CN118265545A - 不对称双苯并咪唑sting激动剂免疫缀合物及其用途 - Google Patents
不对称双苯并咪唑sting激动剂免疫缀合物及其用途 Download PDFInfo
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Abstract
本发明提供了式(I)的免疫缀合物:Ab‑[L‑D]p,所述免疫缀合物包含通过与一个或多个STING激动剂部分缀合而连接的抗体。本发明还提供包含反应性官能团的STING激动剂‑接头中间体化合物。这类中间体组合物是用于通过接头或连接部分形成所述免疫缀合物的合适底物。本发明进一步提供用所述免疫缀合物治疗癌症的方法。
Description
相关申请的交叉引用
本非临时申请要求2021年10月4日提交的美国临时申请第63/251,805号的优先权的权益,该临时申请通过引用整体并入。
技术领域
本发明总体上涉及一种免疫缀合物,其包含与一种或多种STING激动剂不对称双苯并咪唑分子缀合的抗体。
背景技术
STING(干扰素基因的刺激物),也称为跨膜蛋白173(TMEM173)和MPYS/MITA/ERIS,是人类中由STING1基因编码的蛋白质。STING广泛表达,特别是在免疫细胞、肺和卵巢中。当细胞被诸如病毒、分枝杆菌和细胞内寄生虫的细胞内病原体感染时,STING通过诱导I型干扰素产生而在先天免疫中发挥作用。由STING介导的I型干扰素通过经由自分泌信号传导与分泌干扰素的同一细胞结合,并经由旁分泌信号传导与附近细胞结合,从而保护受感染细胞和附近细胞免受局部感染。STING在通过不同分子机制的I型干扰素信号传导中作为直接胞质DNA传感器(CDS)和衔接蛋白。STING已被证明通过TBK1激活下游转录因子STAT6和IRF3,这些转录因子负责抗病毒反应和针对细胞内病原体的先天免疫反应。与STING结合并作为激动剂的化合物已被证明在与人PBMC一起孵育时诱导促炎细胞因子(包括1型干扰素)的分泌(WO 2017/175147)。STING调节剂可用于治疗各种病症,例如过敏性疾病、神经退行性疾病、癌前综合征和癌症,并且还可用于免疫原性组合物或疫苗佐剂。
需要用于递送抗体和免疫佐剂的新组合物和方法,以便到达难以接近的肿瘤和/或扩展癌症患者及其他受试者的治疗选择。
发明内容
本发明总体上涉及免疫缀合物,其包含通过接头与一个或多个STING激动剂部分共价连接的抗体,并且具有式I:
Ab-[L-D]p I
或其药学上可接受的盐,
其中:
Ab是抗体;
p是1至8的整数;
D是具有下式的STING激动剂部分:
其中Xa、Xb、R1、R2a、R2b和R3中的一者连接至接头L。
本发明进一步涉及这类免疫缀合物在治疗特别是癌症的疾病中的用途。
本发明的另一方面是双苯并咪唑-接头化合物。
本发明的另一方面是一种用于治疗癌症的方法,所述方法包括施用治疗有效量的免疫缀合物,所述免疫缀合物包含通过缀合至一个或多个双苯并咪唑部分连接的抗体。
本发明的另一方面是包含通过缀合至一个或多个双苯并咪唑部分连接的抗体的免疫缀合物用于治疗癌症的用途。
本发明的另一方面是一种通过将一个或多个双苯并咪唑部分与抗体缀合来制备免疫缀合物的方法。
具体实施方式
现在将详细参考本发明的某些实施方案,其实施例在所附的结构和化学式中说明。虽然将结合列举的实施方案描述本发明,但将要理解的是,它们并不旨在将本发明限于这些实施方案。相反,本发明旨在涵盖所有的替代、修改和等同方案,这些可以被包括在如权利要求所限定的本发明的范围内。
本领域技术人员将会认识到,许多方法和材料类似或等同于本文描述的那些,它们可用于实施本发明。本发明决不限于所描述的方法和材料。
定义
术语“免疫缀合物”是指通过接头与佐剂部分共价键合的抗体构建体。术语“佐剂”是指能够在暴露于佐剂的受试者中引发免疫反应的物质。短语“佐剂部分”是指如本文所述例如通过接头与抗体构建体共价键合的佐剂。佐剂部分可在与抗体构建体结合时或在将免疫缀合物施用于受试者后从抗体构建体切割(例如,酶促切割)后引发免疫反应。
术语“免疫刺激剂”和“免疫刺激性”等同地使用并且是指在接头体内切割后能够在暴露于免疫刺激部分或免疫刺激化合物的受试者中引发免疫反应的部分、物质或佐剂。术语“佐剂部分”或“免疫刺激部分”是指这样的佐剂,其通过弹性蛋白酶底物、肽接头共价结合到细胞结合剂,如抗体构建体,如本文所述。佐剂部分可在与抗体构建体结合时或在将免疫缀合物施用于受试者后从抗体构建体切割(例如,酶促切割)后引发免疫反应。免疫缀合物允许在结合靶抗原时靶向递送活性佐剂部分。
术语“模式识别受体”(PRR)是指种系编码的宿主传感器,其检测病原体的典型分子并调节先天免疫系统的功能(Mahla,RS等人(2013)Frontiers in Immunology 4:248;Kumar,H等人(2011)Intl.Rev.of Immun.30:16-34;Schroder K等人(2010)Cell 140(6):821-832)。PRR是主要由树突状细胞、巨噬细胞、单核细胞、中性粒细胞和上皮细胞等先天免疫系统细胞表达的蛋白质,用于识别与微生物病原体相关的病原体相关分子模式(PAMP)和与细胞损伤或死亡期间释放的宿主细胞成分相关的损伤相关分子模式(DAMP)。PRR也被称为原始模式识别受体,因为它们在免疫系统的其他部分之前进化,特别是在适应性免疫之前。PRR还介导抗原特异性适应性免疫反应的启动和炎症细胞因子的释放。PRR包括但不限于:Toll样受体(TLR)、STING样受体、RIG-I样受体(RLR)、NOD样受体(NLR)、C型凝集素样受体(CLR)和DNA传感器。
“佐剂”是指能够在暴露于所述佐剂的受试者中引发免疫反应的物质。短语“佐剂部分”是指如本文所述例如通过接头与抗体构建体共价键合的佐剂。佐剂部分可在与抗体构建体结合时或在将免疫缀合物施用于受试者后从抗体构建体切割(例如,酶促切割)后引发免疫反应。
术语“抗体”以最广泛的含义使用,并且具体涵盖单克隆抗体(包括全长单克隆抗体)、多克隆抗体、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即可。如本文所用,“抗体片段”及其所有语法变型被定义为包含完整抗体的抗原结合位点或可变区的完整抗体的一部分,其中该部分不含完整抗体的Fc区的恒定重链结构域(即CH2、CH3和CH4,取决于抗体同种型)。抗体片段的实例包括Fab、Fab’、Fab’-SH、F(ab’)2和Fv片段;双抗体;任何抗体片段,其为具有由一个连续氨基酸残基的不间断序列组成的一级结构的多肽(本文称为“单链抗体片段”或“单链多肽”),包括但不限于(1)单链Fv(scFv)分子;(2)仅含有一个轻链可变结构域的单链多肽,或其含有轻链可变结构域的三个CDR的片段,而不具有相关的重链部分;(3)仅含有一个重链可变区的单链多肽,或其含有重链可变区的三个CDR的片段,而不具有相关的轻链部分;(4)包含来自非人物种的单Ig结构域或其他特异性单结构域结合模块的纳米抗体;和(5)由抗体片段形成的多特异性或多价结构。在包含一条或多条重链的抗体片段中,重链可以含有在完整抗体的非Fc区中发现的任何恒定结构域序列(例如,IgG同种型中的CH1),和/或可以含有在完整抗体中发现的任何铰链区序列,和/或可以含有融合至或位于铰链区序列或重链恒定结构域序列中的亮氨酸拉链序列。
“抗体”是指包含来自免疫球蛋白基因或其片段的抗原结合区(包括互补决定区(CDR))的多肽。术语“抗体”具体涵盖单克隆抗体(包括全长单克隆抗体)、多克隆抗体、多特异性抗体(例如,双特异性抗体)和表现出所需生物活性的抗体片段。示例性免疫球蛋白(抗体)结构单元包含四聚体。每个四聚体由两对相同的多肽链组成,每对具有通过二硫键连接的一条“轻”(约25kDa)链和一条“重”链(约50-70kDa)。每条链由被称为免疫球蛋白结构域的结构域组成。这些结构域按大小和功能分为不同的类别,例如轻链和重链上的可变结构域或区域(分别为VL和VH)以及轻链和重链上的恒定结构域或区域(分别为CL和CH)。每条链的N-末端界定了具有约100至110个或更多个氨基酸的可变区,被称为互补位,主要负责抗原识别,即抗原结合结构域。轻链被分类为κ或λ。重链被分类为γ、μ、α、δ或ε,它们分别又定义了免疫球蛋白类别IgG、IgM、IgA、IgD和IgE。IgG抗体是由四条肽链组成的约150kDa的大分子。IgG抗体含有约50kDa的两条相同的γ类重链和约25kDa的两条相同的轻链,因此具有四聚体四级结构。两条重链彼此连接,并通各自通过二硫键与轻链连接。所得四聚体具有两个相同的半体,它们一起形成Y样形状。叉的每一端含有相同的抗原结合结构域。人有四个IgG亚类(IgG1、IgG2、IgG3和IgG4),它们按在血清中的丰度顺序命名(即,IgG1是最丰度的)。通常,抗体的抗原结合结构域在与癌细胞结合的特异性和亲和力方面将最为关键。
靶向特定抗原的抗体包括具有至少一个靶向特定抗原的抗原结合区的双特异性或多特异性抗体。在一些实施方案中,靶向单克隆抗体是具有至少一个靶向肿瘤细胞的抗原结合区的双特异性抗体。此类抗原包括但不限于:间皮素、前列腺特异性膜抗原(PSMA)、PD-L1、HER2、Trop2、CEA、EGFR、5T4、Nectin4、CD19、CD20、CD22、CD30、CD47、CD70、B7H3、B7H4(也称为08E)、蛋白酪氨酸激酶7(PTK7)、磷脂酰肌醇蛋白聚糖-3、RG1、岩藻糖基-GMl、CTLA-4和CD44(WO 2017/196598)。
“抗体构建体”是指包含(i)抗原结合结构域和(ii)Fc结构域的抗体或融合蛋白。
在一些实施方案中,结合剂是抗原结合抗体“片段”,其是包含抗体的至少抗原结合区的构建体,单独或与一起构成抗原结合构建体的其它组分一起。许多不同类型的抗体“片段”是本领域中已知的,包括例如(i)Fab片段,其是由VL、VH、CL和CH1结构域组成的单价片段,(ii)F(ab’)2片段,其是包含在铰链区通过二硫键连接的两个Fab片段的二价片段,(iii)由抗体的单臂的VL和VH结构域组成的Fv片段,(iv)Fab’片段,其是采用温和还原条件破坏F(ab’)2片段的二硫桥产生的,(v)二硫化物稳定的Fv片段(dsFv),和(vi)单链Fv(scFv),其是通过合成接头连接的Fv片段的两个结构域(即,VL和VH)组成的单价分子,所述合成接头使得两个结构域能够作为单个多肽链合成。
抗体或抗体片段可以是更大构建体的一部分,例如抗体片段与另外的区域的缀合物或融合构建体。例如,在一些实施方案中,抗体片段可以与如本文所述的Fc区融合。在其它实施方案中,抗体片段(例如,Fab或scFv)可以是嵌合抗原受体或嵌合T细胞受体的一部分,例如通过与跨膜结构域(任选具有居间接头或“茎”(例如,铰链区))和任选的细胞间信号传导结构域融合。例如,抗体片段可以与T细胞受体的γ和/或δ链融合,以提供结合Trop2的T细胞受体样构建体。在又另一个实施方案中,抗体片段是包含CD1或CD3结合结构域和接头的双特异性T细胞接合物(BiTE)的一部分。
“表位”意指与抗原结合结构域结合的抗原的任何抗原决定簇或表位决定簇(即,在抗原结合结构域的互补位)。抗原决定簇通常由分子的化学活性表面组群组成,如氨基酸或糖侧链,并且通常具有特定的三维结构特征以及特定的电荷特征。
术语“Fc受体”或“FcR”是指与抗体的Fc区结合的受体。Fc受体主要有三类:(1)与IgG结合的FcγR,(2)与IgA结合的FcαR,和(3)与IgE结合的FcεR。FcγR家族包括若干成员,如FcγI(CD64)、FcγRIIA(CD32A)、FcγRIIB(CD32B)、FcγRIIIA(CD16A)和FcγRIIIB(CD16B)。Fcγ受体在对IgG的亲和力方面不同,并且对IgG亚类(例如,IgG1、IgG2、IgG3和IgG4)也具有不同的亲和力。
如本文所用,短语“免疫检查点抑制剂”是指抑制免疫检查点分子活性的任何调节剂。免疫检查点抑制剂可包括但不限于免疫检查点分子结合蛋白、小分子抑制剂、抗体(包括具有至少一个靶向免疫检查点蛋白的抗原结合区的双特异性和多特异性抗体,例如,不专门靶向免疫检查点蛋白的双特性或多特异性抗体,以及作为双重免疫调节剂(同时靶向两个免疫调节靶标),这会导致抑制性靶标的阻断、抑制性细胞的耗竭和/或效应细胞的激活;肿瘤靶向免疫调节剂(通过靶向肿瘤抗原和共刺激分子(例如CD40或4-1BB)将有效的共刺激定向到肿瘤浸润免疫细胞);NK细胞重定向器(通过靶向肿瘤抗原和CD16A将NK细胞重定向到恶性细胞);或T-细胞重定向器(通过靶向肿瘤抗原和CD3将T细胞重定向到恶性细胞)的抗体)、抗体衍生物(包括Fc融合体、Fab片段和scFv)、抗体药物缀合物、反义寡核苷酸、siRNA、适体、肽和肽模拟物。
如本文所提到的核酸或氨基酸序列“同一性”可通过将所关注的核酸或氨基酸序列与参考核酸或氨基酸序列进行比较来确定。同一性百分比是与所关注的最佳比对的序列与参考序列之间相同(即,是同一)的核苷酸或氨基酸残基数除以最长序列的长度(即,所关注的序列或参考序列任一者的长度,以较长者为准)。可以使用可获得的软件程序进行序列的比对和同一性百分比的计算。此类程序的实例包括CLUSTAL-W、T-Coffee和ALIGN(用于核酸和氨基酸序列的比对)、BLAST程序(例如BLAST 2.1、BL2SEQ、BLASTp、BLASTn等)和FASTA程序(例如、FASTA3x、FASTM和SSEARCH)(用于序列比对和序列相似性搜索)。序列比对算法还公开于例如以下文献中:Altschul等人,J.Molecular Biol.,215(3):403-410(1990);Beigert等人,Proc.Natl.Acad.Sci.USA,106(10):3770-3775(2009);Durbin等人编著,Biological Sequence Analysis:Probalistic Models of Proteins and NucleicAcids,Cambridge University Press,Cambridge,UK(2009);Soding,Bioinformatics,21(7):951-960(2005);Altschul等人,Nucleic Acids Res.,25(17):3389-3402(1997);和Gusfield,Algorithms on Strings,Trees and Sequences,Cambridge UniversityPress,Cambridge UK(1997))。序列的同一性百分比(%)也可以例如计算为100x[(同一的位置)/min(TGA,TGB)],其中TGA和TGB是在使TGA和TGB最小化的比对中肽序列A和B中的残基数和内部缺口位置的总和。参见例如Russell等人,J.Mol Biol.,244:332-350(1994)。
结合剂包含一起形成抗原结合位点的Ig重链和轻链可变区多肽。重链和轻链可变区中的每一者为包含通过框架区连接的三个互补决定区(CDR1、CDR2和CDR3)。结合剂可以是本领域中已知的包含Ig重链和轻链的多种类型的结合剂中的任一种。例如,结合剂可以是抗体、抗原结合抗体“片段”或T细胞受体。
“生物仿制药”是指具有与例如sacituzumab相似的活性特性的抗体构建体,sacituzumab是一种先前以戈沙妥珠单抗(sacituzumab govitecan)批准的Trop2靶向抗体构建体(Immunomedics,IMMU-132)。
“改良型生物相似性药物”是指如下抗体构建体,其是对先前批准的抗体构建体的改进,例如sacituzumab或戈沙妥珠单抗。改良型生物相似性药物可具有优于先前批准的抗体构建体的一种或多种修饰(例如,改变的聚糖谱或独特的表位)。
“氨基酸”是指可以掺入肽、多肽或蛋白质中的任何单体单元。氨基酸包括天然存在的α-氨基酸及其立体异构体以及非天然(非天然存在的)氨基酸及其立体异构体。给定氨基酸的“立体异构体”是指具有相同分子式和分子内键但键和原子的三维排列不同的异构体(例如,L-氨基酸和相应的D-氨基酸)。氨基酸可以被糖基化(例如,N-连接的聚糖、O-连接的聚糖、磷酸聚糖、C-连接的聚糖或糖基磷脂酰肌醇化)或去糖基化。氨基酸在本文中可以用通常已知的三字母符号或由IUPAC-IUB生物化学命名委员会推荐的单字母符号表示。
天然存在的氨基酸是由遗传密码编码的那些以及后来经修饰的那些氨基酸,例如羟脯氨酸、γ-羧基谷氨酸和O-磷酸丝氨酸。天然存在的α-氨基酸包括但不限于丙氨酸(Ala)、半胱氨酸(Cys)、天冬氨酸(Asp)、谷氨酸(Glu)、苯丙氨酸(Phe)、甘氨酸(Gly)、组氨酸(His)、异亮氨酸(Ile)、精氨酸(Arg)、赖氨酸(Lys)、亮氨酸(Leu)、甲硫氨酸(Met)、天冬酰胺(Asn)、脯氨酸(Pro)、谷氨酰胺(Gln)、丝氨酸(Ser)、苏氨酸(Thr)、缬氨酸(Val)、色氨酸(Trp)、酪氨酸(Tyr)及其组合。天然存在的α-氨基酸的立体异构体包括但不限于D-丙氨酸(D-Ala)、D-半胱氨酸(D-Cys)、D-天冬氨酸(D-Asp)、D-谷氨酸(D-Glu)、D-苯丙氨酸(D-Phe)、D-组氨酸(D-His)、D-异亮氨酸(D-Ile)、D-精氨酸(D-Arg)、D-赖氨酸(D-Lys)、D-亮氨酸(D-Leu)、D-甲硫氨酸(D-Met)、D-天冬酰胺(D-Asn)、D-脯氨酸(D-Pro)、D-谷氨酰胺(D-Gln)、D-丝氨酸(D-Ser)、D-苏氨酸(D-Thr)、D-缬氨酸(D-Val)、D-色氨酸(D-Trp)、D-酪氨酸(D-Tyr)及其组合。
天然存在的氨基酸包括通过翻译后修饰在蛋白质中形成的那些,如瓜氨酸(Cit)。
非天然(非天然存在的)氨基酸包括但不限于以类似于天然存在的氨基酸的方式起作用的L-或D-构型的氨基酸类似物、氨基酸模拟物、合成氨基酸、N-取代的甘氨酸和N-甲基氨基酸。例如,“氨基酸类似物”可以是具有与天然存在的氨基酸相同的基本化学结构(即,与氢、羧基、氨基键合的碳)但具有修饰的侧链基团或修饰的肽主链的非天然氨基酸,例如高丝氨酸、正亮氨酸、甲硫氨酸亚砜和甲硫氨酸甲基锍。“氨基酸模拟物”是指具有这样的结构的化学化合物,所述结构不同于氨基酸的一般化学结构,但其以类似于天然存在的氨基酸的方式起作用。
“接头”是指将化合物或材料中的两个或更多个部分共价键合的官能团。例如,连接部分可用来将免疫缀合物中的佐剂部分与抗体构建体共价键合。
“连接部分”是指将化合物或材料中的两个或更多个部分共价键合的官能团。例如,连接部分可用来将免疫缀合物中的佐剂部分与抗体共价键合。用于将连接部分连接到蛋白质和其他材料的有用键包括但不限于酰胺、胺、酯、氨基甲酸酯、脲、硫醚、硫代氨基甲酸酯、硫代碳酸酯和硫脲。
“二价”是指含有用于连接两个官能团的两个连接点的化学部分;多价连接部分可具有用于连接进一步的官能团的另外的连接点。二价基团可以用后缀“二基”表示。例如,二价连接部分包括二价聚合物部分如二价聚(乙二醇)、二价环烷基、二价杂环烷基、二价芳基和二价杂芳基。“二价环烷基、杂环烷基、芳基或杂芳基”是指具有用于共价连接分子或材料中的两个部分的两个连接点的环烷基、杂环烷基、芳基或杂芳基。环烷基、杂环烷基、芳基或杂芳基可以是取代的或未取代的。环烷基、杂环烷基、芳基或杂芳基可以被一个或多个选自卤代、羟基、氨基、烷基氨基、酰氨基、酰基、硝基、氰基和烷氧基的基团取代。
波浪线表示特定化学部分的连接点。如果指定的化学部分存在有两条波浪线则应理解该化学部分可以双向使用,即从左到右或从右到左阅读。在一些实施方案中,存在有两条波浪线的特定部分被认为用作从左到右阅读。
“烷基”是指具有所示碳原子数的直链(straight/linear)或支链饱和脂肪族基团。烷基可包括任何数目的碳,例如一至十二个。烷基的实例包括但不限于甲基(Me,-CH3)、乙基(Et,-CH2CH3)、1-丙基(n-Pr,正丙基,-CH2CH2CH3)、2-丙基(i-Pr,异丙基,-CH(CH3)2)、1-丁基(n-Bu,正丁基,-CH2CH2CH2CH3)、2-甲基-1-丙基(i-Bu,异丁基,-CH2CH(CH3)2)、2-丁基(s-Bu,仲丁基,-CH(CH3)CH2CH3)、2-甲基-2-丙基(t-Bu,叔丁基,-C(CH3)3)、1-戊基(正戊基,-CH2CH2CH2CH2CH3)、2-戊基(-CH(CH3)CH2CH2CH3)、3-戊基(-CH(CH2CH3)2)、2-甲基-2-丁基(-C(CH3)2CH2CH3)、3-甲基-2-丁基(-CH(CH3)CH(CH3)2)、3-甲基-1-丁基(-CH2CH2CH(CH3)2)、2-甲基-1-丁基(-CH2CH(CH3)CH2CH3)、1-己基(-CH2CH2CH2CH2CH2CH3)、2-己基(-CH(CH3)CH2CH2CH2CH3)、3-己基(-CH(CH2CH3)(CH2CH2CH3))、2-甲基-2-戊基(-C(CH3)2CH2CH2CH3)、3-甲基-2-戊基(-CH(CH3)CH(CH3)CH2CH3)、4-甲基-2-戊基(-CH(CH3)CH2CH(CH3)2)、3-甲基-3-戊基(-C(CH3)(CH2CH3)2)、2-甲基-3-戊基(-CH(CH2CH3)CH(CH3)2)、2,3-二甲基-2-丁基(-C(CH3)2CH(CH3)2)、3,3-二甲基-2-丁基(-CH(CH3)C(CH3)3、1-庚基、1-辛基等。烷基可以是取代的或未取代的。取代的烷基可以被一个或多个选自卤代、羟基、氨基、氧代(=O)、烷基氨基、酰氨基、酰基、硝基、氰基和烷氧基的基团取代。取代的烷基可以是偕取代的,其中烷基的碳原子形成螺环、环烷基例如环丙基、环丁基、环戊基或环己基。
术语“烷基二基”是指二价烷基。烷基二基的实例包括但不限于亚甲基(-CH2-)、亚乙基(-CH2CH2-)、亚丙基(-CH2CH2CH2-)等。烷基二基也可称为“亚烷基”。烷基二基可以是取代的或未取代的。取代的烷基二基可以被一个或多个选自卤代、羟基、氨基、氧代(=O)、烷基氨基、酰氨基、酰基、硝基、氰基和烷氧基的基团取代。取代的烷基二基可以是偕取代的,其中烷基的碳原子形成螺环、环烷基例如环丙基、环丁基、环戊基或环己基。
“烯基”是指具有指示的碳原子数和至少一个碳-碳双键sp2的直链(线性)或支链不饱和脂族基团。烯基可包括两个至约12个或更多的碳原子。烯基是具有“顺式”和“反式”取向或替代而言“E”和“Z”取向的基团。实例包括但不限于乙烯基或乙烯基(-CH=CH2)、烯丙基(-CH2CH=CH2)、丁烯基、戊烯基及其异构体。烯基可以是取代的或未取代的。“取代的烯基”可以被一个或多个选自卤代、羟基、氨基、氧代(=O)、烷基氨基、酰氨基、酰基、硝基、氰基和烷氧基的基团取代。
术语“亚烯基”或“烯基二基”是指直链或支链二价烃基。实例包括但不限于亚乙烯基或亚乙烯基(-CH=CH-)、烯丙基(-CH2CH=CH-)等。
“炔基”是指具有指示的碳原子数和至少一个碳-碳三键sp的直链(线性)或支链不饱和脂族基团。炔基可包括两个至约12个或更多的碳原子。例如,C2-C6炔基包括但不限于乙炔基(-C≡CH)、丙炔基(炔丙基,-CH2C≡CH)、丁炔基、戊炔基、己炔基及其异构体炔基可以是取代的或未取代的。“取代的炔基”可以被一个或多个选自卤代、羟基、氨基、氧代(=O)、烷基氨基、酰氨基、酰基、硝基、氰基和烷氧基的基团取代。
术语“亚炔基”或“炔基二基”是指二价炔基。
术语“碳环”、“碳环基”、“碳环状环”和“环烷基”是指饱和或部分不饱和的单环、稠合双环、螺环或桥接多环状环体系,其含有3至12个环原子,或所示原子数。饱和单环碳环状环包括例如环丙基、环丁基、环戊基、环己基和环辛基。饱和双环和多环碳环状环包括例如降冰片烷、[2.2.2]双环辛烷、十氢萘和金刚烷。碳环基团也可以是部分不饱和的,在环中具有一个或多个双键或三键。部分不饱和的代表性碳环基团包括但不限于环丁烯、环戊烯、环己烯、环己二烯(1,3-和1,4-异构体)、环庚烯、环庚二烯、环辛烯、环辛二烯(1,3-、1,4-和1,5-异构体)、降冰片烯和降冰片二烯。
术语“环烷基二基”是指二价环烷基。
“芳基”是指通过从母体芳族环体系的单个碳原子上移除一个氢原子得到的6-20个碳原子(C6-C20)的一价芳族烃基。芳基可以是单环的,稠合以形成双环或三环基团,或通过键连接以形成联芳基。代表性的芳基包括苯基、萘基和联苯基。其它芳基包括具有亚甲基连接基团的苄基。一些芳基具有6至12个环成员,如苯基、萘基或联苯基。其它芳基具有6至10个环成员,如苯基或萘基。
术语“亚芳基”或“芳基二基”意指通过从母体芳族环体系的两个碳原子上移除两个氢原子得到的6-20个碳原子(C6-C20)的二价芳族烃基。一些芳基二基可以在示例性结构中表示为“Ar”。芳基二基包括包含与饱和、部分不饱和的环或芳族碳环状环稠合的芳族环的双环基团。典型的芳基二基包括但不限于衍生自苯(苯基二基)、取代的苯、萘、蒽、亚联苯基、亚茚基、亚茚满基、1,2-二氢萘、1,2,3,4-四氢萘基等的基团。芳基二基基团也称为“亚芳基”,并且任选地被一个或多个本文所述的取代基取代。
术语“杂环”、“杂环基”和“杂环状环”在本文中可互换使用,并且是指饱和或部分不饱和(即,在环内具有一个或多个双键和/或三键)的3至约20个环原子的碳环基团,其中至少一个环原子是选自氮、氧、磷和硫的杂原子,其余环原子是C,其中一个或多个环原子任选地被一个或多个下述取代基独立地取代。杂环可以是具有3至7个环成员(2至6个碳原子和1至4个选自N、O、P和S的杂原子)的单环或具有7至10个环成员(4至9个碳原子和1至6个选自N、O、P和S的杂原子)的双环,例如:双环[4,5]、[5,5]、[5,6]或[6,6]体系。杂环描述于Paquette,Leo A.;“Principles of Modern Heterocyclic Chemistry”(W.A.Benjamin,New York,1968),特别是第1章、第3章、第4章、第6章、第7章和第9章;“The Chemistry ofHeterocyclic Compounds,A series of Monographs”(John Wiley&Sons,New York,1950至今),特别是第13卷、第14卷、第16卷、第19卷和第28卷;和J.Am.Chem.Soc.(1960)82:5566中。“杂环基”还包括其中杂环基团与饱和的、部分不饱和的环或芳族碳环或杂环环稠合或者形成螺环体系的基团。杂环环的示例包括但不限于吗啉-4-基、哌啶-1-基、哌嗪基、哌嗪-4-基-2-酮、哌嗪-4-基-3-酮、吡咯烷-1-基、硫代吗啉-4-基、S-二氧代硫吗啉-4-基、氮杂环辛烷-1-基、氮杂环丁烷-1-基、八氢吡啶并[1,2-a]吡嗪-2-基、[1,4]二氮杂环庚烷-1-基、吡咯烷基、四氢呋喃基、二氢呋喃基、四氢噻吩基、四氢哌喃基、二氢哌喃基、四氢噻喃基、哌啶基、吗啉基、硫吗啉基、噻烷基、哌嗪基、高哌嗪基、氮杂环丁烷基、氧杂环丁烷基、硫杂环丁烷基、高哌啶基、氧杂环庚烷基、硫杂环庚烷基、氧氮杂环庚烷基、二氮杂环庚烷基、硫氮杂环庚烷基、2-吡咯啉基、3-吡咯啉基、二氢吲哚基、2H-哌喃基、4H-哌喃基、二噁烷基、1,3-二氧戊环基、吡唑啉基、二噻烷基、二硫戊环基、二氢哌喃基、二氢噻吩基、二氢呋喃基、吡唑烷基咪唑啉基、咪唑烷基、3-氮杂双环[3.1.0]己烷基、3-氮杂双环[4.1.0]庚烷基、氮杂双环[2.2.2]己烷基、3H-吲哚基喹嗪基和N-吡啶基脲。“杂环基”还包括本定义范围内的螺杂环基部分。螺杂环基部分的实例包括但不限于2-氧杂螺[4.5]癸烷、2-氧杂-8-氮杂螺[4.5]癸烷、氮杂螺[2.5]辛基和氮杂螺[2.4]庚基子结构。其中2个环原子被氧代(=O)部分取代的杂环基团的实例是嘧啶酮基和1,1-二氧代-硫代吗啉基。本文的杂环基团任选独立地被一个或多个本文所述的取代基取代。
术语“杂环基二基”是指3至约20个环原子的二价饱和或部分不饱和(即,在环内具有一个或多个双键和/或三键)碳环基团,其中至少一个环原子是选自氮、氧、磷和硫的杂原子,剩余的环原子是C,其中一个或多个环原子任选独立地被一个或多个如所述的取代基取代。5元和6元杂环基二基的实例包括吗啉基二基、哌啶基二基、哌嗪基二基、吡咯烷基二基、二噁烷基二基、硫代吗啉基二基和S-二氧代硫代吗啉基二基。
术语“杂芳基”是指5、6或7元环的单价芳族基团,并且包括含有一个或多个碳原子以及一个或多个独立地选自氮、氧和硫的杂原子的约5-20个原子的稠环体系(其中的至少一个是芳族的)。杂芳基基团的示例是吡啶基(包括例如2-羟基吡啶基)、咪唑基、咪唑并吡啶基、嘧啶基(包括例如4-羟基嘧啶基)、吡唑基、三唑基、吡嗪基、四唑基、呋喃基、噻吩基、异噁唑基、噻唑基、噁二唑基、噁唑基、异噻唑基、吡咯基、喹啉基、异喹啉基、四氢异喹啉基、吲哚基、苯并咪唑基、苯并呋喃基、噌啉基、吲唑基、吲嗪基、酞嗪基、哒嗪基、三嗪基、异吲哚基、蝶啶基、嘌呤基、噁二唑基、噻二唑基、噻二唑基、呋呫基、苯并呋呫基、苯并噻吩基、苯并噻唑基、苯并噁唑基、喹唑啉基、喹喔啉基、萘啶基和呋喃并吡啶基。杂芳基任选独立地被一个或多个本文所述的取代基取代。
术语“杂芳基二基”是指5、6或7元环的二价芳族基团,并且包括含有一个或多个碳原子以及一个或多个独立地选自氮、氧和硫的杂原子的5-20个原子的稠环体系(其中的至少一个是芳族的)。5元和6元杂芳基二基的实例包括吡啶基二基、咪唑基二基、嘧啶基二基、吡唑基二基、三唑基二基、吡嗪基二基、四唑基二基、呋喃基二基、噻吩基二基、异噁唑基二基二基、噻唑基二基、噁二唑基二基、噁唑基二基、异噻唑基二基和吡咯基二基。
杂环或杂芳基在可能的情况下可以是碳(碳连接)或氮(氮连接)键合的。举例而非限制,碳键合的杂环或杂芳基键合在吡啶的2、3、4、5或6位;哒嗪的3、4、5或6位;嘧啶的2、4、5或6位;吡嗪的2、3、5或6位;呋喃、四氢呋喃、硫代呋喃、噻吩、吡咯或四氢吡咯的2、3、4或5位;噁唑、咪唑或噻唑的2、4或5位;异噁唑、吡唑或异噻唑的3、4或5位;氮丙啶的2或3位;氮杂环丁烷的2、3或4位;喹啉的2、3、4、5、6、7或8位;或异喹啉的1、3、4、5、6、7或8位。
举例而非限制,氮键合的杂环或杂芳基键合在氮丙啶、氮杂环丁烷、吡咯、吡咯烷、2-吡咯啉、3-吡咯啉、咪唑、咪唑烷、2-咪唑啉、3-咪唑啉、吡唑、吡唑啉、2-吡唑啉、3-吡唑啉、哌啶、哌嗪、吲哚、吲哚啉、1H-吲唑的1位;异吲哚或异吲哚啉的2位;吗啉的4位;和咔唑或β-咔啉的9位。
术语“卤代”和“卤素”本身或作为另一取代基的一部分是指氟(F)、氯(Cl)、溴(Br)或碘(I)原子。
术语“羰基”本身或作为另一取代基的一部分,是指C(O)、C(=O)或–C(=O)–,即与氧双键键合并与具有羰基的部分中的两个其他基团键合的碳原子。
如本文所用,短语“季铵盐”是指已被烷基取代基(例如,C1-C4烷基,如甲基、乙基、丙基或丁基)季铵化的叔胺。
术语“治疗(treat/treatment/treating)”是指成功治疗或改善损伤、病理、疾患(例如,癌症)或症状(例如,认知障碍)的任何标志,包括任何客观或主观参数,如减轻;缓解;减少症状或使患者更容易忍受症状、损伤、病理或疾患;降低症状进展的速率;减少症状或疾患的频率或持续时间;或者在一些情况下预防症状发作。症状的治疗或改善可基于任何客观或主观参数,包括例如身体检查的结果。
术语“癌症”、“赘生物”和“肿瘤”在本文中用于指这样的细胞,其表现出自主的、不受调控的生长,使得细胞表现出以细胞增殖显著失控为特征的异常生长表型。在本发明的上下文中用于检测、分析和/或治疗的所关注的细胞包括癌细胞(例如,来自患有癌症的个体的癌细胞)、恶性癌细胞、转移前癌细胞、转移性癌细胞和非转移性癌细胞。几乎每种组织的癌症都是已知的。短语“癌症负担”是指受试者体内的癌细胞数量或癌症体积。减少癌症负担相应地是指减少受试者体内的癌细胞数量或癌细胞体积。本文使用的术语“癌细胞”是指作为癌细胞的任何细胞(例如,来自个体可被治疗的任何癌症,例如,从患有癌症的个体中分离)或来源于癌细胞,例如癌细胞的克隆。例如,癌细胞可来自已确立的癌细胞系,可以是分离自患有癌症的个体的原代细胞,可以是来自分离自患有癌症的个体的原代细胞的子代细胞等。在一些实施方案中,该术语也可以指癌细胞的一部分,如癌细胞的亚细胞部分、细胞膜部分或细胞裂解物。许多类型的癌症是本领域技术人员已知的,包括实体肿瘤如癌、肉瘤、成胶质细胞瘤、黑素瘤、淋巴瘤和骨髓瘤,以及循环癌如白血病。
如本文所用,术语“癌症”包括任何形式的癌症,包括但不限于实体肿瘤癌症(例如,皮肤癌、肺癌、前列腺癌、乳腺癌、胃癌、膀胱癌、结肠癌、卵巢癌、胰腺癌、肾癌、肝癌、成胶质细胞瘤、髓母细胞瘤、平滑肌肉瘤、头颈部鳞状细胞癌、黑素瘤和神经内分泌癌)和液体癌(例如,血液学癌症);癌;软组织肿瘤;肉瘤;畸胎瘤;黑素瘤;白血病;淋巴瘤;和脑癌,包括微小残留病,并且包括原发性肿瘤和转移性肿瘤两者。
癌症的“病理学”包括损害患者健康的所有现象。这包括但不限于异常或不可控的细胞生长、转移、干扰邻近细胞的正常功能、以异常水平释放细胞因子或其它分泌产物、抑制或加重炎症或免疫反应、瘤形成、癌前病变、恶性肿瘤,以及侵袭周围或远处的组织或器官,如淋巴结。
如本文所用,短语“癌症复发”和“肿瘤复发”及其语法变型是指肿瘤或癌细胞在癌症诊断后的进一步生长。特别地,当癌组织中发生进一步的癌细胞生长时,可能会发生复发。类似地,“肿瘤扩散”发生在肿瘤细胞散布到局部或远处组织和器官时,因此,肿瘤扩散涵盖肿瘤转移。当肿瘤生长局部扩散以通过压迫、破坏或阻止正常器官功能损害受累组织的功能时,就会发生“肿瘤侵袭”。
如本文所用,术语“转移”是指癌性肿瘤在器官或身体部位中的生长,其与原始癌性肿瘤的器官没有直接联系。转移将被理解为包括微转移,其是在与原始癌性肿瘤的器官没有直接联系的器官或身体部位中存在不可检测量的癌细胞。转移也可以被定义为过程的若干步骤,如癌细胞从原始肿瘤部位离开,以及癌细胞迁移和/或侵入身体的其它部位。
短语“有效量”和“治疗有效量”是指诸如免疫缀合物的物质产生施用的治疗效果的剂量或量。确切的剂量将取决于治疗的目的,并且将可由本领域技术人员采用已知的技术确定(参见例如,Lieberman,Pharmaceutical Dosage Forms(第1-3卷,1992);Lloyd,TheArt,Science and Technology of Pharmaceutical Compounding(1999);Pickar,DosageCalculations(1999);Goodman&Gilman’s The Pharmacological Basis ofTherapeutics,第11版(McGraw-Hill,2006);和Remington:The Science and Practice ofPharmacy,第22版,(Pharmaceutical Press,London,2012))。在癌症的情况下,治疗有效量的免疫缀合物可减少癌细胞的数量;缩小肿瘤尺寸;抑制(即,在一定程度上减缓且优选停止)癌细胞向外周器官的浸润;抑制(即,在一定程度上减缓且优选停止)肿瘤转移;在一定程度上抑制肿瘤生长;和/或在一定程度上缓解与癌症相关的一种或多种症状。就免疫缀合物可以阻止现有癌细胞生长和/或杀死现有癌细胞的程度而言,其可以是细胞抑制性的和/或细胞毒性的。对于癌症治疗,功效可以例如通过评定疾病进展时间(time to diseaseprogression,TTP)和/或确定反应率(response rate,RR)来测量
“接受者”、“个体”、“受试者”、“宿主”和“患者”可互换使用,并且是指需要诊断、治疗或疗法的任何哺乳动物受试者(例如,人)。用于治疗目的的“哺乳动物”是指被归类为哺乳动物的任何动物,包括人、家养动物和农场动物以及动物园动物、赛场动物或宠物动物,如狗、马、猫、母牛、绵羊、山羊、猪、骆驼等。在某些实施方案中,哺乳动物是人。
本发明的上下文中的短语“协同佐剂”或“协同组合”包括两种免疫调节剂的组合,如受体激动剂、细胞因子和佐剂多肽,其组合相对于任一者的单独施用引发免疫的协同效应。特别地,本文公开的免疫缀合物包含要求保护的佐剂和抗体构建体的协同组合。这些协同组合在施用后引发更大的免疫效应,例如相对于不存在其它部分的情况下施用抗体构建体或佐剂。进一步地,与单独施用抗体构建体或佐剂时相比,可以施用的免疫缀合物的量减少(如通过作为免疫缀合物的一部分施用的抗体构建体的总数量或佐剂的总数量来测量)。
如本文所用,术语“施用”是指对受试者进行肠胃外、静脉内、腹膜内、肌内、肿瘤内、病灶内、鼻内或皮下施用、口服施用、作为栓剂施用、局部接触、鞘内施用或植入缓释装置,例如微型渗透泵。
如本文用于修饰数值的术语“约”和“大约”表示围绕该数值的紧密范围。因此,如果“X”是所述值,则“约X”或“大约X”表示0.9X至1.1X的值,例如0.95X至1.05X或0.99X至1.01X。提到“约X”或“大约X”具体表示至少值X、0.95X、0.96X、0.97X、0.98X、0.99X、1.01X、1.02X、1.03X、1.04X和1.05X。因此,“约X”和“大约X”旨在教导和提供对例如“0.98X”的权利要求限制的书面描述支持。
抗体
本发明的免疫缀合物包含抗体。本发明的实施方案的范围包括本文所述的抗体构建体或抗原结合结构域的功能变体。如本文所用的术语“功能变体”是指具有与亲本抗体构建体或抗原结合结构域具有实质或显著序列同一性或相似性的抗原结合结构域的抗体构建体,所述功能性变体保留了其为变体的抗体构建体或抗原结合结构域的生物活性。功能变体涵盖例如本文所述的抗体构建体或抗原结合结构域(亲本抗体构建体或抗原结合结构域)的那些变体,其以与亲本抗体构建体或抗原结合结构域相似的程度、相同的程度或更高的程度保留了识别靶细胞的能力。
关于抗体构建体或抗原结合结构域,功能变体与所述抗体构建体或抗原结合结构域在氨基酸序列上可以例如具有至少约30%、约50%、约75%、约80%、约85%、约90%、约91%、约92%、约93%、约94%、约95%、约96%、约97%、约98%、约99%或更高的同一性。
功能变体可例如包含具有至少一个保守氨基酸取代的亲本抗体构建体或抗原结合结构域的氨基酸序列。替代地或另外地,功能变体可包含具有至少一个非保守氨基酸取代的亲本抗体构建体或抗原结合结构域的氨基酸序列。在这种情况下,优选非保守氨基酸取代不干扰或抑制功能变体的生物活性。非保守氨基酸取代可增强功能变体的生物活性,使得功能变体的生物活性与亲本抗体构建体或抗原结合结构域相比增加。
包含本发明的免疫缀合物的抗体包括Fc工程化变体。在一些实施方案中,Fc区中导致与一种或多种Fc受体的结合受到调节的突变可包括以下突变中的一者或多者:SD(S239D)、SDIE(S239D/I332E)、SE(S267E)、SELF(S267E/L328F)、SDIE(S239D/I332E)、SDIEAL(S239D/I332E/A330L)、GA(G236A)、ALIE(A330L/I332E)、GASD ALIE(G236A/S239D/A330L/I332E)、V9(G237D/P238D/P271G/A330R)和V11(G237D/P238D/H268D/P271G/A330R),和/或在以下氨基酸处的一个或多个突变:E345R、E233、G237、P238、H268、P271、L328和A330。用于调节Fc受体结合的另外的Fc区修饰描述于例如US 2016/0145350、US 7416726和US 5624821中,上述专利文献特此以全文引用的方式并入本文。
组成本发明的免疫缀合物的抗体包括聚糖变体,如无岩藻糖基化。在一些实施方案中,结合剂的Fc区被修饰成与天然未修饰的Fc区相比具有改变的Fc区糖基化模式。
本发明的抗体构建体或抗原结合结构域的氨基酸取代优选为保守氨基酸取代。保守氨基酸取代是本领域中已知的,并且包括这样的氨基酸取代,其中具有某些物理和/或化学特性的氨基酸被交换为具有相同或相似化学或物理特性的另一种氨基酸。例如,保守氨基酸取代可以是酸性/带负电荷的极性氨基酸取代为另一种酸性/带负电荷的极性氨基酸(例如,Asp或Glu)、具有非极性侧链的氨基酸取代为另一种具有非极性侧链的氨基酸(例如,Ala、Gly、Val、Ile、Leu、Met、Phe、Pro、Trp、Cys、Val等)、碱性/带正电荷的极性氨基酸取代为另一种碱性/带正电荷的极性氨基酸(例如,Lys、His、Arg等)、具有极性侧链的不带电荷的氨基酸取代为另一种具有极性侧链的不带电荷的氨基酸(例如,Asn、Gln、Ser、Thr、Tyr等)、具有β-支链侧链的氨基酸取代为另一种具有β-支链侧链的氨基酸(例如,Ile、Thr和Val)、具有芳族侧链的氨基酸取代为另一种具有芳族侧链的氨基酸(例如,His、Phe、Trp和Tyr)等。
抗体构建体或抗原结合结构域可基本上由本文所述的一个或多个指定氨基酸序列组成,使得其它组分(例如,其它氨基酸)不实质性改变抗体构建体或抗原结合结构域功能变体的生物活性。
在一些实施方案中,免疫缀合物中的抗体含有修饰的Fc区,其中所述修饰调节Fc区与一种或多种Fc受体的结合。
在一些实施方案中,免疫缀合物中的抗体(例如,与至少两个佐剂部分缀合的抗体)在Fc区含有一个或多个修饰(例如,氨基酸插入、缺失和/或取代),与Fc区中缺乏突变的天然抗体相比,所述一个或多个修饰导致与一种或多种Fc受体(例如,FcγRI(CD64)、FcγRIIA(CD32A)、FcγRIIB(CD32B)、FcγRIIIA(CD16a)和/或FcγRIIIB(CD16b))的结合受到调节(例如,增加的结合或减少的结合)。在一些实施方案中,免疫缀合物中的抗体在Fc区含有减少抗体的Fc区与FcγRIIB的结合的一个或多个修饰(例如,氨基酸插入、缺失和/或取代)。在一些实施方案中,免疫缀合物中的抗体在抗体的Fc区中含有一个或多个修饰(例如,氨基酸插入、缺失和/或取代),其减少抗体与FcγRIIB的结合,同时与在Fc区中缺乏突变的天然抗体相比维持与FcγRI(CD64)、FcγRIIA(CD32A)和/或FcRγIIIA(CD16a)相同的结合或与之结合增加。在一些实施方案中,免疫缀合物中的抗体在Fc区中含有增加抗体的Fc区与FcγRIIB的结合的一个或多个修饰。
在一些实施方案中,通过抗体的Fc区中相对于抗体的天然Fc区的突变提供受调节的结合。突变可以在CH2结构域、CH3结构域或其组合中。“天然Fc区”与“野生型Fc区”同义,并且包含与见于自然界中的Fc区的氨基酸序列同一或与见于天然抗体(例如,西妥昔单抗)中的Fc区的氨基酸序列同一的氨基酸序列。天然序列人Fc区包括天然序列人IgG1 Fc区、天然序列人IgG2 Fc区、天然序列人IgG3 Fc区和天然序列人IgG4 Fc区以及其天然存在的变体。天然序列Fc包括Fc的各种同种异型(Jefferis等人,(2009)mAbs,1(4):332-338)。
在一些实施方案中,免疫缀合物的抗体的Fc区被修饰以具有与天然未修饰的Fc区相比改变的Fc区糖基化模式。
人免疫球蛋白在每条重链的Cγ2结构域中的Asn297残基处被糖基化。这种N-连接的寡糖由核心七糖N-乙酰葡糖胺4甘露糖3(GlcNAc4Man3)组成。已知用内切糖苷酶或PNG酶F移除七糖导致抗体Fc区的构象变化,这可显著降低与激活FcγR的抗体结合亲和力,并导致效应功能降低。核心七糖通常用半乳糖、二等分GlcNAc、岩藻糖或唾液酸修饰,这会有差别地影响Fc与激活和抑制性FcγR的结合。另外,已证明α2,6-唾液酸化增强体内抗炎活性,而无岩藻糖基化(afucosylation)导致FcγRIIIa结合改善,并使抗体依赖性细胞毒性和抗体依赖性吞噬作用增加10倍。特定的糖基化模式因此可用于控制炎症效应功能。
在一些实施方案中,改变糖基化模式的修饰是突变。例如,在Asn297处的取代。在一些实施方案中,Asn297突变为谷氨酰胺(N297Q)。在例如US 7416726、US2007/0014795以及US2008/0286819中描述了用调节FcγR调控的信号传导的抗体来控制免疫反应的方法,上述专利文献特此以引用的方式全文并入。
在一些实施方案中,免疫缀合物的抗体被修饰成以非天然存在的糖基化模式含有工程化Fab区。例如,可以对杂交瘤进行基因工程化以分泌具有特定突变的无岩藻糖基化mAb、去唾液酸化mAb或去糖基化Fc,所述特定突变使得能够增加FcRγIIIa结合和效应功能。在一些实施方案中,免疫缀合物的抗体被工程化为无岩藻糖基化。
在一些实施方案中,免疫缀合物中的抗体的整个Fc区与不同的Fc区交换,从而使抗体的Fab区与非天然Fc区缀合。例如,西妥昔单抗的Fab区通常包含IgG1 Fc区,可以与IgG2、IgG3、IgG4或IgA缀合,或者纳武单抗的Fab区通常包含IgG4 Fc区,可以与IgG1、IgG2、IgG3、IgA1或IgG2缀合。在一些实施方案中,具有非天然Fc结构域的Fc修饰的抗体还包含一个或多个氨基酸修饰,如IgG4 Fc内的S228P突变,其调节所述Fc结构域的稳定性。在一些实施方案中,具有非天然Fc结构域的Fc修饰的抗体还包含一个或多个本文所述的调节Fc与FcR结合的氨基酸修饰。
在一些实施方案中,当与天然未修饰的抗体相比时,调节Fc区与FcR结合的修饰不改变抗体的Fab区与其抗原的结合。在其它实施方案中,当与天然未修饰的抗体相比时,调节Fc区与FcR结合的修饰还增加抗体的Fab区与其抗原的结合。
在一些实施方案中,免疫缀合物中的抗体含有修饰的Fc区,其中所述修饰调节Fc区与一种或多种Fc受体的结合。
在一些实施方案中,通过包含能够结合TGFβ1的转化生长因子β1(TGFβ1)受体或其片段来修饰Fc区。例如,受体可以是TGFβ受体II(TGFβRII)。在一些实施方案中,TGFβ受体是人TGFβ受体。在一些实施方案中,IgG具有与TGFβRII细胞外结构域(ECD)的C-末端融合,如US 9676863中所述,该专利文献并入本文。“Fc接头”可用于将IgG连接至TGFβRII细胞外结构域。Fc接头可以是短的柔性肽,其允许分子进行正确的三维折叠,同时维持与靶标的结合特异性。在一些实施方案中,TGFβ受体的N-末端与抗体构建体的Fc融合(有或没有Fc接头)。在一些实施方案中,抗体构建体重链的C-末端与TGFβ受体融合(有或没有Fc接头)。在一些实施方案中,抗体构建体重链的C-末端赖氨酸残基突变为丙氨酸。
在一些实施方案中,免疫缀合物中的抗体是糖基化的。
在一些实施方案中,免疫缀合物中的抗体是经半胱氨酸工程化的抗体,所述抗体通过在经工程化的半胱氨酸可用于缀合但不干扰免疫球蛋白折叠和组装或改变抗原结合和效应功能的位点处的半胱氨酸取代来提供佐剂、标记或药物部分与抗体的位点特异性缀合(Junutula等人,(2008)Nature Biotech.,26(8):925-932;Dornan等人(2009)Blood 114(13):2721-2729;US 7521541;US 7723485;US 2012/0121615;WO 2009/052249)。“半胱氨酸工程化抗体”或“半胱氨酸工程化抗体变体”是其中抗体的一个或多个残基被半胱氨酸残基取代的抗体。半胱氨酸工程化抗体可以作为具有均匀化学计量的噻吩并氮杂接头化合物与噻吩并氮杂佐剂部分缀合(例如,在具有单个工程化半胱氨酸位点的抗体中,每个抗体最多两个噻吩并氮杂部分)。
在一些实施方案中,半胱氨酸工程化抗体用于制备免疫缀合物。免疫缀合物可在轻链上的位点(例如149-赖氨酸位点(LC K149C))或重链上的位点(例如122-丝氨酸位点(HC S122C))引入反应性半胱氨酸硫醇残基,如通过Kabat编号进行编号。在其它实施方案中,半胱氨酸工程化抗体具有在重链的118-丙氨酸位点(EU编号)(HC A118C)处引入的半胱氨酸残基。此位点替代地按顺序编号编号为121,或者按Kabat编号编号为114。在其他实施方案中,半胱氨酸工程化抗体具有引入到以下中描述的位点处的半胱氨酸残基:Bhakta,S.等人,(2013)“Engineering THIOMABs for Site-Specific Conjugation of Thiol-Reactive Linkers”,Laurent Ducry(ed.),Antibody-Drug Conjugates,Methods inMolecular Biology,第1045卷,第189-203页;WO 2011/156328;US 9000130。
免疫检查点抑制剂
在一些实施方案中,免疫缀合物的抗体是免疫检查点抑制剂。在一些实施方案中,免疫检查点抑制剂降低一种或多种免疫检查点蛋白的表达或活性。在另一个实施方案中,免疫检查点抑制剂减少一种或多种免疫检查点蛋白与其配体之间的相互作用。降低免疫检查点分子的表达和/或活性的抑制性核酸也可以用于本文公开的方法中。
免疫检查点抑制剂纳武单抗和阿特朱单抗可以被修饰以包括IgG1 Fc,并且随后转化为本发明的免疫缀合物。
大多数检查点抗体被设计为不具有杀死细胞,而是阻断信号传导的效应功能。本发明的免疫缀合物可以添加回引发髓样细胞激活和促炎反应所需的“效应功能”。
在一些实施方案中,免疫检查点抑制剂是细胞毒性T淋巴细胞抗原4(CTLA4,也称为CD152)、具有Ig和ITIM结构域的T细胞免疫受体(TIGIT)、糖皮质激素诱导的TNFR相关蛋白(GITR,也称为TNFRSF18)、诱导型T细胞共刺激(ICOS,也称为CD278)、CD96、脊髓灰质炎病毒受体相关2(PVRL2,也称为CD112R)、程序性细胞死亡蛋白1(PD-1,也称为CD279)、程序性细胞死亡1配体1(PD-L1,也称为B7-H3和CD274)、程序性细胞死亡配体2(PD-L2,也称为B7-DC和CD273)、淋巴细胞激活基因3(LAG-3,也称为CD223)、B7-H4、杀伤性免疫球蛋白受体(KIR)、肿瘤坏死因子受体超家族成员4(TNFRST4,也称为OX40和CD134)及其配体OX40L(CD252)、吲哚胺2,3-双加氧酶1(IDO-1)、吲哚胺2,3-双加氧酶2(IDO-2)、癌胚抗原相关细胞粘附分子1(CEACAM1)、B和T淋巴细胞衰减因子(BTLA,也称为CD272)、T细胞膜蛋白3(TIM3)、腺苷A2A受体(A2Ar)和T细胞激活的V结构域Ig抑制因子(VISTA蛋白)。在一些实施方案中,免疫检查点抑制剂是CTLA4、PD-1或PD-L1的抑制剂。
在一些实施方案中,抗体选自:伊匹单抗(也称为)、派姆单抗(也称为)、纳武单抗(也称为)、阿特朱单抗(也称为)、阿维鲁单抗(也称为)和度伐利尤单抗(也称为)。
在一些实施方案中,免疫检查点抑制剂是CTLA4的抑制剂。在一些实施方案中,免疫检查点抑制剂是针对CTLA4的抗体。在一些实施方案中,免疫检查点抑制剂是针对CTLA4的单克隆抗体。在一些实施方案中,免疫检查点抑制剂是针对CTLA4的人或人源化抗体。在一些实施方案中,免疫检查点抑制剂降低一种或多种免疫检查点蛋白如CTLA4的表达或活性。
在一些实施方案中,免疫检查点抑制剂是PD-1的抑制剂。在一些实施方案中,免疫检查点抑制剂是针对PD-1的抗体。在一些实施方案中,免疫检查点抑制剂是针对PD-1的单克隆抗体。在一些实施方案中,免疫检查点抑制剂是针对PD-1的人或人源化抗体。在一些实施方案中,免疫检查点抑制剂降低一种或多种免疫检查点蛋白如PD-1的表达或活性。
在一些实施方案中,免疫检查点抑制剂是PD-L1的抑制剂。在一些实施方案中,免疫检查点抑制剂是针对PD-L1的抗体。在一些实施方案中,免疫检查点抑制剂是针对PD-L1的单克隆抗体。在一些实施方案中,免疫检查点抑制剂是针对PD-L1的人或人源化抗体。在一些实施方案中,免疫检查点抑制剂降低一种或多种免疫检查点蛋白如PD-L1的表达或活性。在一些实施方案中,免疫检查点抑制剂减少PD-1和PD-L1之间的相互作用。
在一些实施方案中,免疫检查点抑制剂是PD-L2的抑制剂。在一些实施方案中,免疫检查点抑制剂是针对PD-L2的抗体。在一些实施方案中,免疫检查点抑制剂是针对PD-L2的单克隆抗体。在一些实施方案中,免疫检查点抑制剂是针对PD-L2的人或人源化抗体。在一些实施方案中,免疫检查点抑制剂降低一种或多种免疫检查点蛋白如PD-L2的表达或活性。在一些实施方案中,免疫检查点抑制剂减少PD-1和PD-L2之间的相互作用。
在一些实施方案中,免疫检查点抑制剂是LAG-3的抑制剂。在一些实施方案中,免疫检查点抑制剂是针对LAG-3的抗体。在一些实施方案中,免疫检查点抑制剂是针对LAG-3的单克隆抗体。在一些实施方案中,免疫检查点抑制剂是针对LAG-3的人或人源化抗体。在一些实施方案中,免疫检查点抑制剂降低一种或多种免疫检查点蛋白如LAG-3的表达或活性。
在一些实施方案中,免疫检查点抑制剂是B7-H4的抑制剂。在一些实施方案中,免疫检查点抑制剂是针对B7-H4的抗体。在一些实施方案中,免疫检查点抑制剂是针对B7-H4的单克隆抗体。在一些实施方案中,免疫检查点抑制剂是针对B7-H4的人或人源化抗体。在一些实施方案中,免疫检查点抑制剂降低一种或多种免疫检查点蛋白如B7-H4的表达或活性。
在一些实施方案中,免疫检查点抑制剂是KIR的抑制剂。在一些实施方案中,免疫检查点抑制剂是针对KIR的抗体。在一些实施方案中,免疫检查点抑制剂是针对KIR的单克隆抗体。在一些实施方案中,免疫检查点抑制剂是针对KIR的人或人源化抗体。在一些实施方案中,免疫检查点抑制剂降低一种或多种免疫检查点蛋白如KIR的表达或活性。
在一些实施方案中,免疫检查点抑制剂是TNFRSF4的抑制剂。在一些实施方案中,免疫检查点抑制剂是针对TNFRSF4的抗体。在一些实施方案中,免疫检查点抑制剂是针对TNFRSF4的单克隆抗体。在一些实施方案中,免疫检查点抑制剂是针对TNFRSF4的人或人源化抗体。在一些实施方案中,免疫检查点抑制剂降低一种或多种免疫检查点蛋白如TNFRSF4的表达或活性。
在一些实施方案中,免疫检查点抑制剂是OX40L的抑制剂。在一些实施方案中,免疫检查点抑制剂是针对OX40L的抗体。在一些实施方案中,免疫检查点抑制剂是针对OX40L的单克隆抗体。在一些实施方案中,免疫检查点抑制剂是针对OX40L的人或人源化抗体。在一些实施方案中,免疫检查点抑制剂降低一种或多种免疫检查点蛋白如OX40L的表达或活性。在一些实施方案中,免疫检查点抑制剂减少TNFRSF4和OX40L之间的相互作用。在一些实施方案中,免疫检查点抑制剂是IDO-1的抑制剂。在一些实施方案中,免疫检查点抑制剂是针对IDO-1的抗体。在一些实施方案中,免疫检查点抑制剂是针对IDO-1的单克隆抗体。在一些实施方案中,免疫检查点抑制剂是针对IDO-1的人或人源化抗体。在一些实施方案中,免疫检查点抑制剂降低一种或多种免疫检查点蛋白如IDO-1的表达或活性。
在一些实施方案中,免疫检查点抑制剂是IDO-2的抑制剂。在一些实施方案中,免疫检查点抑制剂是针对IDO-2的抗体。在一些实施方案中,免疫检查点抑制剂是针对IDO-2的单克隆抗体。在一些实施方案中,免疫检查点抑制剂是针对IDO-2的人或人源化抗体。在一些实施方案中,免疫检查点抑制剂降低一种或多种免疫检查点蛋白如IDO-2的表达或活性。
在一些实施方案中,免疫检查点抑制剂是CEACAM1的抑制剂。在一些实施方案中,免疫检查点抑制剂是针对CEACAM1的抗体。在一些实施方案中,免疫检查点抑制剂是针对CEACAM1的单克隆抗体。在一些实施方案中,免疫检查点抑制剂是针对CEACAM1的人或人源化抗体。在一些实施方案中,免疫检查点抑制剂降低一种或多种免疫检查点蛋白如CEACAM1的表达或活性。
在一些实施方案中,免疫检查点抑制剂是BTLA的抑制剂。在一些实施方案中,免疫检查点抑制剂是针对BTLA的抗体。在一些实施方案中,免疫检查点抑制剂是针对BTLA的单克隆抗体。在一些实施方案中,免疫检查点抑制剂是针对BMA的人或人源化抗体。在一些实施方案中,免疫检查点抑制剂降低一种或多种免疫检查点蛋白如BTLA的表达或活性。
在一些实施方案中,免疫检查点抑制剂是TIM3的抑制剂。在一些实施方案中,免疫检查点抑制剂是针对TIM3的抗体。在一些实施方案中,免疫检查点抑制剂是针对TIM3的单克隆抗体。在一些实施方案中,免疫检查点抑制剂是针对TIM3的人或人源化抗体。在一些实施方案中,免疫检查点抑制剂降低一种或多种免疫检查点蛋白如TIM3的表达或活性。
在一些实施方案中,免疫检查点抑制剂是A2Ar的抑制剂。在一些实施方案中,免疫检查点抑制剂是针对A2Ar的抗体。在一些实施方案中,免疫检查点抑制剂是针对A2Ar的单克隆抗体。在一些实施方案中,免疫检查点抑制剂是针对A2Ar的人或人源化抗体。在一些实施方案中,免疫检查点抑制剂降低一种或多种免疫检查点蛋白如A2Ar的表达或活性。
在一些实施方案中,免疫检查点抑制剂是VISTA蛋白的抑制剂。在一些实施方案中,免疫检查点抑制剂是针对VISTA蛋白的抗体。在一些实施方案中,免疫检查点抑制剂是针对VISTA蛋白的单克隆抗体。在一些实施方案中,免疫检查点抑制剂是针对VISTA蛋白的人或人源化抗体。在一些实施方案中,免疫检查点抑制剂降低一种或多种免疫检查点蛋白如VISTA蛋白的表达或活性。
抗体靶标
在一些实施方案中,免疫缀合物的抗体能够结合选自以下的一种或多种靶标(例如,特异性结合选自以下的靶标):5T4、ABL、ABCF1、ACVR1、ACVR1B、ACVR2、ACVR2B、ACVRL1、ADORA2A、聚集蛋白聚糖、AGR2、AICDA、AIF1、AIGI、AKAP1、AKAP2、AMH、AMHR2、ANGPT1、ANGPT2、ANGPTL3、ANGPTL4、ANPEP、APC、APOC1、AR、芳香酶、ATX、AX1、AZGP1(锌-a-糖蛋白)、B7.1、B7.2、B7-H1、BAD、BAFF、BAG1、BAI1、BCR、BCL2、BCL6、BDNF、BLNK、BLR1(MDR15)、BIyS、BMP1、BMP2、BMP3B(GDFIO)、BMP4、BMP6、BMP8、BMPRTA、BMPR1B、BMPR2、BPAG1(网蛋白)、BRCA1、C19orflO(IL27w)、C3、C4A、C5、C5R1、CANT1、CAPRIN-1、CASP1、CASP4、CAV1、CCBP2(D6/JAB61)、CCLI(1-309)、CCLI1(嗜酸性粒细胞趋化因子(eotaxin))、CCL13(MCP-4)、CCL15(MIP-Id)、CCL16(HCC-4)、CCL17(TARC)、CCL18(PARC)、CCL19(MIP-3b)、CCL2(MCP-1)、MCAF、CCL20(MIP-3a)、CCL21(MEP-2)、SLC、exodus-2、CCL22(MDC/STC-1)、CCL23(MPIF-I)、CCL24(MPIF-2/嗜酸性粒细胞趋化因子-2)、CCL25(TECK)、CCL26(嗜酸性粒细胞趋化因子-3)、CCL27(CTACK/ILC)、CCL28、CCL3(MIP-Ia)、CCL4(MIPIb)、CCL5(RANTES)、CCL7(MCP-3)、CCL8(mcp-2)、CCNA1、CCNA2、CCND1、CCNE1、CCNE2、CCR1(CKR1/HM145)、CCR2(mcp-IRB/RA)、CCR3(CKR3/CMKBR3)、CCR4、CCR5(CMKBR5/ChemR13)、CCR6(CMKBR6/CKR-L3/STRL22/DRY6)、CCR7(CKR7/EBI1)、CCR8(CMKBR8/TERI/CKR-L1)、CCR9(GPR-9-6)、CCRL1(VSHK1)、CCRL2(L-CCR)、CD164、CD19、CDIC、CD2、CD20、CD21、CD200、CD-22、CD24、CD27、CD28、CD3、CD33、CD35、CD37、CD38、CD3E、CD3G、CD3Z、CD4、CD38、CD40、CD40L、CD44、CD45RB、CD47、CD52、CD69、CD72、CD74、CD79A、CD79B、CD8、CD80、CD81、CD83、CD86、CD137、CD152、CD274、CDH1(E-钙粘蛋白)、CDH1O、CDH12、CDH13、CDH18、CDH19、CDH2O、CDH5、CDH7、CDH8、CDH9、CDK2、CDK3、CDK4、CDK5、CDK6、CDK7、CDK9、CDKN1A(p21Wap1/Cip1)、CDKN1B(p27Kip1)、CDKN1C、CDKN2A(p16INK4a)、CDKN2B、CDKN2C、CDKN3、CEBPB、CERI、CHGA、CHGB、几丁质酶、CHST1O、CKLFSF2、CKLFSF3、CKLFSF4、CKLFSF5、CKLFSF6、CKLFSF7、CKLFSF8、CLDN3、CLDN7(封闭蛋白(claudin)-7)、CLDN18.2(封闭蛋白18.2)、CLN3、CLU(簇蛋白)、CMKLR1、CMKOR1(RDC1)、CNR1、COL18A1、COLIA1、COL4A3、COL6A1、CR2、Cripto、CRP、CSF1(M-CSF)、CSF2(GM-CSF)、CSF3(GCSF)、CTL8、CTNNB1(b-连环蛋白)、CTSB(组织蛋白酶B)、CX3CL1(SCYD1)、CX3CR1(V28)、CXCL1(GRO1)、CXCL1O(IP-IO)、CXCLI1(1-TAC/IP-9)、CXCL12(SDF1)、CXCL13、CXCL14、CXCL16、CXCL2(GRO2)、CXCL3(GRO3)、CXCL5(ENA-78/LIX)、CXCL6(GCP-2)、CXCL9(MIG)、CXCR3(GPR9/CKR-L2)、CXCR4、CXCR6(TYMSTR/STRL33/Bonzo)、CYB5、CYC1、CYSLTR1、DAB2IP、DES、DKFZp451J0118、DNCL1、DPP4、E2F1、Engel、Edge、Fennel、EFNA3、EFNB2、EGF、EGFR、ELAC2、ENG、Enola、ENO2、ENO3、EPHA1、EPHA2、EPHA3、EPHA4、EPHA5、EPHA6、EPHA7、EPHA8、EPHA9、EPRA10、EPHB1、EPHB2、EPHB3、EPHB4、EPHB5、EPHB6、EPHRIN-A1、EPHRIN-A2、EPHRINA3、EPHRIN-A4、EPHRIN-A5、EPHRIN-A6、EPHRIN-B1、EPHRIN-B2、EPHRIN-B3、EPHB4、EPG、ERBB2(Her-2)、EREG、ERK8、雌激素受体、Earl、ESR2、F3(TF)、FADD、法尼基转移酶、FasL、FASNf、FCER1A、FCER2、FCGR3A、FGF、FGF1(aFGF)、FGF10、FGF11、FGF12、FGF12B、FGF13、FGF14、FGF16、FGF17、FGF18、FGF19、FGF2(bFGF)、FGF20、FGF21、FGF22、FGF23、FGF3(int-2)、FGF4(HST)、FGF5、FGF6(HST-2)、FGF7(KGF)、FGF8、FGF9、FGFR3、FIGF(VEGFD)、FILI(EPSILON)、FBL1(ZETA)、FLJ12584、FLJ25530、FLRT1(纤连蛋白)、FLT1、FLT-3、FOS、FOSL1(FRA-1)、FY(DARC)、GABRP(GABAa)、GAGEB1、GAGEC1、GALNAC4S-6ST、GATA3、GD2、GDF5、GFI1、GGT1、GM-CSF、GNAS1、GNRH1、GPR2(CCR10)、GPR31、GPR44、GPR81(FKSG80)、GRCC1O(C1O)、GRP、GSN(凝溶胶蛋白)、GSTP1、HAVCR2、HDAC、HDAC4、HDAC5、HDAC7A、HDAC9、Hedgehog、HGF、HIF1A、HIP1、组胺和组胺受体、HLA-A、HLA-DRA、HLA-E、HM74、HMOXI、HSP90、HUMCYT2A、ICEBERG、ICOSL、ID2、IFN-a、IFNA1、IFNA2、IFNA4、IFNA5、EFNA6、BFNA7、IFNB1、IFNγ、IFNW1、IGBP1、IGF1、IGFIR、IGF2、IGFBP2、IGFBP3、IGFBP6、DL-1、ILIO、ILIORA、ILIORB、IL-1、IL1R1(CD121a)、IL1R2(CD121b)、IL-IRA、IL-2、IL2RA(CD25)、IL2RB(CD122)、IL2RG(CD132)、IL-4、IL-4R(CD123)、IL-5、IL5RA(CD125)、IL3RB(CD131)、IL-6、IL6RA、(CD126)、IR6RB(CD130)、IL-7、IL7RA(CD127)、IL-8、CXCR1(IL8RA)、CXCR2、(IL8RB/CD128)、IL-9、IL9R(CD129)、IL-10、IL10RA(CD210)、IL10RB(CDW210B)、IL-11、IL11RA、IL-12、IL-12A、IL-12B、IL-12RB1、IL-12RB2、IL-13、IL13RA1、IL13RA2、IL14、IL15、IL15RA、IL16、IL17、IL17A、IL17B、IL17C、IL17R、IL18、IL18BP、IL18R1、IL18RAP、IL19、ILIA、ILIB、ILIF10、ILIF5、IL1F6、ILIF7、IL1F8、DL1F9、ILIHYI、ILIR1、ILIR2、ILIRAP、ILIRAPLI、ILIRAPL2、ILIRL1、IL1RL2、ILIRN、IL2、IL20、IL20RA、IL21R、IL22、IL22R、IL22RA2、IL23、DL24、IL25、IL26、IL27、IL28A、IL28B、IL29、IL2RA、IL2RB、IL2RG、IL3、IL30、IL3RA、IL4、IL4、IL6ST(糖蛋白130)、ILK、INHA、INHBA、INSL3、INSL4、IRAK1、IRAK2、ITGA1、ITGA2、ITGA3、ITGA6(α6整合素)、ITGAV、ITGB3、ITGB4(β4整合素)、JAG1、JAK1、JAK3、JTB、JUN、K6HF、KAI1、KDR、KITLG、KLF5(GC BoxBP)、KLF6、KLK10、KLK12、KLK13、KLK14、KLK15、KLK3、KLK4、KLK5、KLK6、KLK9、KRT1、KRT19(角蛋白19)、KRT2A、KRTHB6(头发特异性II型角蛋白)、LAMA5、LEP(瘦素)、Lingo-p75、Lingo-Troy、LPS、LTA(TNF-b))、LTB、LTB4R(GPR16)、LTB4R2、LTBR、MACMARCKS、MAG或OMgp、MAP2K7(c-Jun)、MCP-1、MDK、MIB1、中期因子(midkine)、MIF、MISRII、MJP-2、MK、MKI67(Ki-67)、MMP2、MMP9、MS4A1、MSMB、MT3(金属硫连接素-UI)、mTOR、MTSS1、MUC1(粘蛋白)、MYC、MYD88、NCK2、神经蛋白聚糖(neurocan)、Nectin-4、NFKBI、NFKB2、NGFB(NGF)、NGFR、NgR-Lingo、NgRNogo66、(Nogo)、NgR-p75、NgR-Troy、NMEI(NM23A)、NOTCH、NOTCH1、NOX5、NPPB、NROB1、NROB2、NRID1、NR1D2、NR1H2、NR1H3、NR1H4、NR112、NR113、NR2C1、NR2C2、NR2E1、NR2E3、NR2F1、NR2F2、NR2F6、NR3C1、NR3C2、NR4A1、NR4A2、NR4A3、NR5A1、NR5A2、NR6A1、NRP1、NRP2、NT5E、NTN4、ODZI、OPRDI、P2RX7、PAP、PART1、PATE、PAWR、PCA3、PCDGF、PCNA、PDGFA、PDGFB、PDGFRA、PDGFRB、PECAMI、聚乙二醇天冬酰胺酶、PF4(CXCL4)、PGF、PGR、磷酸聚糖、PIAS2、PI3激酶、PIK3CG、PLAU(uPA)、PLG、PLXDCI、PKC、PKC-β、PPBP(CXCL7)、PPID、PR1、PRKCQ、PRKD1、PRL、PROC、PROK2、PSAP、PSCA、PTAFR、PTEN、PTGS2(COX-2)、PIN、RAC2(P21Rac2)、RANK、RANK配体、RARB、RGS1、RGS13、RGS3、RNFI1O(ZNF144)、Ron、ROBO2、RXR、S100A2、SCGB 1D2(亲脂蛋白B)、SCGB2A1(乳房珠蛋白2)、SCGB2A2(乳房珠蛋白1)、SCYE1(内皮单核细胞激活细胞因子)、SDF2、SERPENA1、SERPINA3、SERPINB5(maspin)、SERPINEI(PAI-I)、SERPINFI、SHIP-1、SHIP-2、SHB1、SHB2、SHBG、SfcAZ、SLC2A2、SLC33A1、SLC43A1、SLIT2、SPP1、SPRR1B(Spr1)、ST6GAL1、STAB1、STATE、STEAP、STEAP2、TB4R2、TBX21、TCP1O、TDGF1、TEK、TGFA、TGFB1、TGFB1I1、TGFB2、TGFB3、TGFBI、TGEBR1、TGFBR2、TGFBR3、THIL、THBS1(血小板反应蛋白-1)、THBS2、THBS4、THPO、TIE(Tie-1)、TIMP3、组织因子、TLR1、TLR2、TLR3、TLR4、TLR5、TLR6、TLR7、TLR8、TLR9、TLR10、TLR11、TNF、TNF-a、TNFAIP2(B94)、TNFAIP3、TNFRSF11A、TNFRSF1A、TNFRSF1B、TNFRSF21、TNFRSF5、TNFRSF6(Fas)、TNFRSF7、TNFRSF8、TNFRSF9、TNFSF1O(TRAIL)、TNFSF11(TRANCE)、TNFSF12(APO3L)、TNFSF13(April)、TNFSF13B、TNSF14(HVEM-L)、TNFRSF14(HVEM)、TNFSF15(VEGI)、TNFSF18、TNFSF4(OX40配体)、TNFSF5(CD40配体)。TNFSF6(FasL)、TNFSF7(CD27配体)、TNFSF8(CD30配体)、TNFSF9(4-1BB配体)、TOLLIP、Toll样受体、TOP2A(拓扑异构酶1ia)、TP53、TPM1、TPM2、TRADD、TRAF1、TRAF2、TRAF3、TRAF4、TRAF5、TRAF6、TRKA、TREM1、TREM2、TROP2、TRPC6、TSLP、TWEAK、酪氨酸酶、uPAR、VEGF、VEGFB、VEGFC、多功能蛋白聚糖、VHL C5、VLA-4、Wnt-1、XCL1(鼓室趋化素)、XCL2(SCM-Ib)、XCRI(GPR5/CCXCR1)、YYI、ZFPM2、CLEC4C(BDCA-2、DLEC、CD303、CLECSF7)、CLEC4D(MCL、CLECSF8)、CLEC4E(Mincle)、CLEC6A(Dectin-2)。CLEC5A(MDL-1、CLECSF5)、CLEC1B(CLEC-2)、CLEC9A(DNGR-1)、CLEC7A(Dectin-1)、PDGFRa、SLAMF7、GP6(GPVI)、LILRA1(CD85I)、LILRA2(CD85H、ILT1)、LILRA4(CD85G、ILT7)、LILRA5(CD85F、ILT11)、LILRA6(CD85b、ILT8)、NCR1(CD335、LY94、NKp46)、NCR3(CD335、LY94、NKp46)、NCR3(CD337、NKp30)、OSCAR、TARM1、CD300C、CD300E、CD300LB(CD300B)、CD300LD(CD300D)、KIR2DL4(CD158D)、KIR2DS、KLRC2(CD159C、NKG2C)、KLRK1(CD314、NKG2D)、NCR2(CD336、NKp44)、PILRB、SIGLEC1(CD169,SN)、SIGLEC14、SIGLEC15(CD33L3)、SIGLEC16、SIRPalpha、SIRPB1(CD172B)、TREM1(CD354)、TREM2和KLRF1(NKp80)。
在一些实施方案中,抗体结合FcR.γ偶联受体。在一些实施方案中,FcR.γ偶联受体选自由以下组成的组:GP6(GPVI)、LILRA1(CD85I)、LILRA2(CD85H、ILT1)、LILRA4(CD85G、ILT7)、LILRA5(CD85F、ILT11)、LILRA6(CD85b、ILT8)、NCR1(CD335、LY94、NKp46)、NCR3(CD335、LY94、NKp46)、NCR3(CD337、NKp30)、OSCAR和TARM1。
在一些实施方案中,抗体结合DAP12偶联受体。在一些实施方案中,DAP12偶联受体选自由以下组成的组:CD300C、CD300E、CD300LB(CD300B)、CD300LD(CD300D)、KIR2DL4(CD158D)、KIR2DS、KLRC2(CD159C、NKG2C)、KLRK1(CD314、NKG2D)、NCR2(CD336、NKp44)。PILRB、SIGLEC1(CD169、SN)、SIGLEC14、SIGLEC15(CD33L3)、SIGLEC16、SIRPB1(CD172B)、TREM1(CD354)和TREM2。
在一些实施方案中,抗体结合携带hemITAM的受体。在一些实施方案中,携带hemITAM的受体是KLRF1(NKp80)。
在一些实施方案中,抗体能够结合选自以下的一种或多种靶标:CLEC4C(BDCA-2、DLEC、CD303、CLECSF7)、CLEC4D(MCL、CLECSF8)、CLEC4E(Mincle)、CLEC6A(Dectin-2)、CLEC5A(MDL-1、CLECSF5)、CLEC1B(CLEC-2)、CLEC9A(DNGR-1)和CLEC7A(Dectin-1)。在一些实施方案中,抗体能够结合CLEC6A(Dectin-2)或CLEC5A。在一些实施方案中,抗体能够结合CLEC6A(Dectin-2)。
在一些实施方案中,抗体能够结合选自以下的一种或多种靶标(例如,特异性结合选自以下的靶标):ATP5I(Q06185)、OAT(P29758)、AIFM1(Q9Z0X1)、AOFA(Q64133)、MTDC(P18155)、CMC1(Q8BH59)、PREP(Q8K411)、YMEL1(O88967)、LPPRC(Q6PB66)、LONM(Q8CGK3)、ACON(Q99KI0)、ODO1(Q60597)、IDHP(P54071)、ALDH2(P47738)、ATPB(P56480)、AATM(P05202)、TMM93(Q9CQW0)、ERGI3(Q9CQE7)、RTN4(Q99P72)、CL041(Q8BQR4)、ERLN2(Q8BFZ9)、TERA(Q01853)、DAD1(P61804)、CALX(P35564)、CALU(O35887)、VAPA(Q9WV55)、MOGS(Q80UM7)、GANAB(Q8BHN3)、ERO1A(Q8R180)、UGGG1(Q6P5E4)、P4HA1(Q60715)、HYEP(Q9D379)、CALR(P14211)、AT2A2(O55143)、PDIA4(P08003)、PDIA1(P09103)、PDIA3(P27773)、PDIA6(Q922R8)、CLH(Q68FD5)、PPIB(P24369)、TCPG(P80318)、MOT4(P57787)、NICA(P57716)、BASI(P18572)、VAPA(Q9WV55)、ENV2(P11370)、VAT1(Q62465)、4F2(P10852)、ENOA(P17182)、ILK(O55222)、GPNMB(Q99P91)、ENV1(P10404)、ERO1A(Q8R180)、CLH(Q68FD5)、DSG1A(Q61495)、AT1A1(Q8VDN2)、HYOU1(Q9JKR6)、TRAP1(Q9CQN1)、GRP75(P38647)、ENPL(P08113)、CH60(P63038)和CH10(Q64433)。在前面的列表中,登录号在括号中示出。
在一些实施方案中,抗体结合选自CDH1、CD19、CD20、CD29、CD30、CD38、CD40、CD47、EpCAM、MUC1、MUC16、EGFR、Her2、SLAMF7和gp75的抗原。在一些实施方案中,抗原选自CD19、CD20、CD47、EpCAM、MUC1、MUC16、EGFR和HER2。在一些实施方案中,抗体结合选自Tn抗原和Thomsen-Friedenreich抗原的抗原。
在一些实施方案中,抗体或Fc融合蛋白选自:阿巴伏单抗(abagovomab)、阿巴西普(abatacept)(也称为)、阿昔单抗(abciximab)(也称为c7E3Fab)、阿达木单抗(adalimumab)(也称为)、阿德木单抗(adecatumumab)、阿仑单抗(alemtuzumab)(也称为MabCampath或Campath-1H)、阿妥莫单抗(altumomab)、阿非莫单抗(afelimomab)、马安那莫单抗(anatumomab mafenatox)、阿尼莫单抗(anetumumab)、安如珠单抗(anrukizumab)、阿泊珠单抗(apolizumab)、阿西莫单抗(arcitumomab)、阿塞珠单抗(aselizumab)、阿利珠单抗(atlizumab)、阿托木单抗(atorolimumab)、巴匹组单抗(bapineuzumab)、巴利昔单抗(basiliximab)(也称为)、巴维昔单抗(bavituximab)、贝妥莫单抗(bectumomab)(也称为LYMPH)、贝利木单抗(belimumab)(也称为)、柏替木单抗(bertilimumab)、贝索单抗(besilesomab)、贝伐珠单抗(bevacizumab)(也称为)、巴比西单抗(biciromab brallobarbital)、莫比伐珠单抗(bivatuzumabmertansine)、坎帕斯(campath)、康纳单抗(canakinumab)(也称为ACZ885)、莫坎妥珠单抗(cantuzumab mertansine)、卡罗单抗(capromab)(也称为)、卡妥索单抗(catumaxomab)(也称为)、西利珠单抗(cedelizumab)(也称为 )、培塞利珠单抗(certolizumab pegol)、西妥昔单抗(cetuximab)(也称为)、克立昔单抗(clenoliximab)、达西组单抗(dacetuzumab)、达昔单抗(dacliximab)、达克珠单抗(daclizumab)(也称为ZE)、地诺单抗(denosumab)(也称为AMG 162)、地莫单抗(detumomab)、阿托度单抗(dorlimomab aritox)、达匹利珠单抗(dorlixizumab)、度妥木单抗(duntumumab)、德里姆单抗(durimulumab)、德木鲁单抗(durmulumab)、依美昔单抗(ecromeximab)、依库珠单抗(eculizumab)(也称为)、埃巴单抗(edobacomab)、依决洛单抗(edrecolomab)(也称为Mab17-1A、)、依法珠单抗(efalizumab)(也称为)、依芬古单抗(efungumab)(也称为)、艾西莫单抗(elsilimomab)、培恩莫单抗(enlimomab pegol)、西依匹莫单抗(epitumomab cituxetan)、依法珠单抗(efalizumab)、依匹莫单抗(epitumomab)、依帕珠单抗(epratuzumab)、厄利珠单抗(erlizumab)、厄妥索单抗(ertumaxomab)(也称为)、依那西普(etanercept)(也称为)、埃达组单抗(etaracizumab)(也称为埃妥珠单抗(etaratuzumab)、)、艾韦单抗(exbivirumab)、法索单抗(fanolesomab)(也称为)、法拉莫单抗(faralimomab)、泛维珠单抗(felvizumab)、芳妥珠单抗(fontolizumab)(也称为)、加利昔单抗(galiximab)、更汀芦单抗(gantenerumab)、加维莫单抗(gavilimomab)(也称为)、奥吉妥珠单抗(gemtuzumab ozogamicin)(也称为)、戈利木单抗(golimumab)(也称为CNTO 148)、戈利昔单抗(gomiliximab)、伊巴组单抗(ibalizumab)(也称为TNX-355)、替伊莫单抗(ibritumomabtiuxetan)(也称为 )、伊戈伏单抗(igovomab)、英西单抗(imciromab)、英夫利昔单抗(infliximab)(也称为)、伊诺莫单抗(inolimomab)、奥英妥珠单抗(inotuzumab ozogamicin)、伊匹单抗(ipilimumab)(也称为MDX-010、MDX-101)、伊妥木单抗(iratumumab)、凯利昔单抗(keliximab)、拉贝妥珠单抗(labetuzumab)、来马索单抗(lemalesomab)、莱布利珠单抗(lebrilizumab)、乐德木单抗(lerdelimumab)、来沙木单抗(lexatumumab)(也称为HGS-ETR2、ETR2-ST01)、雷妥木单抗(lexitumumab)、利韦单抗(libivirumab)、林妥珠单抗(lintuzumab)、卢卡木单抗(lucatumumab)、鲁昔单抗(lumiliximab)、马帕木单抗(mapatumumab)(也称为HGSETR1、TRM-1)、马司莫单抗(maslimomab)、马妥珠单抗(matuzumab)(也称为EMD72000)、美泊利单抗(mepolizumab)(也称为 )、美替木单抗(metelimumab)、米拉组单抗(milatuzumab)、明瑞莫单抗(minretumomab)、米妥莫单抗(mitumomab)、莫罗木单抗(morolimumab)、莫维珠单抗(motavizwnab)(也称为)、莫罗单抗(muromonab)(也称为OKT3)、他那可单抗(nacolomab tafenatox)、埃托那普妥莫单抗(naptumomab estafenatox)、那他珠单抗(natalizumab)(也称为)、奈巴库单抗(nebacumab)、奈瑞莫单抗(nerelimomab)、尼妥珠单抗(nimotuzumab)(也称为THERACIM )、莫诺非莫单抗(nofetumomabmerpentan)(也称为)、奥克立珠单抗(ocrelizumab)、奥度莫单抗(odulimomab)、奥法木单抗(ofatumumab)、奥马珠单抗(omalizumab)(也称为)、奥戈伏单抗(oregovomab)(也称为OV)、奥昔珠单抗(otelixizumab)、帕吉昔单抗(pagibaximab)、帕利珠单抗(palivizumab)(也称为)、帕尼单抗(panitumumab)(也称为ABX-EGF、)、帕考珠单抗(pascolizumab)、派姆单抗(pemtumomab)(也称为)、帕妥珠单抗(也称为2C4、)、培克珠单抗(pexelizumab)、平妥莫单抗(pintumomab)、普立昔单抗(priliximab)、普托木单抗(pritumumab)、雷珠单抗(ranibizumab)(也称为)、雷昔库单抗(raxibacumab)、瑞加韦单抗(regavirumab)、瑞利珠单抗(reslizumab)、利妥昔单抗(rituximab)(也称为)、罗维珠单抗(rovelizumab)、卢利珠单抗(ruplizumab)、沙妥莫单抗(satumomab)、司韦单抗(sevirumab)、西罗珠单抗(sibrotuzumab)、西利珠单抗(siplizumab)(也称为MEDI-507)、索土珠单抗(sontuzumab)、司他芦单抗(stamulumab)(也称为MYO-029)、硫索单抗(sulesomab)(也称为)、替他珠单抗(tacatuzumab tetraxetan)、他度珠单抗(tadocizumab)、他利珠单抗(talizumab)、帕他莫单抗(taplitumomab paptox)、替非组单抗(tefibazumab)(也称为)、阿替莫单抗(telimomab aritox)、替奈昔单抗(teneliximab)、替利组单抗(teplizumab)、替西木单抗(ticilimumab)、托珠单抗(tocilizumab)(也称为)、托拉珠单抗(toralizumab)、托西莫单抗(tositumomab)、曲妥珠单抗(trastuzumab)(也称为 )、曲美木单抗(tremelimumab)(也称为CP-675,206)、西莫白介素单抗(tucotuzumab celmoleukin)、妥韦单抗(tuvirumab)、乌珠单抗(urtoxazumab)、乌司奴单抗(ustekinumab)(也称为CNTO 1275)、伐利昔单抗(vapaliximab)、维妥组单抗(veltuzumab)、维帕莫单抗(vepalimomab)、维西珠单抗(visilizumab)(也称为)、伏洛昔单抗(volociximab)(也称为M200)、伏妥莫单抗(votumumab)(也称为)、扎芦木单抗(zalutumumab)、扎木单抗(zanolimumab)(也称为HuMAX-CD4)、齐拉木单抗(ziralimumab)、阿佐莫单抗(zolimomabaritox)、达雷木单抗(daratumumab)、埃罗妥昔单抗(elotuxumab)、奥比托珠单抗(obintunzumab)、奥拉单抗(olaratumab)、维布妥昔单抗(brentuximab vedotin)、阿波西普(afibercept)、阿巴西普、贝拉西普(belatacept)、阿波西普、依那西普、罗米司亭(romiplostim)、SBT-040(序列在US2017/0158772中列出)。在一些实施方案中,抗体是利妥昔单抗。
在一个示例性实施方案中,本发明的免疫缀合物包含如下抗体构建体,所述抗体构建体包含特异性识别和结合PD-L1的抗原结合结构域。
程序性死亡配体1(PD-L1、分化簇274、CD274、B7-同源物1或B7-H1)属于B7蛋白超家族,并且是程序性细胞死亡蛋白1(PD-1、PDCD1、分化簇279或CD279)的配体。PD-L1还可以与B7.1(CD80)相互作用,并且这种相互作用被认为抑制T细胞启动。PD-L1/PD-1轴在抑制适应性免疫反应中发挥着重要作用。更具体地说,据信PD-L1与其受体PD-1的接合会递送抑制T细胞的激活和增殖的信号。与PD-L1结合并阻止配体与PD-1受体结合的剂防止这种免疫抑制,并且因此可以在需要时增强免疫反应,例如用于治疗癌症或感染。PD-L1/PD-1途径也有助于预防自身免疫,因此针对PD-L1的激动剂或递送免疫抑制有效负载的剂可能有助于治疗自身免疫性病症。
PD-L1抗体可以是内化的,如WO 2021/150701中所述并通过引用并入本文,或者PD-L1抗体可以是非内化的,如WO 2021/150702中所述并通过引用并入本文。
几种靶向PD-L1的抗体已被开发用于治疗癌症,包括阿特朱单抗(TECENTRIQTM)、度伐利尤单抗(IMFINZITM)和阿维鲁单抗(BAVENCIOTM)。然而,仍然需要新的PD-L1结合剂,包括以高亲和力结合PD-L1并有效阻止PD-L1/PD-1信号传导的剂,以及可以将治疗有效负载递送至表达PD-L1的细胞的剂。此外,需要新的PD-L1结合剂来治疗自身免疫性病症和感染。
在一个示例性实施方案中,本发明的免疫缀合物包含如下抗体构建体,所述抗体构建体包含特异性识别和结合HER2的抗原结合结构域。
在某些实施方案中,本发明的免疫缀合物包含抗HER2抗体。在本发明的一个实施方案中,本发明的免疫缀合物的抗HER2抗体包括人源化抗HER2抗体,例如huMAb4D5-1、huMAb4D5-2、huMAb4D5-3、huMAb4D5-4、huMAb4D5-5、huMAb4D5-6、huMAb4D5-7和huMAb4D5-8,如在US 5821337的表3中所述,该专利以引用的方式具体并入本文。这些抗体含有人框架区和与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,其以商品名HERCEPTINTM(Genentech,Inc.)商购可得。
曲妥珠单抗(CAS180288-69-1,huMAb4D5-8,rhuMAb HER2,Genentech)是一种重组DNA来源的IgG1κ单克隆抗体,其是鼠抗HER2抗体(4D5)的人源化形式,在基于细胞的测定中以高亲和力(Kd=5nM)与HER2的细胞外结构域选择性结合(US5677171;US 5821337;US 6054297;US 6165464;US 6339142;US 6407213;US 6639055;US6719971;US 6800738;US 7074404;Coussens等人,(1985)Science 230:1132-9;Slamon等人,(1989)Science 244:707-12;Slamon等人,(2001)New Engl.J.Med.344:783-792)。
在本发明的实施方案中,抗体构建体或抗原结合结构域包含曲妥珠单抗的CDR区。在本发明的实施方案中,抗HER2抗体还包含曲妥珠单抗的框架区。在本发明的实施方案中,抗HER2抗体还包含曲妥珠单抗的一个或两个可变区。
在本发明的另一实施方案中,本发明的免疫缀合物的抗HER2抗体包括人源化抗HER2抗体,例如人源化2C4,如US 7862817中所述。示例性人源化2C4抗体有帕妥珠单抗(CAS登记号380610-27-5)、PERJETATM(Genentech,Inc.)。帕妥珠单抗是一种HER二聚化抑制剂(HDI),并且用于抑制HER2与其它HER受体(如EGFR/HER1、HER2、HER3和HER4)形成活性异二聚体或同二聚体的能力。参见例如Harari和Yarden,Oncogene 19:6102-14(2000);Yarden和Sliwkowski.Nat Rev Mol Cell Biol 2:127-37(2001);Sliwkowski Nat Struct Biol10:158-9(2003);Cho等人,Nature 421:756-60(2003);和Malik等人,Pro Am Soc CancerRes 44:176-7(2003)。PERJETATM被批准用于治疗乳腺癌。
在本发明的实施方案中,抗体构建体或抗原结合结构域包含帕妥珠单抗的CDR区。在本发明的实施方案中,抗HER2抗体还包含帕妥珠单抗的框架区。在本发明的实施方案中,抗HER2抗体还包含帕妥珠单抗的一个或两个可变区。
在示例性实施方案中,本发明的免疫缀合物包含抗体构建体,所述抗体构建体包含特异性识别和结合CEA的抗原结合结构域。癌胚抗原相关的细胞粘附分子5(CEACAM5)也称为CD66e(分化簇66e),是癌胚抗原(CEA)基因家族的成员。
在示例性实施方案中,本发明的免疫缀合物包含抗体构建体,所述抗体构建体包含特异性识别和结合CEA的抗原结合结构域。
癌胚抗原(CEA、CD66e、CEACAM5)的表达升高已经牵涉到瘤形成的各个生物学方面,尤其是肿瘤细胞粘附、转移、细胞免疫机制的阻断以及具有抗凋亡功能。CEA也被用作许多癌症的血液标志物。拉贝珠单抗(CEA-CIDETM,Immunomedics,CAS注册号219649-07-7),也称为MN-14和hMN14,是一种人源化IgG1单克隆抗体并且已被研究用于治疗结直肠癌(Blumenthal,R.等人(2005)Cancer Immunology Immunotherapy 54(4):315-327)。与喜树碱类似物缀合的拉贝珠单抗(戈维替康拉贝珠单抗,IMMU-130)靶向癌胚抗原相关的细胞粘附分子5(CEACAM5)并且正被在患有复发或难治性转移性结直肠癌的患者中进行研究(Sharkey,R.等人,(2018),Molecular Cancer Therapeutics 17(1):196-203;Cardillo,T.等人(2018)Molecular Cancer Therapeutics 17(1):150-160)。
在一个示例性实施方案中,本发明的免疫缀合物包含如下抗体构建体,所述抗体构建体包含特异性识别和结合TROP2的抗原结合结构域。肿瘤相关钙信号转导因子2(TROP-2)是一种由TACSTD2基因编码的跨膜糖蛋白(Linnenbach AJ,等人(1993)Mol CellBiol.13(3):1507–15;Calabrese G,等人(2001)Cytogenet Cell Genet.92(1–2):164–5).。Trop2是一种细胞内钙信号转导因子,在许多癌症中差异表达,并向细胞发出自我更新、增殖、侵袭和存活的信号。Trop2被认为是干细胞标志物,并在许多正常组织中表达,但相比之下,它在许多癌症中过表达(Ohmachi T,等人,(2006)Clin.Cancer Res.,12(10),3057-3063;Muhlmann G,等人,(2009)J.Clin.Pathol.,62(2),152-158;Fong D,等人,(2008)Br.J.Cancer,99(8),1290-1295;Fong D,等人,(2008)Mod.Pathol.,21(2),186-191;Ning S,等人,(2013)Neurol.Sci.,34(10),1745-1750)。Trop2的过表达具有预后意义。已经提出了几种与Trop2相互作用的配体。Trop2通过不同的通路向细胞发出信号,并受到若干转录因子的复杂网络的转录调控。
人TROP2(TACSTD2:肿瘤相关钙信号转导因子2、GA733-1、EGP-1、M1S1;以下称为hTrop2)是由323个氨基酸残基组成的单次跨膜1型细胞膜蛋白。虽然先前已经提出参与对于人滋养层细胞和癌细胞来说常见的免疫抵抗的细胞膜蛋白的存在(Faulk W P,等人,Proc.Natl.Acad.Sci.75(4):1947-1951(1978)),但是在人绒毛膜癌细胞系中由针对细胞膜蛋白的单克隆抗体所识别的抗原分子被鉴定并指定为Trop2,作为在人滋养层细胞中表达的分子之一(Lipinski M,等人,Proc.Natl.Acad.Sci.78(8),5147-5150(1981))。这种分子也被指定为由小鼠单克隆抗体GA733识别的肿瘤抗原GA733-1(Linnenbach A J,等人,Proc.Natl.Acad.Sci.86(1),27-31(1989)),所述小鼠单克隆抗体GA733是通过用由小鼠单克隆抗体RS7-3G11识别的胃癌细胞系或上皮糖蛋白(EGP-1;Basu A,等人,Int.J.Cancer,62(4),472-479(1995))进行免疫获得的,所述小鼠单克隆抗体RS7-3G11是通过用非小细胞肺癌细胞进行免疫获得的。然而,在1995年,Trop2基因被克隆,并且所有这些分子被证实是相同的分子(Fornaro M,等人,Int.J.Cancer,62(5),610-618(1995))。hTrop2的DNA序列和氨基酸序列可在公共数据库上获得,并且可以例如以登录号NM_002353和NP_002344(NCBI)进行参考。
响应于此类暗示与癌症的关联的信息,迄今为止已经建立了多种抗hTROP2抗体并研究了它们的抗肿瘤作用。在这些抗体中,公开了例如在裸小鼠异种移植模型中本身表现出抗肿瘤活性的未缀合抗体(WO 2008/144891;WO 2011/145744;WO 2011/155579;WO2013/077458)以及与细胞毒性药物一起表现出作为ADC的抗肿瘤活性的抗体(WO 2003/074566;WO 2011/068845;WO 2013/068946;US 7999083)。然而,其活性的强度或覆盖范围仍然不足,并且对hTrop2作为治疗靶标的医学需求尚未得到满足。
癌细胞中的TROP2表达与耐药性相关。若干种策略靶向癌细胞上的Trop2,包括抗体、抗体融合蛋白、化学抑制剂、纳米颗粒等。使用这些各种治疗性治疗进行的体外研究和临床前研究已导致了对小鼠体外和体内的肿瘤细胞生长的显著抑制。临床研究已经探索了Trop2作为预后生物标志物和逆转耐药的治疗靶点两者的潜在应用。
戈沙妥珠单抗(Immunomedics,IMMU-132)是一种包含与拓扑异构酶抑制剂药物连接的Trop2定向抗体的抗体药物缀合物,适用于治疗已经接受过至少两次先前疗法的成年患者的转移性三阴性乳腺癌(mTNBC)。戈沙妥珠单抗中的Trop2抗体缀合至伊立替康的活性代谢产物SN-38(US2016/0297890;WO 2015/098099)。
在一个示例性实施方案中,本发明的免疫缀合物包含如下抗体构建体,所述抗体构建体包含特异性识别和结合Caprin-1的抗原结合结构域(Ellis JA,Luzio JP(1995)JBiol Chem.270(35):20717–23;Wang B,等人(2005)J Immunol.175(7):4274–82;SolomonS,等人(2007)Mol Cell Biol.27(6):2324–42)。Caprin-1也称为GPIAP1、GPIP137、GRIP137、M11S1、RNG105、p137GPI和细胞周期相关蛋白1。
细胞质激活/增殖相关蛋白-1(caprin-1)是一种参与细胞周期控制相关基因的调控的RNA结合蛋白。Caprin-1选择性地结合c-Myc和cyclin D2 mRNA,这加速细胞从G1期进展到S期,增强细胞活力并促进细胞生长,表明它可能在肿瘤发生中发挥重要作用(Wang B,等人(2005)J Immunol.175:4274–4282)。Caprin-1单独作用或与其他RNA结合蛋白(例如RasGAP SH3结构域结合蛋白1和脆性X智力迟钝蛋白)组合作用。在肿瘤发生过程中,caprin-1主要通过激活细胞增殖和上调免疫检查点蛋白的表达发挥作用。通过应激颗粒的形成,caprin-1还参与肿瘤细胞适应不利条件的过程,从而导致放疗和化疗抗性。鉴于其在各种临床恶性肿瘤中的作用,caprin-1有潜力用作生物标志物和开发新型治疗剂的靶标(Yang,Z-S,等人(2019)Oncology Letters18:15-21)。
已经描述了用于治疗和检测的靶向caprin-1的抗体(WO 2011/096519;WO 2013/125654;WO 2013/125636;WO 2013/125640;WO 2013/125630;WO 2013/018889;WO 2013/018891;WO 2013/018883;WO 2013/018892;WO 2014/014082;WO 2014/014086;WO 2015/020212;WO 2018/079740)。
在一个示例性实施方案中,本发明的免疫缀合物包含如下抗体构建体,所述抗体构建体包含特异性识别和结合密封蛋白-1(Claudin-1)的抗原结合结构域。
密封蛋白-1是位于细胞与细胞紧密连接处的跨膜蛋白家族密封蛋白的成员,并且它作为HCV进入肝细胞的共受体(Kniesel U,等人(2000).Cell.Mol.Neurobiol.20(1):57–76;Furuse M,等人(1998).J.Cell Biol.141(7):1539–50;Swisshelm K,等人(2005)Adv.Drug Deliv.Rev.57(6):919–28)。密封蛋白1也称为衰老相关上皮膜蛋白、衰老相关上皮膜蛋白1、CLDN1、CLD1、ILVASC、SEMP1。
密封蛋白在管腔上皮片层中含量丰富,在那里它们维持上皮细胞极性。密封蛋白-1在大多数组织中表达,如膀胱、输卵管、肝脏、胰腺、前列腺和皮肤。
在一个示例性实施方案中,本发明的免疫缀合物包含如下抗体构建体,所述抗体构建体包含特异性识别和结合连接蛋白-4(Nectin-4)的抗原结合结构域。
连接蛋白是参与钙依赖性细胞粘附的细胞粘附分子的蛋白质家族(Takai Y.等人(2003)Cancer Science 94(8):655-67;Fuchs,A.等人(2006)Seminars in CancerBiology 16(5):359-366;Miyoshi J.等人(2007)American journal of nephrology 27(6):590-604)。连接蛋白在许多不同组织的细胞之间的结合中发挥着重要作用,包括上皮细胞的中间连接或神经细胞的化学突触。
不对称双苯并咪唑佐剂化合物
本发明的免疫缀合物包含不对称双苯并咪唑佐剂部分,其中一个苯并咪唑基团的N-咪唑通过系链(tether)基团连接至第二苯并咪唑基团的O-苯氧基。系链基团是具有任选的氧的烷基、烯基或炔基。本文所述的不对称双苯并咪唑佐剂部分是引发免疫反应的化合物(即,免疫刺激剂)。一般地,本文所述的佐剂部分是STING激动剂。
某些酰胺基苯并咪唑化合物被证明是具有全身活性的STING受体激动剂(Ramanjulu,J.M.等人(2018)Nature 564:439–443;Barber,G.N.(2015)Nature RevImmunol 15:760–770;US2019/0300513)。
STING是一种二聚体结构,具有大且对称的结合袋。表1的双苯并咪唑化合物在与靶向抗体缀合时被设计为靶向并结合STING的结合袋的开放构象。与小分子激动剂的结合通常会诱导STING蛋白的闭合构象。这引入了接头(特别在“不可切割的”情况下)会干扰结合和激活的风险。据报道,双苯并咪唑通过开放构象结合和激活,我们预测这将更适合接头的连接(Ramanjulu,J.M.等人(2018)Nature564:439–443;Barber,G.N.(2015)Nature RevImmunol 15:760–770)。
表1示出已被制备、通过nmr和质谱被表征,并在生化测定中被测试了与STING的结合的示例性不对称双苯并咪唑化合物(BBI)。IC50值通过根据实施例202的HTRF结合测定来测量。
表1.不对称双苯并咪唑化合物(BBI)
双苯并咪唑接头化合物
本发明的免疫缀合物是通过将抗体与不对称双苯并咪唑接头(BBI-L)化合物缀合来制备的。双苯并咪唑接头化合物包含STING激动剂,即共价连接至接头单元(L)的双苯并咪唑(BBI)部分。接头单元包含影响免疫缀合物的稳定性、渗透性、溶解度及其它药代动力学、安全性和功效特性的官能团和亚基。接头单元包括反应性官能团,其与抗体的反应性官能团反应,即缀合。例如,抗体的亲核基团如赖氨酸侧链氨基与BBI-接头化合物的亲电反应性官能团反应,形成免疫缀合物。还有,例如,抗体的半胱氨酸硫醇与BBI-接头化合物的马来酰亚胺或溴乙酰胺基团反应形成免疫缀合物。
本发明的免疫缀合物的设计考虑包括:(1)防止双苯并咪唑(BBI)部分在体内循环期间过早释放,以及(2)确保BBI部分的生物活性形式在所需作用位点以足够的速率释放。免疫缀合物的复杂结构及其功能特性需要仔细设计和选择分子的每个组分,包括抗体、缀合位点、接头结构和双苯并咪唑化合物。接头决定佐剂释放的机制和速率。
一般而言,接头单元(L)可以是可切割的或不可切割的。可切割的接头单元可以包括作为某些蛋白酶(例如组织蛋白酶)的底物的肽序列,这些蛋白酶识别并切割肽接头单元,从而将STING激动剂与抗体分离(Caculitan NG,等人(2017)Cancer Res.77(24):7027-7037)。
可切割的接头单元可能包括不稳定的官能团,例如酸敏感的二硫基团(Kellogg,BA等人(2011)Bioconjugate Chem.22,717-727;Ricart,A.D.等人(2011)Clin.CancerRes.17,6417-6427;Pillow,T.,等人(2017)Chem.Sci.8,366-370;Zhang D,等人(2016)ACSMed Chem Lett.7(11):988-993)。
在一些实施方案中,接头在生理条件下是不可切割的。本文所用的术语“生理条件”是指20-40摄氏度的温度范围、大气压(即1atm)、约6至约8的pH、以及一种或多种生理酶、蛋白酶、酸和碱。免疫缀合物中抗体和STING激动剂之间的不可切割接头的优点之一是最大限度地减少过早的有效负载释放和相应的毒性。STING是一种广泛表达的受体,因此是一个特别相关的考虑因素。
在一个实施方案中,本发明包括细胞结合剂和免疫刺激部分之间的肽连接单元,即L或接头,其包含基于可以被蛋白酶选择性切割的特定氨基酸残基的线性序列的肽基,所述蛋白酶例如组织蛋白酶、肿瘤相关的弹性蛋白酶或具有蛋白酶样或弹性蛋白酶样活性的酶。肽基可以是约两个至约十二个氨基酸。肽接头内的键的酶切割释放出活性形式的免疫刺激部分。这导致根据本发明的缀合物的组织特异性的增加,并因此导致根据本发明的缀合物在其他组织类型中的毒性的额外降低。
接头为生物培养基(例如培养基或血清)中的免疫缀合物提供足够的稳定性,同时由于其特定的酶促或水解切割性并释放免疫刺激部分(即“有效负载”),在肿瘤组织内提供所需的细胞内作用。
蛋白酶、组织蛋白酶或弹性蛋白酶的酶活性可以在生理条件下催化免疫缀合物的共价键的切割。酶活性是与肿瘤组织相关的细胞的表达产物。作用于靶向肽的切割位点上的酶活性将免疫缀合物转化为不含靶向肽和连接基团的活性免疫刺激药物。切割位点可以被酶特异性识别。组织蛋白酶或弹性蛋白酶可以催化特定肽的C端氨基酸残基和免疫缀合物的免疫刺激部分之间的特定肽键的切割。
在一个实施方案中,本发明包括细胞结合剂和免疫刺激部分之间的连接单元,即L或接头,其包含葡糖醛酸酶(Jeffrey SC,等人(2006)Bioconjug Chem.17(3):831-40)或硫酸酯酶(Bargh JD,等人(2020)Chem Sci.11(9):2375-2380)切割的底物。特别地,L可包含选自下式的Gluc单元:
本发明的免疫缀合物的特异性切割利用免疫系统的肿瘤浸润细胞和白细胞分泌的酶的存在,以促进抗癌药物在肿瘤部位处的激活。
适用于BBI-接头化合物的反应性亲电反应性官能团(式II中的Q)包括但不限于N-羟基琥珀酰亚胺(NHS)酯和N-羟基磺基琥珀酰亚胺(磺基-NHS)酯(胺反应性);碳二亚胺(胺和羧基反应性);羟甲基膦(胺反应性);马来酰亚胺(硫醇反应性);卤代乙酰胺如N-碘乙酰胺(硫醇反应性);芳基叠氮化物(伯胺反应性);氟化芳基叠氮化物(经由碳-氢(C-H)插入而为反应性的);五氟苯基(PFP)酯(胺反应性);四氟苯基(TFP)和磺基四氟苯基(STP)酯(胺反应性);亚氨酸酯(胺反应性);异氰酸酯(羟基反应性);乙烯基砜(硫醇、胺和羟基反应性);吡啶基二硫化物(硫醇反应性);和二苯甲酮衍生物(经由C-H键插入而为反应性的)。另外的试剂包括但不限于在Hermanson,Bioconjugate Techniques第2版,Academic Press,2008中描述的那些。
本发明为免疫缀合物的设计、制备和使用方面的限制和挑战提供了解决方案。一些接头(例如包含肽单元和蛋白酶底物的接头)可能在血流中不稳定,从而在于靶细胞中内化之前释放出不可接受量的佐剂/药物(Khot,A.等人,(2015)Bioanalysis 7(13):1633–1648)。其它接头可提供在血流中的稳定性,但细胞内释放的有效性可能会受到负面影响。提供所需细胞内释放的接头通常在血流中稳定性差。或者说,血流稳定性和细胞内释放通常是逆相关的。此外,在标准缀合过程中,抗体上加载的佐剂/药物部分的量(即载药量)、缀合反应中形成的聚集物的量和可以获得的最终纯化缀合物的产量是相互关联的。例如,聚集物形成通常与同抗体缀合的佐剂/药物部分及其衍生物的当量数正相关。在高载药量的情况下,必须去除所形成的聚集体以用于治疗应用。因此,载药量介导的聚集物形成会降低免疫缀合物产率,并且可能使过程成比例放大变得困难。
示例性实施方案包括STING激动剂,即式II的双苯并咪唑-接头化合物:
其中,
Xa和Xb独立地选自五元杂芳基,其任选地被R5取代;
R1选自由以下组成的组:H、F、Cl、Br、I、-CN、-OH、-O-(C1-C6烷基)和R5;
R2a和R2b独立地选自-C(=O)N(R6)2和R5;
R3选自由以下组成的组:-(C1-C6烷基二基)-、-(C1-C3烷基二基)-O-(C1-C3烷基二基)-、-(C1-C6烷基二基)-O-、-(C1-C3烷基二基)-O-(C1-C3烷基二基)-O-、-(C2-C6烯基二基)-、-(C2-C6烯基二基)-O-、-(C2-C6炔基二基)-、-(C2-C6炔基二基)-O-、-(C1-C6烷基二基)-N(R5)C(=O)-、-(C1-C6烷基二基)-N(R5)S(O)2-、-(C1-C6烷基二基)-N(R5)C(=O)-(C1-C6烷基二基)-、-(C1-C6烷基二基)-N(R5)S(O)2-(C1-C6烷基二基)-、-(C1-C6烷基二基)-N(R6)C(=O)-、-(C1-C6烷基二基)-N(R6)S(O)2-、-(C1-C6烷基二基)-N(R6)C(=O)-(C1-C6烷基二基)-、和-(C1-C6烷基二基)-N(R6)S(O)2-(C1-C6烷基二基)-,其中烷基二基、烯基二基和炔基二基任选地被一个或多个选自以下的基团取代:F、Cl、-OH、-OCH3、-OCH2CH3、-OCH2CH2OCH3、-OCH2CH2OH、-OCH2CH2N(CH3)2、和R5;
其中Xa、Xb、R1、R2a、R2b和R3中的一个被R5取代;
R4选自由以下组成的组:H、C1-C6烷基、C2-C6烯基和C2-C6炔基,其任选地被一个或多个选自以下的基团取代:F、Cl、-OH、-OCH3、-OCH2CH3、-OCH2CH2OCH3、-OCH2CH2OH、-OCH2CH2N(CH3)2;
R5选自由以下组成的组:
-(C1-C12烷基二基)-L;
-(C1-C12烷基二基)-N(R6)-L;
-(C1-C12烷基二基)-O-L;
-(C1-C12烷基二基)-(C2-C20杂环基二基)-L;
-O-(C1-C12烷基二基)-L;
-O-(C1-C12烷基二基)-N(R6)-L;
-O-(C1-C12烷基二基)-O-L;
-O-(C1-C12烷基二基)-(C2-C20杂环基二基)-L;
-O-(C1-C12烷基二基)-(C2-C20杂环基二基)-N(R6)-L;
-OC(=O)N(R6)-L;
-OC(=O)N(R6)-(C1-C12烷基二基)-N(R6)-L;
-N(R6)-L;
-N(R6)-(C1-C12烷基二基)-L;
-N(R6)-(C1-C12烷基二基)-N(R6)-L;
-N(R6)-(C1-C12烷基二基)-O-L;
-N(R6)-(C1-C12烷基二基)-(C2-C20杂环基二基)-L;
-C(=O)N(R6)-L;
-C(=O)N(R6)-(C1-C12烷基二基)-L;
-C(=O)N(R6)-(C1-C12烷基二基)-N(R6)-L;
-C(=O)N(R6)-(C1-C12烷基二基)-O-L;
-(C2-C20杂环基二基)-L;
-S(=O)2-(C2-C20杂环基二基)-L;以及
-S(=O)2-(C2-C20杂环基二基)-(C1-C12烷基二基)-N(R6)-L;
R6独立地为H或C1-C6烷基;
L是选自由以下组成的组的接头:
Q-C(=O)-PEG-;
Q-C(=O)-PEG-Gluc-R7;-
Q-C(=O)-PEG-O-;
Q-C(=O)-PEG-O-C(=O)-;
Q-C(=O)-PEG-C(=O)-;
Q-C(=O)-PEG-C(=O)-PEP-;
Q-C(=O)-PEG-N(R6)-;
Q-C(=O)-PEG-N(R6)-C(=O)-;
Q-C(=O)-PEG-N(R6)-PEG-C(=O)-PEP-;
Q-C(=O)-PEG-N+(R6)2-PEG-C(=O)-PEP-;
Q-C(=O)-PEG-C(=O)-PEP-N(R6)-(C1-C12烷基二基)-;
Q-C(=O)-PEG-C(=O)-PEP-N(R6)-(C1-C12烷基二基)N(R6)C(=O)-(C2-C5单杂环基二基)-;
Q-C(=O)-PEG-SS-(C1-C12烷基二基)-OC(=O)-;
Q-C(=O)-PEG-SS-(C1-C12烷基二基)-C(=O)-;
Q-C(=O)-(C1-C12烷基二基)-C(=O)-PEP-;
Q-C(=O)-(C1-C12烷基二基)-C(=O)-PEP-N(R6)-(C1-C12烷基二基)-;
Q-C(=O)-(C1-C12烷基二基)-C(=O)-PEP-N(R6)-(C1-C12烷基二基)-N(R5)-C(=O);
Q-C(=O)-(C1-C12烷基二基)-C(=O)-PEP-N(R6)-(C1-C12烷基二基)-N(R6)C(=O)-(C2-C5单杂环基二基)-;
Q-(CH2)m-C(=O)N(R6)-PEG-;
Q-(CH2)m-C(=O)N(R6)-PEG-Gluc-R7-;
Q-(CH2)m-C(=O)N(R6)-PEG-O-;
Q-(CH2)m-C(=O)N(R6)-PEG-O-C(=O)-;
Q-(CH2)m-C(=O)N(R6)-PEG-C(=O)-;
Q-(CH2)m-C(=O)N(R6)-PEG-N(R5)-;
Q-(CH2)m-C(=O)N(R6)-PEG-N(R5)-C(=O)-;
Q-(CH2)m-C(=O)N(R6)-PEG-C(=O)-PEP-;
Q-(CH2)m-C(=O)N(R6)-PEG-SS-(C1-C12烷基二基)-OC(=O)-;
Q-(CH2)m-C(=O)-PEP-N(R6)-(C1-C12烷基二基)-;
Q-(CH2)m-C(=O)-PEP-N(R6)-(C1-C12烷基二基)N(R6)C(=O)-;和
Q-(CH2)m-C(=O)-PEP-N(R6)-(C1-C12烷基二基)N(R6)C(=O)-(C2-C5单杂环基二基)-;
PEG具有下式:-(CH2CH2O)n-(CH2)m-;m是1至5的整数,且n是2至50的整数;
Gluc具有下式:
PEP具有下式:
其中AA独立地选自天然或非天然氨基酸侧链,或者AA中的一者或多者和相邻的氮原子形成五元环脯氨酸氨基酸,且波浪线指示连接点;
Cyc选自C6-C20芳基二基和C1-C20杂芳基二基,其任选地被一个或多个选自F、Cl、NO2、-OH、-OCH3和具有如下结构的葡糖醛酸的基团取代:
R7选自由-CH(R8)O-、-CH2-、-CH2N(R8)-和-CH(R8)O-C(=O)-组成的组,其中R8选自H、C1-C6烷基、C(=O)-C1-C6烷基和-C(=O)N(R9)2,其中R9独立地选自由H、C1-C12烷基和-(CH2CH2O)n-(CH2)m-OH组成的组,其中m是1至5的整数,且n是2至50的整数,或者两个R9基团一起形成5或6元杂环基环;
y是2至12的整数;
z是0或1;
Q选自由以下组成的组:N-羟基琥珀酰亚胺基、N-羟基磺基琥珀酰亚胺基、马来酰亚胺和被一个或多个独立地选自F、Cl、NO2和SO3 -的基团取代的苯氧基;且
烷基、烷基二基、烯基、烯基二基、炔基、炔基二基、芳基、芳基二基、碳环基、碳环基二基、杂环基、杂环基二基、杂芳基和杂芳基二基独立且任选被一个或多个独立地选自以下的基团取代:F、Cl、Br、I、-CN、-CH3、-CH2CH3、-CH=CH2、-C≡CH、-C≡CCH3、-CH2CH2CH3、-CH(CH3)2、-CH2CH(CH3)2、-CH2OH、-CH2OCH3、-CH2CH2OH、-C(CH3)2OH、-CH(OH)CH(CH3)2、-C(CH3)2CH2OH、-CH2CH2SO2CH3、-CH2OP(O)(OH)2、-CH2F、-CHF2、-CF3、-CH2CF3、-CH2CHF2、-CH(CH3)CN、-C(CH3)2CN、-CH2CN、-CH2NH2、-CH2NHSO2CH3、-CH2NHCH3、-CH2N(CH3)2、-CO2H、-COCH3、-CO2CH3、-CO2C(CH3)3、-COCH(OH)CH3、-CONH2、-CONHCH3、-CON(CH3)2、-C(CH3)2CONH2、-NH2、-NHCH3、-N(CH3)2、-NHCOCH3、-N(CH3)COCH3、-NHS(O)2CH3、-N(CH3)C(CH3)2CONH2、-N(CH3)CH2CH2S(O)2CH3、-NHC(=NH)H、-NHC(=NH)CH3、-NHC(=NH)NH2、-NHC(=O)NH2、-NO2、=O、-OH、-OCH3、-OCH2CH3、-OCH2CH2OCH3、-OCH2CH2OH、-OCH2CH2N(CH3)2、-O(CH2CH2O)n-(CH2)mCO2H、-O(CH2CH2O)nH、-OCH2F、-OCHF2、-OCF3、-OP(O)(OH)2、-S(O)2N(CH3)2、-SCH3、-S(O)2CH3和-S(O)3H。
式II的双苯并咪唑接头化合物的示例性实施方案包括其中Q选自:
式II的双苯并咪唑接头化合物的示例性实施方案包括其中Q是被一个或多个独立地选自F、Cl、NO2和SO3 -的基团取代的苯氧基。
式II的双苯并咪唑接头化合物的示例性实施方案包括其中Q是2,3,5,6-四氟苯氧基。
式II的双苯并咪唑接头化合物的示例性实施方案包括其中Q是2,3,5,6-四氟-4-磺酸根基-苯氧基。
式II的双苯并咪唑接头化合物的示例性实施方案包括其中Q是马来酰亚胺。
式II的双苯并咪唑接头化合物的示例性实施方案包括其中L选自以下结构:
其中波浪线指示与R5的连接。
表2中示出了不对称双苯并咪唑(STING激动剂)-接头中间体化合物(BBI-L)的示例性实施方案。每种STING激动剂-接头中间体化合物均被制备并且通过nmr,质谱法进行了表征,并且被证明具有所指示的结构和质量。表2的STING激动剂-接头中间体化合物可以证明STING激动剂选择性的意外和出乎意料的特性,其可以预测当缀合至抗体时治疗癌症和其他病症的有用治疗活性。
表2.双苯并咪唑-接头(BBI-L)式II化合物
免疫缀合物
本发明的免疫缀合物诱导免疫效应细胞如髓样细胞以及表达STING的肿瘤细胞本身的靶标特异性激活。肿瘤靶向带来特异性,最大限度地减少脱靶STING激活,并且免疫缀合物使吞噬作用不仅增加效应细胞的激活,还增加免疫复合物摄取以及随后的肿瘤抗原加工和呈递。
免疫缀合物的示例性实施方案包含通过接头共价连接到一种或多种STING激动剂不对称双苯并咪唑(BBI)部分的抗体,并且具有式I:
Ab-[L-D]p I
或其药学上可接受的盐,
其中:
Ab是抗体;
p是1至8的整数;
D是具有下式的STING激动剂部分:
其中,
Xa和Xb独立地选自五元杂芳基,其任选地被R5取代;
R1选自由以下组成的组:H、F、Cl、Br、I、-CN、-OH、-O-(C1-C6烷基)和R5;
R2a和R2b独立地选自-C(=O)N(R6)2和R5;
R3选自由以下组成的组:-(C1-C6烷基二基)-、-(C1-C3烷基二基)-O-(C1-C3烷基二基)-、-(C1-C6烷基二基)-O-、-(C1-C3烷基二基)-O-(C1-C3烷基二基)-O-、-(C2-C6烯基二基)-、-(C2-C6烯基二基)-O-、-(C2-C6炔基二基)-、-(C2-C6炔基二基)-O-、-(C1-C6烷基二基)-N(R5)C(=O)-、-(C1-C6烷基二基)-N(R5)S(O)2-、-(C1-C6烷基二基)-N(R5)C(=O)-(C1-C6烷基二基)-、-(C1-C6烷基二基)-N(R5)S(O)2-(C1-C6烷基二基)-、-(C1-C6烷基二基)-N(R6)C(=O)-、-(C1-C6烷基二基)-N(R6)S(O)2-、-(C1-C6烷基二基)-N(R6)C(=O)-(C1-C6烷基二基)-、和-(C1-C6烷基二基)-N(R6)S(O)2-(C1-C6烷基二基)-,其中烷基二基、烯基二基和炔基二基任选地被一个或多个选自以下的基团取代:F、Cl、-OH、-OCH3、-OCH2CH3、-OCH2CH2OCH3、-OCH2CH2OH、-OCH2CH2N(CH3)2、和R5;
其中Xa、Xb、R1、R2a、R2b和R3中的一个被R5取代;
R4选自由以下组成的组:H、C1-C6烷基、C2-C6烯基和C2-C6炔基,其任选地被一个或多个选自以下的基团取代:F、Cl、-OH、-OCH3、-OCH2CH3、-OCH2CH2OCH3、-OCH2CH2OH、-OCH2CH2N(CH3)2;
R5选自由以下组成的组:
-(C1-C12烷基二基)-*;
-(C1-C12烷基二基)-N(R6)-*;
-(C1-C12烷基二基)-O-*;
-(C1-C12烷基二基)-(C2-C20杂环基二基)-*;
-O-(C1-C12烷基二基)-*;
-O-(C1-C12烷基二基)-N(R6)-*;
-O-(C1-C12烷基二基)-O-*;
-O-(C1-C12烷基二基)-(C2-C20杂环基二基)-*;
-O-(C1-C12烷基二基)-(C2-C20杂环基二基)-N(R6)-*;
-OC(=O)N(R6)-*;
-OC(=O)N(R6)-(C1-C12烷基二基)-N(R6)-*;
-N(R6)-*;
-N(R6)-(C1-C12烷基二基)-*;
-N(R6)-(C1-C12烷基二基)-N(R6)-*;
-N(R6)-(C1-C12烷基二基)-O-*;
-N(R6)-(C1-C12烷基二基)-(C2-C20杂环基二基)-*;
-C(=O)N(R6)-*;
-C(=O)N(R6)-(C1-C12烷基二基)-*;
-C(=O)N(R6)-(C1-C12烷基二基)-N(R6)-*;
-C(=O)N(R6)-(C1-C12烷基二基)-O-*;
-(C2-C20杂环基二基)-*;
-S(=O)2-(C2-C20杂环基二基)-*;以及
-S(=O)2-(C2-C20杂环基二基)-(C1-C12烷基二基)-N(R6)-*;
其中星号*表示L的连接点;
R6独立地为H或C1-C6烷基;
L是选自由以下组成的组的接头:
-C(=O)-PEG-;
-C(=O)-PEG-C(=O)N(R6)-(C1-C12烷基二基)-C(=O)-Gluc-;
-C(=O)-PEG-O-;
-C(=O)-PEG-O-C(=O)-;
-C(=O)-PEG-C(=O)-;
-C(=O)-PEG-C(=O)-PEP-;
-C(=O)-PEG-N(R6)-;
-C(=O)-PEG-N(R6)-C(=O)-;
-C(=O)-PEG-N(R6)-PEG-C(=O)-PEP-;
-C(=O)-PEG-N+(R6)2-PEG-C(=O)-PEP-;
-C(=O)-PEG-C(=O)-PEP-N(R6)-(C1-C12烷基二基)-;
-C(=O)-PEG-C(=O)-PEP-N(R6)-(C1-C12烷基二基)N(R6)C(=O)-(C2-C5单杂环基二基)-;
-C(=O)-PEG-SS-(C1-C12烷基二基)-OC(=O)-;
-C(=O)-PEG-SS-(C1-C12烷基二基)-C(=O)-;
-C(=O)-(C1-C12烷基二基)-C(=O)-PEP-;
-C(=O)-(C1-C12烷基二基)-C(=O)-PEP-N(R6)-(C1-C12烷基二基)-;
-C(=O)-(C1-C12烷基二基)-C(=O)-PEP-N(R6)-(C1-C12烷基二基)-N(R5)-C(=O);
-C(=O)-(C1-C12烷基二基)-C(=O)-PEP-N(R6)-(C1-C12烷基二基)-N(R6)C(=O)-(C2-C5单杂环基二基)-;
-琥珀酰亚胺基-(CH2)m-C(=O)N(R6)-PEG-;
-琥珀酰亚胺基-(CH2)m-C(=O)N(R6)-PEG-C(=O)N(R6)-(C1-C12烷基二基)-C(=O)-Gluc-;
-琥珀酰亚胺基-(CH2)m-C(=O)N(R6)-PEG-O-;
-琥珀酰亚胺基-(CH2)m-C(=O)N(R6)-PEG-O-C(=O)-;
-琥珀酰亚胺基-(CH2)m-C(=O)N(R6)-PEG-C(=O)-;
-琥珀酰亚胺基-(CH2)m-C(=O)N(R6)-PEG-N(R5)-;
-琥珀酰亚胺基-(CH2)m-C(=O)N(R6)-PEG-N(R5)-C(=O)-;
-琥珀酰亚胺基-(CH2)m-C(=O)N(R6)-PEG-C(=O)-PEP-;
-琥珀酰亚胺基-(CH2)m-C(=O)N(R6)-PEG-SS-(C1-C12烷基二基)-OC(=O)-;
-琥珀酰亚胺基-(CH2)m-C(=O)-PEP-N(R6)-(C1-C12烷基二基)-;
-琥珀酰亚胺基-(CH2)m-C(=O)-PEP-N(R6)-(C1-C12烷基二基)N(R6)C(=O)-;和
-琥珀酰亚胺基-(CH2)m-C(=O)-PEP-N(R6)-(C1-C12烷基二基)N(R6)C(=O)-(C2-C5单杂环基二基)-;
PEG具有下式:-(CH2CH2O)n-(CH2)m-;m是1至5的整数,且n是2至50的整数;
Gluc具有下式:
PEP具有下式:
其中AA独立地选自天然或非天然氨基酸侧链,或者AA中的一者或多者和相邻的氮原子形成五元环脯氨酸氨基酸,且波浪线指示连接点;
Cyc选自C6-C20芳基二基和C1-C20杂芳基二基,其任选地被一个或多个选自F、Cl、NO2、-OH、-OCH3和具有如下结构的葡糖醛酸的基团取代:
R7选自由-CH(R8)O-、-CH2-、-CH2N(R8)-和-CH(R8)O-C(=O)-组成的组,其中R8选自H、C1-C6烷基、C(=O)-C1-C6烷基和-C(=O)N(R9)2,其中R9独立地选自由H、C1-C12烷基和-(CH2CH2O)n-(CH2)m-OH组成的组,其中m是1至5的整数,且n是2至50的整数,或者两个R9基团一起形成5或6元杂环基环;
y是2至12的整数;
z是0或1;且
烷基、烷基二基、烯基、烯基二基、炔基、炔基二基、芳基、芳基二基、碳环基、碳环基二基、杂环基、杂环基二基、杂芳基和杂芳基二基独立且任选被一个或多个独立地选自以下的基团取代:F、Cl、Br、I、-CN、-CH3、-CH2CH3、-CH=CH2、-C≡CH、-C≡CCH3、-CH2CH2CH3、-CH(CH3)2、-CH2CH(CH3)2、-CH2OH、-CH2OCH3、-CH2CH2OH、-C(CH3)2OH、-CH(OH)CH(CH3)2、-C(CH3)2CH2OH、-CH2CH2SO2CH3、-CH2OP(O)(OH)2、-CH2F、-CHF2、-CF3、-CH2CF3、-CH2CHF2、-CH(CH3)CN、-C(CH3)2CN、-CH2CN、-CH2NH2、-CH2NHSO2CH3、-CH2NHCH3、-CH2N(CH3)2、-CO2H、-COCH3、-CO2CH3、-CO2C(CH3)3、-COCH(OH)CH3、-CONH2、-CONHCH3、-CON(CH3)2、-C(CH3)2CONH2、-NH2、-NHCH3、-N(CH3)2、-NHCOCH3、-N(CH3)COCH3、-NHS(O)2CH3、-N(CH3)C(CH3)2CONH2、-N(CH3)CH2CH2S(O)2CH3、-NHC(=NH)H、-NHC(=NH)CH3、-NHC(=NH)NH2、-NHC(=O)NH2、-NO2、=O、-OH、-OCH3、-OCH2CH3、-OCH2CH2OCH3、-OCH2CH2OH、-OCH2CH2N(CH3)2、-O(CH2CH2O)n-(CH2)mCO2H、-O(CH2CH2O)nH、-OCH2F、-OCHF2、-OCF3、-OP(O)(OH)2、-S(O)2N(CH3)2、-SCH3、-S(O)2CH3和-S(O)3H。
式I的免疫缀合物的示例性实施方案包括其中Xa和Xb独立地选自由以下组成的组:咪唑基、吡唑基、三唑基、四唑基、呋喃基、噻吩基、异噁唑基、噻唑基、噁二唑基、噁唑基、异噻唑基、吡咯基、噁二唑基和噻二唑基。
式I的免疫缀合物的示例性实施方案包括其中Xa和Xb各自为吡唑基,被一个或多个选自以下的基团取代:-CH3、-CH2CH3、-CH=CH2、-C≡CH、-C≡CCH3、-CH2CH2CH3、-CH(CH3)2和-CH2CH(CH3)2。
式I的免疫缀合物的示例性实施方案包括其中Xa和Xb中的一个被R5取代。
式I的免疫缀合物的示例性实施方案包括其中R1选自由以下组成的组:-OCH3、-OCH2CH3、-OCH2CH2OCH3、-OCH2CH2OH和-OCH2CH2N(CH3)2。
式I的免疫缀合物的示例性实施方案包括其中R1是-OCH3。
式I的免疫缀合物的示例性实施方案包括其中R1是F。
式I的免疫缀合物的示例性实施方案包括其中R2a和R2b各自为-C(=O)NH2。
式I的免疫缀合物的示例性实施方案包括其中R2a和R2b中的一个被R5取代。
式I的免疫缀合物的示例性实施方案包括其中R3选自-CH2CH2-、-CH=CH-和-C≡C-。
式I的免疫缀合物的示例性实施方案包括其中R3是C2-C4烯基二基,其被一个或多个选自F、-OH和-OCH3的基团取代。
式I的免疫缀合物的示例性实施方案包括其中R4是-O-(C1-C12烷基二基)-(C2-C20杂环基二基)-*。
式I的免疫缀合物的示例性实施方案包括其中C1-C12烷基二基是丙基二基,并且C2-C20杂环基二基是哌啶基。
式I的免疫缀合物的示例性实施方案包括其中R1和R4中的一个被R5取代。
式I的免疫缀合物的示例性实施方案包括其中L是-C(=O)-PEG-或-C(=O)-PEG-C(=O)-。
式I的免疫缀合物的示例性实施方案包括其中L连接至抗体的半胱氨酸硫醇。
式I的免疫缀合物的示例性实施方案包括其中对于PEG,m是1或2,且n是2至10的整数,或其中n为10。
式I的免疫缀合物的示例性实施方案包括其中L包含PEP,且PEP是二肽并具有下式:
并且其中AA1和AA2独立地选自H、-CH3、-CH(CH3)2、-CH2(C6H5)、-CH2CH2CH2CH2NH2、-CH2CH2CH2NHC(NH)NH2、-CHCH(CH3)CH3、-CH2SO3H和CH2CH2CH2NHC(O)NH2;或者AA1和AA2形成5元环脯氨酸氨基酸。
式I的免疫缀合物的示例性实施方案包括其中AA1是-CH(CH3)2,且AA2是-CH2CH2CH2NHC(O)NH2。
式I的免疫缀合物的示例性实施方案包括其中AA1和AA2独立地选自GlcNAc天冬氨酸、-CH2SO3H和-CH2OPO3H。
式I的免疫缀合物的示例性实施方案包括其中PEP具有下式:
其中AA1和AA2独立地选自天然存在的氨基酸的侧链。
式I的免疫缀合物的示例性实施方案包括其中L包含PEP,且PEP是三肽,并具有下式:
式I的免疫缀合物的示例性实施方案包括其中L包含PEP,且PEP是四肽并具有下式:
并且其中:
AA1选自由Abu、Ala和Val组成的组;
AA2选自由Nle(O-Bzl)、Oic和Pro组成的组;
AA3选自由Ala和Met(O)2组成的组;且
AA4选自由以下组成的组:Oic、Arg(NO2)、Bpa和Nle(O-Bzl)。
式I的免疫缀合物的示例性实施方案包括其中L包含PEP,且PEP选自由以下组成的组:Ala-Pro-Val、Asn-Pro-Val、Ala-Ala-Val、Ala-Ala-Pro-Ala、Ala-Ala-Pro-Val和Ala-Ala-Pro-Nva。
式I的免疫缀合物的示例性实施方案包括其中L包含PEP,且PEP选自以下结构:
式I的免疫缀合物的示例性实施方案包括其中L选自以下结构:
其中波浪线指示与R5的连接。
本发明包括式I实施方案的特征的所有合理的组合及排列。
在某些实施方案中,本发明的免疫缀合物化合物包括具有免疫刺激活性的那些免疫缀合物化合物。本发明的抗体-药物缀合物向肿瘤组织选择性地递送有效剂量的双苯并咪唑药物,由此可以实现更大的选择性(即,更低的有效剂量),同时相对于未缀合的双苯并咪唑增加了治疗指数(“治疗窗口”)。
载药量由p表示,即式I的免疫缀合物中每个抗体的BBI部分的数量。载药(BBI)量的范围可以是每个抗体1至约8个药物部分(D)。式I的免疫缀合物包括与范围在1至约8个药物部分缀合的抗体的混合物或集合。在一些实施方案中,可与抗体缀合的药物部分的数目受限于反应性或可用的氨基酸侧链残基如赖氨酸和半胱氨酸的数目。在一些实施方案中,通过本文所述的方法将游离半胱氨酸残基引入到抗体氨基酸序列中。在这样的方面中,p可以是1、2、3、4、5、6、7或8及其范围,如1至8或2至5。在任何这样的方面中,p和n相等(即,p=n=1、2、3、4、5、6、7或8,或它们之间的某个范围)。式I的示例性免疫缀合物包括但不限于具有1、2、3或4个工程化半胱氨酸氨基酸的抗体(Lyon,R.等人,(2012)Methods inEnzym.502:123-138)。在一些实施方案中,一个或多个游离半胱氨酸残基已经存在于抗体中形成链内和链间二硫键(天然二硫基),而无需使用工程化,在这种情况下,存在的游离的还原半胱氨酸残基可用于使抗体与药物缀合。在一些实施方案中,在抗体的缀合之前使抗体暴露于还原条件,以便产生一个或多个游离半胱氨酸残基。
对于一些免疫缀合物,p可受限于抗体上的连接位点的数目。例如,在连接是半胱氨酸硫醇的情况下,如在本文所述的某些示例性实施方案中,抗体可具有仅一个或有限数目的半胱氨酸硫醇基团,或者可具有仅一个或有限数目的可与药物连接的足够反应性的硫醇基团。在其它实施方案中,抗体中的一个或多个赖氨酸氨基基团对于与式II的BBI-接头化合物缀合可以是可用的和反应性的。在某些实施方案中,更高的载药量(例如p>5)可能导致某些抗体-药物缀合物的聚集、不溶、毒性或细胞渗透性的丧失。在某些实施方案中,免疫缀合物的平均载药量范围是1至约8;约2至约6;或约3至约5。在某些实施方案中,使抗体经受变性条件以展现反应性亲核基团,如赖氨酸或半胱氨酸。
可以以不同的方式控制免疫缀合物的载量(药物/抗体比率),例如通过:(i)限制BBI-接头中间体化合物相对于抗体的摩尔过量,(ii)限制缀合反应时间或温度,和(iii)部分或限制性还原变性条件以优化抗体反应性。
要理解的是,在抗体的多于一个亲核基团与药物反应的情况下,所得产物是具有与抗体连接的一个或多个药物部分的分布的免疫缀合物化合物的混合物。可以通过双重ELISA抗体测定由混合物计算每个抗体的药物平均数,所述双重ELISA抗体测定对于抗体是特异性的,并且对于药物是特异性的。可以通过质谱法鉴定混合物中的单独免疫缀合物分子,并通过HPLC例如疏水相互作用色谱法来分离(参见例如,McDonagh等人,(2006)Prot.Engr.Design&Selection 19(7):299-307;Hamblett等人,(2004)Clin.CancerRes.10:7063-7070;Hamblett,K.J.等人,“Effect of drug loading on thepharmacology,pharmacokinetics,and toxicity of an anti-CD30 antibody-drugconjugate”,文摘号624,American Association for Cancer Research,2004 AnnualMeeting,2004年3月27-31日,Proceedings of the AACR,第45卷,2004年3月;Alley,S.C.等人,“Controlling the location of drug attachment in antibody-drugconjugates”,文摘号627,American Association for Cancer Research,2004AnnualMeeting,2004年3月27-31日,Proceedings of the AACR,第45卷,2004年3月)。在某些实施方案中,可以通过电泳或色谱法从缀合混合物中分离具有单一加载值的均质免疫缀合物。
式I的免疫缀合物的示例性实施方案选自表3免疫缀合物。可以根据实施例203和204的方法进行免疫缀合物体外活性的评估。
表3.BBI免疫缀合物(IC)
STING激活通常与通过IRF3(干扰素调节因子3)信号传导诱导I/III型IFN(干扰素)相关,但也可以通过NF-κB(激活B细胞的核因子κ-轻链-增强子)通路诱导促炎细胞因子如TNFα(肿瘤坏死因子α)。某些免疫缀合物可表现出引发IFNλ1(干扰素λ1)以及TNFα的能力,这与STING激活(实施例203)一致。
免疫缀合物的组合物
本发明提供了一种组合物,例如药学上或药理学上可接受的组合物或制剂,其包含多种如本文所述的免疫缀合物和任选用于其的载体,例如药学上或药理学上可接受的载体。组合物中的免疫缀合物可以是相同的或不同的,即组合物可包含具有与抗体构建体上的相同位置连接的相同数目的BBI佐剂的免疫缀合物和/或具有与抗体构建体上的不同位置连接的相同数目的BBI佐剂的免疫缀合物、具有与抗体构建体上的相同位置连接的不同数目的佐剂的免疫缀合物或具有与抗体构建体上的不同位置连接的不同数目的佐剂的免疫缀合物。
在示例性实施方案中,包含免疫缀合物化合物的组合物包含免疫缀合物化合物的混合物,其中免疫缀合物化合物的混合物中每个抗体的平均载药(BBI)量为约2至约5。
本发明的免疫缀合物的组合物的平均佐剂与抗体构建体比率(DAR)可为约0.4至约10。技术人员将认识到,在包含本发明的多种免疫缀合物的组合物中,与抗体构建体缀合的BBI佐剂的数目可能因免疫缀合物而异,因此可以将佐剂与抗体构建体(例如,抗体)比率测量为平均值,所述比率可以被称为药物与抗体的比率(DAR)。可以通过任何合适的手方法评估佐剂与抗体构建体(例如,抗体)比率,其中的许多方法是本领域中已知的。
来自缀合反应的免疫缀合物的制剂中的每个抗体的平均佐剂部分数(DAR)可以通过常规方法来表征,如质谱法、ELISA测定和HPLC。也可以确定以p表示的免疫缀合物在组合物中的定量分布。在一些情形下,可以通过诸如反相HPLC或电泳的方法实现均质免疫缀合物的分离、纯化和表征,其中p是来自具有其它载药量的免疫缀合物的某一值。
在一些实施方案中,组合物还包含一种或多种药学上或药理学上可接受的赋形剂。例如,本发明的免疫缀合物可以被配制成用于肠胃外施用,如IV施用或施用到体腔或器官的内腔中。或者,可以将免疫缀合物注射到肿瘤中(肿瘤内)。用于注射的组合物将通常包括免疫缀合物溶解于药学上可接受的载体中的溶液。可以使用的可接受的媒介物和溶剂当中有水和一种或多种盐如氯化钠的等渗溶液,例如林格氏溶液。此外,无菌不挥发油可常规用作溶剂或悬浮介质。为此,可以使用任何温和的不挥发油,包括合成的甘油单酯或甘油二酯。此外,脂肪酸如油酸同样可用于制备注射剂。这些组合物理想地是无菌的,并且通常不含不期望的物质。可以通过常规的熟知灭菌技术对这些组合物进行灭菌。组合物可以含有接近生理条件所需的药学上可接受的辅助物质,如pH调节和缓冲剂、毒性调节剂,例如乙酸钠、氯化钠、氯化钾、氯化钙、乳酸钠等。
组合物可含有任意合适浓度的免疫缀合物。组合物中免疫缀合物的浓度可以广泛变化,并且将根据选择的特定施用模式和患者的需要,主要基于流体体积、粘度、体重等来选择。在某些实施方案中,注射用溶液制剂中的免疫缀合物的浓度范围将是约0.1%(w/w)至约10%(w/w)。
用免疫缀合物治疗癌症的方法
本发明提供了治疗癌症的方法。所述方法包括向有需要的受试者施用治疗有效量的如本文所述的免疫缀合物(例如,作为如本文所述的组合物),所述有需要的受试者例如为患有癌症并需要治疗所述癌症的受试者。所述方法包括施用治疗有效量的本发明的免疫缀合物(IC)。
预期本发明的免疫缀合物可用于治疗各种过度增殖性疾病或病症,例如以肿瘤抗原的过表达为特征的过度增殖性疾病或病症。示例性的过度增殖性病症包括良性或恶性实体肿瘤和血液学病症,如白血病和淋巴样恶性肿瘤。
另一方面,提供了用作药物的免疫缀合物。在某些实施方案中,本发明提供了用于治疗个体的方法的免疫缀合物,所述方法包括向所述个体施用有效量的所述免疫缀合物。在一个这样的实施方案中,所述方法还包括向所述个体施用有效量的至少一种另外的治疗剂,例如,如本文所述。
在进一步的方面中,本发明提供免疫缀合物在制造或制备药物中的用途。在一个实施方案中,所述药物用于治疗癌症,所述方法包括向患有癌症的个体施用有效量的所述药物。在一个这样的实施方案中,所述方法还包括向所述个体施用有效量的至少一种另外的治疗剂,例如,如本文所述。
癌是起源于上皮组织的恶性肿瘤。上皮细胞覆盖身体的外表面,内衬于内腔,并形成腺体组织的衬里。癌的实例包括但不限于腺癌(始于腺(分泌)细胞的癌症,例如乳腺癌、胰腺癌、肺癌、前列腺癌、胃癌、胃食管连接部癌和结肠癌)、肾上腺皮质癌;肝细胞癌;肾细胞癌;卵巢癌;原位癌;导管癌;乳腺癌;基底细胞癌;鳞状细胞癌;移行细胞癌;结肠癌;鼻咽癌;多房囊性肾细胞癌;燕麦细胞癌;大细胞肺癌;小细胞肺癌;非小细胞肺癌;等等。前列腺、胰腺、结肠、脑(通常作为继发性转移)、肺、乳腺和皮肤中均可发现癌。
软组织肿瘤是一组来源于结缔组织的高度多样化的罕见肿瘤。软组织肿瘤的示例包括但不限于腺泡状软组织肉瘤;血管瘤样纤维组织细胞瘤;软骨粘液样纤维瘤;骨骼软骨肉瘤;骨外粘液样软骨肉瘤;透明细胞肉瘤;促结缔组织增生性小圆细胞瘤;隆突性皮肤纤维肉瘤;子宫内膜间质肿瘤;尤因肉瘤;纤维瘤病(硬纤维瘤);婴儿型纤维肉瘤;胃肠道间质瘤;骨巨细胞瘤;腱鞘巨细胞瘤;炎性肌纤维母细胞瘤;子宫平滑肌瘤;平滑肌肉瘤;脂肪母细胞瘤;典型脂肪瘤;梭形细胞或多形性脂肪瘤;非典型脂肪瘤;软骨样脂肪瘤;高分化脂肪肉瘤;粘液样/圆细胞脂肪肉瘤;多形性脂肪肉瘤;粘液样恶性纤维组织细胞瘤;高度恶性纤维组织细胞瘤;粘液纤维肉瘤;恶性周围神经鞘瘤;间皮瘤;神经母细胞瘤;骨软骨瘤;骨肉瘤;原始神经外胚层肿瘤;腺泡状横纹肌肉瘤;胚胎型横纹肌肉瘤;良性或恶性神经鞘瘤;滑膜肉瘤;埃文氏瘤(Evan’s tumor);结节性筋膜炎;韧带样型纤维瘤病;孤立性纤维瘤;隆突性皮肤纤维肉瘤(DFSP);血管肉瘤;上皮样血管内皮瘤;腱鞘巨细胞瘤(TGCT);色素沉着绒毛结节性滑膜炎(PVNS);纤维发育不良;粘液纤维肉瘤;纤维肉瘤;滑膜肉瘤;恶性周围神经鞘瘤;神经纤维瘤;软组织多形性腺瘤;以及来源于成纤维细胞、肌成纤维细胞、组织细胞、血管细胞/内皮细胞和神经鞘细胞的瘤形成。
肉瘤是一种罕见类型的癌症,其起源于间充质来源的细胞,例如身体的骨骼或软组织,包括软骨、脂肪、肌肉、血管、纤维组织或其他结缔或支持组织。不同类型的肉瘤基于癌症形成的位置。例如,骨肉瘤在骨骼中形成,脂肪肉瘤在脂肪中形成,且横纹肌肉瘤在肌肉中形成。肉瘤的实例包括但不限于阿斯金瘤;葡萄状肉瘤;软骨肉瘤;尤因氏肉瘤;恶性血管内皮瘤;恶性神经鞘瘤;骨肉瘤;和软组织肉瘤(例如,肺泡样软组织肉瘤;血管肉瘤;叶状囊肉瘤隆突性皮肤纤维肉瘤(DFSP);硬纤维瘤;促结缔组织增生性小圆细胞瘤;上皮样肉瘤;骨骼外软骨肉瘤;骨骼外骨肉瘤;纤维肉瘤;胃肠道间质瘤(GIST);血管外皮细胞瘤;血管内皮瘤(更通常称为“血管肉瘤”);卡波西肉瘤;平滑肌肉瘤;脂肪肉瘤;淋巴管肉瘤;恶性周围神经鞘瘤(MPNST);神经纤维肉瘤;滑膜肉瘤;和未分化多形性肉瘤)。
畸胎瘤是一种类型的生殖细胞肿瘤,其可含有若干不同类型的组织(例如,可包括源自任何和/或所有三个胚层的组织:内胚层、中胚层和外胚层),包括例如毛发、肌肉和骨骼。畸胎瘤最常发生在女性的卵巢、男性的睾丸和儿童的尾椎骨中。
黑素瘤是一种始于黑素细胞(产生黑色素的细胞)的癌症形式。黑素瘤可始于痣(皮肤黑素瘤),但也可始于其它有色素组织,如眼睛或肠。
默克尔细胞癌是一种罕见的皮肤癌,其通常表现为面部、头部或颈部的肉色或蓝红色结节。默克尔细胞癌也称为皮肤神经内分泌癌。在一些实施方案中,治疗默克尔细胞癌的方法包括施用含有能够结合Trop2的抗体构建体的免疫缀合物(例如,sacituzumab、其生物仿制药,或其改良型生物相似性药物)。在一些实施方案中,在进行施用时,默克尔细胞癌已经转移。
白血病是在形成血液的组织如骨髓中开始的癌症,并且导致产生大量异常的血细胞并进入血流。例如,白血病可起源于通常在血流中成熟的骨髓源性细胞。白血病针对疾病发展和进展的有多快速(例如,急性与慢性)以及受影响的白细胞类型(例如,骨髓与淋巴)来命名。髓样白血病也称为骨髓性或成髓细胞白血病。淋巴样白血病也称为淋巴母细胞或淋巴细胞白血病。淋巴样白血病细胞可聚集在淋巴结中,所述淋巴结会肿胀。白血病的示例包括但不限于急性髓样白血病(AML)、急性淋巴细胞性白血病(ALL)、慢性髓样白血病(CML)和慢性淋巴细胞性白血病(CLL)。
淋巴瘤是始于免疫系统的细胞的癌症。例如,淋巴瘤可起源于通常在淋巴系统中成熟的骨髓源性细胞。有两种基本类别的淋巴瘤。一种类别的淋巴瘤是霍奇金淋巴瘤(HL),其特征是存在被称为里德-斯德伯格氏细胞的细胞类型。HL目前有6种公认的类型。霍奇金淋巴瘤的实例包括结节硬化典型霍奇金淋巴瘤(CHL)、混合细胞性CHL、淋巴细胞耗竭型CHL、富淋巴细胞型CHL和结节性淋巴细胞为主型HL。
另一种类别的淋巴瘤是非霍奇金淋巴瘤(NHL),其包括大量不同的免疫系统细胞的癌症。非霍奇金淋巴瘤可进一步分成具有惰性(缓慢生长)病程的癌症和具有侵袭性(快速生长)病程的癌症。NHL目前有61种公认的类型。非霍奇金淋巴瘤的示例包括但不限于AIDS相关淋巴瘤、间变性大细胞淋巴瘤、血管免疫母细胞淋巴瘤、母细胞性NK细胞淋巴瘤、伯基特淋巴瘤、伯基特样淋巴瘤(小非裂细胞淋巴瘤)、慢性淋巴细胞白血病/小淋巴细胞淋巴瘤、皮肤T细胞淋巴瘤、弥漫性大B细胞淋巴瘤、肠病型T细胞淋巴瘤、滤泡性淋巴瘤、肝脾γ-δT细胞淋巴瘤、T细胞白血病、淋巴母细胞淋巴瘤、套细胞淋巴瘤、边缘区淋巴瘤、鼻T细胞淋巴瘤、小儿淋巴瘤、外周T细胞淋巴瘤、原发性中枢神经系统淋巴瘤、转化淋巴瘤、治疗相关的T细胞淋巴瘤和华氏巨球蛋白血症。
脑癌包括脑组织的任何癌症。脑癌的示例包括但不限于神经胶质瘤(例如,成胶质细胞瘤、星形细胞瘤、少突胶质细胞瘤、室管膜瘤等)、脑膜瘤、垂体腺瘤和前庭神经鞘瘤、原始神经外胚层肿瘤(髓母细胞瘤)。
本发明的免疫缀合物可以单独使用或与疗法中的其它剂组合使用。例如,免疫缀合物可以与至少一种另外的治疗剂如化学治疗剂共同施用。这类组合疗法涵盖组合施用(其中在同一或分开的制剂中包括两种或更多种治疗剂)和单独施用,在后一种情况下,免疫缀合物的施用可以在另外的治疗剂和/或佐剂的施用之前、同时和/或之后进行。免疫缀合物也可以与放射疗法组合使用。
可以通过任意合适的方式施用本发明的免疫缀合物(和任何另外的治疗剂),包括肠胃外、肺内和鼻内施用,并且如果需要局部治疗,则进行病灶内施用。肠胃外输注包括肌内、静脉内、动脉内、腹膜内或皮下施用。可以通过任意合适的途径给药,例如通过注射,如静脉内或皮下注射,这部分地取决于施用是短暂的还是长期的。本文考虑包括但不限于在各种时间点单次或多次施用、推注施用和脉冲输注的各种给药方案。
本文所述的免疫缀合物可用于治疗如sacituzumab、戈沙妥珠单抗、其生物仿制药和改良型生物相似性药物所用于的相同类型的癌症,尤其是乳腺癌,尤其是三阴性(雌激素受体、孕激素受体和过量HER2蛋白测试呈阴性)乳腺癌、膀胱癌和默克尔细胞癌。
在一些实施方案中,本文所述的免疫缀合物可有效治疗膀胱癌、唾液腺癌、子宫内膜癌、尿路癌、尿道上皮癌、肺癌、非小细胞肺癌、默克尔细胞癌、结肠癌、结肠直肠癌、胃癌和乳腺癌。
采用任何合适的给药方案,例如用于sacituzumab、戈沙妥珠单抗、其生物仿制药和其改良型生物相似性药物的给药方案,以任何治疗有效量向有需要的受试者施用免疫缀合物。例如,所述方法可包括施用免疫缀合物以向受试者提供约100ng/kg至约50mg/kg的剂量。免疫缀合物剂量的范围可以是约5mg/kg至约50mg/kg、约10μg/kg至约5mg/kg或约100μg/kg至约1mg/kg。免疫缀合物剂量可以为约100、200、300、400或500μg/kg。免疫缀合物剂量可以为约1、2、3、4、5、6、7、8、9或10mg/kg。免疫缀合物剂量也可以在这些范围之外,这取决于特定的缀合物以及所治疗的癌症的类型和严重程度。施用的频率范围可以从每周单剂量至多剂量,或更频繁。在一些实施方案中,约每月一次至约每周五次施用免疫缀合物。在一些实施方案中,每周一次施用免疫缀合物。
另一方面,本发明提供预防癌症的方法。所述方法包括向受试者施用治疗有效量的免疫缀合物(例如,如上所述的组合物的形式)。在某些实施方案中,受试者易患某种要预防的癌症。例如,所述方法可包括施用免疫缀合物以向受试者提供约100ng/kg至约50mg/kg的剂量。免疫缀合物剂量的范围可以是约5mg/kg至约50mg/kg、约10μg/kg至约5mg/kg或约100μg/kg至约1mg/kg。免疫缀合物剂量可以为约100、200、300、400或500μg/kg。免疫缀合物剂量可以为约1、2、3、4、5、6、7、8、9或10mg/kg。免疫缀合物剂量也可以在这些范围之外,这取决于特定的缀合物以及所治疗的癌症的类型和严重程度。施用的频率范围可以从每周单剂量至多剂量,或更频繁。在一些实施方案中,约每月一次至约每周五次施用免疫缀合物。在一些实施方案中,每周一次施用免疫缀合物。
本发明的一些实施方案提供治疗如上所述的癌症的方法,其中所述癌症是乳腺癌。乳腺癌可起源于乳房的不同区域,并且已经表征了许多不同类型的乳腺癌。例如,本发明的免疫缀合物可用于治疗导管原位癌;浸润性导管癌(例如,管状癌;髓样癌;粘液癌;乳头状癌;或乳腺筛状癌);小叶原位癌;浸润性小叶癌;炎症性乳腺癌;及其它形式的乳腺癌,如三阴性(雌激素受体、孕酮受体和过量的HER2蛋白测试呈阴性)乳腺癌。
在一些实施方案中,癌症对由STING诱导的促炎性反应敏感。
实施例
不对称双苯并咪唑化合物和(BBI-L)式II化合物及中间体的制备
实施例1 1-(3-((5-氨基甲酰基-2-(1-乙基-3-甲基-1H-吡唑-5-甲酰胺基)-1-甲基-1H-苯并[d]咪唑-7-基)氧基)丙基)-2-(1-乙基-3-甲基-1H-吡唑-5-甲酰胺基)-7-甲氧基-1H-苯并[d]咪唑-5-甲酰胺,BBI-1的合成
4-氯-3-甲氧基-5-硝基-苯甲酰胺,1b的制备
将4-氯-3-甲氧基-5-硝基-苯甲酸甲酯1a(15g,61.07mmol,1当量)在NH3·H2O(136.98g,977.13mmol,150.5mL,25%纯度,16当量)中的溶液在50℃搅拌24h。过滤混合物,得到呈淡黄色固体的1b(11.2g,48.57mmol,79.53%产率),其无需进一步纯化即可用于下一步。1H NMR(DMSO-d6,400MHz)δ8.30(s,1H),8.09(s,1H),7.88(s,1H),7.79(s,1H),4.02(s,3H)。
3-甲氧基-4-(甲基氨基)-5-硝基-苯甲酰胺,1c的制备
向1b(3g,13.01mmol,1当量)在DIEA(16.8g,130mmol,22.7mL,10当量)中的溶液中加入甲胺(4.39g,65.0mmol,5当量,HCl),并将其在100mL密封管中在120℃下搅拌24小时。通过添加H2O(100mL)淬灭反应混合物,将其过滤并用水(50mL)洗涤,得到红色固体。将粗产物与MTBE/PE=20/80ml一起在20℃下研磨30分钟,获得呈红色固体的1c(3.2g,粗品)。1HNMR(DMSO-d6,400MHz)δ8.08(s,1H),7.50(s,1H),3.88(s,3H),2.91(d,J=6.8Hz,3H)。
3-氨基-5-甲氧基-4-(甲氨基)苯甲酰胺,1d的制备
向1c(3.2g,14.21mmol,1当量)在MeOH(25mL)、THF(25mL)和H2O(25mL)中的溶液中添加Na2CO3(6.02g,56.8mmol,4当量)和连二亚硫酸钠Na2S2O4(17.3g,99.5mmol,21.6mL,7当量)。将混合物在20℃下搅拌1小时。然后将其减压浓缩以除去MeOH和THF,将残余物用H2O(50mL)稀释并过滤,得到呈黄色固体的1d(2.3g,11.78mmol,82.91%产率),其无需进一步纯化即可用于下一步。1H NMR(DMSO-d6,400MHz)δ6.94(s,1H),6.90(s,1H),3.85(s,3H),2.70(s,3H)。
2-(1-乙基-3-甲基-1H-吡唑-5-甲酰胺基)-7-甲氧基-1-甲基-1H-苯并[d]咪唑-5-甲酰胺,1f的制备
在0℃下向1d(2.1g,10.7mmol,1当量)在DMF(30mL)中的溶液中添加2-乙基-5-甲基-吡唑-3-羰基异硫氰酸酯,1e(2.31g,11.8mmol,1.1当量),并将混合物在相同温度下搅拌0.5h,然后添加Et3N(3.27g,32.3mmol,4.5mL,3当量)和EDCI(6.19g,32.3mmol,3当量),并将该混合物在25℃下再搅拌12h。将反应物倒入NaHCO3水溶液(30mL)中,过滤并用H2O(15mL×3)洗涤,干燥从而得到粗产物。然后将粗产物与CH3CN(50mL)一起在20℃下研磨20分钟,获得呈白色固体的1f(2.9g,8.14mmol,75.65%产率)。1H NMR(DMSO-d6,400MHz)δ7.99(s,1H),7.66(s,1H),7.42-7.35(m,2H),6.66(s,1H),4.62-4.60(m,2H),3.97(s,3H),3.84(s,3H),2.17(s,3H),1.34(t,J=7.2Hz,3H)。
2-[(2-乙基-5-甲基-吡唑-3-羰基)氨基]-7-羟基-1-甲基-苯并咪唑-5-甲酰胺,1g的制备
在0℃向1f(1.2g,3.37mmol,1当量)在DCM(40mL)中的溶液中滴加BBr3(8.44g,33.7mmol,3.2mL,10当量)。添加后,将混合物在20℃搅拌72h。将混合物倒入冰水中,用NaHCO3水溶液调节至pH=6并搅拌30分钟,然后过滤,得到呈白色固体的1g(0.7g,2.04mmol,60.72%产率)。1H NMR(MeOD,400MHz)δ7.54(s,1H),7.29(s,1H),6.85(s,1H),4.67(q,J=7.2Hz,2H),4.09(s,3H),2.30(s,3H),1.45(t,J=7.2Hz,3H)。
N-[3-[6-氨基甲酰基-2-[(2-乙基-5-甲基-吡唑-3-羰基)氨基]-3-甲基-苯并咪唑-4-基]氧基丙基]氨基甲酸叔丁酯,1h的制备
向1g(400mg,1.17mmol,1当量)在DMF(10mL)中的溶液中添加K2CO3(226mg,1.64mmol,1.4当量)和N-(3-溴丙基)氨基甲酸叔丁酯(292mg,1.23mmol,1.05当量),然后在50℃搅拌2小时。通过在0℃下加入冰水(20mL)将反应混合物淬灭,然后用EtOAc(20mL)稀释并用EtOAc(15mL x 2)萃取。将合并的有机层用20mL盐水洗涤,经Na2SO4干燥,过滤并在减压下浓缩。将粗产物与EtOAc/PE=5/1一起在20℃下研磨5分钟,得到呈白色固体的1h(0.57g,粗产物)。
7-(3-氨基丙氧基)-2-[(2-乙基-5-甲基-吡唑-3-羰基)氨基]-1-甲基-苯并咪唑-5-甲酰胺,1i的制备
向1h(0.47g,941umol,1当量)在EtOAc(0.5mL)中的溶液中添加HCl/EtOAc(4M,11.8mL,50当量)。将混合物在25℃下搅拌1小时。然后将混合物浓缩,得到呈白色固体的1i(400mg,917.63umol,97.53%产率,HCl),其直接用于下一步。
7-[3-(4-氨基甲酰基-2-甲氧基-6-硝基-苯胺基)丙氧基]-2-[(2-乙基-5-甲基-吡唑-3-羰基)氨基]-1-甲基-苯并咪唑-5-甲酰胺,1j的制备
向1i(440mg,1.01mmol,1当量,HCl)在丁-1-醇(7.24g,97.71mmol,8.9mL,96.8当量)中的溶液中添加NaHCO3(424mg,5.05mmol,5当量)和DIEA(652mg,5.05mmol,879uL,5当量),然后在20℃下搅拌30min。于20℃在N2下添加中间体1b(244mg,1.06mmol,1.05当量)并于120℃再搅拌12小时。之后,将混合物浓缩,得到残余物,并将残余物用EtOAc(10mL)稀释,随后用冰水(10mL)稀释,并将混合物搅拌10分钟。过滤沉淀,得到呈黄色固体的1j(0.4g,674umol,66.76%产率)。
7-[3-(2-氨基-4-氨基甲酰基-6-甲氧基-苯胺基)丙氧基]-2-[(2-乙基-5-甲基-吡唑-3-羰基)氨基]-1-甲基-苯并咪唑-5-甲酰胺,1k的制备
向1j(100mg,168umol,1当量)在MeOH(0.5mL)和THF(0.5mL)、H2O(0.5mL)中的溶液中添加连二亚硫酸钠(205mg,1.18mmol,7当量)和Na2CO3(71.4mg,674umol,4当量)。将混合物在25℃下搅拌2小时。然后将其浓缩以除去MeOH和THF,将残余物用H2O(5mL)稀释并搅拌5分钟。过滤沉淀,得到呈黄色固体的1k(80mg,142umol,84.26%产率)。
BBI-1的制备
在0℃下向1k(50mg,89umol,1当量)在DMF(1.5mL)中的溶液中添加中间体1e(19mg,98umol,1.1当量)并将溶液搅拌30分钟,然后添加Et3N(27mg,266umol,37uL,3当量)和EDCI(51mg,266umol,3当量)并将混合物在20℃下再搅拌16.5小时。将反应物添加到NaHCO3水溶液(1mL)中,过滤并用H2O(1mL×3)洗涤,干燥从而得到粗产物。将残余物通过制备型HPLC(柱:Phenomenex Luna80*30mm*3um;流动相:[水(TFA)-ACN];B%:25%-55%,8min)纯化,得到呈白色固体的BBI-1(14mg,19.32umol,21.77%产率)。1H NMR(MeOD,400MHz)δ7.63(s,1H),7.56(s,1H),7.41(s,1H),7.28(s,1H),6.80(s,1H),6.51(s,1H),4.75-4.69(m,4H),4.49-4.46(m,2H),4.33-4.30(m,2H),4.04(s,3H),3.79(s,3H),2.51-2.48(m,2H),2.31(s,3H),2.14(s,3H),1.47(t,J=7.2Hz,3H),1.33(t,J=7.2Hz,3H)。LCMS(ESI):C35H40N12O6的质量计算值为724.32m/z,实测值为725.3[M+H]+。
实施例2 1-[4-[6-氨基甲酰基-2-[(2-乙基-5-甲基-吡唑-3-羰基)氨基]-3-甲基-苯并咪唑-4-基]氧基丁基]-2-[(2-乙基-5-甲基-吡咯-3-羰基)胺基]-7-甲氧基-苯并咪唑-5-甲酰胺,BBI-2的合成
N-[4-[6-氨基甲酰基-2-[(2-乙基-5-甲基-吡唑-3-羰基)氨基]-3-甲基-苯并咪唑-4-基]氧基丁基]氨基甲酸叔丁酯,2a的制备
在50℃下向2-[(2-乙基-5-甲基-吡唑-3-羰基)氨基]-7-羟基-1-甲基-苯并咪唑-5-甲酰胺,1g(800mg,2.34mmol,1当量)在DMF(10mL)中的溶液中添加K2CO3(355mg,2.57mmol,1.1当量)并将溶液搅拌0.5h,然后添加N-(4-溴丁基)氨基甲酸叔丁酯(648mg,2.57mmol,527uL,1.1当量)。将混合物在50℃下搅拌12小时。通过在0℃下添加冰水(20mL)来淬灭反应混合物,过滤沉淀,得到呈白色固体的2a(1.2g,粗品),其无需进一步纯化即可用于下一步。1H NMR(MeOD,400MHz)δ7.63(s,1H),7.41(s,1H),6.73(s,1H),4.77-4.67(m,2H),4.32-4.22(m,2H),3.98(s,3H),3.17(t,J=7.2Hz,2H),2.27(s,3H),2.01-1.90(m,2H),1.81-1.70(m,2H),1.49-1.43(m,12H)。
7-(4-氨基丁氧基)-2-[(2-乙基-5-甲基-吡唑-3-羰基)氨基]-1-甲基-苯并咪唑-5-甲酰胺,2b的制备
向2a(1.1g,2.14mmol,1当量)在EtOAc(5mL)中的溶液中添加HCl/EtOAc(4M,26.7mL,50当量)。将混合物在25℃下搅拌0.5小时。然后浓缩混合物,得到呈灰白色固体的2b(0.8g,1.93mmol,90.34%产率)。1H NMR(MeOD,400MHz)δ7.83(s,1H),7.58(s,1H),7.08(s,1H),4.65(q,J=7.2Hz,2H),4.36(t,J=6.0Hz,2H),4.20(s,3H),3.08(t,J=7.2Hz,2H),2.37(s,3H),2.09-2.01(m,2H),2.00-1.90(m,2H),1.49(t,J=7.2Hz,3H)。
7-[3-(4-氨基甲酰基-2-甲氧基-6-硝基-苯胺基)丙氧基]-2-[(2-乙基-5-甲基-吡唑-3-羰基)氨基]-1-甲基-苯并咪唑-5-甲酰胺,2c的制备
向2b(570mg,1.27mmol,1当量,HCl)在丁-1-醇(9.39g,127mmol,11.6mL,100当量)中的溶液中添加DIEA(818mg,6.33mmol,1.10mL,5当量)、NaHCO3(532mg,6.33mmol,5当量)和4-氯-3-甲氧基-5-硝基-苯甲酰胺,1b(292mg,1.27mmol,1当量)。将混合物在120℃下在N2下搅拌15小时。在20℃下通过添加H2O(50mL)淬灭反应混合物,然后将反应混合物用EtOAc(30mL)稀释并用EtOAc(30mL×2)萃取。将合并的有机层用盐水(20mL)洗涤,经Na2SO4干燥,过滤并浓缩。将粗产物与EtOAc/PE=10/1一起在20℃下研磨30分钟,得到呈黄色固体的2c(500mg,842umol,66.49%产率)。
7-[4-(2-氨基-4-氨基甲酰基-6-甲氧基-苯胺基)丁氧基]-2-[(2-乙基-5-甲基-吡唑-3-羰基)氨基]-1-甲基-苯并咪唑-5-甲酰胺,2d的制备
向2c(400mg,658umol,1当量)在MeOH(5mL)、THF(5mL)和H2O(5mL)中的溶液中添加Na2CO3(279mg,2.63mmol,4当量)和BLAH二钠(802mg,4.61mmol,7当量)。将混合物在25℃下搅拌2小时。之后,浓缩反应物以除去MeOH和THF,添加H2O(10mL)并搅拌5分钟。过滤沉淀,得到呈黄色固体的2d(200mg,346umol,52.60%产率)。
BBI-2的制备
在0℃下向2d(50mg,86umol,1当量)在DMF(1mL)中的溶液中添加2-乙基-5-甲基-吡唑-3-羰基异硫氰酸酯,1e(18mg,95umol,1.1当量)并将溶液搅拌30分钟,然后添加Et3N(26mg,259umol,36uL,3当量)和EDCI(49mg,259umol,3当量)。将混合物在20℃下再搅拌2小时。将混合物过滤并通过制备型HPLC(柱:Phenomenex Luna80*30mm*3um;流动相:[水(TFA)-ACN];B%:25%-45%,8min)纯化,得到呈白色固体的BBI-2(26mg,35.19umol,40.66%产率)。1H NMR(DMSO-d6,400MHz)δ8.05-7.90(m,2H),7.68(s,1H),7.62(s,1H),7.40(s,1H),7.37-7.26(m,2H),6.63(s,1H),6.58(s,1H),4.67-4.52(m,4H),4.48-4.44(m 2H),4.23(t,J=4.8Hz,2H),3.95(s,3H),3.67(s,3H),2.17(s,3H),2.11-1.97(m,5H),1.92-1.88(m,2H),1.43-1.23(m,6H)。LCMS(ESI):C36H42N12O6的质量计算值为738.34m/z,实测值为739.3[M+H]+。
实施例3 1-(4-((5-氨基甲酰基-2-(1-乙基-3-甲基-1H-吡唑-5-甲酰胺基)-1-甲基-1H-苯并[d]咪唑-7)氧基)丁基)-2-(1-乙基-3-甲基-1H-吡唑-5-甲酰氨基)-7-(3-(哌嗪-1-基)丙氧基)-1H-苯并[d]咪唑-5-甲酰胺,BBI-3的合成
4-[3-[5-氨基甲酰基-2-[4-[6-氨基甲酰基-2-[(2-乙基-5-甲基-吡唑-3-羰基)氨基]-3-甲基-苯并咪唑-4-基]氧基丁氨基]-3-硝基-苯氧基]丙基]哌嗪-1-甲酸叔丁酯,3b的制备
向7-(4-氨基丁氧基)-2-[(2-乙基-5-甲基-吡唑-3-羰基)氨基]-1-甲基-苯并咪唑-5-甲酰胺,2b(300mg,666umol,1.3当量,HCl)在丁-1-醇(3.68g,49.65mmol,4.5mL,96.8当量)中的溶液中添加NaHCO3(215mg,2.56mmol,99uL,5当量)和DIEA(331mg,2.56mmol,446uL,5当量),并然后在20℃搅拌30分钟,然后于20℃在N2下添加4-[3-(5-氨基甲酰基-2-氯-3-硝基-苯氧基)丙基]哌嗪-1-甲酸叔丁酯,3a(227mg,513umol,1当量),并将溶液在120℃搅拌12小时。将混合物浓缩,得到残余物,然后用EtOAc(20mL)和冰水(30mL)稀释,过滤沉淀,得到呈红色固体的3b(0.4g,粗品)。
4-[3-[3-氨基-5-氨基甲酰基-2-[4-[6-氨基甲酰基-2-[(2-乙基-5-甲基-吡唑-3-羰基)氨基]-3-甲基-苯并咪唑-4-基]氧基丁基氨基]苯氧基]丙基]哌嗪-1-甲酸叔丁酯,3c的制备
向3b(0.4g,488umol,1当量)在THF(5mL)、MeOH(5mL)和H2O(5mL)中的溶液中添加连二亚硫酸钠(595mg,3.42mmol,743uL,7当量)和Na2CO3(207mg,1.95mmol,4当量)。将混合物在25℃下搅拌2小时。添加水(5mL)并将混合物浓缩以除去THF和MeOH,然后过滤,得到呈黄色固体的3c(0.24g,304umol,62.28%产率)。
4-(3-((5-氨基甲酰基-1-(4-((5-氨基甲酰基-2-(1-乙基-3-甲基-1H-吡唑-5-甲酰氨基)-1-甲基-1H-苯并[d]咪唑-7-基)氧基)丁基)-2-(1-乙基-3-甲基-1H-吡唑-5-甲酰氨基)-1H-苯并[d]咪唑-7-基)氧基)丙基)哌嗪-1-甲酸叔丁酯,3d的制备
在0℃下向3c(240mg,304umol,1当量)在DMF(5mL)中的溶液中添加2-乙基-5-甲基-吡唑-3-羰基异硫氰酸酯,1e(65mg,334umol,1.1当量),并将溶液在此温度下搅拌10分钟,然后添加Et3N(92mg,911umol,127uL,3当量)和EDCI(175mg,911umol,3当量)。将混合物在25℃下再搅拌12小时。然后将其倒入NaHCO3水溶液(5mL)中,过滤并用H2O(1mL×3)洗涤滤饼,干燥,得到呈黄色固体的3d(200mg,210umol,69.21%产率)。
BBI-3的制备
向3d(0.2g,210umol,1当量)在EtOAc(1mL)中的溶液中添加HCl/EtOAc(4M,2.63mL,50当量)。将混合物在25℃下搅拌1小时。将反应物浓缩并通过制备型HPLC(柱:Phenomenex Luna 80*30mm*3um;流动相:[水(TFA)-ACN];B%:10%-40%,8min)纯化,得到呈白色固体的BBI-3(70mg,82.26umol,39.12%产率)。1H NMR(MeOD,400MHz)δ7.60(s,2H),7.46(s,1H),7.36(s,1H),6.74(s,1H),6.63(s,1H),4.70(d,J=7.2Hz,2H),4.65-4.60(m,2H),4.37-4.30(m,4H),3.77(s,3H),3.31-3.26(m,4H),2.88-2.84(m,4H),2.79(t,J=7.2Hz,2H),2.30(s,3H),2.21-2.18(m,2H),2.16-2.13(m,5H),2.09-2.01(m,2H),1.47-1.34(m,8H)。LCMS(ESI):C42H54N14O6的质量计算值为850.44m/z,实测值为851.6[M+H]+。
实施例L-1 7-[4-[5-氨基甲酰基-7-[3-[4-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[[2-(2,5-二氧代吡咯-1-基)乙酰基]氨基]乙氧基]乙氧基]乙氧基]乙氧基]乙氧基]乙氧基]乙氧基]乙氧基]乙氧基]乙氧基]乙基]哌嗪-1-基]丙氧基]-2-[(2-乙基-5-甲基-吡唑-3-羰基)氨基]苯并咪唑-1-基]丁氧基]-2-[(2-乙基-5-甲基-吡唑-3-羰基)氨基]-1-甲基-苯并咪唑-5-甲酰胺,BBI-L-1的合成
2-(2,5-二氧吡咯-1-基)-N-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-(2--羟基乙氧基)乙氧基]乙氧基]乙氧基]乙氧基]乙氧基]乙氧基]乙氧基]乙氧基]乙氧基]乙基]乙酰胺,L-1b的制备
向2-(2,5-二氧代吡咯-1-基)乙酸(155mg,997umol,1当量)在DCM(10mL)中的溶液中添加HATU(398mg,1.05mmol,1.05当量)和Et3N(151mg,1.50mmol,208uL,1.5当量)和2-[2-[2-[2-[2-[2-[2-[2-[2-[2-(2-氨基乙氧基)乙氧基]乙氧基]乙氧基]乙氧基]乙氧基]乙氧基]乙氧基]乙氧基]乙氧基]乙醇,L-1a(500mg,997umol,1当量)。将混合物在0℃下搅拌1小时。然后将在冰水(20mL)与DCM(20mL)之间其分配。将有机相分离,用盐水10mL洗涤,经Na2SO4干燥,过滤并在减压下浓缩,得到残余物。将残余物通过快速硅胶色谱法(12g硅胶快速柱,0~100%乙酸乙酯/石油醚至0-50%甲醇/乙酸乙酯梯度的洗脱剂,以45mL/min)纯化,得到呈无色油状物的L-1b(440mg,689umol,69.11%产率)。1H NMR(MeOD,400MHz)δ6.77(s,2H),4.21(s,2H),3.75-3.71(m,2H),3.70-3.59(m,38H),3.59-3.55(m,2H),3.48-3.44(m,2H)。
2-(2,5-二氧代吡咯-1-基)N-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-(2-氧代乙氧基)乙氧基]乙氧基]乙氧基]乙氧基]乙氧基]乙氧基]乙氧基]乙氧基]乙氧基]乙基]乙酰胺,L-1c的制备
在0℃下向L-1b(240mg,376umol,1当量)在DCM(10mL)中的溶液中添加戴斯-马丁(Dess-Martin)高碘烷(1,1,1-三乙酰氧基)-1,1-二氢-1,2-苯碘酰-3-(1H)-酮(CAS登记号87413-09-0)(478mg,1.13mmol,3当量)。将混合物在25℃下搅拌1小时。然后将其过滤并浓缩,得到呈无色油状物的L-1c(0.2g,粗品),其无需进一步纯化即可用于下一步。
BBI-L-1的制备
向7-[4-[5-氨基甲酰基-2-[(2-乙基-5-甲基-吡唑-3-羰基)氨基]-7-(3-哌嗪-1-基丙氧基)苯并咪唑-1-基]丁氧基]-2-[(2-乙基-5-甲基-吡唑-3-羰基)氨基]-1-甲基-苯并咪唑-5-甲酰胺,BBI-3(55mg,51umol,1当量,2TFA)在MeOH(2mL)中的溶液中添加L-1c(97.4mg,153umol,3当量)并在25℃搅拌20分钟,然后添加NaBH3CN(9.61mg,153umol,3当量)。将混合物在25℃下搅拌2小时。之后,将反应物过滤并通过制备型HPLC纯化(柱:Phenomenex Luna 80*30mm*3um;流动相:[水(TFA)-ACN];B%:20%-50%,8min)纯化,得到呈白色固体的BBI-L-121.4mg,14.54umol,28.53%产率)。1H NMR(MeOD,400MHz)δ7.62(s,2H),7.47(s,1H),7.38(s,1H),6.89(s,2H),6.75(s,1H),6.65(s,1H),4.73-4.66(m,2H),4.66-4.60(m,4H),4.39-4.31(m,4H),4.17(s,2H),3.86-3.81(m,2H),3.78(s,3H),3.66-3.62(m,8H),3.61-3.58(m,30H)3.55-3.51(m,2H),3.37(t,J=5.2Hz,4H),3.07-2.74(m,6H),2.30(s,3H),2.25-2.13(m,7H),2.10-2.02(m,2H),1.48-1.28(m,8H)。LCMS(ESI):C70H102N16O19的质量计算值为1470.75m/z,实测值为1471.9[M+H]+。
实施例201免疫缀合物(IC)的制备
在示例性程序中,为了制备基于赖氨酸的缀合,使用ZebaTM旋转脱盐柱(ThermoFisher Scientific),将抗体缓冲液交换到含有100mM硼酸盐、50mM氯化钠、1mM乙二胺四乙酸的pH 8.3的缀合缓冲液中。使用缀合缓冲液将缓冲液交换的抗体的浓度调节至约5-25mg/ml,并进行无菌过滤。将式II的双苯并咪唑-接头(BBI-L)中间体化合物溶于二甲基亚砜(DMSO)或二甲基乙酰胺(DMA)中,浓度为5-20mM。为了缀合,使抗体与4至20摩尔当量的BBI-L混合。在一些情况下,添加多达20%(v/v)的另外的DMA或DMSO以提高BBI-L在缀合缓冲液中的溶解度。使反应在20℃或30℃或37℃下进行约30分钟至4小时。使用两个连续的ZebaTM旋转脱盐柱将所得缀合物从未反应的BBI-L中纯化出来。将柱用pH 7.2的磷酸盐缓冲盐水(PBS)预平衡。使用与XEVOTM G2-XS TOF质谱仪(Waters Corporation)连接的H级ACQUITYTM UPLC(Waters Corporation,Milford,MA)上的C4反相柱,通过液相色谱质谱分析来估计佐剂与抗体比率(DAR)。
在示例性程序中,为了制备基于半胱氨酸的缀合,使用ZebaTM旋转脱盐柱(ThermoFisher Scientific)将抗体缓冲液交换到含有PBS(pH 7.2)与2mM EDTA的缀合缓冲液中。使用2-4摩尔过量的三(2-羧乙基)膦(TCEP)或二硫苏糖醇(DTT)在37℃下还原链间二硫化物30分钟-2小时。使用用缀合缓冲液预平衡的ZebaTM旋转脱盐柱移除过量的TCEP或DTT。使用缀合缓冲液将缓冲液交换的抗体的浓度调节至约5-20mg/ml,并进行无菌过滤。将BBI-L溶于二甲亚砜(DMSO)或二甲基乙酰胺(DMA)中至浓度为5-20mM。为了缀合,使抗体与10-20摩尔当量的BBI-L混合。在一些情况下,添加多达20%(v/v)的另外的DMA或DMSO以提高BBI-L在缀合缓冲液中的溶解度。使反应在20℃下进行约30分钟至4小时。使用两个连续的ZebaTM旋转脱盐柱将所得缀合物从未反应的BBI-L中纯化出来。将柱用pH 7.2的磷酸盐缓冲盐水(PBS)预平衡。使用与XEVOTM G2-XS TOF质谱仪(Waters Corporation)连接的H级ACQUITYTMUPLC(Waters Corporation,Milford,MA)上的C4反相柱,通过液相色谱质谱分析来估计佐剂与抗体比率(DAR)。
在缀合后,为了潜在地去除未反应的BBI-L和/或更高分子量的聚集体,可以使用尺寸排阻色谱法、疏水相互作用色谱法、离子交换色谱法、色谱聚焦、超滤、离心超滤、切向流过滤及其组合来进一步纯化缀合物。
在另一个示例性程序中,使用G-25SEPHADEXTM脱盐柱(Sigma-Aldrich,St.Louis,MO),将抗体缓冲液交换到pH 8.3的含有100mM硼酸、50mM氯化钠、1mM乙二胺四乙酸的缀合缓冲液中。然后使用缓冲液将洗脱液各自调节至约1-10mg/ml的浓度,然后无菌过滤。将抗体预热至20-30℃并与2-20(例如,7-10)摩尔当量的式II的双苯并咪唑-接头(BBI-L)中间体化合物快速混合。使反应在30℃进行约16小时,通过在pH 7.2的磷酸盐缓冲盐水(PBS)中平衡的两个连续G-25脱盐柱上运行将免疫缀合物(IC)与反应物分离,以提供表2的免疫缀合物(IC)。佐剂-抗体比率(DAR)是通过使用连接到XEVOTM G2-XS TOF质谱仪(WatersCorporation)的ACQUITYTM UPLC H类(Waters Corporation,Milford,MA)上的C4反相柱进行液相色谱质谱分析来确定的。
为了缀合,可以将抗体溶解在本领域中已知将不会对抗体的稳定性或抗原结合特异性产生不利影响的水性缓冲系统中。可以使用磷酸盐缓冲盐水。将BBI-L溶解在包含至少一种如本文别处所述的极性非质子溶剂的溶剂系统中。在一些这样的方面中,将BBI-L在pH8的Tris缓冲液(例如,50mM Tris)中溶解至浓度为约5mM、约10mM、约20mM、约30mM、约40mM或约50mM及其范围,如约5mM至约50mM或约10mM至约30mM。在一些方面,将BBI-L溶解在DMSO(二甲亚砜)、DMA(二甲基乙酰胺)或乙腈或另一种合适的偶极非质子溶剂中。
或者在缀合反应中,可以稀释等量过量的BBI-L溶液,并与抗体溶液合并。BBI-L溶液可以合适地用至少一种极性非质子溶剂和至少一种极性质子溶剂稀释,其实例包括水、甲醇、乙醇、正丙醇和乙酸。噻吩并氮杂-接头中间体与抗体的摩尔当量可以为约1.5:1、约3:1、约5:1、约10:1、约15:1或约20:1及其范围,如约1.5:1至约20:1、约1.5:1至约15:1、约1.5:1至约10:1、约3:1至约15:1、约3:1至约10:1、约5:1至约15:1或约5:1至约10:1。可以通过本领域中已知的方法如LC-MS合适地监测反应的完成。缀合反应通常在约1小时至约16小时的范围内完成。反应完成后,可以向反应混合物中添加试剂以淬灭反应。如果抗体硫醇基团与硫醇反应性基团(如BBI-L的马来酰亚胺)反应,则未反应的抗体硫醇基团可与封端试剂反应。合适的封端试剂的一个示例是乙基马来酰亚胺。
在缀合之后,可以通过本领域中已知的纯化方法将免疫缀合物纯化并与未缀合的反应物和/或缀合物聚集体分离,所述纯化方法例如但不限于尺寸排阻色谱法、疏水相互作用色谱法、离子交换色谱法、色谱聚焦、超滤、离心超滤、切向流过滤及其组合。例如,纯化之前可以稀释免疫缀合物,例如在pH 5的20mM琥珀酸钠中稀释。将稀释的溶液施加到阳离子交换柱上,然后用例如至少10个柱体积的pH5的20mM琥珀酸钠洗涤。可以合适地用缓冲液如PBS洗脱缀合物。
实施例202HTRF结合测定
在改编自人STING WT结合测定的生化均相时间分辨荧光(HTRF)结合测定(“HTRF,A guide to Homogeneous Time Resolved Fluorescence”,(2021)PerkinElmer Cisbio;Mathis,G.Clinical Chemistry,41(9):1391–1397)中评估本发明的不对称双苯并咪唑化合物(BBI)。简而言之,将6His标记的STING蛋白与铽穴状化合物标记的抗6His抗体、d2标记的2',3'-cGAMP以及各种浓度的测试物品在384孔板格式中孵育。通过酶标仪分别在665nm和615nm处测量每个孔的供体和受体发射信号,并使用信号比来计算d2标记的2',3'-cGAMP环状二核苷酸结合的抑制百分比。使用根据这些数据生成的剂量反应曲线计算IC50值。
实施例203免疫缀合物的功能评估,PBMC测定
可以使用与表达靶抗原的肿瘤细胞共培养的原代人外周血单核细胞(PBMC)在共培养测定中评估本发明的免疫缀合物。简而言之,PBMC是通过密度离心从健康人供体血液(斯坦福血液中心)中新鲜分离出来的。然后将PBMC与表达抗原的肿瘤细胞以10:1的效应物与靶标比在完全培养基(补充有10%FBS的RPMI)中共培养,并与一系列浓度的指定测试物一起孵育过夜。通过LEGENDPLEXTM细胞因子珠阵列(BioLegend),通过促炎细胞因子(例如IFNλ1和TNFα)的分泌来测量激活。
实施例204体外免疫缀合物活性的评估
该实施例表明本发明的免疫缀合物在引发骨髓激活方面(例如在树突状细胞中)是有效的,并且因此可用于治疗癌症。
人常规树突细胞的分离:通过密度梯度离心从获自健康献血者的人外周血(Stanford Blood Center,Palo Alto,California)中负向选择人常规树突细胞(cDC)。简言之,首先通过使用ROSETTESEPTM人CD3耗竭混合物(Stem Cell Technologies,Vancouver,Canada)从细胞制剂中移除T细胞来富集细胞。然后使用EASYSEPTM人髓样DC富集试剂盒(Stem Cell Technologies)经由负向选择进一步富集cDC。
cDC激活测定:将8x 104个APC与表达ISAC靶抗原的肿瘤细胞以10:1的效应物(cDC)与靶标(肿瘤细胞)比率共培养。将细胞在含有RPMI-1640培养基的96孔板(Corning,Corning,NY)中温育,所述培养基补充有10% FBS和(在指出的情况下)各种浓度的本发明指示的免疫缀合物(如根据上述实施例制备)。过夜温育约18小时之后,收集无细胞上清液,并使用BioLegend LEGENDPLEX细胞因子珠粒阵列分析细胞因子分泌(包括TNFα)。
除了所描述的利用不同的髓样群体的测定之外,还可以采用各种筛选测定法来测量髓样细胞类型的激活。这些可包括以下:分离自健康供体血液的单核细胞、M-CSF分化的巨噬细胞、GM-CSF分化的巨噬细胞、GM-CSF+IL-4单核细胞源性树突细胞、分离自健康供体血液的常规树突细胞(cDC)和极化至免疫抑制状态的髓样细胞(也称为髓样源性抑制细胞或MDSC)。MDSC极化的细胞的实例包括向免疫抑制状态分化的单核细胞,例如M2a MΦ(IL4/IL13)、M2c MΦ(IL10/TGFb)、GM-CSF/IL6 MDSC和肿瘤驯化的单核细胞(tumor-educatedmonocyte,TEM)。可以使用肿瘤条件培养基(例如786.O、MDA-MB-231、HCC1954)进行TEM分化。原发性肿瘤相关髓样细胞还可以包括存在于解离的肿瘤细胞悬浮液中的原发性细胞(Discovery Life Sciences)。
对所述髓样细胞群体的激活的评估可以作为单一培养物或作为与表达所关注的抗原的细胞的共培养物进行,免疫缀合物可经由抗体的CDR区与所关注的抗原结合。温育18-48小时之后,可通过采用流式细胞术上调细胞表面共刺激分子或通过测量分泌的促炎细胞因子来评估激活。对于细胞因子测量,收获无细胞上清液,并采用流式细胞术通过细胞因子珠粒阵列(例如来自Biolegend的LegendPlex)进行分析。
本文引用的所有参考文献(包括出版物、专利申请和专利)以引用的方式特此并入,其程度如同指示每个参考文献单独且具体地以引用的方式并入,并且在本文中全文阐述。
Claims (53)
1.一种免疫缀合物,其包含通过接头与一个或多个STING激动剂部分共价连接的抗体,并且具有式I:
Ab-[L-D]p I
或其药学上可接受的盐,
其中:
Ab是抗体;
p是1至8的整数;
D是具有下式的STING激动剂部分:
其中,
Xa和Xb独立地选自五元杂芳基,其任选地被R5取代;
R1选自由以下组成的组:H、F、Cl、Br、I、-CN、-OH、-O-(C1-C6烷基)和R5;
R2a和R2b独立地选自-C(=O)N(R6)2和R5;
R3选自由以下组成的组:-(C1-C6烷基二基)-、-(C1-C3烷基二基)-O-(C1-C3烷基二基)-、-(C1-C6烷基二基)-O-、-(C1-C3烷基二基)-O-(C1-C3烷基二基)-O-、-(C2-C6烯基二基)-、-(C2-C6烯基二基)-O-、-(C2-C6炔基二基)-、-(C2-C6炔基二基)-O-、-(C1-C6烷基二基)-N(R5)C(=O)-、-(C1-C6烷基二基)-N(R5)S(O)2-、-(C1-C6烷基二基)-N(R5)C(=O)-(C1-C6烷基二基)-、-(C1-C6烷基二基)-N(R5 )S(O)2-(C1-C6烷基二基)-、-(C1-C6烷基二基)-N(R6)C(=O)-、-(C1-C6烷基二基)-N(R6)S(O)2-、-(C1-C6烷基二基)-N(R6)C(=O)-(C1-C6烷基二基)-和-(C1-C6烷基二基)-N(R6)S(O)2-(C1-C6烷基二基)-,其中烷基二基、烯基二基和炔基二基任选地被一个或多个选自以下的基团取代:F、Cl、-OH、-OCH3、-OCH2CH3、-OCH2CH2OCH3、-OCH2CH2OH、-OCH2CH2N(CH3)2和R5;
其中Xa、Xb、R1、R2a、R2b和R3中的一个被R5取代;
R4选自由以下组成的组:H、C1-C6烷基、C2-C6烯基和C2-C6炔基,其任选地被一个或多个选自以下的基团取代:F、Cl、-OH、-OCH3、-OCH2CH3、-OCH2CH2OCH3、-OCH2CH2OH、-OCH2CH2N(CH3)2;
R5选自由以下组成的组:
-(C1-C12烷基二基)-*;
-(C1-C12烷基二基)-N(R6)-*;
-(C1-C12烷基二基)-O-*;
-(C1-C12烷基二基)-(C2-C20杂环基二基)-*;
-O-(C1-C12烷基二基)-*;
-O-(C1-C12烷基二基)-N(R6)-*;
-O-(C1-C12烷基二基)-O-*;
-O-(C1-C12烷基二基)-(C2-C20杂环基二基)-*;
-O-(C1-C12烷基二基)-(C2-C20杂环基二基)-N(R6)-*;
-OC(=O)N(R6)-*;
-OC(=O)N(R6)-(C1-C12烷基二基)-N(R6)-*;
-N(R6)-*;
-N(R6)-(C1-C12烷基二基)-*;
-N(R6)-(C1-C12烷基二基)-N(R6)-*;
-N(R6)-(C1-C12烷基二基)-O-*;
-N(R6)-(C1-C12烷基二基)-(C2-C20杂环基二基)-*;
-C(=O)N(R6)-*;
-C(=O)N(R6)-(C1-C12烷基二基)-*;
-C(=O)N(R6)-(C1-C12烷基二基)-N(R6)-*;
-C(=O)N(R6)-(C1-C12烷基二基)-O-*;
-(C2-C20杂环基二基)-*;
-S(=O)2-(C2-C20杂环基二基)-*;以及
-S(=O)2-(C2-C20杂环基二基)-(C1-C12烷基二基)-N(R6)-*;其中星号*表示L的连接点;
R6独立地为H或C1-C6烷基;
L是选自由以下组成的组的接头:
-C(=O)-PEG-;
-C(=O)-PEG-C(=O)N(R6)-(C1-C12烷基二基)-C(=O)-Gluc-;
-C(=O)-PEG-O-;
-C(=O)-PEG-O-C(=O)-;
-C(=O)-PEG-C(=O)-;
-C(=O)-PEG-C(=O)-PEP-;
-C(=O)-PEG-N(R6)-;
-C(=O)-PEG-N(R6)-C(=O)-;
-C(=O)-PEG-N(R6)-PEG-C(=O)-PEP-;
-C(=O)-PEG-N+(R6)2-PEG-C(=O)-PEP-;
-C(=O)-PEG-C(=O)-PEP-N(R6)-(C1-C12烷基二基)-;
-C(=O)-PEG-C(=O)-PEP-N(R6)-(C1-C12烷基二基)N(R6)C(=O)-(C2-C5单杂环基二基)-;
-C(=O)-PEG-SS-(C1-C12烷基二基)-OC(=O)-;
-C(=O)-PEG-SS-(C1-C12烷基二基)-C(=O)-;
-C(=O)-(C1-C12烷基二基)-C(=O)-PEP-;
-C(=O)-(C1-C12烷基二基)-C(=O)-PEP-N(R6)-(C1-C12烷基二基)-;
-C(=O)-(C1-C12烷基二基)-C(=O)-PEP-N(R6)-(C1-C12烷基二基)-N(R5)-C(=O);
-C(=O)-(C1-C12烷基二基)-C(=O)-PEP-N(R6)-(C1-C12烷基二基)-N(R6)C(=O)-(C2-C5单杂环基二基)-;
-琥珀酰亚胺基-(CH2)m-C(=O)N(R6)-PEG-;
-琥珀酰亚胺基-(CH2)m-C(=O)N(R6)-PEG-C(=O)N(R6)-(C1-C12烷基二基)-C(=O)-Gluc-;
-琥珀酰亚胺基-(CH2)m-C(=O)N(R6)-PEG-O-;
-琥珀酰亚胺基-(CH2)m-C(=O)N(R6)-PEG-O-C(=O)-;
-琥珀酰亚胺基-(CH2)m-C(=O)N(R6)-PEG-C(=O)-;
-琥珀酰亚胺基-(CH2)m-C(=O)N(R6)-PEG-N(R5)-;
-琥珀酰亚胺基-(CH2)m-C(=O)N(R6)-PEG-N(R5)-C(=O)-;
-琥珀酰亚胺基-(CH2)m-C(=O)N(R6)-PEG-C(=O)-PEP-;
-琥珀酰亚胺基-(CH2)m-C(=O)N(R6)-PEG-SS-(C1-C12烷基二基)-OC(=O)-;
-琥珀酰亚胺基-(CH2)m-C(=O)-PEP-N(R6)-(C1-C12烷基二基)-;
-琥珀酰亚胺基-(CH2)m-C(=O)-PEP-N(R6)-(C1-C12烷基二基)N(R6)C(=O)-;和
-琥珀酰亚胺基-(CH2)m-C(=O)-PEP-N(R6)-(C1-C12烷基二基)N(R6)C(=O)-(C2-C5单杂环基二基)-;
PEG具有下式:-(CH2CH2O)n-(CH2)m-;m是1至5的整数,且n是2至50的整数;
Gluc具有下式:
PEP具有下式:
其中AA独立地选自天然或非天然氨基酸侧链,或者AA中的一者或多者和相邻的氮原子形成五元环脯氨酸氨基酸,且波浪线指示连接点;
Cyc选自C6-C20芳基二基和C1-C20杂芳基二基,其任选地被一个或多个选自F、Cl、NO2、-OH、-OCH3和具有如下结构的葡糖醛酸的基团取代:
R7选自由-CH(R8)O-、-CH2-、-CH2N(R8)-和-CH(R8)O-C(=O)-
组成的组,其中R8选自H、C1-C6烷基、C(=O)-C1-C6烷基和-C(=O)N(R9)2,其中R9独立地选自由H、C1-C12烷基和-(CH2CH2O)n-(CH2)m-OH组成的组,其中m是1至5的整数,且n是2至50的整数,或者两个R9基团一起形成5或6元杂环基环;
y是2至12的整数;
z是0或1;且
烷基、烷基二基、烯基、烯基二基、炔基、炔基二基、芳基、芳基二基、碳环基、碳环基二基、杂环基、杂环基二基、杂芳基和杂芳基二基独立且任选被一个或多个独立地选自以下的基团取代:F、Cl、Br、I、-CN、-CH3、-CH2CH3、-CH=CH2、-C≡CH、-C≡CCH3、-CH2CH2CH3、-CH(CH3)2、-CH2CH(CH3)2、-CH2OH、-CH2OCH3、-CH2CH2OH、-C(CH3)2OH、-CH(OH)CH(CH3)2、-C(CH3)2CH2OH、-CH2CH2SO2CH3、-CH2OP(O)(OH)2、-CH2F、-CHF2、-CF3、-CH2CF3、-CH2CHF2、-CH(CH3)CN、-C(CH3)2CN、-CH2CN、-CH2NH2、-CH2NHSO2CH3、-CH2NHCH3、-CH2N(CH3)2、-CO2H、-COCH3、-CO2CH3、-CO2C(CH3)3、-COCH(OH)CH3、-CONH2、-CONHCH3、-CON(CH3)2、-C(CH3)2CONH2、-NH2、-NHCH3、-N(CH3)2、-NH COCH3、-N(CH3)COCH3、-NHS(O)2CH3、-N(CH3)C(CH3)2CONH2、-N(CH3)CH2CH2S(O)2CH3、-NHC(=NH)H、-NHC(=NH)CH3、-NHC(=NH)NH2、-NHC(=O)NH2、-NO2、=O、-OH、-OCH3、-OCH2CH 3、-OCH2CH2OCH3、-OCH2CH2OH、-OCH2CH2N(CH3)2、-O(CH2CH2O)n-(CH2)mCO2H、-O(CH2CH2O)nH、-OCH2F、-OCHF2、-OCF3、-OP(O)(OH)2、-S(O)2N(CH3)2、-SCH3、-S(O)2CH3和-S(O)3H。
2.如权利要求1所述的免疫缀合物,其中所述抗体是免疫检查点抑制剂。
3.如权利要求1所述的免疫缀合物,其中所述抗体是具有结合PD-L1的抗原结合结构域的抗体构建体。
4.如权利要求3所述的免疫缀合物,其中所述抗体选自由以下组成的组:阿特珠单抗、度伐利尤单抗和阿维鲁单抗,或其生物仿制药或改良型生物相似性药物。
5.如权利要求1所述的免疫缀合物,其中所述抗体是具有结合HER2的抗原结合结构域的抗体构建体。
6.如权利要求5所述的免疫缀合物,其中所述抗体选自由以下组成的组:曲妥珠单抗和帕妥珠单抗,或其生物仿制药或改良型生物相似性药物。
7.如权利要求1所述的免疫缀合物,其中所述抗体是具有结合CEA的抗原结合结构域的抗体构建体。
8.如权利要求7所述的免疫缀合物,其中所述抗体是拉贝珠单抗或其生物仿制药或改良型生物相似性药物。
9.如权利要求1所述的免疫缀合物,其中所述抗体是具有结合TROP2的抗原结合结构域的抗体构建体。
10.如权利要求9所述的免疫缀合物,其中所述抗体是sacituzumab,或其生物仿制药或改良型生物相似性药物。
11.如权利要求1至10中任一项所述的免疫缀合物,其中Xa和Xb独立地选自由以下组成的组:咪唑基、吡唑基、三唑基、四唑基、呋喃基、噻吩基、异噁唑基、噻唑基、噁二唑基、噁唑基、异噻唑基、吡咯基、噁二唑基和噻二唑基。
12.如权利要求11所述的免疫缀合物,其中Xa和Xb各自为吡唑基,被一个或多个选自以下的基团取代:-CH3、-CH2CH3、-CH=CH2、-C≡CH、-C≡CCH3、-CH2CH2CH3、-CH(CH3)2和-CH2CH(CH3)2。
13.如权利要求1至10中任一项所述的免疫缀合物,其中Xa和Xb中的一个被R5取代。
14.如权利要求1至10中任一项所述的免疫缀合物,其中R1选自由以下组成的组:-OCH3、-OCH2CH3、-OCH2CH2OCH3、-OCH2CH2OH和-OCH2CH2N(CH3)2。
15.如权利要求14所述的免疫缀合物,其中R1是-OCH3。
16.如权利要求1至10中任一项所述的免疫缀合物,其中R1是F。
17.如权利要求1至10中任一项所述的免疫缀合物,其中R2a和R2b各自为-C(=O)NH2。
18.如权利要求1至10中任一项所述的免疫缀合物,其中R2a和R2b中的一个被R5取代。
19.如权利要求1至10中任一项所述的免疫缀合物,其中R3选自-CH2CH2-、-CH=CH-和-C≡C-。
20.如权利要求1至10中任一项所述的免疫缀合物,其中R3是C2-C4烯基二基,其被一个或多个选自F、-OH和-OCH3的基团取代。
21.如权利要求1至10中任一项所述的免疫缀合物,其中R4是-O-(C1-C12烷基二基)-(C2-C20杂环基二基)-*。
22.如权利要求21所述的免疫缀合物,其中C1-C12烷基二基是丙基二基并且C2-C20杂环基二基是哌啶基。
23.如权利要求1至10中任一项所述的免疫缀合物,其中R1和R4中的一个被R5取代。
24.如权利要求1至10中任一项所述的免疫缀合物,其中L是-C(=O)-PEG-或-C(=O)-PEG-C(=O)-。
25.如权利要求1至10中任一项所述的免疫缀合物,其中L连接至所述抗体的半胱氨酸硫醇。
26.如权利要求1至10中任一项所述的免疫缀合物,其中对于所述PEG,m是1或2,且n是2至10的整数。
27.如权利要求26所述的免疫缀合物,其中n是10。
28.如权利要求1至10中任一项所述的免疫缀合物,其中L包含PEP,并且PEP是二肽且具有下式:
29.如权利要求28所述的免疫缀合物,其中AA1和AA2独立地选自H、-CH3、-CH(CH3)2、-CH2(C6H5)、-CH2CH2CH2CH2NH2、-CH2CH2CH2NHC(NH)NH2、-CHCH(CH3)CH3、-CH2SO3H和-CH2CH2CH2NHC(O)NH2;或者AA1和AA2形成5元环脯氨酸氨基酸。
30.如权利要求28所述的免疫缀合物,其中AA1是-CH(CH3)2,且AA2是-CH2CH2CH2NHC(O)NH2。
31.如权利要求28所述的免疫缀合物,其中AA1和AA2独立地选自GlcNAc天冬氨酸、-CH2SO3H和-CH2OPO3H。
32.如权利要求28所述的免疫缀合物,其中PEP具有下式:
其中AA1和AA2独立地选自天然存在的氨基酸的侧链。
33.如权利要求1至10中任一项所述的免疫缀合物,其中L包含PEP,并且PEP是三肽且具有下式:
34.如权利要求1至10中任一项所述的免疫缀合物,其中L包含PEP,并且PEP是四肽且具有下式:
35.如权利要求34所述的免疫缀合物,其中
AA1选自由Abu、Ala和Val组成的组;
AA2选自由Nle(O-Bzl)、Oic和Pro组成的组;
AA3选自由Ala和Met(O)2组成的组;且
AA4选自由Oic、Arg(NO2)、Bpa和Nle(O-Bzl)组成的组。
36.如权利要求1至10中任一项所述的免疫缀合物,其中L包含PEP,且PEP选自由以下组成的组:Ala-Pro-Val、Asn-Pro-Val、Ala-Ala-Val、Ala-Ala-Pro-Ala、Ala-Ala-Pro-Val和Ala-Ala-Pro-Nva。
37.如权利要求1至10中任一项所述的免疫缀合物,其中L包含PEP,且PEP选自以下结构:
38.如权利要求1至10中任一项所述的免疫缀合物,其中L选自以下结构:
其中波浪线指示与R5的连接。
39.一种具有式II的STING激动剂-接头中间体化合物:
其中,
Xa和Xb独立地选自五元杂芳基,其任选地被R5取代;
R1选自由以下组成的组:H、F、Cl、Br、I、-CN、-OH、-O-(C1-C6烷基)和R5;
R2a和R2b独立地选自-C(=O)N(R6)2和R5;
R3选自由以下组成的组:-(C1-C6烷基二基)-、-(C1-C3烷基二基)-O-(C1-C3烷基二基)-、-(C1-C6烷基二基)-O-、-(C1-C3烷基二基)-O-(C1-C3烷基二基)-O-、-(C2-C6烯基二基)-、-(C2-C6烯基二基)-O-、-(C2-C6炔基二基)-、-(C2-C6炔基二基)-O-、-(C1-C6烷基二基)-N(R5)C(=O)-、-(C1-C6烷基二基)-N(R5)S(O)2-、-(C1-C6烷基二基)-N(R5)C(=O)-(C1-C6烷基二基)-、-(C1-C6烷基二基)-N(R5)S(O)2-(C1-C6烷基二基)-、-(C1-C6烷基二基)-N(R6)C(=O)-、-(C1-C6烷基二基)-N(R6)S(O)2-、-(C1-C6烷基二基)-N(R6)C(=O)-(C1-C6烷基二基)-和-(C1-C6烷基二基)-N(R6)S(O)2-(C1-C6烷基二基)-,其中烷基二基、烯基二基和炔基二基任选地被一个或多个选自以下的基团取代:F、Cl、-OH、-OCH3、-OCH2CH3、-OCH2CH2OCH3、-OCH2CH2OH、-OCH2CH2N(CH3)2和R5;
其中Xa、Xb、R1、R2a、R2b和R3中的一个被R5取代;
R4选自由以下组成的组:H、C1-C6烷基、C2-C6烯基和C2-C6炔基,其任选地被一个或多个选自以下的基团取代:F、Cl、-OH、-OCH3、-OCH2CH3、-OCH2CH2OCH3、-OCH2CH2OH、-OCH2CH2N(CH3)2;
R5选自由以下组成的组:
-(C1-C12烷基二基)-L;
-(C1-C12烷基二基)-N(R6)-L;
-(C1-C12烷基二基)-O-L;
-(C1-C12烷基二基)-(C2-C20杂环基二基)-L;
-O-(C1-C12烷基二基)-L;
-O-(C1-C12烷基二基)-N(R6)-L;
-O-(C1-C12烷基二基)-O-L;
-O-(C1-C12烷基二基)-(C2-C20杂环基二基)-L;
-O-(C1-C12烷基二基)-(C2-C20杂环基二基)-N(R6)-L;
-OC(=O)N(R6)-L;
-OC(=O)N(R6)-(C1-C12烷基二基)-N(R6)-L;
-N(R6)-L;
-N(R6)-(C1-C12烷基二基)-L;
-N(R6)-(C1-C12烷基二基)-N(R6)-L;
-N(R6)-(C1-C12烷基二基)-O-L;
-N(R6)-(C1-C12烷基二基)-(C2-C20杂环基二基)-L;
-C(=O)N(R6)-L;
-C(=O)N(R6)-(C1-C12烷基二基)-L;
-C(=O)N(R6)-(C1-C12烷基二基)-N(R6)-L;
-C(=O)N(R6)-(C1-C12烷基二基)-O-L;
-(C2-C20杂环基二基)-L;
-S(=O)2-(C2-C20杂环基二基)-L;以及
-S(=O)2-(C2-C20杂环基二基)-(C1-C12烷基二基)-N(R6)-L;R6独立地为H或C1-C6烷基;
L是选自由以下组成的组的接头:
Q-C(=O)-PEG-;
Q-C(=O)-PEG-Gluc-R7;-
Q-C(=O)-PEG-O-;
Q-C(=O)-PEG-O-C(=O)-;
Q-C(=O)-PEG-C(=O)-;
Q-C(=O)-PEG-C(=O)-PEP-;
Q-C(=O)-PEG-N(R6)-;
Q-C(=O)-PEG-N(R6)-C(=O)-;
Q-C(=O)-PEG-N(R6)-PEG-C(=O)-PEP-;
Q-C(=O)-PEG-N+(R6)2-PEG-C(=O)-PEP-;
Q-C(=O)-PEG-C(=O)-PEP-N(R6)-(C1-C12烷基二基)-;
Q-C(=O)-PEG-C(=O)-PEP-N(R6)-(C1-C12烷基二基)N(R6)C(=O)-(C2-C5单杂环基二基)-;
Q-C(=O)-PEG-SS-(C1-C12烷基二基)-OC(=O)-;
Q-C(=O)-PEG-SS-(C1-C12烷基二基)-C(=O)-;
Q-C(=O)-(C1-C12烷基二基)-C(=O)-PEP-;
Q-C(=O)-(C1-C12烷基二基)-C(=O)-PEP-N(R6)-(C1-C12烷基二基)-;
Q-C(=O)-(C1-C12烷基二基)-C(=O)-PEP-N(R6)-(C1-C12烷基二基)-N(R5)-C(=O);
Q-C(=O)-(C1-C12烷基二基)-C(=O)-PEP-N(R6)-(C1-C12烷基二基)-N(R6)C(=O)-(C2-C5单杂环基二基)-;
Q-(CH2)m-C(=O)N(R6)-PEG-;
Q-(CH2)m-C(=O)N(R6)-PEG-Gluc-R7-;
Q-(CH2)m-C(=O)N(R6)-PEG-O-;
Q-(CH2)m-C(=O)N(R6)-PEG-O-C(=O)-;
Q-(CH2)m-C(=O)N(R6)-PEG-C(=O)-;
Q-(CH2)m-C(=O)N(R6)-PEG-N(R5)-;
Q-(CH2)m-C(=O)N(R6)-PEG-N(R5)-C(=O)-;
Q-(CH2)m-C(=O)N(R6)-PEG-C(=O)-PEP-;
Q-(CH2)m-C(=O)N(R6)-PEG-SS-(C1-C12烷基二基)-OC(=O)-;
Q-(CH2)m-C(=O)-PEP-N(R6)-(C1-C12烷基二基)-;
Q-(CH2)m-C(=O)-PEP-N(R6)-(C1-C12烷基二基)N(R6)C(=O)-;和
Q-(CH2)m-C(=O)-PEP-N(R6)-(C1-C12烷基二基)N(R6)C(=O)-(C2-C5单杂环基二基)-;
PEG具有下式:-(CH2CH2O)n-(CH2)m-;m是1至5的整数,且n是2至50的整数;
Gluc具有下式:
PEP具有下式:
其中AA独立地选自天然或非天然氨基酸侧链,或者AA中的一者或多者和相邻的氮原子形成五元环脯氨酸氨基酸,且波浪线指示连接点;
Cyc选自C6-C20芳基二基和C1-C20杂芳基二基,其任选地被一个或多个选自F、Cl、NO2、-OH、-OCH3和具有如下结构的葡糖醛酸的基团取代:
R7选自由-CH(R8)O-、-CH2-、-CH2N(R8)-和-CH(R8)O-C(=O)-组成的组,其中R8选自H、C1-C6烷基、C(=O)-C1-C6烷基和-C(=O)N(R9)2,其中R9独立地选自由H、C1-C12烷基和-(CH2CH2O)n-(CH2)m-OH组成的组,其中m是1至5的整数,且n是2至50的整数,或者两个R9基团一起形成5或6元杂环基环;
y是2至12的整数;
z是0或1;
Q选自由以下组成的组:N-羟基琥珀酰亚胺基、N-羟基磺基琥珀酰亚胺基、马来酰亚胺和被一个或多个独立地选自F、Cl、NO2和SO3 -的基团取代的苯氧基;且
烷基、烷基二基、烯基、烯基二基、炔基、炔基二基、芳基、芳基二基、碳环基、碳环基二基、杂环基、杂环基二基、杂芳基和杂芳基二基独立且任选被一个或多个独立地选自以下的基团取代:F、Cl、Br、I、-CN、-CH3、-CH2CH3、-CH=CH2、-C≡CH、-C≡CCH3、-CH2CH2CH3、-CH(CH3)2、-CH2CH(CH3)2、-CH2OH、-CH2OCH3、-CH2CH2OH、-C(CH3)2OH、-CH(OH)CH(CH3)2、-C(CH3)2CH2OH、-CH2CH2SO2CH3、-CH2OP(O)(OH)2、-CH2F、-CHF2、-CF3、-CH2CF3、-CH2CHF2、-CH(CH3)CN、-C(CH3)2CN、-CH2CN、-CH2NH2、-CH2NHSO2CH3、-CH2NHCH3、-CH2N(CH3)2、-CO2H、-COCH3、-CO2CH3、-CO2C(CH3)3、-COCH(OH)CH3、-CONH2、-CONHCH3、-CON(CH3)2、-C(CH3)2CONH2、-NH2、-NHCH3、-N(CH3)2、-NH COCH3、-N(CH3)COCH3、-NHS(O)2CH3、-N(CH3)C(CH3)2CONH2、-N(CH3)CH2CH2S(O)2CH3、-NHC(=NH)H、-NHC(=NH)CH3、-NHC(=NH)NH2、-NHC(=O)NH2、-NO2、=O、-OH、-OCH3、-OCH2CH 3、-OCH2CH2OCH3、-OCH2CH2OH、-OCH2CH2N(CH3)2、-O(CH2CH2O)n-(CH2)mCO2H、-O(CH2CH2O)nH、-OCH2F、-OCHF2、-OCF3、-OP(O)(OH)2、-S(O)2N(CH3)2、-SCH3、-S(O)2CH3和-S(O)3H。
40.如权利要求39所述的STING激动剂-接头中间体化合物,其中Q选自:
41.如权利要求39所述的STING激动剂-接头中间体化合物,其中Q是被一个或多个独立地选自F、Cl、NO2和SO3 -的基团取代的苯氧基。
42.如权利要求40所述的STING激动剂-接头中间体化合物,其中Q是2,3,5,6-四氟苯氧基。
43.如权利要求40所述的STING激动剂-接头中间体化合物,其中Q是2,3,5,6-四氟-4-磺酸根基-苯氧基。
44.如权利要求40所述的STING激动剂-接头中间体化合物,其中Q是马来酰亚胺。
45.如权利要求39所述的STING激动剂-接头中间体化合物,其中L选自以下结构:
其中波浪线指示与R5的连接。
46.一种选自表2的STING激动剂-接头中间体化合物。
47.一种免疫缀合物,其通过将抗体与权利要求39至46中任一项所述的STING激动剂-接头中间体化合物缀合而制备。
48.一种药物组合物,其包含治疗有效量的权利要求1至10中任一项所述的免疫缀合物和一种或多种药学上可接受的稀释剂、媒介物、载体或赋形剂。
49.一种用于治疗癌症的方法,所述方法包括向有需要的患者施用治疗有效量的根据权利要求1至10中任一项所述的免疫缀合物。
50.如权利要求49所述的方法,其中所述癌症对由STING激动所诱导的促炎反应敏感。
51.如权利要求49所述的方法,其中所述癌症选自膀胱癌、唾液腺癌、子宫内膜癌、尿路癌、尿道上皮癌、肺癌、非小细胞肺癌、默克尔细胞癌、结肠癌、结肠直肠癌、胃癌和乳腺癌。
52.根据权利要求1至10中任一项所述的免疫缀合物用于治疗癌症的用途。
53.一种制备权利要求1至10中任一项所述的式I的免疫缀合物的方法,其中将权利要求39所述的STING激动剂-接头中间体化合物与所述抗体缀合。
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
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US63/251,805 | 2021-10-04 |
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