CN117192118A - 一种抗cldn 18.2和cd47的双特异性抗体治疗疾病的用途 - Google Patents
一种抗cldn 18.2和cd47的双特异性抗体治疗疾病的用途 Download PDFInfo
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Abstract
本发明公开了一种抗CLDN 18.2和CD47的双特异性抗体治疗疾病的用途。本发明公开了所述双特异性抗体或其抗原结合片段在制备诊断、预防和/或治疗胰腺癌和/或结直肠癌的药物中的应用,所述双特异性抗体包含特异性结合CD47的第一抗原结合域和特异性结合CLDN 18.2的第二抗原结合域。本发明还公开了所述双特异性抗体或其抗原结合片段与铂类药物联合在制备诊断、预防和/或治疗胃癌、结直肠癌和胰腺癌的药物中的应用,以及包含所述双特异性抗体或其抗原结合片段的药物组合物和套装药盒。本发明所述双特异性抗体在治疗肿瘤的应用中效果优异,能够有效抑制胃癌、结直肠癌和胰腺癌,且无非预期毒性,其单独使用、或联合奥沙利铂使用均能有效抑制肿瘤的生长。
Description
技术领域
本发明属于生物医药领域,具体涉及一种抗CLDN 18.2和CD47的双特异性抗体治疗疾病的用途。
背景技术
双特异性抗体,是指一个抗体分子可以与两个不同抗原或者与同一抗原的两个不同抗原表位相结合。其可通过与靶细胞和功能细胞进行相互作用,进而增强肿瘤细胞杀伤功能,在肿瘤的靶向治疗中具有广阔的应用前景。
CLDN
18.2
1998年,日本京都大学的研究人员首次发现并命名了Claudins。Claudins是存在于上皮细胞和内皮细胞紧密连接部分的整合素膜蛋白,构成了细胞旁的屏障和孔,并参与控制上皮细胞间细胞间空间分子的流动。它们有四个跨膜结构域,其中N端和C端都存在于细胞质中。研究发现,Claudins蛋白与上皮细胞维持渗透压、屏障功能以及细胞极性密切相关,参与了对病原体的免疫防御过程,在肿瘤的发生发展过程中存在表达模式的改变。将Claudins谱系作为特异性标志蛋白的靶向治疗肿瘤的研究得到广泛关注。
CLDN 18.2(Claudins 18.2)蛋白属于Claudins家族成员,是Claudins 18的亚型之一,在多种原发性恶性肿瘤的发生发展过程中往往出现异常高表达的情况。最初被发现能持续、稳定地表达于多种胃癌组织,但随后的研究表明,其也能在乳腺癌、结直肠癌、肝癌以及非小细胞肺癌等多种原发恶性肿瘤中异常激活和过度表达,尤其是消化系统恶性肿瘤,如胃癌、胰腺癌、食管癌。
正常情况下,CLDN 18.2蛋白埋藏在上皮细胞的细胞膜内,而恶性肿瘤中细胞的紧密连接状态被破坏,使得肿瘤细胞表面的CLDN 18.2暴露出来,成为可攻击的靶点。因此,CLDN 18.2成为具有巨大潜力的抗肿瘤靶点,针对CLDN 18.2的新药项目包括了单抗、双抗、CAR-T等多种类型,竞争激烈。
Zolbetuximab(IMAB362)就是一种针对靶点CLDN 18.2的药物,是一种嵌合的IgG1单克隆抗体,在肿瘤细胞表面与CLDN18.2特异结合,从而引发抗体依赖性细胞毒性(ADCC)、补体依赖性细胞毒性(CDC),凋亡和抑制细胞增殖。临床前研究已经成功地证实了它具有清除癌细胞和控制疾病的强大能力。随后,通过多个I/II期临床试验也评估了其较好的临床疗效和安全性。
CD47
CD47属于免疫球蛋白超家族,分子量约为50kDa,是一个拥有5个跨膜域的跨膜糖蛋白,广泛表达在几乎所有的正常细胞表面。目前已知的CD47的天然配体有三种:整合素(Integrin)、血小板反应蛋白-1(Thrombospondin-1,TSP-1)和信号调节蛋白α(Signal-regulatory proteinα,SIRPα)。CD47及其配体主要参与细胞黏附、细胞迁移、细胞吞噬以及维持机体免疫稳态等功能。
巨噬细胞是人体先天性免疫的重要组成部分,在人体内吞噬衰老细胞和死亡细胞。在肿瘤组织中巨噬细胞可以通过吞噬作用清除肿瘤细胞,但是研究发现,其吞噬作用会被CD47-SIRPα免疫检查点通路所抑制,当CD47和SIRPα结合后,会引起ITIM(Immunoreceptor tyrosine-based inhibitory motif,免疫受体酪氨酸抑制基序)中酪氨酸的磷酸化,磷酸化的ITIM随后募集并激活酪氨酸酯酶SHP1/2蛋白,活化后的酪氨酸酯酶进一步将细胞内的一系列蛋白去磷酸化并紊乱相关的生物学功能,使肿瘤细胞的吞噬功能被抑制,最终起到阻止肿瘤细胞被清除,逃避免疫监视的效果。因此阻断SIRPα或CD47 可以激活巨噬细胞对肿瘤细胞的杀伤作用,使得CD47抗体开发成为治疗肿瘤的一种思路。
综上所述,CLDN 18.2与CD47两个靶点前者特异存在于肿瘤细胞表面,后者于免疫微环境高度相关,同时攻击两者在抗肿瘤靶向治疗方面存在可预见的协同作用。抗 CLDN18.2和CD47双特异性抗体可以选择性地靶向表达CLDN 18.2和CD47的癌细胞,可通过ADCC、ADCP等Fc端功能对肿瘤细胞进行杀伤,并阻断靶细胞上的CD47/SIRPa 相互作用,激活针对该细胞的先天免疫系统,进一步杀伤靶细胞。并且一条臂与CLDN 18.2结合且另一臂与CD47结合的双特异性抗体在选择性靶向表达两种抗原的细胞时,在亲和力方面,与任一臂相比,双特异性抗体与同时表达两者抗原的细胞上的两种抗原结合可导致亲和力增加。且预计双特异性抗体可对仅表达CD47(但不表达CLDN 18.2)的细胞具有较弱的活性。这可以帮助避免靶向表达某些CD47但不表达CLDN 18.2的正常细胞,可以增加抗CLDN 18.2和CD47双特异性抗体的安全性和/或耐受性。
专利WO2021003082就公开了一种抗CLDN 18.2与CD47的双特异性抗体,其所述抗体能够结合表达CLDN 18.2和CD47的癌细胞,诱导ADCC作用,并阻断CD47与 SIRPα的结合,诱导巨噬细胞介导的吞噬作用,且与人类红细胞的结合极少,毒性较低,与上述猜测相符合。但未知此类双抗在体内抗肿瘤效果如何,在体内的复杂环境中是否还能维持体外实验的结果。
发明内容
为解决现有技术中尚无有效的抗CLDN 18.2与CD47的双特异性抗体在体内进行治疗的报道的问题,本发明提供一种抗CLDN 18.2和CD47的双特异性抗体及其应用,本发明人发现,此抗CLDN 18.2和CD47的双特异性抗体治疗肿瘤效果优异,且无非预期毒性。
为解决上述技术问题,本发明提供的技术方案之一为:一种靶向CLDN 18.2和CD47的双特异性抗体或其抗原结合片段在制备诊断、预防和/或治疗胰腺癌和/或结直肠癌的药物中的应用,所述双特异性抗体包含特异性结合CD47的第一抗原结合域和特异性结合CLDN 18.2的第二抗原结合域。
本发明提供了所述抗CLDN 18.2和CD47的双特异性抗体的序列表(包括CDR区、轻链重链可变区以及全序列)。
所述第一抗原结合域的LCDR1的氨基酸序列如SEQ ID NO:1所示,LCDR2的氨基酸序列如SEQ ID NO:2所示,LCDR3的氨基酸序列如SEQ ID NO:3所示,HCDR1的氨基酸序列如SEQ ID NO:4所示,HCDR2的氨基酸序列如SEQ ID NO:5所示,以及 HCDR3的氨基酸序列如SEQ ID NO:6所示。
如技术方案之一所述的应用,所述第二抗原结合域包含免疫球蛋白单可变结构域VHH。
在本发明的优选技术方案中,所述第二抗原结合域的HCDR1的氨基酸序列如SEQID NO:7所示,HCDR2的氨基酸序列如SEQ ID NO:8所示,以及HCDR3的氨基酸序列如SEQ IDNO:9所示。
如技术方案之一所述的应用,所述第一抗原结合域和第二抗原结合域的轻链可变区和/或重链可变区的框架区为人源框架区。
在本发明的优选技术方案中,所述第一抗原结合域的轻链可变区的氨基酸序列如SEQ ID NO:10所示。
在本发明的优选技术方案中,所述第一抗原结合域的重链可变区的氨基酸序列如SEQ ID NO:12所示。
在本发明的优选技术方案中,所述第二抗原结合域的重链可变区的氨基酸序列如SEQ ID NO:14所示。
如技术方案之一所述的应用,所述第一抗原结合域的轻链恒定区为人κ轻链恒定区,和/或,所述第一抗原结合域的重链恒定区为人IgG1的重链恒定区。
在本发明的优选技术方案中,所述第一抗原结合域的轻链恒定区的氨基酸序列如SEQ ID NO:11所示。
在本发明的优选技术方案中,所述第一抗原结合域的重链恒定区的氨基酸序列如SEQ ID NO:13所示。
如技术方案之一所述的应用,所述第一抗原结合域的重链和所述第二抗原结合域的重链之间用接头连接。
在本发明的较佳技术方案中,所述第二抗原结合域的重链用接头连接在所述第一抗原结合域的重链的C端。
在本发明的更佳技术方案中,第一抗原结合域的重链的氨基酸序列如SEQ ID NO:16 所示,和/或,所述接头的氨基酸序列如SEQ ID NO:18所示。
如技术方案之一所述的应用,所述双特异性抗体包含长链和短链,所述短链包含如 SEQ ID NO:15所示的氨基酸序列,所述长链包含如SEQ ID NO:17所示的氨基酸序列。
本发明提供一种如本发明所述的抗CLDN 18.2和CD47的双特异性抗体例如注射液在治疗和/或预防肿瘤的产品中应用。此外,本发明还提供了该抗CLDN 18.2和CD47的双特异性抗体例如注射液与化疗药物联合在治疗和/或预防肿瘤的产品中应用。
为解决上述技术问题,本发明提供的技术方案之二为:一种靶向CLDN 18.2和CD47的双特异性抗体或其抗原结合片段与铂类药物联合在制备诊断、预防和/或治疗肿瘤的药物中的应用,所述双特异性抗体或其抗原结合片段如技术分方案之一所述的应用中所定义,所述肿瘤为CLDN 18.2和/或CD47阳性肿瘤;
在本发明的较佳技术方案中,所述肿瘤为消化系统肿瘤;
在本发明的更佳技术方案中,所述消化系统肿瘤为胰腺癌或胃肠道肿瘤;
在本发明的进一步更佳技术方案中,所述胃肠道肿瘤为胃癌或结直肠癌。
如技术方案之二所述的应用,所述铂类药物选自顺铂、卡铂和奥沙利铂。
在本发明的具体技术方案中,所述铂类药物为奥沙利铂。
上述应用中,所述化疗药物是所述肿瘤临床治疗指南中推荐的基础化学疗法方案,例如铂类药物(顺铂、卡铂、奥沙利铂)为基础的化学疗法方案等。铂类药物通过抑制瘤细胞DNA的复制和转录,从而对瘤细胞产生直接的细胞毒作用,具有广谱抗癌活性,是最常用的化疗药物。化药药物直接杀伤瘤细胞,可以释放细胞内肿瘤相关抗原等物质,进而增强肿瘤免疫原性,与免疫调节类药物具有协同增效作用。
本领域技术人员能够通过铂类药物得知,本发明具体可以使用顺铂、卡铂、奥沙利铂等,但是在实际临床应用上,顺铂毒性相对较大,卡铂施用不方便,故奥沙利铂为相对较优技术方案,但不应当将本发明的保护范围限制于此。
为解决上述技术问题,本发明提供的技术方案之三为:一种药物组合物,其包含如技术方案之一所述的应用中所定义的靶向CLDN 18.2和CD47的双特异性抗体或其抗原结合片段,以及铂类药物。
在本发明的具体技术方案中,所述铂类药物选自顺铂、卡铂和奥沙利铂,优选奥沙利铂。
为解决上述技术问题,本发明提供的技术方案之四为:一种套装药盒,其包含药盒A 和药盒B,其中:
所述药盒A包含如技术方案之一所述的应用中所定义的靶向CLDN 18.2和CD47的双特异性抗体或其抗原结合片段。
所述药盒B含有其他抗肿瘤抗体或者包含所述其他抗肿瘤抗体的药物组合物,和/或由激素制剂、靶向小分子制剂、蛋白酶体抑制剂、成像剂、诊断剂、化疗剂、溶瘤药物、细胞毒性剂、细胞因子、共刺激分子的激活剂、抑制性分子的抑制剂以及疫苗组成的群组中的一种或多种。
在本发明的较佳技术方案中,所述化疗剂优选铂类药物。
在本发明的更佳技术方案中,所述铂类药物选自顺铂、卡铂和奥沙利铂,优选奥沙利铂。
本发明抗体由2条相同的轻链和2条相同的重链共价交联而成,含577个氨基酸,其重链VH和轻链VL共同组成了能够特异性结合CD47的结构域,而C端连接了一个针对CLDN18.2的重链抗体VHH结构域。本发明抗体抗CLDN18.2端与人、鼠、食蟹猴具有交叉反应,抗CD47端与人、食蟹猴有交叉反应。本发明抗体能靶向作用于肿瘤细胞表面的CLDN 18.2分子,并阻断CD47/SIRPα相互作用介导的免疫抑制,通过Fc端激活机体NK细胞和巨噬细胞活性,通过ADCC、ADCP等Fc端功能对CLDN 18.2阳性肿瘤细胞进行杀伤,发挥抗肿瘤作用。
在此基础上,探讨本发明抗体在小鼠实体瘤模型上的抗肿瘤疗效。
本发明提供了本发明抗体在过表达CLDN 18.2的BxPC3、HT29与NUGC4三个细胞系的荷瘤鼠模型中治疗癌症的效果。在过表达CLDN 18.2的NUGC4人胃癌细胞系的荷瘤鼠模型中探究了本发明抗体与临床常用铂类化药奥沙利铂联合使用的治疗效果。在过表达CLDN18.2的HT29人结肠癌模型中对比了本发明抗体与CLDN18.2靶点单抗药物IMAB362和CD47靶点单抗药物Hu5F9-G4的治疗效果。(IMAB362,由安斯泰来公司开发的针对CLDN18.2的人鼠嵌合抗体,本申请中使用的IMAB362为按照专利 US20180127489中报道的抗体序列进行自制获得;Hu5F9-G4,由Forty Seven公司开发的针对CD47的人源化单克隆抗体,本申请中使用的Hu5F9-G4为按照专利 US20200283520A1中报道的抗体序列进行自制获得。)
本发明抗体在过表达CLDN 18.2的BxPC3、HT29与NUGC4三个细胞系的荷瘤鼠模型中皆有剂量依赖的抗肿瘤效果,高剂量抑瘤率皆超过80%,最高可超过100%,达到完全抑制肿瘤生长的效果。且相对于单抗来说,有显著的抗肿瘤优势,联合化疗药物也有很好的增效,提示本发明抗体在临床中对CLDN 18.2阳性的胰腺癌、结直肠癌和胃癌等癌症有较好的治疗潜力。
本发明所用试剂和原料均市售可得。
本发明的积极进步效果在于:
本发明使用抗CLDN 18.2和CD47双特异性抗体在治疗肿瘤的应用中效果优异,能够有效抑制胃癌、结直肠癌、胰腺癌,且无非预期毒性,其单独使用、或联合奥沙利铂使用均能有效抑制肿瘤的生长。
附图说明
图1A为用BLI法本发明双抗A与CLDN18.2亲和力测定。
图1B为用BLI法本发明双抗A与CD47亲和力测定。
图1C为ELISA法测定本发明双抗A与CD47结合活性。
图2为双抗A对BxPC3-hCLDN18.2荷瘤小鼠移植瘤的疗效-肿瘤体积。
图3为双抗A对BxPC3-hCLDN18.2荷瘤小鼠移植瘤的疗效-肿瘤展示图。
图4为双抗A对BxPC3-hCLDN18.2荷瘤小鼠移植瘤的疗效-肿瘤重量。
图5为双抗A对BxPC3-hCLDN18.2荷瘤小鼠体重的影响。
图6为双抗A对HT29-hCLDN18.2荷瘤小鼠移植瘤的疗效-肿瘤体积。
图7为双抗A对HT29-hCLDN18.2荷瘤小鼠移植瘤的疗效-肿瘤展示图。
图8为双抗A对HT29-hCLDN18.2荷瘤小鼠移植瘤的疗效-肿瘤重量。
图9为双抗A对HT29-hCLDN18.2荷瘤小鼠体重的影响。
图10为双抗A对NUGC-4-hCLDN18.2荷瘤小鼠移植瘤的疗效-肿瘤体积。
图11为双抗A对NUGC-4-hCLDN18.2荷瘤小鼠移植瘤的疗效-肿瘤展示图(X:该只小鼠肿瘤完全消除)。
图12为双抗A对NUGC-4-hCLDN18.2荷瘤小鼠移植瘤的疗效-肿瘤重量。
图13为双抗A对NUGC-4-hCLDN18.2荷瘤小鼠体重的影响。
图14为给药抗体对HT29-hCLDN18.2小鼠移植瘤的疗效-肿瘤体积。
图15为给药抗体对HT29-hCLDN18.2荷瘤小鼠移植瘤的疗效-肿瘤展示图。
图16为给药抗体对HT29-hCLDN18.2荷瘤小鼠移植瘤的疗效-肿瘤重量。
图17为本发明抗体对HT29-hCLDN18.2荷瘤小鼠体重的影响。
图18为双抗A联合奥沙利铂对NUGC-4-hCLDN18.2小鼠移植瘤的疗效-肿瘤体积。
图19为双抗A联合奥沙利铂对NUGC-4-hCLDN18.2荷瘤小鼠移植瘤的疗效-肿瘤展示图。
图20为双抗A联合奥沙利铂对NUGC-4-hCLDN18.2荷瘤小鼠移植瘤的疗效-肿瘤重量。
图21为双抗A联合奥沙利铂对NUGC-4-hCLDN18.2荷瘤小鼠体重的影响。
图22a为双抗A在NUGC-4细胞上的阻断人CD47与受体SIRPα结合的能力。
图22b为双抗A在hCLDN18.2-NUGC-4细胞上的阻断人CD47与受体SIRPα结合的能力。
图23a和图23b为双抗A在小鼠体内对肿瘤生长的抑制作用。
具体实施方式
术语解释
在一些实施方案中,本发明的药物组合物包含合适的药学上可接受的载体例如药用辅料,如本领域中已知的药用载体、药用赋形剂,包括缓冲剂。如本发明所用,“药学上可接受的载体”或“药用载体”包括生理上相容的任何和全部溶剂、分散介质、等渗剂和吸收延迟剂等。适用于本发明的药用载体可以是无菌液体,如水和油,包括那些石油、动物、植物或合成来源的,如花生油、大豆油、矿物油、芝麻油等。当静脉内施用药物组合物时,水是优选的载体。还可以将盐水溶液和水性右旋糖以及甘油溶液用作液体载体,特别是用于可注射溶液。合适的赋形剂包括淀粉、葡萄糖、乳糖、蔗糖、明胶、麦芽、米、面粉、白垩、硅胶、硬脂酸钠、甘油单硬脂酸酯、滑石、氯化钠、干燥的脱脂乳、甘油、丙烯、二醇、水、乙醇等。对于赋形剂的使用及其用途,亦参见“Handbook of Pharmaceutical Excipients”,第五版,R.C.Rowe、P.J.Seskey和S.C.Owen,Pharmaceutical Press,London, Chicago。若期望的话,所述组合物还可以含有少量的润湿剂或乳化剂,或pH缓冲剂。这些组合物可以采用溶液、悬浮液、乳剂、片剂、丸剂、胶囊剂、粉末、持续释放配制剂等的形式。口服配制剂可以包含标准药用载体和/或赋形剂,如药用级甘露醇、乳糖、淀粉、硬脂酸镁、糖精。可以通过将具有所需纯度的本发明的抗体或其抗原结合片段与一种或多种任选的药用辅料(Remington’s Pharmaceutical Sciences,第16版,Osol,A.编(1980))混合来制备包含本发明所述的药物制剂或药物组合物,优选地以冻干制剂或水溶液的形式。本发明的药物组合物或制剂还可以包含超过一种活性成分,所述活性成分是被治疗的特定适应症所需的,优选具有不会不利地彼此影响的互补活性的那些活性成分。例如,理想的是还提供其它抗肿瘤活性成分,例如其它抗体、抗肿瘤活性剂、小分子药物或免疫调节剂等。所述活性成分以对于目的用途有效的量合适地组合存在。可制备持续释放制剂。持续释放制剂的合适实例包括含有本发明的抗体或其抗原结合片段的固体疏水聚合物的半渗透基质,所述基质呈成形物品,例如薄膜或微囊形式。
在本发明中,上述所列CDR的氨基酸序列均是按照Kabat定义规则所示出的。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(Chothia等人.(1989)Nature 342:877-883,Al-Lazikani等人,Journal of Molecular Biology,273,927-948(1997))、基于抗体序列可变性的Kabat (Kabat等人,U.S.Department of Health and Human Services,NationalInstitutes of Health (1987))、AbM(University of Bath),Contact(UniversityCollege London)、国际 ImMunoGeneTics database(IMGT)(万维网imgt.cines.fr/),以及基于利用大量晶体结构的近邻传播聚类(affinity propagation clustering)的NorthCDR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。
本发明所用氨基酸三字母代码和单字母代码如本领域技术人员知晓,或参见文献(J. Biol.Chem,243,p3558(1968))中所述。
如本发明所用,“载体”表示构建体,其能够将一种或多种所关注的基因或序列递送入宿主细胞并且优选在宿主细胞中表达所述基因或序列。载体的实例包括但不限于病毒载体、裸DNA或RNA表达载体、质粒、粘粒或噬菌体载体、与阳离子凝聚剂相关的DNA 或RNA表达载体、包囊化于脂质体中的DNA或RNA表达载体以及某些真核细胞,例如生产细胞。
在本发明实施例中,实验结束时将各组小鼠安乐处死。使用Excel统计软件:平均值以AVE计算;SD值以STDEV计算;SEM值以STDEV/SQRT(每组动物数)计算;使用 GraphPadPrism6.0软件作图,组间差异P值以Student's t test分析。
在本发明实施例中,肿瘤体积(TV)计算公式为:TV=0.5×长径×短径2。
抑瘤率TGItv(%):用于评价药物抗肿瘤活性的作用,抑瘤率(%)=[1-(TVt-TVinitial)/(CVt- CVinitial)]×100%,其中,TVt表示治疗组每次测量时的肿瘤体积;TVinitial表示分组给药时治疗组的肿瘤体积;CVt表示对照组每次测量时的肿瘤体积;CVinitial表示分组给药时对照组的肿瘤体积。
为进一步阐述本发明所采取的技术手段及其效果,以下结合实施例和附图对本发明作进一步地说明,以下实施例中“双抗A”即为本发明的抗CLDN 18.2和CD47的双特异性抗体,本申请人在先专利申请202111214360.8及PCT/CN2022/082008全文为本申请引用和参考。可以理解的是,此处所描述的具体实施方式仅仅用于解释本发明,而非对本发明的限定。
实施例中未注明具体技术或条件者,按照本领域内的文献所描述的技术或条件,或者按照产品说明书进行。所用试剂或仪器未注明生产厂商者,均为可通过正规渠道商购获得的常规产品。
制备实施例1本发明抗体的制备
1.抗体表达质粒的构建
将抗体重链和轻链基因分别连接到克隆T载体并经测序确认,利用限制性内切酶Nhe Ⅰ和SalⅠ将轻链和重链基因分别亚克隆到Mu-H和/>Mu-P表达载体并经测序和酶切确认后,最终获得重组质粒。
2.抗体的表达
重组质粒通过电穿孔方式共转染至CHO-K1宿主细胞以表达,并用本领域常规方法进行亲和纯化。
本发明抗体双抗A的序列和结构
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:7、8和9;VHH的氨基酸序列示于SEQ ID NO:14),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:1、2和3;重链可变区的氨基酸序列示于SEQ ID NO:12,轻链可变区的氨基酸序列示于SEQ ID NO:10)。将抗体A7H3L3的重链可变区融合至人IgG1重链恒定区(SEQ ID NO:13)形成抗体A7H3L3的重链(SEQ ID NO:16),轻链可变区融合至人κ轻链恒定区(SEQ ID NO:11)形成抗体A7H3L3的轻链(SEQ ID NO:15)。
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SIRP α抑制性信号。
本发明的抗CD47-CLDN18.2双特异性抗体双抗A的结构如下:
长链结构(从N端至C端):
VHCD47-CH1-Hinge-CH2-CH3-Linker-VHHCLDN18.2
短链结构(从N端至C端):
VLCD47-CL(即SEQ ID NO:15)
其中,Linker(接头)的序列为(SEQ ID NO:18):GGGGSGGGGS
完整的双特异性抗体双抗A的长链全长序列如(SEQ ID NO:17)所示。
实施例1
本发明双抗A的体外药效学
(1)抗原亲和力、结合活性、特异性
使用BLI(生物膜干涉)技术进行抗原亲和力研究,结果显示本发明双抗A与人CLDN18.2的亲和力较高,亲和力常数KD=1.87×10-9M,参见附图1A;与人CD47的亲和力较低,亲和力常数KD=2.18×10-8M,参见附图1B。
用ELISA法进行抗原结合活性研究,结果显示本发明双抗A可以特异性结合CLDN18.2(EC50=121ng/mL)和CD47(EC50=46.2ng/mL),并呈现典型的量效关系曲线,参见图1C。
竞争结合试验显示,本发明双抗A可以在ELISA水平有效地阻断CD47与配体SIRPα的结合,结合活性结果为IC50=2.2μg/mL。
(2)红细胞凝集实验
红细胞凝集实验结果显示,本发明双抗A与阴性对照均不会引起人红细胞凝集,显著优于CD47靶点的阳性对照药Hu5F9-G4(对照药为按照专利US20200283520A1中报道的抗体序列进行自制获得),说明其对人红细胞安全性较好。
实施例2
本发明抗体在皮下移植BxPC-3-hCLDN18.2胰腺癌细胞的CB-17SCID小鼠模型中评价抗肿瘤作用
将表达hCLDN18.2的BxPC3细胞(购自康源博创生物科技(北京)有限公司)皮下接种于39只CB-17SCID小鼠(购自北京维通利华实验动物技术有限公司上海分公司),每只小鼠接种1×107个细胞。接种细胞后第10天,根据动物肿瘤体积和动物体重,挑取 32只小鼠随机分成4组,每组8只,包括PBS对照组、双抗A低剂量组(1mg/kg)、双抗A中剂量组(3mg/kg)和双抗A高剂量组(10mg/kg)。分组当天定义为D1天,并于 D1开始给药,尾静脉注射和腹腔注射交替给药,一周给药两次。试验过程中每天进行动物一般状态观察,并一周进行两次肿瘤体积和体重测量。
本次试验给药至D50,D54试验结束,将小鼠安乐处死,并剖取肿瘤进行称重。
本试验结束时各组瘤体积、瘤重及相应抑瘤率如表1所示。根据试验过程中肿瘤体积绘制肿瘤生长曲线,如图2所示。与PBS对照组相比,双抗A各给药组可不同程度抑制BxPC3-hCLDN18.2肿瘤的生长,根据瘤体积进行抑瘤率TGItv计算,1、3、10mg/kg 三个剂量组TGItv分别为47.12%、85.90%、86.48%。将各组小鼠的D54肿瘤体积进行统计学差异比较,与PBS对照组相比,3mg/kg剂量组和10mg/kg剂量组瘤体积的降低差异极显著(P<0.01)。
本次试验肿瘤展示图和小鼠的肿瘤重量见图3和图4所示。根据肿瘤重量进行抑瘤率TGItw计算,各组TGItw及P值统计分析如表1所示。与PBS对照组相比,本发明抗体能够剂量依赖性地降低BxPC3-hCLDN18.2肿瘤的重量,1、3、10mg/kg三个剂量组 TGItw分别为44.16%、80.00%、74.46%。10mg/kg剂量组瘤重抑瘤率低于3mg/kg剂量组可能是由于给药时间较长,使得药效已达到饱和。将各组小鼠的D54肿瘤重量进行统计学差异比较,与PBS对照组相比,3mg/kg剂量组和10mg/kg剂量组瘤重量的降低差异极显著(P<0.01)。
表1双抗A对BxPC3-hCLDN18.2荷瘤小鼠移植瘤的疗效
给药过程中,各组小鼠体重呈正常增长趋势,如图5所示。各给药组小鼠一般观察未见明显异常,提示目前给药剂量动物耐受良好。各组小鼠体重数据如表2所示。
表2 BxPC3-hCLDN18.2荷瘤小鼠体重数据(g)
实施例3
本发明抗体在皮下移植HT29-hCLDN18.2结直肠癌细胞的CB-17SCID小鼠模型中评价抗肿瘤作用
将表达hCLDN18.2的HT29细胞(购自康源博创生物科技(北京)有限公司)皮下接种于39只CB-17SCID小鼠,每只小鼠接种5×106个细胞。接种细胞后第6天,根据动物肿瘤体积和动物体重,挑取32只小鼠随机分成4组,每组8只,包括PBS对照组、双抗A低剂量组(1mg/kg)、双抗A中剂量组(3mg/kg)和双抗A高剂量组(10mg/kg)。分组当天定义为D1天,并于D1开始给药,尾静脉注射和腹腔注射交替给药,一周给药两次。试验过程中每天进行动物一般状态观察,并一周进行两次肿瘤体积和体重测量。
本次试验给药至D32,D36试验结束,将小鼠安乐处死,并剖取肿瘤进行称重。
本试验结束时各组瘤体积、瘤重及相应抑瘤率如表3所示。根据试验过程中肿瘤体积绘制肿瘤生长曲线,如图6所示。与PBS对照组相比,双抗A各给药组可不同程度抑制HT29-hCLDN18.2肿瘤的生长,根据瘤体积进行抑瘤率TGItv计算,1、3、10mg/kg 三个剂量组TGItv分别为39.30%、48.54%、82.27%。将各组小鼠的D36肿瘤体积进行统计学差异比较,与PBS对照组相比,1mg/kg剂量组、3mg/kg剂量组和10mg/kg剂量组瘤体积的降低差异极显著(P<0.01)。
本次试验肿瘤展示图和小鼠的肿瘤重量见图7和图8所示。根据肿瘤重量进行抑瘤率TGItw计算,各组TGItw及P值统计分析如表3所示。与PBS对照组相比,本发明抗体能够剂量依赖性地降低HT29-hCLDN18.2肿瘤的重量,1、3、10mg/kg三个剂量组 TGItw分别为23.29%、31.53%、73.46%。将各组小鼠的D36肿瘤重量进行统计学差异比较,与PBS对照组相比,3mg/kg剂量组瘤重量的降低差异显著(P<0.05),10mg/kg剂量组瘤重量的降低差异极显著(P<0.01)。
表3双抗A对HT29-hCLDN18.2荷瘤小鼠移植瘤的疗效
给药过程中,各给药组小鼠体重呈正常增长趋势,在D29后,对照组小鼠由于受肿瘤体积的影响,身体状况变差,体重降低,如图9所示。各给药组小鼠一般观察未见明显异常,提示目前给药剂量动物耐受良好。各组小鼠体重数据如表4所示。
表4 HT29-hCLDN18.2荷瘤小鼠体重数据(g)
分组 | D1 | D4 | D8 | D11 | D15 | D18 | D22 | D25 | D29 | D32 | D36 |
G1-PBS | 18.75 | 18.50 | 18.54 | 18.71 | 19.09 | 18.72 | 18.83 | 18.56 | 19.03 | 18.22 | 17.65 |
G2-双抗A-1mg/kg | 19.62 | 19.19 | 19.92 | 19.95 | 19.60 | 19.73 | 20.21 | 19.74 | 19.96 | 19.38 | 19.54 |
G3-双抗A-3mg/kg | 18.88 | 18.63 | 19.22 | 18.90 | 19.08 | 19.08 | 19.44 | 19.13 | 19.53 | 19.20 | 19.50 |
G4-双抗A-10mg/kg | 18.84 | 18.78 | 19.30 | 19.10 | 19.21 | 18.99 | 19.58 | 18.97 | 19.49 | 19.01 | 19.46 |
实施例4
本发明抗体在皮下移植NUGC-4-hCLDN18.2胃癌细胞的CB-17SCID小鼠模型中评价抗肿瘤作用
将表达hCLDN18.2的NUGC-4细胞(采用慢病毒转染的方式构建过表达外源人CLDN18.2的胃癌细胞株NUGC-4;其中,原始NUGC-4细胞株表达内源CD47,购自 BNCC菌种库,编号BNCC341962)皮下接种于44只CB-17SCID小鼠,每只小鼠接种 3×106个细胞。接种细胞后第6天,根据动物肿瘤体积,挑取28只小鼠随机分成4组,每组7只,包括PBS对照组、双抗A低剂量组(3mg/kg)、双抗A中剂量组(10mg/kg) 和双抗A高剂量组(20mg/kg)。分组当天定义为D1天,并于D1开始给药,尾静脉注射给药,一周给药两次。试验过程中每天进行动物一般状态观察,并一周进行两次肿瘤体积和体重测量。
本次试验给药至D27,D29试验结束,将小鼠安乐处死,并剖取肿瘤进行称重。
本试验结束时各组瘤体积、瘤重及相应抑瘤率如表5所示。根据试验过程中肿瘤体积绘制肿瘤生长曲线,如图10所示。与PBS对照组相比,双抗A各给药组可不同程度抑制NUGC-4-hCLDN18.2肿瘤的生长,根据瘤体积进行抑瘤率TGItv计算,3、10、20 mg/kg三个剂量组TGItv分别为32.28%、90.07%、106.32%。将各组小鼠的D29肿瘤体积进行统计学差异比较,与PBS对照组相比,10mg/kg剂量组和20mg/kg剂量组瘤体积的降低均差异极显著(P<0.01)。在本次试验中,截至D29试验结束,双抗A中剂量10 mg/kg组有1只小鼠肿瘤全部缓解(肿瘤消失),3只小鼠肿瘤部分缓解(肿瘤体积小于分组体积);双抗A高剂量20mg/kg组动物肿瘤全部缓解。
本次试验肿瘤展示图和小鼠的肿瘤重量见图11和图12所示。根据肿瘤重量进行抑瘤率TGItw计算,各组TGItw及P值统计分析如表5所示。与PBS对照组相比,双抗A 抗体能够剂量依赖性地降低NUGC-4-hCLDN18.2肿瘤的重量,3、10、20mg/kg三个剂量组TGItw分别为29.23%、86.15%、100.00%。将各组小鼠的D29肿瘤重量进行统计学差异比较,与PBS对照组相比,10mg/kg剂量组和20mg/kg剂量组瘤重量的降低差异极显著(P<0.01)。
表5双抗A对NUGC-4-hCLDN18.2荷瘤小鼠移植瘤的疗效
给药至D8,PBS对照组体重出现异常下降,原因是这组中有一笼小鼠的水瓶发生漏水,导致小鼠缺水体重下降,更换水瓶后小鼠体重迅速恢复正常。给药过程中,各组小鼠体重呈正常增长趋势,如图13所示,一般观察未见明显异常,提示在目前给药剂量下动物耐受良好。各试验组小鼠体重数据如表6所示。
表6 NUGC-4-hCLDN18.2荷瘤小鼠体重数据(g)
实施例5
本发明抗体对比单靶点抗体在皮下移植HT29-hCLDN18.2结直肠癌细胞的CB-17SCID小鼠模型中评价抗肿瘤作用
将上述表达hCLDN18.2的HT29-hCLDN18.2细胞皮下接种于34只CB-17SCID小鼠,每只小鼠接种5×106个细胞。接种细胞后第7天,根据动物肿瘤体积和动物体重,挑取28只随机分成4组,每组7只,包括PBS对照组、CLDN18.2单抗(IMAB362)组 (10mg/kg)、CD47单抗(Hu5F9-G4)组(10mg/kg)和双抗A组(10mg/kg)。分组当天定义为D1,并于分组当天开始给药,CLDN18.2单抗(IMAB362)、CD47单抗(Hu5F9- G4)和双抗A抗体均为尾静脉注射和腹腔注射交替给药,每周给药两次。试验过程中每天进行动物一般状态观察,并一周进行两次肿瘤体积和体重测量。
本次试验给药至D26,D29试验结束,将小鼠安乐处死,并剖取肿瘤进行称重。
根据试验过程中肿瘤体积绘制肿瘤生长曲线如图14所示。根据终末瘤体积进行TGItv计算,如表7所示。与PBS对照组相比,各给药组均可不同程度抑制HT29- hCLDN18.2肿瘤的生长。其中,CLDN18.2单抗(IMAB362)组、CD47单抗(Hu5F9-G4) 组、双抗A组TGItv分别为26.60%、21.07%、84.99%。与PBS对照组相比,CLDN18.2 单抗(IMAB362)组和CD47单抗(Hu5F9-G4)组瘤体积的降低无显著性差异(P>0.05),双抗A组瘤体积的降低均具有统计学意义。且双抗A组瘤体积分别与CLDN18.2单抗 (IMAB362)组、CD47单抗(Hu5F9-G4)组相比,均显著性降低,具有统计学意义。
表7给药抗体对HT29-hCLDN18.2荷瘤小鼠移植瘤的疗效(TGItv)
本次试验肿瘤展示图和小鼠的肿瘤重量见图15和图16,根据瘤重进行TGItw计算,如表8所示。CLDN18.2单抗(IMAB362)组、CD47单抗(Hu5F9-G4)组、双抗A组 TGItw分别为20.59%、16.30%、78.67%。与PBS对照组相比,CLDN18.2单抗(IMAB362) 组和CD47单抗(Hu5F9-G4)组瘤重的降低无显著性差异(P>0.05),双抗A组瘤重的降低均具有统计学意义。且双抗A组瘤重分别与CLDN18.2单抗(IMAB362)组、CD47单抗(Hu5F9-G4)组相比,均显著性降低,具有统计学意义。
表8给药抗体对HT29-hCLDN18.2荷瘤小鼠移植瘤的疗效(TGItw)
给药过程中,各组小鼠体重呈正常平稳增长趋势,个别小鼠因肿瘤体积较大,导致后期小鼠体重稍有下降,如图17所示,一般观察未见明显异常,提示所有小鼠在目前的给药剂量下均耐受良好。各组小鼠体重数据如表9所示。
表9 HT29-hCLDN18.2荷瘤小鼠不同组别小鼠体重数据(g)
实施例6
本发明抗体联合奥沙利铂在皮下移植HT29-hCLDN18.2细胞的CB-17SCID小鼠模型中评价抗肿瘤作用
将上述表达hCLDN18.2的NUGC-4-hCLDN18.2细胞皮下接种于64只CB-17SCID 小鼠,每只小鼠接种3×106个细胞。接种细胞后第7天,根据动物肿瘤体积,挑取48只随机分成6组,每组8只,包括PBS对照组、奥沙利铂单药组(4mg/kg)、双抗A低剂量组(3mg/kg)、双抗A高剂量组(6mg/kg)、双抗A低剂量联合用药组(4mg/kg+3 mg/kg)和双抗A高剂量联合用药组(4mg/kg+6mg/kg)。分组当天定义为D1,并于分组当天开始给药。奥沙利铂为尾静脉注射,每周给药一次;双抗A抗体为腹腔注射和尾静脉注射交替给药,每周给药两次。
本次试验给药至D24,D27试验结束,当天称重量瘤并剥取肿瘤称瘤重。
根据试验过程中肿瘤体积绘制肿瘤生长曲线如图18所示。根据终末瘤体积进行TGItv计算,如表10所示。
与PBS对照组相比,各给药组均可不同程度抑制NUGC-4-hCLDN18.2肿瘤的生长。其中,奥沙利铂单药组、双抗A低剂量组、双抗A高剂量组TGItv分别为26.74%、42.28%、60.31%,双抗A低剂量联合用药组和双抗A高剂量联合用药组TGItv分别为73.41%、79.79%。双抗A低剂量联合用药组的TGItv显著高于相同剂量的奥沙利铂单药组和双抗 A低剂量组,组间瘤体积的差异均具有统计学意义;双抗A高剂量联合用药组TGItv显著高于相同剂量的奥沙利铂单药组和双抗A高剂量组,组间瘤体积差异均具有统计学意义。
表10双抗A联合奥沙利铂对NUGC-4-hCLDN18.2小鼠移植瘤的疗效(TGItv)
本次试验肿瘤展示图和小鼠的肿瘤重量见图19和图20,根据瘤重进行TGItw计算,如表11所示。奥沙利铂单药组、双抗A低剂量组、双抗A高剂量组TGItw分别为23.19%、34.78%、55.07%,双抗A低剂量联合用药组和双抗A高剂量联合用药组TGItw分别为62.32%、72.46%。双抗A低剂量联合用药组的TGItw显著高于相同剂量的奥沙利铂单药组和双抗A低剂量组,组间瘤重的差异均具有统计学意义;双抗A高剂量联合用药组的抑瘤率TGItw显著高于相同剂量的奥沙利铂单药组和双抗A高剂量组,与奥沙利铂单药组比,瘤重的差异具有统计学意义;与双抗A高剂量组比,瘤重的差异无统计学意义。
表11双抗A联合奥沙利铂对NUGC-4-hCLDN18.2小鼠移植瘤的疗效(TGItw)
给药过程中,各组小鼠体重维持稳定,如图21所示,一般观察未见明显异常,提示在目前给药剂量下动物耐受良好。各试验组小鼠体重数据如表12所示。
表12 NUGC-4-hCLDN18.2荷瘤小鼠不同组别小鼠体重数据(g)
BW | D1 | D4 | D7 | D10 | D14 | D17 | D21 | D24 | D27 |
G1-PBS | 17.20 | 17.38 | 17.57 | 18.02 | 17.90 | 18.71 | 18.40 | 19.11 | 18.46 |
G2-Oxa-4mg/kg,QW | 17.50 | 17.25 | 17.64 | 17.70 | 17.36 | 17.60 | 17.58 | 17.67 | 16.94 |
G3-双抗A-3mg/kg,BIW | 17.68 | 18.34 | 18.22 | 18.35 | 18.42 | 18.64 | 17.84 | 18.49 | 18.59 |
G4-双抗A-6mg/kg,BIW | 18.21 | 18.54 | 18.50 | 18.52 | 18.26 | 18.61 | 18.31 | 18.80 | 18.44 |
G5-Oxa-4mg/kg+双抗A-3mg/kg,QW+BIW | 17.58 | 17.67 | 17.72 | 17.48 | 17.68 | 17.87 | 17.35 | 17.52 | 17.65 |
G6-Oxa-4mg/kg+双抗A-6mg/kg,QW+BIW | 18.06 | 18.24 | 18.41 | 18.04 | 18.25 | 18.57 | 17.87 | 17.70 | 17.88 |
实施例7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和上述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(WO2018075857A1中1F8抗体)、F4AM4-IgG1(在附图中简称为F4AM4;重链的氨基酸序列为SEQ ID NO:19,轻链的氨基酸序列为SEQ ID NO:20)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22a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);而双抗A几乎没有阻断能力。
在hCLDN18.2-NUGC-4细胞上的结果如图22b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,双抗A在hCLDN18.2-NUGC-4细胞上的阻断能力显著提高,并且优于抗体 1F8;双抗A和1F8阻断hCLDN18.2-NUGC-4上CD47与SIRPα结合的IC50分别为0.765 μg/mL(4.476nM)和11.98μg/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,双抗A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。
实施例8抗CD47-CLDN18.2双特异性抗体的体内抑瘤实验
8.1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联合给药组和双抗A 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、双抗A10.6mg/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23a和表13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,其中双抗A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,这表明双抗 A对CLDN18.2的结合可以增强其对CD47和SIRPα结合的阻断效果。
表13双特异性抗体在小鼠体内的抑瘤率
天数 | NA3S-H1 | A7H3L3 | 双抗A | 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% |
8.2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,双抗A。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,双抗A采用等摩尔剂量进行给药,即5.3mg/kg。其余与实施例8.1一致。
结果如图23b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);双抗A组所有小鼠中的肿瘤被完全抑制,抑瘤率接近100%(第34天)。该结果证明了双抗A的肿瘤抑制效果显著优于抗CLDN18.2单抗NA3S-H1。
申请人声明,本发明通过上述实施例来说明本发明的详细方法,但本发明并不局限于上述详细方法,即不意味着本发明必须依赖上述详细方法才能实施。
SEQUENCE LISTING
<110> 宝船生物医药科技(上海)有限公司
<120> 一种抗CLDN 18.2和CD47的双特异性抗体治疗疾病的用途
<130> P22010370C
<160> 20
<170> PatentIn version 3.5
<210> 1
<211> 11
<212> PRT
<213> Artificial Sequence
<220>
<223> 抗CD47抗体 LCDR1
<400> 1
Arg Ala Ser Gln Asp Ile Ser Asn His Leu Asn
1 5 10
<210> 2
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> 抗CD47抗体 LCDR2
<400> 2
Tyr Thr Ser Arg Ile His Ser
1 5
<210> 3
<211> 8
<212> PRT
<213> Artificial Sequence
<220>
<223> 抗CD47抗体 LCDR3
<400> 3
Gln Gln Gly Tyr Thr Leu Pro Phe
1 5
<210> 4
<211> 5
<212> PRT
<213> Artificial Sequence
<220>
<223> 抗CD47抗体 HCDR1
<400> 4
Asp Ile Tyr Ile Tyr
1 5
<210> 5
<211> 17
<212> PRT
<213> Artificial Sequence
<220>
<223> 抗CD47抗体 HCDR2
<400> 5
Lys Ile Asp Pro Ala Asn Gly Asn Thr Lys Tyr Asp Gln Lys Phe Gln
1 5 10 15
Gly
<210> 6
<211> 8
<212> PRT
<213> Artificial Sequence
<220>
<223> 抗CD47抗体 HCDR3
<400> 6
Gly Tyr Gly Ser Gly Phe Ala Tyr
1 5
<210> 7
<211> 5
<212> PRT
<213> Artificial Sequence
<220>
<223> 抗CLDN18.2抗体 HCDR1
<400> 7
Ile Pro Val Met Gly
1 5
<210> 8
<211> 16
<212> PRT
<213> Artificial Sequence
<220>
<223> 抗CLDN18.2抗体 HCDR2
<400> 8
Gly Ile Ser Thr Gly Gly Thr Thr Asn Tyr Gly Asp Ser Val Lys Gly
1 5 10 15
<210> 9
<211> 12
<212> PRT
<213> Artificial Sequence
<220>
<223> 抗CLDN18.2抗体 HCDR3
<400> 9
Leu Val Val Ser Gly Ile Gly Ser Thr Leu Glu Val
1 5 10
<210> 10
<211> 107
<212> PRT
<213> Artificial Sequence
<220>
<223> 抗CD47抗体 轻链可变区
<400> 10
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> 11
<211> 107
<212> PRT
<213> Artificial Sequence
<220>
<223> 抗CD47抗体 轻链恒定区
<400> 11
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> 12
<211> 117
<212> PRT
<213> Artificial Sequence
<220>
<223> 抗CD47抗体重链可变区
<400> 12
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> 13
<211> 330
<212> PRT
<213> Artificial Sequence
<220>
<223> 抗CD47抗体重链恒定区
<400> 13
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> 14
<211> 120
<212> PRT
<213> Artificial Sequence
<220>
<223> 抗CLDN18.2抗体重链可变区氨基酸序列
<400> 14
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly 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> 15
<211> 234
<212> PRT
<213> Artificial Sequence
<220>
<223> 抗CD47抗体轻链氨基酸序列(双抗A短链)
<220>
<221> SIGNAL
<222> (1)..(20)
<223> 信号肽
<400> 15
Met Glu Thr Asp Thr Leu Leu Leu Trp Val Leu Leu Leu Trp Val Pro
1 5 10 15
Gly Ser Thr Gly Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser
20 25 30
Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asp
35 40 45
Ile Ser Asn His Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro
50 55 60
Lys Leu Leu Ile Tyr Tyr Thr Ser Arg Ile His Ser Gly Val Pro Ser
65 70 75 80
Ser Phe Arg Gly Ser Gly Ser Gly Thr Asp Tyr Thr Leu Thr Ile Ser
85 90 95
Ser Leu Gln Pro Glu Asp Ile Ala Thr Tyr Phe Cys Gln Gln Gly Tyr
100 105 110
Thr Leu Pro Phe Thr Phe Gly Ser Gly Thr Lys Leu Glu Ile Lys Arg
115 120 125
Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln
130 135 140
Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr
145 150 155 160
Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser
165 170 175
Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr
180 185 190
Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys
195 200 205
His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro
210 215 220
Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
225 230
<210> 16
<211> 467
<212> PRT
<213> Artificial Sequence
<220>
<223> 抗CD47抗体重链氨基酸序列
<220>
<221> SIGNAL
<222> (1)..(20)
<223> 信号肽
<400> 16
Met Glu Thr Asp Thr Leu Leu Leu Trp Val Leu Leu Leu Trp Val Pro
1 5 10 15
Gly Ser Thr Gly Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys
20 25 30
Lys Pro Gly Ala Ser Val Lys Val Ser Cys Lys Ala Ser Gly Phe Asn
35 40 45
Ile Lys Asp Ile Tyr Ile Tyr Trp Val Arg Gln Ala Pro Gly Gln Gly
50 55 60
Leu Glu Trp Ile Gly Lys Ile Asp Pro Ala Asn Gly Asn Thr Lys Tyr
65 70 75 80
Asp Gln Lys Phe Gln Gly Arg Ala Thr Ile Thr Ala Asp Thr Ser Thr
85 90 95
Asn Thr Ala Tyr Leu Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala
100 105 110
Val Tyr Tyr Cys Ala Arg Gly Tyr Gly Ser Gly Phe Ala Tyr Trp Gly
115 120 125
Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser
130 135 140
Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala
145 150 155 160
Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val
165 170 175
Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala
180 185 190
Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val
195 200 205
Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His
210 215 220
Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Ala Glu Pro Lys Ser Cys
225 230 235 240
Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly
245 250 255
Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
260 265 270
Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His
275 280 285
Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val
290 295 300
His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr
305 310 315 320
Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly
325 330 335
Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile
340 345 350
Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val
355 360 365
Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser
370 375 380
Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu
385 390 395 400
Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro
405 410 415
Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val
420 425 430
Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met
435 440 445
His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser
450 455 460
Pro Gly Lys
465
<210> 17
<211> 597
<212> PRT
<213> Artificial Sequence
<220>
<223> 双抗A长链
<220>
<221> SIGNAL
<222> (1)..(20)
<223> 信号肽
<400> 17
Met Glu Thr Asp Thr Leu Leu Leu Trp Val Leu Leu Leu Trp Val Pro
1 5 10 15
Gly Ser Thr Gly Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys
20 25 30
Lys Pro Gly Ala Ser Val Lys Val Ser Cys Lys Ala Ser Gly Phe Asn
35 40 45
Ile Lys Asp Ile Tyr Ile Tyr Trp Val Arg Gln Ala Pro Gly Gln Gly
50 55 60
Leu Glu Trp Ile Gly Lys Ile Asp Pro Ala Asn Gly Asn Thr Lys Tyr
65 70 75 80
Asp Gln Lys Phe Gln Gly Arg Ala Thr Ile Thr Ala Asp Thr Ser Thr
85 90 95
Asn Thr Ala Tyr Leu Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala
100 105 110
Val Tyr Tyr Cys Ala Arg Gly Tyr Gly Ser Gly Phe Ala Tyr Trp Gly
115 120 125
Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser
130 135 140
Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala
145 150 155 160
Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val
165 170 175
Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala
180 185 190
Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val
195 200 205
Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His
210 215 220
Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Ala Glu Pro Lys Ser Cys
225 230 235 240
Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly
245 250 255
Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
260 265 270
Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His
275 280 285
Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val
290 295 300
His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr
305 310 315 320
Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly
325 330 335
Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile
340 345 350
Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val
355 360 365
Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser
370 375 380
Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu
385 390 395 400
Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro
405 410 415
Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val
420 425 430
Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met
435 440 445
His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser
450 455 460
Pro Gly Lys Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gln Val Gln
465 470 475 480
Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg
485 490 495
Leu Ser Cys Ala Ala Ser Gly Ser Ile Phe Asn Ile Pro Val Met Gly
500 505 510
Trp Tyr Arg Gln Ala Pro Gly Lys Gln Arg Glu Leu Val Ala Gly Ile
515 520 525
Ser Thr Gly Gly Thr Thr Asn Tyr Gly Asp Ser Val Lys Gly Arg Phe
530 535 540
Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr Leu Gln Met Asn
545 550 555 560
Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys Asn Val Leu Val
565 570 575
Val Ser Gly Ile Gly Ser Thr Leu Glu Val Trp Gly Gln Gly Thr Leu
580 585 590
Val Thr Val Ser Ser
595
<210> 18
<211> 10
<212> PRT
<213> Artificial Sequence
<220>
<223> Linker
<400> 18
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
1 5 10
<210> 19
<211> 452
<212> PRT
<213> Artificial Sequence
<220>
<223> F4AM4-IgG1重链
<400> 19
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> 20
<211> 214
<212> PRT
<213> Artificial Sequence
<220>
<223> F4AM4-IgG1 轻链
<400> 20
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 (10)
1.一种靶向CLDN 18.2和CD47的双特异性抗体或其抗原结合片段在制备诊断、预防和/或治疗胰腺癌和/或结直肠癌的药物中的应用,所述双特异性抗体包含特异性结合CD47的第一抗原结合域和特异性结合CLDN 18.2的第二抗原结合域;
所述第一抗原结合域的LCDR1的氨基酸序列如SEQ ID NO:1所示,LCDR2的氨基酸序列如SEQ ID NO:2所示,LCDR3的氨基酸序列如SEQ ID NO:3所示,HCDR1的氨基酸序列如SEQID NO:4所示,HCDR2的氨基酸序列如SEQ ID NO:5所示,以及HCDR3的氨基酸序列如SEQ IDNO:6所示。
2.如权利要求1所述的应用,其特征在于,所述第二抗原结合域包含免疫球蛋白单可变结构域VHH;
优选地,所述第二抗原结合域的HCDR1的氨基酸序列如SEQ ID NO:7所示,HCDR2的氨基酸序列如SEQ ID NO:8所示,以及HCDR3的氨基酸序列如SEQ ID NO:9所示。
3.如权利要求2所述的应用,其特征在于,所述第一抗原结合域和第二抗原结合域的轻链可变区和/或重链可变区的框架区为人源框架区;优选地,
所述第一抗原结合域的轻链可变区的氨基酸序列如SEQ ID NO:10所示;和/或,
所述第一抗原结合域的重链可变区的氨基酸序列如SEQ ID NO:12所示;和/或,
所述第二抗原结合域的重链可变区的氨基酸序列如SEQ ID NO:14所示。
4.如权利要求3所述的应用,其特征在于,所述第一抗原结合域的轻链恒定区为人κ轻链恒定区,和/或,所述第一抗原结合域的重链恒定区为人IgG1的重链恒定区;优选地,
所述第一抗原结合域的轻链恒定区的氨基酸序列如SEQ ID NO:11所示;和/或,
所述第一抗原结合域的重链恒定区的氨基酸序列如SEQ ID NO:13所示。
5.如权利要求4所述的应用,其特征在于,所述第一抗原结合域的重链和所述第二抗原结合域的重链可变区之间用接头连接;
较佳地,所述第二抗原结合域的重链可变区用接头连接在所述第一抗原结合域的重链的C端;
更佳地,第一抗原结合域的重链的氨基酸序列如SEQ ID NO:16所示,和/或,所述接头的氨基酸序列如SEQ ID NO:18所示。
6.如权利要求5所述的应用,其特征在于,所述双特异性抗体包含长链和短链,所述短链包含如SEQ ID NO:15所示的氨基酸序列,所述长链包含如SEQ ID NO:17所示的氨基酸序列。
7.一种靶向CLDN 18.2和CD47的双特异性抗体或其抗原结合片段与铂类药物联合在制备诊断、预防和/或治疗肿瘤的药物中的应用,其特征在于,所述双特异性抗体或其抗原结合片段如权利要求1~6任一项所述的应用中所定义,所述肿瘤为CLDN 18.2和/或CD47阳性肿瘤;
较佳地,所述肿瘤为消化系统肿瘤;
更佳地,所述消化系统肿瘤为胰腺癌或胃肠道肿瘤;
进一步更佳地,所述胃肠道肿瘤为胃癌或结直肠癌。
8.如权利要求7所述的应用,其特征在于,所述铂类药物选自顺铂、卡铂和奥沙利铂;
优选地,所述铂类药物为奥沙利铂。
9.一种药物组合物,其特征在于,所述药物组合物包含如权利要求1~6任一项所述的应用中所定义的靶向CLDN 18.2和CD47的双特异性抗体或其抗原结合片段,以及铂类药物;
较佳地,所述铂类药物选自顺铂、卡铂和奥沙利铂;
更佳地,所述铂类药物为奥沙利铂。
10.一种套装药盒,其特征在于,所述套装药盒包含药盒A和药盒B,其中:
所述药盒A包含如权利要求1~6任一项所述的应用中所定义的靶向CLDN 18.2和CD47的双特异性抗体或其抗原结合片段;
所述药盒B含有其他抗肿瘤抗体或者包含所述其他抗肿瘤抗体的药物组合物,和/或由激素制剂、靶向小分子制剂、蛋白酶体抑制剂、成像剂、诊断剂、化疗剂、溶瘤药物、细胞毒性剂、细胞因子、共刺激分子的激活剂、抑制性分子的抑制剂以及疫苗组成的群组中的一种或多种;
较佳地,所述化疗剂优选铂类药物;
更佳地,所述铂类药物选自顺铂、卡铂和奥沙利铂,优选奥沙利铂。
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