CN115666642A - 含有α-烯醇酶抗体的药物缀合物和其用途 - Google Patents
含有α-烯醇酶抗体的药物缀合物和其用途 Download PDFInfo
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- CN115666642A CN115666642A CN202180034808.XA CN202180034808A CN115666642A CN 115666642 A CN115666642 A CN 115666642A CN 202180034808 A CN202180034808 A CN 202180034808A CN 115666642 A CN115666642 A CN 115666642A
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Abstract
一种免疫缀合物,所述免疫缀合物包括抗ENO‑1抗体或其结合片段以及治疗剂或标记物,并具有下式:Ab‑(L‑D)m,其中Ab为所述抗ENO‑1抗体或其结合片段,L为连接子或直接键,D为治疗剂或标记物,m为1至12的整数。所述抗体可为单克隆抗体,其可为人源化抗体或全人类抗体。一种治疗炎性疾病、免疫病症或癌症的方法,所述方法包括向需要这种治疗的受试者施用药学有效量的免疫缀合物,所述免疫缀合物包含针对ENO‑1的抗体或其结合片段,以及与所述抗体共价缀合的治疗剂。
Description
本申请要求2020年5月11日提交的美国临时案第63/022,702号的优先权,其出于所有目的以引用的方式并入本文。
发明领域
本发明涉及一种含有抗人类α-烯醇酶蛋白(ENOlase protein,ENO-1)抗体的抗体-药物缀合物和其治疗用途。本发明还涉及一种用于治疗炎性疾病或免疫病症的方法,或通过对受试者施用抗α-烯醇酶蛋白(ENO-1)抗体-药物缀合物(antibody-drug conjugate,ADC)来抑制肿瘤生长以及转移。
背景技术
抗体-药物缀合物(Antibody-drug conjugates,ADCs)可提供标靶疗法以治疗各种疾病或病症,如癌症。ADCs为包含与生物活性剂(如细胞毒性剂或药物)相关的抗体的复杂分子。通过结合抗体的独特标靶与药物的治疗效果,抗体-药物缀合物可区分正常以及癌细胞,进而最小化副作用。
ADCs通常包括细胞毒性药物(例如,微管蛋白抑制剂或DNA烷基化剂),其偶联至特异性靶向标记物(例如肿瘤标记物)的抗体。抗体在体内追踪这些蛋白质并将其自身连接到癌细胞的表面。抗体与所述标靶蛋白(抗原)之间的结合触发肿瘤细胞内的信号,然后将所述ADC内化。在所述ADC内化后,可释放所述细胞毒性药物并杀死所述肿瘤。由于所述特异性标靶,所述药物具有较低的副作用。
α-烯醇酶(Enolase-1,ENO-1)是一种多功能蛋白,首先被发现作为糖分解途径的关键酶。在正常情况下,ENO-1在细胞质液中表达。然而,ENO-1还被发现在许多癌细胞的细胞表面上作为纤维蛋白溶酶原受体表达以及在活化的造血细胞(例如中性粒细胞、淋巴细胞以及单核细胞)上表达。已知纤维蛋白溶酶原受体蛋白的上调可诱导尿激酶纤维蛋白溶酶原活化系统的级联反应,并导致细胞外基质降解。结果导致癌细胞转移增加以及免疫细胞的浸润。炎性刺激物,例如LPS,会通过翻译后修饰以及易位至细胞表面而上调在人类血液单核细胞以及在U937单核细胞上ENO-1细胞表面的表达。
据信ENO-1的易位由MAP激酶信号传递途径调节。这代表ENO-1在细胞表面表达的增加可能在炎性疾病中具有重要的作用。针对ENO-1的自身抗体已在可变自身免疫以及炎性疾病中被发现,包括红斑性狼疮、全身性硬化症、贝雪氏病(Behcet's disease)、溃疡性结肠炎以及克罗恩氏病(Crohn's disease)。已知通过ENO-1的纤维蛋白溶酶原受体活性,ENO-1通过增加单核细胞和巨噬细胞的侵袭活性而在类风湿性关节炎患者的疾病进展中具有关键作用。
总而言之,具有在细胞表面上调的ENO-1表达作为增加侵袭活性的纤维蛋白溶酶原受体的单核细胞对多发性硬化症、类风湿性关节炎,以及相关免疫病症的疾病进展非常重要。因此,以在单核细胞的细胞表面上的ENO-1为标靶具有良好的潜力来治疗炎性疾病,例如多发性硬化症、类风湿性关节炎、克罗恩氏病、溃疡性结肠炎,以及全身性红斑性狼疮,或相关免疫病症,如慢性阻塞性肺病(chronic obstructive pulmonary disease,COPD)、气喘、过敏、牛皮癣、第1型糖尿病、动脉粥样硬化以及骨质疏松症。
此外,作为纤维蛋白溶酶原受体的癌细胞表面上的ENO-1的表达可增加所述癌细胞的侵袭活性。因此,ENO-1也是癌症治疗的潜在目标。
尽管针对ENO-1的抗体是有用的,但仍需使用抗ENO-1ADCs的改进治疗剂。
发明内容
本发明涉及一种含有ENO-1抗体的抗体-药物缀合物和其治疗用途。
本发明的一个方面涉及一种免疫缀合物。根据本公开的一个具体实施方式的免疫缀合物包括抗ENO-1抗体或其结合片段以及治疗剂或标记物,并具有下式:Ab-(L-D)m,其中Ab为抗ENO-1抗体或其结合片段,L为连接子或直接键,D为治疗剂或标记物,m为1至12的整数。
根据本发明的任何具体实施方式,所述Ab可包含重链可变结构域,所述重链可变结构域具有三个互补区域,包括HCDR1(GYTFTSCVMN;SEQ ID NO:1)、HCDR2(YINPYNDGTKYNEKFKG;SEQ ID NO:2)以及HCDR3(EGFYYGNFDN;SEQ ID NO:3),以及轻链可变结构域,所述轻链可变结构域具有三个互补区域,包括LCDR1(RASENIYSYLT;SEQ ID NO:4)、LCDR2(NAKTLPE;SEQ ID NO:5)以及LCDR3(QHHYGTPYT;SEQ ID NO:6)。
根据本发明的任何具体实施方式,所述Ab可包含重链可变结构域,所述重链可变结构域具有三个互补区域,包括HCDR1(GYTFTSXVMN,其中X为除半胱氨酸以外的任何氨基酸;SEQ ID NO:7)、HCDR2(YINPYNDGTKYNEKFKG;SEQ ID NO:2)以及HCDR3(EGFYYGNFDN;SEQID NO:3),以及轻链可变结构域,所述轻链可变结构域具有三个互补区域,包括LCDR1(RASENIYSYLT;SEQ ID NO:4)、LCDR2(NAKTLPE;SEQ ID NO:5)以及LCDR3(QHHYGTPYT;SEQID NO:6)。
所述连接子L可为直接键,其中有效负载D与所述抗体或其结合片段直接连接(缀合)。连接子可为蛋白质修饰或缀合物中常用的任何连接子,例如短肽(例如val-cit)、短的有机分子连接子(例如琥珀酰亚胺基-4(N-马来酰亚胺甲基)环己烷-1-甲酸酯,succinimidyl-4(N-maleimidomethyl)cyclohexane-1-carboxylate,SMCC),或类似物。
所述有效负载D可为治疗剂,例如细胞毒性剂。可与本发明的具体实施方式一起使用的细胞毒性剂的实例可包括化疗药美登木素生物碱(maytansinoid)(例如DM1或DM4)、单甲基澳瑞他汀E(monomethyl auristatin E,MMAE)、单甲基澳瑞他汀F(MMAF)、紫杉醇等。
所述有效负载D可被用于诊断或成像的标签或试剂。成像剂的实例可包括二亚乙基三胺五乙酸(Diethylenetriaminepentaacetic acid,DTPA)或1,4,7,10-四氮环十二烷-1,4,7,10-四乙酸(1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid,DOTA)。
根据本发明的某些具体实施方式,所述抗体可为单克隆抗体,其可为人源化抗体或全人类抗体。
本发明的一个方面涉及用于诊断表达ENO-1的细胞或组织或者使其成像的方法。根据本发明的一个具体实施方式的方法可包括给与受试者上述免疫缀合物。
根据本发明的某些具体实施方式,人类ENO-1蛋白相关的疾病或病症可能是因为人类ENO-1蛋白的异常活化或表达而产生的任何病症。这类疾病的实例包括人类ENO-1蛋白与其配体异常相互作用,进而改变细胞粘附或细胞信号性质。细胞粘附或细胞信号传递性质的这种改变可导致肿瘤疾病和/或发炎或免疫病症。
本发明的一个方面涉及治疗炎性疾病或免疫病症的方法,如多发性硬化、类风湿性关节炎、克罗恩氏病、溃疡性结肠炎、全身性红斑性狼疮、或相对免疫病症,如慢性阻塞性肺病(COPD)、异位性皮炎、特发性肺纤维化、非酒精性脂肪肝炎、气喘、过敏、牛皮癣、牛皮癣性关节炎、第1型糖尿病、动脉粥样硬化、骨质疏松症、系统性硬化、病毒诱导肺炎或巨噬细胞活化综合征。
本发明的一个方面涉及治疗癌症的方法。根据本发明的一个具体实施方式的方法可包括对需要癌症治疗的受试者施用药学上有效量的上述免疫缀合物。所述癌症是一种高度ENO-1表达的癌症,如肺癌、乳腺癌、胰腺癌、肝癌、直肠癌以及前列腺癌。
本领域技术人员将理解,药学上有效量取决于许多因素,如患者病症、年龄、疾病状态、施用途径等,且这种有效量可基于常规实践中的这些因素来确定,而无需过度实验。
本发明的其它方面将通过以下描述变得显而易见。
附图说明
图1所示为HuL001-SMCC-DM1的PLRP-HPLC结果。实施例7描述缀合反应基本上完成,且仅留下抗ENO-1抗体以及ADCs的残留量。
图2所示为HuL001-SPP-DM4的PLRP-HPLC结果。实施例7描述缀合反应基本上完成,且仅留下抗ENO-1抗体以及ADCs的残留量。
图3所示为HuL001-mal-vc-MMAE的HIC结果。实施例7描述缀合反应基本上完成,且仅留下抗ENO-1抗体以及ADCs的残留量。
图4所示为HuL001-Ph-MMAF的PLRP-HPLC结果。实施例7描述缀合反应基本上完成,且仅留下抗ENO-1抗体以及ADCs的残留量。
图5所示为HuL001-mal-vc-类固醇的HIC结果。实施例7描述缀合反应基本上完成,且仅留下抗ENO-1抗体以及ADCs的残留量。
图6所示为HuL001-SMCC-DM1的LC/MS结果。细节描述于实施例8中。
图7所示为HuL001-SPP-DM4的LC/MS结果。细节描述于实施例8中。
图8所示为HuL001-mal-vc-MMAE的降低的LC/MS结果。细节描述于实施例8中。
图9所示为HuL001-Ph-MMAF的LC/MS结果。细节描述于实施例8中。
图10所示为HuL001-mal-vc-类固醇的降低的LC/MS结果。细节描述于实施例8中。
图11所示为在LPS刺激的B细胞癌细胞系DHL-4中的HuL001-SPP-DM4的体外细胞毒性结果。细节描述于实施例9中。
图12所示为无论LPS的刺激如何,在分离的正常人类B细胞中的HuL001-SMCC-DM1没有可检测的体外细胞毒性。细节描述于实施例9中。
图13所示为无论LPS的刺激如何,在分离的正常人类B细胞中的HuL001-mal-vc-MMAE没有可检测的体外细胞毒性。细节描述于实施例9中。
图14所示为,相较于HuL001,HuL001-mal-vc-类固醇对于在LPS处理的人类单核细胞系THP-1中的TNF-α以及CCL2分泌物具有优异的抗发炎作用。细节描述于实施例10。
图15所示为在PC-3异种移植前列腺癌模型中的HuL001-SMCC-DM1体内疗效。相较于媒剂对照组,以HuL001-SMCC-DM1处理能够抑制肿瘤生长。如实施例11中所述进行详细的程序。
图16所示为在C57BL/6EAE疾病模型中HuL001-SMCC-DM1的体内疗效。相较于PBS对照组甚至组,以HuL001-SMCC-DM1处理能够减缓EAE小鼠的疾病症状的进展。如实施例12中所述进行详细的程序。
图17所示为在C57BL/6博莱霉素诱导的肺纤维化疾病模型中HuL001-SMCC-DM1的体内疗效。相较于博莱霉素处理组,以HuL001-SMCC-DM1处理能够弱化肺纤维化小鼠体重的减轻以及肺重量的增加。如实施例13中所述进行详细的程序。
具体实施方式
一般定义
除非另有说明,否则本发明的实施将采用本领域技术内的分子生物学、微生物学、重组DNA以及免疫学的常规技术。这些技术在文献中被充分解释。参见例如《分子克隆实验室手册(Molecular Cloning A Laboratory Manual)》,第2版,由Sambrook、Fritch以及Maniatis编辑(冷泉港实验室出版社,1989年);《DNA克隆(DNA Cloning)》,第I和II卷(D.N.Glover编辑,1985年);《动物细胞培养(Culture Of Animal Cells)》(R.I.Froundney,Alan R.Liss公司,1987年);《固定化细胞和酶(Immobilized Cells AndEnzymes)》(IRL出版社,1986年);B.Perbal,《分子克隆实用手册(A Practical Guide ToMolecular Cloning)》(1984年);《酶学方法(Methods In Enzymology)》博士论文(Academic出版社公司,纽约);《哺乳动物细胞的基因转移载体(Gene Transfer VectorsFor Mammalian Cells)》(J.H.Miller以及M.P.Calos编辑,1987年,冷泉港实验室);《酶学方法(Methods In Enzymology)》,第154和155卷(Wu等人编辑),《细胞和分子生物学中的免疫化学方法(Immunochemical Methods In Cell And Molecular Biology)》(Mayer与Walker编辑,Academic出版社,伦敦,1987年);《抗体:实验室手册(Antibodies:ALaboratory Manual)》,由Harlow与Lane编辑(冷泉港实验室出版社,1988年);以及《实验免疫学手册(Handbook Of Experimental Immunology)》,第I-IV卷(D.M.Weir与C.Blackwell编辑,1986年)。
术语“抗体”以及“免疫球蛋白”在最广泛的意义上可互换地使用,包括单克隆抗体(例如全长或完整的单克隆抗体)、多克隆抗体、单价、多价抗体、多特异性抗体(例如双特异性抗体,只要它们表达出所需的生物活性)并且还可包括某些抗体片段(如本文更详细描述的)。抗体可为嵌合、人类的、人源化的和/或亲和力成熟的。
术语“变量”是指以下事实:可变结构域的某些部分在抗体之间的序列差异很大,并用于每种特定抗体对其特定抗原的结合和特异性。然而,可变性并非均匀地分布在整个抗体的可变结构域中。它集中在轻链和重链可变结构域两者都存在的一个名为互补性决定区域(complementarity-determining regions,CDRs)或高变异区域的三个区段。可变结构域的较高度保守的部分称为框架(framework,FR)。天然重链以及轻链的可变结构域各自包括四个FR区域,主要采用β-褶板构造,通过三个CDRs连接,其形成环连接,并在一些情况下形成所述β-褶板结构的一部分。每个链中的CDRs在FR区附近保持在一起,并与来自其它链的CDRs接在一起,有助于形成抗体的抗原结合位点(参见Kabat等人,《具有免疫学意义的蛋白质序列(Sequences of Proteins of Immunological Interest)》,第五版,国家卫生研究院,贝塞斯达市,马里兰州(1991年))。恒定结构域不直接涉及将抗体结合到抗原,但表达出各种效应功能,例如抗体在抗体依赖性细胞毒性中的参与。
抗体可为全长的,或可包含具有抗原结合部分的抗体的片段(或多个片段),包括但不限于Fab、F(ab')2、Fab'、F(ab)'、Fv、单链Fv(scFv)、二价scFv(bi-scFv)、三价scFv(tri-scFv)、Fd、dAb片段(例如,Ward等人,Nature,341:544-546(1989年))、CDR、双体、三体、四体、线性抗体、单链抗体分子以及由抗体片段形成的多特异性抗体。通过使用重组方法或合成连接子通过连接抗体片段产生的单链抗体也包括于本发明内。Bird等人,Science,1988年,242:423-426。Huston等人,Proc.Natl.Acad.Sci.USA,1988年,85:5879-5883。
具有可变重链区以及可变轻链区的抗体,所述可变重链区以及所述可变轻链区与由参考抗体所产生的抗体的可变重链区以及可变轻链区具有至少约70%、至少约75%、至少约80%、至少约81%、至少约82%、至少约为83%、至少约84%、至少约85%、至少约86%、至少约87%、至少约88%、至少约89%、至少约90%、至少约91%、至少约92%、至少约93%、至少约94%、至少约95%、至少约96%、至少约97%、至少约98%、至少约99%或约100%的同源性,也可与ENO-1结合。同源性可存在于氨基酸或核苷酸序列的层级。
术语“可变结构域残基的Kabat编号”或“氨基酸位置的Kabat编号”和其变化形式是指用于重链可变结构域或轻链可变结构域的Kabat等人抗体汇编的编号系统,Kabat等人,《具有免疫学意义的蛋白质序列(Sequences of Proteins of ImmunologicalInterest)》,第5版,公共卫生服务部,国家卫生研究院,贝塞斯达市,马里兰州(1991年)。使用所述编号系统,实际的线性氨基酸序列可能包含更少或更多对应于可变结构域的FR或HVR的缩短或插入的氨基酸。例如,重链可变结构域可包括在H2残基52之后的单个氨基酸插入(根据Kabat的残基52a)以及在重链FR残基82之后的插入残基(例如,根据Kabat的残基82a、82b,以及82c等)。可通过在给定的抗体序列的同源区与“标准”Kabat编号序列进行比对来确定所述给定的抗体的残基的Kabat编号。
术语“癌症”以及“癌症的”是指或描述哺乳动物中的生理病症,所述生理病症通常的特征在于由不受控的细胞生长/增殖。癌症的实例包括但不限于恶性肿瘤、淋巴瘤(例如霍奇金氏(Hodgkin)以及非霍奇金氏淋巴瘤)、胚细胞瘤、肉瘤以及血癌。这些癌症的更具体的实例包括鳞状细胞癌、小细胞肺癌、非小细胞肺癌、肺腺癌、肺鳞状癌、腹膜癌、肝细胞癌、胃肠癌、胰腺癌、神经胶质母细胞瘤、宫颈癌、卵巢癌、肝脏癌、膀胱癌、肝癌、乳腺癌、结肠癌、结肠直肠癌、子宫内膜或子宫癌、唾腺癌、肾癌、肝脏癌、前列腺癌、外阴癌、甲状腺癌、肝癌、血癌以及其它淋巴增生病变,以及各种类型的头颈癌。
如本文所用,“治疗”是指试图改变所处理的个体或细胞的自然过程的临床干预,且可用于预防或在临床病理过程中进行。治疗的理想效果包括预防疾病的发生或复发、减轻症状、对疾病的任何直接或间接病理后果的减少、预防或减少发炎和/或组织/器官损伤、降低疾病进展的速度、改善或缓和疾病状态以及缓解或改善预后。在一些具体实施方式中,本发明的抗体用于延迟疾病或病症的发展。
“个体”或“受试者”为脊椎动物。在某些具体实施方式中,所述脊椎动物为哺乳动物。哺乳动物包括但不限于农场动物(如奶牛)、竞赛动物、宠物(如猫、狗和马)、灵长类动物、小鼠以及大鼠。在某些具体实施方式中,所述脊椎动物为人类。
“有效量”是指在剂量以及所需时间内的有效量,以达到所需的治疗或预防效果。
本发明的物质/分子的“治疗有效量”可根据例如个体的疾病状态、年龄、性别以及体重等因素,以及所述物质/分子的能力而变化,以在所述个体内引发所需的反应。治疗有效量也是所述物质/分子的任何毒性或有害作用都被治疗有益作用所超过的量。“预防有效量”是指在剂量以及所需时间内有效的量,以达到所需的预防效果。通常但不一定,由于预防剂量用于染病前或染病早期阶段的受试者中,所述预防有效量将小于所述治疗有效量。
如本文所用的术语“治疗剂”是指抑制或防止细胞功能和/或导致细胞破坏的物质。所述术语目的在于包括放射性同位素(例如211At、131I、125I、90Y、186Re、188Re、153Sm、212Bi、32P、60C以及镏-177、锶-89以及钐(153Sm)的放射性同位素)、免疫调节剂、细胞毒性剂,以及毒素,例如小分子毒素或细菌、真菌、植物或动物来源的酶促活性毒素,包括合成类似物和其衍生物。
“细胞毒性剂”为一种可用于治疗癌症的化合物。化学治疗剂的实例包括美登木素生物碱1(maytansinoids 1,DM1)、美登木素生物碱4(DM4)、单甲基澳瑞他汀E(Monomethylauristatin E,MMAE)、单甲基澳瑞他汀F(MMAF)、蒽环素(anthracycline)、吡咯洛唑二氮杂(pyrrolobenzodiazepine)、α-蝇蕈素(α-amanitin)、微管溶素(tubulysin)、苯二氮平类药物、厄洛替尼(erlotinib)(Genentech/OSI制药公司)、硼替佐米(Bortezomib)(Millenium制药公司)、氟维司群(Fulvestrant)(Astrazeneca公司)、舒尼替尼(Sunitinib)(Su11248,Pfizer公司)、来曲唑(letrozole)(Novartis公司)、甲磺酸伊马替尼(imatinib)(Novartis公司)、PTK787/ZK 222584(Novartis公司)、奥沙利铂(Oxaliplatin)(Sanofi公司)、菊白叶酸(leucovorin)、雷帕霉素(Sirolimus,Wyeth公司)、拉帕替尼(lapatinib)(GSK572016,GlaxoSmithKline公司)、洛那法尼(lonafarnib)(SCH 66336)、索拉非尼(sorafenib)(Bay43-9006,Bayer Labs.公司),以及吉非替尼(gefitinib)(Astrazeneca公司)、AG1478、AG1571(SU 5271;Sugen公司),烷基化试剂,如噻替哌(thiotepa)以及环膦酰胺;亚烷基磺酸盐,如白消安(busulfan)、英丙舒凡(improsulfan)以及哌泊舒凡(piposulfan);氮丙啶类,如苯唑多巴(benzodopa)、卡波醌(carboquone)、米得哌(meturedopa)以及乌得哌(uredopa);吖环丙烷(ethylenimines)以及甲基蜜胺类(methylamelamines),包括六甲蜜胺(altretamine)、三乙烯三聚氰胺(triethylenemelamine)、三亚乙基磷酰胺(triethylenephosphoramide)、三亚乙基硫代磷酰胺(triethylenethiophosphoramide)以及三甲基蜜胺(trimethylomelamine);内酯(acetogenins)(特别是布拉他辛(bullatacin)以及布拉他辛酮(bullatacinone));一种喜树碱(camptothecin)(包括合成模拟托普乐肯(Topotecan));苔藓虫素(bryostatin);卡利斯他汀(callystatin);CC-1065(包括其阿多来新(adozelesin)、卡折来新(carzelesin)以及比塞莱新(bizelesin)合成类似物);念珠藻素(cryptophycins)(特别是念珠藻素1以及念珠藻素8);尾海兔素(dolastatin);杜卡霉素(duocarmycin)(包括合成类似物,KW-2189以及CB1-TM1);艾榴塞洛素(eleutherobin);胰抑素(pancratistatin);珊瑚素(sarcodictyin);海绵素(spongistatin);氮芥剂如氯芥苯丁酸(chlorambucil)、萘氮芥(chlornaphazine)、氯萘嗪(cholophosphamide)、环磷酰胺(cholophosphamide)、雌莫司汀(estramustine)、异环磷酰胺(ifosfamide)、甲氯乙胺(mechlorethamine)、盐酸甲乙胺盐酸盐(mechlorethamine oxide hydrochloride)、美法仑(melphalan)、新氮芥(novembichin)、苯芥胆甾醇(phenesterine)、泼尼氮芥(prednimustine)、曲磷胺(trofosfamide)、尿嘧啶氮芥(uracil mustard);亚硝基脲(nitrosureas),如卡莫司汀(carmustine)、氯脲霉素(chlorozotocin)、福莫司汀(fotemustine)、洛莫司汀(lomustine)、尼莫司汀(nimustine)以及雷诺氮芥(ranimustine);抗生素,如烯二炔抗生素(例如,卡奇霉素(calicheamicin),尤其是卡奇霉素γ1以及卡奇霉素ω1(Angew Chem.Intl.Ed.Engl.(1994年)33:183-186);达尼霉素(dynemicin),包括达尼霉素A;双磷酸盐类,如氯磷酸盐(clodronate);埃司帕霉素(esperamicin);以及新卡他汀发色团(neocarzinostatin chromophore)以及相关的色素蛋白烯二炔抗生素发色团)、阿克拉霉素(aclacinomysins)、放线菌霉素(actinomycin)、安曲霉素(authramycin)、茜素(azaserine)、博莱霉素(bleomycins)、放线菌素(cactinomycin)、卡拉霉素(carabicin)、洋红霉素(caminomycin)、嗜癌菌素(carzinophilin)、色霉素(chromomycinis)、放线菌素(dactinomycin)、道诺霉素(daunorubicin)、地托比星(detorubicin)、6-重氮-5-氧代-L-正亮氨酸、阿霉素(doxorubicin)(包括吗啉代阿霉素、氰基吗啉代阿霉素、2-吡咯啉-阿霉素以及去氧阿霉素)、表柔比星(epirubicin)、依索比星(esorubicin)、艾达霉素(idarubicin)、麻西罗霉素(marcellomycin),丝裂霉素(mitomycins),如丝裂霉素C、霉酚酸(mycophenolicacid)、诺加霉素(nogalamycin)、橄榄霉素(olivomycins)、培洛霉素(peplomycin)、泊非霉素(potfiromycin)、嘌呤霉素(puromycin)、喹纳霉素(quelamycin)、罗多比星(rodorubicin)、链黑菌素(streptonigrin)、链脲佐菌素(streptozocin)、结核菌素(tubercidin)、乌苯美司(ubenimex)、新制癌菌素(zinostatin)、佐柔比星(zorubicin);抗代谢物,如甲氨蝶呤(methotrexate)以及5-氟尿嘧啶(5-fluorouracil,5-FU);叶酸类似物,如二甲叶酸(denopterin)、蝶罗呤(pteropterin)、三甲曲沙(trimetrexate);嘌呤类似物,如氟达拉滨(fludarabine)、6-巯基嘌呤(6-mercaptopurine)、硫咪嘌呤(thiamiprine)、硫鸟嘌呤(thioguanine);嘧啶类似物,如安西他滨(ancitabine)、阿扎胞苷(azacitidine)、6-氮尿苷(6-azauridine)、卡莫呋(carmofur)、阿糖胞苷(cytarabine)、双去氧尿苷(dideoxyuridine)、去氧氟尿苷(doxifluridine)、伊诺他滨(enocitabine)、氟尿苷(floxuridine);雄激素,如钙雌酮(calusterone)、屈他雄酮丙酸酯(dromostanolonepropionate)、环硫雄醇(epitiostanol)、美雄烷(mepitiostane)、睾内酯酮(testolactone);抗肾上腺剂,如氨鲁米特(aminoglutethimide)、米托坦(mitotane)、曲洛司坦(trilostane);叶酸补充剂,如醛叶酸(folinic acid);乙酰格雷酮(aceglatone);醛磷酰胺糖苷(aldophosphamide glycoside);氨基乙酰丙酸(aminolevulinic acid);恩尿嘧啶(eniluracil);安吖啶(amsacrine);阿莫司汀(bestrabucil);比生群(bisantrene);依达曲沙(edatraxate);地磷酰胺(defofamine);秋水仙胺(demecolcine);地吖醌(diaziquone);艾福米辛(elformithine);依利醋铵(elliptinium acetate);埃博霉素(epothilone);依托格鲁(etoglucid);硝酸镓;羟基脲;香菇多糖(lentinan);氯尼达明(lonidainine);美登木素生物碱(maytansinoids),如美登素(maytansine)以及安丝菌素(ansamitocins);米托脲腙(mitoguazone);米托蒽醌(mitoxantrone);莫哌达醇(mopidanmol);硝拉维林(nitraerine);喷司他丁(pentostatin);蛋胺氮芥(phenamet);吡柔比星(pirarubicin);洛索蒽醌(losoxantrone);鬼臼酸(podophyllinic acid);2-乙基酰肼(ethylhydrazide);甲基芐肼(procarbazine);多糖复合物(JHS NaturalProducts公司,尤金市,奥勒冈州);雷佐生(razoxane);根霉素(rhizoxin);西佐喃(sizofiran);锗螺胺(spirogermanium);细交链孢菌酮酸(tenuazonic acid);三亚胺醌(Triaziquone);2,2',2”-三氯三乙胺(trichlorotriethylamine);新月毒素(trichothecenes)(特别是T-2毒素、粘液霉素A(verracurin A)、罗丹丁A(roridin A)以及蛇形菌素(anguidine));乌拉坦(urethan);长春地辛(vindesine);达卡巴仁(dacarbazine);甘露醇氮芥(mannomustine);二溴甘露醇(mitobronitol);二溴卫矛醇(mitolactol);溴丙哌嗪(pipobroman);甲托辛(gacytosine);阿糖胞苷(arabinoside)(“Ara-C”);环磷酰胺(cyclophosphamide);噻替哌(thiotepa);类紫杉醇(taxoids),例如紫杉醇(paclitaxel)(Bristol-Myers Squibb Oncology公司,普林斯顿,纽泽西州),ABRAXANETM不含Cremophor,紫杉醇的白蛋白工程化纳米粒子制剂(AmericanPharmaceutical Partners,绍姆堡,伊利诺州),以及欧洲紫杉醇(docetaxel)(Rorer公司,安东尼,法国);苯丁酸氮芥(chloranbucil);吉西他滨(gemcitabine);6-硫鸟嘌呤(6-thioguanine);巯基嘌呤(mercaptopurine);甲氨蝶呤(methotrexate);铂类似物,如顺铂(cisplatin)以及卡铂(carboplatin);长春花碱(vinblastine);铂;依托泊苷(etoposide)(VP-16);异环磷酰胺(ifosfamide);米托葱醌(mitoxantrone);长春新碱(vincristine);温诺平(vinorelbine);米托葱醌(novantrone);替尼泊苷(teniposide);依达曲沙(edatrexate);柔红霉素(daunomycin);氨基蝶呤(aminopterin);希罗达(xeloda);伊班膦酸(ibandronate);CPT-11;拓扑异构酶抑制剂RFS 2000;二氟甲基鸟氨酸(difluoromethylornithine,DMFO);类维生素A(retinoids),如视黄酸(retinoic acid);卡培他滨(capecitabine)(Roche公司);以及上述任何一种的药学上可接受的盐、酸或衍生物。
示例性ADC连接子
所述ADC的合适示例性连接子描述于例如美国专利第7,595,292号(PCT公开号WO2005/007197)中。针对连接子的整个内容在此引入作为参考。所述连接子L通过不包含二硫化物基团的共价键将抗体附着至药物部分体上。所述连接子为双功能或多功能部分体,其可用于将一种或多种治疗剂或标记物(D)以及抗体单元(Ab)连接起来以形成式(I)的抗体-药物缀合物(ADCs)。使用具有反应性官能度以将所述药物连接至所述抗体上的连接子可方便地制备抗体-药物缀合物(ADCs)。半胱氨酸硫醇,或胺类,例如抗体(Ab)的N端或氨基酸侧链如赖氨酸,可与连接子试剂、药物部分体或药物连接子试剂的官能基团形成键结。
所述连接子优选为细胞外稳定的。在运输或递送至细胞前,所述抗体-药物缀合物(ADCs)优选为稳定且保持完整的,即所述抗体与所述药物部分体保持连结。所述连接子在标靶细胞外稳定,且可在细胞内以一定的有效速率切割。有效的连接子将:(i)保持所述抗体的特异性结合特性;(ii)允许细胞内递送所述缀合物或药物部分体;(iii)保持稳定和完整,即未切割,直至所述缀合物已递送或运输至其目标位点;以及(iv)保持细胞毒性、细胞杀伤作用或所述治疗剂或标记部分体的细胞抑制效果。所述ADC的稳定性可通过标准分析技术,例如质谱、HPLC,以及分离/分析技术LC/MS来测量。
所述抗体以及所述治疗剂或标记部分体的共价附着需要所述连接子具有两个反应性官能基团,即在反应意义上的二价。对附着有用的两个或更多个功能或生物活性部分体的二价连接子试剂,例如肽、核酸、药物、毒素、抗体、不完全抗原以及报导子基团为已知的,且已经描述其所得到的缀合物的方法(Hermanson,G.T.(1996年)BioconjugateTechniques;Academic Press出版社:纽约,p234-242)。
通常,所述抗体-药物缀合物化合物包含介于所述治疗剂或标记单元以及所述抗体单元之间的连接子单元。在某些具体实施方式中,所述连接子在细胞内条件下可裂解,使得所述连接子的切割在细胞内环境中释放来自所述抗体的所述药物单元。在其它具体实施方式中,所述连接子单元不可切割,且所述药物例如通过抗体降解释放。
在某些具体实施方式中,所述连接子由存在于所述细胞内环境中的切割剂(例如在溶酶体或胞内体或胞膜窖内)裂解。所述连接子可为例如通过细胞内肽酶或蛋白酶切割的肽基连接子,包括但不限于溶酶体或胞内体蛋白酶。在某些具体实施方式中,所述肽基连接子为至少两个氨基酸长或至少三个氨基酸长。切割剂可包括组织蛋白酶B和D以及血浆纤维溶素,所有这些都是已知用于水解二肽药物衍生物,导致标靶细胞内的活性药物的释放(参见例如Dubowchik与Walker,1999年,Pharm.Therapeutics 83:67-123)。最典型为肽基连接子,其被存在于158P1D7表达细胞中的酶裂解。例如,可使用由在癌组织中高度表达的硫醇依赖性蛋白酶组织蛋白酶-B所切割的肽基连接子(例如Phe-Leu或Gly-Phe-Leu-Gly连接子)。这些连接子的其它实例描述于例如美国专利第6,214,345号中,其全文并出于所有目的以引用方式并入本文。在特定具体实施方式中,通过细胞内蛋白酶裂解的肽基连接子为Val-Cit连接子或Phe-Lys连接子(参见例如美国专利第6,214,345号,其描述带有所述val-cit连接子的阿霉素(doxorubicin)的合成)。使用所述治疗剂的细胞内蛋白水解释放的一个优点是当缀合时所述试剂通常为减弱的,且所述缀合物的血清稳定性通常很高。
在其它具体实施方式中,所述可切割连接子为pH敏感的,即对某些pH值的水解敏感。通常,在酸性条件下可水解pH敏感的连接子。例如,可使用可在溶酶体中可水解的酸不稳定的连接子(例如腙、缩胺脲、硫半卡腙、顺式乌头酰胺、原酸酯、缩醛、缩酮等)。(参见例如美国专利第5,122,368号;第5,824,805号;第5,622,929号;Dubowchik与Walker,1999年,Pharm.Therapeutics 83:67-123;Neville等人,1989年,Biol.Chem.264:14653-14661)。这种连接子在中性pH条件下相对稳定,例如血液中的环境,但在低于pH 5.5或5.0,溶酶体的近似pH下则不稳定。在某些具体实施方式中,所述可水解连接子为硫代醚连接子(例如通过酰基腙键连接到所述治疗剂上的硫醚(参见例如美国专利第5,622,929号))。
在其它具体实施方式中,所述连接子在还原条件下可裂解(例如,二硫化物连接子)。各种二硫键连接子为本领域已知的,包括例如可使用SATA(N-琥珀酰亚胺基-S-乙酰硫代乙酸酯)、SPDP(N-琥珀酰亚胺基-3-(2-吡啶二硫基)丙酸盐)、SPDB(N-琥珀酰亚胺基-3-(2-吡啶二硫基)丁酸盐)以及SMPT(N-琥珀酰亚胺基-氧基羰基-α-甲基-α-(2-吡啶基-二硫基)甲苯)、SPDB以及SMPT形成的二硫键连接子。(参见例如Thorpe等人,1987年,CancerRes.47:5924-5931;Wawrzynczak等人,In Immunoconjugates:Antibody Conjugates inRadioimagery and Therapy of Cancer(CW Vogel编辑,牛津大学出版社,1987年。另见美国专利第4,880,935号)。
在其它特定具体实施方式中,所述连接子为丙二酸连接子(Johnson等人,1995年,Anticancer Res.15:1387-93)、马来酰亚胺苯甲酰连接子(Lau等人,1995年,Bioorg-Med-Chem.3(10):1299-1304),或3'-N-酰胺类似物(Lau等人,1995年,Bioorg-Med-Chem.3(10):1305-12)。
在其它具体实施方式中,所述连接子单元不可切割,且通过抗体降解释放药物。(参见美国专利公开第2005/0238649号,其全文并出于所有目的以引用方式并入本文)。
通常,所述连接子对细胞外环境基本上不敏感。如本文所用,在涉及连接子的内容中,“对细胞外环境基本上不敏感”,代表在抗体-药物缀合物化合物的样品中不超过约20%、通常不超过约15%、更通常不超过约10%、甚至更通常不超过约5%、不超过约3%、或不超过约1%的所述连接子,当所述抗体-药物缀合物化合物存在于细胞外环境中(例如,在血浆中)所述连接子被裂解。例如,通过将血浆与所述抗体-药物缀合物化合物一起孵育一段预定的时间段(例如,2、4、8、16,或24小时),然后定量在血浆中存在的游离药物量,可确定所述连接子是否基本上对所述细胞外环境基本上不敏感。
在其它非相互排斥的具体实施方式中,所述连接子促进细胞内化。在某些具体实施方式中,当与治疗剂缀合时,所述连接子促进细胞内化(即,在如本文所述的抗体-药物缀合物化合物的连接子-治疗剂部分体的环境中)。
各种可与本发明组合物以及方法一起使用的各种示例性连接子描述于PCT专利公开第WO 2004-010957号、美国专利公开第2006/0074008号、美国专利公开第20050238649号,以及美国专利公开第2006/0024317号(以引用方式将每个整体并入本文并用于所有目的)。
本发明的具体实施方式涉及含有ENO-1抗体的抗体-药物缀合物和其治疗用途。ENO-1为一种多功能蛋白质,其被发现在许多癌细胞的细胞表面上作为纤维蛋白溶酶原受体表达以及在活化的造血细胞(例如中性粒细胞、淋巴细胞以及单核细胞)上表达。因此,基于针对ENO-1的抗体的ADCs可为有用的诊断和/或处理剂。
然而,快速的内化或缺乏治疗性抗体的ADCC活性可能导致抗体无效以及抗性。因此,需要增强基于抗ENO-1的治疗剂的治疗效果。一种方法是以抗ENO-1抗体(即,抗体-药物缀合物)将有效负载缀合。通过将抗ENO-1抗体缀合至有效负载(即,ADCs),本发明的具体实施方式比裸抗ENO-1抗体更有效,进而能够使用较少的抗体。
根据本发明的具体实施方式,抗ENO-1抗体或其结合片段可偶联至药物、诊断剂或治疗剂。因此,本文所用的术语“抗体-药物缀合物”(ADC)可指抗体部分(其可为整个抗体或其结合片段)偶联至有效负载(其可为药物、诊断剂或治疗剂)。
本发明的ADCs包含用于治疗或诊断用途的有效负载。相较于裸抗ENO-1抗体,这些ADCs具有更好的生物活性,且需要更少的量来达到所需的效果。
以下具体实例将说明本发明的具体实施方式。本发明所属技术领域中具有通常知识者将理解的是,这些示例仅用于说明,且在不脱离本发明的范围的情况下,可进行其它修改以及变化。
实施例
除非另有说明,否则每个1H NMR数据均500MHz获得。除非另有说明,否则本文使用的缩写如下:
BU:丁基;BN:芐基;BOC:叔丁氧基羰基;BOP:苯并三唑-1-基氧基三/二甲基氨基鏻六氟磷酸盐;DCC:二环己基碳二亚胺;DMF:N,N-二甲基甲酰胺;DMAP:4-二甲基氨基吡啶;EDC:1-(3-二甲基氨基丙基)3-乙基碳二亚胺盐酸盐;EtOAc:乙酸乙酯;Eq.:当量;HOBt:羟基苯齐唑;LAH:氢化铝锂;MeOH:甲醇;MHz:百万赫;MS(ES):质谱计-电子喷雾;NMP:N-甲基吡咯烷酮;Ph:苯基;Pr:丙基;TEA:三乙胺;THF:四氢呋喃;TLC:薄层色层分析;Tetrakis:四(三苯基膦)钯。
实施例1.抗ENO-1抗体的制备
根据本发明的具体实施方式,用于产生抗ENO-1抗体的一般方法包括获得产生针对ENO-1的单克隆抗体的杂交瘤。用于生产单克隆抗体的方法为本领域已知的,并且在此将不再阐述。简单地说,小鼠以抗原(ENO-1)和合适的佐剂攻毒。然后,收获免疫小鼠的脾脏细胞并与杂交瘤融合。阳性克隆株可使用任何已知方法,例如ELISA来鉴定用于结合ENO-1抗原的能力。在一个具体实施方式中,所述抗ENO-1抗体为HuL001。示例性抗体HuL001如美国专利公开案第US2019/0322762号中所述,其内容以引用方式全文并入。
请求保护的发明的抗体-药物缀合物(ADCs)可特异性地以ENO-1为标靶。这些ADCs可使用任何与ENO-1特异性结合的抗体。例如,请求保护的发明的ADCs可使用小鼠或人源化抗ENO-1抗体,或其scFv或Fab片段。示例性抗ENO-1抗体,例如HuL001可包括具有三个互补区域的重链可变结构域,包括HCDR1(GYTFTSCVMN;SEQ ID NO:1)、HCDR2(YINPYNDGTKYNEKFKG;SEQ ID NO:2)以及HCDR3(EGFYYGNFDN;SEQ ID NO:3),以及具有三个互补区域的轻链可变结构域,包括LCDR1(RASENIYSYLT;SEQ ID NO:4)、LCDR2(NAKTLPE;SEQID NO:5)以及LCDR3(QHHYGTPYT;SEQ ID NO:6)。另一示例性抗ENO-1抗体可包含具有三个互补区域的重链可变结构域,包括HCDR1(GYTFTSXVMN,其中X为除半胱氨酸以外的任何氨基酸;SEQ ID NO:7)、HCDR2(YINPYNDGTKYNEKFKG;SEQ ID NO:2)以及HCDR3(EGFYYGNFDN;SEQID NO:3),以及具有三个互补区域的轻链可变结构域,包括LCDR1(RASENIYSYLT;SEQ IDNO:4),LCDR2(NAKTLPE;SEQ ID NO:5)以及LCDR3(QHHYGTPYT;SEQ ID NO:6)。
根据本发明的具体实施方式,所述抗体可为小鼠抗体。或者,所述抗体可为嵌合抗体(例如与小鼠可变区偶联的人类恒定区域)或人源化抗体(例如移植在人类免疫球蛋白的框架区域的小鼠CDRs)或完全人类抗体。
可通过从杂交瘤获得CDR序列并将所述CDR序列克隆至人类框架序列中以产生人源化抗体来使单克隆抗体人源化。可使用本领域已知的用于识别CDR序列的任何常用方法。本发明中的CDR区域以Kabat编号方法识别。首先,产生抗ENO-1的杂交瘤(例如小鼠杂交瘤)。可以标准方法产生这种杂交瘤,用于生产单克隆抗体。然后分离杂交瘤的总RNA,例如使用试剂。然后,从所述总RNA合成cDNA,例如使用第一链cDNA合成试剂盒(Superscript III)以及寡核苷酸(dT20)引物或Ig-3'恒定区引物。
然后从cDNA中克隆免疫球蛋白基因的重链和轻链可变区。例如,使用小鼠Ig-5'引物组(Novagen公司),通过PCR从小鼠杂交瘤cDNA扩增抗ENO-1mAb的VH和VL可变区。可使用CloneJetTMPCR克隆试剂盒(Ferments)将PCR产物直接克隆到合适的载体(例如pJET1.2载体)中。所述pJET1.2载体含有致死插入片段,只有在将所需基因克隆到所述致死区域时,才能在选择条件下生存。这有助于选择重组菌落。最后,筛选重组菌落,选出所需的克隆株,分离并测序这些克隆株的DNAs。免疫球蛋白(Ig)核苷酸序列可在国际免疫原性信息系统(IGMT)网站上分析。
抗体表达和纯化
针对抗体生产,分离的克隆株可在任何合适的细胞中表达。举例来说,将F293细胞(Life technologies公司)以表达抗ENO-1mAb的质粒转染并培养7天。使用蛋白质A亲和柱(GE公司)从培养基中纯化抗ENO-1抗体。蛋白质浓度可以Bio-rad蛋白质分析试剂盒测定并以12% SDS-PAGE分析,使用本领域已知的方法或根据制造商的说明书进行分析。
根据本发明的具体实施方式,任何这些抗ENO-1抗体可用于制备抗体-药物缀合物(ADCs),如以下实施例所示。
实施例2.HuL001-SMCC-DM1缀合物的制备
在本实施例中,ADCs含有DM1,其为用于癌症治疗的一种美登木素生物碱(maytansinoid)。美登素(maytansine),一种苯并金刚大环内酯(benzoansamacrolide),为一种高效的以微管为标靶的化合物,其在次纳摩尔的浓度下可诱导有丝分裂抑制并杀肿瘤细胞。DM1在微管的尖端结合以抑制微管的动态,即抑制微管的组装。DM1为一种美登木素生物碱(maytansinoid),其系统性毒性少于美登素(maytansine)。在本实施例中,使用SMCC-DM1,其为具有反应性连接子SMCC的DM1,与抗体反应以制备抗体药物缀合物。SMCC-DM1可从商业来源获得,如Medkoo Biosciences公司或ALB Technology公司。
例如,将HuL001(70mg)的缓冲液交换为pH 6.5柠檬酸钠缓冲液,并调节至5mg/mL。将SMCC-DM1(5mM,溶于DMA中,16当量)的溶液缓慢加入到HuL001溶液中。将反应混合物在37℃下在振荡培养箱(150rpm)中孵育18小时。具有30kDa NMWL的Amicon Ultra-15离心过滤器以及25mM柠檬酸钠pH 6.5用于HuL001-SMCC-DM1的浓缩以及除去SMCC-DM1。ADC浓度:5.478mg/ml,ADC产率:16.5mg(23.5%),平均DAR:3.87。
实施例3.HuL001-SPP-DM4缀合物的制备
在本实施例中,ADC包含DM4,这是另一种美登素(maytansine)类似物。DM4也是一种有效的以微管为标靶的化合物,可在有丝分裂阶段抑制细胞增殖。本发明的某些具体实施方式可使用DM4。
在本实施例中,将HuL001(70mg)的缓冲液交换为pH 6.5柠檬酸钠缓冲液,并调节至5mg/mL。将SPP-DM4(10mM溶于DMA中,15当量)的溶液中缓慢加入到HuL001溶液中。将反应混合物在37℃下在振荡培养箱(150rpm)中孵育18小时。具有30kDa NMWL的Amicon Ultra-15离心过滤器以及25mM柠檬酸钠pH 6.5用于HuL001-SMCC-DM4的浓缩以及除去SPP-DM4。ADC浓度:3.65mg/mL,ADC产量:34.3mg(49%),平均DAR:3.18。
实施例4.HuL001-mal-vc-MMAE缀合物的制备
单甲基澳瑞他汀E(MMAE)为一种抗肿瘤剂,其通过阻断微管蛋白的聚合来抑制细胞分裂。其源自海洋无壳软体动物(尾海兔素(dolastatin)类药物)中产生的肽。MMAE已被证明为ADCs的有用有效负载。
ADCs中的连接子可能对生物活性产生重大影响。例如,体内研究显示,肽连接的缀合物可诱导已建立的肿瘤异种移植物的消退和治愈,治疗指数高达60倍。这些缀合物说明了连接子技术、药物效力以及缀合方法在制定用于癌症治疗的安全以及有效的mAb药物缀合物中的重要性。
本发明的某些具体实施方式涉及通过溶酶体上可切割的二肽(缬氨酸-瓜氨酸(valine-citrulline,vc))与抗体连接的MMAEs,vc已经显现出改善ADC效率。在本实施例中,将HuL001(1mg)的缓冲液交换为pH 7.4 PBS/EDTA缓冲液,并调节至5mg/mL。将TCEP(10mM,3当量)的水溶液缓慢加入到HuL001溶液中。通过在37℃下孵育2小时,减少抗体中的二硫键。然后将mal-PEG2-vc-PAB-MMAE(10mM溶于DMA,10当量)的溶液缓慢加入蛋白质溶液中。将反应混合物在25℃下在振荡培养箱(150rpm)孵育2小时。然后使用100mM NAC(20当量)来淬灭过量的mal-vc-类固醇。使用具有10kDa NMWL的Amicon Ultra-15离心过滤器以及缓冲液(pH 6.0PBS以及137mM NaCl)用于HuL001-mal-vc-MMAE的浓缩以及去除mal-PEG2-vc-PAB-MMAE。ADC浓度:3.7mg/ml,ADC产率:0.481mg(48.1%),平均DAR:3.64。
实施例5.HuL001-Ph-MMAF缀合物的制备
本发明的某些具体实施方式涉及含有单甲基澳瑞他汀F(MMAF)的ADCs,MMAF为MMAE的类似物。将HuL001(37mg)的缓冲液交换为pH 7.4PBS缓冲液,并调节至5mg/mL。将OSu-ph-MMAF(5mM溶于DMA,5当量)的溶液缓慢加入蛋白质溶液中。将反应混合物在37℃下在振荡培养箱(150rpm)中孵育1小时。具有30kDa NMWL的Amicon Ultra-15离心机过滤器以及25mM柠檬酸钠pH 6.5用于HuL001-ph-MMAF的浓缩以及去除OSu-ph-MMAF。ADC浓度:7.8mg/ml,ADC产率:34.1mg(92.1%),平均DAR:3.09。
实施例6.HuL001-mal-vc-类固醇缀合物的制备
在本实施例中,将HuL001(1mg)的缓冲液交换为pH 7.4PBS/EDTA缓冲液,并调节至10mg/ml。将TCEP的水溶液(10mM,4当量)缓慢加入蛋白质溶液中。通过在37℃下孵育1.5小时,减少抗体中的二硫键。然后将mal-vc-类固醇(10mM溶于DMSO,10当量)的溶液缓慢加入蛋白质溶液中。将反应混合物在0℃下在振荡培养箱(150rpm)中孵育18小时。然后使用100mM NAC(20当量)来淬灭过量的mal-vc-类固醇。具有30kDa NMWL的Amicon Ultra-15离心机过滤器以及缓冲液(pH 6.0PBS以及137mM NaCl)用于HuL001-mal-vc-类固醇的浓缩以及去除mal-vc-类固醇。ADC浓度:2.2mg/ml,ADC产率:0.33mg(33%),平均DAR:5.2。
实施例7.PLRP-HPLC或HIC分析
通过PLRP-HPLC或HIC分析根据请求保护的发明具体实施方式的各种ADCs。图1-5所示为缀合反应基本上完成,且仅留下抗ENO-1抗体以及ADCs的残留量。
实施例8.完整或降低的LC/MS分析
评估药物-抗体比(drug-to-antibody ratio,DAR)对于监测目标抗体的有效负载缀合效率是重要的。药物-抗体比可能影响抗ENO-1ADC产品的治疗效果。完整的液相色层分析-质谱(LC-MS)是测定赖氨酸连接抗体-药物缀合物(ADCs)的药物-抗体比(DAR)以及药物负荷分布的选择方法。降低的LC-MS为测定半胱氨酸连接ADCs的DAR以及药物负荷分布的选择方法。峰的面积百分比表示特定药物载体ADCs物种的相对分布。然后使用百分比峰面积信息以及药物负载数来计算加权平均DAR。
图5-10说明根据请求保护的发明的具体实施方式的ADCs的LC-MS分析的实例(抗ENO-1ADCs),这表示附着在抗体上的各种药物的分布,其中最丰富的物种有1~12种附着在抗体上的药物。这些实施例中平均药物-抗体比(DAR)的范围为3.18-5.2。具有附着于一抗体的多个相同药物将确保所述药物更有效地将被递送至细胞中。
实施例9.细胞毒性分析
抗ENO-1 ADC产物的细胞激素诱导的细胞毒性作用已在ENO-1依赖性细胞系中展示,所述细胞系衍生自不同的人类癌症,包括淋巴瘤、肺癌、乳腺癌、胰腺癌以及弥漫性大B细胞淋巴瘤(diffuse large B cell lymphoma,DLBCL)。各种细胞系,例如U937、A549、MDA-MB-231、MCF-7、MBA-MD-453、MBA-MD-175、PANC-1、Raji、Su-DHL-4、Toledo、GA-10或HT分别以细胞激素TGF-β、MCP-1或IL-6活化4小时以模拟炎性肿瘤微环境,并与连续稀释抗体溶液再孵育72小时。通过使用细胞计数(CCK-8)试剂盒测量细胞存活率,并计算IC50的值。测试的细胞HuL001的IC50高于测试的最高浓度(1000nM)。结果表示,抗ENO-1ADC产品特异性地抑制各种细胞系的细胞激素诱导的(20ng/ml TGF-β,100ng/mL MCP-1,50ng/ml IL-6)促发炎表面ENO-1。表1和表2显示,在大多数细胞系中,HuL001-SMCC-DM1以及HuL001-mal-vc-MMAE的IC50在活化后显著降低到个位数含量以反映细胞毒性效应。图11表示DLBCL细胞系DHL-4中HuL001-SPP-DM4的IC50的个位数含量。图12和图13表示在存在或不存在LPS刺激的情况下,在分离的正常人类B细胞中没有可检测的HuL001或HuL001-SMCC-DM1以及HuL001-mal-vc-MMAE的体外细胞毒性。总之,根据本发明的ADC有效地杀死癌细胞,尤其是在细胞激素模拟时,而不影响正常细胞的活力。它被认为是针对性癌症治疗的潜在候选者。
表1在细胞激素刺激的癌细胞系中HuL001-SMCC-DM1的体外细胞毒性结果
表2在细胞激素刺激的癌细胞系中HuL001-mal-vc-MMAE的体外细胞毒性结果
实施例10.细胞激素分析
在人类单核细胞细胞系THP-1中证明了抗ENO-1-类固醇ADC的抗发炎作用。以LPS刺激THP-1细胞以诱导ENO-1表面表达以及促发炎细胞激素TNF-α以及CCL2的分泌。图14表示,相较于抗ENO-1抗体,抗ENO-1-类固醇ADC的卓越抗发炎作用。
实施例11.抗ENO-1 ADC的前列腺癌模型
在实验去势抵抗性前列腺癌模型中评估了HuL001-SMCC-DM1。使用雄性4~6周龄裸(nu/nu)小鼠(Lasco有限公司,中国台湾)。在接种之前,以PBS洗涤去势抵抗性人类前列腺癌细胞系PC-3细胞,以PBS和Matrigel以1:1重新悬浮所述细胞至107个细胞/ml的终浓度。将细胞(106个/100μl)皮下植入小鼠的右侧。在平均肿瘤体积达到100mm3(植入后6天)后,将小鼠随机分配至对照组和处理组,其分别以PBS(5ml/kg)作为媒剂对照或HuL001-SMCC-DM1(1或9mg/kg)施用。HuL001-SMCC-DM1通过腹膜内注射一次每6天给与一次,总共2个剂量,直至研究结束。每天进行体重以及肿瘤体积测量。根据下式测定皮下肿瘤的体积:肿瘤体积=较短的直径2×较长的直径/2,通过腹膜内注射剂量。图15表示HuL001-SMCC-DM1抑制肿瘤生长而不造成体重的减损。
实施例12.抗ENO-1 ADC的EAE疾病模型
在C57BL/6小鼠中,在实验性自身免疫脑脊髓炎(experimental autoimmuneencephalomyelitis,EAE)中评估HuL001-SMCC-DM1,这是人类发炎脱髓疾病、多发性硬化症的最常用的实验模型。向10至12周龄的雌性C57BL/6小鼠皮下注射100微克在弗氏完全佐剂中的MOG p35-55,然后腹膜内注射100ng百日咳毒素。在第二天,给与另一剂量的100ng百日咳毒素。每天观察动物,临床症状评估如下:0,没有迹象;1,尾巴活性下降;2,轻度单肢轻瘫或不完全麻痹;3,严重的后躯轻瘫;4,截瘫和/或四肢轻瘫;5,濒临死亡或死亡。将小鼠随机分为3组,其中10只小鼠在对照组以及组(Teva制药公司),以及5只小鼠在HuL001-SMCC-DM1组中。疾病发病(疾病评分≥1)的日期被设定为第1天。HuL001-SMCC-DM1组的EAE小鼠在第1、8以及15天皮下注射。COPAXONE组的EAE小鼠自第1天至第18天每天皮下注射。图16所示为相较于PBS对照组甚至组,HuL001-SMCC-DM1的治疗能够减缓EAE小鼠的疾病症状的进展。
实施例13.抗ENO-1 ADC的IPF疾病模型
以在C57BL/6小鼠中博莱霉素诱导的肺纤维化评估HuL001-SMCC-DM1,这是人类纤维化疾病,特发性肺纤维化最常用的实验模型。气管内给与单一剂量的博莱霉素(3mg/kg)至7至9周龄雄性C57BL/6小鼠。将小鼠随机分为3组,其中3只小鼠在假手术组,6只小鼠分别在博莱霉素组以及HuL001-SMCC-DM1组。以博莱霉素攻毒的日期被设定为第0天。HuL001-SMCC-DM1组小鼠在第1、8以及15天皮下注射。图17说明相较于博莱霉素组,以HuL001-SMCC-DM1治疗能够减少体重的损失以及肺重量的增加。通过HuL001-SMCC-DM1处理减少了支气管肺泡灌洗液(bronchial alveolar lavage fluid,BALF)中的肺羟脯氨酸含量以及TGF-β含量。
除非另外定义,否则所有技术以及科学术语以及本文所用的任何首字母缩略词都具有本发明领域中普通技术人员通常理解的相同含义。虽然可以使用与本文所述的那些相似或相当的任何组合物、方法、试剂盒以及用于传达信息的装置实施本发明,但本文描述本发明的优选组合物、方法、试剂盒以及用于传达信息的装置。
本文引用的所有参考文献均在此以引用方式通过法律允许的全部程度并入本文。这些参考文献的讨论仅仅是总结其作者所作的主张。不承认任何参考文献(或任何参考文献的一部分)为相关的现有技术。申请人保留质疑任何引用文献的准确性和相关性的权利。
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<110> 上毅生物科技股份有限公司
<120> 含有α-烯醇酶抗体的药物缀合物和其用途
<130> 21P0246(21Q0233)
<150> US63/022,702
<151> 2020-05-11
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<170> PatentIn version 3.5
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Claims (16)
1.一种特异性结合ENO-1的免疫缀合物,所述免疫缀合物包括:
Ab-(L-D)m(I)的通式,
其中Ab为抗ENO-1抗体或其结合片段,L为连接子或直接键,D为治疗剂或标记物,m为1至12的整数。
2.根据权利要求1所述的免疫缀合物,其中所述抗体为单克隆抗体。
3.根据权利要求1所述的免疫缀合物,其中所述抗体为小鼠抗体、人类抗体、嵌合抗体、人源化抗体或其抗体片段。
4.根据权利要求1所述的免疫缀合物,其中所述治疗剂包含细胞毒性剂、免疫调节剂、放射性同位素以及毒素。
5.根据权利要求1所述的免疫缀合物,其中所述细胞毒性剂包含美登木素生物碱1(DM1)、美登木素生物碱4(DM4)、单甲基澳瑞他汀E(MMAE)、单甲基澳瑞他汀F(MMAF)、蒽环素、吡咯洛唑二氮杂,α-蝇蕈素、微管溶素、苯二氮平类药物、厄洛替尼、硼替佐米、氟维司群、舒尼替尼、来曲唑、甲磺酸伊马替尼、PTK787/ZK 222584、奥沙利铂、菊白叶酸、雷帕霉素、拉帕替尼、洛那法尼、索拉非尼以及吉非替尼、AG1478、AG1571,烷基化试剂,包括噻替哌或环膦酰胺;亚烷基磺酸盐,包括白消安、英丙舒凡或哌泊舒凡;氮丙啶类,包括苯唑多巴、卡波醌、米得哌或乌得哌;吖环丙烷以及甲基蜜胺类,包括六甲蜜胺、三乙烯三聚氰胺、三亚乙基磷酰胺、三亚乙基硫代磷酰胺以及三甲基蜜胺;内酯;喜树碱;苔藓虫素;卡利斯他汀;CC-1065;念珠藻素;尾海兔素;杜卡霉素;艾榴塞洛素;胰抑素;珊瑚素;海绵素;氮芥剂包括氯芥苯丁酸、萘氮芥、氯萘嗪、环磷酰胺、雌莫司汀、异环磷酰胺、甲氯乙胺、盐酸甲乙胺盐酸盐、美法仑、新氮芥、苯芥胆甾醇、泼尼氮芥、曲磷胺或尿嘧啶氮芥;亚硝基脲,包括卡莫司汀、氯脲霉素、福莫司汀、洛莫司汀、尼莫司汀或雷诺氮芥;抗生素,如烯二炔抗生素,包括卡奇霉素,尤其是卡奇霉素γ1以及卡奇霉素ω1;达尼霉素,包括达尼霉素A;双磷酸盐类,包括氯磷酸盐;埃司帕霉素;以及新卡他汀发色团以及相关的色素蛋白烯二炔抗生素发色团、阿克拉霉素、放线菌霉素、安曲霉素、茜素、博莱霉素、放线菌素、卡拉霉素、洋红霉素、嗜癌菌素、色霉素、放线菌素、道诺霉素、地托比星、6-重氮-5-氧代-L-正亮氨酸、阿霉素、表柔比星、依索比星、艾达霉素、麻西罗霉素,丝裂霉素,包括丝裂霉素C、霉酚酸、诺加霉素、橄榄霉素、培洛霉素、泊非霉素、嘌呤霉素、喹纳霉素、罗多比星、链黑菌素、链脲佐菌素、结核菌素、乌苯美司、新制癌菌素、佐柔比星;抗代谢物,包括甲氨蝶呤以及5-氟尿嘧啶(5-FU);叶酸类似物,包括二甲叶酸、蝶罗呤、三甲曲沙;嘌呤类似物,包括氟达拉滨、6-巯基嘌呤、硫咪嘌呤、硫鸟嘌呤;嘧啶类似物,包括安西他滨、阿扎胞苷、6-氮尿苷、卡莫呋、阿糖胞苷、双去氧尿苷、去氧氟尿苷、伊诺他滨、氟尿苷;雄激素,包括钙雌酮、屈他雄酮丙酸酯、环硫雄醇、美雄烷、睾内酯酮;抗肾上腺剂,包括氨鲁米特、米托坦、曲洛司坦;叶酸补充剂,包括醛叶酸;乙酰格雷酮;醛磷酰胺糖苷;氨基乙酰丙酸;恩尿嘧啶;安吖啶;阿莫司汀;比生群;依达曲沙;地磷酰胺;秋水仙胺;地吖醌;艾福米辛;依利醋铵;埃博霉素;依托格鲁;硝酸镓;羟基脲;香菇多糖;氯尼达明;美登木素生物碱,包括美登素以及安丝菌素;米托脲腙;米托蒽醌;莫哌达醇;硝拉维林;喷司他丁;蛋胺氮芥;吡柔比星;洛索蒽醌;鬼臼酸;2-乙基酰肼;甲基芐肼;多糖复合物;雷佐生;根霉素;西佐喃;锗螺胺;细交链孢菌酮酸;三亚胺醌;2,2',2”-三氯三乙胺;新月毒素;乌拉坦;长春地辛;达卡巴仁;甘露醇氮芥;二溴甘露醇;二溴卫矛醇;溴丙哌嗪;甲托辛;阿糖胞苷;环磷酰胺;噻替哌;类紫杉醇,紫杉醇,紫杉醇的白蛋白工程化纳米粒子制剂,以及欧洲紫杉醇;苯丁酸氮芥;吉西他滨;6-硫鸟嘌呤;巯基嘌呤;甲氨蝶呤;铂类似物,包括顺铂以及卡铂;长春花碱;铂;依托泊苷(VP-16);异环磷酰胺;米托葱醌;长春新碱;温诺平;米托葱醌;替尼泊苷;依达曲沙;柔红霉素;氨基蝶呤;希罗达;伊班膦酸;CPT-11;拓扑异构酶抑制剂RFS 2000;二氟甲基鸟氨酸(DMFO);类维生素A,包括视黄酸;卡培他滨;以及上述任何一种的药学上可接受的盐、酸或衍生物。
6.根据权利要求1所述的免疫缀合物,其中所述标记物包括诊断或成像试剂。
7.根据权利要求1所述的免疫缀合物,其中所述抗体包含
重链可变结构域,所述重链可变结构域具有三个互补区域,包括
HCDR1(GYTFTSCVMN;SEQ ID NO:1),
HCDR2(YINPYNDGTKYNEKFKG;SEQ ID NO:2),以及
HCDR3(EGFYYGNFDN;SEQ ID NO:3);以及
轻链可变结构域,所述轻链可变结构域具有三个互补区域,包括
LCDR1(RASENIYSYLT;SEQ ID NO:4),
LCDR2(NAKTLPE;SEQ ID NO:5),以及
LCDR3(QHHYGTPYT;SEQ ID NO:6)。
8.根据权利要求1所述的免疫缀合物,其中所述抗体包含
重链可变结构域,所述重链可变结构域具有三个互补区域,包括
HCDR1(GYTFTSXVMN,其中X为除半胱氨酸以外的任何氨基酸;SEQ ID NO:7),
HCDR2(YINPYNDGTKYNEKFKG;SEQ ID NO:2),以及
HCDR3(EGFYYGNFDN;SEQ ID NO:3);以及
轻链可变结构域,所述轻链可变结构域具有三个互补区域,包括
LCDR1(RASENIYSYLT;SEQ ID NO:4),
LCDR2(NAKTLPE;SEQ ID NO:5),以及
LCDR3(QHHYGTPYT;SEQ ID NO:6)。
9.一种用于诊断表达ENO-1的细胞或组织或者使其成像的组合物,所述组合物包含根据权利要求6所述的免疫缀合物。
10.一种用于治疗炎性疾病、免疫病症或表达ENO-1的癌症的药物组合物,所述药物组合物包含根据权利要求1至5中任一项所述的免疫缀合物。
11.根据权利要求10所述的药物组合物,其中所述抗体包含
重链可变结构域,所述重链可变结构域具有三个互补区域,包括
HCDR1(GYTFTSCVMN;SEQ ID NO:1),
HCDR2(YINPYNDGTKYNEKFKG;SEQ ID NO:2),以及
HCDR3(EGFYYGNFDN;SEQ ID NO:3);以及
轻链可变结构域,所述轻链可变结构域具有三个互补区域,包括
LCDR1(RASENIYSYLT;SEQ ID NO:4),
LCDR2(NAKTLPE;SEQ ID NO:5),以及
LCDR3(QHHYGTPYT;SEQ ID NO:6)。
12.根据权利要求10所述的药物组合物,其中所述抗体包含
重链可变结构域,所述重链可变结构域具有三个互补区域,包括
HCDR1(GYTFTSXVMN,其中X为除半胱氨酸以外的任何氨基酸;SEQ ID NO:7),
HCDR2(YINPYNDGTKYNEKFKG;SEQ ID NO:2),以及
HCDR3(EGFYYGNFDN;SEQ ID NO:3);以及
轻链可变结构域,所述轻链可变结构域具有三个互补区域,包括
LCDR1(RASENIYSYLT;SEQ ID NO:4),
LCDR2(NAKTLPE;SEQ ID NO:5),以及
LCDR3(QHHYGTPYT;SEQ ID NO:6)。
13.根据权利要求10所述的药物组合物,其中所述炎性疾病或所述免疫病症包含多发性硬化症、类风湿性关节炎、克罗恩氏病、溃疡性结肠炎、全身性红斑性狼疮、慢性阻塞性肺病(COPD)、异位性皮炎、特发性肺纤维化、非酒精性脂肪肝炎、气喘、过敏、牛皮癣、牛皮癣性关节炎、第1型糖尿病、动脉粥样硬化、骨质疏松症、系统性硬化、病毒诱导肺炎或巨噬细胞活化综合征。
14.根据权利要求10所述的药物组合物,其中所述癌症包含血癌、多发性骨髓瘤、胃癌、皮肤癌、肺癌、黑色素瘤、肾癌、肝癌、骨髓瘤、前列腺癌、乳腺癌、直肠癌、胃癌、胰腺癌、甲状腺癌、血液性癌症、淋巴瘤、血癌、皮肤癌、卵巢癌、膀胱癌、尿路上皮癌、头颈癌或所述癌症的转移性病变。
15.一种治疗炎性疾病、免疫病症或癌症的方法,所述方法包含向有需要的受试者施用有效量的根据权利要求1至8中任一项所述的免疫缀合物,或根据权利要求10至14中任一项所述的药物组合物。
16.一种根据权利要求1至8中任一项所述的免疫缀合物或根据权利要求10至14中任一项所述的药物组合物在制备治疗炎性疾病、免疫病症或表达ENO-1的癌症的药物中的用途。
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