium Pharmaceuticals, Inc. Diagnosing and treating female reproductive tract or chilhood cancer with pmsa antibodies
EP1709081B1 (en) 2004-01-16 2011-04-06 Regeneron Pharmaceuticals, Inc. Fusion polypeptides capable of activating receptors
DE602005022830D1 (de) 2004-02-16 2010-09-23 Micromet Ag Weniger immunogene bindungsmoleküle
EP1730194B1 (en) 2004-03-30 2011-11-02 Yissum Research Development Company of the Hebrew University of Jerusalem Bi-specific antibodies for targeting cells involved in allergic-type reactions, compositions and uses thereof
CA2606138A1 (en) 2004-04-19 2005-10-27 Proscan Rx Pharma Prostate cancer diagnosis and treatment
JP5848861B2 (ja) 2004-04-20 2016-01-27 ジェンマブ エー／エスＧｅｎｍａｂ Ａ／Ｓ Ｃｄ２０に対するヒトモノクローナル抗体
US7378504B2 (en) 2004-06-03 2008-05-27 Medarex, Inc. Human monoclonal antibodies to Fc gamma receptor I (CD64)
WO2005123129A2 (en) 2004-06-14 2005-12-29 Regents Of The University Of California Methods of redistributing apical target antigens to detect and treat cellular proliferative disease
US20060008415A1 (en) 2004-06-25 2006-01-12 Protein Design Labs, Inc. Stable liquid and lyophilized formulation of proteins
WO2006008096A1 (en) 2004-07-16 2006-01-26 Micromet Ag Expression-enhanced polypeptides
WO2006020258A2 (en) 2004-07-17 2006-02-23 Imclone Systems Incorporated Novel tetravalent bispecific antibody
EP1978032A3 (en) 2004-07-22 2009-02-18 Erasmus University Medical Center Rotterdam Binding molecules
MX2007001638A (es) 2004-08-11 2009-02-12 Trubion Pharmaceuticals Inc Proteinas de fusion del dominio de unión.
US20060204493A1 (en) 2004-09-02 2006-09-14 Genentech, Inc. Heteromultimeric molecules
US7393662B2 (en) 2004-09-03 2008-07-01 Centocor, Inc. Human EPO mimetic hinge core mimetibodies, compositions, methods and uses
US8066989B2 (en) 2004-11-30 2011-11-29 Trion Pharma Gmbh Method of treating tumor growth and metastasis by using trifunctional antibodies to reduce the risk for GvHD in allogeneic antitumor cell therapy
ATE525400T1 (de) 2004-12-01 2011-10-15 Trion Pharma Gmbh Verwendung trifunktionaler antikörper zur risikoreduzierung von gvhd in einer allogenetischen anti-tumor zelltherapie
WO2006063150A2 (en) 2004-12-08 2006-06-15 Immunomedics, Inc. Methods and compositions for immunotherapy and detection of inflammatory and immune-dysregulatory disease, infectious disease, pathologic angiogenesis and cancer
WO2006074399A2 (en) 2005-01-05 2006-07-13 Biogen Idec Ma Inc. Multispecific binding molecules comprising connecting peptides
RS50785B (sr) 2005-01-05 2010-08-31 F-Star Biotechnologische Forschungs-Und Entwicklungsges M.B.H. Domeni sintetskih imunoglobulina sa svojstvima vezivanja, konstruisani u svojstvima molekula, koji se razlikuju od regiona, koji određuju komplementarnost
KR100616666B1 (ko) 2005-01-27 2006-08-28 삼성전기주식회사 카본나노튜브에 구아니딘기를 형성하는 방법,구아니딘기가 형성된 카본나노튜브를 기판에 부착하는방법 및 이에 따라 제조된 카본나노튜브 및 기판
BRPI0607796A2 (pt) 2005-02-18 2009-06-13 Medarex Inc composto ou um sal farmaceuticamente aceitável do mesmo, processo para preparação e uso do mesmo, e, composição farmacêutica
NZ556661A (en) 2005-02-18 2010-10-29 Medarex Inc Human monoclonal antibodies to prostate specific membrance antigen (PSMA)
GB0504767D0 (en) 2005-03-08 2005-04-13 Ares Trading Sa Lipocalin protein
WO2006106905A1 (ja) 2005-03-31 2006-10-12 Chugai Seiyaku Kabushiki Kaisha 会合制御によるポリペプチド製造方法
PL1874821T3 (pl) 2005-04-26 2013-09-30 Trion Pharma Gmbh Kombinacja przeciwciał i glikokortykoidów do leczenia raka
US8034902B2 (en) 2005-05-04 2011-10-11 Quark Pharmaceuticals, Inc. Recombinant antibodies against CD55 and CD59 and uses thereof
US20060263367A1 (en) 2005-05-23 2006-11-23 Fey Georg H Bispecific antibody devoid of Fc region and method of treatment using same
EP1726650A1 (en) 2005-05-27 2006-11-29 Universitätsklinikum Freiburg Monoclonal antibodies and single chain antibody fragments against cell-surface prostate specific membrane antigen
US7736647B2 (en) 2005-06-15 2010-06-15 Monoclonal Antibodies Therapeutics Anti-CD71 monoclonal antibodies and uses thereof for treating malignant tumor cells
WO2007002222A2 (en) 2005-06-20 2007-01-04 Psma Development Company, Llc Psma antibody-drug conjugates
US20080213273A1 (en) 2005-07-25 2008-09-04 Trubion Pharmaceuticals Inc. Single dose use of CD20-specific binding molecules
US20080279850A1 (en) 2005-07-25 2008-11-13 Trubion Pharmaceuticals, Inc. B-Cell Reduction Using CD37-Specific and CD20-Specific Binding Molecules
EP1912675B1 (en) 2005-07-25 2014-02-12 Emergent Product Development Seattle, LLC B-cell reduction using cd37-specific and cd20-specific binding molecules
WO2007024715A2 (en) 2005-08-19 2007-03-01 Abbott Laboratories Dual variable domain immunoglobin and uses thereof
US7612181B2 (en) 2005-08-19 2009-11-03 Abbott Laboratories Dual variable domain immunoglobulin and uses thereof
EP1940881B1 (en) 2005-10-11 2016-11-30 Amgen Research (Munich) GmbH Compositions comprising cross-species-specific antibodies and uses thereof
AR056142A1 (es) 2005-10-21 2007-09-19 Amgen Inc Metodos para generar el anticuerpo igg monovalente
US10183986B2 (en) 2005-12-15 2019-01-22 Industrial Technology Research Institute Trimeric collagen scaffold antibodies
NZ569359A (en) 2005-12-20 2011-11-25 Morphosys Ag Novel collection of HCDR3 regions and uses therefor
MX2008010561A (es) 2006-02-15 2009-03-02 Imclone Systems Inc Anticuerpos funcionales.
CN103539857A (zh) 2006-03-30 2014-01-29 葛兰素集团有限公司 针对β-淀粉样蛋白肽的抗体
US11046784B2 (en) 2006-03-31 2021-06-29 Chugai Seiyaku Kabushiki Kaisha Methods for controlling blood pharmacokinetics of antibodies
JP2009539841A (ja) 2006-06-06 2009-11-19 トラークス，インコーポレイテッド 自己免疫疾患の治療における抗ｃｄ３抗体の投与
US8409577B2 (en) 2006-06-12 2013-04-02 Emergent Product Development Seattle, Llc Single chain multivalent binding proteins with effector function
WO2008051448A2 (en) 2006-10-19 2008-05-02 Tolerx, Inc. Methods and compositions for efficient removal of protein a from binding molecule preparations
US7846434B2 (en) 2006-10-24 2010-12-07 Trubion Pharmaceuticals, Inc. Materials and methods for improved immunoglycoproteins
EP2076538A2 (en) 2006-10-24 2009-07-08 Trubion Pharmaceuticals, Inc. Materials and methods for improved immunoglycoproteins
WO2008079713A2 (en) 2006-12-21 2008-07-03 Macrogenics Inc. Methods for the treatment of lada and other adult-onset autoimmune diabetes using immunosuppressive monoclonal antibodies with reduced toxicity
WO2008119566A2 (en) 2007-04-03 2008-10-09 Micromet Ag Cross-species-specific bispecific binders
US20080260738A1 (en) 2007-04-18 2008-10-23 Moore Margaret D Single chain fc, methods of making and methods of treatment
WO2008153636A1 (en) 2007-05-04 2008-12-18 Cellsignaling Technology, Inc. Phospho-specific antibodies to p13k regulatory subunit and uses thereof
CA2684932A1 (en) 2007-05-09 2008-11-20 Novartis Ag Substituted imidazopyridazines as pi3k lipid kinase inhibitors
US20090252729A1 (en) 2007-05-14 2009-10-08 Farrington Graham K Single-chain Fc (scFc) regions, binding polypeptides comprising same, and methods related thereto
WO2008150485A2 (en) 2007-05-29 2008-12-11 Wyeth Erbb2 binding proteins and use thereof
EP2158207B1 (en) 2007-06-12 2011-05-25 F. Hoffmann-La Roche AG Thiazoliopyrimidines and their use as inhibitors of phosphatidylinositol-3 kinase
WO2008152394A1 (en) 2007-06-12 2008-12-18 F.Hoffmann-La Roche Ag Pharmaceutical compounds
WO2008152387A1 (en) 2007-06-12 2008-12-18 F.Hoffmann-La Roche Ag Quinazoline derivatives as pi3 kinase inhibitors
US20090148447A1 (en) 2007-07-06 2009-06-11 Trubion Pharmaceuticals, Inc. Binding Peptides Having a C-terminally Disposed Specific Binding Domain
CA2695382A1 (en) 2007-08-01 2009-02-05 The Government Of The United States Of America, As Represented By The Se Cretary, Department Of Health Of Human Services, National Institutes Of A fold-back diabody diphtheria toxin immunotoxin and methods of use
PE20140196A1 (es) 2007-08-09 2014-03-19 Boehringer Ingelheim Int Anticuerpos anti-cd37
EP2033657A1 (de) 2007-09-04 2009-03-11 Trion Pharma Gmbh Intraoperative trifunktionale Antikörper-Applikation zur Prophylaxe intraperitonealer Tumorzelldissemination
TWI471134B (zh) 2007-09-12 2015-02-01 Genentech Inc 肌醇磷脂３－激酶抑制劑化合物及化療劑之組合及使用方法
JP2010539239A (ja) 2007-09-17 2010-12-16 グラクソスミスクライン・リミテッド・ライアビリティ・カンパニー Ｐｉ３キナーゼ阻害剤としてのピリドピリミジン誘導体
ES2399774T3 (es) 2007-09-24 2013-04-03 Genentech, Inc. Compuestos de tiazolopirimidina inhibidores de PI3K y métodos de uso
JP5410431B2 (ja) 2007-09-27 2014-02-05 セントロ ナシオナル デ インベスティガシオネス オンコロヒカス（セエネイオ） イミダゾロチアジアゾール類のプロテインキナーゼ阻害剤としての使用
WO2009046294A2 (en) 2007-10-03 2009-04-09 Cornell University Treatment of proliferative disorders using antibodies to psma
US20110160232A1 (en) 2007-10-04 2011-06-30 Pingda Ren Certain chemical entities and therapeutic uses thereof
US20110009403A1 (en) 2007-10-05 2011-01-13 S*Bio Pte Ltd. 2-morpholinylpurines as inhibitors of pi3k
ES2406129T3 (es) 2007-10-05 2013-06-05 Verastem, Inc. Derivados de purina sustituidos con pirimidina
KR20100083170A (ko) 2007-10-16 2010-07-21 와이어쓰 엘엘씨 티에노피리미딘 및 피라졸로피리미딘 화합물 및 이의 ｍＴＯＲ 키나제 및 ＰＩ3 키나제 억제제로서의 용도
US20100311736A1 (en) 2007-10-22 2010-12-09 Glaxosmithkline Llc Pyridosulfonamide derivatives as p13 kinase inhibitors
GB0721095D0 (en) 2007-10-26 2007-12-05 Piramed Ltd Pharmaceutical compounds
JP5638955B2 (ja) 2007-10-26 2014-12-10 エフ．ホフマン−ラ ロシュ アーゲーＦ． Ｈｏｆｆｍａｎｎ−Ｌａ Ｒｏｃｈｅ Ａｋｔｉｅｎｇｅｓｅｌｌｓｃｈａｆｔ Ｐｉ３キナーゼ阻害剤として有用なプリン誘導体
WO2009059030A1 (en) 2007-10-31 2009-05-07 Burnham Institute For Medical Research Pyrazole derivatives as kinase inhibitors
WO2009058361A1 (en) 2007-10-31 2009-05-07 Dynavax Technologies Corp. Inhibition of type i ifn production
AU2008321099A1 (en) 2007-11-13 2009-05-22 Icos Corporation Inhibitors of human phosphatidyl-inositol 3-kinase delta
WO2009066084A1 (en) 2007-11-21 2009-05-28 F. Hoffmann-La Roche Ag 2 -morpholinopyrimidines and their use as pi3 kinase inhibitors
UA102828C2 (en) 2007-11-27 2013-08-27 Целльзом Лимитед Amino triazoles as p13k inhibitors
US20090149458A1 (en) 2007-11-27 2009-06-11 Wyeth PYRROLO[3,2-d]PYRIMIDINE COMPOUNDS AND THEIR USE AS PI3 KINASE AND mTOR KINASE INHIBITORS
US8227577B2 (en) 2007-12-21 2012-07-24 Hoffman-La Roche Inc. Bivalent, bispecific antibodies
US9266967B2 (en) 2007-12-21 2016-02-23 Hoffmann-La Roche, Inc. Bivalent, bispecific antibodies
JP6013733B2 (ja) 2008-04-11 2016-10-25 エマージェント プロダクト デベロップメント シアトル， エルエルシー Ｃｄ３７免疫治療薬および二機能性化学療法薬とのその組合せ
US20110189093A1 (en) 2008-04-14 2011-08-04 Proscan Rx Pharma Prostate specific membrane antigen antibodies and antigen binding fragments
ITTO20080313A1 (it) 2008-04-22 2009-10-23 Marco Colombatti Anticorpo monoclonale isolato o suo frammento legante l'antigene specifico di membrana della prostata, suoi coniugati e suoi usi
CA2729749A1 (en) 2008-07-02 2010-01-07 Emergent Product Development Seattle, Llc Tnf-a antagonist multi-target binding proteins
NZ590667A (en) 2008-07-02 2013-01-25 Emergent Product Dev Seattle Tgf-b antagonist multi-target binding proteins
WO2010003101A2 (en) 2008-07-02 2010-01-07 Trubion Pharmaceuticals, Inc. Il6 immunotherapeutics
US20110158995A1 (en) 2008-07-28 2011-06-30 Renault S.A.S Multi-Specific Binding Proteins Targeting B Cell Disorders
ES2438495T3 (es) 2008-09-08 2014-01-17 Psma Development Company, L.L.C. Compuestos para exterminar células cancerosas que expresan PSMA, resistentes a taxano
CA2736408A1 (en) 2008-09-26 2010-04-01 Roche Glycart Ag Bispecific anti-egfr/anti-igf-1r antibodies
ME02485B (me) 2008-10-01 2017-02-20 Amgen Res Munich Gmbh Bispecifično jednolančano protutijelo psmaxcd3 s međuvrsnom specifičnošću
AU2009299794B2 (en) 2008-10-01 2015-08-13 Amgen Research (Munich) Gmbh Cross-species-specific single domain bispecific single chain antibody
EP2352763B2 (en) 2008-10-01 2022-09-21 Amgen Research (Munich) GmbH Bispecific single chain antibodies with specificity for high molecular weight target antigens
KR20170091801A (ko) 2008-10-02 2017-08-09 압테보 리서치 앤드 디벨롭먼트 엘엘씨 Ｃｄ86 길항제 다중-표적 결합 단백질
US8268314B2 (en) 2008-10-08 2012-09-18 Hoffmann-La Roche Inc. Bispecific anti-VEGF/anti-ANG-2 antibodies
EA032828B1 (ru) 2008-10-10 2019-07-31 Аптево Рисёрч Энд Девелопмент Ллс Иммунотерапевтические средства против комплекса tcr
WO2010057047A1 (en) 2008-11-13 2010-05-20 Trubion Pharmaceutics, Inc. Cd37 immunotherapeutic combination therapies and uses thereof
HRP20221259T1 (hr) 2009-02-13 2022-12-09 Immunomedics, Inc. Imunokonjugati s intracelularnom vezom koja se može rascijepiti
EP2419451A4 (en) 2009-04-14 2012-11-14 Proscan Rx Pharma Inc ANTIBODIES DIRECTED AGAINST THE PROSTATE-SPECIFIC MEMBRANE ANTIGEN
ES2708124T3 (es) 2009-04-27 2019-04-08 Oncomed Pharm Inc Procedimiento para preparar moléculas heteromultiméricas
TW201100543A (en) 2009-05-27 2011-01-01 Hoffmann La Roche Tri-or tetraspecific antibodies
KR101962476B1 (ko) 2009-07-03 2019-03-26 아비펩 피티와이 리미티트 면역성 접합체 및 그 제조방법
EP2516467A2 (en) 2009-12-23 2012-10-31 Emergent Product Development Seattle, LLC Compositions comprising tnf-alpha and il-6 antagonists and methods of use thereof
KR101961495B1 (ko) 2009-12-23 2019-03-22 아비펩 피티와이 리미티트 면역-컨쥬게이트 및 그 제조방법 ２
US20130129723A1 (en) 2009-12-29 2013-05-23 Emergent Product Development Seattle, Llc Heterodimer Binding Proteins and Uses Thereof
TWI653333B (zh) 2010-04-01 2019-03-11 安進研究（慕尼黑）有限責任公司 跨物種專一性之ＰＳＭＡｘＣＤ３雙專一性單鏈抗體
US8557961B2 (en) 2010-04-02 2013-10-15 Amunix Operating Inc. Alpha 1-antitrypsin compositions and methods of making and using same
CN103154025B (zh) 2010-08-02 2015-07-01 宏观基因有限公司 共价双抗体及其用途
US8962804B2 (en) 2010-10-08 2015-02-24 City Of Hope Meditopes and meditope-binding antibodies and uses thereof
PL2647707T3 (pl) 2010-11-30 2019-02-28 Chugai Seiyaku Kabushiki Kaisha Środek terapeutyczny wywołujący cytotoksyczność
WO2012088290A2 (en) 2010-12-22 2012-06-28 Abbott Laboratories Tri-variable domain binding proteins and uses thereof
JP2014515598A (ja) 2011-03-10 2014-07-03 エイチシーオー アンティボディ， インク． 二重特異性三鎖抗体様分子
AU2012229048B2 (en) 2011-03-16 2016-01-21 Amgen Inc Fc variants
TWI671315B (zh) 2011-03-28 2019-09-11 法商賽諾菲公司 具有交叉結合區定向之雙重可變區類抗體結合蛋白
BR112013027224A8 (pt) 2011-04-22 2018-08-14 Emergent Product Dev Seattle Proteínas de ligação de antígeno de membrana específico de próstata e composições e métodos relacionados
WO2012158818A2 (en) 2011-05-16 2012-11-22 Fabion Pharmaceuticals, Inc. Multi-specific fab fusion proteins and methods of use
EP2525222A1 (en) 2011-05-17 2012-11-21 Markus M. Heiss Initial relative lymphocyte count as predictive biomarker
PE20141521A1 (es) 2011-08-23 2014-10-25 Roche Glycart Ag Moleculas biespecificas de union a antigeno activadoras de celulas t
RU2605390C2 (ru) 2011-08-23 2016-12-20 Рош Гликарт Аг Биспецифические антитела, специфичные к антигенам, активирующим т-клетки, и опухолевому антигену, и способы их применения
US9718893B2 (en) 2011-12-19 2017-08-01 Synimmune Gmbh Bispecific antibody molecule
KR101963230B1 (ko) 2011-12-26 2019-03-29 삼성전자주식회사 복수개의 단일 항체를 포함하는 단백질 복합체
PT2802607T (pt) 2012-01-13 2018-01-03 Univ Wuerzburg J Maximilians Complementação funcional bipartida induzida por duplo antigénio
WO2013121175A1 (en) 2012-02-16 2013-08-22 Ucl Business Plc Lysosome-cleavable linker
GB201203442D0 (en) 2012-02-28 2012-04-11 Univ Birmingham Immunotherapeutic molecules and uses
AU2013224919B2 (en) 2012-03-01 2017-12-07 Amgen Research (Munich) Gmbh Long life polypeptide binding molecules
JP2015510877A (ja) 2012-03-09 2015-04-13 ユーシーエル ビジネス パブリック リミテッド カンパニー 抗体の化学修飾
JP2015523852A (ja) 2012-05-14 2015-08-20 ジェネンテック， インコーポレイテッド 腫瘍の診断と治療のための組成物と方法
HUE059815T2 (hu) 2012-05-18 2022-12-28 Aptevo Res & Development Llc Bispecifikus SCFV immunofuziós (BIF) kötõdés a CD123-hoz és a CD3-hoz
US20130309234A1 (en) 2012-05-18 2013-11-21 Trion Pharma Gmbh Correlation of de novo-induced tumor-associated humoral immune responses with improved clinical outcome
ES2672974T3 (es) 2012-06-01 2018-06-19 Ibc Pharmaceuticals, Inc. Complejos multiméricos con estabilidad in vivo, farmacocinética y eficacia mejoradas
EP2869845B1 (en) 2012-07-06 2019-08-28 Genmab B.V. Dimeric protein with triple mutations
CA2878843A1 (en) 2012-07-13 2014-01-16 Zymeworks Inc. Bispecific asymmetric heterodimers comprising anti-cd3 constructs
US9315567B2 (en) 2012-08-14 2016-04-19 Ibc Pharmaceuticals, Inc. T-cell redirecting bispecific antibodies for treatment of disease
US9682143B2 (en) 2012-08-14 2017-06-20 Ibc Pharmaceuticals, Inc. Combination therapy for inducing immune response to disease
HUE057701T2 (hu) 2012-09-11 2022-05-28 Medivation Prostate Therapeutics Llc Enzalutamid kiszerelési formái
KR20140036905A (ko) 2012-09-18 2014-03-26 삼성전자주식회사 이중특이 항체를 포함하는 단백질 복합체
JOP20200236A1 (ar) * 2012-09-21 2017-06-16 Regeneron Pharma الأجسام المضادة لمضاد cd3 وجزيئات ربط الأنتيجين ثنائية التحديد التي تربط cd3 وcd20 واستخداماتها
RU2015117393A (ru) 2012-10-08 2016-12-10 Роше Гликарт Аг Лишенные fc антитела, содержащие два Fab-фрагмента, и способы их применения
KR101911438B1 (ko) 2012-10-31 2018-10-24 삼성전자주식회사 이중 특이 항원 결합 단백질 복합체 및 이중 특이 항체의 제조 방법
JP2016503295A (ja) 2012-11-07 2016-02-04 ファイザー・インク 抗ｉｌ−１３受容体アルファ２抗体および抗体−薬物コンジュゲート
JP6571527B2 (ja) 2012-11-21 2019-09-04 ウーハン ワイゼットワイ バイオファルマ カンパニー リミテッドＷｕｈａｎ Ｙｚｙ Ｂｉｏｐｈａｒｍａ Ｃｏ．， Ｌｔｄ． 二重特異性抗体
WO2014100490A1 (en) 2012-12-19 2014-06-26 Adimab, Llc Multivalent antibody analogs, and methods of their preparation and use
US10329350B2 (en) 2012-12-26 2019-06-25 Industrial Technology Research Institute Method for producing a multivalent fab fragment with collagen-like peptide
TR201815254T4 (tr) 2013-01-02 2018-11-21 Glenmark Pharmaceuticals Sa Tl1a'ya bağlanan anti̇korlar ve bunlarin kullanimlari
EP3620473A1 (en) 2013-01-14 2020-03-11 Xencor, Inc. Novel heterodimeric proteins
WO2014151438A1 (en) 2013-03-15 2014-09-25 Emergent Product Development Seattle, Llc Multispecific anti-cd37 antibodies and related compositions and methods
WO2014143807A2 (en) 2013-03-15 2014-09-18 Stromatt Scott Anti-cd37 antibody and bcr pathway antagonist combination therapy for treatment of b-cell malignancies and disorders
JP7020909B2 (ja) 2014-07-25 2022-02-16 シトムクス セラピューティクス，インコーポレイティド 抗－ｃｄ３抗体、活性化可能抗－ｃｄ３抗体、多重特異的抗－ｃｄ３抗体、多重特異的活性化可能抗－ｃｄ３抗体、及びそれらの使用方法
WO2016094873A2 (en) 2014-12-12 2016-06-16 Emergent Product Development Seattle, Llc Receptor tyrosine kinase-like orphan receptor 1 binding proteins and related compositions and methods
CA2976360A1 (en) 2015-02-11 2016-08-18 Aptevo Research And Development Llc Compositions and methods for combination therapy with prostate-specific membrane antigen binding proteins

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011090762A1 (en) * 2009-12-29 2011-07-28 Emergent Product Development Seattle, Llc Heterodimer binding proteins and uses thereof
WO2012162067A2 (en) * 2011-05-21 2012-11-29 Macrogenics, Inc. Cd3-binding molecules capable of binding to human and non-human cd3
CN104487587A (zh) * 2012-04-20 2015-04-01 新兴产品开发西雅图有限公司 Cd3结合多肽

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
Induction of specific nonresponsiveness in unprimed human T cells by anti-CD3 antibody and alloantigen;C Anasetti等;《J Exp Med》;19901201;第172卷(第6期);第1691-1700页 *

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