CN115991784A - 抗cd47-cldn18.2双特异性抗体及其用途 - Google Patents
抗cd47-cldn18.2双特异性抗体及其用途 Download PDFInfo
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Abstract
本发明属于生物医药领域。具体地,本发明涉及抗CD47‑CLDN18.2双特异性抗体及其用途。
Description
技术领域
本发明属于生物医药领域。具体地,本发明涉及抗CD47-CLDN18.2双特异性抗体及其用途。
背景技术
CD47是一种广泛表达于细胞表面的跨膜糖蛋白,属于免疫球蛋白超家族,可与信号调节蛋白α(Signal regulatory proteinα,SIRPα)、血小板反应蛋白(Thrombospondin-1,TSP1)以及整合素(Integrin)相互作用,介导细胞凋亡、增殖、免疫等一系列的反应。已经证实,通过使用抗CD47抗体阻断CD47-SIRPα通路能够有效地介导对肿瘤细胞的吞噬作用,从而在体内抑制各种血液肿瘤和实体肿瘤的生长。然而,CD47不仅在肿瘤细胞上高表达,在正常细胞上,例如红细胞上也有大量CD47的表达,靶向CD47的疗法可能会引发不期望的副作用。现有技术中公开的一些抗CD47抗体(参见例如US20160304609)结合红细胞,这不仅引发严重的贫血反应,而且在给药上需要高达30mg/kg的给药剂量,这些特性给抗CD47抗体的临床应用带来了极大的挑战。
CLDN18属于Claudins蛋白家族成员,由Shoichiro Tsukita等在1998年发现,其是构成上皮细胞紧密连接的重要分子,决定了上皮细胞的渗透性,也起到阻挡细胞膜表面蛋白和脂质扩散的作用 (Gunzel,D.and A.S.Yu(2013)Physiol Rev 932:525-569)。人的CLDN18基因具有两个不同的1号外显子,转录后经过可变剪接最终生成仅在N端具有不同序列的两个蛋白亚型CLDN18.1和 CLDN18.2。由于其在肿瘤细胞和正常组织中的表达特异性,CLDN18.2目前已经成为非常有潜力的抗肿瘤药物作用靶点。WO2016165762A1公开了抗CLDN18.2抗体IMAB362(Zolbetuximab),其在胃癌临床二期试验中表现出比标准化疗显著延长生存期(13.2对8.4个月),在CLDN18.2高表达患者中优势更明显。
WO2021003082A1公开了抗CLDN18.2和CD47双特异性抗体,其基本不结合人红细胞。但仍然需要开发新的靶向CLDN18.2和CD47的双特异性抗体,为癌症治疗提供更多的可能性。
发明内容
在一方面,本发明提供一种双特异性抗体,其包含结合CD47的第一抗原结合部分以及结合 CLDN18.2的第二抗原结合部分,其中所述第一抗原结合部分包含重链可变区(VH)和轻链可变区(VL),所述重链可变区包含:1)HCDR1,其包含SEQ ID NO:4的氨基酸序列;2) HCDR2,其包含SEQ ID NO:5的氨基酸序列;和3)HCDR3,其包含SEQ ID NO:6的氨基酸序列;并且所述轻链可变区包含:1)LCDR1,其包含SEQ ID NO:7的氨基酸序列;2) LCDR2,其包含SEQ ID NO:8的氨基酸序列;和3)LCDR3,其包含SEQ ID NO:9的氨基酸序列。
在一实施方案中,所述第二抗原结合部分包含结合CLDN18.2的免疫球蛋白单可变结构域 (VHH)。优选地,所述免疫球蛋白单可变结构域包含:CDR1,其包含SEQ ID NO:13的氨基酸序列;CDR2,其包含SEQ ID NO:14的氨基酸序列;以及CDR3,其包含SEQ ID NO:15的氨基酸序列。
在又一方面,本发明提供一种分离的多核苷酸,其编码本发明的双特异性抗体。
本发明还提供一种表达载体,其包含本发明的多核苷酸。
在另一方面,本发明提供一种宿主细胞,其包含本发明的多核苷酸或表达载体。
本发明还涉及抗体缀合物,其包含与至少一种治疗剂缀合的本发明的双特异性抗体。
在又一方面,本发明涉及一种药物组合物,其包含本发明的双特异性抗体或者抗体缀合物,以及药学上可接受的载剂。
本发明还涉及本发明的双特异性抗体、抗体缀合物或者药物组合物在制备用于治疗癌症的药物中的用途。
附图说明
图1显示抗CD47-CLDN18.2双特异性抗体的示意性结构。
图2a和图2b显示抗CD47-CLDN18.2双特异性抗体与红细胞上CD47的结合活性。
图3a和图3b显示抗CD47-CLDN18.2双特异性抗体在表达单靶点和双靶点的肿瘤细胞上的结合活性,其中,图3a显示抗CD47-CLDN18.2双特异性抗体在NUGC-4细胞上的结合活性,图3b显示抗CD47-CLDN18.2双特异性抗体在hCLDN18.2-NUGC-4细胞上的结合活性。
图4a、图4b和图4c显示抗CD47-CLDN18.2双特异性抗体在表达单靶点和双靶点的肿瘤细胞上的阻断人CD47与受体SIRPα结合的能力,其中,图4a显示抗CD47-CLDN18.2双特异性抗体在NUGC-4细胞上的阻断人CD47与受体SIRPα结合的能力,图4b和图4c显示抗CD47-CLDN18.2双特异性抗体在hCLDN18.2-NUGC-4细胞上的阻断人CD47与受体SIRPα结合的能力。
图5a和图5b显示抗CD47-CLDN18.2双特异性抗体在小鼠体内对肿瘤生长的抑制作用。
具体实施方式
定义
在本发明中,除非另有说明,否则本文中使用的科学和技术名词具有本领域技术人员所通常理解的含义。并且,本文中所用的蛋白质和核酸化学、分子生物学、细胞和组织培养、微生物学、免疫学相关术语和实验室操作步骤均为相应领域内广泛使用的术语和常规步骤。同时,为了更好地理解本发明,下面提供相关术语的定义和解释。
如本文所用,表述“包括”、“包含”、“含有”和“具有”是开放式的,表示包括所列举的元素、步骤或组分但不排除其他未列举的元素、步骤或组分。表述“由……组成”不包括未指定的任何元素、步骤或组分。表述“基本上由……组成”是指范围限于指定的元素、步骤或组分,加上不显著影响要求保护的主题的基本和新颖性质的任选存在的元素、步骤或组分。应当理解,表述“基本上由……组成”和“由……组成”涵盖在表述“包括”的含义之内。
如本文所用,“抗体”指免疫球蛋白或其片段,其通过至少一个抗原结合位点特异性结合抗原表位。在本文中,抗体的定义涵盖抗原结合片段。术语“抗体”包括多特异性抗体(例如双特异性抗体)、人抗体、非人抗体、人源化抗体、嵌合抗体、单域抗体以及抗原结合片段。抗体可以是合成的(例如通过化学偶联或生物偶联产生的)、酶促处理得到的或重组产生的。本文所提供的抗体包括任何免疫球蛋白类型(例如,IgG、IgM、IgD、IgE、IgA和IgY)、任何类别(例如IgG1、IgG2、 IgG3、IgG4、IgA1和IgA2)或亚类(例如,IgG2a和IgG2b)。抗体可以是“单价”、“二价”、“三价”或“四价”或更多价抗体,是指其包含1、2、3、4个或更多个抗原结合位点。
如本文所用,“全长抗体”通常包含四条多肽:两条重链(HC)和两条轻链(LC)。每条轻链从 N端(氨基酸端)到C端(羧基端)包含“轻链可变区(VL)”和“轻链恒定区(CL)”。每条重链从N端至C端包含“重链可变区(VH)”以及“重链恒定区(CH)”。一般而言,全长抗体的重链恒定区从N端至C端可以包含CH1-铰链区(hinge)-CH2-CH3。在某些免疫球蛋白类型(例如IgM 和IgE)中,重链恒定区从N端至C端可以包含CH1-铰链区-CH2-CH3-CH4。
轻链可变区和重链可变区各自可以包含三个高度可变的“互补决定区(CDR)”和四个相对保守的“框架区(FR)”,并且从N端至C端以FR1-CDR1-FR2-CDR2-FR3-CDR3-FR4的次序连接。在本文中,轻链可变区的CDR(CDRL或LCDR)可以称为LCDR1、LCDR2和LCDR3,重链可变区的CDR(CDRH或HCDR)可以称为HCDR1、HCDR2和HCDR3。
在本发明中,CDR的氨基酸序列均是按照AbM定义规则所示出的(本发明的权利要求中也是按照AbM定义规则所示出的序列)。但是,本领域人员公知,在本领域中可以通过多种方法来定义抗体的CDR,例如基于抗体的三维结构和CDR环的拓扑学的Chothia(参见例如Chothia,C.et al., Nature,342,877-883(1989);和Al-Lazikani,B.et al.,J.Mol.Biol.,273,927-948(1997))、基于抗体序列可变性的Kabat(参见例如Kabat,E.A.etal.(1991)Sequences of Proteins of Immunological Interest,Fifth Edition,U.S.Department of Health and Human Services,NIH Publication No.91-3242)、 AbM(Martin,A.C.R.and J.Allen(2007)“Bioinformatics tools for antibodyengineering,”in S.Dübel (ed.),Handbook of Therapeutic Antibodies.Weinheim:Wiley-VCH Verlag,pp.95–118)、Contact (MacCallum,R.M.et al.,(1996)J.Mol.Biol.262:732-745)、IMGT(Lefranc,M.-P.,2011(6), IMGT,the InternationalImMunoGeneTics Information System Cold Spring Harb Protoc.;和Lefranc,M.- P.etal.,Dev.Comp.Immunol.,27,55-77(2003)),以及基于利用大量晶体结构的近邻传播聚类(affinity propagation clustering)的North CDR定义。本领域技术人员应当理解的是,除非另有规定,否则术语给定抗体或其区(例如可变区)的“CDR”及“互补决定区”应理解为涵盖如通过本发明描述的上述已知方案中的任何一种界定的互补决定区。虽然本发明的权利要求中请求保护的范围是基于AbM定义规则所示出的序列,但是根据其他CDR的定义规则所对应的氨基酸序列也应当落在本发明的保护范围中。
因此,在涉及用本发明定义的具体CDR序列限定抗体时,所述抗体的范围还涵盖了这样的抗体,其可变区序列包含所述的具体CDR序列,但是由于应用了不同的方案(例如不同的指派系统规则或组合)而导致其所声称的CDR边界与本发明所定义的具体CDR边界不同。
如本文所用,术语“框架区”和“构架区”可以互换使用。如本文中所使用的,术语“框架区”、“构架区”或“FR”残基是指抗体可变区中除了如上定义的CDR序列以外的那些氨基酸残基。
如本文所用,“单域抗体(sdAb)”或“纳米抗体”是指包含单个免疫球蛋白可变结构域(单可变结构域)作为功能性抗原结合片段的抗体。与全长抗体的可变区类似,单可变结构域通常包含形成抗原结合位点的CDR1、CDR2和CDR3以及起支持作用的框架区。单可变结构域可以例如是重链抗体的可变结构域(variable domain of heavy-chain antibody,VHH)、鲨鱼的IgNAR可变结构域、人轻链抗体可变结构域和重链抗体可变结构域。
如本文所用,氨基酸序列的“百分比(%)序列相同性”、“序列相同性”具有本领域公认的定义,其指通过序列比对(例如通过人工检视或可公知的算法)确定的两个多肽序列之间相同的百分比。可以使用本领域技术人员已知的方法确定,例如使用可公开获得的计算机软件如BLAST、BLAST- 2、Clustal Omega和FASTA软件。
在本文中,“源自”或“衍生自”参考氨基酸序列的氨基酸序列与参考氨基酸序列的部分或者全部相同或同源。例如,衍生自人免疫球蛋白的重链恒定区的氨基酸序列可以与其所源自的人免疫球蛋白重链恒定区的野生型序列具有至少80%、至少85%、至少90%、至少91%、至少92%、至少 93%、至少94%、至少95%、至少96%、至少97%、至少98%、至少99%或100%序列相同性。
可以修饰多肽中的非关键区域(例如抗体的CDR区、框架区的非关键氨基酸、恒定区的氨基酸),例如进行一个或多个氨基酸的取代、添加和/或缺失,而不改变多肽的功能。本领域技术人员应当理解多肽中非关键区域的氨基酸可以用合适的保守氨基酸取代,并且一般不改变其生物活性 (参见,例如Watson et al.,Molecular Biology of the Gene,4th Edition,1987,The Benjamin/Cummings Pub.co.,p.224)。合适的保守取代是本领域技术人员熟知的。在某些情况下,氨基酸取代是非保守取代。本领域技术人员应当理解,可以对抗体或抗体片段进行氨基酸突变或修饰来改变其性能,例如改变抗体糖基化修饰的类型,改变形成链间二硫键的能力,或者为抗体缀合物的制备提供活性基团。包含这类氨基酸突变或修饰的抗体或其抗原结合片段也涵盖在本发明的双特异性抗体的范围之内。
本发明的抗CD47-CLDN18.2双特异性抗体或者编码其的多核苷酸可以是分离的。如本文所用,表述“分离的”是指物质(例如多核苷酸或多肽)与其存在的来源或环境是分离的,即基本上不包含其他任何成分。
在本文中,术语“多核苷酸”和“核酸”可以互换用于表示包含至少两个连接的核苷酸或核苷酸衍生物的寡聚体或聚合物,通常可以包括脱氧核糖核酸(DNA)和核糖核酸(RNA)。
在本文中,“载体”是用于将外源多核苷酸导入宿主细胞的媒介,当载体转化入适当的宿主细胞时,外源多核苷酸得以扩增或表达。载体通常保持游离,但是可以设计为使基因或其部分整合入基因组的染色体。如本文所用,载体的定义涵盖质粒、线性化质粒、病毒载体、粘粒、噬菌体载体、噬菌粒、人工染色体(例如,酵母人工染色体和哺乳动物人工染色体)等。病毒载体包括但不限于逆转录病毒载体(包括慢病毒载体)、腺病毒载体、腺相关病毒载体、疱疹病毒载体、痘病毒载体和杆状病毒载体等。
如本文所用,术语“表达”是指产生RNA和/或多肽。
如本文所用,“表达载体”指能够表达感兴趣的多核苷酸(包括DNA和RNA)的载体。例如,在表达载体中,可以将编码感兴趣多肽的多核苷酸序列(包括DNA和RNA)与能够影响多核苷酸序列表达的调控序列(如启动子和核糖体结合位点)可操作地连接。调控序列可以包含启动子和终止子序列,并且任选地可以包含复制起点、选择标记、增强子、多腺苷酸化信号等。表达载体可以是质粒、噬菌体载体、重组病毒或其他载体,当引入适当的宿主细胞时,导致感兴趣的多核苷酸的表达。合适的表达载体是本领域技术人员公知的。本领域技术人员可以根据需要将表达载体制备为在宿主细胞中可复制、在宿主细胞中保持游离或者整合入宿主细胞基因组的载体。
如本文所用,“宿主细胞”是用于接受、保持、复制或扩增载体的细胞。宿主细胞还可以用来表达多核苷酸或载体所编码的多肽。宿主细胞可以是真核细胞或原核细胞。原核细胞例如大肠杆菌 (E.coli)或枯草芽孢杆菌(Bacillus subtilis),真菌细胞例如酵母细胞或曲霉属、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、HeLa细胞、NSO细胞或 HEK293细胞)。
如本文所用,术语“治疗”指对疾病/症状的改善,例如使疾病/症状减轻或消失、防止或减缓疾病/症状的发生、进展和/或恶化。因此,治疗包括预防、治疗和/或治愈。
如本文中所使用的,术语“药学上可接受的载剂”是指在药理学和/或生理学上与受试者和活性成分相容的载剂,其是本领域公知的(参见例如Remington'sPharmaceutical Sciences.Edited by Gennaro AR,19th ed.Pennsylvania:MackPublishing Company,1995),并且包括但不限于:pH调节剂、表面活性剂、佐剂、离子强度增强剂、稀释剂、维持渗透压的试剂、延迟吸收的试剂、防腐剂。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、阴离子或者非离子型表面活性剂,例如Tween-80。离子强度增强剂包括但不限于氯化钠。防腐剂包括但不限于各种抗细菌试剂和抗真菌试剂,例如对羟苯甲酸酯、三氯叔丁醇、苯酚、山梨酸等。维持渗透压的试剂包括但不限于糖、氯化钠及其类似物。延迟吸收的试剂包括但不限于单硬脂酸盐和明胶。稀释剂包括但不限于水、水性缓冲液(如缓冲盐水)、醇和多元醇(如甘油)等。防腐剂包括但不限于各种抗细菌试剂和抗真菌试剂,例如硫柳汞、2-苯氧乙醇、对羟苯甲酸酯、三氯叔丁醇、苯酚、山梨酸等。稳定剂具有本领域技术人员通常理解的含义,其能够稳定药物中的活性成分的期望活性,包括但不限于谷氨酸钠、明胶、SPGA(Sucrose-Phosphate-Glutamate-Albumin)、糖类(如山梨醇、甘露醇、淀粉、蔗糖、乳糖、葡聚糖、或葡萄糖)、氨基酸(如谷氨酸、甘氨酸)、蛋白质(如干燥乳清、白蛋白或酪蛋白)或其降解产物(如乳白蛋白水解物)等。
如本文所用,哺乳动物的实例包括但不限于人、非人灵长类动物、大鼠、小鼠、牛、马、猪、羊、羊驼、狗、猫等。在本文中,术语“受试者”是指哺乳动物,例如人。在一些实施方案中,受试者是人。在一些实施方案中,受试者是癌症患者、怀疑患有癌症或处于患癌风险中的人或者动物。
抗CD47-CLDN18.2双特异性抗体
本发明提供一种抗CD47-CLDN18.2双特异性抗体,其包含结合CD47的第一抗原结合部分以及结合CLDN18.2的第二抗原结合部分,其中所述第一抗原结合部分包含重链可变区(VH)和轻链可变区(VL),
所述重链可变区包含:
1)HCDR1,其包含SEQ ID NO:4的氨基酸序列或其变体;
2)HCDR2,其包含SEQ ID NO:5的氨基酸序列或其变体;和
3)HCDR3,其包含SEQ ID NO:6的氨基酸序列或其变体;以及
所述轻链可变区包含:
1)LCDR1,其包含SEQ ID NO:7的氨基酸序列或其变体;
2)LCDR2,其包含SEQ ID NO:8的氨基酸序列或其变体;和
3)LCDR3,其包含SEQ ID NO:9的氨基酸序列或其变体;
其中,所述变体与其所源自的序列相比具有1个或2个氨基酸的取代、添加和/或缺失。
在一具体实施方案中,第一抗原结合部分包含特异性结合CD47的第一抗原结合部分,所述第一抗原结合部分包含重链可变区(VH)和轻链可变区(VL),
所述重链可变区包含:
1)HCDR1,其包含SEQ ID NO:4的氨基酸序列;
2)HCDR2,其包含SEQ ID NO:5的氨基酸序列;和
3)HCDR3,其包含SEQ ID NO:6的氨基酸序列;并且
所述轻链可变区包含:
1)LCDR1,其包含SEQ ID NO:7的氨基酸序列;
2)LCDR2,其包含SEQ ID NO:8的氨基酸序列;和
3)LCDR3,其包含SEQ ID NO:9的氨基酸序列。
在一实施方案中,所述VH包含:1)SEQ ID NO:10的氨基酸序列;或者2)与SEQ IDNO:10具有至少80%、至少85%、至少90%、至少91%、至少92%、至少93%、至少94%、至少95%、至少96%、至少97%、至少98%、至少99%序列相同性的氨基酸序列;和/或
所述VL包含:1)SEQ ID NO:11的氨基酸序列;或者2)与SEQ ID NO:11具有至少80%、至少85%、至少90%、至少91%、至少92%、至少93%、至少94%、至少95%、至少96%、至少97%、至少98%、至少99%序列相同性的氨基酸序列。
在一实施方案中,所述VH包含SEQ ID NO:10的氨基酸序列,并且所述VL包含SEQID NO:11的氨基酸序列。
第一抗原结合部分可以包含任何形式的抗原结合片段,例如scFv、dsFv、scdsFv、Fab、Fab'或 F(ab')2。根据本发明,第一抗原结合部分特异性结合至癌细胞表面的CD47而不结合或基本不结合红细胞上的CD47,使得本发明的双特异性抗体不会引起红细胞凝集。
第二抗原结合部分可以包含任何形式的抗原结合片段,包括但不限于scFv、dsFv、scdsFv、 Fab、Fab'、F(ab')2和单可变结构域。在一些实施方案中,第二抗原结合部分包含特异性结合 CLD18.2的免疫球蛋白单可变结构域。与CLD18.2特异性结合的免疫球蛋白单可变结构域描述于例如CN112480248A和WO2020238730A1,其内容整体援引加入本文。在一实施方案中,所述免疫球蛋白单可变结构域包含:CDR1,其包含SEQ ID NO:13的氨基酸序列或其变体;CDR2,其包含SEQ ID NO:14的氨基酸序列或其变体;以及CDR3,其包含SEQ IDNO:15的氨基酸序列或其变体;其中,所述变体与其所源自的序列相比具有1个或2个氨基酸的取代、添加和/或缺失。在一具体实施方案中,所述免疫球蛋白单可变结构域包含:CDR1,其包含SEQ ID NO:13的氨基酸序列;CDR2,其包含SEQ ID NO:14的氨基酸序列;以及CDR3,其包含SEQ ID NO:15 的氨基酸序列。在一实施方案中,所述免疫球蛋白单可变结构域包含SEQ ID NO:12的氨基酸序列。在又一实施方案中,所述免疫球蛋白单可变结构域包含与SEQID NO:12的氨基酸序列具有至少80%、至少85%、至少90%、至少91%、至少92%、至少93%、至少94%、至少95%、至少96%、至少97%、至少98%或至少99%序列相同性的氨基酸序列。
在一些实施方案中,第一抗原结合部分和第二抗原结合部分通过接头连接。接头可以是肽接头或化学键,优选肽接头。示例性的肽接头可以包括但不限于聚甘氨酸(G)、聚丙氨酸(A)、聚丝氨酸(S)或其组合,例如GGAS、GGGS、GGGSG或者(G4S)n,其中n为1-20的整数。优选地, n为1-5的整数。在一具体实施方案中,肽接头包含SEQ ID NO:22或SEQ ID NO:23的氨基酸序列。
在一些实施方案中,本发明的抗CD47-CLDN18.2双特异性抗体进一步包含免疫球蛋白恒定区。免疫球蛋白恒定区可以是任何物种的免疫球蛋白的重链恒定区(CH)和轻链恒定区(CL)。重链恒定区可以衍生自任何亚型(例如IgA、IgD、IgE、IgG和IgM)、类别(例如IgG1、IgG2、IgG3、IgG4、 IgA1和IgA2)或亚类(例如,IgG2a和IgG2b)的免疫球蛋白的重链恒定区或其组合。在优选的实施方案中,重链恒定区至少包含Fc区,例如IgG1的重链恒定区可以包括:铰链区的全部或部分- CH2-CH3或者CH1-铰链区-CH2-CH3。轻链恒定区可以衍生自λ(Lambda)轻链或κ(Kappa)轻链恒定区。在一优选实施方案中,重链恒定区为人IgG1的重链恒定区。在一实施方案中,重链恒定区包含SEQ ID NO:2的氨基酸序列。在一优选实施方案中,轻链恒定区为人κ轻链恒定区。在一实施方案中,轻链恒定区包含SEQ ID NO:3的氨基酸序列。
在一实施方案中,第一抗原结合部分的VH和VL分别融合至重链恒定区和轻链恒定区的N端,并且第二抗原结合部分的单可变结构域任选地通过接头融合至所述VH的N端、所述VL的N端、所述重链恒定区的C端或者所述轻链恒定区的C端。
在一些实施方案中,抗CD47-CLDN18.2双特异性抗体包含第一多肽和第二多肽,所述第一多肽包含第一抗原结合部分的VH和重链恒定区,第二多肽包含第一抗原结合部分的VL和轻链恒定区,第二抗原结合部分的单可变结构域任选地通过接头融合至所述VH或VL的N端或者所述重链恒定区或轻链恒定区的C端。在一实施方案中,单可变结构域任选地通过接头融合至所述VH 的N端或者所述重链恒定区的C端,所述第一多肽又可以称为融合重链。在一实施方案中,融合重链具有如下所述式(Ⅰ)或式(Ⅲ)的结构。在另一实施方案中,第二抗原结合部分的单可变结构域任选地通过接头融合至所述VL的N端或轻链恒定区的C端,所述第二多肽又可以称为融合轻链。在一实施方案中,融合轻链具有如下所述式(Ⅳ)或式(Ⅵ)的结构。
在一实施方案中,第一多肽具有式(Ⅰ)的结构:
VH-CH-Linker-VHH 式(Ⅰ),
第二多肽具有式(Ⅱ)的结构:
VL-CL 式(Ⅱ),
其中
VH和VL分别为如上所述第一抗原结合部分的重链可变区和轻链可变区;
VHH为如上所述免疫球蛋白单可变结构域;
CH和CL分别为如上所述重链恒定区和轻链恒定区;
Linker为接头。
在一实施方案中,第一多肽具有式(Ⅰ)的结构,其包含SEQ ID NO:20的氨基酸序列;第二多肽具有式(Ⅱ)的结构,其包含SEQ ID NO:17的氨基酸序列。
在一实施方案中,第一多肽具有式(Ⅲ)的结构:
VHH-Linker-VH-CH 式(Ⅲ),
第二多肽具有式(Ⅱ)的结构,
其中
VHH为如上所述免疫球蛋白单可变结构域;
VH为如上所述第一抗原结合部分的重链可变区;
CH为如上所述重链恒定区;
式(Ⅱ)如上所定义;
Linker为接头。
在一实施方案中,第一多肽具有式(Ⅲ)的结构,其包含SEQ ID NO:16的氨基酸序列;第二多肽具有式(Ⅱ)的结构,其包含SEQ ID NO:17的氨基酸序列。
在一实施方案中,第一多肽具有式(Ⅲ)的结构,其包含SEQ ID NO:21的氨基酸序列;第二多肽具有式(Ⅱ)的结构,其包含SEQ ID NO:17的氨基酸序列。
在又一实施方案中,第一多肽具有式(Ⅲ)的结构,第二多肽具有式(Ⅳ)的结构:
VHH-Linker-VL-CL 式(Ⅳ),
其中
式(Ⅲ)如上所定义;
VHH为如上所述免疫球蛋白单可变结构域;
VL为如上所述第一抗原结合部分的轻链可变区;
CL为如上所述轻链恒定区;
Linker为接头。
在一实施方案中,第一多肽具有式(Ⅲ)的结构,其包含SEQ ID NO:16的氨基酸序列;第二多肽具有式(Ⅳ)的结构,其包含SEQ ID NO:19的氨基酸序列。
在另一实施方案中,第一多肽具有式(Ⅴ)的结构:
VH-CH 式(Ⅴ),
第二多肽具有式(Ⅳ)的结构,
其中
式(Ⅳ)如上所定义;
VH为如上所述第一抗原结合部分的重链可变区;
CH为如上所述重链恒定区;
Linker为接头。
在一实施方案中,第一多肽具有式(Ⅴ)的结构,其包含SEQ ID NO:18的氨基酸序列;第二多肽具有式(Ⅳ)的结构,其包含SEQ ID NO:19的氨基酸序列。
在另一实施方案中,第一多肽具有式(Ⅴ)的结构,第二多肽具有式(Ⅵ)的结构:
VL-CL-Linker-VHH 式(Ⅵ),
其中
式(Ⅴ)如上所定义;
VHH为如上所述免疫球蛋白单可变结构域;
VL为如上所述第一抗原结合部分的轻链可变区;
CL为如上所述轻链恒定区;
Linker为接头。
在一些实施方案中,本发明的抗CD47-CLDN18.2双特异性抗体能够:
1)阻断癌细胞表面的CD47结合至SIRPα;
2)诱导巨噬细胞对表达CD47和CLDN18.2的癌细胞的吞噬;和/或
3)结合表达CD47和CLDN18.2的癌细胞而不结合或基本不结合红细胞。
多核苷酸、载体和宿主细胞
在另一方面,本发明提供一种分离的多核苷酸,其包含编码本发明的抗CD47-CLDN18.2双特异性抗体的多核苷酸序列。
可以利用本领域已知的方法获得本发明的多核苷酸,例如,分离自噬菌体展示文库、酵母展示文库、免疫动物、永生化的细胞(例如,小鼠B细胞杂交瘤细胞、EBV介导的永生化B细胞)或者化学合成。本发明的多核苷酸可以针对用于表达的宿主细胞进行密码子优化。
在又一方面,本发明还提供包含本发明的多核苷酸的载体。在一些实施方案中,将本发明的多核苷酸克隆入表达载体。表达载体可以进一步包含额外的多核苷酸序列,例如调控序列和抗生素抗性基因。表达载体还可以包含编码额外的多肽的多核苷酸序列。额外的多肽可以是例如促进抗体或抗原结合片段的检测和/或分离的多肽,包括但不限于亲和标签(例如聚组氨酸标签(His6)或谷胱甘肽S-转移酶(GST)标签)、包含蛋白酶切割位点的多肽和报告蛋白(例如荧光蛋白)。
在一实施方案中,本发明的多核苷酸制备为重组核酸。可使用本领域众所周知的技术制备重组核酸,例如化学合成、DNA重组技术(例如聚合酶链式反应(PCR)技术)等(参见Sambrook,J., E.F.Fritsch,and T.Maniatis.(1989).Molecular cloning:a laboratorymanual,2nd ed.Cold Spring Harbor Laboratory,Cold Spring Harbor,N.Y.)。
本发明的多核苷酸可以存在于一种或多种表达载体中。在一些实施方案中,表达载体为DNA 质粒,例如用于在细菌、酵母或哺乳动物细胞中表达的DNA质粒。在另一些实施方案中,表达载体为病毒载体。在其他实施方案中,表达载体为噬菌体载体或噬菌粒载体。
本发明还提供一种宿主细胞,其包含至少一种如上所述的多核苷酸或载体。可以采用本领域已知的各种方法将本发明的多核苷酸或表达载体导入合适的宿主细胞中。这类方法包括但不限于脂质体转染、电穿孔、病毒转导和磷酸钙转染等。
在优选的实施方案中,宿主细胞用于表达本发明的抗CD47-CLDN18.2双特异性抗体。宿主细胞的实例包括但不限于原核细胞(例如细菌,例如大肠杆菌)和真核细胞(例如酵母、昆虫细胞、哺乳动物细胞)。
适合于抗体表达的哺乳动物宿主细胞包括但不限于骨髓瘤细胞、HeLa细胞、HEK细胞(例如 HEK 293细胞)、中国仓鼠卵巢(CHO)细胞和其他适于表达抗体的哺乳动物细胞。
本发明还提供一种产生本发明的抗CD47-CLDN18.2双特异性抗体的方法,其包括以下步骤:
(Ⅰ)在合适条件下培养本发明的宿主细胞以表达抗CD47-CLDN18.2双特异性抗体,以及
(Ⅱ)从宿主细胞或其培养物分离所述抗体。
在一些实施方案中,使用单一的载体,其包含编码重链和轻链的多核苷酸序列。在一些实施方案中,使用两种载体,其中一种载体编码抗体的轻链,而另一种编码抗体的重链。在一些实施方案中,宿主细胞还包含伴侣质粒,其可以帮助提高抗体的溶解性、稳定性和/或折叠。从宿主细胞或其培养基中分离和纯化抗体的技术是本领域技术人员所熟知的。
抗体缀合物
本发明还提供一种抗体缀合物,其包含与至少一种治疗剂缀合的本发明的抗CD47-CLDN18.2双特异性抗体。抗体-药物缀合物(ADC)是一种典型的抗体缀合物,其中所述治疗剂可以例如为细胞毒性剂。
如本文所用,“缀合”是指两个或多个部分通过共价或非共价作用相互连接。在优选的实施方案中,所述缀合是共价缀合。
治疗剂可以选自细胞毒性剂、治疗性抗体(例如与另外的抗原特异性结合的抗体或其抗原结合片段)、放射性同位素、寡核苷酸及其类似物(例如干扰RNA)、生物活性肽、蛋白毒素(例如白喉毒素、蓖麻毒素)和酶(例如脲酶)。
细胞毒性剂是指抑制或降低细胞的活性、功能和/或杀死细胞的物质。细胞毒性剂的实例可以包括但不限于:类美登素(maytansinoid)(例如美登素(maytansine)、奥利斯他汀类(例如 MMAF、MMAE、MMAD)、多司他汀(duostatin)、念珠藻环肽(cryptophycin)、长春花生物碱类(例如长春碱、长春新碱)、秋水仙碱类、海兔毒素类、紫杉烷、紫杉醇、多西他赛、卡巴他赛、烯二炔类抗生素、细胞松弛素类、喜树碱类、蒽环类抗生素(例如道诺霉素(daunorubicin)、二羟基蒽二酮(dihydroxyanthracindione)、多柔比星(doxorubicin))、细胞毒性抗生素(例如丝裂霉素 (mitomycin)、放线菌素(actinomycin)、倍癌霉素(duocarmycin)(例如CC-1065)、金霉素 (auromycin)、多霉素(duomycin)、卡奇霉素(calicheamicin)、内孢霉素(endomycin)、酚霉素 (phenomycin))、阿霉素、柔红霉素、卡奇霉素、顺铂(cisplatin)、溴化乙锭(ethidiumbromide)、博来霉素、丝裂霉素、光辉霉素、普拉地内酯、鬼臼毒素、依托泊苷(etoposide)、米托蒽醌、5-氟尿嘧啶、阿糖胞苷、吉西他滨、巯嘌呤、喷司他丁、氟达拉滨、克拉屈滨、奈拉滨、卡莫司汀、洛莫司汀、甲氨蝶呤、苯丙氨酸氮芥、替尼泊苷(tenoposide)、糖皮质激素等。
放射性同位素可以选自例如212Bi、213Bi、131I、125I、111In、177Lu、186Re、188Re、153Sm、90Y。用放射性同位素标记的抗体又可称为放射免疫缀合物。
在优选的实施方案中,所述生物活性多肽是具有治疗活性、结合活性或酶活性的多肽或蛋白。生物活性多肽的非限制性实例可以包括但不限于:蛋白毒素(例如白喉毒素、蓖麻毒素)、酶(例如脲酶、辣根过氧化物酶)、细胞因子。
在一实施方案中,治疗剂为具有抗肿瘤生物活性的分子。具有抗肿瘤生物活性的分子包括但不限于细胞毒性剂、化疗剂、放射性同位素、免疫检查点抑制剂、靶向肿瘤特异性抗原的抗体和其他抗肿瘤药物。在优选一实施方案中,治疗剂为细胞毒性剂。在又一优选实施方案中,治疗剂为放射性同位素。
可以利用本领域已知的任何技术将治疗剂与本发明的抗CD47-CLDN18.2双特异性抗体通过接头缀合。所述接头可以包含用于共价缀合的活性基团,例如胺、羟胺、马来酰亚胺基、羧基、苯基、硫醇、巯基或羟基。接头可为可切割的或不可切割的。可切割的接头例如酶可切割的接头(例如,包含蛋白酶切割位点的肽)、pH敏感的接头(例如,腙类接头)或可还原的接头(例如,二硫键)。
在一实施方案中,接头包含选自胺、羟胺、马来酰亚胺基、羧基、苯基、硫醇、巯基和羟基的活性基团。在一实施方案中,接头为化学键。在一实施方案中,接头包含氨基酸或2-10个氨基酸组成的肽。氨基酸可以是天然或非天然氨基酸。
在一些实施方案中,在与本发明的抗CD47-CLDN18.2双特异性抗体缀合之前,先将治疗剂和接头缀合形成中间体。在一些实施方案中,中间体通过与本发明的抗CD47-CLDN18.2双特异性抗体的巯基形成硫醚键而连接。这类中间体的结构和制备方法以及使用其制备抗体缀合物的方法描述于例如国际专利申请公布号WO2019114666,其相关内容整体援引加入本文。
药物组合物
本发明还提供药物组合物,其包含本发明的抗CD47-CLDN18.2双特异性抗体或者抗体缀合物,以及药学上可接受的载剂。
药学上可接受的载剂可以包括但不限于:稀释剂、粘合剂和胶粘剂、润滑剂、崩解剂、防腐剂、媒介物、分散剂、助流剂、甜味剂、包衣、赋形剂、防腐剂、抗氧化剂(如抗坏血酸、盐酸半胱氨酸、硫酸氢钠、焦亚硫酸钠、亚硫酸钠、抗坏血酸棕榈酸酯、丁羟茴醚(BHA)、丁羟甲苯 (BHT)、卵磷脂、没食子酸丙酯、α-生育酚、柠檬酸、乙二胺四乙酸(EDTA)、山梨糖醇、酒石酸、磷酸等)、增溶剂、胶凝剂、软化剂、溶剂(例如,水、酒精、乙酸和糖浆)、缓冲剂 (例如,磷酸盐缓冲剂、组氨酸缓冲剂和乙酸盐缓冲剂)、表面活性剂(例如非离子表面活性剂,例如聚山梨酯80、聚山梨酯20、泊洛沙姆或聚乙二醇)、抗细菌剂、抗真菌剂、等渗剂(例如海藻糖、蔗糖、甘露醇、山梨醇、乳糖、葡萄糖)、吸收延迟剂、螯合剂和乳化剂。对于包含抗体或者抗体缀合物的组合物而言,合适的载剂可以选自缓冲剂(例如柠檬酸盐缓冲液、乙酸盐缓冲液、磷酸盐缓冲液、组氨酸缓冲液、组氨酸盐缓冲液)、等渗剂(例如海藻糖、蔗糖、甘露醇、山梨醇、乳糖、葡萄糖)、非离子表面活性剂(例如聚山梨酯80、聚山梨酯20、泊洛沙姆)或其组合。
本文提供的药物组合物可以为多种剂型,包括但不限于固体、半固体、液体、粉末或冻干形式。优选地,所述药物组合物适合于静脉内、肌内、皮下、肠胃外、脊柱或表皮施用(如通过注射或输注)。对于包含抗体或者抗体缀合物的组合物而言,优选的剂型通常可以为例如注射液和冻干粉。
可通过本领域已知的任何方法,例如通过全身或局部施用,将本文提供的药物组合物给药于受试者。给药途径包括但不限于肠胃外(例如,静脉内、腹膜内、皮内、肌肉内、皮下或腔内)、局部(例如瘤内)、硬膜外或粘膜(例如鼻内、口服、阴道、直肠、舌下或局部)。本领域技术人员应当理解,确切的给药剂量将取决于各种因素,例如药物组合物的代谢动力学性质、治疗的持续时间、特定化合物的排泄速率、治疗目的、给药途径和受试者的状况,例如患者的年龄、健康状况、体重、性别、饮食、病史,以及医学领域公知的其他因素。给药方法可以为例如注射或输注。
作为一般性指导,本发明的抗CD47-CLDN18.2双特异性抗体的给药剂量范围可以为约 0.0001至100mg/kg,更通常为0.01至20mg/kg受试者体重。例如,给药剂量可以是0.3mg/kg 体重、1mg/kg体重、3mg/kg体重、5mg/kg体重,10mg/kg体重或20mg/kg体重,或在1-20 mg/kg范围内。示例性的治疗方案需要每周给药一次、每两周一次、每三周一次、每四周一次、每月一次、每3个月一次、每3-6个月一次、或起始给药间隔略短后期给药间隔加长。给药方式可以是静脉滴注。
治疗
在又一方面,本发明涉及本发明的抗CD47-CLDN18.2双特异性抗体、抗体缀合物或者药物组合物在制备用于治疗受试者中疾病的药物中的用途。
本发明还涉及本发明的抗CD47-CLDN18.2双特异性抗体、抗体缀合物或者药物组合物,其用于治疗疾病。
本发明还提供一种治疗受试者中疾病的方法,所述方法包括向所述受试者给药治疗有效量的本发明的抗CD47-CLDN18.2双特异性抗体、抗体缀合物或者药物组合物。
在一实施方案中,如上所述的疾病为癌症。如本文所用,“癌症”包括但不限于血液癌和实体瘤。癌症还可以是转移性癌。“转移”是指癌细胞从其原始部位扩散到身体的其他部分。例如,抗CD47- CLDN18.2双特异性抗体可以用于治疗CLDN18.2阳性的癌症。在优选的实施方案中,抗CD47- CLDN18.2双特异性抗体用于治疗CD47和CLDN18.2阳性的癌症。在一些实施方案中,所述癌症为胃癌。
试剂盒
本发明还提供试剂盒,其包含本发明的抗CD47-CLDN18.2双特异性抗体、抗体缀合物或者药物组合物,以及使用说明。试剂盒还可以包含合适的容器。在某些实施方案中,试剂盒还包含给药的装置。通常,试剂盒还包括标签,其用于表明试剂盒内容物的预期用途和/或使用方法。术语“标签”包括在试剂盒上或与试剂盒一起提供的或以其他方式随试剂盒提供的任何书面的或记录的材料。
有益效果
本发明的抗CD47-CLDN18.2双特异性抗体可以至少实现以下的有益效果:
1)阻断癌细胞表面的CD47结合至SIRPα;
2)诱导巨噬细胞对表达CD47和CLDN18.2的癌细胞的吞噬;和/或
3)结合表达CD47和CLDN18.2的癌细胞而不结合或基本不结合红细胞。
此外,相比于单独靶向CD47的单克隆抗体,本发明的抗CD47-CLDN18.2双特异性抗体对 CD47和CLDN18.2阳性的肿瘤细胞有更高的结合活性,并且对CD47和SIRPα相互作用阻断效果更强。
实施例
以下实施例旨在仅对本发明进行举例说明,因此并不应被视为以任何方式限制本发明。
材料与方法
1.抗体表达质粒的构建
通过DNA重组技术制备编码抗体重链和轻链的DNA片段,随后将其分别克隆至表达载体 pcDNA3.4-TOPO(Invitrogen)以获得抗体的重链和轻链表达质粒。在大肠杆菌DH5α中扩增并随后提取和纯化抗体重链和轻链表达质粒。
2.抗体的表达和纯化
所有抗体通过ExpiCHO瞬转表达系统(Thermo Fisher,A29133)表达(参见WO2020238730A1),并采用MabSelect SuRe LX(GE,17547403)进行亲和纯化。
3.SDS-PAGE鉴定抗体纯度
还原溶液制备:将2μg的待测抗体或IPI(Ipilimlumab;参比)加入5×SDS上样缓冲液(含有终浓度为5mM的DTT)中,100℃干浴加热10min,冷却到室温后,12000rpm离心5min,取上清。将上清加入Bis-tris 4-15%梯度胶(金斯瑞)中进行蛋白凝胶电泳。随后通过考马斯亮蓝染色使蛋白条带显色,脱色后用EPSON V550彩色扫描仪扫描,通过ImageJ按照峰面积归一法计算蛋白条带纯度。
4.SEC-HPLC鉴定抗体纯度
Agilent HPLC 1100色谱柱(XBridge BEH SEC 3.5μm,7.8mm I.D.×30cm,Waters)流速设为 0.8mL/min,进样体积20μL,VWD检测器波长为280nm和214nm。流动相采用150mmol/L磷酸缓冲液,pH 7.4,所有样品均使用流动相稀释成0.5mg/mL,然后依次进样空白溶液和样品溶液。按照面积归一法计算样品中高分子聚集物、抗体单体和低分子聚集物的百分比。
5.差示扫描荧光法鉴定抗体稳定性
差示扫描荧光法(differential scanning fluorimetry;DSF)能够根据蛋白质图谱中的荧光变化过程提供有关蛋白质结构稳定性的信息,检测蛋白的构型变化,获得蛋白质的熔解温度(Tm)。
制备待测抗体样品溶液0.2mg/mL,并以PBS和IPI(Ipilimlumab;0.2mg/mL)作为参比。测试样品一式三份以19μL/孔加入96孔板(Nunc)中,然后在每个孔中加入1μL的100×SYPRO orange染料,用移液枪吹打混匀,准备上机。样品热稳定测试采用ABI 7500 FASTRT-PCR仪器,试验类型选择熔解曲线,采用连续模式,扫描温度范围为25~95℃,升温速率为1%,25℃平衡5 min,在升温过程中采集数据,报告基团选择“ROX”,淬灭基团选择“None”,反应体积20μL,以熔解曲线一阶导数的第一个峰谷对应的温度确定为抗体的熔解温度Tm。
实施例1抗CD47-CLDN18.2双特异性抗体的设计
本实施例描述了示例性抗CD47-CLDN18.2双特异性抗体:其中,结合CLDN18.2的臂采用一种特异性识别人CLDN18.2而不识别CLDN18.1的抗CLDN18.2单域抗体NA3S-H1(CDR1、CDR2和CDR3的氨基酸序列分别示于SEQ ID NO:13、14和15;VHH的氨基酸序列示于SEQ IDNO:12),结合CD47的臂采用抗CD47人源化抗体A7H3L3的抗原结合结构域(HCDR1、 HCDR2和HCDR3的氨基酸序列分别示于SEQ ID NO:4、5和6;LCDR1、LCDR2和LCDR3的氨基酸序列分别示于SEQ ID NO:7、8和9;重链可变区的氨基酸序列示于SEQ ID NO:10,轻链可变区的氨基酸序列示于SEQ ID NO:11)。将抗体A7H3L3的重链可变区融合至人IgG1重链恒定区(SEQ IDNO:2)形成抗体A7H3L3的重链,轻链可变区融合至人κ轻链恒定区(SEQ ID NO:3)形成抗体A7H3L3的轻链。抗CLDN18.2单域抗体NA3S-H1已经公布于 WO2020238730A1,其体外ADCC和CDC的细胞杀伤效应以及在人CLDN18.2-HEK29T-SCID 肿瘤移植模型上的肿瘤抑制试验都表现出了极好的药效。人源化抗体A7H3L3与红细胞上的CD47结合很弱,是比较理想用于双特异性抗体的候选抗体,同时双特异性抗体的设计因为结合 CLDN18.2会使得抗CD47抗体A7H3L3结合臂更好的结合表达双靶点的肿瘤细胞,同时更好的阻断SIRPα抑制性信号。
根据抗CLDN18.2单域抗体(VHH)NA3S-H1的价数、位置以及接头(Linker)的长度进行了双特异性抗体设计,设计了5种双特异性抗体(分别为B8-B12),示例性双特异性抗体结构如表1和图1所示,对应的氨基酸序列提供于表2中,其中Linker1的序列为GGGGSGGGGS(SEQ ID NO:22),Linker2的序列为GGGGS(SEQ ID NO:23)。
表1抗CD47-CLDN18.2双特异性抗体结构
表2抗CD47-CLDN18.2双特异性抗体氨基酸序列
抗体名称 | 重链氨基酸序列 | 轻链氨基酸序列 |
B8 | SEQ ID NO:16 | SEQ ID NO:17 |
B9 | SEQ ID NO:18 | SEQ ID NO:19 |
B10 | SEQ ID NO:20 | SEQ ID NO:17 |
B11 | SEQ ID NO:16 | SEQ ID NO:19 |
B12 | SEQ ID NO:21 | SEQ ID NO:17 |
实施例2抗CD47-CLDN18.2双特异性抗体与红细胞上CD47的结合活性
通过流式细胞术测定双特异性抗体在红细胞上是否有结合。使用申请人自研的另一抗CD47抗体F4AM4-IgG1(在附图中简称为F4AM4;重链的氨基酸序列为SEQ ID NO:24,轻链的氨基酸序列为SEQ ID NO:25)作为阳性对照抗体。F4AM4-IgG1在(本实施例的实验开展之前进行的)一系列功能验证实验中表现出强结合红细胞的CD47,因而在本实施例中被选用作阳性对照。
具体方法如下:从1mL抗凝处理的人血液中分离红细胞,离心后吸去上清,PBS润洗两次后,加入1mL PBS并重悬。使用PBS将红细胞稀释至1×107/mL,以每孔50μL吸取红细胞加入到96 孔圆底细胞培养板中,然后等体积加入梯度稀释的待测抗体,充分混匀,置于4℃孵育1h。接着再用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,CytoFLEX AOO-1-1102)检测结合至红细胞上抗体的量 (表示为平均荧光强度(MFI))。
抗体对红细胞的结合活性示于图2a和2b。如图2a和2b所示,即使在非常高的浓度(150 μg/mL)下,相对于F4AM4-IgG1在红细胞上的强结合,所有抗CD47-CLDN18.2双特异性抗体几乎都不结合红细胞或者结合活性极低;在高浓度(15μg/mL)下,B9、B10和B11与阴性对照 IgG1对红细胞的结合没有显著差异,具体数值见表3。由此可见,本发明的双特异性抗体对红细胞上的CD47结合活性较低,基本不会引发红细胞凝集。
表3双特异性抗体在红细胞上的结合的平均荧光强度(MFI)
B8 | B9 | B10 | B11 | B12 | A7H3L3 | IgG1 | F4AM4-IgG1 | |
15μg/mL MFI | 988 | 239 | 534 | 238 | 1615 | 463 | 303 | 63000 |
150μg/mL MFI | 2145 | 1220 | 2493 | 847 | 2526 | 608 | 901 | >63000 |
实施例3抗CD47-CLDN18.2双特异性抗体在表达单靶点和双靶点的肿瘤细胞上的结合活性
通过流式细胞术测定了抗CD47-CLDN18.2双特异性抗体B10对NUGC-4细胞(表达内源 CD47,购自BNCC菌种库,编号BNCC341962)和hCLDN18.2-NUGC-4细胞(采用慢病毒转染的方式构建过表达外源人CLDN18.2(氨基酸序列SEQ ID NO:1)的胃癌细胞株NUGC-4,同时表达内源CD47)的结合活性。作为比较,还测定了抗体1F8(WO2018075857A1中1F8抗体)和F4AM4-IgG1对这两种细胞株的结合活性。人IgG1用作同种型阴性对照。
具体方法如下:取1×105个NUGC-4细胞或hCLDN18.2-NUGC-4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梯度稀释的待测抗体,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)0.5 μg,在4℃孵育1h;然后将细胞用FACS缓冲液润洗三次后用200μL FACS缓冲液重悬,最后通过流式细胞仪(Beckman,CytoFLEX AOO-1-1102)检测结合至红细胞上抗体的量(表示为平均荧光强度(MFI))。
抗体对NUGC-4细胞和hCLDN18.2-NUGC-4细胞的结合活性分别示于图3a和3b。如图3a所示,双特异性抗体B10在肿瘤细胞NUGC-4上的结合活性较弱,且稍弱于抗体1F8。如图3b所示,双特异性抗体B10在CD47和CLDN18.2都表达的hCLDN18.2-NUGC-4细胞上具有明显优于抗体 1F8的结合活性。基于此,双特异性抗体B10虽然在CD47单靶点表达的细胞上结合弱于1F8,然而在CD47和CLDN18.2双靶点表达的细胞上结合却优于1F8。该结果证明了双特异性抗体B10可同时结合肿瘤细胞中的CLDN18.2和CD47,增加了结合肿瘤细胞的能力。
实施例4抗CD47-CLDN18.2双特异性抗体在表达单靶点和双靶点的肿瘤细胞上阻断CD47与 SIRPα结合的能力
通过流式细胞术测定了抗CD47-CLDN18.2双特异性抗体阻断NUGC-4和hCLDN18.2-NUGC-4 细胞上CD47与SIRPα结合的能力。作为比较,还测定了抗体1F8、F4AM4-IgG1和A7H3L3阻断 NUGC-4和hCLDN18.2-NUGC-4肿瘤细胞上CD47与SIRPα结合的能力。
具体方法如下:取1×105个NUGC-4细胞或hCLDN18.2-NUGC-4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2%FBS的1×PBS缓冲液)润洗一次;然后向润洗后的细胞中加入梯度稀释的待测抗体,孵育1h;用FACS缓冲液润洗细胞两次后加入 100μL的1μg/mL SIRPα-mFc(ACRO,SIA-H52A8),在4℃孵育1h;经FACS缓冲液润洗三次,加入100μL 1:200稀释的PE标记的羊抗鼠Fc二抗(Abcam,ab98742),在4℃孵育1h后离心去上清,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)检测结合至细胞上的SIRPα-mFc的量(表示为平均荧光强度(MFI))。
在NUGC-4细胞上的结果如图4a所示:抗体F4AM4-IgG1能够有效的阻断CD47与SIRPα的结合,IC50为0.033μg/mL(0.226nM);抗体1F8具有较弱的阻断效果,IC50为15.36μg/mL(105.6nM);而双特异性抗体B10几乎没有阻断能力。
在hCLDN18.2-NUGC-4细胞上的结果如图4b所示:抗体F4AM4-IgG1在此肿瘤细胞上依然具有强的阻断能力,IC50为0.056μg/mL(0.383nM);相比于在NUGC-4细胞上的阻断能力,双特异性抗体B10在hCLDN18.2-NUGC-4细胞上的阻断能力显著提高,并且优于抗体1F8;B10和1F8 阻断hCLDN18.2-NUGC-4上CD47与SIRPα结合的IC50分别为0.765μg/mL(4.476nM)和11.98 μg/mL(82.34nM);另外,抗CLDN18.2单域抗体NA3S-H1因为只结合CLDN18.2,因而没有任何阻断效果。基于此,双特异性抗体B10虽然在CD47单靶点表达的细胞上的阻断活性弱于抗体 1F8,然而在CD47和CLDN18.2双靶点表达的细胞上阻断活性明显优于抗体1F8,将发挥更强的阻断CD47与受体SIRPα结合的能力。
还测定了其它的双特异性抗体在hCLDN18.2-NUGC-4细胞上的阻断能力,结果如图4c所示。在双特异性抗体B8-B12中,双特异性抗体B10具有最强的阻断活性。
实施例5抗CD47-CLDN18.2双特异性抗体的体内抑瘤实验
5.1体内抑瘤实验1
6-7周龄雌性裸鼠(16-18g)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3×106个hCLDN18.2-NUGC-4细胞对裸鼠进行左侧腋窝皮下注射(第0天),待小鼠皮下荷瘤体积达到300-400mm3左右时(第20天),剔除肿瘤体积差异较大的小鼠样本,然后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、NA3S-H1单抗给药组、A7H3L3单抗给药组、NA3S-H1+A7H3L3联合给药组和双特异性抗体B10给药组。以NA3S-H1单抗5mg/kg作为标准,其它所有药物均采用等摩尔剂量进行给药,即分别为A7H3L3单抗9.4mg/kg、NA3S-H1+ A7H3L3联合5mg/kg+9.4mg/kg、双特异性抗体B10 10.6mg/kg。每个星期两次给药,分别是腹膜内注射(i.p.)和静脉注射(i.v.)两种方式交替给药。随时观察和记录肿瘤长(mm)和宽(mm),计算其肿瘤体积(V),计算方式为:V=(长×宽2)/2,抑瘤率TGI(%)=(1-给药组肿瘤平均体积/PBS处理组肿瘤平均体积)×100%。
抗体抑瘤的结果如图5a和表4所示,从中可以看出:在此等摩尔剂量下,NA3S-H1单抗给药组几乎没有表现出肿瘤抑制效果,其它组都表现出一定的肿瘤抑制效果,其中双特异性抗体B10的效果最好,在第39天之前达到接近54.54%的抑瘤率,肿瘤大小接近第20天肿瘤初始体积,且优于联合用药(A7H3L3+NA3S-H1(9.4+5mpk))的结果,这表明双特异性抗体B10对CLDN18.2 的结合可以增强其对CD47和SIRPα结合的阻断效果。
表4双特异性抗体在小鼠体内的抑瘤率
天数 | NA3S-H1 | A7H3L3 | B10 | A7H3L3+NA3S-H1 |
25 | 2.96% | -1.31% | 3.41% | 12.73% |
28 | 8.76% | 2.17% | 27.69% | 18.40% |
32 | -5.33% | 3.73% | 40.26% | 19.30% |
35 | -6.94% | 2.10% | 44.31% | 19.49% |
39 | 2.01% | 15.00% | 54.54% | 33.71% |
42 | -7.26% | 14.65% | 51.45% | 30.84% |
46 | -8.69% | 24.65% | 48.33% | 32.59% |
49 | -5.94% | 25.18% | 45.12% | 25.62% |
5.2体内抑瘤实验2
随机分组(每组8只小鼠):分别是PBS处理组,单抗NA3S-H1给药组,双特异性抗体B10 给药组。在接种当天(第0天)进行首次给药,每个星期给药两次,以NA3S-H1单抗2.5mg/kg作为标准,双特异性抗体B10采用等摩尔剂量进行给药,即5.3mg/kg。其余与实施例5.1一致。
结果如图5b所示,在此等摩尔剂量下,NA3S-H1单抗给药组表现出一定的肿瘤抑制效果,抑瘤率约为54.99%(第34天);双特异性抗体B10组所有小鼠中的肿瘤被完全抑制,抑瘤率接近 100%(第34天)。该结果证明了双特异性抗体B10的肿瘤抑制效果显著优于抗CLDN18.2单抗 NA3S-H1。
实施例6抗CD47-CLDN18.2双特异性抗体的理化性质测定
6.1 SDS-PAGE纯度鉴定
采用还原SDS-PAGE鉴定双特异性抗体B10的纯度。双特异性抗体B10的重链和轻链主带的表观相对分子量分别是65kD左右和25kD左右,符合预期大小,且纯度约90%。
6.2 SEC-HPLC纯度鉴定
使用SEC-HPLC检测双特异性抗体B10的单体纯度。通过SEC-HPLC测定的双特异性抗体 B10的单体纯度大于94%。
6.3双特异性抗体B10的DSF热稳定性检测
采用DSF法检测了双特异性抗体B10的Tm值,以评估其热稳定性。结果表明,双特异性抗体B10具有两个熔解峰,第一个峰Tm值为69.85±0.06℃,第二个峰Tm值为80.60±0.16℃,表明双特异性抗体B10具有良好的热稳定性。
尽管本发明的具体实施方式已经得到详细的描述,但本领域技术人员将理解:根据本文公开的所有教导,可以对细节进行各种修改和变动,并且这些改变均在本发明的保护范围之内。本发明的保护范围由所附权利要求及其任何等同物给出。
序列表
<110> 宝船生物医药科技(上海)有限公司
三优生物医药(上海)有限公司
<120> 抗CD47-CLDN18.2双特异性抗体及其用途
<130> I2021TC5932CS
<160> 25
<170> PatentIn version 3.5
<210> 1
<211> 261
<212> PRT
<213> Homo sapiens
<400> 1
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> 2
<211> 330
<212> PRT
<213> Artificial Sequence
<220>
<223> 人IgG1重链恒定区
<400> 2
Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys
1 5 10 15
Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr
20 25 30
Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser
35 40 45
Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser
50 55 60
Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr
65 70 75 80
Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys
85 90 95
Lys Ala Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys
100 105 110
Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro
115 120 125
Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys
130 135 140
Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp
145 150 155 160
Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu
165 170 175
Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu
180 185 190
His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn
195 200 205
Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly
210 215 220
Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu
225 230 235 240
Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr
245 250 255
Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn
260 265 270
Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe
275 280 285
Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn
290 295 300
Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr
305 310 315 320
Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
325 330
<210> 3
<211> 107
<212> PRT
<213> Artificial Sequence
<220>
<223> 人Kappa轻链恒定区
<400> 3
Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu
1 5 10 15
Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe
20 25 30
Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln
35 40 45
Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser
50 55 60
Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu
65 70 75 80
Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser
85 90 95
Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
100 105
<210> 4
<211> 10
<212> PRT
<213> Artificial Sequence
<220>
<223> A7H3L3-HCDR1
<400> 4
Gly Phe Asn Ile Lys Asp Ile Tyr Ile Tyr
1 5 10
<210> 5
<211> 10
<212> PRT
<213> Artificial Sequence
<220>
<223> A7H3L3-HCDR2
<400> 5
Lys Ile Asp Pro Ala Asn Gly Asn Thr Lys
1 5 10
<210> 6
<211> 8
<212> PRT
<213> Artificial Sequence
<220>
<223> A7H3L3-HCDR3
<400> 6
Gly Tyr Gly Ser Gly Phe Ala Tyr
1 5
<210> 7
<211> 11
<212> PRT
<213> Artificial Sequence
<220>
<223> A7H3L3-LCDR1
<400> 7
Arg Ala Ser Gln Asp Ile Ser Asn His Leu Asn
1 5 10
<210> 8
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> A7H3L3-LCDR2
<400> 8
Tyr Thr Ser Arg Ile His Ser
1 5
<210> 9
<211> 9
<212> PRT
<213> Artificial Sequence
<220>
<223> A7H3L3-LCDR3
<400> 9
Gln Gln Gly Tyr Thr Leu Pro Phe Thr
1 5
<210> 10
<211> 117
<212> PRT
<213> Artificial Sequence
<220>
<223> A7H3L3-VH
<400> 10
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Phe Asn Ile Lys Asp Ile
20 25 30
Tyr Ile Tyr Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Lys Ile Asp Pro Ala Asn Gly Asn Thr Lys Tyr Asp Gln Lys Phe
50 55 60
Gln Gly Arg Ala Thr Ile Thr Ala Asp Thr Ser Thr Asn Thr Ala Tyr
65 70 75 80
Leu Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Tyr Gly Ser Gly Phe Ala Tyr Trp Gly Gln Gly Thr Leu
100 105 110
Val Thr Val Ser Ser
115
<210> 11
<211> 107
<212> PRT
<213> Artificial Sequence
<220>
<223> A7H3L3-VL
<400> 11
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asp Ile Ser Asn His
20 25 30
Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Tyr Thr Ser Arg Ile His Ser Gly Val Pro Ser Ser Phe Arg Gly
50 55 60
Ser Gly Ser Gly Thr Asp Tyr Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Ile Ala Thr Tyr Phe Cys Gln Gln Gly Tyr Thr Leu Pro Phe
85 90 95
Thr Phe Gly Ser Gly Thr Lys Leu Glu Ile Lys
100 105
<210> 12
<211> 120
<212> PRT
<213> Artificial Sequence
<220>
<223> NA3S-H1
<400> 12
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly 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> 13
<211> 8
<212> PRT
<213> Artificial Sequence
<220>
<223> NA3S-H1 CDR1
<400> 13
Gly Ser Ile Phe Asn Ile Pro Val
1 5
<210> 14
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> NA3S-H1 CDR2
<400> 14
Ile Ser Thr Gly Gly Thr Thr
1 5
<210> 15
<211> 14
<212> PRT
<213> Artificial Sequence
<220>
<223> NA3S-H1 CDR3
<400> 15
Asn Val Leu Val Val Ser Gly Ile Gly Ser Thr Leu Glu Val
1 5 10
<210> 16
<211> 577
<212> PRT
<213> Artificial Sequence
<220>
<223> B8/B11重链
<400> 16
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 Gly Gly Gly Gly Ser Gly Gly Gly
115 120 125
Gly Ser Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro
130 135 140
Gly Ala Ser Val Lys Val Ser Cys Lys Ala Ser Gly Phe Asn Ile Lys
145 150 155 160
Asp Ile Tyr Ile Tyr Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu
165 170 175
Trp Ile Gly Lys Ile Asp Pro Ala Asn Gly Asn Thr Lys Tyr Asp Gln
180 185 190
Lys Phe Gln Gly Arg Ala Thr Ile Thr Ala Asp Thr Ser Thr Asn Thr
195 200 205
Ala Tyr Leu Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr
210 215 220
Tyr Cys Ala Arg Gly Tyr Gly Ser Gly Phe Ala Tyr Trp Gly Gln Gly
225 230 235 240
Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe
245 250 255
Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu
260 265 270
Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp
275 280 285
Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu
290 295 300
Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser
305 310 315 320
Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro
325 330 335
Ser Asn Thr Lys Val Asp Lys Lys Ala Glu Pro Lys Ser Cys Asp Lys
340 345 350
Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro
355 360 365
Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser
370 375 380
Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp
385 390 395 400
Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn
405 410 415
Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val
420 425 430
Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu
435 440 445
Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys
450 455 460
Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr
465 470 475 480
Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr
485 490 495
Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu
500 505 510
Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu
515 520 525
Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys
530 535 540
Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu
545 550 555 560
Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly
565 570 575
Lys
<210> 17
<211> 214
<212> PRT
<213> Artificial Sequence
<220>
<223> B8/B10/B12轻链
<400> 17
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asp Ile Ser Asn His
20 25 30
Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Tyr Thr Ser Arg Ile His Ser Gly Val Pro Ser Ser Phe Arg Gly
50 55 60
Ser Gly Ser Gly Thr Asp Tyr Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Ile Ala Thr Tyr Phe Cys Gln Gln Gly Tyr Thr Leu Pro Phe
85 90 95
Thr Phe Gly Ser Gly Thr Lys Leu Glu Ile Lys Arg Thr Val Ala Ala
100 105 110
Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly
115 120 125
Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala
130 135 140
Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln
145 150 155 160
Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser
165 170 175
Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr
180 185 190
Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser
195 200 205
Phe Asn Arg Gly Glu Cys
210
<210> 18
<211> 447
<212> PRT
<213> Artificial Sequence
<220>
<223> B9重链
<400> 18
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Phe Asn Ile Lys Asp Ile
20 25 30
Tyr Ile Tyr Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Lys Ile Asp Pro Ala Asn Gly Asn Thr Lys Tyr Asp Gln Lys Phe
50 55 60
Gln Gly Arg Ala Thr Ile Thr Ala Asp Thr Ser Thr Asn Thr Ala Tyr
65 70 75 80
Leu Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Tyr Gly Ser Gly Phe Ala Tyr Trp Gly Gln Gly Thr Leu
100 105 110
Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu
115 120 125
Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys
130 135 140
Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser
145 150 155 160
Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser
165 170 175
Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser
180 185 190
Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn
195 200 205
Thr Lys Val Asp Lys Lys Ala Glu Pro Lys Ser Cys Asp Lys Thr His
210 215 220
Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val
225 230 235 240
Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr
245 250 255
Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu
260 265 270
Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys
275 280 285
Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser
290 295 300
Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys
305 310 315 320
Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile
325 330 335
Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro
340 345 350
Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu
355 360 365
Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn
370 375 380
Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser
385 390 395 400
Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg
405 410 415
Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu
420 425 430
His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
435 440 445
<210> 19
<211> 344
<212> PRT
<213> Artificial Sequence
<220>
<223> B9/B11轻链
<400> 19
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 Gly Gly Gly Gly Ser Gly Gly Gly
115 120 125
Gly Ser Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser
130 135 140
Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asp Ile Ser
145 150 155 160
Asn His Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu
165 170 175
Leu Ile Tyr Tyr Thr Ser Arg Ile His Ser Gly Val Pro Ser Ser Phe
180 185 190
Arg Gly Ser Gly Ser Gly Thr Asp Tyr Thr Leu Thr Ile Ser Ser Leu
195 200 205
Gln Pro Glu Asp Ile Ala Thr Tyr Phe Cys Gln Gln Gly Tyr Thr Leu
210 215 220
Pro Phe Thr Phe Gly Ser Gly Thr Lys Leu Glu Ile Lys Arg Thr Val
225 230 235 240
Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys
245 250 255
Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg
260 265 270
Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn
275 280 285
Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser
290 295 300
Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys
305 310 315 320
Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr
325 330 335
Lys Ser Phe Asn Arg Gly Glu Cys
340
<210> 20
<211> 577
<212> PRT
<213> Artificial Sequence
<220>
<223> B10重链
<400> 20
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Phe Asn Ile Lys Asp Ile
20 25 30
Tyr Ile Tyr Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Lys Ile Asp Pro Ala Asn Gly Asn Thr Lys Tyr Asp Gln Lys Phe
50 55 60
Gln Gly Arg Ala Thr Ile Thr Ala Asp Thr Ser Thr Asn Thr Ala Tyr
65 70 75 80
Leu Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Tyr Gly Ser Gly Phe Ala Tyr Trp Gly Gln Gly Thr Leu
100 105 110
Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu
115 120 125
Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys
130 135 140
Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser
145 150 155 160
Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser
165 170 175
Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser
180 185 190
Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn
195 200 205
Thr Lys Val Asp Lys Lys Ala Glu Pro Lys Ser Cys Asp Lys Thr His
210 215 220
Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val
225 230 235 240
Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr
245 250 255
Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu
260 265 270
Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys
275 280 285
Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser
290 295 300
Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys
305 310 315 320
Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile
325 330 335
Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro
340 345 350
Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu
355 360 365
Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn
370 375 380
Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser
385 390 395 400
Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg
405 410 415
Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu
420 425 430
His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys Gly
435 440 445
Gly Gly Gly Ser Gly Gly Gly Gly Ser Gln Val Gln Leu Val Glu Ser
450 455 460
Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala
465 470 475 480
Ala Ser Gly Ser Ile Phe Asn Ile Pro Val Met Gly Trp Tyr Arg Gln
485 490 495
Ala Pro Gly Lys Gln Arg Glu Leu Val Ala Gly Ile Ser Thr Gly Gly
500 505 510
Thr Thr Asn Tyr Gly Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg
515 520 525
Asp Asn Ala Lys Asn Thr Val Tyr Leu Gln Met Asn Ser Leu Lys Pro
530 535 540
Glu Asp Thr Ala Val Tyr Tyr Cys Asn Val Leu Val Val Ser Gly Ile
545 550 555 560
Gly Ser Thr Leu Glu Val Trp Gly Gln Gly Thr Leu Val Thr Val Ser
565 570 575
Ser
<210> 21
<211> 572
<212> PRT
<213> Artificial Sequence
<220>
<223> B12重链
<400> 21
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 Gly Gly Gly Gly Ser Gln Val Gln
115 120 125
Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala Ser Val Lys
130 135 140
Val Ser Cys Lys Ala Ser Gly Phe Asn Ile Lys Asp Ile Tyr Ile Tyr
145 150 155 160
Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Ile Gly Lys Ile
165 170 175
Asp Pro Ala Asn Gly Asn Thr Lys Tyr Asp Gln Lys Phe Gln Gly Arg
180 185 190
Ala Thr Ile Thr Ala Asp Thr Ser Thr Asn Thr Ala Tyr Leu Glu Leu
195 200 205
Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Gly
210 215 220
Tyr Gly Ser Gly Phe Ala Tyr Trp Gly Gln Gly Thr Leu Val Thr Val
225 230 235 240
Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser
245 250 255
Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys
260 265 270
Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu
275 280 285
Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu
290 295 300
Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr
305 310 315 320
Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val
325 330 335
Asp Lys Lys Ala Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro
340 345 350
Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe
355 360 365
Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val
370 375 380
Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe
385 390 395 400
Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro
405 410 415
Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr
420 425 430
Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val
435 440 445
Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala
450 455 460
Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg
465 470 475 480
Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly
485 490 495
Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro
500 505 510
Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser
515 520 525
Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln
530 535 540
Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His
545 550 555 560
Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
565 570
<210> 22
<211> 10
<212> PRT
<213> Artificial Sequence
<220>
<223> Linker1
<400> 22
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
1 5 10
<210> 23
<211> 5
<212> PRT
<213> Artificial Sequence
<220>
<223> Linker2
<400> 23
Gly Gly Gly Gly Ser
1 5
<210> 24
<211> 452
<212> PRT
<213> Artificial Sequence
<220>
<223> F4AM4-IgG1重链
<400> 24
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Met Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Ser
20 25 30
Val Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Tyr Ile Asn Pro Tyr Thr Asp Gly Thr Lys Tyr Ala Gln Lys Phe
50 55 60
Gln Gly Arg Ala Thr Leu Thr Ser Asp Lys Ser Thr Ser Thr Ala Tyr
65 70 75 80
Met Glu Phe Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Gly Arg Pro Tyr Tyr Gly Thr Arg Tyr Gly Ser Trp Phe Ala Tyr Trp
100 105 110
Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro
115 120 125
Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr
130 135 140
Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr
145 150 155 160
Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro
165 170 175
Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr
180 185 190
Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn
195 200 205
His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Ala Glu Pro Lys Ser
210 215 220
Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu
225 230 235 240
Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu
245 250 255
Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser
260 265 270
His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu
275 280 285
Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr
290 295 300
Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn
305 310 315 320
Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro
325 330 335
Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln
340 345 350
Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val
355 360 365
Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val
370 375 380
Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro
385 390 395 400
Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr
405 410 415
Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val
420 425 430
Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu
435 440 445
Ser Pro Gly Lys
450
<210> 25
<211> 214
<212> PRT
<213> Artificial Sequence
<220>
<223> F4AM4-IgG1轻链
<400> 25
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asp Ile Ser Asn Tyr
20 25 30
Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Tyr Thr Ser Arg Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Tyr Thr Leu Thr Ile Ser Asn Leu Gln Pro
65 70 75 80
Glu Asp Ile Ala Thr Tyr Tyr Cys Gln Gln Gly Lys Asn Tyr Pro Phe
85 90 95
Thr Phe Gly Ser Gly Thr Lys Leu Glu Ile Lys Arg Thr Val Ala Ala
100 105 110
Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly
115 120 125
Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala
130 135 140
Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln
145 150 155 160
Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser
165 170 175
Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr
180 185 190
Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser
195 200 205
Phe Asn Arg Gly Glu Cys
210
Claims (12)
1.一种双特异性抗体,其包含结合CD47的第一抗原结合部分以及结合CLDN18.2的第二抗原结合部分,其中所述第一抗原结合部分包含重链可变区(VH)和轻链可变区(VL),
所述重链可变区包含:
1)HCDR1,其包含SEQ ID NO:4的氨基酸序列;
2)HCDR2,其包含SEQ ID NO:5的氨基酸序列;和
3)HCDR3,其包含SEQ ID NO:6的氨基酸序列;并且
所述轻链可变区包含:
1)LCDR1,其包含SEQ ID NO:7的氨基酸序列;
2)LCDR2,其包含SEQ ID NO:8的氨基酸序列;和
3)LCDR3,其包含SEQ ID NO:9的氨基酸序列。
2.权利要求1的双特异性抗体,其中
所述重链可变区包含:1)SEQ ID NO:10的氨基酸序列;或者2)与SEQ ID NO:10具有至少80%、至少85%、至少90%、至少91%、至少92%、至少93%、至少94%、至少95%、至少96%、至少97%、至少98%、至少99%序列相同性的氨基酸序列;和/或
所述轻链可变区包含:1)SEQ ID NO:11的氨基酸序列;或者2)与SEQ ID NO:11具有至少80%、至少85%、至少90%、至少91%、至少92%、至少93%、至少94%、至少95%、至少96%、至少97%、至少98%、至少99%序列相同性的氨基酸序列;
优选地,所述重链可变区包含SEQ ID NO:10的氨基酸序列,并且所述轻链可变区包含SEQ ID NO:11的氨基酸序列。
3.权利要求1或2的双特异性抗体,其中所述第二抗原结合部分包含结合CLDN18.2的免疫球蛋白单可变结构域(VHH);
优选地,所述免疫球蛋白单可变结构域包含:
CDR1,其包含SEQ ID NO:13的氨基酸序列;
CDR2,其包含SEQ ID NO:14的氨基酸序列;以及
CDR3,其包含SEQ ID NO:15的氨基酸序列;
更优选地,所述免疫球蛋白单可变结构域包含:1)SEQ ID NO:12的氨基酸序列;或者2)与SEQ ID NO:12的氨基酸序列具有至少80%、至少85%、至少90%、至少91%、至少92%、至少93%、至少94%、至少95%、至少96%、至少97%、至少98%或至少99%序列相同性的氨基酸序列。
4.权利要求1-3中任一项的双特异性抗体,其中所述第一抗原结合部分和所述第二抗原结合部分通过接头连接。
5.权利要求1-4中任一项的双特异性抗体,其进一步包含免疫球蛋白的重链恒定区(CH)和轻链恒定区(CL);
优选地,所述重链恒定区为人IgG1的重链恒定区,和/或所述轻链恒定区为人κ轻链恒定区;
更优选地,所述重链恒定区包含SEQ ID NO:2的氨基酸序列;和/或所述轻链恒定区包含SEQ ID NO:3的氨基酸序列。
6.权利要求5的双特异性抗体,其包含第一多肽和第二多肽,
其中
所述第一多肽从N端至C端具有如下结构:
VH-CH-Linker-VHH,
所述第二多肽从N端至C端具有如下结构:
VL-CL,
其中
VH和VL分别为如权利要求1或2中所定义的重链可变区和轻链可变区;
VHH为如权利要求3中所定义的免疫球蛋白单可变结构域;
CH和CL分别为如权利要求5中所定义的重链恒定区和轻链恒定区;
Linker为接头;
优选地,所述第一多肽包含SEQ ID NO:20的氨基酸序列,所述第二多肽包含SEQ IDNO:17的氨基酸序列。
7.一种分离的多核苷酸,其编码权利要求1-6中任一项的双特异性抗体。
8.一种表达载体,其包含权利要求7的多核苷酸。
9.一种宿主细胞,其包含权利要求7的多核苷酸或权利要求8的表达载体。
10.一种抗体缀合物,其包含与至少一种治疗剂缀合的权利要求1-6中任一项的双特异性抗体。
11.一种药物组合物,其包含权利要求1-6中任一项的双特异性抗体或者权利要求10的抗体缀合物,以及药学上可接受的载剂。
12.权利要求1-6中任一项的双特异性抗体、权利要求10的抗体缀合物或者权利要求11的药物组合物在制备用于治疗癌症的药物中的用途;优选地,所述癌症为胃癌。
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CN202111214360.8A CN115991784A (zh) | 2021-10-19 | 2021-10-19 | 抗cd47-cldn18.2双特异性抗体及其用途 |
PCT/CN2022/082008 WO2023065594A1 (zh) | 2021-10-19 | 2022-03-21 | 抗cd47-cldn18.2双特异性抗体及其用途 |
CN202280001058.0A CN116267016B (zh) | 2021-10-19 | 2022-03-21 | 抗cd47-cldn18.2双特异性抗体及其用途 |
TW111139359A TW202321297A (zh) | 2021-10-19 | 2022-10-18 | 抗cd47-cldn18.2雙特異性抗體及其用途 |
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CN114075284A (zh) * | 2020-08-17 | 2022-02-22 | 上海元宋生物技术有限公司 | Cd47结合分子及其用途 |
CN116836291A (zh) * | 2023-08-25 | 2023-10-03 | 宝船生物医药科技(上海)有限公司 | 抗cd47-cldn18.2双特异性抗体的抗独特型抗体及其制备方法和应用 |
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DK2569013T3 (da) | 2010-05-14 | 2017-02-13 | Univ Leland Stanford Junior | Humaniserede og kimære monoklonale antistoffer til cd47 |
WO2016165762A1 (en) | 2015-04-15 | 2016-10-20 | Ganymed Pharmaceuticals Ag | Drug conjugates comprising antibodies against claudin 18.2 |
US20200140565A1 (en) | 2016-10-20 | 2020-05-07 | I-Mab | Novel cd47 monoclonal antibodies and uses thereof |
CN113698414A (zh) | 2017-12-15 | 2021-11-26 | 四川科伦博泰生物医药股份有限公司 | 生物活性物偶联物及其制备方法和用途 |
WO2019242505A1 (zh) * | 2018-06-17 | 2019-12-26 | 上海健信生物医药科技有限公司 | 靶向cldn18.2的抗体、双特异性抗体、adc和car及其应用 |
CN111518214B (zh) * | 2019-02-03 | 2023-09-22 | 上海健信生物医药科技有限公司 | 靶向cldn18.2的双特异性抗体及其制备方法和应用 |
JP7401538B2 (ja) * | 2018-10-22 | 2023-12-19 | シャンハイ、ケンパーソー、バイオテクノロジー、カンパニー、リミテッド | 抗cldn18.2抗体およびその使用 |
US20230192840A1 (en) * | 2018-12-28 | 2023-06-22 | Sichuan Kelun-Biotech Biopharmaceutical Co., Ltd. | Antibody and use thereof |
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 |
CN111978402B (zh) * | 2019-05-24 | 2022-06-28 | 三优生物医药(上海)有限公司 | 新型cldn18.2结合分子 |
TW202108627A (zh) | 2019-05-24 | 2021-03-01 | 大陸商三優生物醫藥(上海)有限公司 | 新型cldn18.2結合分子 |
WO2021003082A1 (en) | 2019-07-03 | 2021-01-07 | Phanes Therapeutics, Inc. | Anti-claudin 18.2/anti-cd47 bispecific antibodies and uses thereof |
CN112707965A (zh) * | 2019-09-30 | 2021-04-27 | 和铂医药(苏州)有限公司 | 靶向cldn18.2的抗体及其制备方法和应用 |
CN112480248B (zh) | 2020-11-24 | 2023-05-05 | 三优生物医药(上海)有限公司 | 与cld18a2特异性结合的分子 |
-
2021
- 2021-10-19 CN CN202111214360.8A patent/CN115991784A/zh active Pending
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2022
- 2022-03-21 WO PCT/CN2022/082008 patent/WO2023065594A1/zh unknown
- 2022-03-21 CN CN202280001058.0A patent/CN116267016B/zh active Active
- 2022-10-18 TW TW111139359A patent/TW202321297A/zh unknown
Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN114075284A (zh) * | 2020-08-17 | 2022-02-22 | 上海元宋生物技术有限公司 | Cd47结合分子及其用途 |
CN114075284B (zh) * | 2020-08-17 | 2023-11-17 | 上海元宋生物技术有限公司 | Cd47结合分子及其用途 |
CN116836291A (zh) * | 2023-08-25 | 2023-10-03 | 宝船生物医药科技(上海)有限公司 | 抗cd47-cldn18.2双特异性抗体的抗独特型抗体及其制备方法和应用 |
CN116836291B (zh) * | 2023-08-25 | 2023-11-07 | 宝船生物医药科技(上海)有限公司 | 抗cd47-cldn18.2双特异性抗体的抗独特型抗体及其制备方法和应用 |
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WO2023065594A1 (zh) | 2023-04-27 |
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