CN114206935B - 新型cldn18.2结合分子 - Google Patents
新型cldn18.2结合分子 Download PDFInfo
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- CN114206935B CN114206935B CN202080038303.6A CN202080038303A CN114206935B CN 114206935 B CN114206935 B CN 114206935B CN 202080038303 A CN202080038303 A CN 202080038303A CN 114206935 B CN114206935 B CN 114206935B
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Abstract
新型CLDN18.2结合分子。编码该CLDN18.2结合分子的核酸分子,用于表达CLDN18.2结合分子的表达载体和宿主细胞。产生该CLDN18.2结合分子的方法及其用途。
Description
优先权信息
本申请要求2019年5月24日提交的中国专利申请201910437800.2和201910437806.X的优先权,其全部内容通过提述并入本文。
序列表
本申请包含序列表,并且其全部内容通过引用并入本文。
技术领域
本申请一般而言涉及抗体。更具体地,本申请涉及特异性识别CLDN18.2的单结构域抗体、其制备方法及其用途。
背景技术
细胞连接是细胞间的联系结构,是多细胞有机体中相邻细胞之间相互联系、协同作用的重要基础。一般而言,动物细胞有四种类型的连接∶紧密连接、粘着连接、间隙连接和桥粒/半桥粒。
紧密连接,也称为封闭连接,是在内皮细胞或者上皮细胞间形成的结构,可以防止组织间的物质从细胞间隙中扩散,从而只能通过主动运输进入细胞。紧密连接的结构由几十种Claudin蛋白通过细胞内和细胞间的蛋白质相互作用形成,而这些蛋白质的表达具有一定的组织特异性。CLDN18就是紧密连接中存在的Claudin蛋白中的一种重要的蛋白质。
CLDN18是具有四次跨膜区域的膜蛋白,含有两个胞外结构域。人体内存在两种CLDN18变体,分别是CLDN18.1和CLDN18.2。两者分布于不同的组织,前者主要表达在肺上皮细胞中,后者则特异性表达在胃上皮细胞中,且在胃干细胞中不表达。在蛋白序列上,CLDN18.1和CLDN18.2的序列相似度极高,两者的主要差别在N端,在第一个胞外结构域两者仅存在8个氨基酸的差别;除了N端之外,C端序列完全一致。
抗体疗法正在成为治疗癌症患者的最有前途的方法之一。CLDN18.2由于其在肿瘤细胞和正常组织中的表达特异性,目前已经成为非常有潜力的一个抗体药物作用靶点。然而,由于CLDN18.1和CLDN18.2的序列相似性极高,使得开发只针对CLDN18.2而不针对CLDN18.1的抗体极其困难,世界范围内鲜有报道。截止目前,德国Ganymed公司研制的IMAB362是唯一针对CLDN18.2靶点的临床在研抗体。IMAB362是一种由两条蛋白重链和两条蛋白轻链组成的单克隆抗体。目前,尚不存在靶向CLDN18.2的单结构域抗体。
单结构域抗体简称单域抗体(single domain antibody,sdAb),是由单个单体可变抗体结构域(如抗体重链可变结构域)组成的抗体。像整个抗体(如IgG)一样,它能够选择性结合特定的抗原。但单结构域抗体的分子量却远小于由两条蛋白重链和两条蛋白轻链组成的常见抗体。第一个单结构域抗体是由骆驼科动物中发现的重链抗体改造而来的(Hamers-Casterman C,Atarhouch T,Muyldermans S,Robinson G,Hamers C,Songa EB,Bendahman N,Hamers R(1993)Naturally occurring antibodies devoid of lightchains.Nature 363(6428):446–448.);这些骆驼科动物中发现的重链抗体也被称为VHH片段。目前,对单结构域抗体的大多数研究基于重链可变结构域。
单结构域抗体具有许多优点。例如,它们通常表现出较高的溶解度、良好的热稳定性和组织渗透性,单结构域抗体由于存在第二对分子内二硫键还可耐受木瓜蛋白酶等的降解;此外,单结构域抗体可以在酵母、植物和哺乳动物细胞等多种宿主细胞中表达,且表达量较高,使得其具有极高的成本优势。单结构域抗体的优势使其适用于各种生物技术和治疗应用。例如,它们可用于治疗疾病,包括但不限于癌症、感染性疾病、炎症性疾病和神经退行性疾病。
虽然目前已经有靶向CLDN18.2靶点的临床在研单克隆抗体药物,但作为治疗剂,仍有继续开发靶向CLDN18.2靶点抗体的迫切需要。本领域希望开发新的靶向CLDN18.2的抗体,特别是只特异性识别CLDN18.2而不识别CLDN18.1的单结构域抗体。
发明内容
广义而言,本公开提供抗体的新型化合物、制备方法、组合物和制品。本公开提供的益处广泛地适用于抗体治疗和诊断领域。更具体而言,本公开提供了靶向CLDN18.2的单结构域抗体,以及制备所述抗体的方法、用于表达所述抗体的表达载体和宿主细胞等。本公开的抗体提供了治疗或预防与Claudin蛋白相关、特别是与CLDN18.2相关的病症的方法及其应用。
本发明人首次发现,能够特异性结合人CLDN18.2的胞外结构域1(ECD1)的CLDN18.2结合分子(如靶向CLDN18.2的单结构域抗体)。
本公开至少包括以下实施方案,其分别以“N”(其中“N”表示数字)的方式进行排序和列举。以下列举非穷尽性的,并且本领域技术人员可对不同的技术方案进行组合。
1.CLDN18.2结合分子,其包含至少一个免疫球蛋白单可变结构域,其中所述免疫球蛋白单可变结构域包含选自以下任一组的CDR1、CDR2和CDR3:
(a)CDR1包含与SEQ ID NO:1至少80%、85%、90%或95%相同的氨基酸序列,CDR2包含与SEQ ID NO:2至少80%、85%、90%或95%相同的氨基酸序列,和CDR3包含与SEQ IDNO:3至少80%、85%、90%或95%相同的氨基酸序列;和
(b)CDR1包含与SEQ ID NO:30至少80%、85%、90%或95%相同的氨基酸序列,CDR2包含与SEQ ID NO:31至少80%、85%、90%或95%相同的氨基酸序列,和CDR3包含与SEQ ID NO:32至少80%、85%、90%或95%相同的氨基酸序列。
2.实施方案1的CLDN18.2结合分子,其中:
(a)CDR1在氨基酸序列上与SEQ ID NO:1存在不超过2个氨基酸的氨基酸添加、缺失或取代的差异,CDR2在氨基酸序列上与SEQ ID NO:2存在不超过2个氨基酸的氨基酸添加、缺失或取代的差异,和/或CDR3在氨基酸序列上与SEQ ID NO:3存在不超过2个氨基酸的氨基酸添加、缺失或取代的差异;或
(b)CDR1在氨基酸序列上与SEQ ID NO:30存在不超过2个氨基酸的氨基酸添加、缺失或取代的差异,CDR2在氨基酸序列上与SEQ ID NO:31存在不超过2个氨基酸的氨基酸添加、缺失或取代的差异,和/或CDR3在氨基酸序列上与SEQ ID NO:32存在不超过2个氨基酸的氨基酸添加、缺失或取代的差异。
3.实施方案1的CLDN18.2结合分子,其中:
(a)CDR1在氨基酸序列上与SEQ ID NO:1存在1个氨基酸的氨基酸添加、缺失或取代的差异,CDR2在氨基酸序列上与SEQ ID NO:2存在1个氨基酸的氨基酸添加、缺失或取代的差异,和/或CDR3在氨基酸序列上与SEQ ID NO:3存在1个氨基酸的氨基酸添加、缺失或取代的差异;或
(b)CDR1在氨基酸序列上与SEQ ID NO:30存在1个氨基酸的氨基酸添加、缺失或取代的差异,CDR2在氨基酸序列上与SEQ ID NO:31存在1个氨基酸的氨基酸添加、缺失或取代的差异,和/或CDR3在氨基酸序列上与SEQ ID NO:32存在1个氨基酸的氨基酸添加、缺失或取代的差异。
4.前述实施方案中任一项的CLDN18.2结合分子,其中所述CLDN18.2结合分子是针对CLDN18.2的抗体或其抗原结合片段。
5.前述实施方案中任一项的CLDN18.2结合分子,其中所述免疫球蛋白单可变结构域是VHH;例如,来自骆驼科动物(例如羊驼)的VHH。
6.前述实施方案中任一项的CLDN18.2结合分子,其中所述免疫球蛋白单可变结构域包含选自以下任一组的CDR1、CDR2和CDR3:
(a)如SEQ ID NO:1所示的氨基酸序列的CDR1,如式ISRGGX1T所示的氨基酸序列的CDR2,其中X1为T或S,和如式NAQAWDX2GTX3RYLEV所示的氨基酸序列的CDR3,其中X2为P或V,X3为F或I;和
(b)如SEQ ID NO:30、33、34、35、36、38、39或40所示的氨基酸序列的CDR1,如式X4STGGTT所示的氨基酸序列的CDR2,其中X4为I或M,和如式NVLVX5SGIGSX6LEV所示的氨基酸序列的CDR3,其中X5为I或V,X6为H或T。
7.前述实施方案中任一项的CLDN18.2结合分子,其中所述免疫球蛋白单可变结构域包含:
(a)如SEQ ID NO:1所示的氨基酸序列的CDR1,如SEQ ID NO:2所示的氨基酸序列的CDR2和如SEQ ID NO:3所示的氨基酸序列的CDR3;
(b)如SEQ ID NO:1所示的氨基酸序列的CDR1,如SEQ ID NO:4所示的氨基酸序列的CDR2和如SEQ ID NO:5所示的氨基酸序列的CDR3;或
(c)如SEQ ID NO:1所示的氨基酸序列的CDR1,如SEQ ID NO:2所示的氨基酸序列的CDR2和如SEQ ID NO:6所示的氨基酸序列的CDR3;
(d)如SEQ ID NO:30所示的氨基酸序列的CDR1,如SEQ ID NO:31所示的氨基酸序列的CDR2和如SEQ ID NO:32所示的氨基酸序列的CDR3;
(e)如SEQ ID NO:30所示的氨基酸序列的CDR1,如SEQ ID NO:31所示的氨基酸序列的CDR2和如SEQ ID NO:37所示的氨基酸序列的CDR3;
(f)如SEQ ID NO:33所示的氨基酸序列的CDR1,如SEQ ID NO:31所示的氨基酸序列的CDR2和如SEQ ID NO:62所示的氨基酸序列的CDR3;
(g)如SEQ ID NO:33所示的氨基酸序列的CDR1,如SEQ ID NO:31所示的氨基酸序列的CDR2和如SEQ ID NO:37所示的氨基酸序列的CDR3;
(h)如SEQ ID NO:34所示的氨基酸序列的CDR1,如SEQ ID NO:31所示的氨基酸序列的CDR2和如SEQ ID NO:37所示的氨基酸序列的CDR3;
(i)如SEQ ID NO:35所示的氨基酸序列的CDR1,如SEQ ID NO:31所示的氨基酸序列的CDR2和如SEQ ID NO:62所示的氨基酸序列的CDR3;
(j)如SEQ ID NO:36所示的氨基酸序列的CDR1,如SEQ ID NO:31所示的氨基酸序列的CDR2和如SEQ ID NO:62所示的氨基酸序列的CDR3;
(k)如SEQ ID NO:38所示的氨基酸序列的CDR1,如SEQ ID NO:31所示的氨基酸序列的CDR2和如SEQ ID NO:62所示的氨基酸序列的CDR3;
(l)如SEQ ID NO:39所示的氨基酸序列的CDR1,如SEQ ID NO:41所示的氨基酸序列的CDR2和如SEQ ID NO:37所示的氨基酸序列的CDR3;或
(m)如SEQ ID NO:40所示的氨基酸序列的CDR1,如SEQ ID NO:31所示的氨基酸序列的CDR2和如SEQ ID NO:37所示的氨基酸序列的CDR3。
8.前述实施方案中任一项的CLDN18.2结合分子,其中所述免疫球蛋白单可变结构域包含选自下组的任一种:
(a)SEQ ID NO:7的氨基酸序列,与SEQ ID NO:7至少80%、85%、90%或95%相同的氨基酸序列,或与SEQ ID NO:7相比具有一个或多个(例如,1、2、3、4、5、6、7、8、9或10个)氨基酸的添加、缺失和/或取代的氨基酸序列;
(b)SEQ ID NO:47所示的氨基酸序列,与SEQ ID NO:47至少80%、85%、90%或95%相同的氨基酸序列,或与SEQ ID NO:47相比具有一个或多个(例如,1、2、3、4、5、6、7、8、9或10个)氨基酸的添加、缺失和/或取代的氨基酸序列。
9.前述实施方案中任一项的CLDN18.2结合分子,其中所述免疫球蛋白单可变结构域为:
(a)在SEQ ID NO:7的以下位点中的一个或多个发生修饰(例如,氨基酸的取代):第1、4、5、14、16、35、47、56、58、65、92、102、105或121位氨基酸;或
(b)在SEQ ID NO:47的以下位点中的一个或多个发生修饰(例如,氨基酸的取代和/或添加):第1、4、5、11、27、28、29、30、31、32、35、51、75、76、92、100、106或120位氨基酸。
10.前述实施方案中任一项的CLDN18.2结合分子,其中所述免疫球蛋白单可变结构域包含以下序列或由以下序列组成:SEQ ID NO:7-14、SEQ ID NO:42-51和63中的任一者。
11.前述实施方案中任一项的CLDN18.2结合分子,其中所述CLDN18.2结合分子是单结构域抗体,例如重链单结构域抗体;嵌合抗体;或人源化抗体。
12.前述实施方案中任一项的CLDN18.2结合分子,其中所述免疫球蛋白单可变结构域与另一分子融合,所述另一分子是例如免疫球蛋白(例如IgG)的Fc结构域或荧光蛋白。
13.实施方案12的CLDN18.2结合分子,其中所述CLDN18.2结合分子是包含来自骆驼科动物的VHH与人IgG(例如,人IgG1或IgG4)的Fc结构域的嵌合抗体。
14.实施方案13的CLDN18.2结合分子,其中所述CLDN18.2结合分子是包含来自羊驼的VHH与人IgG1的Fc结构域的嵌合抗体。
15.前述实施方案中任一项的CLDN18.2结合分子,其中所述CLDN18.2结合分子结合人CLDN18.2的胞外结构域1(ECD1)。
16.CLDN18.2结合分子,其与前述实施方案中任一项的CLDN18.2结合分子竞争相同表位。
17.前述实施方案中任一项的CLDN18.2结合分子,其特异性结合CLDN18.2,但不结合CLDN18.1。
18.分离的核酸分子,其包含编码如前述实施方案中任一项所定义的CLDN18.2结合分子的核酸序列。
19.实施方案18的分离的核酸分子,其包含以下序列或由以下序列组成:SEQ IDNO:22-29、SEQ ID NO:52-61和64中的任一者。
20.一种表达载体,其包含实施方案18或19的分离的核酸分子。
21.一种宿主细胞,其包含实施方案20的表达载体。
22.实施方案21的宿主细胞,所述宿主细胞是细菌细胞(例如大肠杆菌(E.coli)),真菌细胞(例如酵母)或哺乳动物细胞。
23.一种药物组合物,其包含至少一种如实施方案1-17中任一项所定义的CLDN18.2结合分子和药学上可接受的载体。
24.制备如实施方案1-17中任一项所定义的CLDN18.2结合分子的方法,包括以下步骤:
-在实施方案21或22的宿主细胞中表达实施方案1-17中任一项所定义的CLDN18.2结合分子;和
-从宿主细胞分离CLDN18.2结合分子。
25.治疗受试者中与CLDN18.2相关的病症的方法,所述方法包括:向所述受试者施用治疗有效量的实施方案1-17中任一项所定义的CLDN18.2结合分子。
26.实施方案25所述的方法,其中所述与CLDN18.2相关的病症包括涉及表达CLDN18.2的细胞的疾病或与表达CLDN18.2的细胞相关的疾病。
27.实施方案25或26所述的方法,其中所述与CLDN18.2相关的病症包括癌症。
28.实施方案27所述的方法,其中所述癌症包括骨癌、血癌、肺癌、肝癌、胰腺癌、皮肤癌、头颈癌、皮肤或眼内黑素瘤、子宫癌、卵巢癌、直肠癌、肛区癌、胃癌、结肠癌、乳腺癌、***癌、子宫癌、性器官和生殖器官癌、霍奇金病、食管癌、小肠癌、内分泌***癌症、甲状腺癌、甲状旁腺癌、肾上腺癌、软组织肉瘤、膀胱癌、肾癌、肾细胞癌、肾盂癌、中枢神经***(CNS)肿瘤、神经外胚层癌症、脊柱轴肿瘤、胶质瘤、脑脊膜瘤和垂体腺瘤。
29.实施方案28所述的方法,其中所述癌症为胃癌。
30.如实施方案1-17中任一项所定义的CLDN18.2结合分子在制备用于治疗或预防与CLDN18.2相关的病症的药物中的用途。
31.用于治疗或诊断与CLDN18.2相关的病症的试剂盒,其包含容器,所述容器包含实施方案1-17中任一项所定义的CLDN18.2结合分子。
以上内容是概括性的描述,必要时可包含细节的简化、概括和省略。因此,本领域技术人员将认识到,该概括性的描述仅是举例说明性的,并不意图以任何方式进行限制。本文所述的方法、组合物和/或装置和/或其他主题的其它方面、特征和优势将在本文所示的教导中变得明显。提供概括性的描述以简化地介绍一些选择的概念,这些概括性的描述将在下面的详细描述中进一步描述。以上概括性的描述不旨在确定所要求保护的主题的关键特征或基本特征,也不旨在用作确定所要求保护的主题的范围的辅助手段。此外,贯穿本申请引用的所有参考文献、专利和公开的专利申请的内容通过引用整体并入本文。
附图说明
图1a和1b显示实施例1中过表达细胞株和肿瘤细胞株的流式细胞术鉴定结果。其中,图1a显示人CLDN18.2-HEK293T、人CLDN18.1-HEK293、鼠CLDN18.2-HEK293和鼠CLDN18.1-HEK293过表达细胞株的流式细胞术鉴定结果;图1b显示人CLDN18.2-KATOIII肿瘤细胞株的流式细胞术鉴定结果。
图2a和2b显示多个候选抗体之间的序列比较。其中,显示了候选抗体的可变区全长序列以及其中的CDR序列,并标示了候选抗体之间的氨基酸序列差异。
图3a显示候选抗体NA1-S在人CLDN18.2-HEK293T、人CLDN18.1-HEK293、鼠CLDN18.2-HEK293和鼠CLDN18.1-HEK293过表达细胞株上的交叉结合实验结果。图3b显示候选抗体NA3-S、NA5-S和NA6-S在人CLDN18.2-HEK293T、人CLDN18.1-HEK293、鼠CLDN18.2-HEK293和鼠CLDN18.1-HEK293过表达细胞株上的交叉结合实验结果。
图4a和4b显示候选抗体NA1-S和对照抗体在细胞水平上的结合比较实验结果。其中,图4a显示抗体NA1-S在人CLDN18.2-HEK293T过表达细胞上的流式水平比较实验结果;图4b显示抗体NA1-S和对照抗体在人CLDN18.2-KATOIII肿瘤细胞株上的流式水平比较实验结果。
图5a-c显示候选抗体NA3-S、NA5-S、NA6-S和对照抗体在细胞水平上的结合比较实验结果。其中,图5a显示抗体NA3-S、NA6-S在人CLDN18.2-HEK293T过表达细胞上的流式水平比较实验结果;图5b显示抗体NA5-S在人CLDN18.2-HEK293T过表达细胞上的流式水平比较实验结果;图5c显示抗体NA3-S、NA5-S、NA6-S和对照抗体在人CLDN18.2-KATOIII肿瘤细胞株上的流式水平比较实验结果。
图6a和6b显示候选抗体NA1-S在人CLDN18.2-HEK293T过表达细胞株以及人CLDN18.2-KATOIII肿瘤细胞株上介导的补体依赖的细胞毒性作用(CDC)。其中,图6a显示抗体NA1-S在人CLDN18.2-HEK293T上介导的CDC;图6b显示抗体NA1-S在人CLDN18.2-KATOIII肿瘤细胞株上介导的CDC。
图7a-d显示候选抗体NA3-S、NA5-S和NA6-S在人CLDN18.2-HEK293T过表达细胞株以及人CLDN18.2-KATOIII肿瘤细胞株上介导的补体依赖的细胞毒性作用(CDC)。其中,图7a显示抗体NA3-S在人CLDN18.2-HEK293T上介导的CDC细胞毒性效应;图7b和7c分别显示NA5-S和NA6-S在人CLDN18.2-HEK293T细胞上的CDC杀伤效应;图7d显示抗体NA3-S在人CLDN18.2-KATOIII肿瘤细胞株上介导的CDC。
图8a-d显示候选抗体NA1-S和NA3-S在人CLDN18.2-HEK293T以及人CLDN18.2-KATOIII肿瘤细胞株上介导的抗体依赖的细胞介导的细胞毒性作用(ADCC)。其中,图8a和8c显示抗体NA1-S和NA3-S在人CLDN18.2-HEK293T细胞株上介导的ADCC;图8b和8d显示抗体NA1-S和NA3-S在人CLDN18.2-KATOIII肿瘤细胞株上介导的ADCC。
图9a和9b显示了候选抗体NA1-S和NA3-S在人CLDN18.2-HEK293T异种移植模型中的肿瘤抑制效果。其中,小鼠采用的是免疫缺陷小鼠SCID,而NA1-S和IMAB362的给药剂量根据质量浓度计算给药,给药方式采用的是尾静脉和腹腔交叉给药。
图10a-i显示候选抗体NA1-S、NA3-S和IMAB362结合CLDN18.2的表位以及结合的关键氨基酸位点。其中,图10a-b显示了候选抗体NA1-S(图10a)或NA3-S(图10b)与IMAB362在人CLDN18.2-HEK293T上与IMAB362的竞争结合试验;图10c-d显示了抗体IMAB362在人CLDN18.2-HEK293T上与NA1-S(图10c)或NA3-S(图10d)的竞争结合试验。图10e采用抗CLDN18抗体测定人CLDN18.2突变体细胞株上的突变或者野生CLDN18.2的表达水平;图10f-g显示了NA1-S(图10f)或NA3-S(图10g)和IMAB362在人CLDN18.2突变体细胞株上与CLDN18.2突变体的结合水平;图10h-i显示了NA1-S(图10h)或NA3-S(图10i)和IMAB362在人CLDN18.2突变体细胞株上相对于野生细胞株的相对结合百分比。
图11a-b显示了NA1-S(图11a)或NA3-S(图11b)和IMAB362在Fab-ZAP存在下对CLDN18.2-HEK293T的细胞杀伤效率,其中试验以hIgG和Fab-ZAP作为对照,而Fab-ZAP与细胞长时间孵育也对细胞具有一定的毒性作用。
图12显示了NA3-S在序列经过人源化修饰前后在CLDN18.2-HEK293T细胞的结合活性,其中NA3S-H1为人源化后分子。
图13比较了高浓度下NA3S-H1和IMAB362在CLDN18.1-HEK293T细胞上的抗体结合强度和抗体结合阳性率。其中,图13a显示了不同浓度的NA3S-H1和IMAB362在CLDN18.1-HEK293T细胞上的结合强度,而图13b显示了高浓度下(100μg/ml),NA3S-H1和IMAB362在CLDN18.1-HEK293T细胞上的结合阳性率,试验都以同种型抗体作为对照。
图14显示了人源化分子NA3S-H1在人CLDN18.2-KATOIII胃癌细胞上的CDC细胞杀伤效率,其中对照抗体为IMAB362。
图15显示了NA3S-H1和IMAB362介导NK细胞在不同靶细胞上的ADCC细胞杀伤效应。其中,图15a显示了以人CLDN18.2-KATOIII为靶细胞,NA3S-H1和IMAB362介导的ADCC细胞杀伤效应;图15b显示了以人CLDN18.2-HEK293T为靶细胞,NA3S-H1和IMAB362介导的ADCC细胞杀伤效应。
发明详述
虽然本发明可以以许多不同的形式来实施,但在此公开的是验证本发明原理的其具体的举例说明性实施方案。应该强调的是,本发明不限于所举例说明的具体实施方案。此外,本文使用的任何章节标题仅用于组织目的,并不被解释为限制所描述的主题。
除非在此另外定义,否则与本发明结合使用的科学和技术术语将具有本领域普通技术人员通常理解的含义。此外,除非上下文另有要求,单数形式的术语应包括复数形式,复数形式的术语应包括单数形式。更具体地,如在本说明书和所附权利要求中所使用的,除非上下文另外明确指出,否则单数形式“一”、“一个”和“该”包括复数指示物。因此,例如,提及“一种蛋白质”包括多种蛋白质;提及“一个细胞”包括细胞的混合物等。在本申请中,除非另有说明,否则使用“或”意指“和/或”。此外,术语“包含”以及其他形式(诸如“包括”和“含有”)的使用不是限制性的。此外,说明书和所附权利要求中提供的范围包括端点和端点之间的所有值。
通常,与本文描述的细胞和组织培养、分子生物学、免疫学、微生物学、遗传学和蛋白质以及核酸化学和杂交有关的术语以及其技术是本领域众所周知和常用的术语。除非另有说明,否则本发明的方法和技术通常根据本领域公知的常规方法进行,并如在本说明书全文中引用和讨论的各种通用和更具体的参考文献中所述进行。参见例如Abbas等人,Cellular and Molecular Immunology,6th ed.,W.B.Saunders Company(2010);SambrookJ.&Russell D.Molecular Cloning:A Laboratory Manual,3rd ed.,Cold Spring HarborLaboratory Press,Cold Spring Harbor,N.Y.(2000);Ausubel等人,Short Protocols inMolecular Biology:A Compendium of Methods from Current Protocols in MolecularBiology,Wiley,John&Sons,Inc.(2002);Harlow and Lane Using Antibodies:ALaboratory Manual,Cold Spring Harbor Laboratory Press,Cold Spring Harbor,N.Y.(1998);和Coligan等人,Short Protocols in Protein Science,Wiley,John&Sons,Inc.(2003)。与本文描述的分析化学,合成有机化学和药物化学有关的术语以及实验室程序和技术是本领域中众所周知和常用的术语。此外,本文使用的任何章节标题仅用于组织目的,并且不被解释为限制所描述的主题。
定义
为了更好地理解本发明,相关术语的定义和解释提供如下。
如本文所用,术语“抗体”或“Ab”通常是指表现出所需生物学或结合活性的任何形式的抗体。它包括但不限于人源化抗体、完全人抗体、嵌合抗体和单结构域抗体。抗体可以包含重链和轻链。重链可分为μ、δ、γ、α和ε,它们分别将抗体的同种型定义为IgM、IgD、IgG、IgA和IgE。每条重链由重链可变区(VH)和重链恒定区(CH)组成。重链恒定区由3个结构域(CH1,CH2和CH3)组成。每条轻链由轻链可变区(VL)和轻链恒定区(CL)组成。VH和VL区可以进一步分为相对保守的区域(称为框架区(FR))和由FR间隔开的高变区(称为互补决定区(CDR))。每个VH和VL由以下顺序的3个CDR和4个FR组成:从N端到C端的FR1,CDR1,FR2,CDR2,FR3,CDR3,FR4。氨基酸在各种区域或结构域中的分布遵循Kabat Sequences of Proteinsof Immunological Interest(National Institutes of Health,Bethesda,Md.(1987and1991))或Chothia&Lesk(1987)J.Mol.Biol.196:901-917;Chothia等人,(1989)Nature342:878-883中的定义。抗体可以具有不同的抗体同种型,例如IgG(包括例如IgG1,IgG2,IgG3或IgG4亚型),IgA1,IgA2,IgD,IgE或IgM抗体。
如本文所用的术语“人源化抗体”是指其中来源于另一种哺乳动物物种如小鼠的种系的CDR序列已被移植到人框架序列上的抗体。可以在人框架序列内进行额外的框架区修饰。
如本文所用的术语“嵌合抗体”广义上是指含有来自一种抗体的一个或多个区和来自一种或多种其他抗体的一个或多个区的工程化抗体。具体而言,嵌合抗体包含衍生自非人动物抗体的可变区和另一抗体的恒定区,例如包含小鼠来源的可变区和人来源的恒定区。嵌合抗体还可指对至少两种不同抗原具有特异性的多特异性抗体。
如本文所用的术语“CLDN18.2结合分子”意指特异性结合CLDN18.2的分子。
如本文所用的术语“CLDN18.2抗体”、“针对CLDN18.2的抗体”、“特异性结合CLDN18.2的抗体”、“特异性靶向CLDN18.2的抗体”、“特异性识别CLDN18.2的抗体”可互换地使用,意指能够与Claudin蛋白CLDN18.2特异性结合的抗体。特别地,在具体实施方案中,意指与人CLDN18.2特异性结合的抗体,特别是与人CLDN18.2特异性结合而不与人CLDN18.1特异性结合的抗体。人CLDN18.2和人CLDN18.1的氨基酸序列分别如SEQ ID NO:15和SEQ IDNO:16所示;小鼠CLDN18.2和小鼠CLDN18.1的氨基酸序列分别如SEQ ID NO:17和SEQ IDNO:18所示。
如本文所用的术语“免疫球蛋白单可变结构域”或“ISV”在本文中通常定义为这样的氨基酸序列:其包含免疫球蛋白折叠或在适合的条件下(如生理条件下)能够形成免疫球蛋白折叠(即通过折叠),即从而形成免疫球蛋白可变结构域(例如,VH,VL或VHH结构域);和形成(或在适合的条件下能够形成)免疫球蛋白可变结构域,其包含功能性抗原结合位点(在其不需要与另一个免疫球蛋白可变结构域相互作用(如VH-VL相互作用)以形成功能性抗原结合位点的意义上)。
如本文所用的术语“Ka”旨在表示特定抗体-抗原相互作用的缔合速率,而本文所用的术语“Kd”旨在表示特定抗体-抗原相互作用的解离速率。如本文所用,术语“KD”或“KD值”旨在表示特定抗体-抗原相互作用的解离常数,其从Kd与Ka的比率(即,Kd/Ka)获得并且表示为摩尔浓度(M)。抗体的KD值可以使用本领域良好建立的方法来确定。确定抗体KD值的优选方法是通过使用表面等离子体共振,优选使用生物传感器***如***。
如本文所用的术语“特异性结合”或“特异性结合至”是指两个分子之间例如抗体和抗原之间的非随机结合反应。
如本文所用,“抑制结合”、“阻断结合”或“竞争相同表位”的能力是指抗体抑制两个分子的结合至任何可检测的程度的能力。在一些实施方案中,阻断两个分子之间结合的抗体将两个分子之间的结合相互作用抑制至少50%。在一些实施方案中,该抑制可以大于60%,大于70%,大于80%或大于90%。
如本文所用的术语“高亲和力”的抗体是指针对靶抗原具有1×10-7M或更低,更优选5×10-8M或更低,甚至更优选1×10-8M或更低,甚至更优选5×10-9M或更低,和甚至更优选1×10-9M或更低的KD值的抗体。
如本文所用的术语“EC50”,也被称为“半数有效浓度”,是指在特定的暴露时间后诱导在基线和最大值之间的50%的应答的药物、抗体或毒剂的浓度。在本申请的上下文中,EC50的单位为“nM”。如本文所用,术语“表位”是指免疫球蛋白或抗体特异性结合的抗原部分。“表位”也被称为“抗原决定簇”。表位或抗原决定簇通常由分子例如氨基酸、碳水化合物或糖侧链的化学活性表面基团组成,并且通常具有特定的三维结构和特定的电荷特征。例如,表位通常包含独特立体构象中的至少3、4、5、6、7、8、9、10、11、12、13、14或15个连续或不连续的氨基酸,其可以是“线性表位”或“构象表位”。参见例如Epitope Mapping Protocolsin Methods in Molecular Biology,Vol.66,G.E.Morris,Ed.(1996)。在线性表位中,蛋白质和相互作用分子(例如抗体)之间的所有相互作用位点沿蛋白质的一级氨基酸序列线性存在。在构象表位中,相互作用位点跨越蛋白质中彼此分离的氨基酸残基。取决于通过本领域技术人员已知的常规技术检测的结合相同表位的竞争性,可以筛选抗体。例如,可以进行竞争或交叉竞争研究以获得彼此竞争或交叉竞争结合抗原(例如CLDN18.2)的抗体。在国际专利申请WO 03/048731中描述了用于获得结合相同表位的抗体的高通量方法,其基于它们的交叉竞争。
如本文所用,术语“分离的”是指通过人工方式从天然状态获得的物质或组分的状态。如果某种“分离的”物质或组分天然存在,则可能是因为其所处的天然环境发生了变化,或者从天然环境下分离出该物质或组分,或者两者兼而有之。例如,某种未分离的多核苷酸或多肽天然存在于某个活体动物体内,从该天然状态分离的相同的高纯度多核苷酸或多肽被称为分离的多核苷酸或多肽。术语“分离的”既不排除混合的人造或合成物质,也不排除不影响分离的物质的活性的其他不纯物质。
如本文所用,术语“分离的抗体”旨在指基本上不含具有不同抗原特异性的其他抗体的抗体。此外,分离的抗体可以基本上不含其他细胞材料和/或化学物质。
如本文所用,术语“载体”是指可以在其中***多核苷酸的核酸媒介物。当载体允许***其中的多核苷酸编码的蛋白质的表达时,该载体称为表达载体。该载体可以通过转化、转导或转染入宿主细胞而使携带的遗传物质元件在宿主细胞中表达。载体是本领域技术人员所熟知的,包括但不限于质粒,噬菌体,粘粒,人工染色体如酵母人工染色体(YAC)、细菌人工染色体(BAC)或P1衍生人工染色体(PAC),噬菌体如λ噬菌体或M13噬菌体和动物病毒。可用作载体的动物病毒包括但不限于逆转录病毒(包括慢病毒),腺病毒,腺伴随病毒,疱疹病毒(如单纯疱疹病毒),痘病毒,杆状病毒,***瘤病毒,乳多空病毒(如SV40)。载体可以包含用于控制表达的多个元件,包括但不限于启动子序列,转录起始序列,增强子序列,选择元件和报道基因。另外,载体可以包含复制起点。
如本文所用,术语“宿主细胞”是指可以导入载体的任何种类的细胞***,包括但不限于原核细胞如大肠杆菌(E.coli)或枯草芽孢杆菌(Bacillus subtilis),真菌细胞如酵母细胞或曲霉属(Aspergillus),昆虫细胞如S2果蝇细胞或Sf9,以及动物细胞如成纤维细胞,CHO细胞,COS细胞,NSO细胞,HeLa细胞,BHK细胞,HEK293细胞或人细胞。
利用宿主细胞生产本发明的抗体的方法是本领域常规的,包括在原核或真核细胞中表达抗体,然后分离抗体,并通常纯化至可药用的纯度。如在一些实施方案中,通过本领域已知的标准技术将编码抗体的核酸***到表达载体并将表达载体导入合适的原核或真核宿主细胞,在足以产生本发明的抗体或其功能性片段的条件和时间下培养宿主细胞,如CHO细胞、NSO细胞、SP2/0细胞、HEK293细胞、COS细胞、PER.C6(R)细胞、酵母或大肠杆菌细胞,并从细胞(裂解后的上清液或细胞)中回收抗体及对抗体进行纯化。用于生产抗体的常规方法是本领域现有技术已知的,描述在例如Makrides,S.C.,Protein Expr.Purif.17(1999)183-202;Geisse,S.等人,Protein Expr.Purif.8(1996)271-282;Kaufman,R.J.,Mol.Biotechnol.16(2000)151-160;Werner,R.G.,Drug Res.48(1998)870-880的综述文章中。
如本文所用,术语“同一性”是指通过比对和比较序列确定的两个或更多个多肽分子或两个或更多个核酸分子的序列之间的关系。“百分比同一性”是指比较分子中氨基酸或核苷酸之间相同残基的百分比,并基于被比较的最小分子的大小计算。对于这些计算,比对中的间隙(如果有的话)优选通过特定的数学模型或计算机程序(即“算法”)来寻址。可以用于计算比对的核酸或多肽的同一性的方法包括在Computational Molecular Biology,(Lesk,A.M.,ed.),1988,New York:Oxford University Press;BiocomputingInformatics and Genome Projects,(Smith,D.W.,ed.),1993,New York:AcademicPress;Computer Analysis of Sequence Data,Part I,(Griffin,A.M.,and Griffin,H.G.,eds.),1994,New Jersey:Humana Press;von Heinje,G.,1987,Sequence Analysisin Molecular Biology,New York:Academic Press;Sequence Analysis Primer,(Gribskov,M.and Devereux,J.,eds.),1991,New York:M.Stockton Press;和Carillo等人,1988,SIAMJ.Applied Math.48:1073中描述的那些。
如本文所用,术语“免疫原性”是指刺激生物体中特异性抗体或致敏淋巴细胞形成的能力。它不仅指抗原刺激特定免疫细胞活化、增殖和分化以最终产生免疫效应物质如抗体和致敏淋巴细胞的性质,还指抗体或致敏T淋巴细胞的特异性免疫应答可以在用抗原刺激生物体后在生物体的免疫***中形成。免疫原性是抗原最重要的特性。抗原是否能够成功诱导宿主中免疫应答的产生取决于三个因素:抗原的性质,宿主的反应性和免疫手段。
如本文所用,术语“转染”是指将核酸引入真核细胞特别是哺乳动物细胞的过程。用于转染的方案和技术包括但不限于脂质转染,化学和物理方法转染如电穿孔。许多转染技术在本领域是公知的,参见例如Graham等人,1973,Virology 52:456;Sambrook等人,2001,Molecular Cloning:A Laboratory Manual;Davis等人,1986,Basic Methods inMolecular Biology,Elsevier;Chu et al,1981,Gene 13:197。
如本文所用,术语“荧光激活细胞分选”或“FACS”是指专门类型的流式细胞术。它提供了根据每个细胞的特定光散射和荧光特征,将生物细胞的异质混合物以每次一个细胞分拣到两个或更多个容器中的方法(FlowMetric.“Sorting Out Fluorescence ActivatedCell Sorting”.2017-11-09)。用于进行FACS的仪器是本领域技术人员已知的并且对于公众是可商购获得的。这种仪器的实例包括Becton Dickinson(Foster City,CA)的FACSStar Plus、FACScan和FACSort仪器、来自Coulter Epics Division(Hialeah,FL)的EpicsC和来自Cytomation(Colorado Springs,Colorado)的MoFlo。
术语“受试者”包括任何人或非人动物,优选人。
如本文所用,术语“与CLDN18.2相关的病症”是指由CLDN18.2(如人CLDN18.2)的增加或减少的表达或活性引起、加重或以其它方式与其相关的任何病症。
如本文所用,术语“癌症”是指引发医学病症的任何肿瘤或恶性细胞生长、增殖或转移介导的实体瘤或非实体瘤如白血病。
本文在治疗病情的情况中使用的术语“治疗”一般涉及人或动物的治疗和疗法,其中实现了一些期望的治疗效果,例如,抑制病情进展,包括进展速度下降,进展速度停滞,病情消退,病情改善和病情治愈。还包括了作为预防措施(即预防)的治疗。对于癌症,“治疗”可能是指抑制或减缓肿瘤或恶性细胞生长、增殖或转移或其某种组合。对于肿瘤,“治疗”包括去除全部或部分肿瘤、抑制或减缓肿瘤生长和转移、预防或延迟肿瘤的发展或其某种组合。
如本文所用,术语“治疗有效量”涉及活性化合物或包含活性化合物的材料、组合物或剂型的量,其在按照所需的治疗方案施用时有效用于产生与合理的益处/风险比相称的某些所需的治疗效果。具体而言,“治疗有效量”意指抗体或其抗原结合部分有效治疗与CLDN18.2相关的病症的量或浓度。
如本文所用,术语“药学上可接受”是指载体、稀释剂、赋形剂和/或其盐在化学和/或物理上与制剂中的其他成分相容,并且与接受者在生理学上相容。
如本文所用,术语“药学上可接受的载体和/或赋形剂”是指在药理学和/或生理学上与受试者和活性剂相容的载体和/或赋形剂,其在本领域中是公知的(参见例如,Remington's Pharmaceutical Sciences.Edited by Gennaro AR,19thed.Pennsylvania:Mack Publishing Company,1995),并且包括但不限于pH调节剂,表面活性剂,佐剂和离子强度增强剂。例如,pH调节剂包括但不限于磷酸盐缓冲液;表面活性剂包括但不限于阳离子、阴离子或非离子表面活性剂,例如Tween-80;离子强度增强剂包括但不限于氯化钠。
如本文所用,术语“佐剂”是指非特异性免疫增强剂,其在与抗原一起递送至生物体或被提前递送至生物体时可以增强生物体中的对抗原的免疫应答或改变免疫应答的类型。现有技术中存在多种佐剂,包括但不限于铝佐剂(例如氢氧化铝),弗氏佐剂(例如弗氏完全佐剂和弗氏不完全佐剂),短小棒状杆菌,脂多糖,细胞因子等。弗氏佐剂是目前动物实验中最常用的佐剂。氢氧化铝佐剂更常用于临床试验。
CLDN18.2结合分子
在一些方面,本公开包含CLDN18.2结合分子。
一般来说,CLDN18.2结合分子可以包括任何特异性结合CLDN18.2的分子。在一些情况下,“CLDN18.2结合分子”可以包括“CLDN18.2拮抗剂”。CLDN18.2结合分子或CLDN18.2拮抗剂可以是多肽或蛋白质,例如抗体,更具体地说是特异性结合CLDN18.2(如人CLDN18.2)的抗体。
抗体包括但不限于嵌合抗体、人源化抗体或单结构域抗体等。在具体的实施方案中,CLDN18.2结合分子是单结构域抗体,其通常是指由单个单体可变抗体结构域组成的抗体。像整个抗体一样,单结构域抗体能够选择性结合特定抗原。
更具体而言,CLDN18.2结合分子是重链单结构域抗体,其可与术语“VHH”、“VHH抗体”、“VHH结构域”、“VHH抗体片段”、“VHH”或“纳米抗体”等互换使用。来自骆驼科抗体的VHH分子是已知的最小完整抗原结合结构域之一(约15KDa,或是常规IgG的1/10),因此非常适合递送至致密组织和进入大分子之间的有限空间。
本文公开的单结构域抗体可由本领域技术人员根据本领域已知的方法或任何未来的方法制备。例如,可以使用本领域已知的方法获得VHH,例如通过免疫骆驼并从中获得与靶抗原结合并中和靶抗原的VHH,或者通过使用本领域已知的分子生物学技术克隆本发明的VHH的文库,然后通过使用噬菌体展示进行选择。在一些实施方案中,本发明的单结构域抗体在骆驼科动物中天然产生,即,使用本文对于其它抗体描述的技术,用CLDN18.2或其片段免疫骆驼来生产。
在一些实施方案中,通过用所需抗原免疫美洲驼或羊驼并随后分离编码重链抗体的mRNA来获得单结构域抗体。通过逆转录和聚合酶链反应,产生含有数百万克隆的单结构域抗体的基因文库。筛选技术如噬菌体展示和核糖体展示有助于鉴定结合抗原的克隆。其中噬菌体展示是在噬菌体上合成抗体文库,用感兴趣的抗原或其抗体结合部分筛选文库,并分离结合抗原的噬菌体,从其中可以获得免疫反应性片段。用于制备和筛选这种文库的方法是本领域众所周知的,并且用于产生噬菌体展示文库的试剂盒可商购获得(例如,Pharmacia重组噬菌体抗体***,目录号27-9400-01;以及Stratagene SurfZAPTM噬菌体展示试剂盒,目录号240612)。还有其他方法和试剂可用于产生和筛选抗体展示文库(参见例如Barbas等人,Proc.Natl.Acad.Sci.USA88:7978-7982(1991))。
当最有效的克隆被鉴定时,可通过例如亲和力成熟或人源化优化其DNA序列,以防止人体对抗抗体的免疫反应。
因此,可通过以下方式获得本发明的单结构域抗体:(1)分离天然存在的重链抗体的VHH结构域;(2)通过表达编码天然存在的VHH结构域的核苷酸序列;(3)通过天然存在的VHH结构域的“人源化”或通过表达编码这种人源化VHH结构域的核酸;(4)通过来自任何动物物种,特别是哺乳动物物种,例如来自人的天然存在的VH结构域的“骆驼化”,或通过表达编码这种骆驼化VH结构域的核酸;(5)通过“结构域抗体”或“dAb”的“骆驼化”(参见例如Ward等人,1989,Nature 341:544-546),或通过表达编码这种骆驼化VH结构域的核酸;(6)通过使用合成或半合成技术制备蛋白质、多肽或其他氨基酸序列;(7)通过使用用于核酸合成的技术制备编码VHH的核酸,然后表达由此获得的核酸;和/或(8)通过前述的任何组合。基于本文的公开内容,用于执行前述内容的合适方法和技术对于本领域技术人员将是清楚的,并且包括例如下文更详细描述的方法和技术。
单结构域抗体通常通过从免疫动物获得的血液、***或脾淋巴细胞的cDNA经PCR克隆可变结构域库至噬菌体展示载体中而产生。通常通过在固定化抗原(例如涂布在试管塑料表面的抗原,固定在链霉抗生物素蛋白珠上的生物素化抗原或细胞表面上表达的膜蛋白)上淘选相应文库来选择抗原特异性单结构域抗体。通过体外模拟该策略可以提高sdAb的亲和力,例如通过CDR区的定点诱变和在增加的严格条件(更高温度,高或低盐浓度,高或低pH和低抗原浓度)下对固定化抗原进行进一步的淘选(Wesolowski等人.,Singledomain antibodies:promising experimental and therapeutic tools in infectionand immunity.Med Microbiol Immunol(2009)198:157-174)。
用于制备特异性结合抗原或表位的VHH的方法描述于参考文献中,参见例如:R.van der Linden等人.,Journal of Immunological Methods,240(2000)185-195;Li等人.,J Biol Chem.,287(2012)13713-13721;Deffar等人.,African Journal ofBiotechnology Vol.8(12),pp.2645,17June,2009和WO94/04678。
在一些实施方案中,CLDN18.2结合分子中的VHH与抗体的Fc结构域(例如IgG(例如IgG1或IgG4)的Fc结构域)融合。通过将VHH融合至Fc结构域,可以更有效地募集效应功能,例如ADCC和CDC。而且,VHH与Fc结构域的融合可以帮助CLDN18.2结合分子形成二聚体,并且还可以帮助延长CLDN18.2结合分子的体内半衰期。
如本文所用,术语“抗体依赖的细胞介导的细胞毒性作用”或“ADCC”是指与某些细胞毒性效应细胞(例如天然杀伤(NK)细胞,嗜中性粒细胞和巨噬细胞)上存在的Fc受体(FcR)结合的分泌的抗体使这些细胞毒性效应细胞能够特异性结合携带抗原的靶细胞并随后用细胞毒素杀死靶细胞的细胞毒性形式。抗体“武装”细胞毒性细胞对于这种杀伤是绝对需要的。介导ADCC的主要细胞NK细胞仅表达FcγRIII,而单核细胞表达FcγRI,FcγRII和FcγRIII。造血细胞上的FcR表达总结在Ravetch and Kinet,Annu.Rev.Immunol 9:457-92(1991)的464页的表3中。为了评估感兴趣分子的ADCC活性,可以进行体外ADCC测定,例如美国专利US5500362或US5821337中所述的测定方法。可用于此类测定的效应细胞包括外周血单核细胞(PBMC)和自然杀伤(NK)细胞。可选或另外地,感兴趣分子的ADCC活性可以在体内评估,例如在如Clynes等人PNAS(USA)95:652-656(1998)公开的动物模型中评估。
术语“补体依赖的细胞毒性作用”或“CDC”是指在补体存在下靶细胞的裂解。经典补体途径的激活由补体***的第一组分(C1q)与结合其同源抗原的抗体(适当的亚类)结合而启动。为了评估补体活化,可以执行CDC测定,通过例如Gazzano-Santoro等人,J.Immunol.Methods 202:163(1996)中所述的方法。
为了便于描述,在下文中将CLDN18.2结合分子描述为CLDN18.2抗体。
能够特异性结合CLDN18.2的特定表位的CLDN18.2抗体
在一个方面,本发明涉及特异性结合CLDN18.2、而不结合或基本不结合CLDN18.1的单结构域抗体。
本发明人首次发现,能够特异性结合人CLDN18.2的胞外结构域1(ECD1)的CLDN18.2结合分子(如靶向CLDN18.2的单结构域抗体)。
如前所述,CLDN18.2有两个胞外结构域(ECD),其中人CLDN18.2的全长序列如SEQID NO:15所示。其中,ECD1为SEQ ID NO:15的第28-80位氨基酸,如SEQ ID NO:19所示。
SEQ ID NO:15:
MAVTACQGLGFVVSLIGIAGIIAATCMDQWSTQDLYNNPVTAVFNYQGLWRSCVRESSGFTECRGYFTLLGLPAMLQAVRALMIVGIVLGAIGLLVSIFALKCIRIGSMEDSAKANMTLTSGIMFIVSGLCAIAGVSVFANMLVTNFWMSTANMYTGMGGMVQTVQTRYTFGAALFVGWVAGGLTLIGGVMMCIACRGLAPEETNYKAVSYHASGHSVAYKPGGFKASTGFGSNTKNKKIYDGGARTEDEVQSYPSKHDYV
SEQ ID NO:19:
DQWSTQDLYNNPVTAVFNYQGLWRSCVRESSGFTECRGYFTLLGLPAMLQAVR
此外,小鼠CLDN18.2如SEQ ID NO:17所示。
SEQ ID NO:17:
MSVTACQGLGFVVSLIGFAGIIAATCMDQWSTQDLYNNPVTAVFNYQGLWRSCVRESSGFTECRGYFTLLGLPAMLQAVRALMIVGIVLGVIGILVSIFALKCIRIGSMDDSAKAKMTLTSGILFIISGICAIIGVSVFANMLVTNFWMSTANMYSGMGGMGGMVQTVQTRYTFGAALFVGWVAGGLTLIGGVMMCIACRGLTPDDSNFKAVSYHASGQNVAYRPGGFKASTGFGSNTRNKKIYDGGARTEDDEQSHPTKYDYV
对于人和小鼠的CLDN18.1而言,其序列分别如SEQ ID NO:16和SEQ ID NO:18所示。
SEQ ID NO:16:
MSTTTCQVVAFLLSILGLAGCIAATGMDMWSTQDLYDNPVTSVFQYEGLWRSCVRQSSGFTECRPYFTILGLPAMLQAVRALMIVGIVLGAIGLLVSIFALKCIRIGSMEDSAKANMTLTSGIMFIVSGLCAIAGVSVFANMLVTNFWMSTANMYTGMGGMVQTVQTRYTFGAALFVGWVAGGLTLIGGVMMCIACRGLAPEETNYKAVSYHASGHSVAYKPGGFKASTGFGSNTKNKKIYDGGARTEDEVQSYPSKHDYV
SEQ ID NO:18:
MATTTCQVVGLLLSLLGLAGCIAATGMDMWSTQDLYDNPVTAVFQYEGLWRSCVQQSSGFTECRPYFTILGLPAMLQAVRALMIVGIVLGVIGILVSIFALKCIRIGSMDDSAKAKMTLTSGILFIISGICAIIGVSVFANMLVTNFWMSTANMYSGMGGMGGMVQTVQTRYTFGAALFVGWVAGGLTLIGGVMMCIACRGLTPDDSNFKAVSYHASGQNVAYRPGGFKASTGFGSNTRNKKIYDGGARTEDDEQSHPTKYDYV
包含与特定序列具有序列同一性的CDR的CLDN18.2抗体
在一些实施方案中,本公开的CLDN18.2抗体包含至少一个免疫球蛋白单可变结构域(例如VHH),其中所述VHH包含CDR1、CDR2和CDR3,并且其中CDR1包含与SEQ ID NO:1至少80%相同的氨基酸序列,CDR2包含与SEQ ID NO:2至少80%相同的氨基酸序列,和CDR3包含与SEQ ID NO:3至少80%相同的氨基酸序列。
除非另有说明,否则将氨基酸分配给每个CDR可以根据以下提供的编号方案之一:Kabat等人(1991)Sequences of Proteins of Immunological Interest(5th Ed.),USDept.of Health and Human Services,PHS,NIH,NIH Publication no.91-3242;Chothia等人,1987,PMID:3681981;Chothia等人,1989,PMID:2687698;MacCallum等人,1996,PMID:8876650;或Dubel,Ed.(2007)Handbook of Therapeutic Antibodies,3rd Ed.,Wily-VCHVerlag GmbH and Co.。
抗体序列中的可变区和CDR可以根据本领域已经开发的一般规则(如上所述,例如Kabat编号***)或通过将序列与已知可变区的数据库比对来鉴定。在Kontermann andDubel,eds.,Antibody Engineering,Springer,New York,NY,2001和Dinarello等人,Current Protocols in Immunology,John Wiley and Sons Inc.,Hoboken,NJ,2000中描述了鉴定这些区域的方法。抗体序列的示例性数据库描述于并可获自www.bioinf.org.uk/abs上的“Abysis”网站(由Department of Biochemistry&Molecular Biology UniversityCollege London,London,England的A.C.Martin维护)和VBASE2网站www.vbase2.org,如Retter等人,Nucl.Acids Res.,33(Database issue):D671-D674(2005)中所述。优选使用Abysis数据库分析序列,其整合了来自Kabat、IMGT和蛋白质数据库(PDB)的序列数据与来自PDB的结构数据,参见Dr.Andrew C.R.Martin所著的书中的Protein Sequence andStructure Analysis of Antibody Variable Domains.In:Antibody Engineering LabManual(Ed.:Duebel,S.and Kontermann,R.,Springer-Verlag,Heidelberg,ISBN-13:978-3540413547,也可在网站bioinforg.uk/abs上获得)。Abysis数据库网站还包括已经开发用于识别可以根据本文的教导使用的CDR的一般规则。
两个氨基酸序列之间的百分比同一性可以使用E.Meyers和W.Miller的算法(Comput.Appl.Biosci.,4:11-17(1988))确定,该算法已被并入ALIGN程序(版本2.0),使用PAM120权重残基表,空位长度罚分为12,空位罚分为4。另外,两个氨基酸序列之间的百分比同一性可以通过Needleman和Wunsch的算法(J.Mol.Biol.48:444-453(1970))确定,其已并入GCG软件包(可从http://www.gcg.com获得)中的GAP程序中,使用Blossum 62矩阵或PAM250矩阵,空隙权重为16、14、12、10、8、6或4,长度权重为1、2、3、4、5或6。
另外地或可选地,本发明的蛋白质序列可以进一步用作“查询序列”来执行针对公共数据库的搜索以例如识别相关序列。这种搜索可以使用Altschul,等人(1990)J.MoI.Biol.215:403-10的XBLAST程序(版本2.0)来执行。可用XBLAST程序进行BLAST蛋白质搜索,得分=50,字长=3,以获得与本发明的抗体分子同源的氨基酸序列。为了获得用于比较目的的空位比对,可使用空位BLAST,如Altschul等人,(1997)Nucleic Acids Res.25(17):3389-3402中所述的。当使用BLAST和空位BLAST程序时,可以使用各个程序(例如,XBLAST和NBLAST)的默认参数,参见www.ncbi.nlm.nih.gov。
在另一些实施方案中,CDR的氨基酸序列可以与上文给出的各个序列至少85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同。
包含具有氨基酸添加、缺失或取代的CDR的CLDN18.2抗体
在一些实施方案中,本公开的CLDN18.2抗体包含至少一个免疫球蛋白单可变结构域(例如VHH),其中所述VHH包含CDR1、CDR2和CDR3,并且其中CDR1在氨基酸序列上与SEQ IDNO:1存在不超过2个氨基酸的氨基酸添加、缺失或取代的差异;CDR2在氨基酸序列上与SEQID NO:2存在不超过2个氨基酸的氨基酸添加、缺失或取代的差异;和/或CDR3在氨基酸序列上与SEQ ID NO:3存在不超过2个氨基酸的氨基酸添加、缺失或取代的差异。例如,CDR1、CDR2和CDR3分别与SEQ ID NO:1、SEQ ID NO:2和SEQ ID NO:3所示的氨基酸序列存在仅一个氨基酸的氨基酸添加、缺失或取代的差异。
优选地,分离的抗体或其抗原结合部分的CDR含有不多于2个氨基酸或不多于1个氨基酸的保守取代。如本文所用,术语“保守取代”是指不会不利地影响或改变包含氨基酸序列的蛋白质/多肽的基本性质的氨基酸取代。例如,保守取代可以通过本领域已知的标准技术(例如定点诱变和PCR介导的诱变)引入。保守氨基酸取代包括其中氨基酸残基被具有相似侧链的另一氨基酸残基取代的取代,例如物理或功能相似的残基(例如具有相似的大小,形状,电荷,化学性质包括形成共价键或氢键的能力等)被相应的氨基酸残基的取代。本领域已经定义了具有相似侧链的氨基酸残基家族。这些家族包括具有碱性侧链的氨基酸(例如赖氨酸,精氨酸和组氨酸),具有酸性侧链的氨基酸(例如天冬氨酸和谷氨酸),具有不带电荷的极性侧链的氨基酸(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,色氨酸),具有非极性侧链的氨基酸(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),具有β-分支侧链的氨基酸(例如苏氨酸,缬氨酸,异亮氨酸)和具有芳香族侧链的氨基酸(例如酪氨酸,苯丙氨酸,色氨酸,组氨酸)。因此,相应的氨基酸残基优选被来自相同侧链家族的另一个氨基酸残基取代。用于鉴定氨基酸保守取代的方法在本领域中是公知的(参见例如Brummell等人,Biochem.32:1180-1187(1993);Kobayashi等人,Protein Eng.12(10):879-884(1999);和Burks等人,Proc.Natl.Acad.Sci.USA 94:412-417(1997),其通过引用并入本文)。
在某些实施方案中,CLDN18.2抗体的免疫球蛋白单可变结构域包含:
i)如SEQ ID NO:1所示的氨基酸序列的CDR1;
ii)如式ISRGGX1T所示的氨基酸序列的CDR2,其中X1为T或S;和
iii)如式NAQAWDX2GTX3RYLEV所示的氨基酸序列的CDR3,其中X2为P或V,X3为F或I。
在某些实施方案中,CLDN18.2抗体的免疫球蛋白单可变结构域包含:
i)如SEQ ID NO:30、33、34、35、36、38、39或40所示的氨基酸序列的CDR1;
ii)如式X4STGGTT所示的氨基酸序列的CDR2,其中X4为I或M;和
iii)如式NVLVX5SGIGSX6LEV所示的氨基酸序列的CDR3,其中X5为I或V,X6为H或T。
包含CDR的CLDN18.2抗体
在一些实施方案中,本公开的CLDN18.2抗体包含至少一个免疫球蛋白单可变结构域(例如VHH),其中所述VHH包含CDR1、CDR2和CDR3,并且其中CDR1、CDR2和CDR3选自:
(a)包含SEQ ID NO:1所示的氨基酸序列的CDR1,包含SEQ ID NO:2所示的氨基酸序列的CDR2和包含SEQ ID NO:3所示的氨基酸序列的CDR3;
(b)包含SEQ ID NO:1所示的氨基酸序列的CDR1,包含SEQ ID NO:4所示的氨基酸序列的CDR2和包含SEQ ID NO:5所示的氨基酸序列的CDR3;或
(c)包含SEQ ID NO:1所示的氨基酸序列的CDR1,包含SEQ ID NO:2所示的氨基酸序列的CDR2和包含SEQ ID NO:6所示的氨基酸序列的CDR3。
在一些实施方案中,本公开的CLDN18.2抗体包含至少一个免疫球蛋白单可变结构域(例如VHH),其中所述VHH包含CDR1、CDR2和CDR3,并且其中CDR1、CDR2和CDR3选自:
(a)包含SEQ ID NO:30所示的氨基酸序列的CDR1,包含SEQ ID NO:31所示的氨基酸序列的CDR2和包含SEQ ID NO:32所示的氨基酸序列的CDR3;
(b)包含SEQ ID NO:30所示的氨基酸序列的CDR1,包含SEQ ID NO:31所示的氨基酸序列的CDR2和包含SEQ ID NO:37所示的氨基酸序列的CDR3;
(c)包含SEQ ID NO:33所示的氨基酸序列的CDR1,包含SEQ ID NO:31所示的氨基酸序列的CDR2和包含SEQ ID NO:62所示的氨基酸序列的CDR3;
(d)包含SEQ ID NO:33所示的氨基酸序列的CDR1,包含SEQ ID NO:31所示的氨基酸序列的CDR2和包含SEQ ID NO:37所示的氨基酸序列的CDR3;
(e)包含SEQ ID NO:34所示的氨基酸序列的CDR1,包含SEQ ID NO:31所示的氨基酸序列的CDR2和包含SEQ ID NO:37所示的氨基酸序列的CDR3;
(f)包含SEQ ID NO:35所示的氨基酸序列的CDR1,包含SEQ ID NO:31所示的氨基酸序列的CDR2和包含SEQ ID NO:62所示的氨基酸序列的CDR3;
(g)包含SEQ ID NO:36所示的氨基酸序列的CDR1,包含SEQ ID NO:31所示的氨基酸序列的CDR2和包含SEQ ID NO:62所示的氨基酸序列的CDR3;
(h)包含SEQ ID NO:38所示的氨基酸序列的CDR1,包含SEQ ID NO:31所示的氨基酸序列的CDR2和包含SEQ ID NO:62所示的氨基酸序列的CDR3;
(i)包含SEQ ID NO:39所示的氨基酸序列的CDR1,包含SEQ ID NO:41所示的氨基酸序列的CDR2和包含SEQ ID NO:37所示的氨基酸序列的CDR3;或
(j)包含SEQ ID NO:40所示的氨基酸序列的CDR1,包含SEQ ID NO:31所示的氨基酸序列的CDR2和包含SEQ ID NO:37所示的氨基酸序列的CDR3。
在一些实施方案中,本公开的CLDN18.2抗体包含至少一个免疫球蛋白单可变结构域(例如VHH),其中所述VHH包含CDR1、CDR2和CDR3,并且其中CDR1、CDR2和CDR3选自:
(a)如SEQ ID NO:1所示的氨基酸序列的CDR1,如SEQ ID NO:2所示的氨基酸序列的CDR2和如SEQ ID NO:3所示的氨基酸序列的CDR3;
(b)如SEQ ID NO:1所示的氨基酸序列的CDR1,如SEQ ID NO:4所示的氨基酸序列的CDR2和如SEQ ID NO:5所示的氨基酸序列的CDR3;或
(c)如SEQ ID NO:1所示的氨基酸序列的CDR1,如SEQ ID NO:2所示的氨基酸序列的CDR2和如SEQ ID NO:6所示的氨基酸序列的CDR3。
在一些实施方案中,本公开的CLDN18.2抗体包含至少一个免疫球蛋白单可变结构域(例如VHH),其中所述VHH包含CDR1、CDR2和CDR3,并且其中CDR1、CDR2和CDR3选自:
(a)如SEQ ID NO:30所示的氨基酸序列的CDR1,如SEQ ID NO:31所示的氨基酸序列的CDR2和如SEQ ID NO:32所示的氨基酸序列的CDR3;
(b)如SEQ ID NO:30所示的氨基酸序列的CDR1,如SEQ ID NO:31所示的氨基酸序列的CDR2和如SEQ ID NO:37所示的氨基酸序列的CDR3;
(c)如SEQ ID NO:33所示的氨基酸序列的CDR1,如SEQ ID NO:31所示的氨基酸序列的CDR2和如SEQ ID NO:62所示的氨基酸序列的CDR3;
(d)如SEQ ID NO:33所示的氨基酸序列的CDR1,如SEQ ID NO:31所示的氨基酸序列的CDR2和如SEQ ID NO:37所示的氨基酸序列的CDR3;
(e)如SEQ ID NO:34所示的氨基酸序列的CDR1,如SEQ ID NO:31所示的氨基酸序列的CDR2和如SEQ ID NO:37所示的氨基酸序列的CDR3;
(f)如SEQ ID NO:35所示的氨基酸序列的CDR1,如SEQ ID NO:31所示的氨基酸序列的CDR2和如SEQ ID NO:62所示的氨基酸序列的CDR3;
(g)如SEQ ID NO:36所示的氨基酸序列的CDR1,如SEQ ID NO:31所示的氨基酸序列的CDR2和如SEQ ID NO:62所示的氨基酸序列的CDR3;
(h)如SEQ ID NO:38所示的氨基酸序列的CDR1,如SEQ ID NO:31所示的氨基酸序列的CDR2和如SEQ ID NO:62所示的氨基酸序列的CDR3;
(i)如SEQ ID NO:39所示的氨基酸序列的CDR1,如SEQ ID NO:41所示的氨基酸序列的CDR2和如SEQ ID NO:37所示的氨基酸序列的CDR3;和
(j)如SEQ ID NO:40所示的氨基酸序列的CDR1,如SEQ ID NO:31所示的氨基酸序列的CDR2和如SEQ ID NO:37所示的氨基酸序列的CDR3。
通过VHH序列定义的CLDN18.2抗体
在一些实施方案中,本公开的CLDN18.2抗体包含至少一个(例如,一个)免疫球蛋白单可变结构域(例如VHH),其中所述VHH包含:
(A)SEQ ID NO:7、47或63所示的氨基酸序列;
(B)与SEQ ID NO:7、47或63至少80%、85%、90%或95%相同的氨基酸序列;或
(C)与SEQ ID NO:7、47或63相比具有一个或多个(例如,1、2、3、4、5、6、7、8、9或10个)氨基酸的添加、缺失和/或取代的氨基酸序列。
在一些实施方案中,本公开的CLDN18.2抗体包含至少一个(例如,一个)免疫球蛋白单可变结构域(例如VHH),其中所述VHH:
(A)由SEQ ID NO:7、47或63所示的氨基酸序列组成;
(B)由与SEQ ID NO:7、47或63至少80%、85%、90%或95%相同的氨基酸序列组成;或
(C)由与SEQ ID NO:7、47或63相比具有一个或多个(例如,1、2、3、4、5、6、7、8、9或10个)氨基酸的添加、缺失和/或取代的氨基酸序列组成。
在其他实施方案中,所述VHH的氨基酸序列可以与上述各个序列至少85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同。作为说明性实例,抗体可以包含与SEQ ID NO:7、47或63具有至少85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%序列同一性的VHH。
在一些进一步的实施方案中,本公开的CLDN18.2抗体可以包含重链可变区中的氨基酸的保守取代或修饰。本领域理解的是,可以进行某些不消除抗原结合性质的保守序列修饰。参见例如Brummell等人(1993)Biochem 32:1180-8;de Wildt等人(1997)Prot.Eng.10:835-41;Komissarov等人(1997)J.Biol.Chem.272:26864-26870;Hall等人(1992)J.Immunol.149:1605-12;Kelley and O’Connell(1993)Biochem.32:6862-35;Adib-Conquy等人(1998)Int.Immunol.10:341-6和Beers等人(2000)Clin.Can.Res.6:2835-43。
在某些实施方案中,本公开的单结构域CLDN18.2抗体在SEQ ID NO:7的以下位点中的一个或多个发生修饰(例如,氨基酸的取代):第1、4、5、14、16、35、47、56、58、65、92、102、105或121位氨基酸。在某些实施方案中,本公开的单结构域CLDN18.2抗体在SEQ IDNO:47的以下位点中的一个或多个发生修饰(例如,氨基酸的取代):第1、4、5、11、27、28、29、30、31、32、35、51、75、76、92、100、106或120位氨基酸。
在某些具体实施方案中,本公开的单结构域CLDN18.2抗体的可变区包含SEQ IDNO:7-14和SEQ ID NO:42-51、63中的任一者。
在某些具体实施方案中,本公开的单结构域CLDN18.2抗体的可变区由SEQ ID NO:7-14和SEQ ID NO:42-51、63中的任一者组成。
编码本公开的抗体的核酸分子
在一些方面,本发明涉及分离的核酸分子,其包含编码本公开的CLDN18.2抗体或其可变区片段的核酸序列。
本发明的核酸可以使用标准分子生物学技术获得。对于从免疫球蛋白基因文库获得的抗体(例如,使用噬菌体展示技术),编码这种抗体的核酸可以从基因文库中回收。
本发明的示例性核酸分子的序列如SEQ ID NO:22-29、SEQ ID NO:52-61和64中任一者所示。
在一些实施方案中,所述核酸分别与SEQ ID NO:22-29和52-61、64中任一者所示的核酸分子具有至少80%(例如至少85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%)的序列同一性。在一些实施方案中,同一性的百分比源自遗传密码的简并性,并且编码的蛋白质序列保持不变。
可以使用本领域已知的重组技术将编码本公开的CLDN18.2抗体的核酸分子***载体以进一步克隆(扩增DNA)或用于表达。许多载体是可用的。载体或载体组分通常包括但不限于以下一种或多种:信号序列,复制起点,一个或多个标记基因,增强子元件,启动子(例如SV40,CMV,EF-1α),和转录终止序列。选择标记基因有助于选择导入了载体的宿主细胞(参见例如美国专利号4,399,216;4,634,665和5,179,017)。例如,通常选择标记基因赋予载体已经导入其中的宿主细胞对药物(例如G418,潮霉素或甲氨蝶呤)的抗性。在一个实施方案中,选择标记基因可以包括二氢叶酸还原酶(DHFR)基因(用于具有甲氨蝶呤选择/扩增的dhfr-宿主细胞)和neo基因(用于G418选择)。在另一个实施方案中,抗体可以通过本领域已知的同源重组产生。编码单克隆抗体的DNA易于使用常规方法分离和测序(例如,通过使用能够与编码抗体重链的基因特异性结合的寡核苷酸探针)。
在一些实施方案中,载体***包括哺乳动物、细菌、酵母***等,并包括质粒,例如,但不限于,pALTER,pBAD,pcDNA,pCal,pL,pET,pGEMEX,pGEX,pCI,pCMV,pEGFP,pEGFT,pSV2,pFUSE,pVITRO,pVIVO,pMAL,pMONO,pSELECT,pUNO,pDUO,Psg5L,pBABE,pWPXL,pBI,p15TV-L,pPro18,pTD,pRS420,pLexA,pACT2.2等等,以及其他实验室和商业可用的载体。合适的载体可以包括质粒或病毒载体(例如复制缺陷型逆转录病毒,腺病毒和腺伴随病毒)。在本发明的一个实施方案中,载体可以是pET,例如含有六组氨酸标签和c-Myc-标签基因的pETbac。
包含编码本公开的CLDN18.2抗体的核酸序列的载体可以被引入宿主细胞用于克隆或基因表达。用于在本文的载体中克隆或表达DNA的合适宿主细胞是原核生物、酵母或高等真核生物细胞。用于该目的的合适原核生物包括真细菌,例如革兰氏阴性或革兰氏阳性生物体,例如肠杆菌科如埃希氏菌属,例如大肠杆菌,肠杆菌属,欧文氏菌属,克雷伯氏菌属,变形杆菌属,沙门氏菌属,例如鼠伤寒沙门氏菌,沙雷氏菌属,例如粘质沙雷氏菌和志贺氏菌,以及芽孢杆菌属如枯草芽孢杆菌和地衣芽孢杆菌,假单胞菌属如铜绿假单胞菌和链霉菌。
除了原核生物以外,真核微生物如丝状真菌或酵母是合适的用于表达本公开的CLDN18.2抗体的宿主细胞。酿酒酵母或普通面包酵母是低等真核宿主微生物中最常用的。然而,许多其它属、种和菌株通常是可获得的并且可用于本发明,例如粟酒裂殖酵母(Schizosaccharomyces pombe);克鲁维酵母属(Kluyveromyces)宿主,例如乳克鲁维酵母(K.lactis)、脆壁克鲁维酵母(K.fragilis)(ATCC 12,424)、保加利亚克鲁维酵母(K.bulgaricus)(ATCC 16,045)、威克曼氏克鲁维酵母(K.wickeramii)(ATCC 24,178)、K.waltii(ATCC 56,500)、果蝇克鲁维酵母(K drosophilarum)(ATCC 36,906)、耐热克鲁维酵母(K.thermotolerans)和马克斯克鲁维氏酵母(K.marxianus);西洋蓍霉(yarrowia)(EP402,226);巴斯德毕赤酵母(pichia pastoris)(EP 183,070);念珠菌属(Candida);Trichoderma reesia(EP 244,234);粗糙链孢霉(Neurospora crassa);许旺氏酵母属(schwanniomyces)如西方许旺氏酵母(schwanniomyces occidentalis);和丝状真菌,例如链孢霉属(Neurospora)、青霉属(Penicillium)、Tolypocladium以及曲霉属宿主如构巢曲霉(A.nidulans)和黑曲霉(A.niger)。
用于表达本公开的CLDN18.2抗体的其他合适的宿主细胞来源于多细胞生物体。无脊椎动物细胞的实例包括植物和昆虫细胞。目前已经从下述宿主中鉴定了大量的杆状病毒株和变体以及相应的容许型昆虫宿主细胞:草地夜蛾(Spodoptera Frugiperda,毛虫)、埃及伊蚊(Aedes aegypti,蚊子)、白纹伊蚊(Aedes albopictus,蚊子)、Drosophilamelanogaster(果蝇)和家蚕蛾(Bombyx mori)。用于转染的各种病毒株是公众可获得的,例如苜蓿银纹夜蛾(Autographa californica)NPV的L-1变体和家蚕NPV的Bm-5株,并且根据本公开,这些病毒可以用于CLDN18.2抗体在合适的宿主细胞中表达的转染过程,特别是用于转染草地贪夜蛾(Spodoptera frugiperda)细胞。棉花、玉米、马铃薯、大豆、矮牵牛花、番茄和烟草的植物细胞培养物也可用作宿主。
以上述用于本公开的CLDN18.2抗体产生的载体转化宿主细胞,并在用于诱导启动子、选择转化体或扩增编码所需序列的基因的根据需要修改的常规营养培养基中培养。
用于产生本公开的CLDN18.2抗体的宿主细胞可以在各种培养基中培养。诸如Ham's F10(Sigma),Minimal Essential Medium(MEM),(Sigma),RPMI-1640(Sigma)和Dulbecco's Modified Eagle's Medium(DMEM,Sigma)的商业上可获得的培养基适于培养宿主细胞。此外,Ham等人.,Meth.Enz.58:44(1979),Barnes等人.,Anal.Biochem.102:255(1980),U.S.Pat.No.4,767,704;4,657,866;4,927,762;4,560,655;或5,122,469;WO 90/03430;WO 87/00195;或U.S.Pat.Re.30,985中描述的任何培养基可用作宿主细胞的培养基。必要时可以用激素和/或其他生长因子(如胰岛素,转铁蛋白或表皮生长因子),盐(如氯化钠,钙,镁和磷酸盐),缓冲液(如HEPES),核苷酸(如腺苷和胸腺嘧啶),抗生素(如GENTAMYCIN药物),微量元素(定义为无机化合物,通常以微摩尔范围内的终浓度存在)和葡萄糖或等同能量来源添加至任何这些培养基。任何其他必需的补充剂也可以以本领域技术人员已知的适当浓度包含在内。诸如温度、pH等培养条件是与之前选择用于表达的宿主细胞一起使用的那些,并且对普通技术人员而言将是明显的。
当使用重组技术时,抗体可以在细胞内,在周质空间中产生,或者直接分泌到培养基中。如果抗体在细胞内产生,作为第一步,例如通过离心或超滤除去微粒碎片(宿主细胞或裂解片段)。Carter等人,Bio/Technology 10:163-167(1992)描述了分离分泌到大肠杆菌周质空间的抗体的方法。简而言之,在约30分钟内,在乙酸钠(pH3.5),EDTA和苯甲基磺酰氟(PMSF)的存在下融化细胞。细胞碎片可以通过离心去除。在抗体分泌到培养基中的情况下,通常首先使用市售的蛋白质浓缩过滤器,例如Amicon或Millipore Pellicon超滤单元浓缩来自这种表达***的上清液。蛋白酶抑制剂例如PMSF可包括在任何前述步骤中以抑制蛋白水解,并可包含抗生素以防止外来污染物的生长。
可以使用例如羟基磷灰石层析,凝胶电泳,透析,DEAE-纤维素离子交换层析,硫酸铵沉淀,盐析和亲和层析来纯化从细胞制备的抗体,其中亲和层析是优选的纯化技术。
在任何初步纯化步骤之后,包含目标抗体和污染物的混合物可以使用pH介于约2.5-4.5之间的洗脱缓冲液进行低pH疏水相互作用色谱,优选在低盐浓度(例如约0-0.25M盐)下进行。
药物组合物
在一些方面,本发明涉及药物组合物,其包含至少一种如本文所公开的CLDN18.2结合分子(例如,本公开的CLDN18.2抗体)和药学上可接受的载体。
药物组合物的组分
药物组合物可以任选地含有一种或多种另外的药物活性成分,例如另一种抗体或药物。本发明的药物组合物还可以与例如另一种免疫刺激剂、抗癌剂、抗病毒剂或疫苗组合施用,使得抗CLDN18.2抗体增强对疫苗的免疫反应。药学上可接受的载体可以包括例如药学上可接受的液体,凝胶或固体载体,水性介质,非水性介质,抗微生物剂,等渗剂,缓冲剂,抗氧化剂,麻醉剂,悬浮/分散剂,螯合剂,稀释剂,佐剂,赋形剂或无毒的辅助物质,本领域已知的各种组分的组合或更多。
合适的组分可以包括例如抗氧化剂,填充剂,粘合剂,崩解剂,缓冲剂,防腐剂,润滑剂,调味剂,增稠剂,着色剂,乳化剂或稳定剂如糖和环糊精。合适的抗氧化剂可包括例如甲硫氨酸,抗坏血酸,EDTA,硫代硫酸钠,铂,过氧化氢酶,柠檬酸,半胱氨酸,巯基甘油,巯基乙酸,巯基山梨糖醇,丁基甲基苯甲醚,丁基化羟基甲苯和/或丙基砷酸盐。如本发明所公开的,在包含还原抗体或其抗原结合片段的一种或多种抗氧化剂如甲硫氨酸的含有本发明公开的组合物的抗体或抗原结合片段的溶剂中,其可被氧化。氧化还原可防止或减少结合亲和力的降低,从而增强抗体稳定性并延长保质期。因此,在一些实施方案中,本发明提供了包含一种或多种抗体或其抗原结合片段和一种或多种抗氧化剂如甲硫氨酸的组合物。本发明进一步提供了多种方法,其中将抗体或其抗原结合片段与一种或多种抗氧化剂如甲硫氨酸混合。从而,抗体或其抗原结合片段可以被防止氧化,以延长其保质期和/或增加活性。
为了进一步说明,药学上可接受的载体可以包括例如水性载体,例如氯化钠注射液,林格氏注射液,等渗右旋糖注射液,无菌水注射液或右旋糖和乳酸林格氏注射液,非水性载体如植物来源的固定油,棉籽油,玉米油,芝麻油或花生油,抑菌剂或抑真菌浓度的抗微生物剂,等渗剂如氯化钠或葡萄糖,缓冲剂如磷酸盐或柠檬酸盐缓冲剂,抗氧化剂如硫酸氢钠,局部麻醉剂如盐酸普鲁卡因,悬浮剂和分散剂如羧甲基纤维素钠,羟丙基甲基纤维素或聚乙烯吡咯烷酮,乳化剂如聚山梨酯80(TWEEN-80),螯合剂如EDTA(乙二胺四乙酸)或EGTA(乙二醇四乙酸),乙醇,聚乙二醇,丙二醇,氢氧化钠,盐酸,柠檬酸或乳酸。用作载体的抗微生物剂可以添加到包含酚或甲酚、汞制剂、苯甲醇、氯丁醇、对羟基苯甲酸甲酯和对羟基苯甲酸丙酯、硫柳汞、苯扎氯铵和苄索氯铵的多剂量容器中的药物组合物中。合适的赋形剂可以包括例如水,盐水,右旋糖,甘油或乙醇。合适的无毒辅助物质可以包括例如润湿剂或乳化剂,pH缓冲剂,稳定剂,溶解度增强剂或诸如乙酸钠,脱水山梨糖醇单月桂酸酯,三乙醇胺油酸酯或环糊精的试剂。
施用、制剂和剂量
本发明的药物组合物可以通过各种途径体内施用至有需要的受试者,所述途径包括但不限于口服,静脉内,动脉内,皮下,肠胃外,鼻内,肌内,颅内,心内,心室内,气管内,口腔,直肠,腹膜内,皮内,局部,经皮和鞘内,或者通过植入或吸入。本发明的药物组合物可以配制成固体、半固体、液体或气体形式的制剂;包括但不限于片剂,胶囊剂,粉剂,颗粒剂,软膏剂,溶液剂,栓剂,灌肠剂,注射剂,吸入剂和气雾剂。根据预期的应用和治疗方案可以选择合适的制剂和施用途径。
用于肠内施用的合适制剂包括硬或软的明胶胶囊,丸剂,片剂,包括包衣片剂,酏剂,混悬剂,糖浆剂或吸入剂及其控释剂型。
适用于肠胃外施用(例如通过注射)的制剂包括活性成分溶解、悬浮于其中或以其他方式提供的(例如,在脂质体或其他微粒中)的水性或非水性、等渗、无热原、无菌液体(例如溶液,混悬液)。这些液体可以另外含有其它药学上可接受的成分,例如抗氧化剂,缓冲剂,防腐剂,稳定剂,抑菌剂,悬浮剂,增稠剂和使制剂与预期接受者的血液(或其他相关体液)等渗的溶质。赋形剂的实例包括例如水,醇,多元醇,甘油,植物油等。适用于此类制剂的等渗载体的实例包括氯化钠注射液,林格溶液或乳酸林格氏注射液。类似地,特定剂量方案(即剂量,时间和重复)将取决于具体个体和个体的病史以及诸如药代动力学(例如半衰期,清除率等)的经验考虑。
施用频率可以在治疗过程中确定和调整,并且基于减少增殖或致瘤细胞的数量,维持这种肿瘤细胞的减少,减少肿瘤细胞的增殖或延迟转移的发展。在一些实施方案中,施用的剂量可以被调节或减少以控制潜在的副作用和/或毒性。或者,本发明的用于治疗的药物组合物的持续连续释放制剂可能是合适的。
本领域技术人员将会理解,合适的剂量可因患者而异。确定最佳剂量通常涉及治疗益处水平与任何风险或有害副作用的平衡。所选择的剂量水平将取决于多种因素,包括但不限于特定化合物的活性,施用,施用时间,化合物清除速率,治疗持续时间,其他联合使用的药物、化合物和/或材料,病症的严重程度,以及物种,患者的性别、年龄、体重、病情、一般健康状况和以前的病史。化合物的量和施用途径最终由医生、兽医或临床医师决定,但通常选择剂量以达到实现所需效果的作用部位处的局部浓度,而不会导致实质性的有害或不利副作用。
通常,CLDN18.2结合分子可以以各种剂量范围施用。在一些实施方案中,本文提供的CLDN18.2结合分子可以以约0.01mg/kg至约100mg/kg(例如约0.01mg/kg,约0.5mg/kg,约1mg/kg,约2mg/kg,约5mg/kg,约10mg/kg,约15mg/kg,约20mg/kg,约25mg/kg,约30mg/kg,约35mg/kg,约40mg/kg,约45mg/kg,约50mg/kg,约55mg/kg,约60mg/kg,约65mg/kg,约70mg/kg,约75mg/kg,约80mg/kg,约85mg/kg,约90mg/kg,约95mg/kg,或约100mg/kg)的治疗有效剂量施用。在这些实施方案的某些中,抗体以约50mg/kg或更低的剂量施用,并且在这些实施方案中的某些中,剂量为10mg/kg或更低,5mg/kg或更低,1mg/kg或更低,0.5mg/kg或更低,或者0.1mg/kg或更低。在某些实施方案中,施用剂量可以在治疗过程中改变。例如,在某些实施方案中,初始施用剂量可以高于后续施用剂量。在某些实施方案中,取决于受试者的反应,施用剂量可以在治疗过程中变化。
无论如何,本发明的抗体或其抗原结合部分优选根据需要施用于有需要的受试者。本领域技术人员可以确定施用频率,例如主治医生基于所治疗病症、所治疗受试者的年龄、所治疗病症的严重程度、所治疗受试者的一般健康状况等的考虑。
在某些优选的实施方案中,涉及本发明的抗体或其抗原结合部分的治疗过程将包含在数周或数月的时间内施用的多剂量的所选药物产品。更具体地说,本发明的抗体或其抗原结合部分可以每天,每两天,每四天,每周,每十天,每两周,每三周,每月,每六周,每两个月,每十周或每三个月施用。就此而言,可以理解的是,可以基于患者响应和临床实践来改变剂量或者调整间隔。
在给予一次或多次施用的个体中也可凭经验确定所公开的用于治疗的药物组合物的剂量和方案。例如,可给予个体增量剂量的如本文所述的药物组合物。在选定的实施方案中,剂量可分别根据经验确定,或根据观察到的副作用或毒性逐渐增加或减少。为了评估所选择的组合物的功效,可以跟踪特定疾病、病症或病情的标志物。对于癌症,这些包括通过触诊或视觉观察直接测量肿瘤大小,通过X射线或其他成像技术间接测量肿瘤大小;通过直接肿瘤活组织检查和肿瘤样本的显微镜检查评估的改善;测量根据本文所述方法鉴定的间接肿瘤标志物(例如用于***癌的PSA)或致瘤性抗原,疼痛或***减轻;与肿瘤相关的言语、视力、呼吸或其他失能的改善;食欲增加;或通过接受的测试测量的生活质量的提高或生存期的延长。本领域技术人员将明白,剂量将根据个体、肿瘤病情的类型、肿瘤病情的阶段、肿瘤病情是否已开始转移至个体中的其他位置以及过去使用的治疗和并行使用的治疗而变化。
用于肠胃外施用(例如静脉内注射)的相容制剂可包含浓度为约10μg/ml至约100mg/ml的如本文提供的CLDN18.2结合分子。在一些实施方案中,CLDN18.2结合分子的浓度可包括20μg/ml,40μg/ml,60μg/ml,80μg/ml,100μg/ml,200μg/ml,300μg/μg/ml,400μg/ml,500μg/ml,600μg/ml,700μg/ml,800μg/ml,900μg/ml或1mg/ml。在其他优选的实施方案中,CLDN18.2结合分子的浓度将包括2mg/ml,3mg/ml,4mg/ml,5mg/ml,6mg/ml,8mg/ml,10mg/ml,12mg/ml,14mg ml,16mg/ml,18mg/ml,20mg/ml,25mg/ml,30mg/ml,35mg/ml,40mg/ml,45mg/ml,50mg/ml,60mg/ml,70mg/ml,80mg/ml,90mg/ml或100mg/ml。若以摩尔浓度计算,在一些实施方案中,CLDN18.2结合分子的浓度可包括例如133nM,266nM,400nM,533nM,667nM,1.3μM,2μM,2.67μM,3.33μM,4μM,4.67μM,5.33μM,6μM或6.67μM。
本发明的应用
本发明的CLDN18.2结合分子具有许多体外和体内用途。
治疗疾病
与CLDN18.2相关的病症和障碍可以是与免疫相关的疾病或病症,包括但不限于“涉及表达CLDN18.2的细胞的疾病”或“与表达CLDN18.2的细胞相关的疾病”或类似表述,意指CLDN18.2在患病组织或器官的细胞中表达。在一个实施方案中,与对应健康组织或器官中的状态相比,CLDN18.2在患病组织或器官的细胞中的表达提高。提高是指提高至少10%,特别地至少20%、至少50%、至少100%、至少200%、至少500%、至少1000%、至少10000%或甚至更多。在一个实施方案中,表达仅见于患病组织,而相应健康组织中的表达被抑制。根据本发明,与表达CLDN18.2的细胞相关的疾病包括癌症疾病。此外,根据本发明,癌症疾病优选为其中癌细胞表达CLDN18.2的那些。
术语“癌症疾病”或“癌症”是指或描述个体中通常以不受调节的细胞生长为特征的生理状况。癌症的实例包括但不限于上皮癌、淋巴瘤、母细胞瘤、肉瘤和白血病。更特别地,这样的癌症的实例包括骨癌、血癌、肺癌、肝癌、胰腺癌、皮肤癌、头颈癌、皮肤或眼内黑素瘤、子宫癌、卵巢癌、直肠癌、肛区癌、胃癌、结肠癌、乳腺癌、***癌、子宫癌、性器官和生殖器官癌、霍奇金病(Hodgkin′s Disease)、食管癌、小肠癌、内分泌***癌症、甲状腺癌、甲状旁腺癌、肾上腺癌、软组织肉瘤、膀胱癌、肾癌、肾细胞癌、肾盂癌、中枢神经***(CNS)肿瘤、神经外胚层癌症、脊柱轴肿瘤、胶质瘤、脑脊膜瘤和垂体腺瘤。根据本发明的术语“癌症”还包括癌症转移。优选地,“癌症疾病”的特征在于表达CLDN18.2的细胞,以及癌细胞表达CLDN18.2。表达CLDN18.2的细胞优选是癌细胞,优选本文中所述的癌症的癌细胞。
根据本公开,术语“肿瘤”或“肿瘤疾病”是指细胞(被称为赘生性细胞、肿瘤发生性细胞或肿瘤细胞)的异常生长,优选形成肿胀或病变。“肿瘤细胞”意指通过迅速的不受控制的细胞增殖而生长并且在引发新生长的刺激停止之后继续生长的异常细胞。肿瘤显示出结构组织和与正常组织的功能协调的部分或完全缺失,并且通常形成独特的组织团块,其可以是良性的、恶化前的或恶性的。根据本发明,“癌症疾病”优选为“肿瘤疾病”。然而,通常术语“癌症”和“肿瘤”在本文中可互换使用。
在一个实施方案中,根据本公开的癌症涉及表达CLDN18.2的癌细胞。在一个实施方案中,癌症是CLDN18.2阳性的。在一个实施方案中,CLDN18.2的表达是位于细胞的表面。在一个实施方案中,至少50%,优选60%、70%、80%或90%的癌细胞是CLDN18.2阳性的,和/或至少40%,优选至少50%的癌细胞对CLDN18.2的表面表达呈阳性。在一个实施方案中,至少95%或至少98%的癌细胞是CLDN18.2阳性的。在一个实施方案中,至少60%、至少70%、至少80%或至少90%的癌细胞对于CLDN18.2的表面表达是阳性的。
在一个实施方案中,表达CLDN18.2的癌症、涉及表达CLDN18.2的癌细胞的癌症或CLDN18.2阳性癌症选自:胃癌、食管癌、胰腺癌、肺癌(例如非小细胞肺癌(NSCLC))、卵巢癌、结肠癌、肝癌、头颈癌和胆囊癌,及其转移,特别是胃癌转移(例如克鲁肯贝格瘤)、腹膜转移和***转移。在一个实施方案中,癌症是腺癌,特别是晚期腺癌。特别优选的癌症疾病是胃、食管、胰管、胆管、肺和卵巢的腺癌。在一个实施方案中,癌症选自胃癌、食管癌(特别是下食管癌)、食管-胃接合部的癌症和胃食管癌。在一个特别优选的实施方案中,癌症是胃食管癌,例如转移性、顽固性或复发性晚期胃食管癌。
此外,本公开的抗体或其抗原结合部分可以与化学疗法或放射疗法组合使用。
与化疗组合使用
抗体或其抗原结合部分可以与抗癌剂、细胞毒性剂或化学治疗剂组合使用。
术语“抗癌剂”或“抗增殖剂”意指可用于治疗细胞增殖性病症例如癌症的任何药剂,并且包括但不限于细胞毒性剂,细胞抑制剂,抗血管生成剂,放射疗法和放射治疗剂,靶向抗癌剂,BRM,治疗性抗体,癌症疫苗,细胞因子,激素疗法,放射疗法和抗转移剂和免疫治疗剂。应该理解的是,在如上所述的选定实施方案中,此类抗癌剂可以包含缀合物并且可以在施用之前与公开的位点特异性抗体结合。更具体而言,在一些实施方案中,将选择的抗癌剂连接至工程化抗体的不配对半胱氨酸以提供如本文所述的工程化偶联物。因此,这样的工程化缀合物被明确地考虑在本发明的范围内。在其他实施方案中,所公开的抗癌剂将与包含如上所述的不同治疗剂的位点特异性缀合物组合施用。
如本文所用,术语“细胞毒性剂”是指对细胞有毒并降低或抑制细胞功能和/或引起细胞破坏的物质。在一些实施方案中,该物质是源自活生物体的天然存在的分子。细胞毒性剂的实例包括但不限于细菌(例如,白喉毒素,假单胞菌内毒素和外毒素,葡萄球菌肠毒素A),真菌(例如α-八叠球菌素,局限曲霉素),植物(相思豆毒蛋白,蓖麻毒素,蒴莲根毒素,槲寄生素,美洲商陆抗病毒蛋白,皂草素,白树毒素,momoridin,天花粉蛋白,大麦毒素,油桐(Aleurites fordii)蛋白,石竹素蛋白,Phytolacca mericana蛋白(PAPI,PAPII和PAP-S),苦瓜抑制剂,麻风树毒蛋白,巴豆毒素,石碱草抑制剂,白树毒素,mitegellin,局限曲霉素,酚霉素,新霉素和单端孢霉烯族化合物)或动物(例如细胞毒性RNA酶,如胞外胰腺RNA酶;DNA酶I,包括其片段和/或变体)的小分子毒素或酶促活性毒素。
为了本发明的目的,“化学治疗剂”包括非特异性降低或抑制癌细胞的生长、增殖和/或存活的化学化合物(例如细胞毒性剂或细胞抑制剂)。这些化学试剂通常针对细胞生长或***所需的细胞内过程,因此对于通常快速生长和***的癌细胞特别有效。例如,长春新碱使微管解聚,从而抑制细胞进入有丝***。通常,化学治疗剂可以包括抑制或被设计用于抑制癌细胞或可能变成性或产生致瘤后代(例如TIC)的细胞的任何化学药剂。这些药剂通常是组合使用的,并且通常是最有效的,例如,在诸如CHOP或FOLFIRI的方案中。
可以与本发明的位点特异性构建体组合使用的抗癌剂(作为位点特异性缀合物的组分或未缀合状态)的实例包括但不限于烷化剂、烷基磺酸盐、氮丙啶、乙烯亚胺和甲基三聚氰胺、多聚乙酰(acetogenins)、喜树碱、苔藓抑素、卡利士他汀(callystatin)、CC-1065、克瑞托欣(cryptophycins)、多拉司他汀、多卡米星、艾榴素(eleutherobin)、水鬼蕉碱、沙克迪因(sarcodictyin)、海绵素(spongistatin)、氮芥、抗生素、烯二炔类抗生素、dynemicin、双膦酸盐、埃斯波霉素、色素蛋白烯二炔抗生素发色团、阿克拉霉素类(aclacinomysins)、放线菌素、安曲霉素、偶氮丝氨酸、博莱霉素、放线菌素C、卡拉宾辛(carabicin)、洋红霉素、嗜癌霉素、色霉素类(chromomycinis)、更生霉素、柔红霉素、地托比星、6-重氮基-5-氧代-L-正亮氨酸、多柔比星、表柔比星、依索比星、伊达比星、麻西罗霉素、丝裂霉素、霉酚酸、诺加霉素、橄榄霉素、培洛霉素、博地霉素(potfiromycin)、嘌呤霉素、三铁阿霉素、罗多比星、链黑菌素、链脲菌素、杀结核菌素、乌苯美司、净司他丁、佐柔比星;抗-代谢物、埃罗替尼、威罗菲尼、克唑替尼、索拉非尼、依鲁替尼、恩杂鲁胺、叶酸类似物、嘌呤类似物、雄激素、抗-肾上腺素、叶酸补充剂如弗林酸(frolinic acid)、醋葡醛内酯、醛磷酰胺糖苷、氨基乙酰丙酸、恩尿嘧啶、安吖啶、贝斯布希(bestrabucil)、比生群、依达曲沙、迪夫法明(defofamine)、秋水仙胺、地吖醌、艾夫尼辛(elfornithine)、依利醋铵、爱波喜龙、依托格鲁、硝酸镓、羟基脲、香菇多糖、氯尼达明、美坦生类化合物(maytansinoids)、米托胍腙、米托蒽醌、莫丹摩尔(mopidanmol)、尼特林(nitraerine)、喷司他丁、蛋氨氮芥、吡柔比星、洛索蒽醌、鬼臼酸、2-乙基肼、丙卡巴肼、多糖复合物(JHS Natural Products,Eugene,OR)、雷佐生;根霉素;西佐喃;锗螺胺;替奴佐酸;三亚胺醌;2,2',2”-三氯三乙胺;单端孢霉烯类(尤其是T-2毒素、维拉库林A(verracurin A)、杆孢菌素A和蛇形菌素);乌拉坦;长春地辛;达卡巴嗪;甘露莫司汀;二溴甘露醇;二溴卫矛醇;哌泊溴烷;卡西托欣(gacytosine);***糖苷(“Ara-C”);环磷酰胺;噻替派;紫杉烷类;苯丁酸氮芥(chloranbucil);/>吉西他滨;6-硫代鸟嘌呤;巯嘌呤;氨甲喋呤;铂类似物;长春碱;铂;依托泊苷(VP-16);异环磷酰胺;米托蒽醌;长春新碱,长春瑞滨;诺消灵;替尼泊苷;依达曲沙;柔红霉素;氨基蝶呤;希罗达;伊班膦酸盐;伊立替康(Camptosar,CPT-11);拓扑异构酶抑制剂RFS 2000;二氟甲基鸟氨酸;类视色素;卡培他滨;考布他汀;甲酰四氢叶酸;奥沙利铂;PKC-α、Raf、H-Ras、EGFR和VEGF-A的抑制剂(其减少细胞增殖),以及上述任一项的药学上可接受的盐、酸或衍生物。这一定义中还包括用于调节或抑制对肿瘤的激素作用的抗激素剂,诸如抗***和选择性***受体调节剂,抑制调节肾上腺中的***产生的芳香酶的芳香酶抑制剂,和抗-雄激素;以及曲沙他滨(1,3-二氧杂环戊烷核苷胞嘧啶类似物);反义寡核苷酸、核酶诸如VEGF表达抑制剂和HER2表达抑制剂;疫苗,/>rIL-2;/>拓扑异构酶1抑制剂;/>rmRH;长春瑞滨和埃斯波霉素,以及上述任一项的药学上可接受的盐、酸或衍生物。
与放射疗法组合使用
本发明还提供了抗体或其抗原结合部分与放射疗法(即,用于在肿瘤细胞内局部诱导DNA损伤的任何机制,例如γ-照射,X-射线,UV-照射,微波,电子发射等)的组合。还考虑了使用放射性同位素至肿瘤细胞的定向递送的联合疗法,并且所公开的缀合物可以与靶向的抗癌剂或其他靶向手段结合使用。通常,放射疗法在约1周至约2周的时间段内以脉冲方式施用。放射疗法可以对患有头颈癌的受试者施用约6至7周。任选地,放射疗法可以作为单剂量或作为多个顺序剂量施用。
诊断
本发明提供了用于检测、诊断或监测增殖性病症的体外和体内方法以及筛选来自患者的细胞以鉴定肿瘤细胞包括致瘤细胞的方法。这样的方法包括鉴定用于治疗的患有癌症的个体或监测癌症的进展,包括将患者或从患者获得的样品(体内或体外)与本文所述的抗体接触,并检测样品中与结合的或游离的靶分子的结合的抗体的存在或不存在或结合水平。在一些实施方案中,抗体将包含可检测标记或报道分子。
在一些实施方案中,抗体与样品中特定细胞的结合可表示样品可能含有致瘤细胞,从而表明具有癌症的个体可用本文所述的抗体有效治疗。
可以通过多种测定法分析样品,例如放射免疫测定法,酶免疫测定法(例如ELISA),竞争结合测定法,荧光免疫测定法,免疫印迹测定法,Western印迹分析和流式细胞术测定法。兼容的体内诊断或诊断测定可以包括本领域公知的成像或监测技术,例如本领域技术人员已知的磁共振成像,计算机化断层摄影(例如CAT扫描),正电子断层扫描(例如PET扫描),放射线照相术,超声波等。
药物包装和试剂盒
本发明还提供了包含一个或多个剂量的抗体或其抗原结合部分的一个或多个容器的药物包装和试剂盒。在一些实施方案中,提供单位剂量,其中单位剂量含有预定量的组合物,所述组合物包含例如抗体或其抗原结合部分,具有或不具有一种或多种其他试剂。对于其他实施方案,这种单位剂量以一次性使用的预充式注射用注射器供应。在其他实施方案中,单位剂量中包含的组合物可以包含盐水、蔗糖或类似物;缓冲液,如磷酸盐等;和/或配制在稳定和有效的pH范围内。或者,在一些实施方案中,所述组合物是缀合物组合物,其可以作为冻干粉末提供并在加入合适的液体(例如无菌水或盐溶液)后重建。容器上或与容器相关联的任何标签指示封装的缀合物组合物用于治疗选择的肿瘤疾病状况。在一些优选的实施方案中,组合物包含一种或多种抑制蛋白质聚集的物质,包括但不限于蔗糖和精氨酸。
本发明还提供了用于产生位点特异性缀合物以及任选地一种或多种抗癌剂的单剂量或多剂量施用单元的试剂盒。该试剂盒包括容器以及在容器上或与容器相关联的标签或包装插页。合适的容器包括例如瓶,小瓶,注射器等。容器可以由多种材料形成,例如玻璃或塑料,并且包含药学有效量的所公开的缀合或非缀合形式的缀合物。在其他优选实施例中,容器包括无菌存取口(例如容器可以是静脉内溶液袋或具有可被皮下注射针头刺穿的塞子的小瓶)。这样的试剂盒通常在合适的容器中包含工程化偶联物的药学上可接受的制剂,并且任选地在相同或不同的容器中包含一种或多种抗癌剂。试剂盒还可以含有其他药学上可接受的制剂,用于诊断或组合治疗。例如,除了本发明的抗体或其抗原结合部分之外,这样的试剂盒可以含有任何一种或多种抗癌剂,例如化学治疗剂或放射治疗剂;抗血管生成剂;抗转移剂;靶向抗癌剂;细胞毒性剂;和/或其他抗癌剂。
更具体地说,试剂盒可以具有含有所公开的抗体或其抗原结合部分的单个容器,其含有或不含另外的组分,或者它们可以具有用于每种所需试剂的不同容器。在提供用于缀合的组合治疗剂的情况下,可以按摩尔当量组合或一种组分多于另一种的方式预混合单一溶液。或者,试剂盒的缀合物和任何任选的抗癌剂可以在施用于患者之前分开保存在不同的容器中。试剂盒还可以包含用于容纳无菌药学上可接受的缓冲液或其他稀释剂例如抑菌注射用水(BWFI)、磷酸盐缓冲盐水(PBS)、林格氏溶液和葡萄糖溶液的第二/第三容器装置。
当试剂盒的组分以一种或多种液体溶液提供时,液体溶液优选为水溶液,特别优选无菌水溶液或盐水溶液。然而,试剂盒的组分可以作为干粉提供。当试剂或组分以干粉形式提供时,可以通过添加合适的溶剂来重构粉末。可以设想溶剂也可以提供于另一个容器中。
如上简要所述,所述试剂盒还可含有向患者施用抗体或其抗原结合部分和任何任选组分的工具,例如一种或多种针,I.V.袋或注射器,或者甚至滴眼器、移液管或其他类似装置,通过其可以将制剂注射或引入动物体内或将其施用于身体的患病区域。本发明的试剂盒通常还包括用于容纳小瓶或类似物的装置以及用于商业销售的其他紧密封闭的部件,例如注射或吹塑塑料容器,其中放置并且保持所需的小瓶和其他装置。
本发明的优势
针对CLDN18.2、特别是人CLDN18.2开发抗体至少具有如下优势:
第一,人CLDN18.2高表达于癌症细胞,而在正常细胞中,仅特异性表达于胃上皮细胞中,因此毒副作用低,成药可能性更高;
第二,CLDN18.2表达于胃上皮细胞的紧密连接中,相对较松散的癌症细胞,抗体不易于作用;即使上皮细胞被抗体杀伤,上皮细胞之下的干细胞因为不表达CLDN18.2,可以通过分化进而补充损伤的胃上皮细胞;
第三,针对CLDN18.2的抗体不仅可以通过ADCC和CDC杀伤细胞,还可以通过抗体交联CLDN18.2从而介导细胞的凋亡,而且可以一定程度抑制细胞的增殖。
至今,还没有针对CLND18.2的纳米抗体,纳米抗体作为一种新型的抗体,已经有一个抗体caplacizumab获批上市,充分说明纳米抗体的可成药性。此种抗体相对于其它抗体具有显著的优点,如其半衰期长短可通过化学修饰或者蛋白融合改造进行调节,渗透性强,可识别普通抗体不可及的隐蔽表位,耐胃蛋白酶,耐酸,耐热,易生产,而且因为是单链,易于和其它类型抗体组装为双价抗体和多价抗体。
在本发明的部分实施方案中,针对CLDN18.2的抗体是通过羊驼免疫库筛选得到,在此基础上,C末端和IgG1的Fc片段融合,目前部分候选抗体在细胞水平CDC和ADCC的实验结果都表现出比对照抗体更好或至少相当的活性。结合CLDN18.2靶点的特性,此抗体用于癌症的免疫治疗,具有更低的毒副作用和更佳的临床药效,将给患者提供更多的药物选择。
实施例
通过参考以下实施例将更容易地理解本文一般地描述的本发明,这些实施例是以举例说明的方式提供的,并且不旨在限制本发明。这些实施例并不旨在表示下面的实验是全部或仅进行的实验。
实施例1
过表达细胞株以及肿瘤细胞株的构建与鉴定
在本实施例中,分别构建了不同类型的过表达细胞株以及肿瘤细胞株,并对其进行流式鉴定。
1.过表达细胞株的构建与鉴定
将全长人CLDN18.1(SEQ ID NO:16)、鼠CLDN18.2(SEQ ID NO:17)、鼠CLDN18.1(SEQ ID NO:18)的核酸序列构建至pLVX-puro质粒(Clontech,Cat#632164)上。然后,将所得到的质粒通过电转化至HEK293细胞(CRL-1573TM)中。通过筛选,得到表达全长人CLDN18.1的过表达细胞株(人CLDN18.1-HEK293)、表达鼠CLDN18.2的过表达细胞株(鼠CLDN18.2-HEK293)和表达鼠CLDN18.1的过表达细胞株(鼠CLDN18.1-HEK293)。其后,通过IMAB362抗体(根据专利US20180127489A1所披露的序列信息表达、纯化制得)以及识别C端CLDN18胞内段(GFKASTGFGSNTKN,SEQ ID NO:21)的抗CLDN18抗体[34H14L15](Abcam,ab203563)进行流式细胞术鉴定,获得成功转化的过表达细胞株,具体方法如下。
1.1电转化
首先,复苏及培养HEK293细胞,连续传代2-3次,转染前一天将细胞以3×105个/mL的密度接种至细胞培养皿中,第二天待细胞汇合度达到约70%即可使用。用含体积百分比为0.25%的EDTA的Trypsin(Gibco,25200-072)消化细胞2min后收集细胞,于常温、100g离心细胞5min弃上清后加入1×DPBS(源培,B210)重悬细胞并计数,取5×106个细胞离心并收集,用250μL Buffer R(Invitrogen,NeonTMKit,PK10096)缓冲液重悬细胞,并向其中加入25μg目的质粒,用移液器轻轻混合均匀。后将悬液置入电转仪(Invitrogen,NeonTMTransfection System,MP922947)进行电转化,设置的反应条件为1100V/20ms/2次进行电转。
1.2细胞培养
电转化后,将所得到的细胞分别转移至含有体积百分比为10%FBS(Gibco,15140-141)且不含抗生素的DMEM培养基(Gibco,11995065)中,然后将细胞接种入10cm×10cm细胞培养皿中培养48h,接着以平均0.5个/孔的密度将细胞分装至96孔细胞培养板中,加入终浓度为2μg/mL的嘌呤霉素(Gibco,A111138-03)作为筛选压力,2周左右观察细胞株克隆生长情况,并挑取形成克隆的细胞株进行鉴定。1.3过表达细胞株的流式鉴定
将上述1.2节获得的细胞株,通过流式细胞术进行鉴定,具体如下。
1.3.1人CLDN18.2-HEK293T和鼠CLDN18.2-HEK293细胞株的流式鉴定
对于人CLDN18.2-HEK293T(康源博创,KC-0986)和鼠CLDN18.2-HEK293细胞株,直接采用IMAB362抗体进行鉴定。
取1×105个细胞,低速离心(300g)去上清。将离心管底部的细胞通过配制好的FACS缓冲液(含体积百分比为2%FBS的1×PBS缓冲液)润洗一次,然后向润洗后的细胞中加入12.5μg/mL抗体IMAB362,在4℃孵育1h,接着再用上述FACS缓冲液润洗三次,加入PE标记的山羊抗人IgG Fc抗体(Abcam,ab98596)0.5μg,在4℃孵育1h。其后,经FACS缓冲液润洗三次,并向细胞中加入200μL FACS缓冲液重悬细胞,最后通过流式细胞仪(Beckman,CytoFLEXAOO-1-1102)进行检测。
1.3.2人CLDN18.1-HEK293和鼠CLDN18.1-HEK293细胞株的流式鉴定
由于IMAB362抗体只识别CLDN18.2而不识别CLDN18.1,因此需要结合其它方法对人CLDN18.1-HEK293、鼠CLDN18.1-HEK293细胞株进行鉴定。考虑到人CLDN18.1和鼠CLDN18.1的序列一致性,首先按细胞破膜试剂盒(eBioscience,88-8824-00)的说明书方法对细胞进行固定和破膜,然后根据抗CLDN18抗体[34H14L15]对C端CLDN18胞内段的识别结果及与IMAB362抗体的特异性结合结果进行流式细胞术鉴定。
具体方法如下:取1×105个细胞,低速离心(300g),去上清。将离心管底部的细胞用FACS缓冲液润洗一次,然后向润洗后的细胞中加入200μL IC固定液(eBioscience,00-8222),在4℃孵育1h,接着用破膜缓冲液(eBioscience,00-8333)润洗两次,加入前述抗CLDN18抗体,在4℃孵育1h。再次用上述破膜缓冲液润洗三遍之后,加入Alexa488荧光标记的驴抗兔IgG H&L(abcam,ab150073)0.5μg,在4℃孵育1h,最后通过流式细胞仪(Beckman,CytoFLEX AOO-1-1102)进行检测。
同时采用前述1.3.1的方法,用IMAB362抗体测定是否结合人CLDN18.1-HEK293和鼠CLDN18.1-HEK293细胞株。
流式鉴定的结果如图1a所示。从图1a中可以看出:抗CLDN18抗体可以识别人CLDN18.2-HEK293T、人CLDN18.1-HEK293、鼠CLDN18.2-HEK293、鼠CLDN18.1-HEK293、HEK293和HEK293T细胞;而抗体IMAB362仅识别鼠CLDN18.2-HEK293、人CLDN18.2-HEK293T,不识别鼠CLDN18.1-HEK293、人CLDN18.1-HEK293。这说明人CLDN18.2-HEK293T、人CLDN18.1-HEK293、鼠CLDN18.2-HEK293、鼠CLDN18.1-HEK293四个细胞株都成功地表达了对应的CLDN18蛋白。
2.过表达肿瘤细胞株的构建与鉴定
对于过表达人CLDN18.2的胃癌细胞株KATOIII(人CLDN18.2-KATOIII肿瘤细胞株)的构建则是采用慢病毒转染的方式,并通过抗体IMAB362进行鉴定。具体方法如下:
取状态良好的人胃癌细胞KATOIII(HTB-103TM)5×104个,以30:1的MOI比例加入包装好的含有人CLDN18.2序列(SEQ ID NO:15)的慢病毒,充分混匀,然后加入含有8μg/mL聚凝胺(Polybrene,Sigma,107689)的IMDM完全培养基(Gibco,12440061),混合均匀,于37℃、5%CO2的恒温培养箱中孵育20h后去除培养基,更换新鲜的IMDM完全培养基继续孵育24h,然后以平均0.5个细胞/孔的密度将转染后的KATOIII细胞接种至96孔板中,并添加终浓度为2μg/mL嘌呤霉素进行抗性加压筛选,于37℃、5%CO2的恒温培养箱中培养2-3周,并挑取克隆进行鉴定。/>
以上述1.3.1节同样的方式,通过抗体IMAB362对经抗性筛选的细胞株进行流式鉴定。
流式鉴定的结果如图1b所示。从图1b中可以看出,没有转染CLDN18.2的KATOIII细胞几乎不被抗体IMAB362识别,说明此KATOIII细胞株上几乎不表达CLDN18.2或者表达量极低;通过慢病毒转染而成功构建的人CLDN18.2-KATOIII肿瘤细胞株能够被抗体IMAB362识别,说明此细胞株构建成功。
实施例2
动物免疫和血清免疫效价检测
1.免疫接种
在本实施例中,采用的是羊驼免疫。具体操作如下:免疫原采用细胞株人CLDN18.2-HEK293T(康源博创,KC-0986)和含人CLDN18.2 ECD1(SEQ ID NO:19)的hCLDN18.2-pLVX-puro质粒。分别用2×107个人CLDN18.2-HEK293T细胞(皮下多点注射)和2mg质粒(肌肉多点注射)按周交替免疫羊驼(南昌大佳生物饲养),羊驼代号为NSY002,总计免疫8次。最后,用2×107个人CLDN18.2-HEK293T细胞进行加免。
2.血清免疫效价测定
免疫效价测定是通过ELISA方法根据免疫血清在抗原重组蛋白CLDN18.2(金斯瑞,CP0007)上的信号进行测定。具体方法如下。
在免疫效价测定的前一天,将抗原重组蛋白CLDN18.2用PBS稀释到1μg/mL,获得稀释液。将30μL稀释液加入到Elisa板中,于4℃包被过夜。在免疫效价测定当日,包被板用PBS润洗两遍,然后用含有体积百分比为5%脱脂奶粉的PBST室温封闭两小时,再用PBS润洗两遍。在另外一块96孔稀释板上将未经免疫的阴性血清和免疫后血清用PBS进行稀释,首孔1000倍稀释,然后后续7个孔采用2倍梯度稀释。稀释好的血清对应加入到包被了抗原重组蛋白CLDN18.2的第一块Elisa板中,37°孵育1h,PBS洗两遍后以1:5000加入二抗MonoRabTM兔抗骆驼科VHH抗体(金斯瑞,A01862-200),最后通过酶标仪(Molecular Devices,SpecterMax 190)在450nm波长下读取OD值。结果如表1所示,羊驼免疫效价大致在1:8000左右。
表1
实施例3
羊驼免疫库构建和筛选
动物免疫结束之后,将羊驼采血80mL,通过Ficoll-Paque密度梯度分离液(GE,17144003S)分离PBMC用于羊驼免疫库构建。具体方法如下:
取Ficoll-Paque密度梯度分离液15mL缓缓加入至50mL离心管中,然后缓缓加入15mL采集的羊驼血液,使得两种液体保持清晰的分离界面。在15℃左右以下述条件进行离心:400g,20min,加速度为3,减速为0。离心之后,整个液面分为四层,上层为血浆混合物,下层为红细胞和粒细胞,中层为Ficoll-Paque液体,在上、中层交界处有以PBMC为主的白色云雾层狭窄带,即PBMC细胞层。先用无菌巴氏吸管小心地吸去上层的血浆混合物,然后再用新的无菌巴氏吸管吸取PBMC,获得分离的PBMC。用PBS润洗两遍,4℃,1500rpm水平离心10min,最后用1.5mL PBS重悬,通过细胞计数仪(CountStar,CountStar Altair)计数。
将分离的PBMC抽取其RNA,并通过反转录试剂盒(TaKaRa,6210A)反转录成cDNA。由于羊驼抗体的分子形式不同于普通抗体,其不含有轻链而且重链不含有CH1,因此在VHgermline基因前端和CH2上通过设计引物,PCR得到两个不同大小的片段,通过割胶回收较小的目的片段;通过比对VHH抗体所有V基因和J基因的所有序列,设计含有NcoI和NotI酶切位点的简并引物,然后以回收的DNA片段产物为模板扩增所有的VHH基因,最后通过双酶切和连接将目的抗体基因片段***至噬菌体展示用载体上,其中VHH在C端融合了GIII基因。连接产物通过回收试剂盒(Omega,D6492-02)回收,最后通过电转仪(Bio-Rad,MicroPulser)转化至感受态大肠杆菌SS320(Lucigen,MC1061 F)中,并涂布于具有氨苄抗性的2-YT固体平板(由胰蛋白胨1.5%,酵母提取物1%,NaCl 0.5%,琼脂1.5%,按质量体积g/mL配制而成)。为了计算库容,以1μL菌液稀释后在平板上形成的克隆来计算所有电转化形成的总克隆数,即库容容量。此免疫库的库容为1×109cfu。
基于库容容量,挑取50个OD(1个OD为5×108cfu)的羊驼库菌加入到新鲜的2-YT液体培养基中,使得初始OD值为0.05。置于37℃,220rpm培养至对数生长期,此时以5倍于细菌数的数量加入VSCM13辅助噬菌体,充分混匀,静置30min,然后在220rpm条件下培养1h,通过10000rpm离心5min后,弃上清,置换至C+/K+2-YT培养基中,并于30℃,220rpm培养过夜。次日,13000g离心10min,其上清通过加入20%PEG/NaCl(由体积浓度为20%的PEG6000和2.5MNaCl配制而成),沉淀得到羊驼库对应的噬菌体,经PBS润洗一次之后,用于噬菌体筛选。
采用细胞筛选的方法,以人CLDN18.2-HEK293T细胞株作为筛选抗原,从噬菌体展示库中筛选针对人CLDN18.2的抗体,具体方法如下所述。在T25培养方瓶中培养人CLDN18.2-HEK293T或者人CLDN18.1-HEK293。当生长至90%左右密度时,此时生长状态最佳,去除培养上清,并用PBS(源培,B310KJ)润洗一次,然后加入5mL 4%多聚甲醛(生工,E672002-0500)进行固定1h,最后用PBS润洗两次,便可作为抗原材料用于噬菌体的细胞筛选。筛选时,羊驼库对应的噬菌体首先和固定的人CLDN18.1-HEK293细胞培养方瓶室温孵育1h,然后吸取经过吸附后的上清噬菌体,和固定的人CLDN18.2-HEK293T细胞培养方瓶孵育2h。PBS润洗两次后,加入3mL甘氨酸-HCl(pH2.0)轻轻混匀10min,以洗脱特异性结合目的膜蛋白CLDN18.2的噬菌体,接着将洗脱上清侵染对数期的SS320菌体(Lucigen,60512-1),静置30min,然后220rpm条件下培养1h,再通过加入VSCM13辅助噬菌体,静置30min,继续在220rpm条件下培养1h,离心并置换至C+/K+2-YT培养基中,最终得到的噬菌体继续用于第二轮的筛选。如此反复,并对每轮随机挑选的10个克隆进行序列分析,结果发现经过3轮的筛选,第三轮筛选后序列富集明显。
挑取第三轮筛选的克隆于96孔板中制备噬菌体上清,通过噬菌体ELISA筛选针对CLDN18.2重组蛋白的阳性克隆,然后挑取所有阳性克隆测序分析,接着将序列唯一的克隆制备噬菌体上清进一步在流式水平上验证,筛选到只结合人CLDN18.2而不结合人CLDN18.1的候选抗体。
具体流式水平验证方法如下:
首先分别取1×105个人CLDN18.2-HEK293T与人CLDN18.1-HEK293细胞,500g低速离心去上清,细胞用如1.3.1所述的FACS缓冲液润洗后,加入用10%FBS(Gibco,15140-141)封闭1h的噬菌体制备上清,在4℃孵育1h,然后用FACS缓冲液润洗两次,以1:50加入抗M13鼠源单克隆抗体(Sino Biological,11973-MM05T),并在4℃孵育1h。然后用FACS缓冲液润洗两次,加入APC标记的抗鼠Fc二抗(Jackson,115136071),在4℃孵育1h,以FACS缓冲液润洗两次,最后通过流式细胞仪(Beckman,CytoFLEX AOO-1-1102)进行检测。
具体结果如下表2所示:
表2
以上结果表明,本公开的抗体均能够特异性结合人CLDN18.2。
分别以克隆号对相应的候选抗体进行命名。各候选抗体的氨基酸序列如下表3和4所示。
表3本公开的部分示例性抗体(候选抗体)的CDR序列
表4本公开的部分示例性抗体(候选抗体)的可变区序列
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对筛选到的多个候选抗体之间的氨基酸序列进行比较,其结果如图2所示。
各候选抗体之间的可变区氨基酸序列同一性比较如下表5-1和5-2所示。
表5-1
表5-2
实施例4
嵌合VHH-Fc(hIgG1)抗体的产生和表达
CLDN18.2在胃癌等癌症细胞上高表达,针对此类肿瘤相关靶点的抗体药物可以通过补体依赖的细胞毒性作用(CDC)和抗体依赖的细胞介导的细胞毒性作用(ADCC)来杀伤肿瘤。本实施例在实施例3筛选到的候选纳米抗体基础上设计嵌合抗体,并进行表达用于后续的CDC和ADCC实验。考虑到靶点的特殊性,在将候选纳米抗体基因构建到瞬转表达质粒pcDNA3.4(Thermofisher,A14697)上时,在候选纳米抗体的C端融合人IgG1 Fc片段(EPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK,SEQ ID NO:20),这个片段包括连接区和IgG1的恒定区,用以介导ADCC和CDC等效应。本实施例选取了候选纳米抗体A-2-4,在其基础上融合了人IgG1 Fc片段,得到嵌合抗体NA1-S(在本公开中也称为“候选抗体NA1-S”、“抗体NA1-S”或“NA1-S抗体”),选取了候选纳米抗体A18-1-63、A18-1-42和A293-34,在各自基础上融合了人IgG1 Fc片段,分别得到嵌合抗体NA3-S(在本公开中也称为“候选抗体NA3-S”、“抗体NA3-S”或“NA3-S抗体”,其为候选纳米抗体A18-1-63与人IgG1 Fc融合得到的嵌合抗体)、NA5-S(在本公开中也称为“候选抗体NA5-S”、“抗体NA5-S”或“NA5-S抗体”,其为候选纳米抗体A18-1-42与人IgG1 Fc融合得到的嵌合抗体)和NA6-S(在本公开中也称为“候选抗体NA6-S”、“抗体NA6-S”或“NA6-S抗体”,其为候选纳米抗体A293-34与人IgG1 Fc融合得到的嵌合抗体)。
抗体NA1-S、NA3-S、NA5-S和NA6-S的表达采用的是ExpiCHO瞬转表达***(Gibco,A29133),具体方法如下:
转染当天,确认细胞密度为7×106至1×107个活细胞/mL左右,细胞活率>98%,此时用37℃预热的新鲜ExpiCHO表达培养基25mL将细胞调整到终浓度为6×106个细胞/mL,用4℃预冷的OptiPROTMSFM 1mL稀释目的质粒(共25μg),同时用920μL OptiPROTMSFM稀释80μLExpiFectamineTMCHO,再将两者混合并轻轻吹打混匀制备成ExpiFectamineTMCHO/质粒DNA混合液,室温孵育1-5min之后转移到准备好的细胞悬液中,缓慢加入并同时轻轻摇晃细胞悬液,最后置于细胞培养摇床中,在37℃,8%CO2条件下培养。
在转染后18-22个小时内添加ExpiCHOTMEnhancer和ExpiCHOTMFeed,摇瓶放置于32℃摇床和5%CO2条件下继续培养,在转染后第五天,添加相同体积的ExpiCHOTMFeed,缓慢加入的同时轻轻混匀细胞混悬液,转染12-15天后,将细胞表达上清高速离心(15000g,10min),所得上清用Protein A(Millipore,P2545)进行亲和纯化,然后用100mM乙酸钠(pH3.0)洗脱目的蛋白,接着用1M Tris-HCl中和,最后所得蛋白(即抗体NA1-S、NA3-S、NA5-S或NA6-S)用浓缩管(Millipore,UFC901096)的方法置换至PBS缓冲液当中。
实施例5
候选抗体的特异性结合和物种交叉特异性结合测定
以候选抗体NA1-S为例,用含0.25%EDTA的Trypsin(Gibco,25200-072)消化生长状态良好的人CLDN18.2-HEK293T、HEK293T、HEK293、人CLDN18.1-HEK293、鼠CLDN18.2-HEK293和鼠CLDN18.1-HEK293细胞,取1×105个细胞和10μg/mL候选抗体NA1-S孵育1h,另外以hIgG1同型抗体作为对照。用FACS缓冲液润洗两次,然后和0.5μg PE标记的山羊抗人IgG-Fc二抗(Abcam,ab98596)在4℃孵育1h。其后,用FACS缓冲液洗三次,通过流式细胞仪(Beckman,CytoFLEX AOO-1-1102)检测候选抗体在细胞上的结合。采用与NA1-S相同的方法测定候选抗体NA3-S、NA5-S和NA6-S的特异性结合及物种交叉特异性。
流式检测的结果(如图3所示)显示,类似于对照抗体IMAB362,候选抗体NA1-S(图3a)、NA3-S、NA5-S和NA6-S(图3b)均特异性结合人CLDN18.2-HEK293T和鼠CLDN18.2-HEK293,而在HEK293T、HEK293、人CLDN18.1-HEK293和鼠CLDN18.1HEK293细胞上不结合。这说明候选抗体NA1-S、NA3-S、NA5-S和NA6-S能够特异性结合CLDN18.2而不结合CLDN18.1,而且在人和鼠CLDN18.2上交叉识别。
实施例6
候选抗体在人CLDN18.2-HEK293T细胞株和人CLDN18.2-KATOIII肿瘤细胞株上结合能力的比较
取培养状态良好的人CLDN18.2-HEK293T细胞,与三倍梯度稀释后的候选抗体NA1-S、NA3-S、NA5-S和NA6-S分别在4℃孵育1h。经FACS缓冲液润洗两遍,然后加入PE标记的山羊抗人IgG-Fc抗体(Abcam,ab98596)0.5μg,在4℃孵育1h,再经FACS缓冲液润洗两遍之后,通过流式细胞仪检测。
流式检测结果如图4a、图5a和图5b所示,结果显示:在人CLDN18.2-HEK293T细胞上,候选抗体均表现出来和对照抗体相当的细胞结合活性。
采用相同的方法测定候选抗体NA1-S、NA3-S、NA5-S和NA6-S在人CLDN18.2-KATOIII肿瘤细胞株上的结合能力。流式检测结果如图4b和图5c所示,结果显示:在人CLDN18.2-KATOIII肿瘤细胞株上,候选抗体均表现出来和对照抗体相当的细胞结合活性。
实施例7
候选抗体的补体依赖的细胞毒性作用(CDC)
采用MTS法测定候选抗体的CDC细胞杀伤效应。候选抗体NA1-S、NA3-S、NA5-S和NA6-S由于包含有IgG1 Fc片段,可以通过CDC对细胞进行杀伤,而MTS试剂能够被活细胞产生的NADPH或者NADH还原成一种有色化合物,因此颜色的深浅代表了抗体介导CDC的杀伤效果。具体操作方法如下:
以候选抗体NA1-S为例。先经trypsin消化培养状态良好的人CLDN18.2-HEK293T细胞之后,取5×104个细胞和稀释5倍的兔血清混合,然后分别加入梯度稀释的候选抗体NA1-S或对照抗体IMAB362各50μL,于37℃孵育3h。然后,向候选抗体NA1-S或对照抗体IMAB362中分别加入MTS试剂(Promega,G3580)30μL,充分混合均匀,置于37℃、5%CO2的恒温培养箱培养4h,期间观察培养基颜色变化,通过酶标仪测定492nm波长下的OD值。其中以10%TritonX-100加靶细胞作为全裂解的对照,以只加靶细胞作为空白阴性对照,以兔补体加靶细胞作为背景阴性对照。
细胞杀伤率按如下公式计算:细胞杀伤率(%)=(候选抗体孔OD值-背景孔OD值)/(全裂解孔OD值-空白孔OD值)×100%。
候选抗体NA1-S在人CLDN18.2-HEK293T肿瘤细胞上的CDC杀伤效应结果如图6a所示。从图6a中可以看出,相对于对照抗体IMAB362,候选抗体NA1-S在等摩尔浓度下展示出更强的CDC细胞杀伤效应,NA1-S的EC50为0.5289nM,而IMAB362的EC50为0.936nM。采用同样的方法测定候选抗体NA3-S、NA5-S和NA6-S在人CLDN18.2-HEK293T细胞上的CDC杀伤效应,其结果如图7a-c所示。从图7a-c中可以看出,相对于对照抗体IMAB362,候选抗体NA3-S、NA5-S和NA6-S在等摩尔浓度下也展示出相当的CDC细胞杀伤效果。
采用同样的方法测定候选抗体NA1-S在人CLDN18.2-KATOIII肿瘤细胞上的CDC杀伤效应,其结果如图6b所示。从图6b中可以看出,NA1-S在等摩尔浓度下展示出比对照抗体IMAB362更强的CDC细胞杀伤效应,其中NA1-S的EC50为1.91nM,而IMAB362的EC50为50.86nM。采用与NA1-S相同的方法测定候选抗体NA3-S、NA5-S和NA6-S的CDC效应,与NA1-S类似,它们也有相比对照抗体IMAB362更强的CDC细胞杀伤效应。例如NA3-S在等摩尔浓度下展示出比对照抗体IMAB362更强的CDC细胞杀伤效应,其中纳米抗体NA3-S的EC50为4.831nM,而IMAB362的EC50为85.83nM(图7d)。
实施例8
抗体依赖的细胞介导的细胞毒作用(ADCC)
利用乳酸脱氢酶(LDH)释放法检测ADCC效应。其原理是:抗体的可变区结合靶细胞上的目标抗原,当抗体的Fc段与PBMC中的NK效应细胞上的FcRIIIa(又名CD16a)结合后,NK细胞会释放穿孔素、颗粒酶等裂解靶细胞,然后通过LDH乳酸脱氢酶试剂盒(Takara,MK401)可以检测细胞上清中乳酸脱氢酶的释放,以此来测定NK细胞对靶细胞的杀伤程度。具体操作如下:
在96孔细胞培养板中每孔加入50μL密度为2×105个/mL的人CLDN18.2-HEK293T细胞,置于37℃培养箱中培养过夜(16-20h)。加入梯度稀释的候选抗体NA1-S或NA3-S 50μL,混匀后于37℃培养箱孵育20min,再加入复苏好的5×105个/孔的人PBMC细胞(效应细胞/靶细胞比例为50:1),37℃培养箱孵育4h后,通过300g离心得到上清,然后加入LDH检测试剂,反应60min,最后通过酶标仪(Molecular Devices,SpectraMax190)测定在492nm波长下的OD值并进行检测结果的分析。其中以10%Triton X-100加靶细胞作为全裂解的对照,以只加靶细胞作为空白阴性对照,以PBMC加靶细胞作为背景阴性对照。
细胞杀伤率按如下公式计算:杀伤率(%)=(候选抗体孔OD值-背景孔OD值)/(全裂解孔OD值-空白孔OD值)×100%
结果(图8a和8c)显示,候选抗体NA1-S和NA3-S在等摩尔浓度下均具有和对照抗体IMAB362相当的细胞杀伤活性。
采用同样的方法测定候选抗体NA1-S或NA3-S在人CLDN18.2-KATOIII肿瘤细胞上的ADCC杀伤效应,结果如图8b和8d所示。图8b的结果显示,NA1-S在等摩尔浓度下展示出比对照抗体IMAB362更强的ADCC细胞杀伤效应,其中,候选抗体的杀伤效率高达45%,而IMAB362对照抗体的杀伤效率只有17%。图8d的结果显示,NA3-S在等摩尔浓度下也展示出比对照抗体IMAB362更强的ADCC细胞杀伤效应,其中,候选抗体的杀伤效率近50%,而IMAB362对照抗体的杀伤效率只有20-25%。
实施例9
体内抑瘤实验(以人CLDN18.2-HEK293T作为成瘤细胞株)
实验使用6-8周龄,雌性SCID小鼠(体重24-26g)。实验小鼠饲养在恒温恒湿的独立通风盒内,饲养室温度21-24℃,湿度30-53%。
将1×107个人CLDN18.2-HEK293T细胞进行右侧腋窝皮下接种注射。待皮下瘤块体积达80-100mm3时,剔除肿瘤体积差异较大的小鼠样本,依据肿瘤体积进行随机分组(每组8只小鼠):分别是PBS处理组,IMAB362抗体处理组,候选抗体NA1-S处理组。细胞接种6天后即开始用抗体处理(候选抗体NA1-S根据分子量采用与IMAB362抗体等摩尔浓度的剂量,换算成质量浓度分别为2.5mg/kg和5mg/kg),每个星期两次给药处理,分别是静脉注射和腹膜内注射两种方式交替给药。随时观察和记录肿瘤长(mm)和宽(mm),计算其肿瘤生长体积(V),计算方式为:V=(长×宽2)/2。以同样的方法对候选抗体NA3-S进行测试,其中候选抗体NA3-S根据分子量采用与IMAB362抗体等摩尔浓度的剂量,换算成质量浓度分别为5mg/kg和10mg/kg。
抗体抑瘤的结果如图9a-b所示,从中可以看出:相对于对照抗体IMAB362,候选抗体NA1-S在此质量剂量下在低浓度的抑制肿瘤生长方面的效果与高浓度的对照抗体相似,肿瘤生长抑制率为55%左右。候选抗体NA3-S在低质量浓度剂量下在抑制肿瘤生长方面的效果与高浓度对照抗体相似,几乎都可以完成抑制肿瘤的生长。
实施例10
候选抗体在人CLDN18.2上的结合表位测定
候选抗体和对照抗体IMAB362都特异性结合CLDN18.2而不结合CLDN18.1,而CLDN18.2和CLDN18.1的膜外区域只有在ECD1区域有8个氨基酸的差别,因此推测候选抗体和对照抗体IMAB362的抗原结合表位在ECD1区域上,为了确认候选抗体和IMAB362的抗原结合位置是否一致,本实施例采用了竞争结合的方法,具体方法如下:
将传代2-4次且生长状态良好的CLDN18.2-HEK293T细胞用于实验,4℃、300g离心去除上清,随后将细胞用FACS缓冲液重悬,计数后将细胞密度调整为2×106个细胞/mL,以每孔100μL加至新的96孔圆底板中,4℃、300g离心并去除上清。
以候选抗体NA1-S为例,配制FACS缓冲液(1X PBS+2%FBS)并使用FACS缓冲液将竞争抗体NA1-S(或IMAB362)进行梯度稀释,同样使用FACS缓冲液将生物素标记的IMAB362(或者NA1-S)蛋白稀释至13.4nM,分别向96孔板中加入100μL梯度稀释液和100μL生物素标记蛋白稀释液,用排枪轻轻吹打混匀并将96孔板放置于4℃孵育1h。将孵育后的抗体和细胞混合液于4℃、300g离心并去除上清,随后向对应孔中各加入200μL的FACS缓冲液并重悬细胞,4℃、300g离心去上清;重复此步骤2次。使用FACS缓冲液将PE标记的链霉亲和素(eBioscience,12-4317-87)以1:200进行稀释,使用排枪向对应细胞中加入200μL/孔并轻轻吹打重悬细胞,随后将细胞放置于4℃避光孵育30min,孵育结束后将细胞于4℃、300g离心去除上清,加入FACS缓冲液重悬细胞,重复该步骤两次。最后通过流式细胞仪(Beckman,CytoFLEX AOO-1-1102)检测。
流式结果如图10a显示,随着NA1-S浓度的增加,IMAB362-biotin在CLDN18.2-HEK293T细胞上的结合减少,同样在如图10c中的流式结果显示随着IMAB362浓度的增加,NA1-S-biotin在CLDN18.2-HEK293T细胞上的结合减少,这些都说明NA1-S和IMAB362在CLDN18.2上的抗原表位类似。NA3-S的结果如图10b和10d显示,其与NA1-S相似。
为了进一步了解NA1-S或NA3-S和IMAB362在CLDN18.2上的关键氨基酸位点,基于CLDN18.2和CLDN18.1在ECD1存在8个氨基酸差别,本实施例构建了8个突变体HEK293T细胞株,将CLDN18.2上的8个差别氨基酸分别突变成对应CLDN18.1的氨基酸,然后通过测定待测抗体在野生株和突变株上的结合能力差别判断此氨基酸是否为抗体结合的关键氨基酸。具体方法如下:
首先,测定CLDN18.2野生和突变体HEK293T细胞株的表达情况,方法如1.3.2的方法,按细胞破膜试剂盒(eBioscience,88-8824-00)的说明书方法对细胞进行固定和破膜,然后根据抗CLDN18抗体[34H14L15]对C端CLDN18胞内段的结合能力判定表达情况,结果如图10e,各个突变细胞株以及野生株的CLDN18.2都有较高的表达。
基于此,参考1.3.1的方法,测定候选抗体NA1-S或NA3-S和IMAB362在CLDN18.2野生和突变体HEK293T细胞株上的结合强度,同时将候选抗体的结合强度除以各个细胞株的表达水平,并以候选抗体在野生株的结合作为100%进行归一化处理作为最终的相对结合强度,如图10f-i,CLDN18.2ECD1上的3个位点分别是Q29,Q47和E56对于NA1-S和NA3-S在人CLDN18.2-HEK293T的结合非常关键,而A42,E56和G65是IMAB362结合CLDN18.2的3个关键氨基酸。
实施例11
候选抗体介导的Fab-ZAP细胞杀伤效应
CLDN18.2在多种肿瘤上都高表达,而且在正常组织中其特异性的表达在胃上皮细胞的紧密连接结构中,因此有可能成为理想的ADC药物靶点。本实验通过抗体介导Fab-ZAP内吞的细胞毒性来检测抗体的内吞活性,其中Fab-ZAP(Atsbio,IT-51-100)是一种连接了saporin(皂素)的抗Fc区域的Fab片段,saporin是一种核糖体抑制剂,能够抑制蛋白质的合成而使细胞死亡。Fab-ZAP和CLDN18.2的抗体孵育后使CLDN18.2的抗体带上Fab-ZAP,当CLDN18.2的抗体内吞时,Fab-ZAP随着抗体进入到细胞内,从而杀死细胞,然后通过MTS(Promega,G3580)检测细胞的活性来检测并比较候选抗体和对照抗体的内吞活性。具体方法如下:
取处于对数生长期的CLDN18.2-HEK293T细胞,用胰酶(0.25%(w/v)Trypsin0.53mM EDTA)消化细胞至细胞间不黏连,产生间隙,用完全培养基终止消化。充分混匀细胞后,细胞计数并测定其活率。将细胞密度调整为4x 104细胞/mL,以每孔50μL加至细胞培养板并置于37℃细胞培养箱孵育16小时。同时用DMEM完全培养基稀释Fab-ZAP至2μg/mL,以此为稀释液进一步将候选抗体NA1-S或NA3-S和对照抗体进行梯度稀释,并用排枪取50μL加入至细胞培养板中与CLDN18.2-HEK293T轻轻吹打混匀,将细胞培养板放入37℃细胞培养箱继续孵育72小时。接着使用排枪向每孔中加入20μL MTS并轻轻吹打混匀,37℃孵育2-4小时,最后将细胞板用台式离心机以1000rpm的转速离心5分钟后,于酶标仪(MolecularDevices,SpectraMax190)中读取数据,检测波长为492nm。
结果如图11a-b,相对于对照抗体IMAB362,候选抗体NA1-S和NA3-S可以更有效的通过Fab-ZAP对目标细胞CLDN18.2-HEK293T进行杀伤,NA1-S和IMAB362的IC50分别为0.1nM和0.24nM,NA3-S和IMAB362的IC50分别为0.07nM和0.32nM。这不仅充分说明了候选抗体可以通过CLDN18.2进入细胞,而且优于对照抗体IMAB362,有潜力用于开发ADC抗体偶联药物。
实施例12
候选抗体NA3-S的人源化改造
相对鼠源抗体,羊驼来源纳米抗体和人源抗体的同源性较高,但其结构特殊,因此在NA3-S人源化设计过程中,选择了最接近人的种系基因germline,而且在做回复突变时兼顾抗体的结构维持不变,最终设计了一系列人源化抗体,其中NA3S-H1为最优的分子,其抗体序列见下表。
可变区序列(SEQ ID NO:63):
QVQLVESGGGLVQPGGSLRLSCAASGSIFNIPVMGWYRQAPGKQRELVAGISTGGTTNYGDSVKGRFTISRDNAKNTVYLQMNSLKPEDTAVYYCNVLVVSGIGSTLEVWGQGTLVTVSS
其中斜体加粗的V(第5位)和S(最后一位)是人源化位点。编码该可变区序列的核苷酸序列如SEQ ID NO:64所示。
为了考察NA3-S人源化后亲和力是否不下降,采用了1.3.1所述方法比较NA3-S和NA3S-H1在CLDN18.2-HEK293T细胞上的结合能力,结果如图12,人源化的分子NA3S-H1和母本抗体NA3-S具备相似的亲和力,且优于对照抗体IMAB362。
实施例13
候选抗体NA3S-H1在高浓度下的结合特异性
CLDN18.2和CLDN18.1的候选抗体结合区域ECD1上只存在8个氨基酸的差别,而后者表达于肺部上皮细胞中,因此抗体药物如果非特异性结合CLDN18.1将导致严重的肺部损伤或者毒性从而限制临床的应用,因此本实施例在体外采用不同浓度的抗体(包括100μg/mL高浓度)和CLDN18.1-HEK293孵育,方法如1.3.1所述,将不同浓度的抗体和目标细胞CLDN18.1-HEK293在4℃孵育1h,接着再用上述FACS缓冲液润洗三次,加入PE标记的山羊抗人IgG Fc抗体(Abcam,ab98596)0.5μg(0.5mg/ml),在4℃孵育1h。其后,经FACS缓冲液润洗三次,并向细胞中加入200μL FACS缓冲液重悬细胞,最后通过流式细胞仪(Beckman,CytoFLEX AOO-1-1102)进行检测,记录结合强度和细胞结合阳性率。
结果如图13a显示,在结合强度方面,NA3S-H1和对照抗体IMAB362在CLDN18.1-HEK293的结合不随着浓度的增加而增加,与同种型对照的结合强度几乎一致,而在图13b的细胞结合阳性率方面,即使在100μg/mL高浓度下,NA3S-H1和IMAB362的阳性率都非常微弱在0.04-0.18%之间,其中NA3S-H1三次重复的阳性率为0.145%、0.17%和0.173%,IMAB362三次重复的阳性率为0.042%、0.128%和0.041%,同种型对照hIgG1三次重复的阳性率为0.063%、0.233%和0.115%。综合图13a和13b的结果,NA3S-H1和对照抗体IMAB362都不结合CLDN18.1-HEK293细胞,都能够特异性结合CLDN18.2而不结合CLDN18.1。
实施例14
候选抗体NA3S-H1的补体依赖的细胞毒性作用(CDC)
本实施例比较人源化分子NA3S-H1和对照抗体IMAB362的补体依赖的细胞毒性作用,参考实施例7的方法进行测定,简单来讲,取5×104个CLDN18.2-KATOIII细胞和稀释5倍的兔血清混合,然后分别加入梯度稀释的候选抗体NA3S-H1或对照抗体IMAB362各50μL,于37℃孵育3h。接着加入MTS试剂(Promega,G3580)30μL,充分混合均匀,置于37℃、5%CO2的恒温培养箱培养4h,期间观察培养基颜色变化,最后通过酶标仪测定492nm波长下的OD值,其中以10%Triton X-100加靶细胞作为全裂解的对照,以只加靶细胞作为空白阴性对照,以兔补体加靶细胞作为背景阴性对照,用以推算抗体的细胞杀伤效果。
结果如图14,NA3S-H1比对照抗体IMAB362具有更强的CDC细胞杀伤效应,其中NA3S-H1的EC50为10.41nM,而IMAB362的EC50为149.4nM。
实施例15
人源化抗体NA3S-H1介导NK细胞的细胞毒作用(ADCC)
本实施例比较了人源化抗体NA3S-H1和对照抗体介导的细胞毒作用,方法采用实施例8的方法,通过将梯度稀释的候选抗体与固定比例的靶标细胞以及人PBMC细胞孵育4h后,采用LDH乳酸脱氢酶试剂盒(Takara,MK401)方法并在492nm波长下检测细胞上清中乳酸脱氢酶的释放,以此来测定抗体介导NK细胞对靶细胞的杀伤效果。
图15a和15b显示了抗体介导NK细胞对CLDN18.2-KATOIII或者CLDN18.2-HEK293T的细胞杀伤效果,结果表明候选抗体NA3S-H1和对照抗体IMAB362介导的ADCC效应相近。
本领域技术人员将进一步认识到,在不脱离其精神或中心特征的情况下,本发明可以以其他具体形式来实施。由于本发明的前述描述仅公开了其示例性实施方案,应该理解的是,其他变化被认为是在本发明的范围内。因此,本发明不限于在此详细描述的特定实施方案。相反,应当参考所附权利要求来指示本发明的范围和内容。
序列表
<110> 三优生物医药(上海)有限公司
<120> 新型CLDN18.2结合分子
<130> IDC216058
<160> 64
<170> PatentIn version 3.5
<210> 1
<211> 8
<212> PRT
<213> 人工序列
<400> 1
Gly Asn Ile Phe Arg Ile Asp Thr
1 5
<210> 2
<211> 7
<212> PRT
<213> 人工序列
<400> 2
Ile Ser Arg Gly Gly Thr Thr
1 5
<210> 3
<211> 15
<212> PRT
<213> 人工序列
<400> 3
Asn Ala Gln Ala Trp Asp Pro Gly Thr Phe Arg Tyr Leu Glu Val
1 5 10 15
<210> 4
<211> 7
<212> PRT
<213> 人工序列
<400> 4
Ile Ser Arg Gly Gly Ser Thr
1 5
<210> 5
<211> 15
<212> PRT
<213> 人工序列
<400> 5
Asn Ala Gln Ala Trp Asp Pro Gly Thr Ile Arg Tyr Leu Glu Val
1 5 10 15
<210> 6
<211> 15
<212> PRT
<213> 人工序列
<400> 6
Asn Ala Gln Ala Trp Asp Val Gly Thr Ile Arg Tyr Leu Glu Val
1 5 10 15
<210> 7
<211> 121
<212> PRT
<213> 人工序列
<400> 7
Glu Val Gln Val Gln Glu Ser Gly Gly Gly Leu Val Gln Ala Gly Thr
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Asn Ile Phe Arg Ile Asp
20 25 30
Thr Met Gly Trp Tyr Arg Gln Ala Pro Gly Lys Gln Arg Glu Leu Val
35 40 45
Ala Gly Ile Ser Arg Gly Gly Thr Thr Thr Tyr Ala His Ser Val Lys
50 55 60
Glu Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Met Tyr Leu
65 70 75 80
Gln Met Asn Ser Leu Lys Ser Glu Asp Thr Ala Gly Tyr Tyr Cys Asn
85 90 95
Ala Gln Ala Trp Asp Pro Gly Thr Phe Arg Tyr Leu Glu Val Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ala
115 120
<210> 8
<211> 121
<212> PRT
<213> 人工序列
<400> 8
Glu Val Gln Val Gln Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Asn Ile Phe Arg Ile Asp
20 25 30
Thr Met Gly Trp Tyr Arg Gln Ala Pro Gly Lys Gln Arg Glu Leu Val
35 40 45
Ala Gly Ile Ser Arg Gly Gly Thr Thr Thr Tyr Ala His Ser Val Lys
50 55 60
Glu Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Met Tyr Leu
65 70 75 80
Gln Met Asn Ser Leu Lys Ser Glu Asp Thr Ala Gly Tyr Tyr Cys Asn
85 90 95
Ala Gln Ala Trp Asp Pro Gly Thr Phe Arg Tyr Leu Glu Val Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ala
115 120
<210> 9
<211> 121
<212> PRT
<213> 人工序列
<400> 9
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Asn Ile Phe Arg Ile Asp
20 25 30
Thr Met Gly Trp Tyr Arg Gln Ala Pro Gly Lys Gln Arg Glu Leu Val
35 40 45
Ala Gly Ile Ser Arg Gly Gly Thr Thr Thr Tyr Ala His Ser Val Lys
50 55 60
Glu Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Met Tyr Leu
65 70 75 80
Gln Met Asn Ser Leu Lys Ser Glu Asp Thr Ala Gly Tyr Tyr Cys Asn
85 90 95
Ala Gln Ala Trp Asp Pro Gly Thr Phe Arg Tyr Leu Glu Val Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ala
115 120
<210> 10
<211> 121
<212> PRT
<213> 人工序列
<400> 10
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Asn Ile Phe Arg Ile Asp
20 25 30
Thr Met Gly Trp Tyr Arg Gln Ala Pro Gly Lys Gln Arg Glu Phe Val
35 40 45
Ala Gly Ile Ser Arg Gly Gly Ser Thr Asn Tyr Ala His Ser Val Lys
50 55 60
Glu Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Met Tyr Leu
65 70 75 80
Gln Met Asn Ser Leu Lys Ser Glu Asp Thr Ala Gly Tyr Tyr Cys Asn
85 90 95
Ala Gln Ala Trp Asp Pro Gly Thr Ile Arg Tyr Leu Glu Val Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 11
<211> 121
<212> PRT
<213> 人工序列
<400> 11
Glu Val Gln Leu Gln Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Asn Ile Phe Arg Ile Asp
20 25 30
Thr Met Gly Trp Tyr Arg Gln Ala Pro Gly Lys Gln Arg Glu Phe Val
35 40 45
Ala Gly Ile Ser Arg Gly Gly Ser Thr Asn Tyr Ala His Ser Val Lys
50 55 60
Glu Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Met Tyr Leu
65 70 75 80
Gln Met Asn Ser Leu Lys Ser Glu Asp Thr Ala Gly Tyr Tyr Cys Asn
85 90 95
Ala Gln Ala Trp Asp Pro Gly Thr Ile Arg Tyr Leu Glu Val Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ala
115 120
<210> 12
<211> 121
<212> PRT
<213> 人工序列
<400> 12
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Asn Ile Phe Arg Ile Asp
20 25 30
Thr Met Gly Trp Tyr Arg Gln Ala Pro Gly Lys Gln Arg Glu Phe Val
35 40 45
Ala Gly Ile Ser Arg Gly Gly Ser Thr Asn Tyr Ala His Ser Val Lys
50 55 60
Glu Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Met Tyr Leu
65 70 75 80
Gln Met Asn Ser Leu Lys Ser Glu Asp Thr Ala Gly Tyr Tyr Cys Asn
85 90 95
Ala Gln Ala Trp Asp Pro Gly Thr Ile Arg Tyr Leu Glu Val Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ala
115 120
<210> 13
<211> 121
<212> PRT
<213> 人工序列
<400> 13
Glu Val Gln Val Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Asn Ile Phe Arg Ile Asp
20 25 30
Thr Met Val Trp Tyr Arg Gln Ala Pro Gly Lys Gln Arg Glu Leu Val
35 40 45
Ala Gly Ile Ser Arg Gly Gly Thr Thr Asn Tyr Ala His Ser Val Lys
50 55 60
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Met Tyr Leu
65 70 75 80
Gln Met Asn Ser Leu Lys Ser Glu Asp Thr Ala Thr Tyr Tyr Cys Asn
85 90 95
Ala Gln Ala Trp Asp Val Gly Thr Ile Arg Tyr Leu Glu Val Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ala
115 120
<210> 14
<211> 121
<212> PRT
<213> 人工序列
<400> 14
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Asn Ile Phe Arg Ile Asp
20 25 30
Thr Met Val Trp Tyr Arg Gln Ala Pro Gly Lys Gln Arg Glu Leu Val
35 40 45
Ala Gly Ile Ser Arg Gly Gly Thr Thr Asn Tyr Ala His Ser Val Lys
50 55 60
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Met Tyr Leu
65 70 75 80
Gln Met Asn Ser Leu Lys Ser Glu Asp Thr Ala Thr Tyr Tyr Cys Asn
85 90 95
Ala Gln Ala Trp Asp Val Gly Thr Ile Arg Tyr Leu Glu Val Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ala
115 120
<210> 15
<211> 261
<212> PRT
<213> 人
<400> 15
Met Ala Val Thr Ala Cys Gln Gly Leu Gly Phe Val Val Ser Leu Ile
1 5 10 15
Gly Ile Ala Gly Ile Ile Ala Ala Thr Cys Met Asp Gln Trp Ser Thr
20 25 30
Gln Asp Leu Tyr Asn Asn Pro Val Thr Ala Val Phe Asn Tyr Gln Gly
35 40 45
Leu Trp Arg Ser Cys Val Arg Glu Ser Ser Gly Phe Thr Glu Cys Arg
50 55 60
Gly Tyr Phe Thr Leu Leu Gly Leu Pro Ala Met Leu Gln Ala Val Arg
65 70 75 80
Ala Leu Met Ile Val Gly Ile Val Leu Gly Ala Ile Gly Leu Leu Val
85 90 95
Ser Ile Phe Ala Leu Lys Cys Ile Arg Ile Gly Ser Met Glu Asp Ser
100 105 110
Ala Lys Ala Asn Met Thr Leu Thr Ser Gly Ile Met Phe Ile Val Ser
115 120 125
Gly Leu Cys Ala Ile Ala Gly Val Ser Val Phe Ala Asn Met Leu Val
130 135 140
Thr Asn Phe Trp Met Ser Thr Ala Asn Met Tyr Thr Gly Met Gly Gly
145 150 155 160
Met Val Gln Thr Val Gln Thr Arg Tyr Thr Phe Gly Ala Ala Leu Phe
165 170 175
Val Gly Trp Val Ala Gly Gly Leu Thr Leu Ile Gly Gly Val Met Met
180 185 190
Cys Ile Ala Cys Arg Gly Leu Ala Pro Glu Glu Thr Asn Tyr Lys Ala
195 200 205
Val Ser Tyr His Ala Ser Gly His Ser Val Ala Tyr Lys Pro Gly Gly
210 215 220
Phe Lys Ala Ser Thr Gly Phe Gly Ser Asn Thr Lys Asn Lys Lys Ile
225 230 235 240
Tyr Asp Gly Gly Ala Arg Thr Glu Asp Glu Val Gln Ser Tyr Pro Ser
245 250 255
Lys His Asp Tyr Val
260
<210> 16
<211> 261
<212> PRT
<213> 人
<400> 16
Met Ser Thr Thr Thr Cys Gln Val Val Ala Phe Leu Leu Ser Ile Leu
1 5 10 15
Gly Leu Ala Gly Cys Ile Ala Ala Thr Gly Met Asp Met Trp Ser Thr
20 25 30
Gln Asp Leu Tyr Asp Asn Pro Val Thr Ser Val Phe Gln Tyr Glu Gly
35 40 45
Leu Trp Arg Ser Cys Val Arg Gln Ser Ser Gly Phe Thr Glu Cys Arg
50 55 60
Pro Tyr Phe Thr Ile Leu Gly Leu Pro Ala Met Leu Gln Ala Val Arg
65 70 75 80
Ala Leu Met Ile Val Gly Ile Val Leu Gly Ala Ile Gly Leu Leu Val
85 90 95
Ser Ile Phe Ala Leu Lys Cys Ile Arg Ile Gly Ser Met Glu Asp Ser
100 105 110
Ala Lys Ala Asn Met Thr Leu Thr Ser Gly Ile Met Phe Ile Val Ser
115 120 125
Gly Leu Cys Ala Ile Ala Gly Val Ser Val Phe Ala Asn Met Leu Val
130 135 140
Thr Asn Phe Trp Met Ser Thr Ala Asn Met Tyr Thr Gly Met Gly Gly
145 150 155 160
Met Val Gln Thr Val Gln Thr Arg Tyr Thr Phe Gly Ala Ala Leu Phe
165 170 175
Val Gly Trp Val Ala Gly Gly Leu Thr Leu Ile Gly Gly Val Met Met
180 185 190
Cys Ile Ala Cys Arg Gly Leu Ala Pro Glu Glu Thr Asn Tyr Lys Ala
195 200 205
Val Ser Tyr His Ala Ser Gly His Ser Val Ala Tyr Lys Pro Gly Gly
210 215 220
Phe Lys Ala Ser Thr Gly Phe Gly Ser Asn Thr Lys Asn Lys Lys Ile
225 230 235 240
Tyr Asp Gly Gly Ala Arg Thr Glu Asp Glu Val Gln Ser Tyr Pro Ser
245 250 255
Lys His Asp Tyr Val
260
<210> 17
<211> 264
<212> PRT
<213> 小鼠
<400> 17
Met Ser Val Thr Ala Cys Gln Gly Leu Gly Phe Val Val Ser Leu Ile
1 5 10 15
Gly Phe Ala Gly Ile Ile Ala Ala Thr Cys Met Asp Gln Trp Ser Thr
20 25 30
Gln Asp Leu Tyr Asn Asn Pro Val Thr Ala Val Phe Asn Tyr Gln Gly
35 40 45
Leu Trp Arg Ser Cys Val Arg Glu Ser Ser Gly Phe Thr Glu Cys Arg
50 55 60
Gly Tyr Phe Thr Leu Leu Gly Leu Pro Ala Met Leu Gln Ala Val Arg
65 70 75 80
Ala Leu Met Ile Val Gly Ile Val Leu Gly Val Ile Gly Ile Leu Val
85 90 95
Ser Ile Phe Ala Leu Lys Cys Ile Arg Ile Gly Ser Met Asp Asp Ser
100 105 110
Ala Lys Ala Lys Met Thr Leu Thr Ser Gly Ile Leu Phe Ile Ile Ser
115 120 125
Gly Ile Cys Ala Ile Ile Gly Val Ser Val Phe Ala Asn Met Leu Val
130 135 140
Thr Asn Phe Trp Met Ser Thr Ala Asn Met Tyr Ser Gly Met Gly Gly
145 150 155 160
Met Gly Gly Met Val Gln Thr Val Gln Thr Arg Tyr Thr Phe Gly Ala
165 170 175
Ala Leu Phe Val Gly Trp Val Ala Gly Gly Leu Thr Leu Ile Gly Gly
180 185 190
Val Met Met Cys Ile Ala Cys Arg Gly Leu Thr Pro Asp Asp Ser Asn
195 200 205
Phe Lys Ala Val Ser Tyr His Ala Ser Gly Gln Asn Val Ala Tyr Arg
210 215 220
Pro Gly Gly Phe Lys Ala Ser Thr Gly Phe Gly Ser Asn Thr Arg Asn
225 230 235 240
Lys Lys Ile Tyr Asp Gly Gly Ala Arg Thr Glu Asp Asp Glu Gln Ser
245 250 255
His Pro Thr Lys Tyr Asp Tyr Val
260
<210> 18
<211> 264
<212> PRT
<213> 小鼠
<400> 18
Met Ala Thr Thr Thr Cys Gln Val Val Gly Leu Leu Leu Ser Leu Leu
1 5 10 15
Gly Leu Ala Gly Cys Ile Ala Ala Thr Gly Met Asp Met Trp Ser Thr
20 25 30
Gln Asp Leu Tyr Asp Asn Pro Val Thr Ala Val Phe Gln Tyr Glu Gly
35 40 45
Leu Trp Arg Ser Cys Val Gln Gln Ser Ser Gly Phe Thr Glu Cys Arg
50 55 60
Pro Tyr Phe Thr Ile Leu Gly Leu Pro Ala Met Leu Gln Ala Val Arg
65 70 75 80
Ala Leu Met Ile Val Gly Ile Val Leu Gly Val Ile Gly Ile Leu Val
85 90 95
Ser Ile Phe Ala Leu Lys Cys Ile Arg Ile Gly Ser Met Asp Asp Ser
100 105 110
Ala Lys Ala Lys Met Thr Leu Thr Ser Gly Ile Leu Phe Ile Ile Ser
115 120 125
Gly Ile Cys Ala Ile Ile Gly Val Ser Val Phe Ala Asn Met Leu Val
130 135 140
Thr Asn Phe Trp Met Ser Thr Ala Asn Met Tyr Ser Gly Met Gly Gly
145 150 155 160
Met Gly Gly Met Val Gln Thr Val Gln Thr Arg Tyr Thr Phe Gly Ala
165 170 175
Ala Leu Phe Val Gly Trp Val Ala Gly Gly Leu Thr Leu Ile Gly Gly
180 185 190
Val Met Met Cys Ile Ala Cys Arg Gly Leu Thr Pro Asp Asp Ser Asn
195 200 205
Phe Lys Ala Val Ser Tyr His Ala Ser Gly Gln Asn Val Ala Tyr Arg
210 215 220
Pro Gly Gly Phe Lys Ala Ser Thr Gly Phe Gly Ser Asn Thr Arg Asn
225 230 235 240
Lys Lys Ile Tyr Asp Gly Gly Ala Arg Thr Glu Asp Asp Glu Gln Ser
245 250 255
His Pro Thr Lys Tyr Asp Tyr Val
260
<210> 19
<211> 53
<212> PRT
<213> 人
<400> 19
Asp Gln Trp Ser Thr Gln Asp Leu Tyr Asn Asn Pro Val Thr Ala Val
1 5 10 15
Phe Asn Tyr Gln Gly Leu Trp Arg Ser Cys Val Arg Glu Ser Ser Gly
20 25 30
Phe Thr Glu Cys Arg Gly Tyr Phe Thr Leu Leu Gly Leu Pro Ala Met
35 40 45
Leu Gln Ala Val Arg
50
<210> 20
<211> 232
<212> PRT
<213> 人
<400> 20
Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala
1 5 10 15
Pro Glu Leu Leu Gly Gly 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 Glu Tyr Lys Cys Lys 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 Lys
225 230
<210> 21
<211> 14
<212> PRT
<213> 人工序列
<400> 21
Gly Phe Lys Ala Ser Thr Gly Phe Gly Ser Asn Thr Lys Asn
1 5 10
<210> 22
<211> 360
<212> DNA
<213> 人工序列
<400> 22
gaggtgcagg tgcaggagtc tgggggaggc ctggtacagg ctgggacctc tctgagactc 60
tcctgtgcag cctctggcaa catcttccgt atcgatacca tgggctggta ccgccaggct 120
ccaggaaagc agcgcgagtt ggtcgcaggt atttctcgtg gtggtacaac aacctatgca 180
cactccgtga aggaacgatt caccatctcc agagacaacg ccaagaacac gatgtatctg 240
caaatgaaca gcctgaaatc tgaggacacg gccggctatt attgtaatgc acaggcgtgg 300
gatcctggta catttcggta tctcgaagtt tggggccagg gcaccctggt cactgtctca 360
<210> 23
<211> 360
<212> DNA
<213> 人工序列
<400> 23
gaggtgcagt tggtggagtc tgggggaggc ttggtacagc ctggggggtc tctgagactc 60
tcctgtgcag cctctggcaa catcttccgt atcgatacca tgggctggta ccgccaggct 120
ccaggaaagc agcgcgagtt cgtcgcaggt attagtcgtg gtggtagcac aaactatgca 180
cactccgtga aggaacgatt caccatctcc agagacaacg ccaagaacac gatgtatctg 240
caaatgaaca gcctgaaatc tgaggacacg gccggctatt attgtaatgc acaggcgtgg 300
gatcctggta caatccggta tctcgaagtt tggggccagg gcaccctggt cactgtctca 360
<210> 24
<211> 360
<212> DNA
<213> 人工序列
<400> 24
gaggtgcagg tgcaggagtc tgggggaggc ttggtacagc ctggggggtc tctgagactc 60
tcctgtgcag cctctggcaa catcttccgt atcgatacca tgggctggta ccgccaggct 120
ccaggaaagc agcgcgagtt ggtcgcaggt atttctcgtg gtggtacaac aacctatgca 180
cactccgtga aggaacgatt caccatctcc agagacaacg ccaagaacac gatgtatctg 240
caaatgaaca gcctgaaatc tgaggacacg gccggctatt attgtaatgc acaggcgtgg 300
gatcctggta catttcggta tctcgaagtt tggggccagg gcaccctggt cactgtctca 360
<210> 25
<211> 363
<212> DNA
<213> 人工序列
<400> 25
caggtgcagc tcgtggagtc tgggggaggc ttggtacagc ctggggggtc tctgagactc 60
tcctgtgcag cctctggcaa catcttccgt atcgatacca tgggctggta ccgccaggct 120
ccaggaaagc agcgcgagtt cgtcgcaggt attagtcgtg gtggtagcac aaactatgca 180
cactccgtga aggaacgatt caccatctcc agagacaacg ccaagaacac gatgtatctg 240
caaatgaaca gcctgaaatc tgaggacacg gccggctatt attgtaatgc acaggcgtgg 300
gatcctggta caatccggta tctcgaagtt tggggccagg gcaccctggt caccgtgtcc 360
tca 363
<210> 26
<211> 360
<212> DNA
<213> 人工序列
<400> 26
caggtgcagc tcgtggagtc tgggggaggc ttggtacagc ctggggggtc tctgagactc 60
tcctgtgcag cctctggcaa catcttccgt atcgatacca tgggctggta ccgccaggct 120
ccaggaaagc agcgcgagtt ggtcgcaggt atttctcgtg gtggtacaac aacctatgca 180
cactccgtga aggaacgatt caccatctcc agagacaacg ccaagaacac gatgtatctg 240
caaatgaaca gcctgaaatc tgaggacacg gccggctatt attgtaatgc acaggcgtgg 300
gatcctggta catttcggta tctcgaagtt tggggccagg gcaccctggt cactgtctca 360
<210> 27
<211> 360
<212> DNA
<213> 人工序列
<400> 27
gaggtgcagt tggtggagtc tgggggaggc ttggtacagc ctggggggtc tctgagactc 60
tcctgtgcag cctctggcaa catcttccgt atcgatacca tggtgtggta ccgccaggct 120
ccaggaaagc agcgcgagtt ggtcgcaggt atttctcgtg gtggtaccac aaactatgca 180
cactccgtga agggccgatt caccatctcc agagacaacg ccaagaacac gatgtatctg 240
caaatgaaca gcctgaaatc tgaggacacg gccacgtatt attgtaatgc acaggcgtgg 300
gatgttggta caatccggta tctcgaagtt tggggccagg gcaccctggt cactgtctca 360
<210> 28
<211> 360
<212> DNA
<213> 人工序列
<400> 28
gaggtgcagc tgcaggagtc tgggggaggc ttggtacagc ctggggggtc tctgagactc 60
tcctgtgcag cctctggcaa catcttccgt atcgatacca tgggctggta ccgccaggct 120
ccaggaaagc agcgcgagtt cgtcgcaggt attagtcgtg gtggtagcac aaactatgca 180
cactccgtga aggaacgatt caccatctcc agagacaacg ccaagaacac gatgtatctg 240
caaatgaaca gcctgaaatc tgaggacacg gccggctatt attgtaatgc acaggcgtgg 300
gatcctggta caatccggta tctcgaagtt tggggccagg gcaccctggt cactgtctca 360
<210> 29
<211> 360
<212> DNA
<213> 人工序列
<400> 29
gaggtgcagg tcgtggagtc tgggggaggc ttggtacagc ctggggggtc tctgagactc 60
tcctgtgcag cctctggcaa catcttccgt atcgatacca tggtgtggta ccgccaggct 120
ccaggaaagc agcgcgagtt ggtcgcaggt atttctcgtg gtggtaccac aaactatgca 180
cactccgtga agggccgatt caccatctcc agagacaacg ccaagaacac gatgtatctg 240
caaatgaaca gcctgaaatc tgaggacacg gccacgtatt attgtaatgc acaggcgtgg 300
gatgttggta caatccggta tctcgaagtt tggggccagg gcaccctggt cactgtctca 360
<210> 30
<211> 8
<212> PRT
<213> 人工序列
<400> 30
Gly Ser Ile Phe Asn Ile Pro Val
1 5
<210> 31
<211> 7
<212> PRT
<213> 人工序列
<400> 31
Ile Ser Thr Gly Gly Thr Thr
1 5
<210> 32
<211> 14
<212> PRT
<213> 人工序列
<400> 32
Asn Val Leu Val Val Ser Gly Ile Gly Ser Thr Leu Glu Val
1 5 10
<210> 33
<211> 8
<212> PRT
<213> 人工序列
<400> 33
Gly Ser Ile Phe Asn Leu Pro Val
1 5
<210> 34
<211> 8
<212> PRT
<213> 人工序列
<400> 34
Gly Thr Ile Phe Asn Ile Pro Val
1 5
<210> 35
<211> 8
<212> PRT
<213> 人工序列
<400> 35
Gly Ile Ile Phe Asn Ile Pro Val
1 5
<210> 36
<211> 8
<212> PRT
<213> 人工序列
<400> 36
Gly Thr Ile Phe Asn Leu Pro Val
1 5
<210> 37
<211> 14
<212> PRT
<213> 人工序列
<400> 37
Asn Val Leu Val Ile Ser Gly Ile Gly Ser His Leu Glu Val
1 5 10
<210> 38
<211> 8
<212> PRT
<213> 人工序列
<400> 38
Gly Ser Ile Leu His Ile Pro Val
1 5
<210> 39
<211> 8
<212> PRT
<213> 人工序列
<400> 39
Gly Ser Ile Phe His Ile Val Val
1 5
<210> 40
<211> 8
<212> PRT
<213> 人工序列
<400> 40
Gly Thr Phe Phe Asn Ile Pro Val
1 5
<210> 41
<211> 7
<212> PRT
<213> 人工序列
<400> 41
Met Ser Thr Gly Gly Thr Thr
1 5
<210> 42
<211> 119
<212> PRT
<213> 人工序列
<400> 42
Glu Val Gln Val Gln Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Ser Ile Phe Asn Ile Pro
20 25 30
Val Met Ser Trp Tyr Arg Gln Ala Pro Gly Lys Gln Arg Glu Leu Val
35 40 45
Ala Gly Ile Ser Thr Gly Gly Thr Thr Asn Tyr Gly Asp Ser Val Lys
50 55 60
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Thr Thr Val Tyr Leu
65 70 75 80
Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys Asn
85 90 95
Val Leu Val Ile Ser Gly Ile Gly Ser His Leu Glu Val Trp Gly Gln
100 105 110
Gly Thr Leu Val Thr Val Ser
115
<210> 43
<211> 119
<212> PRT
<213> 人工序列
<400> 43
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Ser Ile Phe Asn Leu Pro
20 25 30
Val Met Ser Trp Tyr Arg Gln Ala Pro Gly Lys Gln Arg Glu Leu Val
35 40 45
Ala Gly Ile Ser Thr Gly Gly Thr Thr Asn Tyr Gly Asp Ser Val Lys
50 55 60
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr Leu
65 70 75 80
Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys Asn
85 90 95
Val Leu Val Ile Ser Gly Ile Gly Ser His Leu Glu Val Trp Gly Gln
100 105 110
Gly Thr Leu Val Thr Val Ser
115
<210> 44
<211> 119
<212> PRT
<213> 人工序列
<400> 44
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Thr Ile Phe Asn Ile Pro
20 25 30
Val Met Gly Trp Tyr Arg Gln Ala Pro Gly Lys Gln Arg Glu Leu Val
35 40 45
Ala Gly Ile Ser Thr Gly Gly Thr Thr Asn Tyr Gly Asp Ser Val Lys
50 55 60
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr Leu
65 70 75 80
Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys Asn
85 90 95
Val Leu Val Ile Ser Gly Ile Gly Ser His Leu Glu Val Trp Gly Gln
100 105 110
Gly Thr Leu Val Thr Val Ser
115
<210> 45
<211> 119
<212> PRT
<213> 人工序列
<400> 45
Glu Val Gln Leu Gln Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Ile Ile Phe Asn Ile Pro
20 25 30
Val Met Ser Trp Tyr Arg Gln Ala Pro Gly Lys Gln Arg Glu Leu Val
35 40 45
Ala Gly Ile Ser Thr Gly Gly Thr Thr Asn Tyr Gly Asp Ser Val Lys
50 55 60
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr Leu
65 70 75 80
Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys Asn
85 90 95
Val Leu Val Val Ser Gly Ile Gly Ser His Leu Glu Val Trp Gly Gln
100 105 110
Gly Thr Leu Val Thr Val Ser
115
<210> 46
<211> 119
<212> PRT
<213> 人工序列
<400> 46
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Ser Ile Phe Asn Leu Pro
20 25 30
Val Met Ser Trp Tyr Arg Gln Ala Pro Gly Lys Gln Arg Glu Leu Val
35 40 45
Ala Gly Ile Ser Thr Gly Gly Thr Thr Asn Tyr Gly Asp Ser Val Lys
50 55 60
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr Leu
65 70 75 80
Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys Asn
85 90 95
Val Leu Val Val Ser Gly Ile Gly Ser His Leu Glu Val Trp Gly Gln
100 105 110
Gly Thr Leu Val Thr Val Ser
115
<210> 47
<211> 119
<212> PRT
<213> 人工序列
<400> 47
Gln Val Gln Leu Gln Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Ser Ile Phe Asn Ile Pro
20 25 30
Val Met Gly Trp Tyr Arg Gln Ala Pro Gly Lys Gln Arg Glu Leu Val
35 40 45
Ala Gly Ile Ser Thr Gly Gly Thr Thr Asn Tyr Gly Asp Ser Val Lys
50 55 60
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr Leu
65 70 75 80
Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys Asn
85 90 95
Val Leu Val Val Ser Gly Ile Gly Ser Thr Leu Glu Val Trp Gly Gln
100 105 110
Gly Thr Leu Val Thr Val Ser
115
<210> 48
<211> 119
<212> PRT
<213> 人工序列
<400> 48
Glu Val Gln Leu Gln Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Thr Ile Phe Asn Leu Pro
20 25 30
Val Met Ser Trp Tyr Arg Gln Ala Pro Gly Lys Gln Arg Glu Leu Val
35 40 45
Ala Gly Ile Ser Thr Gly Gly Thr Thr Asn Tyr Gly Asp Ser Val Lys
50 55 60
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Arg Asn Thr Val Tyr Leu
65 70 75 80
Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys Asn
85 90 95
Val Leu Val Val Ser Gly Ile Gly Ser His Leu Glu Val Trp Gly Gln
100 105 110
Gly Thr Leu Val Thr Val Ser
115
<210> 49
<211> 120
<212> PRT
<213> 人工序列
<400> 49
Glu Val Gln Val Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Ser Ile Leu His Ile Pro
20 25 30
Val Met Ser Trp Tyr Arg Gln Ala Pro Gly Lys Gln Arg Glu Leu Val
35 40 45
Ala Gly Ile Ser Thr Gly Gly Thr Thr Asn Tyr Gly Asp Ser Val Lys
50 55 60
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr Leu
65 70 75 80
Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Ala Tyr Tyr Cys Asn
85 90 95
Val Leu Val Val Ser Gly Ile Gly Ser His Leu Glu Val Trp Gly Gln
100 105 110
Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 50
<211> 119
<212> PRT
<213> 人工序列
<400> 50
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Ser Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Ser Ile Phe His Ile Val
20 25 30
Val Met Gly Trp Tyr Arg Gln Ala Pro Gly Lys Gln Arg Glu Leu Val
35 40 45
Ala Gly Met Ser Thr Gly Gly Thr Thr Asn Tyr Gly Asp Ser Val Lys
50 55 60
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr Leu
65 70 75 80
Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys Asn
85 90 95
Val Leu Val Ile Ser Gly Ile Gly Ser His Leu Glu Val Trp Gly Gln
100 105 110
Gly Thr Leu Val Thr Val Ser
115
<210> 51
<211> 119
<212> PRT
<213> 人工序列
<400> 51
Gln Val Gln Leu Gln Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Thr Phe Phe Asn Ile Pro
20 25 30
Val Met Gly Trp Tyr Arg Gln Ala Pro Gly Lys Gln Arg Glu Leu Val
35 40 45
Ala Gly Ile Ser Thr Gly Gly Thr Thr Asn Tyr Gly Asp Ser Val Lys
50 55 60
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr Leu
65 70 75 80
Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys Asn
85 90 95
Val Leu Val Ile Ser Gly Ile Gly Ser His Leu Glu Val Trp Gly Gln
100 105 110
Gly Thr Leu Val Thr Val Ser
115
<210> 52
<211> 360
<212> DNA
<213> 人工序列
<400> 52
gaggtgcagg tgcaggagtc tgggggaggc ctggtacagg ctgggacctc tctgagactc 60
tcctgtgcag cctctggcaa catcttccgt atcgatacca tgggctggta ccgccaggct 120
ccaggaaagc agcgcgagtt ggtcgcaggt atttctcgtg gtggtacaac aacctatgca 180
cactccgtga aggaacgatt caccatctcc agagacaacg ccaagaacac gatgtatctg 240
caaatgaaca gcctgaaatc tgaggacacg gccggctatt attgtaatgc acaggcgtgg 300
gatcctggta catttcggta tctcgaagtt tggggccagg gcaccctggt cactgtctca 360
<210> 53
<211> 360
<212> DNA
<213> 人工序列
<400> 53
gaggtgcagg tggtggagtc tgggggaggc ttggtgcagc ccggggggtc tctgagactc 60
tcctgtgcag cctctggaag catcttgcat atccctgtca tgagctggta ccgccaggct 120
ccagggaagc agcgcgagtt ggtcgcaggt attagtaccg gtggtactac aaactatgga 180
gactccgtga agggccgatt caccatctcc agagacaacg ccaagaacac ggtgtatctg 240
caaatgaaca gcctgaaacc tgaagacacg gccgcttatt actgtaatgt cctggtagta 300
agtggtattg ggagccatct cgaagtttgg ggccagggca ccctggtcac cgtgtcctca 360
<210> 54
<211> 357
<212> DNA
<213> 人工序列
<400> 54
gaggtgcagt tggtggagtc tgggggaggc ttggtgcagc ccggggggtc tctgagactc 60
tcctgtgcag cctctggaag catcttcaat cttcctgtca tgagctggta ccgccaggct 120
ccagggaagc agcgcgagtt ggtcgcagga attagtaccg gaggtactac aaactatgga 180
gactccgtga agggccgatt caccatctcc agagacaacg ccaagaacac ggtgtatctg 240
caaatgaaca gcctgaaacc tgaagacacg gccgtctatt actgtaatgt cctggtaata 300
agtggtattg ggagccatct cgaagtttgg ggccagggca ccctggtcac tgtctca 357
<210> 55
<211> 357
<212> DNA
<213> 人工序列
<400> 55
gaggtgcagc tgcaggagtc tgggggaggc ttggtgcagc ccggggggtc tctgagactc 60
tcctgtgcag cctctggaat catcttcaat atccctgtca tgagctggta ccgccaggct 120
ccagggaagc agcgcgagtt ggtcgcaggt attagtaccg gtggtactac aaactatgga 180
gactccgtga agggccgatt caccatctcc agagacaacg ccaagaacac ggtgtatctg 240
caaatgaaca gcctgaaacc tgaagacacg gccgtctatt actgtaatgt cctggtagta 300
agtggtattg ggagccatct cgaagtttgg ggccagggca ccctggtcac tgtctca 357
<210> 56
<211> 357
<212> DNA
<213> 人工序列
<400> 56
gaggtgcagg tgcaggagtc tgggggaggc ttggtgcagc ccggggggtc tctgagactc 60
tcctgtgcag cctctggaag catcttcaat atccctgtca tgagctggta ccgccaggct 120
ccagggaagc agcgcgagtt ggtcgcaggt attagtaccg gtggtactac aaactatgga 180
gactccgtga agggccgatt caccatctcc agagacaacg ccaagaccac ggtgtatctg 240
caaatgaaca gcctgaaacc tgaagacacg gccgtctatt actgtaatgt cctggtaata 300
agtggtattg ggagccatct cgaagtttgg ggccagggca ccctggtcac tgtctca 357
<210> 57
<211> 357
<212> DNA
<213> 人工序列
<400> 57
caggtgcagc tggtggagtc tgggggaggc ttggtgcagc ccggggggtc tctgagactc 60
tcctgtgcag cctctggaac catcttcaat atccctgtca tgggctggta ccgccaggct 120
ccagggaagc agcgcgagtt ggtcgcaggt attagtactg gtggtactac aaactatgga 180
gactccgtga agggccgatt caccatctcc agagacaacg ccaagaacac ggtgtatctg 240
cagatgaaca gcctgaaacc tgaagacacg gccgtctatt actgtaatgt cctggtaata 300
agtggtattg ggagccatct cgaagtttgg ggccagggca ccctggtcac tgtctca 357
<210> 58
<211> 357
<212> DNA
<213> 人工序列
<400> 58
caggtgcagc tgcaggagtc tgggggaggc ttggtgcagc ccggggggtc tctgagactc 60
tcctgtgcag cctctggaag catcttcaat atccctgtca tgggctggta ccgccaggct 120
ccagggaagc agcgcgagtt ggtcgcaggt attagtactg gtggtactac aaactatgga 180
gactccgtga agggccgatt caccatctcc agagacaacg ccaagaacac ggtgtatctg 240
caaatgaaca gcctgaaacc tgaagacacg gccgtctatt actgtaatgt cctggtagta 300
agtggtattg ggagcactct cgaagtttgg ggccagggca ccctggtcac tgtctca 357
<210> 59
<211> 357
<212> DNA
<213> 人工序列
<400> 59
gaggtgcagc tgcaggagtc tgggggaggc ttggtgcagc ccggggggtc tctgagactc 60
tcctgtgcag cctctggaac catcttcaat ctccctgtca tgagctggta ccgccaggct 120
ccagggaagc agcgcgagtt ggtcgcaggt attagtaccg gtggtactac aaattatgga 180
gactccgtga agggacgatt caccatctcc agagacaacg ccaggaacac ggtgtatctg 240
caaatgaaca gcctgaaacc tgaagacacg gccgtctatt actgtaatgt cctggtagta 300
agtggtattg ggagccatct cgaagtttgg ggccagggca ccctggtcac tgtctca 357
<210> 60
<211> 357
<212> DNA
<213> 人工序列
<400> 60
caggtgcagc tgcaggagtc tgggggaggc ttggtgcagc ccggggggtc tctgagactc 60
tcctgtgcag cctctggaac cttcttcaat atccctgtca tgggctggta ccgccaggct 120
ccagggaagc agcgcgagtt ggtcgcaggt attagtaccg gtggtactac aaactatgga 180
gactccgtga agggccgatt caccatctcc agagacaacg ccaagaacac ggtgtatctg 240
cagatgaaca gcctgaaacc tgaagacacg gccgtctatt actgtaatgt cctggtaata 300
agtggtattg ggagccatct cgaagtttgg ggccagggca ccctggtcac tgtctca 357
<210> 61
<211> 357
<212> DNA
<213> 人工序列
<400> 61
caggtgcagc tggtagagtc tgggggaggc tcggtgcagc ccggggggtc tctgagactc 60
tcctgtgcag cctctggaag catcttccat atcgttgtca tgggctggta ccgccaggct 120
ccagggaagc agcgcgagtt ggtcgcaggt atgagtaccg gtggtactac aaactatgga 180
gactccgtga agggccgatt caccatctcc agagacaacg ccaagaacac ggtgtatctg 240
caaatgaaca gcctgaaacc tgaagacacg gccgtctact actgtaatgt cctggtaatt 300
agtggtattg ggagccatct cgaagtttgg ggccagggca ccctggtcac tgtctca 357
<210> 62
<211> 14
<212> PRT
<213> 人工序列
<400> 62
Asn Val Leu Val Val Ser Gly Ile Gly Ser His Leu Glu Val
1 5 10
<210> 63
<211> 120
<212> PRT
<213> 人工序列
<400> 63
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Ser Ile Phe Asn Ile Pro
20 25 30
Val Met Gly Trp Tyr Arg Gln Ala Pro Gly Lys Gln Arg Glu Leu Val
35 40 45
Ala Gly Ile Ser Thr Gly Gly Thr Thr Asn Tyr Gly Asp Ser Val Lys
50 55 60
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr Leu
65 70 75 80
Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys Asn
85 90 95
Val Leu Val Val Ser Gly Ile Gly Ser Thr Leu Glu Val Trp Gly Gln
100 105 110
Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 64
<211> 360
<212> DNA
<213> 人工序列
<400> 64
caggtgcagc tggtggagtc cggcggcgga ctggtgcagc ctggaggatc cctgcggctg 60
tcctgcgctg ctagcggcag catcttcaac atccccgtga tgggctggta caggcaggct 120
cccggcaagc agcgggagct ggtggctgga atcagcaccg gcggcaccac caactatggc 180
gacagcgtga agggcaggtt caccatcagc agggataacg ctaagaatac cgtgtacctg 240
cagatgaaca gcctgaagcc tgaggatacc gccgtgtact attgcaatgt gctggtggtg 300
agcggcatcg gcagcaccct ggaggtgtgg ggccagggaa ccctggtgac agtgagctcc 360
Claims (27)
1.CLDN18.2结合分子,其包含免疫球蛋白单可变结构域,所述免疫球蛋白单可变结构域是VHH,其中所述VHH包含选自以下任一组的CDR1、CDR2和CDR3:
(a)如SEQ ID NO:30的氨基酸序列所示的CDR1,如SEQ ID NO:31的氨基酸序列所示的CDR2和如SEQ ID NO:32的氨基酸序列所示的CDR3,并且所述VHH包含如SEQ ID NO:63所示的氨基酸序列;
(b)如SEQ ID NO:30的氨基酸序列所示的CDR1,如SEQ ID NO:31的氨基酸序列所示的CDR2和如SEQ ID NO:37的氨基酸序列所示的CDR3;或
(c)如SEQ ID NO:33所示的氨基酸序列的CDR1,如SEQ ID NO:31所示的氨基酸序列的CDR2和如SEQ ID NO:62所示的氨基酸序列的CDR3;
(d)如SEQ ID NO:33所示的氨基酸序列的CDR1,如SEQ ID NO:31所示的氨基酸序列的CDR2和如SEQ ID NO:37所示的氨基酸序列的CDR3;
(e)如SEQ ID NO:34所示的氨基酸序列的CDR1,如SEQ ID NO:31所示的氨基酸序列的CDR2和如SEQ ID NO:37所示的氨基酸序列的CDR3;
(f)如SEQ ID NO:35所示的氨基酸序列的CDR1,如SEQ ID NO:31所示的氨基酸序列的CDR2和如SEQ ID NO:62所示的氨基酸序列的CDR3;或
(g)如SEQ ID NO:36所示的氨基酸序列的CDR1,如SEQ ID NO:31所示的氨基酸序列的CDR2和如SEQ ID NO:62所示的氨基酸序列的CDR3。
2.权利要求1的CLDN18.2结合分子,其中所述CLDN18.2结合分子是针对CLDN18.2的抗体或其抗原结合片段。
3.前述权利要求中任一项的CLDN18.2结合分子,其中所述VHH是来自骆驼科动物的VHH。
4.权利要求1-2中任一项的CLDN18.2结合分子,其中所述VHH包含选自以下的任一种:
与SEQ ID NO:42-46和48中任一项至少80%、85%、90%或95%相同的氨基酸序列,或与SEQ ID NO:42-46和48中任一项相比在框架区中具有一个或多个氨基酸的添加、缺失和/或取代的氨基酸序列。
5.权利要求4的CLDN18.2结合分子,其中所述VHH包含以下序列或由以下序列组成:SEQID NO:42-46、48和63中的任一者。
6.权利要求1-2中任一项的CLDN18.2结合分子,其中所述CLDN18.2结合分子是单结构域抗体、嵌合抗体或人源化抗体。
7.权利要求1-2中任一项的CLDN18.2结合分子,其中所述免疫球蛋白单可变结构域与免疫球蛋白的Fc结构域或荧光蛋白融合。
8.权利要求7的CLDN18.2结合分子,其中所述免疫球蛋白为IgG。
9.权利要求8的CLDN18.2结合分子,其中所述CLDN18.2结合分子是包含来自骆驼科动物的VHH与人IgG的Fc结构域的嵌合抗体,或包含来自骆驼科动物的VHH经人源化后所得VHH与人IgG的Fc结构域的人源化抗体。
10.权利要求9的CLDN18.2结合分子,其中所述人IgG是人IgG1或IgG4。
11.权利要求10的CLDN18.2结合分子,其中所述CLDN18.2结合分子是包含来自羊驼的VHH与人IgG1的Fc结构域的嵌合抗体。
12.权利要求1的CLDN18.2结合分子,其中所述CLDN18.2结合分子结合人CLDN18.2的胞外结构域1(ECD1)。
13.权利要求1的CLDN18.2结合分子,其特异性结合CLDN18.2,但不结合CLDN18.1。
14.分离的核酸分子,其包含编码如前述权利要求中任一项所定义的CLDN18.2结合分子的核酸序列。
15.权利要求14的分离的核酸分子,其包含以下序列或由以下序列组成:SEQ ID NO:52、54-57、59和64中的任一者。
16.一种表达载体,其包含权利要求14或15的分离的核酸分子。
17.一种宿主细胞,其包含权利要求16的表达载体。
18.权利要求17的宿主细胞,所述宿主细胞是细菌细胞、真菌细胞或哺乳动物细胞。
19.权利要求18的宿主细胞,其中所述细菌细胞是大肠杆菌和/或所述真菌细胞是酵母。
20.一种药物组合物,其包含至少一种如权利要求1-13中任一项所定义的CLDN18.2结合分子和药学上可接受的载体。
21.制备如权利要求1-13中任一项所定义的CLDN18.2结合分子的方法,包括以下步骤:
-在权利要求18或19的宿主细胞中表达权利要求1-13中任一项所定义的CLDN18.2结合分子;和
-从宿主细胞分离CLDN18.2结合分子。
22.如权利要求1-13中任一项所定义的CLDN18.2结合分子在制备用于治疗或预防与CLDN18.2相关的病症的药物中的用途。
23.权利要求22的用途,其中所述与CLDN18.2相关的病症包括涉及表达CLDN18.2的细胞的疾病或与表达CLDN18.2的细胞相关的疾病。
24.权利要求22或23的用途,其中所述与CLDN18.2相关的病症是癌症。
25.权利要求24的用途,其中所述癌症包括骨癌、血癌、肺癌、肝癌、胰腺癌、皮肤癌、头颈癌、皮肤或眼内黑素瘤、子宫癌、卵巢癌、直肠癌、肛区癌、胃癌、结肠癌、乳腺癌、***癌、性器官和生殖器官癌、霍奇金病、食管癌、小肠癌、内分泌***癌症、甲状腺癌、甲状旁腺癌、肾上腺癌、软组织肉瘤、膀胱癌、肾癌、肾细胞癌、肾盂癌、中枢神经***(CNS)肿瘤、神经外胚层癌症、脊柱轴肿瘤、胶质瘤、脑脊膜瘤和垂体腺瘤。
26.权利要求25的用途,其中所述癌症为胃癌。
27.用于治疗或诊断与CLDN18.2相关的病症的试剂盒,其包含容器,所述容器包含权利要求1-13中任一项所定义的CLDN18.2结合分子。
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CN111978403B (zh) * | 2019-05-24 | 2023-08-04 | 三优生物医药(上海)有限公司 | 新型cldn18.2结合分子 |
WO2022174809A1 (en) * | 2021-02-19 | 2022-08-25 | Suzhou Transcenta Therapeutics Co., Ltd. | Anti-cldn18.2 antibody conjugates |
WO2022237666A1 (zh) * | 2021-05-08 | 2022-11-17 | 荣昌生物制药(烟台)股份有限公司 | 一种抗Claudin18.2抗体及其抗体药物偶联物 |
CN115611983A (zh) | 2021-07-14 | 2023-01-17 | 三优生物医药(上海)有限公司 | Cldn18.2结合分子及其用途 |
WO2023016348A1 (en) * | 2021-08-09 | 2023-02-16 | Harbour Biomed (Shanghai) Co., Ltd | Cldn18.2-targeting antibody, bispecific antibody and use thereof |
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CN114206935A (zh) | 2022-03-18 |
EP3978532A1 (en) | 2022-04-06 |
WO2020238730A1 (zh) | 2020-12-03 |
KR20220012262A (ko) | 2022-02-03 |
JP2022533804A (ja) | 2022-07-25 |
US20220396616A1 (en) | 2022-12-15 |
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CA3141504A1 (en) | 2020-12-03 |
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