CN107652219A - 四马来酰亚胺型连接子及其应用 - Google Patents
四马来酰亚胺型连接子及其应用 Download PDFInfo
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- CN107652219A CN107652219A CN201710691056.XA CN201710691056A CN107652219A CN 107652219 A CN107652219 A CN 107652219A CN 201710691056 A CN201710691056 A CN 201710691056A CN 107652219 A CN107652219 A CN 107652219A
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- C07D207/44—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having three double bonds between ring members or between ring members and non-ring members
- C07D207/444—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having three double bonds between ring members or between ring members and non-ring members having two doubly-bound oxygen atoms directly attached in positions 2 and 5
- C07D207/448—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having three double bonds between ring members or between ring members and non-ring members having two doubly-bound oxygen atoms directly attached in positions 2 and 5 with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms, e.g. maleimide
- C07D207/452—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having three double bonds between ring members or between ring members and non-ring members having two doubly-bound oxygen atoms directly attached in positions 2 and 5 with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms, e.g. maleimide with hydrocarbon radicals, substituted by hetero atoms, directly attached to the ring nitrogen atom
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- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
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- C07K7/04—Linear peptides containing only normal peptide links
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Landscapes
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- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
本发明涉及四马来酰亚胺型连接子及其应用。特别地,本发明涉及式I所示的化合物,以及其作为连接子在制备抗体药物偶联物中的用途。通过该连接子制得的抗体药物偶联物具有较高的均一性和稳定性,可以有效用于肿瘤等各种疾病的治疗。式I中各基团的定义与说明书中相同。
Description
技术领域
本发明涉及一种新型四马来酰亚胺型连接子以及由该连接子制备的抗体药物偶联物,以及该抗体药物偶联物在治疗肿瘤或其它疾病中的用途。
背景技术
抗体药物偶联物(Antibody-Drug Conjugates,ADCs)是一类新型靶向治疗药物,主要应用于癌症、自身免疫性疾病等治疗领域。其基本设计思想最早源于保罗·埃尔利希(Paul Ehrlich)于1913年首次提出的“魔术子弹(magic bullet)”及药物靶向输送(drugtargeting)概念,即通过适当载体将药物靶向输送到疾患部位。然而,受制于抗体及高活性细胞毒性药物技术的制约,直到2000年第一个用于治疗急性髓样白血病(AML)的抗体药物偶联物(MylotargTM)才被FDA批准上市。近期,西雅图基因公司(Seattle Genetics)研制的用于治疗霍奇金淋巴瘤(HL)/复发性间变性大细胞淋巴瘤(ALCL)的新药AdcetrisTM(2011)及健泰科生物技术公司(Genentech)研制的用于治疗乳腺癌的新药KadcylaTM(2013)相继通过FDA批准上市,则标志着抗体药物偶联物在肿瘤治疗领域的应用进入了快速发展阶段。
抗体药物偶联物通常由三部分组成:抗体或抗体类配体,高活性细胞毒性药物,和将配体与细胞毒性药物偶联起来的连接子。其作用机制如下:抗体或抗体类配体特异性地识别细胞表面抗原并与之结合;形成的结合物以内吞的方式进入细胞内,同时将高活性细胞毒性药物带入;抗体被酶解或连接子自身断裂,高活性细胞毒性药物以适当的活性成分形式释放出来,杀死目标细胞。
在传统的抗体药物偶联物结构中,高活性的细胞毒性药物通常是通过双官能团连接子连接在抗体表面的赖氨酸残基,或者链间二硫键还原得到的半胱氨酸残基上,最佳的药物/抗体比值(Drug/Antibody Ratio,DAR)为2-4。选用赖氨酸残基作为偶联位点时,由于抗体表面分布着大量的赖氨酸残基(超过80个)以及偶联反应的非选择性,因而导致偶联数目和位点的不确定性,进而导致生成的抗体药物偶联物的严重非均一性。例如,KadcylaTM的平均DAR值为3.5,DAR值分布(DAR Distribution)为0-8(Rapid Commun.MassSpectrom.2005,19,1806-1814)。同样,当选用半胱氨酸残基作为偶联位点时,尽管抗体的链间二硫键只有四个(IgG1),但为达到最佳平均DAR值(2-4)的要求,需要部分还原链间二硫键(Bioconjugate Chem.2005,16,1282-1290)。由于现有的还原剂(DTT,TCEP等)无法选择性地还原链间二硫键,因此生成的偶联物也不是均一的产物,而是由多种组分组成,其主要组分的DAR值为0、2、4、6、8。同时,对应每一种特定DAR值的组分,都存在由于连接位点不同而形成的异构体,从而导致一定的非均一性。抗体药物偶联物产品的非均一性可以导致各成员组分间药物动力学性质、效价以及毒性的不均一性。例如,具有较高DAR值的组分在体内被清除得更快,并导致更高的毒性(Bioconjugate Chem.2011,22,1994-2004)。
针对上述现有技术中制备抗体药物偶联物的缺陷,需要开发新的连接子技术,从而达到定点偶联的目的。
发明内容
本发明旨在提供一种可用于化学偶联方法制备抗体药物偶联物的新型四马来酰亚胺型连接子,以及由该新型连接子制备的抗体药物偶联物,及其在治疗肿瘤等各种疾病中的用途。
发明人经过多年的深入研究,开发了新型的四马来酰亚胺型连接子。这类连接子结构中含有四个马来酰亚胺基团,可以同时偶联抗体链间的半胱氨酸残基或其它氨基酸残基。四马来酰亚胺型连接子与抗体偶联后的产品不仅平均DAR值~2,即平均每个抗体分子上面偶联2个药物分子,而且主要组分为DAR~2的组分(可达90%以上)。这种连接子技术具有普适性,可以应用到绝大多数抗体如IgG1上,因而具有广阔的应用前景。
因此,本发明第一方面提供一种如式I所示的化合物或其药学上可接受的盐,
其中,
P、Q各自独立地选自CR10、N或芳基;
S、T各自独立地选自C=O或O;
X、Y各自独立地选自-C(O)N(R11)-、-N(R12)C(O)-或-O-;
Z选自CR13、N或芳基;
U选自C=O或O;
J选自-COOH、-OH、或-NHR14;
h、i、j、k、l、m、p、q、s、t、x、y、u和w各自独立地选自0或1;
R1、R2、R3、R4、R5、R6、R7、R8和R9各自独立地选自C1-C6亚烷基、或骨架内含O的C1-C6亚烷基;
R10、R11、R12、R13和R14各自独立地选自H或C1-C6烷基。
在本发明一个优选的实施方案中,根据本发明所述的式I所示的化合物或其药学上可接受的盐,其中,
P、Q各自独立地选自CR10或N;
R10选自H或C1-C6烷基。
在本发明另一个优选的实施方案中,根据本发明所述的式I所示的化合物或其药学上可接受的盐,其中,
X、Y各自独立地选自-C(O)N(R11)-;
x和y各自独立地选自0或1;
R11选自H或C1-C6烷基。
在本发明另一个优选的实施方案中,根据本发明所述的式I所示的化合物或其药学上可接受的盐,其中,
Z选自CR13、N或C6-C10芳基优选苯基;
R13选自H或C1-C6烷基。
在本发明另一个优选的实施方案中,根据本发明所述的式I所示的化合物或其药学上可接受的盐,其中,
R1、R2、R3和R4各自独立地选自C1-C6亚烷基;
h、i、j和k各自独立地选自0或1。
在本发明另一个优选的实施方案中,根据本发明所述的式I所示的化合物或其药学上可接受的盐,其中,
S、T各自独立地选自C=O或O;
R5、R6各自独立地选自C1-C6亚烷基;
l、m各自独立地选自0或1;
s、t各自独立地选自0或1。
在本发明另一个优选的实施方案中,根据本发明所述的式I所示的化合物或其药学上可接受的盐,其中,
R7、R8各自独立地选自C1-C6亚烷基、或骨架内含O的C1-C6亚烷基;
p、q各自独立地选自0或1。
在本发明另一个优选的实施方案中,根据本发明所述的式I所示的化合物或其药学上可接受的盐,其中,
U选自C=O或O;
R9选自C1-C6亚烷基;
u和w各自独立地选自0或1。
在本发明另一个优选的实施方案中,根据本发明所述的的式I所示的化合物或其药学上可接受的盐,其中,J选自-COOH、OH或NH2。
本发明典型的式I所示的化合物,包括但不限于:
或其药学上可接受的盐。
本发明进一步提供一种如式II所示的化合物,
V-A-D
II
其中,
V为根据权利要求1至10中任一项所述的式I所示的化合物;
A是任选其它连接子部分;
D是药物分子部分;
其中V通过末端基团J与连接子A或药物D的一端反应相连接。
本发明进一步提供一种如式III所示的抗体药物偶联物,
其中,
L是抗体或抗体片段;
V是为根据权利要求1至10中任一项所述的式I所示的化合物;
A是任选其它连接子部分;
D是药物分子部分;
n为1至4的整数;
其中V通过末端基团J与连接子A或药物分子D的一端反应相连接,通过四个马来酰亚胺部分与L中半胱氨酸或其它氨基酸残基反应相连接。
在本发明一个优选的实施方案中,根据本发明所述的式III所示的抗体药物偶联物,其中,所述A是除四马来酰亚胺连接子以外的任意其它连接子,包括可断裂连接子或不可断裂连接子。
在本发明另一个优选的实施方案中,根据本发明所述的式III所示的抗体药物偶联物,其中,所述A的结构如式C–Ee–Ff或式Gg所示,
其中,
C是可断裂连接子;
E和F是自杀式连接子;
e和f各自独立地为0至5的整数;
G是不可断裂连接子;
g是0至5的整数。
在本发明另一个优选的实施方案中,根据本发明所述的式III所示的抗体药物偶联物,其为式IV所示的抗体药物偶联物:
其中,
L是抗体或抗体片段;
A是除四马来酰亚胺连接子以外的任意其它连接子,包括可断裂连接子或不可断裂连接子;
D是药物分子部分;
四个马来酰亚胺基团的一端同时偶联到同一抗体或抗体片段上;
P、Q各自独立地选自CR10、N或芳基;
S、T各自独立地选自C=O或O;
X、Y各自独立地选自-C(O)N(R11)-、-N(R12)C(O)-或-O-;
Z选自CR13、N或芳基;
U选自C=O或O;
J’选自C=O、O、或NR14;
h、i、j、k、l、m、p、q、s、t、x、y、u和w各自独立地选自0或1;
R1、R2、R3、R4、R5、R6、R7、R8和R9各自独立地选自C1-C6亚烷基、或骨架内含O的C1-C6亚烷基;
R10、R11、R12、R13和R14各自独立地选自H或C1-C6烷基。
在本发明另一个优选的实施方案中,根据本发明所述的式III所示的抗体药物偶联物,其中,所述抗体为针对细胞表面受体和肿瘤相关抗原的抗体。
在本发明另一个优选的实施方案中,根据本发明所述的式III所示的抗体药物偶联物,其中,所述抗体为IgG1抗体。
在本发明另一个优选的实施方案中,根据本发明所述的式III所示的抗体药物偶联物,其中,所述药物为细胞毒性药物、治疗自身免疫疾病的药物和抗炎症的药物。
本发明进一步提供一种药物组合物,其含有根据本发明所述的式III所示的抗体药物偶联物以及药学上可接受的载体。
本发明进一步提供根据本发明所述的式I所示的化合物作为连接子在制备抗体药物偶联物中的用途。
本发明进一步提供根据本发明所述的式III所示的抗体药物偶联物或含有其的药物组合物在制备治疗癌症、自身免疫性疾病和炎症性疾病的药物中的用途。
发明详述
本发明提供的四马来酰亚胺型连接子包含四个马来酰亚胺单元和第五个偶联基团。四个马来酰亚胺单元用于交联抗体链间的半胱氨酸残基(还原后)或其它氨基酸残基,而第五个偶联基团用于与小分子药物或药物-连接子单元偶联,如下方案1所示:
方案1
所产生的抗体药物偶联物可用于靶向输送药物到达目标细胞群体,例如肿瘤细胞。抗体药物偶联物可以特异性的与细胞表面蛋白结合,所产生的结合物随即被细胞内吞。在细胞内,药物以活性药物形式释放出来产生功效。
本发明所述的抗体包括嵌合抗体、人源化抗体、人抗体;可与抗原结合的抗体片段;或者抗体Fc融合蛋白;或者蛋白。
本发明所述的药物是高活性药物,包括但不局限于,美登素类(Maytansinoids)、耳抑素肽类(Auristatins)、卡奇霉素类(Calicheamicins)、阿霉素类(doxorubicins)、苯并二吡咯类抗生素类(Duocarmycins和CC-1065)、吡咯并苯二氮卓二聚体类(PBD dimers),tubulysin类等。在某些情况下,药物可以是聚乙二醇。
药物或药物-任选其它连接子单元通过四马来酰亚胺型连接子与抗体偶联,生成链间交联的偶联物。与传统的抗体药物偶联物相比,应用本发明方法制备的抗体药物偶联物的主要组分是DAR~2的组分,且DAR值分布更窄,从而大幅提升了产品均一性及药理学特性均一性。
抗体
如本文所用,“抗体”或“抗体单元”在其所属的范围内,包括抗体结构的任何部分。这一单元可以结合、反应性关联、或者络合一个受体、抗原、或者靶向细胞群体具有的其他受体单元。抗体可以是任何蛋白或蛋白类分子,它可以结合、络合、或者与待治疗或生物改造的细胞群体的一部分发生反应。
本发明中组成抗体药物偶联物的抗体最好保持其原有野生状态时的抗原结合能力。因此,本发明中的抗体能够(最好专一性地)与抗原结合。涉及的抗原包括,例如,肿瘤相关抗原(TAA),细胞表面受体蛋白和其他细胞表面分子,细胞存活调节因子,细胞增殖调节因子,与组织生长与分化相关的分子(如已知或预知的具有功能性的),淋巴因子,细胞因子,参与细胞循环调节的分子,参与血管生成的分子,以及与血管生成有关的分子(如已知或预知的具有功能性的)。肿瘤相关因子可以是簇分化因子(如CD蛋白)。与本发明中所述抗体结合的抗原可以是上述分类中一个或一个子集,而其它的子集则包含其它的具有特殊性质的分子/抗原(与目标抗原相比)。
应用在抗体药物偶联物中的抗体,包括但不局限于,针对细胞表面受体和肿瘤相关抗原的抗体。这样的肿瘤相关抗原是本领域所熟知的,可以通过本领域熟知的抗体制备方法和信息来制备。为了开发可用于癌症诊断与治疗的有效的细胞水平目标物,研究人员力图找寻跨膜或其他肿瘤相关多肽。这些目标物能够特异性地表达在一种或多种癌症细胞表面,而在一种或多种非癌细胞表面表达很少或不表达。通常,相对于非癌细胞表面而言,这样的肿瘤相关多肽在癌细胞表面更加过度表达。确认这样的肿瘤相关因子,可大大提高基于抗体治疗癌症的专一靶向特性。
肿瘤相关抗原,包括但不局限于,以下列出的肿瘤相关抗原(1)-(36)。为方便起见,为本领域所熟知的抗原相关信息标示如下,包括名称、其它名称、基因库登录号。与肿瘤相关抗原对应的核酸和蛋白序列可参见公开数据库,例如Genbank。抗体靶向对应的肿瘤相关抗原包括所有的氨基酸序列变种和同种,与参考文献中确认的序列具有至少70%、80%、85%、90%、或95%的同源性,或者具备与引用文献中的肿瘤相关抗原序列具有完全一致的生物性质和特征。
肿瘤相关抗原(1)-(36):
(1)BMPR1B(骨形态发生蛋白受体-IB型,Genbank登录号NM_001203);
(2)E16(LAT1,SLC7A5,Genbank登录号NM_003486);
(3)STEAP1(六次跨膜的前列腺上皮抗原,Genbank登录号NM_012449);
(4)0772P(CA125,MUC16,Genbank登录号AF361486);
(5)MPF(MPF,MSLN,SMR、巨核细胞强化因子,间皮素,Genbank登录号NM_005823);
(6)Napi3b(NAPI-3B,NPTIIb,SLC34A2,溶质载运体家族34(磷酸钠)成员2,II型钠依赖型磷酸转运子3b,Genbank登录号NM_006424);
(7)Sema 5b(FLJ10372,KIAA1445,Mm.42015,SEMA5B,SEMAG,脑信号蛋白5b Hlog,sema结构域,七个血小板反应蛋白重复序列(1型和类1型),跨膜结构域(TM)和短胞质结构域,(脑信号蛋白)5B,Genbank登录号AB040878);
(8)PSCA hlg(2700050C12Rik,C530008016Rik,RIKEN cDNA2700050C12,RIKENcDNA 2700050C12基因,Genbank登录号AY358628);
(9)ETBR(内皮缩血管肽B型受体,Genbank登录号AY275463);
(10)MSG783(RNF124,假拟蛋白FLJ20315,Genbank登录号NM_017763);
(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1,六次跨膜的前列腺上皮抗原2,六次跨膜的前列腺蛋白,Genbank登录号AF455138);
(12)TrpM4(BR22450,FLJ20041,TRPM4,TRPM4B,瞬时受体电势阳离子通道,亚家族M,成员4,Genbank登录号NM_017636);
(13)CRIPTO(CR,CR1,CRGF,CRIPTO,TDGF1,畸胎瘤衍生生长因子,Genbank登录号NP_003203或NM_003212);
(14)CD21(CR2(补体受体2)或C3DR(C3d/EB病毒受体)或Hs.73792,Genbank登录号M26004);
(15)CD79b(CD79B,CD79β,IGb(免疫球蛋白相关β),B29,Genbank登录号NM_000626);
(16)FcRH2(IFGP4,IRTA4,SPAP1A(含有磷酸酶锚定蛋白1a的SH2结构域),SPAP1B,SPAP1C,Genbank登录号NM_030764);
(17)HER2(ErbB2,Genbank登录号M11730);
(18)NCA(CEACAM6,Genbank登录号M18728);
(19)MDP(DPEP1,Genbank登录号BC017023);
(20)IL20Rα(IL20Ra,ZCYTOR7,Genbank登录号AF184971);
(21)Brevican(BCAN,BEHAB,Genbank登录号AF229053);
(22)EphB2R(DRT,ERK,Hek5,EPHT3,Tyro5,Genbank登录号NM_004442);
(23)ASLG659(B7h,Genbank登录号AX092328);
(24)PSCA(前列腺干细胞抗原前体,Genbank登录号AJ297436);
(25)GEDA(Genbank登录号AY260763);
(26)BAFF-R(B细胞活化因子受体,BLyS受体3,BR3,Genbank登录号AF116456);
(27)CD22(B细胞受体CD22-B同种型,Genbank登录号AK026467);
(28)CD79a(CD79A,CD79α,免疫球蛋白相关α,能够与Igβ(CD79B)发生共价作用并在表面与Ig M分子形成复合物,转导参与B细胞分化信号的B细胞特异性蛋白,Genbank登录号NP_001774.1);
(29)CXCR5(伯基特氏(Burkitt’s)淋巴瘤受体1,被CXCL13趋化因子活化的G蛋白偶联受体,在淋巴细胞迁移和体液防御中发挥作用,在HIV-2感染以及可能在艾滋病,淋巴瘤,骨髓瘤,和白血病中发挥作用,Genbank登录号NP_001701.1);
(30)HLA-DOB(MHCII类分子的Beta亚基(Ia抗原),其结合肽并将其呈递到CD4+T淋巴小细胞,Genbank登录号NP_002111.1);
(31)P2X5(嘌呤受体P2X配体门控离子通道5,由胞外ATP门控的离子通道,可能涉及突触传递和神经新生,其缺陷可能导致特发性逼尿肌不稳定的病理生理状况,Genbank登录号NP_002552.2);
(32)CD72(B细胞分化抗原CD72,Lyb-2,Genbank登录号NP_001773.1);
(33)LY64(淋巴细胞抗原64(RP105),富含亮氨酸重复的I型膜蛋白(LRR)家族,调节B细胞活化和凋亡,功能的丧失与系统性红斑狼疮患者疾病活动增加有关,Genbank登录号NP_005573.1);
(34)FcRH1(Fc受体样蛋白1,推定的免疫球蛋白Fc结构域受体,包含C2型类Ig样和ITAM结构域,可能在B淋巴细胞分化中起作用,Genbank登录号NP_443170.1);
(35)IRTA2(易位相关免疫球蛋白超家族受体2,推定的免疫受体,可能在B细胞发育和淋巴瘤产生中起作用;由易位导致的基因失调发生在一些B细胞恶性病上,Genbank登录号NP_112571.1);
(36)TENB2(推定的跨膜蛋白聚糖,与生长因子的EGF/调蛋白(heregulin)家族和卵泡抑素(follistatin)相关,Genbank登录号AF179274)。
药物
如本文所用,“药物”或者代号“D”泛指任何具有期望的生物活性,并具有反应性官能团以便制备本发明偶联物的化合物。期望的生物活性包括,诊断、治愈、缓解、治疗、预防人或其它动物的疾病。因此,只要具有必需的反应性官能团,术语“药物”涉及的化合物包括正式国家药典,以及例如美国正式同种疗法药典,正式全国处方集,或者其任何增补本等确认的药物。典型的药物列于医师案头用药参考(PDR)和美国食品药品监督管理局(FDA)的橙皮书。随着新型药物不断被发现和发展,本专利规定这些药物也应纳入本发明所述偶联药物的前药。
优选地,药物是指一种用于癌症治疗的细胞毒性药物;一种具有期望生物活性的蛋白或多肽,例如一种毒素,如相思子毒素、蓖麻毒素A、假单胞菌外毒素、和白喉毒素;其他合适的蛋白包括肿瘤坏死因子、α-干扰素、β-干扰素、神经原生长因子、血小板衍生生长因子、组织型纤酶溶原生长因子、以及生物反应调节制剂,例如淋巴因子、白细胞介素-1(IL-1)、白细胞介素-2(IL-2)、白细胞介素-6(IL-6)、粒细胞巨噬细胞集落刺激因子(GM-CSF)、粒细胞集落刺激因子、或其它生长因子。
一方面,药物是美登素(maytansine)或类美登素(maytansinoids)。美登素化合物通过抑制微管蛋白的微管形成来抑制细胞增殖(Science 1975,189,1002-1005;US5208020)。类美登素是美登素的衍生物。美登素和类美登素都具有高效的细胞毒性,但是它们在癌症治疗的临床应用上具有很大的局限性,这主要是源于此类分子对肿瘤的低选择性。但是,这种高细胞毒性促使它们成为抗体药物偶联物的首选药物部分。以下列出了美登素、类美登素、以及在抗体药物偶联物应用中经常利用的三个类美登素分子结构。
合成类美登素的主要原料是美登醇(maytansinol),主要由安丝菌素(ansamitocins)水解得到。安丝菌素可以通过发酵的方式制备。安丝菌素衍生物(WO 2012/061590)和丙氨酰基美登醇(US 2012/0121615)据报道也可作为抗体药物偶联物的药物“弹头”(这两类分子结构如下所示)。
另一方面,药物可以是耳抑素肽类(auristatins)药物。耳抑素肽类药物是海兔毒素10(dolastatin 10)的类似物,而后者是从海洋软体动物海兔体内分离出来的具有生物活性的多肽(US7498298)。海兔毒素10通过结合微管蛋白(与长春新碱同样的结合区域)而抑制微管蛋白聚合。海兔毒素10、耳抑素肽PE、耳抑素肽E均是线性多肽,含有四个氨基酸(其中三个氨基酸是海兔毒素类化合物所独有的)和C-端酰胺基团。两个代表性的耳抑素肽类化合物,单甲基耳抑素肽E(MMAE)和单甲基耳抑素肽F(MMAF),均是抗体药物偶联物的首选药物部分。
另一方面,药物是Tubulysins类药物。Tubulysins是从粘细菌中提取出来的一类天然产物,能有效抑制微管蛋白的聚合,因此具有抗细胞有丝分裂的活性,其中TubulysinD的活性最好。Tubulysin D是一个复杂的四肽化合物,其结构中含有O-酰基/N,O-缩醛官能团,因此在酸性和碱性条件下都不稳定。US2011/0021568和US2013/0224228分别披露了一系列tubulysin的类似物,其结构中去除了以上不稳定官能团,同时又具有高细胞活性。
另一方面,药物可以是卡奇霉素类(calichemicins)药物。卡奇霉素类药物是抗肿瘤抗生素,通过结合DNA小沟并促使特定位点双螺旋DNA断裂,而导致细胞凋亡。卡奇霉素类药物具有体外亚皮克摩尔级别的高活性,但是它们的低治疗指数排除了临床应用前景。然而这种高活性却是它们成为抗体药物偶联物的理想候选药物(如吉妥单抗和inotuzumabOzogamicin)。
另一方面,药物可以是阿霉素类(doxorubicins)。阿霉素能够嵌入DNA双螺旋结构从而阻断DNA复制,因此被用作化疗药物。但是由于阿霉素类较低的细胞毒性(针对人源癌细胞系,半数抑制浓度为0.1-0.2微摩尔,而用于抗体药物偶联物的细胞毒性药物活性通常为亚纳摩尔级),导致其在抗体药物偶联物中的应用并不普遍。
另一方面,药物可以是苯并二吡咯类抗生素(duocarmycins、CC-1065等)和其它的环丙基吡咯吲哚-4-酮(cyclopropapyrroloind-4-one,CPI)衍生物。这类化合物是有效的DNA小沟结合-烷基化试剂。环丙苯并吲哚-4-酮(cyclopropabenzindol-4-one,CBI)类似物的化学结构更稳定,生物活性更高,而且与它们含有天然CPI烷基化亚基的父系化合物相比更容易合成。一个代表性的CBI衍生物是酚羟基保护衍生物CBI(见下式),其具有弱化的前药毒性和增强的水溶性。
另一方面,药物可以是吡咯并苯二氮卓类(pyrrolo[2,1-c][1,4]benzodiazepines,PBD)或者PBD二聚体类(PBD dimers)。PBD是一类由链霉菌产生的天然产物,其独特特性在于能够在DNA小沟,确切是在嘌呤-鸟嘌呤-嘌呤序列处,形成非扭曲的共价加和物。应用PBD作为部分小分子策略靶向锁定DNA序列以及作为新型的抗癌和抗菌药物引起了越来越多的兴趣(Biochemistry 2008,47,11818-11829)。应用一个柔性碳链连接两个PBD单元的C8/C8’的羟基基团,所得的二聚体具有增强的生物活性(WO2011/130616)。PBD二聚体被认为是可以产生序列选择性的DNA损伤,例如倒序的5′-Pu-GATC-Py-3′链间交联,从而导致其生物活性。这些化合物已被证明是高效的细胞毒性药物,可作为抗体药物偶联物的备选药物。
另一方面,药物并不仅仅局限于上述提到的类别,还包括所有可用于抗体药物偶联物的药物。
连接子
本文所述术语“连接子”或“抗体药物偶联物的连接子”是指一种具有双官能团或多官能团的分子,可分别与蛋白/抗体分子和药物分子反应,因此做为一种“桥梁”将蛋白/抗体与药物分子连接起来。按照在细胞内药物释放的机制,“连接子”或“抗体药物偶联物的连接子”可被分为两类:不可断裂连接子(non-cleavable linker)和可断裂连接子(cleavable linker)。
不可断裂连接子是一种相对比较稳定的连接子,其结构很难在体内环境下降解断裂。对于含有不可断裂连接子的抗体药物偶联物,其药物释放机制为:偶联物与抗原结合并被细胞内吞后,抗体在溶酶体中被酶解,释放出由小分子药物、连接子、和抗体氨基酸残基共同组成的活性分子。由此带来的药物分子结构改变并不减弱其细胞毒性,但由于活性分子是带电荷的(氨基酸残基),从而导致其不能渗入邻近细胞。因此,此类活性药物不能杀死邻近不表达靶向抗原(抗原阴性细胞)的肿瘤细胞(旁观者效应,bystander effect)(Bioconjugate Chem.2010,21,5-13)。常见的不可断裂连接子例如MC连接子和MCC连接子等。
可断裂连接子,顾名思义,可以在目标细胞内断裂并释放出活性药物(小分子药物本身)。可断裂连接子可分为两个主要的类别:化学不稳定连接子和酶不稳定连接子。
化学不稳定连接子可以由于血浆和细胞质性质的不同而选择性的断裂。这样的性质包括pH值、谷胱甘肽浓度等。
对pH值敏感的连接子,通常又称为酸断裂连接子。这样的连接子在血液的中性环境下相对稳定(pH 7.3-7.5),但是在弱酸性的内涵体(pH 5.0-6.5)和溶酶体(pH 4.5-5.0)内将会被水解。第一代的抗体药物偶联物大多应用这类连接子,例如腙、碳酸酯、缩醛、缩酮类。由于酸断裂连接子有限的血浆稳定性,基于此类连接子的抗体药物偶联物通常具有较短的半衰期(2-3天)。这种较短的半衰期在一定程度上限制了pH敏感连接子在新一代抗体药物偶联物中的应用。
对于谷胱甘肽敏感的连接子,又称二硫键连接子。药物释放是基于细胞内谷胱甘肽的高浓度(毫摩尔范围)与血液中相对较低的谷胱甘肽浓度(微摩尔范围)差异引起的。对于肿瘤细胞而言尤其如此,其低含氧量导致还原酶的活性增强,因而导致更高的谷胱甘肽浓度。二硫键具有热力学稳定性,因此在血浆中具有较好的稳定性。
酶不稳定连接子,如肽连接子,能够更好地控制药物释放。肽连接子能够被溶酶体内蛋白酶,如组织蛋白酶(Cathepsin B)或纤溶酶(在一些肿瘤组织中此类酶含量增加)有效地切断。这种肽连接被认为在血浆循环中非常稳定,这是因为细胞外不合宜的pH值及血清蛋白酶抑制剂导致蛋白酶通常在细胞外不具备活性。鉴于较高的血浆稳定性和良好的细胞内断裂选择性和有效性,酶不稳定连接子被广泛用做抗体药物偶联物的可断裂连接子。典型的酶不稳定连接子例如vc连接子等。
自杀式连接子一般嵌合在可断裂连接子与活性药物之间,或者本身就是可断裂连接子的一部分。自杀式连接子的作用机制是:当可断裂连接子在合宜的条件下断裂后,自杀式连接子能够自发地进行结构重排,进而释放与之连接的活性药物。常见的自杀式连接子如对氨基苄醇类(PAB)等。
抗体药物偶联物
本发明提供的抗体药物偶联物由抗体、四马来酰亚胺型连接子、任选其它连接子和药物组成,所述其它连接子包括可断裂连接子组合或不可断裂连接子。
抗体是球状蛋白,含有一系列氨基酸位点可用于偶联药物-连接子。由于其三级和四级结构,只有溶剂可及的氨基酸残基可供偶联。事实上,高收率的偶联通常发生在赖氨酸残基的ε-氨基基团或半胱氨酸残基的巯基基团上。
抗体蛋白表面的大量赖氨酸侧链导致大量的位点可供药物偶联,从而导致生成的抗体药物偶联物是混合物,含有不同的药物偶联数量(药物/抗体比值,DAR)和偶联位点。
与传统偶联方式得到的抗体药物偶联物相比,应用本发明的四马来酰亚胺型连接子得到的偶联产品,不仅平均DAR值接近2,位于最佳抗体药物偶联物平均DAR值(2-4)范围内,而且其DAR值分布范围非常窄,主要组分为DAR~2的组分(可达90%以上)。此外,偶联产品不含有裸抗(DAR=0),这一组分对细胞毒杀不起作用。同时,偶联产品也不含有重度偶联产品(例如DAR>6),这一组分在体内的清除速度很快(相对于低DAR的组分而言)。因此,本发明提供的抗体药物偶联物产品均一性得到很大的改善。
定义
术语“烷基”指饱和脂肪族烃基团,其为包含1至20个碳原子的直链或支链基团,优选含有1至12个碳原子的烷基,更优选含有1至6个碳原子的烷基。非限制性实例包括甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、仲丁基、正戊基、1,1-二甲基丙基、1,2-二甲基丙基、2,2-二甲基丙基、1-乙基丙基、2-甲基丁基、3-甲基丁基、正己基、1-乙基-2-甲基丙基、1,1,2-三甲基丙基、1,1-二甲基丁基、1,2-二甲基丁基、2,2-二甲基丁基、1,3-二甲基丁基、2-乙基丁基、2-甲基戊基、3-甲基戊基、4-甲基戊基、2,3-二甲基丁基、正庚基、2-甲基己基、3-甲基己基、4-甲基己基、5-甲基己基、2,3-二甲基戊基、2,4-二甲基戊基、2,2-二甲基戊基、3,3-二甲基戊基、2-乙基戊基、3-乙基戊基、正辛基、2,3-二甲基己基、2,4-二甲基己基、2,5-二甲基己基、2,2-二甲基己基、3,3-二甲基己基、4,4-二甲基己基、2-乙基己基、3-乙基己基、4-乙基己基、2-甲基-2-乙基戊基、2-甲基-3-乙基戊基、正壬基、2-甲基-2-乙基己基、2-甲基-3-乙基己基、2,2-二乙基戊基、正癸基、3,3-二乙基己基、2,2-二乙基己基,及其各种支链异构体等。更优选的是含有1至6个碳原子的低级烷基,非限制性实施例包括甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、仲丁基、正戊基、1,1-二甲基丙基、1,2-二甲基丙基、2,2-二甲基丙基、1-乙基丙基、2-甲基丁基、3-甲基丁基、正己基、1-乙基-2-甲基丙基、1,1,2-三甲基丙基、1,1-二甲基丁基、1,2-二甲基丁基、2,2-二甲基丁基、1,3-二甲基丁基、2-乙基丁基、2-甲基戊基、3-甲基戊基、4-甲基戊基、2,3-二甲基丁基等。烷基可以是取代的或非取代的,当被取代时,取代基可以在任何可使用的连接点上被取代,所述取代基优选为一个或多个以下基团,其独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、氧代基、羧基或羧酸酯基。
术语“亚烷基”是指烷基的一个氢原子进一步被取代,例如:“亚甲基”指-CH2-、“亚乙基”指-(CH2)2-、“亚丙基”指-(CH2)3-、“亚丁基”指-(CH2)4-等。
术语“烯基”指由至少由两个碳原子和至少一个碳-碳双键组成的如上定义的烷基,例如乙烯基、1-丙烯基、2-丙烯基、1-、2-或3-丁烯基等。烯基可以是取代的或非取代的,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、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基。
术语“炔基”指由至少由两个碳原子和至少一个碳-碳三键组成的如上定义的烷基,例如乙炔基、丙炔基、丁炔基等。炔基可以是取代的或非取代的,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、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基。
术语“亚烯基”是含有直链、支链或碳环的不饱和烃基,因去除母体烯烃的同一或两个不同碳原子上的两个氢原子而产生了两个单价基中心。如1,2-亚乙烯基(-CH=CH-),1,3-亚丙烯基(-CH2CH=CH-)等。
术语“亚炔基”是含有直链,支链或碳环的不饱和烃基,因去除母体炔烃的同一或两个不同碳原子上的两个氢原子而产生了两个单价基中心。如亚乙炔基(-CH≡CH-),1,3-亚丙炔基(-CH2C≡CH-)等。
术语“亚芳基”是指6-12个碳原子芳族烃基,因去除母体芳环系统的两个不同碳原子上的两个氢原子而产生了两个单价基中心,如1,2-亚苯基,1,3-亚苯基,1,4-亚苯基等。
术语“环烷基”指饱和或部分不饱和单环或多环环状烃取代基,环烷基环包含3至20个碳原子,优选包含3至12个碳原子,更优选包含3至6个碳原子。单环环烷基的非限制性实例包括环丙基、环丁基、环戊基、环戊烯基、环己基、环己烯基、环己二烯基、环庚基、环庚三烯基、环辛基等;多环环烷基包括螺环、稠环和桥环的环烷基。
术语“螺环烷基”指5至20元的单环之间共用一个碳原子(称螺原子)的多环基团,其可以含有一个或多个双键,但没有一个环具有完全共轭的π电子系统。优选为6至14元,更优选为7至10元。根据环与环之间共用螺原子的数目将螺环烷基分为单螺环烷基、双螺环烷基或多螺环烷基,优选为单螺环烷基和双螺环烷基。更优选为4元/4元、4元/5元、4元/6元、5元/5元或5元/6元单螺环烷基。螺环烷基的非限制性实例包括:
术语“稠环烷基”指5至20元,系统中的每个环与体系中的其他环共享毗邻的一对碳原子的全碳多环基团,其中一个或多个环可以含有一个或多个双键,但没有一个环具有完全共轭的π电子系统。优选为6至14元,更优选为7至10元。根据组成环的数目可以分为双环、三环、四环或多环稠环烷基,优选为双环或三环,更优选为5元/5元或5元/6元双环烷基。稠环烷基的非限制性实例包括:
术语“桥环烷基”指5至20元,任意两个环共用两个不直接连接的碳原子的全碳多环基团,其可以含有一个或多个双键,但没有一个环具有完全共轭的π电子系统。优选为6至14元,更优选为7至10元。根据组成环的数目可以分为双环、三环、四环或多环桥环烷基,优选为双环、三环或四环,更有选为双环或三环。桥环烷基的非限制性实例包括:
所述环烷基环可以稠合于芳基、杂芳基或杂环烷基环上,其中与母体结构连接在一起的环为环烷基,非限制性实例包括茚满基、四氢萘基、苯并环庚烷基等。环烷基可以是任选取代的或非取代的,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、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、氧代基、羧基或羧酸酯基。
术语“杂环基”指饱和或部分不饱和单环或多环环状烃取代基,其包含3至20个环原子,其中一个或多个环原子为选自氮、氧或S(O)m(其中m是整数0至2)的杂原子,但不包括-O-O-、-O-S-或-S-S-的环部分,其余环原子为碳。优选包含3至12个环原子,其中1~4个是杂原子;最优选包含3至8个环原子,其中1~3个是杂原子;最优选包含5至6个环原子,其中1~2或1~3个是杂原子。单环杂环基的非限制性实例包括吡咯烷基、咪唑烷基、四氢呋喃基、四氢噻吩基、二氢咪唑基、二氢呋喃基、二氢吡唑基、二氢吡咯基、哌啶基、哌嗪基、吗啉基、硫代吗啉基、高哌嗪基、吡喃基等,优选1、2、5-噁二唑基、吡喃基或吗啉基。多环杂环基包括螺环、稠环和桥环的杂环基。
术语“螺杂环基”指5至20元的单环之间共用一个原子(称螺原子)的多环杂环基团,其中一个或多个环原子为选自氮、氧或S(O)m(其中m是整数0至2)的杂原子,其余环原子为碳。其可以含有一个或多个双键,但没有一个环具有完全共轭的π电子系统。优选为6至14元,更优选为7至10元。根据环与环之间共用螺原子的数目将螺杂环基分为单螺杂环基、双螺杂环基或多螺杂环基,优选为单螺杂环基和双螺杂环基。更优选为4元/4元、4元/5元、4元/6元、5元/5元或5元/6元单螺杂环基。螺杂环基的非限制性实例包括:
术语“稠杂环基”指5至20元,系统中的每个环与体系中的其他环共享毗邻的一对原子的多环杂环基团,一个或多个环可以含有一个或多个双键,但没有一个环具有完全共轭的π电子系统,其中一个或多个环原子为选自氮、氧或S(O)m(其中m是整数0至2)的杂原子,其余环原子为碳。优选为6至14元,更优选为7至10元。根据组成环的数目可以分为双环、三环、四环或多环稠杂环基,优选为双环或三环,更优选为5元/5元或5元/6元双环稠杂环基。稠杂环基的非限制性实例包括:
术语“桥杂环基”指5至14元,任意两个环共用两个不直接连接的原子的多环杂环基团,其可以含有一个或多个双键,但没有一个环具有完全共轭的π电子系统,其中一个或多个环原子为选自氮、氧或S(O)m(其中m是整数0至2)的杂原子,其余环原子为碳。优选为6至14元,更优选为7至10元。根据组成环的数目可以分为双环、三环、四环或多环桥杂环基,优选为双环、三环或四环,更有选为双环或三环。桥杂环基的非限制性实例包括:
所述杂环基环可以稠合于芳基、杂芳基或环烷基环上,其中与母体结构连接在一起的环为杂环基,其非限制性实例包括:
等。
杂环基可以是任选取代的或非取代的,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、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、氧代基、羧基或羧酸酯基。
术语“芳基”指具有共轭的π电子体系的6至14元全碳单环或稠合多环(也就是共享毗邻碳原子对的环)基团,优选为6至10元,例如苯基和萘基。更优选苯基。所述芳基环可以稠合于杂芳基、杂环基或环烷基环上,其中与母体结构连接在一起的环为芳基环,其非限制性实例包括:
芳基可以是取代的或非取代的,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、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、羧基或羧酸酯基。
术语“杂芳基”指包含1至4个杂原子、5至14个环原子的杂芳族体系,其中杂原子选自氧、硫和氮。杂芳基优选为5至10元,含1至3个杂原子;更优选为5元或6元,含1至2个杂原子;优选例如咪唑基、呋喃基、噻吩基、噻唑基、吡唑基、噁唑基、吡咯基、四唑基、吡啶基、嘧啶基、噻二唑、吡嗪基等,优选为咪唑基、噻唑基、吡唑基或嘧啶基、噻唑基;更有选吡唑基或噻唑基。所述杂芳基环可以稠合于芳基、杂环基或环烷基环上,其中与母体结构连接在一起的环为杂芳基环,其非限制性实例包括:
杂芳基可以是任选取代的或非取代的,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、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、羧基或羧酸酯基。
“任选”或“任选地”意味着随后所描述的事件或环境可以但不必发生,该说明包括该事件或环境发生或不发生的场合。例如,“任选被烷基取代的杂环基团”意味着烷基可以但不必须存在,该说明包括杂环基团被烷基取代的情形和杂环基团不被烷基取代的情形。
“取代的”指基团中的一个或多个氢原子,优选为最多5个,更优选为1~3个氢原子彼此独立地被相应数目的取代基取代。不言而喻,取代基仅处在它们的可能的化学位置,本领域技术人员能够在不付出过多努力的情况下确定(通过实验或理论)可能或不可能的取代。例如,具有游离氢的氨基或羟基与具有不饱和(如烯属)键的碳原子结合时可能是不稳定的。
“药物组合物”表示含有一种或多种本文所述化合物或其生理学上/可药用的盐或前体药物与其他化学组分的混合物,以及其他组分例如生理学/可药用的载体和赋形剂。药物组合物的目的是促进对生物体的给药,利于活性成分的吸收进而发挥生物活性。
“药学上可接受的盐”是指本发明化合物的盐,这类盐用于哺乳动物体内时具有安全性和有效性,且具有应有的生物活性。
本文所述术语“药物/抗体比值(Drug/Antibody Ratio,DAR)”是指每个抗体分子上偶联的药物个数。因为抗体药物偶联物样品含有多种不同DAR值的组分,因此“平均DAR值”和“DAR值分布”这两个概念更适合用来描述抗体药物偶联物的组成。平均DAR值是一个样品中总药物分子数与总抗体数的比值,而DAR值分布是指样品中各不同DAR值组分的含量分布。
本发明式I所示的化合物在药学上可接受的盐,可以为酸式加成盐或碱式加成盐。酸可选择无机酸包括但不限于盐酸、硫酸、磷酸、氢溴酸;酸还可选择有机酸包括但不限于柠檬酸、马来酸、草酸,甲酸、乙酸、丙酸、乙醇酸、苯甲酸、富马酸、三氟乙酸、琥珀酸、酒石酸、乳酸、谷氨酸、天门冬氨酸、水杨酸、丙酮酸、甲磺酸、苯磺酸、对苯磺酸。碱可选择无机碱包括但不限于氢氧化钠、氢氧化钾、氢氧化镁、氢氧化钙;碱还可选择有机碱包括但不限于氢氧化铵、三乙胺、精氨酸或赖氨酸。
本发明另一方面可以将抗体药物偶联物制备成临床上可使用的药物组合物。根据临床适应症,给药途径与方式,其药用制剂包括但不限于口服制剂如片剂、凝胶剂、软/硬胶囊、乳剂、分散性粉剂、颗粒剂、水/油悬乳剂;注射剂包括静脉注射剂、肌肉注射剂、腹腔注射剂、直肠给药栓剂、颅内注射剂,这些剂型可为水溶液也可为油类溶液;局部制剂包括霜剂、软膏剂、凝胶剂、水/油溶液以及包合物制剂;吸入剂型包括细粉、液体气溶胶以及适合于体内植入的各种剂型。
本发明的药物组合物根据需要加入常规药用辅料。这些辅料应符合药物制剂制备工艺规则,与活性成分相兼容。固体口服制剂辅料选用但不限于甘露醇、乳糖、淀粉、硬脂酸镁、纤维素、葡萄糖、蔗糖、环糊精以及促进肠吸收分子载体维生素E-PEG1000。口服制剂可加入适当的着色剂、甜味剂、矫味剂及防腐剂
本领域技术人员熟知,药物的给药剂量依赖于多种因素,包括但并非限定于以下因素:所用特定化合物的活性、病人的年龄、病人的体重、病人的健康状况、病人的行被、病人的饮食、给药时间、给药方式、排泄的速率、药物的组合等。另外,最佳的治疗方式如治疗的模式、通式化合物的日用量或可药用的盐的种类可以根据传统的治疗方案来验证。
对于四马来酰亚胺型连接子而言,马来酰亚胺基团之间的距离(碳链长度)可能会影响四马来酰亚胺型连接子对抗体链间交联的方式和效率。用于偶联其它连接子-药物的侧链长度和组成,也可能对抗体药物偶联物的性质及药物的活性施加影响。为此,发明人合成了一系列具有不同“尺寸”的四马来酰亚胺型连接子,用以考察以上所述的影响因素。
抗体药物偶联物的制备方法
本发明的抗体药物偶联物可以通过以下方法制备。
方法1:如下方案2所示。
方案2
步骤1:将任选其它的连接子(A)与四马来酰亚胺连接子(V)偶联得到连接子分子(V-A);
步骤2:将连接子分子(V-A)与药物分子(D)偶联,得到四马来酰亚胺型连接子-任选其他连接子-药物分子(V-A-D);
步骤3:抗体(L)链间二硫键被还原剂还原产生共8个巯基基团;
步骤4:V-A-D与还原后的抗体巯基或其它氨基酸残基交联,得到抗体药物偶联物
方法2:如下方案3所示。
方案3
步骤1:将任选其它的连接子(A)与药物分子(D)偶联得到任选其它连接子-药物分子(A-D);
步骤2:将四马来酰亚胺型连接子(V)与任选其它连接子-药物分子(A-D)偶联,得到四马来酰亚胺型连接子-任选其他连接子-药物分子(V-A-D);
步骤3:抗体(L)链间二硫键被还原剂还原产生共8个巯基基团;
步骤4:V-A-D与还原后的抗体巯基或其它氨基酸残基交联,得到抗体药物偶联物
用途
本发明提供的抗体药物偶联物,靶向瞄准特殊的细胞群体,与细胞表面特异蛋白(抗原)结合,结合物内吞进入细胞内,药物以活性形式释放到细胞内。
本发明提供的抗体药物偶联物,靶向瞄准特殊的细胞群体,与细胞表面特异蛋白(抗原)结合,发生功效;或者在细胞外释放药物,药物渗入细胞内产生功效。
本发明提供治疗动物体内癌症或其他肿瘤的治疗方法,所述方法包括向患有癌症或其他肿瘤的动物施用治疗有效量的根据本发明所述的抗体药物偶联物。
本发明提供治疗自免疫疾病或炎症疾病的治疗方法,所述方法包括向患有自免疫疾病或炎症疾病的患者施用治疗有效量的根据本发明所述的抗体药物偶联物。
本发明提到的上述特征,或实施例提到的特征可以任意组合。本发明说明书所公开的所有特征可与任何组合物形式并用,说明书中所公开的各个特征,可以任何可提供相同、均等或相似目的的替代性特征取代。因此除有特别说明,所公开的特征仅为均等或相似特征的一般性例子。
本发明的主要优点在于:
1、本发明首次提供了能够控制抗体药物偶联物平均DAR~2,并且具有较高均一性的偶联技术。
2、本发明提供的新型四马来酰亚胺型连接子,结构中含有四个马来酰亚胺基团,可以同时偶联抗体链间的半胱氨酸残基或其它氨基酸残基,通过简单的化学方法与抗体偶联。但与传统的偶联方式相比,应用这种连接子得到的偶联物主要组分为DAR~2的组分(可达90%以上),DAR值分布非常窄,因此生成的产品均一性得到了很大程度的提高。
3、本发明提供的偶联方法适用于绝大多数抗体如IgG1,从而可以避免对每一种抗体进行繁琐的重组改造以引入定点偶联位点,因此具有广泛的应用前景。
附图说明
图1显示了本发明的抗体药物偶联物H-5-vcMMAE的非变性质谱(Native MS)测定结果。
图2a-2b显示了基于四马来酰亚胺型连接子的抗体药物偶联物的聚丙烯酰胺凝胶电泳(SDS-PAGE)测定结果,其中图2a为抗体药物偶联物H-1-vcMMAE至H-6-vcMMAE(分别对应1-6)的SDS-PAGE谱图;图2b为抗体药物偶联物H-7-vcMMAE至H-12-vcMMAE(分别对应7-12)的SDS-PAGE谱图。
图3a-3m显示了抗体药物偶联物的疏水作用色谱(HIC)测定结果。其中,图3a-3l分别对应H-1-vcMMAE至H-12-vcMMAE;图3m对应P-7-vcMMAE。
具体实施方式
下面结合具体实施例,进一步阐述本发明。应理解,这些实施例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,通常按照常规条件或按照制造厂商所建议的条件。所有反应都是在氮气保护下进行的(氢化反应除外)。
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技术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。文中所述的实施方法与材料仅作示范用。
缩略语
Ab 抗体
Ac 乙酰基
ACN 乙腈
ADC 抗体药物偶联物
BOC(Boc) 叔丁氧羰基
Cbz 苄氧羰基
t-Bu 叔丁基
DCM 二氯甲烷
DIPEA 二异丙基乙基胺
DMF N,N-二甲基甲酰胺
ELISA 酶联免疫吸附测定
EtOAc 乙酸乙酯
Eq(eq) 当量
g 克
h 小时
HATU O-(7-氮杂苯并三唑-1-基)-N,N,N′,N′-四甲基脲六氟磷
酸酯
HOSu N-羟基琥珀酰亚胺
HIC 疏水作用色谱
HPLC 高效液相色谱
LC-MS 液相色谱-质谱联用
mAb 单克隆抗体
min 分钟
mL 毫升
MS 质谱
nm 纳米
μg 微克
μL 微升
PE 石油醚
RP-HPLC 反相-高效液相色谱
prep-RP-HPLC 制备用反相-高效液相色谱
rt 室温
Rt 保留时间
SDS-PAGE 聚丙烯酰胺凝胶电泳
SEC 尺寸排阻色谱
TEA 三乙胺
TFA 三氟乙酸
THF 四氢呋喃
TLC 薄层色谱
TsCl 对甲苯磺酰氯
除非另外说明,所有的无水试剂都是直接从供应商购买的,并保存在氮气下。购买的所有其它试剂和溶剂都是高纯度的,并且使用前不经过进一步纯化。
核磁共振波谱是在Bruker Avance III 500兆核磁共振波谱仪上采集的。化学位移(δ)单位是ppm,以四甲基硅烷为参照系(化学位移为0)。
液相色谱-质谱联用分析方法中,低分辨质谱数据是在一台与惠普Agilent 1200高效液相色谱仪接口的Agilent 6110(酸法)或6120B(碱法)质谱仪上采集的。
方法1:酸法高效液相色谱方法采用沃特世Sunfire C18反相色谱柱(4.60×50mm,3.5μm)进行分离,洗脱液梯度为1.4分钟内5%-95%B相(乙腈,含0.01%TFA)在A相(水相,含0.01%TFA)中,流速为2.0mL/min,柱温为50℃;
方法2:酸法高效液相色谱方法采用沃特世Sunfire C18反相色谱柱(4.60×50mm,3.5μm)进行分离,洗脱液梯度为1.4分钟内5%-95%B相(乙腈,含0.01%TFA)在A相(水相,含0.01%TFA)中,流速为2.3mL/min,柱温为50℃;
方法3:酸法高效液相色谱方法采用沃特世Sunfire C18反相色谱柱(3.0×30mm,2.5μm)进行分离,洗脱液梯度为1.5分钟内5%-95%B相(乙腈,含0.01%TFA)在A相(水相,含0.01%TFA)中,流速为1.5mL/min,柱温为50℃;
方法4:酸法高效液相色谱方法采用沃特世Sunfire C18反相色谱柱(4.6×50mm,3.5μm)进行分离,洗脱液梯度为1.2分钟内5%-95%B相(乙腈,含0.01%TFA)在A相(水相,含0.01%TFA)中,流速为2.0mL/min,柱温为50℃;
方法5:碱法高效液相色谱方法采用沃特世Xbridge C18反相色谱柱(4.60×50mm,3.5μm)进行分离,洗脱液梯度为1.5分钟内5%-95%B相(乙腈)在A相(水相,含10mM碳酸氢铵)中,流速为2.0mL/min,柱温为40℃。
制备用反相-高效液相色谱纯化(prep-RP-HPLC)是在吉尔森(Gilson)仪器上完成的,使用的分离柱为沃特世Sunfire C18反相色谱柱(250×19mm,10μm)。
方法6:酸法制备。流动相:A:含0.1%TFA的水相;B:ACN。流速:20mL/min。
使用的细胞系是SK-BR-3人乳腺癌细胞,该细胞系是从ATCC得到的。Her2抗原购自义翘神州公司(北京)。赫赛汀生物类似物(抗体H,IgG1)购自嘉和生物药业有限公司(上海)。帕妥珠单抗生物类似物(抗体P,IgG1)购自上海瀚香生物科技有限公司(上海)。酶标抗抗体购自西格玛公司(上海)。底物溶液购自Decent生物技术公司(上海)。Cell CountingKit-8(CCK-8)细胞增殖-毒性检测试剂盒购自Dojindo公司(上海)。
实施例1化合物1(连接子1)的合成
将(S)-4,5-二氨基戊酸二盐酸盐(15)(10mg,49μmol,根据TetrahedronAsymmetry,1993,4,91-100发表的方法制备)和化合物16(38mg,98μmol,根据WO2014114207公开的方法制备)溶于DMF(0.5mL),然后向溶液中加入DIPEA(25mg,196μmol)。反应液在室温搅拌2小时,然后用RP-HPLC纯化(方法6:8分钟内32%-60%B→4分钟内95%B)得到白色固体状化合物1(12mg)。
LC-MS(方法1):Rt=1.39min;m/z(ES+)681.1(M+H)+。
1H NMR(500MHz,CD3OD)δ6.80(s,4H),6.78(s,4H),4.20-4.12(m,2H),4.01-3.96(m,2H),3.92-3.87(m,1H),3.71-3.66(m,2H),3.37-3.32(m,1H),3.11-3.07(m,1H),2.42-2.30(m,4H),2.28-2.08(m,6H),1.83-1.76(m,1H),1.66-1.59(m,1H)。
实施例2化合物2(连接子2)的合成
将2-(1,3-二氨基-2-丙氧基)乙酸二盐酸盐(17)(10mg,45μmol,根据WO2014114207公开的方法制备)和化合物16(35mg,90μmol)溶于DMF(0.5mL),然后向溶液中加入DIPEA(23mg,180μmol)。反应液在室温搅拌4小时,然后用RP-HPLC纯化(方法6:8分钟内30%-60%B→4分钟内95%B)得到白色固体状化合物2(9mg)。
LC-MS(方法2):Rt=1.63min;m/z(ES+)697.0(M+H)+。
1H NMR(500MHz,CD3OD)δ6.79(s,4H),6.78-6.76(m,4H),4.22(s,2H),4.18-4.14(m,2H),4.00-3.95(m,2H),3.70-3.66(m,2H),3.50-3.45(m,1H),3.31-3.27(m,1H),3.24-3.23(d,2H),3.18-3.14(m,1H),2.46-2.38(m,2H),2.29-2.17(m,4H),2.14-2.08(m,2H)。
实施例3化合物3(连接子3)的合成
将4,5-二(2,5-二氧代-2,5-二氢-1H-吡咯烷基)戊酸(18)(10mg,65μmol,根据WO2014114207公开的方法制备)和3,5-二氨基苯甲酸(38mg,130μmol)溶于DMF(0.6mL),然后向溶液中加入HATU(62mg,160μmol)和DIPEA(18mg,140μmol)。反应液在室温搅拌18小时,然后用RP-HPLC纯化(方法6:8分钟内40%-70%B→4分钟内95%B)得到白色固体状化合物3(6mg)。
LC-MS(方法2):Rt=1.74min;m/z(ES+)700.8(M+H)+。
1H NMR(500MHz,DMSO-d6)δ10.03(s,2H),8.02(s,1H),7.84(s,2H),7.01(s,4H),6.98(s,4H),4.09-4.02(m,2H),3.84-3.75(m,2H),3.65-3.61(m,2H),2.33-2.25(m,6H),2.06-1.95(m,2H)。
实施例4化合物4(连接子4)的合成
将2-(1,4-二氨基-2-丁氧基)乙酸二盐酸盐(19)(20mg,85μmol,根据WO2014114207公开的方法制备)和化合物16(66mg,170μmol)溶于DMF(0.4mL),然后向溶液中加入DIPEA(44mg,340μmol)。反应液在室温搅拌4小时,然后用RP-HPLC纯化(方法6:8分钟内35%-60%B→4分钟内95%B)得到白色固体状化合物4(9mg)。
LC-MS(方法1):Rt=1.41min;m/z(ES+)711.1(M+H)+。
1H NMR(500MHz,CD3OD)δ6.80(s,4H),6.77(s,4H),4.21(s,2H),4.18-4.12(m,2H),4.00-3.94(m,2H),3.70-3.65(m,2H),3.55-3.51(m,1H),3.49-3.35(m,1H),3.30-3.14(m,3H),2.46-2.38(m,2H),2.29-2.17(m,4H),2.15-2.08(m,2H),1.68-1.63(m,2H)。
实施例5化合物5(连接子5)的合成
步骤1:5-(二(2-(苄氧羰基氨基)乙基)氨基)-5-氧代戊酸(21)的制备
将二(2-(苄氧羰基氨基)乙基)胺盐酸盐(20)(815mg,2mmol,根据EuropeanJournal of Medicinal Chemistry,2009,44,678-688发表的方法制备)和TEA(0.70mL,5mmol)溶于DMF(5mL),然后向其中滴加戊二酸酐(228mg,2mmol)的DMF溶液(1mL)。反应液在室温搅拌过夜,然后向其中加入水(20mL),用DCM萃取(15mL×3)。合并的有机相依次用饱和食盐水洗涤,无水硫酸钠干燥,过滤并减压浓缩。残余物通过硅胶柱色谱法纯化(洗脱剂:DCM/MeOH 30:1),得到淡黄色固体化合物21(872mg)。
LC-MS(方法3):Rt=1.21min;m/z(ES+)486.3(M+H)+。
步骤2:5-(二(2-氨基乙基)氨基)-5-氧代戊酸二氢溴酸盐(22)的制备
将HBr的乙酸溶液(33%,3mL)滴加到化合物21(522mg,1.1mmol)中,然后将混合物在室温搅拌15min。向反应液中加入乙醚(20mL),析出的黄色固体通过离心分离。向所得固体中加入乙醚(10mL)后经离心分离,同样过程重复3次。将得到的分离物真空干燥(60℃),得到黄色固体化合物22的氢溴酸盐(350mg)。
LC-MS(方法4):Rt=0.28min;m/z(ES+)218.0(M+H)+。
步骤3:化合物5的制备
将化合物22的氢溴酸盐(45mg,119μmol)和化合物16(50mg,128μmol)溶于DMF(5mL),然后向溶液中加入DIPEA(37mg,287μmol)。反应液在室温搅拌2小时,然后用RP-HPLC纯化(方法6:8分钟内30%-60%B→4分钟内95%B)得到白色固体状化合物5(30mg)。
LC-MS(方法2):Rt=1.62min;m/z(ES+)765.9(M+H)+。
1H NMR(500MHz,DMSO-d6)δ7.95(t,1H),7.84(t,1H),7.00(s,4H),6.97(d,4H),4.01-3.95(m,2H),3.80-3.75(m,2H),3.61-3.56(m,2H),3.25-3.16(m,4H),3.15-3.06(m,4H),2.27(t,2H),2.23-2.15(m,4H),2.04-1.98(m,4H),1.96-1.88(m,2H),1.72-1.66(m,2H)。
实施例6化合物6(连接子6)的合成
步骤1:(2-(叔丁氧羰基氨基乙基))(3-(叔丁氧羰基氨基丙基))胺(23)的制备
向甲苯(30mL)中依次加入CDI(2.9g,18.0mmoL)、叔丁醇(1.33g,18.0mmoL)和氢氧化钾(24mg,0.43mmoL),将混合物于60℃搅拌3小时。然后,将N-(2-氨基乙基)-1,3-丙二胺(1.0g,8.55mmol)加入上述溶液中,将混合物于60℃继续搅拌3小时。将反应液冷却至室温,减压浓缩除去溶剂。向残余物中加入DCM(50mL),然后用水洗涤(30mL×3)。有机相经无水硫酸钠干燥,过滤,减压浓缩,得到无色油状物化合物23(1.0g)。粗品不经纯化,直接进行下一步反应。
步骤2:4-((2-(叔丁氧羰基氨基)乙基)(3-(叔丁氧羰基氨基)丙基)氨基)-4-氧代丁酸(24)的制备
将化合物23(1.0g)溶于DCM(15mL)中,然后依次加入丁二酸酐(0.47g,4.73mmol)和DIPEA(1.22g,9.46mmol)。将混合物在室温搅拌18小时,然后用水洗涤(30mL×2)。有机相经无水硫酸钠干燥,过滤,减压浓缩,得到无色油状物化合物24(1.2g)。粗品不经纯化,直接用于下一步反应。
LC-MS(方法5):Rt=1.68min;m/z(ES+)418.3(M+H)+。
步骤3:4-((2-氨基乙基)(3-氨基丙基)氨基)-4-氧代丁酸(25)的制备
向化合物24(1.2g)中依次加入1,4-二氧六环(6mL)和浓盐酸(3mL),将混合物在室温搅拌2小时。将反应液减压浓缩除去溶剂,然后将残余物溶于甲苯,继续将溶液减压浓缩除去溶剂(此过程重复3次)。残余物经真空干燥,得到淡黄色固体化合物25(520mg)。
LC-MS(方法5):Rt=0.32min;m/z(ES+)218.2(M+H)+。
步骤4:化合物6的制备
将化合物25(24mg,83μmol)和化合物16(65mg,166μmol)溶于DMF(0.4mL),然后向溶液中加入DIPEA(43mg,332μmol)。反应液在室温搅拌4小时,然后用RP-HPLC纯化(方法6:8分钟内32%-60%B→4分钟内95%B)得到白色固体状化合物6(8mg)。
LC-MS(方法2):Rt=1.58min;m/z(ES+)766.2(M+H)+。
1H NMR(500MHz,CD3OD)δ6.80-6.78(m,8H),4.19-4.13(m,2H),4.01-3.95(m,2H),3.70-3.67(m,2H),3.48-3.36(m,5H),3.30-3.06(m,3H),2.68-2.62(m,4H),2.44-2.38(m,2H),2.25-2.06(m,6H),1.82-1.70(m,2H)。
实施例7化合物7(连接子7)的合成
步骤1:二(3-叔丁氧羰基氨基丙基)胺(26)的制备
向甲苯(30mL)中依次加入CDI(3.4g,21mmoL)、叔丁醇(1.55g,21mmoL)和氢氧化钾(28mg,0.50mmoL),将混合物于60℃搅拌3小时。然后,将N-(3-氨基丙基)-1,3-丙二胺(1.31g,10mmol)加入上述溶液中,将混合物于60℃继续搅拌3小时。将反应液冷却至室温,减压浓缩除去溶剂。向残余物中加入DCM(50mL),然后用水洗涤(30mL×3)。有机相经无水硫酸钠干燥,过滤,减压浓缩,得到白色固体化合物26(1.0g)。粗品不经纯化,直接进行下一步反应。
步骤2:4-(二(3-(叔丁氧羰基氨基)丙基)氨基)-4-氧代丁酸(27)的制备
将化合物26(1.0g)溶于DCM(15mL),然后依次加入丁二酸酐(0.36g,3.6mmol)和DIPEA(0.78g,6.0mmol)。将混合物于室温搅拌18小时,然后将反应液减压浓缩除去溶剂。残余物通过硅胶柱色谱法纯化(洗脱剂:DCM/MeOH 15:1),得到无色油状物化合物27(420mg)。
步骤3:4-(二(3-氨基丙基)氨基)-4-氧代丁酸(28)的制备
将化合物27(420mg)溶于二氯甲烷(900μL)中,然后将溶液冷却至0℃,加入TFA(300uL)。将混合物在室温搅拌3小时,然后将反应液减压浓缩除去溶剂。将残余物溶于甲苯,继续将溶液浓缩除去溶剂(此过程重复3次)。残余物经真空干燥,得到淡黄色油状物化合物28(480mg)。
LC-MS(方法4):Rt=0.28,0.34min;m/z(ES+)232.2(M+H)+。
步骤4:化合物7的制备
将化合物28(60mg,130μmol)和化合物16(101mg,260μmol)溶于DMF(0.6mL),然后向溶液中加入DIPEA(67mg,520μmol)。反应液在室温搅拌2小时,然后用RP-HPLC纯化(方法6:8分钟内35%-58%B→4分钟内95%B),得到白色固体状化合物7(35mg)。
LC-MS(方法2):Rt=1.47min;m/z(ES+)780.2(M+H)+。
1H NMR(500MHz,CD3OD)δ6.80-6.78(m,8H),4.18-4.13(m,2H),4.00-3.95(m,2H),3.71-3.67(m,2H),3.42-3.35(m,4H),3.25-3.08(m,4H),2.68-2.67(m,4H),2.45-2.38(m,2H),2.25-2.08(m,6H),1.86-1.80(m,2H),1.73-1.68(m,2H)。
实施例8化合物8(连接子8)的合成
步骤1:3,5-二(2-(叔丁氧羰基氨基)乙氧基)苯甲酸甲酯(29)的制备
将3,5-二羟基苯甲酸甲酯(200mg,1.19mmol)和2-溴乙基氨基甲酸叔丁酯(666mg,2.98mmol)溶于DMF(10mL)中,然后加入碳酸钾(411mg,2.98mmol)。将混合物于50℃搅拌18小时,然后将反应液减压浓缩除去溶剂。残余物通过硅胶柱色谱法纯化(洗脱剂:PE/EA 10:1),得到无色油状物化合物29(450mg)。
LC-MS(方法1):Rt=1.97min;m/z(ES+)477.0(M+Na)+。
步骤2:3,5-二(2-氨基乙氧基)苯甲酸(30)的制备
将化合物29(200mg)溶于1,4-二氧六环(1mL)中,然后向其中加入浓盐酸(1mL)。将混合物于80℃搅拌2小时,然后将反应液减压浓缩除去溶剂。向残余物中加入甲苯(3mL),然后减压浓缩除去溶剂,同样操作重复数次直至得到固体。向固体中加入乙酸乙酯打浆,然后将混合物过滤。所得固体经真空干燥,得到棕色固体化合物30(100mg)。其未经纯化,直接用于下一步反应。
LC-MS(方法1):Rt=0.32min;m/z(ES+)241.0(M+H)+。
步骤3:化合物8的制备
将化合物30(10mg,32μmol)和化合物16(25mg,64μmol)溶于DMF(0.5mL),然后向溶液中加入DIPEA(17mg,128μmol)。反应液在室温搅拌2小时,然后用RP-HPLC纯化(方法6:8分钟内35%-65%B→4分钟内95%B)得到白色固体状化合物8(6mg)。
LC-MS(方法4):Rt=1.34min;m/z(ES+)789.2(M+H)+。
1H NMR(500MHz,DMSO-d6)δ8.05(t,2H),7.04(d,2H),7.00(s,4H),6.96(s,4H),6.72(t,1H),4.02-3.94(m,6H),3.80-3.74(m,2H),3.61-3.56(m,2H),3.37-3.33(m,4H),2.23-2.14(m,2H),2.06(t,4H),1.98-1.90(m,2H)。
实施例9化合物9(连接子9)的合成
步骤1:二(2-(2-羟基乙氧基)乙基)氨基甲酸叔丁酯(32)的制备
将二(2-(2-羟基乙氧基)乙基)胺(31)(4.2g,21.8mmol,根据Journal of OrganicChemistry,1995,60,6097-6102发表的方法制备)和TEA溶于DCM(30mL)中,然后向其中加入二叔丁基二碳酸酯(5.69g,26.1mmol)。反应液在室温搅拌18小时,然后减压浓缩除去溶剂。残余物通过硅胶柱色谱法纯化(洗脱剂:DCM/MeOH30:1→15:1)得到淡黄色油状物化合物32(2.3g)。
LC-MS(方法1):Rt=1.41min;m/z(ES+)316.1(M+Na)+。
步骤2:二(2-(2-对甲苯磺酸基乙氧基)乙基)氨基甲酸叔丁酯(33)的制备
将化合物32(2.3g,7.85mmol)和TEA(3.17g,31.4mmol)溶于DCM(40mL)中,然后向其中缓慢加入TsCl(4.49g,23.6mmol)。反应液在室温搅拌18小时,然后减压浓缩除去溶剂。残余物通过硅胶柱色谱法纯化(洗脱剂:PE/EA3:1),得到无色油状物化合物33(3.3g)。
LC-MS(方法4):Rt=1.88min;m/z(ES+)624.2(M+Na)+。
步骤3:二(2-(2-对甲苯磺酸基乙氧基)乙基)胺(34)的制备
将化合物33(3.3g,5.49mmol)溶于二氯甲烷(9mL)中,然后将溶液冷却至0℃,加入TFA(3mL)。将混合物在室温搅拌2小时,然后将反应液减压浓缩除去溶剂。将残余物溶于DCM,用饱和碳酸氢钠溶液萃取。水相用DCM(10mL)萃取,然后将有机相合并,无水硫酸钠干燥,过滤,减压浓缩,得到无色油状物化合物34(2.5g)。粗品未经纯化,直接用于下一步反应。
步骤4:4-(二(2-(2-(对甲苯磺酰氧基)乙氧基)乙基)氨基)-4-氧代丁酸(35)的制备
将化合物34(2.5g,4.99mmol)溶于DCM(15mL)中,然后依次加入丁二酸酐(0.75g,7.48mmol)和DIPEA(1.93g,15.0mmol)。将反应液在室温搅拌2小时,然后加入水(20mL)萃取。有机相经无水硫酸钠干燥,过滤,减压浓缩,得到无色油状物。其进一步通过硅胶柱色谱法纯化(洗脱剂:DCM/MeOH 20:1),得到无色油状物化合物35(1.6g)。
LC-MS(方法4):Rt=1.64min;m/z(ES+)602.1(M+H)+。
步骤5:4-(二(2-(2-叠氮基乙氧基)乙基)氨基)-4-氧代丁酸(36)的制备
将化合物35(1.6g,2.66mmol)溶于DMF(10mL)中,然后加入叠氮化钠(0.52g,7.99mmol)。将混合物于50℃搅拌5小时,然后将反应液减压浓缩除去溶剂。残余物通过硅胶柱色谱法纯化(洗脱剂:DCM/MeOH 20:1),得到无色油状物化合物36(600mg)。
LC-MS(方法1):Rt=1.55min;m/z(ES+)344.1(M+H)+。
步骤6:4-(二(2-(2-氨基乙氧基)乙基)氨基)-4-氧代丁酸(37)的制备
将化合物36(600mg,1.75mmol)溶于THF(10mL)和水(126μL)中,然后加入三苯基膦(1.37g,5.25mmol)。将混合物在室温搅拌18小时,有不溶于溶剂的油状物出现在反应瓶壁和底部。小心将THF移去,无色油状物继续用THF(3mL)洗3次,然后加入水(10mL)。将所得溶液冻干,得到白色固体状化合物37(500mg)。
LC-MS(方法5):Rt=0.35,0.46min;m/z(ES+)292.1(M+H)+。
步骤7:化合物9的制备
将化合物37(20mg,68μmol)和化合物16(53mg,137μmol)溶于DMF(0.6mL),然后向溶液中加入DIPEA(71mg,548μmol)。反应液在室温搅拌2小时,然后用RP-HPLC纯化(方法6:8分钟内30%-60%B→4分钟内95%B),得到白色固体状化合物9(9mg)。
LC-MS(方法2):Rt=1.61min;m/z(ES+)840.0(M+H)+。
1H NMR(500MHz,DMSO-d6)δ7.83-7.79(m,2H),7.00(s,4H),6.97(s,4H),4.00-3.94(m,2H),3.79-3.74(m,2H),3.60-3.56(m,2H),3.50-3.47(m,4H),3.39(s,4H),3.36-3.29(m,4H),3.15-3.09(m,4H),2.55(t,2H),2.39(t,2H),2.21-2.14(m,2H),2.03-2.01(m,4H),1.95-1.88(m,2H)。
实施例10化合物10(连接子10)的合成
将化合物38(15mg,54μmol,根据WO2014114207公开的方法制备)和化合物39(44mg,108μmol,根据WO2014114207公开的方法制备)溶于DMF(0.6mL)中,然后加入DIPEA(28mg,216μmol)。反应液在室温搅拌2小时,然后用RP-HPLC纯化(方法6:8分钟内37%-58%B→4分钟内95%B),得到白色固体状的化合物10(15mg)。
LC-MS(方法2):Rt=1.63min;m/z(ES+)784.0(M+H)+。
1H NMR(500MHz,DMSO-d6)δ11.98(br s,1H),7.59(t,1H),7.44(t,1H),7.05(s,8H),3.88(s,2H),3.85(s,2H),3.82-3.77(m,2H),3.52-3.50(m,8H),3.29-3.19(m,6H),3.15-3.12(m,2H),2.49(t,2H),2.41(t,2H)。
实施例11化合物11(连接子11)的合成
将化合物38(15mg,54μmol)和化合物40(45mg,108μmol,根据WO2014114207公开的方法制备)溶于DMF(0.5mL),然后加入DIPEA(28mg,216μmol)。反应液在室温搅拌2小时,然后用RP-HPLC纯化(方法6:8分钟内38%-58%B→4分钟内95%B),得到白色固体状化合物11(14mg)。
LC-MS(方法2):Rt=1.65min;m/z(ES+)812.0(M+H)+。
1H NMR(500MHz,DMSO-d6)δ12.01(br s,1H),7.75(t,1H),7.62(t,1H),7.04(s,4H),7.00(s,4H),4.02-3.95(m,2H),3.84-3.79(m,2H),3.58-3.45(m,10H),3.33-3.19(m,8H),2.53(t,2H),2.40(t,2H),1.66-1.56(m,4H)。
实施例12化合物12(连接子12)的合成
将化合物38(15mg,54μmol)和化合物41(50mg,108μmol,根据WO2014114207公开的方法制备)溶于DMF(0.5mL),然后加入DIPEA(28mg,216μmol)。反应液在室温搅拌2小时,然后用RP-HPLC纯化(方法6:8分钟内35%-60%B→4分钟内95%B)得到白色固体状化合物12(14mg)。
LC-MS(方法2):Rt=1.58min;m/z(ES+)894.0(M+H)+。
1H NMR(500MHz,DMSO-d6)δ7.97(t,1H),7.82(t,1H),7.04(s,4H),6.96(s,4H),3.58(t,4H),3.52(t,4H),3.39-3.38(m,8H),3.29(t,2H),3.23(t,2H),3.19-3.16(m,2H),3.12-3.08(m,2H),2.51-2.50(m,2H),2.41(t,2H),2.35-2.32(m,4H),2.23-2.18(m,4H)。
实施例13化合物13(连接子13)的合成
步骤1:4-(二(3-(2,2,2-三氟乙酰胺基)丙基)氨基)-4-氧代丁基氨基甲酸叔丁酯(44)的制备
将4-(叔丁氧羰基氨基)丁酸(42)(203mg,1.0mmol,根据US2015/111864公开的方法制备)和二(3-(2,2,2-三氟乙酰胺基)丙基)氨基(43)(388mg,1.2mmol,根据WO2006/20779公开的方法制备)溶于DMF(3mL),然后向溶液中加入HATU(456mg,1.2mmol)和DIPEA(258mg,2mmol)。反应液在室温搅拌3小时,然后浓缩,残余物用RP-HPLC纯化(方法6:8分钟内45%-75%B→4分钟内95%B)得到无色胶状固体44(250mg)。
LC-MS(方法1):Rt=1.81min;m/z(ES+)409.0(M+H)+。
1H NMR(500MHz,CDCl3)δ8.34(br s,1H),7.949(s,1H),5.03(br s,1H),3.42-3.30(m,4H),3.30-3.17(m,4H),3.09(s,2H),2.39-2.27(m,2H),1.91-1.82(m,2H),1.82-1.73(m,2H),1.73-1.63(m,2H),1.37(s,9H)。
步骤2,3:4-(二(3-(4,5-二(2,5-二氧代-2,5-二氢-1H-吡咯-1-基)戊酰胺基)丙基)氨基)-4-氧代丁基氨基甲酸叔丁酯(46)的制备
将化合物44(20mg,39μmol)溶于甲醇(1mL),然后向溶液中加入氨水(28%,1mL)。反应液回流4小时,然后浓缩除去溶剂。残余物溶于甲醇,然后浓缩,此过程重复三次。
将所得中间体45溶于N,N-二甲基甲酰胺(1mL)和二氯甲烷(1mL),然后向其中加入化合物18(35mg,0.12mmol)、HATU(60mg,0.158mmol)和DIPEA(30mg,0.23mmol)。反应液在室温搅拌2小时,然后浓缩除去溶剂,所得残余物用RP-HPLC纯化(方法6:8分钟内50%-80%B→4分钟内95%B),得到白色固体状化合物46(20mg)。
LC-MS(方法3):Rt=1.33min;m/z(ES+)865.5(M+H)+。
1H NMR(500MHz,DMSO-d6)δ7.81(t,1H),7.72(t,1H),7.00(s,4H),6.98(s,2H),6.97(s,2H),6.80(t,1H),4.02-3.94(m,2H),3.82-3.73(m,2H),3.64-3.54(m,2H),3.24-3.10(m,4H),3.05-2.85(m,6H),2.26-2.12(m,4H),2.08-1.86(m,6H),1.63-1.43(m,6H),1.37(s,9H)。
步骤4化合物13的制备
将化合物46(20mg,23μmol)溶于二氯甲烷(3mL),然后向其中加入三氟乙酸(1mL)。反应液在室温搅拌1小时,浓缩除去溶剂,所得残余物用RP-HPLC纯化(方法6:8分钟内30%-60%B→4分钟内95%B),得到白色固体状化合物13的三氟乙酸盐(10mg)。
LC-MS(方法2):Rt=1.46min;m/z(ES+)765.0(M+H)+。
1H NMR(500MHz,DMSO-d6)δ7.83(t,1H),7.78-7.68(m,4H),7.01(s,4H),6.99(s,2H),6.98(s,2H),4.02-3.94(m,2H),3.82-3.74(m,2H),3.63-3.55(m,2H),3.19(t,4H),3.06-2.88(m,4H),2.86-2.77(m,2H),2.37(t,2H),2.26-2.12(m,2H),2.09-1.87(m,6H),1.80-1.71(m,2H),1.64-1.46(m,4H)。
实施例14化合物14(连接子14)的合成
步骤1:4-羟基-N,N-二(3-(2,2,2-三氟乙酰胺基)丙基)丁酰胺(48)的制备
将4-羟基丁酸钠(47)(126mg,1.0mmol,根据WO2014/152127公开的方法制备)和二(3-(2,2,2-三氟乙酰胺基)丙基)胺(388mg,1.2mmol,根据WO2006/20779公开的方法制备)溶于DMF(3mL),然后向溶液中加入HATU(456mg,1.2mmol)和DIPEA(258mg,2mmol)。反应液在室温搅拌3小时,然后浓缩,所得残余物用RP-HPLC纯化(方法6:8分钟内40%-70%B→4分钟内95%B)得到无色胶状固体48(68mg)。
LC-MS(方法5):Rt=1.55min;m/z(ES+)410.0(M+H)+。
1H NMR(500MHz,DMSO-d6)δ9.48(t,1H),9.37(t,1H),3.39(t,2H),3.31-3.05(m,8H),2.29(t,2H),1.81-1.70(m,2H),1.70-1.57(m,4H)。
步骤2,3:化合物14的制备
将化合物48(20mg,49μmol)溶于甲醇(1mL),然后向溶液中加入氨水(28%,1mL)。反应液回流2小时,然后浓缩除去溶剂。残余物溶于甲醇,然后浓缩,此过程重复三次。
将所得中间体49溶于N,N-二甲基甲酰胺(1mL)和二氯甲烷(1mL),然后向其中加入化合物18(43mg,0.15mmol)、HATU(74mg,0.20mmol)和DIPEA(38mg,0.29mmol)。反应液在室温搅拌2小时,然后浓缩除去溶剂,所得残余物用RP-HPLC纯化(方法6:8分钟内35%-65%B→4分钟内95%B),得到白色固体状化合物14(5mg)。
LC-MS(方法2):Rt=1.62min;m/z(ES+)765.9(M+H)+。
1H NMR(500MHz,DMSO-d6)δ7.82(t,1H),7.72(t,1H),7.00(s,4H),6.98(s,2H),6.97(s,2H),4.02-3.94(m,2H),3.82-3.73(m,2H),3.62-3.56(m,2H),3.37(t,2H),3.24-3.13(m,4H),3.03-2.87(m,4H),2.26(t,2H),2.23-2.13(m,2H),2.08-1.87(m,6H),1.68-1.43(m,6H)。
实施例15四马来酰亚胺连接子-药物1-vcMMAE的合成
将化合物1(4.1mg,6μmol)和NH2-vcMMAE(TFA盐,6.7mg,6μmol,根据WO2013/173337公开的方法制备)溶于DMF(300μL)中,然后依次加入DIPEA(2.3mg,9μmol)和HATU(3.4mg,9μmol)。反应液在室温搅拌18小时,然后用prep-RP-HPLC纯化(方法6:8分钟内45-75%B→4分钟内95%B),得到白色粉末状固体1-vcMMAE(4.8mg)。
LC-MS(方法2):Rt=1.84min;m/z(ES+)892.8[1/2(M+2H)]+。
实施例16其它四马来酰亚胺连接子-药物的合成
其它四马来酰亚胺连接子-药物的合成采用与实施例15的1-vcMMAE合成相同的方法,除了用本发明的连接子化合物2至12分别替换实施例15中的化合物1。得到的连接子-药物及其表征数据见表1,按照化合物2至12的编号将产物编号为2-vcMMAE至12-vcMMAE。
表1本发明连接子-药物化合物及其表征
实施例17抗体药物偶联物的合成和表征
向抗体H(IgG1)溶液(2-10mg/mL,25mM硼酸-硼酸钠缓冲液,25mM氯化钠,1mM二乙烯三胺五乙酸,pH值7.0-8.0)中加入三(2-羧乙基)膦盐酸盐(10eq,储备液浓度10mM)。反应液于37℃恒温摇床内孵育2小时。将反应液冷却至约10℃,经超滤(Merck MilliporeUltra,50000MWCO)或凝胶过滤置换缓冲液(100mM磷酸二氢钾-磷酸氢二钾,100mM氯化钠,1mM二乙烯三胺五乙酸,pH 7.0-8.0),加入二甲亚砜和实施例15制得的化合物1-vcMMAE(二甲亚砜储备液,3-6当量),并保证反应液中二甲亚砜体积占比达15%左右。偶联反应在10℃进行0.5小时。
向反应液加入过量的半胱氨酸溶液,以淬灭未反应的化合物1-vcMMAE,淬灭反应在10℃进行30分钟。将反应液先经超滤(Merck MilliporeUltra,50000MWCO)或凝胶过滤除去1-vcMMAE-半胱氨酸加合物以及过量的半胱氨酸,然后经由0.22μm孔径的过滤装置(Merck Millex-GV Filter)除菌,得到抗体药物偶联物H-1-vcMMAE,并在4℃条件下保存。
利用上述制备方法,以H为抗体,以2-vcMMAE至12-vcMMAE分别代替1-vcMMAE,制得本发明其它抗体药物偶联物H-2-vcMMAE至H-12-vcMMAE;以P为抗体,以7-vcMMAE代替1-vcMMAE,制得抗体药物偶联物P-7-vcMMAE。
1)平均DAR值测定
平均DAR值是通过紫外吸收的方法进行测定(Clin.Cancer Res.2004,10,7063-7070;WO 2011/039721)。所用仪器为安捷伦1100高效液相色谱仪,色谱柱为尺寸排阻色谱(SEC)柱(TSKgel G3000SWXL,7.8*300mm,东曹生物)。
DAR=(εAb248-R*εAb280)/(R*εD280-εD248)
其中,εAb248和εAb280分别是抗体在248nm和280nm的摩尔消光系数,εD280和εD248分别是vcMMAE在248nm和280nm的摩尔消光系数。R=A248/A280,其中A248和A280分别是本发明抗体药物偶联物在248nm和280nm的吸光率(本发明中采用的是SEC色谱上的单体峰面积)。
本发明抗体药物偶联物的平均DAR值测定结果如下表2所示。
表2本发明抗体药物偶联物的平均DAR值结果(连接子-药物相对抗体的当量数是3)
抗体药物偶联物 | 平均DAR值 | 抗体药物偶联物 | 平均DAR值 |
H-1-vcMMAE | 1.99 | H-7-vcMMAE | 1.99 |
H-2-vcMMAE | 1.99 | H-8-vcMMAE | N/A |
H-3-vcMMAE | N/A | H-9-vcMMAE | 1.96* |
H-4-vcMMAE | 1.96 | H-10-vcMMAE | 2.46* |
H-5-vcMMAE | 2.05 | H-11-vcMMAE | 2.75 |
H-6-vcMMAE | 1.88 | H-12-vcMMAE | 2.51 |
P-7-vcMMAE | 2.20*& |
N/A:不可得。
*:连接子-药物相对抗体的当量数是4.
&:DAR值计算方法采用HIC色谱法,参考Anal.Chem.2013,85,1699-1704。
如上表2可知,采用本发明的四马来酰亚胺型连接子得到的抗体药物偶联物的平均DAR值能够很好的控制在2左右,而这一结果是由于本发明的连接子能够定点精准地控制偶联位点和数量所产生的。
2)非变性质谱分析(Native MS)
取400μg本发明的抗体药物偶联物H-5-vcMMAE样品,加入8μL糖苷酶PNGase F(NewEngland Biolabs,美国),在37℃孵育过夜(15小时)。将脱糖的抗体药物偶联物样品置换到醋酸铵缓冲液(20mM,pH 7.0)中,并将此缓冲液置换过程重复进行5次。
实验中使用的质谱仪为高分辨的Orbitrap Exactive Plus EMR(Thermo FisherScientific,德国),离子源为TriVersa(Advion,美国)。将样品浓度调至2μg/μl,采用直接进样法,采集正离子模式下的质谱数据。采集的非变性质谱数据使用软件Protein Deconvolution 4.0(Thermo Fisher Scientific,德国)进行分析处理。
抗体药物偶联物H-5-vcMMAE的非变性质谱测定结果如图1所示。从该图中可以看出,DAR=2的组分是主要组分。
3)聚丙烯酰胺凝胶电泳(SDS-PAGE)
SDS-PAGE是在XCellMini-Cell蛋白垂直电泳槽(赛默飞世尔)上使用NuPAGETM4-12%Bis-Tris蛋白胶(赛默飞世尔)测定的:将不低于10μg的样品与相应的上样缓冲液混合,70℃水浴上加热10min;按顺序将样品和标准蛋白(5μL/孔)加入到浓缩胶梳孔中,在200伏条件下泳胶50min;将泳好的胶取出,用去离子水冲洗一遍,然后加入SimplyBlueTMSafeStain(赛默飞世尔)并在摇床上染色3h;染色后的胶用去离子水冲洗三遍,在摇床上脱色4小时;脱色后的胶取出后转移到成像仪上记录凝胶图像。
SDS-PAGE测定结果如图2a-2b所示,样品H-1-vcMMAE至H-12-vcMMAE中的主要成分是完整抗体HHLL(完整抗体药物偶联物)和半抗体HL(完整抗体药物偶联物在实验条件下失去重链间的相互作用而得到)。此结果验证了本发明公开的四马来酰亚胺型连接子可以对还原后的抗体不同链间起到交联的作用,从而有效地控制每个抗体上偶联的药物数量(DAR)。
4)疏水作用色谱(HIC)分析
疏水作用色谱是在安捷伦1100(AgILent 1100)色谱仪上测定的。固定相采用TSKgel丁基-NPR柱(4.6×35mm,2.5μm,东曹(上海)生物科技有限公司)。洗脱梯度为线性梯度,25分钟内从100%缓冲液A[50mM磷酸钾(pH 7.0)+1.5M硫酸铵]置换到100%缓冲液B[80%v/v 50mM磷酸钾(pH 7.0)+20%v/v异丙醇]。流速为0.8mL/min,柱温设在30℃,检测波长设在230nm和280nm。
HIC分析结果如附图3a-3m所示,样品H-1-vcMMAE至H-12-vcMMAE,以及P-7-vcMMAE中的主要成分是DAR=2的组分。此结果验证了本发明公开的四马来酰亚胺型连接子可以有效地控制抗体药物偶联物的DAR值及其分布。
试验例1本发明的抗体药物偶联物对抗原的亲和力测定
酶联免疫吸附测定(ELISA)
采用间接ELISA方法考察待测抗体或抗体药物偶联物与对应抗原的结合能力:将Her2抗原与固相载体(96孔酶标板)连接,形成固相抗原,洗涤除去未结合的抗原;加梯度稀释的本发明制得的抗体药物偶联物或其对应的抗体,其中的特异抗体与抗原结合,形成固相抗原-抗体复合物,未结合固相抗原的抗体或抗体药物偶联物经洗涤除去;加酶标抗抗体,使其与结合在固相抗原上的抗体或ADC抗体结合,未结合的抗抗体经洗涤除去;加入底物溶液,用酶标仪读取450nm/630nm处的光密度值,绘制曲线,计算EC50。
本发明的抗体药物偶联物对Her2抗原的亲和力测定结果如表3所示。
表3本发明抗体药物偶联物对Her2抗原的亲和力测定结果
由上表3可知,采用本发明公开的四马来酰亚胺连接子得到的抗体药物偶联物,其对抗原的亲和力与裸抗H相比,无显著性差异。
试验例2本发明的抗体药物偶联物抑制细胞增殖抑制的作用
细胞增殖实验(Cell Proliferation Assay)
抗体或抗体药物偶联物的细胞抑制活性是通过以下方法测定的:将表达肿瘤相关抗原或受体蛋白的哺乳动物细胞(本试验采用表达Her2抗原的人乳腺癌细胞SK-BR-3)接种在96孔板上,每孔接种8000个细胞,悬浮于DMEM高糖细胞培养基(GIBCO)200μL;ADC样品初始浓度2μg/mL,用含2%FBS(GIBCO)的DMEM高糖细胞培养基进行3倍梯度稀释;移除原培养基,每孔加入200μLADC样品,继续孵育72小时;移除原培养基,每孔加入CCK-8显色液100μL,继续培养30分钟;用酶标仪读取450nm/630nm的吸光度值,绘制曲线,计算(I)C50。
本发明的抗体药物偶联物抑制细胞增殖作用的结果如表4所示。
表4本发明抗体药物偶联物抑制细胞增殖作用的结果
抗体药物偶联物 | IC50(ng/mL) | 抗体药物偶联物 | IC50(ng/mL) |
H-1-vcMMAE | 5.1 | H-7-vcMMAE | 8.8 |
H-2-vcMMAE | 7.9 | H-8-vcMMAE | 9.1 |
H-3-vcMMAE | 7.7 | H-9-vcMMAE | 5.1 |
H-4-vcMMAE | 8.8 | H-10-vcMMAE | 6.3 |
H-5-vcMMAE | 8.6 | H-11-vcMMAE | 6.1 |
H-6-vcMMAE | 9.4 | H-12-vcMMAE | 7.4 |
P-7-vcMMAE | 8.8 |
结论:本发明制得的抗体药物偶联物均具有良好的细胞增殖抑制作用。
在本发明提及的所有文献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 (21)
1.一种如式I所示的化合物或其药学上可接受的盐,
其中,
P、Q各自独立地选自CR10、N或芳基;
S、T各自独立地选自C=O或O;
X、Y各自独立地选自-C(O)N(R11)-、-N(R12)C(O)-或-O-;
Z选自CR13、N或芳基;
U选自C=O或O;
J选自-COOH、-OH、或-NHR14;
h、i、j、k、l、m、p、q、s、t、x、y、u和w各自独立地选自0或1;
R1、R2、R3、R4、R5、R6、R7、R8和R9各自独立地选自C1-C6亚烷基、或骨架内含O的C1-C6亚烷基;
R10、R11、R12、R13和R14各自独立地选自H或C1-C6烷基。
2.根据权利要求1所述的式I所示的化合物或其药学上可接受的盐,其中,
P、Q各自独立地选自CR10或N;
R10选自H或C1-C6烷基。
3.根据权利要求1或2所述的式I所示的化合物或其药学上可接受的盐,其中,
X、Y各自独立地选自-C(O)N(R11)-;
x和y各自独立地选自0或1;
R11选自H或C1-C6烷基。
4.根据权利要求1至3中任一项所述的式I所示的化合物或其药学上可接受的盐,其中,
Z选自CR13、N或C6-C10芳基优选苯基;
R13选自H或C1-C6烷基。
5.根据权利要求1至4中任一项所述的式I所示的化合物或其药学上可接受的盐,其中,
R1、R2、R3和R4各自独立地选自C1-C6亚烷基;
h、i、j和k各自独立地选自0或1。
6.根据权利要求1至5中任一项所述的式I所示的化合物或其药学上可接受的盐,其中,
S、T各自独立地选自C=O或O;
R5、R6各自独立地选自C1-C6亚烷基;
l、m各自独立地选自0或1;
s、t各自独立地选自0或1。
7.根据权利要求1至6中任一项所述的式I所示的化合物或其药学上可接受的盐,其中,
R7、R8各自独立地选自C1-C6亚烷基、或骨架内含O的C1-C6亚烷基;
p、q各自独立地选自0或1。
8.根据权利要求1至7中任一项所述的式I所示的化合物或其药学上可接受的盐,其中,
U选自C=O或O;
R9选自C1-C6亚烷基;
u和w各自独立地选自0或1。
9.根据权利要求1至8中任一项所述的式I所示的化合物或其药学上可接受的盐,其中,J选自-COOH、OH或NH2。
10.根据权利要求1至9中任一项所述的式I所示的化合物或其药学上可接受的盐,其中所述化合物选自:
11.一种如式II所示的化合物,
V-A-D
II
其中,
V为根据权利要求1至10中任一项所述的式I所示的化合物;
A是任选其它连接子部分;
D是药物分子部分;
其中V通过末端基团J与连接子A或药物分子D的一端反应相连接。
12.一种如式III所示的抗体药物偶联物,
其中,
L是抗体或抗体片段-;
V是为根据权利要求1至10中任一项所述的式I所示的化合物;
A是任选其它连接子部分;
D是药物分子部分;
n为1至4的整数;
其中V通过末端基团J与连接子A或药物分子D的一端反应相连接,通过四个马来酰亚胺部分与L中的半胱氨酸或其它氨基酸残基反应相连接。
13.根据权利要求12所述的式III所示的抗体药物偶联物,其中,所述A是除四马来酰亚胺连接子以外的任意其它连接子,包括可断裂连接子或不可断裂连接子。
14.根据权利要求12或13所述的式III所示的抗体药物偶联物,其中,所述A的结构如式C–Ee–Ff或式Gg所示,
其中,
C是可断裂连接子;
E和F是自杀式连接子;
e和f各自独立地为0至5的整数;
G是不可断裂连接子;
g是0至5的整数。
15.根据权利要求12至14中任一项所述的式III所示的抗体药物偶联物,其为式IV所示的抗体药物偶联物:
其中,
L是抗体或抗体片段;
A是除四马来酰亚胺连接子以外的任意其它连接子,包括可断裂连接子或不可断裂连接子;
D是药物分子部分;
四个马来酰亚胺基团的一端同时偶联到同一抗体或抗体片段上;
P、Q各自独立地选自CR10、N或芳基;
S、T各自独立地选自C=O或O;
X、Y各自独立地选自-C(O)N(R11)-、-N(R12)C(O)-或-O-;
Z选自CR13、N或芳基;
U选自C=O或O;
J’选自C=O、O、或NR14;
h、i、j、k、l、m、p、q、s、t、x、y、u和w各自独立地选自0或1;
R1、R2、R3、R4、R5、R6、R7、R8和R9各自独立地选自C1-C6亚烷基、或骨架内含O的C1-C6亚烷基;
R10、R11、R12、R13和R14各自独立地选自H或C1-C6烷基。
16.根据权利要求12至15中任一项所述的式III所示的抗体药物偶联物,其中,所述抗体为针对细胞表面受体和肿瘤相关抗原的抗体。
17.根据权利要求12至16中任一项所述的式III所示的抗体药物偶联物,其中,所述抗体为IgG1抗体。
18.根据权利要求12至17中任一项所述的式III所示的抗体药物偶联物,其中,所述药物为细胞毒性药物、治疗自身免疫疾病的药物和抗炎症的药物。
19.一种药物组合物,其含有根据权利要求12至18中任一项所述的式III所示的抗体药物偶联物以及药学上可接受的载体。
20.根据权利要求1至10中任一项所述的式I所示的化合物作为连接子在制备抗体药物偶联物中的用途。
21.根据权利要求12至18中任一项所述的式III所示的抗体药物偶联物,或根据权利要求19所述的药物组合物,在制备治疗癌症、自身免疫性疾病和炎症性疾病的药物中的用途。
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CN107652219B (zh) | 2021-06-08 |
US20210128668A1 (en) | 2021-05-06 |
JP2020530481A (ja) | 2020-10-22 |
CA3070893A1 (en) | 2019-02-21 |
WO2019033773A1 (en) | 2019-02-21 |
KR102604938B1 (ko) | 2023-11-21 |
KR20200038954A (ko) | 2020-04-14 |
EP3668838A1 (en) | 2020-06-24 |
JP7239558B2 (ja) | 2023-03-14 |
US11666623B2 (en) | 2023-06-06 |
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AU2018317230B2 (en) | 2022-06-02 |
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