CN110139674A - 制备抗体药物缀合物的方法 - Google Patents
制备抗体药物缀合物的方法 Download PDFInfo
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- CN110139674A CN110139674A CN201780075175.0A CN201780075175A CN110139674A CN 110139674 A CN110139674 A CN 110139674A CN 201780075175 A CN201780075175 A CN 201780075175A CN 110139674 A CN110139674 A CN 110139674A
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Abstract
本文描述的主题涉及制备某些抗体‑药物缀合物(ADC)的方法,其中所述抗体通过接头与药物连接,其中所述药物含有具有仲氮的杂芳基且所述接头经由仲氮附接至药物。所得缀合物可用于治疗各种疾病和病症。
Description
对相关申请的交叉引用
本申请要求2016年10月5日提交的美国临时申请62/404,514的优先权,该申请的内容通过引用整体并入本文。
参考经由EFS-WEB提交为文本文件的序列表
序列表的正式副本经由EPO文件管理器作为ASCII格式的序列表(文件名是SEQLIST_ST25.TXT,于2017年10月3日创建且大小是73.3千字节)以电子方式提交且与说明书同时提交。该ASCII格式的文档中包含的序列表是说明书的一部分且其全部内容通过引用并入本文。
技术领域
本文描述的主题涉及制备某些抗体-药物缀合物(ADC)的方法,其中抗体通过接头与药物连接,其中药物含有具有仲氮的杂芳基且接头经由仲氮附接至药物。
背景技术
肿瘤学家用于治疗癌症的主要治疗方式是手术切除、放射疗法和经典化学治疗药物。不幸的是,手术切除对于许多肿瘤或癌症形式来说不是可行的选择。此外,放射疗法和化学治疗药物不是仅针对患病细胞且因此常见的情况是脱靶于健康细胞发生损伤。
通过利用肿瘤细胞内肿瘤特异性抗原表达或特定蛋白质的不适当过表达或活化正在开发更特异性靶向肿瘤细胞的治疗剂。然而,肿瘤细胞易于突变且可对特异性靶向肿瘤细胞的药物产生抗性。
抗体疗法可提供更具靶向性的疗法同时具有较低的脱靶毒性。使用抗体-药物缀合物(ADC)局部递送细胞毒性剂或细胞抑制剂可提供药物部分向肿瘤的递送及其中的细胞内积累。设计ADC的努力集中在单克隆抗体(mAb)的选择性及药物作用机制、药物连接和药物/抗体比(载量)上。
在上述努力中,药物接头的设计是重要的,因为它影响ADC的功效和安全性。接头需要在全身循环期间提供足够的稳定性,但允许药物以活性形式快速有效地细胞内释放。
然而,目前可用于形成接头和药物之间的连接的化学官能团是有限的。这限制了可用于ADC的接头和药物。因此,需要允许在ADC的生产中使用具有不同化学官能团的药物的方法。
发明内容
在实施方案中,本文描述的主题涉及制备式I的ADC的方法。
在实施方案中,本文描述的主题涉及式I的ADC。
在实施方案中,本文描述的主题涉及制备式III化合物的方法。
在实施方案中,本文描述的主题涉及式III化合物。
还描述了其他实施方案。
附图说明
图1是显示用CNJ-1(HER2,蓝色迹线)或CNJ-2(B7H4,红色迹线)处理的MCF7-neo/HER2细胞中ERα水平降低的图。
图2是显示用CNJ-3(HER2,蓝色迹线)或CNJ-4(B7H4,红色迹线)处理的MCF7-neo/HER2细胞中ERα水平降低的图。
图3是显示在缓冲液和来自不同物种的全血中24小时内测量的CNJ-1的稳定性的一组图。DAR=具有指定药物抗体比率的抗体-药物缀合物。
图4是显示在缓冲液和来自不同物种的全血中24小时内测量的CNJ-3的稳定性的一组图。DAR=具有指定药物抗体比率的抗体-药物缀合物。
图5是显示在用CNJ-3(HER2)或CNJ-4(B7H4)单次IV处理后小鼠MCF7-neo/HER2肿瘤中ERα水平降低的图。时间点=第4天。误差棒=平均值的标准误差。
图6是显示在用CNJ-3(HER2)或CNJ-4(B7H4)单次IV处理后小鼠MCF7-neo/HER2肿瘤中ERα水平降低的图;替代统计分析。时间点=第4天。误差棒=平均值的标准误差。
具体实施方式
本文描述了通过接头将抗体与生物活性分子缀合的方法,所述接头与生物活性分子结构中包含的仲氮共价结合。如下所述,所述方法提供易于与抗体缀合的式II和III化合物。式II和III化合物含有由生物活性分子上的仲氮和接头部分上的氧基羰基形成的氨基甲酸酯。然后可将式II和III化合物与多种抗体、经工程化改造的抗体、抗体片段等缀合以制备式I的ADC。
现在将在下文中更全面地描述本发明公开的主题。然而,本发明所属领域的技术人员将会想到本文所述的本公开主题的许多修改及其他实施方案,其具有前述描述中呈现的教导的益处。因此,应理解本公开主题不限于所公开的具体实施例且修改及其他实施方案旨在包括在所附权利要求书的范围内。换言之,本文所述的主题涵盖所有替换、修改和等同物。如果所并入的文献、专利和类似材料中的一个或多个与本申请不同或相矛盾,包括但不限于定义的术语、术语用法、所述技术等,则以本申请为准。除非另外定义,否则本文使用的所有技术和科学术语具有与本领域普通技术人员通常理解的含义相同的含义。本文提及的所有出版物、专利申请、专利及其他参考文献都通过引用整体并入。
I.定义
本文使用的术语“烷基”是指含有1至12个碳原子的直链或支链烃基。烷基的实例包括甲基、乙基、正丙基、异丙基、叔丁基和正戊基。烷基可任选取代有一个或多个取代基。
术语“取代基”是指代替分子上的氢原子的原子或原子团。术语“取代”表示指定的分子带有一个或多个取代基。取代基的实例包括烷基、环烷基、芳基、杂芳基、羟基、腈基团、卤素、烷氧基、卤代烷氧基、芳基烷氧基、酰基氧基、烷基硫基、磺酸酯基团、氨基、烷基氨基、酰基氨基、氨甲酰基、烷基氨甲酰基或硝基。
术语“烷氧基”是指-O-烷基。烷氧基可任选取代有一个或多个取代基。
术语“卤代烷氧基”是指被一个或多个卤素取代基取代的-O-烷基。卤代烷氧基的实例包括三氟甲氧基和2,2,2-三氟乙氧基。
术语“芳基烷氧基”是指被芳基取代基取代的-O-烷基。芳基烷氧基的实例是O-苄基。
术语“烷基氨基”是指进一步取代有一个或两个烷基的氨基取代基。
术语“烷基硫基”是指-S-烷基。烷基硫基可任选取代有一个或多个取代基。
术语“酰基氨基”是指进一步取代有-CO-R基团的氨基取代基。酰基氨基的实例包括乙酰氨基和2-苯基乙酰氨基。
术语“所述式的化合物”或“式的化合物”是指选自式II、III、V、VI、VII、VIII、IX、X和XI所定义的化合物的任何化合物。
术语“苄基”是指具有式C6H5CH2的烃,其中与所述基团的附接点在CH2位置。苄基可在芳环上取代。在一个实施方案中,芳基的0、1、2、3、4或5个原子可被取代基取代。
本文使用的术语“卤素”、“卤基”或“卤代”是指-F、-Cl、-Br或-I。
术语“环烷基”是指具有至少一个饱和环或具有至少一个非芳族环的烃3-8元单环或7-14元二环环系,其中非芳族环可具有一定的不饱和度。环烷基可任选取代有一个或多个取代基。在一个实施方案中,环烷基的每个环的0、1、2、3或4个原子可被取代基取代。环烷基的代表性实例包括环丙基、环戊基、环己基、环丁基、环庚基、环戊烯基、环戊二烯基、环己烯基、环己二烯基等。
术语“芳基”是指烃单环、二环或三环芳族环系统。芳基可任选取代有一个或多个取代基。在一个实施方案中,芳基的每个环的0、1、2、3、4、5或6个原子可被取代基取代。芳基的实例包括苯基、萘基、蒽基、芴基、茚基、薁基等。
术语“杂芳基”是指芳族5-8元单环、8-12元二环或11-14元三环体系,如果是单环,则具有1-4个环杂原子,如果是双环,则具有1-6个杂原子或如果是三环的,则具有1-9个杂原子,所述杂原子选自O、N或S,其余环原子是碳(除非另有说明,否则具有适当的氢原子)。杂芳基可具有一种、两种或更多种不同的互变异构形式。杂芳基可任选取代有一个或多个取代基。在一个实施方案中,杂芳基的每个环的0、1、2、3或4个原子可被取代基取代。此类杂芳基的非限制性实例包括咪唑基、喹啉基、异喹啉基、吲哚基、吲唑基、哒嗪基、吡啶基、吡咯基、吡唑基、吡嗪基、喹喔啉基、吡喃基、嘧啶基、呋喃基、噻吩基、三唑基、噻唑基、咔啉基、四唑基、苯并呋喃基、硫吗啉基、砜基团、噁唑基、苯并噁唑基、苯并咪唑基、苯并噻唑基、氧代哌啶基、氧代吡咯烷基、氧代氮杂基、氮杂基、异噁唑基、异噻唑基、呋咱基、噻二唑基、氧杂硫杂环戊烷基、吖啶基、菲啶基和苯并噌啉基等。
术语“互变异构体”或“互变异构形式”是指不同能量的结构异构体,其可经由低能垒相互转化。例如,质子互变异构体(也称为质子互变异构体)包括经由质子迁移的互变例如酮-烯醇和亚胺-烯胺异构化。价电子互变异构体包括通过重组一些键合电子的相互转换。
术语“杂环烷基”是指含有至少一个选自氮、氧和硫的杂原子的环或环系统,其中所述杂原子在非芳族环中。杂环烷基环任选与其他杂环烷基环和/或非芳族烃环和/或苯环稠合或以其他方式附接。杂环烷基的实例包括例如哌嗪基、吗啉基、1,2,3,4-四氢异喹啉基、哌啶基、四氢呋喃基、吡咯烷基、吡啶酮基和吡唑烷基。杂环烷基可被取代。
除非在权利要求中另外定义,否则本文使用的术语“任选”意指随后描述的事件可发生或可不发生且包括发生的事件和不发生的事件。
除非另外定义,否则本文使用的短语“任选取代”、“取代”或其变体表示任选的取代,包括多个取代度,具有一个或多个取代基例如一个,两个或三个。该短语不应被解释为本文描述和描绘的取代的重复。
术语“手性”是指具有镜像配偶体不可重叠性质的分子,而术语“非手性”是指可与其镜像配偶体重叠的分子。如本文所用,手性原子使用“R”和“S”命名法来指定所述手性原子的绝对构型。
术语“非对映异构体”是指具有两个或更多个不对称中心且其分子不互为镜像的立体异构体。
术语“对映异构体”是指互为不可重叠镜像的化合物的两种立体异构体。两种对映异构体的等摩尔混合物称为“外消旋混合物”或“外消旋体”。
术语“异构体”或“立体异构体”是指具有相同化学构成但原子或基团的在空间上的排列不同的化合物。
本文使用的“离去基团”是在缀合反应中被亲核试剂置换的基团。离去基团可以是阴离子或中性分子。阴离子离去基团可以是例如卤化物和磺酸酯。置换离去基团的基团可以是例如亲核试剂。“亲核试剂”或“亲核基团”是具有未共用成对电子的化学物质(例如任何Lewis碱)且可以是中性的或具有负电荷。亲核试剂在化学反应过程中提供电子对以形成化学键。亲核基团的非限制性实例包括含氧基团(例如羟基、烷氧基或酰基氧基)、含硫基团(例如巯基、烷基硫基或磺酸酯)、含氮基团(例如氨基、烷基氨基、酰基氨基、硝基、叠氮基或异氰酸基)和卤素。
术语“保护基团”是指在制备化合物或抗体-药物缀合物期间用于保护官能团(例如伯胺或仲胺、羧酸或硫醇)的化学部分。关于保护基团及其用途的一般描述参见T.W.Greene,Protective Groups in Organic Synthesis,John Wiley&Sons,New York,1991。
合适的氨基保护基团包括乙酰基、三氟乙酰基、叔丁氧基羰基(Boc)、苄基氧基羰基(CBz或CBZ)和9-芴基亚甲基氧基羰基(Fmoc)。合适的硫醇保护基团是例如未取代的或取代的苄基例如苄基、对甲氧基苄基、4-甲基苄基、3,4-二甲基苄基、对羟基苄基、对乙酰氧基苄基和对硝基苄基、二苯基甲基、三苯甲基、叔丁基、乙酰基、苯甲酰基等,其中更优选酸不稳定保护基团。酸不稳定的硫醇保护基团可以是例如三苯甲基、芴基、二甲氧基苄基、甲氧基苄基、2,4,6-三甲基苄基、呫吨基、二茂铁基、甲氧基甲基、异丁氧基甲基和二苯基甲基。合适的羧酸保护基团可以是例如支链和非支链烷基和甲硅烷基。
通常,保护基团的种类并不重要,只要它对化合物其他位置上的任何后续反应的条件是稳定的且可以在适当的时间点除去而不会对分子的其余部分产生不利影响。
本文使用的“接触”是指试剂紧密接近,从而可发生反应。
本文使用的“环境温度”或“室温”是指约20至25℃范围内的温度。
短语“药学上可接受的”表示该物质或组合物必须在化学和/或毒理学上与制剂包含的其他成分和/或用其治疗的受试者相容。
本文使用的短语“药学上可接受的盐”是指本文所述主题的化合物的药学上可接受的有机或无机盐。示例性盐包括但不限于硫酸盐、柠檬酸盐、乙酸盐、草酸盐、氯化物、溴化物、碘化物、硝酸盐、硫酸氢盐、磷酸盐、酸式磷酸盐、异烟酸盐、乳酸盐、水杨酸盐、酸式柠檬酸盐、酒石酸盐、油酸盐、鞣酸盐、泛酸盐、酒石酸氢盐、抗坏血酸盐、琥珀酸盐、马来酸盐、龙胆酸盐、富马酸盐、葡萄糖酸盐、葡萄糖醛酸盐、糖酸盐、甲酸盐、苯甲酸盐、谷氨酸盐、甲磺酸盐、乙磺酸盐、苯磺酸盐、对甲苯磺酸盐、双羟萘酸盐(即1,1’-亚甲基-二(2-羟基-3-萘酸盐))、碱金属(例如钠和钾)盐、碱土金属(例如镁)盐和铵盐。药学上可接受的盐可涉及另一种分子例如乙酸根离子、琥珀酸根离子或其他抗衡离子的包合物。抗衡离子可以是稳定母体化合物上电荷的任何有机或无机部分。此外,药学上可接受的盐在其结构中可具有多于一个带电原子。在多个带电原子是药学上可接受的盐的一部分的实例中,盐可具有多个抗衡离子。因此,药学上可接受的盐可具有一个或多个带电原子和/或一个或多个抗衡离子。
其他非药学上可接受的盐可用于制备本文所述的化合物且应认为这些盐形成本申请的另一方面。这些盐例如草酸盐或三氟乙酸盐虽然本身不是药学上可接受的,但可用于制备可用作获得本文所述化合物及其药学上可接受的盐的中间体的盐。
ADC的组件也可用“残基”、“部分”或“基团”来描述,其是指与另一种组件共价结合的组件。
术语“共价结合”或“共价连接”是指通过共用一对或多对电子形成的化学键。
本文的术语“抗体”以其最广泛的含义使用且具体涵盖单克隆抗体、多克隆抗体、二聚体、多聚体、多特异性抗体(例如双特异性抗体)和抗体片段,只要它们表现出所需的生物活性(Miller等(2003)Jour.of Immunology170:4854-4861)。抗体可以是鼠、人、人源化、嵌合的抗体或来源于其他物种。抗体是由免疫系统产生的能够识别和结合特异性抗原的蛋白质(Janeway,C.,Travers,P.,Walport,M.,Shlomchik(2001)Immuno Biology,5th Ed.,Garland Publishing,New York)。靶抗原通常具有由多种抗体上的CDR识别的大量结合位点(也称作表位)。特异性结合不同表位的各抗体具有不同的结构。因此,一种抗原可具有多于一种相应的抗体。抗体包括全长免疫球蛋白分子或全长免疫球蛋白分子的免疫活性部分即含有免疫特异性结合感兴趣的靶标的抗原或其部分的分子,这类靶标包括但不限于癌细胞或产生与自身免疫性疾病相关的自身免疫性抗体的细胞。本文公开的免疫球蛋白可具有免疫球蛋白分子的任意类型(例如IgG、IgE、IgM、IgD和IgA)、类别(例如IgG1、IgG2、IgG3、IgG4、IgA1和IgA2)或亚类。免疫球蛋白可来源于任意物种。然而,在一个方面中,免疫球蛋白来源于人、鼠或兔。
本文使用的“还原的抗体”是指其中至少一个半胱氨酸具有游离巯基的抗体。
本文使用的术语“酸性条件”是指pH低于7.0的环境且特别是适于裂解离去基团或保护基团的条件,例如pH小于1.0,小于2.0,小于3.0,小于4.0,小于5.0或小于6.0。
本文使用的“还原剂”是使另一种物质经历还原并在该过程中被氧化的试剂。在抗体存在下,还原剂可用于稳定游离半胱氨酸并还原二硫键。还原剂的非限制性实例是2-巯基乙醇、2-巯基乙胺、二硫苏糖醇和三(2-羧基乙基)膦。
本文使用的“氧化剂”是使另一种物质经历氧化且在该过程中被还原的物质。氧化剂的非限制性实例是DHAA。
本文使用的“缓冲液”是当向其中添加酸或碱时抵抗pH变化的溶液。缓冲液通常涉及弱酸或弱碱及其一种盐。缓冲液的非限制性实例是Tris、HEPES、PBS(磷酸盐缓冲盐水)、三乙基乙酸铵缓冲液和三乙基碳酸氢铵缓冲液。
本文使用的术语“抗体片段”包含全长抗体的一部分,一般是其抗原结合区或可变区。抗体片段的实例包括:Fab、Fab’、F(ab’)2和Fv片段;双抗体;线性抗体;微抗体(Olafsen等(2004)Protein Eng.Design&Sel.17(4):315-323);通过Fab表达文库制备的片段;抗独特型(抗Id)抗体;CDR(互补决定区);上述任意的免疫特异性结合癌细胞抗原、病毒抗原或微生物抗原的表位结合片段;单链抗体分子;和由抗体片段形成的多特异性抗体。
本文使用的术语“单克隆抗体”是指从基本上同质的抗体群中获得的抗体,即除可能少量存在的可能天然发生的突变之外,包含该群体的各抗体是相同的。单克隆抗体是高度特异的靶向单个抗原位点的抗体。此外,与包括靶向不同决定簇(表位)的不同抗体的多克隆抗体制品相反,每种单克隆抗体只靶向抗原上的单一决定簇。除其特异性外,单克隆抗体的优点还在于它们可以不被其他抗体污染的方式合成。修饰语“单克隆”表示获自基本上同质的抗体群的抗体特性并非解释为需要由任何特定方法生产抗体。例如,可通过首先由Kohler等(1975)Nature,256:495描述的杂交瘤方法制备用于本发明的单克隆抗体或可通过重组DNA方法制备(例如参见:US4816567;US5807715)。例如,还可使用Clackson等(1991)Nature,352:624-628;Marks等(1991)J.Mol.Biol.,222:581-597所述的技术从噬菌体抗体文库分离单克隆抗体。
本文的单克隆抗体具体包括“嵌合”抗体,其中重链和/或轻链的一部分与衍生自特定物种或属于特定抗体类别或亚类的抗体中的相应序列相同或同源,而所述链的剩余部分与来源于另一物种或属于另一抗体类别或亚类的抗体中的相应序列相同或同源,本文还包括这类抗体的片段,只要它们展示期望的生物学活性(US4816567;和Morrison等(1984)Proc.Natl.Acad.Sci.USA,81:6851-6855)。本文感兴趣的嵌合抗体包括“灵长化(primatized)”抗体,其包含来源于非人的灵长类(例如旧域猴(Old World Monkey)、猿(Ape)等)的可变域抗原-结合序列和人恒定区序列。
术语“嵌合”抗体是指重链和/或轻链的一部分来源于特定来源或物种,而重链和/或轻链的其余部分来源于不同的来源或物种的抗体。
抗体的“类别”是指其重链所具有的恒定域或恒定区的类型。存在五种主要抗体类别:IgA、IgD、IgE、IgG和IgM,而且这些类别中的若干种可进一步分成亚类(同种型),例如IgG1、IgG2、IgG3、IgG4、IgA1和IgA2。对应于不同的免疫球蛋白类别的重链恒定域分别称为α、δ、ε、γ和μ。
本文使用的术语“完整抗体”是包含VL和VH结构域及轻链恒定域(CL)和重链恒定域CH1、CH2和CH3的抗体。恒定域可以是天然序列恒定域(例如人天然序列恒定域)或其氨基酸序列变体。完整抗体可具有一种或多种“效应器功能”,是指归因于抗体的Fc恒定区(天然序列Fc区或氨基酸序列变体Fc区)的那些生物活性。抗体效应器功能的实例包括C1q结合;补体依赖的细胞毒性;Fc受体结合;抗体依赖性细胞介导的细胞毒性(ADCC);胞吞作用;和细胞表面受体(例如B细胞受体和BCR)的下调。
本文使用的术语“Fc区”意指免疫球蛋白重链中至少含有恒定区一部分的C末端区。所述术语包括天然序列Fc区和变体Fc区。在一个实施方案中,人IgG重链Fc区从Cys226或从Pro230延伸至重链的羧基末端。然而,Fc区的C末端赖氨酸(Lys447)可存在或不存在。除非本文中另有规定,否则Fc区或恒定区中的氨基酸残基的编号方式依照EU编号系统,又称作EU索引,如记载于Kabat等,Sequences of Proteins of Immunological Interest,5th Ed.Public Health Service,National Institutes of Health,Bethesda,MD,1991。
本文使用的术语“框架”或“FR”是指除高变区(HVR)残基以外的可变域残基。通常,可变域的FR由4个FR域构成:FR1、FR2、FR3和FR4。因此,HVR和FR序列在VH(或VL)中通常以如下序列出现:FR1-H1(L1)-FR2-H2(L2)-FR3-H3(L3)-FR4。
术语“全长抗体”、“完整抗体(intact antibody)”和“整抗体(whole antibody)”在本文中可互换用于指结构基本上类似于天然抗体结构或重链含有如本文中所定义的Fc区的抗体。
“人抗体”是指具有与由人或人细胞生成的或利用人抗体全集或其他人抗体编码序列从非人来源衍生的抗体的氨基酸序列对应的氨基酸序列的抗体。人抗体的此定义明确排除包含非人抗原结合残基的人源化抗体。
“人源化”抗体是指包含来自非人HVR的氨基酸残基和来自人FR的氨基酸残基的嵌合抗体。在某些实施方案中,人源化抗体会包含基本上所有至少一个且典型地两个可变域,其中所有或基本上所有HVR(例如CDR)都对应于非人抗体的那些HVR且所有或基本上所有FR都对应于人抗体的那些FR。人源化抗体任选地可包含来源于人抗体的抗体恒定区的至少一部分。抗体(例如非人抗体)的“人源化形式”是指已进行人源化的抗体。
“分离的抗体”是已与其天然环境的组件分离的抗体。在一些实施方案中,抗体被纯化至大于95%或99%纯度,如通过例如电泳(例如SDS-PAGE、等电聚焦(IEF)、毛细管电泳)或色谱(例如离子交换或反相HPLC)所测定。关于用于评估抗体纯度的方法的综述,参见例如Flatman等,J.Chromatogr.B848:79-87(2007)。
“分离的核酸”是指已与其天然环境的组件分离的核酸分子。分离的核酸包括通常含有所述核酸分子但所述核酸分子存在于染色体外或处在与其天然染色体位置不同的染色体位置的细胞中所含有的核酸分子。
“编码抗体的分离的核酸”是指编码抗体重链和轻链(或其片段)的一种或多种核酸分子,包括处于单一载体或独立载体中的此类核酸分子和存在于宿主细胞中的一个或多个位置上的此类核酸分子。
“裸抗体”是指未与异源部分(例如细胞毒性部分)或放射性标记缀合的抗体。裸抗体可存在于药物制剂中。
“天然抗体”是指具有变化结构的天然存在的免疫球蛋白分子。例如,天然IgG抗体是由二硫键键合的两个同一轻链和两个同一重链构成的约150,000道尔顿的异源四聚体多糖蛋白。从N末端至C末端,各重链具有可变区(VH,也称为可变重链结构域或重链可变域),随后是三个恒定域(CH1、CH2和CH3)。类似地,从N末端至C末端,各轻链具有可变区(VL,也称为可变轻链结构域或轻链可变域),随后是一个恒定轻链(CL)结构域。抗体的轻链可基于其恒定域的氨基酸序列而指定为两种类型(称为κ和λ)之一。
关于参考多肽序列的“氨基酸序列同一性百分比(%)”定义为在将候选序列与参考多肽序列对准且必要时引入间隙以实现最大序列同一性百分比且不将任何保守取代视为序列同一性的一部分之后,候选序列中与参考多肽序列中的氨基酸残基同一的氨基酸残基的百分比。出于确定氨基酸序列同一性百分比的目的,对准可用本领域中的技术范围内的各种方式来实现,例如使用公开可得的计算机软件,例如BLAST、BLAST-2、ALIGN或Megalign(DNASTAR)软件。本领域技术人员可确定用于对准序列的适当参数,包括在所比较的序列全长上实现最大对准所需的任何算法。然而,出于本文中的目的,使用序列比较计算机程序ALIGN-2来产生氨基酸序列同一性%值。ALIGN-2序列比较计算机程序是由Genentech,Inc.授权且源代码已与用户文件一起提交至美国版权局(Washington D.C.,20559),以美国版权登记号TXU510087登记于此。ALIGN-2程序可公开得自Genentech,Inc.(South San Francisco,California)或可由源代码汇编。ALIGN-2程序应经过汇编以用于UNIX操作系统,包括数字UNIX V4.0D。所有序列比较参数都由ALIGN-2程序设定且不加变化。
在采用ALIGN-2进行氨基酸序列比较的情况下,如下计算指定氨基酸序列A相对于、与或针对指定氨基酸序列B的氨基酸序列同一性%(其可替代地表述为指定氨基酸序列A相对于、与或针对指定氨基酸序列B具有或包含某一氨基酸序列同一性%):
100×分数X/Y
其中X是由序列比对程序ALIGN-2在该程序的A与B比对中评分为同一匹配的氨基酸残基数且其中Y是B中的氨基酸残基总数。应了解,如果氨基酸序列A的长度与氨基酸序列B的长度不相等,则A相对于B的氨基酸序列同一性%将不等于B相对于A的氨基酸序列同一性%。除非另外明确说明,否则本文中使用的所有氨基酸序列同一性%值都如前一段中所述,使用ALIGN-2计算机程序来获得。
根据其重链恒定域的氨基酸序列,可将完整抗体指定为不同“类别”。存在5种主要类别的完整免疫球蛋白抗体:IgA、IgD、IgE、IgG和IgM且可将其中的几种进一步分成“亚类”(亚型),例如IgG1、IgG2、IgG3、IgG4、IgA1和IgA2。对应于不同抗体类别的重链恒定域分别称作α、δ、ε、γ和μ。不同类别免疫球蛋白的亚单位结构和三维构型是众所周知的。Ig形式包括铰链-修饰形式或无铰链形式(Roux等(1998)J.Immunol.161:4083-4090;Lund等(2000)Eur.J.Biochem.267:7246-7256;US2005/0048572;US2004/0229310)。
本文使用的术语“人共有框架”是指代表人免疫球蛋白VL或VH框架序列选集中最常存在的氨基酸残基的框架。通常,人免疫球蛋白VL或VH序列的选集来自于可变域序列亚组。通常,序列亚组是如Kabat等,Sequences of Proteins of Immunological Interest,第5版,NIH Publication 91-3242,Bethesda MD(1991),第1-3卷中的亚组。在一个实施方案中,对于VL,所述亚组是如Kabat等,同上中的亚组κI。在一个实施方案中,对于VH,所述亚组是如Kabat等,同上中的亚组III。
出于本文的目的,“受体人框架”是包含来源于人免疫球蛋白框架或如下文所定义的人共有框架的轻链可变域(VL)框架或重链可变域(VH)框架的氨基酸序列的框架。“来源于”人免疫球蛋白框架或人共有框架的受体人框架可包含与其相同的氨基酸序列或其可含有氨基酸序列变化。在一些实施方案中,氨基酸变化的数目是10或更少、9或更少、8或更少、7或更少、6或更少、5或更少、4或更少、3或更少或2或更少。在一些实施方案中,VL受体人框架与VL人免疫球蛋白框架序列或人共有框架序列在序列上同一。
本文使用的术语“可变区”或“可变域”是指参与抗体与抗原结合的抗体重链或轻链结构域。天然抗体的重链和轻链可变域(分别是VH和VL)通常具有类似的结构,各结构域包含4个保守框架区(FR)和3个高变区(HVR)。(参见例如Kindt等,Kuby Immunology,第6版,W.H.Freeman and Co.,第91页(2007)。)单一VH或VL结构域可足以赋予抗原结合特异性。此外,结合特定抗原的抗体可使用来自于结合所述抗原的抗体的VH或VL结构域来分别筛选互补VL或VH结构域文库而加以分离。参见例如Portolano等,J.Immunol.150:880-887(1993);Clarkson等,Nature 352:624-628(1991)。
本文使用的术语“高变区”或“HVR”是指抗体可变域中在序列方面高变和/或形成结构被限定的环(“高变环”)的各区域。通常,天然四链抗体包含6个HVR;3个在VH中(H1、H2、H3)且3个在VL中(L1、L2、L3)。HVR通常包含来自高变环和/或来自“互补性决定区”(CDR)的氨基酸残基,后者具有最高序列变异性和/或参与抗原识别。示例性高变环存在于氨基酸残基26-32(L1)、50-52(L2)、91-96(L3)、26-32(H1)、53-55(H2)和96-101(H3)。(Chothia和Lesk,J.Mol.Biol.196:901-917(1987)。)示例性CDR(CDR-L1、CDR-L2、CDR-L3、CDR-H1、CDR-H2和CDR-H3)存在于氨基酸残基24-34(L1)、50-56(L2)、89-97(L3)、31-35B(H1)、50-65(H2)和95-102(H3)。(Kabat等,Sequences of Proteins of Immunological Interest,第5版,Public Health Service,National Institutes of Health,Bethesda,MD(1991)。)除VH中的CDR1以外,CDR通常包含形成高变环的氨基酸残基。CDR还包含“特异性决定残基”或“SDR”,其是接触抗原的残基。SDR包含在被称为缩短CDR或a-CDR的CDR区内。示例性a-CDR(a-CDR-L1、a-CDR-L2、a-CDR-L3、a-CDR-H1、a-CDR-H2和a-CDR-H3)存在于氨基酸残基31-34(L1)、50-55(L2)、89-96(L3)、31-35B(H1)、50-58(H2)和95-102(H3)。(参见Almagro和Fransson,Front.Biosci.13:1619-1633(2008)。)在本文中,除非另外指出,否则可变域中的HVR残基及其他残基(例如FR残基)是根据Kabat等,同上进行编号。
“效应器功能”是指可归因于抗体Fc区的生物活性,其随抗体同种型而变化。抗体效应器功能的实例包括:C1q结合和补体依赖性细胞毒性(CDC);Fc受体结合;抗体依赖性细胞介导的细胞毒性(ADCC);胞吞作用;细胞表面受体(例如B细胞受体)的下调;及B细胞活化。
术语“表位”是指抗原分子上与抗体结合的特定位点。
“表位4D5”或“4D5表位”或“4D5”是HER2的细胞外域中与抗体4D5(ATCC CRL10463)和曲妥珠单抗结合的区域。此表位接近HER2的跨膜域且在HER2的结构域IV内。为了筛选结合4D5表位的抗体,可进行例如Antibodies,A Laboratory Manual,Cold SpringHarbor Laboratory,Ed Harlow and David Lane(1988)中所述的常规交叉阻断测定。或者,可进行表位图谱分析以评估抗体是否结合HER2的4D5表位(例如HER2(SEQ ID NO:39)中从约残基550至约残基610的区域(包括端点)中的任何一个或多个残基)。
“表位2C4”或“2C4表位”是HER2的细胞外域中与抗体2C4结合的区域。为了筛选结合2C4表位的抗体,可进行例如Antibodies,A Laboratory Manual,Cold Spring HarborLaboratory,Ed Harlow and David Lane(1988)中所述的常规交叉阻断测定。或者,可进行表位图谱分析以评估抗体是否结合HER2的2C4表位。表位2C4包含来自HER2细胞外域中的结构域II的残基。2C4抗体和帕妥珠单抗在结构域I、II和III的接合处与HER2细胞外域结合(Franklin等,Cancer Cell 5:317-328(2004))。
“亲和力”是指分子(例如抗体)的单一结合位点与其结合搭配物(例如抗原)之间的非共价相互作用总和的强度。除非另外指出,否则本文使用的“结合亲和力”是指体现结合对的成员(例如抗体和抗原)之间的1:1相互作用的固有结合亲和力。分子X对其搭配物Y的亲和力通常可由解离常数(Kd)表示。亲和力可通过本领域中已知的常用方法,包括本文中所述的方法来测量。以下描述用于测量结合亲和力的特定说明性和示例性实施方案。在某些实施方案中,本文所述的抗体的解离常数(Kd)≤1μM、≤100nM、≤10nM、≤5nm、≤4nM、≤3nM、≤2nM、≤1nM、≤0.1nM、≤0.01nM或≤0.001nM(例如10-8M或更少,例如10-8M至10- 13M,例如10-9M至10-13M)。
“亲和力成熟”抗体是指在一个或多个高变区(HVR)中具有一处或多处改变的抗体,与不具有此类改变的亲本抗体相比,此类改变导致所述抗体对抗原的亲和力的改善。
本文使用的术语“游离半胱氨酸氨基酸”是指已经工程化改造到亲代抗体中的带有硫醇官能团(-SH)的且未配对作为分子内或分子间二硫键桥的半胱氨酸残基。
本文使用的术语“氨基酸”意指甘氨酸、丙氨酸、缬氨酸、亮氨酸、异亮氨酸、苯丙氨酸、脯氨酸、丝氨酸、苏氨酸、酪氨酸、半胱氨酸、蛋氨酸、赖氨酸、精氨酸、组氨酸、色氨酸、天冬氨酸、谷氨酸、天冬酰胺、谷氨酰胺或瓜氨酸。
本文使用的术语“接头”、“接头单元”或“连接物(link)”意指包含使药物共价附接至抗体的原子链的化学部分。在各个实施方案中,接头是二价基,指定为L1。
本文使用的术语“多个”是指两个或更多个缀合物。每个缀合物可与多个缀合物中的任何其他缀合物相同或不同。
本文中的其他术语、定义和缩写包括:野生型(“WT”);经半胱氨酸工程化改造的突变体抗体(“thio”);轻链(“LC”);重链(“HC”);6-马来酰亚胺己酰基(“MC”);马来酰亚胺丙酰基(“MP”);缬氨酸-瓜氨酸(“val-cit”或“vc”),丙氨酸-苯丙氨酸(“ala-phe”),对氨基苄基(“PAB”)和对氨基苄氧基羰基(“PABC”);A118C(EU编号)=A121C(序列编号)=重链的A114C(Kabat编号)轻链的K149C(Kabat编号)。本文还提供除此之外的其他定义和缩写。
下面还提供了其他定义。
II.抗体-药物缀合物(ADC)和制备方法
本文所述的抗体-药物缀合物(ADC)分子包含经由接头(L1)与药物缀合的抗体。ADC的通式I是:
Ab―(L1―D)p I
其中D是生物活性分子例如药物;L1是与Ab及与D共价结合的接头;且p值是约1至约10或约1至约9或约1至约8或约1至约7或约1至约6或约1至约5或约1至约4或约1至约3。在一个实施方案中,p是约2。
本文所述的方法可用于制备式I的ADC及其中多于一个(即1至10的整数个)接头-生物活性分子与式I中的单一抗体缀合的ADC。
在实施方案中,本申请涉及制备式I的抗体-药物缀合物或其药学上可接受的盐的方法:
Ab―(L1―D)p I
其中
Ab是抗体;
L1是连接部分;
D是生物活性分子,其包含含有仲氮的杂芳基,其中L1与所述仲氮共价键合;且
p是约1、2、3、4、5、6、7、8、9或10且优选p是约2;
所述方法包括:
i.使式II化合物与抗体接触:
T-L1-D II
其中
L1和D如上所述,
T是具有结构R5-S的离去基团,
其中R5是任选取代的吡啶,
其中制备式I的抗体-药物缀合物。
如在上述任何实施方案中,本申请涉及一种方法,其中
L1具有如下结构:
其中
R1、R2、R3和R4独立选自H、任选取代的支链或直链C1-C5烷基和任选取代的C3-C6环烷基或R3和R4与和它们结合的碳原子一起形成C3-C6环烷基环,
其中所述任选取代的烷基或环烷基可取代有烷基、环烷基、芳基、杂芳基、羟基、腈基团、卤素、烷氧基、卤代烷氧基、芳基烷氧基、酰基氧基、烷基硫基、磺酸酯基团、氨基、烷基氨基、酰基氨基、氨甲酰基、烷基氨甲酰基或硝基。
如在上述任何实施方案中的方法,其中T-L1-D具有下式:
其中R5选自任选取代的吡啶和硝基吡啶。
如在上述任何实施方案中的方法,其中R5是5-硝基吡啶。
如在上述任何实施方案中的方法,其中R1、R2、R3和R4独立选自H和任选取代的支链或直链C1-C5烷基。
如在上述任何实施方案中的方法,其中R1、R2、R3和R4中的一个是任选取代的支链或直链C1-C5烷基且其他是H。
如在上述任何实施方案中的方法,其中所述任选取代的支链或直链C1-C5烷基是甲基。
如在上述任何实施方案中的方法,其中R1是甲基且R2、R3和R4各自是H。
如在上述任何实施方案中的方法,其中所述式I的抗体-药物缀合物具有如下结构:
其中p是1、2、3、4、5、6、7、8、9或10且优选p是约2。
如在上述任何实施方案中的方法,其中所述式I的抗体-药物缀合物具有如下结构:
其中p是1、2、3、4、5、6、7、8、9或10且优选p是约2。
如在上述任何实施方案中的方法,其中所述Ab是经半胱氨酸工程化的抗体或其变体。
如在上述任何实施方案中的方法,其中所述抗体结合HER2或B7-H4。
如在上述任何实施方案中的方法,其中所述抗体结合HER2。
如在上述任何实施方案中的方法,其中所述接触包括:
i.使所述Ab与合适的还原剂接触以制备还原的Ab,
ii.氧化所述还原的Ab以制备Ab’且
iii.使所述Ab’与T-L1-D在合适的缓冲液存在下接触。
如在上述任何实施方案中的方法,其中所述缓冲液的pH是约8.5。
如在上述任何实施方案中的方法,其中所述接触包括:
i.使所述Ab与摩尔过量的DTT在环境温度接触以制备还原的Ab,
ii.纯化所述还原的Ab,
iii.用DHAA在环境温度氧化所述经纯化的还原的Ab以制备Ab’,
iv.纯化所述Ab’,
v.使所述经纯化的Ab’与T-L1-D在缓冲溶液中在约8.5的pH接触以制备Ab-L1-D且
vi.纯化所述Ab-L1-D。
如在上述任何实施方案中的方法,其中L1的羰基与D的杂芳基的所述仲氮共价结合,其中所述杂芳基选自:
如在上述任何实施方案中的方法,其中所述杂芳基选自:
如在上述任何实施方案中的方法,其中所述杂芳基选自:
如在上述任何实施方案中的方法,其中所述杂芳基是:
如在上述任何实施方案中的方法,其中D选自:
如在上述任何实施方案中的方法,其中D是:
如在上述任何实施方案中的方法,其中D是:
如在上述任何实施方案中的方法,其中式I的抗体-药物缀合物选自:
其中p是1、2、3、4、5、6、7、8、9或10且优选p是约2。
如在上述任何实施方案中的方法,其中所述抗体是抗HER2 7C2LC K149C或抗B7H41D11v1.9varD LC K149C。
在实施方案中,本申请涉及式IV的抗体-药物缀合物或其药学上可接受的盐:
其中
Ab是抗体;
R1、R2、R3和R4独立选自H、任选取代的支链或直链C1-C5烷基和任选取代的C3-C6环烷基或R3和R4与和它们结合的碳原子一起形成C3-C6环烷基环,
其中所述任选取代的烷基或环烷基可取代有烷基、环烷基、芳基、杂芳基、羟基、腈基团、卤素、烷氧基、卤代烷氧基、芳基烷氧基、酰基氧基、烷基硫基、磺酸酯基团、氨基、烷基氨基、酰基氨基、氨甲酰基、烷基氨甲酰基或硝基;
D是包含含有仲氮的杂芳基的生物活性分子,其中式IV中的羰基与D中的仲氮共价键合;且
p是1、2、3、4、5、6、7、8、9或10且优选p是约2。
如在上述任何实施方案中,本申请涉及抗体-药物缀合物,其中R1、R2、R3和R4独立选自H和任选取代的支链或直链C1-C5烷基。
如在上述任何实施方案中,本申请涉及抗体-药物缀合物,其中R1、R2、R3和R4中的一个是任选取代的支链或直链C1-C5烷基且其他是H。
如在上述任何实施方案中,本申请涉及抗体-药物缀合物,其中所述任选取代的支链或直链C1-C5烷基是甲基。
如在上述任何实施方案中,本申请涉及抗体-药物缀合物,其中R1是甲基且R2、R3和R4各自是H。
如在上述任何实施方案中,本申请涉及抗体-药物缀合物,其中所述式IV的抗体-药物缀合物具有如下结构:
其中p是1、2、3、4、5、6、7、8、9或10且优选p是约2。
如在上述任何实施方案中,本申请涉及抗体-药物缀合物,其中所述式IV的抗体-药物缀合物具有如下结构:
其中p是1、2、3、4、5、6、7、8、9或10且优选p是约2。
如在上述任何实施方案中,本申请涉及抗体-药物缀合物,其中所述Ab是经半胱氨酸工程化的抗体或其变体。
如在上述任何实施方案中,本申请涉及抗体-药物缀合物,其中所述抗体结合HER2或B7-H4。
如在上述任何实施方案中,本申请涉及抗体-药物缀合物,其中所述抗体结合HER2。
如在上述任何实施方案中,本申请涉及抗体-药物缀合物,其中式IV的羰基与D的杂芳基的仲氮共价结合,其中所述杂芳基选自:
如在上述任何实施方案中,本申请涉及抗体-药物缀合物,其中所述杂芳基选自:
如在上述任何实施方案中,本申请涉及抗体-药物缀合物,其中所述杂芳基选自:
如在上述任何实施方案中,本申请涉及抗体-药物缀合物,其中所述杂芳基是:
如在上述任何实施方案中,本申请涉及抗体-药物缀合物,其中D选自:
如在上述任何实施方案中,本申请涉及抗体-药物缀合物,其中D是:
如在上述任何实施方案中,本申请涉及抗体-药物缀合物,其中D是:
如在上述任何实施方案中,本申请涉及选自以下的抗体-药物缀合物:
其中p是1、2、3、4、5、6、7、8、9或10且优选p是约2。
如在上述任何实施方案中,本申请涉及抗体-药物缀合物,其具有以下结构:
其中所述抗体是抗HER2 7C2LC K149C且p是1、2、3、4、5、6、7、8、9或10且优选p是约2。
如在上述任何实施方案中,本申请涉及抗体-药物缀合物,其具有以下结构:
其中所述抗体是抗B7H4 1D11v1.9varD LC K149C且p是1、2、3、4、5、6、7、8、9或10且优选p是约2。
在实施方案中,本申请涉及制备式III化合物的方法:
其中
R1、R2、R3和R4独立选自H、任选取代的支链或直链C1-C5烷基和任选取代的C3-C6环烷基或R3和R4与和它们结合的碳原子一起形成C3-C6环烷基环,
其中所述任选取代的烷基或环烷基可取代有烷基、环烷基、芳基、杂芳基、羟基、腈基团、卤素、烷氧基、卤代烷氧基、芳基烷氧基、酰基氧基、烷基硫基、磺酸酯基团、氨基、烷基氨基、酰基氨基、氨甲酰基、烷基氨甲酰基或硝基;且
D是包含含有仲氮的杂芳基的生物活性分子,其中式III中的羰基与D中的仲氮共价键合;
R5选自任选取代的吡啶和硝基吡啶;
所述方法包括:
i.使式V化合物与化合物D接触:
其中LG是离去基团且PG是保护基团,
以制备式VI化合物:
且
ii.使式VI化合物在酸性条件下脱保护以制备式III化合物:
如在上述任何实施方案中的方法,其中所述保护基团PG是适于硫醇保护的保护基团。
如在上述任何实施方案中的方法,其中所述保护基团PG是酸不稳定性保护基团。
如在上述任何实施方案中的方法,其中所述保护基团PG选自三苯甲基、芴基、二甲氧基苄基、甲氧基苄基、2,4,6-三甲基苄基,呫吨基、二茂铁基、甲氧基甲基、异丁氧基甲基和二苯基甲基。
如在上述任何实施方案中的方法,其中所述保护基团PG是三苯甲基。
如在上述任何实施方案中的方法,其中所述离去基团LG是适于被亲核试剂置换的基团。
如在上述任何实施方案中的方法,其中所述离去基团LG是卤素。
如在上述任何实施方案中的方法,其中所述离去基团LG是氯。
如在上述任何实施方案中的方法,其中R5是硝基吡啶。
如在上述任何实施方案中的方法,其中R5是5-硝基吡啶。
在实施方案中,本申请涉及式III化合物:
其中
R1、R2、R3和R4独立选自H、任选取代的支链或直链C1-C5烷基和任选取代的C3-C6环烷基或R3和R4与和它们结合的碳原子一起形成C3-C6环烷基环,
其中所述任选取代的烷基或环烷基可取代有烷基、环烷基、芳基、杂芳基、羟基、腈基团、卤素、烷氧基、卤代烷氧基、芳基烷氧基、酰基氧基、烷基硫基、磺酸酯基团、氨基、烷基氨基、酰基氨基、氨甲酰基、烷基氨甲酰基或硝基;
R5选自任选取代的吡啶和硝基吡啶;且
D是包含含有仲氮的杂芳基的生物活性分子,其中式III中的羰基与D中的仲氮共价键合。
如在上述任何实施方案中的化合物,其中R5是5-硝基吡啶。
如在上述任何实施方案中的化合物,其中R1是甲基且R2、R3和R4各自是H。
如在上述任何实施方案中的化合物,其中R1是甲基且具有R立体化学。
如在上述任何实施方案中,其中式III化合物选自:
在实施方案中,本申请涉及制备式IV的抗体-药物缀合物或其药学上可接受的盐的方法:
其中
Ab是抗体;
R1、R2、R3和R4独立选自H、任选取代的支链或直链C1-C5烷基和任选取代的C3-C6环烷基或R3和R4与和它们结合的碳原子一起形成C3-C6环烷基环,
其中所述任选取代的烷基或环烷基可取代有烷基、环烷基、芳基、杂芳基、羟基、腈基团、卤素、烷氧基、卤代烷氧基、芳基烷氧基、酰基氧基、烷基硫基、磺酸酯基团、氨基、烷基氨基、酰基氨基、氨甲酰基、烷基氨甲酰基或硝基;
D是包含含有仲氮的杂芳基的生物活性分子,其中式IV中的羰基与D中的仲氮共价键合;且
p是1、2、3、4、5、6、7、8、9或10且优选2;
所述方法包括:
i.使式V化合物与化合物D接触:
其中LG是离去基团且PG是保护基团,
以制备式VI化合物:
ii.使式VI化合物与二硫化物R5-S-S-R5在酸性条件下接触以制备式III化合物:
其中R5是任选取代的吡啶;且
iii.使式III化合物与抗体接触以制备式IV的抗体-药物缀合物。
在实施方案中,本申请涉及制备式VII化合物的方法:
其中
PG是保护基团;且
D是包含含有仲氮的杂芳基的生物活性分子,其中式VII中的酯羰基与D中的仲氮形成氨基甲酸酯;
所述方法包括:
i.使式VIII化合物:
与式IX化合物接触:
其中LG是离去基团,
以制备式VII化合物。
如在上述任何实施方案中的方法,其中式VII化合物是:
在一个实施方案中,本申请涉及通过如以上任何实施方案中的方法制备的抗体-药物缀合物。
在一个实施方案中,本申请涉及通过如以上任何实施方案中的方法制备的式III化合物。
如在上述任何实施方案中的方法,其中所述杂芳基选自吲哚基、吲唑基、苯并咪唑基、苯并三唑基、吡咯基、吡咯并吡啶基、咪唑基、三唑基和四唑基。
如在上述任何实施方案中的方法,其中所述D选自细胞毒剂;生长抑制剂;抗生素;毒素;抗肿瘤剂或抗癌剂;烷化剂;烷基磺酸酯;氮杂环丙烷;乙撑亚胺和甲基蜜胺(methylamelamine);acetogenins;拓扑异构酶1抑制剂;蛋白酶体抑制剂;EGFR抑制剂;酪氨酸激酶抑制剂;丝氨酸-苏氨酸激酶抑制剂;法尼基转移酶抑制剂;抗激素剂;选择性雌激素受体调节剂(SERM);抗雌激素;芳香酶抑制剂;促黄体激素释放激素激动剂;性类固醇;雌激素;和雄激素/类视黄醇;雌激素受体下调因子(ERD);抗雄激素;免疫抑制剂;非甾体抗炎药(NSAID);抗炎剂;环氧合酶抑制剂,白三烯受体拮抗剂;嘌呤拮抗剂;类固醇;二氢叶酸还原酶抑制剂;和抗疟疾剂。
如在上述任何实施方案中的方法,其中所述D选自鹅膏毒素(amanitin)、长春碱(vinblastine)、长春新碱(vincristine)、倍癌霉素A(duocarmycin A)、倍癌霉素SA(duocarmycin SA)、CC-1065、阿多来新(adozelesin)、U-76074、U-73073、卡折来新(carzelesin)(U-80244)、KW-2189、diazonamide A、埃索美拉唑(esomeprazole)、阿立哌唑(aripiprazole)、缬沙坦(valsartan)、兰索拉唑(lansoprazole)、雷贝拉唑(rabeprazole)、培美曲塞(pometrexed)、奥美沙坦(olmesartan)、他达拉非(tadalafil)、泮托拉唑(pantoprazole)、坎地沙坦(candosartan)、奥美拉唑(omeprazole)、舒尼替尼(sunitinib)、培美曲塞(pemetrexed)、阿来替尼(alectinib)、达卡巴嗪(dacarbazine)、司马沙尼(semaxanib)、达西斯特(dacinostat)、多韦替尼(dovitinib)、甲苯达唑(mebendazole)和匹莫苯丹(pimobendan)。
化合物可通过合成路线合成,所述合成路线包括与化学领域中公知的那些类似的方法,特别是根据本文所包含的描述,和述于以下针对其他杂环化合物的那些:Comprehensive Heterocyclic Chemistry II,编辑Katritzky和Rees,Elsevier,1997,例如第3卷;Liebigs Annalen der Chemie,(9):1910-16,(1985);Helvetica Chimica Acta,41:1052-60,(1958);Arzneimittel-Forschung,40(12):1328-31,(1990),其中的每个都通过引用明确地并入。起始物质通常可从商业来源获得,例如Aldrich Chemicals(Milwaukee,WI)或者使用本领域技术人员公知的方法容易地制备(例如通过LouisF.Fieser和Mary Fieser,Reagents for Organic Synthesis,v.1-23,Wiley,N.Y.(1967-2006ed.)或Beilsteins Handbuch der organischen Chemie,4,Aufl.ed.Springer-Verlag,Berlin,包括附录(也可经由Beilstein在线数据库获得)。DTT是指二硫苏糖醇。DHAA是指脱氢抗坏血酸。
用于合成化合物的合成化学转化和保护基团方法(保护和脱保护)及必需试剂和中间体是本领域已知的,包括例如R.Larock,Comprehensive Organic Transformations,VCH Publishers(1989);T.W.Greene和P.G.M.Wuts,Protective Groups in OrganicSynthesis,3rd Ed.,John Wiley and Sons(1999);和L.Paquette,ed.,Encyclopedia ofReagents for Organic Synthesis,John Wiley and Sons(1995)及其后续版本。
化合物可单独制备或作为包含至少2种,例如5至1000种化合物或10至100种化合物的化合物库制备。式I的化合物库可通过本领域技术人员已知的操作,使用溶液相或固相化学,通过组合的“分裂和混合(split and mix)”途径来制备或通过多平行合成(multipleparallel syntheses)来制备。因此,根据另一方面,其提供了包含至少2种化合物或其药学上可接受的盐的化合物库。
纯化抗体的方法在本领域中是公知的。任何已知的方法可用于纯化如本文所述的抗体、还原的抗体等。
通用操作和实施例提供了制备化合物的示例性方法。本领域技术人员应理解可使用其他合成路线来合成化合物。尽管在方案、通用操作和实施例中描述和讨论了特定的起始物质和试剂,但是可容易地替换其他起始物质和试剂以提供各种衍生物和/或反应条件。此外,根据本公开内容,使用本领域技术人员公知的常规化学方法,可进一步修饰通过所述方法制备的许多示例性化合物。
一般地,本申请描述了以例如通用方案A的方式制备ADC的方法:
反应条件:
A:在合适溶剂中的合适碱。
B:提供游离半胱氨酸硫醇以与接头反应的反应条件。在一个实施方案中,步骤B可包括:i)使Ab与还原剂接触;ii)纯化经还原的抗体;iii)使经纯化的抗体与氧化剂接触以形成Ab’;和iv)纯化Ab’。
C:在合适溶剂中的合适碱。
方案1描绘了制备如本文所述的药物二硫化物-接头分子的合成路线。
方案2描绘了制备如本文所述的药物二硫化物-接头分子的合成路线。
方案3描绘了制备如本文所述的药物-经保护的肽接头分子的合成路线。
方案4描绘了制备药物-肽接头的合成路线。
本文描述的ADC由以下组件构成:
1.抗体(Ab)
如本文所述,抗体(例如单克隆抗体(mAB))用于将药物递送至靶细胞例如表达药物所靶向的特定蛋白质的细胞。
a.人抗体
在某些实施方案中,本文中提供的抗体是人抗体。可使用本领域中已知的多种技术来生成人抗体。人抗体通常记载于van Dijk和van de Winkel,Curr.Opin.Pharmacol.5:368-74(2001)和Lonberg,Curr.Opin.Immunol.20:450-459(2008)。
可通过对转基因动物施用免疫原来制备人抗体,所述转基因动物已经修饰为响应抗原性攻击而生成完整人抗体或具有人可变区的完整抗体。此类动物通常含有整个或部分人免疫球蛋白基因座,其替换内源免疫球蛋白基因座或者其在染色体外存在或随机整合入动物的染色体中。在此类转基因小鼠中,通常已经将内源免疫球蛋白基因座灭活。关于自转基因动物获得人抗体的方法的综述参见Lonberg,Nat.Biotech.23:1117-1125(2005)。还可参见例如美国专利No.6,075,181和6,150,584,其描述了XENOMOUSETM技术;美国专利No.5,770,429,其描述了技术;美国专利No.7,041,870,其描述了K-M技术,和美国专利申请公开文本No.US 2007/0061900,其描述了技术。可例如通过与不同人恒定区组合进一步修饰来自由此类动物生成的完整抗体的人可变区。
也可通过基于杂交瘤的方法生成人抗体。已经描述了用于生成人单克隆抗体的人骨髓瘤和小鼠-人异源骨髓瘤细胞系(参见例如Kozbor,J.Immunol.133:3001(1984);Brodeuri等,Monoclonal Antibody Production Techniques and Applications,pp.51-63(Marcel Dekker,Inc.,New York,1987);和Boerneri等,J.Immunol.147:86(1991))。经由人B细胞杂交瘤技术生成的人抗体也记载于Li等,Proc.Natl.Acad.Sci.USA,103:3557-3562(2006)。其他方法包括那些记载于例如美国专利No.7,189,826(其描述了自杂交瘤细胞系生成单克隆人IgM抗体)和Ni,Xiandai Mianyixue,26(4):265-268(2006)(其描述了人-人杂交瘤)。人杂交瘤技术(Trioma技术)也记载于Vollmers和Brandlein,Histologyand Histopathology,20(3):927-937(2005)及Vollmers和Brandlein,Methods andFindings in Experimental and Clinical Pharmacology,27(3):185-91(2005)。
也可如下生成人抗体,即分离选自人衍生的噬菌体展示文库的Fv克隆可变域序列。然后,可将此类可变域序列与期望的人恒定域组合。下文描述了自抗体文库选择人抗体的技术。
b.文库衍生的抗体
可通过对组合文库筛选具有期望的一种或多种活性的抗体来分离ADC中使用的抗体。例如,用于生成噬菌体展示文库及对此类文库筛选拥有期望结合特征的抗体的多种方法是本领域中已知的。此类方法综述于例如Hoogenboom等,于Methods in MolecularBiology 178:1-37(O’Brien等,ed.,Human Press,Totowa,NJ,2001)且进一步记载于例如McCafferty等,Nature348:552-554;Clackson等,Nature 352:624-628(1991);Marks等,J.Mol.Biol.222:581-597(1992);Marks和Bradbury,于Methods in MolecularBiology248:161-175(Lo,ed.,Human Press,Totowa,NJ,2003);Sidhu等,J.Mol.Biol.338(2):299-310(2004);Lee等,J.Mol.Biol.340(5):1073-1093(2004);Fellouse,Proc.Natl.Acad.Sci.USA 101(34):12467-12472(2004);和Lee等,J.Immunol.Methods284(1-2):119-132(2004)。
在某些噬菌体展示方法中,将VH和VL基因的全集分别通过聚合酶链式反应(PCR)克隆并在噬菌体文库中随机重组,然后可对所述噬菌体文库筛选抗原结合噬菌体,如记载于Winter等,Ann.Rev.Immunol.,12:433-455(1994)。噬菌体通常以单链Fv(scFv)片段或以Fab片段展示抗体片段。来自经免疫来源的文库提供针对免疫原的高亲和力抗体,而不需要构建杂交瘤。或者,可(例如自人)克隆未免疫全集以在没有任何免疫的情况中提供针对一大批非自身和还有自身抗原的抗体的单一来源,如由Griffiths等,EMBO J,12:725-734(1993)描述的。最后,也可通过自干细胞克隆未重排的V基因区段并使用含有随机序列的PCR引物编码高度可变的CDR3区并在体外实现重排来合成生成未免疫文库,如由Hoogenboom和Winter,J.Mol.Biol.,227:381-388(1992)所描述的。描述人抗体噬菌体文库的专利公开文本包括例如:美国专利No.5,750,373及美国专利公开文本No.2005/0079574、2005/0119455、2005/0266000、2007/0117126、2007/0160598、2007/0237764、2007/0292936和2009/0002360。
自人抗体文库分离的抗体或抗体片段被认为是本文中的人抗体或人抗体片段。
c.嵌合抗体和人源化抗体
在某些实施方案中,本文中提供的抗体是嵌合抗体。某些嵌合抗体记载于例如美国专利No.4,816,567;和Morrison等,Proc.Natl.Acad.Sci.USA,81:6851-6855(1984)。在一个实例中,嵌合抗体包含非人可变区(例如自小鼠、大鼠、仓鼠、家兔、或非人灵长类,例如猴衍生的可变区)和人恒定区。在又一个实例中,嵌合抗体是“类转换的”抗体,其中类或亚类已经自亲本抗体的类或亚类改变。嵌合抗体包括其抗原结合片段。
在某些实施方案中,嵌合抗体是人源化抗体。通常,将非人抗体人源化以降低对人的免疫原性同时保留亲本非人抗体的特异性和亲和力。通常,人源化抗体包含一个或多个可变域,其中HVR,例如CDR(或其部分)自非人抗体衍生,而FR(或其部分)自人抗体序列衍生。任选地,人源化抗体还会至少包含人恒定区的一部分。在一些实施方案中,将人源化抗体中的一些FR残基用来自非人抗体(例如衍生HVR残基的抗体)的相应残基替换,例如以恢复或改善抗体特异性或亲和力。
人源化抗体及其生成方法综述于例如Almagro和Fransson,Front.Biosci.13:1619-1633(2008)且进一步记载于例如Riechmann等,Nature332:323-329(1988);Queen等,Proc.Nat’l Acad.Sci.USA86:10029-10033(1989);美国专利No.5,821,337、No.7,527,791、No.6,982,321和No.7,087,409;Kashmiri等,Methods 36:25-34(2005)(记载SDR(a-CDR)嫁接);Padlan,Mol.Immunol.28:489-498(1991)(记载“重修表面”);Dall’Acqua等,Methods 36:43-60(2005)(记载“FR改组”);及Osbourn等,Methods36:61-68(2005)和Klimka等,Br.J.Cancer,83:252-260(2000)(记载FR改组的“引导选择”办法)。
可用于人源化的人框架区包括但不限于:使用“最佳拟合(best-fit)”方法选择的框架区(参见例如Sims等,J.Immunol.151:2296(1993));自轻或重链可变区的特定亚组的人抗体的共有序列衍生的框架区(参见例如Carter等,Proc.Natl.Acad.Sci.USA,89:4285(1992);和Presta等,J.Immunol.,151:2623(1993));人成熟的(体细胞突变的)框架区或人种系框架区(参见例如Almagro和Fransson,Front.Biosci.13:1619-1633(2008));和通过筛选FR文库衍生的框架区(参见例如Baca等,J.Biol.Chem.272:10678-10684(1997)和Rosok等,J.Biol.Chem.271:22611-22618(1996))。
d.多特异性抗体
在某些实施方案中,本文提供的抗体是多特异性抗体,例如双特异性抗体。本文使用的术语“多特异性抗体”是指包含具有多表位特异性(即,能够结合一个分子上的两个或更多个不同表位或能够结合两个或更多个不同的分子上的表位)的抗原结合结构域的抗体。
在一些实施方案中,多特异性抗体是对至少两种不同抗原结合位点具有结合特异性的单克隆抗体(例如双特异性抗体)。在一些实施方案中,多特异性抗体的第一抗原结合结构域和第二抗原结合结构域可结合一个且相同分子内的两个表位(分子内结合)。例如,多特异性抗体的第一抗原结合结构域和第二抗原结合结构域可结合相同蛋白质分子上的两个不同表位。在某些实施方案中,多特异性抗体结合的两个不同表位是通常不同时被一种单特异性抗体(例如一种常规抗体)或一个免疫球蛋白单可变结构域结合的表位。在一些实施方案中,多特异性抗体的第一抗原结合结构域和第二抗原结合结构域可结合位于两个不同分子内的表位(分子间结合)。例如,多特异性抗体的第一抗原结合结构域可结合一个蛋白质分子上的一个表位,而多特异性抗体的第二个抗原结合结构域可结合不同蛋白质分子上的另一个表位,从而使两个分子交联。
在一些实施方案中,多特异性抗体(例如双特异性抗体)的抗原结合结构域包含两个VH/VL单元,其中第一VH/VL单元结合第一表位且第二VH/VL单元结合第二表位,其中每个VH/VL单元包含重链可变域(VH)和轻链可变域(VL)。此类多特异性抗体包括但不限于全长抗体,具有两个或更多个VL和VH结构域的抗体,和抗体片段(例如Fab、Fv、dsFv、scFv、双抗体、双特异性双抗体和三抗体,共价或非共价连接的抗体片段)。进一步包含重链可变区的至少一部分和/或轻链可变区的至少一部分的VH/VL单元也可称为“臂(arm)”或“半聚体(hemimer)”或“半抗体(half antibody)”。在一些实施方案中,半聚体包含足够的重链可变区部分以允许与第二半聚体形成分子内二硫键。在一些实施方案中,半聚体包含杵突变(hole mutation)或臼突变(knob mutation),例如以允许与包含互补臼突变或杵突变的第二半聚体或半抗体的异二聚化。杵突变和臼突变将在下面进一步讨论。
在某些实施方案中,本文提供的多特异性抗体可以是双特异性抗体。本文使用的术语“双特异性抗体”是指包含抗原结合结构域的多特异性抗体,所述抗原结合结构域能够结合一个分子上的两个不同表位或能够结合两个不同分子上的表位。双特异性抗体在本文中也可称为具有“双重特异性”或是“双重特异性的”。示例性双特异性抗体可结合蛋白质和任何其他抗原。在某些实施方案中,结合特异性之一是针对蛋白质而另一种是针对CD3。参见例如美国专利No.5,821,337。在某些实施方案中,双特异性抗体可结合相同蛋白质分子的两个不同表位。在某些实施方案中,双特异性抗体可结合两种不同蛋白质分子上的两个不同表位。双特异性抗体也可用于将细胞毒性剂定位于表达蛋白质的细胞。双特异性抗体可制备成全长抗体或抗体片段。
制备多特异性抗体的技术包括但不限于具有不同特异性的两个免疫球蛋白重链-轻链对的重组共表达(参见Milstein和Cuello,Nature 305:537(1983),WO 93/08829,和Traunecker等,EMBO J.10:3655(1991))和“杵臼(knob-in-hole)”工程化(参见例如美国专利No.5,731,168、WO2009/089004、US2009/0182127、US2011/0287009、Marvin和Zhu,ActaPharmacol.Sin.(2005)26(6):649-658,和Kontermann(2005)Acta Pharmacol.Sin.,26:1-9)。本文使用的术语“杵臼(knob-into-hole)”或“KnH”技术是指通过在它们相互作用的界面处将突起(杵)引入一个多肽且将空腔(臼)引入另一多肽而在体外或体内将两个多肽配对在一起的技术。例如,KnH已被引入抗体的Fc:Fc结合界面、CL:CH1界面或VH/VL界面(参见例如US 2011/0287009、US2007/0178552、WO 96/027011、WO 98/050431,Zhu等,1997,Protein Science 6:781-788,和WO2012/106587)。在一些实施方案中,KnH在多特异性抗体的制备过程中驱动两条不同重链的配对。例如,在其Fc区中具有KnH的多特异性抗体可进一步包含与每个Fc区连接的单个可变域或者进一步包含与相似或不同的轻链可变域配对的不同重链可变域。KnH技术也可用于将两个不同的受体细胞外结构域配对在一起或配对包含不同靶识别序列的任何其他多肽序列(例如包括亲和体(affibody)、肽体(peptibody)和其他Fc融合体)。
本文使用的术语“杵突变”是指在多肽与另一多肽相互作用的界面处将突起(杵)引入该多肽中的突变。在一些实施方案中,另一多肽具有臼突变。
本文使用的术语“臼突变”是指在多肽与另一多肽相互作用的界面处将空腔(臼)引入该多肽中的突变。在一些实施方案中,另一多肽具有杵突变。
“突起”是指至少一个氨基酸侧链,其从第一多肽的界面突出并因此可定位在相邻界面(即第二多肽的界面)的补偿空腔中,从而稳定异多聚体,因此,例如相对于同多聚体形成而有利于异多聚体形成。突起可存在于原始界面中或可合成引入(例如通过改变编码界面的核酸)。在一些实施方案中,改变编码第一多肽的界面的核酸以编码突起。为实现此目的,编码第一多肽界面中的至少一个“原始”氨基酸残基的核酸被编码至少一个“引进”氨基酸残基的核酸替换,所述氨基酸残基具有比原始氨基酸残基更大的侧链体积。应理解可存在多于一个原始和相应的引进残基。各种氨基残基的侧链体积显示在例如US2011/0287009的表1中。引入“突起”的突变可称为“杵突变”。
在一些实施方案中,用于形成突起的引进残基是天然存在的氨基酸残基,其选自精氨酸(R)、苯丙氨酸(F)、酪氨酸(Y)和色氨酸(W)。在一些实施方案中,引进残基是色氨酸或酪氨酸。在一些实施方案中,用于形成突起的原始残基具有小的侧链体积,例如丙氨酸、天冬酰胺、天冬氨酸、甘氨酸、丝氨酸、苏氨酸或缬氨酸。
“空腔”是指至少一个氨基酸侧链,其从第二多肽的界面凹进并因此在第一多肽的相邻界面上容纳相应的突起。空腔可存在于原始界面中或可合成引入(例如通过改变编码界面的核酸)。在一些实施方案中,改变编码第二多肽的界面的核酸以编码空腔。为实现此目的,编码第二多肽界面中至少一个“原始”氨基酸残基的核酸被编码至少一个“引进”氨基酸残基的DNA替换,所述氨基酸残基具有比原始氨基酸更小的侧链体积。残留。应理解可存在多于一个原始和相应的引进残基。在一些实施方案中,用于形成空腔的引进残基是天然存在的氨基酸残基,其选自丙氨酸(A)、丝氨酸(S)、苏氨酸(T)和缬氨酸(V)。在一些实施方案中,引进残基是丝氨酸、丙氨酸或苏氨酸。在一些实施方案中,用于形成空腔的原始残基具有大的侧链体积,例如酪氨酸、精氨酸、苯丙氨酸或色氨酸。引入“空腔”的突变可称为“臼突变”。
突起在空腔中是“可定位的”,这意味着突起和空腔在第一多肽和第二多肽的界面上各自的空间位置分别及突起和孔腔的尺寸使得突起可位于空腔中而没有显著扰乱第一和第二多肽在界面处的正常关联。由于例如Tyr、Phe和Trp之类的突起通常不垂直地从界面的轴线延伸且具有优选的构象,因此在某些情况下,突起与相应的空腔的对准可依赖于基于三维结构对突起/空腔对的建模,例如通过X射线晶体学或核磁共振(NMR)获得的三维结构。这可使用本领域广泛接受的技术来实现。
在一些实施方案中,IgG1恒定区中的杵突变是T366W(EU编号方式)。在一些实施方案中,IgG1恒定区中的臼突变包含选自T366S、L368A和Y407V(EU编号方式)的一种或多种突变。在一些实施方案中,IgG1恒定区中的臼突变包含T366S、L368A和Y407V(EU编号方式)。
在一些实施方案中,IgG4恒定区中的杵突变是T366W(EU编号方式)。在一些实施方案中,IgG4恒定区中的臼突变包含选自T366S、L368A和Y407V(EU编号方式)的一种或多种突变。在一些实施方案中,IgG4恒定区中的臼突变包含T366S、L368A和Y407V(EU编号方式)。
也可通过用于生成抗体Fc-异二聚体分子的工程化静电操纵效应(WO 2009/089004 A1);交联两种或更多种抗体或片段(参见例如美国专利No.4,676,980和Brennan等,Science,229:81(1985));使用亮氨酸拉链来生成双特异性抗体(参见例如Kostelny等,J.Immunol.148(5):1547-1553(1992));使用用于生成双特异性抗体片段的“双抗体”技术(参见例如Hollinger等,Proc.Natl.Acad.Sci.USA,90:6444-6448(1993));及使用单链Fv(sFv)二聚体(参见例如Gruber等,J.Immunol.,152:5368(1994));及制备三特异性抗体(如例如Tutt等,J.Immunol.147:60(1991)中所描述的)来生成多特异性抗体。
本文中还包括具有三个或更多个功能性抗原结合位点的经工程化改造抗体,包括“章鱼抗体”或“双重可变域免疫球蛋白”(DVD)(参见例如US 2006/0025576 A1和Wu等Nature Biotechnology(2007)).)。本文中的抗体或片段还包括包含结合靶蛋白及另一种不同抗原的抗原结合位点的“双重作用FAb”或“DAF”(参见例如US 2008/0069820)。
e.抗体片段
在某些实施方案中,本文提供的抗体是抗体片段。抗体片段包括但不限于Fab、Fab’、Fab’-SH、F(ab’)2、Fv和scFv片段及下文描述的其他片段。关于某些抗体片段的综述,参见Hudson等Nat.Med.9:129-134(2003)。关于scFv片段的综述,参见例如Pluckthün,于The Pharmacology of Monoclonal Antibodies,vol.113,Rosenburg和Moore编辑,(Springer-Verlag,New York),pp.269-315(1994);还参见WO 93/16185;和美国专利No.5,571,894和No.5,587,458。对于包含补救受体结合表位残基并具有增加的体内半衰期的Fab和F(ab’)2片段的讨论,参见美国专利号No.5,869,046。
双抗体是具有两个抗原结合位点的抗体片段,所述抗原结合位点可以是二价或双特异性的。参见例如EP 404,097;WO 1993/01161;Hudson等,Nat.Med.9:129-134(2003);和Hollinger等,Proc.Natl.Acad.Sci.USA 90:6444-6448(1993)。三抗体和四抗体也描述于Hudson等,Nat.Med.9:129-134(2003)。
单域抗体是包含抗体的全部或部分重链可变域或者全部或部分轻链可变域的抗体片段。在某些实施方案中,单域抗体是人单域抗体(Domantis,Inc.,Waltham,MA;参见例如美国专利No.6,248,516B1)。
抗体片段可通过各种技术制备,包括但不限于完整抗体的蛋白水解消化及重组宿主细胞(例如大肠杆菌或噬菌体)的产生,如本文所述。
f.抗体变体
在某些实施方案中,涵盖本文中提供的抗体的氨基酸序列变体。例如,可能期望改善抗体的结合亲和力和/或其他生物学特性。可通过将适当的修饰引入编码抗体的核苷酸序列中或者通过肽合成来制备抗体的氨基酸序列变体。此类修饰包括例如对抗体的氨基酸序列内的残基的删除、和/或插入和/或取代。可进行删除、插入和取代的任何组合以得到最终的构建体,只要最终的构建体拥有期望的特征,例如抗原结合。
i.取代、插入和删除变体
在某些实施方案中,提供具有一处或多处氨基酸取代的抗体变体。取代诱变感兴趣的位点包括HVR和FR。保守取代在表1中在“优选的取代”的标题下显示。更实质的变化在表1中在“示例性取代”的标题下提供且如下文参照氨基酸侧链类别进一步描述的。可将氨基酸取代引入感兴趣的抗体中且对产物筛选期望的活性,例如保留/改善的抗原结合、降低的免疫原性、或改善的ADCC或CDC。
表1.氨基酸取代
初始残基 | 示例性取代 | 优选的取代 |
Ala(A) | Val;Leu;Ile | Val |
Arg(R) | Lys;Gln;Asn | Lys |
Asn(N) | Gln;His;Asp;Lys;Arg | Gln |
Asp(D) | Glu;Asn | Glu |
Cys(C) | Ser;Ala | Ser |
Gln(Q) | Asn;Glu | Asn |
Glu(E) | Asp;Gln | Asp |
Gly(G) | Ala | Ala |
His(H) | Asn;Gln;Lys;Arg | Arg |
Ile(I) | Leu;Val;Met;Ala;Phe;正亮氨酸 | Leu |
Leu(L) | 正亮氨酸;Ile;Val;Met;Ala;Phe | Ile |
Lys(K) | Arg;Gln;Asn | Arg |
Met(M) | Leu;Phe;Ile | Leu |
Phe(F) | Trp;Leu;Val;Ile;Ala;Tyr | Tyr |
Pro(P) | Ala | Ala |
Ser(S) | Thr | Thr |
Thr(T) | Val;Ser | Ser |
Trp(W) | Tyr;Phe | Tyr |
Tyr(Y) | Trp;Phe;Thr;Ser | Phe |
Val(V) | Ile;Leu;Met;Phe;Ala;正亮氨酸 | Leu |
按照共同的侧链特性,氨基酸可如下分组:
(1)疏水性的:正亮氨酸、Met、Ala、Val、Leu、Ile;
(2)中性、亲水性的:Cys、Ser、Thr、Asn、Gln;
(3)酸性的:Asp、Glu;
(4)碱性的:His、Lys、Arg;
(5)影响链取向的残基:Gly、Pro;
(6)芳香族的:Trp、Tyr、Phe。
非保守取代会需要用这些类别之一的成员替换另一个类别的。
一类取代变体涉及取代亲本抗体(例如人源化或人抗体)的一个或多个高变区残基。通常,为进一步研究选择的所得变体相对于亲本抗体会具有某些生物学性质的修饰(例如改善)(例如升高的亲和力、降低的免疫原性)和/或会基本上保留亲本抗体的某些生物学性质。一种示例性取代变体是亲和力成熟抗体,其可例如使用基于噬菌体展示的亲和力成熟技术例如本文中所描述的那些技术来方便地生成。简言之,将一个或多个HVR残基突变并将变体抗体在噬菌体上展示并对其筛选特定的生物学活性(例如结合亲和力)。
可在HVR中做出变化(例如取代),例如以改善抗体亲和力。可在HVR“热点”中,即由在体细胞成熟过程期间以高频率经历突变的密码子编码的残基(参见例如Chowdhury,Methods Mol.Biol.207:179-196(2008)),和/或SDR(a-CDR)做出此类变化,对所得变体VH或VL测试结合亲和力。通过次级文库的构建和再选择进行的亲和力成熟已经记载于例如Hoogenboom等,于Methods in Molecular Biology 178:1-37(O’Brien等编辑,HumanPress,Totowa,NJ,(2001))。在亲和力成熟的一些实施方案中,通过多种方法(例如易错PCR、链改组、或寡核苷酸指导的诱变)中的任一种将多样性引入为成熟选择的可变基因。然后创建次级文库。然后筛选文库以鉴定具有期望亲和力的任何抗体变体。另一种引入多样性的方法涉及HVR定向方法,其中将数个HVR残基(例如一次4-6个残基)随机化。可例如使用丙氨酸扫描诱变或建模来特异性鉴定涉及抗原结合的HVR残基。具体地,经常靶向CDR-H3和CDR-L3。
在某些实施方案中,可在一个或多个HVR内发生取代、插入或删除,只要此类变化不实质性降低抗体结合抗原的能力。例如,可在HVR中做出保守变化(例如保守取代,如本文中提供的),其没有实质性降低结合亲和力。此类变化可在HVR“热点”或SDR以外。在上文提供的变体VH和VL序列的某些实施方案中,每个HVR或是未改变的或是含有不多于1、2或3处氨基酸取代。
一种可用于鉴定抗体中可作为诱变靶位的残基或区域的方法称作“丙氨酸扫描诱变”,如记载于Cunningham和Wells(1989)Science,244:1081-1085。在这种方法中,鉴定一个残基或一组靶残基(例如带电荷的残基例如arg、asp、his、lys和glu)并用中性或带负电荷的氨基酸(例如丙氨酸或多聚丙氨酸)替换以确定抗体与抗原的相互作用是否受到影响。可在对初始取代表明功能敏感性的氨基酸位置引入进一步的取代。或者/另外,使用抗原-抗体复合物的晶体结构来鉴定抗体与抗原之间的接触点。作为取代的候选,可靶向或消除此类接触残基和邻近残基。可筛选变体以确定它们是否含有期望性质。
氨基酸序列插入包括长度范围是1个残基至含有100或更多个残基的多肽的氨基和/或羧基末端融合及单个或多个氨基酸残基的序列内插入。末端插入的实例包括具有N末端甲硫氨酰基残基的抗体。抗体分子的其他插入变体包括抗体的N或C末端与酶(例如对于ADEPT)或增加抗体的血清半衰期的多肽的融合物。
ii.经半胱氨酸工程化的抗体变体
在某些实施方案中,可能期望创建经半胱氨酸工程化的抗体,例如“THIOMABTM抗体”,其中抗体的一个或多个残基用半胱氨酸残基取代。在特定实施方案中,取代的残基存在于抗体的可接近位点。通过用半胱氨酸取代那些残基,反应性硫醇基团由此定位于抗体的可接近位点且可用于将抗体缀合至其他部分,例如药物或接头L1-药物中间体,以创建ADC,如本文中进一步描述的。在某些实施方案中,可用半胱氨酸取代以下残基中的任意一个或多个:轻链的V205(Kabat编号方式);重链的A140(EU编号方式);重链的L174(EU编号方式);重链的Y373(EU编号方式);轻链的K149(Kabat编号方式);重链的A118(EU编号方式);和重链Fc区的S400(EU编号方式)。在具体的实施方案中,本文描述的抗体包含HC-A140C(EU编号方式)半胱氨酸取代。在具体的实施方案中,本文描述的抗体包含LC-K149C(Kabat编号方式)半胱氨酸取代。在具体的实施方案中,本文描述的抗体包含HC-A118C(EU编号方式)半胱氨酸取代。
可如例如美国专利No.7,521,541中所述产生经半胱氨酸工程化的抗体。
在某些实施方案中,抗体包含以下重链半胱氨酸取代之一:
表2.HC半胱氨酸取代
链(HC/LC) | 残基 | EU突变位点# | Kabat突变位点# |
HC | T | 114 | 110 |
HC | A | 140 | 136 |
HC | L | 174 | 170 |
HC | L | 179 | 175 |
HC | T | 187 | 183 |
HC | T | 209 | 205 |
HC | V | 262 | 258 |
HC | G | 371 | 367 |
HC | Y | 373 | 369 |
HC | E | 382 | 378 |
HC | S | 424 | 420 |
HC | N | 434 | 430 |
HC | Q | 438 | 434 |
在某些实施方案中,抗体包含以下轻链半胱氨酸取代之一:
表3.LC半胱氨酸取代
链(HC/LC) | 残基 | EU突变位点# | Kabat突变位点# |
LC | I | 106 | 106 |
LC | R | 108 | 108 |
LC | R | 142 | 142 |
LC | K | 149 | 149 |
LC | V | 205 | 205 |
非限制性示例性hu7C2.v2.2.LA轻链(LC)K149C THIOMABTM抗体分别具有SEQ IDNO:26和30的重链和轻链氨基酸序列。非限制性示例性hu7C2.v2.2.LA重链(HC)A118CTHIOMABTM抗体分别具有SEQ ID NO:31和25的重链和轻链氨基酸序列。
ADC包括经半胱氨酸工程化的抗体,其中野生型或亲代抗体中的一个或多个氨基酸被半胱氨酸替换。由此可工程化改造(即,使其突变)任何形式的抗体。例如,可将亲代Fab抗体片段工程化改造,以形成经半胱氨酸工程化改造的Fab,在本文中称作“ThioFab”。类似地,可将亲代单克隆抗体工程化改造,以形成“ThioMab”。应当注意的是,单一位点突变在ThioFab中产生单一经工程化改造的半胱氨酸残基,而单一位点突变在ThioMab中产生两个经工程化改造的半胱氨酸残基,这是因IgG抗体的二聚化特性所致。评价被半胱氨酸(Cys)残基替换的(“经工程化改造的”)突变体的新引入的经工程化改造的半胱氨酸硫醇反应性。硫醇反应值是0至1.0范围内的相对数值范围且可对任意经半胱氨酸工程化的抗体进行测量。ADC中使用的经半胱氨酸工程化的抗体的硫醇反应值的范围是0.6至1.0;0.7至1.0;或0.8至1.0。
为了通过诱变制备经半胱氨酸工程化的抗体,通过本领域已知的多种方法制备编码起始多肽的氨基酸序列变体的DNA。这些方法包括但不限于通过定点(或寡核苷酸介导的)诱变、PCR诱变和较早制备的编码多肽的DNA的盒式诱变制备。也可通过限制性片段操作或通过与合成的寡核苷酸的重叠延伸PCR来构建重组抗体的变体。诱变引物编码半胱氨酸密码子替换。可使用标准诱变技术来产生编码此类突变体经半胱氨酸工程化的抗体的DNA。一般指导可参见Sambrook等,Molecular Cloning,A Laboratory Manual,Cold SpringHarbor Laboratory Press,Cold Spring Harbor,N.Y.,1989;和Ausubel等,CurrentProtocols in Molecular Biology,Greene Publishing andWiley-Interscience,NewYork,N.Y.,1993。
半胱氨酸氨基酸可在抗体的反应位点进行工程化改造且不形成链内或分子间二硫键(Junutula等,2008b Nature Biotech.,26(8):925-932;Dornan等(2009)Blood 114(13):2721-2729;US 7521541;US 7723485;WO2009/052249,Shen等(2012)NatureBiotech.,30(2):184-191;Junutula等(2008)Jour of Immun.Methods 332:41-52)。经工程化改造的半胱氨酸硫醇可与具有硫醇反应性的接头试剂或本文所述的接头-药物中间体、亲电基团例如马来酰亚胺或α-卤代酰胺反应,以形成具有经半胱氨酸工程化的抗体(ThioMab)和药物残基的ADC。药物部分的位置由此可以是设计好的、受控的和已知的。由于经工程化改造的半胱氨酸硫醇基团通常以高产率与硫醇反应性接头试剂或接头-药物中间体反应,所以药物/抗体比率(“PAR”)是可以控制的。在重链或轻链上单个位点通过取代引入半胱氨酸氨基酸对抗体进行工程化改造给出了对称抗体上的两个新的半胱氨酸。可实现接近2的PAR和接近同质化的缀合产品。
经半胱氨酸工程化的抗体优选保持其野生型亲代抗体对应物的抗原结合能力。因此,经半胱氨酸工程化的抗体能够结合抗原,优选特异性结合抗原。此类抗原包括例如肿瘤相关抗原(TAA)、细胞表面受体蛋白和其他细胞表面分子、跨膜蛋白、信号传导蛋白、细胞存活调节因子、细胞增殖调节因子、与组织发育或分化相关(例如已知或怀疑在功能上相关)的分子、淋巴因子、细胞因子、涉及细胞周期调节的分子、涉及血管发生的分子和与血管发生相关(例如已知或怀疑在功能上相关)的分子。肿瘤相关抗原可以是分化簇因子(即CD蛋白)。能够结合经半胱氨酸工程化的抗体的抗原可以是上述类型之一的亚组中的成员,其中所述类型中另一亚组包含具有不同特性的其他分子/抗原(就感兴趣的抗原而言)。
通过链内二硫化物基团的还原和再氧化与接头或接头-药物中间体缀合制备经半胱氨酸工程化的抗体。
iii.糖基化变体
在某些实施方案中,改变本文中提供的抗体以提高或降低抗体糖基化的程度。可通过改变氨基酸序列,使得创建或消除一个或多个糖基化位点来方便地实现对抗体添加或删除糖基化位点。
在抗体包含Fc区的情况中,可改变附接于Fc区的碳水化合物。由哺乳动物细胞生成的天然抗体通常包含分支的、双触角寡糖,其一般通过N连接附接于Fc区的CH2域的Asn297。参见例如Wright等,TIBTECH15:26-32(1997)。寡糖可包括各种碳水化合物,例如甘露糖、N-乙酰葡糖胺(GlcNAc)、半乳糖和唾液酸及附接于双触角寡糖结构“主干”中的GlcNAc的岩藻糖。在一些实施方案中,可对抗体中的寡糖进行修饰以创建具有某些改良性质的抗体变体。
在一个实施方案中,提供抗体变体,其具有缺乏附接(直接或间接)于Fc区的岩藻糖的碳水化合物结构。例如,此类抗体中的岩藻糖的量可以是1%至80%、1%至65%、5%至65%或20%至40%。通过相对于附接于Asn297的所有糖结构(例如复合的、杂合的和高甘露糖的结构)的总和,计算Asn297处糖链内岩藻糖的平均量来确定岩藻糖的量,如通过MALDI-TOF质谱所测量的,例如如WO 2008/077546中所描述。Asn297是指位于Fc区中的约第297位(Fc区残基的Eu编号方式)的天冬酰胺残基;然而,Asn297也可由于抗体中的微小序列变异而位于第297位上游或下游约±3个氨基酸,即在第294位和第300位之间。此类岩藻糖基化变体可具有改善的ADCC功能。参见例如美国专利公开文本No.US 2003/0157108(Presta,L.);US 2004/0093621(Kyowa Hakko Kogyo Co.,Ltd)。涉及“脱岩藻糖基化的”或“岩藻糖缺乏的”抗体变体的公开文本/出版物的实例包括:US 2003/0157108;WO 2000/61739;WO2001/29246;US 2003/0115614;US 2002/0164328;US 2004/0093621;US 2004/0132140;US2004/0110704;US 2004/0110282;US 2004/0109865;WO 2003/085119;WO 2003/084570;WO2005/035586;WO 2005/035778;WO 2005/053742;WO 2002/031140;Okazaki等,J.Mol.Biol.336:1239-1249(2004);Yamane-Ohnuki等,Biotech.Bioeng.87:614(2004)。能够生成脱岩藻糖基化抗体的细胞系的实例包括蛋白质岩藻糖基化缺陷的Lec13 CHO细胞(Ripka等,Arch.Biochem.Biophys.249:533-545(1986);美国专利申请No US 2003/0157108A1,Presta,L;和WO 2004/056312A1,Adams等,尤其在实施例11),和敲除细胞系,例如α-1,6-岩藻糖基转移酶基因FUT8敲除CHO细胞(参见例如Yamane-Ohnuki等,Biotech.Bioeng.87:614(2004);Kanda,Y.等,Biotechnol.Bioeng.,94(4):680-688(2006);和WO 2003/085107)。
进一步提供具有两分型寡糖的抗体变体,例如其中附接于抗体Fc区的双触角寡糖是通过GlcNAc两分的。此类抗体变体可具有降低的岩藻糖基化和/或改善的ADCC功能。此类抗体变体的实例记载于例如WO 2003/011878(Jean-Mairet等);美国专利No.6,602,684(Umana等);和US 2005/0123546(Umana等)。还提供在附接于Fc区的寡糖中具有至少一个半乳糖残基的抗体变体。此类抗体变体可具有改善的CDC功能。此类抗体变体记载于例如WO1997/30087(Patel等);WO 1998/58964(Raju,S.);和WO 1999/22764(Raju,S.)。
iv.Fc区变体
在某些实施方案中,可将一处或多处氨基酸修饰引入本文中提供的抗体的Fc区中,由此生成Fc区变体。Fc区变体可包含在一个或多个氨基酸位置包含氨基酸修饰(例如取代)的人Fc区序列(例如人IgG1、IgG2、IgG3或IgG4Fc区)。
在某些实施方案中,本文所述的主题涉及拥有一些但不是所有效应器功能的抗体变体,所述效应器功能使其成为如下应用的期望候选物,其中抗体的体内半衰期是重要的,而某些效应器功能(例如补体和ADCC)是不必要的或有害的。可进行体外和/或体内细胞毒性测定法以确认CDC和/或ADCC活性的降低/消减。例如,可进行Fc受体(FcR)结合测定法以确保抗体缺乏FcγR结合(因此有可能缺乏ADCC活性),但是保留FcRn结合能力。介导ADCC的主要细胞NK细胞仅表达FcγRIII,而单核细胞表达FcγRI、FcγRII和FcγRIII。在Ravetch和Kinet,Annu.Rev.Immunol.9:457-492(1991)的第464页上的表3中汇总了造血细胞上的FcR表达。评估感兴趣分子的ADCC活性的体外测定法的非限制性实例记载于美国专利No.5,500,362(参见例如Hellstrom,I.等,Proc.Nat’l Acad.Sci.USA 83:7059-7063(1986))和Hellstrom,I等,Proc.Nat’l Acad.Sci.USA 82:1499-1502(1985);5,821,337(参见Bruggemann,M.等,J.Exp.Med.166:1351-1361(1987))。或者,可采用非放射性测定方法(参见例如用于流式细胞术的ACTITM非放射性细胞毒性测定法(CellTechnology,Inc.MountainView,CA;和CytoTox非放射性细胞毒性测定法(Promega,Madison,WI))。对于此类测定法有用的效应器细胞包括外周血单个核细胞(PBMC)和天然杀伤(NK)细胞。或者/另外,可在体内评估感兴趣分子的ADCC活性,例如在动物模型中,例如Clynes等,Proc.Nat’lAcad.Sci.USA 95:652-656(1998)中披露的内容。也可实施C1q结合测定法以确认抗体不能结合C1q且因此缺乏CDC活性。参见例如WO 2006/029879和WO 2005/100402中的C1q和C3c结合ELISA。为了评估补体激活,可实施CDC测定法(参见例如Gazzano-Santoro等,J.Immunol.Methods 202:163(1996);Cragg,M.S.等,Blood 101:1045-1052(2003);及Cragg,M.S.和M.J.Glennie,Blood 103:2738-2743(2004))。也可使用本领域中已知的方法来实施FcRn结合和体内清除/半衰期测定(参见例如Petkova,S.B.等,Int’l.Immunol.18(12):1759-1769(2006))。
在一些实施方案中,可将一个或多个氨基酸修饰引入本文提供的抗体的Fc部分中,以增加IgG与新生儿Fc受体的结合。在某些实施方案中,按照EU编号方式,抗体包含以下三个突变:M252Y、S254T和T256E(“YTE突变”)(美国专利No.8,697,650;还参见Dall’Acqua等,Journal of Biological Chemistry 281(33):23514-23524(2006))。在某些实施方案中,YTE突变不影响抗体结合其同源抗原的能力。在某些实施方案中,与天然(即非YTE突变体)抗体相比,YTE突变增加抗体的血清半衰期。在一些实施方案中,与天然(即非YTE突变体)抗体相比,YTE突变使抗体的血清半衰期增加3倍。在一些实施方案中,与天然(即非YTE突变体)抗体相比,YTE突变使抗体的血清半衰期增加2倍。在一些实施方案中,YTE突变使抗体的血清半衰期增加4倍。在一些实施方案中,与天然(即非YTE突变体)抗体相比,YTE突变使抗体的血清半衰期增加至少5倍。在一些实施方案中,与天然(即非YTE突变体)抗体相比,YTE突变使抗体的血清半衰期增加至少10倍。参见例如美国专利No.8,697,650;还参见Dall’Acqua等,Journal of Biological Chemistry 281(33):23514-23524(2006)。
在某些实施方案中,YTE突变体提供调节抗体的抗体依赖性细胞介导的细胞毒性(ADCC)活性的手段。在某些实施方案中,YTEO突变体提供调节针对人抗原的人源化IgG抗体的ADCC活性的手段。参见例如美国专利No.8,697,650;还参见Dall’Acqua等,Journal ofBiological Chemistry281(33):23514-23524(2006)。
在某些实施方案中,YTE突变体允许同时调节血清半衰期、组织分布和抗体活性(例如IgG抗体的ADCC活性)。参见例如美国专利No.8,697,650;还参见Dall’Acqua等,Journal of Biological Chemistry281(33):23514-23524(2006)。
具有降低的效应器功能的抗体包括具有一个或多个Fc区残基238、265、269、270、297、327和329(按照EU编号方式)的取代的抗体(美国专利No.6,737,056)。此类Fc突变体包括在两个或更多个氨基酸位置265、269、270、297和327(按照EU编号方式)处具有取代的Fc突变体,包括所谓的“DANA”Fc突变体,其具有残基265和297(按照EU编号方式)处取代为丙氨酸(即按照EU编号方式的D265A和N297A)(美国专利No.7,332,581)。在某些实施方案中,Fc突变体包含以下两个氨基酸取代:D265A和N297A。在某些实施方案中,Fc突变体由以下两个氨基酸取代构成:D265A和N297A。
在某些实施方案中,野生型人Fc区的第329位(EU编号方式)(P329)的脯氨酸被甘氨酸或精氨酸或足以破坏Fc/Fcγ受体界面内的脯氨酸三明治结构(sandwich)的氨基酸残基取代,所述界面在Fc的P329与FcgRIII的色氨酸残基W87和W110之间形成(Sondermann等:Nature 406,267-273(20July2000))。在进一步的实施方案中,Fc变体中的至少一个另外的氨基酸取代是S228P、E233P、L234A、L235A、L235E、N297A、N297D或P331S且在另一个实施方案中,所述至少一个另外的氨基酸取代是人IgG1Fc区的L234A和L235A或人IgG4Fc区的S228P和L235E(全部按照EU编号方式)(美国专利No.8,969,526,其全部内容通过引用并入)。
在某些实施方案中,多肽包含野生型人IgG Fc区的Fc变体,其中所述多肽具有被甘氨酸取代的人IgG Fc区的P329且其中所述Fc变体在人IgG1Fc区的L234A和L235A或人IgG4Fc区的S228P和L235E处包含至少两个另外的氨基酸取代且其中残基按照EU编号方式编号(美国专利No.8,969,526,其全部内容通过引用并入)。在某些实施方案中,包含P329G、L234A和L235A(EU编号方式)取代的多肽对人FcγRIIIA和FcγRIIA表现出降低的亲和力,用于下调ADCC至由包含野生型人IgG Fc区的多肽诱导的ADCC的至少20%,和/或下调ADCP(美国专利No.8,969,526,其全部内容通过引用并入)。
在一个具体实施方案中,包含野生型人Fc多肽的Fc变体的多肽包含三重突变:在Pro329、L234A和L235A突变位置的氨基酸取代(按照EU编号方式)(P329/LALA)(美国专利No.8,969,526,其全部内容通过引用并入)。在具体的实施方案中,多肽包含以下氨基酸取代:P329G、L234A和L235A(按照EU编号方式)。
描述了具有改善的或降低的对FcR的结合的某些抗体变体(参见例如美国专利No.6,737,056;WO 2004/056312;和Shields等,J.Biol.Chem.9(2):6591-6604(2001))。
在某些实施方案中,抗体变体包含具有改善ADCC的一处或多处氨基酸取代,例如Fc区的位置298、333和/或334(EU编号方式)处的取代区。
在一些实施方案中,在Fc区中做出改变,其导致改变的(即改善的或降低的)C1q结合和/或补体依赖性细胞毒性(CDC),例如如美国专利No.6,194,551;WO 99/51642;和Idusogie等,J.Immunol.164:4178-4184(2000)中所述。
具有延长的半衰期和改善的对新生儿Fc受体(FcRn)的结合的抗体记载于US2005/0014934 A1(Hinton等),新生儿Fc受体(FcRn)负责将母体IgG转移至胎儿(Guyer等,J.Immunol.117:587(1976)和Kim等,J.Immunol.24:249(1994))。那些抗体包含其中具有改善Fc区对FcRn的结合的一处或多处取代的Fc区。此类Fc变体包括那些(按照EU编号方式)在Fc区残基238、256、265、272、286、303、305、307、311、312、317、340、356、360、362、376、378、380、382、413、424或434中的一处或多处具有取代,例如Fc区残基434的取代(美国专利No.7,371,826)。还可参见Duncan&Winter,Nature 322:738-40(1988);美国专利No.5,648,260;美国专利No.5,624,821;和WO 94/29351,其涉及Fc区变体的其他实例。
g.抗体衍生物
在某些实施方案中,可进一步修饰本文中提供的抗体以含有本领域已知的且易于获得的另外的非蛋白质性质部分。适合于抗体衍生化的部分包括但不限于水溶性聚合物。水溶性聚合物的非限制性实例包括但不限于聚乙二醇(PEG)、乙二醇/丙二醇共聚物、羧甲基纤维素、葡聚糖、聚乙烯醇、聚乙烯吡咯烷酮、聚-1,3-二氧戊环、聚-1,3,6-三噁烷、乙烯/马来酸酐共聚物、聚氨基酸(均聚物或随机共聚物)、和葡聚糖或聚(n-乙烯吡咯烷酮)聚乙二醇、丙二醇均聚物、聚环氧丙烷/环氧乙烷共聚物、聚氧乙基化多元醇(例如甘油)、聚乙烯醇及它们的混合物。由于其在水中的稳定性,聚乙二醇丙醛在生产中可能具有优势。聚合物可以是任何分子量,而且可以是分支的或不分支的。附接至抗体的聚合物的数目可以变化,而且如果附接多于一个聚合物,那么它们可以是相同或不同的分子。通常,可根据下述考虑来确定用于衍生化的聚合物的数目和/或类型,包括但不限于抗体要改进的具体性质或功能、抗体衍生物是否会用于指定条件下的疗法等。
在另一个实施方案中,提供抗体和可通过暴露于辐射而选择性加热的非蛋白质性质部分的缀合物。在一个实施方案中,非蛋白质性质部分是碳纳米管(Kam等,Proc.Natl.Acad.Sci.USA 102:11600-11605(2005))。辐射可以是任何波长的,而且包括但不限于对普通细胞没有损害,但是将非蛋白质性质部分加热至抗体-非蛋白质性质部分附近的细胞被杀死的温度的波长。
h.肿瘤相关抗原
抗体,包括但不限于经半胱氨酸工程化的抗体,其可用于治疗癌症的本文所述的ADC中,包括但不限于针对细胞表面受体和肿瘤相关抗原(TAA)的抗体。某些肿瘤相关抗原是本领域已知的且可使用本领域公知的方法和信息制备用于产生抗体。为了发现用于癌症诊断和治疗的有效细胞靶标,研究人员已经寻求鉴定与一种或多种正常非癌细胞相比在一种或多种特定类型的癌细胞表面上特异性表达的跨膜或其他肿瘤相关多肽。通常,与非癌细胞表面上相比,此类肿瘤相关多肽在癌细胞表面上更丰富地表达。此类肿瘤相关细胞表面抗原多肽的鉴定已经产生了经由基于抗体的疗法更特异性靶向癌细胞以进行破坏的能力。
肿瘤相关抗原TAA的实例包括但不限于下面列出的那些。为方便起见,下面列出了与这些抗原相关的信息,所有这些都是本领域已知的且遵循美国国立生物技术信息中心(National Center for Biotechnology Information,NCBI)的核酸和蛋白质序列鉴定惯例,包括名称、替代名称、Genbank登录号和主要参考文献。对应于下面列出的TAA的核酸和蛋白质序列可在公共数据库例如GenBank中获得。由抗体靶向的肿瘤相关抗原包括相对于引用的参考文献中鉴定的序列具有至少约70%、80%、85%、90%或95%序列同一性的所有氨基酸序列变体和同种型,和/或表现出与具有所引用得参考文献中发现的序列的TAA基本相同的生物学性质或特征。例如,具有变体序列的TAA通常能够以所列的相应序列特异性结合与所述TAA特异性结合的抗体。本文具体引用的参考文献中的序列和公开内容明确地通过引用并入。
i.重组方法和组合物
可使用重组方法和组合物生产抗体,例如如美国专利No.4,816,567中所述。在一个实施方案中,提供编码本文所述抗体的分离的核酸。所述核酸可编码包含抗体的VL的氨基酸序列和/或包含抗体的VH的氨基酸序列(例如抗体的轻链和/或重链)。在进一步的实施方案,提供包含此类核酸的一种或多种载体(例如表达载体)。在进一步的实施方案中,提供包含此类核酸的宿主细胞。在一个此类实施方案中,宿主细胞包含(例如已经用其改造):(1)包含核酸的载体,所述核酸编码包含抗体的VL的氨基酸序列和包含抗体的VH的氨基酸序列或(2)包含核酸的第一载体,所述核酸编码包含抗体的VL的氨基酸序列及包含核酸的第二载体,所述核酸编码包含抗体的VH的氨基酸序列。在一个实施方案中,宿主细胞是真核细胞例如中华仓鼠卵巢(CHO)细胞或淋巴样细胞(例如Y0、NS0、Sp20细胞)。在一个实施方案中,提供制备抗体的方法,其中所述方法包括在适于抗体表达的条件下培养上文提供的包含编码抗体的核酸的宿主细胞及任选地从该宿主细胞(或宿主细胞培养基)回收抗体。
对于抗体的重组生产,将编码抗体的核酸,例如如上文所述,分离并插入用于在宿主细胞中进一步克隆和/或表达的一种或多种载体中。此类核酸可容易地分离并使用常规操作测序(例如通过使用能够特异性结合编码抗体的重链和轻链基因的寡核苷酸探针)。用于克隆或表达编码抗体的载体的合适的宿主细胞包括本文所述的原核细胞或真核细胞。例如,可在细菌中产生抗体,特别是当不需要糖基化和Fc效应器功能时。对于细菌中抗体片段和多肽的表达,参见例如美国专利No.5,648,237、5,789,199和5,840,523(还参见Charlton,Methods in Molecular Biology,Vol.248(B.K.C.Lo编辑,Humana Press,Totowa,NJ,2003),pp.245-254,描述了大肠杆菌中抗体片段的表达)。在表达之后,可将抗体以可溶性级分形式从细菌细胞糊中分离并可进一步纯化。
除了原核生物,真核微生物例如丝状真菌或酵母也是抗体编码载体的合适克隆或表达宿主,包括真菌和酵母菌株,其糖基化途径已经被“人源化”,从而生产具有部分或完全人糖基化模式的抗体。参见Gerngross,Nat.Biotech.22:1409-1414(2004),和Li等,Nat.Biotech.24:210-215(2006)。
对于糖基化抗体的表达的合适的宿主细胞也可来源于多细胞生物体(无脊椎动物和脊椎动物)。无脊椎动物细胞的实例包括植物和昆虫细胞。已鉴定了许多可与昆虫细胞一起使用杆状病毒株,特别是用于草地夜蛾(Spodoptera frugiperda)细胞转染。
植物细胞培养物也可用作宿主。参加例如美国专利No.5,959,177、6,040,498、6,420,548、7,125,978和6,417,429(描述用于在转基因植物中删除抗体的PLANTIBODIESTM技术)。
脊椎动物细胞也可用作宿主。例如,适于在悬浮液中生长的哺乳动物细胞系可能是有用的。其他有用的哺乳动物宿主细胞系的实例是用SV40(COS-7)转化的猴肾CV1系;人胚肾系(如例如Graham等,J.Gen Virol.36:59(1977)中所述的293或293细胞);幼仓鼠肾细胞(BHK);鼠支持细胞(如例如Mather,Biol.Reprod.23:243-251(1980)中所述的TM4细胞);猴肾细胞(CV1);非洲绿猴肾细胞(VERO-76);人宫颈癌细胞(HELA);犬肾细胞(MDCK);Buffalo大鼠肝细胞(BRL 3A);人肺细胞(W138);人肝细胞(Hep G2);小鼠乳房肿瘤(MMT060562);TRI细胞,如例如Mather等,Annals N.Y.Acad.Sci.383:44-68(1982)中所述;MRC5细胞;和FS4细胞。其他有用的哺乳动物宿主细胞系包括中华仓鼠卵巢(CHO)细胞,包括DHFR-CHO细胞(Urlaub等,Proc.Natl.Acad.Sci.USA 77:4216(1980));和骨髓瘤细胞系例如Y0、NS0和Sp2/0。对于某些适于抗体生产的哺乳动物宿主细胞系,参见例如Yazaki和Wu,Methods in Molecular Biology,Vol.248(B.K.C.Lo编辑,Humana Press,Totowa,NJ),pp.255-268(2003)。
现在参考抗体亲和力,在实施方案中,所述抗体结合一种或多种选自(1)-(53)的肿瘤相关抗原或细胞表面受体:
(1)BMPR1B(骨形态发生受体-IB型,Genbank登记号NM_001203)
ten Dijke,P.等Science 264(5155):101-104(1994),Oncogene14(11):1377-1382(1997));WO2004063362(权利要求2);WO2003042661(权利要求12);US2003134790-A1(第38-39页);WO2002102235(权利要求13;第296页);WO2003055443(第91-92页);WO200299122(实施例2;第528-530页);WO2003029421(权利要求6);WO2003024392(权利要求2;图112);WO200298358(权利要求1;第183页);WO200254940(第100-101页);WO200259377(第349-350页);WO200230268(权利要求27;第376页);WO200148204(实施例;图4);
NP_001194骨形态发生蛋白受体,IB型/pid=NP_001194.1
交叉引用:MIM:603248;NP_001194.1;AY065994
(2)E16(LAT1,SLC7A5,Genbank登记号NM_003486)
Biochem.Biophys.Res.Commun.255(2),283-288(1999),Nature395(6699):288-291(1998),Gaugitsch,H.W.等(1992)J.Biol.Chem.267(16):11267-11273);WO2004048938(实施例2);WO2004032842(实施例IV);WO2003042661(权利要求12);WO2003016475(权利要求1);WO200278524(实施例2);WO200299074(权利要求19;第127-129页);WO200286443(权利要求27;第222、393页);WO2003003906(权利要求10;第293页);WO200264798(权利要求33;第93-95页);WO200014228(权利要求5;第133-136页);US2003224454(图3);WO2003025138(权利要求12;第150页);
NP_003477溶质载体家族7(阳离子氨基酸转运蛋白,y+系统),成员5/pid=NP_003477.3-智人
交叉引用:MIM:600182;NP_003477.3;NM_015923;NM_003486_1
(3)STEAP1(前列腺六跨膜上皮抗原,Genbank登记号NM_012449)
Cancer Res.61(15),5857-5860(2001),Hubert,R.S.等(1999)Proc.Natl.Acad.Sci.U.S.A.96(25):14523-14528);WO2004065577(权利要求6);WO2004027049(图1L);EP1394274(实施例11);WO2004016225(权利要求2);WO2003042661(权利要求12);US2003157089(实施例5);US2003185830(实施例5);US2003064397(图2);WO200289747(实施例5;第618-619页);WO2003022995(实施例9;图13A,实施例53;第173页,实施例2;图2A);
NP_036581前列腺六跨膜上皮抗原
交叉引用:MIM:604415;NP_036581.1;NM_012449_1
(4)0772P(CA125,MUC16,Genbank登记号AF361486)
J.Biol.Chem.276(29):27371-27375(2001));WO2004045553(权利要求14);WO200292836(权利要求6;图12);WO200283866(权利要求15;第116-121页);US2003124140(实施例16);US 798959。交叉引用:GI:34501467;AAK74120.3;AF361486_1
(5)MPF(MPF,MSLN,SMR,巨核细胞强化因子,间皮素,Genbank登记号NM_005823)Yamaguchi,N.等Biol.Chem.269(2),805-808(1994),Proc.Natl.Acad.Sci.U.S.A.96(20):11531-11536(1999),Proc.Natl.Acad.Sci.U.S.A.93(1):136-140(1996),J.Biol.Chem.270(37):21984-21990(1995));WO2003101283(权利要求14);(WO2002102235(权利要求13;第287-288页);WO2002101075(权利要求4;第308-309页);WO200271928(第320-321页);WO9410312(第52-57页);交叉引用:MIM:601051;NP_005814.2;NM_005823_1
(6)Napi2b(Napi3b,NAPI-3B,NPTIIb,SLC34A2,溶质载体家族34(磷酸钠),成员2,II型钠依赖性磷酸转运蛋白3b,Genbank登记号NM_006424)
J.Biol.Chem.277(22):19665-19672(2002);Genomics 62(2):281-284(1999);Feild,J.A.等(1999)Biochem.Biophys.Res.Commun.258(3):578-582);WO2004022778(权利要求2);EP1394274(实施例11);WO2002102235(权利要求13;第326页);EP875569(权利要求1;第17-19页);WO200157188(权利要求20;第329页);WO2004032842(实施例IV);WO200175177(权利要求24;第139-140页);
交叉引用:MIM:604217;NP_006415.1;NM_006424_1
(7)Sema 5b(FLJ10372,KIAA1445,Mm.42015,SEMA5B,SEMAG,脑信号蛋白(semaphorin)5b Hlog,sema结构域,七血小板反应蛋白重复(seven thrombospondinrepeats)(1型和类1型),跨膜结构域(TM)和短胞质域,(脑信号蛋白)5B,Genbank登记号AB040878)
Nagase T.等(2000)DNA Res.7(2):143-150);WO2004000997(权利要求1);WO2003003984(权利要求1);WO200206339(权利要求1;第50页);WO200188133(权利要求1;第41-43,48-58页);WO2003054152(权利要求20);WO2003101400(权利要求11);登记号:Q9P283;EMBL;AB040878;BAA95969.1.Genew;HGNC:10737;
(8)PSCA hlg(2700050C12Rik,C530008O16Rik,RIKEN cDNA2700050C12,RIKENcDNA 2700050C12基因,Genbank登记号AY358628);Ross等(2002)Cancer Res.62:2546-2553;US2003129192(权利要求2);US2004044180(权利要求12);US2004044179(权利要求11);US2003096961(权利要求11);US2003232056(实施例5);WO2003105758(权利要求12);US2003206918(实施例5);EP1347046(权利要求1);WO2003025148(权利要求20);
交叉引用:GI:37182378;AAQ88991.1;AY358628_1
(9)ETBR(内皮缩血管肽B型受体,Genbank登记号AY275463);
Nakamuta M.等Biochem.Biophys.Res.Commun.177,34-39,1991;Ogawa Y.等Biochem.Biophys.Res.Commun.178,248-255,1991;Arai H.等Jpn.Circ.J.56,1303-1307,1992;Arai H.等J.Biol.Chem.268,3463-3470,1993;Sakamoto A.,Yanagisawa M.等Biochem.Biophys.Res.Commun.178,656-663,1991;Elshourbagy N.A.等J.Biol.Chem.268,3873-3879,1993;Haendler B.等J.Cardiovasc.Pharmacol.20,s1-S4,1992;Tsutsumi M.等Gene 228,43-49,1999;Strausberg R.L.等Proc.Natl.Acad.Sci.U.S.A.99,16899-16903,2002;Bourgeois C.等J.Clin.Endocrinol.Metab.82,3116-3123,1997;Okamoto Y.等Biol.Chem.272,21589-21596,1997;Verheij J.B.等Am.J.Med.Genet.108,223-225,2002;Hofstra R.M.W.等Eur.J.Hum.Genet.5,180-185,1997;Puffenberger E.G.等Cell 79,1257-1266,1994;Attie T.等,Hum.Mol.Genet.4,2407-2409,1995;Auricchio A.等Hum.Mol.Genet.5:351-354,1996;Amiel J.等Hum.Mol.Genet.5,355-357,1996;Hofstra R.M.W.等Nat.Genet.12,445-447,1996;Svensson P.J.等Hum.Genet.103,145-148,1998;Fuchs S.等Mol.Med.7,115-124,2001;Pingault V.等(2002)Hum.Genet.111,198-206;WO2004045516(权利要求1);WO2004048938(实施例2);WO2004040000(权利要求151);WO2003087768(权利要求1);WO2003016475(权利要求1);WO2003016475(权利要求1);WO200261087(图1);WO2003016494(图6);WO2003025138(权利要求12;第144页);WO200198351(权利要求1;第124-125页);EP522868(权利要求8;图2);WO200177172(权利要求1;第297-299页);US2003109676;US6518404(图3);US5773223(权利要求1a;Col 31-34);WO2004001004;
(10)MSG783(RNF124,推定蛋白FLJ20315,Genbank登记号NM_017763);
WO2003104275(权利要求1);WO2004046342(实施例2);
WO2003042661(权利要求12);WO2003083074(权利要求14;第61页);
WO2003018621(权利要求1);WO2003024392(权利要求2;图93);
WO200166689(实施例6);
交叉引用:LocusID:54894;NP_060233.2;NM_017763_1
(11)STEAP2(HGNC_8639,IPCA-1,PCANAP1,STAMP1,STEAP2,STMP,前列腺癌相关基因1,前列腺癌相关蛋白1,前列腺六跨膜上皮抗原2,六跨膜前列腺蛋白,Genbank登记号AF455138)
Lab.Invest.82(11):1573-1582(2002));WO2003087306;US2003064397(权利要求1;图1);WO200272596(权利要求13;第54-55页);WO200172962(权利要求1;图4B);WO2003104270(权利要求11);WO2003104270(权利要求16);US2004005598(权利要求22);WO2003042661(权利要求12);US2003060612(权利要求12;图10);WO200226822(权利要求23;图2);WO200216429(权利要求12;图10);
交叉引用:GI:22655488;AAN04080.1;AF455138_1
(12)TrpM4(BR22450,FLJ20041,TRPM4,TRPM4B,瞬时型受体电位阳离子通道,亚家族M,成员4,Genbank登记号NM_017636)
Xu,X.Z.等Proc.Natl.Acad.Sci.U.S.A.98(19):10692-10697(2001);Cell109(3):397-407(2002);J.Biol.Chem.278(33):30813-30820(2003));US2003143557(权利要求4);WO200040614(权利要求14;第100-103页);WO200210382(权利要求1;图9A);WO2003042661(权利要求12);WO200230268(权利要求27;第391页);US2003219806(权利要求4);WO200162794(权利要求14;图1A-D);
交叉引用:MIM:606936;NP_060106.2;NM_017636_1
(13)CRIPTO(CR,CR1,CRGF,CRIPTO,TDGF1,畸胎瘤衍生的生长因子,Genbank登记号NP_003203或NM_003212)
Ciccodicola,A.等EMBO J.8(7):1987-1991(1989);Am.J.Hum.Genet.49(3):555-565(1991));US2003224411(权利要求1);WO2003083041(实施例1);WO2003034984(权利要求12);WO200288170(权利要求2;第52-53页);WO2003024392(权利要求2;图58);WO200216413(权利要求1;第94-95,105页);WO200222808(权利要求2;图1);US5854399(实施例2;Col 17-18);US5792616(图2);
交叉引用:MIM:187395;NP_003203.1;NM_003212_1
(14)CD21(CR2(补体受体2)或C3DR(C3d/EB病毒受体)或Hs.73792,Genbank登记号M26004)
Fujisaku等(1989)J.Biol.Chem.264(4):2118-2125);Weis J.J.等J.Exp.Med.167,1047-1066,1988;Moore M.等Proc.Natl.Acad.Sci.U.S.A.84,9194-9198,1987;Barel M.等Mol.Immunol.35,1025-1031,1998;Weis J.J.等Proc.Natl.Acad.Sci.U.S.A.83,5639-5643,1986;Sinha S.K.等(1993)J.Immunol.150,5311-5320;WO2004045520(实施例4);US2004005538(实施例1);WO2003062401(权利要求9);WO2004045520(实施例4);WO9102536(图9.1-9.9);WO2004020595(权利要求1);
登记号:P20023;Q13866;Q14212;EMBL;M26004;AAA35786.1.
(15)CD79b(CD79B,CD79β,IGb(免疫球蛋白相关β),B29,Genbank登记号NM_000626或11038674)
Proc.Natl.Acad.Sci.U.S.A.(2003)100(7):4126-4131;Blood(2002)100(9):3068-3076;Muller等(1992)Eur.J.Immunol.22(6):1621-1625);WO2004016225(权利要求2,图140);WO2003087768,US2004101874(权利要求1,第102页);WO2003062401(权利要求9);WO200278524(实施例2);US2002150573(权利要求5,第15页);US5644033;WO2003048202(权利要求1,第306和309页);WO99/558658,US6534482(权利要求13,图17A/B);WO200055351(权利要求11,第1145-1146页);
交叉引用:MIM:147245;NP_000617.1;NM_000626_1
(16)FcRH2(IFGP4,IRTA4,SPAP1A(含有SH2结构域的磷酸酶锚定蛋白1a),SPAP1B,SPAP1C,Genbank登记号NM_030764,AY358130)
Genome Res.13(10):2265-2270(2003);Immunogenetics 54(2):87-95(2002);Blood 99(8):2662-2669(2002);Proc.Natl.Acad.Sci.U.S.A.98(17):9772-9777(2001);Xu,M.J.等(2001)Biochem.Biophys.Res.Commun.280(3):768-775;WO2004016225(权利要求2);WO2003077836;WO200138490(权利要求5;图18D-1-18D-2);WO2003097803(权利要求12);WO2003089624(权利要求25);
交叉引用:MIM:606509;NP_110391.2;NM_030764_1
(17)HER2(ErbB2,Genbank登记号M11730)
Coussens L.等Science(1985)230(4730):1132-1139);Yamamoto T.等Nature319,230-234,1986;Semba K.等Proc.Natl.Acad.Sci.U.S.A.82,6497-6501,1985;Swiercz J.M.等J.Cell Biol.165,869-880,2004;Kuhns J.J.等J.Biol.Chem.274,36422-36427,1999;Cho H.-S.等Nature 421,756-760,2003;EhsaniA.等(1993)Genomics 15,426-429;WO2004048938(实施例2);WO2004027049(图1I);WO2004009622;WO2003081210;WO2003089904(权利要求9);WO2003016475(权利要求1);US2003118592;WO2003008537(权利要求1);WO2003055439(权利要求29;图1A-B);WO2003025228(权利要求37;图5C);WO200222636(实施例13;第95-107页);WO200212341(权利要求68;图7);WO200213847(第71-74页);WO200214503(第114-117页);WO200153463(权利要求2;第41-46页);WO200141787(第15页);WO200044899(权利要求52;图7);WO200020579(权利要求3;图2);US5869445(权利要求3;Col 31-38);WO9630514(权利要求2;第56-61页);EP1439393(权利要求7);WO2004043361(权利要求7);WO2004022709;WO200100244(实施例3;图4);
登记号:P04626;EMBL;M11767;AAA35808.1.EMBL;M11761;AAA35808.1.
(18)NCA(CEACAM6,Genbank登记号M18728);
Barnett T.等Genomics 3,59-66,1988;Tawaragi Y.等Biochem.Biophys.Res.Commun.150,89-96,1988;Strausberg R.L.等Proc.Natl.Acad.Sci.U.S.A.99:16899-16903,2002;WO2004063709;EP1439393(权利要求7);WO2004044178(实施例4);WO2004031238;WO2003042661(权利要求12);WO200278524(实施例2);WO200286443(权利要求27;第427页);WO200260317(权利要求2);
登记号:P40199;Q14920;EMBL;M29541;AAA59915.1.EMBL;M18728;
(19)MDP(DPEP1,Genbank登记号BC017023)
Proc.Natl.Acad.Sci.U.S.A.99(26):16899-16903(2002));WO2003016475(权利要求1);WO200264798(权利要求33;第85-87页);JP05003790(图6-8);WO9946284(图9);
交叉引用:MIM:179780;AAH17023.1;BC017023_1
(20)IL20Rα(IL20Ra,ZCYTOR7,Genbank登记号AF184971);
Clark H.F.等Genome Res.13,2265-2270,2003;Mungall A.J.等Nature 425,805-811,2003;Blumberg H.等Cell 104,9-19,2001;Dumoutier L.等J.Immunol.167,3545-3549,2001;Parrish-Novak J.等J.Biol.Chem.277,47517-47523,2002;Pletnev S.等(2003)Biochemistry 42:12617-12624;Sheikh F.等(2004)J.Immunol.172,2006-2010;EP1394274(实施例11);US2004005320(实施例5);WO2003029262(第74-75页);WO2003002717(权利要求2;第63页);WO200222153(第45-47页);US2002042366(第20-21页);WO200146261(第57-59页);WO200146232(第63-65页);WO9837193(权利要求1;第55-59页);
登记号:Q9UHF4;Q6UWA9;Q96SH8;EMBL;AF184971;AAF01320.1.
(21)Brevican(BCAN,BEHAB,Genbank登记号AF229053)
Gary S.C.等Gene 256,139-147,2000;Clark H.F.等Genome Res.13,2265-2270,2003;Strausberg R.L.等Proc.Natl.Acad.Sci.U.S.A.99,16899-16903,2002;US2003186372(权利要求11);US2003186373(权利要求11);US2003119131(权利要求1;图52);US2003119122(权利要求1;图52);US2003119126(权利要求1);US2003119121(权利要求1;图52);US2003119129(权利要求1);US2003119130(权利要求1);US2003119128(权利要求1;图52);US2003119125(权利要求1);WO2003016475(权利要求1);WO200202634(权利要求1);
(22)EphB2R(DRT,ERK,Hek5,EPHT3,Tyro5,Genbank登记号NM_004442)
Chan,J.and Watt,V.M.,Oncogene 6(6),1057-1061(1991);Oncogene10(5):897-905(1995);Annu.Rev.Neurosci.21:309-345(1998);Int.Rev.Cytol.196:177-244(2000));WO2003042661(权利要求12);WO200053216(权利要求1;第41页);WO2004065576(权利要求1);WO2004020583(权利要求9);WO2003004529(第128-132页);WO200053216(权利要求1;第42页);
交叉引用:MIM:600997;NP_004433.2;NM_004442_1
(23)ASLG659(B7h,Genbank登记号AX092328)
US20040101899(权利要求2);WO2003104399(权利要求11);WO2004000221(图3);US2003165504(权利要求1);US2003124140(实施例2);US2003065143(图60);WO2002102235(权利要求13;第299页);US2003091580(实施例2);WO200210187(权利要求6;图10);WO200194641(权利要求12;图7b);WO200202624(权利要求13;图1A-1B);US2002034749(权利要求54;第45-46页);WO200206317(实施例2;第320-321页,权利要求34;第321-322页);WO200271928(第468-469页);WO200202587(实施例1;图1);WO200140269(实施例3;第190-192页);WO200036107(实施例2;第205-207页);WO2004053079(权利要求12);WO2003004989(权利要求1);WO200271928(第233-234,452-453页);WO0116318;
(24)PSCA(前列腺干细胞抗原前体,Genbank登记号AJ297436)
Reiter R.E.等Proc.Natl.Acad.Sci.U.S.A.95,1735-1740,1998;Gu Z.等Oncogene 19,1288-1296,2000;Biochem.Biophys.Res.Commun.(2000)275(3):783-788;WO2004022709;EP1394274(实施例11);US2004018553(权利要求17);WO2003008537(权利要求1);WO200281646(权利要求1;第164页);WO2003003906(权利要求10;第288页);WO200140309(实施例1;图17);US2001055751(实施例1;图1b);WO200032752(权利要求18;图1);WO9851805(权利要求17;第97页);WO9851824(权利要求10;第94页);WO9840403(权利要求2;图1B);
登记号:O43653;EMBL;AF043498;AAC39607.1.
(25)GEDA(Genbank登记号AY260763);
AAP14954脂肪瘤HMGIC融合-配偶体类蛋白/pid=AAP14954.1-智人
物种:智人(人类);WO2003054152(权利要求20);WO2003000842(权利要求1);WO2003023013(实施例3,权利要求20);US2003194704(权利要求45);
交叉引用:GI:30102449;AAP14954.1;AY260763_1
(26)BAFF-R(B细胞活化因子受体,BLyS受体3,BR3,Genbank登记号AF116456);BAFF受体/pid=NP_443177.1-智人
Thompson,J.S.等Science 293(5537),2108-2111(2001);WO2004058309;WO2004011611;WO2003045422(实施例;第32-33页);WO2003014294(权利要求35;图6B);WO2003035846(权利要求70;第615-616页);WO200294852(Col 136-137);WO200238766(权利要求3;第133页);WO200224909(实施例3;图3);
交叉引用:MIM:606269;NP_443177.1;NM_052945_1;AF132600
(27)CD22(B细胞受体CD22-B同工型,BL-CAM,Lyb-8,Lyb8,SIGLEC-2,FLJ22814,Genbank登记号AK026467);
Wilson等(1991)J.Exp.Med.173:137-146;WO2003072036(权利要求1;图1);
交叉引用:MIM:107266;NP_001762.1;NM_001771_1
(28)CD79a(CD79A,CD79α,免疫球蛋白相关α(一种与Igβ(CD79B)共价相互作用且在表面上与Ig M分子形成复合物且转导涉及B细胞分化的信号的B细胞特异性蛋白),pI:4.84,MW:25028TM:2[P]Gene Chromosome:19q13.2,Genbank登记号NP_001774.10)
WO2003088808,US20030228319;WO2003062401(权利要求9);US2002150573(权利要求4,第13-14页);WO9958658(权利要求13,图16);WO9207574(图1);US5644033;Ha等(1992)J.Immunol.148(5):1526-1531;Mueller等(1992)Eur.J.Biochem.22:1621-1625;Hashimoto等(1994)Immunogenetics 40(4):287-295;Preud’homme等(1992)Clin.Exp.Immunol.90(1):141-146;Yu等(1992)J.Immunol.148(2)633-637;Sakaguchi等(1988)EMBO J.7(11):3457-3464;
(29)CXCR5(伯基特淋巴瘤受体1(一种由CXCL13趋化因子活化且在淋巴细胞迁移和体液防御中起作用且在HIV-2感染中起作用且可能在AIDS、淋巴瘤、黑素瘤和白血病的发展中起作用的G蛋白偶联受体),372aa,pI:8.54MW:41959TM:7[P]Gene Chromosome:11q23.3,Genbank登记号NP_001707.1)
WO2004040000;WO2004015426;US2003105292(实施例2);US6555339(实施例2);WO200261087(图1);WO200157188(权利要求20,第269页);WO200172830(第12-13页);WO200022129(实施例1,第152-153页,实施例2,第254-256页);WO9928468(权利要求1,第38页);US5440021(实施例2,col 49-52);WO9428931(第56-58页);WO9217497(权利要求7,图5);Dobner等(1992)Eur.J.Immunol.22:2795-2799;Barella等(1995)Biochem.J.309:773-779;
(30)HLA-DOB(MHC II类分子的β亚基(Ia抗原)(其与肽结合且将其递呈给CD4+T淋巴细胞),273aa,pI:6.56MW:30820TM:1[P]Gene Chromosome:6p21.3,Genbank登记号NP_002111.1)
Tonnelle等(1985)EMBO J.4(11):2839-2847;Jonsson等(1989)Immunogenetics29(6):411-413;Beck等(1992)J.Mol.Biol.228:433-441;Strausberg等(2002)Proc.Natl.Acad.Sci USA 99:16899-16903;Servenius等(1987)J.Biol.Chem.262:8759-8766;Beck等(1996)J.Mol.Biol.255:1-13;Naruse等(2002)Tissue Antigens 59:512-519;WO9958658(权利要求13,图15);US6153408(Col 35-38);US5976551(col 168-170);US6011146(col 145-146);Kasahara等(1989)Immunogenetics 30(1):66-68;Larhammar等(1985)J.Biol.Chem.260(26):14111-14119;
(31)P2X5(嘌呤能受体P2X配体门控离子通道5(一种由胞外ATP门控的可能涉及突触传递和神经发生且其缺陷可促成特发性逼尿肌不稳定性病理生理学的离子通道),422aa),pI:7.63,MW:47206TM:1[P]Gene Chromosome:17p13.3,Genbank登记号NP_002552.2)
Le等(1997)FEBS Lett.418(1-2):195-199;WO2004047749;WO2003072035(权利要求10);Touchman等(2000)Genome Res.10:165-173;WO200222660(权利要求20);WO2003093444(权利要求1);WO2003087768(权利要求1);WO2003029277(第82页);
(32)CD72(B细胞分化抗原CD72,Lyb-2)蛋白质完整序列maeaity...tafrfpd(1..359;359aa),pI:8.66,MW:40225TM:1[P]GeneChromosome:9p13.3,Genbank登记号NP_001773.1)
WO2004042346(权利要求65);WO2003026493(第51-52,57-58页);WO200075655(第105-106页);Von Hoegen等(1990)J.Immunol.144(12):4870-4877;Strausberg等(2002)Proc.Natl.Acad.Sci USA99:16899-16903;
(33)LY64(淋巴细胞抗原64(RP105),调节B细胞活化和凋亡且其功能缺失与患有系统性红斑狼疮的患者的疾病活动增加有关的富含亮氨酸重复(LRR)家族的I型膜蛋白,661aa,pI:6.20,MW:74147TM:1[P]Gene Chromosome:5q12,Genbank登记号NP_005573.1)
US2002193567;WO9707198(权利要求11,第39-42页);Miura等(1996)Genomics 38(3):299-304;Miura等(1998)Blood 92:2815-2822;WO2003083047;WO9744452(权利要求8,第57-61页);WO200012130(第24-26页);
(34)FcRH1(Fc受体样蛋白1,可能在B淋巴细胞分化中起作用的含有C2型Ig样结构域和ITAM结构域的免疫球蛋白Fc结构域的推定受体,429aa,pI:5.28,MW:46925TM:1[P]Gene Chromosome:1q21-1q22,Genbank登记号NP_443170.1)
WO2003077836;WO200138490(权利要求6,图18E-1-18-E-2);Davis等(2001)Proc.Natl.Acad.Sci USA 98(17):9772-9777;WO2003089624(权利要求8);EP1347046(权利要求1);WO2003089624(权利要求7);
(35)FCRH5(IRTA2,免疫球蛋白超家族受体易位相关,在B细胞发育和淋巴瘤的生成中具有可能的作用的推定的免疫受体;由于易位所导致的基因失调在某些B细胞恶性肿瘤中发生;977aa,pI:6.88MW:106468TM:1[P]Gene Chromosome:1q21,Genbank登记号Human:AF343662,AF343663,AF343664,AF343665,AF369794,AF397453,AK090423,AK090475,AL834187,AY358085;Mouse:AK089756,AY158090,AY506558;NP_112571.1
WO2003024392(权利要求2,图97);Nakayama等(2000)Biochem.Biophys.Res.Commun.277(1):124-127;WO2003077836;WO200138490(权利要求3,图18B-1-18B-2);
(36)TENB2(TMEFF2,tomoregulin,TPEF,HPP1,TR,与EGF/调蛋白家族生长因子和卵泡抑素有关的推定的跨膜蛋白聚糖,374aa,NCBI登记号AAD55776,AAF91397,AAG49451,NCBI RefSeq:NP_057276;NCBI Gene:23671;OMIM:605734;SwissProt Q9UIK5;Genbank登记号AF179274;AY358907,CAF85723,CQ782436
WO2004074320(SEQ ID NO 810);JP2004113151(SEQ ID NOS 2,4,8);WO2003042661(SEQ ID NO 580);WO2003009814(SEQ ID NO 411);EP1295944(第69-70页);WO200230268(第329页);WO200190304(SEQ ID NO 2706);US2004249130;US2004022727;WO2004063355;US2004197325;US2003232350;US2004005563;US2003124579;Horie等(2000)Genomics67:146-152;Uchida等(1999)Biochem.Biophys.Res.Commun.266:593-602;Liang等(2000)Cancer Res.60:4907-12;Glynne-Jones等(2001)Int JCancer.Oct15;94(2):178-84;
(37)PMEL17(银同系物;SILV;D12S53E;PMEL17;SI;SIL);ME20;gp100)BC001414;BT007202;M32295;M77348;NM_006928;McGlinchey,R.P.等(2009)Proc.Natl.Acad.Sci.U.S.A.106(33),13731-13736;Kummer,M.P.等(2009)J.Biol.Chem.284(4),2296-2306;
(38)TMEFF1(具有EGF样和两个卵泡抑素样结构域的跨膜蛋白1;Tomoregulin-1);H7365;C9orf2;C9ORF2;U19878;X83961;NM_080655;NM_003692;Harms,P.W.(2003)GenesDev.17(21),2624-2629;Gery,S.等(2003)Oncogene 22(18):2723-2727;
(39)GDNF-Ra1(GDNF家族受体α1;GFRA1;GDNFR;GDNFRA;RETL1;TRNR1;RET1L;GDNFR-alpha1;GFR-ALPHA-1);U95847;BC014962;NM_145793NM_005264;Kim,M.H.等(2009)Mol.Cell.Biol.29(8),2264-2277;Treanor,J.J.等(1996)Nature 382(6586):80-83;
(40)Ly6E(淋巴细胞抗原6复合物,基因座E;Ly67,RIG-E,SCA-2,TSA-1);NP_002337.1;NM_002346.2;de Nooij-van Dalen,A.G.等(2003)Int.J.Cancer103(6),768-774;Zammit,D.J.等(2002)Mol.Cell.Biol.22(3):946-952;WO2013/17705;
(41)TMEM46(shisa同系物2(Xenopus laevis);SHISA2);NP_001007539.1;NM_001007538.1;Furushima,K.等(2007)Dev.Biol.306(2),480-492;Clark,H.F.等(2003)Genome Res.13(10):2265-2270;
(42)Ly6G6D(淋巴细胞抗原6复合物,基因座G6D;Ly6-D,MEGT1);NP_067079.2;NM_021246.2;Mallya,M.等(2002)Genomics 80(1):113-123;Ribas,G.等(1999)J.Immunol.163(1):278-287;
(43)LGR5(含有富含亮氨酸的重复的G蛋白偶联受体5;GPR49,GPR67);NP_003658.1;NM_003667.2;Salanti,G.等(2009)Am.J.Epidemiol.170(5):537-545;Yamamoto,Y.等(2003)Hepatology 37(3):528-533;
(44)RET(ret原癌基因;MEN2A;HSCR1;MEN2B;MTC1;PTC;CDHF12;Hs.168114;RET51;RET-ELE1);NP_066124.1;NM_020975.4;Tsukamoto,H.等(2009)Cancer Sci.100(10):1895-1901;Narita,N.等(2009)Oncogene28(34):3058-3068;
(45)LY6K(淋巴细胞抗原6复合物,基因座K;LY6K;HSJ001348;FLJ35226);NP_059997.3;NM_017527.3;Ishikawa,N.等(2007)Cancer Res.67(24):11601-11611;deNooij-van Dalen,A.G.等(2003)Int.J.Cancer103(6):768-774;
(46)GPR19(G蛋白偶联受体19;Mm.4787);NP_006134.1;NM_006143.2;Montpetit,A.and Sinnett,D.(1999)Hum.Genet.105(1-2):162-164;O’Dowd,B.F.等(1996)FEBSLett.394(3):325-329;
(47)GPR54(KISS1受体;KISS1R;GPR54;HOT7T175;AXOR12);NP_115940.2;NM_032551.4;Navenot,J.M.等(2009)Mol.Pharmacol.75(6):1300-1306;Hata,K.等(2009)Anticancer Res.29(2):617-623;
(48)ASPHD1(含有天冬氨酸β-羟化酶结构域的1;LOC253982);NP_859069.2;NM_181718.3;Gerhard,D.S.等(2004)Genome Res.14(10B):2121-2127;
(49)Tyrosinase(TYR;OCAIA;OCA1A;酪氨酸酶;SHEP3);NP_000363.1;NM_000372.4;Bishop,D.T.等(2009)Nat.Genet.41(8):920-925;Nan,H.等(2009)Int.J.Cancer 125(4):909-917;
(50)TMEM118(环指蛋白,跨膜2;RNFT2;FLJ14627);NP_001103373.1;NM_001109903.1;Clark,H.F.等(2003)Genome Res.13(10):2265-2270;Scherer,S.E.等(2006)Nature 440(7082):346-351;
(51)GPR172A(G蛋白偶联受体172A;GPCR41;FLJ11856;D15Ertd747e);NP_078807.1;NM_024531.3;Ericsson,T.A.等(2003)Proc.Natl.Acad.Sci.U.S.A.100(11):6759-6764;Takeda,S.等(2002)FEBS Lett.520(1-3):97-101。
(52)CD33,一种唾液酸结合的免疫球蛋白样凝集素家族的成员,是67-kDa糖基化的跨膜蛋白。除了定向的骨髓单核细胞和红系祖细胞外,CD33还在大多数髓系和单核细胞白血病细胞上表达。在最早的多能干细胞、成熟粒细胞、淋巴细胞或非造血细胞中未见(Sabbath等,(1985)J.Clin.Invest.75:756-56;Andrews等,(1986)Blood 68:1030-5)。CD33在其细胞质尾部含有两个酪氨酸残基,每个残基后面是存在于许多抑制性受体中的与基于免疫受体酪氨酸的抑制基序(ITIM)类似的疏水性残基。
(53)CLL-1(CLEC12A、MICL和DCAL2),编码C型凝集素/C型凝集素样结构域(CTL/CTLD)超家族的成员。该家族的成员享有共同的蛋白质折叠并在炎症和免疫应答中具有多种功能(例如细胞粘附、细胞-细胞信号传导、糖蛋白转换(turnover))和作用。由该基因编码的蛋白质是粒细胞和单核细胞功能的负调节物。已经描述了该基因的几种可变剪接的转录变体,但尚未确定这些变体中的一些的全长性质。该基因与染色体12p13上的天然杀伤基因复合区中的其他CTL/CTLD超家族成员密切相关(Drickamer K(1999)Curr.Opin.Struct.Biol.9(5):585-90;van Rhenen A等,(2007)Blood 110(7):2659-66;Chen CH等(2006)Blood 107(4):1459-67;Marshall AS等(2006)Eur.J.Immunol.36(8):2159-69;Bakker AB等(2005)Cancer Res.64(22):8443-50;Marshall AS等(2004)J.Biol.Chem.279(15):14792-802)。已显示CLL-1是II型跨膜受体,其包含单个C型凝集素样结构域(预测其不结合钙或糖)、茎区、跨膜结构域和含有ITIM基序的短细胞质尾部。
如本文所述,ADC包含抗体例如选自以下的抗体:
抗Ly6E抗体
在某些实施方案中,ADC可包含抗Ly6E抗体。淋巴细胞抗原6复合物,基因座E(Ly6E),也称作视黄酸诱导的基因E(RIG-E)和干细胞抗原2(SCA-2)。它是一种GPI连接的,长131个氨基酸,约8.4kDa的蛋白质,功能未知,无已知的结合配偶物。它最初鉴定为在小鼠中的未成熟胸腺细胞,胸腺髓质上皮细胞中表达的转录物(Mao等(1996)Proc.Natl.Acad.Sci.U.S.A.93:5910-5914)。在一些实施方案中,本文所述的主题提供包含PCT公开文本No.WO 2013/177055中所描述的抗Ly6E抗体的ADC。
在一些实施方案中,本文所述的主题提供包含抗Ly6E抗体的ADC,所述抗体包含至少1、2、3、4、5或6个选自以下的HVR:(a)包含SEQ ID NO:12的氨基酸序列的HVR-H1;(b)包含SEQ ID NO:13的氨基酸序列的HVR-H2;(c)包含SEQ ID NO:14的氨基酸序列的HVR-H3;(d)包含SEQ ID NO:9的氨基酸序列的HVR-L1;(e)包含SEQ ID NO:10的氨基酸序列的HVR-L2;和(f)包含SEQ ID NO:11的氨基酸序列的HVR-L3。
在一个方面,本文所述的主题提供包含抗体的ADC,所述抗体包含至少1个、至少2个或全部3个选自以下的VH HVR序列:(a)包含SEQ ID NO:12的氨基酸序列的HVR-H1;(b)包含SEQ ID NO:13的氨基酸序列的HVR-H2;和(c)包含SEQ ID NO:14的氨基酸序列的HVR-H3。在进一步的实施方案中,所述抗体包含:(a)包含SEQ ID NO:12的氨基酸序列的HVR-H1;(b)包含SEQ ID NO:13的氨基酸序列的HVR-H2;和(c)包含SEQ ID NO:14的氨基酸序列的HVR-H3。
在另一方面,本文所述的主题提供包含抗体的ADC,所述抗体包含至少1个、至少2个或全部3个选自以下的VL HVR序列:(a)包含SEQ ID NO:9的氨基酸序列的HVR-L1;(b)包含SEQ ID NO:10的氨基酸序列的HVR-L2;和(c)包含SEQ ID NO:11的氨基酸序列的HVR-L3。在一个实施方案中,所述抗体包含:(a)包含SEQ ID NO:9的氨基酸序列的HVR-L1;(b)包含SEQ ID NO:10的氨基酸序列的HVR-L2;和(c)包含SEQ ID NO:11的氨基酸序列的HVR-L3。
在另一方面,ADC包含抗体,所述抗体包含:(a)VH结构域,其包含至少1个、至少2个或全部3个选自以下的VH HVR序列:(i)包含SEQ ID NO:12的氨基酸序列的HVR-H1,(ii)包含SEQ ID NO:13的氨基酸序列的HVR-H2,和(iii)包含选自SEQ ID NO:14的氨基酸序列的HVR-H3;和(b)VL结构域,其包含至少1个、至少2个或全部3个选自以下的VL HVR序列:(i)包含SEQ ID NO:9的氨基酸序列的HVR-L1,(ii)包含SEQ ID NO:10的氨基酸序列的HVR-L2,和(c)包含SEQ ID NO:11的氨基酸序列的HVR-L3。
在另一方面,本文所述的主题提供包含抗体的ADC,所述抗体包含:(a)包含SEQ IDNO:12的氨基酸序列的HVR-H1;(b)包含SEQ ID NO:13的氨基酸序列的HVR-H2;(c)包含SEQID NO:14的氨基酸序列的HVR-H3;(d)包含SEQ ID NO:9的氨基酸序列的HVR-L1;(e)包含SEQ ID NO:10的氨基酸序列的HVR-L2;和(f)包含SEQ ID NO:11的氨基酸序列的HVR-L3。
在上述实施方案任一项中,ADC的抗Ly6E抗体是人源化的。在一个实施方案中,抗Ly6E抗体包含上述实施方案中任一项所述的HVR且进一步包含人受体框架,例如人免疫球蛋白框架或人共有框架。
在另一方面,ADC的抗Ly6E抗体包含与SEQ ID NO:8的氨基酸序列具有至少90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%序列同一性的重链可变域(VH)序列。在某些实施方案中,与SEQ ID NO:8的氨基酸序列具有至少90%、91%、92%、93%、94%、95%、96%、97%、98%或99%同一性的VH序列相对于参比序列含有取代(例如保守取代)、插入或删除,但是包含该序列的抗Ly6E抗体保留了与Ly6E结合的能力。在某些实施方案中,总计1至10个氨基酸已在SEQ ID NO:8中被取代、插入和/或缺失。在某些实施方案中,总计1至5个氨基酸已在SEQ ID NO:8中被取代、插入和/或缺失。在某些实施方案中,取代、插入或缺失发生在HVR外部的区域(即FR中)。任选地,所述抗Ly6E抗体包含SEQ ID NO:8的VH序列,包括该序列的翻译后修饰。在具体实施方案中,所述VH包含1、2或3个选自以下的HVR:(a)包含SEQ ID NO:12的氨基酸序列的HVR-H1,(b)包含SEQ ID NO:13的氨基酸序列的HVR-H2,和(c)包含SEQ ID NO:14的氨基酸序列的HVR-H3。
在另一方面,提供ADC的抗Ly6E抗体,其中所述抗体包含与SEQ ID NO:7的氨基酸序列具有至少90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%序列同一性的轻链可变域(VL)。在某些实施方案中,与SEQ ID NO:7的氨基酸序列具有至少90%、91%、92%、93%、94%、95%、96%、97%、98%或99%同一性的VL序列相对于参比序列含有取代(例如保守取代)、插入或删除,但是包含该序列的抗Ly6E抗体保留了与Ly6E结合的能力。在某些实施方案中,总计1至10个氨基酸已在SEQ ID NO:7中被取代、插入和/或缺失。在某些实施方案中,总计1至5个氨基酸已在SEQ ID NO:7中被取代、插入和/或缺失。在某些实施方案中,取代、插入或缺失发生在HVR外部的区域(即FR中)。任选地,所述抗Ly6E抗体包含SEQ ID NO:7的VL序列,包括该序列的翻译后修饰。在具体实施方案中,所述VL包含1、2或3个选自以下的HVR:(a)包含SEQ ID NO:9的氨基酸序列的HVR-L1;(b)包含SEQ ID NO:10的氨基酸序列的HVR-L2;和(c)包含SEQ ID NO:11的氨基酸序列的HVR-L3。
在另一方面,提供包含抗Ly6E抗体的ADC,其中所述抗体包含上文提供的实施方案中任一项所述的VH,和上文提供的实施方案中任一项所述的VL。
在一个实施方案中,提供ADC,其中所述抗体分别包含SEQ ID NO:8和SEQ ID NO:7的VH和VL序列,包括这些序列的翻译后修饰。
在另一方面,本文提供包含抗体的ADC,所述抗体结合与本文提供的抗Ly6E抗体相同的表位。例如,在某些实施方案中,提供包含抗体的ADC,所述抗体结合与抗Ly6E抗体相同的表位,所述抗Ly6E抗体分别包含SEQ ID NO:8的VH序列和SEQ ID NO:7的VL序列。
在另一方面,上述实施方案中任一项所述的ADC的抗Ly6E抗体是单克隆抗体,包括人抗体。在一个实施方案中,ADC的抗Ly6E抗体是抗体片段,例如Fv、Fab、Fab’、scFv、双抗体或F(ab’)2片段。在另一实施方案中,所述抗体是基本上全长抗体,例如如本文定义的IgG1抗体、IgG2a抗体或其他抗体类别或同工型。在一些实施方案中,ADC包含含有重链和轻链的抗Ly6E抗体,所述重链和轻链分别包含SEQ ID NO:16和15的氨基酸序列。
表4.Ly6E抗体序列
抗HER2抗体
在某些实施方案中,ADC包含抗HER2抗体。在一个实施方案中,ADC的抗HER2抗体包含人源化抗HER2抗体,例如huMAb4D5-1、huMAb4D5-2、huMAb4D5-3、huMAb4D5-4、huMAb4D5-5、huMAb4D5-6、huMAb4D5-7和huMAb4D5-8,如US 5821337的表3中所描述,其通过引用明确并入本文。这些抗体含有人框架区,其具有与HER2结合的鼠抗体(4D5)的互补决定区。人源化抗体huMAb4D5-8也称为曲妥珠单抗(trastuzumab),可以商品名商购获得。在另一实施方案中,ADC的抗HER2抗体包含人源化抗HER2抗体,例如人源化2C4,如US7862817中所述。示例性人源化2C4抗体是帕妥珠单抗(pertuzumab),可以商品名商购获得。
在另一实施方案中,ADC的抗HER2抗体包含人源化7C2抗HER2抗体。人源化7C2抗体是抗HER2抗体。
在一些实施方案中,本文描述了包含抗HER2抗体的ADC,所述抗体包含至少1、2、3、4、5或6个选自以下的HVR:(a)包含SEQ ID NO:22的氨基酸序列的HVR-H1;(b)包含SEQ IDNO:23、27或28的氨基酸序列的HVR-H2;(c)包含SEQ ID NO:24或29的氨基酸序列的HVR-H3;(d)包含SEQ ID NO:19的氨基酸序列的HVR-L1;(e)包含SEQ ID NO:20的氨基酸序列的HVR-L2;和(f)包含SEQ ID NO:21的氨基酸序列的HVR-L3。在一些实施方案中,本文描述了包含抗HER2抗体的ADC,所述抗体包含至少1、2、3、4、5或6个选自以下的HVR:(a)包含SEQ ID NO:22的氨基酸序列的HVR-H1;(b)包含SEQ ID NO:23的氨基酸序列的HVR-H2;(c)包含SEQ IDNO:24的氨基酸序列的HVR-H3;(d)包含SEQ ID NO:19的氨基酸序列的HVR-L1;(e)包含SEQID NO:20的氨基酸序列的HVR-L2;和(f)包含SEQ ID NO:21的氨基酸序列的HVR-L3.
在一个方面,本文描述了包含抗体的ADC,所述抗体包含至少1个、至少2个或全部3个选自以下的VH HVR序列:(a)包含SEQ ID NO:22的氨基酸序列的HVR-H1;(b)包含SEQ IDNO:23、27或28的氨基酸序列的HVR-H2;和(c)包含SEQ ID NO:24或29的氨基酸序列的HVR-H3。在一个方面,本文描述了包含抗体的ADC,所述抗体包含至少1个、至少2个或全部3个选自以下的VH HVR序列:(a)包含SEQ ID NO:22的氨基酸序列的HVR-H1;(b)包含SEQ ID NO:23的氨基酸序列的HVR-H2;和(c)包含SEQ ID NO:24的氨基酸序列的HVR-H3。在进一步的实施方案中,所述抗体包含:(a)包含SEQ ID NO:68的氨基酸序列的HVR-H1;(b)包含SEQ IDNO:23、27或28的氨基酸序列的HVR-H2;和(c)包含SEQ ID NO:24或29的氨基酸序列的HVR-H3。在进一步的实施方案中,所述抗体包含:(a)包含SEQ ID NO:22的氨基酸序列的HVR-H1;(b)包含SEQ ID NO:23的氨基酸序列的HVR-H2;和(c)包含SEQ ID NO:24的氨基酸序列的HVR-H3。
在另一方面,本文描述了包含抗体的ADC,所述抗体包含至少1个、至少2个或全部3个选自以下的VL HVR序列:(a)包含SEQ ID NO:19的氨基酸序列的HVR-L1;(b)包含SEQ IDNO:20的氨基酸序列的HVR-L2;和(c)包含SEQ ID NO:21的氨基酸序列的HVR-L3。在一个实施方案中,所述抗体包含:(a)包含SEQ ID NO:19的氨基酸序列的HVR-L1;(b)包含SEQ IDNO:20的氨基酸序列的HVR-L2;和(c)包含SEQ ID NO:21的氨基酸序列的HVR-L3。
在另一方面,ADC包含抗体,所述抗体包含:(a)VH结构域,其包含至少1个、至少2个或全部3个选自以下的VH HVR序列:(i)包含SEQ ID NO:22的氨基酸序列的HVR-H1,(ii)包含SEQ ID NO:23、27或28的氨基酸序列的HVR-H2,和(iii)包含选自SEQ ID NO:24或29的氨基酸序列的HVR-H3;和(b)VL结构域,其包含至少1个、至少2个或全部3个选自以下的VL HVR序列:(i)包含SEQ ID NO:19的氨基酸序列的HVR-L1,(ii)包含SEQ ID NO:20的氨基酸序列的HVR-L2,和(c)包含SEQ ID NO:21的氨基酸序列的HVR-L3。在另一方面,ADC包含抗体,所述抗体包含:(a)VH结构域,其包含至少1个、至少2个或全部3个选自以下的VH HVR序列:(i)包含SEQ ID NO:22的氨基酸序列的HVR-H1,(ii)包含SEQ ID NO:23的氨基酸序列的HVR-H2,和(iii)包含选自SEQ ID NO:24的氨基酸序列的HVR-H3;和(b)VL结构域,其包含至少1个、至少2个或全部3个选自以下的VL HVR序列:(i)包含SEQ ID NO:19的氨基酸序列的HVR-L1,(ii)包含SEQ ID NO:20的氨基酸序列的HVR-L2,和(c)包含SEQ ID NO:21的氨基酸序列的HVR-L3。
在另一方面,本文描述了包含抗体的ADC,所述抗体包含:(a)包含SEQ ID NO:22的氨基酸序列的HVR-H1;(b)包含SEQ ID NO:23、27或28的氨基酸序列的HVR-H2;(c)包含SEQID NO:24或29的氨基酸序列的HVR-H3;(d)包含SEQ ID NO:19的氨基酸序列的HVR-L1;(e)包含SEQ ID NO:20的氨基酸序列的HVR-L2;和(f)包含SEQ ID NO:21的氨基酸序列的HVR-L3。在另一方面,本文描述了包含抗体的ADC,所述抗体包含:(a)包含SEQ ID NO:22的氨基酸序列的HVR-H1;(b)包含SEQ ID NO:23的氨基酸序列的HVR-H2;(c)包含SEQ ID NO:24的氨基酸序列的HVR-H3;(d)包含SEQ ID NO:19的氨基酸序列的HVR-L1;(e)包含SEQ ID NO:20的氨基酸序列的HVR-L2;和(f)包含SEQ ID NO:21的氨基酸序列的HVR-L3。
在上述实施方案任一项中,ADC的抗HER2抗体是人源化的。在一个实施方案中,ADC的抗HER2抗体包含上述实施方案中任一项所述的HVR且进一步包含人受体框架,例如人免疫球蛋白框架或人共有框架。
在另一方面,ADC的抗HER2抗体包含与SEQ ID NO:18的氨基酸序列具有至少90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%序列同一性的重链可变域(VH)序列。在某些实施方案中,与SEQ ID NO:18的氨基酸序列具有至少90%、91%、92%、93%、94%、95%、96%、97%、98%或99%同一性的VH序列相对于参比序列含有取代(例如保守取代)、插入或删除,但是包含该序列的抗HER2抗体保留了与HER2结合的能力。在某些实施方案中,总计1至10个氨基酸已在SEQ ID NO:18中被取代、插入和/或缺失。在某些实施方案中,总计1至5个氨基酸已在SEQ ID NO:18中被取代、插入和/或缺失。在某些实施方案中,取代、插入或缺失发生在HVR外部的区域(即FR中)。任选地,所述抗HER2抗体包含SEQ ID NO:18的VH序列,包括该序列的翻译后修饰。在具体实施方案中,所述VH包含1、2或3个选自以下的HVR:(a)包含SEQ ID NO:22的氨基酸序列的HVR-H1,(b)包含SEQ ID NO:23的氨基酸序列的HVR-H2,和(c)包含SEQ ID NO:24的氨基酸序列的HVR-H3。
在另一方面,提供ADC的抗HER2抗体,其中所述抗体包含与SEQ ID NO:17的氨基酸序列具有至少90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%序列同一性的轻链可变域(VL)。在某些实施方案中,与SEQ ID NO:17的氨基酸序列具有至少90%、91%、92%、93%、94%、95%、96%、97%、98%或99%同一性的VL序列相对于参比序列含有取代(例如保守取代)、插入或删除,但是包含该序列的抗HER2抗体保留了与HER2结合的能力。在某些实施方案中,总计1至10个氨基酸已在SEQ ID NO:17中被取代、插入和/或缺失。在某些实施方案中,总计1至5个氨基酸已在SEQ ID NO:17中被取代、插入和/或缺失。在某些实施方案中,取代、插入或缺失发生在HVR外部的区域(即FR中)。任选地,所述抗HER2抗体包含SEQ ID NO:17的VL序列,包括该序列的翻译后修饰。在具体实施方案中,所述VL包含1、2或3个选自以下的HVR:(a)包含SEQ ID NO:19的氨基酸序列的HVR-L1;(b)包含SEQ ID NO:20的氨基酸序列的HVR-L2;和(c)包含SEQ ID NO:21的氨基酸序列的HVR-L3。
在另一方面,提供包含抗HER2抗体的ADC,其中所述抗体包含上文提供的实施方案中任一项所述的VH,和上文提供的实施方案中任一项所述的VL。
在一个实施方案中,提供包含抗体的ADC,其中所述抗体分别包含SEQ ID NO:18和SEQ ID NO:17的VH和VL序列,包括这些序列的翻译后修饰。
在一个实施方案中,提供包含抗体的ADC,其中所述抗体包含SEQ ID NO:30的人源化7C2.v2.2.LA(hu7C2)K149Cκ轻链序列。
在一个实施方案中,提供包含抗体的ADC,其中所述抗体包含SEQ ID NO:31的Hu7C2A118C IgG1重链序列。
在另一方面,本文提供包含抗体的ADC,所述抗体结合与本文提供的抗HER2抗体相同的表位。例如,在某些实施方案中,提供了ADC,其包含结合与抗HER2抗体相同表位的抗体,所述抗体分别包含SEQ ID NO:18的VH序列和SEQ ID NO:17的VL序列。
在另一方面,上述实施方案中任一项所述的ADC的抗HER2抗体是单克隆抗体,包括人抗体。在一个实施方案中,ADC的抗HER2抗体是抗体片段,例如Fv、Fab、Fab’、scFv、双抗体或F(ab’)2片段。在另一实施方案中,ADC包含抗体,所述抗体是基本上全长抗体,例如如本文定义的IgG1抗体、IgG2a抗体或其他抗体类别或同工型。
表5.人源化7C2抗HER2抗体序列
抗MUC16抗体
在某些实施方案中,ADC包含抗MUC16抗体。
在一些实施方案中,本文描述了包含抗MUC16抗体的ADC,所述抗体包含至少1、2、3、4、5或6个选自以下的HVR:(a)包含SEQ ID NO:35的氨基酸序列的HVR-H1;(b)包含SEQ IDNO:36的氨基酸序列的HVR-H2;(c)包含SEQ ID NO:37的氨基酸序列的HVR-H3;(d)包含SEQID NO:32的氨基酸序列的HVR-L1;(e)包含SEQ ID NO:33的氨基酸序列的HVR-L2和(f)包含SEQ ID NO:34的氨基酸序列的HVR-L3。
在一个方面,本文描述了包含抗体的ADC,所述抗体包含至少1个、至少2个或全部3个选自以下的VH HVR序列:(a)包含SEQ ID NO:35的氨基酸序列的HVR-H1;(b)包含SEQ IDNO:36的氨基酸序列的HVR-H2;(c)包含SEQ ID NO:37的氨基酸序列的HVR-H3。在进一步的实施方案中,所述抗体包含:(a)包含SEQ ID NO:35的氨基酸序列的HVR-H1;(b)包含SEQ IDNO:36的氨基酸序列的HVR-H2;(c)包含SEQ ID NO:37的氨基酸序列的HVR-H3。
在另一方面,本文描述了包含抗体的ADC,所述抗体包含至少1个、至少2个或全部3个选自以下的VL HVR序列:(a)包含SEQ ID NO:32的氨基酸序列的HVR-L1;(b)包含SEQ IDNO:33的氨基酸序列的HVR-L2;和(c)包含SEQ ID NO:34的氨基酸序列的HVR-L3。在一个实施方案中,所述抗体包含:(a)包含SEQ ID NO:32的氨基酸序列的HVR-L1;(b)包含SEQ IDNO:33的氨基酸序列的HVR-L2;和(c)包含SEQ ID NO:34的氨基酸序列的HVR-L3。
在另一方面,ADC包含抗体,所述抗体包含:(a)VH结构域,其包含至少1个、至少2个或全部3个选自以下的VH HVR序列:(i)包含SEQ ID NO:35的氨基酸序列的HVR-H1,(ii)包含SEQ ID NO:36的氨基酸序列的HVR-H2,和(iii)包含选自SEQ ID NO:37的氨基酸序列的HVR-H3;和(b)VL结构域,其包含至少1个、至少2个或全部3个选自以下的VL HVR序列:(i)包含SEQ ID NO:32的氨基酸序列的HVR-L1,(ii)包含SEQ ID NO:33的氨基酸序列的HVR-L2,和(c)包含SEQ ID NO:34的氨基酸序列的HVR-L3。
在另一方面,本文描述了包含抗体的ADC,所述抗体包含:(a)包含SEQ ID NO:35的氨基酸序列的HVR-H1;(b)包含SEQ ID NO:36的氨基酸序列的HVR-H2;(c)包含SEQ ID NO:37的氨基酸序列的HVR-H3;(d)包含SEQ ID NO:32的氨基酸序列的HVR-L1;(e)包含SEQ IDNO:33的氨基酸序列的HVR-L2;和(f)包含SEQ ID NO:34的氨基酸序列的HVR-L3。
在上述实施方案任一项中,ADC的抗MUC16抗体是人源化的。在一个实施方案中,抗MUC16抗体包含上述实施方案中任一项所述的HVR且进一步包含人受体框架,例如人免疫球蛋白框架或人共有框架。
在另一方面,ADC的抗MUC16抗体包含与SEQ ID NO:39的氨基酸序列具有至少90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%序列同一性的重链可变域(VH)序列。在某些实施方案中,与SEQ ID NO:39的氨基酸序列具有至少90%、91%、92%、93%、94%、95%、96%、97%、98%或99%同一性的VH序列相对于参比序列含有取代(例如保守取代)、插入或删除,但是包含该序列的抗MUC16抗体保留了与MUC16结合的能力。在某些实施方案中,总计1至10个氨基酸已在SEQ ID NO:39中被取代、插入和/或缺失。在某些实施方案中,总计1至5个氨基酸已在SEQ ID NO:39中被取代、插入和/或缺失。在某些实施方案中,取代、插入或缺失发生在HVR外部的区域(即FR中)。任选地,所述抗MUC16抗体包含SEQID NO:39的VH序列,包括该序列的翻译后修饰。在具体实施方案中,所述VH包含1、2或3个选自以下的HVR:(a)包含SEQ ID NO:35的氨基酸序列的HVR-H1,(b)包含SEQ ID NO:36的氨基酸序列的HVR-H2,和(c)包含SEQ ID NO:37的氨基酸序列的HVR-H3。
在另一方面,提供ADC的抗MUC16抗体,其中所述抗体包含与SEQ ID NO:38的氨基酸序列具有至少90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%序列同一性的轻链可变域(VL)。在某些实施方案中,与SEQ ID NO:38的氨基酸序列具有至少90%、91%、92%、93%、94%、95%、96%、97%、98%或99%同一性的VL序列相对于参比序列含有取代(例如保守取代)、插入或删除,但是包含该序列的抗MUC16抗体保留了与MUC16结合的能力。在某些实施方案中,总计1至10个氨基酸已在SEQ ID NO:38中被取代、插入和/或缺失。在某些实施方案中,总计1至5个氨基酸已在SEQ ID NO:38中被取代、插入和/或缺失。在某些实施方案中,取代、插入或缺失发生在HVR外部的区域(即FR中)。任选地,所述抗MUC16抗体包含SEQ ID NO:38的VL序列,包括该序列的翻译后修饰。在具体实施方案中,所述VL包含1、2或3个选自以下的HVR:(a)包含SEQ ID NO:32的氨基酸序列的HVR-L1;(b)包含SEQ IDNO:33的氨基酸序列的HVR-L2;和(c)包含SEQ ID NO:34的氨基酸序列的HVR-L3。
在另一方面,提供包含抗MUC16抗体的ADC,其中所述抗体包含上文提供的实施方案中任一项所述的VH,和上文提供的实施方案中任一项所述的VL。
在一个实施方案中,提供ADC,其中所述抗体分别包含SEQ ID NO:39和SEQ ID NO:38的VH和VL序列,包括这些序列的翻译后修饰。
在另一方面,本文提供包含抗体的ADC,所述抗体结合与本文提供的抗MUC16抗体相同的表位。例如,在某些实施方案中,提供了ADC,其包含结合与抗MUC16抗体相同表位的抗体,所述抗体分别包含SEQ ID NO:39的VH序列和SEQ ID NO:38的VL序列。
在另一方面,上述实施方案中任一项所述的ADC的抗MUC16抗体是单克隆抗体,包括人抗体。在一个实施方案中,ADC的抗MUC16抗体是抗体片段,例如Fv、Fab、Fab’、scFv、双抗体或F(ab’)2片段。在另一实施方案中,所述抗体是基本上全长抗体,例如如本文定义的IgG1抗体、IgG2a抗体或其他抗体类别或同工型。
表6.MUC16抗体序列
抗STEAP-1抗体
在某些实施方案中,ADC包含抗STEAP-1抗体。
在一些实施方案中,本文描述了包含抗STEAP-1抗体的ADC,所述抗体包含至少1、2、3、4、5或6个选自以下的HVR:(a)包含SEQ ID NO:40的氨基酸序列的HVR-H1;(b)包含SEQID NO:41的氨基酸序列的HVR-H2;(c)包含SEQ ID NO:42的氨基酸序列的HVR-H3;(d)包含SEQ ID NO:43的氨基酸序列的HVR-L1;(e)包含SEQ ID NO:44的氨基酸序列的HVR-L2和(f)包含SEQ ID NO:45的氨基酸序列的HVR-L3。
在一个方面,本文描述了包含抗体的ADC,所述抗体包含至少1个、至少2个或全部3个选自以下的VH HVR序列:(a)包含SEQ ID NO:40的氨基酸序列的HVR-H1;(b)包含SEQ IDNO:41的氨基酸序列的HVR-H2;(c)包含SEQ ID NO:42的氨基酸序列的HVR-H3。在进一步的实施方案中,所述抗体包含:(a)包含SEQ ID NO:40的氨基酸序列的HVR-H1;(b)包含SEQ IDNO:41的氨基酸序列的HVR-H2;(c)包含SEQ ID NO:42的氨基酸序列的HVR-H3。
在另一方面,本文描述了包含抗体的ADC,所述抗体包含至少1个、至少2个或全部3个选自以下的VL HVR序列:(a)包含SEQ ID NO:43的氨基酸序列的HVR-L1;(b)包含SEQ IDNO:44的氨基酸序列的HVR-L2;和(c)包含SEQ ID NO:45的氨基酸序列的HVR-L3。在一个实施方案中,所述抗体包含:(a)包含SEQ ID NO:43的氨基酸序列的HVR-L1;(b)包含SEQ IDNO:44的氨基酸序列的HVR-L2;和(c)包含SEQ ID NO:45的氨基酸序列的HVR-L3。
在另一方面,ADC包含抗体,所述抗体包含:(a)VH结构域,其包含至少1个、至少2个或全部3个选自以下的VH HVR序列:(i)包含SEQ ID NO:40的氨基酸序列的HVR-H1,(ii)包含SEQ ID NO:41的氨基酸序列的HVR-H2,和(iii)包含选自SEQ ID NO:42的氨基酸序列的HVR-H3;和(b)VL结构域,其包含至少1个、至少2个或全部3个选自以下的VL HVR序列:(i)包含SEQ ID NO:43的氨基酸序列的HVR-L1,(ii)包含SEQ ID NO:44的氨基酸序列的HVR-L2,和(c)包含SEQ ID NO:45的氨基酸序列的HVR-L3。
在另一方面,本文描述了包含抗体的ADC,所述抗体包含:(a)包含SEQ ID NO:40的氨基酸序列的HVR-H1;(b)包含SEQ ID NO:41的氨基酸序列的HVR-H2;(c)包含SEQ ID NO:42的氨基酸序列的HVR-H3;(d)包含SEQ ID NO:43的氨基酸序列的HVR-L1;(e)包含SEQ IDNO:44的氨基酸序列的HVR-L2;和(f)包含SEQ ID NO:45的氨基酸序列的HVR-L3。
在上述实施方案任一项中,ADC的抗STEAP-1抗体是人源化的。在一个实施方案中,抗STEAP-1抗体包含上述实施方案中任一项所述的HVR且进一步包含人受体框架,例如人免疫球蛋白框架或人共有框架。
在另一方面,ADC的抗STEAP-1抗体包含与SEQ ID NO:46的氨基酸序列具有至少90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%序列同一性的重链可变域(VH)序列。在某些实施方案中,与SEQ ID NO:46的氨基酸序列具有至少90%、91%、92%、93%、94%、95%、96%、97%、98%或99%同一性的VH序列相对于参比序列含有取代(例如保守取代)、插入或删除,但是包含该序列的抗STEAP-1抗体保留了与STEAP-1结合的能力。在某些实施方案中,总计1至10个氨基酸已在SEQ ID NO:46中被取代、插入和/或缺失。在某些实施方案中,总计1至5个氨基酸已在SEQ ID NO:46中被取代、插入和/或缺失。在某些实施方案中,取代、插入或缺失发生在HVR外部的区域(即FR中)。任选地,所述抗STEAP-1抗体包含SEQ ID NO:46的VH序列,包括该序列的翻译后修饰。在具体实施方案中,所述VH包含1、2或3个选自以下的HVR:(a)包含SEQ ID NO:40的氨基酸序列的HVR-H1,(b)包含SEQ ID NO:41的氨基酸序列的HVR-H2,和(c)包含SEQ ID NO:42的氨基酸序列的HVR-H3。
在另一方面,提供ADC的抗STEAP-1抗体,其中所述抗体包含与SEQ ID NO:47的氨基酸序列具有至少90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%序列同一性的轻链可变域(VL)。在某些实施方案中,与SEQ ID NO:47的氨基酸序列具有至少90%、91%、92%、93%、94%、95%、96%、97%、98%或99%同一性的VL序列相对于参比序列含有取代(例如保守取代)、插入或删除,但是包含该序列的抗STEAP-1抗体保留了与STEAP-1结合的能力。在某些实施方案中,总计1至10个氨基酸已在SEQ ID NO:47中被取代、插入和/或缺失。在某些实施方案中,总计1至5个氨基酸已在SEQ ID NO:47中被取代、插入和/或缺失。在某些实施方案中,取代、插入或缺失发生在HVR外部的区域(即FR中)。任选地,所述抗STEAP-1抗体包含SEQ ID NO:47的VL序列,包括该序列的翻译后修饰。在具体实施方案中,所述VL包含1、2或3个选自以下的HVR:(a)包含SEQ ID NO:43的氨基酸序列的HVR-L1;(b)包含SEQ ID NO:44的氨基酸序列的
HVR-L2;和(c)包含SEQ ID NO:45的氨基酸序列的HVR-L3。
在另一方面,通过包含抗STEAP-1抗体的ADC,其中所述抗体包含上文提供的实施方案中任一项所述的VH,和上文提供的实施方案中任一项所述的VL。
在一个实施方案中,提供ADC,其中所述抗体分别包含SEQ ID NO:46和SEQ ID NO:47的VH和VL序列,包括这些序列的翻译后修饰。
在另一方面,本文提供包含抗体的ADC,所述抗体结合与本文提供的抗STEAP-1抗体相同的表位。例如,在某些实施方案中,提供了ADC,其包含结合与抗STEAP-1抗体相同表位的抗体,所述抗体分别包含SEQ ID NO:46的VH序列和SEQ ID NO:47的VL序列。
在另一方面,上述实施方案中任一项所述的ADC的抗STEAP-1抗体是单克隆抗体,包括人抗体。在一个实施方案中,ADC的抗STEAP-1抗体是抗体片段,例如Fv、Fab、Fab’、scFv、双抗体或F(ab’)2片段。在另一实施方案中,所述抗体是基本上全长抗体,例如如本文定义的IgG1抗体、IgG2a抗体或其他抗体类别或同工型。
表7.STEAP抗体序列
抗NaPi2b抗体
在某些实施方案中,ADC包含抗NaPi2b抗体。
在一些实施方案中,本文描述了包含抗NaPi2b抗体的ADC,所述抗体包含至少1、2、3、4、5或6个选自以下的HVR:(a)包含SEQ ID NO:48的氨基酸序列的HVR-H1;(b)包含SEQ IDNO:49的氨基酸序列的HVR-H2;(c)包含SEQ ID NO:50的氨基酸序列的HVR-H3;(d)包含SEQID NO:51的氨基酸序列的HVR-L1;(e)包含SEQ ID NO:52的氨基酸序列的HVR-L2和(f)包含SEQ ID NO:53的氨基酸序列的HVR-L3。
在一个方面,本文描述了包含抗体的ADC,所述抗体包含至少1个、至少2个或全部3个选自以下的VH HVR序列:(a)包含SEQ ID NO:48的氨基酸序列的HVR-H1;(b)包含SEQ IDNO:49的氨基酸序列的HVR-H2;(c)包含SEQ ID NO:50的氨基酸序列的HVR-H3。在进一步的实施方案中,所述抗体包含:(a)包含SEQ ID NO:48的氨基酸序列的HVR-H1;(b)包含SEQ IDNO:49的氨基酸序列的HVR-H2;(c)包含SEQ ID NO:50的氨基酸序列的HVR-H3。
在另一方面,本文描述了包含抗体的ADC,所述抗体包含至少1个、至少2个或全部3个选自以下的VL HVR序列:(a)包含SEQ ID NO:51的氨基酸序列的HVR-L1;(b)包含SEQ IDNO:52的氨基酸序列的HVR-L2;和(c)包含SEQ ID NO:53的氨基酸序列的HVR-L3。在一个实施方案中,所述抗体包含:(a)包含SEQ ID NO:51的氨基酸序列的HVR-L1;(b)包含SEQ IDNO:52的氨基酸序列的HVR-L2;和(c)包含SEQ ID NO:53的氨基酸序列的HVR-L3。
在另一方面,ADC包含抗体,所述抗体包含:(a)VH结构域,其包含至少1个、至少2个或全部3个选自以下的VH HVR序列:(i)包含SEQ ID NO:48的氨基酸序列的HVR-H1,(ii)包含SEQ ID NO:49的氨基酸序列的HVR-H2,和(iii)包含选自SEQ ID NO:50的氨基酸序列的HVR-H3;和(b)VL结构域,其包含至少1个、至少2个或全部3个选自以下的VL HVR序列:(i)包含SEQ ID NO:51的氨基酸序列的HVR-L1,(ii)包含SEQ ID NO:52的氨基酸序列的HVR-L2,和(c)包含SEQ ID NO:53的氨基酸序列的HVR-L3。
在另一方面,本文描述了包含抗体的ADC,所述抗体包含:(a)包含SEQ ID NO:48的氨基酸序列的HVR-H1;(b)包含SEQ ID NO:49的氨基酸序列的HVR-H2;(c)包含SEQ ID NO:50的氨基酸序列的HVR-H3;(d)包含SEQ ID NO:51的氨基酸序列的HVR-L1;(e)包含SEQ IDNO:52的氨基酸序列的HVR-L2;和(f)包含SEQ ID NO:53的氨基酸序列的HVR-L3。
在上述实施方案任一项中,ADC的抗NaPi2b抗体是人源化的。在一个实施方案中,抗NaPi2b抗体包含上述实施方案中任一项所述的HVR且进一步包含人受体框架,例如人免疫球蛋白框架或人共有框架。
在另一方面,ADC的抗NaPi2b抗体包含与SEQ ID NO:54的氨基酸序列具有至少90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%序列同一性的重链可变域(VH)序列。在某些实施方案中,与SEQ ID NO:54的氨基酸序列具有至少90%、91%、92%、93%、94%、95%、96%、97%、98%或99%同一性的VH序列相对于参比序列含有取代(例如保守取代)、插入或删除,但是包含该序列的抗NaPi2b抗体保留了与NaPi2b结合的能力。在某些实施方案中,总计1至10个氨基酸已在SEQ ID NO:54中被取代、插入和/或缺失。在某些实施方案中,总计1至5个氨基酸已在SEQ ID NO:54中被取代、插入和/或缺失。在某些实施方案中,取代、插入或缺失发生在HVR外部的区域(即FR中)。任选地,所述抗NaPi2b抗体包含SEQ ID NO:54的VH序列,包括该序列的翻译后修饰。在具体实施方案中,所述VH包含1、2或3个选自以下的HVR:(a)包含SEQ ID NO:48的氨基酸序列的HVR-H1,(b)包含SEQ ID NO:49的氨基酸序列的HVR-H2,和(c)包含SEQ ID NO:50的氨基酸序列的HVR-H3.
在另一方面,提供ADC的抗NaPi2b抗体,其中所述抗体包含与SEQ ID NO:55的氨基酸序列具有至少90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%序列同一性的轻链可变域(VL)。在某些实施方案中,与SEQ ID NO:55的氨基酸序列具有至少90%、91%、92%、93%、94%、95%、96%、97%、98%或99%同一性的VL序列相对于参比序列含有取代(例如保守取代)、插入或删除,但是包含该序列的抗NaPi2b抗体保留了与NaPi2b结合的能力。在某些实施方案中,总计1至10个氨基酸已在SEQ ID NO:55中被取代、插入和/或缺失。在某些实施方案中,总计1至5个氨基酸已在SEQ ID NO:55中被取代、插入和/或缺失。在某些实施方案中,取代、插入或缺失发生在HVR外部的区域(即FR中)。任选地,所述抗NaPi2b抗体包含SEQ ID NO:55的VL序列,包括该序列的翻译后修饰。在具体实施方案中,所述VL包含1、2或3个选自以下的HVR:(a)包含SEQ ID NO:51的氨基酸序列的HVR-L1;(b)包含SEQ IDNO:52的氨基酸序列的HVR-L2;和(c)包含SEQ ID NO:53的氨基酸序列的HVR-L3。
在另一方面,提供包含抗NaPi2b抗体的ADC,其中所述抗体包含上文提供的实施方案中任一项所述的VH,和上文提供的实施方案中任一项所述的VL。
在一个实施方案中,提供ADC,其中所述抗体分别包含SEQ ID NO:54和SEQ ID NO:55的VH和VL序列,包括这些序列的翻译后修饰。
在另一方面,本文提供包含抗体的ADC,所述抗体结合与本文提供的抗NaPi2b抗体相同的表位。例如,在某些实施方案中,提供了ADC,其包含结合与抗NaPi2b抗体相同表位的抗体,所述抗体分别包含SEQ ID NO:54的VH序列和SEQ ID NO:55的VL序列。
在另一方面,上述实施方案中任一项所述的ADC的抗NaPi2b抗体是单克隆抗体,包括人抗体。在一个实施方案中,ADC的抗NaPi2b抗体是抗体片段,例如Fv、Fab、Fab’、scFv、双抗体或F(ab’)2片段。在另一实施方案中,所述抗体是基本上全长抗体,例如如本文定义的IgG1抗体、IgG2a抗体或其他抗体类别或同工型。
表8.NaPi2b抗体序列
抗CD79b抗体
在某些实施方案中,ADC包含抗CD79b抗体。
在一些实施方案中,本文描述了包含抗CD79b抗体的ADC,所述抗体包含至少1、2、3、4、5或6个选自以下的HVR:(a)包含SEQ ID NO:58的氨基酸序列的HVR-H1;(b)包含SEQ IDNO:59的氨基酸序列的HVR-H2;(c)包含SEQ ID NO:60的氨基酸序列的HVR-H3;(d)包含SEQID NO:61的氨基酸序列的HVR-L1;(e)包含SEQ ID NO:62的氨基酸序列的HVR-L2;和(f)包含SEQ ID NO:63的氨基酸序列的HVR-L3。
在一个方面,本文描述了包含抗体的ADC,所述抗体包含至少1个、至少2个或全部3个选自以下的VH HVR序列:(a)包含SEQ ID NO:58的氨基酸序列的HVR-H1;(b)包含SEQ IDNO:59的氨基酸序列的HVR-H2;和(c)包含SEQ ID NO:60的氨基酸序列的HVR-H3。在进一步的实施方案中,所述抗体包含:(a)包含SEQ ID NO:58的氨基酸序列的HVR-H1;(b)包含SEQID NO:59的氨基酸序列的HVR-H2;和(c)包含SEQ ID NO:60的氨基酸序列的HVR-H3。
在另一方面,本文描述了包含抗体的ADC,所述抗体包含至少1个、至少2个或全部3个选自以下的VL HVR序列:(a)包含SEQ ID NO:61的氨基酸序列的HVR-L1;(b)包含SEQ IDNO:62的氨基酸序列的HVR-L2;和(c)包含SEQ ID NO:63的氨基酸序列的HVR-L3。在一个实施方案中,所述抗体包含:(a)包含SEQ ID NO:61的氨基酸序列的HVR-L1;(b)包含SEQ IDNO:62的氨基酸序列的HVR-L2;和(c)包含SEQ ID NO:63的氨基酸序列的HVR-L3。
在另一方面,ADC包含抗体,所述抗体包含:(a)VH结构域,其包含至少1个、至少2个或全部3个选自以下的VH HVR序列:(i)包含SEQ ID NO:58的氨基酸序列的HVR-H1,(ii)包含SEQ ID NO:59的氨基酸序列的HVR-H2,和(iii)包含选自SEQ ID NO:60的氨基酸序列的HVR-H3;和(b)VL结构域,其包含至少1个、至少2个或全部3个选自以下的VL HVR序列:(i)包含SEQ ID NO:61的氨基酸序列的HVR-L1,(ii)包含SEQ ID NO:62的氨基酸序列的HVR-L2,和(c)包含SEQ ID NO:63的氨基酸序列的HVR-L3。
在另一方面,本文描述了包含抗体的ADC,所述抗体包含:(a)包含SEQ ID NO:58的氨基酸序列的HVR-H1;(b)包含SEQ ID NO:59的氨基酸序列的HVR-H2;(c)包含SEQ ID NO:60的氨基酸序列的HVR-H3;(d)包含SEQ ID NO:61的氨基酸序列的HVR-L1;(e)包含SEQ IDNO:62的氨基酸序列的HVR-L2;和(f)包含SEQ ID NO:63的氨基酸序列的HVR-L3。
在上述实施方案任一项中,ADC的抗CD79b抗体是人源化的。在一个实施方案中,抗CD79b抗体包含上述实施方案中任一项所述的HVR且进一步包含人受体框架,例如人免疫球蛋白框架或人共有框架。
在另一方面,ADC的抗CD79b抗体包含与SEQ ID NO:56的氨基酸序列具有至少90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%序列同一性的重链可变域(VH)序列。在某些实施方案中,与SEQ ID NO:56的氨基酸序列具有至少90%、91%、92%、93%、94%、95%、96%、97%、98%或99%同一性的VH序列相对于参比序列含有取代(例如保守取代)、插入或删除,但是包含该序列的抗CD79b抗体保留了与CD79b结合的能力。在某些实施方案中,总计1至10个氨基酸已在SEQ ID NO:56中被取代、插入和/或缺失。在某些实施方案中,总计1至5个氨基酸已在SEQ ID NO:56中被取代、插入和/或缺失。在某些实施方案中,取代、插入或缺失发生在HVR外部的区域(即FR中)。任选地,所述抗CD79b抗体包含SEQID NO:8的VH序列,包括该序列的翻译后修饰。在具体实施方案中,所述VH包含1、2或3个选自以下的HVR:(a)包含SEQ ID NO:58的氨基酸序列的HVR-H1,(b)包含SEQ ID NO:59的氨基酸序列的HVR-H2,和(c)包含SEQ ID NO:60的氨基酸序列的HVR-H3。
在另一方面,提供ADC的抗CD79b抗体,其中所述抗体包含与SEQ ID NO:57的氨基酸序列具有至少90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%序列同一性的轻链可变域(VL)。在某些实施方案中,与SEQ ID NO:57的氨基酸序列具有至少90%、91%、92%、93%、94%、95%、96%、97%、98%或99%同一性的VL序列相对于参比序列含有取代(例如保守取代)、插入或删除,但是包含该序列的抗CD79b抗体保留了与CD79b结合的能力。在某些实施方案中,总计1至10个氨基酸已在SEQ ID NO:57中被取代、插入和/或缺失。在某些实施方案中,总计1至5个氨基酸已在SEQ ID NO:57中被取代、插入和/或缺失。在某些实施方案中,取代、插入或缺失发生在HVR外部的区域(即FR中)。任选地,所述抗CD79b抗体包含SEQ ID NO:57的VL序列,包括该序列的翻译后修饰。在具体实施方案中,所述VL包含1、2或3个选自以下的HVR:(a)包含SEQ ID NO:61的氨基酸序列的HVR-L1;(b)包含SEQ IDNO:62的氨基酸序列的HVR-L2;和(c)包含SEQ ID NO:63的氨基酸序列的HVR-L3。
在另一方面,本文描述了包含抗CD79b抗体的ADC,其中所述抗体包含上文提供的实施方案中任一项所述的VH,和上文提供的实施方案中任一项所述的VL。
在一个实施方案中,提供ADC,其中所述抗体分别包含SEQ ID NO:56和SEQ ID NO:57的VH和VL序列,包括这些序列的翻译后修饰。
在另一方面,本文提供包含抗体的ADC,所述抗体结合与本文提供的抗CD79b抗体相同的表位。例如,在某些实施方案中,提供了ADC,其包含结合与抗CD79b抗体相同表位的抗体,所述抗体分别包含SEQ ID NO:56的VH序列和SEQ ID NO:57的VL序列。
在另一方面,上述实施方案中任一项所述的ADC的抗CD79b抗体是单克隆抗体,包括人抗体。在一个实施方案中,ADC的抗CD79b抗体是抗体片段,例如Fv、Fab、Fab’、scFv、双抗体或F(ab’)2片段。在另一实施方案中,所述抗体是基本上全长抗体,例如如本文定义的IgG1抗体、IgG2a抗体或其他抗体类别或同工型。
表9.CD79b抗体序列
抗CD22抗体
在某些实施方案中,ADC可包含抗CD22抗体,其包含3个轻链高变区(HVR-L1、HVR-L2和HVR-L3)和3个重链高变区(HVR-H1、HVR-H2和HVR-H3)。在一个实施方案中,ADC的抗CD22抗体包含3个轻链高变区和3个重链高变区(SEQ ID NO:66-71),其序列如下所示。在一个实施方案中,ADC的抗CD22抗体包含SEQ ID NO:72的可变轻链序列和SEQ ID NO:73的可变重链序列。在一个实施方案中,本文所述主题的ADC的抗CD22抗体包含SEQ ID NO:74的轻链序列和SEQ ID NO:75的重链序列:
表10.抗CD22抗体
抗CD33抗体
在某些实施方案中,ADC可包含抗CD33抗体,其包含3个轻链高变区和3个重链高变区,其序列(SEQ ID NO:76-81)如下所示。在一个实施方案中,ADC的抗CD33抗体包含SEQ IDNO:82的可变轻链序列和SEQ ID NO:83的可变重链序列。
表11
在一个实施方案中,ADC的抗CD33序列包含SEQ ID NO:84的轻链序列和SEQ IDNO:85的重链序列。在一个实施方案中,ADC的抗CD33序列包含3个轻链高变区和3个重链高变区,其序列(Seq ID NO:84-89)如下所示。在一个实施方案中,ADC的抗CD33序列包含SEQID NO:90的可变轻链序列和SEQ ID NO:91的可变重链序列。在一个实施方案中,ADC的抗CD33序列包含SEQ ID NO:92的可变轻链序列和SEQ ID NO:93的可变重链序列。在一个实施方案中,本文所述主题的ADC的抗CD33序列包含SEQ ID NO:94的可变轻链序列和SEQ IDNO:95的可变重链序列。在一个实施方案中,本文所述主题的ADC的抗CD33序列包含SEQ IDNO:96的可变轻链序列和SEQ ID NO:97的可变重链序列。
表12
抗体亲和力
在某些实施方案中,本文中提供的抗体具有≤1μM、≤100nM、≤50nM、≤10nM、≤5nM、≤1nM、≤0.1nM、≤0.01nM、或≤0.001nM且任选≥10-13M(例如10-8M或更少,例如10-8M至10-13M,例如10-9M至10-13M)的解离常数(Kd)。
在一个实施方案中,Kd是通过如下述测定法所述用Fab型式的感兴趣抗体及其抗原实施的放射性标记抗原结合测定法(RIA)测量的。通过在存在未标记抗原的滴定系列的情况中用最小浓度的(125I)标记抗原平衡Fab,然后用抗Fab抗体包覆板捕捉结合的抗原来测量Fab对抗原的溶液结合亲和力(参见例如Chen等,J.Mol.Biol.293:865-881(1999))。为了建立测定法的条件,将多孔板(Thermo Scientific)用50mM碳酸钠(pH9.6)中的5μg/ml捕捉用抗Fab抗体(Cappel Labs)包覆过夜,随后用PBS中的2%(w/v)牛血清白蛋白于室温(约23℃)封闭2-5小时。在非吸附板(Nunc#269620)中,将100pM或26pM[125I]-抗原与连续稀释的感兴趣Fab混合(例如与Presta等,Cancer Res.57:4593-4599(1997)中抗VEGF抗体,Fab-12的评估一致)。然后将感兴趣Fab温育过夜;然而,温育可持续更长时段(例如约65个小时)以确保达到平衡。此后,将混合物转移至捕捉板,于室温温育(例如1小时)。然后除去溶液并用PBS中的0.1%聚山梨酯20洗板8次。板干燥后,添加150μl/孔闪烁液(MICROSCINT-20TM;Packard),然后在TOPCOUNTTM伽马计数仪(Packard)上对板计数10分钟。选择各Fab给出小于或等于最大结合的20%的浓度用于竞争性结合测定法。
按照另一个实施方案,Kd是使用表面等离振子共振测定法使用或(BIAcore,Inc.,Piscataway,NJ)于25℃使用固定化抗原CM5芯片在约10个响应单位(RU)测量的。简言之,按照供应商的说明书用N-乙基-N’-(3-二甲基氨基丙基)-碳二亚胺盐酸盐(EDC)和N-羟基琥珀酰亚胺(NHS)活化羧甲基化葡聚糖生物传感器芯片(CM5,BIACORE,Inc.)。将抗原用10mM乙酸钠(pH 4.8)稀释至5μg/ml(约0.2μM),然后以5μl/分钟的流速注射以获得约10个响应单位(RU)的偶联蛋白质。注入抗原后,注入1M乙醇胺以封闭未反应基团。为了动力学测量,于25℃以约25μl/分钟的流速注入在含0.05%聚山梨酯20(TWEEN-20TM)表面活性剂的
PBS(PBST)中两倍连续稀释的Fab(0.78nM至500nM)。使用简单一对一朗格缪尔(Langmuir)结合模型(Evaluation软件版本3.2)通过同时拟合结合和解离传感图计算结合速率(kon)和解离速率(koff)。平衡解离常数(Kd)以比率koff/kon计算。参见例如Chen等,J.Mol.Biol.293:865-881(1999)。如果根据上文表面等离振子共振测定法,结合速率超过106M-1s-1,那么可使用荧光淬灭技术来确定结合速率,即根据分光计例如配备了断流装置的分光光度计(Aviv Instruments)或8000系列SLM-AMINCOTM分光光度计(ThermoSpectronic)中用搅拌比色杯进行的测量,在存在浓度渐增的抗原的情况下,测量PBS(pH 7.2)中20nM抗抗原抗体(Fab形式)于25℃的荧光发射强度(激发=295nm;发射=340nm,16nm带通)的升高或降低。
2.接头(L1)
如本文所述,“接头”(L1)是双功能或多功能部分,其可用于将一个或多个药物部分(D)与抗体(Ab)连接以形成ADC。在一些实施方案中,可使用具有反应性官能团的L1以共价附接至药物和抗体来制备ADC。例如,在一些实施方案中,抗体(Ab)的半胱氨酸硫醇可与接头的反应性官能团或接头L1-药物中间体形成键以制备ADC。具体地,接头的化学结构可对ADC的功效和安全性具有显著影响(Ducry&Stump,Bioconjugate Chem,2010,21,5-13)。选择合适的接头影响适当的药物递送至靶细胞的预期细胞区室。
接头通常可分为两类:可切割的(例如肽、腙或二硫化物)或不可切割的(例如硫醚)。可通过溶酶体酶(例如组织蛋白酶B)水解的肽接头例如缬氨酸-瓜氨酸(Val-Cit)已经用于将药物与抗体连接(US 6,214,345)。它们特别有用,部分原因在于它们在体循环中的相对稳定性和在肿瘤中有效释放药物的能力。然而,天然肽代表的化学空间是有限的;因此,需要具有多种非肽接头,其作用类似于肽且可被溶酶体蛋白酶有效切割。更多样的非肽结构可产生肽接头不能提供的新的有益性质。本文提供了可被溶酶体酶切割的接头L1的不同类型的非肽接头。
a.肽模拟物接头
本文提供了用于ADC的不同类型的非肽肽模拟物接头,其可被溶酶体酶切割。例如,二肽(例如Val-Cit)中间的酰胺键被酰胺模拟物替代;和/或用非氨基酸部分(例如环烷基二羰基结构(例如环大小=4或5))替代整个氨基酸(例如Val-Cit二肽中的缬氨酸氨基酸)。
当L1是肽模拟物接头时,它由下式表示
—Str—(PM)—Sp—
其中
Str是与Ab共价附接的延伸单元(stretcher unit);
Sp是与生物活性部分共价附接的键或间隔单元(spacer unit);
PM是选自以下的非肽化学部分:
W是-NH-杂环烷基-或杂环烷基;
Y是杂芳基、芳基、-C(O)C1-C6亚烷基、C1-C6亚烷基-NH2、C1-C6亚烷基-NH-CH3、C1-C6亚烷基-N-(CH3)2、C1-C6烯基或C1-C6亚烷基;
每个R6独立地是C1-C10烷基、C1-C10烯基、(C1-C10烷基)NHC(NH)NH2或(C1-C10烷基)NHC(O)NH2;
R7和R8各自独立地是H、C1-C10烷基、C1-C10烯基、芳基烷基或杂芳基或R7和R8一起可形成C3-C7环烷基;
R9和R10各自独立地是C1-C10烷基、C1-C10烯基、芳基烷基、杂芳基、(C1-C10烷基)OCH2-或R9和R10可形成C3-C7环烷基环;
p值是约1至约10;
在实施方案中,Y是杂芳基;R9和R10一起形成环丁基环。
在实施方案中,Y是选自以下的部分:
在实施方案中,Str是由下式表示的化学部分:
其中R11选自C1-C10亚烷基、C1-C10烯基、C3-C8环烷基、(C1-C8亚烷基)O-和C1-C10亚烷基-C(O)N(Ra)-C2-C6亚烷基,其中每个亚烷基可被1至5个选自以下的取代基取代:卤素、三氟甲基、二氟甲基、氨基、烷基氨基、氰基、磺酰基、磺酰胺基团、亚砜基团、羟基、烷氧基、酯基团、羧酸基团、烷基硫基、C3-C8环烷基、C4-C7杂环烷基、芳基、芳基烷基和杂芳基,每个Ra独立地是H或C1-C6烷基;Sp是—Ar—Rb—,其中Ar是芳基或杂芳基,Rb是(C1-C10亚烷基)O-。
在实施方案中,Str具有下式:
其中R12选自C1-C10亚烷基、C1-C10烯基、(C1-C10亚烷基)O-、N(Rc)-(C2-C6亚烷基)-N(Rc)和N(Rc)-(C2-C6亚烷基);其中每个Rc独立地是H或C1-C6烷基;Sp是—Ar—Rb—,其中Ar是芳基或杂芳基,Rb是(C1-C10亚烷基)O-或-C1-C6亚烷基-C(O)NH-。
在实施方案中,L是由下式表示的非肽化学部分:
其中R6是C1-C6烷基、C1-C6烯基、(C1-C6烷基)NHC(NH)NH2或(C1-C6烷基)NHC(O)NH2;
R7和R8各自独立地是H或C1-C10烷基。
在实施方案中,L是由下式表示的非肽化学部分:
其中R6是C1-C6烷基、(C1-C6烷基)NHC(NH)NH2或(C1-C6烷基)NHC(O)NH2;R9和R10一起形成C3-C7环烷基环。
在实施方案中,L是由下式表示的非肽化学部分:
其中R6是C1-C6烷基、(C1-C6烷基)NHC(NH)NH2或(C1-C6烷基)NHC(O)NH2。
在一些实施方案中,所述接头可以是肽模拟物接头例如WO2015/095227、WO2015/095124或WO2015/095223中所述的那些,所述文献的全部内容通过引用并入本文。
b.非肽模拟物接头
在一个方面,接头L1与抗体形成二硫键且所述接头具有如下结构:
其中R1、R2、R3和R4独立选自H、任选取代的支链或直链C1-C5烷基和任选取代的C3-C6环烷基或R3和R4与和它们结合的碳原子一起形成C3-C6环烷基环。所述接头如下与抗体和药物共价结合:
在另一方面,接头L1具有能够与具有其中存在游离硫醇的半胱氨酸的抗体反应以形成共价键的官能团。非限制性示例性的此类反应性官能团包括马来酰亚胺、卤代乙酰胺、α-卤代乙酰基、活化酯例如琥珀酰亚胺酯、4-硝基苯酯、五氟苯酯、四氟苯酯、酸酐、酰氯、磺酰氯、异氰酸酯和异硫氰酸酯。参见例如Klussman等(2004),Bioconjugate Chemistry 15(4):765-773的第766页的缀合方法和本文的实施例。
在一些实施方案中,接头具有能够与抗体上存在的亲电子基团反应的官能团。示例性的此类亲电子基团包括但不限于醛和酮羰基。在一些实施方案中,接头的反应性官能团的杂原子可与抗体上的亲电子基团反应并与抗体单元形成共价键。非限制性示例性的此类反应性官能团包括但不限于酰肼、肟、氨基、肼、缩氨基硫脲(thiosemicarbazone)、肼羧酸盐和芳基酰肼。
接头可包含一个或多个接头组件。示例性接头组件包括6-马来酰亚胺己酰基(“MC”)、马来酰亚胺丙酰基(“MP”)、缬氨酸-瓜氨酸(“val-cit”或“vc”)、丙氨酸-苯丙氨酸(“ala-phe”)、对氨基苄氧基羰基(“PAB”)、N-琥珀酰亚胺基4-(2-吡啶基硫基)戊酸酯(“SPP”)和4-(N-马来酰亚胺基甲基)环己烷-1-羧酸酯(“MCC”)。各种接头组件是本领域已知的,其中一些在下面描述。
接头可以是促进药物释放的“可切割的接头”。非限制性示例性可切割接头包括酸不稳定性接头(例如包含腙)、蛋白酶敏感性(例如肽酶敏感性)接头、光不稳定性接头或含二硫化物的接头(Chari等,Cancer Research52:127-131(1992);US 5208020)。
在某些实施方案中,接头具有下式:
-Aa-Ww-Yy-
其中A是“延伸单元”且a是0至1的整数;W是“氨基酸单元”且w是0至12的整数;Y是“间隔单元”且y是0、1或2。此类接头的示例性实施方案描述于美国专利No.7,498,298中,其通过引用明确并入本文。
在一些实施方案中,接头组件包含使抗体与另一个接头组件或生物活性部分连接的“延伸单元”。非限制性示例性延伸单元如下所示(其中波浪线表示与抗体、生物活性或其他接头组件共价附接的位点):
3.药物(D)
本文使用的术语“药物”是指包含含仲氮的杂芳基的生物活性分子。术语“仲氮”是指可用于共价官能化的氮。也就是说,药物具有含仲氮的杂芳基,其中所述氮能够如本文进一步定义的那样与接头(L1)形成共价键。仲氮可存在于药物分子的任意部分内的药物中,无论是高度取代的核心官能团还是可取代或可不取代的侧链部分(pendant piece)的一部分。例如,药物可含有杂芳基例如吲哚、吲唑、苯并咪唑、苯并三唑、吡咯、吡咯并吡啶、咪唑、三唑、四唑等。具体实例包括但不限于以下杂芳基结构:
杂芳基也可按交替的互变异构形式存在,如可参见以下非限制性实例:
上述杂芳基可按许多形式被取代,例如另外的官能化或稠合环。仲氮可按结构如N-H表示。应理解这意味着在ADC中,N-H是指药物在ADC中的附接点:
本文使用的术语“生物活性分子”是指能够在生物学背景(例如生物体、细胞、体外模型或体内系统)中执行功能或作用或刺激或响应功能的小分子。特别是,能够治疗受试者的疾病或病症的小分子。该功能可与受体、酶、离子通道、靶标等相关。
有用的药物可包括抑制或阻止细胞功能和/或引起细胞死亡或破坏的细胞毒性剂;生长抑制剂;酶及其片段,例如核溶酶;抗生素;毒素,例如小分子毒素或细菌、真菌、植物或动物来源的酶活性毒素,包括其片段和/或变体;抗肿瘤剂或抗癌剂,例如烷化剂;烷基磺酸酯;氮杂环丙烷类;乙撑亚胺类和甲基蜜胺类;acetogenin(特别是Bullatacin和Bullatacinone);反义寡核苷酸,特别是那些抑制与异常细胞增殖有关的信号传导通路中基因表达的寡核苷酸;拓扑异构酶1抑制剂;蛋白酶体抑制剂;EGFR抑制剂;酪氨酸激酶抑制剂;丝氨酸-苏氨酸激酶抑制剂;法尼基转移酶抑制剂;和任何上述的药学上可接受的盐、酸或衍生物。
另外的药物包括“抗激素剂”或“内分泌治疗剂”,其用于调节、减少、阻断或抑制可促进癌症生长的激素的作用。它们本身可以是激素,包括但不限于:具有混合激动剂/拮抗剂特性的抗雌激素;选择性雌激素受体调节剂(SERM);没有激动剂性质的纯抗雌激素;芳香酶抑制剂,包括甾体芳香酶抑制剂和非甾体芳香酶抑制剂;促黄体激素释放激素激动剂;性类固醇;雌激素;和雄激素/类视黄醇;雌激素受体下调因子(ERD);抗雄激素;和任何上述的药学上可接受的盐、酸或衍生物。
本文用于辅助疗法的术语“免疫抑制剂”是指用于抑制或掩盖本文所治疗的哺乳动物免疫系统的物质。这将包括抑制细胞因子产生、下调或抑制自身抗原表达或掩盖MHC抗原的物质;非甾体抗炎药(NSAID);抗炎剂;环氧合酶抑制剂、白三烯受体拮抗剂;嘌呤拮抗剂;类固醇;二氢叶酸还原酶抑制剂;抗疟剂。
包含含仲氮的杂芳基的药物的非限制性实例是鹅膏毒素、长春碱、长春新碱、倍癌霉素A、倍癌霉素SA、CC-1065、阿多来新、U-76074、U-73073、卡折来新(U-80244)、KW-2189、diazonamide A、埃索美拉唑、阿立哌唑、缬沙坦、兰索拉唑、雷贝拉唑、培美曲塞、奥美沙坦、他达拉非、泮托拉唑、坎地沙坦、奥美拉唑、舒尼替尼、培美曲塞、阿来替尼、达卡巴嗪、司马沙尼、达西斯特、多韦替尼、甲苯达唑和匹莫苯丹。药物的实例还包括以下化合物:
另外,本领域普通技术人员将认识到存在更多包含含氮杂芳基的生物活性分子的实例,其尚未接受正式名称,但仍已经历将所述分子置于如本文定义的类别中的测试。
本文描述的主题还包括式I的抗体-药物缀合物的药学上可接受的盐。
如果式I的抗体-药物缀合物是阳离子的或具有可以是阳离子的官能团(例如NH2可以是NH3 +),则可通过本领域可用的任何合适的方法制备所需的药学上可接受的盐,例如用无机酸,例如盐酸、氢溴酸、硫酸、硝酸、甲磺酸、磷酸等或用有机酸,例如乙酸、马来酸、琥珀酸、扁桃酸酸、富马酸、丙二酸、丙酮酸、草酸、乙醇酸、水杨酸、吡喃糖苷酸(例如葡萄糖醛酸或半乳糖醛酸)、α羟基酸(例如柠檬酸或酒石酸)、氨基酸(例如天冬氨酸或谷氨酸)、芳香族酸(例如苯甲酸或肉桂酸)、磺酸(对甲苯磺酸或乙磺酸)等处理游离碱。
如果式I的抗体-药物缀合物是阴离子的或具有可以是阴离子的官能团(例如-COOH可以是-COO-),则可通过任何合适的方法制备所需的药学上可接受的盐,例如用无机或有机碱,例如胺(伯、仲或叔胺)、碱金属氢氧化物或碱土金属氢氧化物等处理游离酸。合适的盐的说明性实例包括但不限于衍生自氨基酸(例如甘氨酸和精氨酸)、氨、伯胺、仲胺和叔胺及环状胺(例如哌啶、吗啉和哌嗪)的有机盐,和衍生自钠、钙、钾、镁、锰、铁、铜、锌、铝和锂的无机盐。
其他合适的盐的说明性实例包括但不限于衍生自氨基酸(例如甘氨酸和精氨酸)、氨、伯胺、仲胺和叔胺及环状胺(例如哌啶、吗啉和哌嗪)的有机盐,和衍生自钠、钙、钾、镁、锰、铁、铜、锌、铝和锂的无机盐。
提供以下实施例是为了说明而不是为了限制。
实施例
实施例1.分析型LCMS条件
条件A
实验在SHIMADZU 20A HPLC(具有PDA检测器)和SHIMADZU 2010EV MSD质谱仪上使用ESI作为电离源进行。LC分离使用MK RP18e25-2mm柱以1.5mL/min流速进行。溶剂A是1.5mL TFA/4L水,溶剂B是0.75mL TFA/4L乙腈。梯度如下构成:5-95%溶剂B经0.7分钟,接着在95%B保持0.4分钟,然后平衡0.4分钟。LC柱温度是50℃。在220nm和254nm监测UV吸光度并对所有实验应用质谱全扫描。
条件B
实验在Agilent 1290UHPLC和Agilent MSD(6140)质谱仪上使用ESI作为电离源进行。LC分离使用Phenomenex XB-C18,1.7μm,50×2.1mm柱,以0.4mL/min流速进行。溶剂A是含0.1%甲酸的水,溶剂B是含0.1%甲酸的乙腈。梯度如下构成:2-98%溶剂B经7分钟,接着在98%B保持1.5分钟,然后平衡1.5分钟。LC柱温度是40℃。在220nm和254nm监测UV吸光度并对所有实验应用质谱全扫描。
条件C
实验在配有Waters LCT Premier XE质谱仪的Waters Acquity UPLC上使用ESI电离进行。LC分离使用Acquity UPLC BEH C18,1.7μm,2.1×50mm柱和0.6mL/min流速进行。溶剂A是含0.05%甲酸的水,溶剂B是含0.05%甲酸的乙腈。梯度如下构成:2-98%溶剂B经5分钟,接着在98%B保持0.5分钟,然后平衡0.5分钟。LC柱温度是40℃。在220nm和254nm监测UV吸光度并对所有实验应用质谱全扫描。
实施例2.(E)-3-(3,5-二氟-4-((1R,3R)-2-(2-氟-2-甲基丙基)-3-甲基-9-(((R)-2-((5-硝基吡啶-2-基)二硫基)丙氧基)羰基)-2,3,4,9-四氢-1H-吡啶并[3,4-b]吲哚-1-基)苯基)丙烯酸(化合物8)的合成
步骤1:(E)-3-(3,5-二氟-4-((1R,3R)-2-(2-氟-2-甲基丙基)-3-甲基-2,3,4,9-四氢-1H-吡啶并[3,4-b]吲哚-1-基)苯基)丙烯酸
向化合物1(按照J.Med.Chem.2015,58,8128制备;500mg,1.1mmol)于MeOH(100mL)/水(25mL)中的溶液中添加NaOH水溶液(3.0M,9.0mL,27mmol)。将混合物在25℃搅拌18小时后,将其浓缩至约5.0mL,倒入1.0M HCl(10mL)中并用EtOAc(3×50.0mL)萃取。合并的有机层经Na2SO4干燥并浓缩,得到粗品2(400mg,83%),其是黄色固体。该物质直接用于下一步。
步骤2:(E)-3-(3,5-二氟-4-((1R,3R)-2-(2-氟-2-甲基丙基)-3-甲基-2,3,4,9-四氢-1H-吡啶并[3,4-b]吲哚-1-基)苯基)丙烯酸叔丁酯
向化合物2(400.0mg,0.90mmol)于DCM(5.0mL)中的溶液中添加2,2,2-三氯亚氨代乙酸叔丁酯(15mL,83.89mmol)。将混合物在25℃搅拌60小时,用水(3×50.0mL)、盐水(50.0mL)洗涤并经Na2SO4干燥。浓缩有机层并通过柱色谱(10%EtOAc/石油醚)纯化,得到3(310mg,69%),其是黄色固体。
步骤3:(R)-2-(三苯甲基硫基)丙-1-醇
将TFA(0.40mL,5.23mmol)添加至化合物4(如WO 2013055987中所述制备;482.0mg,5.23mmol)和三苯基甲醇(953mg,3.66mmol)于CHCl3(25mL)中的溶液中。将混合物在25℃搅拌5小时,然后用DCM(25mL)稀释。将所得溶液用饱和NaHCO3(50.0mL)洗涤,经Na2SO4干燥并减压浓缩。通过快速柱色谱(20%EtOAc/石油醚,Rf=0.5)纯化残余物,得到化合物5(600mg,34%),其是黄色油状物。
步骤4:氯甲酸(R)-2-(三苯甲基硫基)丙基酯
在0℃历经2分钟向化合物5(600mg,1.79mmol)于DCM(5.0mL)中的溶液中添加双光气(497mg,2.51mmol)。然后历经1分钟添加DIEA(232mg,1.79mmol)。将混合物在0℃搅拌1小时,然后在25℃搅拌2.0小时。将反应混合物浓缩并溶于THF(1.0mL)。然后添加庚烷直至白色固体出现。该固体通过硅藻土过滤除去。减压浓缩滤液,得到化合物6(710mg,99.7%),其是白色固体。该物质直接用于下一步。
步骤5:(1R,3R)-1-(4-((E)-3-(叔丁氧基)-3-氧代丙-1-烯-1-基)-2,6-二氟苯基)-2-(2-氟-2-甲基丙基)-3-甲基-1,2,3,4-四氢-9H-吡啶并[3,4-b]吲哚-9-甲酸(R)-2-(三苯甲基硫基)丙基酯
在0℃向化合物3(140.0mg,0.280mmol)于DMF(2.0mL)中的溶液中添加氢化钠(60%,7.41mg,0.310mmol)。将所得混合物在25℃搅拌30分钟,然后添加化合物6(111mg,0.280mmol)于DMF(1.0mL)中的溶液。将混合物在25℃搅拌1.0小时后,将其减压浓缩并通过柱色谱(10%EtOAc/石油醚,Rf=0.6)纯化残余物,得到化合物7(92mg,38%)。LCMS(条件A):RT=1.12min,m/z=859.3[M+H]+。
步骤6:(E)-3-(3,5-二氟-4-((1R,3R)-2-(2-氟-2-甲基丙基)-3-甲基-9-(((R)-2-((5-硝基吡啶-2-基)二硫基)丙氧基)羰基)-2,3,4,9-四氢-1H-吡啶并[3,4-b]吲哚-1-基)苯基)丙烯酸
将TFA(0.30mL)添加至化合物7(80.0mg,0.090mmol)、三异丙基硅烷(16.2mg,0.10mmol)和2,2’-二硫基双(5-硝基吡啶)(86.7mg,0.280mmol)于DCM(1.0mL)中的溶液中。将混合物在25℃搅拌18小时后,添加甲苯(40.0mL)。浓缩混合物并通过柱色谱(50%EtOAc/石油醚)纯化残余物,得到化合物8(27.2mg,37%),其是黄色固体。LCMS(条件A):RT=0.92min,m/z=715.0[M+Na]+;1H NMR(400MHz,CDCl3)δ9.12(s,1H),8.10-8.04(m,2H),7.70-7.68(d,J=8.8Hz,1H),7.51-7.42(m,2H),7.24-7.23(m,3H),7.12-6.89(m,1H),6.32-6.28(d,J=15.9Hz,1H),5.76(br,1H),4.22-4.18(m,2H),3.27-3.15(m,1H),2.67-2.45(m,4H),2.22-2.11(m,1H),1.41-1.36(m,3H),1.19-1.07(m,3H),0.89-0.81(m,3H)。
实施例3.(E)-3-(3,5-二氟-4-((1R,3R)-2-(2-氟-2-甲基丙基)-3-甲基-9-((2-((5-硝基吡啶-2-基)二硫基)乙氧基)羰基)-2,3,4,9-四氢-1H-吡啶并[3,4-b]吲哚-1-基)苯基)丙烯酸(化合物13)的合成
步骤1:2-(三苯甲基硫基)乙-1-醇
将TFA(2.2mL,28mmol)添加至化合物9(2.0mL,28.5mmol)和三苯基甲醇(5.2g,20mmol)于CHCl3(100mL)中的溶液中。将混合物在25℃搅拌4小时,然后用DCM(75mL)稀释。将所得溶液用饱和NaHCO3(200mL)洗涤,经MgSO4干燥,过滤并减压浓缩。通过快速柱色谱(0-40%iPrOAc/庚烷)纯化残余物,得到化合物10(2.1g,33%),其是白色固体。1H NMR(400MHz,CDCl3)δ7.47-7.38(m,5H),7.32-7.15(m,10H),3.41(q,J=6.2Hz,2H),2.48(t,J=6.2Hz,2H),1.48(t,J=6.1Hz,1H)。
步骤2:氯甲酸2-(三苯甲基硫基)乙基酯
在0℃历经2分钟向化合物10(1.5mg,4.7mmol)于DCM(30mL)中的溶液中添加双光气(1.3g,6.6mmol)。然后历经1分钟添加DIEA(0.82mL,4.7mmol)。将混合物在0℃搅拌1小时,然后在25℃搅拌3小时。将反应混合物浓缩并重新溶于THF(10mL)。添加庚烷直至白色固体出现(约30mL)。该固体通过硅藻土过滤除去。减压浓缩滤液,得到粗化合物11,其是黄色油状物。该物质直接用于下一步。
步骤3:(1R,3R)-1-(4-((E)-3-(叔丁氧基)-3-氧代丙-1-烯-1-基)-2,6-二氟苯基)-2-(2-氟-2-甲基丙基)-3-甲基-1,2,3,4-四氢-9H-吡啶并[3,4-b]吲哚-9-甲酸2-(三苯甲基硫基)乙基酯
在0℃将氢化钠(60%,61mg,1.53mmol)添加至化合物3(693mg,1.39mmol)于DMF(25mL)中的溶液中。将所得混合物在25℃搅拌30分钟,然后添加化合物11(532mg,1.39mmol)于DMF(5.0mL)中的溶液。将混合物在25℃搅拌10分钟后,减压除去挥发物。将残余物在iPrOAc(2×150mL)和0.5M HCl(150mL)之间分配。将合并的有机层经MgSO4干燥,过滤并减压浓缩。通过柱色谱(0-20%iPrOAc/庚烷)纯化残余物,得到化合物12(189mg,16%),其是白色泡沫状物。1H NMR(400MHz,CDCl3)δ8.14(d,J=7.5Hz,1H),7.49-7.13(m,11H),6.79(d,J=10.5Hz,2H),6.23(d,J=15.9Hz,1H),5.74-5.70(m,1H),4.99(七重峰,J=6.3Hz,1H),3.86(t,J=7.0Hz,1H),3.84-3.76(m,1H),3.72-3.62(m,1H),3.36-3.24(m,1H),2.68(dd,J=16.7,4.6Hz,1H),2.63-2.42(m,6H),2.36-2.27(m,1H),1.54(s,3H),1.53(s,9H),1.44(d,J=21.7Hz,3H),1.27(d,J=21.1Hz,3H),1.12(d,J=6.7Hz,3H)。
步骤4:(E)-3-(3,5-二氟-4-((1R,3R)-2-(2-氟-2-甲基丙基)-3-甲基-9-((2-((5-硝基吡啶-2-基)二硫基)乙氧基)羰基)-2,3,4,9-四氢-1H-吡啶并[3,4-b]吲哚-1-基)苯基)丙烯酸
将TFA(0.30mL)添加至化合物12(18mg,0.021mmol)、三异丙基硅烷(16.2mg,0.10mmol)和2,2’-二硫基双(5-硝基吡啶)(20mg,0.064mmol)于DCM(1.0mL)中的溶液中。将混合物在25℃搅拌16小时后,添加甲苯(40.0mL)。浓缩混合物,经反相HPLC(柱=Gemini-NXC18 5um,110A,50×30mm,温度=25℃;洗脱液:A=0.1%甲酸水溶液,B=乙腈;50-90%B历经10分钟,流速=60mL/min;检测=270nm)纯化残余物,得到化合物13(7.0mg,50%),其是灰白色固体。LCMS(条件B):RT=7.24min,m/z=701.2[M+H]+;1HNMR(400MHz,DMSO-d6)δ9.13(d,J=2.6Hz,1H),8.36(dd,J=8.8,2.7Hz,1H),8.09-7.99(m,1H),7.91(d,J=8.9Hz,1H),7.59-7.50(m,1H),7.43(d,J=16.0Hz,1H),7.33-7.25(m,3H),6.58(d,J=16.0Hz,1H),5.75(s,1H),4.50-4.35(m,2H),3.23-3.03(m,5H),2.80-2.52(m,4H),1.39(d,J=21.5Hz,3H),1.26(d,J=21.1Hz,3H),1.10(d,J=6.7Hz,3H)。
实施例4.6-(苄基氧基)-1H-吲哚-1,2-二甲酸1-(4-((S)-2-((S)-2-((叔丁氧基羰基)氨基)-3-甲基丁酰氨基)-5-脲基戊酰氨基)苄基)酯·2-甲基酯(化合物17)的合成
步骤1:6-(苄基氧基)-1H-吲哚-1,2-二甲酸2-甲基酯·1-(4-硝基苯基)酯
在0℃将氢化钠(60%,235mg,5.88mmol)添加至化合物14(1.74g,6.19mmol)于THF(50mL)中的溶液中。将所得混合物在25℃搅拌2.5小时并添加氯甲酸4-硝基-苯基酯(1.22g,5.88mmol)于THF(15mL)中的溶液。将混合物在25℃搅拌4.0小时后,将其通过硅藻土过滤。减压浓缩滤液,得到黄色油状物。将该物质溶于Et2O(100mL)和庚烷(40mL)的混合物并将所得溶液减压浓缩直至固体出现(约80mL体积)。通过真空过滤收集固体并空气干燥过夜,得到粗品15(1.22g),其混杂有显著量(约33%)的未知杂质。该物质无需进一步纯化即用于下一步骤。
步骤2:6-(苄基氧基)-1H-吲哚-1,2-二甲酸1-(4-((S)-2-((S)-2-((叔丁氧基羰基)氨基)-3-甲基丁酰氨基)-5-脲基戊酰氨基)苄基)酯·2-甲基酯
将粗化合物15(135mg,约0.252mmol)、二肽16(如WO 2015162293和WO 2015162293中所述制备;0.028g,0.036mmol)和DMAP(0.030g,0.246mmol)于DMF(10mL)中的溶液在25℃搅拌5天。然后减压除去挥发物,通过制备型HPLC(柱=Gemini-NX C18 5um,110A,50×30mm,温度=25℃;洗脱液:A=0.1%氢氧化铵水溶液,B=乙腈;40-80%B历经10分钟,流速=60mL/min;检测=254nm)纯化残余物,得到化合物17(0.028g,14%),其是灰白色固体。LCMS(条件B):RT=6.22min,m/z=787.4[M+H]+;1HNMR(400MHz,DMSO-d6)δ10.13(s,1H),7.99(d,J=7.7Hz,1H),7.69-7.59(m,3H),7.54(d,J=2.3Hz,1H),7.48-7.30(m,7H),7.28(d,J=0.8Hz,1H),7.04(dd,J=8.7,2.3Hz,1H),6.74(d,J=8.9Hz,1H),5.95(t,J=5.9Hz,1H),5.40(br s,2H),5.36(s,2H),5.09(s,2H),4.50-4.41(m,1H),3.87-3.81(m,1H),3.71(s,3H),3.07-2.88(m,2H),2.01-1.90(m,1H),1.73-1.52(m,2H),1.38(s,9H),0.86(d,J=6.8Hz,3H),0.81(d,J=6.8Hz,3H)。
实施例5.6-(苄基氧基)-1H-吲哚-1,2-二甲酸2-甲基酯·1-(2-(三苯甲基硫基)乙基)酯(化合物18)的合成
在0℃将氢化钠(60%,78mg,1.96mmol)添加至化合物14(500mg,1.78mmol)于DMF(15mL)中的溶液中。将所得混合物在25℃搅拌45分钟,然后添加化合物11(681mg,1.78mmol)于DMF(5.0mL)中的溶液。将混合物在25℃搅拌1.0小时后,将其在iPrOAc(2×150mL)和0.5M HCl(150mL)之间分配。合并的有机层经MgSO4干燥,过滤并减压浓缩。通过柱色谱(0-30%iPrOAc/庚烷)纯化残余物,得到化合物18(440mg,39%),其是白色泡沫。LCMS(条件C):RT=5.26min,m/z=628.1[M+H]+;1H NMR(400MHz,DMSO-d6)δ7.63(dd,J=8.7,0.4Hz,1H),7.56(dt,J=2.2,0.6Hz,1H),7.44-7.20(m,21H),7.05(dd,J=8.7,2.3Hz,1H),5.15(s,2H),4.13(t,J=6.3Hz,2H),3.75(s,3H),2.57(t,J=6.3Hz,2H)。
实施例6.抗体-药物缀合物的合成
抗HER2 7C2LC K149C和抗B7H4 1D11LC K149C经由经工程化改造的LC K149C半胱氨酸残基与化合物8或化合物13缀合。将10mg/mL的给定抗体于50mM Tris(pH 8.5)中的溶液用50摩尔过量的DTT在环境温度还原16-18小时。使用SP HP阳离子交换色谱纯化还原的抗体。将于50mM Tris pH8中的经纯化抗体使用15摩尔过量的DHAA于DMA中的溶液在环境温度再氧化2-3小时。将抗体使用SP HP阳离子交换柱再次纯化以除去DHAA和聚集物。将3至5倍摩尔当量的化合物8或13的DMF溶液添加至5-10mg/mL经纯化的抗体于100mM Tris pH8.5-9.0中的溶液中,然后添加另外的DMF,使最终浓度是10%DMF。然后将偶联反应混合物在环境温度温育3至4小时。使用以下方法之一纯化缀合的抗体:使用HiTrap SP HP树脂的阳离子交换色谱法或通过Zeba spin 7kDa MWCO脱盐树脂,然后使用葡聚糖包覆的木炭除去过量的游离药物。通过用10kDa MWCO Slide-a-Lyzer透析盒透析到20mM乙酸组氨酸pH5.5、240mM蔗糖、0.02%聚山梨酯-20中对所得纯化的缀合物进行配制。
使用缀合反应条件和任一种纯化方案产生的缀合物典型地提供50-80%的蛋白质产率。在聚集(SEC HPLC)、药物与抗体比率(LC/MS)、缀合的硝基吡啶二硫化物(硝基PDS)物质的百分比(LC/MS)和最终缀合物中存在的游离药物的量(LC/MS)方面对所有缀合物进行表征。在所有缀合物中,<5%的与抗体的缀合物质是由与硝基PDS硫缀合而不是与二硫键的药物侧上的硫缀合而产生的硝基PDS。每种缀合物的详细表征数据在下表13中提供。
表13.
实施例7.生物学测定
全血样品制备
在小鼠(CB17SCID)、大鼠(Sprague-Dawley)、食蟹猴和人全血浆及缓冲液(0和24小时时间点)中产生稳定性样品。通过Bioreclamation收集血液,然后冷运输过夜并在到达时立即制备样品。为了制备稳定性样品,在缓冲液(1×PBS,0.5%BSA,15ppm proclin)中制备源缀合物的初始稀释液,使得所有分子的浓度均为1mg/mL。然后进行1:10×稀释(36μL的1mg/mL初始稀释+324μL血液或缓冲液)以产生最终化合物浓度为100μg/mL的稳定性样品。混合后,将150μL全血/缓冲液稳定性样品等分为针对两个不同时间点的分开的两组管。然后将0小时时间点置于-80℃冰箱中,将24小时时间点置于37℃培养箱中的振荡器上。当24小时样品达到给定时间点时,它们也被置于-80℃冰箱中。
用于全血样品的稳定性测定的亲和力捕获LC-MS测定
使用亲和力捕获LC-MS测定评价全血稳定性样品。首先,用HBS-EP缓冲液(GEHealthcare,Sunnyvale,CA)将链霉亲和素包覆的磁珠(Life Technologies Corporation,Grand Island,NY)洗涤2次,然后使用KingFisher Flex(Thermo Fisher Scientific,Waltham,MA)与生物素化的HER2抗独特型抗体混合并在室温温和搅拌2小时。2小时后,将SA-珠/生物素-xId Ab复合物用HBS-EP缓冲液洗涤2次,与稀释的全血稳定性样品混合,然后在室温温和搅拌2小时。2小时后,将SA-珠/生物素-xId Ab/样品复合物用HBS-EP缓冲液洗涤2次,与去糖基化酶PNGase F(New England BioLabs,Ipswich,MA)混合并在37℃温和搅拌温育过夜。温育过夜后,将去糖基化的SA-珠/生物素-xId Ab/样品复合物用HBS-EP缓冲液洗涤2次,然后用水(Optima H2O,Fisher Scientific,Pittsburgh,PA)洗涤2次,最后用10%乙腈洗涤1次。将珠子置于30%乙腈/0.1%甲酸中进行洗脱,其中将其在室温伴随温和搅拌温育30分钟,然后收集珠子。将洗脱的样品进样并加载到保持在65℃的ThermoScientific PepSwift RP整体柱(500μm×5cm)上。使用Waters Acquity UPLC系统以20μL/min流速用以下梯度在柱上分离样品:0-2分钟时20%B(95%乙腈+0.1%甲酸);2.5分钟时35%B;5分钟时65%B;5.5分钟时95%B;6分钟时5%B。将柱直接偶联用于在线检测,使用以正ESI操作的Waters Synapt G2-S Q-ToF质谱,获得质量范围是500至5000Th(m/z)。
乳腺癌细胞ERα高含量荧光成像测定(F10)
MCF7-neo/HER2乳腺癌细胞在第1天以每孔10,000个细胞的密度接种于384孔聚赖氨酸包覆的组织培养板(Greiner#T-3101-4)(50μL/孔RPMI(不含酚红),10%FBS(炭剥离),含有L-谷氨酰胺)。第2天,将抗体缀合物在室温解冻并在37℃生长培养基中各自稀释至60μg/mL,接着在384孔板(Ref:781091)上进行20点2×连续稀释。将来自连续稀释的10μL每种样品转移至细胞板的孔中。ADC的最高工作浓度是10μg/mL。没有处理细胞板第1、2、23和24列以用于数据归一化,而第3-22列则包含ADC稀释液。用化合物处理后,将细胞板在37℃培养箱中保存72小时。固定和透化在第5天使用Biotek EL406洗板机和分配器如下进行。通过在Biotek EL406上使用蠕动泵5μL盒直接向每孔中的50μL细胞培养基中添加15μL 16%多聚甲醛(Electron Microscopy Sciences#15710-S)固定细胞(甲醛的最终浓度是3.7%w/v)。将样品温育30分钟。抽吸孔内容物,向每个孔中添加50μL/孔含有0.5%w/v牛血清白蛋白和0.5%v/v Triton X-100(抗体稀释缓冲液)的磷酸盐缓冲盐水(PBS)。将样品温育30分钟。吸出孔内容物并用100μL/孔的PBS洗涤3次。雌激素受体α(ESR1)的免疫荧光染色使用Biotek EL406洗板机和分配器如下进行。从孔中吸出孔上清液并分配25μL/孔的在抗体稀释缓冲液中1:1000稀释的抗ESR1mAb(F10)(Santa Cruz sc-8002)。将样品在室温温育2小时,然后用100μL/孔的PBS洗涤4次。将25μL/孔的二抗溶液(以1:1000稀释的Alexafluor488缀合物抗小鼠IgG(LifeTechnologies#A21202)和在抗体稀释缓冲液中稀释的1μg/mLHoechst 33342)分配至每个孔中。将样品在室温温育2小时,然后使用Biotek EL406用100μL/孔的PBS洗涤3次。使用Cellomics Arrayscan V(Thermo)进行ESR1的定量荧光成像。对于两个通道而言,样品的荧光图像[通道1:XF53Hoechst(DNA染色);通道2:XF53FITC(ESR1染色)]使用Cellomics VTI Arrayscan使用Bioapplication“Compartmental Analysis”使用自动曝光(基于DMSO对照孔)设置“峰值目标百分位数”设置为25%目标饱和度来获得。通道1(DNA染色)用于定义核区域(Circ)。测量“Mean_CircAvgIntCh2”即核区域内的Alexafluor488荧光强度(ESR1)基于每个细胞测量并在所有测量的细胞上取平均值。使用GraphPadPrism 6进行数据分析,使用经DMSO和未经一抗对照处理的样品来定义ESR1的0%和100%变化。剂量-响应log(抑制剂)vs.响应用于定义曲线的拐点(EC50)和最大效应的坪(plateau)。
MCF7-neo/HER2衍生的肿瘤中ERα水平的体内调节
人乳腺癌MCF7细胞最初从美国典型培养物保藏中心(Rockville,MD)获得并在Genentech进行工程化改造以过表达HER2以产生MCF7-neo/HER2。在肿瘤细胞植入前4天,55只雌性NCR裸鼠(Taconic)随意取用含有0.8μg/mL17β-雌二醇(Sigma;St.Louis,MO)/0.003%乙醇的雌激素强化水。将重悬于50%无酚红的基质胶(Becton DickinsonBioscience;San Jose,CA)和Hank平衡盐溶液中的MCF7-neo/HER2细胞皮下接种在2/3乳腺脂肪垫中。每只小鼠注射5×106个细胞。监测肿瘤直至它们达到约400mm3的肿瘤体积。在肿瘤植入后17天(给药缀合物前4天),将小鼠分成5组,每组4只小鼠,除去雌激素强化水并用随意取用的常规饮用水替代。在肿瘤植入后21天,指定为研究的第1天,以200μL体积给予小鼠单次静脉内注射媒介物(20mM乙酸组氨酸pH 5.5,240mM蔗糖,0.02%聚山梨酯20),CNJ-1(HER2)(2、10或25mg/kg)或CNJ-2(B7H4)(25mg/kg)。经由眼眶后取血收集给药后24小时的血液并处理得到血清。第4天,对所有小鼠实施安乐死并收集肿瘤和血液。将肿瘤在-80℃快速冷冻并处理血液得到血清。
对于蛋白质提取,将每个冷冻的肿瘤转移至tissueTUBE(Covaris)并使用设定为冲击水平5的cryoPREP冲击器(Covaris)进行冷冻破碎。将一半粉碎的肿瘤样品重悬于300μL细胞提取缓冲液(FNN0011,Life Technologies)中,所述细胞提取缓冲液补充有蛋白酶抑制剂混合物(Roche)、磷酸酶抑制剂混合物(Sigma)并含有一个1/8”Coneball(Glenmills)和两个3mm Zirconia珠(Glenmills)。将样品在Geno Grinder(SPEX Sample Prep)中以1,500rpm匀化1.5分钟并通过离心(14,000rpm,4℃,10分钟)两次使提取物干净。通过BCA测定(Thermo Fisher Scientific)确定蛋白质浓度。对于每个肿瘤样品,使用MOPS缓冲液(Thermo Fisher Scientific)在4-12%NuPAGE Bis-Tris凝胶上分离26μg总蛋白并转移至硝酸纤维素膜。将膜在Odyssey封闭缓冲液(LI-COR,目录号927-40000)中封闭1小时并与针对ERα的一抗(稀释度1:1000,Novus Biologicals,目录号NBP2-26481)和β-微管蛋白(稀释度1:1000,LI-COR,目录号926-42212)温育过夜。三次在PBS-吐温中洗涤15分钟后,将膜与二抗IR Dye 800CW驴抗兔(稀释度1:10,000,LI-COR,目录号926-32213)和IR Dye 680RD驴抗小鼠(稀释度1:10,000,LI-COR,目录号926-68072)温育45分钟。三次在PBS-吐温中洗涤15分钟后,使用Odyssey CLx仪器(LI-COR)扫描膜并定量ERα和微管蛋白水平。使用Excel计算ERα/微管蛋白比率和平均值的标准误差(SEM)并使用Prism 6(Graphpad)绘图。
已经努力确保关于所使用的数字(例如量、温度等)的准确性,但是应该考虑一些实验误差和偏差。
本领域技术人员将认识到与本文所述的那些类似或等同的许多方法和材料,其可用于实践本文所述的主题。本公开绝不仅限于所描述的方法和材料。
除非另外定义,否则本文使用的技术和科学术语具有与本申请所属领域的普通技术人员通常理解的含义相同的含义且与以下内容相符:Singleton等(1994)Dictionary ofMicrobiology and Molecular Biology,第2版,J.Wiley&Sons,New York,NY;和Janeway,C.,Travers,P.,Walport,M.,Shlomchik(2001)Immunobiology,第5版,GarlandPublishing,New York。
在整个说明书和权利要求书中,除非上下文另有要求,否则词语“包括”、“包含”和“含有”以非排他性的含义使用。应理解本文描述的实施方案包括“由实施方案组成”和/或“基本上由实施方案组成”。
本文使用的术语“约”,在提及值时,意在涵盖以下偏差:在一些实施方案中,指定量±50%;在一些实施方案中,指定量±20%;在一些实施方案中,指定量±10%;在一些实施方案中,指定量±5%;在一些实施方案中,指定量±1%;在一些实施方案中,指定量±0.5%;且在一些实施方案中,指定量±0.1%;因为此类偏差适合于实施所公开的方法或使用所公开的组合物。
在提供一系列值的情况下,应理解除非上下文另有明确规定,否则在范围的上限和下限与所述范围内的任何其他所述或中间值之间的每个中间值,至下限单位的十分之一,均涵盖在内。除了在所述范围内的任何特别排除的限制之外,还涵盖可独立地包括在较小的范围内的这些小范围的上限和下限。如果所述范围包括一个或两个界限值,则还包括排除这些界限值中的一个或两个的范围。
受益于前述描述和相关附图中呈现的教导,本申请所属领域的技术人员将想到本文阐述的许多修改和其他实施方案。因此,应理解主题不限于所公开的特定实施方案且修改和其他实施方案旨在包括在所附权利要求的范围内。尽管本文采用了特定术语,但它们仅以一般性和描述性意义使用,而不是出于限制的目的。
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<110> 豪夫迈·罗氏有限公司(F. Hoffmann-La Roche AG)
基因泰克公司(Genentech, Inc.)
<120> 制备抗体药物缀合物的方法
<130> P33806-WO
<140>
<141>
<150> 62/404,514
<151> 2016-10-05
<160> 98
<170> PatentIn version 3.5
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Trp Met Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Met Ile His Pro Leu Asp Ala Glu Ile Arg Ala Asn Gln Lys Phe
50 55 60
Arg Asp Arg Val Thr Ile Thr Val Asp Thr Ser Thr Ser 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 Thr Tyr Asp Gly Gly Phe Glu Tyr Trp Gly Gln Gly Thr
100 105 110
Leu Val Thr Val Ser Ser
115
<210> 19
<211> 15
<212> PRT
<213> 智人
<400> 19
Arg Ala Ser Gln Ser Val Ser Gly Ser Arg Phe Thr Tyr Met His
1 5 10 15
<210> 20
<211> 7
<212> PRT
<213> 智人
<400> 20
Tyr Ala Ser Ile Leu Glu Ser
1 5
<210> 21
<211> 10
<212> PRT
<213> 智人
<400> 21
Gln His Ser Trp Glu Ile Pro Pro Trp Thr
1 5 10
<210> 22
<211> 5
<212> PRT
<213> 智人
<400> 22
Gly Tyr Trp Met Asn
1 5
<210> 23
<211> 17
<212> PRT
<213> 智人
<400> 23
Met Ile His Pro Leu Asp Ala Glu Ile Arg Ala Asn Gln Lys Phe Arg
1 5 10 15
Asp
<210> 24
<211> 9
<212> PRT
<213> 智人
<400> 24
Gly Thr Tyr Asp Gly Gly Phe Glu Tyr
1 5
<210> 25
<211> 219
<212> PRT
<213> 智人
<400> 25
Asp Ile Val Met Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly
1 5 10 15
Glu Arg Ala Thr Ile Asn Cys Arg Ala Ser Gln Ser Val Ser Gly Ser
20 25 30
Arg Phe Thr Tyr Met His Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro
35 40 45
Lys Leu Leu Ile Lys Tyr Ala Ser Ile Leu Glu Ser Gly Val Pro Asp
50 55 60
Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser
65 70 75 80
Ser Leu Gln Ala Glu Asp Val Ala Val Tyr Tyr Cys Gln His Ser Trp
85 90 95
Glu Ile Pro Pro Trp Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
100 105 110
Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu
115 120 125
Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe
130 135 140
Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln
145 150 155 160
Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser
165 170 175
Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu
180 185 190
Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser
195 200 205
Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
210 215
<210> 26
<211> 448
<212> PRT
<213> 智人
<400> 26
Glu 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 Tyr Ser Phe Thr Gly Tyr
20 25 30
Trp Met Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Met Ile His Pro Leu Asp Ala Glu Ile Arg Ala Asn Gln Lys Phe
50 55 60
Arg Asp Arg Val Thr Ile Thr Val Asp Thr Ser Thr Ser 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 Thr Tyr Asp Gly Gly Phe Glu Tyr Trp Gly Gln Gly Thr
100 105 110
Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro
115 120 125
Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly
130 135 140
Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn
145 150 155 160
Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln
165 170 175
Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser
180 185 190
Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser
195 200 205
Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr
210 215 220
His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser
225 230 235 240
Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg
245 250 255
Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro
260 265 270
Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala
275 280 285
Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val
290 295 300
Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr
305 310 315 320
Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr
325 330 335
Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu
340 345 350
Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys
355 360 365
Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser
370 375 380
Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp
385 390 395 400
Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser
405 410 415
Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala
420 425 430
Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
435 440 445
<210> 27
<211> 17
<212> PRT
<213> 智人
<400> 27
Met Ile His Pro Met Asp Ser Glu Ile Arg Ala Asn Gln Lys Phe Arg
1 5 10 15
Asp
<210> 28
<211> 17
<212> PRT
<213> 智人
<400> 28
Met Ile His Pro Leu Asp Ser Glu Ile Arg Ala Asn Gln Lys Phe Arg
1 5 10 15
Asp
<210> 29
<211> 9
<212> PRT
<213> 智人
<400> 29
Gly Thr Tyr Asp Gly Gly Phe Lys Tyr
1 5
<210> 30
<211> 219
<212> PRT
<213> 智人
<400> 30
Asp Ile Val Met Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly
1 5 10 15
Glu Arg Ala Thr Ile Asn Cys Arg Ala Ser Gln Ser Val Ser Gly Ser
20 25 30
Arg Phe Thr Tyr Met His Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro
35 40 45
Lys Leu Leu Ile Lys Tyr Ala Ser Ile Leu Glu Ser Gly Val Pro Asp
50 55 60
Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser
65 70 75 80
Ser Leu Gln Ala Glu Asp Val Ala Val Tyr Tyr Cys Gln His Ser Trp
85 90 95
Glu Ile Pro Pro Trp Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
100 105 110
Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu
115 120 125
Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe
130 135 140
Tyr Pro Arg Glu Ala Lys Val Gln Trp Cys Val Asp Asn Ala Leu Gln
145 150 155 160
Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser
165 170 175
Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu
180 185 190
Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser
195 200 205
Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
210 215
<210> 31
<211> 448
<212> PRT
<213> 智人
<400> 31
Glu 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 Tyr Ser Phe Thr Gly Tyr
20 25 30
Trp Met Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Met Ile His Pro Leu Asp Ala Glu Ile Arg Ala Asn Gln Lys Phe
50 55 60
Arg Asp Arg Val Thr Ile Thr Val Asp Thr Ser Thr Ser 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 Thr Tyr Asp Gly Gly Phe Glu Tyr Trp Gly Gln Gly Thr
100 105 110
Leu Val Thr Val Ser Ser Cys Ser Thr Lys Gly Pro Ser Val Phe Pro
115 120 125
Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly
130 135 140
Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn
145 150 155 160
Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln
165 170 175
Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser
180 185 190
Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser
195 200 205
Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr
210 215 220
His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser
225 230 235 240
Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg
245 250 255
Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro
260 265 270
Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala
275 280 285
Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val
290 295 300
Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr
305 310 315 320
Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr
325 330 335
Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu
340 345 350
Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys
355 360 365
Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser
370 375 380
Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp
385 390 395 400
Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser
405 410 415
Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala
420 425 430
Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
435 440 445
<210> 32
<211> 11
<212> PRT
<213> 智人
<400> 32
Lys Ala Ser Asp Leu Ile His Asn Trp Leu Ala
1 5 10
<210> 33
<211> 8
<212> PRT
<213> 智人
<400> 33
Tyr Gly Ala Thr Ser Leu Glu Thr
1 5
<210> 34
<211> 9
<212> PRT
<213> 智人
<400> 34
Gln Gln Tyr Trp Thr Thr Pro Phe Thr
1 5
<210> 35
<211> 11
<212> PRT
<213> 智人
<400> 35
Gly Tyr Ser Ile Thr Asn Asp Tyr Ala Trp Asn
1 5 10
<210> 36
<211> 17
<212> PRT
<213> 智人
<400> 36
Gly Tyr Ile Ser Tyr Ser Gly Tyr Thr Thr Tyr Asn Pro Ser Leu Lys
1 5 10 15
Ser
<210> 37
<211> 9
<212> PRT
<213> 智人
<400> 37
Ala Arg Trp Ala Ser Gly Leu Asp Tyr
1 5
<210> 38
<211> 108
<212> PRT
<213> 智人
<400> 38
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 Lys Ala Ser Asp Leu Ile His Asn Trp
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Gly Ala Thr Ser Leu Glu Thr Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Trp Thr Thr Pro Phe
85 90 95
Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg
100 105
<210> 39
<211> 116
<212> PRT
<213> 智人
<400> 39
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Tyr Ser Ile Thr Asn Asp
20 25 30
Tyr Ala Trp Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp
35 40 45
Val Gly Tyr Ile Ser Tyr Ser Gly Tyr Thr Thr Tyr Asn Pro Ser Leu
50 55 60
Lys Ser Arg Phe Thr Ile Ser Arg Asp Thr Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Trp Ala Ser Gly Leu Asp Tyr Trp Gly Gln Gly Thr Leu Val
100 105 110
Thr Val Ser Ser
115
<210> 40
<211> 11
<212> PRT
<213> 智人
<400> 40
Gly Tyr Ser Ile Thr Ser Asp Tyr Ala Trp Asn
1 5 10
<210> 41
<211> 17
<212> PRT
<213> 智人
<400> 41
Gly Tyr Ile Ser Asn Ser Gly Ser Thr Ser Tyr Asn Pro Ser Leu Lys
1 5 10 15
Ser
<210> 42
<211> 15
<212> PRT
<213> 智人
<400> 42
Glu Arg Asn Tyr Asp Tyr Asp Asp Tyr Tyr Tyr Ala Met Asp Tyr
1 5 10 15
<210> 43
<211> 17
<212> PRT
<213> 智人
<400> 43
Lys Ser Ser Gln Ser Leu Leu Tyr Arg Ser Asn Gln Lys Asn Tyr Leu
1 5 10 15
Ala
<210> 44
<211> 7
<212> PRT
<213> 智人
<400> 44
Trp Ala Ser Thr Arg Glu Ser
1 5
<210> 45
<211> 9
<212> PRT
<213> 智人
<400> 45
Gln Gln Tyr Tyr Asn Tyr Pro Arg Thr
1 5
<210> 46
<211> 124
<212> PRT
<213> 智人
<400> 46
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Val Ser Gly Tyr Ser Ile Thr Ser Asp
20 25 30
Tyr Ala Trp Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp
35 40 45
Val Gly Tyr Ile Ser Asn Ser Gly Ser Thr Ser Tyr Asn Pro Ser Leu
50 55 60
Lys Ser Arg Phe Thr Ile Ser Arg Asp Thr Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Glu Arg Asn Tyr Asp Tyr Asp Asp Tyr Tyr Tyr Ala Met Asp
100 105 110
Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 47
<211> 113
<212> PRT
<213> 智人
<400> 47
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 Lys Ser Ser Gln Ser Leu Leu Tyr Arg
20 25 30
Ser Asn Gln Lys Asn Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys
35 40 45
Ala Pro Lys Leu Leu Ile Tyr Trp Ala Ser Thr Arg Glu Ser Gly Val
50 55 60
Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr
65 70 75 80
Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln
85 90 95
Tyr Tyr Asn Tyr Pro Arg Thr Phe Gly Gln Gly Thr Lys Val Glu Ile
100 105 110
Lys
<210> 48
<211> 10
<212> PRT
<213> 智人
<400> 48
Gly Phe Ser Phe Ser Asp Phe Ala Met Ser
1 5 10
<210> 49
<211> 18
<212> PRT
<213> 智人
<400> 49
Ala Thr Ile Gly Arg Val Ala Phe His Thr Tyr Tyr Pro Asp Ser Met
1 5 10 15
Lys Gly
<210> 50
<211> 13
<212> PRT
<213> 智人
<400> 50
Ala Arg His Arg Gly Phe Asp Val Gly His Phe Asp Phe
1 5 10
<210> 51
<211> 16
<212> PRT
<213> 智人
<400> 51
Arg Ser Ser Glu Thr Leu Val His Ser Ser Gly Asn Thr Tyr Leu Glu
1 5 10 15
<210> 52
<211> 7
<212> PRT
<213> 智人
<400> 52
Arg Val Ser Asn Arg Phe Ser
1 5
<210> 53
<211> 9
<212> PRT
<213> 智人
<400> 53
Phe Gln Gly Ser Phe Asn Pro Leu Thr
1 5
<210> 54
<211> 120
<212> PRT
<213> 智人
<400> 54
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Ser Phe Ser Asp Phe
20 25 30
Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Thr Ile Gly Arg Val Ala Phe His Thr Tyr Tyr Pro Asp Ser Met
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg His Arg Gly Phe Asp Val Gly His Phe Asp Phe Trp Gly Gln
100 105 110
Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 55
<211> 113
<212> PRT
<213> 智人
<400> 55
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 Ser Ser Glu Thr Leu Val His Ser
20 25 30
Ser Gly Asn Thr Tyr Leu Glu Trp Tyr Gln Gln Lys Pro Gly Lys Ala
35 40 45
Pro Lys Leu Leu Ile Tyr Arg Val Ser Asn Arg Phe Ser Gly Val Pro
50 55 60
Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile
65 70 75 80
Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Phe Gln Gly
85 90 95
Ser Phe Asn Pro Leu Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
100 105 110
Arg
<210> 56
<211> 117
<212> PRT
<213> 智人
<400> 56
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Tyr Thr Phe Ser Ser Tyr
20 25 30
Trp Ile Glu Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Ile
35 40 45
Gly Glu Ile Leu Pro Gly Gly Gly Asp Thr Asn Tyr Asn Glu Ile Phe
50 55 60
Lys Gly Arg Ala Thr Phe Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Thr Arg Arg Val Pro Ile Arg Leu Asp Tyr Trp Gly Gln Gly Thr Leu
100 105 110
Val Thr Val Ser Ser
115
<210> 57
<211> 112
<212> PRT
<213> 智人
<400> 57
Asp Ile Gln Leu Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Lys Ala Ser Gln Ser Val Asp Tyr Glu
20 25 30
Gly Asp Ser Phe Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro
35 40 45
Lys Leu Leu Ile Tyr Ala Ala Ser Asn Leu Glu Ser Gly Val Pro Ser
50 55 60
Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser
65 70 75 80
Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser Asn
85 90 95
Glu Asp Pro Leu Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg
100 105 110
<210> 58
<211> 10
<212> PRT
<213> 智人
<400> 58
Gly Tyr Thr Phe Ser Ser Tyr Trp Ile Glu
1 5 10
<210> 59
<211> 18
<212> PRT
<213> 智人
<400> 59
Gly Glu Ile Leu Pro Gly Gly Gly Asp Thr Asn Tyr Asn Glu Ile Phe
1 5 10 15
Lys Gly
<210> 60
<211> 10
<212> PRT
<213> 智人
<400> 60
Thr Arg Arg Val Pro Ile Arg Leu Asp Tyr
1 5 10
<210> 61
<211> 15
<212> PRT
<213> 智人
<400> 61
Lys Ala Ser Gln Ser Val Asp Tyr Glu Gly Asp Ser Phe Leu Asn
1 5 10 15
<210> 62
<211> 7
<212> PRT
<213> 智人
<400> 62
Ala Ala Ser Asn Leu Glu Ser
1 5
<210> 63
<211> 9
<212> PRT
<213> 智人
<400> 63
Gln Gln Ser Asn Glu Asp Pro Leu Thr
1 5
<210> 64
<211> 219
<212> PRT
<213> 智人
<400> 64
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 Ser Ser Glu Thr Leu Val His Ser
20 25 30
Ser Gly Asn Thr Tyr Leu Glu Trp Tyr Gln Gln Lys Pro Gly Lys Ala
35 40 45
Pro Lys Leu Leu Ile Tyr Arg Val Ser Asn Arg Phe Ser Gly Val Pro
50 55 60
Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile
65 70 75 80
Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Phe Gln Gly
85 90 95
Ser Phe Asn Pro Leu Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
100 105 110
Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu
115 120 125
Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe
130 135 140
Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln
145 150 155 160
Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser
165 170 175
Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu
180 185 190
Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser
195 200 205
Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
210 215
<210> 65
<211> 450
<212> PRT
<213> 智人
<400> 65
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Ser Phe Ser Asp Phe
20 25 30
Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Thr Ile Gly Arg Val Ala Phe His Thr Tyr Tyr Pro Asp Ser Met
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg His Arg Gly Phe Asp Val Gly His Phe Asp Phe Trp Gly Gln
100 105 110
Gly Thr Leu Val Thr Val Ser Ser Cys Ser Thr Lys Gly Pro Ser Val
115 120 125
Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala
130 135 140
Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser
145 150 155 160
Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val
165 170 175
Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro
180 185 190
Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys
195 200 205
Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp
210 215 220
Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly
225 230 235 240
Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile
245 250 255
Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu
260 265 270
Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His
275 280 285
Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg
290 295 300
Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys
305 310 315 320
Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu
325 330 335
Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr
340 345 350
Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu
355 360 365
Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp
370 375 380
Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val
385 390 395 400
Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp
405 410 415
Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His
420 425 430
Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro
435 440 445
Gly Lys
450
<210> 66
<211> 16
<212> PRT
<213> 智人
<400> 66
Arg Ser Ser Gln Ser Ile Val His Ser Val Gly Asn Thr Phe Leu Glu
1 5 10 15
<210> 67
<211> 7
<212> PRT
<213> 智人
<400> 67
Lys Val Ser Asn Arg Phe Ser
1 5
<210> 68
<211> 9
<212> PRT
<213> 智人
<400> 68
Phe Gln Gly Ser Gln Phe Pro Tyr Thr
1 5
<210> 69
<211> 10
<212> PRT
<213> 智人
<400> 69
Gly Tyr Glu Phe Ser Arg Ser Trp Met Asn
1 5 10
<210> 70
<211> 17
<212> PRT
<213> 智人
<400> 70
Arg Ile Tyr Pro Gly Asp Gly Asp Thr Asn Tyr Ser Gly Lys Phe Lys
1 5 10 15
Gly
<210> 71
<211> 11
<212> PRT
<213> 智人
<400> 71
Asp Gly Ser Ser Trp Asp Trp Tyr Phe Asp Val
1 5 10
<210> 72
<211> 113
<212> PRT
<213> 智人
<400> 72
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 Ser Ser Gln Ser Ile Val His Ser
20 25 30
Val Gly Asn Thr Phe Leu Glu Trp Tyr Gln Gln Lys Pro Gly Lys Ala
35 40 45
Pro Lys Leu Leu Ile Tyr Lys Val Ser Asn Arg Phe Ser Gly Val Pro
50 55 60
Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile
65 70 75 80
Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Phe Gln Gly
85 90 95
Ser Gln Phe Pro Tyr Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
100 105 110
Arg
<210> 73
<211> 120
<212> PRT
<213> 智人
<400> 73
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Tyr Glu Phe Ser Arg Ser
20 25 30
Trp Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Gly Arg Ile Tyr Pro Gly Asp Gly Asp Thr Asn Tyr Ser Gly Lys Phe
50 55 60
Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Asp Gly Ser Ser Trp Asp Trp Tyr Phe Asp Val Trp Gly Gln
100 105 110
Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 74
<211> 219
<212> PRT
<213> 智人
<400> 74
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 Ser Ser Gln Ser Ile Val His Ser
20 25 30
Val Gly Asn Thr Phe Leu Glu Trp Tyr Gln Gln Lys Pro Gly Lys Ala
35 40 45
Pro Lys Leu Leu Ile Tyr Lys Val Ser Asn Arg Phe Ser Gly Val Pro
50 55 60
Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile
65 70 75 80
Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Phe Gln Gly
85 90 95
Ser Gln Phe Pro Tyr Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
100 105 110
Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu
115 120 125
Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe
130 135 140
Tyr Pro Arg Glu Ala Lys Val Gln Trp Cys Val Asp Asn Ala Leu Gln
145 150 155 160
Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser
165 170 175
Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu
180 185 190
Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser
195 200 205
Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
210 215
<210> 75
<211> 450
<212> PRT
<213> 智人
<400> 75
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Tyr Glu Phe Ser Arg Ser
20 25 30
Trp Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Gly Arg Ile Tyr Pro Gly Asp Gly Asp Thr Asn Tyr Ser Gly Lys Phe
50 55 60
Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Asp Gly Ser Ser Trp Asp Trp Tyr Phe Asp Val Trp Gly Gln
100 105 110
Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val
115 120 125
Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala
130 135 140
Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser
145 150 155 160
Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val
165 170 175
Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro
180 185 190
Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys
195 200 205
Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp
210 215 220
Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly
225 230 235 240
Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile
245 250 255
Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu
260 265 270
Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His
275 280 285
Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg
290 295 300
Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys
305 310 315 320
Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu
325 330 335
Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr
340 345 350
Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu
355 360 365
Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp
370 375 380
Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val
385 390 395 400
Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp
405 410 415
Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His
420 425 430
Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro
435 440 445
Gly Lys
450
<210> 76
<211> 16
<212> PRT
<213> 智人
<400> 76
Arg Ser Ser Gln Ser Leu Leu His Ser Asn Gly Tyr Asn Tyr Leu Asp
1 5 10 15
<210> 77
<211> 7
<212> PRT
<213> 智人
<400> 77
Leu Gly Val Asn Ser Val Ser
1 5
<210> 78
<211> 9
<212> PRT
<213> 智人
<400> 78
Met Gln Ala Leu Gln Thr Pro Trp Thr
1 5
<210> 79
<211> 5
<212> PRT
<213> 智人
<400> 79
Asn His Ala Ile Ser
1 5
<210> 80
<211> 17
<212> PRT
<213> 智人
<400> 80
Gly Ile Ile Pro Ile Phe Gly Thr Ala Asn Tyr Ala Gln Lys Phe Gln
1 5 10 15
Gly
<210> 81
<211> 8
<212> PRT
<213> 智人
<400> 81
Glu Trp Ala Asp Val Phe Asp Ile
1 5
<210> 82
<211> 112
<212> PRT
<213> 智人
<400> 82
Glu Ile Val Leu Thr Gln Ser Pro Leu Ser Leu Pro Val Thr Pro Gly
1 5 10 15
Glu Pro Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Leu Leu His Ser
20 25 30
Asn Gly Tyr Asn Tyr Leu Asp Trp Tyr Leu Gln Lys Pro Gly Gln Ser
35 40 45
Pro Gln Leu Leu Ile Tyr Leu Gly Val Asn Ser Val Ser Gly Val Pro
50 55 60
Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile
65 70 75 80
Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Met Gln Ala
85 90 95
Leu Gln Thr Pro Trp Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
100 105 110
<210> 83
<211> 117
<212> PRT
<213> 智人
<400> 83
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Ile Phe Ser Asn His
20 25 30
Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Gly Ile Ile Pro Ile Phe Gly Thr Ala Asn Tyr Ala Gln Lys Phe
50 55 60
Gln Gly Arg Val Thr Ile Thr Ala Asp Glu Ser Thr Ser Thr Ala Phe
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Glu Trp Ala Asp Val Phe Asp Ile Trp Gly Gln Gly Thr Met
100 105 110
Val Thr Val Ser Ser
115
<210> 84
<211> 11
<212> PRT
<213> 智人
<400> 84
Arg Ala Ser Gln Gly Ile Arg Asn Asp Leu Gly
1 5 10
<210> 85
<211> 7
<212> PRT
<213> 智人
<400> 85
Ala Ala Ser Ser Leu Gln Ser
1 5
<210> 86
<211> 9
<212> PRT
<213> 智人
<400> 86
Leu Gln His Asn Ser Tyr Pro Trp Thr
1 5
<210> 87
<211> 5
<212> PRT
<213> 智人
<400> 87
Gly Asn Tyr Met Ser
1 5
<210> 88
<211> 16
<212> PRT
<213> 智人
<400> 88
Leu Ile Tyr Ser Gly Asp Ser Thr Tyr Tyr Ala Asp Ser Val Lys Gly
1 5 10 15
<210> 89
<211> 10
<212> PRT
<213> 智人
<400> 89
Asp Gly Tyr Tyr Val Ser Asp Met Val Val
1 5 10
<210> 90
<211> 107
<212> PRT
<213> 智人
<400> 90
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 Gly Ile Arg Asn Asp
20 25 30
Leu Gly Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Arg Leu Ile
35 40 45
Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Leu Gln His Asn Ser Tyr Pro Trp
85 90 95
Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys
100 105
<210> 91
<211> 118
<212> PRT
<213> 智人
<400> 91
Glu Val Gln Leu Val Glu Ser Gly Gly Ala Leu Ile Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Val Ala Ser Gly Phe Thr Ile Ser Gly Asn
20 25 30
Tyr Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Leu Ile Tyr Ser Gly Asp Ser Thr Tyr Tyr Ala Asp Ser Val Lys
50 55 60
Gly Arg Phe Asn Ile Ser Arg Asp Ile Ser Lys Asn Thr Val Tyr Leu
65 70 75 80
Gln Met Asn Ser Leu Arg Val Glu Asp Thr Ala Val Tyr Tyr Cys Val
85 90 95
Arg Asp Gly Tyr Tyr Val Ser Asp Met Val Val Trp Gly Lys Gly Thr
100 105 110
Thr Val Thr Val Ser Ser
115
<210> 92
<211> 107
<212> PRT
<213> 智人
<400> 92
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 Gly Ile Arg Asn Asp
20 25 30
Leu Gly Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Arg Leu Ile
35 40 45
Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Leu Gln His Asn Ser Tyr Pro Trp
85 90 95
Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys
100 105
<210> 93
<211> 118
<212> PRT
<213> 智人
<400> 93
Glu Val Gln Leu Val Glu Ser Gly Gly Ala Leu Ile Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Val Ala Ser Gly Phe Thr Ile Ser Gly Asn
20 25 30
Tyr Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Leu Ile Tyr Ser Gly Asp Ser Thr Tyr Tyr Ala Asp Ser Val Lys
50 55 60
Gly Arg Phe Thr Ile Ser Arg Asp Ile Ser Lys Asn Thr Val Tyr Leu
65 70 75 80
Gln Met Asn Ser Leu Arg Val Glu Asp Thr Ala Val Tyr Tyr Cys Val
85 90 95
Arg Asp Gly Tyr Tyr Val Ser Asp Met Val Val Trp Gly Lys Gly Thr
100 105 110
Thr Val Thr Val Ser Ser
115
<210> 94
<211> 107
<212> PRT
<213> 智人
<400> 94
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 Gly Ile Arg Asn Asp
20 25 30
Leu Gly Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Arg Leu Ile
35 40 45
Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Leu Gln His Asn Ser Tyr Pro Trp
85 90 95
Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys
100 105
<210> 95
<211> 118
<212> PRT
<213> 智人
<400> 95
Glu Val Gln Leu Val Glu Ser Gly Gly Ala Leu Ile Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Val Ala Ser Gly Phe Thr Ile Ser Gly Asn
20 25 30
Tyr Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Leu Ile Tyr Ser Gly Asp Ser Thr Tyr Tyr Ala Asp Ser Val Lys
50 55 60
Gly Arg Phe Ser Ile Ser Arg Asp Ile Ser Lys Asn Thr Val Tyr Leu
65 70 75 80
Gln Met Asn Ser Leu Arg Val Glu Asp Thr Ala Val Tyr Tyr Cys Val
85 90 95
Arg Asp Gly Tyr Tyr Val Ser Asp Met Val Val Trp Gly Lys Gly Thr
100 105 110
Thr Val Thr Val Ser Ser
115
<210> 96
<211> 107
<212> PRT
<213> 智人
<400> 96
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 Gly Ile Arg Asn Asp
20 25 30
Leu Gly Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Arg Leu Ile
35 40 45
Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Leu Gln His Asn Ser Tyr Pro Trp
85 90 95
Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys
100 105
<210> 97
<211> 118
<212> PRT
<213> 智人
<400> 97
Glu Val Gln Leu Val Glu Ser Gly Gly Ala Leu Ile Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Val Ala Ser Gly Phe Thr Ile Ser Gly Asn
20 25 30
Tyr Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Leu Ile Tyr Ser Gly Asp Ser Thr Tyr Tyr Ala Asp Ser Val Lys
50 55 60
Gly Arg Phe Ala Ile Ser Arg Asp Ile Ser Lys Asn Thr Val Tyr Leu
65 70 75 80
Gln Met Asn Ser Leu Arg Val Glu Asp Thr Ala Val Tyr Tyr Cys Val
85 90 95
Arg Asp Gly Tyr Tyr Val Ser Asp Met Val Val Trp Gly Lys Gly Thr
100 105 110
Thr Val Thr Val Ser Ser
115
<210> 98
<211> 1255
<212> PRT
<213> 智人
<400> 98
Met Glu Leu Ala Ala Leu Cys Arg Trp Gly Leu Leu Leu Ala Leu Leu
1 5 10 15
Pro Pro Gly Ala Ala Ser Thr Gln Val Cys Thr Gly Thr Asp Met Lys
20 25 30
Leu Arg Leu Pro Ala Ser Pro Glu Thr His Leu Asp Met Leu Arg His
35 40 45
Leu Tyr Gln Gly Cys Gln Val Val Gln Gly Asn Leu Glu Leu Thr Tyr
50 55 60
Leu Pro Thr Asn Ala Ser Leu Ser Phe Leu Gln Asp Ile Gln Glu Val
65 70 75 80
Gln Gly Tyr Val Leu Ile Ala His Asn Gln Val Arg Gln Val Pro Leu
85 90 95
Gln Arg Leu Arg Ile Val Arg Gly Thr Gln Leu Phe Glu Asp Asn Tyr
100 105 110
Ala Leu Ala Val Leu Asp Asn Gly Asp Pro Leu Asn Asn Thr Thr Pro
115 120 125
Val Thr Gly Ala Ser Pro Gly Gly Leu Arg Glu Leu Gln Leu Arg Ser
130 135 140
Leu Thr Glu Ile Leu Lys Gly Gly Val Leu Ile Gln Arg Asn Pro Gln
145 150 155 160
Leu Cys Tyr Gln Asp Thr Ile Leu Trp Lys Asp Ile Phe His Lys Asn
165 170 175
Asn Gln Leu Ala Leu Thr Leu Ile Asp Thr Asn Arg Ser Arg Ala Cys
180 185 190
His Pro Cys Ser Pro Met Cys Lys Gly Ser Arg Cys Trp Gly Glu Ser
195 200 205
Ser Glu Asp Cys Gln Ser Leu Thr Arg Thr Val Cys Ala Gly Gly Cys
210 215 220
Ala Arg Cys Lys Gly Pro Leu Pro Thr Asp Cys Cys His Glu Gln Cys
225 230 235 240
Ala Ala Gly Cys Thr Gly Pro Lys His Ser Asp Cys Leu Ala Cys Leu
245 250 255
His Phe Asn His Ser Gly Ile Cys Glu Leu His Cys Pro Ala Leu Val
260 265 270
Thr Tyr Asn Thr Asp Thr Phe Glu Ser Met Pro Asn Pro Glu Gly Arg
275 280 285
Tyr Thr Phe Gly Ala Ser Cys Val Thr Ala Cys Pro Tyr Asn Tyr Leu
290 295 300
Ser Thr Asp Val Gly Ser Cys Thr Leu Val Cys Pro Leu His Asn Gln
305 310 315 320
Glu Val Thr Ala Glu Asp Gly Thr Gln Arg Cys Glu Lys Cys Ser Lys
325 330 335
Pro Cys Ala Arg Val Cys Tyr Gly Leu Gly Met Glu His Leu Arg Glu
340 345 350
Val Arg Ala Val Thr Ser Ala Asn Ile Gln Glu Phe Ala Gly Cys Lys
355 360 365
Lys Ile Phe Gly Ser Leu Ala Phe Leu Pro Glu Ser Phe Asp Gly Asp
370 375 380
Pro Ala Ser Asn Thr Ala Pro Leu Gln Pro Glu Gln Leu Gln Val Phe
385 390 395 400
Glu Thr Leu Glu Glu Ile Thr Gly Tyr Leu Tyr Ile Ser Ala Trp Pro
405 410 415
Asp Ser Leu Pro Asp Leu Ser Val Phe Gln Asn Leu Gln Val Ile Arg
420 425 430
Gly Arg Ile Leu His Asn Gly Ala Tyr Ser Leu Thr Leu Gln Gly Leu
435 440 445
Gly Ile Ser Trp Leu Gly Leu Arg Ser Leu Arg Glu Leu Gly Ser Gly
450 455 460
Leu Ala Leu Ile His His Asn Thr His Leu Cys Phe Val His Thr Val
465 470 475 480
Pro Trp Asp Gln Leu Phe Arg Asn Pro His Gln Ala Leu Leu His Thr
485 490 495
Ala Asn Arg Pro Glu Asp Glu Cys Val Gly Glu Gly Leu Ala Cys His
500 505 510
Gln Leu Cys Ala Arg Gly His Cys Trp Gly Pro Gly Pro Thr Gln Cys
515 520 525
Val Asn Cys Ser Gln Phe Leu Arg Gly Gln Glu Cys Val Glu Glu Cys
530 535 540
Arg Val Leu Gln Gly Leu Pro Arg Glu Tyr Val Asn Ala Arg His Cys
545 550 555 560
Leu Pro Cys His Pro Glu Cys Gln Pro Gln Asn Gly Ser Val Thr Cys
565 570 575
Phe Gly Pro Glu Ala Asp Gln Cys Val Ala Cys Ala His Tyr Lys Asp
580 585 590
Pro Pro Phe Cys Val Ala Arg Cys Pro Ser Gly Val Lys Pro Asp Leu
595 600 605
Ser Tyr Met Pro Ile Trp Lys Phe Pro Asp Glu Glu Gly Ala Cys Gln
610 615 620
Pro Cys Pro Ile Asn Cys Thr His Ser Cys Val Asp Leu Asp Asp Lys
625 630 635 640
Gly Cys Pro Ala Glu Gln Arg Ala Ser Pro Leu Thr Ser Ile Ile Ser
645 650 655
Ala Val Val Gly Ile Leu Leu Val Val Val Leu Gly Val Val Phe Gly
660 665 670
Ile Leu Ile Lys Arg Arg Gln Gln Lys Ile Arg Lys Tyr Thr Met Arg
675 680 685
Arg Leu Leu Gln Glu Thr Glu Leu Val Glu Pro Leu Thr Pro Ser Gly
690 695 700
Ala Met Pro Asn Gln Ala Gln Met Arg Ile Leu Lys Glu Thr Glu Leu
705 710 715 720
Arg Lys Val Lys Val Leu Gly Ser Gly Ala Phe Gly Thr Val Tyr Lys
725 730 735
Gly Ile Trp Ile Pro Asp Gly Glu Asn Val Lys Ile Pro Val Ala Ile
740 745 750
Lys Val Leu Arg Glu Asn Thr Ser Pro Lys Ala Asn Lys Glu Ile Leu
755 760 765
Asp Glu Ala Tyr Val Met Ala Gly Val Gly Ser Pro Tyr Val Ser Arg
770 775 780
Leu Leu Gly Ile Cys Leu Thr Ser Thr Val Gln Leu Val Thr Gln Leu
785 790 795 800
Met Pro Tyr Gly Cys Leu Leu Asp His Val Arg Glu Asn Arg Gly Arg
805 810 815
Leu Gly Ser Gln Asp Leu Leu Asn Trp Cys Met Gln Ile Ala Lys Gly
820 825 830
Met Ser Tyr Leu Glu Asp Val Arg Leu Val His Arg Asp Leu Ala Ala
835 840 845
Arg Asn Val Leu Val Lys Ser Pro Asn His Val Lys Ile Thr Asp Phe
850 855 860
Gly Leu Ala Arg Leu Leu Asp Ile Asp Glu Thr Glu Tyr His Ala Asp
865 870 875 880
Gly Gly Lys Val Pro Ile Lys Trp Met Ala Leu Glu Ser Ile Leu Arg
885 890 895
Arg Arg Phe Thr His Gln Ser Asp Val Trp Ser Tyr Gly Val Thr Val
900 905 910
Trp Glu Leu Met Thr Phe Gly Ala Lys Pro Tyr Asp Gly Ile Pro Ala
915 920 925
Arg Glu Ile Pro Asp Leu Leu Glu Lys Gly Glu Arg Leu Pro Gln Pro
930 935 940
Pro Ile Cys Thr Ile Asp Val Tyr Met Ile Met Val Lys Cys Trp Met
945 950 955 960
Ile Asp Ser Glu Cys Arg Pro Arg Phe Arg Glu Leu Val Ser Glu Phe
965 970 975
Ser Arg Met Ala Arg Asp Pro Gln Arg Phe Val Val Ile Gln Asn Glu
980 985 990
Asp Leu Gly Pro Ala Ser Pro Leu Asp Ser Thr Phe Tyr Arg Ser Leu
995 1000 1005
Leu Glu Asp Asp Asp Met Gly Asp Leu Val Asp Ala Glu Glu Tyr
1010 1015 1020
Leu Val Pro Gln Gln Gly Phe Phe Cys Pro Asp Pro Ala Pro Gly
1025 1030 1035
Ala Gly Gly Met Val His His Arg His Arg Ser Ser Ser Thr Arg
1040 1045 1050
Ser Gly Gly Gly Asp Leu Thr Leu Gly Leu Glu Pro Ser Glu Glu
1055 1060 1065
Glu Ala Pro Arg Ser Pro Leu Ala Pro Ser Glu Gly Ala Gly Ser
1070 1075 1080
Asp Val Phe Asp Gly Asp Leu Gly Met Gly Ala Ala Lys Gly Leu
1085 1090 1095
Gln Ser Leu Pro Thr His Asp Pro Ser Pro Leu Gln Arg Tyr Ser
1100 1105 1110
Glu Asp Pro Thr Val Pro Leu Pro Ser Glu Thr Asp Gly Tyr Val
1115 1120 1125
Ala Pro Leu Thr Cys Ser Pro Gln Pro Glu Tyr Val Asn Gln Pro
1130 1135 1140
Asp Val Arg Pro Gln Pro Pro Ser Pro Arg Glu Gly Pro Leu Pro
1145 1150 1155
Ala Ala Arg Pro Ala Gly Ala Thr Leu Glu Arg Pro Lys Thr Leu
1160 1165 1170
Ser Pro Gly Lys Asn Gly Val Val Lys Asp Val Phe Ala Phe Gly
1175 1180 1185
Gly Ala Val Glu Asn Pro Glu Tyr Leu Thr Pro Gln Gly Gly Ala
1190 1195 1200
Ala Pro Gln Pro His Pro Pro Pro Ala Phe Ser Pro Ala Phe Asp
1205 1210 1215
Asn Leu Tyr Tyr Trp Asp Gln Asp Pro Pro Glu Arg Gly Ala Pro
1220 1225 1230
Pro Ser Thr Phe Lys Gly Thr Pro Thr Ala Glu Asn Pro Glu Tyr
1235 1240 1245
Leu Gly Leu Asp Val Pro Val
1250 1255
Claims (65)
1.制备式I的抗体-药物缀合物或其药学上可接受的盐的方法:
Ab―(L1―D)p I
其中
Ab是抗体;
L1是连接部分;
D是生物活性分子,其包含含有仲氮的杂芳基,其中L1与所述仲氮共价键合;且
p是1、2、3、4、5、6、7、8、9或10;
所述方法包括:
i.使式II化合物与抗体接触:
T-L1-D II
其中
L1和D如上所述,
T是具有结构R5-S的离去基团,
其中R5是任选取代的吡啶,
其中制备式I的抗体-药物缀合物。
2.权利要求1的方法,其中
L1具有如下结构:
其中
R1、R2、R3和R4独立选自H、任选取代的支链或直链C1-C5烷基和任选取代的C3-C6环烷基或R3和R4与和它们结合的碳原子一起形成C3-C6环烷基环,
其中所述任选取代的烷基或环烷基可取代有烷基、环烷基、芳基、杂芳基、羟基、腈基团、卤素、烷氧基、卤代烷氧基、芳基烷氧基、酰基氧基、烷基硫基、磺酸酯基团、氨基、烷基氨基、酰基氨基、氨甲酰基、烷基氨甲酰基或硝基。
3.权利要求1的方法,其中T-L1-D具有下式:
其中R5选自任选取代的吡啶和硝基吡啶。
4.权利要求3的方法,其中R5是5-硝基吡啶。
5.权利要求2的方法,其中R1、R2、R3和R4独立选自H和任选取代的支链或直链C1-C5烷基。
6.权利要求5的方法,其中R1、R2、R3和R4中的一个是任选取代的支链或直链C1-C5烷基且其他是H。
7.权利要求6的方法,其中所述任选取代的支链或直链C1-C5烷基是甲基。
8.权利要求7的方法,其中R1是甲基且R2、R3和R4各自是H。
9.权利要求8的方法,其中所述式I的抗体-药物缀合物具有如下结构:
其中p是1、2、3、4、5、6、7、8、9或10。
10.权利要求8的方法,其中所述式I的抗体-药物缀合物具有如下结构:
其中p是1、2、3、4、5、6、7、8、9或10。
11.权利要求1的方法,其中所述Ab是经半胱氨酸工程化的抗体。
12.权利要求1的方法,其中所述抗体结合HER2或B7-H4。
13.权利要求1的方法,其中所述抗体结合HER2。
14.权利要求2的方法,其中L1的羰基与D的杂芳基的所述仲氮共价结合,其中所述杂芳基选自:
15.权利要求14的方法,其中所述杂芳基选自:
16.权利要求15的方法,其中所述杂芳基选自:
17.权利要求16的方法,其中所述杂芳基是:
18.权利要求17的方法,其中D选自:
19.权利要求18的方法,其中D是:
20.权利要求18的方法,其中D是:
21.权利要求18的方法,其中式I的抗体-药物缀合物选自:
其中p是1、2、3、4、5、6、7、8、9或10。
22.权利要求1的方法,其中所述抗体是抗HER2或抗B7H4。
23.式IV的抗体-药物缀合物或其药学上可接受的盐:
其中
Ab是抗体;
R1、R2、R3和R4独立选自H、任选取代的支链或直链C1-C5烷基和任选取代的C3-C6环烷基或R3和R4与和它们结合的碳原子一起形成C3-C6环烷基环,
其中所述任选取代的烷基或环烷基可取代有烷基、环烷基、芳基、杂芳基、羟基、腈基团、卤素、烷氧基、卤代烷氧基、芳基烷氧基、酰基氧基、烷基硫基、磺酸酯基团、氨基、烷基氨基、酰基氨基、氨甲酰基、烷基氨甲酰基或硝基;
D是包含含有仲氮的杂芳基的生物活性分子,其中式IV中的羰基与D中的仲氮共价键合;且
p是1、2、3、4、5、6、7、8、9或10。
24.权利要求23的抗体-药物缀合物,其中R1、R2、R3和R4独立选自H和任选取代的支链或直链C1-C5烷基。
25.权利要求24的抗体-药物缀合物,其中R1、R2、R3和R4中的一个是任选取代的支链或直链C1-C5烷基且其他是H。
26.权利要求25的抗体-药物缀合物,其中所述任选取代的支链或直链C1-C5烷基是甲基。
27.权利要求26的抗体-药物缀合物,其中R1是甲基且R2、R3和R4各自是H。
28.权利要求27的抗体-药物缀合物,其中所述式IV的抗体-药物缀合物具有如下结构:
其中p是1、2、3、4、5、6、7、8、9或10。
29.权利要求27的抗体-药物缀合物,其中所述式IV的抗体-药物缀合物具有如下结构:
其中p是1、2、3、4、5、6、7、8、9或10。
30.权利要求23的抗体-药物缀合物,其中所述Ab是经半胱氨酸工程化的抗体或其变体。
31.权利要求23的抗体-药物缀合物,其中所述抗体结合HER2或B7-H4。
32.权利要求31的抗体-药物缀合物,其中所述抗体结合HER2。
33.权利要求23的抗体-药物缀合物,其中式IV的羰基与D的杂芳基的仲氮共价结合,其中所述杂芳基选自:
34.权利要求33的抗体-药物缀合物,其中所述杂芳基选自:
35.权利要求34的抗体-药物缀合物,其中所述杂芳基选自:
36.权利要求35的抗体-药物缀合物,其中所述杂芳基是:
37.权利要求23的抗体-药物缀合物,其中D选自:
38.权利要求37的抗体-药物缀合物,其中D是:
39.权利要求37的抗体-药物缀合物,其中D是:
40.权利要求23的抗体-药物缀合物,其选自:
其中p是1、2、3、4、5、6、7、8、9或10。
41.权利要求40的抗体-药物缀合物,其具有以下结构:
其中所述抗体是抗HER2且p是1、2、3、4、5、6、7、8、9或10。
42.权利要求40的抗体-药物缀合物,其具有以下结构:
其中所述抗体是抗B7H4且p是1、2、3、4、5、6、7、8、9或10。
43.制备式III化合物的方法:
其中
R1、R2、R3和R4独立选自H、任选取代的支链或直链C1-C5烷基和任选取代的C3-C6环烷基或R3和R4与和它们结合的碳原子一起形成C3-C6环烷基环;
其中所述任选取代的烷基或环烷基可取代有烷基、环烷基、芳基、杂芳基、羟基、腈基团、卤素、烷氧基、卤代烷氧基、芳基烷氧基、酰基氧基、烷基硫基、磺酸酯基团、氨基、烷基氨基、酰基氨基、氨甲酰基、烷基氨甲酰基或硝基;且
D是包含含有仲氮的杂芳基的生物活性分子,其中式III中的羰基与D中的仲氮共价键合;
R5选自任选取代的吡啶和硝基吡啶;
所述方法包括:
i.使式V化合物与化合物D接触:
其中LG是离去基团且PG是保护基团,
以制备式VI化合物:
且
ii.使式VI化合物在酸性条件下脱保护以制备式III化合物:
44.权利要求43的方法,其中所述保护基团PG是适于硫醇保护的保护基团。
45.权利要求44的方法,其中所述保护基团PG是酸不稳定性保护基团。
46.权利要求45的方法,其中所述保护基团PG选自三苯甲基、芴基、二甲氧基苄基、甲氧基苄基、2,4,6-三甲基苄基,呫吨基、二茂铁基、甲氧基甲基、异丁氧基甲基和二苯基甲基。
47.权利要求46的方法,其中所述保护基团PG是三苯甲基。
48.权利要求43的方法,其中所述离去基团LG是适于被亲核试剂置换的基团。
49.权利要求48的方法,其中所述离去基团LG是卤素。
50.权利要求49的方法,其中所述离去基团LG是氯。
51.权利要求43的方法,其中R5是硝基吡啶。
52.权利要求43的方法,其中R5是5-硝基吡啶。
53.式III化合物:
其中
R1、R2、R3和R4独立选自H、任选取代的支链或直链C1-C5烷基和任选取代的C3-C6环烷基或R3和R4与和它们结合的碳原子一起形成C3-C6环烷基环;
其中所述任选取代的烷基或环烷基可取代有烷基、环烷基、芳基、杂芳基、羟基、腈基团、卤素、烷氧基、卤代烷氧基、芳基烷氧基、酰基氧基、烷基硫基、磺酸酯基团、氨基、烷基氨基、酰基氨基、氨甲酰基、烷基氨甲酰基或硝基;
R5选自任选取代的吡啶和硝基吡啶;
且
D是包含含有仲氮的杂芳基的生物活性分子,其中式III中的羰基与D中的仲氮共价键合。
54.权利要求53的化合物,其中R5是5-硝基吡啶。
55.权利要求53的化合物,其中R1是甲基且R2、R3和R4各自是H。
56.权利要求55的化合物,其中R1是甲基且具有R立体化学。
57.权利要求53的化合物,其中式III化合物选自:
58.制备式IV的抗体-药物缀合物或其药学上可接受的盐的方法:
其中
Ab是抗体;
R1、R2、R3和R4独立选自H、任选取代的支链或直链C1-C5烷基和任选取代的C3-C6环烷基或R3和R4与和它们结合的碳原子一起形成C3-C6环烷基环,
其中所述任选取代的烷基或环烷基可取代有烷基、环烷基、芳基、杂芳基、羟基、腈基团、卤素、烷氧基、卤代烷氧基、芳基烷氧基、酰基氧基、烷基硫基、磺酸酯基团、氨基、烷基氨基、酰基氨基、氨甲酰基、烷基氨甲酰基或硝基;
D是包含含有仲氮的杂芳基的生物活性分子,其中式IV中的羰基与D中的仲氮共价键合;且
p是1、2、3、4、5、6、7、8、9或10;
所述方法包括:
i.使式V化合物与化合物D接触:
其中LG是离去基团且PG是保护基团,
以制备式VI化合物:
ii.使式VI化合物与二硫化物R5-S-S-R5在酸性条件下接触以制备式III化合物:
其中R5是任选取代的吡啶;且
iii.使式III化合物与抗体接触以制备式IV的抗体-药物缀合物。
59.制备式VII化合物的方法:
其中
PG是保护基团;且
D是包含含有仲氮的杂芳基的生物活性分子,其中式VII中的酯羰基与D中的仲氮形成氨基甲酸酯;
所述方法包括:
i.使式VIII化合物与式IX化合物接触:
其中LG是离去基团,
以制备式VII化合物。
60.权利要求59的方法,其中式VII化合物是:
61.权利要求1的方法,其中所述杂芳基选自吲哚基团、吲唑基团、苯并咪唑基团、苯并三唑基团、吡咯基团、吡咯并吡啶基团、咪唑基团、三唑基团和四唑基团。
62.权利要求1的方法,其中所述D选自细胞毒剂;生长抑制剂;抗生素;毒素;抗肿瘤剂或抗癌剂;烷化剂;烷基磺酸酯;氮杂环丙烷类;乙撑亚胺类和甲基蜜胺类;acetogenins;拓扑异构酶1抑制剂;蛋白酶体抑制剂;EGFR抑制剂;酪氨酸激酶抑制剂;丝氨酸-苏氨酸激酶抑制剂;法尼基转移酶抑制剂;抗激素剂;选择性雌激素受体调节剂(SERM);抗雌激素;芳香酶抑制剂;促黄体激素释放激素激动剂;性类固醇;雌激素;和雄激素/类视黄醇;雌激素受体下调因子(ERD);抗雄激素;免疫抑制剂;非甾体抗炎药(NSAID);抗炎剂;环氧合酶抑制剂,白三烯受体拮抗剂;嘌呤拮抗剂;类固醇;二氢叶酸还原酶抑制剂;和抗疟疾剂。
63.权利要求62的方法,其中所述D选自鹅膏毒素、长春碱、长春新碱、倍癌霉素A、倍癌霉素SA、CC-1065、阿多来新、U-76074、U-73073、卡折来新(U-80244)、KW-2189、diazonamideA、埃索美拉唑、阿立哌唑、缬沙坦、兰索拉唑、雷贝拉唑、pometrexed、奥美沙坦、他达拉非、泮托拉唑、坎地沙坦、奥美拉唑、舒尼替尼、培美曲塞、阿来替尼、达卡巴嗪、司马沙尼、达西斯特、多韦替尼、甲苯达唑和匹莫苯丹。
64.通过权利要求1的方法制备的抗体-药物缀合物。
65.通过权利要求43的方法制备的式III化合物。
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US20190201544A1 (en) | 2019-07-04 |
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