CN111417409A - 吡咯并苯并二氮杂*缀合物 - Google Patents
吡咯并苯并二氮杂*缀合物 Download PDFInfo
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- CN111417409A CN111417409A CN201880071505.3A CN201880071505A CN111417409A CN 111417409 A CN111417409 A CN 111417409A CN 201880071505 A CN201880071505 A CN 201880071505A CN 111417409 A CN111417409 A CN 111417409A
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Abstract
一种式I的缀合物,其中Ab为在每条重链上具有至少一个自由缀合位点的经修饰抗体。
Description
背景技术
一些吡咯并苯并二氮杂(PBD)具有识别和结合特异性DNA序列的能力;优选的序列是PuGPu。第一PBD抗肿瘤抗生素安曲霉素(anthramycin)发现于1965年(Leimgruber等,J.Am.Chem.Soc.,87,5793-5795(1965);Leimgruber等,J.Am.Chem.Soc.,87,5791-5793(1965))。自那以后,已报道了许多天然存在的PBD,并且已开发了用于各种类似物的10种以上的合成路线(Thurston等,Chem.Rev.1994,433-465(1994))。家族成员包括修道院霉素(abbeymycin)(Hochlowski等,J.Antibiotics,40,145-148(1987))、契卡霉素(chicamycin)(Konishi等,J.Antibiotics,37,200-206(1984))、DC-81(日本专利58-180487;Thurston等,Chem.Brit.,26,767-772(1990);Bose等,Tetrahedron,48,751-758(1992))、甲基氨茴霉素(mazethramycin)(Kuminoto等,J.Antibiotics,33,665-667(1980))、新茴霉素(neothramycin)A和B(Takeuchi等,J.Antibiotics,29,93-96(1976))、泊罗霉素(porothramycin)(Tsunakawa等,J.Antibiotics,41,1366-1373(1988))、普拉卡素(prothracarcin)(Shimizu等,J.Antibiotics,29,2492-2503(1982);Langley和Thurston,J.Org.Chem.,52,91-97(1987))、西班米星(sibanomicin)(DC-102)(Hara等,J.Antibiotics,41,702-704(1988);Itoh等,J.Antibiotics,41,1281-1284(1988))、矛霉素(sibiromycin)(Leber等,J.Am.Chem.Soc.,110,2992-2993(1988))以及托马霉素(tomamycin)(Arima等,J.Antibiotics,25,437-444(1972))。PBD具有以下一般结构:
它们的不同之处在于其芳香族A环和吡咯并C环两者中的取代基的数目、类型和位置以及C环的饱和度。在B环中,在N10-C11位置处存在亚胺(N=C)、甲醇胺(NH-CH(OH))或甲醇胺甲基醚(NH-CH(OMe)),所述N10-C11位置为负责烷基化DNA的亲电子中心。所有已知的天然产物在手性C11a位置处具有(S)-构型,当从C环朝向A环观察时,所述手性C11a位置为所述天然产物提供右手扭转。这给予它们与B型DNA的小沟具有等螺旋性(isohelicity)的适当三维形状,从而导致在结合位点处的滑动配合(snug fit)(Kohn,AntibioticsIII.Springer-Verlag,New York,第3-11页(1975);Hurley和Needham-VanDevanter,Acc.Chem.Res.,19,230-237(1986))。它们在小沟中形成加合物的能力使得它们能够干扰DNA加工,因此使得它们可用作抗肿瘤剂。
先前已经公开,此分子的生物活性可通过将两个PBD单元通过它们的C8/C’-羟基官能团经由柔性亚烷基接头接合在一起而加强(Bose,D.S.等,J.Am.Chem.Soc.,114,4939-4941(1992);Thurston,D.E.等,J.Org.Chem.,61,8141-8147(1996))。PBD二聚体被认为形成序列选择性DNA损伤,如回文5’-Pu-GATC-Py-3’股间交联(Smellie,M.等,Biochemistry,42,8232-8239(2003);Martin,C.等,Biochemistry,44,4135-4147),认为所述股间交联主要负责所述PBD二聚体的生物活性。
PBD二聚体的一个实例是SG2000(SJG-136):
(Gregson,S.等,J.Med.Chem.,44,737-748(2001);Alley,M.C.等,CancerResearch,64,6700-6706(2004);Hartley,J.A.等,Cancer Research,64,6693-6699(2004)),其已经作为独立剂参与临床试验,例如,NCT02034227研究了所述剂在治疗急性骨髓性白血病和慢性淋巴细胞性白血病中的用途(参见:https://www.clinicaltrials.gov/ct2/show/NCT02034227)。
携带C2芳基取代基的二聚PBD化合物,诸如SG2202(ZC-207),公开于WO 2005/085251中:
以及WO2006/111759中,所述PBD化合物的亚硫酸氢盐,例如SG2285(ZC-423):
这些化合物已经显示出为高度可用的细胞毒性剂(Howard,P.W.等,Bioorg.Med.Chem.(2009),doi:10.1016/j.bmcl.2009.09.012)。
WO 2007/085930描述了具有用于连接至细胞结合剂(如抗体)的接头基团的二聚体PBD化合物的制备。接头存在于连接二聚体的单体PBD单元的桥中。
具有用于连接至细胞结合剂(如抗体)的接头基团的二聚体PBD化合物描述于WO2011/130598中。这些化合物中的接头连接于可用的N10位置中的一个,并且通常因酶对接头基团的作用而被裂解。如果用封端基团保护未结合的N10位置,那么所例示的封端基团具有与连接至抗体的接头相同的裂解触发物。
具有用于与细胞结合剂(如抗体)连接的接头基团的二聚体PBD化合物还描述于WO2011/130613、WO 2011/130616、WO 2013/053873、WO 2013/053871、WO 2013/041606、WO2013/055993、WO2013/055990、WO 2014/057073和WO 2015/052321中。这些化合物中的接头通过C2位置连接于PBD核心,并且通常因酶对接头基团的作用而被裂解。
尤其感兴趣的是他力林(talirine),其在与抗CD33抗体缀合时形成瓦达图昔单抗他力林(Vadastuximab talirine)(SGN-CD33A)(Sutherland,M等,Blood 2013 122:1455-1463;doi:10.1182/blood-2013-03-491506)。此ADC正在进行用于治疗AML的临床试验。SGN-CD33A具有以下一般结构:
发明内容
本发明提供了PBD以及相关PBD二聚体缀合物,其中PBD与被修饰以便在每条重链上具有至少一个自由缀合位点的抗体缀合,并且其中所述缀合是经由PBD的两个C2基团上的取代基经由相应接头实现的。
本发明还提供了适于与经修饰抗体缀合的PBD和相关二聚体药物接头,其中所述二聚体在两个C2基团上的取代基上均具有连接基团。
本发明的第一方面提供了一种式I的缀合物:
其中
Ab为在每条重链上具有至少一个自由缀合位点的经修饰抗体;
R2具有式IIIa、式IIIb或式IIIc:
其中A是C5-7芳基,并且
(i)Q1是单键,并且Q2选自单键和-Z-(CH2)n-,其中Z选自单键、O、S和NH,并且n为1至3;或
(ii)Q1是-CH=CH-,并且Q2是单键;
其中;
RC1、RC2和RC3独立地选自H和未取代的C1-2烷基;
其中Q选自O-RL1、S-RL1和NRN-RL1,并且RN选自H、甲基和乙基
RL1是用于与抗体(Ab)连接的接头;
R2’选自与R2相同的基团并且与相同的抗体连接;
R6和R9独立地选自H、R、OH、OR、SH、SR、NH2、NHR、NRR’、硝基、Me3Sn以及卤基;
其中R和R’独立地选自任选取代的C1-12烷基、C3-20杂环基以及C5-20芳基;
R7选自H、R、OH、OR、SH、SR、NH2、NHR、NRR’、硝基、Me3Sn以及卤基;
R″为C3-12亚烷基,它的链可间杂有一个或多个杂原子,例如O、S、NRN2(其中RN2为H或C1-4烷基),和/或芳族环,例如苯或吡啶;
Y和Y'选自O、S或NH;
R10和R11一起在它们所结合的氮原子与碳原子之间形成双键,或;
R10是H并且R11选自OH、ORA和SOzM;
R30和R31一起在它们所结合的氮原子与碳原子之间形成双键,或;
R30是H并且R31选自OH、ORA和SOzM;
R6’、R7’和R9’选自分别与R6、R7和R9相同的基团。
据认为,相比于由异质混合物组成的具有较高DAR的ADC而言,通过降低最小有效剂量需要,有效地具有1的药物抗体比率(DAR)的此类ADC可提供显著的优点,包括降低的脱靶毒性和增强的治疗窗口。
本发明的第二方面包括一种具有式II的化合物:
及所述化合物的盐和溶剂合物,
其中R6、R7、R9、R10、R11、Y、R”、Y’、R6’、R7’、R9’、R30和R31如本发明的第一方面所定义;
R12具有式IVa、式IVb或式IVc:
其中A是C5-7芳基,并且
(i)Q1是单键,并且Q2选自单键和-Z-(CH2)n-,其中Z选自单键、O、S和NH,并且n为1至3;或
(ii)Q1是-CH=CH-,并且Q2是单键;
其中;
RC1、RC2和RC3独立地选自H和未取代的C1-2烷基;
其中Q*选自O-RG1、S-RG1和NRN-RG1,并且RN选自H、甲基和乙基
RG1是用于与抗体连接的接头;
R12’选自与R12相同的基团。
本发明的第三方面提供了本发明的第一方面的缀合物在制造用于治疗增殖性疾病的药物中的用途。第三方面还提供了用于治疗增殖性疾病的本发明的第一方面的缀合物。第三方面还提供了一种治疗增殖性疾病的方法,所述方法包括向有需要的患者施用治疗有效量的本发明的第一方面的缀合物。
本领域的普通技术人员能够容易地确定候选缀合物是否治疗任何特定细胞类型的增殖性疾患。例如,可以方便地用来评估由特定化合物提供的活性的测定描述于以下实施例中。
本发明的第四方面提供了本发明的第一方面的缀合物的合成,所述合成包括将本发明的第二方面的化合物(药物接头)与如本发明的第一方面所定义的抗体缀合。
附图说明
图1示出了(A)适合在本发明中使用的经修饰抗体的示意图,(B)包含本发明的PBD的抗体药物缀合物的示意图;
图2示出了赫塞汀-Flexmab的重链序列和轻链序列。
定义
取代基
如本文所用的短语“任选取代的”涉及可为未取代的或可为取代的亲本基团。
除非另外指明,否则如本文所用的术语“取代的”涉及携带一个或多个取代基的亲本基团。术语“取代基”在本文中以常规意义使用并且是指共价连接至亲本基团或在适当时与亲本基团融合的化学部分。多种取代基是众所周知的,并且它们的形成和引入到各种亲本基团中的方法也是众所周知的。
取代基的实例在下面有更详细描述。
C1-12烷基:如本文所用的术语“C1-12烷基”是指通过从具有1至12个碳原子的烃化合物的碳原子处移除氢原子获得的一价部分,所述一价部分可以是脂肪族或脂环族的,并且它可以是饱和或不饱和的(例如部分不饱和的、完全不饱和的)。如本文所用的术语“C1-4烷基”是指通过从具有1至4个碳原子的烃化合物的碳原子处移除氢原子获得的一价部分,所述一价部分可以是脂肪族或脂环族的,并且它可以是饱和或不饱和的(例如部分不饱和的、完全不饱和的)。因此,术语“烷基”包括以下论述的亚类烯基、炔基、环烷基等。
饱和烷基的实例包括但不限于甲基(C1)、乙基(C2)、丙基(C3)、丁基(C4)、戊基(C5)、己基(C6)以及庚基(C7)。
饱和的直链烷基的实例包括但不限于甲基(C1)、乙基(C2)、正丙基(C3)、正丁基(C4)、正戊基(n-pentyl)(戊基(amyl))(C5)、正己基(C6)以及正庚基(C7)。
饱和的支链烷基的实例包括异丙基(C3)、异丁基(C4)、仲丁基(C4)、叔丁基(C4)、异戊基(C5)以及新戊基(C5)。
C2-12烯基:如本文所用的术语“C2-12烯基”是指具有一个或多个碳-碳双键的烷基。
不饱和烯基的实例包括但不限于乙烯基(ethenyl)(乙烯基(vinyl),-CH=CH2)、1-丙烯基(-CH=CH-CH3)、2-丙烯基(烯丙基,-CH-CH=CH2)、异丙烯基(1-甲基乙烯基,-C(CH3)=CH2)、丁烯基(C4)、戊烯基(C5)以及己烯基(C6)。
C2-12炔基:如本文所用的术语“C2-12炔基”是指具有一个或多个碳-碳三键的烷基。
不饱和炔基的实例包括但不限于乙炔基(-C≡CH)和2-丙炔基(炔丙基,-CH2-C≡CH)。
C3-12环烷基:如本文所用的术语“C3-12环烷基”是指也是环基的烷基;即,通过从环状烃(碳环)化合物的脂环环原子处移除氢原子获得的一价部分,所述部分具有3至7个碳原子,包括3至7个环原子。
环烷基的实例包括但不限于衍生自以下的那些环烷基:
饱和的单环烃化合物:
环丙烷(C3)、环丁烷(C4)、环戊烷(C5)、环己烷(C6)、环庚烷(C7)、甲基环丙烷(C4)、二甲基环丙烷(C5)、甲基环丁烷(C5)、二甲基环丁烷(C6)、甲基环戊烷(C6)、二甲基环戊烷(C7)以及甲基环己烷(C7);
不饱和的单环烃化合物:
环丙烯(C3)、环丁烯(C4)、环戊烯(C5)、环己烯(C6)、甲基环丙烯(C4)、二甲基环丙烯(C5)、甲基环丁烯(C5)、二甲基环丁烯(C6)、甲基环戊烯(C6)、二甲基环戊烯(C7)以及甲基环己烯(C7);以及
饱和的多环烃化合物:
降蒈烷(norcarane)(C7)、降蒎烷(norpinane)(C7)、降莰烷(norbornane)(C7)。
C3-20杂环基:如本文所用的术语“C3-20杂环基”是指通过从杂环化合物的环原子处移除氢原子获得的一价部分,所述部分具有3至20个环原子,其中的1至10个环原子为环杂原子。优选地,各环均具有3至7个环原子,其中的1至4个环原子为环杂原子。
在此上下文中,前缀(例如C3-20、C3-7、C5-6等)表示环原子的数目或环原子的数目的范围,无论是碳原子还是杂原子。例如,如本文所用的术语“C5-6杂环基”是指具有5个或6个环原子的杂环基。
单环杂环基的实例包括但不限于衍生自以下的那些单环杂环基:
N1:氮丙啶(C3)、氮杂环丁烷(C4)、吡咯烷(四氢吡咯)(C5)、吡咯啉(例如,3-吡咯啉、2,5-二氢吡咯)(C5)、2H-吡咯或3H-吡咯(异吡咯、异唑(isoazole))(C5)、哌啶(C6)、二氢吡啶(C6)、四氢吡啶(C6)、氮杂(C7);
O1:环氧乙烷(C3)、氧杂环丁烷(C4)、氧杂环戊烷(四氢呋喃)(C5)、氧杂环戊二烯(oxole)(二氢呋喃)(C5)、噁烷(四氢吡喃)(C6)、二氢吡喃(C6)、吡喃(C6)、氧杂环庚三烯(C7);
S1:硫杂丙环(thiirane)(C3)、硫杂环丁烷(thietane)(C4)、硫杂环戊烷(thiolane)(四氢噻吩)(C5)、噻烷(四氢噻喃)(C6)、硫杂环庚烷(thiepane)(C7);
O2:二氧杂环戊烷(C5)、二噁烷(C6)和二氧杂环庚烷(C7);
O3:三噁烷(C6);
N2:咪唑烷(C5)、吡唑烷(二氮杂环戊烷(diazolidine))(C5)、咪唑啉(C5)、吡唑啉(二氢吡唑)(C5)、哌嗪(C6);
N1O1:四氢噁唑(C5)、二氢噁唑(C5)、四氢异噁唑(C5)、二氢异噁唑(C5)、吗啉(C6)、四氢噁嗪(C6)、二氢噁嗪(C6)、噁嗪(C6);
N1S1:噻唑啉(C5)、噻唑烷(C5)、硫代吗啉(C6);
N2O1:噁二嗪(C6);
O1S1:噁噻唑(oxathiole)(C5)和氧硫杂环己烷(oxathiane)(噻噁烷(thioxane))(C6);以及
N1O1S1:噁噻嗪(C6)。
取代的单环杂环基的实例包括衍生自呈环状形式的糖类的杂环基,所述糖类例如呋喃糖(C5),如阿拉伯呋喃糖、来苏呋喃糖、核呋喃糖和木呋喃糖;以及吡喃糖(C6),如阿洛吡喃糖(allopyranose)、阿卓吡喃糖(altropyranose)、葡萄吡喃糖、甘露吡喃糖、古洛吡喃糖(gulopyranose)、艾杜吡喃糖(idopyranose)、半乳吡喃糖以及太洛吡喃糖(talopyranose)。
C5-20芳基:如本文所用的术语“C5-20芳基”是指通过从芳族化合物的芳族环原子处移除氢原子获得的一价部分,所述部分具有3至20个环原子。如本文所用的术语“C5-7芳基”是指通过从芳族化合物的芳族环原子处移除氢原子获得的一价部分,所述部分具有5至7个环原子并且如本文所用的术语“C5-10芳基”是指通过从芳族化合物的芳族环原子处移除氢原子获得的一价部分,所述部分具有5至10个环原子。优选地,每个环具有5至7个环原子。
在此上下文中,前缀(例如C3-20、C5-7、C5-6、C5-10等)表示环原子的数目或环原子的数目的范围,无论是碳原子还是杂原子。例如,如本文所用的术语“C5-6芳基”是指具有5个或6个环原子的芳基。
环原子可以全部是碳原子,如在“碳芳基”中。
碳芳基的实例包括但不限于衍生自苯(即苯基)(C6)、萘(C10)、薁(azulene)(C10)、蒽(C14)、菲(C14)、萘并萘(C18)以及嵌二萘(C16)的那些碳芳基。
包括其中的至少一个环为芳族环的稠环的芳基的实例包括但不限于衍生自茚满(例如2,3-二氢-1H-茚)(C9)、茚(C9)、异茚(C9)、四氢化萘(1,2,3,4-四氢萘(C10)、二氢苊(C12)、芴(C13)、非那烯(phenalene)(C13)、醋菲(acephenanthrene)(C15)以及醋蒽(aceanthrene)(C16)的基团。
另选地,环原子可包括一个或多个杂原子,如在“杂芳基”中。单环杂芳基的实例包括但不限于衍生自以下的那些单环杂芳基:
N1:吡咯(唑)(C5)、吡啶(吖嗪)(C6);
O1:呋喃(氧杂环戊二烯)(C5);
S1:噻吩(硫杂环戊二烯)(C5);
N1O1:噁唑(C5)、异噁唑(C5)、异噁嗪(C6);
N2O1:噁二唑(呋咱)(C5);
N3O1:噁三唑(C5);
N1S1:噻唑(C5)、异噻唑(C5);
N2:咪唑(1,3-二唑)(C5)、吡唑(1,2-二唑)(C5)、哒嗪(1,2-二嗪)(C6)、嘧啶(1,3-二嗪)(C6)(例如,胞嘧啶、胸腺嘧啶、尿嘧啶)、吡嗪(1,4-二嗪)(C6);
N3:三唑(C5)、三嗪(C6);以及,
N4:四唑(C5)。
包含稠环的杂芳基的实例包括但不限于:
C9(具有2个稠环),其衍生自苯并呋喃(O1)、异苯并呋喃(O1)、吲哚(N1)、异吲哚(N1)、中氮茚(N1)、吲哚啉(N1)、异吲哚啉(N1)、嘌呤(N4)(例如,腺嘌呤、鸟嘌呤)、苯并咪唑(N2)、吲唑(N2)、苯并噁唑(N1O1)、苯并异噁唑(N1O1)、苯并二氧杂环戊二烯(O2)、苯并呋咱(N2O1)、苯并三唑(N3)、苯并硫代呋喃(S1)、苯并噻唑(N1S1)、苯并噻二唑(N2S);
C10(具有2个稠环),其衍生自苯并吡喃(O1)、异苯并吡喃(O1)、二氢吡喃(O1)、异二氢吡喃(O1)、苯并二噁烷(O2)、喹啉(N1)、异喹啉(N1)、喹嗪(N1)、苯并噁嗪(N1O1)、苯并二嗪(N2)、吡啶并吡啶(N2)、喹喔啉(N2)、喹唑啉(N2)、噌啉(N2)、酞嗪(N2)、二氮杂萘(N2)、蝶啶(N4);
C13(具有3个稠环),其衍生自咔唑(N1)、二苯并呋喃(O1)、二苯并噻吩(S1)、咔啉(N2)、萘嵌间二氮杂苯(N2)、吡啶并吲哚(N2);以及,
C14(具有3个稠环),其衍生自吖啶(N1)、呫吨(O1)、噻吨(S1)、二苯并对二噁英(oxanthrene)(O2)、吩噁噻(O1S1)、吩嗪(N2)、吩噁嗪(N1O1)、吩噻嗪(N1S1)、噻蒽(S2)、菲啶(N1)、菲咯啉(N2)、吩嗪(N2)。
无论是单独还是为另一取代基的一部分的以上基团均可自身任选被一个或多个选自自身及以下列出的另外取代基的基团取代。
卤基:-F、-Cl、-Br和-I。
羟基:-OH。
醚:-OR,其中R是醚取代基,例如,C1-7烷基(也称为C1-7烷氧基,以下进行讨论)、C3-20杂环基(也称为C3-20杂环基氧基)或C5-20芳基(也称为C5-20芳基氧基),优选C1-7烷基。
烷氧基:-OR,其中R为烷基,例如,C1-7烷基。C1-7烷氧基的实例包括但不限于-OMe(甲氧基)、-OEt(乙氧基)、-O(nPr)(正丙氧基)、-O(iPr)(异丙氧基)、-O(nBu)(正丁氧基)、-O(sBu)(仲丁氧基)、-O(iBu)(异丁氧基)以及-O(tBu)(叔丁氧基)。
缩醛:-CH(OR1)(OR2),其中R1和R2独立地为缩醛取代基,例如,C1-7烷基、C3-20杂环基或C5-20芳基,优选C1-7烷基,或在“环状”缩醛基团的情况下,R1和R2与它们所连接的两个氧原子以及它们所连接的碳原子一起,形成具有4至8个环原子的杂环。缩醛基团的实例包括但不限于-CH(OMe)2、-CH(OEt)2和-CH(OMe)(OEt)。
半缩醛:-CH(OH)(OR1),其中R1为半缩醛取代基,例如,C1-7烷基、C3-20杂环基或C5-20芳基,优选C1-7烷基。半缩醛基团的实例包括但不限于-CH(OH)(OMe)和-CH(OH)(OEt)。
缩酮:-CR(OR1)(OR2),其中R1和R2如对于缩醛所定义,并且R是除氢之外的缩酮取代基,例如,C1-7烷基、C3-20杂环基或C5-20芳基,优选C1-7烷基。缩酮基团的实例包括但不限于-C(Me)(OMe)2、-C(Me)(OEt)2、-C(Me)(OMe)(OEt)、-C(Et)(OMe)2、-C(Et)(OEt)2以及-C(Et)(OMe)(OEt)。
半缩酮:-CR(OH)(OR1),其中R1如对于半缩醛所定义,并且R是除氢之外的半缩酮取代基,例如,C1-7烷基、C3-20杂环基或C5-20芳基,优选C1-7烷基。半缩醛基团的实例包括但不限于-C(Me)(OH)(OMe)、-C(Et)(OH)(OMe)、-C(Me)(OH)(OEt)以及-C(Et)(OH)(OEt)。
氧代基(酮基、-酮):=O。
硫酮(硫代酮):=S。
亚胺基(亚胺):=NR,其中R为亚胺基取代基,例如,氢、C1-7烷基、C3-20杂环基或C5-20芳基,优选为氢或C1-7烷基。酯基的实例包括但不限于=NH、=NMe、=NEt及=NPh。
甲酰基(甲醛(carbaldehyde,carboxaldehyde)):-C(=O)H。
酰基(酮基):-C(=O)R,其中R是酰基取代基,例如,C1-7烷基(也称为C1-7烷基酰基或C1-7烷酰基)、C3-20杂环基(也称为C3-20杂环基酰基)或C5-20芳基(也称为C5-20芳基酰基),优选为C1-7烷基。酰基的实例包括但不限于-C(=O)CH3(乙酰基)、-C(=O)CH2CH3(丙酰基)、-C(=O)C(CH3)3(叔丁酰基)和-C(=O)Ph(苯甲酰基、酰苯基(phenone))。
羧基(羧酸):-C(=O)OH。
硫代羧基(硫代羧酸):-C(=S)SH。
硫醇羧基(硫醇羧酸):-C(=O)SH。
硫酮羧基(硫酮羧酸):-C(=S)OH。
亚胺酸:-C(=NH)OH。
异羟肟酸:-C(=NOH)OH。
酯(羧酸酯、羧酸的酯、氧基羰基):-C(=O)OR,其中R是酯取代基,例如,C1-7烷基、C3-20杂环基或C5-20芳基,优选为C1-7烷基。酯基的实例包括但不限于-C(=O)OCH3、-C(=O)OCH2CH3、-C(=O)OC(CH3)3和-C(=O)OPh。
酰氧基(反酯):-OC(=O)R,其中R是酰氧基取代基,例如,C1-7烷基、C3-20杂环基或C5-20芳基,优选为C1-7烷基。酰氧基的实例包括但不限于-OC(=O)CH3(乙酰氧基)、-OC(=O)CH2CH3、-OC(=O)C(CH3)3、-OC(=O)Ph和-OC(=O)CH2Ph。
氧基羰基氧基:-OC(=O)OR,其中R是酯取代基,例如,C1-7烷基、C3-20杂环基或C5-20芳基,优选C1-7烷基。酯基的实例包括但不限于-OC(=O)OCH3、-OC(=O)OCH2CH3、-OC(=O)OC(CH3)3和-OC(=O)OPh。
氨基:-NR1R2,其中R1和R2独立地为氨基取代基,例如,氢、C1-7烷基(也称为C1-7烷基氨基或二-C1-7烷基氨基)、C3-20杂环基或C5-20芳基,优选为H或C1-7烷基,或,在“环状”氨基的情况下,R1和R2与它们所连接的氮原子一起形成具有4至8个环原子的杂环。氨基可以是伯(-NH2)、仲(-NHR1)或叔(-NHR1R2),并且在阳离子形式中,可以是季(-+NR1R2R3)。氨基的实例包括但不限于-NH2、-NHCH3、-NHC(CH3)2、-N(CH3)2、-N(CH2CH3)2和-NHPh。环状氨基的实例包括但不限于氮杂环丙烷基、氮杂环丁烷基、吡咯烷子基、哌啶子基、哌嗪子基、吗啉代基以及硫吗啉代基。
酰胺基(氨基甲酰基、氨甲酰基、氨基羰基、羧基酰胺):-C(=O)NR1R2,其中R1和R2独立地为氨基取代基,如针对氨基所定义。酰胺基的实例包括但不限于-C(=O)NH2、-C(=O)NHCH3、-C(=O)N(CH3)2、-C(=O)NHCH2CH3和-C(=O)N(CH2CH3)2,以及其中R1和R2与它们所连接的氮原子一起形成杂环结构的酰胺基,例如哌啶子基羰基、吗啉代羰基、硫吗啉代羰基和哌嗪子基羰基。
硫代酰胺基(硫代氨甲酰基):-C(=S)NR1R2,其中R1和R2独立地为氨基取代基,如针对氨基所定义。酰胺基的实例包括但不限于-C(=S)NH2、-C(=S)NHCH3、-C(=S)N(CH3)2和-C(=S)NHCH2CH3。
酰基酰胺基(Acylamido)(酰基氨基):-NR1C(=O)R2,其中R1是酰胺取代基,例如,氢、C1-7烷基、C3-20杂环基或C5-20芳基,优选为氢或C1-7烷基,并且R2是酰基取代基,例如,C1-7烷基、C3-20杂环基或C5-20芳基,优选为氢或C1-7烷基。酰基酰胺基团的实例包括但不限于-NHC(=O)CH3、-NHC(=O)CH2CH3和-NHC(=O)Ph。R1和R2可一起形成环状结构,如例如在琥珀酰亚胺基、马来酰亚胺基和邻苯二甲酰亚胺基中:
氨基羰基氧基:-OC(=O)NR1R2,其中R1和R2独立地为氨基取代基,如针对氨基所定义。氨基羰基氧基的实例包括但不限于-OC(=O)NH2、-OC(=O)NHMe、-OC(=O)NMe2和-OC(=O)NEt2。
脲基:-N(R1)CONR2R3,其中R2和R3独立地为氨基取代基,如针对氨基所定义,并且R1是脲基取代基,例如,氢、C1-7烷基、C3-20杂环基或C5-20芳基,优选为氢或C1-7烷基。脲基的实例包括但不限于-NHCONH2、-NHCONHMe、-NHCONHEt、-NHCONMe2、-NHCONEt2、-NMeCONH2、-NMeCONHMe、-NMeCONHEt、-NMeCONMe2和-NMeCONEt2。
胍基:-NH-C(=NH)NH2。
四唑基:具有四个氮原子和一个碳原子的五元芳族环,
亚胺基:=NR,其中R为亚胺基取代基,例如,氢、C1-7烷基、C3-20杂环基或C5-20芳基,优选为H或C1-7烷基。亚胺基的实例包括但不限于=NH、=NMe和=NEt。
脒(脒基):-C(=NR)NR2,其中每个R为脒取代基,例如,氢、C1-7烷基、C3-20杂环基或C5-20芳基,优选为H或C1-7烷基。脒基团的实例包括但不限于-C(=NH)NH2、-C(=NH)NMe2和-C(=NMe)NMe2。
硝基:-NO2。
亚硝基:-NO。
叠氮基:-N3。
氰基(腈、甲腈):-CN。
异氰基:-NC。
氰酰基:-OCN。
异氰酰基:-NCO。
氰硫基(硫氰酰基):-SCN。
异氰硫基(异硫氰酰基):-NCS。
硫氢基(Sulfhydryl)(硫醇基、巯基):-SH。
硫醚(thioether)(硫醚(sulfide)):-SR,其中R为硫醚取代基,例如,C1-7烷基(也称为C1-7烷硫基)、C3-20杂环基或C5-20芳基,优选为C1-7烷基。C1-7烷硫基的实例包括但不限于-SCH3和-SCH2CH3。
二硫醚:-SS-R,其中R为二硫醚取代基,例如,C1-7烷基、C3-20杂环基或C5-20芳基,优选C1-7烷基(本文也称为C1-7烷基二硫醚)。C1-7烷基二硫醚基团的实例包括但不限于-SSCH3和-SSCH2CH3。
锍化物(亚磺酰基、亚砜):-S(=O)R,其中R为锍化物取代基,例如,C1-7烷基、C3-20杂环基或C5-20芳基,优选为C1-7烷基。锍化物基团的实例包括但不限于-S(=O)CH3和-S(=O)CH2CH3。
砜(磺酰基):-S(=O)2R,其中R为砜取代基,例如,C1-7烷基、C3-20杂环基或C5-20芳基,优选为C1-7烷基,包括例如氟化或全氟化的C1-7烷基。砜基团的实例包括但不限于-S(=O)2CH3(甲烷磺酰基、甲磺酰基)、-S(=O)2CF3(三氟甲磺酰基)、-S(=O)2CH2CH3(乙磺酰基)、-S(=O)2C4F9(九氟丁磺酰基)、-S(=O)2CH2CF3(三氟乙磺酰基)、-S(=O)2CH2CH2NH2(牛磺酰基)、-S(=O)2Ph(苯基磺酰基、苯磺酰基)、4-甲基苯基磺酰基(甲苯磺酰基)、4-氯苯基磺酰基(氯苯磺酰基)、4-溴苯基磺酰基(溴苯磺酰基)、4-硝基苯基(硝苯磺酰基)、2-萘磺酸酯(萘磺酰基)以及5-二甲基氨基-萘-1-基磺酸酯(丹磺酰基)。
亚磺酸(亚磺基):-S(=O)OH、-SO2H。
磺酸(磺基):-S(=O)2OH、-SO3H。
亚磺酸酯(亚磺酸的酯):-S(=O)OR,其中R为亚磺酸酯取代基,例如,C1-7烷基、C3-20杂环基或C5-20芳基,优选为C1-7烷基。亚磺酸酯基团的实例包括但不限于-S(=O)OCH3(甲氧基亚磺酰基;甲基亚磺酸酯)和-S(=O)OCH2CH3(乙氧基亚磺酰基;乙基亚磺酸酯)。
磺酸酯(磺酸的酯):-S(=O)2OR,其中R为磺酸酯取代基,例如,C1-7烷基、C3-20杂环基或C5-20芳基,优选为C1-7烷基。磺酸酯基团的实例包括但不限于-S(=O)2OCH3(甲氧基磺酰基;甲基磺酸酯)和-S(=O)2OCH2CH3(乙氧基磺酰基;乙基磺酸酯)。
亚磺酰氧基:-OS(=O)R,其中R为亚磺酰氧基取代基,例如,C1-7烷基、C3-20杂环基或C5-20芳基,优选为C1-7烷基。亚磺酰氧基的实例包括但不限于-OS(=O)CH3和-OS(=O)CH2CH3。
磺酰氧基:-OS(=O)2R,其中R为磺酰氧基取代基,例如,C1-7烷基、C3-20杂环基或C5-20芳基,优选为C1-7烷基。磺酰氧基的实例包括但不限于-OS(=O)2CH3(甲磺酸酯)和-OS(=O)2CH2CH3(乙磺酸酯)。
硫酸酯:-OS(=O)2OR;其中R为硫酸酯取代基,例如,C1-7烷基、C3-20杂环基或C5-20芳基,优选为C1-7烷基。硫酸酯基团的实例包括但不限于-OS(=O)2OCH3和-SO(=O)2OCH2CH3。
氨磺酰基(sulfamyl)(氨磺酰基(sulfamoyl);亚磺酸酰胺;亚磺酰胺):-S(=O)NR1R2,其中R1和R2独立地为氨基取代基,如针对氨基所定义。氨磺酰基的实例包括但不限于-S(=O)NH2、-S(=O)NH(CH3)、-S(=O)N(CH3)2、-S(=O)NH(CH2CH3)、-S(=O)N(CH2CH3)2和-S(=O)NHPh。
磺酰氨基(sulfonamido)(氨亚磺酰基;磺酸酰胺;磺酰胺):-S(=O)2NR1R2,其中R1和R2独立地为氨基取代基,如对于氨基所定义。磺酰氨基的实例包括但不限于-S(=O)2NH2、-S(=O)2NH(CH3)、-S(=O)2N(CH3)2、-S(=O)2NH(CH2CH3)、-S(=O)2N(CH2CH3)2和-S(=O)2NHPh。
磺酸氨基:-NR1S(=O)2OH,其中R1为氨基取代基,如针对氨基所定义。磺酸氨基的实例包括但不限于-NHS(=O)2OH和-N(CH3)S(=O)2OH。
磺氨基:-NR1S(=O)2R,其中R1为氨基取代基,如针对氨基所定义,并且R为磺氨基取代基,例如,C1-7烷基、C3-20杂环基或C5-20芳基,优选为C1-7烷基。磺氨基的实例包括但不限于-NHS(=O)2CH3和-N(CH3)S(=O)2C6H5。
亚磺氨基:-NR1S(=O)R,其中R1为氨基取代基,如针对氨基所定义,并且R为亚磺氨基取代基,例如,C1-7烷基、C3-20杂环基或C5-20芳基,优选为C1-7烷基。亚磺氨基的实例包括但不限于-NHS(=O)CH3和-N(CH3)S(=O)C6H5。
膦基(膦):-PR2,其中R为膦基取代基,例如,-H、C1-7烷基、C3-20杂环基或C5-20芳基,优选为-H、C1-7烷基或C5-20芳基。膦基的实例包括但不限于-PH2、-P(CH3)2、-P(CH2CH3)2、-P(t-Bu)2和-P(Ph)2。
磷基:-P(=O)2。
氧膦基(氧化膦):-P(=O)R2,其中R为氧膦基取代基,例如,C1-7烷基、C3-20杂环基或C5-20芳基,优选为C1-7烷基或C5-20芳基。氧膦基的实例包括但不限于-P(=O)(CH3)2、-P(=O)(CH2CH3)2、-P(=O)(t-Bu)2和-P(=O)(Ph)2。
膦酸(膦酰基):-P(=O)(OH)2。
膦酸酯(膦酰基酯):-P(=O)(OR)2,其中R为膦酸酯取代基,例如,-H、C1-7烷基、C3-20杂环基或C5-20芳基,优选为-H、C1-7烷基或C5-20芳基。膦酸酯基团的实例包括但不限于-P(=O)(OCH3)2、-P(=O)(OCH2CH3)2、-P(=O)(O-t-Bu)2和-P(=O)(OPh)2。
磷酸(膦酰基氧基):-OP(=O)(OH)2。
磷酸酯(膦酰基氧基酯):-OP(=O)(OR)2,其中R为磷酸酯取代基,例如,-H、C1-7烷基、C3-20杂环基或C5-20芳基,优选为-H、C1-7烷基或C5-20芳基。磷酸酯基团的实例包括但不限于-OP(=O)(OCH3)2、-OP(=O)(OCH2CH3)2、-OP(=O)(O-t-Bu)2和-OP(=O)(OPh)2。
亚磷酸:-OP(OH)2。
亚磷酸酯:-OP(OR)2,其中R为亚磷酸酯取代基,例如,-H、C1-7烷基、C3-20杂环基或C5-20芳基,优选为-H、C1-7烷基或C5-20芳基。亚磷酸酯基团的实例包括但不限于-OP(OCH3)2、-OP(OCH2CH3)2、-OP(O-t-Bu)2和-OP(OPh)2。
亚磷酰胺:-OP(OR1)-NR2 2,其中R1和R2为亚磷酰胺取代基,例如,-H、(任选取代的)C1-7烷基、C3-20杂环基或C5-20芳基,优选为-H、C1-7烷基或C5-20芳基。亚磷酰胺基团的实例包括但不限于-OP(OCH2CH3)-N(CH3)2、-OP(OCH2CH3)-N(i-Pr)2和-OP(OCH2CH2CN)-N(i-Pr)2。
磷酰胺酯:-OP(=O)(OR1)-NR2 2,其中R1和R2为磷酰胺酯取代基,例如,-H、(任选取代的)C1-7烷基、C3-20杂环基或C5-20芳基,优选为-H、C1-7烷基或C5-20芳基。磷酰胺酯基团的实例包括但不限于-OP(=O)(OCH2CH3)-N(CH3)2、-OP(=O)(OCH2CH3)-N(i-Pr)2和-OP(=O)(OCH2CH2CN)-N(i-Pr)2。
亚烷基
C3-12亚烷基:如本文所用的术语“C3-12亚烷基”是指通过从具有3至12个碳原子(除非另外指出)的烃化合物上移除2个氢原子(从同一个碳原子处移除两个氢原子或从两个不同碳原子处各移除一个氢原子)而获得的双齿物部分,所述双齿物部分可以是脂肪族的或脂环族的,并且它可以是饱和的、部分不饱和的或完全不饱和的。因此,术语“亚烷基”包括以下论述的亚类亚烯基、亚炔基、亚环烷基等。
直链饱和C3-12亚烷基的实例包括但不限于-(CH2)n-,其中n为3至12的整数,例如,-CH2CH2CH2-(亚丙基)、-CH2CH2CH2CH2-(亚丁基)、-CH2CH2CH2CH2CH2-(亚戊基)和-CH2CH2CH2CH-2CH2CH2CH2-(亚庚基)。
支链饱和C3-12亚烷基的实例包括但不限于-CH(CH3)CH2-、-CH(CH3)CH2CH2-、-CH(CH3)CH2CH2CH2-、-CH2CH(CH3)CH2-、-CH2CH(CH3)CH2CH2-、-CH(CH2CH3)-、-CH(CH2CH3)CH2-和-CH2CH(CH2CH3)CH2-。
直链部分不饱和的C3-12亚烷基(C3-12亚烯基和亚炔基)的实例包括但不限于-CH=CH-CH2-、-CH2-CH=CH2-、-CH=CH-CH2-CH2-、-CH=CH-CH2-CH2-CH2-、-CH=CH-CH=CH-、-CH=CH-CH=CH-CH2-、-CH=CH-CH=CH-CH2-CH2-、-CH=CH-CH2-CH=CH-、-CH=CH-CH2-CH2-CH=CH-和-CH2-C≡C-CH2-。
支链部分不饱和的C3-12亚烷基(C3-12亚烯基和亚炔基)的实例包括但不限于-C(CH3)=CH-、-C(CH3)=CH-CH2-、-CH=CH-CH(CH3)-和-C≡C-CH(CH3)-。
脂环族饱和的C3-12亚烷基(C3-12亚环烷基)的实例包括但不限于亚环戊基(例如亚环戊-1,3-基)和亚环己基(例如,亚环己-1,4-基)。
脂环族部分不饱和的C3-12亚烷基(C3-12亚环烷基)的实例包括但不限于亚环戊烯基(例如4-亚环戊烯-1,3-基)、亚环己烯基(例如2-亚环己烯-1,4-基;3-亚环己烯-1,2-基;2,5-亚环己二烯-1,4-基)。
配体单元
在本发明中使用的配体单元是细胞结合剂,更具体地为在每条重链上具有至少一个缀合位点的经修饰抗体或其抗原结合片段。根据本发明适用的特定的经修饰抗体的实例公开于WO 2012/064733(作为PCT/US2011/059775提交)中,所述文献以引用方式并入本文。
抗体
抗体
术语“抗体”在本文中是在最广泛的意义上加以使用并且具体地涵盖单克隆抗体、多克隆抗体、二聚体、多聚体、多特异性抗体(例如,双特异性抗体)以及抗体片段,只要它们显示所期望的生物活性即可(Miller等(2003)Jour.of Immunology 170:4854-4861)。抗体可以是鼠、人、人源化的、嵌合的或来源于其它物种。抗体是由免疫系统生成的能够识别并结合特定抗原的蛋白质。(Janeway,C.、Travers,P.、Walport,M.、Shlomchik(2001)ImmunoBiology,第5版,Garland Publishing,New York)。靶抗原通常具有通过多个抗体上的CDR识别的许多结合位点,也称为表位。特异性结合不同表位的各个抗体具有不同的结构。因此,一种抗原可具有多于一种的对应抗体。抗体包括全长免疫球蛋白分子或全长免疫球蛋白分子的免疫活性部分,即含有免疫特异性地结合目标靶标的抗原或其部分的抗原结合位点的分子,此类靶标包括但不限于产生与自身免疫疾病相关的自身免疫抗体的一种或多种癌细胞。免疫球蛋白可以属于免疫球蛋白分子的任何类型(例如,IgG、IgE、IgM、IgD和IgA)、类别(例如,IgG1、IgG2、IgG3、IgG4、IgA1和IgA2)或亚类。免疫球蛋白可以源自任何物种,包括人、鼠、或兔来源。
“抗体片段”包含全长抗体的一部分,通常为所述全长抗体的抗原结合区或可变区。抗体片段的实例包括F(ab')2和scFv片段,以及以上任一者的免疫特异性地结合于癌细胞抗原、病毒抗原或微生物抗原的二聚体表位结合片段、单链抗体分子;以及由抗体片段形成的多特异性抗体。
适用于本发明的经修饰抗体包括其中缺乏硫醇基团的氨基酸残基已被天然链间半胱氨酸残基取代的那些抗体。抗体可在每条重链中包括至少一个另外的包含适于与接头缀合的反应性基团的氨基酸残基的取代。另外的取代氨基酸可以是半胱氨酸或非天然氨基酸。被取代的位置可选自下文列出的那些位置:
适用于本发明的经修饰抗体的实例包括在被并入本文的WO 2012/064733中公开的Flexmab结构。此类Flexmab在抗体的铰链区中具有含游离硫醇基团的半胱氨酸,所述半胱氨酸可用作用于通过本发明的PBD的N10基团连接的缀合位点。
适用于本发明的经修饰抗体的其它实例包括其中半胱氨酸已经插入抗体中的选定位点中的那些经修饰抗体。这些经修饰抗体描述于Dimasi,N.等,MolecularPharmaceutics,2017,14,1501-1516(DOI:10.1021/acs.molpharmaceut.6b00995)和WO2015/157595中。具体来说,已经通过在S239位之后(即,239位与240位之间)插入半胱氨酸进行修饰的抗体是有用的。
参考被并入本文的WO 2012/064733的第60页至第62页中所列。在一些实施方案中,抗体可以是肿瘤相关抗原,例如:HER2(ErbB2);EPHA2(EPH受体A2);CD19;IL2RA(白介素2受体,α)。
用于本发明的实施方案的肿瘤相关抗原和同源抗体在下文列出,并且更详细地描述于被并入本文的WO 2017/186894的第14页至第86页。
(1)BMPR1B(骨形态发生蛋白受体IB型)
(2)E16(LAT1、SLC7A5)
(3)STEAP1(前列腺的六跨膜上皮抗原)
(4)0772P(CA1 25、MUC16)
(5)MPF(MPF、MSLN、SMR、巨核细胞增强因子、间皮素)
(6)Napi3b(NAPI-3B,NPTIIb,SLC34A2,溶质载体家族34(磷酸钠),成员2,II型钠依赖性磷酸转运蛋白3b)
(7)Sema 5b(FLJ10372,KIAA1445,Mm.42015,SEMA5B,SEMAG,信号素(Semaphorin)5b Hlog,25sema结构域,7个血小板反应蛋白重复(1型和1型样),跨膜结构域(TM)和短细胞质结构域(信号素)5B)
(8)PSCAhlg(2700050C12Rik,C530008O16Rik,RIKEN cDNA2700050C12,RIKENcDNA2700050C12基因)
(9)ETBR(内皮素B型受体)
(10)MSG783(RNF124,假定蛋白FLJ20315)
(11)STEAP2(HGNC_8639,IPCA-1,PCANAP1,STAMP1,STEAP2,STMP,前列腺癌相关基因1,前列腺癌相关蛋白1,前列腺的六跨膜上皮抗原2,六跨膜前列腺蛋白)
(12)TrpM4(BR22450,FLJ20041,TRPM4,TRPM4B,瞬时受体电位阳离子5通道,亚家族M,成员4)
(13)CRIPTO(CR,CR1,CRGF,CRIPTO,TDGF1,畸胎癌源性生长因子)
(14)CD21(CR2(补体受体2)或C3DR(C3d/埃-巴二氏病毒受体(Epstein Barrvirus receptor))或Hs.73792)
(15)CD79b(CD79B,CD79β,IGb(免疫球蛋白相关β),B29)
(16)FcRH2(IFGP4,IRTA4,SPAP1A(SH2结构域,含磷酸酶锚定蛋白1a),SPAP1B,SPAP1C)
(17)HER2(ErbB2)
(18)NCA(CEACAM6)
(19)MDP(DPEP1)
(20)IL20R-α(IL20Ra,ZCYTOR7)
(21)短蛋白聚糖(Brevican)(BCAN,BEHAB)
(22)EphB2R(DRT,ERK,Hek5,EPHT3,Tyro5)
(23)ASLG659(B7h)
(24)PSCA(前列腺干细胞抗原前体)
(25)GEDA
(26)BAFF-R(B细胞活化因子受体,BLyS受体3,BR3)
(27)CD22(B细胞受体CD22-B同种型,BL-CAM,Lyb-8,Lyb8,SIGLEC-2,FLJ22814)
(27a)CD22(CD22分子)
(28)CD79a(CD79A,CD79α),免疫球蛋白相关的α、B细胞特异性蛋白,其与Igβ(CD79B)发生共价相互作用并与Ig M分子在表面上形成复合物,转导涉及B细胞分化的信号,pI:4.84,MW:25028 TM:2[P]基因染色体:19q13.2)。
(29)CXCR5(伯基特淋巴瘤受体1,G蛋白偶联受体,其被CXCL13趋化因子活化,在淋巴细胞迁移和体液性防御中起作用,在HIV-2感染中以及也许在AIDS、淋巴瘤、骨髓瘤、和白血病的发展中起作用);372aa,pI:8.54 MW:41959 TM:7[P]基因染色体:11q23.3,
(30)HLA-DOB(II类MHC分子(Ia抗原)的β亚基,其结合肽并且20将它们呈递到CD4+T淋巴细胞);273aa,pI:6.56,MW:30820.TM:1[P]基因染色体:6p21.3)
(31)P2X5(嘌呤能受体P2X配体门控离子通道5,由细胞外ATP门控的离子通道,可能涉及突触传递和神经发生,缺乏可能有助于特发性逼尿肌不稳定的病理生理学);422aa),pI:7.63,MW:47206 TM:1[P]基因染色体:17p13.3)。
(32)CD72(B细胞分化抗原CD72,Lyb-2);359aa,pI:8.66,MW:40225,TM:1 5[P]基因染色体:9p13.3)。
(33)LY64(淋巴细胞抗原64(RP105),富含亮氨酸重复(LRR)家族的I型膜蛋白,调节B细胞活化和细胞凋亡,在患有全身性红斑狼疮的患者中功能的丧失与增加的疾病活性相关);661aa,pI:6.20,MW:74147 TM:1[P]基因染色体:5q12)。
(34)FcRH1(Fc受体样蛋白1,用于免疫球蛋白Fc结构域的假定受体,其含有C2型Ig样和ITAM结构域,在B淋巴细胞分化中可能具有作用);429aa,pI:5.28,MW:46925 TM:1[P]基因染色体:1q21-1q22)
(35)IRTA2(免疫球蛋白超家族受体易位相关的2,假定的免疫受体,其可能在B细胞的发育和淋巴瘤发生中具有作用;在一些B细胞恶性疾病中基因通过易位发生去调节);977aa,pI:6.88,MW:106468,TM:1[P]基因染色体:1q21)
(36)TENB2(TMEFF2,肿瘤调节蛋白(tomoregulin),TPEF,HPP1,TR,推定的跨膜蛋白多糖,与生长因子和滤泡抑素的EGF/调蛋白(heregulin)家族相关);374aa)
(37)PSMA–FOLH1(叶酸水解酶(前列腺特异性膜抗原)1)
(38)SST(生长抑素受体;注意:存在5种亚型)
(38.1)SSTR2(生长抑素受体2)
(38.2)SSTR5(生长抑素受体5)
(38.3)SSTR1
(38.4)SSTR3
(38.5)SSTR4
AvB6–两种亚基(39+40)
(39)ITGAV(整联蛋白,αV)
(40)ITGB6(整联蛋白,β6)
(41)CEACAM5(癌胚抗原相关细胞粘附分子5)
(42)MET(met原癌基因;肝细胞生长因子受体)
(43)MUC1(粘蛋白1(Mucin 1),细胞表面相关的)
(44)CA9(碳酸酐酶IX)
(45)EGFRvIII(表皮生长因子受体(EGFR),转录变体3,
(46)CD33(CD33分子)
(47)CD19(CD19分子)
(48)IL2RA(白细胞介素2受体,α);NCBI参考序列:NM_000417.2);
(49)AXL(AXL受体酪氨酸激酶)
(50)CD30-TNFRSF8(肿瘤坏死因子受体超家族,成员8)
(51)BCMA(B细胞成熟抗原)-TNFRSF17(肿瘤坏死因子受体超家族,成员17)
(52)CT Ags–CTA(睾丸癌抗原(Cancer Testis Antigen))
(53)CD174(Lewis Y)-FUT3(岩藻糖基转移酶3(半乳糖苷3(4)-L-岩藻糖基转移酶,路易斯血型(Lewis blood group))
(54)CLEC14A(C型凝集素结构域家族14,成员A;Genbank登录号NM175060)
(55)GRP78–HSPA5(热休克70kDa蛋白5(葡萄糖调节蛋白,78kDa)
(56)CD70(CD70分子)L08096
(57)干细胞特异性抗原。例如:
·5T4(见以下条目(63))
·CD25(见以上条目(48))
·CD32
·LGR5/GPR49
·Prominin/CD133
(58)ASG-5
(59)ENPP3(外核苷酸焦磷酸酶/磷酸二酯酶3)
(60)PRR4(富含脯氨酸4(泪腺的))
(61)GCC–GUCY2C(鸟苷酸环化酶2C(热稳定肠毒素受体))
(62)Liv-1–SLC39A6(溶质载体家族39(锌转运蛋白),成员6)
(63)5T4,滋养层糖蛋白,TPBG–TPBG(滋养层糖蛋白)
(64)CD56–NCMA1(神经细胞粘附分子1)
(65)CanAg(肿瘤相关抗原CA242)
(66)FOLR1(叶酸盐受体1)
(67)GPNMB(糖蛋白(跨膜)nmb)
(68)TIM-1–HAVCR1(甲型肝炎病毒细胞受体1)
(69)RG-1/前列腺肿瘤靶Mindin–Mindin/RG-1
(70)B7-H4–VTCN1(含T细胞活化抑制剂的V-set结构域1
(71)PTK7(PTK7蛋白酪氨酸激酶7)
(72)CD37(CD37分子)
(73)CD138-SDC1(多配体聚糖1(syndecan 1))
(74)CD74(CD74分子,主要组织相容性复合物,II类不变链)
(75)密封蛋白(Claudin)–CL(Claudin)
(76)EGFR(表皮生长因子受体)
(77)Her3(ErbB3)–ERBB3(v-erb-b2成红细胞白血病病毒致癌基因同系物3(禽))
(78)RON-MST1R(巨噬细胞刺激1受体(c-met相关酪氨酸激酶))
(79)EPHA2(EPH受体A2)
(80)CD20–MS4A1(跨膜4结构域,亚家族A,成员1)
(81)腱生蛋白C–TNC(Tenascin C)
(82)FAP(成纤维细胞活化蛋白,α)
(83)DKK-1(Dickkopf 1同系物(光滑爪蟾(Xenopus laevis))
(84)CD52(CD52分子)
(85)CS1-SLAMF7(SLAM家族成员7)
(86)内皮糖蛋白-ENG(Endoglin)
(87)膜联蛋白A1-ANXA1(Annexin A1)
(88)V-CAM(CD106)-VCAM1(血管细胞粘附分子1)
接头单元与配体单元的连接
配体单元可通过二硫键与接头单元相连接。
在一个实施方案中,配体单元与药物接头之间的连接在配体单元的半胱氨酸残基的硫醇基团与药物接头单元的马来酰亚胺基团之间形成。用于连接的其它可能的基团和所得的连接基团在下文示出。
配体单元的半胱氨酸残基可用于与接头单元的官能团的反应以形成连接。在例如其中配体单元为抗体的其它实施方案中,抗体的硫醇基团可参与链间二硫键。这些链间键可通过例如在与接头单元的官能团反应之前用DTT处理抗体而转化成游离硫醇基团。
在一些实施方案中,将半胱氨酸残基引入抗体的重链或轻链中。通过取代将半胱氨酸插入抗体重链或轻链中的位置包括并入本文的所公布的美国申请2007-0092940和国际专利公布WO 2008/070593中所描述的那些位置。
治疗方法
本发明的化合物可以用于治疗方法。还提供了一种治疗方法,所述治疗方法包括将治疗有效量的式I的缀合物施用给需要治疗的受试者。术语“治疗有效量”是足以对患者显示益处的量。这样的益处可以是至少改善至少一种症状。施用的实际量以及施用的速率和时程将取决于待治疗对象的特性和严重性。治疗处方,例如对剂量的决定,是在全科医生和其它医生的责任范围内。
可以单独地或与其它治疗组合施用缀合物(同时或相继地,其取决于待治疗的疾患)。治疗和疗法的实例包括但不限于化疗(施用活性剂,包括,例如药物;手术;以及放射疗法。
根据本发明和根据本发明应用的药物组合物,除活性成分(即,式I的缀合物)之外,还可以包含药学上可接受的赋形剂、载体、缓冲剂、稳定剂或其它物质(本领域技术人员众所周知的)。此类物质应为无毒的并且应不干扰活性成分的功效。载体或其它物质的确切性质将取决于施用途径,所述施用途径可以是口服、或通过注射,例如皮肤、皮下、或静脉内注射。
用于口服施用的药物组合物可以是片剂、胶囊剂、粉剂或液体形式。片剂可以包含固体载体或佐剂。液体药物组合物通常包含液体载体,诸如水、石油、动物油或植物油、矿物油或合成油。可包含生理盐水溶液、葡萄糖或其它糖溶液或二醇类如乙二醇、丙二醇或聚乙二醇。胶囊剂可以包含固体载体如明胶。
对于静脉内、皮肤或皮下注射、或在病痛部位处的注射,活性成分将具有肠胃外可接受的水性溶液的形式,所述水性溶液是无热原的并具有适宜的pH、等渗性和稳定性。本领域的相关技术人员使用例如等渗媒介物如氯化钠注射液、林格氏注射液、乳酸林格氏注射液完全能够制备合适的溶液。根据需要,可以包含防腐剂、稳定剂、缓冲剂、抗氧化剂和/或其它添加剂。
缀合物可用于治疗增殖性疾病和自身免疫疾病。术语“增殖性疾病”是指过度或异常细胞的不需要的或不受控制的细胞增殖,这是不期望的,诸如赘生物或增生性生长(无论是在体外还是体内)。
增殖性疾患的实例包括但不限于良性、恶性前、和恶性细胞增殖,包括但不限于赘生物和肿瘤(例如组织细胞瘤、神经胶质瘤、星形细胞瘤、骨瘤)、癌症(例如肺癌、小细胞肺癌、胃肠癌、肠癌、结肠癌、乳腺癌、卵巢癌、前列腺癌、睾丸癌、肝癌、肾癌、膀胱癌、胰腺癌、脑癌、肉瘤、骨肉瘤、卡波西肉瘤(Kaposi's sarcoma)、黑素瘤)、白血病、银屑癣、骨疾病、纤维增殖性病症(例如结缔组织的纤维增殖性病症)、以及动脉粥样硬化。其它所关注的癌症包括但不限于血液学;恶性肿瘤,如白血病和淋巴瘤,如非霍奇金淋巴瘤(non-Hodgkinlymphoma)、以及亚型如DLBCL、边缘区、套区和滤泡、霍奇金淋巴瘤、AML、以及B或T细胞来源的其它癌症。
自身免疫疾病的实例包括以下:类风湿性关节炎、自身免疫性脱髓鞘疾病(例如,多发性硬化症、变态反应性脑脊髓炎)、银屑病性关节炎、内分泌眼病、葡萄膜视网膜炎、全身性红斑狼疮、重症肌无力、格雷夫斯病(Graves’disease)、肾小球肾炎、自身免疫性肝病、炎症性肠病(例如,克罗恩病(Crohn’s disease))、过敏性反应、变态反应、舍格伦综合症(syndrome)、I型糖尿病、原发性胆汁性肝硬化、韦氏肉芽肿病(Wegener’sgranulomatosis)、纤维肌痛症、多肌炎、皮肌炎、多发性内分泌衰竭、施密特氏综合征(Schmidt’s syndrome)、自身免疫性葡萄膜炎、爱迪生氏病(Addison’s disease)、肾上腺炎、甲状腺炎、桥本氏甲状腺炎(Hashimoto’s thyroiditis)、自身免疫性甲状腺疾病、恶性贫血、胃萎缩、慢性肝炎、狼疮样肝炎、动脉粥样硬化、亚急性皮肤型红斑狼疮、甲状旁腺功能减退症、德雷斯勒综合征(Dressler’s syndrome)、自身免疫性血小板减少症、特发性血小板减少性紫癜、溶血性贫血、寻常型天疱疮、天疱疮、疱疹样皮炎、斑秃、类天疱疮、硬皮病、进行性全身性硬化症、CREST综合征(钙质沉着、雷诺氏现象(Raynaud’s phenomenon)、食道运动功能障碍、指端硬化以及毛细管扩张)、男性和女性自身免疫性不孕、强直性脊柱炎、溃疡性结肠炎、混合性结蒂组织病、结节性多动脉炎、全身性坏死性血管炎、特应性皮肤炎、特应性鼻炎、古巴士德氏综合征(Goodpasture’s syndrome)、查加斯病(Chagas’disease)、结节病、风湿热、哮喘、复发性流产、抗磷脂综合征、农民肺、多形性红斑、心脏切开后综合征、库欣综合征(Cushing’s syndrome)、自身免疫性慢性活动性肝炎、养鸟人肺(bird-fancier’s lung)、中毒性表皮坏死松解症、奥尔波特综合征(Alport’s syndrome)、肺泡炎、过敏性肺泡炎、纤维性肺泡炎、间质性肺病、结节性红斑、坏疽性脓皮病、输血反应、高安氏动脉炎(Takayasu’s arteritis)、风湿性多肌痛、颞动脉炎、血吸虫病、巨细胞动脉炎、蛔虫病、曲霉病、桑普特综合征(Sampter’s syndrome)、湿疹、淋巴瘤样肉芽肿病、贝切特氏病(Behcet’s disease)、卡普兰综合征(Caplan’s syndrome)、川崎氏病(Kawasaki’sdisease)、登革热、脑脊髓炎、心内膜炎、心内膜心肌纤维化、眼内炎、持久性隆起性红斑(erythema elevatum et diutinum)、银屑病、胎儿成红细胞增多症、嗜酸细胞性筋膜炎、舒尔曼综合征(Shulman’s syndrome)、费尔蒂氏综合征(Felty’s syndrome)、丝虫病、睫状体炎、慢性睫状体炎、异时睫状体炎、富克斯氏睫状体炎、IgA肾病、亨-舍二氏紫癜(Henoch-Schonlein purpura)、移植物抗宿主病、移植排斥反应、心肌症、伊顿-兰伯特综合征(Eaton-Lambert syndrome)、复发性多软骨炎、冷沉球蛋白血症、华氏巨球蛋白血症(Waldenstrom’s macroglobulemia)、埃文氏综合征(Evan’s syndrome)以及自身免疫性性腺衰竭。
在一些实施方案中,自身免疫性疾病是B淋巴细胞的失调(例如,全身性红斑狼疮、古巴士德氏综合征、类风湿性关节炎以及I型糖尿病)、Th1淋巴细胞的失调(例如,类风湿性关节炎、多发性硬化症、银屑病、舍格伦综合征、桥本氏甲状腺炎、格雷夫斯病、原发性胆汁性肝硬化、韦氏肉芽肿病、肺结核、或移植物抗宿主病)、或Th2淋巴细胞的失调(例如,特应性皮炎、系统性红斑狼疮、特应性哮喘、鼻结膜炎、过敏性鼻炎、欧门氏综合征(Omenn’ssyndrome)、全身性硬化症、或慢性移植物抗宿主病)。一般而言,涉及树突状细胞的病症涉及Th1淋巴细胞或Th2淋巴细胞的失调。在一些实施方案中,自身免疫性病症是T细胞介导的免疫学病症。
在一些实施方案中,所施用的缀合物的量在约0.01mg/kg/剂量至约10mg/kg/剂量的范围内。在一些实施方案中,所施用的缀合物的量在约0.01mg/kg/剂量至约5mg/kg/剂量的范围内。在一些实施方案中,所施用的缀合物的量在约0.05mg/kg/剂量至约5mg/kg/剂量的范围内。在一些实施方案中,所施用的缀合物的量在约0.1mg/kg/剂量至约5mg/kg/剂量的范围内。在一些实施方案中,所施用的缀合物的量在约0.1mg/kg/剂量至约4mg/kg/剂量的范围内。在一些实施方案中,所施用的缀合物的量在约0.05mg/kg/剂量至约3mg/kg/剂量的范围内。在一些实施方案中,所施用的缀合物的量在约0.1mg/kg/剂量至约3mg/kg/剂量的范围内。在一些实施方案中,所施用的缀合物的量在约0.1mg/kg/剂量至约2mg/kg/剂量的范围内。
药物负载量
药物负载量(p)是每个细胞结合剂(例如抗体)的PBD药物的平均数量。在本发明中,其通常为1。然而,任何组合物可包含其中PBD被缀合的抗体和其中PBD未被缀合的抗体。因此,对于组合物,药物负载量(或DAR)可小于1,例如0.75和更高、0.80和更高、0.85和更高、0.90和更高或0.95和更高。
一般合成路线
PBD化合物的合成在以下参考文献中进行了广泛论述,论述内容以引用方式并入本文:
a)WO 00/12508(第14至30页);
b)WO 2005/023814(第3至10页);
c)WO 2004/043963(第28至29页);以及
d)WO 2005/085251(第30至39页)。
合成路线
式II的本发明的化合物:
可以通过以与WO2010/043880、WO2011/130613、WO2011/130616和WO2013/041606中公开的方式类似的方式构建C2连接基团进行合成。在C2连接基团相同的情况下,它们可以并行合成。在C2连接基团不同的情况下,可以类似于先前参考文献中的方式使用正交保护来顺序合成所述基团。
药物缀合物的合成
可通常如Doronina等,Nature Biotechnology,2003,21,778-784)中所述将抗体缀合至药物接头化合物。简单地说,在37℃下用三(羧乙基)膦盐酸盐(TCEP)还原在pH 7.4的含有50mM硼酸钠的PBS中的抗体(4-5mg/mL)。还原链间二硫化物的反应的进展通过与5,5’-二硫代双(2-硝基苯甲酸)的反应进行监测并且使其进行直到实现期望水平的硫醇基/mAb。然后将还原的抗体冷却至0℃并且每抗体用3当量的药物-接头进行烷基化。1小时后,通过添加5当量N-乙酰半胱氨酸将反应淬灭。通过在PD-10柱上进行凝胶过滤来移除淬灭的药物-接头。然后通过0.22μm注射过滤器将ADC无菌过滤。可分别在280nm和329nm处进行光谱分析来确定蛋白质浓度,其中针对在280nm处的药物吸光度的贡献进行校正。可使用尺寸排阻色谱确定抗体聚集的程度,并且可使用RP-HPLC确定剩余的NAC淬灭的药物-接头的水平。
另外优选项
以下优选项可应用于如上所述的本发明的所有方面,或者可以涉及单个方面。优选项可以任何组合被组合在一起。
R6’、R7’、R9’和Y’选自分别与R6、R7、R9和Y相同的基团。在一些实施方案中,R6’、R7’、R9’和Y’分别与R6、R7、R9和Y相同。
二聚体连接
在一些实施方案中,Y和Y’均为O。
在一些实施方案中,R”是不具有取代基的C3-7亚烷基。在这些实施方案的一些中,R”是C3、C5或C7亚烷基。具体地讲,R”可以是C3或C5亚烷基。
在其它实施方案中,R”是下式的基团:
其中r为1或2。
R6至R9
在一些实施方案中,R9是H。
在一些实施方案中,R6选自H、OH、OR、SH、NH2、硝基和卤基,并且可选自H或卤基。在这些实施方案的一些中,R6是H。
在一些实施方案中,R7选自H、OH、OR、SH、SR、NH2、NHR、NRR’以及卤基。在这些实施方案的一些中,R7选自H、OH和OR,其中R选自任选取代的C1-7烷基、C3-10杂环基以及C5-10芳基。R可更优选地为C1-4烷基,它可以是或可以不是被取代的。感兴趣的取代基为C5-6芳基(例如苯基)。7位上特别优选的取代基为OMe和OCH2Ph。其它特别感兴趣的取代基为二甲氨基(即–NMe2);-(OC2H4)qOMe,其中q为0至2;含氮C6杂环基,包括吗啉代基、哌啶子基和N-甲基-哌嗪子基。
这些实施方案和优选项分别适用于R9’、R6’和R7’。
R10和R11
在一些实施方案中,R10和R11一起在它们所结合的氮原子与碳原子之间形成双键。
在一些实施方案中,R11为OH。
在一些实施方案中,R11为OMe。
在一些实施方案中,R11为SOzM,其中z为2或3并且M为一价的药学上可接受的阳离子。
R30和R31
在一些实施方案中,R30和R31一起在它们所结合的氮原子与碳原子之间形成双键。
在一些实施方案中,R31为OH。
在一些实施方案中,R31为OMe。
在一些实施方案中,R31为SOzM,其中z为2或3并且M为一价的药学上可接受的阳离子。
R10、R11、R30和R31
在一些实施方案中,R30和R31分别与R10和R11相同。
R2/R12
在一些实施方案中,R2具有式IIIa。
在R2具有式IIIa时,其中的A可以是苯基或C5-7杂芳基,例如呋喃基、噻吩基和吡啶基。在一些实施方案中,A优选为苯基。
Q2-X可以处于C5-7芳基的任何可用环原子上,但是优选地处于和连接化合物的其余部分的键不相邻的环原子上,即,它优选地在连接化合物的其余部分的键的β或γ位。因此,在C5-7芳基(A)为苯基的情况下,取代基(Q2-X)优选地处于间位或对位,并且更优选处于对位。
在一些实施方案中,Q1为单键。在这些实施方案中,Q2选自单键和-Z-(CH2)n-,其中Z选自单键、O、S和NH并且是1至3。在这些实施方案的一些中,Q2为单键。在其它实施方案中,Q2为-Z-(CH2)n-。在这些实施方案中,Z可以是O或S并且n可以是1或n可以是2。在其它这些实施方案中,Z可以是单键并且n可以是1。
在其它实施方案中,Q1为-CH=CH-。
在其它实施方案中,R2具有式IIIb。在这些实施方案中,RC1、RC2和RC3独立地选自H和未取代的C1-2烷基。在一些优选实施方案中,RC1、RC2和RC3均为H。在其它实施方案中,RC1、RC2和RC3均为甲基。在某些实施方案中,RC1、RC2和RC3独立地选自H和甲基。
X是选自包括以下的清单的基团:O-RL1、S-RL1、CO2-RL1、CO-RL1、NH-C(=O)-RL1、NHNH-RL1、CONHNH-RL1、NRNRL1,其中RN选自包括H和C1-4烷基的组。X可以优选地为:O-RL1、S-RL1、CO2-RL1、NH-C(=O)-RL1或NRNRL1。尤其优选的基团包括:O-RL1、S-RL1和NH-RL1,其中NH-RL1是最优选的基团。
在一些实施方案中,R2具有式IIIc。在这些实施方案中,优选的是,Q为NRN-RL1。在其它实施方案中,Q为O-RL1。在另外的实施方案中,Q为S-RL1。RN优选地选自H和甲基。在一些实施方案中,RN为H。在其它实施方案中,RN为甲基。
在一些实施方案中,R2可以是-A-CH2-X和-A-X。在这些实施方案中,X可以是O-RL1、S-RL1、CO2-RL1、CO-RL1和NH-RL1。在尤其优选的实施方案中,X可以是NH-RL1。
在适当时,以上优选项适用于R12(其中RL1被RG1替代)。
以上优选项也适用于R2’和R12’。
这些实施方案和优选项也适用于本发明的第二方面。
其中
R1a选自甲基和苄基;
RL1、R10、R11、R30和R31如其它地方所定义。
接头(RL1和RG1)
在一些实施方案中,RL1是QX-Z-GLL。
在一些实施方案中,RG1是QX-Z-GL。
QX
在一个实施方案中,QX是氨基酸残基。氨基酸可以是天然氨基酸或非天然氨基酸。
在一个实施方案中,QX选自:Phe、Lys、Val、Ala、Cit、Leu、Ile、Arg和Trp,其中Cit是瓜氨酸。
在一个实施方案中,QX包括二肽残基。二肽中的氨基酸可以是天然氨基酸和非天然氨基酸的任何组合。在一些实施方案中,二肽包含天然氨基酸。在接头是组织蛋白酶不稳定接头的情况下,二肽是组织蛋白酶介导的裂解的作用位点。则二肽是组织蛋白酶的识别位点。
在一个实施方案中,QX选自:
CO-Phe-Lys-NH、
CO-Val-Ala-NH、
CO-Val-Lys-NH、
CO-Ala-Lys-NH、
CO-Val-Cit-NH、
CO-Phe-Cit-NH、
CO-Leu-Cit-NH、
CO-Ile-Cit-NH、
CO-Phe-Arg-NH,以及
CO-Trp-Cit-NH;
其中Cit是瓜氨酸。
优选地,QX选自:
CO-Phe-Lys-NH、
CO-Val-Ala-NH、
CO-Val-Lys-NH、
CO-Ala-Lys-NH、
CO-Val-Cit-NH。
最优选地,QX选自CO-Phe-Lys-NH、CO-Val-Cit-NH和CO-Val-Ala-NH。
感兴趣的其它二肽组合包括:
CO-Gly-Gly-NH、
CO-Pro-Pro-NH,以及
CO-Val-Glu-NH。
可使用其它二肽组合,包括Dubowchik等,Bioconjugate Chemistry,2002,13,855-869(其通过引用并入本文)所述的那些二肽组合。
在一些实施方案中,QX是三肽残基。三肽中的氨基酸可以是天然氨基酸和非天然氨基酸的任何组合。在一些实施方案中,三肽包含天然氨基酸。当接头是组织蛋白酶不稳定接头时,三肽是组织蛋白酶介导的裂解的作用位点。则三肽是组织蛋白酶的识别位点。
在一个实施方案中,在适当时,氨基酸侧链被化学保护。侧链保护基可以是如下文所论述的基团。受保护的氨基酸序列可被酶裂解。例如,包含Boc侧链保护的Lys残基的二肽序列可被组织蛋白裂解。
氨基酸侧链的保护基团是本领域熟知的,并且描述于Novabiochem目录中并且如上所述。
Z
Z是:
其中a=0至5,b=0至16,c=0或1,d=0至5并且e是0或1。
a可以是0、1、2、3、4或5。在一些实施方案中,a是0至3。在这些实施方案的一些中,a是0或1。在另外的实施方案中,a是0。
b可以是0、1、2、3、4、5、6、7、8、9、10、11、12、13、14、15或16。在一些实施方案中,b是0至12。在这些实施方案的一些中,b是0至8,并且可以是0、2、4或8。
c可以是0或1。
d可以是0、1、2、3、4或5。在一些实施方案中,d是0至3。在这些实施方案的一些中,d是1或2。在另外的实施方案中,d是2。
e可以是0或1。
在Z的一些实施方案中,a是0,b是0,c是0,d是5并且e是1。
在Z的一些实施方案中,a是0,c是1,d是2,e是1,并且b可以是0至8。在这些实施方案的一些中,b是0、4或8。
GLL
GLL可选自:
其中Ar代表C5-6亚芳基,例如亚苯基并且X代表C1-4烷基。
在一些实施方案中,GLL选自GLL1-1和GLL1-2。在这些实施方案的一些中,GLL是GLL1-1。
GL
GL可选自
其中Ar代表C5-6亚芳基,例如亚苯基,并且X代表C1-4烷基。
在一些实施方案中,GL选自GL1-1和GL1-2。在这些实施方案的一些中,GL是GL1-1。
在一个特定实施方案中,本发明的第一方面包括式Id的缀合物:
在一个特定实施方案中,本发明的第一方面包括式Ie的缀合物:
其中m是2至8的整数。
在一个特定实施方案中,本发明的第二方面,药物接头(DL)具有式(Id’):
在一个特定实施方案中,本发明的第二方面,药物接头(DL)具有式(Ie’):
其中m是2至8的整数。
在一些实施方案中,每个RL1是不同的。在其它实施方案中,两个RL1是相同的。
在一些实施方案中,每个RG1是不同的。在其它实施方案中,两个RG1是相同的。
具体地,在其中连接基团不同的实施方案中,差异可仅在G基团中,使得连接基团的其余部分是相同的(以使裂解触发物是相同的)。
在本发明的一些实施方案中,C11取代基可相对于相邻基团处于以下立体化学布置:
在其它实施方案中,C11取代基可相对于相邻基团处于以下立体化学布置:
特别感兴趣的化合物包括实施例的那些化合物。
实施例
在铝板上利用荧光指示剂,使用Merck Kieselgel 60 F254硅胶,通过薄层色谱(TLC)监测反应进展。
除非另有说明,否则借助于UV光或碘蒸气来实现TLC的可视化。
利用Merck Kieselgel 60 F254硅胶进行快速色谱。萃取和色谱溶剂购自FisherScientific,U.K.且不经进一步纯化即使用。所有化学品均购自Aldrich、Lancaster或BDH。
1H和13C NMR光谱在Bruker Avance 400光谱仪上获得。耦合常数以赫兹(Hz)给出。化学位移是以从四甲基硅烷往低磁场的每百万分数(ppm)报告。自旋多重性被描述为s(单峰)、bs(宽单峰)、d(双重峰)、t(三重峰)、q(四重峰)、p(五重峰)和m(多重峰)。
LC/MS条件如下:
利用具有Shimadzu LCMS-2020四极MS的Shimadzu Nexera系列LC/MS,并借助于电喷射离子化,来获得LCMS数据。流动相A-0.1%甲酸的水溶液。流动相B-0.1%甲酸的乙腈溶液。
LCMS 3min:初始组成为5%B,保持0.25min,然后经2min时间段从5%B增加至100%B。将所述组成在100%B下保持0.50min,然后在0.05分钟内回到5%B,并且保持0.05min。总梯度运行时间等于3min。流速0.8mL/min。波长检测范围:190至800nm。烘箱温度:50℃。柱:Waters Acquity UPLC BEH Shield RP18 1.7μm 2.1x50mm。
LCMS 15min:初始组成为5%B,保持1min,然后经9min时间段从5%B增加至100%B。将所述组成在100%B下保持2min,然后在0.10分钟内回到5%B,并且在5%B下保持3min。总梯度运行时间等于15min。流速0.6mL/min。波长检测范围:190至800nm。烘箱温度:50℃。柱:ACE Excel 2 C18-AR,2μ,3.0x 100mm。
实施例1
化合物(1)是WO2010/043880的化合物8a。
a)(11aS,11a'S)-8,8'-(丙烷-1,3-二基双(氧基))双(2-(4-氨基苯基)-7-甲氧
基-10-((2-(三甲基甲硅烷基)乙氧基)甲基)-1,11a-二氢-5H-苯并[e]吡咯并[1,2-a][1,
4]二氮杂
-5,11(10H)-二酮)(2)
将Pd(PPh3)4(164mg,0.14mmol)添加到双烯醇三氟甲磺酸酯1(4g,3.6mmol)、硼酸酯(1.96g,8.9mmol)和Na2CO3(3.41g,32.2mmol)在甲苯/MeOH/H2O(80mL)的2:1:1混合物中的经搅拌混合物中。在氮气氛下将反应混合物在30℃下搅拌1h,所述时间过后,所有的双烯醇三氟甲磺酸酯1均已反应。接着将反应混合物蒸发至干燥,然后将残余物吸收于CH2Cl2(150mL)中并且用H2O(2x 75mL)、盐水(75mL)洗涤,干燥(MgSO4),过滤并且减压蒸发以提供粗产物。通过快速色谱(梯度洗脱:1:1v/v己烷/EtOAc至100%EtOAc)进行的纯化得到为深橙色泡沫状产物2(3.08g,86%)。LC/MS 1.88min(ES+)m/z=1003.30[M+H]+。
b)((2S,2'S)-(((2S,2'S)-((((11aS,11a'S)-(丙烷-1,3-二基双(氧基))双(7-甲
氧基-5,11-二氧代-10-((2-(三甲基甲硅烷基)乙氧基)甲基)-5,10,11,11a-四氢-1H-苯并
[e]吡咯并[1,2-a][1,4]二氮杂
-8,2-二基))双(4,1-亚苯基))双(氮烷二基))双(1-氧代
丙烷-1,2-二基))双(氮烷二基))双(3-甲基-1-氧代丁烷-1,2-二基))二氨基甲酸二烯丙基
酯(3)
向2(2.71g,2.7mmol)在无水CH2Cl2(40mL)中的溶液中添加受保护的肽(1.61g,5.9mmol)和EEDQ(1.46mg,5.9mmol)。在室温下搅拌混合物,直到反应完全(16h)。然后将反应混合物用H2O(2x 50mL)、盐水(50mL)洗涤,干燥(MgSO4),过滤并减压蒸发以提供粗产物。通过快速色谱(梯度洗脱:100%CHCl3至93/7CHCl3/MeOH)进行的纯化得到为黄色泡沫状产物3。LC/MS 1.90min(ES+)m/z=1511.65[M+H]+。
c)(2S,2'S)-N,N'-((2S,2'S)-((((11aS,11a'S)-(丙烷-1,3-二基双(氧基))双
(7-甲氧基-5,11-二氧代-10-((2-(三甲基甲硅烷基)乙氧基)甲基)-5,10,11,11a-四氢-
1H-苯并[e]吡咯并[1,2-a][1,4]二氮杂
-8,2-二基))双(4,1-亚苯基))双(氮烷二基))双
(1-氧代丙烷-1,2-二基))双(2-氨基-3-甲基丁酰胺)(4)
将吡咯烷(1.1mL,13mmol)和Pd(PPh3)4(183mg,0.16mmol)添加到3(假设100%,2.69mmol)在无水CH2Cl2(40mL)中的溶液中。将反应混合物用CH2Cl2(60mL)稀释并且用H2O(2x 100mL)和盐水(100mL)洗涤有机相。将有机相经MgSO4干燥、过滤并在减压下通过旋转蒸发移除过量溶剂。通过快速色谱(梯度洗脱:100%CHCl3至93/7CHCl3/MeOH)进行的纯化得到黄色泡沫状产物4(1.5g,41%收率。LC/MS 1.33min(ES+)m/z=1344.40([M+H]+。
d)N,N'-((2S,2'S)-(((2S,2'S)-((((11aS,11a'S)-(丙烷-1,3-二基双(氧基))双
(7-甲氧基-5-氧代-5,11a-二氢-1H-苯并[e]吡咯并[1,2-a][1,4]二氮杂
-8,2-二基))双
(4,1-亚苯基))双(氮烷二基))双(1-氧代丙烷-1,2-二基))双(氮烷二基))双(3-甲基-1-氧
代丁烷-1,2-二基))双(6-(2,5-二氧代-2,5-二氢-1H-吡咯-1-基)己酰胺)(5)
在-78℃、氩气氛下,将Super-(0.186mL,1M,在THF中)的溶液逐滴添加到SEM-二内酰胺4(100mg,0.074mmol)在无水THF(5mL)中的溶液中。添加经5分钟完成,以便保持反应混合物的内部温度稳定。40分钟后,将等分试样用水淬灭以进行LC/MS分析,其显示反应完全。向反应混合物中添加水(20mL)并且移除冷浴。用CH2Cl2(3x 50mL)萃取有机层并且将合并的有机物用盐水(100mL)洗涤、用MgSO4干燥,过滤并且在减压下通过旋转蒸发移除溶剂。在用氩吹扫的圆底烧瓶中,将粗产物溶解于无水CH2Cl2中。添加马来酰亚胺己酸(31.4mg,0.148mmol)和EDCI.HCl(28.5mg,0.148mmol)并且将混合物在室温下搅拌。几个小时后,添加更多的马来酰亚胺己酸(5mg)和EDCI.HCl(5mg)以推动反应完全。通过反相HPLC纯化粗物质以得到80%纯度的产物5(2.2mg,2%收率)。LC/MS 1.46min(ES+)m/z=1438.25[M+H]+;LC/MS15min 6.20min(ES+)m/z=1438.20[M+H]+。
实施例2
N,N'-((2S,2'S)-(((2S,2'S)-((((11aS,11a'S)-(丙烷-1,3-二基双(氧基))双
(7-甲氧基-5-氧代-5,11a-二氢-1H-苯并[e]吡咯并[1,2-a][1,4]二氮杂
-8,2-二基))
双(4,1-亚苯基))双(氮烷二基))双(1-氧代丙烷-1,2-二基))双(氮烷二基))双(3-甲基-1-
氧代丁烷-1,2-二基))双(1-(3-(2,5-二氧代-2,5-二氢-1H-吡咯-1-基)丙酰胺基)-3,6,9,
12,15,18,21,24-八氧杂二十七烷-27-酰胺)(6)
在-78℃、氩气氛下,将Super-(0.37mL,1M,在THF中)的溶液逐滴添加到SEM-二内酰胺4(200mg,0.15mmol)在无水THF(5mL)中的溶液中。添加经5分钟完成,以便保持反应混合物的内部温度稳定。40分钟后,将等分试样用水淬灭以进行LC/MS分析,其显示反应完全。向反应混合物中添加水(20mL)并且移除冷浴。用CH2Cl2(3x 50mL)萃取有机层并且将合并的有机物用盐水(100mL)洗涤、用MgSO4干燥,过滤并且在减压下通过旋转蒸发移除溶剂。在用氩吹扫的圆底烧瓶中,将粗产物溶解于无水CH2Cl2中。添加Mal-dPEG8-OH酸(31.4mg,0.148mmol)和EDCI.HCl(28.5mg,0.148mmol)并且将混合物在室温下搅拌,直到反应完全。通过反相HPLC纯化粗物质以得到82%纯度的产物6(37mg,11%收率)。LC/MS1.38min(ES+)m/z=1101.05[M+2H]2+;LC/MS15min 5.84min(ES+)m/z=1101.05[M+2H]2+。
赫塞汀-Flexmab和NIP228-Flexmab抗体的产生
概要
细胞系SKBR-3(HER2+,1.5×106个受体/细胞)、MDA-MB-453(HER2+,7.7×104个受体/细胞)和MCF-7(HER2-)获自ATCC并且使用制造商推荐的培养基(SKBR-3:McCoys 5A+10%FBS,MDA-MB-453:DMEM+10%FBS,以及MCF-7:DMEM+10%FBS)维持在T175组织培养烧瓶(Corning)中。将用于转染的293F细胞(Invitrogen)维持在293F Freestyle培养基(Invitrogen)中。将SKBR-3、MDA-MB-453和MCF-7细胞在具有5%CO2的37℃培养箱中培养。将293F细胞在具有8%CO2且在120rpm下旋转的摇瓶(2L,Corning)中,在37℃下培养。所有试剂购自Sigma Aldrich、VWR或JT Baker,除非另外指明,并且不经另外的纯化即使用。
赫塞汀-Flexmab和NIP228-Flexmab抗体的设计和构建
使用赫塞汀野生型抗体作为模板对赫塞汀-Flexmab进行工程化。赫塞汀-Flexmab的轻链由两个突变F118C和C214V组成,而重链含有三个突变L124C、C216V和C225V(参见图1和图2)。轻链中的F118C突变与重链中的L124C突变形成二硫键。此工程化二硫化物不是溶剂暴露的,而是用于保留轻链与重链之间的共价连键。C222铰链半胱氨酸保持不被修饰并且用作与基于pBD的药物接头的位点特异性缀合的位置。赫塞汀-Flexmab的轻链和重链序列针对哺乳动物表达进行了密码子优化并且购自GeneArt(Life Technologies)。利用标准分子生物学技术,使用BssHII/NheI位点(轻链)和SalI/NotI位点(重链)将经优化的赫塞汀-Flexmab构建体亚克隆到MedImmune专有的哺乳动物表达载体中,所述表达载体含有用于分泌的IgG轻链信号肽和用于重组表达的巨细胞病毒启动子。完整的哺乳动物表达质粒pOE-赫塞汀-Flexmab通过DNA测序进行确认。阴性对照NIP228-Flexmab抗体如针对赫塞汀-Flexmab所述的那样,同时使用野生型NIP228抗体(MedImmune专有)作为模板生成。
赫塞汀-Flexmab和NIP228-Flexmab抗体的表达和纯化
赫塞汀-Flexmab和NIP228-Flexmab抗体的表达和纯化根据先前公开的方法(Dimasi,N.等,Journal of Molecular Biology,2009,393,672-692;DOI:10.1016/j.jmb.2009.08.032)进行。在瞬时293F表达和蛋白A纯化之后,在4℃下使用Slide-A-Lyzer渗析盒(10kDa MWCO,Thermo)将抗体配制到缀合缓冲液(1X PBS,0.1mM EDTA,pH 7.2)中并且使用Vivaspin浓缩器(10kDa MWCO,GE Healthcare)浓缩至8.0mg/mL(赫塞汀-Flexmab)和5.52mg/mL(NIP228-Flexmab)。最终浓度使用Nanodrop分光光度计(A280,Thermo)确定。赫塞汀-Flexmab和NIP228-Flexmab的6天后的瞬时表达收率分别为500mg/L和150mg/L。
缀合
按照Dimasi,N.等,Molecular Pharmaceutics,2017,14,1501-1516(DOI:10.1021/acs.molpharmaceut.6b00995)中所述的方法产生被工程化为具有插入在239位与240位之间的半胱氨酸的赫塞汀和R347抗体。
使用化合物6对以下抗体进行缀合:Herceptin-C239i;和R347-C239i,其中抗体浓度为4.0mg/ml,化合物6为6当量,运行时间为1小时。观察到形成DAR=1物类。
上文提及的所有文件和其它参考文献均以引用方式并入本文。
Claims (90)
1.一种式I的缀合物:
其中
Ab为在每条重链上具有至少一个自由缀合位点的经修饰抗体
R2具有式IIIa、式IIIb或式IIIc:
其中A是C5-7芳基,并且
(i)Q1是单键,并且Q2选自单键和-Z-(CH2)n-,其中Z选自单键、O、S和NH,并且n为1至3;或
(ii)Q1是-CH=CH-,并且Q2是单键;
其中;
RC1、RC2和RC3独立地选自H和未取代的C1-2烷基;
其中Q选自O-RL1、S-RL1和NRN-RL1,并且RN选自H、甲基和乙基
RL1是用于与所述抗体(Ab)连接的接头;
R2’选自与R2相同的基团并且与相同的抗体连接;
R6和R9独立地选自H、R、OH、OR、SH、SR、NH2、NHR、NRR’、硝基、Me3Sn以及卤基;
其中R和R’独立地选自任选取代的C1-12烷基、C3-20杂环基以及C5-20芳基;
R7选自H、R、OH、OR、SH、SR、NH2、NHR、NRR’、硝基、Me3Sn以及卤基;
R″为C3-12亚烷基,链可间杂有一个或多个杂原子,例如O、S、NRN2(其中RN2为H或C1-4烷基),和/或芳族环,例如苯或吡啶;
Y和Y'选自O、S或NH;
R10和R11一起在它们所结合的氮原子与碳原子之间形成双键,或;
R10是H并且R11选自OH、ORA和SOzM;
R30和R31一起在它们所结合的氮原子与碳原子之间形成双键,或;
R30是H并且R31选自OH、ORA和SOzM;
R6’、R7’和R9’选自分别与R6、R7和R9相同的基团。
2.根据权利要求1所述的缀合物,其中Y和Y’均为O。
3.根据权利要求1或权利要求2所述的缀合物,其中R”为C3-7亚烷基。
5.根据权利要求1至4中任一项所述的缀合物,其中R9为H。
6.根据权利要求1至5中任一项所述的缀合物,其中R6为H。
7.根据权利要求1至6中任一项所述的缀合物,其中R7选自H、OH和OR。
8.根据权利要求7所述的缀合物,其中R7为C1-4烷氧基。
9.根据权利要求1至8中任一项所述的缀合物,其中R10和R11一起在它们所结合的氮原子与碳原子之间形成双键。
10.根据权利要求1至8中任一项所述的缀合物,其中R10为H并且R11为OH。
11.根据权利要求1至8中任一项所述的缀合物,其中R10为H并且R11为OMe。
12.根据权利要求1至8中任一项所述的缀合物,其中R10为H并且R11为SOzM,其中z为2或3并且M为一价的药学上可接受的阳离子。
13.根据权利要求1至12中任一项所述的缀合物,其中R30和R31一起在它们所结合的氮原子与碳原子之间形成双键。
14.根据权利要求1至12中任一项所述的缀合物,其中R30为H并且R31为OH。
15.根据权利要求1至12中任一项所述的缀合物,其中R30为H并且R31为OMe。
16.根据权利要求1至12中任一项所述的缀合物,其中R30为H并且R31为SOzM,其中z为2或3并且M为一价的药学上可接受的阳离子。
17.根据权利要求1至16中任一项所述的缀合物,其中R2具有式IIIa并且A是苯基。
18.根据权利要求1至17中任一项所述的缀合物,其中R2具有式IIIa并且Q2-X优选地处于和连接化合物的其余部分的键不相邻的环原子上。
19.根据权利要求1至18中任一项所述的缀合物,其中R2具有式IIIa并且Q1为单键。
20.根据权利要求19所述的缀合物,其中Q2为单键。
21.根据权利要求19所述的缀合物,其中Q2为Z-(CH2)n-,其中Z可以是O或S并且n为1或2。
22.根据权利要求1至18中任一项所述的缀合物,其中R2具有式IIIa并且Q1为-CH=CH-。
23.根据权利要求1至16中任一项所述的缀合物,其中R2具有式IIIb,并且RC1、RC2和RC3均为H。
24.根据权利要求1至16中任一项所述的缀合物,其中R2具有式IIIb,并且RC1、RC2和RC3均为甲基。
25.根据权利要求1至16中任一项所述的缀合物,其中R2具有式IIIb,并且RC1、RC2和RC3独立地选自H和甲基。
26.根据权利要求1至23中任一项所述的缀合物,其中X选自由以下组成的组:O-RL1、S-RL1、CO2-RL1、NH-C(=O)-RL1和NRNRL1。
27.根据权利要求24所述的缀合物,其中X选自由O-RL1、S-RL1和NH-RL1组成的组。
28.根据权利要求25所述的缀合物,其中X为NH-RL1。
29.根据权利要求1至16中任一项所述的缀合物,其中R2具有式III,并且Q为NRN-RL1。
30.根据权利要求27所述的缀合物,其中RN为H。
31.根据权利要求27所述的缀合物,其中RN为甲基。
32.根据权利要求1至16中任一项所述的缀合物,其中R2具有式III,并且Q为O-RL1或S-RL1。
33.根据权利要求1至30中任一项所述的缀合物,其中R2’、R6’、R7’、R9’、R30、R31和Y’分别与R2、R6、R7、R9、R10、R11和Y相同。
36.根据权利要求33所述的缀合物,其中Qx是选自Phe、Lys、Val、Ala、Cit、Leu、Ile、Arg和Trp的氨基酸残基。
37.根据权利要求33所述的缀合物,其中Qx是选自以下的二肽残基:
CO-Phe-Lys-NH、
CO-Val-Ala-NH、
CO-Val-Lys-NH、
CO-Ala-Lys-NH、
CO-Val-Cit-NH、
CO-Phe-Cit-NH、
CO-Leu-Cit-NH、
CO-Ile-Cit-NH、
CO-Phe-Arg-NH,以及
CO-Trp-Cit-NH。
38.根据权利要求34所述的缀合物,其中QX选自CO-Phe-Lys-NH、CO-Val-Cit-NH和CO-Val-Ala-NH。
39.根据权利要求33所述的缀合物,其中Qx是三肽残基。
40.根据权利要求1至36中任一项所述的缀合物,其中a为0至3。
41.根据权利要求37所述的缀合物,其中a是0。
42.根据权利要求1至38中任一项所述的缀合物,其中b为0至12。
43.根据权利要求39所述的缀合物,其中b是0至8。
44.根据权利要求1至40中任一项所述的缀合物,其中d是0至3。
45.根据权利要求41所述的缀合物,其中d是2。
46.根据权利要求1至36中任一项所述的缀合物,其中a是0,b是0,c是0,d是5并且e是1。
47.根据权利要求1至36中任一项所述的缀合物,其中0,c是1,d是2,e是1,并且b可以是0至8。
48.根据权利要求44所述的缀合物,其中b是0、4或8。
49.根据权利要求1至45中任一项所述的缀合物,其中Ar为亚苯基。
50.根据权利要求1至46中任一项所述的缀合物,其中GLL选自GLL1-1和GLL1-2。
51.根据权利要求47所述的缀合物,其中GLL是GLL1-1。
54.根据权利要求1至50中任一项所述的缀合物,其中在每条重链上具有至少一个自由缀合位点的所述经修饰抗体为IgG1、IgG2、IgG3或IgG4抗体。
55.根据权利要求51所述的缀合物,其中在每条重链上具有至少一个自由缀合位点的所述经修饰抗体为人抗体。
56.根据权利要求51所述的缀合物,其中在每条重链上具有至少一个自由缀合位点的所述经修饰抗体为人源化抗体。
57.根据权利要求51至53中任一项所述的缀合物,其中缺乏硫醇基团的氨基酸残基已被天然链间半胱氨酸残基取代。
58.根据权利要求54所述的缀合物,其在每条重链中包括至少一个另外的包含适于与接头缀合的反应性基团的氨基酸残基的取代。
59.根据权利要求55所述的缀合物,其中另外取代的氨基酸为半胱氨酸或非天然氨基酸。
61.根据权利要求1至57中任一项所述的缀合物,其用于疗法中。
62.一种药物组合物,其包含根据权利要求1至57中任一项所述的缀合物、药学上可接受的稀释剂、载体或赋形剂。
63.根据权利要求1至57中任一项所述的缀合物或根据权利要求59所述的药物组合物,其用于治疗受试者的增殖性疾病。
64.根据权利要求60所述使用的缀合物,其中所治疗的疾病为癌症。
65.根据权利要求1至57中任一项所述的缀合物或根据权利要求59所述的药物在医学治疗的方法中的用途。
66.一种医学治疗的方法,其包括向患者施用根据权利要求59所述的药物组合物。
67.根据权利要求63所述的方法,其中医学治疗的所述方法是用于治疗癌症。
68.根据权利要求64所述的方法,其中与所述缀合物组合地向所述患者施用化学治疗剂。
69.根据权利要求1至57中任一项所述的缀合物在制造用于治疗增殖性疾病的药物的方法中的用途。
70.一种治疗具有增殖性疾病的哺乳动物的方法,其包括施用有效量的根据权利要求1至57中任一项所述的缀合物或根据权利要求59所述的药物组合物。
71.一种式II的化合物:
及其盐和溶剂合物,
其中R6、R7、R9、R10、R11、Y、R”、Y’、R6’、R7’、R9’、R30和R31如权利要求1至31中任一项所定义;
R12具有式IVa、式IVb或式IVc:
其中A是C5-7芳基,并且
(i)Q1是单键,并且Q2选自单键和-Z-(CH2)n-,其中Z选自单键、O、S和NH,并且n为1至3;或
(ii)Q1是-CH=CH-,并且Q2是单键;
其中;
RC1、RC2和RC3独立地选自H和未取代的C1-2烷基;
其中Q*选自O-RG1、S-RG1和NRN-RG1,并且RN选自H、甲基和乙基
RG1是用于与抗体连接的接头;
R12’选自与R12相同的基团。
73.根据权利要求69所述的化合物,其中Qx是选自Phe、Lys、Val、Ala、Cit、Leu、Ile、Arg和Trp的氨基酸残基。
74.根据权利要求69所述的化合物,其中Qx是选自以下的二肽残基:
CO-Phe-Lys-NH、
CO-Val-Ala-NH、
CO-Val-Lys-NH、
CO-Ala-Lys-NH、
CO-Val-Cit-NH、
CO-Phe-Cit-NH、
CO-Leu-Cit-NH、
CO-Ile-Cit-NH、
CO-Phe-Arg-NH,以及
CO-Trp-Cit-NH。
75.根据权利要求71所述的化合物,其中QX选自CO-Phe-Lys-NH、CO-Val-Cit-NH和CO-Val-Ala-NH。
76.根据权利要求69所述的化合物,其中Qx是三肽残基。
77.根据权利要求69至36中任一项所述的化合物,其中a是0至3。
78.根据权利要求37所述的化合物,其中a是0。
79.根据权利要求69至75中任一项所述的化合物,其中b是0至12。
80.根据权利要求76所述的化合物,其中b是0至8。
81.根据权利要求69至77中任一项所述的化合物,其中d是0至3。
82.根据权利要求78所述的化合物,其中d是2。
83.根据权利要求69至73中任一项所述的化合物,其中a是0,b是0,c是0,d是5并且e是1。
84.根据权利要求69至73中任一项所述的化合物,其中0,c是1,d是2,e是1,并且b可以是0至8。
85.根据权利要求81所述的化合物,其中b是0、4或8。
86.根据权利要求69至82中任一项所述的化合物,其中Ar为亚苯基。
87.根据权利要求69至83中任一项所述的化合物,其中GL选自GL1-1和GL1-2。
88.根据权利要求84所述的化合物,其中GL为GL1-1。
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PCT/EP2018/081079 WO2019096788A1 (en) | 2017-11-14 | 2018-11-13 | Pyrrolobenzodiazepine conjugates |
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