CN116615257A - 硒抗体缀合物 - Google Patents
硒抗体缀合物 Download PDFInfo
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- CN116615257A CN116615257A CN202180078123.5A CN202180078123A CN116615257A CN 116615257 A CN116615257 A CN 116615257A CN 202180078123 A CN202180078123 A CN 202180078123A CN 116615257 A CN116615257 A CN 116615257A
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- compound
- antibody
- gln
- antigen binding
- antibodies
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Abstract
本文提供了包含含硒接头的抗体缀合物,包括抗体药物缀合物。
Description
相关申请
本申请要求2020年11月10日提交的美国临时专利申请号63/112,044的优先权权益,其内容以引用方式整体并入本文。
技术领域
本文提供了包含含硒接头的抗体缀合物,包括抗体药物缀合物(ADC)。
背景技术
ADC结合了抗体特异性的能力与通过有效负载位点特异性地靶向特定类型的细胞或组织的能力。这一领域的研究引起了人们的极大兴趣,并已催生了上市药品,包括(维布妥昔单抗(brentuximab vedotin))和KADCYLATM(恩美曲妥珠单抗(ado-trastuzumab emtansine))。在许多情况下,抗体与有效负载的缀合以非特异性方式进行,由此有效负载未缀合至抗体上的限定位置,从而导致难以纯化的ADC混合物。此外,标准缀合方法导致药物抗体比(DAR)的可变性,从而进一步增加了所得ADC混合物的复杂性。
最近,已经开发出将抗体与有效负载位点特异性缀合的方法。参见,例如,Agarwal等Bioconjugate Chem.2015,26,176-192。然而,这些方法有局限性,包括与某些有效负载和/或化学交叉反应性缺乏相容性。例如,Dennler等(Bioconjugate Chem.2014,25,569-578)开发了一种SAc硫醇接头(C6-SAc),但得出的结论是中间体硫醇的低效脱乙酰化阻碍了该方法的完全成功。
因此,持续需要用于产生ADC的有效的位点特异性方法以及通过此类方法产生的ADC。
发明内容
本文提供了具有连接抗原结合结构域和有效负载的含硒接头的ADC。在一个实施方案中,抗原结合结构域是抗体或其抗原结合片段。在另一个实施方案中,有效负载是治疗剂或成像剂。在另一个实施方案中,治疗剂是细胞毒素。在另一个实施方案中,本文提供的ADC具有式I:
Z-(Gln-NH-L-Se-L1-R)n
或其药学上可接受的盐,其中:
Z是抗原结合结构域;
Gln是抗原结合结构域的谷氨酰胺;
NH是Gln的侧链NH;
L和L1是相同或不同的并且各自为接头;
R是有效负载;并且
n是1至10的整数。
在另一个实施方案中,本文提供的ADC可用于治疗方法或者成像或诊断方法。
附图说明
图1是用于合成本文提供的ADC的方法的描绘,其中Z是抗体,L是亚乙基;L1是接头,在一个实施方案中,其由mc-vc-PAB得到;并且R是有效负载,在一个实施方案中是MMAE。
图2A和2B示出去糖基化的mAb1(degly-mAb1)、去糖基化的mAb1-Se(degly-mAb1-1,在与硒代胱胺和MTG酶反应后)、去糖基化的mAb1-Se-MMAE(degly-mAb1-1-mc-vc-PAB-MMAE,在与mc-vc-PAB-MMAE反应后),以及mAb1与mc-vc-PAB-MMAE的模拟对照反应的质谱术图谱。
图3示出去糖基化的ISOmAb(degly-ISOmAb)、去糖基化的ISOmAb-Se(degly-ISOmAb-1,在与硒代胱胺和MTG酶反应后)和去糖基化的ISOmAb-Se-MMAE(degly-ISOmAb-1-mc-vc-PAB-MMAE,在与mc-vc-PAB-MMAE反应后)的质谱术图谱。
图4示出去糖基化的mAb1-Se-MMAE(degly-mAb1-1-mc-vc-PA B-MMAE)和去糖基化的ISOmAb-Se-MMAE(degly-ISOmAb-1-mc-vc-PAB-MMAE)的尺寸排阻HPLC(SEC)。
图5示出在与本文提供的ADC一起孵育时HER+(SKBR3)和HER2-(H1975)细胞系的细胞活力。
具体实施方式
I.定义
为了便于理解本文阐述的公开内容,以下定义了多个术语。
除非另有定义,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所理解的含义相同的含义。所有专利、申请、已公布的申请和其他出版物均通过引用整体并入。除非另行指出,否则在本文的术语存在多种定义的情况下,以本部分中的定义为准。
除非上下文另外明确规定,否则单数形式“一个”、“一种”和“所述”包括多个指代物。
如本文所用,“受试者”是动物,诸如哺乳动物,包括人,诸如患者。
如本文所用,生物活性是指化合物的体内活性或在体内施用化合物、组合物或其他混合物时产生的生理反应。因此,生物活性包括此类化合物、组合物和混合物的治疗效果和药代动力学行为。可以在设计用于测试此类活性的体外系统中观察生物活性。
如本文所用,“抗原结合结构域”是指能够特异性结合感兴趣的特定抗原的任何肽、多肽、核酸分子、支架型分子、肽展示分子或含有多肽的构建体。如本文所用,“抗原结合结构域”包括抗体和抗体的抗原结合片段。除非明确指定为来自非人物种,否则本文中对蛋白质、多肽和蛋白质片段的所有提及均旨在指相应蛋白质、多肽或蛋白质片段的人型式。
如本文所用,术语“特异性结合”等是指抗原结合结构域与特定抗原形成复合物,其特征在于解离常数(KD)为500pM或更小,并且在普通测试条件下不结合其他无关抗原。
如本文所用,“无关抗原”是彼此具有小于95%的氨基酸同一性的蛋白质、肽或多肽。
如本文所用,术语“抗体”是指包含至少一个特异性结合特定抗原(例如,人HER2)或与其相互作用的互补决定区(CDR)的任何抗原结合分子或分子复合物。术语“抗体”包括包含通过二硫键相互连结的四条多肽链(两条重(H)链和两条轻(L)链)以及其多聚体(例如IgM)的免疫球蛋白分子。每条重链包含重链可变区(本文中缩写为HCVR或VH)和重链恒定区。重链恒定区包含三个结构域,CH1、CH2和CH3。每条轻链包含轻链可变区(本文中缩写为LCVR或VL)和轻链恒定区。轻链恒定区包含一个结构域(CL1)。VH和VL区可以进一步细分为被称为互补决定区(CDR)的高变区,穿插有被称为框架区(FR)的较保守区。每个VH和VL由三个CDR和四个FR组成,从氨基端到羧基端按以下顺序排列:FR1、CDR1、FR2、CDR2、FR3、CDR3、FR4。
如本文所用,术语抗体的“抗原结合片段”是指特异性结合抗原以形成复合物的任何天然存在的、酶促可获得的、合成的或基因工程改造的多肽或糖蛋白。
如本文所用,术语“人抗体”是指具有源自人种系免疫球蛋白序列的可变区和恒定区的抗体。尽管如此,人抗体可例如在CDR和尤其CDR3中包括不由人种系免疫球蛋白序列编码的氨基酸残基(例如,在体外通过随机或位点特异性诱变或在体内通过体细胞突变所引入的突变)。然而,如本文所用,术语“人抗体”不旨在包括其中源自另一哺乳动物物种(诸如小鼠)的种系的CDR序列已接枝到人框架序列上的抗体。
如本文所用,术语“重组人抗体”是指通过重组手段制备、表达、形成或分离的所有人抗体,诸如使用转染到宿主细胞中的重组表达载体表达的抗体(下文进一步描述);从重组、组合人抗体文库分离的抗体(下文进一步描述);从对于人免疫球蛋白基因来说为转基因动物的动物(例如小鼠)分离的抗体(参见例如Taylor等(1992)Nucl.Acids Res.20:6287-6295);或通过涉及将人免疫球蛋白基因序列剪接至其他DNA序列的任何其他手段制备、表达、形成或分离的抗体。
如本文在氨基酸序列的上下文中所用,术语“基本上相同(substantialidentity)”或“基本上相同的(substantially identical)”是指当诸如通过程序GAP或BESTFIT使用默认空位权重进行最佳比对时,两个氨基酸序列享有至少95%、98%或99%的序列同一性。
如本文所用,术语“表面等离子共振”是指允许通过检测生物传感器基质内蛋白质浓度的改变来分析实时相互作用的光学现象,例如使用BIAcoreTM系统(Biacore LifeSciences division of GE Healthcare,Piscataway,N.J.)。
如本文所用,术语“KD”是指特定蛋白质-蛋白质相互作用(例如,抗体-抗原相互作用)的平衡解离常数。除非另有说明,否则本文所公开的KD值是指在25℃下通过表面等离子共振测定法确定的KD值。
如本文所用,药学上可接受的盐包括但不限于胺盐,诸如但不限于N,N'-二苄基乙二胺、氯普鲁卡因、胆碱、氨、二乙醇胺和其他羟烷基胺、乙二胺、N-甲基葡糖胺、普鲁卡因、N-苄基苯乙胺、1-对氯苄基-2-吡咯烷-1'-基甲基苯并咪唑、二乙胺和其他烷基胺、哌嗪以及三(羟甲基)氨基甲烷;碱金属盐,诸如但不限于锂、钾和钠;碱土金属盐,诸如但不限于钡、钙和镁;过渡金属盐,诸如但不限于锌;以及无机盐,诸如但不限于磷酸氢钠和磷酸二钠;并且还包括但不限于无机酸盐,诸如但不限于盐酸盐和硫酸盐;以及有机酸盐,诸如但不限于乙酸盐、乳酸盐、苹果酸盐、酒石酸盐、柠檬酸盐、抗坏血酸盐、琥珀酸盐、丁酸盐、戊酸盐、甲磺酸盐和富马酸盐。
如本文所用,治疗是指其中疾病或病症的一种或多种症状被改善或以其他方式有益地改变的任何方式。治疗还包括本文组合物的任何药物用途,诸如用于治疗肿瘤(包括HER2阳性肿瘤,诸如乳腺癌)的用途。
如本文所用,通过施用特定化合物或药物组合物改善特定病症的症状是指可以归因于化合物或药物组合物的施用或与其相关的任何减轻,无论是永久的还是暂时的、持久的还是过渡性的。
如本文所用,IC50是指在测量此类反应的测定中实现最大反应的50%抑制的特定测试化合物的量、浓度或剂量。
在通过其常规化学式(从左到右书写)规定部分的情况下,其同样涵盖从右到左书写结构将得到的化学上相同的部分,例如,-CH2O-等同于-OCH2-。
除非另有说明,否则术语“烷基”本身或作为另一取代基的一部分是指直链(即,非支链)或支链饱和烃基团。术语“亚烷基”本身或作为另一取代基的一部分是指衍生自烷基的二价基团。通常,烷基(或亚烷基)将具有1至24个碳原子,包括具有10个或更少碳原子的那些基团。“低级烷基”或“低级亚烷基”是较短链的烷基或亚烷基,其通常具有六个或更少碳原子。烷基的实例包括但不限于诸如甲基、乙基、正丙基、异丙基、正丁基、叔丁基、异丁基、仲丁基的基团、例如正戊基、正己基、正庚基、正辛基的同系物和异构体等。
除非另有说明,否则术语“烯基”本身或作为另一取代基的一部分是指直链(即,非支链)或支链烃基团,其具有一个或多个碳-碳双键。术语“亚烯基”本身或作为另一取代基的一部分是指衍生自烯基的二价基团。通常,烯基(或亚烯基)将具有1至24个碳原子,包括具有10个或更少碳原子的那些基团。“低级烯基”或“低级亚烯基”是较短链的烯基或亚烯基,其通常具有六个或更少碳原子。烯基的实例包括但不限于乙烯基(vinyl)(即,乙烯基(ethenyl))、2-丙烯基、巴豆基、2-异戊烯基、2-(丁二烯基)、2,4-戊二烯基、3-(1,4-戊二烯基),以及高级同系物和异构体。
除非另有说明,否则术语“炔基”本身或作为另一取代基的一部分是指具有一个或多个碳-碳三键的直链(即,非支链)或支链烃基团,其可以包括二价和多价基团、具有指定的碳原子数(即,C1-C10是指一至十个碳)。炔基的实例包括但不限于乙炔基、1-和3-丙炔基、3-丁炔基,以及高级同系物和异构体。
术语“烷氧基”、“烷基氨基”和“烷硫基”(或硫代烷氧基)以其常规含义使用,并且是指分别通过氧原子、氨基或硫原子附接至分子的其余部分的那些烷基。
除非另外指明,否则术语“杂烷基”本身或与另一术语组合是指由选自由O、N、P、Si和S组成的组的链中杂原子组成的直链或支链烃基团,并且其中氮和硫原子可任选被氧化并且氮原子可具有烷基取代基以满足化合价和/或可任选被季铵化。一个或多个杂原子O、N、P、Si和S可置于杂烷基的任何内部位置。实例包括但不限于-CH2-CH2-O-CH3、-CH2-CH2-NH-CH3、-CH2-CH2-N(CH3)-CH3、-CH2-S-CH2-CH3、-CH2-CH2-S(O)-CH3、-CH2-CH2-S(O)2-CH3、-CH=CH-O-CH3、-CH2-CH=N-OCH3和-CH=CH-N(CH3)-CH3。最多至两个杂原子可以是连续的,诸如像-CH2-NH-OCH3和–CH2-O-Si(CH3)3。类似地,术语“杂亚烷基”本身或作为另一取代基的一部分是指衍生自杂烷基的二价基团,例如但不限于-CH2-CH2-S-CH2-CH2-和–CH2-S-CH2-CH2-NH-CH2-。对于亚烷基和杂亚烷基连接基团,连接基团没有取向是通过连接基团的式被书写的方向来暗示的。例如,式–C(O)2R'-表示–C(O)2R'-和–R'C(O)2-两者。
除非另有说明,否则术语“环烷基”和“杂环烷基”本身或与其他术语组合分别表示“烷基”和“杂烷基”的环状型式,包括二环、三环和桥接二环基团。另外,对于杂环烷基,杂原子可占据杂环附接至分子的其余部分所处的位置处。术语“亚环烷基”和“杂亚环烷基”本身或作为另一取代基的一部分是指衍生自环烷基或杂环烷基的二价基团。环烷基的实例包括但不限于环戊基、环己基、1-环己烯基、3-环己烯基、环庚基、降冰片烷基、双环(2.2.2)辛烷基等。杂环烷基的实例包括但不限于1-(1,2,5,6-四氢吡啶基)、1-哌啶基、2-哌啶基、3-哌啶基、4-吗啉基、3-吗啉基、四氢呋喃-2-基、四氢呋喃-3-基、四氢噻吩-2-基、四氢噻吩-3-基、1-哌嗪基、2-哌嗪基、1-或2-氮杂双环(2.2.2)辛烷基等。
除非另有说明,否则术语“芳基”是指多不饱和的、芳族的烃取代基,其可以是单环或多环(在一个实施方案中,1至3个环),它们稠合在一起或共价连接。术语“杂芳基”是指芳基,其在一个或多个环中含有一至四个选自N、O和S的杂原子,其中氮和硫原子任选地被氧化,并且一个或多个氮原子任选被季铵化。杂芳基可以通过碳或杂原子附接至分子的其余部分。术语“亚芳基”和“杂亚芳基”本身或作为另一取代基的一部分是指衍生自芳基或杂芳基的二价基团。芳基和杂芳基的非限制性实例包括苯基、1-萘基、2-萘基、4-联苯基、1-吡咯基、2-吡咯基、3-吡咯基、3-吡唑基、2-咪唑基、4-咪唑基、吡嗪基、2-噁唑基、4-噁唑基、5-噁唑基、3-异噁唑基、4-异噁唑基、5-异噁唑基、2-噻唑基、4-噻唑基、5-噻唑基、2-呋喃基、3-呋喃基、2-噻吩基、3-噻吩基、2-吡啶基、3-吡啶基、4-吡啶基、2-嘧啶基、4-嘧啶基、5-苯并噻唑基、嘌呤基、2-苯并咪唑基、5-吲哚基、1-异喹啉基、5-异喹啉基、2-喹喔啉基、5-喹喔啉基、3-喹啉基以及6-喹啉基。术语“杂芳基鎓(heteroarylium)”是指在一个或多个杂原子上带正电的杂芳基。
以上术语中的每一个都意在包括指定基团的取代和未取代形式。下面提供了每种类型的基团的取代基部分的非限制性实例。
在一个实施方案中,烷基、杂烷基、亚烷基、烯基、杂亚烷基、杂烯基、炔基、环烷基、杂环烷基、环烯基和杂环烯基的取代基部分选自氘、-OR'、=O、=NR'、=N-OR'、-NR'R"、-SR'、卤基、-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'、-NR-C(NR'R"R'")=NR""、-NR-C(NR'R")=NR'"、-S(O)R'、-S(O)2R'、-S(O)2NR'R"、-NRSO2R'、-CN和–NO2,其数量范围为零至此类基团中的氢原子数。在一个实施方案中,环烷基、杂环烷基、环烯基和杂环烯基的取代基部分还包括取代和未取代的烷基、取代和未取代的烯基以及取代和未取代的炔基。在一个实施方案中,R'、R"、R”'和R””各自独立地为氢、取代或未取代的杂烷基、取代或未取代的环烷基、取代或未取代的杂环烷基、取代或未取代的芳基(例如,被1-3个卤素取代的芳基)、取代或未取代的烷基、烷氧基或硫代烷氧基,或芳基烷基。当本文提供的化合物包括多于一个R基团时,例如,每个R基团独立地选择,当存在多于一个这些基团时,每个R'、R”、R”'和R””基团也是如此。当R'和R”附接至相同的氮原子时,它们可以与氮原子组合形成4元、5元、6元或7元环。例如,-NR'R”旨在包括但不限于1-吡咯烷基和4-吗啉基。由取代基部分的以上论述,本领域技术人员将理解,术语“烷基”意在包括包含结合至除氢基团之外的基团的碳原子的基团,诸如卤代烷基(例如,-CF3和–CH2CF3)和酰基(例如,-C(O)CH3、-C(O)CF3、-C(O)CH2OCH3等)。
在一个实施方案中,芳基和杂芳基的取代基部分选自氘、卤基、取代和未取代的烷基、取代和未取代的烯基,以及取代和未取代的炔基、-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'、-NR-C(NR'R"R'")=NR""、-NR-C(NR'R")=NR'"、-S(O)R'、-S(O)2R'、-S(O)2NR'R"、-NRSO2R'、-CN和–NO2、-R'、-N3、-CH(Ph)2、氟代(C1-C4)烷氧基和氟代(C1-C4)烷基,其数量范围为零至芳环系统上氢的总数;并且其中R'、R"、R"'和R""在一个实施方案中独立地选自氢、取代或未取代的烷基、取代或未取代的杂烷基、取代或未取代的环烷基、取代或未取代的杂环烷基、取代或未取代的芳基和取代或未取代的杂芳基。当本文提供的化合物包括多于一个R基团时,例如,每个R基团独立地选择,当存在多于一个这些基团时,每个R'、R”、R”'和R””基团也是如此。
芳基或杂芳基环的相邻原子上的两个取代基部分可任选地形成式-Q'-C(O)-(CRR')q-Q”-的环,其中Q'和Q”独立地为-NR-、-O-、-CRR'-或单键,并且q是0至3的整数。可替代地,芳基或杂芳基环的相邻原子上的两个取代基部分可任选地被式-A-(CH2)r-B-的取代基替代,其中A和B独立地为-CRR'-、-O-、-NR-、-S-、-S(O)-、-S(O)2-、-S(O)2NR'-或单键,并且r是1至4的整数。如此形成的新环的单键之一可任选地被双键替代。可替代地,芳基或杂芳基环的相邻原子上的取代基部分中的两个可任选地被式–(CRR')s-X'-(CR”R”')d-的取代基替代,其中s和d独立地为0至3的整数,并且X'为-O-、-NR'-、-S-、-S(O)-、-S(O)2-或-S(O)2NR'-。在一个实施方案中,取代基部分R、R'、R"和R'"独立地选自氢、取代或未取代的烷基、取代或未取代的环烷基、取代或未取代的杂环烷基、取代或未取代的芳基,以及取代或未取代的杂芳基。
除非另有说明,否则术语“卤基”本身或作为另一取代基的一部分是指氟、氯、溴或碘原子。另外,诸如“卤代烷基”的术语旨在包括单卤代烷基和多卤代烷基。例如,术语“卤代(C1-C4)烷基”旨在包括但不限于三氟甲基、2,2,2-三氟乙基、4-氯丁基、3-溴丙基等。
如本文所用,术语“氧代基”是指双键键合至碳原子的氧原子。
如本文所用,术语“杂原子”或“环杂原子”旨在包括氧(O)、氮(N)、硫(S)、磷(P)和硅(Si)。
本文提供的某些ADC,包括L和L1,具有不对称碳原子(光学中心)或双键;外消旋体、非对映异构体、互变异构体、几何异构体和单独的异构体涵盖在本公开的范围内。本文提供的ADC不包括本领域中已知的太不稳定而无法合成和/或分离的那些。
II.用于在组合物和方法中使用的ADC
在一个实施方案中,本文提供了用于在本文提供的组合物和方法中使用的ADC,其具有式I:
Z-(Gln-NH-L-Se-L1-R)n
或其药学上可接受的盐,其中:
Z是抗原结合结构域;
Gln是抗原结合结构域的谷氨酰胺
NH是Gln的侧链NH;
L和L1是相同或不同的并且各自为接头;
R是有效负载;并且
n是1至8的整数。
在另一个实施方案中,n是1至6的整数。在另一个实施方案中,n是1至4的整数。在另一个实施方案中,n是2或4。在另一个实施方案中,n是2。
A.抗原结合结构域Z
在一个实施方案中,用于在本文提供的ADC中使用的抗原结合结构域,即式I中的Z,包括与特定抗原特异性地相互作用的任何分子。在某些实施方案中,Z是抗体或抗体的抗原结合片段。在另一个实施方案中,Z是抗体。在另一个实施方案中,Z是包含谷氨酰胺残基的抗体。包含谷氨酰胺残基的抗体可以从天然来源分离或可以被工程改造以包含一个或多个谷氨酰胺残基。用于将谷氨酰胺残基工程改造到抗体多肽链(谷氨酰胺酰基修饰的抗体)中的技术在本领域从业人员的技能范围内。在其他实施方案中,Z是N297Q突变抗体。在另外的实施方案中,Z是具有一个或多个工程改造的LLQG、LLQGG、LLQLLQG、LLQYQG、LLQGA、LLQGSG、SLLQG、LQG、LLQLQ、LLQLLQ、LLQGR、LLQYQGA、LQGG、LGQG或LLQLLQGA位点的抗体。参见,例如,美国专利号9,676,871和美国专利申请公布号2003/0138785。在某些实施方案中,抗体是非糖基化的。在某些实施方案中,Z是为单克隆抗体、人抗体、人源化抗体、骆驼源化抗体或嵌合抗体的抗体。在其他实施方案中,Z是任何同种型(例如,IgG、IgE、IgM、IgD、IgA和IgY)、类(例如,IgG1、IgG2、IgG3、IgG4、IgA1和IgA2)或亚类的抗体。在一些实施方案中,Z具有至少500、600、700、800、900、1000、10000、50000或100000道尔顿的分子量。
在其他实施方案中,可以用于本文提供的ADC中的抗原结合结构域包括抗体、抗体的抗原结合片段、与特定抗原特异性地相互作用的肽(例如,肽体(peptibodies))、与特定抗原特异性地相互作用的受体分子、包含特异性结合特定抗原的受体的配体结合部分的蛋白质、抗原结合支架(例如,DARPin、HEAT重复蛋白、ARM重复蛋白、三角形四肽(tetratricopeptide)重复蛋白以及基于天然存在的重复蛋白的其他支架等(参见,例如,Boersma和Pluckthun,2011,Curr.Opin.Biotechnol.22:849-857,以及其中引用的参考文献)),以及适体或其部分。
用于确定两个分子是否彼此特异性结合的方法是本领域众所周知的并且包括例如平衡透析、表面等离子共振等。例如,如本文所用,抗原结合结构域包括结合特定抗原(例如,靶分子(T)或内化效应子蛋白(E))或其部分的多肽,其KD小于约500pM、小于约400pM、小于约300pM、小于约200pM、小于约100pM、小于约90pM、小于约80pM、小于约70pM、小于约60pM、小于约50pM、小于约40pM、小于约30pM、小于约20pM、小于约10pM、小于约5pM、小于约4pM、小于约2pM、小于约1pM、小于约0.5pM、小于约0.2pM、小于约0.1pM、或小于约0.05pM,如在表面等离子共振测定中所测量的。
在某些实施方案中,用于在本文提供的ADC中使用的抗体或其抗原结合片段的框架区(FR)可与人种系序列相同,或者可以是天然或人工修饰的。氨基酸共有序列可基于两个或更多个CDR的并行分析来定义。
用于鉴定HCVR和LCVR氨基酸序列内的CDR的方法和技术是本领域中熟知的并且可以用于鉴定CDR。可以用于鉴定CDR边界的示例性惯例包括例如Kabat定义、Chothia定义以及AbM定义。一般地说,Kabat定义是基于序列变异性,Chothia定义是基于结构环区的位置,而AbM定义是Kabat与Chothia方法之间的折中方法。参见,例如,Kabat,"Sequences ofProteins of Immunological Interest,"National Institutes of Health,Bethesda,Md.(1991);Al-Lazikani等,J.Mol.Biol.273:927-948(1997);以及Martin等,Proc.Natl.Acad.Sci.USA 86:9268-9272(1989)。公共数据库也可用于鉴定抗体内的CDR序列。
用于在本文提供的ADC中使用的抗原结合结构域可包含完整抗体分子的抗原结合片段或由其组成。可使用诸如蛋白水解消化或重组基因工程技术的任何合适的标准技术例如从完整抗体分子衍生出抗体的抗原结合片段,所述重组基因工程技术涉及编码抗体可变结构域和任选的恒定结构域的DNA的操纵和表达。这种DNA是已知的和/或可容易地从例如商业来源、DNA文库(包括,例如噬菌体-抗体文库)获得,或可以合成。DNA可用化学方法或通过使用分子生物学技术进行测序和操纵,例如以将一个或多个可变结构域和/或恒定结构域排列成合适构型,或引入密码子,产生半胱氨酸残基,修饰、添加或缺失氨基酸等。
用于在本文提供的ADC中使用的抗原结合片段的非限制性实例包括:(i)Fab片段;(ii)F(ab')2片段;(iii)Fd片段;(iv)Fv片段;(v)单链Fv(scFv)分子;(vi)dAb片段;以及(vii)由模拟抗体的高变区的氨基酸残基组成的最小识别单元(例如,分离的互补决定区(CDR),诸如CDR3肽),或限制性FR3-CDR3-FR4肽。在其他实施方案中,抗体的抗原结合片段包括其他工程改造的分子,诸如结构域特异性抗体、单结构域抗体、结构域缺失的抗体、嵌合抗体、CDR移植抗体、双抗体、三抗体、四抗体、微型抗体、纳米抗体(例如,一价纳米抗体、二价纳米抗体等)、小模块免疫药物(SMIP)和鲨鱼可变IgNAR结构域。
在某些实施方案中,抗体的抗原结合片段将包含至少一个可变结构域。可变结构域可具有任何尺寸或氨基酸组成,并且通常将包含至少一个CDR,所述至少一个CDR靠近一个或多个框架序列或与其同框。在具有与VL结构域相关联的VH结构域的抗原结合片段中,VH和VL结构域可以任何适合的排列相对于彼此定位。例如,可变区可以是二聚的并且含有VH-VH、VH-VL或VL-VL二聚体。可替代地,抗体的抗原结合片段可含有单聚VH或VL结构域。
在某些实施方案中,抗体的抗原结合片段可含有共价键联至至少一个恒定结构域的至少一个可变结构域。可存在于用于在本文提供的ADC中使用的抗体的抗原结合片段内的可变结构域和恒定结构域的非限制性、示例性构型包括:(i)VH-CH1;(ii)VH-CH2;(iii)VH-CH3;(iv)VH-CH1-CH2;(v)VH-CH1-CH2-CH3;(vi)VH-CH2-CH3;(vii)VH-CL;(viii)VL-CH1;(ix)VL-CH2;(x)VL-CH3;(xi)VL-CH1-CH2;(xii)VL-CH1-CH2-CH3;(xiii)VL-CH2-CH3;以及(xiv)VL-CL。在可变结构域和恒定结构域的任何构型,包括上文所列的示例性构型中的任一者中,可变结构域和恒定结构域可彼此直接连接或可通过完全或部分铰链或接头区连接。铰链区可由至少2(例如,5、10、15、20、40、60或更多)个氨基酸组成,这在单个多肽分子中在相邻的可变结构域和/或恒定结构域之间产生柔性或半柔性键联。在另外的实施方案中,抗原结合片段可包含上文所列的可变结构域和恒定结构域构型中的任一者彼此和/或与一个或多个单聚VH或VL结构域(例如,通过一个或多个二硫键)非共价缔合的均二聚体或异二聚体(或其他多聚体)。
在另一个实施方案中,本文提供的ADC中所使用的抗原结合结构域可包含人抗体和/或重组人抗体或其抗原结合片段或由其组成。
在另一个实施方案中,本文提供的ADC中所使用的抗原结合结构域可包含重组人抗体或其抗原结合片段或由其组成。在一个实施方案中,此类重组人抗体具有源自人种系免疫球蛋白序列的可变区和恒定区。然而,在某些实施方案中,此类重组人抗体经受体外诱变(或当使用对于人Ig序列来说为转基因动物的动物时,经受体内体细胞诱变),并且因此重组抗体的VH和VL区的氨基酸序列是虽然源自人种系VH和VL序列并且与其有关,但在体内可能不天然存在于人抗体种系谱内的序列。
在另一个实施方案中,本文提供的ADC中所使用的抗原结合结构域还包括双特异性抗原结合分子,诸如双特异性抗体。用于制备双特异性抗体的方法是本领域已知的并且可用于构建用于本文的双特异性抗原结合分子。可以用于本公开的上下文中的示例性双特异性模式包括但不限于例如基于scFv的或双抗体双特异性模式、IgG-scFv融合体、双可变结构域(DVD)-Ig、四源杂交瘤(Quadroma)、杵-臼结构(knobs-into-holes)、共同的轻链(例如,具有杵-臼结构的共同的轻链等)、CrossMab、CrossFab、(SEED)体、亮氨酸拉链、Duobody、IgG1/IgG2、双作用Fab(DAF)-IgG以及Mab2双特异性模式(关于前述模式的综述,参见例如Klein等2012,mAbs 4:6,1-11,以及其中引用的参考文献)。另外参见例如US2018/0134794,其公开了双特异性抗原结合分子。简单来说,双特异性抗原结合分子可包含第一抗原结合结构域(本文也称为“D1”)和第二抗原结合结构域(本文也称为“D2”)。双特异性抗原结合分子同时结合两个单独的表位导致有效的配体阻断,并且使靶标信号传导的激活最小。在某些实施方案中,双特异性抗体的D1和D2结构域彼此不竞争。D1与D2之间不竞争是指衍生D1和D2的相应的单特异性抗原结合蛋白彼此不竞争结合靶标。示例性的抗原结合蛋白竞争测定是本领域已知的。在某些实施方案中,D1和D2结合靶标上的不同(例如,非重叠或部分重叠)表位。双特异性抗原结合分子可使用两个单独的单特异性抗体的抗原结合结构域来构建。例如,可使用本领域已知的标准方法产生单克隆单特异性抗体的集合。如此产生的各个抗体可针对彼此成对地测试其与靶蛋白的交叉竞争。如果两种不同的抗体能够同时结合靶标(即,不相互竞争),那么第一抗体的抗原结合结构域和第二非竞争性抗体的抗原结合结构域可以被工程改造成单一的双特异性抗体。双特异性抗原结合分子可以是单一的多功能多肽,或者它可以是彼此共价或非共价缔合的两个或更多个多肽的多聚体复合物。具有同时结合靶分子的两个单独的不相同表位的能力的任何抗原结合构建体被认为是双特异性抗原结合分子。双特异性抗原结合分子或其变体可使用如本领域技术人员将已知的标准分子生物学技术(例如,重组DNA和蛋白质表达技术)构建。在另一个实施方案中,还提供了双特异性抗体,其中双特异性抗体的一个臂结合第一靶蛋白上的表位,而双特异性抗体的另一个臂结合第二靶蛋白上的第二表位。可以用于本公开的上下文中的其他示例性双特异性模式包括但不限于例如基于scFv的或双抗体双特异性模式、IgG-scFv融合体、双可变结构域(DVD)-Ig、四源杂交瘤、杵-臼结构、共同的轻链(例如,具有杵-臼结构的共同的轻链等)、CrossMab、CrossFab、(SEED)体、亮氨酸拉链、Duobody、IgG1/IgG2、双作用Fab(DAF)-IgG以及Mab2双特异性模式(关于前述模式的综述,参见例如Klein等2012,mAbs 4:6,1-11,以及其中引用的参考文献)。双特异性抗体也可以使用肽/核酸缀合来构建,例如,其中使用具有正交化学反应性的非天然氨基酸来产生位点特异性抗体-寡核苷酸缀合物,然后其自组装成具有限定的组成、化合价和几何结构的多聚体复合物。(参见,例如,Kazane等,J.Am.Chem.Soc.(Epub:2012年12月4日))。
在另一个实施方案中,用于在本文提供的ADC中使用的抗原结合结构域还包括包含本领域已知的任何HCVR、LCVR和/或CDR氨基酸序列的变体的抗体。在一个实施方案中,变体包括本领域已知的具有一个或多个保守取代的任何HCVR、LCVR和/或CDR氨基酸序列的变体。例如,抗原结合结构域包括抗体或其抗原结合片段,其所具有的HCVR、LCVR和/或CDR氨基酸序列相对于本领域已知的任何HCVR、LCVR和/或CDR氨基酸序列具有例如10个或更少、8个或更少、6个或更少、4个或更少等的保守氨基酸取代。在另一个实施方案中,抗原结合结构域包括抗体或其抗原结合片段,还包括与本领域已知的任何HCVR、LCVR和/或CDR氨基酸序列具有实质序列同一性的变体。在某些实施方案中,不相同的残基位置因保守氨基酸取代而不同。“保守氨基酸取代”是氨基酸残基由侧链具有类似化学特性(例如,电荷或疏水性)的另一氨基酸残基取代的取代。一般来说,保守氨基酸取代将基本上不改变蛋白质的功能特性。在两个或更多个氨基酸序列彼此因保守取代而不同的情况下,可调高序列同一性百分比或相似度以校正取代的保守性。用于进行此调整的手段是本领域技术人员熟知的。参见例如Pearson(1994)Methods Mol.Biol.24:307-331。侧链具有类似化学特性的氨基酸组的实例包括(1)脂族侧链:甘氨酸、丙氨酸、缬氨酸、亮氨酸以及异亮氨酸;(2)脂族羟基侧链:丝氨酸和苏氨酸;(3)含酰胺的侧链:天冬酰胺和谷氨酰胺;(4)芳族侧链:苯丙氨酸、酪氨酸以及色氨酸;(5)碱性侧链:赖氨酸、精氨酸以及组氨酸;(6)酸性侧链:天冬氨酸盐和谷氨酸盐,以及(7)含硫的侧链是半胱氨酸和甲硫氨酸。在一个实施方案中,保守氨基酸取代组是:缬氨酸-亮氨酸-异亮氨酸、苯丙氨酸-酪氨酸、赖氨酸-精氨酸、丙氨酸-缬氨酸、谷氨酸盐-天冬氨酸盐,以及天冬酰胺-谷氨酰胺。在另一个实施方案中,保守置换是在Gonnet等(1992)Science 256:1443-1445中所公开的PAM250对数似然矩阵中具有正值的任何变化。“适度保守”置换是在PAM250对数似然矩阵中具有非负值的任何变化。
通常使用序列分析软件测量两个不同氨基酸序列之间的序列同一性。序列分析软件使用分配给各种取代、缺失以及其他修饰(包括保守氨基酸取代)的相似性度量来匹配类似序列。举例来说,GCG软件含有诸如GAP和BESTFIT等程序,这些程序可以在默认参数情况下用于确定紧密相关的多肽(诸如来自不同物种的生物体的同源多肽)之间或野生型蛋白质与其突变蛋白之间的序列同源性或序列同一性。参见例如GCG 6.1版。还可以使用FASTA(GCG 6.1版中的程序)使用默认或推荐参数比较多肽序列。FASTA(例如,FASTA2和FASTA3)提供查询序列与检索序列之间最佳重叠的区域的比对和序列同一性百分比(Pearson(2000)同上)。当将本文提供的序列与含有来自不同生物体的大量序列的数据库相比较时,另一算法是计算机程序BLAST,尤其是BLASTP或TBLASTN,使用默认参数。参见例如Altschul等(1990)J.Mol.Biol.215:403-410和Altschul等(1997)Nucleic Acids Res.25:3389-402。
i.表位定位和相关技术
抗原结合结构域所结合的表位可由靶蛋白的3个或更多个(例如,3个、4个、5个、6个、7个、8个、9个、10个、11个、12个、13个、14个、15个、16个、17个、18个、19个、20个或更多个)氨基酸的单个连续序列组成。可替代地,相关表位可由靶蛋白的多个非相邻氨基酸(或氨基酸序列)组成。在一些实施方案中,表位位于靶蛋白的结合结构域上或附近。在其他实施方案中,表位位于靶蛋白的结合结构域外部。
本领域普通技术人员已知的各种技术可以用于确定与本文提供的ADC中使用的抗原结合结构域相互作用的表位。可以用于确定特定抗原结合结构域的表位或结合结构域的示例性技术包括,例如,定点诱变(例如,丙氨酸扫描诱变、精氨酸扫描诱变等)、肽印迹分析(Reineke,2004,Methods Mol Biol 248:443-463)、蛋白酶保护和肽切割分析。此外,可以采用诸如表位切除、表位提取以及抗原的化学修饰等方法(Tomer,2000,Protein Science9:487-496)。可以用于鉴定与抗原结合结构域相互作用的多肽内的氨基酸的另一方法是通过质谱法检测的氢/氘交换。一般地说,氢/氘交换法涉及对感兴趣的蛋白质进行氘标记,随后使抗原结合结构域结合于氘标记的蛋白质。接着,将蛋白质/抗原结合结构域复合物转移到水中以允许在除由抗原结合结构域保护的残基(这些残基仍为氘标记的)外的所有残基处发生氢-氘交换。在抗原结合结构域解离之后,对靶蛋白进行蛋白酶切割和质谱分析,由此揭示对应于与抗原结合结构域相互作用的特定氨基酸的氘标记的残基。参见例如Ehring(1999)Analytical Biochemistry267(2):252-259;Engen和Smith(2001)Anal.Chem.73:256A-265A。X射线晶体结构分析也可以用于鉴定多肽内与抗原结合结构域相互作用的氨基酸。
ii.人抗体的制备
在一个实施方案中,用于在本文提供的ADC中使用的抗体是完全人抗体。用于产生单克隆抗体,包括完全人单克隆抗体的方法是本领域已知的。任何此类已知方法均可以在本公开的上下文中用于制备特异性结合人蛋白质靶标的人抗体。
使用例如VELOCIMMUNETM技术或用于产生完全人单克隆抗体的任何其他类似的已知方法,最初分离具有人可变区和小鼠恒定区的针对人蛋白质靶标的高亲和力嵌合抗体。针对包括亲和力、配体阻断活性、选择性、表位等在内的期望特征对抗体进行表征和选择。如有必要,将小鼠恒定区替换为期望的人恒定区,例如野生型或修饰的IgG1或IgG4,以产生完全人抗体。虽然所选恒定区可根据特定用途而变化,但高亲和力抗原结合和靶标特异性特征存在于可变区中。在某些情况下,完全人抗体直接从抗原阳性B细胞中分离出来。
iii.生物等效物
用于在本文提供的ADC中使用的抗原结合结构域涵盖具有与所述抗体的那些氨基酸序列不同但保留结合靶蛋白的能力的氨基酸序列的蛋白质。当与亲本序列相比时,此类变体抗原结合结构域包含一个或多个氨基酸添加、缺失或取代,但表现出大体上等效于所描述的抗体的生物活性。
如果例如两种抗原结合结构域是当在类似实验条件下以相同摩尔剂量(单次剂量或多次剂量)施用时吸收速率和程度不显示显著差异的药物等效物或药物替代物,那么这两种抗原结合结构域被认为是生物等效的。如果一些抗原结合结构域在它们的吸收程度方面是等效的,但在它们的吸收速率方面不等效,而又可被认为是生物等效的,因为此类在吸收速率方面的差异是有意的并且在标记中被反映出来,在例如长期使用后不是达到有效体内药物浓度所必需的,并且对于所研究的特定药物产品来说被认为在医学上不重要,那么它们将被认为是等效物或药物替代物。
在一个实施方案中,如果两种抗原结合结构域在它们的安全性、纯度和效力方面不存在临床上有意义的差异,那么它们是生物等效的。
在一个实施方案中,如果患者可在参考产品与生物产品之间转换一次或多次而与未进行此类转换的持续疗法相比没有预期的有害作用风险增加,包括临床上显著的免疫原性变化或有效性减弱,那么这两种抗原结合结构域是生物等效的。
在一个实施方案中,如果两种抗原结合结构域均通过针对一种或多种使用条件的一种或多种常用作用机制(在此类机制已知的情况下)起作用,那么这两种抗原结合结构域是生物等效的。
生物等效性可通过体内和体外方法来证实。生物等效性测量包括例如(a)在人或其他哺乳动物中进行的在血液、血浆、血清或其他生物流体中测量随时间变化的抗原结合结构域或其代谢物的浓度的体内测试;(b)与人体内生物利用率数据相关并且合理预测人体内生物利用率的体外测试;(c)在人或其他哺乳动物中进行的测量随时间变化的抗原结合结构域(或其靶标)的适当急性药理学效应的体内测试;以及(d)确定抗原结合结构域的安全性、功效或生物利用率或生物等效性的完全受控的临床试验。
可通过例如形成残基或序列的各种取代或使生物活性不需要的末端或内部残基或序列缺失来构建用于在本文提供的ADC中使用的抗原结合结构域的生物等效变体。例如,不为生物活性所必需的半胱氨酸残基可缺失或用其他氨基酸替换以防止在复性后形成不必要或不恰当的分子内二硫桥。在其他情形中,生物等效抗原结合结构域可包括变体,所述变体包含改变抗原结合结构域的糖基化特征的氨基酸变化,例如消除或去除糖基化的突变。
iv.物种选择性和物种交叉反应性
在某些实施方案中,用于在本文提供的ADC中使用的抗原结合结构域结合人靶蛋白但不结合来自其他物种的靶蛋白。在其他实施方案中,用于在本文提供的ADC中使用的抗原结合结构域结合人靶蛋白并且结合来自一种或多种非人物种的靶蛋白。例如,用于在本文提供的ADC中使用的抗原结合结构域可结合人靶蛋白,并可根据具体情况结合或不结合小鼠、大鼠、豚鼠、仓鼠、沙鼠、猪、猫、狗、兔、山羊、绵羊、牛、马、骆驼、食蟹猴、狨猴、恒河猴或黑猩猩靶蛋白中的一种或多种。在一个实施方案中,抗原结合结构域特异性结合人靶蛋白和食蟹猴(例如,食蟹猴(Macaca fascicularis))靶蛋白。在其他实施方案中,用于本文的抗原结合结构域结合人靶蛋白但不结合或仅弱结合食蟹猴靶蛋白。
v.示例性抗体和抗原靶标
用于在本文提供的ADC中使用的抗体可以对本领域技术人员认为合适的任何抗原(靶蛋白)具有结合特异性。在某些实施方案中,抗原是跨膜分子(例如,受体)。在一个实施方案中,抗原在肿瘤上表达。在一些实施方案中,结合剂与肿瘤抗原相互作用或与其结合,包括对一种类型的肿瘤具有特异性的抗原或在特定类型的肿瘤上共有、过表达或修饰的抗原。在一个实施方案中,抗原在实体瘤上表达。示例性抗原包括但不限于脂蛋白;α1-抗胰蛋白酶;细胞毒性T淋巴细胞相关抗原(CTLA),诸如CTLA-4;血管内皮生长因子(VEGF);激素或生长因子的受体;蛋白A或D;成纤维细胞生长因子受体2(FGFR2)、EpCAM、GD3、FLT3、PSMA、PSCA、MUC1、MUC16、STEAP、STEAP2、CEA、TENB2、EphA受体、EphB受体、叶酸受体、FOLRI、间皮素、cripto、αvβ6、整合素、VEGF、VEGFR、EGFR、转铁蛋白受体、IRTA1、IRTA2、IRTA3、IRTA4、IRTA5;CD蛋白,诸如CD2、CD3、CD4、CD5、CD6、CD8、CD11、CD14、CD19、CD20、CD21、CD22、CD25、CD26、CD28、CD30、CD33、CD36、CD37、CD38、CD40、CD44、CD52、CD55、CD56、CD59、CD70、CD79、CD80、CD81、CD103、CD105、CD134、CD137、CD138、CD152,或美国公布号2008/0171040或美国公布号2008/0305044中公开的与一种或多种肿瘤相关抗原或细胞表面受体结合的抗体;促红细胞生成素;骨诱导因子;免疫毒素;骨形态发生蛋白(BMP);T细胞受体;表面膜蛋白;整合素,诸如CD11a、CD11b、CD11c、CD18、ICAM、VLA-4和VCAM;肿瘤相关抗原,诸如AFP、ALK、B7H4、BAGE蛋白、β-连环蛋白、brc-abl、BRCA1、BORIS、CA9(碳酸酐酶IX)、半胱天冬酶-8、BCMA、SLAMF7、GPNMB、UPK3A、CD20、CD40、CD123、CDK4、CEA、CLEC12A、c-kit、cMET、CTLA4、细胞周期蛋白-B1、CYP1B1、EGFR、EGFRvIII、内皮因子、Epcam、EphA2、ErbB2/Her2、ErbB3/Her3、ErbB4/Her4、ETV6-AML、Fra-1、FOLR1、GAGE蛋白、GD2、GD3、GloboH、磷脂酰基醇蛋白聚糖-3(glypican-3)、GM3、gp100、Her2、HLA/B-raf、HLA/EBNA1、HLA/k-ras、HLA/MAGE-A3、hTERT、IGF1R、LGR5、LMP2、MAGE蛋白、MART-1、间皮素、ML-IAP、Muc1、Muc16、CA-125、MUM1、NA17、NGEP、NY-BR1、NY-BR62、NY-BR85、NY-ESO1、OX40、p15、p53、PAP、PAX3、PAX5、PCTA-1、PDGFR-α、PDGFR-β、PDGF-A、PDGF-B、PDGF-C、PDGF-D、PLAC1、PRLR、PRAME、PSCA、PSGR、PSMA(FOLH1)、RAGE蛋白、Ras、RGS5、Rho、SART-1、SART-3、Steap-1、Steap-2、STn、存活素、TAG-72、TGF-β、TMPRSS2、Tn、TNFRSF17、TRP-1、TRP-2、酪氨酸酶和uroplakin-3,以及任何上文列出的多肽的片段;细胞表面表达的抗原;MUC16;c-MET;诸如A类清道夫受体的分子,包括清道夫受体A(SR-A),以及其他膜蛋白,诸如B7家族相关成员,包括含V-set和Ig结构域蛋白4(V-set and Ig domain-containing 4,VSIG4)、集落刺激因子1受体(CSF1R)、脱唾液酸糖蛋白受体(ASGPR)和淀粉样蛋白β前体样蛋白2(APLP-2)。在一些实施方案中,抗原是PRLR或HER2。在一些实施方案中,抗原是HER2。在一些实施方案中,抗原是人HER2。在一些实施方案中,抗原是STEAP2。在一些实施方案中,抗原是人STEAP2。在一些实例中,MAGE蛋白选自MAGE-1、-2、-3、-4、-6和-12。在一些实例中,GAGE蛋白选自GAGE-1和GAGE-2。
在某些实施方案中,抗体在一个或多个在EU编号系统中编号为295的重链位置处包含谷氨酰胺残基。在本公开中,该位置被称为谷氨酰胺295,或Gln295,或Q295。本领域技术人员将认识到这是许多抗体的野生型序列中的保守谷氨酰胺残基。在其他实施方案中,可以将抗体工程改造为包含谷氨酰胺残基。在某些实施方案中,抗体包含一个或多个N297Q突变。用于修饰抗体序列以包括谷氨酰胺残基的技术在本领域技术人员的技术范围内(参见,例如,Ausubel等Current Protoc.Mol.Biol.(John Wiley&Sons))。
B.有效负载R
在一个实施方案中,R是治疗剂或成像剂。在另一个实施方案中,R是治疗剂,诸如细胞毒性剂、化学治疗药物或放射性同位素。在其他实施方案中,R是正电子发射体和/或螯合部分。在其他实施方案中,用于在本文提供的ADC中使用的有效负载包括细胞毒素、抗炎剂、类固醇、糖皮质激素、LXR调节剂、抗病毒剂和抗生素。在另一个实施方案中,用于在本文提供的ADC中使用的有效负载是小分子化合物,例如,具有小于2000道尔顿、小于1500道尔顿、小于1000道尔顿、小于750道尔顿或小于500道尔顿的分子量的化合物。
用作本文的有效负载的细胞毒性剂包括对细胞的生长、活力或繁殖有害的任何剂,包括但不限于微管蛋白相互作用剂和DNA损害剂。可以用于本文提供的ADC中的合适的细胞毒性剂和化学治疗剂的实例包括,例如,1-(2-氯乙基)-1,2-二甲磺酰基酰肼、1,8-二羟基-双环[7.3.1]十三烷-4,9-二烯-2,6-二炔-13-酮、1-去氢睾酮、5-氟尿嘧啶、6-巯基嘌呤、6-硫鸟嘌呤、9-氨基喜树碱、放线菌素D、鹅膏蕈碱、氨基喋呤、蛇形菌素(anguidine)、蒽环霉素、安曲霉素(anthramycin)(AMC)、澳瑞他汀(auristatin)、博来霉素(bleomycin)、白消安(busulfan)、丁酸、加利车霉素(calicheamicin)(例如,加利车霉素γ1)、喜树碱、洋红霉素(carminomycin)、卡莫司汀(carmustine)、西马多丁(cemadotin)、顺铂、秋水仙碱、考布他汀(combretastatin)、环磷酰胺、阿糖胞苷、细胞松弛素B、更生霉素(dactinomycin)、道诺霉素(daunorubicin)、达卡巴嗪(decarbazine)、二乙酰氧基戊基多柔比星(diacetoxypentyldoxorubicin)、二溴甘露醇、二羟基炭疽菌素二酮、地索拉唑(disorazole)、尾海兔素(dolastatin)(例如,尾海兔素10)、多柔比星、多卡霉素(duocarmycin)、棘霉素(echinomycin)、伊斯罗宾(eleutherobin)、吐根碱、埃博霉素(epothilone)、埃斯培拉霉素(esperamicin)、雌莫司汀(estramustines)、溴化乙锭、依托泊苷(etoposide)、氟尿嘧啶、格尔德霉素(geldanamycin)、短杆菌素D、糖皮质激素、伊立替康(irinotecan)、纺锤体驱动蛋白(KSP)抑制剂、来普霉素(leptomycin)、环氧长春碱、利多卡因(lidocaine)、洛莫司汀(lomustine)(CCNU)、美登木素(maytansinoid)、二氯甲基二乙胺、美法仑(melphalan)、巯基嘌呤、甲基叶酸、甲氨蝶呤、光辉霉素(mithramycin)、丝裂霉素(mitomycin)、二羟蒽二酮(mitoxantrone)、N8-乙酰基亚精胺、鬼臼毒素、普鲁卡因、普萘洛尔(propranolol)、蝶啶、嘌呤霉素、吡咯并苯并二氮杂(PBD)、根霉素、链脲佐菌素、他利霉素(tallysomycin)、紫杉醇、替诺泊苷(tenoposide)、丁卡因(tetracaine)、噻替哌(thioepa)氮芥苯丁酸、托马霉素(tomaymycin)、拓扑替康(topotecan)、微管溶素(tubulysin)、长春花碱、长春新碱、长春地辛、长春瑞滨以及前述任一者的衍生物。在某些实施方案中,在本文提供的ADC中用作有效负载的细胞毒性剂是美登木素(诸如DM1或DM4)、托马霉素衍生物或尾海兔素衍生物。在其他实施方案中,在本文提供的ADC中用作有效负载的细胞毒性剂是澳瑞他汀,诸如MMAE、MMAF或其衍生物。在一个实施方案中,在本文提供的ADC中用作有效负载的细胞毒性剂是MMAE(单甲基澳瑞他汀E):
本领域中已知的其他细胞毒性剂被设想在本文提供的ADC中用作有效负载,包括例如蛋白质毒素,诸如篦麻毒素、艰难梭菌(C.difficile)毒素、假单胞菌属外毒素、白喉毒素、肉毒杆菌毒素、榄香胶素(bryodin)、皂草素、商陆属毒素(即,商陆毒素(phytolaccatoxin和phytolaccigenin))以及其他毒素,诸如Sapra等,Pharmacol.&Therapeutics,2013,138:452-469中所阐述的那些毒素。在一些实施方案中,有效负载是US2019/0151323、US 2016/0375147、US 9,950,076或US 10,570,151中描述的美登木素;或WO2020/132658中描述的微管溶素。
在某些实施方案中,用于在本文提供的ADC中使用的细胞毒性剂是美登木素,例如美登素(maytansine)的衍生物。合适的美登木素包括DM1、DM4或其衍生物、立体异构体或同位素体。合适的美登木素还包括WO 2014/145090A1、WO 2015/031396A1、US 2016/0375147A1和US 2017/0209591A1中公开的那些。
在一些实施方案中,美登木素具有以下结构:
其中A是任选取代的亚芳基或杂亚芳基。
在一些实施方案中,美登木素具有以下结构:
其中A是任选取代的亚芳基或杂亚芳基。
在一些实施方案中,美登木素具有以下结构:
其中n是1-12的整数并且R1是烷基。
在一些实施方案中,美登木素为:
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在一些实施方案中,美登木素为:
在一些实施方案中,美登木素为:
在其他实施方案中,R是放射性核素。在这些实施方案中,本文提供的ADC是抗体-放射性核素缀合物(ARC)。可以用作本文的有效负载的放射性核素包括,例如,225Ac、212Bi、213Bi、131I、186Re、227Th、222Rn、223Ra、224Ra和90Y。
在某些实施方案中,本文提供的ADC是其中抗原结合结构域缀合至如国际专利公布号WO2014/145090中所述的接头-药物组合物的那些,例如,下文描绘的化合物“7”:
本文还提供了包含与细胞毒性剂缀合的抗原结合结构域的ADC。在某些实施方案中,细胞毒性剂是美登木素。在某些实施方案中,美登木素是具有下式的化合物:
其中n是1-12的整数并且R1是烷基。在某些实施方案中,美登木素为
在某些实施方案中,细胞毒性剂是美登木素,并且美登木素通过不可切割的接头共价附接至抗原结合结构域。在某些实施方案中,细胞毒性剂是美登木素,并且美登木素通过可切割接头共价附接至抗原结合结构域。
在另一个实施方案中,细胞毒性剂是微管溶素。参见,例如,国际专利公布号WO2020/132658。在另一个实施方案中,细胞毒性剂具有下式:
其中
R1是C1-C10烷基;
R3是–C(O)C1-C5烷基、–C(O)N(H)C1-C10烷基或–(C1-C10亚烷基)-NR3aR3b,
其中R3a和R3b在每种情况下独立地为氢、烷基、烯基、炔基、环烷基、芳基、杂芳基和酰基,其中烷基、烯基、炔基、环烷基、芳基、杂芳基和酰基是任选取代的;
R4和R5在每种情况下独立地为氢或C1-C5烷基;
R6是-OH或-NHNH2;
R7在每种情况下独立地为氢、-OH、卤素或-NR7aR7b,
其中R7a和R7b在每种情况下独立地为氢、烷基、烯基、炔基、环烷基、芳基、杂芳基、酰基和氨基酸残基,其中烷基、烯基、炔基、环烷基、芳基、杂芳基和酰基是任选取代的;
R8在每种情况下独立地为氢、氘、–NHR9或卤素,
其中R9是氢、-C1-C5烷基或–C(O)C1-C5烷基,并且
m是1或2;
Q是-CH2-或-O-,其中
当Q是-O-时,则R2是C1-C10烷基、C1-C10炔基、-C1-C10亚烷基-(5元杂芳基)、-C1-C3亚烷基-Q1-(CH2)n芳基,或C1-C3羟烷基;或
当Q是-CH2-时,则R2是C5-C10烷基、C1-C10炔基、-C1-C10亚烷基-(5元杂芳基)、-C1-C3亚烷基-Q1-(CH2)n芳基,或C1-C3羟烷基;并且
Q1是-CH2-或-O-;
其中所述杂芳基是未取代的或被烷基、氨基烷基、羟基烷基、羧基烷基、苄基或苯基取代;
其中所述芳基是未取代的或被硝基或氨基取代;并且
其中n是1至5的整数。
在一些实施方案中,R是US10,711,032或WO 2019/136487中描述的类固醇;WO2020/132483中描述的利福霉素类似物;或者WO 2018/213082或WO 2020/106780中描述的LXR调节剂。
在其他实施方案中,R是正电子发射体和/或螯合部分。在一个实施方案中,正电子发射体包括与螯合部分形成稳定复合物并具有适合免疫-PET成像目的的物理半衰期的那些。在某些实施方案中,正电子发射体包括89Zr、68Ga、64Cu、44Sc和86Y。
在某些实施方案中,R包括螯合部分。用于本文的螯合部分是包含能够螯合正电子发射体的部分的化学部分,即,能够与正电子发射体反应形成配位螯合物。在某些实施方案中,螯合部分包括允许有效负载特定金属并形成金属-螯合剂复合物的那些,所述金属-螯合剂复合物在体内足够稳定以用于诊断用途,例如免疫-PET成像。在另一个实施方案中,螯合部分包括将正电子发射体的解离和在矿物质骨、血浆蛋白和/或骨髓沉积中的积聚最小化至适合诊断用途的程度的那些。
用于本文的螯合部分的非限制性实例包括与正电子发射体89Zr、68Ga、64Cu、44Sc和/或86Y形成稳定复合物的那些。在其他实施方案中,螯合部分包括Nature Protocols,5(4):739,2010;Bioconjugate Chem.,26(12):2579(2015);Chem Commun(Camb),51(12):2301(2015);Mol.Pharmaceutics,12:2142(2015);Mol.Imaging Biol.,18:344(2015);Eur.J.Nucl.Med.Mol.Imaging,37:250(2010);Eur.J.Nucl.Med.Mol.Imaging(2016).doi:10.1007/s00259-016-3499-x;Bioconjugate Chem.,26(12):2579(2015);WO 2015/140212A1;以及US 5,639,879中描述的那些。
在其他实施方案中,螯合部分还包括包含以下的那些:去铁胺(DFO)、1,4,7,10-四氮杂环十二烷-1,4,7,10-四乙酸(DOTA)、二亚乙基三胺五乙酸(DTPA)、乙二胺四乙酸(EDTA)、(1,4,7,10-四氮杂环十二烷-1,4,7,10-四(亚甲基膦)酸(DOTP)、(1R,4R,7R,10R)-α'α”α”'α””-四甲基-1,4,7,10-四氮杂环十二烷-1,4,7,10-四乙酸(DOTMA)、1,4,8,11-四氮杂环十四烷-1,4,8,11-四乙酸(TETA)、H4octapa、H6phospa、H2dedpa、H5decapa、H2azapa、HOPO、DO2A、1,4,7-三氮杂环壬烷-N,N',N”-三乙酸(NOTA)、1,4,7,10-四(氨甲酰基甲基)-1,4,7,10-四氮杂环十二烷(DOTAM)、1,4,8,11-四氮杂双环[6.6.2]十六烷-4,11-二乙酸(CB-TE2A)、1,4,7,10-四氮杂环十二烷(Cyclen)、1,4,8,11-四氮杂环十四烷(Cyclam)、八齿螯合剂、六齿螯合剂、膦酸盐基螯合剂、大环螯合剂、包含大环对苯二甲酰胺配体的螯合剂、双功能螯合剂、镰菌素(fusarinine)C和镰菌素C衍生物螯合剂、三乙酰镰菌素C(TAFC)、铁氧胺E(FOXE)、铁氧胺B(FOXB)、铁色素A(FCHA)等。
C.接头L和L1
i.L
在某些实施方案中,L是连接、连结或键合硒与Gln的侧链NH的任何基团或部分。在一个实施方案中,L可以通过基于转谷氨酰胺酶的化学-酶促缀合与一个或多个谷氨酰胺残基缀合(参见,例如,Dennler等,Bioconjugate Chem.2014,25,569-578)。例如,在存在转谷氨酰胺酶的情况下,抗体的一个或多个谷氨酰胺残基可以偶联至伯胺化合物,诸如含硒的伯胺化合物。在某些实施方案中,伯胺是二硒化物,诸如(H2N-L-Se)2。在一些实施方案中,L是任何二价基团,包括亚烷基、亚烯基、亚环烯基、亚芳基、二价聚乙二醇(PEG)基团以及其组合。
在某些实施方案中,L具有下式之一:
(CH2)n;
(CH2CH2O)n-(CH2)p;
(CH2)n-N(H)C(O)-(CH2)m;
(CH2CH2O)n-N(H)C(O)-(CH2CH2O)m-(CH2)p;
(CH2)n-C(O)N(H)-(CH2)m;
(CH2CH2O)n-C(O)N(H)-(CH2CH2O)m-(CH2)p;
(CH2)n-N(H)C(O)-(CH2CH2O)m-(CH2)p;
(CH2CH2O)n-N(H)C(O)-(CH2)m;
(CH2)n-C(O)N(H)-(CH2CH2O)m-(CH2)p;以及
(CH2CH2O)n-C(O)N(H)-(CH2)m;
其中n是选自1至12的整数;
m是选自0至12的整数;并且
p是选自0至2的整数。
在另一个实施方案中,L是亚烷基。在另一个实施方案中,L是亚乙基。
ii.L1
在某些实施方案中,L1是连接、连结或键合硒与有效负载的任何基团或部分。可例如在Antibody-Drug Conjugates and Immunotoxins,Phillips,G.L.编;SpringerVerlag:New York,2013;Antibody-Drug Conjugates,Ducry,L.编;Humana Press,2013;Antibody-Drug Conjugates,Wang,J.、Shen,W.-C.和Zaro,J.L.编;SpringerInternational Publishing,2015中找到合适的接头。在某些实施方案中,用于本文提供的ADC中的L1基团足够稳定以利用抗原结合结构域的循环半衰期并且同时能够在抗原介导的ADC内化后释放其有效负载。接头L1可以是可切割或不可切割的。用作本文的L1的可切割接头包括在内化之后通过细胞内代谢切割,例如经由水解、还原或酶促反应切割的接头。用作本文的L1的不可切割接头包括在内化后通过抗原结合结构域的溶酶体降解释放所附接的有效负载的接头。合适的L1接头包括但不限于酸不稳定性接头、水解不稳定性接头、酶促可切割接头、还原不稳定性接头、自分解(self-immolative)接头以及不可切割的接头。合适的L1接头还包括但不限于是或包含肽、碳水化合物、葡糖苷酸、聚乙二醇(PEG)单元、腙、mal-己酰基单元、二肽单元、缬氨酸-瓜氨酸单元以及对氨基苯甲基(PAB)单元的那些接头。
本领域中已知的任何接头分子或接头技术可以用作L1来形成或构建本文提供的ADC。在某些实施方案中,L1接头是可切割接头。在其他实施方案中,L1接头是不可切割接头。在某些实施方案中,可以用于本文提供的ADC中的L1接头包括包含例如MC(6-马来酰亚胺基己酰基)、MP(马来酰亚胺基丙酰基)、val-cit(缬氨酸-瓜氨酸)、val-ala(缬氨酸-丙氨酸)、蛋白酶可切割接头中的二肽位点、ala-phe(丙氨酸-苯丙氨酸)、蛋白酶可切割接头中的二肽位点,PAB(对氨基苄氧基羰基)以及它们的变体和组合或由其组成的接头。可以用于本文提供的ADC中的L1接头的另外实例公开于例如美国专利号7,754,681和Ducry,Bioconjugate Chem.,2010,21:5-13以及其中引用的参考文献中。
在某些实施方案中,L1接头在生理条件下是稳定的。在某些实施方案中,L1接头是可切割的,例如在存在酶的情况下或在特定pH范围或值下能够至少释放有效负载部分。在一些实施方案中,L1接头包含酶可切割部分。在一个实施方案中,酶可切割的L1接头包括但不限于肽键、酯键联和腙。在一些实施方案中,L1接头包含组织蛋白酶可切割接头。
在一些实施方案中,L1接头包含不可切割部分。
在一些实施方案中,L1接头包含一个或多个氨基酸。合适的氨基酸包括天然、非天然、标准、非标准、蛋白原性、非蛋白原性以及L-或D-α-氨基酸。在一些实施方案中,L1接头包含丙氨酸、缬氨酸、甘氨酸、亮氨酸、异亮氨酸、甲硫氨酸、色氨酸、苯丙氨酸、脯氨酸、丝氨酸、苏氨酸、半胱氨酸、酪氨酸、天冬酰胺、谷氨酰胺、天冬氨酸、谷氨酸、赖氨酸、精氨酸、组氨酸或瓜氨酸、其衍生物或它们的组合。在某些实施方案中,氨基酸的一个或多个侧链连接至下文所描述的侧链基团。在一些实施方案中,接头包含缬氨酸和瓜氨酸。在一些实施方案中,L1接头包含赖氨酸、缬氨酸和瓜氨酸。在一些实施方案中,L1接头包含赖氨酸、缬氨酸和丙氨酸。在一些实施方案中,L1接头包含缬氨酸和丙氨酸。
在一些实施方案中,L1接头包含自分解基团。自分解基团可以是本领域技术人员已知的任何这样的基团。在特定实施方案中,自分解基团是对氨基苄基(PAB)或其衍生物。可用衍生物包括对氨基苄氧基羰基(PABC)。本领域技术人员将认识到自分解基团能够执行从有效负载释放L1接头的剩余原子的化学反应。
在其他实施方案中,L1基团可以用一个或多个增强基团修饰。在某些实施方案中,增强基团可以连接至L1中的任何氨基酸的侧链。在一个实施方案中,用于连接增强基团的氨基酸包括赖氨酸、天冬酰胺、天冬氨酸盐、谷氨酰胺、谷氨酸盐和瓜氨酸。与增强基团的连接可以是与氨基酸侧链的直接键合,或者连接可以是通过间隔基(spacer)和/或反应性基团的间接连接。在一个实施方案中,间隔基和反应性基团包括本文所述的任一种。在某些实施方案中,增强基团可以是赋予有效负载、接头有效负载或ADC有益效果的任何基团,所述有益效果包括但不限于生物、生化、合成、增溶、成像、检测和反应性效果等。在某些实施方案中,增强基团是亲水基团。在某些实施方案中,增强基团是环糊精。在某些实施方案中,增强基团是烷基、杂烷基、烯基、杂烯基磺酸、杂烯基牛磺酸、杂烯基磷酸或磷酸盐、杂烯基胺(例如,季胺)或杂烯基糖。在某些实施方案中,糖包括但不限于单糖、二糖和多糖。示例性单糖包括葡萄糖、核糖、脱氧核糖、木糖、阿拉伯糖、甘露糖、半乳糖、果糖等。在某些实施方案中,糖包括糖酸诸如葡糖醛酸,还包括缀合形式诸如葡糖苷酸(即,通过葡糖醛酸化)。示例性二糖包括麦芽糖、蔗糖、乳糖、乳果糖、海藻糖等。示例性多糖包括直链淀粉、支链淀粉、糖原、菊粉、纤维素等。环糊精可以是技术人员已知的任何环糊精。在某些实施方案中,环糊精是α环糊精、β环糊精或γ环糊精,或其混合物。在某些实施方案中,环糊精是α环糊精。在某些实施方案中,环糊精是β环糊精。在某些实施方案中,环糊精是γ环糊精。在某些实施方案中,增强基团能够改善ADC的其余部分的溶解度。在某些实施方案中,烷基、杂烷基、烯基或杂烯基磺酸是取代的或未取代的。在某些实施方案中,烷基、杂烷基、烯基或杂烯基磺酸是–(CH2)1-5SO3H、–(CH2)n–NH-(CH2)1-5SO3H、–(CH2)n–C(O)NH-(CH2)1-5SO3H、–(CH2CH2O)m–C(O)NH-(CH2)1-5SO3H、–(CH2)n–N((CH2)1-5C(O)NH(CH2)1-5SO3H)2、–(CH2)n–C(O)N((CH2)1-5C(O)NH(CH2)1-5SO3H)2或–(CH2CH2O)m–C(O)N((CH2)1-5C(O)NH(CH2)1-5SO3H)2,其中n是1、2、3、4或5,并且m是1、2、3、4或5。在一个实施方案中,烷基或烯基磺酸是–(CH2)1-5SO3H。在另一个实施方案中,杂烷基或杂烯基磺酸是–(CH2)n–NH-(CH2)1-5SO3H,其中n是1、2、3、4或5。在另一个实施方案中,烷基、杂烷基、烯基或杂烯基磺酸是–(CH2)n–C(O)NH-(CH2)1-5SO3H,其中n是1、2、3、4或5。在另一个实施方案中,烷基、杂烷基、烯基或杂烯基磺酸是–(CH2CH2O)m–C(O)NH-(CH2)1- 5SO3H,其中m是1、2、3、4或5。在另一个实施方案中,烷基、杂烷基、烯基或杂烯基磺酸是–(CH2)n–N((CH2)1-5C(O)NH(CH2)1-5SO3H)2,其中n是1、2、3、4或5。在另一个实施方案中,烷基、杂烷基、烯基或杂烯基磺酸是–(CH2)n–C(O)N((CH2)1-5C(O)NH(CH2)1-5SO3H)2,其中n是1、2、3、4或5。在另一个实施方案中,烷基、杂烷基、烯基或杂烯基磺酸是–(CH2CH2O)m–C(O)N((CH2)1-5C(O)NH(CH2)1-5SO3H)2,其中m是1、2、3、4或5。
III.ADC的合成
本文还提供了一种合成本文提供的ADC的方法。该方法包括使含有谷氨酰胺的抗原结合结构域与式(H2N-L-Se)2的二硒化物反应以提供式II的化合物的步骤:
其中Z是抗原结合结构域;
每个是Gln的侧链;并且L是接头。在一个实施方案中,抗原结合结构域和二硒化物的反应由转谷氨酰胺酶介导。在另一个实施方案中,转谷氨酰胺酶是鼠转谷氨酰胺酶。在另一个实施方案中,当抗原结合结构域的Gln是N297抗体的Q295时,则在抗原结合结构域与二硒化物反应之前,使抗原结合结构域与PNG酶(PNGase)(诸如但不限于PNG酶F)反应以使N297去糖基化。
在一个实施方案中,式II的化合物接着在小于或等于6的pH下与还原剂反应以形成还原的二硒化物。在另一个实施方案中,式II的化合物与还原剂的反应在小于或等于5,或小于或等于4的pH下进行。在一个实施方案中,还原剂是三(2-羧乙基)膦(TCEP)。在另一个实施方案中,二硒化物的还原在L1-R的存在下进行,其中L1包含与还原的二硒化物反应形成共价键的基团。在一个实施方案中,与还原的二硒化物反应的基团是马来酰亚胺基团、碘乙酰胺基团或溴乙酰胺基团。在一个实施方案中,与还原的二硒化物反应的基团是马来酰亚胺基团。在另一个实施方案中,式II的化合物在L1-R存在下的还原产生本文提供的ADC。
因此,在一个实施方案中,本文提供了一种合成本文提供的ADC的方法,其通过以下方式实现:任选地,当Z-Gln的Gln是N297抗体的Q295时,则在步骤(a)之前使Z-Gln与PNG酶F反应以使N297去糖基化;然后
(a)使Z-Gln与(H2N-L-Se)2和鼠转谷氨酰胺酶反应以形成式II的化合物:
以及
(b)在L1-R的存在下,使步骤(a)的产物与还原剂在小于或等于6的pH下反应,以形成还原的二硒化物,其中L1包含与还原的二硒化物反应形成共价键,从而形成Z-Gln-NH-L-Se-L1-R的基团。
在另一个实施方案中,本文提供了一种合成本文提供的ADC的方法,其通过以下方式实现:任选地,当Z-Gln的Gln是N297抗体的Q295时,则在步骤(a)之前使Z-Gln与PNG酶F反应以使N297去糖基化;然后
(a)使Z-Gln与(H2N-L-Se)2和鼠转谷氨酰胺酶反应以形成式II的化合物:
以及
(b)在L1-R的存在下,使步骤(a)的产物与TCEP在小于或等于6的pH下反应,以形成还原的二硒化物,其中L1包含与还原的二硒化物反应形成共价键,从而形成Z-Gln-NH-L-Se-L1-R的马来酰亚胺基团。
在另一个实施方案中,本文提供了一种根据图1所示的方法合成本文提供的ADC的方法。
在另一个实施方案中,本文提供了一种通过本文公开的方法制备的化合物。在一个实施方案中,通过本文公开的方法制备的化合物是式II的化合物:
在另一个实施方案中,通过本文公开的方法制备的化合物具有式IIa:
IV.药物组合物
本文提供的药物组合物包含治疗有效量的一种或多种本文提供的ADC和药学上可接受的载体。
ADC可以配制成合适的药物制剂。通常,使用本领域熟知的技术和程序将上文所述的ADC配制成药物组合物(参见,例如,Ansel Introduction to Pharmaceutical DosageForms,第七版1999)。
在组合物中,有效浓度的一种或多种ADC或药学上可接受的盐与合适的药物载体混合。在某些实施方案中,组合物中ADC的浓度对于递送在施用后治疗、预防或改善本文公开的疾病或病症的一种或多种症状和/或进展的量是有效的。
通常,组合物被配制用于单剂量施用。为了配制组合物,将一定重量分数的ADC以有效浓度溶解、悬浮、分散或以其他方式混合在选定载体中,使得所治疗的病状得到缓解或改善。适合施用本文提供的ADC的药物载体包括本领域技术人员已知的适合于特定施用方式的任何此类载体。
在一些实施方案中,ADC以足以在不对所治疗的受试者产生不期望的副作用的情况下发挥治疗有用作用的量包括在药学上可接受的载体中。治疗有效浓度可通过在本文描述的和本领域技术人员熟知的体外和体内系统中测试化合物来凭经验确定,然后从中推断用于人的剂量。在一些实施方案中,ADC以实现有效负载的治疗有效浓度的方法施用。在一些实施方案中,使用伴随诊断(参见,例如,Olsen D和Jorgensen J T,Front.Oncol.,2014年5月16日,4:105,doi:10.3389/fonC.2014.00105)确定ADC在具体受试者或受试者群体中的治疗浓度和安全性特征。
药物组合物中的ADC浓度将取决于ADC的吸收、组织分布、失活和排泄速率、ADC的物理化学特征、剂量方案和施用量以及本领域技术人员已知的其他因素。例如,递送的量足以改善本文公开的疾病或病症的一种或多种症状。
组合物可一次施用,或者可分成多个较小的剂量以时间间隔施用。应当理解,精确的剂量和治疗持续时间是所治疗疾病的函数并且可使用已知的测试方案或通过从体内或体外测试数据外推来凭经验确定。应指出的是,浓度和剂量值也可随着待缓解的病状的严重程度而变化。还应理解,对于任何特定受试者,具体剂量方案应根据个体需要和施用组合物或监督组合物施用的人员的专业判断而随时间调整。
组合物可包含其他活性化合物以获得期望的特性组合。出于治疗或预防目的,本文提供的ADC或如本文所述的其药学上可接受的盐也可有利地与一般领域已知的对治疗一种或多种在本文提及的疾病或医学病状具有价值的另一药剂一起施用。应当理解,此类组合疗法构成了本文提供的组合物和治疗方法的另一方面。
V.给药
本文提供的化合物和药物组合物可以某些治疗或预防有效量、某些时间间隔、某些剂型和某些剂量施用方法给药,如下所述。
本文提供的方法包括治疗患者而不考虑受试者的年龄,尽管一些疾病或病症在某些年龄组中更常见。
如有必要,可以重复施用本文提供的ADC或其药学上可接受的盐,例如,直到受试者经历疾病稳定或消退,或直到受试者经历疾病进展或不可接受的毒性。
本文提供的ADC或其药学上可接受的盐可以每天一次(QD)施用,或分成多个日剂量,诸如每天两次(BID)、每天三次(TID)和每天四次(QID)。此外,施用可以是连续的(即,每天施用连续几天或每一天)、间歇的,例如周期性的(即,包括数天、数周或数月的无药休息)。如本文所用,术语“每天”旨在表示治疗性化合物,诸如本文提供的ADC或其药学上可接受的盐,每天施用一次或多于一次,例如,持续一段时间。术语“连续”旨在表示治疗性化合物,诸如本文提供的ADC或其药学上可接受的盐,在至少10天至52周的不间断时期内每天施用。如本文所用的术语“间歇的”或“间歇地”旨在表示以规则或不规则的间隔停止和开始。例如,本文提供的ADC或其药学上可接受的盐的间歇施用是每周施用一至六天、周期性施用(例如,连续二至八周每天施用,然后是持续最多一周不施用的休息期),或隔日施用。如本文所用的术语“循环”旨在表示治疗性化合物,诸如本文提供的ADC或其药学上可接受的盐,每天或连续但有休息期地施用。在一些此类实施方案中,施用是一天一次持续二至六天,然后是持续五至七天不施用的休息期。
VI.治疗方法
在另一个实施方案中,提供了一种用本文提供的ADC或其药学上可接受的盐治疗受试者的方法。在另一个实施方案中,提供了一种用药物组合物治疗受试者的方法,所述药物组合物包含本文提供的ADC或其药学上可接受的盐。药物组合物包含本文公开的ADC或其药学上可接受的盐中的任一种,以及药学上可接受的载体。
本文提供的ADC尤其可用于治疗、预防和/或改善与抗原结合结构域的靶蛋白的表达、信号传导或活性相关或由其介导的任何疾病或病症。
在某些实施方案中,在有效负载是细胞毒性剂的情况下,本文提供的ADC可用于治疗在脑和脑膜、口咽、肺和支气管树、胃肠道、男性和女性生殖道、肌肉、骨骼、皮肤和附件、结缔组织、脾脏、免疫系统、造血细胞和骨髓、肝脏和泌尿道,以及特殊感觉器官诸如眼睛中出现的原发性和/或转移性肿瘤。在某些实施方案中,本文提供的ADC用于治疗一种或多种以下癌症:急性骨髓性白血病、成人T细胞白血病、星形细胞瘤、膀胱癌、乳腺癌、PRLR阳性(PRLR+)乳腺癌、宫颈癌、胆管癌、慢性髓系白血病、结肠癌、结直肠癌、子宫内膜癌、食道癌、胃癌、成胶质细胞瘤、头颈癌(例如,头颈鳞状细胞癌(HNSCC))、卡波西肉瘤、肾癌、平滑肌肉瘤、肝癌、肺癌(例如,小细胞肺癌、非小细胞肺癌(NSCLC))、淋巴瘤、恶性神经胶质瘤、恶性间皮瘤、黑色素瘤、间皮瘤、恶性间皮瘤、MFH/纤维肉瘤、多发性骨髓瘤、鼻咽癌、骨肉瘤、卵巢癌、胰腺癌、前列腺癌、去势抵抗性前列腺癌、肾细胞癌、残余癌(其中“残余癌”是指在用抗癌疗法治疗后一种或多种癌性细胞在受试者中存在或持续存在)、横纹肌肉瘤、小细胞肺癌、胃癌、滑膜肉瘤、甲状腺癌、子宫癌和肾母细胞瘤。在一些实施方案中,癌症是乳腺癌。在一些实施方案中,癌症是前列腺癌。
在本文提供的治疗方法的上下文中,ADC可作为单一疗法(即,作为唯一治疗剂)施用或与一种或多种另外的治疗剂(其实例在本文其他地方描述)组合施用。
VII.具有第二活性剂的组合疗法
本文提供了包含本文提供的ADC中的任一种与一种或多种另外的治疗活性组分的组合的组合物,以及包括向受试者施用此类组合的治疗方法。
本文提供的ADC可与一种或多种另外的治疗活性组分共同配制和/或组合施用,所述治疗活性组分选自由以下组成的组:MET拮抗剂(例如,抗MET抗体(例如,奥那妥组单抗(onartuzumab)、依玛妥珠单抗(emibetuzumab)和H4H14639D)或MET的小分子抑制剂)、EGFR拮抗剂(例如,抗EGFR抗体(例如,西妥昔单抗(cetuximab)或帕尼单抗(panitumumab))或EGFR的小分子抑制剂(例如,吉非替尼(gefitinib)或埃罗替尼(erlotinib)))、诸如Her2/ErbB2、ErbB3或ErbB4等另一EGFR家族成员的拮抗剂(例如,抗ErbB2(例如,曲妥珠单抗(trastuzumab)或T-DM1)、抗ErbB3或抗ErbB4抗体或者ErbB2、ErbB3或ErbB4活性的小分子抑制剂)、EGFRvIII的拮抗剂(例如,抗EGFRvIII抗体)、IGF1R拮抗剂(例如,抗IGF1R抗体)、B-raf抑制剂(例如,维罗非尼(vemurafenib)、索拉非尼(sorafenib)、GDC-0879、PLX-4720)、PDGFR-α抑制剂(例如,抗PDGFR-α抗体)、PDGFR-β抑制剂(例如,抗PDGFR-β抗体或小分子激酶抑制剂诸如甲磺酸伊马替尼(imatinib mesylate)或苹果酸舒尼替尼(sunitinib malate))、PDGF配体抑制剂(例如,抗PDGF-A、-B、-C或-D抗体、适体、siRNA等)、VEGF拮抗剂(例如,VEGF-Trap,诸如阿柏西普(aflibercept),参见例如US 7,087,411(本文中也称为“VEGF抑制融合蛋白”)、抗VEGF抗体(例如,贝伐单抗(bevacizumab))、VEGF受体的小分子激酶抑制剂(例如,舒尼替尼(sunitinib)、索拉非尼(sorafenib)或帕唑帕尼(pazopanib)))、DLL4拮抗剂(例如,US 2009/0142354中公开的抗DLL4抗体)、Ang2拮抗剂(例如,US 2011/0027286中公开的抗Ang2抗体,诸如H1H685P)、FOLH1拮抗剂(例如,抗FOLH1抗体)、STEAP1或STEAP2拮抗剂(例如,抗STEAP1抗体或抗STEAP2抗体)、TMPRSS2拮抗剂(例如,抗TMPRSS2抗体)、MSLN拮抗剂(例如,抗MSLN抗体)、CA9拮抗剂(例如,抗CA9抗体)、尿路斑块蛋白(uroplakin)拮抗剂(例如,抗尿路斑块蛋白(例如,抗UPK3A)抗体)、MUC16拮抗剂(例如,抗MUC16抗体)、Tn抗原拮抗剂(例如,抗Tn抗体)、CLEC12A拮抗剂(例如,抗CLEC12A抗体)、TNFRSF17拮抗剂(例如,抗TNFRSF17抗体)、LGR5拮抗剂(例如,抗LGR5抗体)、一价CD20拮抗剂(例如,一价抗CD20抗体,诸如利妥昔单抗(rituximab))、CD20 x CD3双特异性抗体、PD-1阻断剂(例如,抗PD-1抗体,诸如派姆单抗(pembrolizumab)或纳武单抗(nivolumab))等。可有利地与本文提供的抗体组合施用的其他剂包括,例如,它莫西芬(tamoxifen)、芳香酶抑制剂和细胞因子抑制剂,包括小分子细胞因子抑制剂和结合于诸如IL-1、IL-2、IL-3、IL-4、IL-5、IL-6、IL-8、IL-9、IL-11、IL-12、IL-13、IL-17、IL-18等细胞因子或其相应受体的抗体。
说明性地,PD-1抑制剂诸如抗PD-1抗体可以与如本文所述的ADC组合。
在另一个实施方案中,本文提供了包含本文提供的ADC中的任一种与一种或多种化学治疗剂的组合的药物组合物。化学治疗剂的实例包括烷化剂,诸如噻替哌(thiotepa)和环磷酰胺(CytoxanTM);烷基磺酸盐,诸如白消安(busulfan)、英丙舒凡(improsulfan)和哌泊舒凡(piposulfan);氮丙啶,诸如苯并多巴(benzodopa)、卡波醌(carboquone)、美妥替哌(meturedopa)和乌瑞替哌(uredopa);乙烯亚胺(ethylenimine)和甲基蜜胺(methylamelamine),包括六甲蜜胺、三亚乙基蜜胺(triethylenemelamine)、三亚乙基磷酰胺、三亚乙基硫代磷酰胺和三羟甲蜜胺;氮芥,诸如苯丁酸氮芥、萘氮芥、氯磷酰胺、雌莫司汀、异环磷酰胺、二氯甲基二乙胺(mechlorethamine)、盐酸氧氮芥(mechlorethamineoxidehydrochloride)、美法仑(melphalan)、新恩比兴(novembichin)、苯芥胆甾醇(phenesterine)、泼尼莫司汀(prednimustine)、曲磷胺(trofosfamide)、尿嘧啶氮芥(uracil mustard);硝基脲,诸如卡莫司汀(carmustine)、氯脲霉素(chlorozotocin)、福莫司汀(fotemustine)、洛莫司汀(lomustine)、尼莫斯汀(nimustine)、雷莫司汀(ranimustine);抗生素,诸如阿克拉霉素类(aclacinomysins)、放线菌素、氨茴霉素(authramycin)、偶氮丝氨酸(azaserine)、博来霉素、放线菌素C(cactinomycin)、加利车霉素、卡柔比星(carabicin)、洋红霉素、嗜癌素(carzinophilin)、色霉素(chromomycins)、放线菌素D、道诺霉素、地托比星(detorubicin)、6-重氮-5-氧代-L-正亮氨酸、多柔比星、表柔比星(epirubicin)、依索比星(esorubicin)、依达比星(idarubicin)、麻西罗霉素、丝裂霉素、霉酚酸、诺加霉素(nogalamycin)、橄榄霉素、培洛霉素、泊非霉素(potfiromycin)、嘌呤霉素、三铁阿霉素(quelamycin)、罗多比星(rodorubicin)、链黑菌素、链脲佐菌素、杀结核菌素、乌苯美司(ubenimex)、净司他丁(zinostatin)、佐柔比星(zorubicin);抗代谢物,诸如甲氨蝶呤和5-氟尿嘧啶(5-FU);叶酸类似物,诸如二甲叶酸、甲氨蝶呤、蝶罗呤(pteropterin)、三甲曲沙(trimetrexate);嘌呤类似物,诸如氟达拉滨、6-巯基嘌呤、硫咪嘌呤、硫鸟嘌呤;嘧啶类似物,诸如安西他滨(ancitabine)、阿扎胞苷、6-氮尿苷、卡莫氟、阿糖胞苷、双脱氧尿苷、去氧氟尿苷、依诺他滨(enocitabine)、氟尿苷;雄激素,诸如卡普睾酮、屈他雄酮丙酸酯、环硫雄醇、美雄烷(mepitiostane)、睾内酯;抗肾上腺药(anti-adrenals),诸如氨鲁米特(aminoglutethimide)、米托坦(mitotane)、曲洛司坦(trilostane);叶酸补充剂,诸如亚叶酸(frolinic acid);醋葡醛内酯(aceglatone);醛磷酰胺糖苷;氨基乙酰丙酸;安吖啶;贝他布昔(bestrabucil);比生群(bisantrene);依达曲沙(edatraxate);地弗法明(defofamine);地美可辛(demecolcine);地吖醌(diaziquone);依氟鸟氨酸(elfornithine);依利醋铵;依托格鲁(etoglucid);硝酸镓;羟基脲;香菇多糖;氯尼达明(lonidamine);米托胍腙(mitoguazone);二羟蒽二酮;莫哌达醇(mopidamol);尼曲吖啶(nitracrine);喷司他汀(pentostatin);蛋氨氮芥(phenamet);吡柔比星(pirarubicin);鬼臼酸;2-乙肼;丙卡巴肼;PSKTM;雷佐生(razoxane);西佐喃(sizofiran);锗螺胺;细交链孢菌酮酸;三亚胺醌;2,2',2”-三氯三乙胺;尿烷;长春地辛;达卡巴嗪;甘露醇氮芥;二溴甘露醇;二溴卫矛醇;哌泊溴烷(pipobroman);加息托星(gacytosine);阿拉伯糖苷(“Ara-C”);环磷酰胺;噻替哌;紫杉烷,例如,紫杉醇(TaxolTM,Bristol-Myers SquibbOncology,Princeton,N.J.)和多西他赛(docetaxel)(TaxotereTM;Aventis Antony,France);苯丁酸氮芥;吉西他滨;6-硫鸟嘌呤;巯基嘌呤;甲氨蝶呤;铂类似物,诸如顺铂和卡铂;长春花碱;铂;依托泊苷(VP-16);异环磷酰胺;丝裂霉素C;二羟蒽二酮;长春新碱;长春瑞滨(vinorelbine);诺维本(navelbine);米托蒽醌(novantrone);替尼泊苷(teniposide);道诺霉素;氨蝶呤;希罗达(xeloda);伊班膦酸盐;CPT-11;拓扑异构酶抑制剂RFS 2000;二氟甲基鸟氨酸(DMFO);视黄酸;埃斯佩拉霉素(esperamicins);卡培他滨;以及上述任一者的药学可接受的盐、酸或衍生物。该定义还包括用于调节或抑制激素对肿瘤的作用的抗激素剂,诸如抗雌激素,包括例如它莫西芬、雷洛昔芬(raloxifene)、芳香酶抑制性4(5)-咪唑、4-羟基它莫西芬、曲奥昔芬(trioxifene)、可莫昔芬(keoxifene)、LY117018、奥那司酮(onapristone)和托瑞米芬(toremifene)(Fareston);以及抗雄激素,诸如氟他米特(flutamide)、尼鲁米特(nilutamide)、比卡鲁胺(bicalutamide)、亮丙瑞林(leuprolide)和戈舍瑞林(goserelin);以及上述任一者的药学可接受的盐、酸或衍生物。
本文提供的ADC还可与抗病毒药、抗生素、止痛药、皮质类固醇、类固醇、氧、抗氧化剂、COX抑制剂、保心药、金属螯合剂、IFN-γ和/或NSAID组合施用和/或共同配制。
一种或多种另外的治疗活性组分,例如上文列出的任何剂或其衍生物,可恰好在施用本文提供的ADC之前、与其同时或在其之后不久施用。在另一个实施方案中,提供了药物组合物,其中本文提供的ADC与如本文所述的一种或多种另外的治疗活性组分共同配制。
如本文所用,术语“组合(in combination)”包括使用多于一种疗法(例如,一种或多种预防剂和/或治疗剂)。然而,术语“组合”的使用不限制将疗法(例如,预防剂和/或治疗剂)施用于患有疾病或病症的受试者的顺序。可以在向受试者施用第二疗法(例如,预防剂或治疗剂)之前(例如,5分钟、15分钟、30分钟、45分钟、1小时、2小时、4小时、6小时、12小时、24小时、48小时、72小时、96小时、1周、2周、3周、4周、5周、6周、8周或12周之前)、与其同时或在其之后(例如,5分钟、15分钟、30分钟、45分钟、1小时、2小时、4小时、6小时、12小时、24小时、48小时、72小时、96小时、1周、2周、3周、4周、5周、6周、8周或12周之后)施用第一疗法(例如,本文提供的ADC)。本文还设想了三联疗法。
将本文提供的化合物或其衍生物和一种或多种第二活性剂施用于受试者可以通过相同或不同的施用途径同时或依次发生。用于特定活性剂的特定施用途径的适宜性将取决于活性剂本身(例如,它是否可以口服施用而不在进入血流之前分解)和正在治疗的疾病或病症。
VIII.实施例
以下实施例旨在说明本文提供的某些实施方案,而不限制本公开的范围。
实施例1
抗体去糖基化
使用在PBS pH 7.4中的400U/mg mAb的PNG酶F(NEB P0704L),对两种抗体,即具有源自来自Carter等,PNAS 1992,89,4285的humAb4D5-8的可变区的抗HER2抗体(mAb1)和源自与肿瘤学无关的免疫抗原的非结合同种型对照(ISOmAb),进行去糖基化,在37℃下过夜。使用旋转过滤器(Amicon,30kDa截止值)将反应混合物缓冲液交换至PBS pH 7.4。这允许295Q残基被实施例2中的转谷氨酰胺酶接近以将抗体缀合至最大负载量2。
实施例2
硒代胱胺的细菌转谷氨酰胺酶缀合
将去糖基化的ISOmAb(degly-ISOmAb)和去糖基化的mAb1(degly-mAb1)抗体(实施例1)在PBS pH 7.4中以1mg/mL缀合。添加与抗体相比3倍摩尔过量的硒代胱胺(化合物1,目录号S0520Sigma-Aldrich),并通过添加每mg抗体12单位的细菌转谷氨酰胺酶(Zedira,T1001)来启动酶促反应,并在37℃下孵育4-16小时。通过离子交换色谱(GE Capto SImpRes,使用20mM NaOAc,pH 5和0M NaCl至0.5M NaCl作为梯度)纯化所得缀合物,并将缓冲液交换至20mM NaOAc,pH 5。通过ESI-MS分析缀合物(degly-ISOmAb-1和delgy-mAb1-1),以使用Waters Acquity UPLC确定接头抗体比(LAR)。色谱分离是在C4柱(2.1X50mmACQUITY UPLC BEH蛋白质C4,1.7μm,)上以10min梯度(分钟:流动相B的百分比;0:10%、1:10%、5:90%、7:90%、7.2:10%、10:10%)实现的。流动相A是0.1%的在水中的甲酸并且流动相B是0.1%的在乙腈中的甲酸。流速设置为0.3mL/min。检测器飞行时间(TOF)扫描设置为m/z 500-4500,主要参数如所列出的那样(毛细管电压3.0kV;采样锥80V;离子源补偿电压(Source Offset)100V;离子源温度150℃;去溶剂化温度450℃;锥孔气体0L/hr;去溶剂化气体800L/hr)。使用MassLynx软件中的MaxEnt函数对图谱进行解卷积。当根据强度进行加权时与负载量相对应的所得分子离子在表1中列出。实际质谱术图谱在图2A和2B以及图3中列出。尺寸排阻HPLC确定所有缀合物均为>95%单聚的(表3)。
表1.用于硒代胱胺缀合的ISOmAb和mAb1缀合物中强度加权的平均接头负载量的汇总。
实施例3
缀合mc-VC-PAB-MMAE接头有效负载
将硒代胱胺-抗体(实施例2)在50mM NaOAc,pH 5和10%DMSO中以3-5mg/mL进行缀合。添加与抗体相比12倍摩尔过量的接头-有效负载(mc-VC-PAB-MMAE,Doronina,S.O.等,Nat.Biotechnol.,2003,21,778),并且添加与抗体相比3倍摩尔过量的三(2-羧乙基)膦(TCEP)。将反应物在室温下孵育1小时。通过尺寸排阻色谱(SEC)纯化缀合物。药物抗体比(DAR)通过LC-MS确定(根据实施例2中描述的方法)。当根据强度进行加权时与负载量相对应的所得分子离子在表2中列出。实际质谱术图谱在图2A和2B以及图3中列出。尺寸排阻HPLC(SEC)确定所有缀合物均为>93%单聚的(表3、图4)。
表2.degly-ISOmAb-1-mc-vc-PAB-MMAE和degly-mAb1-1-mc-v c-PAB-MMAE缀合物中的强度加权的平均接头-有效负载负载量的汇总。
表3.1-mc-vc-PAB-MMAE缀合物的纯度(SEC)和DAR(ESI-MS)。
实施例4
体外细胞毒性测定
评估了各种抗体-药物缀合物和裸有效负载在体外杀伤表达抗原的肿瘤细胞的能力。
将SKBR3(Her2+)细胞以每孔8000个细胞接种在96孔板中的完全生长培养基中并使其生长过夜。对于细胞活力曲线,将连续稀释的缀合物或裸有效负载以在100nM至5pM范围内的最终浓度添加到细胞中并孵育3天。NCI H1975(Her2-)细胞使用类似条件作为阴性对照进行实验。为了测量活力,在最后2小时将细胞与CCK8(Dojindo)一起孵育,并在Victor(Perkin Elmer)上确定450nm处的吸光度(OD450)。从所有孔中减去由毛地黄皂苷(40nM)处理的细胞确定的背景OD450水平,并且活力表示为未处理对照的百分比。在10点反应曲线(GraphPad Prism)上由四参数逻辑方程(four-parameter logistic equation)确定IC50值。degly-mAb1-1-mc-vc-PAB-MMAE的IC50为0.035nM。链间二硫键缀合物具有与转谷氨酰胺酶位点特异性硒代胱胺缀合物类似的IC50值。这表明硒代胱胺缀合物对抗体药物缀合物的功能没有影响。针对有效负载当量对IC50值进行校正,并且细胞活力的结果在表4和图5中示出。为了进行比较,根据Doronina,S.O.等,Nat.Biotechnol.,2003,21,778产生mc-vc-PAB-MMAE链间二硫键缀合的分子。
表4
细胞类型 | ADC或有效负载 | IC50(nM) | %杀伤 |
SK-BR-3 | MMAE(有效负载) | 0.191 | 93.6 |
SK-BR-3 | mAb1-mc-vc-PAB-MMAE | 0.016 | 100 |
SK-BR-3 | degly-mAb1-1-mc-vc-PAB-MMAE | 0.035 | 100 |
SK-BR-3 | degly-ISOmAb-1-mc-vc-PAB-MMAE | >100 | - |
NCI H1975 | MMAE(有效负载) | 0.405 | 100 |
NCI H1975 | mAb1-mc-vc-PAB-MMAE | >100 | - |
NCI H1975 | degly-mAb1-1-mc-vc-PAB-MMAE | >100 | - |
NCI H1975 | degly-ISOmAb-1-mc-vc-PAB-MMAE | >100 | - |
本公开的范围不受实施例中公开的实施方案的限制,所述实施例旨在作为各个方面的单一说明,并且任何等同物都在本公开的范围内。除了本文示出和描述的那些之外,本领域技术人员由前文的描述将显而易见地知道各种修改。此类修改旨在落入随附权利要求书的范围内。
在本文引用了各种参考文献,诸如专利、专利申请和公布,其公开内容据此以引用方式整体并入本文。
Claims (37)
1.一种式I的化合物:
Z-Gln-NH-L-Se-L1-R
或其药学上可接受的盐,其中:
Z是抗原结合结构域;
NH是所述Gln的侧链NH;
L和L1是相同或不同的并且各自为接头;并且
R是有效负载。
2.如权利要求1所述的化合物,其中Z是抗体或其抗原结合片段。
3.如权利要求1或2所述的化合物,其中Z是抗体。
4.如权利要求1-3中任一项所述的化合物,其中Z是N297Q突变抗体。
5.如权利要求1-4中任一项所述的化合物,其中Z是具有一个或多个工程改造的LLQG、LLQGG、LLQLLQG、LLQYQG、LLQGA、LLQGSG、SLLQG、LQG、LLQLQ、LLQLLQ、LLQGR、LLQYQGA、LQGG、LGQG或LLQLLQGA位点的抗体。
6.如权利要求1-5中任一项所述的化合物,其中Gln是抗体的Gln295、N297Q突变抗体的Gln297和/或工程改造的LLQG、LLQGG、LLQLLQG、LLQYQG、LLQGA、LLQGSG、SLLQG、LQG、LLQLQ、LLQLLQ、LLQGR、LLQYQGA、LQGG、LGQG或LLQLLQGA位点的Gln。
7.如权利要求1-6中任一项所述的化合物,其中Gln是抗体的Gln295。
8.如权利要求1-7中任一项所述的化合物,其中L是亚烷基、亚烯基、亚环烷基或亚芳基,或其任何组合。
9.如权利要求1-8中任一项所述的化合物,其中L是亚烷基。
10.如权利要求1-9中任一项所述的化合物,其中L是亚乙基。
11.如权利要求1-10中任一项所述的化合物,其中L1包含能够被溶酶体酶切割的部分。
12.如权利要求1-11中任一项所述的化合物,其中L1包含缬氨酸-瓜氨酸。
13.如权利要求1-12中任一项所述的化合物,其中L1包含间隔基。
14.如权利要求1-13中任一项所述的化合物,其中L1包含二价对氨基苄氧基部分。
15.如权利要求1-14中任一项所述的化合物,其中L1包含
16.如权利要求1-15中任一项所述的化合物,其中R是治疗剂或成像剂。
17.如权利要求1-16中任一项所述的化合物,其中R是细胞毒性剂。
18.如权利要求1-17中任一项所述的化合物,其中R是MMAE。
19.如权利要求1-18中任一项所述的化合物,其中L1-R是
20.如权利要求1-19中任一项所述的化合物,其中药物抗体比是1至6。
21.如权利要求1-20中任一项所述的化合物,其中药物抗体比是2至4。
22.如权利要求1-21中任一项所述的化合物,其中药物抗体比是2。
23.一种用于合成如权利要求1-22中任一项所述的化合物的方法,其包括:
(a)使Z-Gln与(H2N-L-Se)2和转谷氨酰胺酶反应;以及
(b)在L1-R的存在下,使步骤(a)的产物与还原剂在小于或等于6的pH下反应,以形成还原的二硒化物,其中L1包含与所述还原的二硒化物反应形成共价键,从而形成Z-Gln-NH-L-Se-L1-R的基团。
24.如权利要求23所述的方法,其中所述转谷氨酰胺酶是细菌转谷氨酰胺酶。
25.如权利要求23或24所述的方法,其中所述还原剂是三(2-羧乙基)膦。
26.如权利要求23-25中任一项所述的方法,其中与所述还原的二硒化物反应的所述基团是马来酰亚胺基团。
27.如权利要求23-26中任一项所述的方法,其中,当Z-Gln的Gln是N297抗体的Q295时,则在步骤(a)之前使所述Z-Gln与PNG酶F反应以使N297去糖基化。
28.一种化合物,其通过如权利要求23-27中任一项所述的方法制备。
29.如权利要求1-22和28中任一项所述的化合物,其中Z是抗HER2抗体。
30.一种药物组合物,其包含如权利要求1-22和28-29中任一项所述的化合物和药学上可接受的载体。
31.一种治疗或诊断受试者的疾病的方法,其包括向所述受试者施用如权利要求1-22和28-29中任一项所述的化合物或如权利要求30所述的药物组合物。
32.如权利要求31所述的方法,其中所述方法治疗疾病。
33.如权利要求31或32所述的方法,其中所述疾病是HER2阳性肿瘤。
34.如权利要求31-33中任一项所述的方法,其中所述疾病是HER2阳性乳腺癌。
35.如权利要求34所述的方法,其中所述HER2阳性乳腺癌是转移性的。
36.一种式II的化合物:
其中:
Z是抗原结合结构域;
每个是Gln的侧链;并且
L是接头。
37.如权利要求36所述的化合物,其具有式IIa:
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