CN115232209B - 靶向gprc5d的抗体及其用途 - Google Patents
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- C07K2319/00—Fusion polypeptide
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Abstract
本发明提供靶向GPRC5D的抗体,以及包含它的多特异性抗体、嵌合抗原受体、抗体偶联物、药物组合物和试剂盒,以及它们在诊断/治疗/预防与GPRC5D表达相关的疾病中的用途。
Description
技术领域
本发明属于免疫治疗领域。更具体地,本发明涉及靶向GPRC5D的抗体,及其在预防和/或治疗和/或诊断疾病中的用途。
背景技术
骨髓瘤是一种起源于骨髓造血组织、以克隆性浆细胞大量增生为特征的恶性肿瘤,由于其易产生多发性骨损害,故也称为多发性骨髓瘤(Multiple Myeloma,MM)。目前,骨髓瘤在血液肿瘤中的发病率仅次于白血病、淋巴瘤,为血液系统第三大恶性肿瘤,几乎所有患者都会出现复发并需要持续治疗,因此复发难治性多发性骨髓瘤患者的存活率较低。
G蛋白偶联受体C5家族亚型D分子(GPRC5D)是2001年首次鉴定出的孤儿非典型C类GPCR。GPRC5D主要表达于MM患者的恶性浆细胞中,使其成为多发性骨髓瘤的理想靶标。
因此,针对GPRC5D靶点进行药物开发、抗体开发具有重要价值和意义。本发明旨在提供一种靶向GPRC5D的抗体,及其在疾病预防和/或治疗和/或诊断中的用途。
发明内容
在第一个方面,本发明提供一种靶向GPRC5D的抗体或其抗原结合片段,其包含:
(1)如SEQ ID NO:1所示的CDR-H1、如SEQ ID NO:2所示的CDR-H2、如SEQ ID NO:3所示的CDR-H3、如SEQ ID NO:4所示的CDR-L1、如SEQ ID NO:5所示的CDR-L2,和如SEQ IDNO:6所示的CDR-L3;或
(2)如SEQ ID NO:7所示的CDR-H1、如SEQ ID NO:8所示的CDR-H2、如SEQ ID NO:9所示的CDR-H3、如SEQ ID NO:10所示的CDR-L1、如SEQ ID NO:11所示的CDR-L2,和如SEQ IDNO:12所示的CDR-L3。
在一个实施方案中,本发明的抗体或其抗原结合片段包含重链可变区和轻链可变区,所述重链可变区与选自SEQ ID NO:13、15、21、24、27、30、33、36、39和42的氨基酸序列具有至少90%同一性,或与选自SEQ ID NO:13、15、21、24、27、30、33、36、39和42的氨基酸序列相比具有一个或几个氨基酸(例如最多1、2、3、4、5、6、7、8、9或10个氨基酸)的修饰,优选最多10个氨基酸的保守性修饰;所述轻链可变区与选自SEQ ID NO:14、16、22、25、28、31、34、37、40和43的氨基酸序列具有至少90%同一性,或与选自SEQ ID NO:14、16、22、25、28、31、34、37、40和43的氨基酸序列相比具有一个或几个氨基酸(例如最多1、2、3、4、5、6、7、8、9或10个氨基酸)的修饰,优选最多10个氨基酸的保守性修饰。优选地,所述修饰是保守性修饰,例如氨基酸的保守性取代、添加和缺失。在一个优选的实施方案中,本发明的抗体或其抗原结合片段包含选自SEQ ID NO:13、15、21、24、27、30、33、36、39和42的重链可变区和选自SEQID NO:14、16、22、25、28、31、34、37、40和43的轻链可变区。
在一个实施方案中,本发明的抗体或其抗原结合片段包含选自以下的重链可变区和轻链可变区:
(a)如SEQ ID NO:13所示的重链可变区和如SEQ ID NO:14所示的轻链可变区;
(b)如SEQ ID NO:15所示的重链可变区和如SEQ ID NO:16所示的轻链可变区;
(c)如SEQ ID NO:21所示的重链可变区和如SEQ ID NO:22所示的轻链可变区;
(d)如SEQ ID NO:24所示的重链可变区和如SEQ ID NO:25所示的轻链可变区;
(e)如SEQ ID NO:27所示的重链可变区和如SEQ ID NO:28所示的轻链可变区;
(f)如SEQ ID NO:30所示的重链可变区和如SEQ ID NO:31所示的轻链可变区;
(g)如SEQ ID NO:33所示的重链可变区和如SEQ ID NO:34所示的轻链可变区;
(h)如SEQ ID NO:36所示的重链可变区和如SEQ ID NO:37所示的轻链可变区;
(i)如SEQ ID NO:39所示的重链可变区和如SEQ ID NO:40所示的轻链可变区;和
(j)如SEQ ID NO:42所示的重链可变区和如SEQ ID NO:43所示的轻链可变区。
任选地,所述重链可变区和轻链可变区与(a)-(j)任一组的重链可变区和轻链可变区相比具有至少90%、91%、92%、93%、94%、95%、96%、97%、98%、99%、100%同一性;
任选地,所述重链可变区和轻链可变区与(a)-(j)任一组的重链可变区和轻链可变区具有一个或几个氨基酸的修饰,例如最多1、2、3、4、5、6、7、8、9或10个氨基酸的修饰;优选地,所述修饰是保守性修饰,例如氨基酸的保守性取代、添加和缺失。
在一个实施方案中,本发明的抗体或其抗原结合片段与选自SEQ ID NO:17、18、23、26、29、32、35、38、41和44的氨基酸序列具有至少90%、91%、92%、93%、94%、95%、96%、97%、98%、99%、100%同一性,或与选自SEQ ID NO:17、18、23、26、29、32、35、38、41和44的氨基酸序列相比具有一个或几个氨基酸(例如最多1、2、3、4、5、6、7、8、9或10个氨基酸)的修饰。优选地,所述修饰是保守性修饰,例如氨基酸的保守性取代、添加和缺失。优选地,本发明的抗体或其抗原结合片段的氨基酸序列选自SEQ ID NO:17、18、23、26、29、32、35、38、41和44。
在一个实施方案中,本发明的抗体或其抗原结合片段是鼠源抗体、嵌合抗体、人源化抗体或人抗体,优选是人源化抗体。
本发明还提供编码上抗体或其抗原结合片段的核酸分子。因此,在一个实施方案中,编码所述抗体或其抗原结合片段的核酸分子与选自SEQ ID NO:45-52的核苷酸序列具有至少90%、91%、92%、93%、94%、95%、96%、97%、98%、99%、100%序列同一性,并且其编码的抗体或其抗原结合片段能够特异性结合GPRC5D抗原。优选地,编码所述抗体或其抗原结合片段的核酸分子选自SEQ ID NO:45-52。
在另一个方面,本发明还提供一种多特异性抗体(优选双特异性抗体或三特异性抗体),其包含如上所述的抗GPRC5D抗体或其抗原结合片段,和一个或多个与其他肿瘤抗原特异性结合的第二抗体或其抗原结合部分。
在一个实施方案中,第二抗体或其抗原结合部分可以具有任何抗体或抗体片段形式,例如全长抗体、Fab、Fab'、F(ab')2、Fv、scFv、scFv-scFv、微抗体、双抗体或sdAb。
本发明还提供包含编码上述抗GPRC5D抗体或其抗原结合片段或多特异性抗体的核酸分子的载体,以及表达所述抗GPRC5D抗体或其抗原结合片段或多特异性抗体的宿主细胞。
在另一个方面,本发明还提供一种重组受体(例如重组TCR受体或嵌合抗原受体),其包含本发明所述的抗GPRC5D抗体或其抗原结合片段或本发明所述的多特异性抗体。优选地,所述重组受体是嵌合抗原受体,其进一步包含跨膜结构域和胞内信号传导结构域。优选地,所述嵌合抗原受体还包含一个或多个共刺激结构域。更优选地,所述嵌合抗原受体包含如本文所提供的抗GPRC5D抗体或其抗原结合片段或多特异性抗体、CD8α或CD28跨膜结构域、CD28和/或4-1BB共刺激结构域,和CD3ζ胞内信号传导结构域。
本发明还提供编码如上所定义的靶向GPRC5D的重组受体的核酸分子,以及包含所述核酸分子的载体。
本发明还提供包含如上所定义的靶向GPRC5D的重组受体的细胞,优选免疫细胞,例如T细胞、NK细胞、NKT细胞、巨噬细胞、树突细胞。在一个优选的实施方案中,所述工程化免疫细胞还包含靶向其他肿瘤抗原的第二重组受体,例如第二嵌合抗原受体或重组TCR受体。
在另一个方面,本发明还提供一种抗体偶联物,其包含本发明所定义的抗GPRC5D抗体或其抗原结合片段和第二功能性结构,其中所述第二功能性结构选自Fc、放射性同位素、延长半衰期的结构部分、可检测标记物和药物。
在一个实施方案中,所述延长半衰期的结构部分选自:白蛋白的结合结构、转铁蛋白的结合结构、聚乙二醇分子、重组聚乙二醇分子、人血清白蛋白、人血清白蛋白的片段和结合人血清白蛋白的白多肽(包括抗体)。在一个实施方案中,可检测标记物选自荧光团、化学发光化合物、生物发光化合物、酶、抗生素抗性基因和造影剂。在一个实施方案中,所述药物选自细胞毒素和免疫调节剂。
在另一个方面,本发明还提供一种检测试剂盒,其包含本发明所述的抗GPRC5D抗体或其抗原结合片段、多特异性抗体、抗体偶联物、工程化免疫细胞或重组受体。
在另一个方面,本发明还提供一种药物组合物,其包含本发明所述的抗GPRC5D抗体或其抗原结合片段、重组受体、多特异性抗体、工程化免疫细胞或抗体偶联物,和一种或多种药学上可接受的赋形剂。
在另一个方面,本发明还提供一种治疗和/或预防和/或诊断与GPRC5D表达相关的疾病的方法,包括向受试者施用如上所述的抗GPRC5D抗体或其抗原结合片段、嵌合抗原受体、多特异性抗体、抗体偶联物、工程化免疫细胞或药物组合物。
发明详述
除非另有说明,否则本文中所使用的所有科学技术术语的含义与本发明所属领域的普通技术人员通常所了解的相同。
抗GPRC5D抗体或其抗原结合片段
如本文所用,术语“抗体”具有本领域技术人员所理解的最广泛的含义,并且包括单克隆抗体(包含完整抗体)、多克隆抗体、多价抗体、多特异性抗体(例如双特异性抗体)、和能够表现期望的生物活性的携带一个或多个CDR序列的抗体片段或合成多肽。本发明所述抗体可为任何种类(例如IgG、IgE、IgM、IgD、IgA等)或亚类(例如IgG1、IgG2、IgG2a、IgG3、IgG4、IgA1、IgA2等)。
如本文所用,术语“抗原结合片段”或“抗体片段”指抗体中保留特异性结合抗原的能力的一个或更多个片段。已经显示,抗体的抗原结合功能可通过全长抗体的片段来实现。本发明中的抗体片段的实例包括但不限于:Fab、Fab'、F(ab')2、Fd、Fd′、Fv、单链抗体(scFv)、二硫键-连接的Fv(sdFv)、线性抗体、具有两个抗原结合位点的“双体”、所述抗原的天然配体或其功能性片段等。因此,除非上下文明确指出,否则本发明的“抗体”涵盖如上定义的抗体片段或抗原结合片段。因此,在一个实施方案中,本发明的抗体选自完整抗体、Fab、Fab'、F(ab')2、Fd、Fd′、Fv、scFv、sdFv、线性抗体和双体。
通常,完整抗体包括通过二硫键连接在一起的两条重链和两条轻链,每条轻链通过二硫键被连至各自的重链,呈“Y”形结构。每条重链包含重链可变区(VH)和重链恒定区,其中重链可变区包含三个互补决定区(CDR):CDR-H1、CDR-H2和CDR-H3,重链恒定区包含三个恒定结构域:CH1、CH2和CH3。每条轻链包含轻链可变区(VL)和轻链恒定区,其中轻链可变区包含三个CDR:CDR-L1、CDR-L2和CDR-L3,轻链恒定区包含一个恒定结构域CL。在重链/轻链可变区中,CDR被更保守的框架区(FR)隔开。重链/轻链的可变区负责与抗原的识别和结合,恒定区则可以介导抗体与宿主组织或因子的结合,包括免疫系统的各种细胞(例如效应细胞)和经典补体系统的第一组分。
可以使用许多本领域熟知的编号方案容易地确定给定CDR或FR的精确氨基酸序列边界,这些方案包括:Kabat等人(1991),“Sequences ofProteins of ImmunologicalInterest,”第5版Public Health Service,NationalInstitutes of Health,贝塞斯达,马里兰州(“Kabat”编号方案);Al-Lazikani等人,(1997)JMB 273,927-948(“Chothia”编号方案);MacCallum等人,J.Mol.Biol.262:732-745(1996),“Antibody-antigeninteractions:Contact analysis and binding sitetopography,”J.Mol.Biol.262,732-745”(“Contact”编号方案);Lefranc MP等人,“IMGTunique numbering forimmunoglobulin and T cell receptor variable domains andIg superfamily V-likedomains,”Dev Comp Immunol,2003年1月;27(1):55-77(“IMGT”编号方案);Honegger A和Plückthun A,“Yet another numbering scheme forimmunoglobulin variable domains:an automatic modeling and analysis tool,”JMol Biol,2001年6月8日;309(3):657-70(“Aho”编号方案);和Martin等人,“Modeling antibody hypervariable loops:acombined algorithm,”PNAS,1989,86(23):9268-9272(“AbM”编号方案)。
给定CDR或FR的边界可能取决于用于鉴定的方案而不同。例如,Kabat方案是基于结构比对,而Chothia方案是基于结构信息。Kabat和Chothia方案的编号都是基于最常见的抗体区域序列长度,其中通过插入字母提供插入(例如“30a”)并且在一些抗体中出现缺失。这两种方案将某些插入和缺失(indel)放置在不同的位置,从而产生不同的编号。Contact方案是基于对复杂晶体结构的分析,并且在许多方面与Chothia编号方案相似。AbM方案是介于Kabat与Chothia定义之间的折衷,其基于Oxford Molecular的AbM抗体建模软件所使用的方案。
因此,除非另有规定,否则应当理解,给定抗体或其区域(如其可变区)的“CDR”涵盖由任何上述方案或其他已知方案所定义的CDR。例如,在指定特定的CDR(例如CDR3)含有给定氨基酸序列的情况下,应理解,这样的CDR还可以具有由任何上述方案或其他已知方案所定义的相应CDR(例如CDR3)的序列。同样,除非另有规定,否则应当理解给定抗体或其区域(如其可变区)的FR涵盖由任何上述方案或其他已知方案所定义的FR。除非特别指出,否则在本文中用于界定CDR和FR的边界的编号方案采用Kabat方案。
“单链抗体”和“scFv”在本文中可互换使用,是指由抗体重链可变区(VH)和轻链可变区(VL)通过接头连接而成的抗体。可以选择接头的最佳长度和/或氨基酸组成。接头的长度会明显影响scFv的可变区折叠和相互作用情况。事实上,如果使用较短的接头(例如在5-10个氨基酸之间),则可以防止链内折叠。关于接头的大小和组成的选择,参见例如,Hollinger等人,1993Proc Natl Acad.Sci.U.S.A.90:6444-6448;美国专利申请公布号2005/0100543、2005/0175606、2007/0014794;以及PCT公布号WO2006/020258和WO2007/024715,其全文通过引用并入本文。常用的接头例如GSTSGSGKPGSGEGSTKG(SEQ ID NO:75)、GGGGSGGGGSGGGGS(SEQ ID NO:76)。scFv可以包含以任何顺序连接的VH和VL,例如VH-接头-VL或VL-接头-VH。
在一个实施方案中,本发明的抗体或其抗原结合片段是鼠源抗体、嵌合抗体、人源化抗体或人抗体,优选是人源化抗体。
如本文所用,术语“嵌合抗体”指这样的抗体,其中每个重链和轻链氨基酸序列的一部分与来自特定物种或者属于特定类别的抗体中相应序列同源,而该链的其余区段则与另一物种或属于另一类别的相应序列同源。一般地,轻链和重链的可变区均来自一个物种的抗体的可变区,而恒定区则与来自另一个物种的抗体序列同源。这种嵌合形式的一个明显优点是可使用易于获得的B细胞或来自非人宿主的杂交瘤从目前已知的来源方便地产生可变区,而与其组合的恒定区来自例如人细胞。所述可变区具有易于制备的优点,并且特异性不受来源的影响,而由于恒定区来自人,因此该抗体在注射时引发人免疫应答的可能性将比恒定区来自非人来源时更低。
如本文所用,“人源化”抗体是指其中所有或基本上所有CDR氨基酸残基源自非人CDR并且所有或基本上所有FR氨基酸残基源自人FR。非人抗体的“人源化形式”是指所述非人抗体的变体,其经历人源化以通常降低对人的免疫原性,同时保留亲本非人抗体的特异性和亲和力。在一些实施方案中,人源化抗体中的一些FR残基被来自非人抗体(例如,衍生CDR残基的抗体)的相应残基取代,例如以恢复或改善抗体特异性或亲和力。
人源化抗体及其制备方法是本领域技术人员熟知的,参见例如Almagro和Fransson,Front.Biosci.13:1619-1633(2008)。可用于人源化的人类框架区包括但不限于:使用“最佳拟合”方法选择的框架区;源自轻链或重链可变区的特定亚组的人类抗体的共有序列的框架区;人类成熟(体细胞突变)框架区或人类种系框架区;以及筛选FR文库得到的框架区。
如本文所用,术语“人抗体”旨在包括具有来自人生殖系免疫球蛋白序列的可变区和恒定区的抗体。本发明的人抗体可包含不是由人生殖系免疫球蛋白序列编码的氨基酸残基(例如,通过体外随机诱变或定点诱变或者通过体内体细胞突变引入的突变)。
在一个实施方案中,本发明提供一种靶向GPRC5D的抗体或其抗原结合片段,其包含:
(1)如SEQ ID NO:1所示的CDR-H1、如SEQ ID NO:2所示的CDR-H2、如SEQ ID NO:3所示的CDR-H3、如SEQ ID NO:4所示的CDR-L1、如SEQ ID NO:5所示的CDR-L2,和如SEQ IDNO:6所示的CDR-L3;或
(2)如SEQ ID NO:7所示的CDR-H1、如SEQ ID NO:8所示的CDR-H2、如SEQ ID NO:9所示的CDR-H3、如SEQ ID NO:10所示的CDR-L1、如SEQ ID NO:11所示的CDR-L2,和如SEQ IDNO:12所示的CDR-L3。
在一个实施方案中,本发明的抗体或其抗原结合片段包含重链可变区和轻链可变区,所述重链可变区与选自SEQ ID NO:13、15、21、24、27、30、33、36、39和42的氨基酸序列具有至少90%同一性,或与选自SEQ ID NO:13、15、21、24、27、30、33、36、39和42的氨基酸序列相比具有一个或几个氨基酸(例如最多1、2、3、4、5、6、7、8、9或10个氨基酸)的修饰;所述轻链可变区与选自SEQ ID NO:14、16、22、25、28、31、34、37、40和43的氨基酸序列具有至少90%同一性,或与选自SEQ ID NO:14、16、22、25、28、31、34、37、40和43的氨基酸序列相比具有一个或几个氨基酸(例如最多1、2、3、4、5、6、7、8、9或10个氨基酸)的修饰。优选地,所述修饰是保守性修饰,例如氨基酸的保守性取代、添加和缺失。在一个优选的实施方案中,本发明的抗体或其抗原结合片段包含选自SEQ ID NO:13、15、21、24、27、30、33、36、39和42的重链可变区和选自SEQ ID NO:14、16、22、25、28、31、34、37、40和43的轻链可变区。
在一个实施方案中,本发明的抗体或其抗原结合片段包含选自以下的重链可变区和轻链可变区:
(a)如SEQ ID NO:13所示的重链可变区和如SEQ ID NO:14所示的轻链可变区;
(b)如SEQ ID NO:15所示的重链可变区和如SEQ ID NO:16所示的轻链可变区;
(c)如SEQ ID NO:21所示的重链可变区和如SEQ ID NO:22所示的轻链可变区;
(d)如SEQ ID NO:24所示的重链可变区和如SEQ ID NO:25所示的轻链可变区;
(e)如SEQ ID NO:27所示的重链可变区和如SEQ ID NO:28所示的轻链可变区;
(f)如SEQ ID NO:30所示的重链可变区和如SEQ ID NO:31所示的轻链可变区;
(g)如SEQ ID NO:33所示的重链可变区和如SEQ ID NO:34所示的轻链可变区;
(h)如SEQ ID NO:36所示的重链可变区和如SEQ ID NO:37所示的轻链可变区;
(i)如SEQ ID NO:39所示的重链可变区和如SEQ ID NO:40所示的轻链可变区;和
(j)如SEQ ID NO:42所示的重链可变区和如SEQ ID NO:43所示的轻链可变区。
任选地,所述重链可变区和轻链可变区与(a)-(j)任一组的重链可变区和轻链可变区相比具有至少90%、91%、92%、93%、94%、95%、96%、97%、98%、99%、100%同一性;
任选地,所述重链可变区和轻链可变区与(a)-(j)任一组的重链可变区和轻链可变区具有一个或几个氨基酸的修饰,例如最多1、2、3、4、5、6、7、8、9或10个氨基酸的修饰;优选地,所述修饰是保守性修饰,例如氨基酸的保守性取代、添加和缺失。
在一个实施方案中,本发明的抗体或其抗原结合片段与选自SEQ ID NO:17、18、23、26、29、32、35、38、41和44的氨基酸序列具有至少90%、91%、92%、93%、94%、95%、96%、97%、98%、99%、100%同一性,或与选自SEQ ID NO:17、18、23、26、29、32、35、38、41和44的氨基酸序列相比具有一个或几个氨基酸(例如最多1、2、3、4、5、6、7、8、9或10个氨基酸)的修饰。优选地,所述修饰是保守性修饰,例如氨基酸的保守性取代、添加和缺失。优选地,本发明的抗体或其抗原结合片段的氨基酸序列选自SEQ ID NO:17、18、23、26、29、32、35、38、41和44。
如本文所用,术语“保守性修饰”是指不会明显影响或改变含有该氨基酸序列的抗体或抗体片段的结合特征的氨基酸修饰。这些保守性修饰包括氨基酸的保守性取代、添加及缺失。修饰可以通过本领域中已知的标准技术,如定点诱变和PCR介导的诱变而引入本发明的嵌合抗原受体中。保守性氨基酸取代是氨基酸残基被具有类似侧链的氨基酸残基置换的取代。具有类似侧链的氨基酸残基家族已在本领域中有定义,包括碱性侧链(例如赖氨酸、精氨酸、组氨酸)、酸性侧链(例如天冬氨酸、谷氨酸)、不带电荷极性侧链(例如甘氨酸、天冬酰胺、谷氨酰胺、丝氨酸、苏氨酸、酪氨酸、半胱氨酸)、非极性侧链(例如丙氨酸、缬氨酸、亮氨酸、异亮氨酸、脯氨酸、苯丙氨酸、甲硫氨酸、色氨酸)、β-分支侧链(例如苏氨酸、缬氨酸、异亮氨酸)及芳香族侧链(例如酪氨酸、苯丙氨酸、色氨酸、组氨酸)。保守性修饰可以例如基于极性、电荷、溶解度、疏水性、亲水性和/或所涉及残基的两亲性质的相似性来进行选择。
如本文所用,术语序列“同一性”表示两个(核苷酸或氨基酸)序列在比对中在相同位置处具有相同残基的程度,并且通常表示为百分数。优选地,同一性在被比较的序列的整体长度上确定。因此,具有完全相同序列的两个拷贝具有100%同一性。本领域技术人员知晓,可以使用一些算法来确定序列同一性,例如Blast(Altschul等(1997)Nucleic AcidsRes.25:3389-3402)、Blast2(Altschul等(1990)J.Mol.Biol.215:403-410)、Smith-Waterman(Smith等(1981)J.Mol.Biol.147:195-197)和ClustalW。
在在一个方面,本发明还提供包含如上所述的抗GPRC5D抗体或其抗原结合片段的多特异性抗体(优选双特异性抗体或三特异性抗体),其还包含一个或多个与其他抗原特异性结合的第二抗体。
如本文所用,术语“多特异性”是指抗原结合蛋白具有多表位特异性(即,能够特异性结合一个生物分子上的两个、三个或更多个不同的表位或能够特异性结合两个、三个或更多个不同的生物分子上的表位)。如本文所用,术语“双特异性”表示抗原结合蛋白具有两种不同的抗原结合特异性。
在一个实施方案中,第二抗体可以具有任何抗体或抗体片段形式,例如全长抗体、Fab、Fab'、(Fab')2、Fv、scFv、scFv-scFv、微抗体、双抗体或sdAb。
因此,在一个实施方案中,所述第二抗体靶向选自以下的抗原:CD2、CD3、CD4、CD5、CD7、CD8、CD14、CD15、CD19、CD20、CD21、CD22、CD23、CD24、CD25、CD30、CD33、CD37、CD38、CD40、CD40L、CD44、CD46、CD47、CD52、CD54、CD56、CD70、CD73、CD80、CD97、CD123、CD126、CD138、CD171、CD 179a、DR4、DR5、TAC、TEM1/CD248、VEGF、GUCY2C、EGP40、EGP-2、EGP-4、CD133、IFNAR1、DLL3、kappa轻链、TIM3、TSHR、CD19、BAFF-R、CLL-1、EGFRvIII、tEGFR、GD2、GD3、BCMA、Tn抗原、PSMA、ROR1、FLT3、FAP、TAG72、CD44v6、CEA、EPCAM、B7H3、KIT、IL-13Ra2、IL-llRa、IL-22Ra、IL-2、间皮素、PSCA、PRSS21、VEGFR2、LewisY、PDGFR-β、SSEA-4、AFP、Folate受体α、ErbB2(Her2/neu)、ErbB3、ErbB4、MUC1、MUC16、EGFR、CS1、NCAM、Claudin18.2、c-Met、Prostase、PAP、ELF2M、Ephrin B2、IGF-I受体、CAIX、LMP2、gpl00、bcr-abl、酪氨酸酶、EphA2、Fucosyl GMl、sLe、GM3、TGS5、HMWMAA、o-乙酰基-GD2、Folate受体β、TEM7R、CLDN6、GPRC5D、CXORF61、ALK、多聚唾液酸、PLAC1、GloboH、NY-BR-1、UPK2、HAVCR1、ADRB3、PANX3、GPR20、LY6K、OR51E2、TARP、WT1、NY-ESO-1、LAGE-la、MAGE-A1、MAGE-A3、MAGE-A6、豆荚蛋白、HPV E6、E7、ETV6-AML、精子蛋白17、XAGE1、Tie 2、MAD-CT-1、MAD-CT-2、Fos相关抗原1、p53、p53突变体、PSA、存活蛋白和端粒酶、PCTA-l/Galectin 8、MelanA/MARTl、Ras突变体、hTERT、肉瘤易位断点、ML-IAP、TMPRSS2 ETS融合基因、NA17、PAX3、雄激素受体、孕酮受体、Cyclin Bl、MYCN、RhoC、TRP-2、CYP1B 1、BORIS、SART3、PAX5、OY-TES 1、LCK、AKAP-4、SSX2、RAGE-1、人端粒酶逆转录酶、RU1、RU2、肠道羧酸酯酶、mut hsp70-2、CD79a、CD79b、CD72、LAIR1、FCAR、LILRA2、CD300LF、CLEC12A、BST2、EMR2、LY75、GPC3、FCRL5、IGLL1、PD1、PDL1、PDL2、TGFβ、APRIL、NKG2D、NKG2D配体,和/或病原体特异性抗原、生物素化分子、由HIV、HCV、HBV和/或其他病原体表达的分子;和/或新表位或新抗原。
核酸、载体、宿主细胞
在另一方面中,本发明涉及编码本发明的抗GPRC5D抗体或多特异性抗体的核酸分子。本发明的核酸可为RNA、DNA或cDNA。根据本发明的一个实施方案,本发明的核酸是基本上分离的核酸。
在一个实施方案中,编码所述抗GPRC5D抗体的核酸分子与选自SEQ ID NO:45-52的核苷酸序列具有至少90%、91%、92%、93%、94%、95%、96%、97%、98%、99%、100%序列同一性,并且其编码的抗GPRC5D抗体能够特异性结合GPRC5D(即,几乎不与非靶标抗原结合)。优选地,编码所述抗GPRC5D抗体的核酸分子如SEQ ID NO:45-52所示。
本发明的核酸也可呈载体形式,可存在于载体中和/或可为载体的一部分,该载体例如质粒、粘端质粒或YAC。载体可尤其为表达载体,即可提供GPRC5D抗体在体外和/或体内(即在适合宿主细胞、宿主有机体和/或表达系统中)表达的载体。该表达载体通常包含至少一种本发明的核酸分子,其可操作地连接至一个或多个适合的表达调控元件(例如启动子、增强子、终止子等)。对所述调控元件及其序列进行选择以便在特定宿主中表达是本领域技术人员熟知的。对本发明的GPRC5D抗体的表达有用或必需的调控元件及其他元件的具体实例包括但不限于启动子、增强子、终止子、整合因子、选择标记物、前导序列、报告基因。
在另一方面中,本发明还提供表达本发明的GPRC5D抗体、多特异性抗体和/或含有本发明的核酸或载体的宿主细胞。本发明的优选宿主细胞为细菌细胞、真菌细胞或哺乳动物细胞。
适合的细菌细胞包括革兰氏阴性细菌菌株(例如大肠杆菌(Escherichia coli)菌株、变形杆菌属(Proteus)菌株及假单胞菌属(Pseudomonas)菌株)及革兰氏阳性细菌菌株(例如芽孢杆菌属(Bacillus)菌株、链霉菌属(Streptomyces)菌株、葡萄球菌属(Staphylococcus)菌株及乳球菌属(Lactococcus)菌株)的细胞。
适合的真菌细胞包括木霉属(Trichoderma)、脉孢菌属(Neurospora)及曲菌属(Aspergillus)的物种的细胞;或者包括酵母属(Saccharomyces)(例如酿酒酵母(Saccharomyces cerevisiae))、裂殖酵母属(Schizosaccharomyces)(例如粟酒裂殖酵母(Schizosaccharomyces pombe))、毕赤酵母属(Pichia)(例如巴斯德毕赤酵母(Pichiapastoris)及嗜甲醇毕赤酵母(Pichia methanolica))及汉森酵母属(Hansenula)的物种的细胞。
适合的哺乳动物细胞包括例如HEK293细胞、CHO细胞、BHK细胞、HeLa细胞、COS细胞等。
然而,本发明也可使用两栖类细胞、昆虫细胞、植物细胞及本领域中用于表达异源蛋白的任何其他细胞。
重组受体
在另一方面,本发明还提供包含如上所述的抗GPRC5D抗体的重组受体,例如重组TCR受体或嵌合抗原受体。优选地,本发明还提供包含如上所述的抗GPRC5D抗体的嵌合抗原受体。
如本文所用,术语“嵌合抗原受体”或“CAR”是指人工构建的杂合多肽,该杂合多肽一般包括配体结合结构域(例如抗体的抗原结合部分)、跨膜结构域、任选的共刺激结构域和细胞内信号传导结构域,各个结构域之间通过接头连接。CAR能够利用抗体的抗原结合特性以非MHC限制性的方式将T细胞和其它免疫细胞的特异性和反应性重定向至所选择的靶标。
在一个实施方案中,本发明提供一种嵌合抗原受体,其包含如上所述的抗GPRC5D抗体或其抗原结合片段或含有所述抗GPRC5D抗体的多特异性抗体、跨膜结构域和胞内信号传导结构域。
如本文所用,术语“跨膜结构域”是指能够使嵌合抗原受体在免疫细胞(例如淋巴细胞、NK细胞或NKT细胞)表面上表达,并且引导免疫细胞针对靶细胞的细胞应答的多肽结构。跨膜结构域可以是天然或合成的,也可以源自任何膜结合蛋白或跨膜蛋白。当嵌合抗原受体与靶抗原结合时,跨膜结构域能够进行信号传导。特别适用于本发明中的跨膜结构域可以源自例如TCRα链、TCRβ链、TCRγ链、TCRδ链、CD3ζ亚基、CD3ε亚基、CD3γ亚基、CD3δ亚基、CD45、CD4、CD5、CD8α、CD9、CD16、CD22、CD33、CD28、CD37、CD64、CD80、CD86、CD134、CD137、CD154及其功能性片段。或者,跨膜结构域可以是合成的并且可以主要地包含疏水性残基如亮氨酸和缬氨酸。优选地,所述跨膜结构域源自CD8α链或CD28,其与SEQ ID NO:53或55所示的氨基酸序列具有至少70%,优选至少80%,更优选至少90%、95%、97%或99%或100%的序列同一性,或其编码序列与SEQ ID NO:54或56所示的核酸分子具有至少70%,优选至少80%,更优选至少90%、95%、97%或99%或100%的序列同一性。
如本文所用,术语“胞内信号传导结构域”是指转导效应子功能信号并指导细胞进行指定功能的蛋白质部分。在一个实施方案中,本发明的嵌合抗原受体包含的胞内信号传导结构域可以是T细胞受体和共受体的胞内区序列,其在抗原受体结合以后一同起作用以引发信号传导,以及这些序列的任何衍生物或变体和具有相同或相似功能的任何合成序列。胞内信号传导结构域可以包含许多免疫受体酪氨酸激活基序(ImmunoreceptorTyrosine-based Activation Motifs,ITAM)。本发明的胞内信号传导结构域的非限制性施例包括但不限于FcRγ、FcRβ、CD3γ、CD3δ、CD3ε、CD3ζ、CD22、GPRC5D9a、GPRC5D9b和CD66d等的胞内区。在优选的实施方式中,本发明CAR的信号传导结构域可以包含CD3ζ胞内区,其与SEQ ID NO:61或63所示的氨基酸序列具有至少70%,优选至少80%,更优选至少90%、95%、97%或99%或100%的序列同一性,或其编码序列与SEQ ID NO:62或64所示的核酸分子具有至少70%,优选至少80%,更优选至少90%、95%、97%或99%或100%的序列同一性。
在一个实施方案中,本发明的嵌合抗原受体还可以包含位于抗体和跨膜结构域之间的铰链区。如本文所用,术语“铰链区”一般是指作用为连接跨膜结构域至抗体的任何寡肽或多肽。具体地,铰链区用来为抗体提供更大的灵活性和可及性。铰链区可以包含最多达300个氨基酸,优选10至100个氨基酸并且最优选25至50个氨基酸。铰链区可以全部或部分源自天然分子,如全部或部分源自CD8、CD4或CD28的胞外区,或全部或部分源自抗体恒定区。或者,铰链区可以是对应于天然存在的铰链序列的合成序列,或可以是完全合成的铰链序列。在优选的实施方式中,所述铰链区包含CD8α、CD28、FcγRIIIα受体、IgG4或IgG1的铰链区部分,更优选CD8α、CD28或IgG4铰链,其与SEQ ID NO:69、71或73所示的氨基酸序列具有至少70%,优选至少80%,更优选至少90%、95%、97%或99%或100%的序列同一性,或其编码序列与SEQ ID NO:70、72或74所示的核苷酸序列具有至少70%,优选至少80%,更优选至少90%、95%、97%或99%或100%的序列同一性。
在一个实施方案中,嵌合抗原受体还可以包含一个或多个共刺激结构域。共刺激结构域可以是来自共刺激分子的细胞内功能性信号传导结构域,其包含所述共刺激分子的整个细胞内部分,或其功能片段。“共刺激分子”是指在T细胞上与共刺激配体特异性结合,由此介导T细胞的共刺激反应(例如增殖)的同源结合配偶体。共刺激分子包括但不限于1类MHC分子、BTLA和Toll配体受体。本发明的共刺激结构域的非限制性施例包括但不限于源自以下蛋白质的胞内区:TLR1、TLR2、TLR3、TLR4、TLR5、TLR6、TLR7、TLR8、TLR9、TLR10、CARD11、CD2、GPRC5D、CD8、CD18、CD27、CD28、CD30、CD40、CD54、CD83、CD134(OX40)、CD137(4-1BB)、CD270(HVEM)、CD272(BTLA)、CD276(B7-H3)、CD278(ICOS)、CD357(GITR)、DAP10、LAT、NKG2C、SLP76、PD-1、LIGHT、TRIM以及ZAP70。优选地,本发明CAR的共刺激结构域来自4-1BB、CD28或4-1BB+CD28。在一个实施方案中,4-1BB共刺激结构域与SEQ ID NO:59所示的氨基酸序列具有至少70%,优选至少80%,更优选至少90%、95%、97%或99%或100%的序列同一性,或其编码序列与SEQ ID NO:60所示的核酸分子具有至少70%,优选至少80%,更优选至少90%、95%、97%或99%或100%的序列同一性。在一个实施方案中,CD28共刺激结构域与SEQ ID NO:57所示的氨基酸序列具有至少70%,优选至少80%,更优选至少90%、95%、97%或99%或100%的序列同一性,或其编码序列与SEQ ID NO:58所示的核酸分子具有至少70%,优选至少80%,更优选至少90%、95%、97%或99%或100%的序列同一性。
在一个实施方案中,本发明的CAR还可以包含信号肽,使得当其在细胞例如T细胞中表达时,新生蛋白质被引导至内质网并随后引导至细胞表面。信号肽的核心可以含有长的疏水性氨基酸区段,其具有形成单个α-螺旋的倾向。在信号肽的末端,通常有被信号肽酶识别和切割的氨基酸区段。信号肽酶可以在移位期间或完成后切割,以产生游离信号肽和成熟蛋白。然后,游离信号肽被特定蛋白酶消化。可用于本发明的信号肽是本领域技术人员熟知的,例如衍生自B2M、CD8α、IgG1、GM-CSFRα等的信号肽。在一个实施方案中,可用于本发明的信号肽来自B2M或CD8α,其与SEQ ID NO:65或67所示的氨基酸序列具有至少70%,优选至少80%,更优选至少90%、95%、97%或99%或100%的序列同一性,或其编码序列与SEQID NO:66或68所示的核酸分子具有至少70%,优选至少80%,更优选至少90%、95%、97%或99%或100%的序列同一性。
在一个实施方案中,所述CAR含有如本文所提供的抗GPRC5D抗体或其抗原结合片段或含有所述抗GPRC5D抗体的多特异性抗体、CD8α或CD28跨膜区、CD28和/或4-1BB共刺激结构域,和CD3ζ胞内信号传导结构域。在该实施方案中,所述CAR还可以进一步包含来自B2M、CD8α、IgG1或GM-CSFRα的信号肽。
本发明还提供编码如上所定义的靶向GPRC5D的嵌合抗原受体的核酸分子,以及包含所述核酸分子的载体。
如本文所用,术语“载体”是用作将(外源)遗传材料转移到宿主细胞中的媒介核酸分子,在该宿主细胞中所述核酸分子可以例如复制和/或表达。载体一般包括靶向载体和表达载体。“靶向载体”是通过例如同源重组或使用特异性靶向位点处序列的杂合重组酶将分离的核酸递送至细胞内部的介质。“表达载体”是用于异源核酸序列(例如编码本发明的嵌合抗原受体多肽的那些序列)在合适的宿主细胞中的转录以及它们的mRNA的翻译的载体。可用于本发明的合适载体是本领域已知的,并且许多可商购获得。在一个实施方案中,本发明的载体包括但不限于质粒、病毒(例如逆转录病毒、慢病毒、腺病毒、牛痘病毒、劳氏肉瘤病毒(RSV、多瘤病毒和腺相关病毒(AAV)等)、噬菌体、噬菌粒、粘粒和人工染色体(包括BAC和YAC)。载体本身通常是核酸分子,通常是包含插入物(转基因)的DNA序列和作为载体“骨架”的较大序列。工程化载体通常还包含在宿主细胞中自主复制的起点(如果需要多核苷酸的稳定表达)、选择标记和限制酶切割位点(如多克隆位点,MCS)。载体可另外包含启动子、多聚腺苷酸尾(polyA)、3’UTR、增强子、终止子、绝缘子、操纵子、选择标记、报告基因、靶向序列和/或蛋白质纯化标签等元件。在一个具体的实施方案中,所述载体是体外转录的载体。
工程化免疫细胞
在一个方面,本发明还提供表达本发明所述重组受体(例如嵌合抗原受体)的工程化免疫细胞。
如本文所用,术语“免疫细胞”是指免疫系统的具有一种或多种效应子功能(例如,细胞毒性细胞杀伤活性、分泌细胞因子、诱导ADCC和/或CDC)的任何细胞。例如,免疫细胞可以是T细胞、巨噬细胞、树突状细胞、单核细胞、NK细胞和/或NKT细胞。在一个实施方案中,免疫细胞衍生自干细胞,例如成体干细胞、胚胎干细胞、脐带血干细胞、祖细胞、骨髓干细胞、诱导多能干细胞、全能干细胞或造血干细胞等。优选地,免疫细胞是T细胞。T细胞可以是任何T细胞,如体外培养的T细胞,例如原代T细胞,或者来自体外培养的T细胞系例如Jurkat、SupT1等的T细胞,或获得自受试者的T细胞。受试者的实例包括人、狗、猫、小鼠、大鼠及其转基因物种。T细胞可以从多种来源获得,包括外周血单核细胞、骨髓、淋巴结组织、脐血、胸腺组织、来自感染部位的组织、腹水、胸膜积液、脾组织及肿瘤。T细胞也可以被浓缩或纯化。T细胞可以处于任何发育阶段,包括但不限于,CD4+/CD8+T细胞、CD4+辅助T细胞(例如Th1和Th2细胞)、CD8+T细胞(例如,细胞毒性T细胞)、肿瘤浸润细胞、记忆T细胞、幼稚T细胞、γδ-T细胞、αβ-T细胞等。在一个优选的实施方案中,免疫细胞是人T细胞。可以使用本领域技术人员已知的多种技术,如Ficoll分离从受试者的血液获得T细胞。
采用本领域已知的常规方法(如通过转导、转染、转化等)可以将编码嵌合抗原受体的核酸序列引入免疫细胞。“转染”是将核酸分子或多核苷酸(包括载体)引入靶细胞的过程。一个例子是RNA转染,即将RNA(比如体外转录的RNA,ivtRNA)引入宿主细胞的过程。该术语主要用于真核细胞中的非病毒方法。术语“转导”通常用于描述病毒介导的核酸分子或多核苷酸的转移。动物细胞的转染通常涉及在细胞膜中打开瞬时的孔或“洞”,以允许摄取材料。可以使用磷酸钙、通过电穿孔、通过细胞挤压或通过将阳离子脂质与材料混合以产生与细胞膜融合并将它们的运载物沉积入内部的脂质体,进行转染。用于转染真核宿主细胞的示例性技术包括脂质囊泡介导的摄取、热休克介导的摄取、磷酸钙介导的转染(磷酸钙/DNA共沉淀)、显微注射和电穿孔。术语“转化”用于描述核酸分子或多核苷酸(包括载体)向细菌中、也向非动物真核细胞(包括植物细胞)中的非病毒转移。因此,转化是细菌或非动物真核细胞的基因改变,其通过细胞膜从其周围直接摄取并随后并入外源遗传材料(核酸分子)而产生。转化可以通过人工手段实现。为了发生转化,细胞或细菌必须处于感受态的状态。对于原核转化,技术可包括热休克介导的摄取、与完整细胞的细菌原生质体融合、显微注射和电穿孔。将核酸或载体引入免疫细胞后,本领域技术人员可以通过常规技术对所得免疫细胞进行扩增和活化。
在一个实施方案中,为减少移植物抗宿主病的风险,所述工程化免疫细胞还包含至少一种选自以下的基因的表达被抑制或沉默:CD52、GR、dCK、TCR/CD3基因(例如TRAC、TRBC、CD3γ、CD3δ、CD3ε、CD3ζ)、MHC相关基因(HLA-A、HLA-B、HLA-C、B2M、HLA-DPA、HLA-DQ、HLA-DRA、TAP1、TAP2、LMP2、LMP7、RFX5、RFXAP、RFXANK、CIITA)和免疫检查点基因,如PD1、LAG3、TIM3、CTLA4、PPP2CA、PPP2CB、PTPN6、PTPN22、PDCD1、HAVCR2、BTLA、CD160、TIGIT、CD96、CRTAM、TNFRSF10B、TNFRSF10A、CASP8、CASP10、CASP3、CASP6、CASP7、FADD、FAS、TGFBRII、TGFRBRI、SMAD2、SMAD3、SMAD4、SMAD10、SKI、SKIL、TGIF1、IL10RA、IL10RB、HMOX2、IL6R、IL6ST、EIF2AK4、CSK、PAG1、SIT、FOXP3、PRDM1、BATF、GUCY1A2、GUCY1A3、GUCY1B2和GUCY1B3。优选地,所述工程化免疫细胞还包含至少一种选自以下的基因的表达被抑制或沉默:TRAC、TRBC、HLA-A、HLA-B、HLA-C、B2M、RFX5、RFXAP、RFXANK、CIITA、PD1、LAG3、TIM3、CTLA4,更优选TRAC、TRBC、HLA-A、HLA-B、HLA-C、B2M、RFX5、RFXAP、RFXANK、CIITA。
抑制基因表达或使基因沉默的方法是本领域技术人员熟知的。例如,可以使用反义RNA、RNA诱饵、RNA适体、siRNA、shRNA/miRNA、反式显性阴性蛋白(TNP)、嵌合/抗体偶联物、趋化因子配体、抗感染性细胞蛋白、细胞内抗体(sFv)、核苷类似物(NRTI)、非核苷类似物(NNRTI)、整合酶抑制剂(寡核苷酸、二核苷酸和化学剂)和蛋白酶抑制剂来抑制基因的表达。另外,也可以通过例如大范围核酸酶、锌指核酸酶、TALE核酸酶或CRISPR系统中的Cas酶介导DNA断裂,从而使基因沉默。
在一个实施方案中,所述工程化免疫细胞还包含靶向其他肿瘤抗原的第二重组受体,例如重组TCR受体或嵌合抗原受体。所述第二重组受体靶向的其他肿瘤抗原可以选自例如CD2、CD3、CD4、CD5、CD7、CD8、CD14、CD15、CD19、CD20、CD21、CD22、CD23、CD24、CD25、CD30、CD33、CD37、CD38、CD40、CD40L、CD44、CD46、CD47、CD52、CD54、CD56、CD70、CD73、CD80、CD97、CD123、CD126、CD138、CD171、CD 179a、DR4、DR5、TAC、TEM1/CD248、VEGF、GUCY2C、EGP40、EGP-2、EGP-4、CD133、IFNAR1、DLL3、kappa轻链、TIM3、TSHR、CD19、BAFF-R、CLL-1、EGFRvIII、tEGFR、GD2、GD3、BCMA、Tn抗原、PSMA、ROR1、FLT3、FAP、TAG72、CD44v6、CEA、EPCAM、B7H3、KIT、IL-13Ra2、IL-llRa、IL-22Ra、IL-2、间皮素、PSCA、PRSS21、VEGFR2、LewisY、PDGFR-β、SSEA-4、AFP、Folate受体α、ErbB2(Her2/neu)、ErbB3、ErbB4、MUC1、MUC16、EGFR、CS1、NCAM、Claudin18.2、c-Met、Prostase、PAP、ELF2M、Ephrin B2、IGF-I受体、CAIX、LMP2、gpl00、bcr-abl、酪氨酸酶、EphA2、Fucosyl GMl、sLe、GM3、TGS5、HMWMAA、o-乙酰基-GD2、Folate受体β、TEM7R、CLDN6、GPRC5D、CXORF61、ALK、多聚唾液酸、PLAC1、GloboH、NY-BR-1、UPK2、HAVCR1、ADRB3、PANX3、GPR20、LY6K、OR51E2、TARP、WT1、NY-ESO-1、LAGE-la、MAGE-A1、MAGE-A3、MAGE-A6、豆荚蛋白、HPV E6、E7、ETV6-AML、精子蛋白17、XAGE1、Tie 2、MAD-CT-1、MAD-CT-2、Fos相关抗原1、p53、p53突变体、PSA、存活蛋白和端粒酶、PCTA-l/Galectin 8、MelanA/MARTl、Ras突变体、hTERT、肉瘤易位断点、ML-IAP、TMPRSS2 ETS融合基因、NA17、PAX3、雄激素受体、孕酮受体、Cyclin Bl、MYCN、RhoC、TRP-2、CYP1B 1、BORIS、SART3、PAX5、OY-TES 1、LCK、AKAP-4、SSX2、RAGE-1、人端粒酶逆转录酶、RU1、RU2、肠道羧酸酯酶、mut hsp70-2、CD79a、CD79b、CD72、LAIR1、FCAR、LILRA2、CD300LF、CLEC12A、BST2、EMR2、LY75、GPC3、FCRL5、IGLL1、PD1、PDL1、PDL2、TGFβ、APRIL、NKG2D、NKG2D配体,和/或病原体特异性抗原、生物素化分子、由HIV、HCV、HBV和/或其他病原体表达的分子。
在一个实施方案中,提供多种免疫细胞,每种免疫细胞被改造为表达一种或多种嵌合抗原受体。例如,在一些实施方案中,将一种免疫细胞改造为表达结合和/或靶向GPRC5D的嵌合抗原受体(例如包含本发明所述抗GPRC5D抗体的CAR),并且将另一种细胞改造为表达结合和/或靶向其他抗原的嵌合抗原受体。在一个实施方案中,免疫细胞也可以表达多特异性嵌合抗原受体,其靶向包括GPRC5D在内的一种或多种抗原。例如,这种多特异性嵌合抗原受体可以包含靶向GPRC5D的多特异性抗体,或者同时包含本发明所述的抗GPRC5D抗体和靶向其他抗原的抗体。在此类实施方案中,所述多种工程化免疫细胞可以一起或单独施用。在一个实施方案中,所述多种免疫细胞可以在同一组合物中或在不同组合物中。细胞的示例性组合物包括本申请以下章节中所描述的组合物。
抗体偶联物
在一个方面,本发明提供一种抗体偶联物,其包含本发明所定义的抗GPRC5D抗体和第二功能性结构,其中所述第二功能性结构选自Fc、放射性同位素、延长半衰期的结构部分、可检测标记物和药物。
在一个实施方案中,本发明提供一种抗体偶联物,其包含本发明所定义的抗GPRC5D抗体和Fc。如本文所用,术语“Fc”用于定义免疫球蛋白重链的C末端区,其包括天然Fc和变体Fc。“天然Fc”是指包含通过消化完整抗体产生的、无论是单体形式或是多聚体形式的非抗原结合片段的分子或序列。产生天然Fc的免疫球蛋白源优选来源于人类。天然Fc片段由可以通过共价连接(例如二硫键)和非共价连接而连接为二聚体或多聚体形式的单体多肽构成。根据类别(例如IgG、IgA、IgE、IgD、IgM)或亚型(例如IgG1、IgG2、IgG3、IgA1、IgGA2)的不同,天然Fc分子单体亚基之间具有1-4个分子间二硫键。天然Fc的一个实例是通过用木瓜蛋白酶消化IgG产生的二硫键连接的二聚体(参见Ellison等(1982),NucleicAcids Res.10:4071-9)。本文所用的术语“天然Fc”一般是指单体、二聚体和多聚体形式。“变体Fc”是指由于至少一个本文定义的“氨基酸修饰”而与“天然”或“野生型”Fc的氨基酸序列不同的氨基酸序列,也称为“Fc变体”。因此,“Fc”也包括单链Fc(scFc),即,由多肽接头连接的两个Fc单体组成的单链Fc,其能够自然折叠成功能性二聚体Fc区域。在一个实施方案中,所述Fc优选是人免疫球蛋白的Fc,更优选是人IgG1的Fc。
在一个实施方案中,本发明提供一种抗体偶联物,其包含本发明所定义的抗GPRC5D抗体和放射性同位素。可用于本发明的放射性同位素的实例包括但不限于At211、I131、I125、Y90、Re186、Re188、Sm153、Bi212、P32、Pb212、99mTc、123I、18F和68Ga。
在一个实施方案中,本发明提供一种抗体偶联物,其包含本发明所定义的抗GPRC5D抗体和延长半衰期的结构部分,所述延长半衰期的结构部分选自白蛋白的结合结构、转铁蛋白的结合结构、聚乙二醇分子、重组聚乙二醇分子、人血清白蛋白、人血清白蛋白的片段和结合人血清白蛋白的白多肽(包括抗体)。
在一个实施方案中,本发明提供一种抗体偶联物,其包含本发明所定义的抗GPRC5D抗体和可检测标记物。术语“可检测标记物”在本文中意指产生可检测信号的化合物。例如,可检测标记物可以是MRI造影剂、闪烁扫描造影剂、X射线成像造影剂、超声造影剂、光学成像造影剂。可检测标记物的实施例包括荧光团(如荧光素、Alexa或花青)、化学发光化合物(如鲁米诺)、生物发光化合物(如荧光素酶或碱性磷酸酶)、酶(如辣根过氧化物酶、葡萄糖-6-磷酸酶、β-半乳糖苷酶)、抗生素(例如卡那霉素、氨苄霉素、氯霉素、四环素等)抗性基因和造影剂(如纳米颗粒或钆)。本领域技术人员可以根据所用的检测系统选择合适的可检测标记物。
在一个实施方案中,本发明提供一种抗体偶联物,其包含本发明所定义的抗GPRC5D抗体和与所述抗GPRC5D抗体偶联的药物,例如细胞毒素或免疫调节剂(即,抗体药物偶联物)。通常药物通过共价与抗体连接,并且通常依赖于接头。在一个实施方案中,所述药物是细胞毒素。在另一个实施方案中,所述药物是免疫调节剂。细胞毒素的实例包括但不限于甲氨蝶呤、氨基蝶呤、6-巯基嘌呤、6-硫鸟嘌呤、阿糖胞苷、5-氟尿嘧啶、达卡巴嗪、氮芥、噻替派、苯丁酸氮芥、美法仑、卡莫司汀(BSNU)、洛莫司汀(CCNU)、1-甲基亚硝基脲、环磷酰胺、氮芥、白消安、二溴甘露醇、链佐星、丝裂霉素、顺-二氯二胺铂(II)(DDP)、顺铂、卡铂、佐柔比星、多柔比星、地托比星、卡米诺霉素、伊达比星、表柔比星、米托蒽醌、放线菌素D、博来霉素、刺孢霉素、光辉霉素、安曲霉素(AMC)、长春新碱、长春花碱、紫杉醇、蓖麻毒素、假单胞菌外毒素、吉西他滨、细胞松弛素B、短杆菌肽D、溴乙锭、依米丁、依托泊苷、替尼泊苷、秋水仙素、二羟基蒽二酮、1-脱氢睾酮、糖皮质激素、普鲁卡因、丁卡因、利多卡因、普萘洛尔、嘌呤霉素、丙卡巴肼、羟基脲、天冬酰胺酶、皮质类固醇、米托坦(O,P'-(DDD))、干扰素,以及它们的组合。免疫调节剂的实例包括但不限于更昔洛韦、依那西普、他克莫司、西罗莫司、伏环孢素、环孢灵、雷帕霉素、环磷酰胺、硫唑嘌呤、霉酚酸酯、甲氨蝶呤、糖皮质素及其类似物、细胞因子、干细胞生长因子、淋巴毒素、肿瘤坏死因子(TNF)、造血因子、白介素(例如IL-1、IL-2、IL-3、IL-6、IL-10、IL-12、IL-18及IL-21)、集落刺激因子(例如G-CSF及(GM-CSF)、干扰素(例如干扰素-α、干扰素-β及干扰素-γ)、命名为“S1因子”的干细胞生长因子、红细胞生成素和血小板生成素,或其组合。
试剂盒和药物组合物
在另一个方面,本发明还提供一种检测试剂盒,其包含本发明所述的抗体、多特异性抗体、抗体偶联物或嵌合抗原受体。
在另一个方面,本发明还提供一种药物组合物,其包含本发明所述的抗体、重组受体例如嵌合抗原受体、多特异性抗体、工程化免疫细胞或抗体偶联物,和一种或多种药学上可接受的赋形剂。
如本文所用,术语“药学上可接受的赋型剂”是指在药理学和/或生理学上与受试者和活性成分相容(即,能够引发所需的治疗效果而不会引起任何不希望的局部或全身作用)的载体和/或赋形剂,其是本领域公知的(参见例如Remington's PharmaceuticalSciences.Edited by Gennaro AR,19th ed.Pennsylvania:Mack Publishing Company,1995)。药学上可接受的赋型剂的实例包括但不限于填充剂、粘合剂、崩解剂、包衣剂、吸附剂、抗粘附剂、助流剂、抗氧化剂、调味剂、着色剂、甜味剂、溶剂、共溶剂、缓冲剂、螯合剂、表面活性剂、稀释剂、润湿剂、防腐剂、乳化剂、包覆剂、等渗剂、吸收延迟剂、稳定剂和张力调节剂。本领域技术人员已知选择合适的赋型剂以制备本发明期望的药物组合物。用于本发明的药物组合物中的示例性赋型剂包括盐水、缓冲盐水、葡萄糖和水。通常,合适的赋形剂的选择尤其取决于所使用的活性剂、待治疗的疾病和药物组合物的期望剂型。
根据本发明的药物组合物可适用于多种途径施用。通常,通过胃肠外完成施用。胃肠外递送方法包括局部、动脉内、肌内、皮下、髓内、鞘内、心室内、静脉内、腹膜内、子宫内、阴道内、舌下或鼻内施用。
根据本发明的药物组合物也可以制备成各种形式,如固态、液态、气态或冻干形式,特别可以是软膏、乳膏、透皮贴剂、凝胶、粉末、片剂、溶液、气雾剂、颗粒、丸剂、混悬剂、乳剂、胶囊、糖浆、酏剂、浸膏剂、酊剂或流浸膏提取物的形式,或者是特别适用于所需施用方法的形式。本发明已知的用于生产药物的过程可包括例如常规混合、溶解、制粒、制糖衣、研磨、乳化、包封、包埋或冻干过程。包含例如本文所述的免疫细胞的药物组合物通常以溶液形式提供,并且优选包含药学上可接受的缓冲剂。
根据本发明的药物组合物还可以与一种或多种适用于治疗和/或预防待治疗疾病的其它药剂组合施用。适用于组合的药剂的优选实例包括已知的抗癌药物,比如顺铂、美登素衍生物、雷查霉素(rachelmycin)、卡里奇霉素(calicheamicin)、多西紫杉醇、依托泊苷、吉西他滨、异环磷酰胺、伊立替康、美法仑、米托蒽醌、sorfimer卟啉钠II(sorfimersodiumphotofrin II)、替莫唑胺、拓扑替康、葡萄糖醛酸曲美沙特(trimetreateglucuronate)、奥利斯他汀E(auristatin E)、长春新碱和阿霉素;肽细胞毒素,比如蓖麻毒素、白喉毒素、假单胞菌细菌外毒素A、DNA酶和RNA酶;放射性核素,比如碘131、铼186、铟111、铱90、铋210和213、锕225和砹213;前药,比如抗体定向的酶前药;免疫刺激剂,比如血小板因子4、黑色素瘤生长刺激蛋白等;抗体或其片段,比如抗CD3抗体或其片段,补体活化剂,异种蛋白结构域,同种蛋白结构域,病毒/细菌蛋白结构域和病毒/细菌肽。此外,本发明的药物组合物也可以与其他一种或多种治疗方法,例如化疗、放疗组合使用。
治疗/预防/诊断用途
在另一个方面,本发明还提供一种治疗和/或预防和/或诊断与GPRC5D表达相关的疾病的方法,包括向受试者施用如上所述的人源化抗体、嵌合抗原受体、多特异性抗体、抗体偶联物、工程化免疫细胞或药物组合物。
在一个实施方案中,与GPRC5D表达相关的疾病包括但不限于GPRC5D阳性的乳腺癌、多发性骨髓瘤、瓦氏巨球蛋白血症、子宫内膜癌、卵巢癌、肺癌、胃癌、前列腺癌、肾癌、肝癌、胰腺癌、结肠直肠癌、食道癌、膀胱癌、子宫颈癌、血液癌、淋巴瘤或恶性黑色素瘤。
下面将参考附图并结合实例来详细说明本发明。需要说明的是,本领域的技术人员应该理解本发明的附图及其实施例仅仅是为了例举的目的,并不能对本发明构成任何限制。在不矛盾的情况下,本申请中的实施例及实施例中的特征可以相互组合。
附图说明
图1:示出了BH395-CAR T细胞、BH398-CAR T细胞和NT细胞中的scFv表达水平。
图2:示出了BH395-CAR T细胞、BH398-CAR T细胞和NT细胞在各种效靶比下靶细胞K562-GPRC5D的杀伤效果。
图3:示出了BH395-CAR T细胞、BH398-CAR T细胞和NT细胞与靶细胞K562-GPRC5D共培养后的脱颗粒作用。
图4:示出了BH395-CAR T细胞、BH398-CAR T细胞和NT细胞与靶细胞K562-GPRC5D共培养后的细胞因子释放水平。
图5:示出了用人源化抗体构建的hCAR-T细胞中的GPRC5D scFv的表达水平。
图6:示出了hCAR-T细胞在各种效靶比下对靶细胞K562-BCMA-GPRC5D和非靶细胞K562-BCMA的杀伤效果。
图7:示出了hCAR-T细胞与靶细胞K562-BCMA-GPRC5D、K562-GPRC5D和非靶细胞K562-BCMA、K562共培养后的脱颗粒作用。
图8:示出了hCAR-T细胞与靶细胞K562-BCMA-GPRC5D、K562-GPRC5D和非靶细胞K562-BCMA、K562共培养后的细胞因子释放水平。
具体实施方式
实施例1.筛选抗GPRC5D抗体
将pLV-GPRC5D质粒通过肌肉注射向适龄的Balb/c小鼠施用,随后每隔2~3周重复免疫注射一次,共计4次。然后,取小鼠脾脏淋巴细胞,与SP2/0骨髓瘤细胞混合并加入PEG介导细胞融合,以制备杂交瘤细胞。使用GPRC5D阳性细胞株通过ELISA或流式细胞术筛选与GPRC5D结合的杂交瘤克隆。经过多轮筛选,获得2个可特异性结合GPRC5D的抗体克隆,命名为BH395和BH398。对两个克隆进行测序,获得其氨基酸序列和核酸序列如下表1所示。
表1.BH395和BH398克隆的氨基酸序列和核酸序列
实施例2.制备靶向GPRC5D的CAR-T细胞并验证其功能
2.1制备CAR-T细胞
合成编码以下蛋白的序列,并将其克隆至pLVX载体(Public Protein/PlasmidLibrary(PPL),货号:PPL00157-4a):CD8α信号肽(SEQ ID No:67)、抗GPRC5D单链抗体(SEQID No:17或18)、CD8α铰链区(SEQ ID No:69)、CD8α跨膜区(SEQ ID No:53)、4-1BB胞内区(SEQ ID No:59)和CD3ζ胞内区(SEQ ID No:61),并通过测序确认目标序列的正确插入。
在无菌管中加入3ml Opti-MEM(Gibco,货号31985-070)稀释上述质粒后,再根据质粒:病毒包装载体:病毒包膜载体=4:2:1的比例加入包装载体psPAX2(Addgene,货号12260)和包膜载体pMD2.G(Addgene,货号12259)。然后,加入120ul X-treme GENE HP DNA转染试剂(Roche,货号06366236001),立即混匀,于室温下孵育15min,然后将质粒/载体/转染试剂混合物逐滴加入到293T细胞的培养瓶中。在24小时和48小时收集病毒,将其合并后,超速离心(25000g,4℃,2.5小时)获得浓缩的慢病毒。
用DynaBeads CD3/CD28 CTSTM(Gibco,货号40203D)激活T细胞,并在37℃和5%CO2下培养1天。然后,加入浓缩的慢病毒,持续培养3天后,获得靶向GPRC5D的BH395-CAR T细胞和BH398-CAR T细胞。未经修饰的野生型T细胞(NT)用作对照。
在37℃和5%CO2下培养11天之后,使用Biotin-SP(long spacer)AffiniPureGoat Anti-Mouse IgG,F(ab')2Fragment Specific(min X Hu,Bov,Hrs Sr Prot)(jackson immunoresearch,货号115-065-072)作为一抗,APC Streptavidin(BDPharmingen,货号554067)作为二抗,通过流式细胞仪检测CAR-T细胞上的抗GPRC5D单链抗体的表达水平,结果如图1所示。
可以看出,本发明制备的CAR-T细胞中的抗GPRC5D单链抗体可以有效表达。
2.2检测CAR-T细胞对靶细胞的杀伤效果
以1x104个细胞/孔的浓度将靶细胞K562-GPRC5D细胞(即,表达GPRC5D的K562细胞)铺入96孔板中,然后以4:1、2:1、1:1的效靶比(即效应T细胞与靶细胞之比)将NT细胞、BH395-CAR T细胞或BH398-CAR T细胞铺入到96孔板进行共培养,16-18小时后利用酶标仪测定荧光值。根据计算公式:(靶细胞荧光均值-样品荧光均值)/靶细胞荧光均值×100%,计算得到杀伤效率,结果如图2所示。
可以看出,在各种效靶比下,本发明的两种CAR T细胞均显示出对靶细胞的强烈杀伤作用。
2.3检测CAR-T细胞的脱颗粒作用
以1×105个细胞/孔的浓度将靶细胞K562-GPRC5D细胞和非靶细胞K562细胞分别铺于96孔板中,按1:1的比例加入BH395-CAR T细胞、BH398-CAR T细胞或NT细胞(阴性对照),然后向各孔加入10μL PE Mouse anti-human CD107a antibody(BD,货号555801),并于37℃、5%CO2条件下避光孵育。1h后,向各孔加入20μL Golgi Stop(BD,货号51-2092K2),并于37℃、5%CO2条件下避光孵育2.5h。然后向各孔加入10μL APC anti-human CD8(BD,货号555369),并于37℃、5%CO2条件下避光孵育0.5h。通过流式细胞术检测各孔细胞样品,并分析CD107a、CD8双阳性细胞占T细胞的比例,结果图3所示。
可以看出,与NT细胞相比,本发明制备的BH395-CAR T细胞和BH398-CAR T细胞对靶细胞K562-GPRC5D细胞均显示出显著升高的特异性的脱颗粒作用。
2.4检测CAR-T细胞的细胞因子释放水平
以1x105个细胞/孔的浓度将靶细胞K562-GPRC5D细胞和非靶细胞K562细胞铺于96孔板中,按1:1的比例分别加入BH395-CAR T细胞、BH398-CAR T细胞或NT细胞(阴性对照),共培养18-24小时后收集细胞共培养上清液。
按照制造商的建议,分别使用Human IL-2DuoSet ELISA Kit(R&D systems,货号DY202)、Human IFN-gamma DuoSet ELISA Kit(R&D systems,货号DY285)检测共培养上清液中IL2和IFN-γ的含量,结果如图4所示。
可以看出,与NT细胞相比,本发明的两种CAR T细胞与靶细胞共培养后,细胞因子IL2(A)和IFN-γ(B)的释放水平均显著升高,并且这种细胞因子释放是特异性的。
实施例3.制备人源化抗GPRC5D抗体
对BH395鼠源抗体进行人源化,具体方法如下:首先通过IGBLAST数据库(https://www.ncbi.nlm.nih.gov/igblast/)检索相似度较高的人源抗体序列,然后将单链抗体中的FR区替换为相应的人源序列;再根据氨基酸残基的不同理化性质对个别氨基酸残基进行替换,最终获得8个人源化抗GPRC5D抗体,其序列如下表2所示。
表2.人源化抗GPRC5D抗体的氨基酸序列和核酸序列
克隆 | VH | VL | scFv(aa) | scFv(nt) |
BH395_V1 | SEQ ID NO:21 | SEQ ID NO:22 | SEQ ID NO:23 | SEQ ID NO:45 |
BH395_V2 | SEQ ID NO:24 | SEQ ID NO:25 | SEQ ID NO:26 | SEQ ID NO:46 |
BH395_V3 | SEQ ID NO:27 | SEQ ID NO:28 | SEQ ID NO:29 | SEQ ID NO:47 |
BH395_V4 | SEQ ID NO:30 | SEQ ID NO:31 | SEQ ID NO:32 | SEQ ID NO:48 |
BH395_V5 | SEQ ID NO:33 | SEQ ID NO:34 | SEQ ID NO:35 | SEQ ID NO:49 |
BH395_V6 | SEQ ID NO:36 | SEQ ID NO:37 | SEQ ID NO:38 | SEQ ID NO:50 |
BH395_V7 | SEQ ID NO:39 | SEQ ID NO:40 | SEQ ID NO:41 | SEQ ID NO:51 |
BH395_V8 | SEQ ID NO:42 | SEQ ID NO:43 | SEQ ID NO:44 | SEQ ID NO:52 |
实施例4.制备包含人源化抗GPRC5D抗体的hCAR-T细胞并验证其功能
合成编码以下蛋白的序列,并将其克隆至pLVX载体(Public Protein/PlasmidLibrary(PPL),货号:PPL00157-4a):B2M信号肽(SEQ ID No:65)、人源化抗GPRC5D单链抗体(选自SEQ ID NO:23、26、29、32、35、38、41和44的任一序列)、CD28铰链区(SEQ ID No:71)、CD28跨膜区(SEQ ID No:55)、CD28胞内区(SEQ ID No:57)和CD3ζ胞内区(SEQ ID No:63),并通过测序确认目标序列的正确插入。
根据实施例2中2.1所述的方法将上述质粒包装为慢病毒,并感染激活的T细胞,获得包含人源化抗抗GPRC5D抗体的hCAR-T细胞。用Biotin-SP(long spacer)AffiniPureGoat Anti-Mouse IgG,F(ab')2Fragment Specific(min X Hu,Bov,Hrs Sr Prot)(jackson immunoresearch,货号115-065-072)作为一抗,PE Streptavidin(Biolegend,货号405204)作为二抗,通过流式细胞仪检测hCAR-T细胞上的抗GPRC5D单链抗体的表达水平,结果如图5所示。
可以看出,用人源化抗GPRC5D单链抗体制备的hCAR-T细胞均能有效表达GPRC5D单链抗体。
根据实施例2中2.2所述的方法检测CAR-T细胞在不同效靶比下对靶细胞K562-BCMA-GPRC5D(即,表达GPRC5D和BCMA的K562细胞)和非靶细胞K562-BCMA(即,仅表达BCMA的K562细胞)的杀伤效果,结果如图6所示。
根据实施例2中2.3所述的方法检测CAR-T细胞与靶细胞(K562-BCMA-GPRC5D和K562-GPRC5D)和非靶细胞(K562-BCMA和K562)共培养后的脱颗粒作用,结果如图7所示。
根据实施例2中2.4所述的方法检测CAR-T细胞与靶细胞(K562-BCMA-GPRC5D和K562-GPRC5D)和非靶细胞(K562-BCMA和K562)共培养后的细胞因子释放水平,结果如图8所示。
从以上结果可以看出,包含不同人源化抗GPRC5D单链抗体的8种hCAR T细胞均能对靶细胞产生显著的特异性杀伤和脱颗粒作用,并且杀伤效果与用鼠源抗GPRC5D单链抗体构建的BH395-CAR T细胞相当,而对非靶细胞则没有明显的杀伤作用。
需要说明的是,以上仅为本发明的优选实施例而已,并不用于限制本发明,对于本领域的技术人员来说,本发明可以有各种更改和变化。本领域技术人员理解的是,凡在本发明的精神和原则之内,所作的任何修改、等同替换、改进等,均应包含在本发明的保护范围之内。
序列表
<110> 南京北恒生物科技有限公司
<120> 靶向GPRC5D的抗体及其用途
<130> BHCN37
<160> 76
<170> SIPOSequenceListing 1.0
<210> 1
<211> 7
<212> PRT
<213> Artificial Sequence(Artificial Sequence)
<220>
<223> CDR-H1
<400> 1
Gly Phe Thr Phe Ser Asn Tyr
1 5
<210> 2
<211> 6
<212> PRT
<213> Artificial Sequence(Artificial Sequence)
<220>
<223> CDR-H2
<400> 2
Ser Asn Gly Gly Arg Ser
1 5
<210> 3
<211> 6
<212> PRT
<213> Artificial Sequence(Artificial Sequence)
<220>
<223> CDR-H3
<400> 3
His Glu Arg Met Asp Phe
1 5
<210> 4
<211> 17
<212> PRT
<213> Artificial Sequence(Artificial Sequence)
<220>
<223> CDR-L1
<400> 4
Lys Ser Ser Gln Ser Val Leu Tyr Ser Ser Asn Gln Lys Asn Tyr Leu
1 5 10 15
Ala
<210> 5
<211> 7
<212> PRT
<213> Artificial Sequence(Artificial Sequence)
<220>
<223> CDR-L2
<400> 5
Trp Ala Ser Thr Arg Glu Ser
1 5
<210> 6
<211> 8
<212> PRT
<213> Artificial Sequence(Artificial Sequence)
<220>
<223> CDR-L3
<400> 6
His Gln Tyr Leu Ser Ser Tyr Thr
1 5
<210> 7
<211> 7
<212> PRT
<213> Artificial Sequence(Artificial Sequence)
<220>
<223> CDR-H1
<400> 7
Gly Phe Thr Phe Thr Asn His
1 5
<210> 8
<211> 6
<212> PRT
<213> Artificial Sequence(Artificial Sequence)
<220>
<223> CDR-H2
<400> 8
Ser Asn Gly Gly Arg Asn
1 5
<210> 9
<211> 8
<212> PRT
<213> Artificial Sequence(Artificial Sequence)
<220>
<223> CDR-H3
<400> 9
His Val Gly Asp Ala Leu Asp Ser
1 5
<210> 10
<211> 17
<212> PRT
<213> Artificial Sequence(Artificial Sequence)
<220>
<223> CDR-L1
<400> 10
Lys Ser Ser Gln Ser Leu Leu Asn Ser Ser Asn Gln Lys Asn Tyr Leu
1 5 10 15
Ala
<210> 11
<211> 7
<212> PRT
<213> Artificial Sequence(Artificial Sequence)
<220>
<223> CDR-L2
<400> 11
Phe Ala Ser Thr Arg Glu Ser
1 5
<210> 12
<211> 9
<212> PRT
<213> Artificial Sequence(Artificial Sequence)
<220>
<223> CDR-L3
<400> 12
Gln Gln His Tyr Ser Thr Pro Tyr Thr
1 5
<210> 13
<211> 115
<212> PRT
<213> Artificial Sequence(Artificial Sequence)
<220>
<223> BH395 VH
<400> 13
Glu Val Gln Leu Leu Glu Ser Gly Gly Asp Leu Val Lys Pro Gly Gly
1 5 10 15
Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asn Tyr
20 25 30
Gly Met Ser Trp Val Arg Gln Thr Pro Asp Lys Arg Leu Glu Trp Val
35 40 45
Ala Thr Ile Ser Asn Gly Gly Arg Ser Thr Tyr Tyr Pro Asp Asn Leu
50 55 60
Arg Gly Arg Val Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Ile Ser Glu Asp Thr Ala Ile Tyr Tyr Cys
85 90 95
Ala Arg His Glu Arg Met Asp Phe Trp Gly Gln Gly Thr Ser Val Thr
100 105 110
Val Ser Ser
115
<210> 14
<211> 113
<212> PRT
<213> Artificial Sequence(Artificial Sequence)
<220>
<223> BH395 VL
<400> 14
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ala Val Ser Ala Gly
1 5 10 15
Glu Lys Val Thr Met Ser Cys Lys Ser Ser Gln Ser Val Leu Tyr Ser
20 25 30
Ser Asn 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 Thr
65 70 75 80
Ile Ser Ser Val Gln Ala Glu Asp Leu Ala Val Tyr Tyr Cys His Gln
85 90 95
Tyr Leu Ser Ser Tyr Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
100 105 110
Arg
<210> 15
<211> 117
<212> PRT
<213> Artificial Sequence(Artificial Sequence)
<220>
<223> BH398 VH
<400> 15
Glu Val Met Leu Val Glu Ser Gly Gly Gly Leu Val Arg Pro Gly Gly
1 5 10 15
Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Thr Asn His
20 25 30
Gly Met Ser Trp Val Arg Gln Thr Pro Glu Lys Arg Leu Glu Trp Val
35 40 45
Ala Thr Ile Ser Asn Gly Gly Arg Asn Thr Tyr Tyr Pro Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Asn Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ser Glu Asp Thr Ala Leu Tyr Tyr Cys
85 90 95
Ala Arg His Val Gly Asp Ala Leu Asp Ser Trp Gly Gln Gly Thr Ser
100 105 110
Val Thr Val Ser Ser
115
<210> 16
<211> 114
<212> PRT
<213> Artificial Sequence(Artificial Sequence)
<220>
<223> BH398 VL
<400> 16
Asp Ile Val Met Thr Gln Ser Pro Ser Ser Leu Ala Met Ser Val Gly
1 5 10 15
Gln Lys Val Thr Met Ser Cys Lys Ser Ser Gln Ser Leu Leu Asn Ser
20 25 30
Ser Asn Gln Lys Asn Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln
35 40 45
Ser Pro Lys Leu Leu Val Tyr Phe Ala Ser Thr Arg Glu Ser Gly Val
50 55 60
Pro Asp Arg Phe Ile Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr
65 70 75 80
Ile Ser Ser Val Gln Ala Glu Asp Leu Ala Asp Tyr Phe Cys Gln Gln
85 90 95
His Tyr Ser Thr Pro Tyr Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile
100 105 110
Lys Arg
<210> 17
<211> 243
<212> PRT
<213> Artificial Sequence(Artificial Sequence)
<220>
<223> BH395 scFv
<400> 17
Glu Val Gln Leu Leu Glu Ser Gly Gly Asp Leu Val Lys Pro Gly Gly
1 5 10 15
Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asn Tyr
20 25 30
Gly Met Ser Trp Val Arg Gln Thr Pro Asp Lys Arg Leu Glu Trp Val
35 40 45
Ala Thr Ile Ser Asn Gly Gly Arg Ser Thr Tyr Tyr Pro Asp Asn Leu
50 55 60
Arg Gly Arg Val Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Ile Ser Glu Asp Thr Ala Ile Tyr Tyr Cys
85 90 95
Ala Arg His Glu Arg Met Asp Phe Trp Gly Gln Gly Thr Ser Val Thr
100 105 110
Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly
115 120 125
Gly Ser Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ala Val Ser
130 135 140
Ala Gly Glu Lys Val Thr Met Ser Cys Lys Ser Ser Gln Ser Val Leu
145 150 155 160
Tyr Ser Ser Asn Gln Lys Asn Tyr Leu Ala Trp Tyr Gln Gln Lys Pro
165 170 175
Gly Gln Ser Pro Lys Leu Leu Ile Tyr Trp Ala Ser Thr Arg Glu Ser
180 185 190
Gly Val Pro Asp Arg Phe Thr Gly Ser Gly Ser Gly Thr Asp Phe Thr
195 200 205
Leu Thr Ile Ser Ser Val Gln Ala Glu Asp Leu Ala Val Tyr Tyr Cys
210 215 220
His Gln Tyr Leu Ser Ser Tyr Thr Phe Gly Gly Gly Thr Lys Leu Glu
225 230 235 240
Ile Lys Arg
<210> 18
<211> 246
<212> PRT
<213> Artificial Sequence(Artificial Sequence)
<220>
<223> BH398 scFv
<400> 18
Glu Val Met Leu Val Glu Ser Gly Gly Gly Leu Val Arg Pro Gly Gly
1 5 10 15
Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Thr Asn His
20 25 30
Gly Met Ser Trp Val Arg Gln Thr Pro Glu Lys Arg Leu Glu Trp Val
35 40 45
Ala Thr Ile Ser Asn Gly Gly Arg Asn Thr Tyr Tyr Pro Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Asn Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ser Glu Asp Thr Ala Leu Tyr Tyr Cys
85 90 95
Ala Arg His Val Gly Asp Ala Leu Asp Ser Trp Gly Gln Gly Thr Ser
100 105 110
Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly
115 120 125
Gly Gly Gly Ser Asp Ile Val Met Thr Gln Ser Pro Ser Ser Leu Ala
130 135 140
Met Ser Val Gly Gln Lys Val Thr Met Ser Cys Lys Ser Ser Gln Ser
145 150 155 160
Leu Leu Asn Ser Ser Asn Gln Lys Asn Tyr Leu Ala Trp Tyr Gln Gln
165 170 175
Lys Pro Gly Gln Ser Pro Lys Leu Leu Val Tyr Phe Ala Ser Thr Arg
180 185 190
Glu Ser Gly Val Pro Asp Arg Phe Ile Gly Ser Gly Ser Gly Thr Asp
195 200 205
Phe Thr Leu Thr Ile Ser Ser Val Gln Ala Glu Asp Leu Ala Asp Tyr
210 215 220
Phe Cys Gln Gln His Tyr Ser Thr Pro Tyr Thr Phe Gly Gly Gly Thr
225 230 235 240
Lys Leu Glu Ile Lys Arg
245
<210> 19
<211> 729
<212> DNA
<213> Artificial Sequence(Artificial Sequence)
<220>
<223> BH395 scFv
<400> 19
gaagtccagt tgctcgaatc tggcggggac ctggtaaaac cgggaggttc tctcaaattg 60
tcttgcgccg caagcgggtt tactttttca aattatggta tgagttgggt ccgacagact 120
cccgataaaa ggcttgagtg ggtagcgacg attagcaatg gggggcgatc cacttattat 180
cctgataacc ttcggggaag agtaaccata tctcgcgaca acgctaaaaa cactttgtat 240
ttgcaaatga acagccttat ctccgaggat acagcgatct actactgcgc tcgacatgaa 300
cggatggatt tctggggtca aggtaccagt gttactgtaa gtagtggggg aggaggttca 360
ggcggtgggg gctccggggg aggtgggagc gacattcaaa tgacccaaag tccatcatcc 420
cttgctgtgt ccgctggtga aaaggttacg atgagctgca agtcttcaca gtctgtattg 480
tacagcagca atcaaaagaa ttatcttgct tggtatcaac agaaaccggg gcagtcacct 540
aaactgctga tatactgggc ttcaactcgg gagtccgggg tgccggatag attcactgga 600
tccggctctg gaacggactt tactttgact atcagcagtg tccaagctga agaccttgcg 660
gtttactact gccaccagta cttgtctagt tatacatttg gaggcgggac aaaacttgaa 720
attaaacgc 729
<210> 20
<211> 738
<212> DNA
<213> Artificial Sequence(Artificial Sequence)
<220>
<223> BH398 scFv
<400> 20
gaagtcatgc ttgtggaatc tggtgggggt ctcgtccgac cgggcggctc acttaaactt 60
tcctgtgctg cctcaggctt cactttcacg aaccacggca tgagctgggt gagacaaaca 120
cctgagaaac gattggagtg ggtggcaaca attagtaacg gcggtcgcaa cacgtactat 180
ccagattcag ttaaaggccg gttcacgatc agccgggaca acgctaagaa taacctctac 240
ctccaaatga actctctcag aagtgaagac actgcccttt attattgtgc aagacacgtt 300
ggcgacgctc tcgacagttg gggtcaaggg acgtcagtca ccgtttcttc aggtggagga 360
ggttctgggg gagggggttc aggcggcggt ggatcagaca tagtgatgac tcaatctcct 420
tccagcctgg ccatgagcgt aggtcagaag gtaactatga gctgtaagtc aagccaatcc 480
ctccttaata gttccaacca aaagaattat cttgcgtggt atcagcaaaa gccagggcaa 540
agtccgaaac ttcttgttta tttcgcttca acacgggagt ccggcgtccc tgaccgcttt 600
attgggagtg ggtccggcac agatttcacg cttaccatta gctctgtcca agccgaggat 660
ctggctgact acttctgcca acagcattat tctacaccgt ataccttcgg cggcggaacg 720
aagctggaga ttaaacgc 738
<210> 21
<211> 115
<212> PRT
<213> Artificial Sequence(Artificial Sequence)
<220>
<223> BH395_V1 VH
<400> 21
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asn Tyr
20 25 30
Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Thr Ile Ser Asn Gly Gly Arg Ser Thr Tyr Tyr Pro Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Ile Tyr Tyr Cys
85 90 95
Ala Arg His Glu Arg Met Asp Phe Trp Gly Gln Gly Thr Ser Val Thr
100 105 110
Val Ser Ser
115
<210> 22
<211> 112
<212> PRT
<213> Artificial Sequence(Artificial Sequence)
<220>
<223> BH395_V1 VL
<400> 22
Asp Ile Gln Met Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly
1 5 10 15
Glu Arg Ala Thr Ile Asn Cys Lys Ser Ser Gln Ser Val Leu Tyr Ser
20 25 30
Ser Asn Gln Lys Asn Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln
35 40 45
Pro Pro Lys Leu Leu Ile Tyr Trp Ala Ser Thr Arg Glu Ser Gly Val
50 55 60
Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr
65 70 75 80
Ile Ser Ser Leu Gln Ala Glu Asp Leu Ala Val Tyr Tyr Cys His Gln
85 90 95
Tyr Leu Ser Ser Tyr Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
100 105 110
<210> 23
<211> 245
<212> PRT
<213> Artificial Sequence(Artificial Sequence)
<220>
<223> BH395_V1 scFV
<400> 23
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asn Tyr
20 25 30
Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Thr Ile Ser Asn Gly Gly Arg Ser Thr Tyr Tyr Pro Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Ile Tyr Tyr Cys
85 90 95
Ala Arg His Glu Arg Met Asp Phe Trp Gly Gln Gly Thr Ser Val Thr
100 105 110
Val Ser Ser Gly Ser Thr Ser Gly Ser Gly Lys Pro Gly Ser Gly Glu
115 120 125
Gly Ser Thr Lys Gly Asp Ile Gln Met Thr Gln Ser Pro Asp Ser Leu
130 135 140
Ala Val Ser Leu Gly Glu Arg Ala Thr Ile Asn Cys Lys Ser Ser Gln
145 150 155 160
Ser Val Leu Tyr Ser Ser Asn Gln Lys Asn Tyr Leu Ala Trp Tyr Gln
165 170 175
Gln Lys Pro Gly Gln Pro Pro Lys Leu Leu Ile Tyr Trp Ala Ser Thr
180 185 190
Arg Glu Ser Gly Val Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr
195 200 205
Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Ala Glu Asp Leu Ala Val
210 215 220
Tyr Tyr Cys His Gln Tyr Leu Ser Ser Tyr Thr Phe Gly Gly Gly Thr
225 230 235 240
Lys Leu Glu Ile Lys
245
<210> 24
<211> 115
<212> PRT
<213> Artificial Sequence(Artificial Sequence)
<220>
<223> BH395_V2 VH
<400> 24
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asn Tyr
20 25 30
Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Ser Ile Ser Asn Gly Gly Arg Ser Thr Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg His Glu Arg Met Asp Phe Trp Gly Gln Gly Thr Ser Val Thr
100 105 110
Val Ser Ser
115
<210> 25
<211> 112
<212> PRT
<213> Artificial Sequence(Artificial Sequence)
<220>
<223> BH395_V2 VL
<400> 25
Asp Ile Gln Met Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly
1 5 10 15
Glu Arg Ala Thr Ile Asn Cys Lys Ser Ser Gln Ser Val Leu Tyr Ser
20 25 30
Ser Asn Gln Lys Asn Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln
35 40 45
Pro Pro Lys Leu Leu Ile Tyr Trp Ala Ser Thr Arg Glu Ser Gly Val
50 55 60
Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr
65 70 75 80
Ile Ser Ser Leu Gln Ala Glu Asp Leu Ala Val Tyr Tyr Cys His Gln
85 90 95
Tyr Leu Ser Ser Tyr Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
100 105 110
<210> 26
<211> 245
<212> PRT
<213> Artificial Sequence(Artificial Sequence)
<220>
<223> BH395_V2 scFV
<400> 26
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asn Tyr
20 25 30
Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Ser Ile Ser Asn Gly Gly Arg Ser Thr Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg His Glu Arg Met Asp Phe Trp Gly Gln Gly Thr Ser Val Thr
100 105 110
Val Ser Ser Gly Ser Thr Ser Gly Ser Gly Lys Pro Gly Ser Gly Glu
115 120 125
Gly Ser Thr Lys Gly Asp Ile Gln Met Thr Gln Ser Pro Asp Ser Leu
130 135 140
Ala Val Ser Leu Gly Glu Arg Ala Thr Ile Asn Cys Lys Ser Ser Gln
145 150 155 160
Ser Val Leu Tyr Ser Ser Asn Gln Lys Asn Tyr Leu Ala Trp Tyr Gln
165 170 175
Gln Lys Pro Gly Gln Pro Pro Lys Leu Leu Ile Tyr Trp Ala Ser Thr
180 185 190
Arg Glu Ser Gly Val Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr
195 200 205
Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Ala Glu Asp Leu Ala Val
210 215 220
Tyr Tyr Cys His Gln Tyr Leu Ser Ser Tyr Thr Phe Gly Gly Gly Thr
225 230 235 240
Lys Leu Glu Ile Lys
245
<210> 27
<211> 115
<212> PRT
<213> Artificial Sequence(Artificial Sequence)
<220>
<223> BH395_V3 VH
<400> 27
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asn Tyr
20 25 30
Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Ser Ile Ser Asn Gly Gly Arg Ser Thr Tyr Tyr Pro Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg His Glu Arg Met Asp Phe Trp Gly Gln Gly Thr Ser Val Thr
100 105 110
Val Ser Ser
115
<210> 28
<211> 112
<212> PRT
<213> Artificial Sequence(Artificial Sequence)
<220>
<223> BH395_V3 VL
<400> 28
Asp Ile Gln Met Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly
1 5 10 15
Glu Arg Ala Thr Ile Asn Cys Lys Ser Ser Gln Ser Val Leu Tyr Ser
20 25 30
Ser Asn Gln Lys Asn Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln
35 40 45
Pro Pro Lys Leu Leu Ile Tyr Trp Ala Ser Thr Arg Glu Ser Gly Val
50 55 60
Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr
65 70 75 80
Ile Ser Ser Leu Gln Ala Glu Asp Leu Ala Val Tyr Tyr Cys His Gln
85 90 95
Tyr Leu Ser Ser Tyr Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
100 105 110
<210> 29
<211> 245
<212> PRT
<213> Artificial Sequence(Artificial Sequence)
<220>
<223> BH395_V3 scFV
<400> 29
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asn Tyr
20 25 30
Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Ser Ile Ser Asn Gly Gly Arg Ser Thr Tyr Tyr Pro Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg His Glu Arg Met Asp Phe Trp Gly Gln Gly Thr Ser Val Thr
100 105 110
Val Ser Ser Gly Ser Thr Ser Gly Ser Gly Lys Pro Gly Ser Gly Glu
115 120 125
Gly Ser Thr Lys Gly Asp Ile Gln Met Thr Gln Ser Pro Asp Ser Leu
130 135 140
Ala Val Ser Leu Gly Glu Arg Ala Thr Ile Asn Cys Lys Ser Ser Gln
145 150 155 160
Ser Val Leu Tyr Ser Ser Asn Gln Lys Asn Tyr Leu Ala Trp Tyr Gln
165 170 175
Gln Lys Pro Gly Gln Pro Pro Lys Leu Leu Ile Tyr Trp Ala Ser Thr
180 185 190
Arg Glu Ser Gly Val Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr
195 200 205
Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Ala Glu Asp Leu Ala Val
210 215 220
Tyr Tyr Cys His Gln Tyr Leu Ser Ser Tyr Thr Phe Gly Gly Gly Thr
225 230 235 240
Lys Leu Glu Ile Lys
245
<210> 30
<211> 115
<212> PRT
<213> Artificial Sequence(Artificial Sequence)
<220>
<223> BH395_V4 VH
<400> 30
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asn Tyr
20 25 30
Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Ser Ile Ser Asn Gly Gly Arg Ser Thr Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg His Glu Arg Met Asp Phe Trp Gly Gln Gly Thr Ser Val Thr
100 105 110
Val Ser Ser
115
<210> 31
<211> 112
<212> PRT
<213> Artificial Sequence(Artificial Sequence)
<220>
<223> BH395_V4 VL
<400> 31
Asp Ile Gln Met Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly
1 5 10 15
Glu Arg Ala Thr Ile Asn Cys Lys Ser Ser Gln Ser Val Leu Tyr Ser
20 25 30
Ser Asn Gln Lys Asn Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln
35 40 45
Pro Pro Lys Leu Leu Ile Tyr Trp Ala Ser Thr Arg Glu Ser Gly Val
50 55 60
Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr
65 70 75 80
Ile Ser Ser Leu Gln Ala Glu Asp Leu Ala Val Tyr Tyr Cys His Gln
85 90 95
Tyr Leu Ser Ser Tyr Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
100 105 110
<210> 32
<211> 245
<212> PRT
<213> Artificial Sequence(Artificial Sequence)
<220>
<223> BH395_V4 scFV
<400> 32
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asn Tyr
20 25 30
Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Ser Ile Ser Asn Gly Gly Arg Ser Thr Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg His Glu Arg Met Asp Phe Trp Gly Gln Gly Thr Ser Val Thr
100 105 110
Val Ser Ser Gly Ser Thr Ser Gly Ser Gly Lys Pro Gly Ser Gly Glu
115 120 125
Gly Ser Thr Lys Gly Asp Ile Gln Met Thr Gln Ser Pro Asp Ser Leu
130 135 140
Ala Val Ser Leu Gly Glu Arg Ala Thr Ile Asn Cys Lys Ser Ser Gln
145 150 155 160
Ser Val Leu Tyr Ser Ser Asn Gln Lys Asn Tyr Leu Ala Trp Tyr Gln
165 170 175
Gln Lys Pro Gly Gln Pro Pro Lys Leu Leu Ile Tyr Trp Ala Ser Thr
180 185 190
Arg Glu Ser Gly Val Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr
195 200 205
Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Ala Glu Asp Leu Ala Val
210 215 220
Tyr Tyr Cys His Gln Tyr Leu Ser Ser Tyr Thr Phe Gly Gly Gly Thr
225 230 235 240
Lys Leu Glu Ile Lys
245
<210> 33
<211> 115
<212> PRT
<213> Artificial Sequence(Artificial Sequence)
<220>
<223> BH395_V5 VH
<400> 33
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asn Tyr
20 25 30
Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Thr Ile Ser Asn Gly Gly Arg Ser Thr Tyr Tyr Pro Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Ile Tyr Tyr Cys
85 90 95
Ala Arg His Glu Arg Met Asp Phe Trp Gly Gln Gly Thr Ser Val Thr
100 105 110
Val Ser Ser
115
<210> 34
<211> 112
<212> PRT
<213> Artificial Sequence(Artificial Sequence)
<220>
<223> BH395_V5 VL
<400> 34
Asp Ile Val Met Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly
1 5 10 15
Glu Arg Ala Thr Ile Thr Cys Lys Ser Ser Gln Ser Val Leu Tyr Ser
20 25 30
Ser Asn Gln Lys Asn Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln
35 40 45
Pro Pro Lys Leu Leu Ile Tyr Trp Ala Ser Thr Arg Glu Ser Gly Val
50 55 60
Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr
65 70 75 80
Ile Ser Ser Leu Gln Ala Glu Asp Leu Ala Val Tyr Tyr Cys His Gln
85 90 95
Tyr Leu Ser Ser Tyr Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
100 105 110
<210> 35
<211> 245
<212> PRT
<213> Artificial Sequence(Artificial Sequence)
<220>
<223> BH395_V5 scFV
<400> 35
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asn Tyr
20 25 30
Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Thr Ile Ser Asn Gly Gly Arg Ser Thr Tyr Tyr Pro Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Ile Tyr Tyr Cys
85 90 95
Ala Arg His Glu Arg Met Asp Phe Trp Gly Gln Gly Thr Ser Val Thr
100 105 110
Val Ser Ser Gly Ser Thr Ser Gly Ser Gly Lys Pro Gly Ser Gly Glu
115 120 125
Gly Ser Thr Lys Gly Asp Ile Val Met Thr Gln Ser Pro Asp Ser Leu
130 135 140
Ala Val Ser Leu Gly Glu Arg Ala Thr Ile Thr Cys Lys Ser Ser Gln
145 150 155 160
Ser Val Leu Tyr Ser Ser Asn Gln Lys Asn Tyr Leu Ala Trp Tyr Gln
165 170 175
Gln Lys Pro Gly Gln Pro Pro Lys Leu Leu Ile Tyr Trp Ala Ser Thr
180 185 190
Arg Glu Ser Gly Val Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr
195 200 205
Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Ala Glu Asp Leu Ala Val
210 215 220
Tyr Tyr Cys His Gln Tyr Leu Ser Ser Tyr Thr Phe Gly Gly Gly Thr
225 230 235 240
Lys Leu Glu Ile Lys
245
<210> 36
<211> 115
<212> PRT
<213> Artificial Sequence(Artificial Sequence)
<220>
<223> BH395_V6 VH
<400> 36
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asn Tyr
20 25 30
Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Ser Ile Ser Asn Gly Gly Arg Ser Thr Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg His Glu Arg Met Asp Phe Trp Gly Gln Gly Thr Ser Val Thr
100 105 110
Val Ser Ser
115
<210> 37
<211> 112
<212> PRT
<213> Artificial Sequence(Artificial Sequence)
<220>
<223> BH395_V6 VL
<400> 37
Asp Ile Val Met Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly
1 5 10 15
Glu Arg Ala Thr Ile Thr Cys Lys Ser Ser Gln Ser Val Leu Tyr Ser
20 25 30
Ser Asn Gln Lys Asn Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln
35 40 45
Pro Pro Lys Leu Leu Ile Tyr Trp Ala Ser Thr Arg Glu Ser Gly Val
50 55 60
Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr
65 70 75 80
Ile Ser Ser Leu Gln Ala Glu Asp Leu Ala Val Tyr Tyr Cys His Gln
85 90 95
Tyr Leu Ser Ser Tyr Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
100 105 110
<210> 38
<211> 245
<212> PRT
<213> Artificial Sequence(Artificial Sequence)
<220>
<223> BH395_V6 scFV
<400> 38
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asn Tyr
20 25 30
Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Ser Ile Ser Asn Gly Gly Arg Ser Thr Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg His Glu Arg Met Asp Phe Trp Gly Gln Gly Thr Ser Val Thr
100 105 110
Val Ser Ser Gly Ser Thr Ser Gly Ser Gly Lys Pro Gly Ser Gly Glu
115 120 125
Gly Ser Thr Lys Gly Asp Ile Val Met Thr Gln Ser Pro Asp Ser Leu
130 135 140
Ala Val Ser Leu Gly Glu Arg Ala Thr Ile Thr Cys Lys Ser Ser Gln
145 150 155 160
Ser Val Leu Tyr Ser Ser Asn Gln Lys Asn Tyr Leu Ala Trp Tyr Gln
165 170 175
Gln Lys Pro Gly Gln Pro Pro Lys Leu Leu Ile Tyr Trp Ala Ser Thr
180 185 190
Arg Glu Ser Gly Val Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr
195 200 205
Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Ala Glu Asp Leu Ala Val
210 215 220
Tyr Tyr Cys His Gln Tyr Leu Ser Ser Tyr Thr Phe Gly Gly Gly Thr
225 230 235 240
Lys Leu Glu Ile Lys
245
<210> 39
<211> 115
<212> PRT
<213> Artificial Sequence(Artificial Sequence)
<220>
<223> BH395_V7 VH
<400> 39
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asn Tyr
20 25 30
Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Ser Ile Ser Asn Gly Gly Arg Ser Thr Tyr Tyr Pro Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg His Glu Arg Met Asp Phe Trp Gly Gln Gly Thr Ser Val Thr
100 105 110
Val Ser Ser
115
<210> 40
<211> 112
<212> PRT
<213> Artificial Sequence(Artificial Sequence)
<220>
<223> BH395_V7 VL
<400> 40
Asp Ile Val Met Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly
1 5 10 15
Glu Arg Ala Thr Ile Thr Cys Lys Ser Ser Gln Ser Val Leu Tyr Ser
20 25 30
Ser Asn Gln Lys Asn Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln
35 40 45
Pro Pro Lys Leu Leu Ile Tyr Trp Ala Ser Thr Arg Glu Ser Gly Val
50 55 60
Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr
65 70 75 80
Ile Ser Ser Leu Gln Ala Glu Asp Leu Ala Val Tyr Tyr Cys His Gln
85 90 95
Tyr Leu Ser Ser Tyr Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
100 105 110
<210> 41
<211> 245
<212> PRT
<213> Artificial Sequence(Artificial Sequence)
<220>
<223> BH395_V7 scFV
<400> 41
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asn Tyr
20 25 30
Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Ser Ile Ser Asn Gly Gly Arg Ser Thr Tyr Tyr Pro Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg His Glu Arg Met Asp Phe Trp Gly Gln Gly Thr Ser Val Thr
100 105 110
Val Ser Ser Gly Ser Thr Ser Gly Ser Gly Lys Pro Gly Ser Gly Glu
115 120 125
Gly Ser Thr Lys Gly Asp Ile Val Met Thr Gln Ser Pro Asp Ser Leu
130 135 140
Ala Val Ser Leu Gly Glu Arg Ala Thr Ile Thr Cys Lys Ser Ser Gln
145 150 155 160
Ser Val Leu Tyr Ser Ser Asn Gln Lys Asn Tyr Leu Ala Trp Tyr Gln
165 170 175
Gln Lys Pro Gly Gln Pro Pro Lys Leu Leu Ile Tyr Trp Ala Ser Thr
180 185 190
Arg Glu Ser Gly Val Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr
195 200 205
Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Ala Glu Asp Leu Ala Val
210 215 220
Tyr Tyr Cys His Gln Tyr Leu Ser Ser Tyr Thr Phe Gly Gly Gly Thr
225 230 235 240
Lys Leu Glu Ile Lys
245
<210> 42
<211> 115
<212> PRT
<213> Artificial Sequence(Artificial Sequence)
<220>
<223> BH395_V8 VH
<400> 42
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asn Tyr
20 25 30
Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Ser Ile Ser Asn Gly Gly Arg Ser Thr Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg His Glu Arg Met Asp Phe Trp Gly Gln Gly Thr Ser Val Thr
100 105 110
Val Ser Ser
115
<210> 43
<211> 112
<212> PRT
<213> Artificial Sequence(Artificial Sequence)
<220>
<223> BH395_V8 VL
<400> 43
Asp Ile Val Met Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly
1 5 10 15
Glu Arg Ala Thr Ile Thr Cys Lys Ser Ser Gln Ser Val Leu Tyr Ser
20 25 30
Ser Asn Gln Lys Asn Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln
35 40 45
Pro Pro Lys Leu Leu Ile Tyr Trp Ala Ser Thr Arg Glu Ser Gly Val
50 55 60
Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr
65 70 75 80
Ile Ser Ser Leu Gln Ala Glu Asp Leu Ala Val Tyr Tyr Cys His Gln
85 90 95
Tyr Leu Ser Ser Tyr Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
100 105 110
<210> 44
<211> 245
<212> PRT
<213> Artificial Sequence(Artificial Sequence)
<220>
<223> BH395_V8 scFV
<400> 44
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asn Tyr
20 25 30
Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Ser Ile Ser Asn Gly Gly Arg Ser Thr Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg His Glu Arg Met Asp Phe Trp Gly Gln Gly Thr Ser Val Thr
100 105 110
Val Ser Ser Gly Ser Thr Ser Gly Ser Gly Lys Pro Gly Ser Gly Glu
115 120 125
Gly Ser Thr Lys Gly Asp Ile Val Met Thr Gln Ser Pro Asp Ser Leu
130 135 140
Ala Val Ser Leu Gly Glu Arg Ala Thr Ile Thr Cys Lys Ser Ser Gln
145 150 155 160
Ser Val Leu Tyr Ser Ser Asn Gln Lys Asn Tyr Leu Ala Trp Tyr Gln
165 170 175
Gln Lys Pro Gly Gln Pro Pro Lys Leu Leu Ile Tyr Trp Ala Ser Thr
180 185 190
Arg Glu Ser Gly Val Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr
195 200 205
Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Ala Glu Asp Leu Ala Val
210 215 220
Tyr Tyr Cys His Gln Tyr Leu Ser Ser Tyr Thr Phe Gly Gly Gly Thr
225 230 235 240
Lys Leu Glu Ile Lys
245
<210> 45
<211> 735
<212> DNA
<213> Artificial Sequence(Artificial Sequence)
<220>
<223> BH395_V1 scFv
<400> 45
gaagtgcagc tggtggaaag cggcggcggc ctggtgaaac cgggcggcag cctgcgcctg 60
agctgcgcgg cgagcggctt tacctttagc aactatggca tgagctgggt gcgccaggcg 120
ccgggcaaag gcctggaatg ggtggcgacc attagcaacg gcggccgcag cacctattat 180
ccggatagcg tgaaaggccg ctttaccatt agccgcgata acgcgaaaaa caccctgtat 240
ctgcagatga acagcctgcg cgcggaagat accgcgattt attattgcgc gcgccatgaa 300
cgcatggatt tttggggcca gggcaccagc gtgaccgtga gcagcggcag caccagcggc 360
agcggcaaac cgggcagcgg cgaaggcagc accaaaggcg atattcagat gacccagagc 420
ccggatagcc tggcggtgag cctgggcgaa cgcgcgacca ttaactgcaa aagcagccag 480
agcgtgctgt atagcagcaa ccagaaaaac tatctggcgt ggtatcagca gaaaccgggc 540
cagccgccga aactgctgat ttattgggcg agcacccgcg aaagcggcgt gccggatcgc 600
tttagcggca gcggcagcgg caccgatttt accctgacca ttagcagcct gcaggcggaa 660
gatctggcgg tgtattattg ccatcagtat ctgagcagct atacctttgg cggcggcacc 720
aaactggaaa ttaaa 735
<210> 46
<211> 735
<212> DNA
<213> Artificial Sequence(Artificial Sequence)
<220>
<223> BH395_V2 scFv
<400> 46
gaagtgcagc tggtggaaag cggcggcggc ctggtgaaac cgggcggcag cctgcgcctg 60
agctgcgcgg cgagcggctt tacctttagc aactatggca tgagctgggt gcgccaggcg 120
ccgggcaaag gcctggaatg ggtggcgagc attagcaacg gcggccgcag cacctattat 180
gcggatagcg tgaaaggccg ctttaccatt agccgcgata acgcgaaaaa caccctgtat 240
ctgcagatga acagcctgcg cgcggaagat accgcggtgt attattgcgc gcgccatgaa 300
cgcatggatt tttggggcca gggcaccagc gtgaccgtga gcagcggcag caccagcggc 360
agcggcaaac cgggcagcgg cgaaggcagc accaaaggcg atattcagat gacccagagc 420
ccggatagcc tggcggtgag cctgggcgaa cgcgcgacca ttaactgcaa aagcagccag 480
agcgtgctgt atagcagcaa ccagaaaaac tatctggcgt ggtatcagca gaaaccgggc 540
cagccgccga aactgctgat ttattgggcg agcacccgcg aaagcggcgt gccggatcgc 600
tttagcggca gcggcagcgg caccgatttt accctgacca ttagcagcct gcaggcggaa 660
gatctggcgg tgtattattg ccatcagtat ctgagcagct atacctttgg cggcggcacc 720
aaactggaaa ttaaa 735
<210> 47
<211> 735
<212> DNA
<213> Artificial Sequence(Artificial Sequence)
<220>
<223> BH395_V3 scFv
<400> 47
gaagtgcagc tggtggaaag cggcggcggc ctggtgaaac cgggcggcag cctgcgcctg 60
agctgcgcgg cgagcggctt tacctttagc aactatggca tgagctgggt gcgccaggcg 120
ccgggcaaag gcctggaatg ggtgagcagc attagcaacg gcggccgcag cacctattat 180
ccggatagcg tgaaaggccg ctttaccatt agccgcgata acgcgaaaaa caccctgtat 240
ctgcagatga acagcctgcg cgcggaagat accgcggtgt attattgcgc gcgccatgaa 300
cgcatggatt tttggggcca gggcaccagc gtgaccgtga gcagcggcag caccagcggc 360
agcggcaaac cgggcagcgg cgaaggcagc accaaaggcg atattcagat gacccagagc 420
ccggatagcc tggcggtgag cctgggcgaa cgcgcgacca ttaactgcaa aagcagccag 480
agcgtgctgt atagcagcaa ccagaaaaac tatctggcgt ggtatcagca gaaaccgggc 540
cagccgccga aactgctgat ttattgggcg agcacccgcg aaagcggcgt gccggatcgc 600
tttagcggca gcggcagcgg caccgatttt accctgacca ttagcagcct gcaggcggaa 660
gatctggcgg tgtattattg ccatcagtat ctgagcagct atacctttgg cggcggcacc 720
aaactggaaa ttaaa 735
<210> 48
<211> 735
<212> DNA
<213> Artificial Sequence(Artificial Sequence)
<220>
<223> BH395_V4 scFv
<400> 48
gaagtgcagc tggtggaaag cggcggcggc ctggtgaaac cgggcggcag cctgcgcctg 60
agctgcgcgg cgagcggctt tacctttagc aactatggca tgagctgggt gcgccaggcg 120
ccgggcaaag gcctggaatg ggtgagcagc attagcaacg gcggccgcag cacctattat 180
gcggatagcg tgaaaggccg ctttaccatt agccgcgata acgcgaaaaa cagcctgtat 240
ctgcagatga acagcctgcg cgcggaagat accgcggtgt attattgcgc gcgccatgaa 300
cgcatggatt tttggggcca gggcaccagc gtgaccgtga gcagcggcag caccagcggc 360
agcggcaaac cgggcagcgg cgaaggcagc accaaaggcg atattcagat gacccagagc 420
ccggatagcc tggcggtgag cctgggcgaa cgcgcgacca ttaactgcaa aagcagccag 480
agcgtgctgt atagcagcaa ccagaaaaac tatctggcgt ggtatcagca gaaaccgggc 540
cagccgccga aactgctgat ttattgggcg agcacccgcg aaagcggcgt gccggatcgc 600
tttagcggca gcggcagcgg caccgatttt accctgacca ttagcagcct gcaggcggaa 660
gatctggcgg tgtattattg ccatcagtat ctgagcagct atacctttgg cggcggcacc 720
aaactggaaa ttaaa 735
<210> 49
<211> 735
<212> DNA
<213> Artificial Sequence(Artificial Sequence)
<220>
<223> BH395_V5 scFv
<400> 49
gaagtgcagc tggtggaaag cggcggcggc ctggtgaaac cgggcggcag cctgcgcctg 60
agctgcgcgg cgagcggctt tacctttagc aactatggca tgagctgggt gcgccaggcg 120
ccgggcaaag gcctggaatg ggtggcgacc attagcaacg gcggccgcag cacctattat 180
ccggatagcg tgaaaggccg ctttaccatt agccgcgata acgcgaaaaa caccctgtat 240
ctgcagatga acagcctgcg cgcggaagat accgcgattt attattgcgc gcgccatgaa 300
cgcatggatt tttggggcca gggcaccagc gtgaccgtga gcagcggcag caccagcggc 360
agcggcaaac cgggcagcgg cgaaggcagc accaaaggcg atattgtgat gacccagagc 420
ccggatagcc tggcggtgag cctgggcgaa cgcgcgacca ttacctgcaa aagcagccag 480
agcgtgctgt atagcagcaa ccagaaaaac tatctggcgt ggtatcagca gaaaccgggc 540
cagccgccga aactgctgat ttattgggcg agcacccgcg aaagcggcgt gccggatcgc 600
tttagcggca gcggcagcgg caccgatttt accctgacca ttagcagcct gcaggcggaa 660
gatctggcgg tgtattattg ccatcagtat ctgagcagct atacctttgg cggcggcacc 720
aaactggaaa ttaaa 735
<210> 50
<211> 735
<212> DNA
<213> Artificial Sequence(Artificial Sequence)
<220>
<223> BH395_V6 scFv
<400> 50
gaagtgcagc tggtggaaag cggcggcggc ctggtgaaac cgggcggcag cctgcgcctg 60
agctgcgcgg cgagcggctt tacctttagc aactatggca tgagctgggt gcgccaggcg 120
ccgggcaaag gcctggaatg ggtggcgagc attagcaacg gcggccgcag cacctattat 180
gcggatagcg tgaaaggccg ctttaccatt agccgcgata acgcgaaaaa caccctgtat 240
ctgcagatga acagcctgcg cgcggaagat accgcggtgt attattgcgc gcgccatgaa 300
cgcatggatt tttggggcca gggcaccagc gtgaccgtga gcagcggcag caccagcggc 360
agcggcaaac cgggcagcgg cgaaggcagc accaaaggcg atattgtgat gacccagagc 420
ccggatagcc tggcggtgag cctgggcgaa cgcgcgacca ttacctgcaa aagcagccag 480
agcgtgctgt atagcagcaa ccagaaaaac tatctggcgt ggtatcagca gaaaccgggc 540
cagccgccga aactgctgat ttattgggcg agcacccgcg aaagcggcgt gccggatcgc 600
tttagcggca gcggcagcgg caccgatttt accctgacca ttagcagcct gcaggcggaa 660
gatctggcgg tgtattattg ccatcagtat ctgagcagct atacctttgg cggcggcacc 720
aaactggaaa ttaaa 735
<210> 51
<211> 735
<212> DNA
<213> Artificial Sequence(Artificial Sequence)
<220>
<223> BH395_V7 scFv
<400> 51
gaagtgcagc tggtggaaag cggcggcggc ctggtgaaac cgggcggcag cctgcgcctg 60
agctgcgcgg cgagcggctt tacctttagc aactatggca tgagctgggt gcgccaggcg 120
ccgggcaaag gcctggaatg ggtgagcagc attagcaacg gcggccgcag cacctattat 180
ccggatagcg tgaaaggccg ctttaccatt agccgcgata acgcgaaaaa caccctgtat 240
ctgcagatga acagcctgcg cgcggaagat accgcggtgt attattgcgc gcgccatgaa 300
cgcatggatt tttggggcca gggcaccagc gtgaccgtga gcagcggcag caccagcggc 360
agcggcaaac cgggcagcgg cgaaggcagc accaaaggcg atattgtgat gacccagagc 420
ccggatagcc tggcggtgag cctgggcgaa cgcgcgacca ttacctgcaa aagcagccag 480
agcgtgctgt atagcagcaa ccagaaaaac tatctggcgt ggtatcagca gaaaccgggc 540
cagccgccga aactgctgat ttattgggcg agcacccgcg aaagcggcgt gccggatcgc 600
tttagcggca gcggcagcgg caccgatttt accctgacca ttagcagcct gcaggcggaa 660
gatctggcgg tgtattattg ccatcagtat ctgagcagct atacctttgg cggcggcacc 720
aaactggaaa ttaaa 735
<210> 52
<211> 735
<212> DNA
<213> Artificial Sequence(Artificial Sequence)
<220>
<223> BH395_V8 scFv
<400> 52
gaagtgcagc tggtggaaag cggcggcggc ctggtgaaac cgggcggcag cctgcgcctg 60
agctgcgcgg cgagcggctt tacctttagc aactatggca tgagctgggt gcgccaggcg 120
ccgggcaaag gcctggaatg ggtgagcagc attagcaacg gcggccgcag cacctattat 180
gcggatagcg tgaaaggccg ctttaccatt agccgcgata acgcgaaaaa cagcctgtat 240
ctgcagatga acagcctgcg cgcggaagat accgcggtgt attattgcgc gcgccatgaa 300
cgcatggatt tttggggcca gggcaccagc gtgaccgtga gcagcggcag caccagcggc 360
agcggcaaac cgggcagcgg cgaaggcagc accaaaggcg atattgtgat gacccagagc 420
ccggatagcc tggcggtgag cctgggcgaa cgcgcgacca ttacctgcaa aagcagccag 480
agcgtgctgt atagcagcaa ccagaaaaac tatctggcgt ggtatcagca gaaaccgggc 540
cagccgccga aactgctgat ttattgggcg agcacccgcg aaagcggcgt gccggatcgc 600
tttagcggca gcggcagcgg caccgatttt accctgacca ttagcagcct gcaggcggaa 660
gatctggcgg tgtattattg ccatcagtat ctgagcagct atacctttgg cggcggcacc 720
aaactggaaa ttaaa 735
<210> 53
<211> 25
<212> PRT
<213> Artificial Sequence(Artificial Sequence)
<220>
<223> CD8α跨膜结构域
<400> 53
Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly Val Leu Leu Leu
1 5 10 15
Ser Leu Val Ile Thr Leu Tyr Cys Lys
20 25
<210> 54
<211> 75
<212> DNA
<213> Artificial Sequence(Artificial Sequence)
<220>
<223> CD8α跨膜结构域
<400> 54
atctacatct gggcgccctt ggccgggact tgtggggtcc ttctcctgtc actggttatc 60
accctttact gcaaa 75
<210> 55
<211> 27
<212> PRT
<213> Artificial Sequence(Artificial Sequence)
<220>
<223> CD28跨膜结构域
<400> 55
Phe Trp Val Leu Val Val Val Gly Gly Val Leu Ala Cys Tyr Ser Leu
1 5 10 15
Leu Val Thr Val Ala Phe Ile Ile Phe Trp Val
20 25
<210> 56
<211> 81
<212> DNA
<213> Artificial Sequence(Artificial Sequence)
<220>
<223> CD28跨膜结构域
<400> 56
ttttgggtcc tcgtcgtagt tggaggggta cttgcctgtt atagcctcct ggttaccgta 60
gcatttatta tattctgggt g 81
<210> 57
<211> 41
<212> PRT
<213> Artificial Sequence(Artificial Sequence)
<220>
<223> CD28共刺激结构域
<400> 57
Arg Ser Lys Arg Ser Arg Leu Leu His Ser Asp Tyr Met Asn Met Thr
1 5 10 15
Pro Arg Arg Pro Gly Pro Thr Arg Lys His Tyr Gln Pro Tyr Ala Pro
20 25 30
Pro Arg Asp Phe Ala Ala Tyr Arg Ser
35 40
<210> 58
<211> 123
<212> DNA
<213> Artificial Sequence(Artificial Sequence)
<220>
<223> CD28共刺激结构域
<400> 58
aggagtaaga ggagcaggct cctgcacagt gactacatga acatgactcc ccgccgcccc 60
gggcccaccc gcaagcatta ccagccctat gccccaccac gcgacttcgc agcctatcgc 120
tcc 123
<210> 59
<211> 40
<212> PRT
<213> Artificial Sequence(Artificial Sequence)
<220>
<223> 4-1BB共刺激结构域
<400> 59
Arg Gly Arg Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg
1 5 10 15
Pro Val Gln Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro
20 25 30
Glu Glu Glu Glu Gly Gly Cys Glu
35 40
<210> 60
<211> 120
<212> DNA
<213> Artificial Sequence(Artificial Sequence)
<220>
<223> 4-1BB共刺激结构域
<400> 60
cggggcagaa agaaactcct gtatatattc aaacaaccat ttatgagacc agtacaaact 60
actcaagagg aagatggctg tagctgccga tttccagaag aagaagaagg aggatgtgaa 120
<210> 61
<211> 113
<212> PRT
<213> Artificial Sequence(Artificial Sequence)
<220>
<223> CD3ζ信号传导结构域
<400> 61
Leu Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr Gln Gln
1 5 10 15
Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu
20 25 30
Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met Gly Gly
35 40 45
Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln
50 55 60
Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu
65 70 75 80
Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu Ser Thr
85 90 95
Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu Pro Pro
100 105 110
Arg
<210> 62
<211> 339
<212> DNA
<213> Artificial Sequence(Artificial Sequence)
<220>
<223> CD3ζ信号传导结构域
<400> 62
ctgagagtga agttcagcag gagcgcagac gcccccgcgt accagcaggg ccagaaccag 60
ctctataacg agctcaatct aggacgaaga gaggagtacg atgttttgga caagagacgt 120
ggccgggacc ctgagatggg gggaaagccg agaaggaaga accctcagga aggcctgtac 180
aatgaactgc agaaagataa gatggcggag gcctacagtg agattgggat gaaaggcgag 240
cgccggaggg gcaaggggca cgatggcctt taccagggtc tcagtacagc caccaaggac 300
acctacgacg cccttcacat gcaggccctg ccccctcgc 339
<210> 63
<211> 114
<212> PRT
<213> Artificial Sequence(Artificial Sequence)
<220>
<223> CD3ζ信号传导结构域
<400> 63
Leu Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr Gln Gln
1 5 10 15
Gly Gln Asn Gln Leu Phe Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu
20 25 30
Phe Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met Gly Gly
35 40 45
Lys Pro Gln Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu
50 55 60
Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly
65 70 75 80
Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu Phe Gln Gly Leu Ser
85 90 95
Thr Ala Thr Lys Asp Thr Phe Asp Ala Leu His Met Gln Ala Leu Pro
100 105 110
Pro Arg
<210> 64
<211> 342
<212> DNA
<213> Artificial Sequence(Artificial Sequence)
<220>
<223> CD3ζ信号传导结构域
<400> 64
ctgagagtga agttcagcag gagcgcagac gcccccgcgt accagcaggg ccagaaccag 60
ctctttaacg agctcaatct aggacgaaga gaggagttcg atgttttgga caagagacgt 120
ggccgggacc ctgagatggg gggaaagccg cagagaagga agaaccctca ggaaggcctg 180
tacaatgaac tgcagaaaga taagatggcg gaggcctaca gtgagattgg gatgaaaggc 240
gagcgccgga ggggcaaggg gcacgatggc cttttccagg gtctcagtac agccaccaag 300
gacacctttg acgcccttca catgcaggcc ctgccccctc gc 342
<210> 65
<211> 20
<212> PRT
<213> Artificial Sequence(Artificial Sequence)
<220>
<223> B2M信号肽
<400> 65
Met Ser Arg Ser Val Ala Leu Ala Val Leu Ala Leu Leu Ser Leu Ser
1 5 10 15
Gly Leu Glu Ala
20
<210> 66
<211> 60
<212> DNA
<213> Artificial Sequence(Artificial Sequence)
<220>
<223> B2M信号肽
<400> 66
atgtcccgct ctgttgcttt ggctgtgctg gcccttttgt cccttagcgg actggaggcc 60
<210> 67
<211> 21
<212> PRT
<213> Artificial Sequence(Artificial Sequence)
<220>
<223> CD8α信号肽
<400> 67
Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu
1 5 10 15
His Ala Ala Arg Pro
20
<210> 68
<211> 63
<212> DNA
<213> Artificial Sequence(Artificial Sequence)
<220>
<223> CD8α信号肽
<400> 68
atggccttac cagtgaccgc cttgctcctg ccgctggcct tgctgctcca cgccgccagg 60
ccg 63
<210> 69
<211> 45
<212> PRT
<213> Artificial Sequence(Artificial Sequence)
<220>
<223> CD8α铰链区
<400> 69
Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala
1 5 10 15
Ser Gln Pro Leu Ser Leu Arg Pro Glu Ala Cys Arg Pro Ala Ala Gly
20 25 30
Gly Ala Val His Thr Arg Gly Leu Asp Phe Ala Cys Asp
35 40 45
<210> 70
<211> 135
<212> DNA
<213> Artificial Sequence(Artificial Sequence)
<220>
<223> CD8α铰链区
<400> 70
accacgacgc cagcgccgcg accaccaaca ccggcgccca ccatcgcgtc gcagcccctg 60
tccctgcgcc cagaggcgtg ccggccagcg gcggggggcg cagtgcacac gagggggctg 120
gacttcgcct gtgat 135
<210> 71
<211> 39
<212> PRT
<213> Artificial Sequence(Artificial Sequence)
<220>
<223> CD28铰链区
<400> 71
Ile Glu Val Met Tyr Pro Pro Pro Tyr Leu Asp Asn Glu Lys Ser Asn
1 5 10 15
Gly Thr Ile Ile His Val Lys Gly Lys His Leu Cys Pro Ser Pro Leu
20 25 30
Phe Pro Gly Pro Ser Lys Pro
35
<210> 72
<211> 117
<212> DNA
<213> Artificial Sequence(Artificial Sequence)
<220>
<223> CD28铰链区
<400> 72
attgaagtta tgtatcctcc tccttaccta gacaatgaga agagcaatgg aaccattatc 60
catgtgaaag ggaaacacct ttgtccaagt cccctatttc ccggaccttc taagccc 117
<210> 73
<211> 12
<212> PRT
<213> Artificial Sequence(Artificial Sequence)
<220>
<223> IgG4铰链区
<400> 73
Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro
1 5 10
<210> 74
<211> 36
<212> DNA
<213> Artificial Sequence(Artificial Sequence)
<220>
<223> IgG4铰链区
<400> 74
gaaagcaaat acgggccgcc gtgtccaccc tgtccg 36
<210> 75
<211> 18
<212> PRT
<213> Artificial Sequence(Artificial Sequence)
<220>
<223> 接头
<400> 75
Gly Ser Thr Ser Gly Ser Gly Lys Pro Gly Ser Gly Glu Gly Ser Thr
1 5 10 15
Lys Gly
<210> 76
<211> 15
<212> PRT
<213> Artificial Sequence(Artificial Sequence)
<220>
<223> 接头
<400> 76
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
1 5 10 15
Claims (27)
1.一种靶向GPRC5D的抗体,其包含:
(1)如SEQ ID NO:1所示的CDR-H1、如SEQ ID NO:2所示的CDR-H2、如SEQ ID NO:3所示的CDR-H3、如SEQ ID NO:4所示的CDR-L1、如SEQ ID NO:5所示的CDR-L2,和如SEQ ID NO:6所示的CDR-L3;或
(2)如SEQ ID NO:7所示的CDR-H1、如SEQ ID NO:8所示的CDR-H2、如SEQ ID NO:9所示的CDR-H3、如SEQ ID NO:10所示的CDR-L1、如SEQ ID NO:11所示的CDR-L2,和如SEQ ID NO:12所示的CDR-L3。
2.权利要求1所述的抗体,所述抗体包含选自以下的重链可变区和轻链可变区:
(a)所述重链可变区与SEQ ID NO:13所示的氨基酸序列具有至少90%同一性,或与SEQID NO:13所示的氨基酸序列相比具有一个或几个氨基酸的保守性修饰;且所述轻链可变区与SEQ ID NO:14所示的氨基酸序列具有至少90%同一性,或与SEQ ID NO:14所示的氨基酸序列相比具有一个或几个氨基酸的保守性修饰;
(b)所述重链可变区与SEQ ID NO:15所示的氨基酸序列具有至少90%同一性,或与SEQID NO:15所示的氨基酸序列相比具有一个或几个氨基酸的保守性修饰;且所述轻链可变区与SEQ ID NO:16所示的氨基酸序列具有至少90%同一性,或与SEQ ID NO:16所示的氨基酸序列相比具有一个或几个氨基酸的保守性修饰;
(c)所述重链可变区与SEQ ID NO:21所示的氨基酸序列具有至少90%同一性,或与SEQID NO:21所示的氨基酸序列相比具有一个或几个氨基酸的保守性修饰;且所述轻链可变区与SEQ ID NO:22所示的氨基酸序列具有至少90%同一性,或与SEQ ID NO:22所示的氨基酸序列相比具有一个或几个氨基酸的保守性修饰;
(d)所述重链可变区与SEQ ID NO:24所示的氨基酸序列具有至少90%同一性,或与SEQID NO:24所示的氨基酸序列相比具有一个或几个氨基酸的保守性修饰;且所述轻链可变区与SEQ ID NO:25所示的氨基酸序列具有至少90%同一性,或与SEQ ID NO:25所示的氨基酸序列相比具有一个或几个氨基酸的保守性修饰;
(e)所述重链可变区与SEQ ID NO:27所示的氨基酸序列具有至少90%同一性,或与SEQID NO:27所示的氨基酸序列相比具有一个或几个氨基酸的保守性修饰;且所述轻链可变区与SEQ ID NO:28所示的氨基酸序列具有至少90%同一性,或与SEQ ID NO:28所示的氨基酸序列相比具有一个或几个氨基酸的保守性修饰;
(f)所述重链可变区与SEQ ID NO:30所示的氨基酸序列具有至少90%同一性,或与SEQID NO:30所示的氨基酸序列相比具有一个或几个氨基酸的保守性修饰;且所述轻链可变区与SEQ ID NO:31所示的氨基酸序列具有至少90%同一性,或与SEQ ID NO:31所示的氨基酸序列相比具有一个或几个氨基酸的保守性修饰;
(g)所述重链可变区与SEQ ID NO:33所示的氨基酸序列具有至少90%同一性,或与SEQID NO:33所示的氨基酸序列相比具有一个或几个氨基酸的保守性修饰;且所述轻链可变区与SEQ ID NO:34所示的氨基酸序列具有至少90%同一性,或与SEQ ID NO:34所示的氨基酸序列相比具有一个或几个氨基酸的保守性修饰;
(h)所述重链可变区与SEQ ID NO:36所示的氨基酸序列具有至少90%同一性,或与SEQID NO:36所示的氨基酸序列相比具有一个或几个氨基酸的保守性修饰;且所述轻链可变区与SEQ ID NO:37所示的氨基酸序列具有至少90%同一性,或与SEQ ID NO:37所示的氨基酸序列相比具有一个或几个氨基酸的保守性修饰;
(i)所述重链可变区与SEQ ID NO:39所示的氨基酸序列具有至少90%同一性,或与SEQID NO:39所示的氨基酸序列相比具有一个或几个氨基酸的保守性修饰;且所述轻链可变区与SEQ ID NO:40所示的氨基酸序列具有至少90%同一性,或与SEQ ID NO:40所示的氨基酸序列相比具有一个或几个氨基酸的保守性修饰;
(j)所述重链可变区与SEQ ID NO:42所示的氨基酸序列具有至少90%同一性,或与SEQID NO:42所示的氨基酸序列相比具有一个或几个氨基酸的保守性修饰;且所述轻链可变区与SEQ ID NO:43所示的氨基酸序列具有至少90%同一性,或与SEQ ID NO:43所示的氨基酸序列相比具有一个或几个氨基酸的保守性修饰。
3.权利要求1所述的抗体,所述抗体选自完整抗体、Fab、Fab'、F(ab')2、Fd、Fd′、Fv、scFv、sdFv、线性抗体、双体。
4.权利要求3所述的抗体,其中所述抗体是scFv,其氨基酸序列与选自SEQ ID NO:17、18、23、26、29、32、35、38、41和44的氨基酸序列具有至少90%同一性,或与选自SEQ ID NO:17、18、23、26、29、32、35、38、41和44的氨基酸序列相比具有一个或几个氨基酸的保守性修饰。
5.权利要求1-4任一项所述的抗体,其中所述抗体是鼠源抗体、嵌合抗体、人源化抗体或人抗体。
6.一种核酸分子,其编码权利要求1-5任一项所述的抗体。
7.权利要求6所述的核酸分子,其与选自SEQ ID NO:45-52的核苷酸序列具有至少90%、91%、92%、93%、94%、95%、96%、97%、98%、99%、100%序列同一性,并且其编码的抗体能够特异性结合GPRC5D。
8.一种多特异性抗体,其包含权利要求1-5任一项所述的抗体和一个或多个与其他抗原特异性结合的第二抗体或其抗原结合部分。
9.权利要求8所述的多特异性抗体,其中所述第二抗体或其抗原结合部分选自全长抗体、Fab、Fab'、F(ab')2、Fv、scFv、scFv-scFv、微抗体、双抗体或sdAb。
10.一种载体,其包含编码权利要求1-5任一项所述的抗体或权利要求8或9所述的多特异性抗体的核酸分子。
11.一种宿主细胞,其表达权利要求1-5任一项所述的抗体或权利要求8或9所述的多特异性抗体。
12.一种重组受体,其包含权利要求1-5任一项所述的抗体或权利要求8或9所述的多特异性抗体。
13.权利要求12所述的重组受体,其中所述重组受体是重组TCR受体或嵌合抗原受体。
14.权利要求13所述的重组受体,其中所述重组受体是嵌合抗原受体,所述嵌合抗原受体进一步包含跨膜结构域和胞内信号传导结构域。
15.权利要求14所述的重组受体,所述跨膜结构域选自以下蛋白质的跨膜结构域:TCRα链、TCRβ链、TCRγ链、TCRδ链、CD3ζ亚基、CD3ε亚基、CD3γ亚基、CD3δ亚基、CD45、CD4、CD5、CD8α、CD9、CD16、CD22、CD33、CD28、CD37、CD64、CD80、CD86、CD134、CD137和CD154。
16.权利要求14所述的重组受体,所述胞内信号传导结构域选自以下蛋白的胞内区:FcRγ、FcRβ、CD3γ、CD3δ、CD3ε、CD3ζ、CD22、CD79a、CD79b和CD66d。
17.权利要求14所述的重组受体,其还包含一个或多个选自以下蛋白质的胞内区的共刺激结构域:TLR1、TLR2、TLR3、TLR4、TLR5、TLR6、TLR7、TLR8、TLR9、TLR10、CARD11、CD2、GPRC5D、CD8、CD18、CD27、CD28、CD30、CD40、CD54、CD83、CD134(OX40)、CD137(4-1BB)、CD270(HVEM)、CD272(BTLA)、CD276(B7-H3)、CD278(ICOS)、CD357(GITR)、DAP10、LAT、NKG2C、SLP76、PD-1、LIGHT、TRIM以及ZAP70。
18.一种工程化免疫细胞,其包含权利要求12-17任一项所述的重组受体。
19.权利要求18所述的工程化免疫细胞,其选自T细胞、NK细胞、NKT细胞、巨噬细胞、树突细胞。
20.权利要求18所述的工程化免疫细胞,其还包含靶向其他肿瘤抗原的第二重组受体。
21.权利要求18-20任一项所述的工程化免疫细胞,还包含至少一种选自以下的基因的表达被抑制或沉默:TRAC、TRBC、HLA-A、HLA-B、HLA-C、B2M、RFX5、RFXAP、RFXANK、CIITA、PD1、LAG3、TIM3和CTLA4。
22.一种抗体偶联物,其包含权利要求1-5任一项所述的抗体或权利要求8或9所述的多特异性抗体,和第二功能性结构,其中所述第二功能性结构选自Fc、放射性同位素、延长半衰期的结构部分、可检测标记物和药物。
23.权利要求22所述的抗体偶联物,其中所述延长半衰期的结构部分选自:白蛋白的结合结构、转铁蛋白的结合结构、聚乙二醇分子、重组聚乙二醇分子、人血清白蛋白、人血清白蛋白的片段和结合人血清白蛋白的白多肽;所述可检测标记物选自荧光团、化学发光化合物、生物发光化合物、酶、抗生素抗性基因和造影剂;所述药物选自细胞毒素和免疫调节剂。
24.一种检测试剂盒,其包含权利要求1-5任一项所述的抗体、权利要求8或9所述的多特异性抗体、权利要求12-17任一项所述的重组受体、权利要求18-21任一项所述的工程化免疫细胞、或权利要求22或23所述的抗体偶联物。
25.一种药物组合物,包含权利要求1-5任一项所述的抗体、权利要求8或9所述的多特异性抗体、权利要求12-17任一项所述的重组受体、权利要求18-21任一项所述的工程化免疫细胞、或权利要求22或23所述的抗体偶联物,和一种或多种药学上可接受的赋形剂。
26.权利要求1-5任一项所述的抗体、权利要求8或9所述的多特异性抗体、权利要求12-17任一项所述的重组受体、权利要求18-21任一项所述的工程化免疫细胞、或权利要求22或23所述的抗体偶联物或权利要求25所述的药物组合物在制备用于治疗和/或预防和/或诊断与GPRC5D表达相关的疾病的药物中的用途。
27.权利要求26所述的用途,其中所述疾病选自GPRC5D阳性的乳腺癌、多发性骨髓瘤、瓦氏巨球蛋白血症、子宫内膜癌、卵巢癌、肺癌、胃癌、前列腺癌、肾癌、肝癌、胰腺癌、结肠直肠癌、食道癌、膀胱癌、子宫颈癌、血液癌、淋巴瘤或恶性黑色素瘤。
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Defining an Optimal Dual-Targeted CAR T-cell Therapy Approach Simultaneously Targeting BCMA and GPRC5D to Prevent BCMA Escape-Driven Relapse in Multiple Myeloma;Carlos Fernández de Larrea等;Blood Cancer Discov;第1卷(第2期);参见全文 * |
GPRC5D is a promising marker for monitoring the tumor load and to target multiple myeloma cells;Yossi Cohen等;Hematology;第18卷(第6期);参见全文 * |
GPRC5D is a target for the immunotherapy of multiple myeloma with rationally designed CAR T cells;Eric L Smith等;Sci Transl Med;第11卷(第484期);参见全文 * |
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