CN116196434A - 抗体-药物偶联物及其制备方法和应用 - Google Patents
抗体-药物偶联物及其制备方法和应用 Download PDFInfo
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- CN116196434A CN116196434A CN202111446804.0A CN202111446804A CN116196434A CN 116196434 A CN116196434 A CN 116196434A CN 202111446804 A CN202111446804 A CN 202111446804A CN 116196434 A CN116196434 A CN 116196434A
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Abstract
本发明提供一种抗体‑药物偶联物及其制备方法和应用,具体地,涉及一种咪唑并喹啉取代磷酸酯类激动剂通过连接子和含有Fab抗原结合结构域和Fc结构域的抗体连接构建的抗体‑药物偶联物及其制备方法和应用,其中,本发明抗体‑药物偶联物具有式(I)所示结构,其中各基团和取代基的定义如说明书中所述。本发明还公开了所述抗体‑药物偶联物的制备方法及其作为免疫激动抗体‑药物偶联物的用途。
Description
技术领域
本发明属于药物领域,具体涉及一种抗体-药物偶联物及其制备方法和应用。
背景技术
Toll样受体(Toll-like receptors,TLRs)是参与非特异性免疫(天然免疫)的一类重要蛋白质分子。当微生物突破机体的物理屏障(如皮肤或粘膜等)时,TLRs可以通过识别来源于微生物的具有保守结构的分子从而刺激产生免疫细胞应答。到目前为止已经确定的TLR至少含有13个成员:其中TLR1/TLR2异质二聚体识别三乙酰基酯肽;TLR2/TLR6异质二聚体识别三乙酰基酯肽;TLR2和TLR4能够识别细菌的表面结构(如脂蛋白、脂磷壁酸、肽聚糖及脂多糖等);TLR3识别双链RNA;TLR5识别细菌鞭毛中的鞭毛蛋白;TLR7和TLR8识别单链RNA;TLR9识别来自细菌和病毒的CpG-ODN;TLR11则识别来自弓形虫的抑制蛋白样分子。TLR1、2、4、5和6主要表达在细胞表面上,而TLR3、7、8和9主要表达在内体中。
TLR7主要是由浆细胞样树突细胞(pDC)表达和配体识别从而诱导干扰素α(INF-α)分泌。TLR8主要由骨髓免疫细胞表达和配体识别从而刺激诱导产生细胞因子,如肿瘤坏死因子α(TNFα)、白介素18(IL18)、白介素12(IL12)和干扰素γ(INF-γ)。TLR8激动剂除了可以刺激促炎细胞因子和趋化因子分泌之外,还可以促进协同刺激分子如CD8+细胞、主要组织相容性复合体分子以及趋化因子受体等的表达。
现有研究表明,激活先天性和适应性免疫反应可以诱导免疫反应,从而提供针对自身免疫、炎症、过敏、哮喘、移植排斥、移植物抗宿主病(GvHD)、感染、癌症和免疫缺陷等病症的一种治疗方法。比如针对乙型肝炎(HBV),激活专职性抗原呈递细胞(pAPCs)和其他肝内的免疫细胞上的TLR8会导致促炎细胞因子分泌,从而增加HBV特异性T细胞响应、激活肝内NK细胞以及促进体内抗病毒免疫系统的重建。
当Toll样受体激动剂进行全身给药时会激活非特异性免疫反应,严重时可能引发致命的细胞因子风暴,极大的限制了TLR激动剂的临床开发与应用。通过将TLR激动剂与抗体偶联来可以特异性靶向相关癌症抗原,实现定点递送,替代了系统性给药,从而避免非特异性免疫反应。同时通过FcγR和TLR的共同作用诱导APC激活,两种信号通路的协同活性提供了增强抗肿瘤髓样细胞功能的能力。
由于Toll样受体在病理学上与多种疾病相关,因此目前还需要新型的Toll样受体调节剂抗体-药物偶联物用于临床治疗。
发明内容
本发明的目的在于提供一类新型的咪唑并喹啉取代磷酸酯类激动剂通过连接子和含有Fab抗原结合结构域和Fc结构域的抗体连接构建的抗体-药物偶联物,具有选择性激动作用和/或更好药效学性能的化合物及其用途。
本发明的第一方面,提供一种抗体-药物偶联物包含
(a)抗体构建体,所述抗体构建体包含(i)未经修饰或经修饰的Fab抗原结合结构域和(ii)未经修饰或经修饰的Fc结构域;
(b)咪唑并喹啉取代磷酸酯类激动剂部分,或其立体异构体、互变异构体、晶型、或其药学上可接受的盐、水合物、溶剂合物或前药;和
(c)连接子,
其中每个咪唑并喹啉取代磷酸酯类激动剂部分经由所述连接子共价结合至所述抗体构建体。
在另一优选例中,所述抗体构建体还包含靶向结合结构域,如靶向抗原结合结构域、靶向FcR结合结构域等。
在另一优选例中,所述抗体构建体为抗体或Fc融合蛋白,优选地为IgG1或IgG4抗体。
在另一优选例中,所述抗原结合结构域结合至癌细胞的抗原。
在另一优选例中,所述抗原结合结构域结合至选自以下的抗原:PD-L1,CLDN18.2,CLDN6,DLL3,MUCl,MUC17,LRCC15,Nectin 4,GPC3,ROR1,ASGR1,CCR8,CDH,CD19,CD20,CD29,CD30,CD38,CD40,CD47,GPC3,EpCAM,EGFR,VEGF,SLAMF7,PDGFRa,gp75,HER2,HER3,TROP2,LIV-1,MUC16,CEACAM1,CEACAM3,CEACAM4,CEACAM5,CEACAM6,CEACAM7,CEACAM8,CEACAMl6,CEACAMl8,CEACAMl9,CEACAM20,CEACAM21,URLC10,NY-ESO-1,GAA,OF A,cyclinBI,WT-1,CEF,VEGRRl,VEGFR2,TTK,MUC1,HPVl6E7,CEA,IMA910,KOC1,SL-701,MART-1,gpl00,tyrosinase,GSK2302050A,survivin,MAGE-3.1,MAGE-10.A2,OVABiP,gp209-2M,melan-A,NA17.A2,KOCl,C016,DEPDC1,MPHOSPH1,MAGE 12,ONT-IO,GD2L,GD3L,GSK2302032A,URLC10,CDCA1,TF,rsPSMA,PSA,MUC-2,TERT,HPVl6,HPVl8,STFII,G17DT,ICT-107,Dex2,hTERT,PAP和TRP2。
在另一优选例中,所述抗原优选结合结构域结合至选自以下的抗原:EGFR,HER2,HER3,TROP2,PD-L1,CLDN18.2,CLDN6,CD38,CD47,DLL3,MUCl,MUC17,LRCC15,Nectin 4,GPC3,ROR1,ASGR1、以及CEACAM5,优选地所述抗原优选结合结构域结合至选自以下的抗原:EGFR、HER2、HER3、以及TROP2。
在另一优选例中,所述抗体选自:阿巴伏单抗、阿巴西普、阿昔单抗、阿达木单抗、阿德木单抗、阿仑单抗、阿妥莫单抗、阿非莫单抗、马安莫单抗、anetumumab、anrukizumab、阿泊珠单抗、阿西莫单抗、阿塞珠单抗、阿特利珠单抗、阿托木单抗、avelumab、巴匹珠单抗、巴利昔单抗、巴维昔单抗、贝妥莫单抗、贝利单抗、柏替木单抗、贝索单抗、贝伐单抗、比西单抗、淏烯比妥、比伐妥珠单抗、坎帕斯、康纳单抗、莫坎妥珠单抗、卡罗单抗、卡妥索单抗、西利珠单抗、赛妥珠单抗、西妥昔单抗、克立昔单抗、达西珠单抗、达昔单抗、达克珠单抗、地诺单抗、地莫单抗、阿托度单抗、多利昔珠单抗、duntumumab、durimulumab、durmulumab、durvalumab、依美昔单抗、依库丽单抗、埃巴单抗、依决洛单抗、依法利珠单抗、依芬古单抗、伊斯利莫、培戈赖莫单抗、西依匹莫单抗、西艾匹莫单抗、epitumomab、依帕珠单抗、厄利珠单抗、厄马索单抗、依那西普、伊瑞西珠、艾韦单抗、法索单抗、法拉莫单抗、泛维珠单抗、冯特利珠单抗、加利昔单抗、gantenerumab、加维莫单抗、吉妥单抗、戈利木单抗、戈利昔单抗、伊巴利珠单抗、替伊莫单抗、伊戈伏单抗、英西单抗、英夫利昔单抗、伊诺莫单抗、奥英妥珠单抗、易普利姆玛、伊妥木单抗、凯利昔单抗、拉贝珠单抗、来马索单抗、1ebrilizumab、乐地单抗、来沙木单抗、lexitumumab、利韦单抗、林妥珠单抗、鲁卡木单抗、鲁昔单抗、马帕木单抗、马司莫单抗、马妥珠单抗、美泊利单抗、美替木单抗、马妥珠单抗、明瑞莫单抗、米妥莫单抗、莫罗木单抗、莫维珠单抗、莫罗单抗、他那可单抗、伊那莫单抗、Nivolumab、那他珠单抗、奈巴库单抗、奈瑞莫单抗、尼妥珠单抗、硫诺莫单抗、ocrelizumab、奥度莫单抗、奥法木单抗、奥马珠单抗、奥戈伏单抗、奥昔珠单抗、pembrolizumab、帕吉昔单抗、帕利珠单抗、帕尼单抗、帕考珠单抗、pemtumomab、帕妥珠单抗、培克珠单抗、平妥莫单抗、普立昔单抗、普托木单抗、兰尼单抗、瑞西巴库、瑞加韦单抗、瑞利珠单抗、利妥昔单抗、罗维珠单抗、芦利珠单抗、沙妥莫单抗、司韦单抗、西罗珠单抗、希普利珠单抗、索土珠单抗、司他莫鲁、硫索单抗、替他珠单抗、他度珠单抗、他利珠单抗、帕他普莫单抗、替非珠单抗、阿替莫单抗、替奈昔单抗、替利珠单抗、替西木单抗、托珠单抗、托利珠单抗、托西莫单抗、曲妥珠单抗、替西木单抗、西莫臼介素单抗、妥韦单抗、乌珠单抗、优特克单抗、伐利昔单抗、维妥珠单抗、维帕莫单抗、维西珠单抗、伏洛昔单抗、伏妥莫单抗、扎鲁目单抗、扎木单抗、齐拉木单抗、阿佐莫单抗、达雷木单抗、elotuxumab、obintunzumab、奥拉木单抗、本妥昔单抗、阿帕西普、阿巴西普、贝拉西普、阿柏西普、依那西普、或咯咪珀咯,优选地Ab选自:帕妥珠单抗(pertuzumab)、曲妥珠单抗(trastuzumab)、或sacituzumab,或含有帕妥珠单抗(pertuzumab)、曲妥珠单抗(trastuzumab)或sacituzumab抗原部分的抗体;或其他含有抗EGFR、HER2、HER3或TROP2抗原的抗体或抗体片段,更优选地,所述抗体选是曲妥珠单抗或帕妥珠单抗。
在另一优选例中,所述抗体-药物偶联物具有式I的结构:
式中:
Ab为抗体构建体,所述抗体构建体包含(i)未经修饰或经修饰的Fab抗原结合结构域和(ii)未经修饰或经修饰的Fc结构域;
L为连接子;
D为咪唑并喹啉取代磷酸酯类激动剂部分、或其立体异构体、互变异构体、晶型、或其药学上可接受的盐、水合物、溶剂合物或前药;
a1和a2为整数或非整数,各自独立地选自0-20。
在另一优选例中,a1为1-10,优选地为1-4。
在另一优选例中,a2为1-15,优选地为1-8。
在另一优选例中,a1为1-4;a2为1-8。
在另一优选例中,Ab选自具有至少一个Fab抗原结合域和一个Fc结构域的抗体结构。
在另一优选例中,Ab为抗体或Fc融合蛋白,更优选地,Ab是曲妥珠单抗或帕妥珠单抗。
在另一优选例中,所述咪唑并喹啉取代磷酸酯类激动剂部分、或其立体异构体、互变异构体、晶型、或其药学上可接受的盐、水合物、溶剂合物或前药具有式II结构
式中:
R1选自取代或未取代的下组基团:氢、C1-C18烷基、氘代C1-C18烷基、卤代C1-C18烷基、C1-C18烷氧基、氘代C1-C18烷氧基、卤代C1-C18烷氧基、卤素、氨基、硝基、羟基、氰基、C3-C18环烷基、4-14元杂环基、C6-C10芳基、5-14元杂芳基、-(CH2)nOR5、-(CH2)nO(CH2)oR5、-(CH2)nSR5、-(CH2)nCOR5、-(CH2)nC(O)OR5、-(CH2)nS(O)mR5、-(CH2)nNR6R7、-(CH2)nC(O)NR6R7、-(CH2)nNR6C(O)R5、-(CH2)nNR6S(O)mR5;其中,所述取代指被选自下组的一个或多个基团取代:氢、氘、C1-C18烷基、氘代C1-C18烷基、卤代C1-C18烷基、C1-C18烷氧基、氘代C1-C18烷氧基、卤代C1-C18烷氧基、卤素、氨基、硝基、羟基、氰基、C3-C18环烷基、4-14元杂环基、C6-C10芳基、5-14元杂芳基、-(CH2)n'OR'5、-(CH2)n'SR'5、-(CH2)n'COR'5、-(CH2)n'C(O)OR'5、-(CH2)n'S(O)m'R'5、-(CH2)n'NR'6R'7、-(CH2)n'C(O)NR'6R'7、-(CH2)n'C(O)NHR'6、-(CH2)n'NR6C(O)R'5、-(CH2)n'NR6S(O)m'R'5;
R2相同或不同,且独立地选自下组:氢、氘、C1-C18烷基、氘代C1-C18烷基、卤代C1-C18烷基、C1-C18烷氧基、氘代C1-C18烷氧基、卤代C1-C18烷氧基、卤素、氨基、硝基、羟基、氰基、C3-C18环烷基、4-14元杂环基、C6-C10芳基、5-14元杂芳基、-(CH2)n”OR”5、-(CH2)n”SR”5、-(CH2)n”COR”5、-(CH2)n”C(O)OR”5、-(CH2)n”S(O)m”R”5、-(CH2)n”NR”6R”7、-(CH2)n”C(O)NR”6R”7、-(CH2)n”C(O)NHR”6、-(CH2)n”NR”6C(O)R”5、-(CH2)n”NR”6S(O)m”R”5;
Z选自取代或未取代的下组基团:C1-C18亚烷基、氘代C1-C18亚烷基、卤代C1-C18亚烷基、C1-C18亚烷氧基、卤代C1-C18亚烷氧基、C3-C18亚环烷基、C1-C18亚烷基C3-C18亚环烷基、C3-C18亚环烷基C1-C18亚烷基、C1-C18亚烷基C3-C18亚环烷基C1-C18亚烷基、4-14元亚杂环基、C6-C10亚芳基、5-14元亚杂芳基,其中所述取代指被选自下组的一个或多个基团取代:氢、氘、C1-C18烷基、氘代C1-C18烷基、卤代C1-C18烷基、C1-C18烷氧基、氘代C1-C18烷氧基、卤代C1-C18烷氧基、卤素、氨基、硝基、羟基、氰基、C3-C18环烷基、4-14元杂环基、C6-C10芳基、5-14元杂芳基、-(CH2)n”'OR”'5、-(CH2)n”'SR”'5、-(CH2)n”'COR”'5、-(CH2)n”'C(O)OR”'5、-(CH2)n”'S(O)m”'R”'5、-(CH2)n”'NR”'6R”'7、-(CH2)n”'C(O)NR”'6R”'7、-(CH2)n”'C(O)NHR”'6、-(CH2)n”'NR”'6C(O)R”'5、-(CH2)n”'NR”'6S(O)m”'R”'5;
Y选自:O、N或NR4;R4选自取代或未取代的下组基团:氢、C1-C18烷基、氘代C1-C18烷基、卤代C1-C18烷基、C1-C18烷氧基、氘代C1-C18烷氧基、卤代C1-C18烷氧基、C3-C18环烷基、4-14元杂环基、C6-C10芳基、5-14元杂芳基,其中所述取代指被选自下组的一个或多个基团取代:氢、氘、C1-C18烷基、氘代C1-C18烷基、卤代C1-C18烷基、C1-C18烷氧基、氘代C1-C18烷氧基、卤代C1-C18烷氧基、卤素、氨基、硝基、羟基、氰基、C3-C18环烷基、4-14元杂环基、C6-C10芳基、5-14元杂芳基、-(CH2)n””OR””5、-(CH2)n””SR””5、-(CH2)n””COR””5、-(CH2)n””C(O)OR””5、-(CH2)n””S(O)m””R””5、-(CH2)n””NR””6R””7、-(CH2)n””C(O)NR””6R””7、-(CH2)n””C(O)NHR””6、-(CH2)n””NR””6C(O)R””5、-(CH2)n””NR””6S(O)m””R””5;
R5、R'5、R”5、R”'5和R””5各自独立地选自取代或未取代的下组基团:氢、氘、C1-C18烷基、氘代C1-C18烷基、卤代C1-C18烷基、C1-C18烷氧基、氘代C1-C18烷氧基、卤代C1-C18烷氧基、氨基、羟基、氰基、C3-C18环烷基4-14元杂环基、C6-C10芳基、5-14元杂芳基,其中所述取代指被选自下组的一个或多个基团取代:氢、氘、C1-C18烷基、氘代C1-C18烷基、卤代C1-C18烷基、C1-C18烷氧基、氘代C1-C18烷氧基、卤代C1-C18烷氧基、卤素、氨基、硝基、羟基、氰基、C3-C18环烷基、4-14元杂环基、C6-C10芳基、5-14元杂芳基、-(CH2)n””'OR8、-(CH2)n””'SR8、-(CH2)n””'COR8、-(CH2)n””'C(O)OR8、-(CH2)n””'S(O)m””'R8、-(CH2)n””'NR8R9、-(CH2)n””'C(O)NR8R9、-(CH2)n””'C(O)NHR9、-(CH2)n””'NR9C(O)R8、-(CH2)n””'NR9S(O)m””'R8;
R6、R7、R'6、R'7、R”6、R”7、R”'6、R”'7、R””6和R””7相同或不同,且各自独立地选自取代或未取代的下组基团:氢、氘、C1-C18烷基、氘代C1-C18烷基、卤代C1-C18烷基、C1-C18烷氧基、氘代C1-C18烷氧基、卤代C1-C18烷氧基、氨基、羟基、C3-C18环烷基、4-14元杂环基、C6-C10芳基、5-14元杂芳基;其中,所述取代指被选自下组的一个或多个基团取代:氢、氘、C1-C18烷基、氘代C1-C18烷基、卤代C1-C18烷基、C1-C18烷氧基、氘代C1-C18烷氧基、卤代C1-C18烷氧基、卤素、氨基、硝基、羟基、氰基、C3-C18环烷基、4-14元杂环基、C6-C10芳基、5-14元杂芳基、-(CH2)n”””OR'8、-(CH2)n”””SR'8、-(CH2)n”””COR'8、-(CH2)n”””C(O)OR'8、-(CH2)n”””S(O)m”””R'8、-(CH2)n”””NR'8R'9、-(CH2)n”””C(O)NR'8R'9、-(CH2)n”””C(O)NHR'9、-(CH2)n”””NR'9C(O)R'8、-(CH2)n”””NR'9S(O)m”””R'8;
R8、R'8、R9和R'9相同或不同,且各自独立地选自取代或未取代的下组基团:氢、氘、C1-C18烷基、氘代C1-C18烷基、卤代C1-C18烷基、C1-C18烷氧基、氘代C1-C18烷氧基、卤代C1-C18烷氧基、氨基、羟基、-COOR16、C3-C18环烷基、5-14元杂环基、C6-C10芳基、5-14元杂芳基,其中,所述取代指被选自下组的一个或多个基团取代:氘、C1-C20烷基、C1-C6烷氧基、C3-C10环烷基、4-10元杂环基、C6-C10芳基、5-10元杂芳基、卤素、氨基、硝基、-COOR16、氰基、羟基、酰基、酰胺基、磺酰基、磺酰胺基;
或者R5和R6以及相邻的原子、R5'和R6'以及相邻的原子、R5”和R6”以及相邻的原子、R5”'和R6”'以及相邻的原子、R5””和R6””以及相邻的原子、R6和R7以及相邻的原子、R6'和R7'以及相邻的原子、R6”和R7”以及相邻的原子、R6”'和R7”'以及相邻的原子、R6””和R7”'以及相邻的原子、R8和R9以及相邻的原子、R8'和R9'以及相邻的原子环合形成4-8元杂环基;
X选自下组:-P(=O)(OH)2、-P(=O)(OH)OP(=O)(OH)2、-P(=O)(OH)OP(=O)(OH)OP(=O)(OH)2、-P(=O)(X1R11)(X2R12)、-P(=O)(X1R11)(X3R14R15)、-P(=O)(X3R14R15)(X3R14R15)、-CH2P(=O)(X1R11)(X2R12)、-CH2P(=O)(X1R11)(X3R14R15)、-CH2P(=O)(X3R14R15)(X3R14R15)、-P(=S)(X1R11)(X2R12)、-P(=S)(X1R11)(X3R14R15)、-P(=S)(X3R14R15)(X3R14R15)、-CH2P(=S)(X1R11)(X2R12)、-CH2P(=S)(X1R11)(X3R14R15)、-CH2P(=S)(X3R14R15)(X3R14R15)、-P(=NR13)(X1R11)(X2R12)、-P(=NR13)(X1R11)(X3R14R15)、-P(=NR13)(X3R14R15)(X3R14R15)、-CH2P(=NR13)(X1R11)(X2R12)、-CH2P(=NR13)(X1R11)(X3R14R15)、-CH2P(=NR13)(X3R14R15)(X3R14R15);
X1、X2各自独立地选自下组:氧、硫、-OCH2O-;
X3为氮;
R11、R12、R13、R14、R15各自独立地选自取代或未取代的下组基团:氢、C1-C20烷基、C1-C20氘代烷基、C1-C20卤代烷基、C3-C10环烷基、4-10元杂环基、C6-C10芳基、5-10元杂芳基、C1-C6烷基C3-C20环烷基、C1-C6烷基4-10元杂环基、C1-C6烷基C6-C10芳基、C1-C6烷基5-10元杂芳基,或者R11和R12与相邻的X1、X2和P结合形成取代的4-7元杂环基,所述取代指被选自下组的一个或多个取代基取代:-R16、-OR16、-COR16、-COOR16、-OCOOR16、-SOR16、-SO2R16、-NHR16、-N(C1-C6烷基)R16、-N(C3-C6环烷基)R16、-N(4-6元杂环基)R16、-N(C6-C10芳基)R16、-N(5-6元杂芳基)R16、-CONHR16、-CON(C1-C6烷基)R16、-CON(C3-C6环烷基)R16、-CON(4-6元杂环基)R16、-CON(C6-C10芳基)R16、-CON(5-6元杂芳基)R16、-NHCOR16、-N(C1-C6烷基)COR16、-N(C3-C6环烷基)COR16、-N(4-6元杂环基)COR16、-N(C6-C10芳基)COR16、-N(5-6元杂芳基)COR16、-SO2NHR16、-SO2N(C1-C6烷基)R16、-SO2N(C3-C6环烷基)R16、-NSO2(4-6元杂环基)R16、-SO2N(C6-C10芳基)R16、-SO2N(5-6元杂芳基)R16、14元14元卤素、硝基、氰基;
R16选自取代或未取代的下组基团:氢、氘、氨基、C1-C18烷基、卤代C1-C20烷基、C1-C18烷氧基、C1-C18氘代烷基、C3-C10环烷基、C3-C10环烯基、4-10元杂环基、C6-C10芳基、卤代C6-C10芳基、5-10元杂芳基、卤代5-10元杂芳基、C1-C20烷基C3-C10环烷基、C1-C20烷基4-10元杂环基、C1-C6烷基C6-C10芳基、C1-C6烷基5-10元杂芳基、C1-C6胺基C3-C10环烷基、C1-C6胺基4-10元杂环基,其中,上述取代是指被选自下组的一个或多个基团取代:氢、氘、硝基、羟基、氰基、卤素、=N-OH、=N-NH2、=N-NH(CH3)、-C(CH3)=N-OH、-C(CH3)=N-NH2、NH2、C1-C18烷基、氘代C1-C18烷基、卤代C1-C18烷基、卤代C1-C18烷基羟基、C3-C20环烷基、4-20元杂环基、C6-C14芳基、5-14元杂芳基、C1-C6烷基C3-C20环烷基、C1-C6烷基4-20元杂环基、C1-C6烷基C6-C14芳基、C1-C6烷基5-14元杂芳基、C1-C18烷氧基、氘代C1-C18烷氧基、卤代C1-C18烷氧基、C3-C20环烷基-O-、4-20元杂环基-O-、C6-C14芳基-O-、5-14元杂芳基-O-、氧代C1-C6烷基、C2-C6酯基、C1-C6胺基、C2-C6酰基、C2-C6酰胺基、C1-C6磺酰基、C2-C6磺酰胺基或C1-C6脲基;其中,所述取代基中的C1-C18烷基、氘代C1-C18烷基、卤代C1-C18烷基、卤代C1-C18烷基羟基、C3-C20环烷基、4-20元杂环基、C6-C14芳基、5-14元杂芳基、C1-C6烷基C3-C20环烷基、C1-C6烷基4-20元杂环基、C1-C6烷基C6-C14芳基、C1-C6烷基5-14元杂芳基、C1-C18烷氧基、氘代C1-C18烷氧基、卤代C1-C18烷氧基、C3-C20环烷基-O-、4-20元杂环基-O-、C6-C14芳基-O-、5-14元杂芳基-O-、氧代C1-C6烷基、C2-C6酯基、C1-C6胺基、C2-C6酰基、C2-C6酰胺基、C1-C6磺酰基、C2-C6磺酰胺基或C1-C6脲基还可进一步被一个或多个Ra取代,其中,Ra选自:卤素、硝基、羟基、氰基、=N-OH、=N-NH2、=N-NH(CH3)、-C(CH3)=N-OH、-C(CH3)=N-NH2、NH2、C1-C6烷基、氘代C1-C6烷基、C1-C6烷基羟基、卤代C1-C6烷基、卤代C1-C6烷基羟基、C3-C6环烷基、C3-C6环烷基-O-、C1-C6烷氧基、氘代C1-C6烷氧基、卤代C1-C6烷氧基、C6-C14芳基、5-14元杂芳基、4-6元杂环基、4-6元杂环基-O-、氧代C1-C6烷基、C2-C6酯基、C1-C6胺基、C2-C6酰基、C2-C6酰胺基、C1-C6磺酰基、C1-C6磺酰胺基或C1-C6脲基;或两个位于相同碳原子上的取代基共同构成-(CH2)1-6-或=O;
x为0、1、2、3或4的整数;
y为1或2的整数;
m、m'、m”、m”'、m””、m””'和m”””各自独立地为1或2的整数;
n、n'、n”、n”'、n””、n””'和n”””各自独立地为0、1、2、3、4、5或6的整数;
o为0、1、2、3、4、5或6的整数。
在另一优选例中,两个位于相同碳原子上的取代基共同构成-(CH2)-、-(CH2)2-、-(CH2)3-或=O。
在另一优选例中,Z选自取代或未取代的下组基团:C1-C6亚烷基、氘代C1-C6亚烷基、卤代C1-C6亚烷基、C1-C6亚烷氧基、卤代C1-C6亚烷氧基、C3-C6亚环烷基、C1-C6亚烷基C3-C6亚环烷基、C3-C6亚环烷基C1-C6亚烷基、C1-C3亚烷基C3-C6亚环烷基C1-C3亚烷基,其中,所述取代指被选自下组的一个或多个基团取代:氢、氘、C1-C6烷基、卤素、氨基、硝基、羟基、氰基、C3-C6环烷基;优选地,Z为
在另一优选例中,X为-P(=O)(OR11)(NR14R15);其中,R11、R14、R15各自独立地选自取代或未取代的下组基团:氢、C1-C6烷基、C1-C6氘代烷基、C1-C6卤代烷基、C3-C10环烷基、4-10元杂环基、C6-C10芳基、5-10元杂芳基、C1-C6烷基C3-C10环烷基、C1-C6烷基4-10元杂环基、C1-C6烷基C6-C10芳基、C1-C6烷基5-10元杂芳基,所述取代指被选自下组的一个或多个取代基取代:-R16、-OR16、-COR16、-COOR16、-OCOOR16、-SOR16、-SO2R16、-NHR16、-N(C1-C6烷基)R16、-N(C3-C6环烷基)R16、-N(4-6元杂环基)R16、-N(C6-C10芳基)R16、-N(5-6元杂芳基)R16、-CONHR16、-CON(C1-C6烷基)R16、-CON(C3-C6环烷基)R16、-CON(4-6元杂环基)R16、-CON(C6-C10芳基)R16、-CON(5-6元杂芳基)R16、-NHCOR16、-N(C1-C6烷基)COR16、-N(C3-C6环烷基)COR16、-N(4-6元杂环基)COR16、-N(C6-C10芳基)COR16、-N(5-6元杂芳基)COR16、-SO2NHR16、-SO2N(C1-C6烷基)R16、-SO2N(C3-C6环烷基)R16、-NSO2(4-6元杂环基)R16、-SO2N(C6-C10芳基)R16、-SO2N(5-6元杂芳基)R16、卤素、硝基、氰基;
R16选自取代或未取代的下组基团:氢、氘、C1-C6烷基、卤代C1-C6烷基C1-C6烷氧基、C1-C6氘代烷基、C3-C6环烷基、C3-C6环烯基、4-6元杂环基、C6-C10芳基、卤代C6-C10芳基、5-10元杂芳基、卤代5-10元杂芳基、C1-C6烷基C3-C6环烷基、C1-C6烷基4-6元杂环基、C1-C6烷基C6-C10芳基、C1-C6烷基5-10元杂芳基、C1-C6胺基C3-C6环烷基、C1-C6胺基4-6元杂环基,其中,所述取代指被一个或多个选自下组的基团取代:羟基、卤素、氨基、氧代基(=O)、=N-OH、=N-NH2、=N-NH(CH3)、C1-C6烷基、C1-C6烷氧基、C3-C6环烷基、4-6元杂环基、C6-C10芳基、5-10元杂芳基、C1-C6烷基C3-C6环烷基、C1-C6烷基4-6元杂环基、C1-C6烷基OH、C3-C6环烷基OH、4-6元杂环基OH、C1-C6烷基C6-C10芳基、C1-C6烷基5-10元杂芳基;其中,所述取代基中的C1-C6烷基、C1-C6烷氧基、C3-C6环烷基、4-6元杂环基、C6-C10芳基、5-10元杂芳基、C1-C6烷基C3-C6环烷基、C1-C6烷基4-6元杂环基、C1-C6烷基OH、C3-C6环烷基OH、4-6元杂环基OH、C1-C6烷基C6-C10芳基、C1-C6烷基5-10元杂芳基还可进一步被一个或多个选自下组的基团取代:羟基、卤素、氨基、氧代基(=O)、=N-OH、=N-NH2、=N-NH(CH3)、C1-C6烷基、C1-C6烷氧基、C3-C6环烷基、4-6元杂环基、C6-C10芳基、5-10元杂芳基、C2-C6酯基、C1-C6胺基、C2-C6酰基、C2-C6酰胺基、C1-C6磺酰基、C1-C6磺酰胺基或C1-C6脲基。
在另一优选例中,所述的咪唑并喹啉取代磷酸酯激动剂部分、或其立体异构体、互变异构体、晶型、或其药学上可接受的盐、水合物、溶剂合物或前药具有式(III-1)或(III-2)所示的结构:
式中:
R1、R2、x、Z、X1、X2、R11和R12如上所述。
在另一优选例中,所述的咪唑并喹啉取代磷酸酯类激动剂部分、或其立体异构体、互变异构体、晶型、或其药学上可接受的盐、水合物、溶剂合物或前药具有式(IV-1)或(IV-2)所示的结构:
R1、R2、x、Z、X1、X3、R11、R14和R15如上所述。
在另一优选例中,所述的咪唑并喹啉取代磷酸酯类化合物类激动剂部分具有式V-1或V-2所示的结构
式中,*表示S或R构型,优选地为S构型。
R1、R2、x、Z、X1、X3、R11、R14和R15如上所述。
在另一优选例中,Z具有S或R构型。
在另一优选例中,Z具有S构型。
在另一优选例中,P具有S或R构型。
在另一优选例中,P具有S构型。
在另一优选例中,R14、R15中至少一个具有S构型。
在另一优选例中,所述的咪唑并喹啉取代磷酸酯激动剂部分选自取代或未取代下组:
优选地,所述的咪唑并喹啉取代磷酸酯激动剂部分选自取代或未取代下组:
在另一优选例中,所述连接子L选自取代或未取代下组:
式中,L1、L2、L3、L4、L5、L6各自独立地选自0-20的整数;
或者选自取代或未取代下组:
式中,L7、L8、L9、L10、L11、L12各自独立地选自0-20的整数;
或者选自取代或未取代下组:
式中,L13、L14、L15各自独立地选自0-20的整数;
或者选自取代或未取代下组:
式中,L16选自0-20的整数,L17选自0-1的整数;
或者选自取代或未取代下组:
式中,L18、L19、L20、L21、L22、L23各自独立地选自0-20的整数;
或者选自取代或未取代下组:
式中,L24、L25、L26各自独立地选自0-20的整数;
或者选自取代或未取代下组:
式中,L27独立地选自0-1的整数;
或者选自取代或未取代下组:
式中,L28、L29、L30、L31、L32、L33各自独立地选自0-20的整数;
或者选自取代或未取代下组:
式中,L34、L35、L36各自独立地选自0-20的整数;
或者选自通过乙烯基和抗体或抗体片段偶联的L选自取代或未取代下组:
式中,L37各自独立地选自0-20的整数;
或者选自取代或未取代下组:
式中,L38各自独立地选自0-20的整数。
在另一优选例中,所述连接子L选自取代或未取代下组:
或者选自取代或未取代下组:
式中,L1、L2、L3、L4、L5、L6各自独立地选自0-20的整数;
式中,L7、L8、L9、L10、L11、L12各自独立地选自0-20的整数;
式中L13、L14、L15各自独立地选自0-20的整数。
在另一优选例中,所述0-20的整数包括:0、1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20。
在另一优选例中,咪唑并喹啉取代磷酸酯类激动剂部分D选自取代或未取代下组:
且L选自取代或未取代下组:
在另一优选例中,咪唑并喹啉取代磷酸酯类激动剂部分D选自取代或未取代下组:
且L选自取代或未取代下组:
式中,L1、L2、L3、L4、L5、L6各自独立地选自0-20的整数;
式中,L7、L8、L9、L10、L11、L12各自独立地选自0-20的整数;
式中,L13、L14、L15各自独立地选自0-20的整数。
在另一优选例中,Ab、L、D为实施例中各具体化合物所对应基团。
在另一优选例中,所述的抗体-药物偶联物选自:抗体-药物偶联物A1、抗体-药物偶联物A2、抗体-药物偶联物A3、抗体-药物偶联物B1、抗体-药物偶联物B2、抗体-药物偶联物B3、抗体-药物偶联物B9。
本发明第二方面,提供一种药物组合物,其包含药学上可接受的载体和一种或多种权利要求1-17中任一项所述的抗体-药物偶联物,优选地,所述药物组合物还包含其它预防和/或治疗选自下组的疾病的药物或联用:炎症、癌症、心血管疾病、感染、免疫性疾病、代谢性疾病。
在另一优选例中,所述药物组合物还包含选自下组的药物:
PD-1抑制剂(nivolumab,pembrolizumab,pidilizumab,cemiplimab,JS-001,SHR-120,BGB-A317,IBI-308,GLS-010,GB-226,STW204,HX008,HLX10,BAT1306,AK105,LZM 009或上述药物的生物类似药)、PD-L1抑制剂(durvalumab,atezolizumab,avelumab,CS1001,KN035,HLX20,SHR-1316,BGB-A333,JS003,CS1003,KL-A167,F 520,GR1405,MSB2311或上述药物的生物类似药)、HER2抗体(如Trastuzumab,Pertuzumab)、HER2抗体-药物偶联物(如Trastuzumab Deruxtecan)、CD20抗体(如rituximab,obinutuzumab,ofatumumab,veltuzumab,tositumomab,131I-tositumomab,ibritumomab,90Y-ibritumomab,90In-ibritumomab,ibritumomab tiuxetan)、CD47抗体(Hu5F9-G4,CC-90002,TTI-621,TTI-622,OSE-172,SRF-231,ALX-148,NI-1701,SHR-1603,IBI188,IMM01)、或其组合。
在另一优选例中,所述药物组合物还包含选自下组的药物:
干扰素α(标准INFα和聚乙醇化的INFα)、核苷类药物(如Telbivudine、Lamivudine、Clevudine、Adefovir、Tenofovir、Besifovir、Tenofovir DisoproxilFumarate(TDF)、Tenofovir Alafenamide Fumarate(TAF)及HDP-PMPA(CMX157)等)、壳蛋白变构调节剂(如BAY41-4109、RG-7907、NVR 3-778、ABI-H0731、ABI-H2158、JNJ-56136379、GLS 4JHS等)、cccDNA抑制剂、TLR3/7/8/9激动剂(如RG-7854、GS9620等)、乙肝病毒进入抑制剂(如Myrcludex B等)、干扰核苷酸(如ARB 1467、ARB 1740等)、HBV表面抗原抑制剂(如RG7834、REP2139、REP2165等)、CRISPER/Cas9、或其组合。
本发明第三方面,提供一种第一方面所述的抗体-药物偶联物或第二方面所述的药物组合物在制备治疗疾病的药物中的用途,其中,所述疾病选自:炎症、癌症、心血管疾病、感染、免疫性疾病、代谢性疾病。
在另一优选例中,所述疾病为感染。
在另一优选例中,所述感染为病毒性感染。
在另一优选例中,所述病毒性感染选自下组:登革热病毒、黄热病毒、西尼罗病毒、日本脑炎病毒、蜱传脑炎病毒、昆津病毒、墨累山谷脑炎病毒、圣路易脑炎病毒、鄂木斯克出血热病毒、牛病毒性腹泻病毒、济卡病毒、病毒感染肝炎、病毒性皮肤病。
在另一优选例中,所述病毒性感染为病毒感染肝炎,优选地,乙型肝炎、丙型肝炎。
在另一优选例中,所述病毒性皮肤病选自下组:尖锐湿疣、传染性软疣、生殖器疱疹、鲜红斑痣。
在另一优选例中,所述疾病为癌症。
在另一优选例中,所述癌症选自下组:肺癌、乳腺癌、前列腺癌、食道癌、结直肠癌、骨癌、肾癌、胃癌、肝癌、大肠癌、黑色素瘤、淋巴瘤、血癌、脑瘤、骨髓瘤、软组织肉瘤、胰腺癌、皮肤癌。
应理解,在本发明范围内中,本发明的上述各技术特征和在下文(如实施例)中具体描述的各技术特征之间都可以互相组合,从而构成新的或优选的技术方案。限于篇幅,在此不再一一累述。
附图说明
图1示出了本发明抗体-药物偶联物A2对细胞因子的激动。
图2示出了参照化合物T785-ISAC对细胞因子的激动。
具体实施方式
本发明人经过长期而深入的研究,意外地制备了一类新型的咪唑并喹啉取代磷酸酯类激动剂通过连接子和含有Fab抗原结合结构域和Fc结构域的抗体连接构建的抗体-药物偶联物有选择性激动作用和/或更好药效学性能的化合物。在此基础上,发明人完成了本发明。
术语
在本发明中,除非特别指出,所用术语具有本领域技术人员公知的一般含义。
术语“抗体-药物偶联物”是指共价结合至如本文所述的非天然存在的化学部分的抗体构建体或抗体。
术语“抗体构建体”是指包含Fab抗原结合结构域和Fc结构域的多肽。抗体构建体可包括或者可为抗体。
术语“抗原结合结构域”是指特异性地结合特定抗原(例如互补位)的蛋白质或蛋白质的一部分。
术语“Fc结构域”是指抗体的片段结晶区或尾区。Fc结构域与Fc受体(FcR)在细胞表面上相互作用。
术语“抗体”是指含有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,该多肽可以特异性地结合并识别抗原。识别出的免疫球蛋白基因包括κ、λ、α、γ、ε和μ恒定区基因,以及可变区基因。“抗体”涵盖但不限于单克隆抗体(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)和抗体片段等。
术语“抗体片段”指包括抗原结合位点的完整抗体的一部分,或完整抗体的可变区,其中该部分没有完整抗体的Fc区的全部重链恒定结构域。抗体片段包括但不限于:
(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,或含有轻链可变结构域的三个CDR而无相关联的重链部分的片段;
(3)仅含有一个重链可变区的单链多肽,或含有重链可变区的三个CDR而无相关联的轻链部分的片段;
(4)纳米抗体;
(5)由抗体片段形成的多特异性或多价结构。在包含一个或多个重链的抗体片段中,重链可含有存在于完整抗体的非Fc区中的任何恒定结构域序列,并且/或者可含有存在于完整抗体中的任何饺链区序列,并且/或者可含有融合于或位于重链的饺链区序列或恒定结构域序列的亮氨酸拉链序列。
术语“IgG抗体”是由四条肽链构成的分子量约为150kDa的大分子。IgG抗体含有两条相同类的约50kDa的g类重链以及两条相同的约25kDa的轻链,从而形成四聚四级结构。重链和轻链、乙基两条重链通过二硫键彼此连接得到的四聚体具有两个相同的半部,它们一起形成类似Y的形状,Y形叉部的各端含有相同的抗原结合位点。在人中存在四种IgG亚型(IgGl、IgG2、IgG3和IgG4),在血清中IgGl丰度最大。
在一些实施方案中,所述“IgG抗体”可以通过突变引入一个或多个半胱氨酸用于和药物偶联,如IgG1单抗通过LC-S121C、LC-K149C、LC-Q124C、LC-V205C、HC-A114C、HC-A118C、HC-A140C、HC-L174C、HC-S239C、HC-E269C、HC-K326C、HC-A327C、HC-S396C、HC-Y373C等定点突变引入半胱氨酸,通过半胱氨酸的SH和药物偶联。
在一些实施方案中,所述“IgG抗体”可以通过突变引入一个或多个非天然氨基酸用于和药物偶联。所述非天然氨基酸包括但不限于p-acetylphenylalanine(pAcF)、para-azidophenylalanine(pAzF)、N6-((2-azidoethoxy)carbonyl)-L-lysine(AzK)、spiro[2.4]hepta-4,6-diene-lysine(SCpHK)、以及cyclopentadiene-lysine(CpHK)等。
在一些实施方案中,所述“IgG抗体”可以通过酶学的方法引入巯基(-SH)、酮(C=O)、或叠氮(N3)等基团用于和药物偶联。如IgG1单抗首先用PNGase F去糖基化,然后在转谷氨酰胺酶(transglutamase)催化下与含有巯基(-SH)、酮(C=O)、或叠氮(N3)等基团胺的底物发生偶联反应,引入巯基(-SH)、酮(C=O)、或叠氮(N3)等基团用于和药物偶联。
术语“FcR”是指结合至抗体的Fc区的受体。已知存在三类主要Fc受体:结合至IgG的FcγR、结合至IgA的FcαR、以及结合至IgE的FcεR。其中FcγR家族包括FcγRI(CD64)、FcγRIIA(CD32A)、FcγRIIB(CD32B)、FcγRIIIA(CD16A)、FcγRIIIB(CD16B)。不同FcγR受体对IgG亚型(IgGl、IgG2、IgG3、IgG4)具有不同的亲和力。
术语“经修饰的Fc结构域”指抗体在Fc区中含有一种或多种修饰,以调节抗体和FcR的结合能力(增强或者降低)。在一些实施方案中,抗体-药物偶联物中的抗体在Fc区中含有一种或多种修饰(例如,氨基酸插入、缺失和/或取代,或改变糖基化模式),使抗体Fc区与FcγRIIB的结合增强或减弱。在一些实施方案中,抗体-药物偶联物中的抗体在Fc区中含有一种或多种修饰(例如,氨基酸插入、缺失和/或取代,或改变糖基化模式)使抗体Fc区与FcγRI(CD64)、FcγRIIA(CD32A)、FcγRIIIA(CD16A)、FcγRIIIB(CD16B)的结合增强或减弱。在一些实施方案中,抗体-药物偶联物中的抗体在Fc区中含有一种或多种修饰(例如,氨基酸插入、缺失和/或取代,或改变糖基化模式),使抗体Fc区与FcγRIIB的结合增强或减弱,同时减弱、维持或增强抗体Fc区与FcγRI(CD64)、FcγRIIA(CD32A)、FcγRIIIA(CD16A)、FcγRIIIB(CD16B)的结合。
在一些实施方案中,所述通过氨基酸插入、缺失和/或取代来修饰Fc区包括以下氨基酸突变:SD(S239D)、SDIE(S239D/I332E)、SE(S267E)、SELF(S267E/L328F)、SDIE(S239D/I332E)、SDIEAL(S239D/I332E/A330L)、GA(G236A)、ALIE(A330L/I332E)、GASDALIE(G236A/S239D/A330L/I332E)、V9(G237D/P238D/P271G/A330R)、以及Vll(G237D/P238D/H268D/P271G/A330R)。在一些实施方案中,氨基酸突变位点还包括:E233、G237、P238、H268、P271、L328和A330等。
在一些实施方案中,抗体-药物偶联物的抗体的Fc区通过改变糖基化模式来修饰。人免疫球蛋白在两条重链的Cγ2结构域中的Asn297(N297)残基处糖基化。N297N连接的低聚糖由N-乙酰葡萄糖胺4甘露糖3(GlcNAc4Man3)构成,该七糖通常用半乳糖(Gal)、等分GlcNAc、岩藻糖(Fuc)或唾液酸(NANA)加以修饰,不同修饰具有不同的FcγR结合能力。研究表明用内切糖苷酶(endoglycosidase)或肽-N糖苷酶(PNGase F)移除七糖导致抗体Fc区的构象变化,显著地降低抗体Fc与FcγR的结合亲和力。
在一些实施方案中,用于改变糖基化模式的修饰指去岩藻糖基化(Afucylation)。去岩藻糖基化可以增强抗体依赖性细胞毒性效应(ADCC)和抗体依赖性吞噬效应(ADCP)10倍以上。在一些实施方案中,用于改变糖基化模式的修饰指采用低密度静置培养,提高半乳糖基化(Galactosylation),增强补体依赖的细胞毒性效应(CDC)。在一些实施方案中,用于改变糖基化模式的修饰指降低末端唾液酸化(Sialylation),增强ADCC效应。在一些实施方案中,用于改变糖基化模式的修饰指提高末端乙酰葡糖胺基化(Acetylglycosamination),增强ADCC效应。在一些实施方案中,用于改变糖基化模式的修饰指用甘露糖苷酶抑制剂处理CHO细胞,能提高甘露糖基化(Mannosylation),去岩藻糖基化,显著提高ADCC效应,略微降低CDC效应。
在一些实施方案中,用于改变糖基化模式的修饰是突变。如Asn297被突变成谷氨酰胺(N297Q)。
在一些实施方案中,所述抗体可以结合一个或多个以下靶标,或者以下同一靶标多个表位:5T4、ABL、ABCFl、ACVRl、ACVRlB、ACVR2、ACVR2B、ACVRLl、ADORA2A、聚集蛋白聚糖、AGR2、AICDA、AIFl、AIGI、AKAPl、AKAP2、AMH、AMHR2、ANGPTl、ANGPT2、ANGPTL3、ANGPTL4、ANPEP、APC、APOCl、AR、芳香酶、ASGR1、ATX、AXl、AZGPl(锌-a-糖蛋白)、B7.1、B7.2、B7-H1、BAD、BAFF、BAGl、BAil、BCR、BCL2、BCL6、BCMA、BDNF、BLNK、BLRl(MDR15)、BiyS、BMPl、BMP2、BMP3B(GDFI 0)、BMP4、BMP6、BMP8、BMPRlA、BMPRlB、BMPR2、BPAGl(网蛋白)、BRCAl、C19orfl0(IL27w)、C3、C4A、C5、C5Rl、CA9、CANTl、CAPRIN—l、CASPl、CASP4、CAVl、CCBP2(D6/JAB61)、CCLl(1—309)、CCLI1(嗜酸细胞活化趋化因子)、CCL13(MCP-4)、CCL15(MIP—Id)、CCL16(HCC-4)、CCLl7(TARC)、CCL18(PARC)、CCL19(MIP-3b)、CCL2(MCP—1)、MCAF、CCL20(MIP-3a)、CCL21(MEP-2)、SLC、exodus-2、CCL22(MDC/STC-I)、CCL23(MPIF-I)、CCL24(MPIF-2/嗜酸细胞活化趋化因子-2)、CCL25(TECK)、CCL26(嗜酸细胞活化趋化因子-3)、CCL27(CTACK/ILC)、CCL28、CCL3(MIP-Ia)、CCL4(MIPib)、CCL5(RANTES)、CCL7(MCP-3)、CCL8(mcp-2)、CCNAl、CCNA2、CCNDl,CCNEl、CCNE2、CCRl(CKR1/HM145)、CCR2(mcp—IRB/RA)、CCR3(CKR3/CMKBR3)、CCR4、CCR5(CMKBR5/ChemR13)、CCR6(CMKBR6/CKR-L3/STRL22/DRY6)、CCR7(CKR7/EBI1)、CCR8或CDw198(CMKBR8/TERI/CKR-Ll)、CCR9(GPR-9-6)、CCRL1(VSHK1)、CCRL2(L-CCR)、CD164、CD19、CDIC、CD2、CD20、CD21、CD200、CD-22、CD24、CD27、CD28、CD3、CD30、CD33、CD35、CD37、CD38、CD3E、CD3G、CD3Z、CD4、CD38、CD40、CD40L、CD44、CD45RB、CD47、CD52、CD69、CD72、CD74、CD79A、CD79B、CDS、CD80、CD81、CD83、CD86、CD137、CD152、CD274、CDHl(E钙粘合素)、CDHlO、CDH12、CDH13、CDH18、CDH19、CDH20、CDH5、CDH7、CDH8、CDH9、CDK2、CDK3、CDK4、CDK5、CDK6、CDK7、CDK9、CDKNlA(p21 Wapl/Cipl)、CDKNlB(p27Kipl)、CDKNlC、CDKN2A(pl6INK4a)、CDKN2B、CDKN2C、CDKN3、CEACAM1、CEACAM5、CEBPB、CERI、CHGA、CHGB、几丁质酶、CHSTlO、CKLFSF2、CKLFSF3、CKLFSF4、CKLFSF5、CKLFSF6、CKLFSF7、CKLFSF8、CLDN3、CLDN6、CLDN7(紧密连接蛋白-7)、CLDN18.2、CLEC4C(BDCA—2,DLEC,CD303,CLECSF7)、CLEC4D(MCL,CLECSF8)、CLEC4E(巨噬细胞诱导的性C型凝集素)、CLEC6A(树突状细胞相关凝集素—2)、CLEC5A(MDL-2)、CLEC9A(DNGR—1)、CLEC7A(树突状细胞相关凝集-1、CLEC11a、CLN3、CLU(丛集素)、CMKLRl、CMKOR1(RDC 1)、CNRl、COL18Al、COLIAl、COL4A3、COL6Al、CR2、Cripto、CRP、CSFl(M—CSF)、CSF2(GM CSF)、CSF3(GCSF)、CTAGlB(NY ESO-1)、CTLA4、CTL8、CTNNBl(b连环蛋白、CTSB(组织蛋白酶B)、CX3CL1(SCYDl)、CX3CR1(V28)、CXCLl(GROl)、CXCLlO(IP-10)、CXCLI 1(1-TAC/IP-9)、CXCL12(SDFl)、CXCL13、CXCL14、CXCL16、CXCL2(GR02)、CXCL3(GR03)、CXCL5(ENA2)、CXCL9(MIG)、CXCR3(GPR9/CKR-L2)、CXCR4、CXCR6(TYMSTR/STRL33/Bonzo)、CD300C、CD300E、CD300LB(CD300B)、CD300LD(CD300D)、CYB5、CYCl、CYSLTRl、DAB2IP、DES、DKFZp451J0118、DNCLl、DPP4、E2Fl、Engel、Edge、Fennel、EFNA3、EFNB2、EGF、EGFR、ELAC2、ENG、Enola、EN02、EN03、EpCAM、EPHAl、EPHA2、EPHA3、EPHA4、EPHA5、EPHA6、EPHA7、EPHA8、EPHA9、EPHAlO、EPHBl、EPHB2、EPHB3、EPHB4、EPHB5、EPHB6、EPHRIN A4、EPHRINA5、EPHRIN A6、EPHRIN Bl、EPHRIN—B3、EPHB4、EPG、ERBB2(HER2)、ERBB3(HER3)、EREG、ERK8、雌激素受体、Earl、ESR2、F3(TF)、FADD、法尼基转移酶、FasL、FASNf、FCERlA、FCER2、FCGR3A、FGF、FGFl(aFGF)、FGFlO、FGFl 1、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)、FILl(EPSILON)、FBLl(ZETA)、FLJ12584、FLJ25530、FLRT1(纤连蛋白)、FLT-1、FLT-3、FOLR1、FOS、FOSL1(FRA-1)、FY(DARC)、GABRP(GABAa)、GAGEBl、GAGECl、GALNAC4S-6ST、GATA3、GD2、GDF5、GFI1、GGT1、GM-CSF、GNASl、GNRHl、GPC3、6ST、GATA3、GD2、GDF5、GFil、GGTl、GM GPR2(CCRlO)、GP6(GPVI)、gp75、GPR31、GPR44、GPR81(FKSG80)、GRCClO(ClO)、GRP、GSN(凝溶胶蛋臼)、GSTPl、HAVCR2、HDAC、HDAC4、HDAC5、HDAC7A、HDAC9、Hedgehog、HGF、HIFlA、HIPl、组胺和组胺受体、HLA-A、HLA-DRA、HLA-E、HM74、HMOXI、HSP90、HUMCYT2A、ICEBERG、ICOSL、ID2、IFNa、IFNAl、IFNA2、IFNA4、IFNA5、IFNA6、IFNA7、IFNBl、IFNγ、IFNWl、IGBPl、IGFl、IGFIR、IGF2、IGFBP2、IGFBP3、IGFBP6、DL-1、DR-5、ILI0、ILI0RA、ILI0RB、IL1、IL1R1(CD121a)、IL1R2(CD121b)、IL1RA、IL2、IL2RA(CD25)、IL2RB(CD122)、IL2RG(CD132)、IL-4、IL-4R(CD123)、IL5、IL5RA(CD125)、IL3RB(CD131)、IL-6、IL6RA,(CD126)、IR6RB(CD130)、IL-7、IL7RA(CD127)、IL-8、CXCRl(IL8RA)、CXCR2,(IL8RB/CD128)、IL-9、IL9R(CD129)、IL-10、ILlORA(CD210)、ILlORB(CDW210B)、IL-11、ILllRA、IL—12、IL—12A、IL—12B、IL-12RB1、IL13、IL13RA1、IL13RA2、IL14、IL15、IL15RA、IL16、ILl7、ILl7A、ILl7B、ILl7C、ILl7R、IL18、IL18BP、IL18Rl、IL18RAP、IL19、ILIA、ILIB、ILIFlO、ILIF5、IL1F6、ILIF7、IL1F8、DL1F9、ILIHYI、ILIRl、IL1R2、ILI RAP、ILIRAPLI、ILIRAPL2、ILIRLl、IL1RL2、ILIRN、IL2、IL20、IL20RA、IL21R、IL22、IL22R、IL22RA2、IL23、DL24、IL25、IL26、IL27、IL28A、IL28B、IL29、IL2RA、IL2RB、IL2RG、IL3、IL30、IL3RA、IL4、1L4、IL6ST(糖蛋臼130)、ILK、INHA、INHBA、INSL3、INSL4、IRAKl、IRAK2、ITGAl、ITGA2、ITGA3、ITGA6(a6整合素)、ITGAV、ITGB3、ITGB4(β4整合素)、JAGl、JAKl、JAK3、JIB、JUN、K6HF、KAil、KDR、KITLG、KIR2DL4(CD158D)、KIR2DS、KLRC2(CD159C,NKG2C)、KLRKl(CD314,NKG2D)、KLF5(GC Box BP)、KLF6、KLKlO、KLK12、KLK13、KLK14、KLK15、KLK3、KLK4、KLK5、KLK6、KLK9、KRTl、KRT19(角蛋白19)、KRT2A、KRTHB6(毛发特异性II型角蛋白)、LlCAM、LAG3、LAMAS、LEP(瘦素)、Lewis Y抗原、Lingo p75、Lingo-Troy、LILRAl(CD85I)、LILRA2(CD85H,ILT1)、LILRA4(CD85G,ILT7)、LILRA5(CD85F,IL Tl 1)、LILRA6(CD85b,ILT8)、LILRBl、LRRC15、LPS、LTA(TNF-b)、LIB、LTB4R(GPR16)、LTB4R2、LTBR、MACMARCKS、MAG或OMgp、MAGEA3、MAGEA6、MAP2K7(c Jun)、MCP l、MDK、MIBl、中期因子、MIF、MISRII、MJP-2、MSLN、MK、MKI67(Ki—6 7)、MMP2、MMP9、MS4Al、MSMB、MT3(金属硫连接蛋白-UI(metal lothionect in—UI))、mTOR、MTSSl、MUCl(粘蛋白)、MUC16、MUC17、MYC、MYD88、NCK2、NCRl(CD335,LY94,NKp46)、NCR3(CD335,LY94,NKp46)、NCR3(CD337,NKp30)、NCR2(CD336,NKp44)、神经蛋白聚糖、Nectin 4、NFKBI、NFKB2、NGFB(NGF)、NGFR、NgR—Lingo、NgRNogo66、(Nogo)、NgR—p75、NgR—Troy、NMEI(NM23a)、NOTCH、NOTCHl、NOX5、NPPB、NROBl、NROB2、NRIDl、NR1D2、NR1H2、NR1H3、NR1H4、NR112、NRl13、NR2Cl、NR2C2、NR2El、NR2E3、NR2Fl、NR2F2、NR2F6、NR3Cl、NR3C2、NR4Al、NR4A2、NR4A3、NR5Al、NR5A2、NR6Al、NRPl、NRP2、NT5E、NTN4、ODZI、OPRDI、P2RX7、PAP、PARTl、PATE、PAWR、PCA3、PCDGF、PCNA、PDGFA、PD-1、PD-L1、PDGFB、PDGFRA、PDGFRB、PECAMI聚乙二醇化的门冬酰胺酶、PF4(CXCL4)、PGF、PGR、肌酸酶蛋白聚糖、PIAS2、PI3激酶、PIK3CG、PLAU(uPA)、PLG、PLXDCI、PKC、PKC—B、PPBP(CXCL 7)、PPID、PRl、PRKCQ、PRKDl、PRL、PROC、PROK2、PSAP、PSCA、PSMA、PTAFR、PTEN、PTGS2(COX—2)、PIN、PVRIG、RAC2(P21Rac2)、RANK、RANK配体、RARB、RGSl、RGS13、RGS3、RNFI10(ZNFl 44)、Ron、ROB02、RORl、RXR、SlOOA2、SCGB 102(亲脂素B)、SCGB2Al(乳腺珠蛋白2)、SCGB2A2(乳腺珠蛋白1)、SCYEl(内皮单核细胞活化细胞因子)、SDF2、SERPENAl、SERPINA3、SERPINB5(乳腺丝抑蛋白)、SERPINEI(PAI—I)、SERPINFI、SHIP-l、SHIP-2、SHBl、SHB2、SHBG、SIGLECl(CD169,SN)、SIGLEC5、SIGLEC6、SIGLEC7、SIGLEC8、SIGLEC9、SIGLEClO、SIGLECll、SIGLEC12、SIGLEC14、SIGLEC15(CD33L3)、SIGLEC16、SIRPA、SIRPBl(CDl72B)、SfcAZ、SLC2A2、SLC33Al、SLC43Al、SLIT2、SPPl、SPRRlB(Sprl)、ST6GAL1、STABl、STATE、STEAP、STEAP2、TB4R2、TBX21、TCPlO、TDGFl、TEK、TGFA、TGFBl、TGFBlI 1、TGFB2、TGFB3、TGFBI、TGFBRl、TGFBR2、TGFBR3、THIL、THB Sl(血小板反应蛋白-1)、THBS2、THBS4、THPO、TIE(Tie-1)、TIGHT、TIMP3、组织因子、Toll样受体、TLRl、TLR2、TLR3、TLR4、TLR5、TLR6、TLR7、TLR8、TLR9、TLRlO、TLRll、TNF、TNF-a、TNFAIP2(B94)、TNFAIP3、TNFRSFilA、TNFRSFlA、TNFRSFlB、TNFRSF21、TNFRSF5、TNFRSF6(Fas)、TNFRSF7、TNFRSF8、TNFRSF9、TNFSFlO(TRAIL)、TNFSFl 1(TRANCE)、TNFSF12(AP03L)、TNFSF13(April)、TNFSF13B、TNFSF14(HVEM—L)、TNFRSF14(HVEM)、TNFSF15(VEG I)、TNFSF18、TNFSF4(0X40配体)、TNFSF5(CD40配体)、TNFSF6(FasL)、TNFSF7(CD27配体)、TNFSF8(CD30配体)、TNFSF9(4-lBB配体)、TOLLIP、TOP2A(拓扑异构酶IIa)、TP53、TPMl、TPM2、TRADD、TRAFl、TRAF2、TRAF3、TRAF4、TRAF5、TRAF6、TRKA、TREMl、TREM2、TROP2、TRPC6、TSLP、TWEAK、酪氨酸酶、uPAR、PDGFRa、SLAMF7、OSCAR、TARMl、PILRB、TREMl(CD354)、TREM2、OKLRFl(NKp80)、VEGF、VEGFB、VEGFC、多功能蛋白聚糖、VHL C5、VISTA、VLA-4、WTl、Wnt-l、XCLl(淋巴细胞趋化因子)、XCL2(SCM-lb)、XCRI(GPR5/CCXCR1)、YYl、ZFPM2。
在一些实施方案中,所述抗体可以结合一个或多个以下靶标,或者以下同一靶标多个表位:HER2、HER3、TROP-2、PD-L1、CLDN18.2、CLDN6、DLL3、MUCl、MUC16、MUC17、LRCC15、CEACAM5、Nectin 4、GPC3、ASGR1、CCR8、CDH、CD19、CD20、CD29、CD30、CD38、CD40、CD47、EpCAM、EGFR、VEGF、SLAMF7、PDGFRa和gp75。
在一些实施方案中,所述抗体可以结合一个或多个以下靶标,或者以下同一靶标多个表位:EGFR、HER2、HER3和TROP2。
在一些实施方案中,所述抗体可以结合一个或多个以下靶标,或者以下同一靶标多个表位:EGFR、HER2和HER3。
术语“表位”指抗原上的任何抗原决定簇,抗体的抗原结合位点(也称为互补位)结合于该抗原决定簇。表位决定簇通常由化学活性的表面分子簇构成,诸如氨基酸或糖侧链,并且通常具有特定三维结构特征以及特定电荷特征。
术语“生物类似物”指尽管有临床失活组分的微小差异,但该生物产品高度类似于参考产品,并且就产品的安全性、纯度和效能而言,该生物产品与参考产品之间不存在临床上有意义的差异。
术语“烷基”是指直链或支链或环状烷烃基,包含1-20个碳原子,如1-18个碳原子,尤其指1-8个碳原子。典型的“烷基”包括甲基、乙基、丙基、异丙基、正丁基、叔丁基、异丁基、戊基、异戊基、庚基、4,4–二甲基戊基,辛基,2,2,4-三甲基戊基,壬基,癸基、十一烷基,十二烷基等等。
术语“C1-C8烷基”指的是直链或支链或环状烷基,包括从1-8个碳原子,如甲基、乙基、丙基、异丙基正丁基、叔丁基、异丁基(如/>)、正戊基、异戊基、正己基、异己基、正庚基、异庚基。“取代烷基”是指烷基中的一个或多个位置被取代,尤其是1-4个取代基,可在任何位置上取代。典型的取代包括但不限于一个或多个以下基团:如氢、氘、卤素(例如,单卤素取代基或多卤素取代基,后者如三氟甲基或包含Cl3的烷基)、腈基、硝基、氧(如=O)、三氟甲基、三氟甲氧基、环烷基、烯基、环烯基、炔基、杂环基、芳基、杂芳基、ORa、SRa、S(=O)Re、S(=O)2Re、P(=O)2Re、S(=O)2ORe、P(=O)2ORe、NRbRc、NRbS(=O)2Re、NRbP(=O)2Re、S(=O)2NRbRc、P(=O)2NRbRc、C(=O)ORd、C(=O)Ra、C(=O)NRbRc、OC(=O)Ra、OC(=O)NRbRc、NRbC(=O)ORe、NRdC(=O)NRbRc、NRdS(=O)2NRbRc、NRdP(=O)2NRbRc、NRbC(=O)Ra、或NRbP(=O)2Re,其中在此出现的Ra可以独立表示氢、氘、烷基、环烷基、烯基、环烯基、炔基、杂环基、芳基或杂芳基,Rb、Rc和Rd可以独立表示氢、氘、烷基、环烷基、杂环基、芳基或杂芳基,或者说Rb和Rc与N原子一起可以形成杂环;Re可以独立表示氢、烷基、环烷基、烯基、环烯基、炔基、杂环基、芳基或杂芳基。上述典型的取代基,如烷基、环烷基、烯基、环烯基、炔基、杂环基、芳基或杂芳基可以任选取代。/>
术语“C1-C18烷氧基”是指具有1至18个碳原子的直链或支链或环状烷氧基,非限制性地包括甲氧基、乙氧基、丙氧基、异丙氧基、丁氧基、-CH2OCH3、-CH2CH2OCH3、-CH(CH3)CH2OCH3、-C(CH3)2CH2OCH3、-OCH2CH2OCH3、-CH2CH2OCH2CH2OCH3、-CH2CH2OCH2CH2OCH2CH3、-CH(CH3)CH2OCH2CH2OCH2CH3、-C(CH3)2CH2OCH2CH2OCH2CH3等。优选为C1-C8烷氧基,更优选C1-C6烷氧基。术语“C1-C18亚烷氧基”是指“C1-C18烷氧基”脱掉一个氢原子所得基团,术语“C1-C8亚烷氧基”、“C1-C6亚烷氧基”具有类似的含义。
术语“烯基”是指直链或支链烃基含有2-18个碳原子,至少一个碳碳双键的取代基。典型的基团包括乙烯基或烯丙基。术语“(C2-C6)烯基”是指直链或支链的含有2-6个碳原子,至少有一个碳碳双键的基团,如乙烯基、丙烯基、2-丙烯基、(E)-2-丁烯基、(Z)-2-丁烯基、(E)-2-甲基-2-丁烯基、(Z)-2-甲基-2-丁烯基、2,3-二甲基-2-丁烯基、(Z)-2-戊烯基、(E)-1-戊烯基、(Z)-1-己烯基、(E)-2-戊烯基、(Z)-2-己烯基、(E)-1-己烯基、(Z)-1-己烯基、(E)-2-己烯基、(Z)-3-己烯基、(E)-3-己烯基和(E)-1,3-己二烯基。“取代烯基”是指烯基中的一个或多个位置被取代,尤其是1-4个取代基,可在任何位置上取代。典型的取代包括但不限于一个或多个以下基团:如氢、氘、卤素(例如,单卤素取代基或多卤素取代基,后者如三氟甲基或包含Cl3的烷基)、氰基、硝基、氧(如=O)、三氟甲基、三氟甲氧基、环烷基、烯基、环烯基、炔基、杂环基、芳基、杂芳基、ORa、SRa、S(=O)Re、S(=O)2Re、P(=O)2Re、S(=O)2ORe,P(=O)2ORe、NRbRc、NRbS(=O)2Re、NRbP(=O)2Re、S(=O)2NRbRc、P(=O)2NRbRc、C(=O)ORd、C(=O)Ra、C(=O)NRbRc、OC(=O)Ra、OC(=O)NRbRc、NRbC(=O)ORe,NRdC(=O)NRbRc、NRdS(=O)2NRbRc、NRdP(=O)2NRbRc、NRbC(=O)Ra、或NRbP(=O)2Re,其中在此出现的Ra可以独立表示氢、氘、烷基、环烷基、烯基、环烯基、炔基、杂环基、芳基或杂芳基,Rb、Rc和Rd可以独立表示氢、氘、烷基、环烷基、杂环基、芳基或杂芳基,或者说Rb和Rc与N原子一起可以形成杂环基;Re可以独立表示氢、氘、烷基、环烷基、烯基、环烯基、炔基、杂环基、芳基或杂芳基。上述典型的取代基,如烷基、环烷基、烯基、环烯基、炔基、杂环基、芳基或杂芳基可以任选取代。
术语“炔基”是指直链或支链烃基含有2-18个碳原子,至少一个碳碳三键的取代基。典型的基团包括乙炔基。术语“(C2-C6)炔基”是指直链或支链的含有2-6个碳原子,至少有一个碳碳三键的基团,如乙炔基、1-丙炔基、2-丙炔基、1-丁炔基、2-丁炔基、1-戊炔基、2-戊炔基、1-己炔基、2-己炔基、3-己炔基。“取代炔基”是指炔基中的一个或多个位置被取代,尤其是1-4个取代基,可在任何位置上取代。典型的取代包括但不限于一个或多个以下基团:如氢、氘、卤素(例如,单卤素取代基或多卤素取代基,后者如三氟甲基或包含Cl3的烷基)、氰基、硝基、氧(如=O)、三氟甲基、三氟甲氧基、环烷基、烯基、环烯基、炔基、杂环基、芳基、芳基、ORa、SRa、S(=O)Re、S(=O)2Re、P(=O)2Re、S(=O)2ORe、P(=O)2ORe、NRbRc、NRbS(=O)2Re、NRbP(=O)2Re、S(=O)2NRbRc、P(=O)2NRbRc、C(=O)ORd、C(=O)Ra、C(=O)NRbRc、OC(=O)Ra、OC(=O)NRbRc、NRbC(=O)ORe、NRdC(=O)NRbRc、NRdS(=O)2NRbRc、NRdP(=O)2NRbRc、NRbC(=O)Ra、或NRbP(=O)2Re,其中在此出现的Ra可以独立表示氢、氘、烷基、环烷基、烯基、环烯基、炔基、杂环基、芳基或杂芳基,Rb、Rc和Rd可以独立表示氢、氘、烷基、环烷基、杂环基、芳基或杂芳基,或者说Rb和Rc与N原子一起可以形成杂环;Re可以独立表示氢、氘、烷基、环烷基、烯基、环烯基、炔基、杂环基、芳基或杂芳基。典型的取代基可以任选取代。
术语“环烷基”是指完全饱和的环状烃类化合物基团,包括1-4个环,每个环中含有3-8个碳原子。“取代环烷基”是指环烷基中的一个或多个位置被取代,尤其是1-4个取代基,可在任何位置上取代。典型的取代包括但不限于一个或多个以下基团:如氢,氘,卤素(例如,单卤素取代基或多卤素取代基,后者如三氟甲基或包含Cl3的烷基)、氰基、硝基、氧(如=O)、三氟甲基、三氟甲氧基、环烷基、烯基、环烯基、炔基、杂环基、芳基、杂芳基、ORa、SRa、S(=O)Re、S(=O)2Re、P(=O)2Re、S(=O)2ORe,P(=O)2ORe、NRbRc、NRbS(=O)2Re、NRbP(=O)2Re、S(=O)2NRbRc、P(=O)2NRbRc、C(=O)ORd、C(=O)Ra、C(=O)NRbRc、OC(=O)Ra、OC(=O)NRbRc、NRbC(=O)ORe,NRdC(=O)NRbRc、NRdS(=O)2NRbRc、NRdP(=O)2NRbRc、NRbC(=O)Ra、或NRbP(=O)2Re,其中在此出现的Ra可以独立表示氢、氘、烷基、环烷基、烯基、环烯基、炔基、杂环基、芳基或杂芳基,Rb、Rc和Rd可以独立表示氢、氘、烷基、环烷基、杂环基、芳基或杂芳基,或者说Rb和Rc与N原子一起可以形成杂环;Re可以独立表示氢、氘、烷基、环烷基、烯基、环烯基、炔基、杂环基、芳基或杂芳基。上述典型的取代基可以任选取代。典型的取代还包括螺环、桥环或稠环取代基,尤其是螺环烷基、螺环烯基、螺环杂环基(不包括杂芳基)、桥环烷基、桥环烯基、桥环杂环基(不包括杂芳基)、稠环烷基、稠环烯基、稠环杂环基或稠环芳基,上述环烷基、环烯基、杂环基和杂芳基可以任选取代。
术语“环烯基”是指部分不饱和的环状烃类化合物基团,包括1-4个环,每个环中含有3-8个碳原子。典型的环烯基如环丁烯基、环戊烯基、环己烯基等等。“取代环烯基”是指环烷基中的一个或多个位置被取代,尤其是1-4个取代基,可在任何位置上取代。典型的取代包括但不限于一个或多个以下基团:如氢、氘、卤素(例如,单卤素取代基或多卤素取代基,后者如三氟甲基或包含Cl3的烷基)、氰基、硝基、氧(如=O)、三氟甲基、三氟甲氧基、环烷基、烯基、环烯基、炔基、杂环基、芳基、杂芳基、ORa、SRa、S(=O)Re、S(=O)2Re、P(=O)2Re、S(=O)2ORe、P(=O)2ORe、NRbRc、NRbS(=O)2Re、NRbP(=O)2Re、S(=O)2NRbRc、P(=O)2NRbRc、C(=O)ORd、C(=O)Ra、C(=O)NRbRc、OC(=O)Ra、OC(=O)NRbRc、NRbC(=O)ORe、NRdC(=O)NRbRc、NRdS(=O)2NRbRc、NRdP(=O)2NRbRc、NRbC(=O)Ra、或NRbP(=O)2Re,其中在此出现的Ra可以独立表示氢、氘、烷基、环烷基、烯基、环烯基、炔基、杂环基、芳基或杂芳基,Rb、Rc和Rd可以独立表示氢、氘、烷基、环烷基、杂环基、芳基或杂芳基,或者说Rb和Rc与N原子一起可以形成杂环基;Re可以独立表示氢、氘、烷基、环烷基、烯基、环烯基、炔基、杂环基、芳基或杂芳基。上述典型的取代基可以任选取代。典型的取代还包括螺环或稠环取代基,尤其是螺环烷基、螺环烯基、螺环杂环基(不包括杂芳基)、稠环烷基、稠环烯基、稠环杂环基或稠环芳基,上述环烷基、环烯基、杂环基和杂芳基可以任选取代。
术语“杂环基”是指完全饱和的或部分不饱和的的环状基团(包含但不限于如4-7元单环,7-11元双环,或8-16元三环系统),其中至少有一个杂原子存在于至少有一个碳原子的环中。每个含有杂原子的杂环可以带有1,2,3或4个杂原子,这些杂原子选自氮原子、氧原子或硫原子,其中氮原子或硫原子可以被氧化,氮原子也可以被季铵化。杂环基团可以连接到环或环系分子的任何杂原子或碳原子的残基上。典型的单环杂环包括但不限于氮杂环丁烷基、吡咯烷基、氧杂环丁烷基、吡唑啉基、咪唑啉基、咪唑烷基、噁唑烷基、异噁唑烷基、噻唑烷基、异噻唑烷基、四氢呋喃基、哌啶基、哌嗪基、2-氧代哌嗪基、2-氧代哌啶基、2-氧代吡咯烷基、六氢吖庚因基、4-哌啶酮基、四氢吡喃基、吗啡啉基、硫代吗啡啉基、硫代吗啡啉亚砜基、硫代吗啡啉砜基、1,3-二噁烷基和四氢-1,1-二氧噻吩等。多环杂环基包括螺环、稠环和桥环的杂环基;其中涉及到的螺环、稠环和桥环的杂环基任选与其他基团通过单键相连接,或者通过环上的任意两个或两个以上的原子与其他环烷基、杂环基、芳基和杂芳基进一步并环连接;杂环基团可以是取代的或者未取代的,当被取代时,取代基优选为一个或多个一下基团,其独立地选自烷基、氘代烷基、卤代烷基、烷氧基、卤代烷氧基、烯基、炔基、烷硫基、烷基氨基、卤素、氨基、硝基、羟基、巯基、氰基、环烷基、杂环基、芳基、杂芳基、环烷硫基、氧代基、羧基和羧酸酯基。
术语“芳基”是指芳香环状烃类化合物基团,具有1-5个环,尤其指单环和双环基团,如苯基、联苯基或萘基。凡含有两个或两个以上芳香环(双环等),芳基基团的芳香环可由单键联接(如联苯),或稠合(如萘、蒽等等)。“取代芳基”是指芳基中的一个或多个位置被取代,尤其是1-3个取代基,可在任何位置上取代。典型的取代包括但不限于一个或多个以下基团:如氢,氘,卤素(例如,单卤素取代基或多卤素取代基,后者如三氟甲基或包含Cl3的烷基)、氰基、硝基、氧(如=O)、三氟甲基、三氟甲氧基、环烷基、烯基、环烯基、炔基、杂环基、芳基、杂芳基、ORa、SRa、S(=O)Re、S(=O)2Re、P(=O)2Re、S(=O)2ORe、P(=O)2ORe、NRbRc、NRbS(=O)2Re、NRbP(=O)2Re、S(=O)2NRbRc、P(=O)2NRbRc、C(=O)ORd、C(=O)Ra、C(=O)NRbRc、OC(=O)Ra、OC(=O)NRbRc、NRbC(=O)ORe,NRdC(=O)NRbRc、NRdS(=O)2NRbRc、NRdP(=O)2NRbRc、NRbC(=O)Ra、或NRbP(=O)2Re,其中在此出现的Ra可以独立表示氢、氘、烷基、环烷基、烯基、环烯基、炔基、杂环基、芳基或杂芳基,Rb、Rc和Rd可以独立表示氢、氘、烷基、环烷基、杂环基、芳基或杂芳基,或者说Rb和Rc与N原子一起可以形成杂环;Re可以独立表示氢、氘、烷基、环烷基、烯基、环烯基、炔基、杂环基、芳基或杂芳基。上述典型的取代基可以任选取代。典型的取代还包括稠环取代基,尤其是稠环烷基、稠环烯基、稠环杂环基或稠环芳基,上述环烷基、环烯基、杂环基和杂环芳基可以任选取代。
术语“杂芳基”指1-3个选自N、O和S的杂原子、5-14个环原子的杂芳族体系。杂芳基优选5至10元环,更优选为5元或6元,例如吡咯基、吡唑基、咪唑基、噁唑基、异噁唑基、噻唑基、噻二唑基、异噻唑基、呋喃基、吡啶基、吡嗪基、嘧啶基、哒嗪基、三氮嗪基、三氮唑基及四氮唑基等。“杂芳基”可以是取代的或者未取代的,当被取代时,取代基优选为一个或多个以下基团,其独立地选自烷基、氘代烷基、卤代烷基、烷氧基、卤代烷氧基、烯基、炔基、烷硫基、烷基氨基、卤素、氨基、硝基、羟基、巯基、氰基、环烷基、杂环基、芳基、杂芳基、环烷硫基、氧代基、羧基和羧酸酯基。
术语“烷基芳基”是指被芳基取代的烷基,通过烷基或芳基与其他部分相连,例如“C1-C6烷基C6-C10芳基”包括-C1-C6烷基C6-C10芳基或C1-C6烷基C6-C10芳基-。“烷基环烷基”、“烷基杂环基”和“烷基芳基”等具有类似含义。
术语“胺基(氨基)”是指带有结构-NRR'的基团,其中R和R'可以独立的代表氢、烷基或取代的烷基、环烷基或取代的环烷基、环烯基或取代的环烯基、芳基或取代的芳基、杂环或取代的杂环,如上文所定义。R和R'在二烷基胺片段中可以相同或不同。优选地,胺基为C1-C6胺基(即含有1-6个碳原子的烷胺基,如C1-C6烷基NH-)。胺基的实例包括但不限:NH2、甲胺基、二甲胺基、乙胺基、二乙胺基、丙胺基、二丙胺基、异丙胺基、二异丙胺基、苯胺基、二苯胺基等。
术语“酯基”是指带有结构-COOR的基团,其中R代表氢、烷基或取代的烷基、环烷基或取代的环烷基、环烯基或取代的环烯基、芳基或取代的芳基、杂环或取代的杂环。优选地,酯基为“C2-C6酯基”(如-COOC1-C5烷基)。酯基的实例包括但不限:-COOCH3、-COOCH2CH3、-COOCH2CH2CH3、-COOCH2CH(CH3)2。
术语“酰胺基”是指带有结构-CONRR'的基团,其中R和R'可以独立的代表氢、烷基或取代的烷基、环烷基或取代的环烷基、环烯基或取代的环烯基、芳基或取代的芳基、杂环或取代的杂环,如上文所定义。优选地,酰胺基为“C1-C6酰胺基”(如-CONHC1-C5烷基或-CONH2)。R和R'在二烷基胺片段中可以相同或不同。酰胺基的实例包括但不限于:-CONH2、-CONHCH3、-CON(CH3)2等。
术语“磺酰胺基”是指带有结构-SO2NRR'或RSO2NR'-的基团,其中R和R'可以独立的代表氢、烷基或取代的烷基、环烷基或取代的环烷基、环烯基或取代的环烯基、芳基或取代的芳基、杂环或取代的杂环,如上文所定义。R和R'在二烷基胺片段中可以相同或不同。磺酰胺基的实例包括但不限:-SO2NH2、-SO2NHCH3、-SO2N(CH3)2、CH3SO2NH-、CH3SO2NCH3-等。本发明中,“C1-C6磺酰胺基”是指C1-C6烷基磺酰胺基,即R和R'的碳原子总数为1-6。
术语“脲基”是指带有结构-NRCONR'R"的基团,其中R、R'和R"可以独立的代表氢、烷基或取代的烷基、环烷基或取代的环烷基、环烯基或取代的环烯基、芳基或取代的芳基、杂环或取代的杂环,如上文所定义。R、R'和R"在二烷基胺片段中可以相同或不同。脲基的实例包括但不限于:-NHCONH2、-NHCONHCH3、-NHCON(CH3)2等。本发明中,“C1-C6脲基”是指C1-C6烷基脲基,即R、R'和R"的碳原子总数为1-6。
术语“卤素”或“卤”是指氯、溴、氟、碘。
术语“卤代”是指被卤素取代。
术语“氘代”是指被氘取代。
在本发明中,术语“取代”指特定的基团上的一个或多个氢原子被特定的取代基所取代。特定的取代基为在前文中相应描述的取代基,或各实施例中所出现的取代基。除非特别说明,某个取代的基团可以在该基团的任何可取代的位点上具有一个选自特定组的取代基,所述的取代基在各个位置上可以是相同或不同的。本领域技术人员应理解,本发明所预期的取代基的组合是那些稳定的或化学上可实现的组合。所述取代基例如(但并不限于):卤素、羟基、羧基(-COOH)、C1-C6烷基、C2-C6烯基、C2-C6炔基、C3-C8环烷基、3-至12元杂环基、芳基、杂芳基、C1-C8醛基、C2-C10酰基、C2-C10酯基、氨基、C1-C6烷氧基、C1-C10磺酰基等。
除非另外说明,假定任何不满价态的杂原子有足够的氢原子补充其价态。
“DAR值”是指药物与抗体的比率(drug antibody ratio)。
活性成分
“活性成分”、“抗体-药物偶联体(ADC)”或“抗体-药物偶联体化合物”可互换使用。
本发明提供了一种抗体-药物偶联物,其包含
(a)抗体构建体,所述抗体构建体包含(i)未经修饰或经修饰的Fab抗原结合结构域和(ii)未经修饰或经修饰的Fc结构域;
(b)咪唑并喹啉取代磷酸酯类激动剂部分,或其立体异构体、互变异构体、晶型、或其药学上可接受的盐、水合物、溶剂合物或前药;和
(c)连接子,
其中每个咪唑并喹啉取代磷酸酯类激动剂部分经由所述连接子共价结合至所述抗体构建体。
优选地,所述抗体-药物偶联体具有式I所示的结构。
本发明中的化合物可能形成的盐也是属于本发明的范围。除非另有说明,本发明中的化合物被理解为包括其盐类。在此使用的术语“盐”,指用无机或有机酸和碱形成酸式或碱式的盐。此外,当本发明中的化合物含一个碱性片段时,它包括但不限于吡啶或咪唑,含一个酸性片段时,包括但不限于羧酸,可能形成的两性离子(“内盐”)包含在术语“盐”的范围内。药学上可接受的(即无毒,生理可接受的)盐是首选,虽然其他盐类也有用,例如可以用在制备过程中的分离或纯化步骤。本发明的化合物可能形成盐,例如,化合物I与一定量如等当量的酸或碱反应,在介质中盐析出来,或在水溶液中冷冻干燥得来。
本发明中的化合物含有的碱性片段,包括但不限于胺或吡啶或咪唑环,可能会和有机或无机酸形成盐。可以成盐的典型的酸包括醋酸盐(如用醋酸或三卤代醋酸,如三氟乙酸)、己二酸盐、藻朊酸盐、抗坏血酸盐、天冬氨酸盐、苯甲酸盐、苯磺酸盐、硫酸氢盐、硼酸盐、丁酸盐、柠檬酸盐、樟脑盐、樟脑磺酸盐、环戊烷丙酸盐、二甘醇酸盐、十二烷基硫酸盐、乙烷磺酸盐、延胡索酸盐、葡庚糖酸盐、甘油磷酸盐、半硫酸盐、庚酸盐、己酸盐、盐酸盐、氢溴酸盐、氢碘酸盐、羟基乙磺酸盐(如,2-羟基乙磺酸盐)、乳酸盐、马来酸盐、甲磺酸盐、萘磺酸盐(如,2-萘磺酸盐)、烟酸盐、硝酸盐、草酸盐、果胶酸盐、过硫酸盐、苯丙酸盐(如3-苯丙酸盐)、磷酸盐、苦味酸盐、新戊酸盐、丙酸盐,水杨酸盐、琥珀酸盐、硫酸盐(如与硫酸形成的)、磺酸盐、酒石酸盐、硫氰酸盐、甲苯磺酸盐如对甲苯磺酸盐、十二烷酸盐等等
本发明的某些化合物可能含有的酸性片段,包括但不限于羧酸,可能会和各种有机或无机碱形成盐。典型的碱形成的盐包括铵盐、碱金属盐如钠、锂、钾盐,碱土金属盐如钙、镁盐,和有机碱形成的盐(如有机胺),如苄星、二环已基胺、海巴胺(与N,N-二(去氢枞基)乙二胺形成的盐)、N-甲基-D-葡糖胺、N-甲基-D-葡糖酰胺、叔丁基胺,以及和氨基酸如精氨酸、赖氨酸等等形成的盐。碱性含氮基团可以与卤化物季铵盐,如小分子烷基卤化物(如甲基、乙基、丙基和丁基的氯化物、溴化物及碘化物),二烷基硫酸盐(如,硫酸二甲酯、二乙酯,二丁酯和二戊酯),长链卤化物(如癸基、十二烷基、十四烷基和十四烷基的氯化物、溴化物及碘化物),芳烷基卤化物(如苄基和苯基溴化物)等等。
本发明中化合物的前药及溶剂合物也在涵盖的范围之内。此处术语“前药”是指一种化合物,在治疗相关疾病时,经过代谢或化学过程的化学转化而产生本发明中的化合物、盐、或溶剂合物。本发明的化合物包括溶剂合物,如水合物。
本发明中的化合物、盐或溶剂合物,可能存在的互变异构形式(例如酰胺和亚胺醚)。所有这些互变异构体都是本发明的一部分。
所有化合物的立体异构体(例如,那些由于对各种取代可能存在的不对称碳原子),包括其对映体形式和非对映形式,都属于本发明的设想范围。本发明中的化合物独立的立体异构体可能不与其他异构体同时存在(例如,作为一个纯的或者实质上是纯的光学异构体具有特殊的活性),或者也可能是混合物,如消旋体,或与所有其他立体异构体或其中的一部分形成的混合物。本发明的手性中心有S或R两种构型,由理论与应用化学国际联合会(IUPAC)1974年建议定义。外消旋形式可通过物理方法解决,例如分步结晶,或通过衍生为非对映异构体分离结晶,或通过手性柱色谱法分离。单个的光学异构体可通过合适的方法由外消旋体得到,包括但不限于传统的方法,例如与光学活性酸成盐后再结晶。
本发明中的化合物,依次通过制备、分离纯化获得的该化合物其重量含量等于或大于90%,例如,等于或大于95%,等于或大于99%(“非常纯”的化合物),在正文描述列出。此处这种“非常纯”本发明的化合物也作为本发明的一部分。
本发明的化合物所有的构型异构体都在涵盖的范围之内,无论是混合物、纯的或非常纯的形式。在本发明化合物的定义包含顺式(Z)和返式(E)两种烯烃异构体,以及碳环和杂环的顺式和反式异构体。
在整个说明书中,基团和取代基可以被选择以提供稳定的片段和化合物。
特定官能团和化学术语定义都详细介绍如下。对本发明来说,化学元素与Periodic Table of the Elements,CAS version,Handbook of Chemistry and Physics,75th Ed.中定义的一致。特定官能团的定义也在其中描述。此外,有机化学的基本原则以及特定官能团和反应性在“Organic Chemistry”,Thomas Sorrell,University ScienceBooks,Sausalito:1999,也有说明,其全部内容纳入参考文献之列。
本发明的某些化合物可能存在于特定的几何或立体异构体形式。本发明涵盖所有的化合物,包括其顺式和反式异构体、R和S对映异构体、非对映体、(D)型异构体、(L)型异构体、外消旋混合物和其它混合物。另外不对称碳原子可表示取代基,如烷基。所有异构体以及它们的混合物,都包涵在本发明中。
按照本发明,同分异构体的混合物含有异构体的比率可以是多样的。例如,在只有两个异构体的混合物可以有以下组合:50:50,60:40,70:30,80:20,90:10,95:5,96:4,97:3,98:2,99:1,或100:0,异构体的所有比率都在本发明范围之内。本专业内一般技术人员容易理解的类似的比率,及为更复杂的异构体的混合物的比率也在本发明范围之内。
本发明还包括同位素标记的化合物,等同于原始化合物在此公开。不过实际上对一个或更多的原子被与其原子量或质量序数不同的原子取代通常会出现。可以列为本发明的化合物同位素的例子包括氢,碳,氮,氧,磷,硫,氟和氯同位素,分别如2H、3H、13C、11C、14C、15N、18O、17O、31P、32P、35S、18F和36Cl。本发明中的化合物,或对映体,非对映体,异构体,或药学上可接受的盐或溶剂化物,其中含有上述化合物的同位素或其他同位素原子都在本发明的范围之内。本发明中某些同位素标记化合物,例如3H和14C的放射性同位素也在其中,在药物和底物的组织分布实验中是有用的。氚,即3H和碳-14,即14C,它们的制备和检测比较容易。是同位素中的首选。此外,较重同位素取代如氘,即2H,由于其很好的代谢稳定性在某些疗法中有优势,例如在体内增加半衰期或减少用量,因此,在某些情况下可以优先考虑。同位素标记的化合物可以用一般的方法,通过用易得的同位素标记试剂替换为非同位素的试剂,用批露在示例中的方案可以制备。
如果要设计一个本发明的化合物特定的对映体的合成,它可以不对称合成制备,或用手性辅剂衍生化,将所产生的非对映混合物分离,再除去手性辅剂而得到纯的对映体。另外,如果分子中含有一个碱性官能团,如氨基酸,或酸性官能团,如羧基,可以用合适的光学活性的酸或碱的与之形成非对映异构体盐,再通过分离结晶或色谱等常规手段分离,然后就得到了纯的对映体。
如本文所述,本发明中的化合物可与任何数量取代基或官能团取而扩大其包涵范围。通常,术语“取代”不论在术语“可选”前面或后面出现,在本发明配方中包括取代基的通式,是指用指定结构取代基,代替氢自由基。当特定结构中的多个在位置被多个特定的取代基取代时,取代基每一个位置可以是相同或不同。本文中所使用的术语“取代”包括所有允许有机化合物取代。从广义上讲,允许的取代基包括非环状的、环状的、支链的非支链的、碳环的和杂环的,芳环的和非芳环的有机化合物。在本发明中,如杂原子氮可以有氢取代基或任何允许的上文所述的有机化合物来补充其价态。此外,本发明是无意以任何方式限制允许取代有机化合物。本发明认为取代基和可变基团的组合在以稳定化合物形式在疾病的治疗上是很好的,例如传染病或增生性疾病。此处术语“稳定”是指具有稳定的化合物,在足够长的时间内检测足以维持化合物结构的完整性,最好是在足够长的时间内都在效,本文在此用于上述目的。
本申请所涉及的化合物及其药学可接受的盐的代谢产物,以及可以在体内转变为本申请所涉及的化合物及其药学可接受的盐的结构的前药,也包含在本申请的权利要求中。
制备方法
本发明提供了抗体-药物偶联物的偶联方法,将咪唑并喹啉取代磷酸酯类激动剂通过连接子连接至含有Fab抗原结合结构域和Fc结构域的抗体构建体,在不改变抗体构建体亲和性的基础上大幅提高特异性免疫反应。典型的适用于本发明的偶联方式,包括但不限于K-Lock、C-Lock、ThioMAB、ThioBridge以及酶促偶联等偶联方式。在C-Lock偶联方式中,药物-连接子分子偶联于抗体序列中的半胱氨酸(C)残基。在K-Lock偶联方式中,药物-连接子分子偶联于抗体序列中的赖氨酸(K)残基。ThiOMAB是用工程化的方法定点引入半胱氨酸,然后与药物分子偶联。ThioBridge是用具有双官能团的药物-连接子分子与抗体偶联形成桥接的抗体-药物偶联物。酶促偶联是用转氨酶等将药物-连接子分子偶联到抗体上。
优选地,所述方法分为两步:
第一步:药物和连接子通过缩合反应(生成酰胺)、取代反应(生成氨基甲酸酯)、Click反应(生成三氮唑)等生成药物-连接子分子;
第二步:药物-连接子分子通过Michael加成反应和抗体上的半胱氨酸(C)残基上的SH偶联,得到抗体-药物偶联物;半胱氨酸(C)残基上的SH可以通过TCEP还原抗体产生,或者通过SATA(S-乙酰巯基乙酸N-羟基琥珀酰亚胺酯)或者SATP(N-琥珀酰亚胺-3-乙酰硫代丙酸酯)和抗体的赖氨酸残基反应产生,或者通过抗体氨基酸定点突变(如LC-V205C、HC-A114C)产生;
或者药物-连接子分子通过缩合或者取代反应和抗体的赖氨酸(K)残基反应生成酰胺键,得到抗体-药物偶联物。
药物组合物和施用方法
本发明所述的药物组合物用于预防和/或治疗以下疾病:炎症、癌症、心血管疾病、感染、免疫性疾病、代谢性疾病。
本发明所述的抗体-药物偶联体可以与已知的治疗或改进相似病状的其他药物联用。联合给药时,原来药物的给药方式和剂量可以保持不变,而同时或随后服用本发明所述的抗体-药物偶联体。当本发明所述的抗体-药物偶联体与其它一种或几种药物同时服用时,可以优选使用同时含有一种或几种已知药物和本发明所述的抗体-药物偶联体的药用组合物。药物联用也包括在重叠的时间段服用本发明所述的抗体-药物偶联体与其它一种或几种已知药物。当本发明所述的抗体-药物偶联体与其它一种或几种药物进行药物联用时,式本发明所述的抗体-药物偶联体或已知药物的剂量可能比它们单独用药的剂量低。
可以与本发明所述的抗体-药物偶联体进行药物联用的药物或活性成分包括但不局限为:干扰素α(标准INFα和聚乙醇化的INFα)、核苷类药物(如Telbivudine、Lamivudine、Clevudine、Adefovir、Tenofovir、Besifovir、Tenofovir Disoproxil Fumarate(TDF)、Tenofovir Alafenamide Fumarate(TAF)及HDP-PMPA(CMX157)等)、壳蛋白变构调节剂(如BAY41-4109、RG-7907、NVR 3-778、ABI-H0731、ABI-H2158、JNJ-56136379、GLS 4JHS等)、cccDNA抑制剂、TLR3/7/8/9激动剂(如RG-7854、GS9620等)、乙肝病毒进入抑制剂(如Myrcludex B等)、干扰核苷酸(如ARB 1467、ARB 1740等)、HBV表面抗原抑制剂(如RG7834、REP2139、REP2165等)、CRISPER/Cas9、PD-1抑制剂(nivolumab,pembrolizumab,pidilizumab,cemiplimab,JS-001,SHR-120,BGB-A317,IBI-308,GLS-010,GB-226,STW204,HX008,HLX10,BAT 1306,AK105,LZM 009或上述药物的生物类似药)、PD-L1抑制剂(durvalumab,atezolizumab,avelumab,CS1001,KN035,HLX20,SHR-1316,BGB-A333,JS003,CS1003,KL-A167,F 520,GR1405,MSB2311或上述药物的生物类似药)、HER2抗体(如Trastuzumab,Pertuzumab)、HER2抗体-药物偶联物(如Trastuzumab Deruxtecan)、CD20抗体(如rituximab,obinutuzumab,ofatumumab,veltuzumab,tositumomab,131I-tositumomab,ibritumomab,90Y-ibritumomab,90In-ibritumomab,ibritumomabtiuxetan)、CD47抗体(Hu5F9-G4,CC-90002,TTI-621,TTI-622,OSE-172,SRF-231,ALX-148,NI-1701,SHR-1603,IBI188,IMM01)等。
本发明所述药物组合物的剂型包括(但并不限于):注射剂、控释型或缓释型或纳米制剂。
本发明的药物组合物包含安全有效量范围内的本发明化合物或其药理上可接受的盐及药理上可以接受的赋形剂或载体。其中“安全有效量”指的是:化合物的量足以明显改善病情,而不至于产生严重的副作用。通常,药物组合物含有1-2000mg本发明化合物/剂,更佳地,含有1-1000mg本发明化合物/剂。。
“药学上可以接受的载体”指的是:一种或多种相容性固体或液体填料或凝胶物质,它们适合于人使用,而且必须有足够的纯度和足够低的毒性。“相容性”在此指的是组合物中各组份能和本发明的化合物以及它们之间相互掺和,而不明显降低化合物的药效。药学上可以接受的载体部分例子有纤维素及其衍生物(如羧甲基纤维素钠、乙基纤维素钠、纤维素乙酸酯等)、明胶、滑石、固体润滑剂(如硬脂酸、硬脂酸镁)、硫酸钙、植物油(如豆油、芝麻油、花生油、橄榄油等)、多元醇(如丙二醇、甘油、甘露醇、山梨醇等)、乳化剂(如)、润湿剂(如十二烷基硫酸钠)、着色剂、调味剂、稳定剂、抗氧化剂、防腐剂、无热原水等。
用于肠胃外注射的组合物可包含生理上可接受的无菌含水或无水溶液、分散液、悬浮液或乳液,和用于重新溶解成无菌的可注射溶液或分散液的无菌粉末。适宜的含水和非水载体、稀释剂、溶剂或赋形剂包括水、乙醇、多元醇及其适宜的混合物。
本发明治疗方法可以单独施用,或者与其它治疗手段或者治疗药物联用。
使用药物组合物时,是将安全有效量的本发明化合物适用于需要治疗的哺乳动物(如人),其中施用时剂量为药学上认为的有效给药剂量,对于60kg体重的人而言,日给药剂量通常为1~2000mg。当然,具体剂量还应考虑给药途径、病人健康状况等因素,这些都是熟练医师技能范围之内的。
本发明还提供了一种治疗方法,它包括步骤:给需要治疗的对象施用本发明中所述抗体-药物偶联体,或施用本发明所述的药物组合物,用于选择性地激动TLR7和/或TLR8。
与现有技术相比,本发明具有以下主要优点:
(1)所述化合物对TLR7和TLR8具有选择性激动作用;
(2)所述化合物对TLR8具有很好的选择性激动作用;
(3)所述化合物具有更好的药效学性能和更低的毒副作用。
下面结合具体实施例,进一步阐述本发明。应理解,这些实施例仅用于说明本发明而不用于限制本发明的范围。下列实施例中未注明具体条件的实验方法,通常按照常规条件如Sambrook等人,分子克隆:实验室手册(New York:Cold Spring Harbor LaboratoryPress,1989)中所述的条件,或按照制造厂商所建议的条件。除非另外说明,否则百分比和份数按重量计算。
除非另行定义,文中所使用的所有专业与科学用语与本领域熟练人员所熟悉的意义相同。此外,任何与所记载内容相似或均等的方法及材料皆可应用于本发明方法中。文中所述的较佳实施方法与材料仅作示范之用。
本发明的小分子化合物结构是通过核磁共振(NMR)和液质联用色谱(LC-MS)来确定的。
NMR是使用Bruker AVANCE-400核磁仪检测的,测定溶剂包含氘代二甲亚砜(DMSO-d6)、氘代丙酮(CD3COCD3)、氘代氯仿(CDCl3)及氘代甲醇(CD3OD)等,内标采用四甲基硅烷(TMS),化学位移以百万分之一(ppm)的单位计量。
液质联用色谱(LC-MS)是使用Waters SQD2质谱仪检测的。HPLC的测定使用Agilent1100高压色谱仪(Microsorb 5 micron C18 100x3.0mm色谱柱)。
薄层层析硅胶板使用青岛GF254硅胶板,TLC采用的是0.15-0.20mm,制备薄层色谱采用的是0.4mm-0.5mm。柱层析一般使用青岛硅胶200-300目硅胶作为载体。
本发明实施例中的起始原料都是已知并有市售的,或者可以采用或按照本领域已报道的文献资料合成的。
除特殊说明外,本发明所有反应均在干燥的惰性气体(如氮气或氩气)保护下通过连续磁力搅拌进行,反应温度均为摄氏度。
实施例通用操作
通用操作1:抗体的浓度测定
使用UV测定器(Evolution 300,Thermo Fisher Scientif ic Inc.),按照制造商规定的方法,进行抗体浓度的测定。
通用操作2:抗体的缓冲液交换(PBS6.0/EDTA)
按照制造商说明书的方法,用含有氯化钠(137mM)及乙二胺四乙酸(EDTA,5mM)的磷酸缓冲液(10mM,pH 6.0)交换抗体水溶液将使用了Sephadex G-25载体的NAP-25柱平衡化。针对一根该NAP-25柱,装填2.5mL抗体水溶液,然后用上述PBS6.0/EDTA缓冲液(3.5mL)洗脱获得抗体缓冲液(PBS6.0/EDTA)(3.5mL)。
通用操作3:抗体的缓冲液交换(PBS6.5/EDTA)
按照制造商规定的方法,用含有氯化钠(50mM)及EDTA(2mM)的磷酸缓冲液(50mM,pH6.5)将使用了Sephadex G-25载体的NAP-25柱平衡化。针对一根该NAP-25柱,装填2.5mL抗体水溶液,然后用上述PBS6.5/EDTA缓冲液(3.5mL)洗脱获取抗体缓冲液(PBS6.5/EDTA)(3.5mL)。
通用操作4:抗体-药物偶联物的蛋白聚合物的分析
按照制造商规定的方法,使用Thermo Fisher Scientif ic Inc.Vanquish高压色谱仪(Protein BEH SEC />3.5uM,7.8mm x 300mm)测定抗体-药物偶联物中单体和聚合物的比例。
通用操作5:DAR的测定(LCMS法)
按照制造商规定的方法,使用Thermo Vanquish UHPLC连接的Thermo QEXACTIVEHF-X(流动相A为0.1%FA水溶液,流动相B为0.1%FA乙腈溶液)测定连接不同药物数目的抗体-药物偶联物的峰强度,根据峰强度计算出每一抗体的药物平均连接数。
实施例I-1抗体-药物偶联物A1的合成
中间体A1-1((S)-(((R)-1-(4-氨基-2-(乙氧基甲基)-1H-咪唑[4,5-c]喹啉-1-基)丙基-2-基)氧)(对氯苯氧)磷酰)-L-丙氨酸戊-4-炔-1酯的制备
第一步:叔丁氧羰基-L-丙氨酸戊-4-炔-1酯的制备
将叔丁氧羰基-L-丙氨酸(1g,5.29mmol)溶解于DCM(10mL)中,加入戊炔醇(533mg,6.34mmol),冰水浴降温,加入DMAP(130mg,1.06mmol),之后滴加入EDCI(1.52g,7.93mmol)的DCM(5mL)混悬液。自然升至室温反应2h。反应完毕,依次用Na2CO3水溶液、饱和食盐水洗。有机相干用Na2SO4干燥,残余物硅胶柱层析分离得到目标产品(1.25g,产率:92.6%)。
LC-MS:m/z 256(M+H)+。
第二步:L-丙氨酸戊-4-炔-1酯盐酸盐的制备
将叔丁氧羰基-L-丙氨酸戊-4-炔-1酯(1.25g,4.9mmol)溶解于EtOAc(0.5mL)中,0℃滴加HCl-EA(4M,6mL)。保持室温反应1h。反应完毕,反应液减压浓缩得到得到目标产品(0.9g,收率96%)。
LC-MS:m/z 156(M+H)+。
第三步:((S)-((4-氯苯酚)(五氟苯酚)磷酰基))-L-丙氨酸戊-4-炔-1酯的制备
向50mL三口瓶中加入三氯氧磷(407mg,2.65mmol,1.1eq)和二氯甲烷(5mL),氮气保护下降温在-70℃滴加对氯苯酚(310mg,2.41mmol,1eq)与N,N-二异丙基乙胺(343mg,2.65mmol,1.1eq)的二氯甲烷(5mL)溶液。10min滴完,在-60℃反应1.5小时。滴加L-丙氨酸戊-4-炔-1酯盐酸盐(460mg,2.4mmol,1.0eq)与N,N-二异丙基乙胺(683mg,5.29mol,2.2eq)的二氯甲烷(6mL)溶液。10min滴完,在-60℃反应1.5小时。在-60℃加五氟苯酚(442mg,2.4mmol,1.0eq)与N,N-二异丙基乙胺(342mg,2.64mmol,1.1eq)的二氯甲烷(5mL)溶液。10min滴完,逐渐升至室温反应16小时。反应液减压浓缩,残余物液相制备得到目标产品(180mg,产率:14%)
LC-MS:m/z 512(M+H)+。
第四步:((S)-(((R)-1-(4-氨基-2-(乙氧基甲基)-1H-咪唑[4,5-c]喹啉-1-基)丙基-2-基)氧)(对氯苯氧)磷酰)-L-丙氨酸戊-4-炔-1酯的制备
将((S)-((4-氯苯酚)(五氟苯酚)磷酰基))-L-丙氨酸戊-4-炔-1酯(180mg,0.35mmol),(R)-1-(4-氨基-2-(乙氧基甲基)-1H-咪唑并[4,5-C]喹啉-1-基)-2-丙醇(74mg,0.25mmol)分散于THF(1.5mL)溶液中,氮气保护下降温至-5℃。滴加叔丁基氯化镁(0.38mL,0.38mmol,1N的THF溶液)。保持温度在-5-2℃之间反应1h。滴加氯化铵水溶液,EtOAc萃取,有机相浓缩。残余物反相制备得到目标产物(76mg,产率:35%)。
LC-MS:m/z 628.86(M+H)+。1H NMR(400MHz,DMSO-d6)δ8.07(d,J=8Hz,1H),7.61(d,J=8Hz,1H),7.43(t,J=8Hz,1H),7.23(t,J=8Hz,1H),7.19(d,J=8Hz,2H),6.61(m,4H),5.96(t,J=12Hz,1H),4.92-4.84(m,3H),4.80-4.73(m,1H),4.60(d,J=12Hz,1H),4.12-4.02(m,2H),3.56-3.44(m,3H),2.81(t,J=4Hz,1H),2.24-2.20(m,2H),1.76-1.71(m,2H),1.51(d,J=8Hz,3H),1.15(t,J=8Hz,3H),1.00(d,J=8Hz,3H)。31P NMR(162MHz,DMSO-d6)δ2.54(s,1P)。
中间体A1-2药物-连接子(A1-2)的合成
第一步:(26-羟基-3,6,9,12,15,18,21,24-八氧二十六烷基)氨基甲酸叔丁酯的制备
25℃下26-氨基-3,6,9,12,15,18,21,24-八氧二十六烷基-1-醇(3.00g,7.26mmol,1.00eq)的DCM(45.0mL)溶液中滴加入Boc2O(1.90g,8.71mmol,2.00mL,1.20eq)的DCM(15.0mL)溶液。得到的反应液在25℃反应16h,然后减压浓缩得到目标产物(3.87g,粗品)。无需纯化,直接用于下一步反应。
LC-MS:m/z 514(M+H)+。
第二步:2,2-二甲基-4-氧-3,8,11,14,17,20,23,26,29-九氧-5-氮杂-三十一烷-31-基4-对甲苯磺酸酯的制备
0℃下,向(26-羟基-3,6,9,12,15,18,21,24-八氧二十六烷基)氨基甲酸叔丁酯(1.50g,2.92mmol,1.00eq)的ACN(15.0mL)溶液中依次加入TEA(591mg,5.84mmol,813uL,2.00eq)、N,N-dimethylmethanamine;hydrochloride(27.9mg,292umol,0.100eq)和TosCl(724mg,3.80mmol,1.30eq)。反应混合物在0℃反应1.5h,随后倒入水中(50mL),再用DCM(3x100mL)萃取。合并的有机相用无水MgSO4干燥后过滤。减压浓缩得到目标产物(1.92g,粗品)。无需纯化,直接用于下一步反应。
LC-MS:m/z 668(M+H)+。
第三步:(26-叠氮-3,6,9,12,15,18,21,24-八氧二十六烷基)氨基甲酸叔丁酯的制备
2,2-二甲基-4-氧-3,8,11,14,17,20,23,26,29-九氧-5-氮杂-三十一烷-31-基-4-对甲苯磺酸酯(961mg,1.44mmol,1.00eq)的DMF(10.0mL)溶液中加入NaN3(380mg,5.85mmol,4.06eq)。得到的混合物在60℃反应2h,然后用饱和Na2CO3水溶液稀释后(40mL)a用EtOAc(3x200mL)萃取。合并的有机相用无水MgSO4干燥后过滤。减压浓缩得到目标产物(1.04g,粗品)。无需纯化,直接用于下一步反应。
LC-MS:m/z 539(M+H)+。
第四步:26-叠氮-3,6,9,12,15,18,21,24-八氧二十六烷基-1-胺的制备
(26-叠氮-3,6,9,12,15,18,21,24-八氧二十六烷基)氨基甲酸叔丁酯(980mg,1.82mmol,1.00eq)的HCl/dioxane(4.00M,15.0mL,33.0eq)溶液在25℃反应0.5h,然后减压浓缩。残余物用饱和NaHCO3水溶液调节pH至7,然后用DCM(3x 100mL)萃取。合并的有机相用无水MgSO4干燥后过滤。减压浓缩得到目标产物(355.2mg,粗品)。无需纯化,直接用于下一步反应。
LC-MS:m/z 439(M+H)+。
第五步:1-(26-叠氮-3,6,9,12,15,18,21,24-八氧二十六烷基)-1H-吡咯-2,5-二酮的制备
将26-叠氮基-3,6,9,12,15,18,21,24-八氧二十六烷基-1-胺(66mg,0.15mmol)溶于碳酸氢钠饱和溶液(2mL)中,搅拌5min后,加入2,5-二氧基-2,5-二氢-1H-吡咯-1-羧酸甲酯(31mg,0.2mmol),0℃下搅拌1h,LCMS监控反应;反应结束后直接用于下一步反应。
第六步:药物-连接子A1-2的的制备
将((S)-(((R)-1-(4-氨基-2-(乙氧基甲基)-1H-咪唑[4,5-c]喹啉-1-基)丙基-2-基)氧)(对氯苯氧)磷酰)-L-丙氨酸戊-4-炔-1酯(57mg,0.09mmol)的四氢呋喃溶液(2ml),加入至上一步得到的反应液中,随后依次加入硫酸铜(90mg,0.57mmol)和L-抗坏血酸钠(100mg,0.57mmol),加完后保持温度40℃搅拌2h。得到的反应液中加入水(50mL),再用乙酸乙酯溶液萃取(3x30mL)。合并的有机相用饱和氯化钠溶液洗一次,经无水硫酸钠干燥后过滤。滤液浓缩后用制备色谱分离得到目标产物(17mg,产率:16.5%)。
LC-MS:m/z 1146.76(M+H)+。1H NMR(400MHz,DMSO-d6)δ8.10(d,J=8.0Hz,1H),7.80(s,1H),7.63(d,J=8.0Hz,1H),7.45(t,J=8.0Hz,1H),7.24(t,J=8.0Hz,1H),7.15(m,2H),7.01(s,1H),6.70(br,1H),6.63(d,J=8.0Hz,2H),5.94(m,1H),4.84(m,4H),4.63(d,J=12.0Hz,1H),4.46(t,J=8.0Hz,2H),4.04(m,2H),3.79(t,J=5.6Hz,2H),3.49(m,37H),2.66(t,J=8.0Hz,2H),1.88(m,2H),1.51(d,J=4.0Hz,3H),1.14(t,J=6.8Hz,3H),1.03(d,J=8.0Hz,3H)。
抗体-药物偶联物A1的制备
用Sephadex G-25将Trastuzumab的组氨酸盐酸盐缓冲液(0.5mL,152nmol;22mg/mL,MW:145100g/mol)置换为PBS buffer-EDTA(pH 6.0),收集抗体液(3.5mL)。向上述Trastuzumab的PBS buffer-EDTA(pH 6.0)液中加入1M磷酸氢二钾水溶液(33微升),随后加入10mmol/L的TCEP(82微升,820nmol,6.35eq),再加入1M磷酸氢二钾水溶液(90微升)调节pH至7.0。反应液在37℃,120自旋摇速反应60min,随后将至15℃,加入中间体A1-2的10mMDMSO溶液(111微升,1109nmol,8.6eq)。得到的反应液在15℃搅拌反应0.5h,然后停止搅拌,在15℃静置1h。在搅拌下加入N-乙酰基半胱氨酸的100mmol/L的水溶液(16.6微升,1664nmol,12.9eq),在15℃搅拌反应30min。用Sephadex G-25将反应液置换为PBS buffer(pH 7.2),收集抗体液(5.35mL)。按照通用操作4测得抗体-药物偶联物A1单体含量97.44%。按照通用操作5测得抗体-药物偶联物A1 DAR为2.6。
实施例I-2抗体-药物偶联物A2的制备
取0.5mL曲妥珠单抗的组氨酸盐酸溶液(22mg,152nmol ,44mg/mL,MW.145100),上柱(柱体积约4mL),用PBS buffer(0.1M磷酸盐,0.15M氯化钠的PBS,pH 7.33)进行淋洗,茚三酮显色,收集到曲妥珠单抗的PBS-A buffer溶液(3.12mL)。取SATA-DMSO(20.9微升,1108nmol,9.2eq)加入静置的曲妥珠单抗的PBS buffer(0.1M磷酸盐,0.15M氯化钠的PBS,pH 7.33)溶液。在25℃,自旋摇速120反应40min。反应完毕,反应液上柱,用PBS buffer(0.1M磷酸盐,0.15M氯化钠的PBS,pH 7.33)进行淋洗,收集抗体溶液(3.5mL)。向静置状态、修饰的曲妥珠单抗的PBS buffer溶液(3400微升,0.1M磷酸盐,0.15M氯化钠的PBS,pH7.33)加入PBS buffer(340微升,0.5M盐酸羟胺,25mM EDTA,pH 72-7.3),在25℃,自旋摇速120反应2.0h。反应完毕,反应液上柱,用PBS-EDTA buffer(EDTA 10mmol/L,pH 7.08)进行淋洗,收集抗体溶液(4.6mL)。向静置状态、修饰的曲妥珠单抗的PBS-EDTA buffer溶液加入中间体A1-2的DMSO溶液(32微升,640nmol,8eq),在25℃,自旋摇速120反应1.5h。静置加入11.4微升N-乙酰半胱氨酸(568nmol,7.1eq)。在25℃,自旋摇速120反应1.0h。反应完毕。上柱,用PBS buffer(0.1M磷酸盐,0.15M氯化钠的PBS,pH 7.33)进行淋洗,收集抗体液(5mL)。按照通用操作4测得抗体-药物偶联物A2单体含量94.44%。按照通用操作5测得抗体-药物偶联物A2 DAR为1.4。
实施例I-3抗体-药物偶联物A3的制备
中间体A3-1 3-(1-(2-(2-(2-氨基乙氧基)乙氧基)乙基)-1H-1,2,3-三唑-4-基)丙基((S)-(((R)-1-(4-氨基-2-(乙氧基甲基)-1H-咪唑[4,5-c]喹啉-1-基)丙烷-2-基)氧基)(4-氯苯氧基)磷酰)-L-丙氨酸酯的制备
将2-(2-(2-叠氮乙基氧基)乙氧基)乙烷-1-胺(14mg,0.08mmol)和((S)-(((R)-1-(4-氨基-2-(乙氧基甲基)-1H-咪唑[4,5-c]喹啉-1-基)丙基-2-基)氧)(对氯苯氧)磷酰)-L-丙氨酸戊-4-炔-1酯(50mg,0.08mmol)溶于四氢呋喃(1mL)和水(1mL)中,随后依次加入硫酸铜(19mg,0.12mmol)和L-抗坏血酸钠(24mg,0.12mmol)。加完后反应液保持温度40℃搅拌0.5h,然后直接用制备液相纯化得到目标产物。
LC-MS:m/z 802(M+H)+。
中间体A3-2药物-连接子(A3-2)的合成
将二异丙基乙胺(20mg,0.15mmol)加入到4-((S)-2-((S)-2-(6-(2,5-二氧基-2,5-二氢-1H-吡咯-1-基)六酰胺基)-3-甲基丁胺基)-5-脲基五酰胺基)苄基(4-硝基苯基)碳酸酯(15mg,0.02mmol)和3-(1-(2-(2-(2-氨基乙氧基)乙氧基)乙基)-1H-1,2,3-三唑-4-基)丙基((S)-(((R)-1-(4-氨基-2-(乙氧基甲基)-1H-咪唑[4,5-c]喹啉-1-基)丙烷-2-基)氧基)(4-氯苯氧基)磷酰)-L-丙氨酸酯(22mg,0.028mmol)的N,N-二甲基甲酰胺(1.5ml)溶液中。反应液在室温搅拌1小时,然后用制备液相分离得到目标产物(16mg,产率:59%)。
LC-MS:m/z 701.83(M+2H)2+。1HNMR(400MHz,DMSO-d6):δ9.96(s,1H),8.07(m,2H),7.78(m,2H),7.60(m,3H),7.45(m,1H),7.21(m,6H),6.99(s,2H),6.61(d,J=8.0Hz,2H),6.55(s,2H),5.96(m,2H),5.40(s,2H),4.84(m,6H),4.59(d,J=12.0Hz,1H),4.44(m,3H),4.18(m,1H),4.03(m,2H),3.78(m,2H),3.49(m,8H),3.02(m,5H),2.67(m,2H),2.13(m,2H),1.91(m,3H),1.48(m,12H),1.19(m,6H),1.01(d,J=4.0Hz,3H),0.83(m,6H)。
抗体-药物偶联物A3的制备
用Sephadex G-25将Trastuzumab的组氨酸盐酸盐缓冲液(0.4mL,121nmol;44mg/mL,MW:145100g/mol,)置换为PBS buffer-EDTA,收集抗体液。收集完毕2.6mL。向上述Trastuzumab的PBS buffer-EDTA液(pH 6.04,27.9℃)中加入1M磷酸氢二钾水溶液(27微升),再加入10mmol/L的TCEP(59微升,586nmol,5.4eq),随后加入1M磷酸氢二钾水溶液(70微升),调节pH在6.99。在37℃,140旋转摇速反应70min。降至15℃,加入中间体A3-2的10mMDMSO溶液(94微升,933nmol,8.6eq)溶液。反应液在15℃搅拌反应0.5h。停止搅拌,在15℃静置70min。搅拌下加入N-乙酰基半胱氨酸的100mmol/L水溶液(14微升,1400nmol,12.9eq),在15-25℃搅拌反应40min。用Sephadex G-25将反应液置换为PBS buffer(pH 7.3),收集抗体液(3.46mL)。按照通用操作4测得抗体-药物偶联物A3单体含量94.5%。按照通用操作5测得抗体-药物偶联物A3 DAR为7.6。
实施例I-4抗体-药物偶联物A4的制备
中间体A4-1 3-(1-(4-(哌嗪-1-基)苄基)-1H-1,2,3-三唑-4-基)丙基((S)-(((R)-1-(4-氨基-2-(乙氧基甲基)-1H-咪唑[4,5-c]喹啉-1-基)丙烷-2-基)氧基)(4-氯苯氧基)磷酰)-L-丙氨酸酯的制备
将戊-4-炔基-1-基(((-1-(4-氨基-2-(乙氧基甲基)-1H咪唑[4,5-c]喹啉-1-基)丙-2-基)氧基)(4-氯苯酚基)磷酰基)-L-丙氨酸酯(30mg,0.05mmol)和1-(4-(叠氮甲基)苯基)哌嗪盐酸盐(13mg,0.05mmol)溶于四氢呋喃(1.5ml)和水(1.5ml)中,随后依次加入硫酸铜(13mg,0.08mmol)和L-抗坏血酸钠(14mg,0.08mmol)。加完后反应液保持温度40℃搅拌0.5h,然后直接用制备液相分离得到目标产物(15mg,产率:35.5%)。
LC-MS:m/z 845(M+H)+。
中间体A4-2药物-连接子(A4-2)的合成1
将3-(1-(4-(哌嗪-1-基)苄基)-1H-1,2,3-三唑-4-基)丙基((S)-(((R)-1-(4-氨基-2-(乙氧基甲基)-1H-咪唑[4,5-c]喹啉-1-基)丙烷-2-基)氧基)(4-氯苯氧基)磷酰)-L-丙氨酸酯(15mg,0.02mmol)和(6-(2,5-二氧基-2,5-二氢-1H-吡咯-1-基)己酰基)甘氨酸甘氨酸-L-苯丙氨酸(14mg,0.03mmol)溶于二氯甲烷(1mL)中,随后加入N,N-二异丙基乙胺(18mg,0.14mmol)。反应液用冰水浴冷却,随后滴加1-丙基磷酸酐(50%wt,38mg,0.06mmol)。加完后反应液在冰水浴下搅拌10分钟,然后减压浓缩。残余物用制备液相分离得到目标产物(11mg,产率:42%)。
LC-MS:m/z 672(M+2Na)2+。1HNMR(400MHz,DMSO-d6):δ8.29(d,J=8.0Hz,1H),8.02(m,3H),7.81(s,1H),7.60(d,J=8.0Hz,1H),7.43(m,1H),7.16(m,10H),6.98(s,2H),6.84(d,J=8.0Hz,2H),6.62(m,4H),5.95(m,1H),5.39(s,2H),4.83(m,5H),4.58(d,J=16.0Hz,1H),4.03(m,2H),3.67(m,4H),3.50(m,2H),2.96(m,7H),2.59(m,4H),2.10(t,2H),1.86(m,2H),1.48(m,8H),1.18(m,8H),1.01(d,J=8.0Hz,3H)。
实施例I-5抗体-药物偶联物A5的制备
中间体A4-2药物-连接子(A5-2)的合成
将3-(1-(4-(哌嗪-1-基)苄基)-1H-1,2,3-三唑-4-基)丙基((S)-(((R)-1-(4-氨基-2-(乙氧基甲基)-1H-咪唑[4,5-c]喹啉-1-基)丙烷-2-基)氧基)(4-氯苯氧基)磷酰)-L-丙氨酸酯(54mg,0.06mmol)和4-((S)-2-((S)-2-(6-(2,5-二氧基-2,5-二氢-1H-吡咯-1-基)六酰胺基)-3-甲基丁胺基)-5-脲基五酰胺基)苄基(4-硝基苯基)碳酸酯(47mg,0.06mmol)溶于N,N-二甲基甲酰胺(2mL)中,随后加入N,N-二异丙基乙胺(54mg,0.42mmol)。加完后反应液室温下搅拌1小时,然后用制备液相分离得到目标产物(35mg,产率:40.4%)。
LC-MS:m/z 720(M-2H)2-。1HNMR(400MHz,DMSO-d6):δ9.98(t,1H),8.06(m,2H),7.78(m,2H),7.59(m,3H),7.43(t,J=8.0Hz,1H),7.30(d,J=8.0Hz,2H),7.16(m,5H),6.99(s,2H),6.90(d,J=8.0Hz,2H),6.61(m,4H),5.95(m,2H),5.40(s,4H),5.02(s,2H),4.83(m,4H),4.58(d,J=12.0Hz,1H),4.38(m,1H),4.18(m,1H),4.02(m,2H),3.50(m,5H),3.36(m,1H),3.30(m,6H),2.64(t,J=8.0Hz,2H),2.15(m,2H),1.90(m,3H),1.51(m,12H),1.16(m,7H),0.99(d,J=8.0Hz,3H),0.83(m,6H)。
实施例II-1抗体-药物偶联物B1的制备
中间体B1-1((S)-(((R)-1-(4-氨基-2-(乙氧基甲基)-1H-咪唑[4,5-c]喹啉-1-基)丙基-2-基)氧)(对氯苯氧)磷酰)-L-丙氨酸-(哌啶-4-氧基)酯的制备
步骤一:1-(叔丁氧羰基)-4-((N-苄氧羰基)-L-丙氨酰氧基)哌啶的制备
将N-苄氧羰基-L-丙氨酸(2g,8.96mmol)溶解于二氯甲烷(20mL)中,加入1-(叔丁氧羰基)-4-哌啶甲醇(2.16g,10.75mmol)。反应液冰水浴降温,加入4-二甲胺基吡啶(219mg,1.80mmol),随后滴加入1-乙基-3(3-二甲基丙胺)碳二亚胺(2.58g,13.44mmol)的二氯甲烷(8mL)混悬液。反应液自然升至室温反应16h。得到的混合物依次用饱和碳酸钠水溶液和饱和氯化钠水溶液洗。有机相用硫酸钠干燥后过滤。滤液减压浓缩,残余物用硅胶柱层析分离得到产物(2.2g,产率:60%)。
LC-MS:m/z 407(M+H)+。
步骤二:1-(叔丁氧羰基)-4-(L-丙氨酰氧基)哌啶的制备
氮气氛围下,将1-(叔丁氧羰基)-4-((N-苄氧羰基)-L-丙氨酰氧基)哌啶(2.2g,5.41mmol)溶解于甲醇(10mL)中,随后加入Pd/C(10%wt,0.5g)。得到的反应液在氢气氛围下反应5h。反应完毕,反应液减压浓缩得到目标产物(1.4g,产率:95%)。无需纯化,直接用于下一步反应。
LC-MS:m/z 273(M+H)+。
步骤三:((S)-((4-氯苯酚((五氟苯酚)磷酰基))-L-丙氨酸-((1-(叔丁氧羰基)哌啶-4氧基)酯的制备
氮气保护下,三氯氧磷(426mg,2.78mmol,1.1eq)溶于二氯甲烷(6mL)。反应液降温至-70℃,随后在10min内滴加对氯苯酚(325mg,2.53mmol,1eq)与N,N-二异丙基乙胺(359mg,2.78mmol,1.1eq)的二氯甲烷(6mL)溶液。得到的反应液在-60℃反应1.5小时,随后在10min内滴加入1-(叔丁氧羰基)-4-(L-丙氨酰氧基)哌啶(688mg,2.53mmol,1.0eq)与N,N-二异丙基乙胺(359mg,2.78mmol,1.1eq)的二氯甲烷(7mL)溶液。得到的反应液在-60℃反应1.5小时,随后在10min内滴加入五氟苯酚(465mg,2.53mmol,1.0eq)与N,N-二异丙基乙胺(359mg,2.78mmol,1.10eq)的二氯甲烷(6mL)溶液。得到的反应液逐渐升至-20℃,并在此温度下反应1.5小时。得到的反应液减压浓缩得,粗品用制备液相分离。包含产品的层析液收集后冷冻干燥。得到的固体加入正庚烷-乙酸乙酯(V:V=10:1,14mL),随后在室温搅拌4h后过滤。固体收集后干燥得到目标产物(500mg,产率:31.4%)。
LC-MS:m/z 629(M+H)+。
步骤四:((S)-(((R)-1-(4-氨基-2-(乙氧基甲基)-1H-咪唑[4,5-c]喹啉-1-基)丙基-2-基)氧)(对氯苯氧)磷酰)-L-丙氨酸-((1-(叔丁氧羰基)哌啶-4-氧基)酯的制备
氮气保护下将((S)-((4-氯苯酚((五氟苯酚)磷酰基))-L-丙氨酸-((1-(叔丁氧羰基)哌啶-4氧基)酯(500mg,0.80mmol)和(R)-1-(4-氨基-2-(乙氧基甲基)-1H-咪唑并[4,5-C]喹啉-1-基)-2-丙醇(205mg,0.68mmol)分散于四氢呋喃(3mL)溶液中,随后降温至-5℃,然后滴加叔丁基氯化镁(0.89mL,0.89mmol,1N四氢呋喃溶液)。得到的混合物保持温度在-5-2℃之间反应1.5h,随后用饱和氯化铵水溶液淬灭,再用乙酸乙酯萃取。有机相合并后减压浓缩,残余物用制备液相分离得到目标产物(250mg,产率:49%)。
LC-MS:m/z 745(M+H)+。
步骤五:((S)-(((R)-1-(4-氨基-2-(乙氧基甲基)-1H-咪唑[4,5-c]喹啉-1-基)丙基-2-基)氧)(对氯苯氧)磷酰)-L-丙氨酸-(哌啶-4-氧基)酯盐酸盐的制备
将((S)-(((R)-1-(4-氨基-2-(乙氧基甲基)-1H-咪唑[4,5-c]喹啉-1-基)丙基-2-基)氧)(对氯苯氧)磷酰)-L-丙氨酸-((1-(叔丁氧羰基)哌啶-4-氧基)酯(250mg,0.33mmol)溶解于二氯甲烷(4mL)中,在0℃滴加三氟乙酸(0.7mL)。得到的混合物升至室温,并在室温反应3h。反应完毕,反应液在0℃滴加碳酸钠水溶液调节pH至8,然后用二氯甲烷萃取。合并的有机相减压浓缩,残余物溶解于乙酸乙酯(2mL)中,随后滴加氯化氢-乙酸乙酯(1M)溶液,调节pH至4,然后加入乙腈和水,混合物冷冻干燥得到目标产物(197mg,产率:82%)。
LC-MS:m/z 645(M+H)+。1H NMR(400MHz,DMSO-d6)δ13.89(s,1H),9.14(m,3H),8.32(d,J=8Hz,1H),7.80(d,J=8Hz,1H),7.72(t,J=8Hz,1H),7.54(t,J=8Hz,1H),7.15(d,J=8Hz,2H),6.60(d,J=8Hz,2H),6.06(t,J=12Hz,1H),4.92-4.89(m,5H),4.67(d,J=12Hz,1H),3.60-3.53(m,3H),3.12-3.04(m,4H),1.95(m,2H),1.75(m,2H),1.58(d,J=8Hz,3H),1.17(t,J=8Hz,3H),1.08(d,J=8Hz,3H)。31P NMR(162MHz,DMSO-d6)δ2.78(s,1P)。
中间体B1-2药物-连接子(B1-2)的制备
将哌啶-4-基(((S)-(((R)-1-(4-氨基-2-(乙氧基甲基)-1H-咪唑[4,5-c]喹啉-1-基)丙基-2-基)氧)(对氯苯氧)磷酰))-L-丙氨酸酯(50mg,0.077mmol)溶解于N,N-二甲基甲酰胺(1mL)中,滴加入马来酰亚胺基己酰-L-缬氨酸-L-瓜氨酸对氨基苄醇对硝基苯基碳酸酯(59mg,0.08mmol)的N,N-二甲基甲酰胺(1.2mL)溶液,随后滴加N,N-二异丙基乙胺(26mg,0.2mmol)。得到的反应液在室温反应1.5h,然后通过制备液相分离得到目标产物(35mg,产率:37%)。
LC-MS:m/z 623(M+2H)2+。1H NMR(400MHz,DMSO-d6)δ9.99(s,1H),8.07(d,J=8Hz,2H),7.79(d,J=8Hz,1H),7.60-7.58(m,3H),7.42(t,J=8Hz,1H),7.29(d,J=8Hz,2H),7.22(t,J=8Hz,1H),7.17(d,J=8Hz,2H),6.88(s,2H),6.63(d,J=8Hz,2H),6.58(s,2H),5.99-5.93(m,2H),5.40(s,2H),5.00(s,2H),4.93-4.73(m,5H),4.60(d,J=16Hz,1H),4.41-4.35(m,1H),4.19(t,J=8Hz,1H),3.59-3.46(m,5H),3.36(t,J=8Hz,2H),3.06-2.92(m,3H),2.22-2.07(m,2H),1.99-1.94(m,1H),1.76(m,3H),1.60-1.34(m,13H),1.22-1.11(m,6H),1.01(d,J=4Hz,3H),0.86-0.81(m,6H)。
抗体-药物偶联物B1的制备
用Sephadex G-25将Trastuzumab的PBS 7.4缓冲液(0.6mL,76.3mg/mL)置换为PBSbuffer-EDTA,收集抗体液(3.35mL,14.3mg/mL)。向上述Trastuzumab的PBS buffer-EDTA液中加入PBS buffer-EDTA(3.35mL)。向3.35mL上述Trastuzumab的PBS buffer-EDTA液(pH6.10,24.4℃)中加入1M磷酸氢二钾水溶液(36μL),加入10mmol/L的TCEP(90 μL,900nmol,5.45eq),测pH6.55。加入1M磷酸氢二钾水溶液(72μL),调节pH在7.0。在37℃,140旋转摇速反应70min。降至15℃,加入DMSO(430μL),15℃搅拌15min。加入中间体B1-2的10mM DMSO溶液(142 μL,1420nmol,8.6eq)溶液。在15℃搅拌反应0.5h。停止搅拌,在15℃静置70min。搅拌下加入N-乙酰基半胱氨酸的水溶液(100mmol/L,21.3μL,2130nmol,12.9eq),在15-25℃搅拌反应40min。用Sephadex G-25将反应液置换为PBS buffer(pH 7.2),收集抗体液5.6mL。按照通用操作4测得抗体-药物偶联物B1单体含量93.7%。按照通用操作5测得抗体-药物偶联物B1 DAR为7.7。
按照实施例II-1同样的制备方法得到以下实施例:
实施例II-2抗体-药物偶联物B2的制备
中间体B2-2药物-连接子(B2-2)的制备
LC-MS:m/z 1157(M+H)+。1H NMR(400MHz,DMSO-d6)δ9.94(s,1H),8.16(d,J=8Hz,1H),8.08(d,J=8Hz,1H),7.82(d,J=8Hz,1H),7.62-7.58(m,3H),7.43(t,J=8Hz,1H),7.31(d,J=8Hz,2H),7.23(t,J=8Hz,1H),7.19(d,J=8Hz,2H),7.0(s,2H),6.65(d,J=8Hz,2H),6.59(s,2H),5.96(t,J=8Hz,1H),5.04(s,2H),4.92-4.74(m,5H),4.63(d,J=16Hz,1H),4.44-4.35(m,1H),4.18(t,J=8Hz,1H),3.57-3.47(m,5H),3.39(t,J=8Hz,3H),2.22-2.08(m,2H),1.99-1.93(m,1H),1.77(s,2H),1.51-1.44(m,9H),1.32(d,J=8Hz,3H),1.21-1.12(m,6H),1.02(d,J=8Hz,3H),0.88-0.82(m,6H)。31P NMR(162MHz,DMSO-d6)δ2.59(s,1H),
抗体-药物偶联物B2的制备
按照通用操作4测得抗体-药物偶联物B2单体含量90.7%。按照通用操作5测得抗体-药物偶联物B2 DAR为5.9。
实施例II-3抗体-药物偶联物B3的制备
中间体B3-2药物-连接子(B3-2)的制备
哌啶-4-基((S)-(R)-1-(4-氨基-2-(乙氧基甲基)-1H-咪唑[4,5-c]喹啉-1-基)丙烷-2-基)氧基)(4-氯苯氧基)磷酰基)-L-丙氨酸酯(45mg,0.07mmol)和28-(2,5-二氧基-2,5-二氢-1H-吡咯-1-基)-23-氧基-4,7,10,13,16,19-六氧基-22-氮杂二十八烷酸(44mg,0.08mmol)溶于二氯甲烷(2mL)中,随后加入N,N-二异丙基乙胺(63mg,0.49mmol)。反应液冰水浴冷却,随后滴加T3P(50%wt,134mg,0.21mmol)。滴加完毕,反应液在冰水浴搅拌10min,然后减压浓缩。残余物用制备液相分离得到目标产物(25mg,产率:30.4%)。
LC-MS:m/z 1173(M+H)+。1H NMR(400MHz,DMSO-d6)δ8.09(t,J=8.0Hz,1H),7.81(m,1H),7.62(d,J=8.0Hz,1H),7.46(t,J=4.0Hz,1H),7.23(m,1H),7.01(s,2H),6.65(m,4H),5.97(m,1H),4.86(m,5H),4.61(d,J=16Hz,1H),3.52(m,29H),318(m,2H),2.59(m,2H),2.05(m,2H),1.73(m,2H),1.49(m,10H),1.18(m,6H),1.03(d,J=8.0Hz,3H)。
抗体-药物偶联物B3的制备
用Sephadex G-25将Trastuzumab的PBS 7.4缓冲液(0.6mL,76.3mg/mL)置换为PBSbuffer-EDTA,收集抗体液(1.54mL,24.9mg/mL)。向上述Trastuzumab的PBS buffer-EDTA液中加入4.62mL PBS buffer-EDTA。向6.16mL上述Trastuzumab的PBS buffer-EDTA液(pH6.14,22.1℃)中加入1M磷酸氢二钾水溶液(57微升)。随后加入10mmol/L的TCEP(143 μL,1428nmol,5.41eq).测pH6.56。加入1M磷酸氢二钾水溶液(380微升),调节pH至7.00。取上述抗体缓冲液3.37mL,在37℃,140旋转摇速反应60min。然后降至15℃,在搅拌下,滴加中间体B3-2的10mM DMSO溶液(114微升,1140nmol,8.65eq)溶液。加完后溶液澄清状态。加完后15℃下搅拌30min,静置1h。搅拌下加入N-乙酰基半胱氨酸的100mmol/L水溶液(17微升,1700nmol,12.88eq),在15-25℃搅拌反应40min。用Sephadex G-25将反应液置换为PBSbuffer(pH 7.2),收集抗体液(6.0mL)。按照通用操作4测得抗体-药物偶联物B3单体含量95.9%。按照通用操作5测得抗体-药物偶联物B3 DAR为5.5。
按实施例II-3的方法以不同起始原料合成以下中间体及抗体-药物偶联物
实施例II-4中间体B4-2药物-连接子(B4-2)
LC-MS:m/z 1261(M+H)+。1H NMR(400MHz,DMSO-d6)δ8.09(t,J=8.0Hz,1H),7.80(m,1H),7.60(d,J=8.0Hz,1H),7.44(t,J=8.0Hz,1H),7.23(m,3H),6.99(s,2H),6.63(m,4H),5.97(m,1H),4.86(m,5H),4.59(d,J=16Hz,1H),3.60(m,2H),3.50(m,30H),318(m,2H),2.57(m,2H),2.05(m,2H),1.72(m,2H),1.47(m,9H),1.18(m,5H),1.03(d,J=8.0Hz,3H)。
实施例II-5中间体B5-2药物-连接子(B5-2)
LC-MS:m/z 1349(M+H)+。1H NMR(400MHz,DMSO-d6)δ8.09(t,J=8.0Hz,1H),7.81(m,1H),7.60(d,J=8.0Hz,1H),7.44(t,J=8.0Hz,1H),7.21(m,3H),6.99(s,0.5H),6.63(m,4H),5.96(m,1H),4.85(m,5H),4.59(d,J=16Hz,1H),3.60(m,2H),3.50(m,38H),3.18(m,2H),2.57(m,2H),2.05(m,2H),1.71(m,2H),1.47(m,9H),1.18(m,5H),1.03(d,J=8.0Hz,3H)。
实施例II-6中间体B6-2药物-连接子(B6-2)
LC-MS:m/z 1060(M+H)+。1H NMR(400MHz,DMSO-d6)δ8.07(d,J=8.0Hz,1H),7.60(d,J=8.0Hz,1H),7.44(t,J=8.0Hz,1H),7.19(m,3H),7.04(s,2H),6.64(m,4H),6.01(m,1H),4.85(m,5H),4.59(d,J=12.0Hz,1H),3.50(m,32H),2.58(m,2H),1.78(m,2H),1.42(m,6H),1.14(t,J=8.0Hz,3H),1.00(d,J=8.0Hz,3H)。
实施例II-7中间体B7-2药物-连接子(B7-2)
LC-MS:m/z 1148(M+H)+。1H NMR(400MHz,DMSO-d6)δ8.07(d,J=8.0Hz,1H),7.60(d,J=8.0Hz,1H),7.44(t,J=8.0Hz,1H),7.20(m,3H),7.04(s,2H),6.63(m,4H),6.01(m,1H),4.85(m,5H),4.59(d,J=12.0Hz,1H),3.50(m,40H),2.58(m,2H),1.78(m,2H),1.42(m,6H),1.14(t,J=8.0Hz,3H),1.00(d,J=8.0Hz,3H)。
实施例II-8中间体B8-2药物-连接子(B8-2)
LC-MS:m/z 1236(M+H)+。1H NMR(400MHz,DMSO-d6)δ8.07(d,J=8.0Hz,1H),7.60(d,J=8.0Hz,1H),7.44(t,J=8.0Hz,1H),7.20(m,3H),7.04(s,2H),6.63(m,4H),6.02(m,1H),4.85(m,5H),4.59(d,J=12.0Hz,1H),3.50(m,48H),2.58(m,2H),1.79(m,2H),1.42(m,6H),1.15(t,J=8.0Hz,3H),1.00(d,J=8.0Hz,3H)。
实施例II-9抗体-药物偶联物B9的制备
中间体B9-1 1-(2-羟基乙酰基)哌啶-4-基((S)-(((R)-1-(4-氨基-2-(乙氧基甲基)-1H-咪唑[4,5-c]喹啉-1-基)丙烷-2-基)氧基)(4-氯苯氧基)磷酰)-L-丙氨酸酯的制备
步骤一:N-(2-叔丁基二苯基硅氧基-乙酰基)-哌啶-(4-基(((S)-(((R)-1-(4-氨基-2-(乙氧基甲基)-1H-咪唑[4,5-c]喹啉-1-基)丙基-2-基)氧)(对氯苯氧)磷酰))-L-丙氨酸酯)的制备
将((S)-(((R)-1-(4-氨基-2-(乙氧基甲基)-1H-咪唑[4,5-c]喹啉-1-基)丙基-2-基)氧)(对氯苯氧)磷酰)-L-丙氨酸-(哌啶-4-氧基)酯盐酸盐(50mg,0.07mmol)溶解于二氯甲烷(2mL)中,加入N,N-二异丙基乙胺(18mg,0.139mmol)和2-((叔丁基二苯基硅基)氧基)乙酸(24mg,0.076mmol)。反应液在冰水浴下滴加丙基磷酸酐(63.5mg,0.083mmol,50%wtin THF)。反应液在室温反应10min,随后减压浓缩。残余物用制备液相分离得到目标产物(50mg,产率:77%)。
LC-MS:m/z 941(M+H)+。
步骤二:中间体B9-1的制备
将N-(2-叔丁基二苯基硅氧基-乙酰基)-哌啶-(4-基(((S)-(((R)-1-(4-氨基-2-(乙氧基甲基)-1H-咪唑[4,5-c]喹啉-1-基)丙基-2-基)氧)(对氯苯氧)磷酰))-L-丙氨酸酯)(40mg,0.042mmol)溶解于甲醇(2mL)中,滴加入氯化氢-二氧六环(0.06mL,4M)。反应液在室温反应1h。然后加二氯甲烷稀释,再用饱和碳酸氢钠水溶液调节pH至6。有机相分离后减压浓缩,残余物用制备液相分离得到目标产物(18mg,产率:60%)。
LC-MS:m/z 703(M+H)+。1H NMR(400MHz,DMSO-d6)δ8.08(d,J=8Hz,1H),7.62(d,J=8Hz,1H),7.43(t,J=8Hz,1H),7.23(t,J=4Hz,1H),7.19(d,J=8Hz,2H),6.65(d,J=8Hz,2H),6.57(s,2H),5.96(t,J=12Hz,1H),4.87-4.74(m,5H),4.62(d,J=12Hz,1H),4.52(t,J=8Hz,1H),4.08(d,J=4Hz,2H),3.66(m,1H),3.54-3.47(m4H),3.24(m,2H),1.77(m,2H),1.51(d,J=4Hz,3H),1.45(m,2H),1.14(t,J=8Hz,3H),1.02(d,J=8Hz,3H)。
中间体B9-2药物-连接子(B9-2)的制备
哌啶-4-基((S)-(R)-1-(4-氨基-2-(乙氧基甲基)-1H-咪唑[4,5-c]喹啉-1-基)丙烷-2-基)氧基)(4-氯苯氧基)磷酰基)-L-丙氨酸酯二盐酸盐(25mg,0.035mmol)和(S)-10-苄基-23-(2,5-二氧基-2,5-二氢-1H-吡咯-1-基)-6,9,12,15,18-五氧基-3-氧代-5,8,11,14,17-五氮杂二十三烷酸(33mg,0.053mmol)溶于二氯甲烷(2mL)中,随后加入N,N-二异丙基乙胺(32mg,0.245mmol)。反应液用冰水浴冷却,随后滴加T3P(50%wt,89mg,0.140mmol)。滴加完毕,反应液在室温搅拌4h然后减压浓缩。残余物用制备液相分离得到目标产物(16mg,产率:36.8%)。
LC-MS:m/z 1243(M+H)+。1H NMR(400MHz,DMSO-d6)δ8.54(t,J=8.0Hz,1H),8.29(t,J=8.0Hz,1H),8.07(m,3H),8.00(t,J=4.0Hz,1H),7.61(m,1H),7.43(m,1H),7.22(m,8H),6.99(s,2H),6.63(d,J=8.0Hz,2H),6.57(s,2H),5.95(m,1H),4.84(m,5H),4.59(m,3H),4.48(m,1H),4.12(s,2H),3.51(m,13H),3.05(m,1H),2.80(m,1H),2.11(t,J=8.0Hz,2H),1.70(m,2H),1.48(m,9H),1.17(m,6H),0.99(d,J=8.0Hz,3H)。
抗体-药物偶联物B9的制备
用Sephadex G-25将Trastuzumab的PBS 7.4缓冲液(0.6mL,76.3mg/mL)置换为PBSbuffer-EDTA,收集抗体液(1.54mL,24.9mg/mL)。向上述Trastuzumab的PBS buffer-EDTA液中加入4.62mL PBS buffer-EDTA。向6.16mL上述Trastuzumab的PBS buffer-EDTA液(pH6.14,22.1℃)中加入1M磷酸氢二钾水溶液(57微升)。随后加入10mmol/L的TCEP(143μL,1428nmol,5.41eq).测pH6.56。加入1M磷酸氢二钾水溶液(380微升),调节pH至7.00。取上述抗体缓冲液3.37mL在37℃,140旋转摇速反应60min。随后降至15℃,在搅拌下,滴加中间体B9-2的10mM DMSO溶液(114 μL,1140nmol,8.65eq)溶液。加完后溶液澄清状态。加完后15℃下搅拌30min,静置1h。搅拌下加入N-乙酰基半胱氨酸的100mmol/L水溶液(17 μL,1700nmol,12.88eq),在15-25℃搅拌反应40min。用Sephadex G-25将反应液置换为PBSbuffer(pH 7.2),收集抗体液(4.2mL)。按照通用操作4测得抗体-药物偶联物B9单体含量96.4%。按照通用操作5测得抗体-药物偶联物B9 DAR为6.4。
按实施例II-9以不同起始原料合成以下中间体及抗体-药物偶联物
实施例II-10
中间体B10-1 1-((S)-2-羟基丙酰基)哌啶-4-基((S)-(((R)-1-(4-氨基-2-(乙氧基甲基)-1H-咪唑[4,5-c]喹啉-1-基)丙烷-2-基)氧基)(4-氯苯氧基)磷酰)-L-丙氨酸酯的制备
LC-MS:m/z 717(M+H)+。1HNMR(400MHz,DMSO-d6)δ8.08(d,J=8Hz,1H),7.62(d,J=8Hz,1H),7.43(t,J=8Hz,1H),7.23(t,J=4Hz,1H),7.19(d,J=8Hz,2H),6.64(d,J=8Hz,2H),6.58(s,2H),5.97(t,J=12Hz,1H),4.87-4.84(m,5H),4.80-4.74(m,1H),4.62(d,J=12Hz,1H),4.42(m,1H),3.69(m,1H),3.61(m,1H),3.54-3.47(m3H),3.40(m,2H),1.79(m,2H),1.51(d,J=4Hz,3H),1.45(m,2H),1.17-1.12(m,6H),1.02(d,J=4Hz,3H)。
实施例II-11
中间体B11-1 1-((R)-2-羟基丙酰基)哌啶-4-基((S)-(((R)-1-(4-氨基-2-(乙氧基甲基)-1H-咪唑[4,5-c]喹啉-1-基)丙烷-2-基)氧基)(4-氯苯氧基)磷酰)-L-丙氨酸酯的制备
LC-MS:m/z 717(M+H)+。1HNMR(400MHz,DMSO-d6)δ8.08(d,J=8Hz,1H),7.62(d,J=8Hz,1H),7.43(t,J=8Hz,1H),7.23(t,J=4Hz,1H),7.19(d,J=8Hz,2H),6.64(d,J=8Hz,2H),6.59(s,2H),5.97(t,J=12Hz,1H),4.87-4.84(m,5H),4.80-4.74(m,1H),4.62(d,J=12Hz,1H),4.42(m,1H),3.74-3.47(m 5H),3.40(m,2H),1.78(m,2H),1.51(d,J=4Hz,3H),1.45(m,2H),1.17-1.12(m,6H),1.02(d,J=4Hz,3H)。
实施例II-12
中间体B12-1 1-(顺式-3-羟基环丁烷-1-甲酰)哌啶-4-基((S)-(((R)-1-(4-氨基-2-(乙氧基甲基)-1H-咪唑[4,5-c]喹啉-1-基)丙烷-2-基)氧基)(4-氯苯氧基)磷酰)-L-丙氨酸酯的制备
LC-MS:m/z 743(M+H)+。1HNMR(400MHz,DMSO-d6)δ8.09(d,J=8Hz,1H),7.62(d,J=8Hz,1H),7.44(t,J=8Hz,1H),7.23(t,J=8Hz,1H),7.20(d,J=8Hz,2H),6.65(s,2H),6.62(s,2H),6.00(t,J=12Hz,1H),5.08(d,J=8Hz,1H),4.88-4.76(m,5H),4.62(d,J=12Hz,1H),3.96(m,1H),3.63(m,1H),3.55-3.47(m,5H),3.28-3.25(m 1H),2.72(m,1H),2.32(m,2H),1.93(m,2H),1.75(m,2H),1.52(d,J=8Hz,3H),1.43(m,2H),1.15(t,J=8Hz,3H),1.02(d,J=4Hz,3H)。
实施例II-13
中间体B13-1 1-(反式-3-羟基环丁烷-1-甲酰)哌啶-4-基((S)-(((R)-1-(4-氨基-2-(乙氧基甲基)-1H-咪唑[4,5-c]喹啉-1-基)丙烷-2-基)氧基)(4-氯苯氧基)磷酰)-L-丙氨酸酯的制备
LC-MS:m/z 743(M+H)+。1HNMR(400MHz,DMSO-d6)δ8.08(d,J=8Hz,1H),7.61(d,J=8Hz,1H),7.43(t,J=8Hz,1H),7.22(t,J=8Hz,1H),7.19(d,J=8Hz,2H),6.65(d,J=12Hz,2H),6.59(s,2H),5.97(t,J=12Hz,1H),5.06(d,J=4Hz,1H),4.87-4.74(m,5H),4.62(d,J=12Hz,1H),4.08(m,1H),3.64(m,1H),3.54-3.47(m,4H),3.40(m,1H),3.21-3.12(m 2H),2.33(m,2H),2.02(m,2H),1.72(m,2H),1.51(d,J=8Hz,3H),1.42(m,2H),1.14(t,J=8Hz,3H),1.02(d,J=8Hz,3H)。
实施例II-14
中间体B14-1 1-(顺式-4-羟基环己烷-1-甲酰)哌啶-4-基((S)-(((R)-1-(4-氨基-2-(乙氧基甲基)-1H-咪唑[4,5-c]喹啉-1-基)丙烷-2-基)氧基)(4-氯苯氧基)磷酰)-L-丙氨酸酯的制备
LC-MS:m/z 771(M+H)+。1HNMR(400MHz,DMSO-d6)δ8.09(d,J=8Hz,1H),7.63(d,J=8Hz,1H),7.44(t,J=8Hz,1H),7.24(t,J=8Hz,1H),7.20(d,J=8Hz,2H),6.66(d,J=8Hz,2H),6.60(s,2H),5.98(t,J=12Hz,1H),4.94-4.75(m,5H),4.63(d,J=12Hz,1H),4.29(d,J=4Hz,1H),4.19-4.12(m,1H),3.80(m,1H),3.67-3.48(m,6H),2.56(m,1H),1.80-1.63(m,6H),1.52(d,J=4Hz,3H),1.47-1.45(m,4H),1.34(m,2H),1.17(t,J=8Hz,3H),1.03(d,J=8Hz,3H)。
实施例II-15
中间体B15-1 1-(反式-4-羟基环己烷-1-甲酰)哌啶-4-基((S)-(((R)-1-(4-氨基-2-(乙氧基甲基)-1H-咪唑[4,5-c]喹啉-1-基)丙烷-2-基)氧基)(4-氯苯氧基)磷酰)-L-丙氨酸酯的制备
LC-MS:m/z 771(M+H)+。1HNMR(400MHz,DMSO-d6)δ8.09(d,J=8Hz,1H),7.62(d,J=8Hz,1H),7.44(t,J=8Hz,1H),7.23(t,J=8Hz,1H),7.20(d,J=8Hz,2H),6.65(s,2H),6.63(s,2H),6.00(t,J=12Hz,1H),4.87-4.74(m,5H),4.62(d,J=12Hz,1H),4.58(d,J=8Hz,1H),,3.64-3.61(m,2H),3.55-3.49(m,4H),3.30(m,2H),1.84(m,3H),1.72(m,1H),1.62(d,J=12Hz,2H),1.52(d,J=4Hz,3H),1.41-1.31(m,4H),1.24-1.18(m,3H),1.15(t,J=8Hz,3H),1.02(d,J=8Hz,3H)。
实施例II-16
中间体B16-1 1-((S)-2-羟基-3-甲基丁酰基)哌啶-4-基((S)-(((R)-1-(4-氨基-2-(乙氧基甲基)-1H-咪唑[4,5-c]喹啉-1-基)丙烷-2-基)氧基)(4-氯苯氧基)磷酰)-L-丙氨酸酯制备
LC-MS:m/z 745(M+H)+。1HNMR(400MHz,DMSO-d6)δ8.08(d,J=8Hz,1H),7.62(d,J=8Hz,1H),7.43(t,J=8Hz,1H),7.23(t,J=8Hz,1H),7.19(d,J=8Hz,2H),6.64(d,J=8Hz,2H),6.59(s,2H),5.97(t,J=12Hz,1H),4.87-4.73(m,5H),4.65-4.56(m,2H),4.06(t,J=8Hz,1H),3.75-3.65(m,2H),3.54-3.42(m,3H),3.42-3.33(m,2H),1.83-1.76(m,3H),1.51(d,J=4Hz,3H),1.45(m,2H),1.14(t,J=8Hz,3H),1.02(d,J=8Hz,3H),0.85(d,J=4Hz,3H),0.79(t,J=8Hz,3H)。
实施例II-17
中间体B17-1 1-((R)-2-羟基-3-甲基丁酰基)哌啶-4-基((S)-(((R)-1-(4-氨基-2-(乙氧基甲基)-1H-咪唑[4,5-c]喹啉-1-基)丙烷-2-基)氧基)(4-氯苯氧基)磷酰)-L-丙氨酸酯制备的制备
LC-MS:m/z 745(M+H)+。1HNMR(400MHz,DMSO-d6)δ8.08(d,J=8Hz,1H),7.62(d,J=8Hz,1H),7.43(t,J=8Hz,1H),7.22(t,J=8Hz,1H),7.19(d,J=8Hz,2H),6.64(d,J=8Hz,2H),6.58(s,2H),5.98(t,J=12Hz,1H),4.87-4.74(m,5H),4.65-4.56(m,2H),4.07-4.03(m,1H),3.78-3.56(m,2H),3.54-3.47(m,3H),3.41-3.33(m,2H),1.83-1.76(m,3H),1.51(d,J=4Hz,3H),1.47(m,2H),1.14(t,J=8Hz,3H),1.02(d,J=8Hz,3H),0.88(d,J=8Hz,3H),0.79(t,J=8Hz,3H)。
实施例II-18
中间体B18-1(1-(2-羟基乙酰氨基)哌啶-4-基)甲基((S)-(((R)-1-(4-氨基-2-(乙氧基甲基)-1H-咪唑[4,5-c]喹啉-1-基)丙烷-2-基)氧基)(4-氯苯氧基)磷酰)-L-丙氨酸酯的制备
LC-MS:m/z 717(M+H)+。1HNMR(400MHz,DMSO-d6)δ8.06(d,J=8.0Hz,1H),7.60(dd,J=4.0Hz,J=8.0Hz,1H),7.44(m,1H),7.20(m,3H),6.65(m,4H),5.95(m,1H),4.85(m,5H),4.59(d,J=12.0Hz,1H),4.45(m,1H),4.31(m,1H),4.05(m,2H),3.84(m,2H),3.62(m,1H),3.50(m,4H),2.88(m,1H),2.52(m,1H),1.78(m,1H),1.61(m,2H),1.49(d,J=8.0Hz,3H),1.14(t,J=8.0Hz,3H),0.99(d,J=8.0Hz,3H)。
实施例II-19
中间体B19-1(反式)-4-((2-羟基乙酰氨基)甲基)环己基((S)-(((R)-1-(4-氨基-2-(乙氧基甲基)-1H-咪唑[4,5-c]喹啉-1-基)丙烷-2-基)氧基)(4-氯苯氧基)磷酰)-L-丙氨酸酯的制备
LC-MS:m/z 731(M+H)+。1HNMR(400MHz,DMSO-d6)δ8.07(d,J=8.0Hz,1H),7.60(d,J=8.0Hz,1H),7.44(m,1H),7.20(m,3H),6.65(m,4H),5.95(m,1H),4.85(m,5H),4.58(m,1H),4.23(m,1H),4.12(s,1H),4.03(s,1H),3.50(m,3H),2.71(m,3H),1.88(m,2H),1.51(m,9H),1.15(t,J=8.0Hz,3H),0.99(d,J=8.0Hz,3H)。
实施例II-20
中间体B20-1
1-(1-羟基环丙基-1-甲酰)哌啶-4-基((S)-(((R)-1-(4-氨基-2-(乙氧基甲基)-1H-咪唑[4,5-c]喹啉-1-基)丙烷-2-基)氧基)(4-氯苯氧基)磷酰)-L-丙氨酸酯的制备
LC-MS:m/z 729(M+H)+。1HNMR(400MHz,DMSO-d6)δ8.08(d,J=8Hz,1H),7.61(d,J=8Hz,1H),7.43(t,J=8Hz,1H),7.23(t,J=8Hz,1H),7.19(d,J=8Hz,2H),6.64(d,J=12Hz,2H),6.58(s,2H),6.32(s,1H),5.99(t,J=12Hz,1H),4.91-4.74(m,5H),4.62(d,J=12Hz,1H),3.84(m,2H),3.56-3.47(m,5H),1.79(s,2H),1.52(d,J=8Hz,3H),1.49(m,2H),1.14(t,J=8Hz,3H),1.02(d,J=8Hz,3H),0.89(m,2H),0.75(m,2H)。
实施例II-21
中间体B21-1 1-(1-(羟基甲基)环丙基-1-甲酰)哌啶-4-基((S)-(((R)-1-(4-氨基-2-(乙氧基甲基)-1H-咪唑[4,5-c]喹啉-1-基)丙烷-2-基)氧基)(4-氯苯氧基)磷酰)-L-丙氨酸酯的制备
LC-MS:m/z 743(M+H)+。1HNMR(400MHz,DMSO-d6)δ8.08(d,J=8Hz,1H),7.62(d,J=8Hz,1H),7.43(t,J=8Hz,1H),7.23(t,J=8Hz,1H),7.19(d,J=8Hz,2H),6.64(d,J=12Hz,2H),6.60(s,2H),5.98(t,J=12Hz,1H),4.88-4.74(m,6H),4.62(d,J=12Hz,1H),3.73(m,2H),3.56-3.47(m,4H),3.44-3.43(m,3H),1.76(s,2H),1.52(d,J=8Hz,3H),1.47(m,2H),1.14(t,J=8Hz,3H),1.02(d,J=8Hz,3H),0.69(m,2H),0.68(m,2H)。
实施例III-1抗体-药物偶联物C1的制备
中间体C1-1 2-(1-(4-乙酰苄基)-1H-1,2,3-三唑-4-基)乙基((S)-(((R)-1-(4-氨基-2-(乙氧基甲基)-1H咪唑[4,5-c]喹啉-1-基)丙烷-2-基)氧基)(4-氯苯氧基)磷酰基)-L-丙氨酸酯制备
丁-3-炔-1-基((S)-(((R)-1-(4-氨基-2-(乙氧基甲基)-1H-咪唑并[4,5-c]喹啉-1-基)丙烷-2-基)氧基(4-氯苯氧基)磷酰基)-L-丙氨酸酯(50mg,0.08mmol)和1-(4-(叠氮甲基)苯基)乙烷-1-酮(19mg,0.11mmol)溶于四氢呋喃(1.5mL)和水(1.5mL)中,随后依次加入硫酸铜(19mg,0.12mmol)和L-抗坏血酸钠(21mg,0.12mmol)。加完后反应液在40℃搅拌0.5h,然后直接用制备液相分离得到目标产物(27mg,产率:42.8%)
LC-MS:m/z 789(M+H)+。1HNMR(400MHz,DMSO-d6)δ8.05(d,J=8.0Hz,1H),8.00(s,1H),7.91(d,J=8.0Hz,2H),7.59(d,J=12.0Hz,1H),7.40(m,3H),7.18(m,3H),6.61(m,4H),5.96(m,1H),5.63(s,2H),4.87(m,4H),4.58(d,J=12.0Hz,1H),4.25(m,2H),3.51(m,3H),2.94(m,2H),2.54(s,3H),1.48(d,J=4.0Hz,3H),1.13(t,J=8.0Hz,3H),0.91(d,J=8.0Hz,3H)。
中间体C1-2药物-连接子(C1-2)的制备
第一步:中间体C1-2-A的制备
将丁-3-炔-1-基((S)-(((R)-1-(4-氨基-2-(乙氧基甲基)-1H-咪唑并[4,5-c]喹啉-1-基)丙烷-2-基)氧基(4-氯苯氧基)磷酰基)-L-丙氨酸酯(92mg,0.15mmol)和(E)-1-(4-(叠氮甲基)苯基)乙烷-1-酮-O-(17-氨基-3,6,9,12,15-五氧十七烷基)肟(136mg,0.3mmol)溶于四氢呋喃(3mL)和水(3mL)中,随后依次加入硫酸铜(36mg,0.23mmol)和L-抗坏血酸钠(41mg,0.23mmol)。加完后反应液在40℃搅拌1h,然后直接用制备液相分离得到目标产物(30mg,产率:18.7%)。
LC-MS:m/z 1067(M+H)+。
第二步:药物-连接子(C1-2)的制备
将中间体C1-2-A(30mg,0.03mmol)和2,5-二氧基-2,5-二氢-1H-吡咯-1-基3-(2,5-二氧基-2,5-二氢-1H-吡咯-1-基)丙酸酯(11mg,0.04mmol)溶于N,N-二甲基甲酰胺(2mL)中,随后加入N,N-二异丙基乙胺(7mg,0.06mmol)。加完后反应液在室温下搅拌1小时,然后直接用制备液相分离得到目标产物(15mg,产率:41%)。
LC-MS:m/z 1218(M+H)+。1HNMR(400MHz,DMSO-d6)δ8.09(d,J=8.4Hz,1H),8.02(t,J=5.2Hz,1H),7.98(s,1H),7.64(m,3H),7.46(t,J=7.6Hz,1H),7.30(d,J=8.0Hz,1H),7.25(t,J=6.8Hz,1H),7.17(d,J=8.8Hz,2H),7.01(m,2H),6.61(d,J=8.4Hz,2H),5.96(m,1H),5.57(s,2H),4.88(m,4H),4.62(d,J=12.8Hz,1H),4.25(m,4H),3.70(t,J=5.2Hz,1H),3.61(t,J=6.8Hz,2H),3.53(m,22H),3.16(m,2H),2.94(d,J=6.8Hz,2H),2.34(d,J=7.2Hz,2H),2.17(s,3H),2.03(m,2H),1.50(d,J=6.0Hz,3H),1.16(t,J=7.2Hz,3H),0.95(d,J=7.2Hz,3H)。
按实施例III-1以不同起始原料合成以下中间体及抗体-药物偶联物
实施例III-2
中间体C2-1戊-4-炔-2-基((S)-(((R)-1-(4-氨基-2-(乙氧基甲基)-1H-咪唑[4,5-c]喹啉-1-基)丙烷-2-基)氧基)(4-氯苯氧基)磷酰)-L-丙氨酸酯的制备
LC-MS:m/z 628(M+H)+。1HNMR(400MHz,DMSO-d6)δ8.08(d,J=4Hz,1H),7.62(d,J=8Hz,1H),7.44(t,J=8Hz,1H),7.24(t,J=8Hz,1H),7.18(d,J=8Hz,2H),6.64-6.59(m,4H),5.99-5.91(m,1H),4.92-4.74(m,5H),4.63(d,J=16Hz,1H),3.57-3.48(m,3H),2.91-2.88(m,1H),2.50-2.43(m,2H),1.51(d,J=4Hz,3H),1.22(t,J=8Hz,3H),1.14(t,J=8Hz,3H),1.02(t,J=8Hz,3H)
中间体C2-2 1-(1-(4-乙酰苄基)-1H-1,2,3-三唑-4-基)丙烷-2-基((S)-(R)-1-(4-氨基-2-(乙氧基甲基)-1H咪唑[4,5-c]喹啉-1-基)丙烷-2-基)氧基)(4-氯苯氧基)磷酰基)-L-丙氨酸酯的制备
LC-MS:m/z 803(M+H)+。1HNMR(400MHz,DMSO-d6)δ8.05(d,J=8.0Hz,1H),7.98(m,1H),7.91(m,2H),7.60(m,1H),7.43(t,J=8.0Hz,1H),7.36(t,J=8.0Hz,2H),7.18(m,3H),6.60(m,4H),5.92(m,1H),5.60(d,J=12.0Hz,2H),4.77(m,7H),3.50(m,3H),2.89(m,2H),2.53(d,J=4.0Hz,3H),1.48(m,3H),1.13(m,6H),0.94(d,J=8.0Hz,1.5H),0.81(d,J=8.0Hz,1.5H)。
生物学测试评价
以下生物学测试例进一步描述解释本发明,但这些实例并非意味着限制本发明的范围。
化合物对TLR7和TLR8激活作用的体外实验
实验步骤
对化合物用DMSO进行1:3系列稀释9个浓度点,双复孔,用Echo加入96孔板中。
将HEK-BlueTM hTLR细胞悬浮在培养液中,然后以50,000细胞/孔的密度种到含有化合物的96孔板中。细胞在5%CO2、37℃条件下培养1天。细胞培养液中的DMSO最终浓度为0.5%。
取20uL细胞培养上清,按照QUANTI-Blue说明书,检测上清中的报告基因SEAP,用酶标仪读取OD650信号值,用于计算化合物对hTLR7和hTLR8的激动活性。
按照CellTiter-Glo说明书,测定细胞活力,用酶标仪读取Luminescence信号值,用于计算化合物的细胞毒性。
应用GraphPad Prism软件计算化合物的EC50和CC50值,并绘出拟合曲线
参照化合物R848结构如下:
本发明中实施例化合物对TLR7和TLR8激动活性见表1。
表1 本发明中实施例化合物酶学活性
抗体-药物偶联物体外免疫偶联活性评价
实验步骤
1.人抗原提呈细胞(效应细胞)的分离
人髓系抗原提呈细胞(APCs)是从健康人外周血中利用ROSETTESEPTM HumanMonocyte Enrichment Cocktail(含有抗CD14、CD16、CD40、CD86、CD123和HLA-DR的单克隆抗体)密度梯度离心法通过阴性筛选得到。未成熟的APCs利用EASYSEPTM Human MonocyteEnrichment Kit(含有抗CD14、CD16、CD40、CD86、CD123和HLA-DR的单克隆抗体)通过阴性筛选提纯至单核细胞(monocyte)>97%纯度。
2.肿瘤细胞的预处理
使用三种具有不同HER2表达水平的肿瘤细胞系:HCC1954、JIMT-1和COLO 205。
HCC1954来源于3级浸润性导管癌,无淋巴结转移。HCC 1954特征为上皮细胞特异性标志物上皮糖蛋白2和细胞角蛋白19阳性,雌激素受体(ER)和孕酮受体(PR)表达阴性。HCC1954过表达HER2(通过酶联免疫吸附试验(ELISA)测定),且过表达水平相对较高。
JIMT-1来源于一位女性导管性乳腺癌(浸润性3级,IIB期)术后放疗后胸腔积液。JIMT-1过表达HER2被认为是“中等”水平的过表达,但对抑制HER2的药物(如曲妥珠单抗)不敏感。
COLO 205来源于男性结肠癌腹水。COLO 205表达癌胚抗原(CEA)、角蛋白、白细胞介素10(IL-10),并被认为在相对“低”水平过表达HER2。
每个细胞系的肿瘤细胞分别以1~10×106个细胞/mL的浓度在含有0.1%胎牛血清(FBS)的PBS中重新悬浮。随后将细胞与2uM羧荧光素琥珀酰亚胺酯(CFSE)孵育,以产生luM的最终浓度。随后加入10mL含10%胎牛血清的完全培养基2分钟后骤冷,用完全培养基洗涤2次。细胞或者在2%多聚甲醛中固定,然后用PBS洗涤三次,或者在使用前保持活性。
3.APCs和肿瘤细胞共培养
2x105个APCs与或不与CFSE标记的肿瘤细胞共孵育。
共孵育时,单核细胞与肿瘤细胞的效应比(E/T)为5:1或10:1。置于96孔板中,含iscove改良dulbecco培养基(IMDM)(Thermo Fisher Scientific),添加10%胎牛血清、100U/mL青霉素、100ug/mL霉素、2mML-谷氨酰胺、丙酮酸钠、非必需氨基酸、以及本发明的不同浓度的未偶联HER2抗体和本专利所述抗体-药物偶联物。18小时后通过流式检测细胞和无细胞上清液。
参照化合物T785-ISAC(Nature Cancervolume2,pages18–33(2021))结构如下:
本发明抗体-药物偶联物A2在单核细胞单独存在、或者单核细胞与HCC1954肿瘤细胞共培养下对细胞因子的激动活性见图1。
参照化合物T785-ISAC在单核细胞单独存在、或者单核细胞与HCC1954肿瘤细胞共培养下对细胞因子的激动活性见图2。
抗体-药物偶联物A2在单核细胞与HCC1954肿瘤细胞的效应比为5:1、或10:1、或仅单核细胞存在等条件下均可剂量依赖性的显著诱导TLR8通路TNFα以及IL12p40等细胞因子的表达;其中,在1uM浓度下,TNFα激动活性增加约是参照化合物T785-ISAC的40倍,IL12p40激动活性增加约是参照化合物T785-ISAC的10倍,因此,本发明化合物对TNFα以及IL12p40等细胞因子的激动活性远优于参照化合物T785-ISAC。
药代动力学(PK)特性评估
食蟹猴(Macaca fascicaris)单次给与本发明所述抗体-药物偶联物(IV或SC,5或10mpK),并在给药后28天评估其PK特性。
药效学(PD)特性评估
1.异种移植瘤模型(Xenograft tumor model)实验方法
实验步骤
肿瘤细胞系购自ATCC(HCC1954)或AddexBio(JIMT-1),并按照生产商的指导方针进行培养。当细胞融合度达到80-90%后用Accutase(STEMCELL Technologies)分离收集细胞,用PBS洗涤,用PBS重新悬浮达到40×106细胞/mL,然后置于冰上不超过2小时。
紧接植入前,将悬浮细胞与等体积Cultrex PathClear基底膜提取物3型(R&DSystems)混合,并将100uL的混合物(2*106个细胞)植入6-8周龄雌性小鼠右侧皮下。
NSG(NOD(non-obese diabetic)-SCID-IL2rg)小鼠、Rag2/IL2rg KO小鼠和SCIDBeige(severe combined immune deficiency)小鼠用于异种移植研究。
每周记录2次肿瘤大小,计算公式为(长×宽2)/2。一旦肿瘤达到50-100mm3,通常在肿瘤植入后1周内开始治疗。初始治疗前,小鼠按肿瘤大小随机分为治疗组。本专利所述抗体-药物偶联物或HER2裸抗体在PBS中以1mg/mL制备,并以5mg/kg腹腔注射。
在本发明提及的所有文献都在本申请中引用作为参考,就如同每一篇文献被单独引用作为参考那样。此外应理解,在阅读了本发明的上述讲授内容之后,本领域技术人员可以对本发明作各种改动或修改,这些等价形式同样落于本申请所附权利要求书所限定的范围。
Claims (18)
1.一种抗体-药物偶联物包含
(a)抗体构建体,所述抗体构建体包含(i)未经修饰或经修饰的Fab抗原结合结构域和(ii)未经修饰或经修饰的Fc结构域;
(b)咪唑并喹啉取代磷酸酯类激动剂部分,或其立体异构体、互变异构体、晶型、或其药学上可接受的盐、水合物、溶剂合物或前药;和
(c)连接子,
其中每个咪唑并喹啉取代磷酸酯类激动剂部分经由所述连接子共价结合至所述抗体构建体。
2.根据权利要求1所述的抗体-药物偶联物,其特征在于,所述抗体构建体还包含靶向结合结构域。
3.根据权利要求1所述的抗体-药物偶联物,其特征在于,所述抗体构建体为抗体或Fc融合蛋白,优选地为IgG1或IgG4抗体。
4.根据权利要求1-3中任一项所述的抗体-药物偶联物,其特征在于,所述抗原结合结构域结合至癌细胞的抗原。
5.根据权利要求1-4中任一项所述的抗体-药物偶联物,其特征在于,所述抗原结合结构域结合至选自以下的抗原:PD-L1,CLDN18.2,CLDN6,DLL3,MUCl,MUC17,LRCC15,Nectin4,GPC3,ROR1,ASGR1,CCR8,CDH,CD19,CD20,CD29,CD30,CD38,CD40,CD47,GPC3,EpCAM,EGFR,VEGF,SLAMF7,PDGFRa,gp75,HER2,HER3,TROP2,LIV-1,MUC16,CEACAM1,CEACAM3,CEACAM4,CEACAM5,CEACAM6,CEACAM7,CEACAM8,CEACAMl6,CEACAMl8,CEACAMl9,CEACAM20,CEACAM21,URLC10,NY-ESO-1,GAA,OF A,cyclin BI,WT-1,CEF,VEGRRl,VEGFR2,TTK,MUC1,HPVl6E7,CEA,IMA910,KOC1,SL-701,MART-1,gpl00,tyrosinase,GSK2302050A,survivin,MAGE-3.1,MAGE-10.A2,OVABiP,gp209-2M,melan-A,NA17.A2,KOCl,C016,DEPDC1,MPHOSPH1,MAGE 12,ONT-IO,GD2L,GD3L,GSK2302032A,URLC10,CDCA1,TF,rsPSMA,PSA,MUC-2,TERT,HPVl6,HPVl8,STFII,G17DT,ICT-107,Dex2,hTERT,PAP和TRP2。
6.根据权利要求1-4中任一项所述的抗体-药物偶联物,其特征在于,所述抗原优选结合结构域结合至选自以下的抗原:EGFR,HER2,HER3,TROP2,PD-L1,CLDN18.2,CLDN6,CD38,CD47,DLL3,MUCl,MUC17,LRCC15,Nectin 4,GPC3,ROR1,ASGR1、以及CEACAM5,优选地所述抗原优选结合结构域结合至选自以下的抗原:EGFR、HER2、HER3、以及TROP2。
7.根据权利要求3-6中任一项所述的抗体-药物偶联物,其特征在于,所述抗体选自:阿巴伏单抗、阿巴西普、阿昔单抗、阿达木单抗、阿德木单抗、阿仑单抗、阿妥莫单抗、阿非莫单抗、马安莫单抗、anetumumab、anrukizumab、阿泊珠单抗、阿西莫单抗、阿塞珠单抗、阿特利珠单抗、阿托木单抗、avelumab、巴匹珠单抗、巴利昔单抗、巴维昔单抗、贝妥莫单抗、贝利单抗、柏替木单抗、贝索单抗、贝伐单抗、比西单抗、淏烯比妥、比伐妥珠单抗、坎帕斯、康纳单抗、莫坎妥珠单抗、卡罗单抗、卡妥索单抗、西利珠单抗、赛妥珠单抗、西妥昔单抗、克立昔单抗、达西珠单抗、达昔单抗、达克珠单抗、地诺单抗、地莫单抗、阿托度单抗、多利昔珠单抗、duntumumab、durimulumab、durmulumab、durvalumab、依美昔单抗、依库丽单抗、埃巴单抗、依决洛单抗、依法利珠单抗、依芬古单抗、伊斯利莫、培戈赖莫单抗、西依匹莫单抗、西艾匹莫单抗、epitumomab、依帕珠单抗、厄利珠单抗、厄马索单抗、依那西普、伊瑞西珠、艾韦单抗、法索单抗、法拉莫单抗、泛维珠单抗、冯特利珠单抗、加利昔单抗、gantenerumab、加维莫单抗、吉妥单抗、戈利木单抗、戈利昔单抗、伊巴利珠单抗、替伊莫单抗、伊戈伏单抗、英西单抗、英夫利昔单抗、伊诺莫单抗、奥英妥珠单抗、易普利姆玛、伊妥木单抗、凯利昔单抗、拉贝珠单抗、来马索单抗、1ebrilizumab、乐地单抗、来沙木单抗、lexitumumab、利韦单抗、林妥珠单抗、鲁卡木单抗、鲁昔单抗、马帕木单抗、马司莫单抗、马妥珠单抗、美泊利单抗、美替木单抗、马妥珠单抗、明瑞莫单抗、米妥莫单抗、莫罗木单抗、莫维珠单抗、莫罗单抗、他那可单抗、伊那莫单抗、Nivolumab、那他珠单抗、奈巴库单抗、奈瑞莫单抗、尼妥珠单抗、硫诺莫单抗、ocrelizumab、奥度莫单抗、奥法木单抗、奥马珠单抗、奥戈伏单抗、奥昔珠单抗、pembrolizumab、帕吉昔单抗、帕利珠单抗、帕尼单抗、帕考珠单抗、pemtumomab、帕妥珠单抗、培克珠单抗、平妥莫单抗、普立昔单抗、普托木单抗、兰尼单抗、瑞西巴库、瑞加韦单抗、瑞利珠单抗、利妥昔单抗、罗维珠单抗、芦利珠单抗、沙妥莫单抗、司韦单抗、西罗珠单抗、希普利珠单抗、索土珠单抗、司他莫鲁、硫索单抗、替他珠单抗、他度珠单抗、他利珠单抗、帕他普莫单抗、替非珠单抗、阿替莫单抗、替奈昔单抗、替利珠单抗、替西木单抗、托珠单抗、托利珠单抗、托西莫单抗、曲妥珠单抗、替西木单抗、西莫臼介素单抗、妥韦单抗、乌珠单抗、优特克单抗、伐利昔单抗、维妥珠单抗、维帕莫单抗、维西珠单抗、伏洛昔单抗、伏妥莫单抗、扎鲁目单抗、扎木单抗、齐拉木单抗、阿佐莫单抗、达雷木单抗、elotuxumab、obintunzumab、奥拉木单抗、本妥昔单抗、阿帕西普、阿巴西普、贝拉西普、阿柏西普、依那西普、或咯咪珀咯,优选地Ab选自:帕妥珠单抗(pertuzumab)、曲妥珠单抗(trastuzumab)、或sacituzumab,或含有帕妥珠单抗(pertuzumab)、曲妥珠单抗(trastuzumab)或sacituzumab抗原部分的抗体;或其他含有抗EGFR、HER2、HER3或TROP2抗原的抗体或抗体片段,更优选地,所述抗体选是曲妥珠单抗或帕妥珠单抗。
9.根据权利要求1-8中任一项所述的抗体-药物偶联物,其特征在于,所述咪唑并喹啉取代磷酸酯类激动剂部分、或其立体异构体、互变异构体、晶型、或其药学上可接受的盐、水合物、溶剂合物或前药具有式II结构
式中:
虚线“-------”表示通过任意位置与L连接;
R1选自取代或未取代的下组基团:氢、C1-C18烷基、氘代C1-C18烷基、卤代C1-C18烷基、C1-C18烷氧基、氘代C1-C18烷氧基、卤代C1-C18烷氧基、卤素、氨基、硝基、羟基、氰基、C3-C18环烷基、4-14元杂环基、C6-C10芳基、5-14元杂芳基、-(CH2)nOR5、-(CH2)nO(CH2)oR5、-(CH2)nSR5、-(CH2)nCOR5、-(CH2)nC(O)OR5、-(CH2)nS(O)mR5、-(CH2)nNR6R7、-(CH2)nC(O)NR6R7、-(CH2)nNR6C(O)R5、-(CH2)nNR6S(O)mR5;其中,所述取代指被选自下组的一个或多个基团取代:氢、氘、C1-C18烷基、氘代C1-C18烷基、卤代C1-C18烷基、C1-C18烷氧基、氘代C1-C18烷氧基、卤代C1-C18烷氧基、卤素、氨基、硝基、羟基、氰基、C3-C18环烷基、4-14元杂环基、C6-C10芳基、5-14元杂芳基、-(CH2)n'OR'5、-(CH2)n'SR'5、-(CH2)n'COR'5、-(CH2)n'C(O)OR'5、-(CH2)n'S(O)m'R'5、-(CH2)n'NR'6R'7、-(CH2)n'C(O)NR'6R'7、-(CH2)n'C(O)NHR'6、-(CH2)n'NR6C(O)R'5、-(CH2)n'NR6S(O)m'R'5;
R2相同或不同,且独立地选自下组:氢、氘、C1-C18烷基、氘代C1-C18烷基、卤代C1-C18烷基、C1-C18烷氧基、氘代C1-C18烷氧基、卤代C1-C18烷氧基、卤素、氨基、硝基、羟基、氰基、C3-C18环烷基、4-14元杂环基、C6-C10芳基、5-14元杂芳基、-(CH2)n”OR”5、-(CH2)n”SR”5、-(CH2)n”COR”5、-(CH2)n”C(O)OR”5、-(CH2)n”S(O)m”R”5、-(CH2)n”NR”6R”7、-(CH2)n”C(O)NR”6R”7、-(CH2)n”C(O)NHR”6、-(CH2)n”NR”6C(O)R”5、-(CH2)n”NR”6S(O)m”R”5;
Z选自取代或未取代的下组基团:C1-C18亚烷基、氘代C1-C18亚烷基、卤代C1-C18亚烷基、C1-C18亚烷氧基、卤代C1-C18亚烷氧基、C3-C18亚环烷基、C1-C18亚烷基C3-C18亚环烷基、C3-C18亚环烷基C1-C18亚烷基、C1-C18亚烷基C3-C18亚环烷基C1-C18亚烷基、4-14元亚杂环基、C6-C10亚芳基、5-14元亚杂芳基,其中所述取代指被选自下组的一个或多个基团取代:氢、氘、C1-C18烷基、氘代C1-C18烷基、卤代C1-C18烷基、C1-C18烷氧基、氘代C1-C18烷氧基、卤代C1-C18烷氧基、卤素、氨基、硝基、羟基、氰基、C3-C18环烷基、4-14元杂环基、C6-C10芳基、5-14元杂芳基、-(CH2)n”'OR”'5、-(CH2)n”'SR”'5、-(CH2)n”'COR”'5、-(CH2)n”'C(O)OR”'5、-(CH2)n”'S(O)m”'R”'5、-(CH2)n”'NR”'6R”'7、-(CH2)n”'C(O)NR”'6R”'7、-(CH2)n”'C(O)NHR”'6、-(CH2)n”'NR”'6C(O)R”'5、-(CH2)n”'NR”'6S(O)m”'R”'5;
Y选自:O、N或NR4;R4选自取代或未取代的下组基团:氢、C1-C18烷基、氘代C1-C18烷基、卤代C1-C18烷基、C1-C18烷氧基、氘代C1-C18烷氧基、卤代C1-C18烷氧基、C3-C18环烷基、4-14元杂环基、C6-C10芳基、5-14元杂芳基,其中所述取代指被选自下组的一个或多个基团取代:氢、氘、C1-C18烷基、氘代C1-C18烷基、卤代C1-C18烷基、C1-C18烷氧基、氘代C1-C18烷氧基、卤代C1-C18烷氧基、卤素、氨基、硝基、羟基、氰基、C3-C18环烷基、4-14元杂环基、C6-C10芳基、5-14元杂芳基、-(CH2)n””OR””5、-(CH2)n””SR””5、-(CH2)n””COR””5、-(CH2)n””C(O)OR””5、-(CH2)n””S(O)m””R””5、-(CH2)n””NR””6R””7、-(CH2)n””C(O)NR””6R””7、-(CH2)n””C(O)NHR””6、-(CH2)n””NR””6C(O)R””5、-(CH2)n””NR””6S(O)m””R””5;
R5、R'5、R”5、R”'5和R””5各自独立地选自取代或未取代的下组基团:氢、氘、C1-C18烷基、氘代C1-C18烷基、卤代C1-C18烷基、C1-C18烷氧基、氘代C1-C18烷氧基、卤代C1-C18烷氧基、氨基、羟基、氰基、C3-C18环烷基4-14元杂环基、C6-C10芳基、5-14元杂芳基,其中所述取代指被选自下组的一个或多个基团取代:氢、氘、C1-C18烷基、氘代C1-C18烷基、卤代C1-C18烷基、C1-C18烷氧基、氘代C1-C18烷氧基、卤代C1-C18烷氧基、卤素、氨基、硝基、羟基、氰基、C3-C18环烷基、4-14元杂环基、C6-C10芳基、5-14元杂芳基、-(CH2)n””'OR8、-(CH2)n””'SR8、-(CH2)n””'COR8、-(CH2)n””'C(O)OR8、-(CH2)n””'S(O)m””'R8、-(CH2)n””'NR8R9、-(CH2)n””'C(O)NR8R9、-(CH2)n””'C(O)NHR9、-(CH2)n””'NR9C(O)R8、-(CH2)n””'NR9S(O)m””'R8;
R6、R7、R'6、R'7、R”6、R”7、R”'6、R”'7、R””6和R””7相同或不同,且各自独立地选自取代或未取代的下组基团:氢、氘、C1-C18烷基、氘代C1-C18烷基、卤代C1-C18烷基、C1-C18烷氧基、氘代C1-C18烷氧基、卤代C1-C18烷氧基、氨基、羟基、C3-C18环烷基、4-14元杂环基、C6-C10芳基、5-14元杂芳基;其中,所述取代指被选自下组的一个或多个基团取代:氢、氘、C1-C18烷基、氘代C1-C18烷基、卤代C1-C18烷基、C1-C18烷氧基、氘代C1-C18烷氧基、卤代C1-C18烷氧基、卤素、氨基、硝基、羟基、氰基、C3-C18环烷基、4-14元杂环基、C6-C10芳基、5-14元杂芳基、-(CH2)n”””OR'8、-(CH2)n”””SR'8、-(CH2)n”””COR'8、-(CH2)n”””C(O)OR'8、-(CH2)n”””S(O)m”””R'8、-(CH2)n”””NR'8R'9、-(CH2)n”””C(O)NR'8R'9、-(CH2)n”””C(O)NHR'9、-(CH2)n”””NR'9C(O)R'8、-(CH2)n”””NR'9S(O)m”””R'8;
R8、R'8、R9和R'9相同或不同,且各自独立地选自取代或未取代的下组基团:氢、氘、C1-C18烷基、氘代C1-C18烷基、卤代C1-C18烷基、C1-C18烷氧基、氘代C1-C18烷氧基、卤代C1-C18烷氧基、氨基、羟基、-COOR16、C3-C18环烷基、5-14元杂环基、C6-C10芳基、5-14元杂芳基,其中,所述取代指被选自下组的一个或多个基团取代:氘、C1-C20烷基、C1-C6烷氧基、C3-C10环烷基、4-10元杂环基、C6-C10芳基、5-10元杂芳基、卤素、氨基、硝基、-COOR16、氰基、羟基、酰基、酰胺基、磺酰基、磺酰胺基;
或者R5和R6以及相邻的原子、R5'和R6'以及相邻的原子、R5”和R6”以及相邻的原子、R5”'和R6”'以及相邻的原子、R5””和R6””以及相邻的原子、R6和R7以及相邻的原子、R6'和R7'以及相邻的原子、R6”和R7”以及相邻的原子、R6”'和R7”'以及相邻的原子、R6””和R7”'以及相邻的原子、R8和R9以及相邻的原子、R8'和R9'以及相邻的原子环合形成4-8元杂环基;
X选自下组:-P(=O)(OH)2、-P(=O)(OH)OP(=O)(OH)2、-P(=O)(OH)OP(=O)(OH)OP(=O)(OH)2、-P(=O)(X1R11)(X2R12)、-P(=O)(X1R11)(X3R14R15)、-P(=O)(X3R14R15)(X3R14R15)、-CH2P(=O)(X1R11)(X2R12)、-CH2P(=O)(X1R11)(X3R14R15)、-CH2P(=O)(X3R14R15)(X3R14R15)、-P(=S)(X1R11)(X2R12)、-P(=S)(X1R11)(X3R14R15)、-P(=S)(X3R14R15)(X3R14R15)、-CH2P(=S)(X1R11)(X2R12)、-CH2P(=S)(X1R11)(X3R14R15)、-CH2P(=S)(X3R14R15)(X3R14R15)、-P(=NR13)(X1R11)(X2R12)、-P(=NR13)(X1R11)(X3R14R15)、-P(=NR13)(X3R14R15)(X3R14R15)、-CH2P(=NR13)(X1R11)(X2R12)、-CH2P(=NR13)(X1R11)(X3R14R15)、-CH2P(=NR13)(X3R14R15)(X3R14R15);
X1、X2各自独立地选自下组:氧、硫、-OCH2O-;
X3为氮;
R11、R12、R13、R14、R15各自独立地选自取代或未取代的下组基团:氢、C1-C20烷基、C1-C20氘代烷基、C1-C20卤代烷基、C3-C10环烷基、4-10元杂环基、C6-C10芳基、5-10元杂芳基、C1-C6烷基C3-C20环烷基、C1-C6烷基4-10元杂环基、C1-C6烷基C6-C10芳基、C1-C6烷基5-10元杂芳基,或者R11和R12与相邻的X1、X2和P结合形成取代的4-7元杂环基,所述取代指被选自下组的一个或多个取代基取代:-R16、-OR16、-COR16、-COOR16、-OCOOR16、-SOR16、-SO2R16、-NHR16、-N(C1-C6烷基)R16、-N(C3-C6环烷基)R16、-N(4-6元杂环基)R16、-N(C6-C10芳基)R16、-N(5-6元杂芳基)R16、-CONHR16、-CON(C1-C6烷基)R16、-CON(C3-C6环烷基)R16、-CON(4-6元杂环基)R16、-CON(C6-C10芳基)R16、-CON(5-6元杂芳基)R16、-NHCOR16、-N(C1-C6烷基)COR16、-N(C3-C6环烷基)COR16、-N(4-6元杂环基)COR16、-N(C6-C10芳基)COR16、-N(5-6元杂芳基)COR16、-SO2NHR16、-SO2N(C1-C6烷基)R16、-SO2N(C3-C6环烷基)R16、-NSO2(4-6元杂环基)R16、-SO2N(C6-C10芳基)R16、-SO2N(5-6元杂芳基)R16、14元14元卤素、硝基、氰基;
R16选自取代或未取代的下组基团:氢、氘、氨基、C1-C18烷基、卤代C1-C20烷基、C1-C18烷氧基、C1-C18氘代烷基、C3-C10环烷基、C3-C10环烯基、4-10元杂环基、C6-C10芳基、卤代C6-C10芳基、5-10元杂芳基、卤代5-10元杂芳基、C1-C20烷基C3-C10环烷基、C1-C20烷基4-10元杂环基、C1-C6烷基C6-C10芳基、C1-C6烷基5-10元杂芳基、C1-C6胺基C3-C10环烷基、C1-C6胺基4-10元杂环基,其中,上述取代是指被选自下组的一个或多个基团取代:氢、氘、硝基、羟基、氰基、卤素、=N-OH、=N-NH2、=N-NH(CH3)、-C(CH3)=N-OH、-C(CH3)=N-NH2、NH2、C1-C18烷基、氘代C1-C18烷基、卤代C1-C18烷基、卤代C1-C18烷基羟基、C3-C20环烷基、4-20元杂环基、C6-C14芳基、5-14元杂芳基、C1-C6烷基C3-C20环烷基、C1-C6烷基4-20元杂环基、C1-C6烷基C6-C14芳基、C1-C6烷基5-14元杂芳基、C1-C18烷氧基、氘代C1-C18烷氧基、卤代C1-C18烷氧基、C3-C20环烷基-O-、4-20元杂环基-O-、C6-C14芳基-O-、5-14元杂芳基-O-、氧代C1-C6烷基、C2-C6酯基、C1-C6胺基、C2-C6酰基、C2-C6酰胺基、C1-C6磺酰基、C2-C6磺酰胺基或C1-C6脲基;其中,所述取代基中的C1-C18烷基、氘代C1-C18烷基、卤代C1-C18烷基、卤代C1-C18烷基羟基、C3-C20环烷基、4-20元杂环基、C6-C14芳基、5-14元杂芳基、C1-C6烷基C3-C20环烷基、C1-C6烷基4-20元杂环基、C1-C6烷基C6-C14芳基、C1-C6烷基5-14元杂芳基、C1-C18烷氧基、氘代C1-C18烷氧基、卤代C1-C18烷氧基、C3-C20环烷基-O-、4-20元杂环基-O-、C6-C14芳基-O-、5-14元杂芳基-O-、氧代C1-C6烷基、C2-C6酯基、C1-C6胺基、C2-C6酰基、C2-C6酰胺基、C1-C6磺酰基、C2-C6磺酰胺基或C1-C6脲基还可进一步被一个或多个Ra取代,其中,Ra选自:卤素、硝基、羟基、氰基、=N-OH、=N-NH2、=N-NH(CH3)、-C(CH3)=N-OH、-C(CH3)=N-NH2、NH2、C1-C6烷基、氘代C1-C6烷基、C1-C6烷基羟基、卤代C1-C6烷基、卤代C1-C6烷基羟基、C3-C6环烷基、C3-C6环烷基-O-、C1-C6烷氧基、氘代C1-C6烷氧基、卤代C1-C6烷氧基、C6-C14芳基、5-14元杂芳基、4-6元杂环基、4-6元杂环基-O-、氧代C1-C6烷基、C2-C6酯基、C1-C6胺基、C2-C6酰基、C2-C6酰胺基、C1-C6磺酰基、C1-C6磺酰胺基或C1-C6脲基;或两个位于相同碳原子上的取代基共同构成-(CH2)1-6-或=O;
x为0、1、2、3或4的整数;
y为1或2的整数;
m、m'、m”、m”'、m””、m””'和m”””各自独立地为1或2的整数;
n、n'、n”、n”'、n””、n””'和n”””各自独立地为0、1、2、3、4、5或6的整数;
o为0、1、2、3、4、5或6的整数。
13.根据权利要求1-12中任一项所述的抗体-药物偶联物,其特征在于,所述连接子L选自取代或未取代下组:
式中,L1、L2、L3、L4、L5、L6各自独立地选自0-20的整数;
或者选自取代或未取代下组:
式中,L7、L8、L9、L10、L11、L12各自独立地选自0-20的整数;
或者选自取代或未取代下组:
式中,L13、L14、L15各自独立地选自0-20的整数;
或者选自取代或未取代下组:
式中,L16选自0-20的整数,L17选自0-1的整数;
或者选自取代或未取代下组:
式中,L18、L19、L20、L21、L22、L23各自独立地选自0-20的整数;
或者选自取代或未取代下组:
式中,L24、L25、L26各自独立地选自0-20的整数;
或者选自取代或未取代下组:
式中,L27独立地选自0-1的整数;
或者选自取代或未取代下组:
式中,L28、L29、L30、L31、L32、L33各自独立地选自0-20的整数;
或者选自取代或未取代下组:
式中,L34、L35、L36各自独立地选自0-20的整数;
或者选自通过乙烯基和抗体或抗体片段偶联的L选自取代或未取代下组:
式中,L37各自独立地选自0-20的整数;
或者选自取代或未取代下组:
式中,L38各自独立地选自0-20的整数。
17.一种药物组合物,其特征在于,包含药学上可接受的载体和一种或多种权利要求1-16中任一项所述的抗体-药物偶联物,优选地,所述药物组合物还包含其它预防和/或治疗选自下组的疾病的药物或联用:炎症、癌症、心血管疾病、感染、免疫性疾病、代谢性疾病。
18.权利要求1-16中任一项所述的抗体-药物偶联物或权利要求17所述的药物组合物在制备治疗疾病的药物中的用途,其中,所述疾病选自:炎症、癌症、心血管疾病、感染、免疫性疾病、代谢性疾病。
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