CN110974975B - 一种快速释放的抗体药物偶联物 - Google Patents

一种快速释放的抗体药物偶联物 Download PDF

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CN110974975B
CN110974975B CN201911271143.5A CN201911271143A CN110974975B CN 110974975 B CN110974975 B CN 110974975B CN 201911271143 A CN201911271143 A CN 201911271143A CN 110974975 B CN110974975 B CN 110974975B
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cancer
antibody
compound
drug conjugate
antibody drug
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CN110974975A (zh
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朱义
万维李
卓识
秦文芳
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Chengdu Bailidote Biological Pharmaceutical Co ltd
Sichuan Baili Pharmaceutical Co Ltd
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Chengdu Bailidote Biological Pharmaceutical Co ltd
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Abstract

本发明公开了一种抗体药物偶联物或其药学上可接受的盐，一种全新的快速释放型抗体药物偶联物用于***或其他疾病，该抗体药物偶联物尤其适用于药物分子结构中含羟基的情况，在体内循环中具有高度稳定性和良好的水溶性。

Description

一种快速释放的抗体药物偶联物
技术领域
本发明属于生物制药技术领域，具体涉及一种快速释放的抗体药物偶联物。
背景技术
抗体药物偶联物(ADC)作为新型的靶向药物，一般由三部分组成：抗体或抗体类配体，小分子药物以及将配体和药物偶联起来的连接子。抗体药物偶联物利用抗体对抗原的特异性识别，将药物分子运输至靶细胞附近并有效释放药物分子，达到治疗目的。2011年8月，美国食品药品监督管理局(FDA)批准西雅图基因公司研制的用于治疗霍奇金淋巴瘤以及复发性变性大细胞淋巴瘤(ALCL)的ADC新药AdecteisTM上市，临床应用已经证明了此类药物的安全性和有效性。
目前在抗体药物偶联物中应用广泛的毒素包括MMAE和T-DM1以及他们的衍生物。在此基础上发展出了适合连接此类毒素的多种Linker技术。Linker的作用是将毒素分子与抗体连接，保证其在体内循环中的稳定，同时在进入靶细胞后可有效释放。常用的linker包括可被组织蛋白酶水解的肽片段和自我降解片段。在进入靶细胞后，在组织蛋白酶或特定PH环境作用下，释放药物分子。已知的此类linker通常与药物分子上的氨基位点连接，以AdecteisTM为例，其在靶细胞内释放机理如下所示：
靶细胞内的组织蛋白酶对Val-Cit二肽选择性切割，产物发生1,6-消除生成氨基碳酸酯结构，后发生碳酸酯消除释放出毒素MMAE。
上述消除方式仅适用于含氨基毒素化合物，对于分子中仅含有羟基可用于连接的情况下，该方法并不适用，对于羟基毒素，目前常用的方法为在甲酰胺与羟基之间***乙二胺片段，该乙二胺片段经1,4-消除释放出毒素。据文献报道(Mol Cancer Ther； 12(6),968-978)，该1,4-消除半衰期约10h，为一个显著限速环节。释放速度的降低可能导致部分毒素在非活性状态下被靶细胞排出胞外而降低ADC药物活力。
可见，开发一种可满足羟基毒素药物的快速释放技术非常必要。西雅图遗传公司在专利(申请号CN201480066385.X)中公布了一种带亚甲基氨基甲酸酯单元的抗体偶联物，可用于带羟基毒素药物的连接。然而，分子中的自分解单元需要经历如上图所示的1,6-消除后释放药物，导致释放时间增加，药效降低。
发明内容
基于以上现有技术，本发明的目的在于提供一种在靶细胞快速释放的抗体偶联物，本发明通过将酶切肽链Lp直接与氨亚甲基自分解结构单元连接，释放速度更快，并且在体内具有高度的稳定性。
一种如式I所示的抗体药物偶联物或其药学上可接受的盐：
其中：
Ab是抗体，抗体片段或蛋白，n表示1～20的整数；
D为药物单元，其具有已纳入亚甲基氨基单元中的羟基官能团结构，O为来自上述羟基官能团中的氧杂原子；
R1、R2及R3为任选的取代基团，或R1、R2连同其所连接的氮及碳原子构成氮杂环丁基、吡咯烷基、哌啶基，且R3为氢；
L1表示L2与Ab之间的连接单元；
L2表示延伸单元或单键；
Lp表示由2～7个氨基酸构成的肽链。
作为优选，其中以共价键连接至该药物单元羟基的自分解结构单元有以下两种结构：
在结构式(a)中，R1、R2及R3独立地为氢、-(CH2-CH2-O)n1-H、-(CH2-CH2-NH)n2-H、-(CH2-CH2-N(CH3))n3-H、-CH2-CH2-N(CH3)2、任选取代的C1～C6烷基、或者任选取代的C连接的C3～C8杂芳基，其中n1、n2、n3分别选自1～6的整数；
在结构式(b)中，由式I中R1及R2连同其所连接的氮及碳原子构成氮杂环丁基、吡咯烷基、哌啶基，且R3为氢，其中m选自0～6的整数；
波浪线表示与Lp的连接位点。
作为优选，其中的Lp肽链构成的氨基酸选自：丙氨酸、精氨酸、天冬酰胺、天冬氨酸、半胱氨酸、谷氨酰胺、谷氨酸、甘氨酸、组氨酸、异亮氨酸、亮氨酸、赖氨酸、甲硫氨酸、苯丙氨酸、脯氨酸、丝氨酸、苏氨酸、色氨酸、酪氨酸或者缬氨酸。
作为优选，药物D选自微管蛋白结合剂、DNA烷化剂、DNA嵌入剂、酶抑制剂、免疫调控剂、肽或核苷酸。
作为优选，自分解结构单元(a)，R2及R3为氢，R1为(-(CH2-CH2-O)n1-H、-(CH2-CH2-NH)n2-H、-(CH2-CH2-N(CH3))n3-H、-CH2-CH2-N(CH3)2、任选取代的C1～C6烷基、任选取代的C连接的C3～C8杂芳基，其中n1、n2、n3选自1～6的整数，其结构为：
作为优选，自分解结构单元(a)，R2及R3为氢，R1为-(CH2-CH2-O)n1-H、-(CH2-CH2-NH)n2-H、-(CH2-CH2-N(CH3))n3-H、-CH2-CH2-N(CH3)2时，其中n1、n2、n3选自1～20的整数，其结构为：
其中，当R1为聚乙二醇结构时，其末端选自羟基、甲氧基、羧基、氨基。
作为优选，自分解结构单元(b)，由式I中R1及R2连同其所连接的氮及碳原子构成氮杂环丁基、吡咯烷基、哌啶基等，R3为氢，其中m选自0～6的整数，优选为五元环、六元环结构单元，其结构为：
作为优选，L1表示Ab与L2的连接单元，其结构为-(琥珀酰亚胺-3-基-N)-(CH2)n4-(＝O)-、-CH2-C(＝O)-NH-(CH2)n5-C(＝O)-、-C(＝O)-环己基(1,4)-CH2-(N-ly-3-diminiccuS)-,-C(＝O)-(CH2)n6-C(＝O)-，-(琥珀酰亚胺-3-基-N)-R4(R5)-(＝O)-，其中n4选自2～8的整数，n5选自1～8的整数，n6选自1～8的整数，在-(琥珀酰亚胺-3-基-N)-结构中3位与抗体连接，1位氮原子与包含该接头结构内的亚甲基连接，其结构为：
R4为C2～C5亚烷基，该亚烷基被任选的R5取代，R5为-(CH2)n7NH-Ac，Ac-NH为氨基酸或寡肽单元。
作为优选，连接单元L1具有以下结构：
R4为C2-C5亚烷基，该亚烷基被任选的R5取代，R5为-(CH2)n7NH-Ac，Ac-NH为选自甘氨酸、丙氨酸、亮氨酸、异亮氨酸、缬氨酸、苯丙氨酸、脯氨酸、色氨酸、丝氨酸、酪氨酸、半胱氨酸、蛋氨酸、天冬酰胺或谷氨酸。
作为优选，L2表示-NH-(CH2-CH2-O)n8-CH2-CH2-C(＝O)-、-S-(CH2)n9-C(＝O)-、或单键，其中n8、n9选自1～6的整数。
作为优选，Lp为可被靶细胞内蛋白酶特异性切割的肽链，选自缬氨酸-半胱氨酸；缬氨酸-丙氨酸；苯丙氨酸-赖氨酸；甘氨酸-甘氨酸-苯丙氨酸-甘氨酸或苯丙氨酸-谷氨酸。
本发明还包括一种抗肿瘤，治疗自身免疫疾病或抗感染药物，含有上述的抗体药物偶联物或其药学上可接受的盐。
所述肿瘤为肺癌、肾癌、尿道癌、结肠癌、直肠癌、***癌、多形性胶质细胞瘤、卵巢癌、胰腺癌、乳腺癌、黑色素瘤、肝癌、膀胱癌、胃癌、食道癌等实体瘤及血液肿瘤。
缩写和定义
除非另有说明，否则如本文所用的以下术语和短语旨在具有以下含义。当本文中使用商标名称时，除非上下文中另有指明，否则商标名称包括所述商标名称产品的产品配方、通用药物和活性药物成分。
术语“亚烷基”是指具有1～20个碳原子的二价直链饱和烃基团，包括从1至10碳原子的基团。亚烷基基团的实施例包括但不限于亚甲基(-CH2-)、亚乙基(-CH2-CH2-)、亚正丙基、亚异丙基、亚正丁基、亚正戊基和亚正己基。
除非另有说明，术语“芳基”指多不饱和、一般是芳族的官能基团，它可以是单环或者稠合或共价连接的多环(至多三个环)。术语“芳杂基”指含有1～5个选自N、O或S的杂原子的芳基(或环)，其中所述氮和硫原子任选被氧化，所述氮原子任选被季铵化。芳杂基团可通过杂原子连接于分子的其余部分。芳基基团的非限制性例子包括：苯基、萘基和二苯基，芳杂基团的非限制性例子包括：吡啶基、哒嗪基、吡嗪基、嘧啶基(pyrimindinyl)、三嗪基、喹啉基、喹喔啉基、喹唑啉基、噌啉基、酞嗪基(phthalaziniyl)、苯并三嗪基、嘌呤基、苯并咪唑基、苯并吡唑基、苯并***基、苯并异唑基、异苯并呋喃基、异吲哚基、吲嗪基、苯并三嗪基、噻吩并吡啶基、噻吩并嘧啶基、吡啶并嘧啶基、咪唑并吡啶、苯并噻唑基(benzothiaxolyl)、苯并呋喃基、苯并噻吩基、吲哚基、喹啉基、异喹啉基、异噻唑基、吡唑基、吲唑基、蝶啶基、咪唑基、***基、四唑基、噁唑基、异噁唑基、噻二唑基、吡咯基、噻唑基、呋喃基、以及噻吩基等。
当描述为“取代的”时，上述芳环和杂芳环***的取代基选自下述可接受的取代基。
除非文中另有说明，“取代基团”可以是选自下述的多种基团：-卤素、-OR’、-NR’R”、-SR’、-SiR’R”R”’、-OC(O)R’、-C(O)R’、-CO2R’、-CONR’R”、-OC(O)NR’R”、-NR’C(O)R”、-NR’-C(O)NR”R”’、-NR’C(O)2R”、-NH-C(NH2)＝NH、-NR’C(NH2)＝NH、-NH-C(NH2)＝NR’、-S(O)R’、-S(O)2R’、-S(O)2NR’R”、-NR’S(O)2R”、-CN和-NO2，取代基数量为0至(2m’+1)，其中m’为该基团中碳原子的总数。R’、R”和R”’各自独立的指代氢、未取代的C1～C8烷基、未取代的芳基、由1-3个卤素取代的芳基、C1～C8烷氧基或C1～C8硫代烷氧基、或未取代的芳基-C1～C4烷基。R’和R”连接于同一个氮原子时，它们可与该氮原子一起形成3-、4-、5-、6-或7-元环。例如，-NR’R”包括1-吡咯烷基和4-吗啉基。
本文中所用的化合物的“衍生物”是指具有与化合物相似的化学结构但还含有至少一个化合物中不存在的化学基团和/或缺少至少一个化合物中存在的化学基团的物质。衍生物所比较的化合物被称为“母体”化合物。通常，“衍生物”可在一个或多个化学反应步骤中由母体化合物产生。
本文所述氮杂环丁基为含一个氮原子的取代或未取代的环丁基。
本文所述亚甲基氨基单元特指将氮原子与氧原子连接在同一亚甲基碳原子上形成的结构单元。
本文所述自分解结构单元系指在组织或细胞内可迅速/缓慢发生分解，成为其他结构单元的分子结构，如本文所述亚甲基氨基单元因氨基与羟基同时连接在同一亚甲基碳原子上，电子云密度太大，可继续分解。
本文所述微管蛋白结合剂系指可与细胞内微管蛋白结合的药物，包括但不限于MMAE、MMAF及其衍生物等。
DNA烷化剂系指可与细胞DNA发生烷基化反应的药物，包括但不限于倍癌霉素等。
DNA嵌入剂系指可***双链DNA相邻碱基对之间的药物分子，包括但不限于PBD及其衍生物等。
酶抑制剂系指可与特定酶发生可逆/不可逆结合的药物，包括但不限于喜树碱类药物。
本文所述抗体，抗体片段或蛋白均为配体单元，是与靶标部分特异性结合的靶向剂。所述抗体，抗体片段或蛋白能够特异性结合至细胞组分或结合至细胞组分或结合至其他感兴趣的靶标分子。靶标部分或靶标通常在细胞表面上。在一些方面中，抗体，抗体片段或蛋白的作用是将药物单元递送至配体单元与之相互作用的特定靶细胞群。配体包括但不限于蛋白质、多肽和肽、以及非蛋白质如糖。合适的配体单元包括：例如抗体，例如全长(完整)抗体及其抗原结合片段。在配体单元是非抗体靶向试剂的实施方式中，其可以是肽或多肽，或非蛋白质分子。这类靶向试剂的示例包括干扰素、淋巴因子、激素、生长因子和集落刺激因子、维生素、营养转运分子、或任何其他细胞结合分子或物质。在一些实施方式中，连接子共价连接至配体的硫原子。在一些方面中，硫原子是半胱氨酸残基的硫原子，其形成抗体的链间二硫键。在另一方面中，硫原子是已经导入配体单元的半胱氨酸残基的硫原子，其形成抗体的链间二硫键。在另一方面中，硫原子是已经导入配体单元的半胱氨酸残基的硫原子(例如，通过定点诱变或化学反应)。在其他方面中，连接子结合的硫原子选自形成抗体的链间二硫键的半胱氨酸残基或已经引入配体单元的额半胱氨酸残基(例如，通过定点诱变或化学反应)。在一些实施方式中，按照Kabat(Kabat E.A等，(1991))《免疫学感兴趣的蛋白质序列》(Sequences of proteins of Immunological Interest),第五版，NIH出版物91-3242)中的EU索引编号***。
如本文所用，“抗体”或“抗体单元”在其所属的范围内，包括抗体结构的任何部分。这一单元可以结合，反应性关联，或者络合一个受体，抗原，或者靶向细胞群体具有的其它受体单元。抗体可以是任何蛋白或蛋白类分子，它可以结合，络合，或者与待治疗或生物改造的细胞群体的一部分发生反应。
本发明中组成抗体药物偶联物的抗体最好保持其原有野生状态时的抗原结合能力。因此，本发明中的抗体能够，最好专一性的与抗原结合。涉及的抗原包括，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，细胞存活调节因子，细胞增殖调节因子，与组织生长与分化相关的分子(如已知或预知的具有功能性的)，淋巴因子，细胞因子，参与细胞循环调节的分子，参与血管生成的分子，以及与血管生成有关的分子(如已知或预知的具有功能性的)。肿瘤相关因子可以是簇分化因子(如CD蛋白)。
应用在抗体药物偶联物中的抗体包括，但不局限于，针对细胞表面受体和肿瘤相关抗原的抗体。这样的肿瘤相关抗原是业内所熟知的，可以通过业内熟知的抗体制备方法和信息来制备。为了开发可用于癌症诊断与治疗的有效的细胞水平目标物，研究人员力图找寻跨膜或其他肿瘤相关多肽。这些目标物能够特异性的表达在一种或多种癌细胞表面，而在一种或多种非癌细胞表面表达很少或不表达。通常，相对于非癌细胞表面而言，这样的肿瘤相关多肽在癌细胞表面更加过度表达。确认这样的肿瘤相关因子，可大大提高基于抗体治疗癌症的专一靶向特性。
肿瘤相关抗原，与肿瘤相关抗原对应的核酸和蛋白序列可参见公开数据库，例如Genbank。抗体靶向对应的肿瘤相关抗原包括所有的氨基酸序列变种和同种，与参考文献中确认的序列具有至少70％，80％，85％，90％，或者95％的同源性，或者具备与引用文献中的肿瘤相关抗原序列具有完全一致的生物性质和特征。
术语“抑制”指，减少了可检测的量，或完全阻止。
术语“癌症”指的是以失调的细胞生长为特征的生理病症或疾病。“肿瘤”包括癌细胞。
术语“自身免疫疾病”是源自针对个体自身的组织或蛋白质的疾病或紊乱。
本文中所用的短语“药学上可接受的盐”指的是，化合物(例如：药物、药物-接头或配体-接头-药物偶联物)的药学上可接受的有机或无机盐。该化合物可含有至少一个氨基或羧基，并且因此可与相应的酸或碱形成加成盐。示例性的盐包括但不限于：硫酸盐、三氟乙酸盐、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、酸性磷酸盐、异烟酸盐、乳酸盐、水杨酸盐、酸性柠檬酸盐、酒石酸盐、油酸盐、单宁酸盐、泛酸盐、酒石酸氢盐、抗坏血酸盐、水杨酸盐、甲酸盐、本甲酸盐、谷氨酸盐、甲磺酸盐、乙磺酸盐、苯磺酸盐、对甲苯磺酸盐，钾盐、钠盐等。另外，药学上可接受的盐在结构中具有超过一个的带电原子。其中多个带电原子是药学上可接受的盐的一部分的示例能有多个抗衡离子。例如，药学上可接受的盐具有一个或多个带电原子和/或一个或多个抗衡离子。
按照在细胞内药物释放的机制，如本文所用，“连接子”或“抗体药物偶联物的连接子”可被分为两类：不可断裂连接子和可断裂连接子。
对于含有不可断裂连接子的抗体药物偶联物，其药物释放机制为：偶联物与抗原结合并被细胞内吞后，抗体在溶酶体中被酶解，释放出由小分子药物，连接子，和抗体氨基酸残基共同组成的活性分子。由此带来的药物分子结构改变并不减弱其细胞毒性，但由于活性分子是带电荷的(氨基酸残基)，从而导致其不能渗入邻近细胞。因此，此类活性药物不能杀死邻近不表达靶向抗原(抗原阴性细胞)的肿瘤细胞(旁观者效应，bystander effect)(Ducry等，2010，Bioconjugate Chem.21:5-13)。
可断裂连接子，顾名思义，可以在目标细胞内断裂并释放出活性药物(小分子药物本身)。可断裂连接子可分为两个主要的类别：化学不稳定连接子和酶不稳定连接子。
化学不稳定连接子可以由于血浆和细胞质性质的不同而选择性的断裂。这样的性质包括pH值，谷胱甘肽浓度等。
对pH值敏感的连接子，通常又称为酸断裂连接子。这样的连接子在血液的中性环境下相对稳定(pH7.3-7.5)，但是在弱酸性的内涵体(pH5.0-6.5)和溶酶体(pH4.5-5.0)内将会被水解。第一代的抗体药物偶联物大多应用这类连接子，例如腙，碳酸酯，缩醛，缩酮类。由于酸断裂连接子有限的血浆稳定性，基于此类连接子的抗体药物偶联物通常具有较短的半衰期(2-3天)。这种较短的半衰期在一定程度上限制了pH敏感连接子在新一代抗体药物偶联物中的应用。
对于谷胱甘肽敏感的连接子，又称二硫键连接子。药物释放是基于细胞内谷胱甘肽的高浓度(毫摩尔范围)与血液中相对较低的谷胱甘肽浓度(微摩尔范围)差异引起的。对于肿瘤细胞而言尤其如此，其低含氧量导致还原酶的活性增强，因而导致更高的谷胱甘肽浓度。二硫键具有热力学稳定性，因此在血浆中具有较好的稳定性。
酶不稳定连接子，如肽连接子，能够更好的控制药物释放。肽连接子能够被溶酶体内蛋白酶，如组织蛋白酶(Cathepsin B)或纤溶酶(在一些肿瘤组织中此类酶含量增加)，有效的切断。这种肽连接被认为在血浆循环中非常稳定，这是因为细胞外不合宜的pH值及血清蛋白酶抑制剂导致蛋白酶通常不具备活性。鉴于较高的血浆稳定性和良好的细胞内断裂选择性和有效性，酶不稳定连接子被广泛用做抗体药物偶联物的可断裂连接子。典型的酶不稳定性连接子包括Val-Cit(vc)，Phe-Lys等。
***式连接子一般嵌合在可断裂连接子与活性药物之间，或者本身就是可断裂连接子的一部分。***式连接子的作用机制是：当可断裂连接子在合宜的条件下断裂后，***式连接子能够自发的进行结构重排，进而释放与之连接的活性药物。常见的***式连接子包括对氨基苄醇类(PAB)和β-葡萄糖醛酸苷类(β-Glucuronide)等。
下面结合具体实施例，进一步阐述本发明，应理解，这些实施例只用于说明本发明，而不用于限制本发明的范围。下列实施例中未注明具体条件的试验方法，通常按照常规条件或按照制造厂商所建议的条件。除非另外说明，否则所有的百分数、比例、比率、或份数按重量计。
除非另行定义，文中所使用的所有专业和科学用于与本领域熟练人员所熟悉的意义相同。
本发明人在对带羟基毒素的ADC综合理解的基础上，设计出一种具有快速释放的抗体药物偶联物，并通过实验惊奇的发现，该类ADC药物可有效保证在血浆中的稳定，同时具有很好的体内药效。
本发明的有益效果如下：
1、提供了一种适合羟基类毒素偶联的抗体-药物偶联技术，适用于自然界中广泛存在的羟基类毒素分子，拓展了ADC类药物毒素选择范围。
2、本发明所采用的偶联羟基的技术与现有技术相比，可更加快速高效的在靶细胞释放，避免了缓慢释放过程中ADC药物药效损失的问题。
3、本发明所提供的抗体偶联药物，在体内循环中具有高度的稳定性，在体内具有极佳的药效。
具体实施方式
下面结合具体实施例，进一步阐述本发明，应理解，这些实施例只用于说明本发明，而不用于限制本发明的范围。下列实施例中未注明具体条件的试验方法，通常按照常规条件或按照制造厂商所建议的条件。除非另外说明，否则所有的百分数、比例、比率、或份数按重量计。
(一)ADC药物的制备
通用步骤A：
本发明下列实施例中采用下述通用步骤A进行ADC药物的偶联制备。
将通过初步的纯化后单体率大于95％的抗体分子，使用超滤离心管换液至含有EDTA的磷酸盐缓冲液中，浓度10mg/ml。加入10倍于抗体摩尔分子数的TCEP，室温下反应2h。使用超滤离心管换液至pH6.5的磷酸缓冲液中，再加入10倍于抗体摩尔分子数的DHAA，室温下反应2h。加入10倍于抗体摩尔分子数的TCEP，室温下反应8h。打开抗体链间二硫键，并用Ellman方法测定游离巯基数，判断二硫键是否全部打开。然后加入10倍于抗体摩尔分子数的待偶联化合物，室温下反应8h。反应结束后，使用截留分子量为30KDa的超滤离心管换液至PBS中，并去除未偶联的偶联化合物。
实施例1化合物1的合成
于50mL单口瓶中加入氨基四甘醇单甲醚(10g,48.3mmol,1.0eq)，三乙胺(13.4mL,96.6mmol,2.0eq)及80mL四氢呋喃，搅拌溶解，降至0℃，滴加溴乙酸叔丁酯(9.42g,48.3mmol,1.0eq)，滴毕，室温反应。TLC监控，反应结束后减压浓缩，残余物中加入水，用二氯甲烷萃取，合并有机相，经饱和食盐水洗涤，无水硫酸钠干燥。过滤，滤液减压浓缩，残余物经柱色谱纯化，得8g化合物1，LC-MS：[M+H]+:322.4。
实施例2化合物2的合成
于50mL单口瓶中加入化合物1(8g，24.9mmol，1.0eq),三乙胺(10.4mL，74.7mmol，3eq)及80mLTHF，搅拌再加入Fmoc-Gly-OSu(10.8g，27.4mmol，1.1eq)，室温反应。TLC监控，反应结束后，减压浓缩，残余物经柱色谱纯化，得12g化合物2，LC-MS：[M+H]+:601.2。
实施例3化合物3的合成
于100mL单口瓶中加入10g化合物2，二氯甲烷50mL，三氟乙酸10mL，室温反应，TLC监控，反应结束，减压浓缩，残余物用甲苯溶解，浓缩，得8.8g化合物3，不经纯化，直接在下一步反应中使用。
实施例4化合物4的合成
于250mL三口瓶中加入化合物3(8.8g，16mmol,1eq)，四乙酸铅(10g，1.4eq，22.6mmol)，100mL甲苯，和300mL干燥四氢呋喃，氮气保护，析出黄色固体，再加入吡啶(1.6mL，1.2eq，19.4mmol)，加热回流反应，TLC监控反应结束。冷至室温，滤去不溶物，浓缩，残余物用乙酸乙酯溶解后，经水、饱和氯化钠洗涤，无水硫酸钠干燥，过滤，浓缩，柱纯化得7g化合物4，LC-MS：[M+H]+:559.2。
实施例5化合物5的合成
于500mL单口瓶中，加入化合物4(7g，1eq，12.5mmol)，100mLTHF，对甲苯磺酸一水合物(0.24g，0.1eq，1.25mmol)，搅拌冷却至0℃，滴加羟乙酸苄酯(4.2g，2eq，25mmol)，滴毕自然升温至室温反应，TLC监控。反应结束，加入饱和NaHCO3溶液，用乙酸乙酯萃取，无水硫酸钠干燥，过滤，浓缩，残余物经柱纯化得5g化合物5，LC-MS：[M+H]+:665.3。
实施例6化合物6的合成
于25mL单口瓶中加入Z-Gly-Gly-Phe-OH(3.52g，8.28mmol，1.1eq)、HOSu(1.0g，9.0mmol，1.2eq)，EDCI(1.72g，9.0mmol，1.2eq)及15mLDMF，室温搅拌备用。
另取25mL单口瓶，加入化合物5(2g，7.5mmol，1eq)，8mLDMF，0℃搅拌，加入DBU(1.25mL，8.28mmol，1.1eq)，TLC监控，Fmoc脱保护完成后，将上述混合液加至此瓶中，室温反应，TLC监测。反应完毕，加入水，乙酸乙酯萃取，无水硫酸钠干燥，过滤，浓缩，残余物经柱纯化得4.4g产品。LC-MS：[M+H]+:838.5。
实施例7化合物7的合成
于50mL单口瓶中加入化合物6(500mg，1eq，0.59mmol)，5％Pd/BaSO4(500mg)，35mLDMF，50℃氢化反应。HPLC监控，反应结束后过滤，得滤液。
向滤液中加入McOSu(367mg，1.19mmol，2eq)，DIEA(197uL，1.19mmol，2eq)，室温反应，HPLC监控，反应结束，浓缩，制备纯化，冻干得产品210mg。LC-MS：[M+H]+:807.3。
实施例8化合物8的合成
于25mL单口瓶中加入化合物7(100mg,0.12mmol,1eq)、依喜替康(54mg,0.129mmol,1eq)、PyBOP(128mg,0.24mmol,2eq)、DIEA(43uL,0.24mmol,2eq)及8mLDMF，室温反应，HPLC监控，制备纯化，冻干得80mg产品，TOF-MS＝1224.5(M+1)。
实施例9化合物9的合成
250mL三口瓶中依次加入Fmoc-Gly(5.94g,20mmol,1.0eq)，EDCI(4.2g,22mmol,1.1eq),HOBT(2.97g,22mmol,1.1eq)和THF(100mL)，搅拌均匀，冰水浴降温后滴加DIEA(3.1g,24mmol,1.2eq)，加完后继续冰水浴反应30min，再加入氨基丁醇(1.96g,22mmol,1.1eq)，加完后升至室温反应4h，TLC检测，原料Fmoc-Gly反应完，后处理：冰水浴下加水淬灭，EA萃取(200mL×2)，合并有机相，依次用饱和食盐水洗，无水硫酸钠干燥，过滤，旋掉大部分EA后析出大量白色固体，过滤，滤饼转移并干燥后得白色固体化合物9(6.0g，82％)。LC-MS：[M+1]:369.4。
实施例10化合物10的合成
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100mL单口瓶中加入化合物9(2.0g,5.4mmol,1.0eq)，DCM(400mL)，溶液浑浊，冰水浴降温，分批加入Dess-Maitin(2.52g,5.94mmol,1.1eq)，氮气保护，加完后升至室温反应4h，TLC检测，原料反应完，过滤后旋干DCM，HPLC(TFA)制备，制备相旋掉大部分MeCN,加入DCM萃取,合并有机相，依次用饱和食盐水洗，无水硫酸钠干燥，过滤，旋干后得到白色固体化合物10(1.52g，76％)。1HNMR(400Mz,DMSO):1.64-2.08(5H,m),3.13-3.20(1H,m),3.40-3.44(1H,m),3.75-3.97(2H,m),4.21-4.29(3H,m),5.38-5.49(1H,m),5.69-5.87(1H,d,J＝4.0Hz),7.32-7.35(2H,m),7.42(3H,t,J＝8.0Hz),7.73(2H,d,J＝8.0Hz),7.90(2H,d,J＝8.0Hz)。
实施例11化合物11的合成
于100mL单口瓶中加入化合物101.13g，3.0mmol，1.0eq),THF(28mL)溶清后加入少量4A分子筛粉末，冰水浴降温后依次加入羟基乙酸苄酯(2.49g，15.0mmol，5.0eq)，对甲苯磺酸一水合物(86mg，0.45mmol，0.15eq)，氮气保护，加完后升至室温反应2h。TLC监控，反应液直接HPLC纯水制备，制备相用EA萃取，EA相依次用饱和食盐水洗，无水硫酸钠干燥，过滤，浓缩后得化合物11(770mg,50％)。1H NMR(400Mz,DMSO):1.75-1.99(4H,m),3.20-3.50(2H,m),3.77-3.80(1H,m),3.99-4.05(1H,m),4.21-4.35(5H,m),5.09-5.16(2H,m),5.37-5.51(1H,没),7.31-7.49(10H,m),7.73(2H,br),7.90(2H,d,,J＝8.0Hz)。
实施例12化合物12的合成
于25mL单口瓶中加入化合物11(450mg，0.88mmol，1.0eq)和5mLDMF，搅拌均匀后，降至0℃，再缓慢加入DBU(160mg，1.05mmol，1.2eq)，加完后升至室温反应。TLC监控，原料反应完。反应液直接在下一步反应中使用。
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实施例13化合物001的合成
树脂合成仪中加入2-CTC树脂(15g，1.0eq)和60mLDMF溶胀30min，抽干溶剂；于100mL单口瓶中加入S1(9.07g，1.5eq),DMF(80mL)，冰水浴下加入DIEA(6.05g，3.0eq)反应10min，将此反应液加入到抽干的树脂中，摇床反应4h；后处理：抽干溶剂后，用DMF洗树脂到中性，再用DCM(60mL*3)洗树脂，干燥后得到18.3g，上载率：0.514mmol/g。
实施例14化合物002的合成
树脂合成仪中加入001树脂(18.3g，1.0eq)和60mLDMF溶胀30min，抽干溶剂，加入20％哌啶/DMF，摇床反应(30min*2次)，抽干溶剂，用DMF(60mL*6)洗树脂，洗到中性，取少量树脂溴酚蓝(1mg/mL)显深蓝色；于100mL单口瓶中加入S2(7.5g，3.0eq),HATU(10.7g，3.0eq),HoBt(3.8g，3.0eq),DMF(50mL)溶解，冰水浴下加入DIEA(6.0g，5.0eq)继续反应10min，将此反应液加入到抽干的树脂中，摇床反应3h，取少量反应的树脂DMF洗至中性，树脂反应完；后处理：抽干溶剂后，用DMF(100mL*6)洗树脂，洗到中性。
实施例15化合物SM-4的合成
树脂002加入1.5％TFA/DCM，合并切下液旋干得粗品6.9g，加入异丙醚冰水浴下搅洗，析出白色固体，过滤后干燥滤饼得到类白色固体(1.52g，100％)MS：[M+1]414.2。
实施例16化合物13的合成
于25mL单口瓶中加入三肽SM-4(398mg，0.96mmol，1.1eq)，EDCI(201mg，1.05mmol，1.2eq)，HOBT(142mg，1.05mmol，1.2eq)和DMF(4mL)，冰水浴下滴加DIEA，氮气保护，继续反应10min，将化合物12(0.88mmol，1.0eq)反应液在冰水浴下缓慢滴加至此反应液中，加完后升至室温反应1.5h，HPLC监测，反应完毕，纯水制备纯化，制备相用EA萃取，EA相依次用饱和食盐水洗，无水硫酸钠干燥，过滤，浓缩后得化合物13(410mg，68％)。1H NMR(400Mz,DMSO):0.84-0.93(2H,m),1.23-1.40(2H,m),1.62-1.96(4H,m),2.05-2.15(1H,m),2.73-2.79(1H,m),3.03-3.09(1H,m),3.34-3.56(2H,m),3.62(2H,d,J＝8.0Hz),3.72-4.06(3H,m),4.12-4.36(3H,m),4.57-4.59(1H,m),5.03(2H,s),5.13-5.17(2H,m),5.40-5.59(1H,m),7.16-7.18(1H,m),7.25(4H,s),7.31-7.39(10H,m),7.49-7.53(1H,m),7.66-7.74(1H,m),8.01(1H,t,J＝8.0Hz),8.15(1H,t,J＝8.0Hz),8.21-8.25(1H,m)。
实施例17化合物14的合成
于25mL单口瓶中加入化合物13(150mg，0.22mmol,1.0eq，)，5％Pd/C(150mg)，DMF(6mL)，40摄氏度氢化反应4h。HPLC监控，原料反应完，反应液过滤，滤液直接投下一步反应。
实施例18化合物15的合成
将化合物14反应液过滤至25mL单口瓶中，冰水浴下依次加入McOSu(134mg，0.44mmol，2.0eq)，DIEA(113mg，0.87mmol,4.0eq)，氮气保护，加完后升至室温反应1h，HPLC监控，纯水制备纯化，制备相直接冻干得化合物15(75mg，52％)，MS：[M-1]655.2。
实施例19化合物16的合成
将化合物15(115mg,0.17mmol,1.0eq)、PyBop(182mg,0.35mmol,2.0eq)溶于干燥DMF(8mL)，冰水浴下加入DIEA(45mg,0.35mmol,2.0eq)，依喜替康(113mg,0.26mmol,1.5eq)，氮气保护，加后升至室温反应1.5h，HPLC监控，原料化合物15反应完，反应液直接HPLC纯水制备，得到化合物16(32.63mg，17％)，LC-MS：[M+1]:1074.2。
实施例20化合物17的合成
将化合物14(102mg，0.22mmol，1.0eq)加到25mL单口瓶中，冰水浴下依次加入SMCC-OSu(134mg，0.44mmol，2.0eq)，DIEA(113mg，0.87mmol,4.0eq)，氮气保护，加完后升至室温反应1h，HPLC监控，纯水制备纯化，制备相直接冻干得化合物17(82mg，55％)，MS：[M-1]681.7。
实施例21化合物19的合成
化合物18采用与化合物14类似得方法制备得到。
将化合物18(130mg，0.25mmol，1.0eq)加到25mL单口瓶中，冰水浴下依次加入McOSu(152mg，0.50mmol，2.0eq)，DIEA(128mg，1.00mmol,4.0eq)，氮气保护，加完后升至室温反应1h，HPLC监控，纯水制备纯化，制备相直接冻干得化合物19(75mg，52％)，MS：[M-1]712.7。
实施例22化合物21的合成
化合物20采用与化合物14类似得方法制备得到。
将化合物20(138mg，0.34mmol，1.0eq)加到25mL单口瓶中，冰水浴下依次加入McOSu(207mg，0.68mmol，2.0eq)，DIEA(174mg，1.36mmol,4.0eq)，氮气保护，加完后升至室温反应1h，HPLC监控，纯水制备纯化，制备相直接冻干得化合物21(81mg，40％)，MS：[M-1]598.6。
实施例23化合物23的合成
化合物22采用与化合物14类似的方法制备得到。
将化合物22(128mg，0.26mmol，1.0eq)加到25mL单口瓶中，冰水浴下依次加入McOSu(158mg，0.52mmol，2.0eq)，DIEA(133mg，1.04mmol,4.0eq)，氮气保护，加完后升至室温反应1h，HPLC监控，纯水制备纯化，制备相直接冻干得化合物23(75mg，42％)，MS：[M-1]685.7。
实施例24化合物24的合成
将化合物21(120mg,1.0eq)、DCC(182mg)溶于干燥DMF(8mL)，冰水浴下加入DIEA(45mg)，双甲基MMAE(CAS:160800-57-7，购自上海瀚香生物科技有限公司，100mg)，氮气保护，加后升至室温反应1.5h，HPLC监控，原料化合物双甲基MMAE反应完，反应液直接HPLC纯水制备，得到化合物24(18mg，17％)，LC-MS：[M+1]:1313.8。
实施例25化合物25的合成
于25mL单口瓶中加入化合物17(43mg，1eq)，SN38(21mg，0.053mmol，1eq)及3mLDMF，室温搅拌，加入TBTU(25.7mg，0.08mmol，1.5eq)和DIEA(8.8uL，0.053mmol，1eq)，室温反应2h，HPLC监测反应进程。反应结束后，制备纯化，冻干得到产品34mg，LC-MS：[M+23]:1079.45。
实施例26对照分子化合物26(带乙二胺释放单元化合物)的合成
参照专利WO2016192527A1完成下式所示对照化合物合成。
实施例27 ADC药物C-01的合成
依通用步骤A，以化合物8为原料，偶联抗HER2抗体Herceptin，制备抗体药物偶联物，以下简称ADC药物，编号C-01。
实施例28 ADC药物C-06的合成
依通用步骤A以化合物16为原料，偶联抗HER2抗体Herceptin，制备ADC药物，编号C-06。实施例29 ADC药物C-07的合成
依通用步骤A以化合物25为原料，偶联抗HER2抗体Herceptin，制备ADC药物，编号C-07。
实施例30 ADC药物C-00的合成
依通用步骤A以实施例26所得阳性化合物为原料，偶联抗HER2抗体Herceptin，制备ADC药物，编号C-00。
(二)体外评价
对实施例27至30得到的ADC药物进行单体率及DAR测定，
1.SEC检测抗体单体率操作
配制SEC流动相50mM PB+300mM NaCl+200mM Arg，IPA＝95:5，调节PH＝6.5。将样品稀释到浓度在1～2mg/ml范围间，再将样品用14000rpm离心5分钟或者用0.22μm滤器过滤以去除样品中大颗粒。将样品瓶放于样品板上，按照《UPLC使用标准操作规程》设置各样品对应的位置、进样体积、进样针数和进样方法。色谱柱型号为：XBridge BEH SEC，200A，1.7μm，4.6*150mm，Waters。
设定检测波长为214nm和280nm，编辑跑样方法为：
时间(min) 流速(ml/min) SEC流动相(％)
0 0.8 100
12 0.8 100
2.RP-HPLC检测DAR操作
配制RP-HPLC流动相：
RP流动相A：0.1％TFA水溶液，RP流动相B：0.1％TFA乙腈。
用样品稀释液将待测样品及对应的抗体对照稀释到1mg/ml，每98ul稀释好的样品中加入2ul DTT储液，同时配制98ul样品稀释液加2ul DTT储液的空白对照，各样品混匀后，于65℃金属浴中加热20min。将处理后的样品14000rpm离心5分钟或者用0.22μm滤器过滤以去除样品中大颗粒，并将内插管放于样品瓶中盖好盖子。
将装好样品的样品瓶放与样品板上，按照《UPLC使用标准操作规程》设置各样品对应的位置、进样体积、进样针数和进样方法。色谱柱型号为：Proteomix RP-1000(4.6*100mm，5μm)，Sepax。
检测波长为：214 nm和280 nm。跑样方法编辑如下：
时间(min) 流速(ml/min) RP流动相A(％) RP流动相B(％)
0 0.5 75 25
3 0.5 75 25
28 0.5 50 50
30 0.5 5 95
32 0.5 5 95
33 0.5 75 25
40 0.5 75 25
通过以上方法，测定结果如下表1所示：
表1单体率及DAR测定结果
以上数据表明，本发明所述ADC药物在较高的DAR下保持了良好的单体率，聚集程度低，血浆稳定性良好。
(三)体外抗肿瘤细胞药效实验
对实施例23至24得到的ADC药物采用MTS法进行体外IC50测定，首先培养肿瘤细胞(BXPC-3，Fadu，SW620，A431)，培养基DMEM(Gibco，10569044)+10％FBS(Biowest：S1580-500),当细胞生长汇合度在(70-80)％时，使用胰酶(Gibco：25200056)通过常规方法对肿瘤细胞进行消化，离心，用对应检测培养基(含1％FBS)重悬计数，将细胞用检测培养基稀释到铺板密度(3500活细胞/孔)后铺入96孔板中，24小时后用检测培养基稀释偶联物(1μM起始，5倍稀释，9个浓度)，将稀释好的偶联物加入对应的细胞孔中，孵育3天，然后每孔加入20ulMTS(Promega，G3581)反应2小时，酶标仪(Molecular Device，型号：SpectraMAX190)490nM读数。通过检测线粒体内的脱氢酶的活性，评价抗体药物偶联物对细胞的增殖抑制作用。
其测定结果如下表2所示：
表2体外IC50测定结果
ADC BXPC-3 Fadu SW620 A431
C-06 33.08 1.37 2.64 2.64
C-07 ～200 1.90 223.18 5.88
以上数据表明，本发明所述ADC药物在多种细胞系中均表现出很好的抗肿瘤活性。
(三)酶切实验
对以上实施例得到药物分子(payload)进行体外酶切实验测定，具体方法：将组织蛋白酶B(Recombinant Human Cathepsin B，购买自近岸科技Novoprotein)，溶于自制PH5.0乙酸钠缓冲液中，配置成浓度50mmol/L，将待测定payload溶于DMF溶液，浓度10mg/ml，取100微升乙酸钠缓冲液、10微升payload溶液，1微升酶溶液混合，于37摄氏度下反应，每隔1h取样HPLC监测payload释放毒素浓度情况，记录毒素浓度达峰时间。测定结果如下表3所示：
表3体外酶切实验测定结果
Payload 毒素完全释放时间
化合物16 约6h
化合物24 约5h
化合物26(对照化合物) 约16h
以上实施例表明，本专利所设计化合物在组织蛋白酶下，毒素释放时间明显优于对照化合物，达到了快速释放的目的。

Claims (8)

1.一种如式I所示的抗体药物偶联物或其药学上可接受的盐：
其中：
Ab是抗体、抗体片段或蛋白，n选自1～20的整数；
D为药物单元，
选自如下结构之一：
R1、R2和R3选自如图所示结构：波浪线表示氮原子与Lp的连接位点；
L1表示L2与Ab之间的连接单元；
L2表示延伸单元或单键；
Lp表示由2～7个氨基酸构成的肽链，Lp与式I中N杂原子之间以酰胺键连接。
2.如权利要求1所述的抗体药物偶联物或其药学上可接受的盐，其特征在于：其中的Lp肽链构成的氨基酸选自：丙氨酸、精氨酸、天冬酰胺、天冬氨酸、半胱氨酸、谷氨酰胺、谷氨酸、甘氨酸、组氨酸、异亮氨酸、亮氨酸、赖氨酸、甲硫氨酸、苯丙氨酸、脯氨酸、丝氨酸、苏氨酸、色氨酸、酪氨酸或者缬氨酸。
3.如权利要求1所述的抗体药物偶联物或其药学上可接受的盐，其特征在于：L1表示Ab与L2的连接单元，其结构为-(琥珀酰亚胺-3-基-N)-(CH2)n4-C(＝O)-、-CH2-C(＝O)-NH-(CH2)n5-C(＝O)-、-C(＝O)-环己基(1,4)-CH2-(N-ly-3-硫代)-,-C(＝O)-(CH2)n6-C(＝O)-或-(琥珀酰亚胺-3-基-N)-R4(R5)-(＝O)-，其中n4选自2～8的整数，n5选自1～8的整数，n6选自1～8的整数，在-(琥珀酰亚胺-3-基-N)-结构中3位与抗体连接，1位氮原子与包含该接头结构内的亚甲基连接，其结构为：
R4为C2～C5亚烷基，该亚烷基被任选的R5取代，R5为-(CH2)n7NH-Ac，Ac-NH
为氨基酸或寡肽单元。
4.如权利要求1所述的抗体药物偶联物或其药学上可接受的盐，其特征在于：
连接单元L1具有以下结构：
R4为C2-C5亚烷基，该亚烷基被任选的R5取代，R5为-(CH2)n7NH-Ac，Ac-NH
为选自甘氨酸、丙氨酸、亮氨酸、异亮氨酸、缬氨酸、苯丙氨酸、脯氨酸、色氨酸、丝氨酸、酪氨酸、半胱氨酸、蛋氨酸、天冬酰胺或谷氨酸。
5.如权利要求1所述的抗体药物偶联物或其药学上可接受的盐，其特征在于：L2表示-NH-(CH2-CH2-O)n8-CH2-CH2-C(＝O)-、-S-(CH2)n9-C(＝O)-、或单键，其中n8、n9分别选自1～6的整数。
6.如权利要求1所述的抗体药物偶联物或其药学上可接受的盐，其特征在于：Lp为可被靶细胞内蛋白酶特异性切割的肽链，选自缬氨酸-半胱氨酸；缬氨酸-丙氨酸；苯丙氨酸-赖氨酸；甘氨酸-甘氨酸-苯丙氨酸-甘氨酸或苯丙氨酸-谷氨酸。
7.一种抗肿瘤、治疗自身免疫疾病或感染性疾病的药物，含有权利要求1～6中任一项所述的抗体药物偶联物或其药学上可接受的盐。
8.如权利要求7所述的药物，其特征在于：所述肿瘤为肺癌、肾癌、尿道癌、结肠癌、直肠癌、***癌、多形性胶质细胞瘤、卵巢癌、胰腺癌、乳腺癌、黑色素瘤、肝癌、膀胱癌、胃癌、食道癌或血液肿瘤。
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