CN111247173A - 抗msln抗体及包含其的用于癌症治疗的药物组合物 - Google Patents
抗msln抗体及包含其的用于癌症治疗的药物组合物 Download PDFInfo
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- CN111247173A CN111247173A CN201880068378.1A CN201880068378A CN111247173A CN 111247173 A CN111247173 A CN 111247173A CN 201880068378 A CN201880068378 A CN 201880068378A CN 111247173 A CN111247173 A CN 111247173A
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Abstract
本发明涉及抗MSLN抗体和包含该抗MSLN抗体的用于癌症治疗的药物组合物。根据本发明的抗MSLN抗体对MSLN具有高亲和力和特异性,因此可以有效地用于癌症的预防或治疗。
Description
技术领域
本发明涉及抗MSLN抗体和包含该抗MSLN抗体的用于治疗癌症的药物组合物。
背景技术
在各种死亡原因中,由癌症所致的死亡频繁发生,占第二大比例。过去已经进行了各种尝试以治疗癌症。目前,关于用于治疗癌症的治疗方法,已经进行了抗癌剂施用、放射或外科手术。然而,此种治疗方法可能在癌症的早期阶段是有效的,而在末期癌症中当癌症已扩散至其他组织或当癌症复发时疗效不佳。
近来,为了治疗癌症而不产生副作用,已经对使用抗体的靶向抗癌剂积极进行了研究。通常,使用抗HER2抗体赫赛汀(Herceptin)来治疗乳腺癌,使用抗血管内皮生长因子(VEGF)抗体阿瓦斯汀(Avastin)来治疗结肠直肠癌。开发使用抗体的靶向抗癌剂的关键在于开发针对癌细胞中过表达的膜表面蛋白的抗体。
同时,间皮素(MSLN)是69kDa至71kDa的前体多肽,并且是存在于腹膜、胸膜和心包腔的间皮层的细胞表面上的糖蛋白。迄今为止,尽管没有清楚地阐明MSLN的功能,但是,据报道,在作为癌细胞或肿瘤细胞的间皮瘤、卵巢癌、胰腺癌、胃癌、肺癌和子宫内膜癌中观察到MSLN的过表达。另外,研究表明,在用这样的抗体处理MSLN过表达的癌细胞的情况下,小鼠/人嵌合抗MSLN抗体抑制癌细胞的生长(Hassan R et al.,Cancer Immun.,19;7:20,2007)。
因此,已经开发了特异性结合MSLN的小鼠抗体。然而,由于异源对象之间缺乏交叉反应性,临床试验并未成功。另外,用小鼠来源的抗体或嵌合抗体治疗的患者所产生的抗体具有引起毒性过度或治疗功效降低的问题。
因此,需要开发在与MSLN具有高亲和力的同时可表现出与人的交叉反应性的抗MSLN抗体。
技术问题
进行本发明以解决现有技术的上述问题。本发明的目的是提供与间皮素(MSLN)具有高结合亲和力的抗体和使用该抗体的具有优异的癌症治疗功效的药物组合物。
然而,本发明要解决的问题不限于上述问题,并且本领域技术人员根据以下描述将清楚地理解未提及的其他问题。
解决问题的方案
在本发明的一个方面,提供了一种抗体,所述抗体包含轻链可变结构域(VL结构域)和重链可变结构域(VH结构域),所述轻链可变结构域由与SEQ ID NO:1的氨基酸序列具有至少80%同一性的序列组成,所述重链可变结构域由与SEQ ID NO:3至5中任一个的氨基酸序列具有至少80%同一性的序列组成。
在本发明的另一方面,提供了编码抗体的轻链可变结构域(VL结构域)和重链可变结构域(VH结构域)的多核苷酸。
在本发明的又另一方面,提供了包含该多核苷酸的表达载体。
在本发明的仍又另一方面,提供了用该表达载体转化的宿主细胞。
在本发明的仍又另一方面,提供了用于生产与MSLN特异性结合的抗体的方法,所述方法包括培养所述宿主细胞的步骤。
在本发明的仍又另一方面,提供了一种用于预防或治疗癌症的药物组合物,所述药物组合物包含抗体或其片段。
发明的有益效果
由于对MSLN的高亲和力和特异性,本发明的抗MSLN抗体可以有效地用于预防或治疗癌症。
应当理解,本发明的效果不限于上述效果,并且包括可从详细描述或本发明的权利要求中所描述的本发明的构造可推断出的所有效果。
附图说明
图1示出了通过分析小鼠/人嵌合MI323 IgG1对表达MSLN的人胰腺癌细胞(AsPC1)的亲和力而获得的结果。
图2示出了通过分析小鼠/人嵌合MI323 IgG1对表达MSLN的人胰腺癌细胞(Capan2)的亲和力而获得的结果。
图3示出了通过分析小鼠/人嵌合MI323 IgG1对表达MSLN的人胸膜间皮瘤(H226)的亲和力而获得的结果。
图4示出了通过分析小鼠/人嵌合MI323 IgG1对表达MSLN的人胰腺癌细胞(PL45)的亲和力而获得的结果。
图5示出了通过分析人源化MI323 IgG1对表达MSLN的人胰腺癌细胞(AsPC1)的亲和力获得的结果。
图6示出了通过分析人源化MI323 IgG1对表达MSLN的人胰腺癌细胞(Capan2)的亲和力获得的结果。
图7示出了通过分析人源化MI323 IgG1对表达MSLN的人胸膜间皮瘤(H226)的亲和力获得的结果。
图8示出了通过分析人源化MI323 IgG1对表达MSLN的人胰腺癌细胞(PL45)的亲和力获得的结果。
具体实施方式
在下文中,将详细描述本发明。
在本发明的一个方面,提供了一种抗体,所述抗体包含轻链可变结构域(VL结构域)和重链可变结构域(VH结构域),所述轻链可变结构域由与SEQ ID NO:1的氨基酸序列具有至少80%同一性的序列组成,所述重链可变结构域由与SEQ ID NO:3至5中任一个的氨基酸序列具有至少80%同一性的序列组成。
轻链可变结构域可以由与SEQ ID NO:1的氨基酸序列具有至少80%、优选至少90%、更优选至少95%、并且最优选至少99%同一性的氨基酸序列组成。
重链可变结构域可以由与SEQ ID NO:3至5中任一个的氨基酸序列具有至少80%、优选至少90%、更优选至少95%、并且最优选至少99%同一性的氨基酸序列组成。
包含轻链可变结构域和重链可变结构域的抗体可以与间皮素(MSLN)特异性结合。在此,该抗体所结合的MSLN可以是人MSLN。也就是说,该抗体可以与来源于人的MSLN或与连接有来源于人的MSLN的癌细胞特异性结合。
如本文所用,术语“MSLN”可以指共同指代存在于动物并且优选存在于人和猴子中的MSLN本身及其任何变体、同种型和旁系同源物的概念。另外,如本文所用,术语“人MSLN”是指来源于人的MSLN。如本文所用,术语“小鼠MSLN”是指来源于小鼠的MSLN。
如本文所用,术语“抗体”是指与特定抗原具有免疫反应性的免疫球蛋白(Ig)分子,即充当特异性识别抗原的受体的蛋白质分子。另外,抗体可以是完整抗体或抗体片段。
在轻链和重链可变结构域中,一些氨基酸可以被置换、***和/或缺失,只要保持与本发明目的一致的性质,例如对MSLN的亲和力和特异性即可。例如,氨基酸的保守置换可以在轻链和/或重链可变结构域中发生。保守置换是指用具有相似性质的另一种氨基酸残基置换原始氨基酸序列。
例如,赖氨酸、精氨酸和组氨酸因其具有碱性侧链而具有相似性质,而天冬氨酸和谷氨酸因其具有酸性侧链而具有相似性质。此外,甘氨酸、天冬酰胺、谷氨酰胺、丝氨酸、苏氨酸、酪氨酸、半胱氨酸和色氨酸因其具有不带电荷的极性侧链而具有相似性质;丙氨酸、缬氨酸、亮氨酸、苏氨酸、异亮氨酸、脯氨酸、苯丙氨酸和甲硫氨酸因其具有非极性侧链而具有相似性质;而酪氨酸、苯丙氨酸、色氨酸和组氨酸因其具有芳族侧链而具有相似性质。
因此,对于本领域技术人员显而易见的是,如上所述的具有相似性质的氨基酸的组内的氨基酸置换不会导致性质的任何显著变化。由于这个原因,经历了由可变结构域内的保守置换所致的变化的抗体也被包括在本发明的范围内,只要此种抗体保持本发明的抗体的性质即可。
另一方面,抗体可以通过与MSLN特异性结合而与表达MSLN的癌细胞特异性结合,特别是与癌细胞的表面特异性结合。在此,表达MSLN的癌细胞可以包括但不限于人癌细胞。
抗体的轻链和重链可变结构域可以由互补决定区(CDR)和框架区(FR)组成。通常,CDR赋予对特定抗原的结合特异性,并且FR起形成抗体的折叠结构的作用,以支持CDR的结合等。
该抗体可以是以现有的小鼠抗MSLN抗体MI323的CDR氨基酸序列以及与MI323相似的人抗体的FR和恒定结构域(Fc)的氨基酸序列为骨架的抗体,其中CDR和FR部分的一些氨基酸残基是被置换的形式,使得这些残基可以与人特异性结合。
该抗体可以包含:轻链CDR1,该轻链CDR1包含SEQ ID NO:9的氨基酸序列;轻链CDR2,该轻链CDR2包含SEQ ID NO:10的氨基酸序列;轻链CDR3,该轻链CDR3包含SEQ ID NO:11的氨基酸序列;重链CDR1,该重链CDR1包含选自由SEQ ID NO:12至14组成的组中任一个的氨基酸序列;重链CDR2,该重链CDR2包含选自由SEQ ID NO:15至17组成的组中任一个的氨基酸序列;和重链CDR3,该重链CDR3包含SEQ ID NO:18的氨基酸序列。
在一种实施方式中,该抗体可以包含:轻链CDR1,该轻链CDR1包括SEQ ID NO:9的氨基酸序列;轻链CDR2,该轻链CDR2包含SEQ ID NO:10的氨基酸序列;轻链CDR3,该轻链CDR3包含SEQ ID NO:11的氨基酸序列;重链CDR1,该重链CDR1包含SEQ ID NO:12的氨基酸序列;重链CDR2,该重链CDR2包括SEQ ID NO:15的氨基酸序列;和重链CDR3,该重链CDR3包含SEQ ID NO:18的氨基酸序列。
该抗体可以包含:轻链CDR1,该轻链CDR1包括SEQ ID NO:9的氨基酸序列;轻链CDR2,该轻链CDR2包含SEQ ID NO:10的氨基酸序列;轻链CDR3,该轻链CDR3包含SEQ ID NO:11的氨基酸序列;重链CDR1,该重链CDR1包含SEQ ID NO:13的氨基酸序列;重链CDR2,该重链CDR2包括SEQ ID NO:16的氨基酸序列;和重链CDR3,该重链CDR3包含SEQ ID NO:18的氨基酸序列。
该抗体可以包含:轻链CDR1,该轻链CDR1包括SEQ ID NO:9的氨基酸序列;轻链CDR2,该轻链CDR2包含SEQ ID NO:10的氨基酸序列;轻链CDR3,该轻链CDR3包含SEQ ID NO:11的氨基酸序列;重链CDR1,该重链CDR1包含SEQ ID NO:14的氨基酸序列;重链CDR2,该重链CDR2包括SEQ ID NO:17的氨基酸序列;和重链CDR3,该重链CDR3包含SEQ ID NO:18的氨基酸序列。
因此,所述抗体可以是特异性结合人MSLN的人源化抗体。当在本文中使用时,术语"人源化抗体"是指含有来源于非人抗体,如小鼠抗体的免疫球蛋白的最小序列的嵌合抗体,并且可以指这样的抗体,其中除了对应于高变区的序列以外,所有部分都被其人对应物替换。
此外,术语"高变区(HVR)"是指显示高可变性或在抗体序列中形成结构确定的环的可变结构域的区域。在用于确定其的定义中,根据Kabat的互补决定区(CDR)定义最常被用于基于序列可变性来对区域进行分类。
也可以使用所述抗体的抗体片段作为所述抗体,只要所述抗体片段保持所述抗体的功能即可。所述抗体或抗体片段可以包括,但不限于,保持与MSLN的结合功能的单链抗体、双抗体、三抗体、四抗体、Fab片段、F(ab')2片段、Fd、scFv、结构域抗体、微抗体(minibody)、scAb、IgD抗体、IgE抗体、IgM抗体、IgG1抗体、IgG2抗体、IgG3抗体、IgG4抗体、抗体恒定结构域的衍生物、基于蛋白质支架(scaffold)的人工抗体等。
所述抗体也可以以通过将所述抗体与具有肿瘤-细胞增殖抑制效力的抗癌药结合而获得的抗体-药物缀合物(ADC)的形式使用。当在本文中使用时,术语"抗癌"包括对癌症的"预防"和"治疗"作用,并且"预防"表示抑制或延缓癌症的任何作用。此外,"治疗"表示改善或有益地改变癌症症状的任何作用。
可用于所述抗体-药物缀合物中的药物包括具有细胞毒性或抑制细胞生长效果的任何化合物,以及所述化合物的部分或官能团。药物的实例包括微管蛋白结构形成抑制剂、减数***抑制剂、RNA聚合酶抑制剂、拓扑异构酶抑制剂、DNA嵌入剂、DNA烷化剂、核糖体抑制剂、miRNA、shRNA、siRNA、放射性同位素和毒素,其中可以使用至少一种化合物。
所述药物可以包括,但不限于:美登醇(maytansinoid);奥利斯他汀(auristatin);尾海兔素(dolastatin);单端孢霉烯(trichothecene);CC1065(NSC298223);卡利奇霉素(calicheamicin);紫杉烷(taxane);蒽环霉素(anthracycline);甲氨蝶呤(methotrexate);阿霉素(adriamycin);长春地辛(vindesine);长春花生物碱(长春新碱(vincristine)、长春花碱(vinblastine)、依托泊苷(etoposide));多柔比星(doxorubicin);美法仑(melphalan);丝裂霉素C(mitomycin C);苯丁酸氮芥(chlorambucil);道诺霉素(daunorubicin);正定霉素(daunomycin);依托泊苷(etoposide);替尼泊苷(teniposide);洋红霉素(carminomycin);氨喋呤(aminopterin);放线菌素D(dactinomycin);丝裂霉素(mitomycins);争光霉素(bleomycins);埃斯培拉霉素(esperamicins);其他烯二炔抗生素;5-氟尿嘧啶(5-fluorouracil);其他氮芥及其立体异构体、同电子排列体、同系物或衍生物;顺铂(cis-platinum)和顺铂同系物;其他嵌入剂酶及其片段,例如,核酸酶、抗生素、毒素(细菌、真菌、植物或动物来源的酶活性毒素或小分子毒素);以及各种抗肿瘤或抗癌剂如顺铂(cisplatin),CPT-11,紫杉醇和多西他赛(docetaxel)。
此外,所述放射性同位素(放射性核素)包括3H、14C、32P、35S、36Cl、51Cr、57Co、58Co、59Fe、90Y、125I、131I、186Re等。也可以使用能够抑制特定癌基因表达的microRNA(miRNA)、siRNA、shRNA等。
抗-MSLN抗体与药物的结合优选地通过使用所述抗体中的氨基酸残基(如赖氨酸或半胱氨酸)的官能团(如硫醇基)的缀合来实现。如有必要,同样可能的是以常用的接头介导的形式进行缀合。也可以使用基于马来酰亚胺或碘乙酰胺的接头。
当将药物与所述抗体或其片段缀合时,从减小对所述抗体或片段与MSLN的结合能力及特异性等的影响的角度出发,所述药物可以被缀合至与抗原结合位点相对的C-端位点,诸如此类。当使用完整抗体而不是其片段时,所述药物可以被缀合至Fc区。
此外,所述抗体也可以用作含有所述抗体的基于嵌合抗原受体(CAR)的治疗剂。此种治疗剂的实例优选地包括,但不限于,嵌合抗原受体T细胞(CAR-T细胞)或嵌合抗原受体自然杀伤细胞(CAR-NK细胞)治疗剂。
所述抗体也可以以含有抗-MSLN抗体的双特异性抗体的形式使用。所述双特异性抗体是具有同时结合两种抗原的能力的抗体,并且通常可以以结合不同抗原的重链和轻链对彼此相连的形式存在。
此外,所述双特异性抗体可以如以下的形式获得:VL和VH经由短接头肽彼此相连的单链抗体片段(scFv's)以scFv1-scFv2(-Fc)的形式连接的双特异性单链抗体、基于单结构域抗体(sdAb)的使用VH的双抗体、和使用来自德国Micromet的BiTE技术(参见http://www.micromet.de)产生的双特异性抗体。
所述双特异性抗体可以以这样的形式存在,其中抗-MSLN抗体与对免疫有效细胞特异性靶分子具有结合能力的抗体或其片段结合。所述免疫有效细胞特异性靶分子可以优选地选自,但不限于:TCR/CD3、CD16(FcγRIIIa)、CD44、CD56、CD69、CD64(FcγRI)、CD89和CD11b/CD18(CR3)。
在本发明的另一方面,提供编码根据本发明的抗体的轻链可变结构域(VL结构域)和重链可变结构域(VH结构域)的多核苷酸以及包含其的表达载体。
本领域技术人员可以从抗-MSLN抗体的氨基酸序列轻易推导出编码所述抗体或抗体片段的重链可变结构域的多核苷酸,即,基因。
当在本文中使用时,术语"表达载体"是指能够在宿主细胞中表达靶蛋白的重组载体,并且表示含有与其可操作相连的必要调控元件从而表达***的基因的基因构建体。编码抗-MSLN抗体的基因可以被***到单独的载体中,也可以以被***到相同载体中的形式使用。
具体地,编码抗-MSLN抗体的氨基酸序列的多核苷酸可以以被***到单独的或相同的载体中的形式使用,并且编码重链或其可变结构域的多核苷酸可以以被***到单独的或相同的载体中的形式使用。
当在本文中使用时,术语"可操作相连"意味着核酸表达调控序列和编码所需的蛋白质的核酸序列功能相连从而执行所需的功能。与重组载体的可操作连接可以使用本领域中熟知的基因重组技术来实现,并且位点特异性DNA剪切和连接可以使用本领域中普遍知道的酶等容易地实现。
除了表达调控元件如启动子、起始密码子、终止密码子、聚腺苷酸化信号和增强子,适用于生产抗-MSLN抗体的表达载体还可以含有用于膜靶向或分泌的信号序列。起始密码子和终止密码子通常被认为是编码免疫原性靶蛋白的核苷酸序列的一部分。此种密码子在施用基因构建体时在受试者中必须是有功能的并且必须与编码序列同框。通常,启动子可以是组成型的或诱导型的。所述启动子可以包括,但不限于:原核启动子,如lac、tac、T3和T7;猿病毒40(SV40)启动子;小鼠乳腺瘤病毒(MMTV)启动子;人免疫缺陷病毒(HIV)启动子,例如,HIV的长端重复(LTR)启动子;莫洛尼病毒(Moloney virus)启动子;巨细胞病毒(CMV)启动子;Epstein bar病毒(EBV)启动子;劳斯氏肉瘤病毒(Rous sarcoma virus)(RSV)启动子;以及β-肌动蛋白启动子,来源于人血红蛋白、人肌肉肌酸、人金属硫蛋白的真核启动子等。
所述表达载体还可以含有选择性标志物,所述选择性标志物允许选择含有该所述表达载体的宿主细胞。所述选择性标志物用于选择用所述载体转化的细胞。对于选择性标志物,可以使用赋予以下选择性表型的标志物:如药物抗性、营养缺陷型、对细胞毒性剂的抗性或表面蛋白质的表达。在用选择剂处理的环境中,仅表达选择性标志物的细胞存活,这允许对转化的细胞进行选择。此外,当载体是可复制的表达载体时,此种载体可以含有复制起点,所述复制起点是复制自其开始的特定核酸序列。
作为用于***外源基因的重组表达载体,可以使用各种形式的载体如质粒、病毒和粘粒。重组载体的类型不受特别限制,只要所述载体具有在包括原核和/或真核细胞在内的各种宿主细胞中表达所需的基因并生产所需的蛋白质的功能即可。优选地,所述载体可以是在具有具备强活性和强表达能力的启动子时能够以与其自然状态相似的形式生产大量外源蛋白质的载体。
各种表达宿主/载体组合可被用于表达抗-MSLN抗体。适用于真核宿主的表达载体包括,但不限于:来源于SV40的表达调控序列、牛***瘤病毒,腺病毒,腺相关病毒,巨细胞病毒和反转录病毒。可用于细菌宿主中的表达载体包括:自大肠杆菌(Escherichia coli)获得的细菌质粒,如pET、pRSET、pBluescript、pGEX2T、pUC载体、colE1、pCR1、pBR322、pMB9及其衍生物;宿主范围广泛的质粒如RP4;可以多种噬菌体λ衍生物如λgt10、λgt11和NM989作为示例的噬菌体DNA;以及其他DNA噬菌体如M13和丝状单链DNA噬菌体。可用于酵母细胞的表达载体可以包括2-微米质粒及其衍生物。可用于昆虫细胞的载体可以是pVL941。
在本发明的又另一个方面,提供用根据本发明的表达载体转化的宿主细胞。所述表达载体可以被***到宿主细胞中以形成转化株。适用于所述载体的宿主细胞可以包括原核细胞,如大肠杆菌(Escherichia coli)、枯草芽孢杆菌(Bacillus subtilis)、链霉菌属(Streptomyces sp.)、假单胞菌属(Pseudomonas sp.)、奇异变形杆菌(Proteusmirabilis)或葡萄球菌属(Staphylococcus sp.)。此外,所述宿主细胞可以包括真核细胞,包括来源于:真菌如曲霉属(Aspergillus sp.),酵母如毕赤酵母(Pichia pastoris)、酿酒酵母(Saccharomyces cerevisiae)、裂殖酵母属(Schizosaccharomyces sp.)和粗糙脉孢菌(Neurospora crassa)的低等真核细胞;和其他低等真核细胞,以及高等真核细胞如昆虫细胞。此外,所述宿主细胞也可以来源于植物或哺乳动物。优选地,可以使用的宿主细胞包括,但不限于:猴肾细胞(COS7细胞)、NSO细胞(小鼠来源的骨髓瘤细胞)、SP2/0细胞(小鼠来源的骨髓瘤细胞)、其他骨髓瘤细胞系、中国仓鼠卵(CHO)细胞、W138细胞(二倍体人细胞培养物)、幼仓鼠肾(BHK)细胞、MDCK、HuT 78细胞、HEK293细胞等,其中CHO细胞是优选的。
当在本文中使用时,术语"转化到宿主细胞中"意在包括用于将核酸引入到生物体、细胞、组织或器官中的任何方法,并且此种转化可以使用根据宿主细胞类型选择的本领域中已知的标准技术进行。具体地,可以使用:电穿孔;原生质体融合;磷酸钙(CaPO4)沉淀;氯化钙(CaCl2)沉淀;使用碳化硅纤维搅动;土壤杆菌介导的转化;PEG、硫酸葡聚糖、lipofectamine或干燥/抑制介导的转化等。然而,本发明不限于此。
在本发明的仍又另一个方面,提供用于生产特异性结合MSLN的抗体的方法,所述方法包括培养所述宿主细胞。具体地,所述用于生产抗体的方法可以包括以下步骤:将编码抗-MSLN抗体的核苷酸序列***载体中以构建重组载体;用重组载体转化宿主细胞并且进行培养;和从培养的转化株分离和纯化人源化抗体。
所述人源化抗体可以通过在营养培养基中培养其中表达重组载体的转化株而大量生产,并且培养基和培养条件可以根据宿主细胞的类型适当地选自本领域中已知的那些。在培养期间,可以适当地调整条件如温度、培养基的pH以及培养时间以适合细胞生长和蛋白质的大量生产。
如上所述的重组生产的抗-MSLN抗体可以从培养基或细胞裂解产物回收。当所述抗体是与膜结合的形式时,可以使用合适的表面活性剂溶液(例如,Triton-X 100)或通过酶切将此种抗体从膜上释放。可以通过各种物理和化学手段如冻融循环、超声处理、机械破碎或细胞裂解剂来分解用于表达人源化抗体的细胞,并且可以使用常规生化分离技术进行分离和纯化。可以使用的生化分离技术包括,但不限于,电泳、离心、凝胶过滤、沉淀、透析、色谱法(离子交换色谱法、亲和色谱法、免疫吸附色谱法、尺寸排阻色谱法等)、等电聚焦等。
在本发明的仍又另一个方面,提供用于预防或治疗癌症的药物组合物,所述药物组合物包含根据本发明的抗体或其片段。
可以用所述药物组合物治疗的癌症的类型可以包括实体癌和血液癌两者,并且优选地可以包括,但不限于表达MSLN的任何癌症,例如,间皮瘤、胰腺癌、卵巢癌、胃癌、肺癌或子宫内膜癌。
所述药物组合物还可以包含药学可接受的载体。作为药学可接受的载体,粘合剂、助滑剂、崩解剂、赋形剂、增溶剂、分散剂、稳定剂、悬浮剂、色素、调味剂等可以用于口服施用;缓冲剂、防腐剂、疼痛缓解剂、增溶剂、等渗剂、稳定剂等可以混合使用以用于注射剂;并且基料(base)、赋形剂、润滑剂、防腐剂等可以用于局部施用。
本发明的药物组合物的制剂可以以各种方式通过与如上所述的药学可接受的载体混合来制备。例如,对于口服施用,所述药物组合物可以被配制成片剂、锭剂、胶囊剂、酏剂、混悬剂、糖浆、圆片剂(wafer)等的形式。对于注射剂,所述药物组合物可以被配制成单位剂量安瓿的形式或多剂量形式。
此外,所述药物组合物可以含有可以提高膜渗透性的表面活性剂。这些表面活性剂可以衍生自甾体或可以包括阳离子脂质如N-[1-(2,3-二油酰基)丙基-N,N,N-三甲基氯化铵(DOTMA),或各种化合物如胆固醇琥珀酸单酯和磷脂酰甘油。然而,所述表面活性剂不限于此。
在本发明的仍又另一个方面,提供用于治疗癌症或抑制癌症生长的方法,所述方法包括向受试者施用所述药物组合物。可以以药学有效量施用包含所述抗-MSLN抗体的所述药物组合物以治疗癌症细胞或其转移或抑制癌症生长。所述有效量可以根据各种因素如癌症类型,患者的年龄、体重,症状的性质和严重性,目前疗法的类型,治疗的数量,剂型以及施用途径而变化,并且可以由相应领域的专家容易地确定。
所述药物组合物可以与以上提及的药学或生理学组分一起或顺序施用,并且也可以与额外的常规治疗剂组合施用,在此种情况下,所述药物组合物可以与常规治疗剂顺序或同时施用。此种施用可以是单次或多次施用。考虑到所有以上因素,重要的是,施用的量是最小量并且允许获得最大效果而没有副作用,并且此种量可以由本领域技术人员容易地确定。
当在本文中使用时,术语"受试者"是指患有可以通过施用所述药物组合物而减轻、抑制或治疗的病症或疾病或处于可以通过施用所述药物组合物而减轻、抑制或治疗的病症或疾病的风险中的哺乳动物,优选是人。
当在本文中使用时,术语"施用"表示以任何合适的方式将预定的物质引入受试者中,并且所述药物组合物可以经由任何途径施用,只要所述途径允许所述药物组合物到达靶组织。此种施用方法可以包括,但不限于:腹膜内施用、静脉内施用、肌肉内施用、皮下施用、皮内施用、口服施用、局部施用、鼻内施用、肺部施用或直肠施用。此处,在口服施用的情况下,从消化蛋白质的角度出发,理想的可能是将用于口服施用的组合物配制成使得活性剂被包被或所述组合物免于在胃中消化。此外,所述药物组合物可以通过任何使得活性成分能够迁移至其靶细胞的设备来施用。
在本发明的仍又另一个方面,提供本发明的抗体用于预防或治疗癌症的用途。
在本发明的仍又另一个方面,提供本发明的抗体用于制备用于预防或治疗癌症的药物的用途。
在本发明的仍又另一个方面,提供用于预防或治疗癌症的方法,所述方法包括向受试者施用本发明的抗体。
本发明的最佳实施方式
在下文中,将通过实施例更详细地描述本发明。为了说明本发明而描述了以下实施例,并且本发明的范围不限于此。
实施例1.人源化抗MSLN抗体的产生
实施例1.1.选择人源化候选抗体
将已知为抗MSLN抗体的小鼠MI323的轻链可变结构域(VL结构域)和重链可变结构域(VH结构域)的氨基酸序列输入基于网络(Web)的数据库(IgBLAST),然后搜索最相似的人胚胎抗体序列。结果,在小鼠MI323的轻链可变区和智人(Homo sapiens)IGKV7-39*01(IMGT基因名称)之间以及在小鼠MI323的重链可变结构域和智人IGHV1-3*01(IMGT基因名称)之间显示出最高的氨基酸序列相似性。
实施例1.2.轻链可变结构域的人源化
具有与MI323的轻链可变结构域最相似性的序列的人胚胎抗体智人IGKV7-39*01(IMGT基因名称)的CDR氨基酸序列被替换为小鼠MI323的CDR序列,以制备部分人源化MI323轻链可变结构域。
为了增强部分人源化MI323轻链可变结构域的抗原结合特性,CDR序列中被认为在抗原结合特性中起重要作用的氨基酸残基被替换为与智人IGKV7-39*01(IMGT基因名称)相同的氨基酸残基。如此制备的人源化MI323轻链可变结构域的氨基酸序列示于下表1中。
参照表1,通过将小鼠MI323轻链可变结构域中的第24个氨基酸残基从赖氨酸(K)改变为精氨酸(R),制备人源化MI323轻链可变结构域。在此,将小鼠MI323轻链可变结构域用作对照,以比较对MSLN抗原的亲和力。
[表1]
实施例1.3重链可变结构域的人源化
具有与MI323的重链可变结构域最相似性的序列的人胚胎抗体智人IGHV1-3*01(IMGT基因名称)的CDR氨基酸序列被替换为小鼠MI323的CDR序列,以制备部分人源化MI323重链可变结构域。
为了增强部分人源化MI323重链可变结构域的抗原结合特性,CDR和框架区(FR)序列中被认为在抗原结合特性中起重要作用的氨基酸残基被替换为与小鼠MI323相同的氨基酸残基。如此制备的人源化MI323重链可变结构域的氨基酸序列示于下表2中。
参照表2,对小鼠MI323重链可变结构域的CDR和FR中的氨基酸残基进行随机修饰,以制备总共3种人源化MI323重链可变结构域。在此,将小鼠MI323重链可变结构域用作对照,以比较对MSLN抗原的亲和力。
[表2]
实施例1.4人源化抗MSLN抗体的克隆
将如上制备的一种轻链可变结构域(VL-1)的基因和MI323的轻链可变结构域的基因各自***到含有κ轻链恒定结构域(κ-CL)的pcDNA3.4动物细胞表达载体中。另外,将三种重链可变结构域(VH-1、VH-2、VH-3)的基因和MI323的重链可变结构域的基因各自***含有IgG1恒定结构域(CH1、铰链、CH2、CH3)的pcDNA3.4动物细胞表达载体中。
κ轻链恒定结构域和IgG1重链恒定结构域的各自的具体氨基酸序列示于下表3中。
[表3]
实施例1.5人源化抗MSLN抗体的转染
转染前24小时,用Expi293培养基将Expi293F细胞以2.0×106个细胞/ml的密度传代,在37℃和8%CO2的条件下在振荡培养箱中以125±10rpm培养。当进行转染时,测量细胞数和细胞活力以确认是否表现出95%或更高的细胞活力。
以7.5×107个细胞将细胞分配在125mL培养瓶中,然后添加Expi293培养基将最终体积调整为25mL(基于30mL)。使用Opti-MEM I培养基,将30μg表达抗体的载体与该培养基混合至总计1.5ml,并在室温下孵育5分钟。对于抗体载体,使用通过组合一种轻链可变结构域的表达载体和三种重链可变结构域的表达载体而获得的总共三种人源化MI323 IgG1抗体。小鼠人嵌合MI323 IgG1抗体用作对照抗体载体。
使用Opti-MEM I培养基,将80μl的转染试剂与该培养基混合至总计1.5ml,并在室温下孵育5分钟。将分别包含载体和转染试剂的Opti-MEM I培养基轻轻混合,并在室温下反应20分钟。然后,将所得物置于含有Expi293F细胞的培养瓶中。在37℃和8%CO2的条件下,在振荡培养箱中以125±10rpm进行孵育达16至20小时。然后,向培养瓶中添加1.5ml转染增强剂I和150μl转染增强剂II,并进行孵育达6天以获得抗体。
实施例1.6抗体纯化
将培养物以4,000rpm离心30分钟,通过0.22μm过滤器过滤,然后去除细胞碎片以获得上清液。将0.2ml的Mabselect Xtra树脂添加到柱中,并使用蛋白质A结合缓冲液以相当于树脂体积的10倍的体积进行平衡。
随后,利用重力将上清液加样到柱上。加样完成后,使用蛋白质A结合缓冲液以相当于树脂体积的10倍的体积洗涤该柱。
然后,将IgG洗脱缓冲液添加到柱中并进行洗脱。通过每1ml洗脱液添加25μl的1.5M Tris-Cl来中和洗脱液。然后,在280nm的OD下测量洗脱液浓度。通过透析使已测量浓度的洗脱液与PBS进行缓冲液交换。
实施例2.测量人源化抗MSLN抗体对重组MSLN的亲和力
使用Octet***来测量根据实施例1产生的人源化抗MSLN抗体(HMI323)对重组MSLN的亲和力。“HMI323”是指“人源化MI323”。
具体地,人重组MSLN以5μg/ml的浓度在1×动力学缓冲液中制备,并用于以200μl/孔处理96孔板。处理后的MSLN固定在anti-Penta His(HIS1K,Cat#18-5121,Fortebio)传感器上。
然后,将根据实施例1产生的三种人源化抗MSLN抗体和小鼠人嵌合MI323 IgG1克隆在1×动力学缓冲液中稀释至50、25、12.5、6.25或3.125nM的浓度,并用这些稀释液以200μl/孔进行处理。对于1×动力学缓冲液,使用通过10×动力学缓冲液(ForteBio,Cat#18-1092)以PBS进行10倍稀释而获得的缓冲液。
分析固定在传感器上的MSLN与几种浓度的抗体之间的相互作用,以计算抗原-抗体亲和力,结果示于下表4中。
[表4]
从表4的结果可以看出,发现HMI323VL-1/HMI323VH-3的组合保持了对MI323最接近的亲和力,并且确定了其他两个克隆显示出与MI323抗体相比稍微降低的亲和力,但总体上保持对MSLN的高亲和力。
实施例3.测量人源化抗MSLN抗体对癌细胞表面表达的MSLN的亲和力
使用流式细胞术来确认根据实施例1生产的人源化抗MSLN抗体(HMI323)是否也显示出对癌细胞表面表达的MSLN的亲和力。
具体地,将H226(间皮瘤)、AsPC-1(胰腺癌)、Capan-2(胰腺癌)和PL45(胰腺癌)细胞系各以1,500rpm离心5分钟,然后用FACS缓冲液(含有3%FBS的PBS)洗涤3次。随后,用FACS缓冲液稀释浓度为3×106个细胞/ml的各癌细胞,并以100μl/孔处理96孔板的每个孔。
然后,将小鼠/人嵌合MI323 IgG1和HMI323VL-1/HMI323VH-3IgG1抗体各自以5μg/ml的浓度添加到每个孔中,与细胞混合,然后在4℃下孵育1小时。随后,以1,500rpm离心5分钟,然后弃去上清液。向其中添加200μl的FACS缓冲液重悬并洗涤细胞,该过程重复进行3次。
然后,将缀合有藻红蛋白(PE)的人IgG抗体在FACS缓冲液中稀释500倍并用于洗涤细胞,该过程重复进行3次。洗涤后的细胞用100μl的BD CytofixTM固定,并用LSRFortessaTM(流式细胞仪)仪器分析每个样品的平均荧光强度(MFI)。分析结果示于图1至图8。
参照图1至图8,发现与人重组MSLN结合的所有抗体也与表达人MSLN的癌细胞特异性结合。
尽管如上所述通过有限数量的实施例和附图描述了实施方式,但是对于本领域技术人员显而易见的是,在不脱离本发明的精神和范围的情况下,可以做出各种改变和修改。例如,即使在所描述的技术以与所描述的方法不同的顺序执行,和/或所描述的组件以与所描述的方法不同的形式组装或组合或被其他组件或等同形式替代或替换的情况下,也可获得期望的结果。
因此,所附权利要求的其他实现方式、其他实施方式以及等同形式均落入所附权利要求的范围内。
<110> 株式会社绿十字
财团法人牧岩生命科学研究所
<120> 抗MSLN抗体及包含其的用于癌症治疗的药物组合物
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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> 9
<211> 11
<212> PRT
<213> 人工序列
<220>
<223> 抗MSLN抗体CDR1(VL)的氨基酸序列
<400> 9
Arg Ala Ser Gln Asp Val Ser Thr Ala Val Ala
1 5 10
<210> 10
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> 抗MSLN抗体CDR2(VL)的氨基酸序列
<400> 10
Ser Ala Ser Tyr Arg Tyr Pro
1 5
<210> 11
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> 抗MSLN抗体CDR3(VL)的氨基酸序列
<400> 11
Gln Gln His Tyr Ser Thr Pro Trp Thr
1 5
<210> 12
<211> 10
<212> PRT
<213> 人工序列
<220>
<223> 抗MSLN抗体CDR1(VH)的氨基酸序列
<400> 12
Gly Tyr Ser Phe Thr Ser Tyr Phe Met His
1 5 10
<210> 13
<211> 10
<212> PRT
<213> 人工序列
<220>
<223> 抗MSLN抗体CDR1(VH)的氨基酸序列
<400> 13
Gly Tyr Ser Phe Thr Ser Tyr Phe Ile Ser
1 5 10
<210> 14
<211> 10
<212> PRT
<213> 人工序列
<220>
<223> 抗MSLN抗体CDR1(VH)的氨基酸序列
<400> 14
Gly Tyr Ser Phe Thr Ser Tyr Phe Ile Gln
1 5 10
<210> 15
<211> 17
<212> PRT
<213> 人工序列
<220>
<223> 抗MSLN抗体CDR2(VH)的氨基酸序列
<400> 15
Trp Ile Phe Pro Gly Asn Gly Asn Thr Lys Tyr Ser Gln Lys Phe Gln
1 5 10 15
Gly
<210> 16
<211> 17
<212> PRT
<213> 人工序列
<220>
<223> 抗MSLN抗体CDR2(VH)的氨基酸序列
<400> 16
Gly Ile Phe Pro Gly Ser Gly Asn Ala Asn Tyr Ala Gln Lys Phe Gln
1 5 10 15
Gly
<210> 17
<211> 17
<212> PRT
<213> 人工序列
<220>
<223> 抗MSLN抗体CDR2(VH)的氨基酸序列
<400> 17
Trp Ile Phe Pro Gly Ser Gly Asn Thr Lys Tyr Ser Gln Lys Phe Gln
1 5 10 15
Gly
<210> 18
<211> 10
<212> PRT
<213> 人工序列
<220>
<223> 抗MSLN抗体CDR3(VH)的氨基酸序列
<400> 18
Ser Gly Gly Tyr Gln Tyr Tyr Phe Asp Tyr
1 5 10
Claims (15)
1.一种抗体,包含:
轻链可变结构域(VL结构域),所述轻链可变结构域由与SEQ ID NO:1的氨基酸序列具有至少80%同一性的序列组成;和
重链可变结构域(VH结构域),所述重链可变结构域由与SEQ ID NO:3至5中任一个的氨基酸序列具有至少80%同一性的序列组成。
2.根据权利要求1所述的抗体,其特征在于,所述抗体与间皮素(MSLN)特异性结合。
3.根据权利要求2所述的抗体,其特征在于,所述MSLN是人MSLN。
4.根据权利要求1所述的抗体,其特征在于,所述抗体与表达MSLN的癌细胞特异性结合。
5.根据权利要求4所述的抗体,其特征在于,所述表达MSLN的癌细胞是人癌细胞。
6.根据权利要求1所述的抗体,其特征在于,所述抗体是人源化抗体。
7.一种多核苷酸,所述多核苷酸编码根据权利要求1所述的抗体的轻链可变结构域(VL结构域)和重链可变结构域(VH结构域)。
8.一种表达载体,所述表达载体包含根据权利要求7所述的多核苷酸。
9.一种宿主细胞,所述宿主细胞用根据权利要求8所述的表达载体转化。
10.一种产生与MSLN特异性结合的抗体的方法,所述方法包括培养根据权利要求9所述的宿主细胞。
11.一种用于预防或治疗癌症的药物组合物,所述药物组合物包含根据权利要求1所述的抗体或其片段。
12.根据权利要求11所述的药物组合物,其特征在于,所述癌症是间皮瘤、胰腺癌、卵巢癌、胃癌、肺癌或子宫内膜癌。
13.根据权利要求1所述的抗体在预防或治疗癌症中的用途。
14.根据权利要求1所述的抗体在制备用于预防或治疗癌症的药物中的用途。
15.一种预防或治疗癌症的方法,所述方法包括将根据权利要求1所述的抗体给药至对象。
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KR1020170136565A KR101966362B1 (ko) | 2017-10-20 | 2017-10-20 | 항-msln 항체 및 이를 포함하는 암 치료용 약학적 조성물 |
PCT/KR2018/012493 WO2019078698A2 (ko) | 2017-10-20 | 2018-10-22 | 항 -msln항체 및 이를포함하는 암치료용 약학적 조성물 |
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CN113874396A (zh) * | 2019-03-29 | 2021-12-31 | 株式会社绿十字 | 包含抗间皮素抗体、抗cd3抗体或抗egfr抗体的融合蛋白、包含所述融合蛋白的双特异性或三特异性抗体,及其用途 |
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CN117396515A (zh) * | 2021-05-19 | 2024-01-12 | 南京再明医药有限公司 | 抗msln抗体及其应用 |
WO2023131276A1 (zh) * | 2022-01-06 | 2023-07-13 | 原启生物科技(上海)有限责任公司 | 靶向msln的抗原结合蛋白及其应用 |
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CN113874396B (zh) * | 2019-03-29 | 2024-01-05 | 株式会社绿十字 | 包含抗间皮素抗体、抗cd3抗体或抗egfr抗体的融合蛋白、包含所述融合蛋白的双特异性或三特异性抗体,及其用途 |
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JP6978598B2 (ja) | 2021-12-08 |
SG11202003278RA (en) | 2020-05-28 |
US11401343B2 (en) | 2022-08-02 |
WO2019078698A3 (ko) | 2019-07-04 |
CA3077009A1 (en) | 2019-04-25 |
EP3699199A2 (en) | 2020-08-26 |
EA202090945A1 (ru) | 2020-07-14 |
JP2021507678A (ja) | 2021-02-25 |
US20200262928A1 (en) | 2020-08-20 |
BR112020007739A2 (pt) | 2020-10-20 |
KR101966362B1 (ko) | 2019-04-05 |
IL274008A (en) | 2020-05-31 |
WO2019078698A2 (ko) | 2019-04-25 |
EP3699199A4 (en) | 2021-06-30 |
CA3077009C (en) | 2023-05-16 |
AU2018351417A1 (en) | 2020-05-28 |
CN111247173B (zh) | 2024-03-29 |
AU2018351417B2 (en) | 2021-12-23 |
MX2020003943A (es) | 2020-08-13 |
MY194272A (en) | 2022-11-25 |
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