CN110072556A - 具有ksp抑制剂的特异性抗体药物缀合物(adc) - Google Patents
具有ksp抑制剂的特异性抗体药物缀合物(adc) Download PDFInfo
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Abstract
描述了驱动蛋白纺锤体蛋白抑制剂的特异性结合剂‑活性物质缀合物(ADC)、这些ADC的有效代谢物、用于制备这些ADC的方法、这些ADC用于治疗和/或预防疾病的用途以及这些ADC用于制备用于治疗和/或预防疾病、特别是过度增生病症和/或血管生成病症(例如癌症)的药剂的用途。
Description
引言和现有技术
本发明涉及驱动蛋白纺锤体蛋白抑制剂的特异性结合剂-活性物质缀合物(ADC)、这些ADC的有效代谢物、制备这些ADC的方法、这些ADC用于治疗和/或预防疾病的用途和这些ADC用于制备治疗和/或预防疾病,特别是过度增生和/或血管生成病症,例如癌症的药剂的用途。此类治疗可作为单一疗法或另外与其它药剂或其它治疗措施联合实施。
癌症是多种多样的组织的不受控细胞生长的后果。在许多情况下,新的细胞渗透到现有组织中(浸润性生长(invasives Wachstum))或它们转移到远端器官中。癌症发生在多种多样的器官中并通常具有组织特异性病程。因此,术语癌症作为上位概念描述不同器官、组织和细胞类型的一大类确定病症。
一些肿瘤在初期可任选通过手术和放射治疗措施除去。转移的肿瘤通常只能用化疗药物姑息治疗。此处的目标是实现改善生活质量和延长寿命的最佳组合。
结合剂蛋白与一个或多个活性物质分子的缀合物是已知的,特别是以所谓“抗体药物缀合物”(ADC)(“接头”)的形式,其中针对肿瘤相关抗原的内化抗体经连接单元(Verknüpfungseinheit)共价连接至细胞毒性剂。在将ADC引入肿瘤细胞中和该缀合物随后离解后,在肿瘤细胞内释放细胞毒性剂本身或由其形成的其他细胞毒性的有效代谢物且可在其内直接和选择性展现其作用。以该方式,相比于癌症的传统化疗,可将对正常组织的损伤保持在明显较窄的界限内[参见例如J. M. Lambert, Curr. Opin. Pharmacol. 5, 543-549(2005); A. M. Wu和P. D. Senter, Nat. Biotechnol. 23, 1137-1146 (2005); P. D.Senter, Curr. Opin. Chem. Biol. 13, 235-244 (2009); L. Ducry和B. Stump,Bioconjugate Chem. 21, 5-13 (2010)]。因此,WO2012/171020描述了ADC,其中多个毒簇分子经聚合物接头连接至抗体。作为可能的毒簇,WO2012/171020尤其提到物质SB 743921、SB715992 (伊斯平斯(Ispinesib))、MK-0371、AZD8477、AZ3146和ARRY-520。
最后提到的物质是所谓的驱动蛋白纺锤体蛋白抑制剂。驱动蛋白纺锤体蛋白(KSP,也称作Eg5、HsEg5、KNSL1或KIF11)是双极有丝分裂纺锤体发挥作用所必需的驱动蛋白样马达蛋白。KSP的抑制导致有丝分裂阻滞并经相对较长时间导致细胞凋亡(Tao等人,Cancer Cell 2005 Jul 8(1), 39-59)。在发现最早的细胞穿透KSP抑制剂Monastrol后,KSP抑制剂已将它们自身确立为一类新型化疗药物(Mayer等人, Science 286: 971-974,1999),且它们是一系列专利申请的主题(例如WO2006/044825;WO2006/002236;WO2005/051922;WO2006/060737;WO03/060064;WO03/040979和WO03/049527)。但是,由于KSP仅在有丝分裂阶段的相对短时期内是活性的,KSP抑制剂在该阶段期间必须以足够高的浓度存在。WO2014/151030公开了包括某些KSP抑制剂的ADC。
具有KSP抑制剂的另外的ADC已公开于专利申请WO2015/096982和WO2016/096610中。
发明概述
尽管有抗体-活性物质缀合物的各种公开内容,本发明的目的是提供在以相对低的浓度施用后展现持久的细胞凋亡作用并因此可用于癌症治疗的物质。此处,从ADC细胞内释放的代谢物的概况(Profil)发挥重要作用。通常,由ADC形成的代谢物为外排泵的底物和/或具有高细胞膜渗透性。两种现象可能造成短的保留时间且因此造成在肿瘤细胞内次优的细胞凋亡作用。
本发明的主题在于具有特异性毒簇接头组成的ADC,其尤其具有与特异性抗-CD123抗体和与抗-CXCR5结合的改进的活性概况。
所述抗体优选为人源化或嵌合的单克隆抗-CD123抗体或抗-CXCR5 抗体。特别优选人源化抗-CD123抗体TPP-8987、TPP-8988和TPP-9476,以及人源化或嵌合的抗-CXCR5抗体TPP-9024、TPP-9574和TPP-9580。
已发现,式(I)的抗体-活性物质缀合物(ADC)和其盐、溶剂化物和这些溶剂化物的盐具有与已知缀合物相比优异的特性,
,
其中
n代表1至8,
AK代表选自TPP-8987、TPP-9476和TPP-8988的抗-CD123抗体,
或
AK代表抗-CXCR5抗体,其优选选自TPP-9574、TPP-9580和TPP-9024,
或
AK代表这些抗体的抗原结合片段,
其中所述抗体或抗原结合片段经由半胱氨酸侧基的硫原子连接。
优选的是式(I)的这些抗体-活性物质缀合物(ADC),其中n代表4至8。
优选的是式(I)的这些抗体-活性物质缀合物(ADC),其中AK代表选自TPP-8987、TPP-9476和 TPP-8988的抗-CD123抗体和这些抗体的抗原结合片段;特别优选地,AK代表TPP-9476以及此抗体的抗原结合片段。
附图说明
图1:结合剂-活性物质缀合物的优选抗体的注释序列。所显示的是IgG的重链和轻链的蛋白序列,以及这些抗体的VH和VL区。在序列下方注释重要区域(IgG中的VH和VL区,以及CDR区(H-CDR1、H-CDR2、H-CDR3、L-CDR1、L-CDR2、L-CDR3))。
图2:结合剂-活性物质缀合物的优选抗体的序列以及靶分子的序列的序列表。
发明详述
本发明提供了人源化抗-CD123抗体或人源化或嵌合单克隆抗-CXCR5抗体的缀合物,其中活性物质分子是经由接头L与抗体连接的驱动蛋白纺锤体蛋白抑制剂(KSP抑制剂)。此处特别优选人源化抗-CD123抗体TPP-8987、TPP-8988和TPP-9476,以及人源化或嵌合抗-CXCR5抗体TPP-9024、TPP-9574和TPP-9580。
结合剂
在最广义上,术语“结合剂”被理解为是指结合该结合剂-活性物质缀合物指向的某些靶细胞群上存在的靶分子上的分子。术语结合剂应以其最广的含义理解并且也包括例如凝集素、能够结合某些糖链上的蛋白质或磷脂结合蛋白。此类结合剂包括,例如,高分子量蛋白质(结合蛋白)、多肽或肽(结合肽)、非肽(例如适体(US5,270,163)(Keefe AD.等人,Nat. Rev. Drug Discov. 2010;9:537-550综述)或维生素)和所有其它细胞结合分子或物质。结合蛋白是例如抗体和抗体片段或拟抗体,例如亲和体(Affibodies)、Adnectins、Anticalins、DARPins、Avimers、纳米抗体(Gebauer M.等人, Curr. Opinion in Chem.Biol. 2009;13:245-255;Nuttall S.D.等人, Curr. Opinion in Pharmacology 2008;8:608-617综述)。结合肽是例如配体/受体对的配体,例如配体/受体对VEGF/KDR的VEGF,如配体/受体对转铁蛋白/转铁蛋白受体的转铁蛋白,或细胞因子/细胞因子受体,如配体/受体对TNFα/TNFα受体的TNFα。
所述结合剂可以是结合蛋白。结合剂的优选的实施方案为抗体、抗原结合抗体片段、多特异性抗体或拟抗体。
文献还公开了有机分子共价偶联(缀合)至结合剂且尤其是抗体的各种可能性。根据本发明优选的是毒簇经由抗体的半胱氨酸残基的一个或多个硫原子和/或经由抗体的赖氨酸残基的一个或多个NH基团缀合至抗体。但是,也可以经由抗体的游离羧基或经由糖残基将毒簇结合至抗体。
“靶分子”在最广义上被理解为是指存在于靶细胞群中的分子并可以是蛋白质(例如生长因子的受体)或非肽分子(例如糖或磷脂)。其优选是受体或抗原。
术语“细胞外”靶分子描述位于细胞外部的连接到细胞上的靶分子,或位于细胞外部的靶分子的一部分,即结合剂可以在完整的细胞上连接到其细胞外靶分子上。细胞外靶分子可锚定在细胞膜中或是细胞膜的组成部分。本领域技术人员了解识别细胞外靶分子的方法。对于蛋白质,这可以通过(一个或多个)跨膜域的测定和蛋白质在该膜中的取向来进行。这些数据通常存放在蛋白质数据库(例如SwissProt)中。
术语“癌症靶分子”描述与相同组织类型的非癌细胞相比更大量存在于一种或多种癌细胞种类上的靶分子。优选地,癌症靶分子与相同组织类型的非癌细胞相比选择性存在于一种或多种癌细胞种类上,其中选择性描述与相同组织类型的非癌细胞相比至少两倍富集在癌细胞上(“选择性癌症靶分子”)。癌症靶分子的使用允许通过根据本发明的缀合物选择性治疗癌细胞。
结合剂可经由键连接到接头。结合剂可经由所述结合剂的杂原子连接。根据本发明,结合剂的可用于连接的杂原子是硫(在一个实施方案中经由结合剂的巯基)、氧(根据本发明借助结合剂的羧基或羟基)和氮(在一个实施方案中经由结合剂的伯或仲胺基或酰胺基)。这些杂原子可存在于天然结合剂中或通过化学方法或分子生物学方法引入。根据本发明,结合剂与毒簇的连接对于结合剂对靶分子的结合活性而言只有轻微影响。在一个优选实施方案中,该连接对于结合剂对靶分子的结合活性而言没有影响。
根据本发明,术语“抗体”应以其最广的含义理解并包括免疫球蛋白分子,例如完整或修饰的单克隆抗体、多克隆抗体或多特异性抗体(例如双特异性抗体)。免疫球蛋白分子优选包含具有通常通过二硫桥连接的四个多肽链(两个重链(H链)和两个轻链(L链))的分子。各重链包含重链可变结构域(缩写为VH)和重链恒定结构域。重链恒定结构域可以例如包含三个结构域CH1、CH2和CH3。各轻链包含可变结构域(缩写为VL)和恒定结构域。轻链恒定结构域包含结构域(缩写为CL)。VH和VL结构域可进一步细分成高变区,也称作互补决定区("complementarity determining region",缩写为CDR),和具有低序列变异性的区("框架区",缩写为FR)。通常,各VH和VL区由三个CDR和最多四个FR构成。例如以下列顺序从氨基末端到羧基末端:FR1、CDR1、FR2、CDR2、FR3、CDR3、FR4。抗体可获自每个对此合适的物种,例如兔、美洲驼、骆驼、小鼠或大鼠。在一个实施方案中,该抗体为人或鼠来源的。该抗体可以例如是人、人源化或嵌合的。
术语“单克隆”抗体是指获自一群基本同质抗体的抗体,即该群的各个抗体除天然存在的突变(其可以少数出现)外是相同的。单克隆抗体以高特异性识别单个抗原结合位点。术语单克隆抗体不涉及特定制备方法。
术语“完整”抗体是指包含抗原结合结构域以及轻链和重链的恒定结构域的抗体。恒定结构域可以是天然存在的结构域或其多个氨基酸位置发生变化的变体,并且也可以是无糖基化的。
术语“修饰的完整”抗体是指借助共价键(例如肽键)经由它们的氨基末端或羧基末端与不源自抗体的另一多肽或蛋白融合的完整抗体。此外,可以修饰抗体,以使得在定义位置处引入反应性半胱氨酸以使偶联至毒簇变容易(参见Junutula等人,Nat Biotechnol.2008 Aug; 26(8):925-32)。
“氨基酸修饰”或“突变”在此处是指在多肽序列中的氨基酸取代、插入和/或缺失。此处优选的氨基酸修饰为取代。“氨基酸取代”或“取代”在此处是指在蛋白序列的特定位置的氨基酸被另一氨基酸替换。例如,取代Y50W描述亲本多肽的变体,其中在位置50的酪氨酸被色氨酸替换。多肽的“变体”描述具有与参照多肽、典型地天然或“亲本”多肽基本上相同的氨基酸序列的多肽。多肽变体可在天然氨基酸序列的特定位置具有一个或多个氨基酸交换、缺失和/或插入。
术语“人”抗体是指可获自人类或为合成人抗体的抗体。“合成”人抗体是部分或甚至完全地可由基于人抗体序列分析的合成序列计算机模拟获得的抗体。人抗体可以例如由从人源性抗体序列库中分离的核酸编码。此类抗体的实例可见于Söderlind等人, NatureBiotech. 2000, 18:853-856。此类“人类”和“合成”抗体还包括通过由PNGaseF去糖基化或通过重链的N297(kabat编号)突变成任何其它氨基酸所产生的无糖基化变体。
术语“人源化”或“嵌合”抗体描述由序列的非人部分和人部分组成的抗体。在这些抗体中,人免疫球蛋白的一部分序列(受体)被非人免疫球蛋白的序列部分(供体)替换。在许多情况下,该供体是鼠免疫球蛋白。在人源化抗体的情况下,受体的CDR的氨基酸被供体的氨基酸替换。有时,框架的氨基酸也被供体的相应氨基酸替换。在一些情况下,该人源化抗体含有既不包含于受体中又不包含于供体中的在抗体的优化过程中引入的氨基酸。在嵌合抗体的情况下,供体免疫球蛋白的可变结构域与人抗体的恒定区融合。此类“人源化”和“嵌合”抗体还包括通过由PNGaseF去糖基化或通过重链的N297(Kabat编号)突变成任何其它氨基酸所产生的无糖基化变体。
如本文所用的术语互补决定区(CDR)是指对于结合至抗原所需的可变抗体结构域的那些氨基酸。通常,各可变区具有三个CDR区,其被称作CDR1、CDR2和CDR3。各CDR区可包含根据Kabat定义的氨基酸和/或根据Chotia定义的高变环的氨基酸。根据Kabat的定义包含例如可变轻链/结构域(VL)的大致氨基酸位置24-34(CDR1)、50-56(CDR2)和89-97(CDR3)和可变重链/结构域(VH)的大致氨基酸位置31-35(CDR1)、50-65(CDR2)和95-102(CDR3)的区域(Kabat等人, Sequences of Proteins of Immunological Interest, 第5版,PublicHealth Service, National Institutes of Health, Bethesda, MD. (1991))。根据Chotia的定义包含例如可变轻链(VL)的大致氨基酸位置26-32(CDR1)、50-52(CDR2)和91–96(CDR3)和可变重链(VH)的大致氨基酸位置26-32(CDR1)、53-55(CDR2)和96-101(CDR3)的区域(Chothia和Lesk;J Mol Biol 196: 901-917 (1987))。在一些情况下,CDR可包含来自根据Kabat和Chotia定义的CDR区的氨基酸。
根据重链恒定结构域的氨基酸序列,可以将抗体分成不同种类。完整抗体有五大类:IgA、IgD、IgE、IgG和IgM,其中几种可分成进一步的亚类(同种型),例如IgG1、IgG2、IgG3、IgG4、IgA1和IgA2。与不同种类对应的重链恒定结构域被称作[alpha/α]、[delta/δ]、[epsilon/ε]、[gamma/γ]和[my/μ]。抗体的三维结构和亚基结构都是已知的。
抗体/免疫球蛋白的术语“功能片段”或“抗原结合抗体片段”被定义为仍包含抗体/免疫球蛋白的抗原结合结构域的抗体/免疫球蛋白片段(例如IgG的可变结构域)。抗体的“抗原结合结构域”通常包含抗体的一个或多个高变区,例如CDR、CDR2和/或CDR3区。但是,抗体的“框架”或“骨架”区在抗体结合至抗原的过程中也可起到作用。框架区构成CDR的骨架。抗原结合结构域优选至少包含可变轻链的氨基酸4至103和可变重链的氨基酸5至109,更优选可变轻链的氨基酸3至107和可变重链的4至111,特别优选为完整的可变轻链和重链,即VL的氨基酸1-109和VH的1至113(根据WO97/08320编号)。
本发明的“功能片段”或“抗原结合抗体片段”非穷举地(nicht abschlieβend)包括Fab、Fab'、F(ab')2和Fv片段、双价抗体、单结构域抗体(DAb)、线性抗体、单链抗体(单链Fv,缩写为scFv);和多特异性抗体,如双和三特异性抗体,其由抗体片段形成,C. A. KBorrebaeck编辑(1995) Antibody Engineering (Breakthroughs in MolecularBiology), Oxford University Press;R. Kontermann & S. Duebel, 编辑 (2001)Antibody Engineering (Springer Laboratory Manual), Springer Verlag)。非“多特异性”或“多功能”抗体的抗体是具有相同结合位点的那些。多特异性抗体可对抗原的不同表位是特异性的或可对多于一种抗原的表位是特异性的(参见例如WO 93/17715;WO 92/08802;WO 91/00360;WO 92/05793;Tutt,等人, 1991, J. Immunol. 147:60 69;美国专利号4,474,893;4,714,681;4,925,648;5,573,920;5,601,819;或Kostelny等人, 1992, J.Immunol. 148: 1547 1553)。可以构建F(ab')2或Fab分子,以使得可以减少或完全防止在Ch1和CL结构域之间发生的分子间二硫化物相互作用的数量。
“表位”是指能特异性结合至免疫球蛋白或T细胞受体的蛋白决定簇。表位决定簇通常由分子的化学活性表面基团如氨基酸或糖侧链或其组合构组成,并通常具有特定的三维结构性质以及特定的电荷性质。
“功能片段”或“抗原结合抗体片段”可经由其氨基末端或羧基末端借助共价键(例如肽键)与不源自抗体的另一多肽或蛋白融合。此外,可如此修饰抗体和抗原结合片段,使得在特定位置处引入反应性半胱氨酸而使偶联至毒簇变容易(参见Junutula等人,NatBiotechnol. 2008 Aug;26(8):925-32)。
多克隆抗体可通过本领域普通技术人员已知的方法制备。单克隆抗体可通过本领域普通技术人员已知的方法制备(Köhler和Milstein, Nature, 256, 495-497, 1975)。人和人源化单克隆抗体可通过本领域普通技术人员已知的方法制备(Olsson等人, MethEnzymol. 92, 3-16,或Cabilly等人,US 4,816,567,或Boss等人,US 4,816,397)。
本领域普通技术人员了解制备人抗体及其片段的各种方法,例如借助转基因小鼠(N Lonberg和D Huszar, Int Rev Immunol. 1995;13(1):65-93)或噬菌体展示技术(Clackson等人, Nature. 1991年8月15日;352(6336):624-8)。本发明的抗体可获自例如由汇集自大量健康志愿者的多种多样抗体的氨基酸序列组成的重组抗体库。抗体也可借助已知的重组DNS技术制备。抗体的核酸序列可通过常规测序获得或可获自可公开访问的数据库。
“分离的”抗体或结合剂已经纯化以除去细胞的其它成分。可能干扰诊断或治疗用途的细胞的污染成分是例如酶、激素或细胞的其它肽或非肽成分。优选已纯化至基于该抗体或结合剂计大于95重量%(例如通过Lowry法、UV-Vis光谱学或通过SDS毛细管凝胶电泳测定)的抗体或结合剂。此外,已纯化至可以决定氨基末端或内部氨基酸序列的至少15个氨基酸或已纯化至同质性的抗体,其中同质性通过SDS-PAGE在还原或非还原条件下测定(可以借助考马斯蓝染色或优选通过银着色进行检测)。但是,通常通过一个或多个纯化步骤制备抗体。
术语“特异性结合”或“特异性地结合”是指结合至预定抗原/靶分子的抗体或结合剂。抗体或结合剂的特异性结合通常描述具有至少10-7 M的亲和力(作为Kd值;即优选为具有比10-7 M更小的Kd值的那些)的抗体或结合剂,其中该抗体或结合剂对预定抗原/靶分子的亲和力为对不是预定抗原/靶分子或密切相关抗原/靶分子的非特异性抗原/靶分子(例如牛血清白蛋白或酪蛋白)的至少两倍。抗体或结合剂的特异性结合不排除抗体或结合剂与多种抗原/靶分子(例如,不同物种的直系同源物)的结合。该抗体优选具有至少10-7 M(作为Kd值;即优选为具有比10-7 M更小的Kd值的那些),优选至少10-8 M,更优选10-9 M至10-11M的亲和力。可以例如借助表面等离子体共振波谱法测定Kd值。
本发明的抗体-活性物质缀合物同样表现出在这些范围内的亲和力。该亲和力优选基本不受活性物质缀合的影响(一般而言,该亲和力降低小于一个量级,换言之,例如最多从10-8 M降低至10-7 M)。
根据本发明使用的抗体也优选以高选择性为特征。当本发明的抗体对靶蛋白表现出的亲和力为对非依赖性的其它抗原,例如人血清白蛋白的至少2倍,优选5倍或更优选10倍(可以例如借助表面等离子体共振波谱法测定亲和力),则存在高选择性。
此外,根据本发明使用的抗体优选是交叉反应性的。为了能够促进和更好地解释临床前研究,例如毒理学或效果研究(例如在异种移植小鼠中),如果根据本发明使用的抗体不仅结合人靶蛋白、还结合用于研究的物种中的物种靶蛋白,则是有利的。在一个实施方案中,根据本发明使用的抗体除人靶蛋白外还对至少一个其它物种的靶蛋白呈交叉反应性。对于毒理学和效果研究,优选使用啮齿科、犬科和非人灵长科的物种。优选的啮齿物种是小鼠和大鼠。优选的非人灵长类动物是猕猴、猩猩和长尾猕猴。
在一个实施方案中,根据本发明使用的抗体除人靶蛋白外还对选自小鼠、大鼠和长尾猕猴(食蟹猴)的至少一个其它物种的靶蛋白呈交叉反应性。尤其优选的是除人靶蛋白外至少对小鼠靶蛋白呈交叉反应性的根据本发明使用的抗体。优选的是对其它非人物种的靶蛋白的亲和力与对人靶蛋白的亲和力相差不大于50倍,特别是不大于10倍的交叉反应性抗体。
针对癌症靶分子的抗体
结合剂,例如抗体或其抗原结合片段所针对的靶分子优选是癌症靶分子。术语“癌症靶分子”描述与相同组织类型的非癌细胞相比更大量存在于一种或多种癌细胞种类上的靶分子。优选地,癌症靶分子与相同组织类型的非癌细胞相比选择性存在于一种或多种癌细胞种类上,其中选择性描述与相同组织类型的非癌细胞相比至少两倍富集在癌细胞上(“选择性癌症靶分子”)。癌症靶分子的使用允许通过根据本发明的缀合物选择性治疗癌细胞。
对抗原,例如癌细胞抗原特异性的抗体可以由本领域普通技术人员借助他熟悉的方法(例如重组表达)制备或可商业获得(例如获自Merck KGaA, 德国)。癌症疗法中的已知市售抗体的实例是Erbitux®(西妥昔单抗,Merck KGaA)、Avastin®(贝伐单抗,Roche)和Herceptin®(曲妥珠单抗,Genentech)。曲妥珠单抗是IgG1κ型重组人源化单克隆抗体,其在细胞基检测中以高亲和力(Kd = 5 nM)结合人表皮生长受体的胞外域。该抗体在CHO细胞中重组产生。所有这些抗体也可通过借助PNGase F去糖基化或通过重链的N297(Kabat编号)突变成任何氨基酸来生产为这些抗体的无糖基化变体。
在本发明中,癌靶分子是
(1)受体蛋白CXCR5 (CD185; SwissProt: P32302; NCBI Gene ID 643, NCBI参考序列:NP_001707.1; SEQ ID NO:61)
(2)表面受体CD123 (IL3RA; NCBI Gene ID: 3563; NCBI参考序列:NP_002174.1;Swiss-Prot: P26951; SEQ ID NO:62)。
在本发明的特别优选的主题中,该结合剂特异性结合选自癌症靶分子CXCR5和CD123的细胞外癌症靶分子。在一个优选实施方案中,该结合剂在结合靶细胞上的细胞外靶分子上后通过该结合而被靶细胞内化。这导致该结合剂-活性物质缀合物(其可以是免疫缀合物或ADC)被靶细胞吸收。随后优选在细胞内,优选借助溶酶体处理该结合剂。
在一个实施方案中,该结合剂是结合蛋白。在一个优选实施方案中,该结合剂是抗体、抗原结合抗体片段、多特异性抗体或拟抗体。
优选的拟抗体是亲和体、Adnectins、Anticalins、DARPins、Avimers或纳米抗体。优选的多特异性抗体是双特异性和三特异性抗体。
在一个优选实施方案中,该结合剂是抗体或抗原结合抗体片段,更优选分离的抗体或分离的抗原结合抗体片段。
优选的抗原结合抗体片段是Fab、Fab'、F(ab')2和Fv片段、双价抗体、DAb、线性抗体和scFv。特别优选的是Fab、双价抗体和scFv。
在一个特别优选的实施方案中,该结合剂是抗体。特别优选的是单克隆抗体或其抗原结合抗体片段。更特别优选的是人、人源化或嵌合抗体或其抗原结合抗体片段。
结合癌症靶分子的抗体或抗原结合抗体片段可由本领域普通技术人员使用已知方法制备,例如化学合成或重组表达。用于癌症靶分子的结合剂可以商业获得或可以由本领域普通技术人员使用已知方法制备,例如化学合成或重组表达。在WO 2007/070538(参见第22页“抗体”)中描述了用于制备抗体或抗原结合抗体片段的其它方法。本领域技术人员知道如所谓的噬菌体展示库(例如Morphosys HuCAL Gold)的方法可编制且可用于发现抗体或抗原结合抗体片段(参见WO 2007/070538,第24页及其后和第70页中的AK实施例1、第72页中的AK实施例2)。例如在第26页中(WO 2007/070538)描述了使用来自B细胞的DNA库制备抗体的其它方法。抗体的人源化方法描述在WO2007070538的第30-32页中并详细描述在Queen等人, Pros. Natl. Acad. Sci. USA 86:10029-10033, 1989或WO 90/0786中。此外,通常蛋白,特别是抗体的重组表达方法是本领域技术人员已知的(参见例如Berger和Kimrnel (Guide to Molecular Cloning Techniques, Methods in Enzymology, Vo1.152, Academic Press, Inc.); Sambrook,等人, (Molecular Cloning: A LaboratoryManual, (第二版, Cold Spring Harbor Laboratory Press; Cold Spring Harbor,N.Y.; 1989) Vol. 1-3); Current Protocols in Molecular Biology, (F. M. Ausabel等人 [编], Current Protocols, Green Publishing Associates, Inc. / John Wiley& Sons, Inc.); Harlow等人, (Monoclonal Antibodies: A Laboratory Manual, ColdSpring Harbor Laboratory Press (19881, Paul [编]); Fundamental Immunology,(Lippincott Williams & Wilkins (1998));和Harlow,等人, (Using Antibodies: ALaboratory Manual, Cold Spring Harbor Laboratory Press (1998))。本领域技术人员知道对于蛋白/抗体的表达所必需的相应载体、启动子和信号肽。常见方法也描述在WO2007/070538第41-45页中。例如在WO 2007/070538第74页及其后的实施例6中描述了制备IgG1抗体的方法。可用于测定抗体在结合至其抗原后的内化的方法是本领域技术人员已知的并例如描述在WO 2007/070538第80页中。本领域技术人员能够使用WO 2007/070538中描述的方法,其已用于与具有另外靶分子特异性的抗体的制备类似地制备碳酸酐酶IX (Mn)抗体。
细菌表达
本领域技术人员知悉可以何种方式在细菌表达的帮助下生产抗体、其抗原结合片段或其变体。
适合用于所需蛋白的细菌表达的表达载体可通过在功能阅读框架内插入编码所需蛋白的DNA序列与合适的翻译起始和翻译终止信号和以功能性启动子共同来构建。所述载体包含一个或多个表型上可选择的标记和复制起点以使得能够保留载体且如果需要,在宿主内进行自身扩增。适合用于转化的原核细胞宿主包括但不限于大肠杆菌、枯草芽孢杆菌(Bacillus subtilis)、鼠伤寒沙门氏菌(Salmonella typhimurium)和来自假单孢菌属(Pseudomonas)、链霉菌属(Streptomyces)和葡萄球菌属(Staphylococcus)属的各种菌种。细菌载体可例如基于噬菌体、质粒或噬菌粒。这些载体可含有可选择标记和细菌复制起点,其可衍生自市售的质粒。许多市售的质粒通常含有众所周知的克隆载体pBR322 (ATCC37017)的元件。在细菌系统中,可以基于待表达的蛋白的目标用途,选择许多有利的表达载体。
在将合适的宿主菌株转化以及宿主菌株生长至适当的细胞密度后,通过合适的手段(例如改变温度或化学诱导)将所选的启动子去-抑制(de-reprimiert)/诱导,并将细胞再培养一段时间。通常通过离心来收获细胞,如果需要以物理方式或化学手段消化,并保留所得的粗提取物用于进一步纯化。
因此,本发明的另一实施方案是表达载体,其包含编码本发明的新颖抗体的核酸。
本发明的抗体或其抗原结合片段包括天然纯化的产物、源自化学合成的产物以及通过重组技术在原核细胞宿主,例如大肠杆菌、枯草芽孢杆菌、鼠伤寒沙门氏菌和来自假单孢菌属、链霉菌属和葡萄球菌属的各种菌种,优选大肠杆菌中所产生的产物。
哺乳动物细胞表达
本领域技术人员知悉可以何种方式在哺乳动物细胞表达的帮助下生产抗体、其抗原结合片段或其变体。
用于在哺乳动物细胞宿主中表达的优选的调控序列包括在哺乳动物细胞中导致高表达的病毒元件,例如衍生自巨细胞病毒(CMV)(例如CMV启动子/增强子)、猿猴病毒40(SV40)(例如SV40启动子/增强子)、来自腺病毒(例如腺病毒主要晚期启动子(AdMLP))和来自多瘤病毒的启动子和/或表达扩增子。抗体的表达可以是组成型或调控型的(例如通过加入或移除小分子诱导剂,例如四环霉素与Tet系统的组合来诱导)。
对于病毒调控元件和其序列的进一步说明,参照,例如Stinski的U.S.5,168,062,Bell等人的U.S.4,510,245以及Schaffner等人的U.S.4,968,615。重组表达载体同样地可包括复制起点和可选择标记(参见,例如U.S.4,399,216、4,634,665和U.S.5,179,017)。合适的可选择标记包括赋予对物质,例如G418、嘌呤霉素、潮霉素、杀稻瘟素、Zeocin/博莱霉素(Bleomycin)或甲氨喋呤的抗性的基因,或当此载体已引入细胞时,导致宿主细胞营养缺陷的可选择标记,例如谷氨酰胺合成酶(Bebbington等人, Biotechnology (N Y). 1992Feb;10(2):169-75)。
例如,二氢叶酸还原酶(DHFR)基因赋予对甲氨喋呤的抗性,neo基因赋予对G418的抗性,来自土曲菌(Aspergillus terreus)的bsd基因赋予对杀稻瘟素的抗性,嘌呤霉素N-乙酰基移转酶赋予对嘌呤霉素的抗性,Sh ble基因产物赋予对博莱霉素(Zeocin)的抗性,而大肠杆菌潮霉素抗性基因(hyg或hph)赋予对潮霉素的抗性。可选择标记,例如DHFR或谷氨酰胺合成酶也有助于结合MTX和MSX的扩增技术。
将表达载体转染至宿主细胞中可借助标准技术来执行,尤其是借助电穿孔、核转染、磷酸钙沉淀、脂质转染、基于聚阳离子的转染,例如基于聚乙烯亚胺(PEI)的转染和DEAE-葡聚糖转染。
适合用于抗体、其抗原结合片段或其变体的表达的哺乳动物宿主细胞包括中国仓鼠卵巢(CHO细胞),例如CHO-K1、CHO-S、CHO-K1SV[包括DHFR-CHO细胞,描述于Urlaub和Chasin, (1980) Proc. Natl. Acad. Sci. USA 77:4216-4220和Urlaub等人, Cell.1983 Jun;33(2):405-12,使用DHFR-可选择标记,如R. J. Kaufman和P. A. Sharp (1982)Mol. Biol. 159:601-621中所述,和其它敲除细胞,如详述于Fan等人, BiotechnolBioeng. 2012 Apr;109(4):1007-15中),NS0骨髓瘤细胞、COS细胞、HEK293细胞、HKB11细胞、BHK21细胞、CAP细胞、EB66细胞和SP2细胞。
抗体、其抗原结合片段或其变体的表达也可于表达系统例如HEK293、HEK293T、HEK293-EBNA、HEK293E、HEK293-6E、HEK293-Freestyle、HKB11、Expi293F、293EBNALT75、CHO-Freestyle、CHO-S、CHO-K1、CHO-K1SV、CHOEBNALT85、CHOS-XE、CHO-3E7或CAP-T细胞(例如,如Durocher等人, Nucleic Acids Res. 2002 Jan 15;30(2):E9)中以瞬时或半稳定方式来进行。
在一些实施方案中,表达载体以所表达的蛋白分泌至其中宿主细胞生长的细胞培养基中的方式来构建。抗体、其抗原结合片段或其变体也可借助本领域技术人员已知的蛋白纯化方法,从细胞培养基中获得。
纯化
抗体、其抗原结合片段或其变体可从重组的细胞培养物中借助众所周知的方法来获得并纯化,该方法例如包括硫酸铵或乙醇沉淀、酸萃取、蛋白A色谱、蛋白G色谱、阴离子或阳离子交换色谱、磷酸纤维素色谱、疏水作用色谱(HIC)、亲和色谱、羟磷灰石色谱和凝集素色谱。高效液相色谱(“HPLC”)同样可用来纯化。参见,例如Colligan, Current Protocols inImmunology,或Current Protocols in Protein Science, John Wiley & Sons, NY,N.Y., (1997-2001),例如第1、4、6、8、9、10章。
本发明的抗体或其抗原结合片段或其变体包括天然纯化产物、化学合成法的产物和借助重组技术于原核或真核宿主细胞中所生产的产物。真核细胞宿主包括,例如酵母细胞、高等植物细胞、昆虫细胞和哺乳动物细胞。根据对于重组表达所选择的宿主细胞,所表达的蛋白可以是糖基化或非糖基化形式。
在一个优选的实施方案中,此抗体被纯化,(1)到高于95重量%的程度,例如通过Lowry法,通过UV-Vis光谱或通过SDS毛细管凝胶电泳法(例如以Caliper LabChip GXII,GX 90或Biorad Bioanalyzer仪器)所测量,和在更优选的实施方案中,大于99重量%,(2)到适合测定至少15个N-末端的残基或内部氨酸序列的程度,或(3)到以SDS-PAGE于还原或非还原条件下借助马考斯蓝染色或优选地银染色所测定的同质性。
通常,分离的抗体借助至少一个蛋白纯化步骤获得。
抗-CD123抗体
根据本发明,可使用抗-CD123抗体。
表述“抗-CD123抗体”或“与CD123特异性结合的抗体”涉及结合癌症靶分子CD123(NCBI参考序列:NP_002174.1;SEQ ID NO:62)的抗体,优选地以足够用于诊断和/或治疗应用的亲和力结合。 在具体实施方案中,所述抗体以≤ 1µM、≤ 100 nM、≤ 10 nM、≤ 1 nM、≤ 0.1 nM、≤ 0.01 nM或≤ 0.001 nM的解离常数(KD)结合CD123。
Sun等人(Sun等人, 1996, Blood 87(1):83-92)描述了结合IL-3Rα的N-末端结构域、CD123的单克隆抗体7G3的生成和性质。美国专利号6,177,078 (Lopez)涉及抗-CD123抗体7G3。此抗体的嵌合变体(CSL360)描述于WO 2009/070844,而人源化版本(CSL362)描述于WO 2012/021934中。7G3抗体的序列公开于EP2426148。此序列构成由CDR移植("CDR接枝")获得的人源化抗体的起始点。
在细胞表面抗原结合后被特别好地内化的抗体是Kuo等人所公开的抗-CD123抗体12F1 (Kuo等人, 2009, Bioconjug Chem. 20(10):1975-82)。抗体12F1以比抗体7G3更高的亲和力与CD123结合,并在细胞表面抗原结合后,明显比7G3更快内化。基于12F1的双特异性scFv免疫融合蛋白公开于WO 2013/173820。抗体TPP-6013是12F1的嵌合变体。
本发明尤其涉及具有衍生自小鼠来源的抗体7G3 (Sun等人, 1996, Blood 87(1):83-92)和12F1(Kuo等人, 2009, Bioconjug Chem. 20(10):1975-82)的抗体或其抗原结合片段或其变体的缀合物,或具有衍生自小鼠来源的抗体12F1(Kuo等人, 2009,Bioconjug Chem. 20(10):1975-82)的抗体或其抗原结合片段或其变体的缀合物。
在本发明的上下文中尤其优选抗-CD123抗体TPP-9476、TPP-8988和TPP-8987。
抗-CXCR5抗体
根据本发明,可使用抗-CXCR5抗体。
表述“抗-CXCR5抗体”或“与CXCR5特异性结合的抗体”涉及结合癌靶分子CXCR5(NCBI参考序列:NP_001707.1;SEQ ID NO:61)的抗体,优选地以足够用于诊断和/或治疗应用的亲和力结合。在具体实施方案中,所述抗体以≤ 1µM、≤ 100 nM、≤ 10 nM、≤ 1 nM、≤ 0.1 nM、≤ 0.01 nM或≤ 0.001 nM的解离常数(KD)结合CXCR5。
结合CXCR5的抗体和抗原结合片段的实例是本领域技术人员已知的并例如描述于EP2195023中。
用于大鼠抗体RF8B2 (ACC2153)的杂交瘤细胞购自DSMZ并通过标准方法鉴定此抗体的序列。制备TPP-9024,此抗体的在位置67具有点突变(S67F)的嵌合变体。此外,大鼠抗体序列构成通过CDR移植(CDR接枝)至人类框架所获得的人源化抗体的起始点。
这些抗体和抗原结合片段可用于本发明的上下文中。
在本发明的上下文中尤其优选人源化抗-CXCR5抗体TPP-9574、TPP-9580和嵌合抗体TPP-9024。
用于根据本发明的结合剂-活性物质缀合物的优选的抗体和其抗原结合抗体片段
在本申请中,结合剂-活性物质缀合物参考如下表中所示的下列优选的抗体:抗-CD123抗体TPP-8987、TPP-8988和TPP-9476以及抗-CXCR5抗体TPP-9024、TPP-9574和TPP-9580。
表:优选抗体的蛋白序列:
TPP-8987、TPP-8988、TPP-9476、TPP-9024、TPP-9574和TPP-9580是在重链可变区(VH)或轻链可变区(VL)中包含一个或多个上表中所给出的CDR序列(H-CDR1、H-CDR2、H-CDR3、L-CDR1、L-CDR2、L-CDR3)的抗体。优选地,所述抗体包含给出的重链可变区(VH)和/或轻链可变区(VL)。优选地,所述抗体包含给出的重链区(IgG重链)和/或给出的轻链区(IgG轻链)。
TPP-8987是包含重链可变区(VH)和轻链可变区(VL)的抗-CD123抗体,所述重链可变区包含如SEQ ID NO:2所示的重链可变CDR1序列(H-CDR1),如SEQ ID NO:3所示的重链可变CDR2序列(H-CDR2)和如SEQ ID NO:4所示的重链可变CDR3序列(H-CDR3),所述轻链可变区包含如SEQ ID NO:6所示的轻链可变CDR1序列(L-CDR1),如SEQ ID NO:7所示的轻链可变CDR2序列(L-CDR2)和如SEQ ID NO:8所示的轻链可变CDR3序列(L-CDR3)。
TPP-8988是包含重链可变区(VH)和轻链可变区(VL)的抗-CD123抗体,所述重链可变区包含如SEQ ID NO:12所示的重链可变CDR1序列(H-CDR1),如SEQ ID NO:13所示的重链可变CDR2序列(H-CDR2)和如SEQ ID NO:14所示的重链可变CDR3序列(H-CDR3),所述轻链可变区包含如SEQ ID NO:16所示的轻链可变CDR1序列(L-CDR1),如SEQ ID NO:17所示的轻链可变CDR2序列(L-CDR2)和如SEQ ID NO:18所示的轻链可变CDR3序列(L-CDR3)。
TPP-9024是包含重链可变区(VH)和轻链可变区(VL)的抗-CXCR5抗体,所述重链可变区包含如SEQ ID NO:22所示的重链可变CDR1序列(H-CDR1),如SEQ ID NO:23所示的重链可变CDR2序列(H-CDR2)和如SEQ ID NO:24所示的重链可变CDR3序列(H-CDR3),所述轻链可变区包含如SEQ ID NO:26所示的轻链可变CDR1序列(L-CDR1),如SEQ ID NO:27所示的轻链可变CDR2序列(L-CDR2)和如SEQ ID NO:28所示的轻链可变CDR3序列(L-CDR3)。
TPP-9476是包含重链可变区(VH)和轻链可变区(VL)的抗-CD123抗体,所述重链可变区包含如SEQ ID NO:32所示的重链可变CDR1序列(H-CDR1),如SEQ ID NO:33所示的重链可变CDR2序列(H-CDR2)和如SEQ ID NO:34所示的重链可变CDR3序列(H-CDR3),所述轻链可变区包含如SEQ ID NO:36所示的轻链可变CDR1序列(L-CDR1),如SEQ ID NO:37所示的轻链可变CDR2序列(L-CDR2)和如SEQ ID NO:38所示的轻链可变CDR3序列(L-CDR3)。
TPP-9574是包含重链可变区(VH)和轻链可变区(VL)的抗-CXCR5抗体,所述重链可变区包含如SEQ ID NO:42所示的重链可变CDR1序列(H-CDR1),如SEQ ID NO:43所示的重链可变CDR2序列(H-CDR2)和如SEQ ID NO:44所示的重链可变CDR3序列(H-CDR3),所述轻链可变区包含如SEQ ID NO:46所示的轻链可变CDR1序列(L-CDR1),如SEQ ID NO:47所示的轻链可变CDR2序列(L-CDR2)和如SEQ ID NO:48所示的轻链可变CDR3序列(L-CDR3)。
TPP-9580是包含重链可变区(VH)和轻链可变区(VL)的抗-CXCR5抗体,所述重链可变区包含如SEQ ID NO:52所示的重链可变CDR1序列(H-CDR1),如SEQ ID NO:53所示的重链可变CDR2序列(H-CDR2)和如SEQ ID NO:54所示的重链可变CDR3序列(H-CDR3),所述轻链可变区包含如SEQ ID NO:56所示的轻链可变CDR1序列(L-CDR1),如SEQ ID NO:57所示的轻链可变CDR2序列(L-CDR2)和如SEQ ID NO:58所示的轻链可变CDR3序列(L-CDR3)。
TPP-8987是优选包含如SEQ ID NO:1所示的重链可变区(VH)和如SEQ ID NO:5所示的轻链可变区(VL)的抗-CD123抗体。
TPP-8988是优选包含如SEQ ID NO:11所示的重链可变区(VH)和如SEQ ID NO:15所示的轻链可变区(VL)的抗-CD123抗体。
TPP-9024是优选包含如SEQ ID NO:21所示的重链可变区(VH)和如SEQ ID NO:25所示的轻链可变区(VL)的抗-CXCR5抗体。
TPP-9476是优选包含如SEQ ID NO:31所示的重链可变区(VH)和如SEQ ID NO:35所示的轻链可变区(VL)的抗-CD123抗体。
TPP-9574是优选包含如SEQ ID NO:41所示的重链可变区(VH)和如SEQ ID NO:45所示的轻链可变区(VL)的抗-CXCR5抗体。
TPP-9580是优选包含如SEQ ID NO:51所示的重链可变区(VH)和如SEQ ID NO:55所示的轻链可变区(VL)的抗-CXCR5抗体。
TPP-8987是优选包含如SEQ ID NO:9所示的重链区和如SEQ ID NO:10所示的轻链区的抗-CD123抗体。
TPP-8988是优选包含如SEQ ID NO:19所示的重链区和如SEQ ID NO:20所示的轻链区的抗-CD123抗体。
TPP-9024是优选包含如SEQ ID NO:29所示的重链区和如SEQ ID NO:30所示的轻链区的抗-CXCR5抗体。
TPP-9476是优选包含如SEQ ID NO:39所示的重链区和如SEQ ID NO:40所示的轻链区的抗-CD123抗体。
TPP-9574是优选包含如SEQ ID NO:49所示的重链区和如SEQ ID NO:50所示的轻链区的抗-CXCR5抗体。
TPP-9580是优选包含如SEQ ID NO:59所示的重链区和如SEQ ID NO:60所示的轻链区的抗-CXCR5抗体。
治疗用途
根据本发明的化合物可用于治疗的过度增生病症特别包括癌症和肿瘤病症类。在本发明上下文中,这些被理解为尤其是指下列病症,但不限于它们:乳腺癌和乳腺肿瘤(乳腺癌包括导管和小叶形式,以及原位(in situ))、呼吸道肿瘤(小细胞和非小细胞癌、支气管癌)、脑肿瘤(例如脑干肿瘤和下丘脑肿瘤、星形细胞瘤、室管膜瘤、胶质母细胞瘤、胶质瘤、髓母细胞瘤、脑膜瘤和神经外胚层和松果体瘤)、消化器官肿瘤(食道、胃、胆囊、小肠、大肠、直肠和肛门癌)、肝肿瘤(尤其是肝细胞癌、胆管细胞癌和混合肝细胞胆管细胞癌)、头颈区的肿瘤(喉、下咽部、鼻咽、口咽、嘴唇和口腔癌,口腔黑色素瘤)、皮肤瘤(基底细胞瘤、Spinaliome、鳞状细胞癌、卡波西肉瘤、恶性黑色素瘤、非黑色素瘤皮肤癌、梅克尔细胞皮肤癌、肥大细胞瘤)、支持和结缔组织肿瘤(尤其是软组织肉瘤、骨肉瘤、恶性纤维组织细胞瘤、软骨肉瘤、纤维肉瘤、血管肉瘤、平滑肌肉瘤、脂肪肉瘤、淋巴肉瘤和横纹肌肉瘤)、眼睛肿瘤(尤其是眼内黑色素瘤和成视网膜细胞瘤)、内分泌和外分泌腺的肿瘤(例如甲状腺和甲状旁腺、胰腺和唾液腺癌、腺癌)、尿道肿瘤(膀胱、阴茎、肾、肾盂和输尿管的肿瘤)和生殖器官肿瘤(在女性中为子宫内膜癌、子宫颈癌、卵巢癌、阴道癌、外阴癌和子宫癌,在男性中为前列腺癌和睾丸癌)。这些还包括实体形式和作为循环细胞的血液、淋巴系统和脊髓的增殖性疾病,如白血病、淋巴瘤和骨髓增生病症,例如急性髓细胞白血病、急性成淋巴细胞性白血病、慢性淋巴细胞性白血病、慢性髓细胞性白血病和毛细胞性白血病和AIDS相关淋巴瘤、霍奇金淋巴瘤、非霍奇金淋巴瘤、皮肤T-细胞淋巴瘤、伯基特氏淋巴瘤和中枢神经系统中的淋巴瘤。
这些在人类中已充分表征的疾病在其它哺乳动物中也以相当的病因学发生,并在此同样可用本发明的化合物治疗。
本文所述针对CD123的抗体-活性物质缀合物(ADC)可用于治疗CD123表达病症,例如CD123表达的癌症病症。通常,此类癌细胞在蛋白(例如使用免疫测定)或RNA水平上具有可测定量的CD123。相比于相同类型的非癌组织,这些癌症组织中的一些显示升高的CD123水平,优选地在相同的患者中测量。任选地,CD123含量在以根据本发明的抗体-活性物质缀合物(ADC)治疗癌症开始之前测量(患者分层)。针对CD123的抗体-活性物质缀合物(ADC)可用于治疗CD123表达病症,例如CD123表达的癌症病症,例如造血和淋巴组织的肿瘤或造血和淋巴恶性肿瘤。与CD123表达有关的癌症病症的实例包括骨髓疾病,例如急性骨髓性白血病(AML)和骨髓增生不良综合征(MDS)。其它类型的癌症包括B-细胞急性淋巴母细胞白血病(B-ALL)、毛细胞白血病、母细胞胞浆性树突细胞瘤(BPDCN)、霍奇金氏淋巴瘤、未成熟T-细胞急性淋巴性白血病(未成熟T-ALL)、伯基特氏淋巴瘤、滤泡淋巴瘤、慢性淋巴性白血病(CLL)、套细胞淋巴瘤(MCL)。本发明所述的方法包括治疗患有CD123-表达癌症的患者,其中所述方法包括施用根据本发明的抗体-活性物质缀合物(ADC)。
用本发明的化合物治疗上述癌症包括实体瘤的治疗及其转移或循环形式的治疗。
在本发明上下文中,术语“治疗”在传统意义上使用并且是指为了对抗、减轻、减弱或缓解疾病或健康异常和改善例如在癌症的情况下因该疾病受损的生存状况而照料、护理和看护患者。
本发明的另外主题因此在于本发明的化合物用于治疗和/或预防病症,特别是上文提到的病症的用途。
本发明的另外主题在于本发明的化合物用于制备治疗和/或预防病症,特别是上文提到的病症的药剂的用途。
本发明的另外主题在于本发明的化合物在治疗和/或预防病症,特别是上文提到的病症的方法中的用途。
本发明的另外主题在于使用有效量的至少一种本发明的化合物治疗和/或预防病症,特别是上文提到的病症的方法。
本发明的化合物可以独自使用或如果需要,与一种或多种其它药理活性物质组合使用,只要这种组合不会造成不合意和不可接受的副作用。因此,本发明的另外主题在于含有至少一种本发明的化合物和一种或多种其它活性物质的药剂,其特别是用于治疗和/或预防上述病症。
例如,本发明的化合物可以与用于治疗癌症的已知抗过度增生、细胞生长抑制、细胞毒性或免疫治疗性物质组合。合适的组合活性物质示例性提及:
131I-chTNT、阿倍瑞克(Abarelix)、阿比特龙、阿柔比星、阿达木单抗、Ado-Trastuzumab Emtansin、阿法替尼、阿柏西普、阿地白介素、阿仑单抗(Alemtuzumab)、阿仑棒酸、阿利维A酸(Alitretinoin)、六甲蜜胺、氨磷汀、氨鲁米特、己基-5-氨基乙酰丙酸酯、氨柔比星、安吖啶、阿那曲唑、安西司亭、茴三硫、Anetumab Ravtansine、血管紧张素II、抗凝血酶III、阿瑞吡坦、阿西莫单抗、Arglabin、三氧化二砷、门冬酰胺酶、阿特珠单抗、阿维鲁单抗、阿西替尼、阿扎胞苷、贝洛替康(Belotecan)、苯达莫司汀、贝索单抗、贝利司他、贝伐单抗(Bevacizumab)、贝沙罗汀(Bexaroten)、比卡鲁胺、比生群、博来霉素、博纳吐单抗、硼替佐米、布舍瑞林、博舒替尼、Brentuximab Vedotin、白消安、卡巴他赛(Cabazitaxel)、卡博替尼、降血钙素、亚叶酸钙、左亚叶酸钙、卡培他滨、卡罗单抗、卡巴咪嗪、卡铂、Carboquon、卡菲偌米布、卡莫氟、卡莫司汀、卡妥索单抗(Catumaxomab)、西乐葆、西莫白介素、色瑞替尼、西妥昔单抗、苯丁酸氮芥、氯地孕酮、氮芥、西多福韦、西那卡塞、顺铂、克拉屈滨、氯膦酸、氯法拉滨(Clofarabin)、考比替尼、Copanlisib、克立他酶(Crisantaspase)、克唑替尼、环磷酰胺、环丙孕酮、阿糖胞苷、达卡巴嗪、放线菌素、达雷木单抗、达拉非尼、Darolutamide、达沙替尼、柔红霉素、地西他滨、地加瑞克、地尼白介素(Denileukin-Diftitox)、地诺塞麦(Denosumab)、地普奥肽、地洛瑞林、右丙亚胺、二溴螺氯铵、二去水矛醇、双氯芬酸、多西他赛、多拉司琼、去氧氟尿苷、多柔比星、多柔比星+雌酮、屈大麻酚、Durvalumab、依决洛单抗、依利醋铵、血管内皮抑素、依诺他滨、恩扎鲁胺、Epacadostat、表柔比星、环硫雄醇、依泊汀α、依泊汀β、依泊汀ζ、依他铂、艾日布林(Eribulin)、埃洛替尼、埃索美拉唑、雌莫司汀、依托泊苷、乙炔雌二醇、依维莫司、依西美坦、法屈唑、芬太尼、氟羚甲基睾丸素、氟尿苷、氟达拉滨、氟尿嘧啶、氟他胺、叶酸、福美坦、福沙吡坦、福莫司汀、氟维司群、钆布醇、加多利道、钆特酸葡胺盐、钆弗塞胺、钆塞酸二钠盐(Gd-EOB-DTPA二钠盐)、硝酸镓、加尼瑞克、吉非替尼、吉西他滨、吉妥单抗(Gemtuzumab)、羧肽酶、谷胱甘肽(Glutoxim)、戈舍瑞林、格兰西龙、粒细胞集落刺激因子(G-CSF)、粒细胞巨噬细胞集落刺激因子(GM-CSF)、二盐酸组胺、组氨瑞林(Histrelin)、羟基脲、I-125粒子、兰索拉唑、依班膦酸-替伊莫单抗(Ibritumomab-Tiuxetan)、依鲁替尼、伊达比星、异环磷酰胺、伊马替尼、咪喹莫特、英丙舒凡(Improsulfan)、吲地司琼、英卡膦酸、巨大戟醇甲基丁烯酸酯、干扰素α、干扰素β、干扰素γ、碘比醇、碘苄胍(123I)、碘美普尔、易普利姆玛(Ipilimumab)、伊立替康、伊曲康唑、伊沙匹隆(Ixabepilon)、伊沙佐米、兰瑞肽、兰索拉唑、Lansoprazol、拉帕替尼(Lapatinib)、Lasocholine、来那度胺(Lenalidomid)、乐伐替尼、来格司亭、蘑菇多糖、来曲唑、亮丙瑞林、左旋四咪唑、左炔诺孕酮、左甲状腺素钠、Lipegfilgrastim、麦角乙脲、乐铂、环己亚硝脲、氯尼达明、马索罗酚、甲羟孕酮、甲地孕酮、美拉胂醇、苯丙氨酸氮芥、美雄烷、巯基嘌呤、美司钠、美沙酮、氨甲喋呤、甲氧呋豆素、甲基氨基酮戊酸盐、甲基泼尼松龙、甲基睾酮、Metirosin、米伐木肽(Mifamurtid)、米特福辛、米铂(Miriplatin)、二溴甘露醇、丙脒腙、二溴卫矛醇、丝裂霉素、米托坦、米托蒽醌、Mogamulizumab、莫拉司亭、莫哌达醇、盐酸吗啡、硫酸吗啡、大麻隆、Nabiximols、那法瑞林、纳洛酮+戊唑辛、纳曲酮、那托司亭、Necitumumab、奈达铂、奈拉滨(Nelarabin)、奈立膦酸、奈妥吡坦/palonosetron、纳武单抗、纳武单抗喷曲肽、尼洛替尼(Nilotinib)、尼鲁米特、尼莫唑、尼妥珠单抗(Nimotuzumab)、嘧啶亚硝脲、尼达尼布、二胺硝吖啶(Nitracrin)、纳武单抗、阿托珠单抗、奥曲肽、奥法木单抗(Ofatumumab)、奥拉帕尼、Olaratumab、高三尖杉酯碱、奥美拉唑、奥坦西隆、奥古蛋白、Orilotimod、奥希替尼、奥沙利铂、羟考酮、羟甲烯龙、Ozogamicin、p53-基因疗法、紫杉醇、帕博西尼、帕利夫明、钯-103粒子、帕洛诺司琼、帕米膦酸、帕尼单抗(Panitumumab)、帕比司他、泮托拉唑、帕唑帕尼(Pazopanib)、培加帕酶、帕母单抗、聚乙二醇干扰素α-2b、派姆单抗、培美曲唑、喷司他丁、培洛霉素、全氟丁烷、培磷酰胺、帕妥株单抗、溶链菌制剂(Picibanil)、毛果芸香碱、吡柔比星、匹克生琼、普乐沙福(Plerixafor)、普卡霉素、聚氨葡糖(Poliglusam)、磷酸聚雌二醇、聚乙烯吡咯烷酮 +透明质酸钠、多糖-K、泊马度胺、帕纳替尼、卟吩姆钠、普拉曲沙(Pralatrexat)、松龙苯芥、泼尼松、甲基苄肼、丙考达唑、普萘洛尔、喹高利特(Quinagolid)、雷贝拉唑、Racotumomab、氯化镭223、拉多替尼、雷诺昔酚、雷替曲塞(Raltitrexed)、雷莫司琼、雷莫芦单抗、雷莫司汀(Ranimustin)、拉布立酶、丙亚胺、Refametinib 、瑞戈非尼(Regorafenib)、利塞膦酸、铼-186依替膦酸盐、利妥昔单抗(Rituximab)、Rogaratinib、罗拉吡坦、罗米地辛(Romidepsin)、罗莫肽、瑞博西尼 、来昔决南钐(153Sm)、沙妥莫单抗、分泌素、司妥昔单抗、Sipuleucel-T、西佐喃、索布佐生、甘氨双唑钠(Natriumglycididazol)、索尼德吉、索拉非尼(Sorafenib)、康力龙、链脲霉素、舒尼替尼、他拉泊芬(Talaporfin)、Talimogen Laherparepvec、他米巴罗汀(Tamibaroten)、他莫昔芬、他喷他多、他索纳明(Tasonermin)、替西白介素(Teceleukin)、锝[99mTc]巯诺莫单抗、99mTc-HYNIC-[Tyr3]-奥曲肽、替加氟、替加氟+吉美嘧啶(Gimeracil)+奥替拉西(Oteracil)、替莫卟吩、替莫唑胺、西罗莫司(Temsirolimus)、表鬼臼毒噻吩糖苷、睾酮、替曲膦(Tetrofosmin)、反应停、硫替派、胸腺法新(Thymalfasin)、促甲状腺素α、硫鸟嘌呤(Tioguanin)、托珠单抗(Tocilizumab)、托泊替康、托瑞米芬、托西莫单抗(Tositumomab)、曲贝替定(Trabectedin)、曲美替尼、曲马多、曲妥珠单抗、曲奥舒凡(Treosulfan)、维甲酸、曲氟尿苷+ Tipiracil、曲美替尼、曲洛司坦、曲普瑞林、氯乙环磷酰胺、促血小板生成素、乌苯美司、戊柔比星(Valrubicin)、凡德他尼(Vandetanib)、伐普肽、瓦他拉尼、维罗非尼(Vemurafenib)、长春碱、长春新碱、长春地辛、长春氟宁、长春瑞宾、维莫德吉、伏立诺他(Vorinostat)、钇-90-玻璃微球、新制癌菌素、净司他丁斯酯、唑来膦酸、佐柔比星。
此外,本发明的化合物可以例如与可例如结合下列靶标的结合剂(例如,抗体)组合:OX-40、CD137/4-1BB、DR3、IDO1/IDO2、LAG-3、CD40。
由于抗体-活性物质缀合物(ADC)的非细胞可渗透毒簇代谢物应当对于适应性免疫系统的细胞无损害效应,所以根据本发明的抗体-活性物质缀合物(ADC)与癌症免疫治疗的组合以用于治疗癌症或肿瘤是本发明的另一主题。细胞毒性抗体-活性物质缀合物的内在作用机制包括直接触发肿瘤细胞的细胞死亡和因此释放可刺激免疫反应的肿瘤抗原。此外,有迹象表明KSP抑制剂毒簇类别在体外诱导所谓免疫细胞死亡(ICD)的标记。因此,本发明的抗体-活性物质缀合物(ADC)与一种或多种癌症免疫治疗的治疗配药或与一种或多种活性物质,优选地针对癌症免疫治疗的分子靶标的抗体的组合,代表用于治疗癌症或肿瘤的优选方法。i)癌症免疫治疗的治疗配药的实例包括免疫调节单克隆抗体和针对癌症免疫治疗的靶标的低分子量物质、疫苗、CAR T细胞、双特异性T-细胞-招募抗体、溶瘤病毒、基于细胞的疫苗接种配药。ii)适用于免疫调节单克隆抗体的所选的癌症免疫治疗的靶标的实例包括CTLA-4、PD-1/PDL-1、OX-40、CD137、DR3、IDO1、IDO2、TDO2、LAG-3、TIM-3 CD40.,ICOS/ICOSL、TIGIT;GITR/GITRL、VISTA、CD70、CD27、HVEM/BTLA、CEACAM1、CEACAM6、ILDR2、CD73、CD47、B7H3、TLR's。因此,根据本发明的抗体-活性物质缀合物(ADC)与癌症治疗的组合,在一个方面,可赋予具有微弱的免疫原性的肿瘤更大的免疫原性并增强癌症免疫治疗的效果,并进一步发挥持久的治疗作用。
此外,根据本发明的化合物也可以与放射疗法和/或外科手术联合使用。
通常,用本发明的化合物与其它细胞生长抑制、细胞毒性或免疫治疗活性剂的组合追求下列目标:
• 与用单一活性物质治疗相比,在减慢肿瘤生长、减小其尺寸或甚至完全消除其方面改进的效果;
•以比单一疗法的情况中更低的剂量使用所用化疗药物的可能性;
•与单独施用相比,更耐受治疗、副作用较少的可能性;
•治疗更广谱的肿瘤病症的可能性;
•实现更高的治疗响应率;
• 与当今标准疗法相比,更长的患者存活时间。
此外,根据本发明的化合物也可以与放射疗法和/或外科手术联合使用。
本发明的另外主题在于包含至少一种本发明化合物通常与一种或多种惰性、无毒性的药学上合适的助剂的药剂,及其用于上述目的的用途。
本发明的化合物可以全身和/或局部发挥作用。为此,它们可通过合适方式,例如肠道外、可能吸入或作为植入物或支架施用。
本发明的化合物可以以适合这些施用途径的施用形式施用。
肠道外施用可以绕开再吸收步骤(例如静脉内、动脉内、心脏内、脊柱内或腰内)或包括再吸收(例如肌肉内、皮下、皮内、经皮或腹膜内)进行。适合肠道外施用的施用形式尤其包括溶液剂、混悬剂、乳剂或冻干产物形式的注射和输液制剂。优选的是肠道外施用,尤其是静脉施用。
通常已经发现,在肠道外施用的情况下有利的是施用约0.1至20 mg/kg,优选约0.3至7 mg/kg体重的量以实现有效结果。
然而,在一些情况下可能必需偏离所示的量,尤其取决于体重、施用途径、个体对活性物质的响应、制剂类型和施用时间点或时间间隔。因此,在一些情况下,少于上述最低量可能是足够的,而在另一些情况下,必须超过所提到的上限。在施用更大量的情况下,可能最好将它们在一天内分成几个单剂。
实施例
下列实施例说明本发明。本发明不限于这些实施例。
除非另行指明,下列测试和实施例中的百分比数据为重量百分比;份数为重量份。液体/液体溶液的溶剂比、稀释比和浓度数据在每种情况下都基于体积。
如果在实验的描述中,未给出关于进行反应的温度的数据,则可假定为室温。
合成途径:
对于实施例,在下列方案中示范性地显示产生实施例的示例性合成途径:合成顺序和保护基团策略可基于目标化合物的途径而不同。
方案1:中间体的合成
[a): 例如三乙酰氧基硼氢化钠, 乙酸, DCM, RT;b) 例如乙酰氧基乙酰氯, NEt3,DCM, RT;c) 例如LiOH, THF/水, RT;d) 例如H2, Pd-C, EtOH, RT;e) 例如Teoc-OSu,NEt3, 二氧杂环己烷, RT;f] 例如Fmoc-Cl, 二异丙基乙胺, 二氧杂环己烷/水2:1, RT]。
方案2:经由开环琥珀酰亚胺合成半胱氨酸连接的ADC
[a):HATU,DMF,N,N-二异丙基乙胺,RT;b):H2,10% Pd-C,甲醇,RT c):1,1'-[(1,5-二氧代吡咯烷-1-基)氧基]-2-氧代乙基}-1H-吡咯-2,5-二酮,N,N-二异丙基乙胺,DMF,在室温下搅拌;d)2,2,2-三氟乙醇,4-8当量的氯化锌,在50℃ 2-6h;e)AK溶解于PBS,在氩气下添加3-4当量的TCEP/PBS缓冲液和在室温下搅拌约30 min,然后添加5-10当量溶解于DMSO中的化合物D,在室温下搅拌约90 min,然后通过以PBS缓冲剂(pH 8)平衡PD 10柱(Sephadex® G-25, GE Healthcare)再缓冲至pH 8,然后在室温下搅拌过夜,然后任选地通过以PBS缓冲剂(pH 7.2)平衡的PD 10柱(Sephadex® G-25, GE Healthcare)纯化,且随后通过超速离心浓缩并以PBS缓冲剂(pH 7.2)设定所需的浓度]。在体内批次的情况下,这随后任选地无菌过滤。
A. 实施例
缩写和首字母缩略词:
ABCB1 ATP-结合盒亚家族B成员1(P-gp和MDR1的同义词)
abs. 纯
Ac 乙酰基
ACN 乙腈
aq. 含水,水溶液
ATP 三磷酸腺苷
BCRP 乳腺癌耐药蛋白,外排转运蛋白
BEP 2-溴-1-乙基吡啶鎓四氟硼酸盐
Boc 叔丁氧基羰基
br. 宽(在NMR中)
Bsp. 例如
C 浓度
ca. 大约、约
CI 化学电离(在MS中)
D 双重峰(在NMR中)
D 天
DAR 药物:抗体比
DC 薄层色谱法
DCI 直接化学电离(在MS中)
DCM 二氯甲烷
Dd 双重双峰(在NMR中)
DMAP 4-N,N-二甲基氨基吡啶
DME 1,2-二甲氧基乙烷
DMEM Dulbecco氏改良的Eagle培养基(用于细胞培养的标准化营养培养基)
DMF N,N-二甲基甲酰胺
DMSO 二甲亚砜
D/P 染料(荧光染料)/蛋白比
DPBS, D-PBS Dulbecco氏磷酸盐缓冲的盐溶液
DSMZ 德国微生物和细胞培养物保藏中心
PBS PBS = DPBS = D-PBS, pH 7.4,来自Sigma, No D8537
Dt 双重三峰(在NMR中)
DTT DL-二硫苏糖醇
d. Th. 理论值的(在化学产率中)
EDC N'-(3-二甲基氨基丙基)-N-乙基碳二亚胺盐酸盐
EGFR 表皮生长因子受体
EI 电子碰撞电离(在MS中)
ELISA 酶联免疫吸附测定法
eq. 当量
ESI 电喷雾电离(在MS中)
ESI-MicroTofq ESI-MicroTofq (质谱仪名称,Tof = 飞行时间和q = 四极)
FCS 胎牛血清
Fmoc (9H-芴-9-基甲氧基)羰基
ges. 饱和
GTP 5'-三磷酸鸟苷
H 小时
HATU O-(7-氮杂苯并三唑-1-基)-N,N,N',N'-四甲基脲鎓六氟磷酸盐
HEPES 4-(2-羟乙基)哌嗪-1-乙烷磺酸
HOAc 乙酸
HOAt 1-羟基-7-氮杂苯并三唑
HOBt 1-羟基-1H-苯并三唑水合物
HOSu N-羟基琥珀酰亚胺
HPLC 高压高效液相色谱法
IC50 半最大抑制浓度
i.m. 肌肉内,施用至肌肉中
i.v. 静脉,施用至静脉中
KPL-4 人肿瘤细胞系
konz. 浓缩
LC-MS 液相色谱法-质谱法联用
LLC-PK1-Zellen Lewis肺癌猪肾细胞系
L-MDR 人MDR1转染的LLC-PK1细胞
M 多重峰(在NMR中)
MDR1 多药耐药蛋白1
MeCN 乙腈
Me 甲基
Min 分钟
MOLM-13 人肿瘤细胞系
MS 质谱法
MTT 溴化3-(4,5-二甲基噻唑-2-基)-2,5-二苯基-2H-四唑鎓
MV-4-11 人肿瘤细胞系
NCI-H292 人肿瘤细胞系
NMM N-甲基吗啉
NMP N-甲基-2-吡咯烷酮
NMR 核磁共振谱法
NMRI 小鼠品系,源自Naval Medical Research Institute (NMRI)
Nude Mäuse 裸小鼠(实验动物)
NSCLC 非小细胞肺癌
PBS 磷酸盐缓冲的盐溶液
Pd/C 活性炭载钯
P-gp P-糖蛋白,转运蛋白
PNGaseF 用于裂解糖的酶
quant. 定量(产率)
quart 四重峰(在NMR中)
quint 五重峰(在NMR中)
Rec-1 人肿瘤细胞系
Rf 保留指数(在DC中)
RT 室温
Rt 保留时间(在HPLC中)
S 单重峰(在NMR中)
s.c. 皮下,在皮肤下施用
SCID小鼠 具有重症联合免疫缺陷的受试小鼠
SK-HEP-1 人肿瘤细胞系
t 三重峰(在NMR中)
TBAF 四正丁基氟化铵
TEMPO (2,2,6,6-四甲基哌啶-1-基)氧基
Teoc 三甲基甲硅烷基乙氧基羰基
Teoc-OSu 1-({[2-(三甲基甲硅烷基)乙氧基]羰基}氧基)吡咯烷-2,5-二酮
tert. 叔
TFA 三氟乙酸
THF 四氢呋喃
T3P® 2,4,6-三丙基-1,3,5,2,4,6-三氧杂三磷杂环己烷2,4,6-三氧化物
UV 紫外光谱法
v/v (溶液的)体积比
Z 苄氧基羰基。
HPLC和LC-MS方法:
方法1 (LC-MS):
仪器:Waters ACQUITY SQD UPLC系统;柱:Waters Acquity UPLC HSS T3 1.8μ 50×1mm;洗脱液A:1l水+0.25ml 99%甲酸,洗脱液B:1l乙腈+0.25ml 99%甲酸;梯度:0.0min 90%A→1.2min 5% A→2.0min 5% A;烘箱:50℃;流动速率:0.40mL/min;UV检测:208-400nm。
方法2 (LC-MS):
MS仪器类型:Waters Synapt G2S;UPLC仪器类型:Waters Acquity I-CLASS;柱:Waters,BEH300,2.1×150mm,C18 1.7μm;洗脱液A:1l水+0.01%甲酸;洗脱液B:1l乙腈+0.01%甲酸;梯度:0.0min 2% B→1.5min 2% B→8.5min 95% B→10.0min 95% B;烘箱:50℃;流动速率:0.50mL/min;UV检测:220nm。
方法3 (LC-MS):
MS仪器:Waters(Micromass) QM;HPLC仪器:Agilent 1100系列;柱:Agilent ZORBAXExtend-C18 3.0×50mm 3.5微米;洗脱液A:1l水+0.01mol碳酸铵,洗脱液B:1l乙腈;梯度:0.0min 98% A→0.2min 98% A→3.0min 5% A→4.5min 5% A;烘箱:40℃;流动速率:1.75mL/min;UV检测:210nm。
方法4 (LC-MS):
MS仪器类型:Waters Synapt G2S;UPLC仪器类型:Waters Acquity I-CLASS;柱:Waters,HSST3,2.1×50mm,C18 1.8μm;洗脱液A:1l水+0.01%甲酸;洗脱液B:1l乙腈+0.01%甲酸;梯度:0.0min 10% B→0.3min 10% B→1.7min 95% B→2.5min 95% B;烘箱:50℃;流动速率:1.20mL/min;UV检测:210nm。
方法5 (LC-MS):
仪器:Waters ACQUITY SQD UPLC系统;柱:Waters Acquity UPLC HSS T3 1.8μ 50×1mm;洗脱液A:1l水+0.25ml 99%甲酸;洗脱液B:1l乙腈+0.25ml 99%甲酸;梯度:0.0min 95%A→6.0min 5% A→7.5min 5% A烘箱:50℃;流动速率:0.35mL/min;UV检测:210-400nm。
方法6 (LC-MS):
仪器:Micromass Quattro Premier与Waters UPLC Acquity;柱:Thermo HypersilGOLD 1.9μ 50×1mm;洗脱液A:1l水+0.5ml 50%甲酸,洗脱液B:1l乙腈+0.5ml 50%甲酸;梯度:0.0min 97% A→0.5min 97% A→3.2min 5% A→4.0min 5% A烘箱:50℃;流动速率:0.3mL/min;UV检测:210nm。
方法7 (LC-MS):
仪器:Agilent MS Quad 6150;HPLC:Agilent 1290;柱:Waters Acquity UPLC HSS T31.8μ 50×2.1mm;洗脱液A:1l水+0.25ml 99%甲酸;洗脱液B:1l乙腈+0.25ml 99%甲酸;梯度:0.0min 90% A→0.3min 90% A→1.7min 5% A→3.0min 5% A烘箱:50℃;流动速率:1.20mL/min;UV检测:205-305nm。
方法8 (LC-MS):
MS仪器类型:Waters Synapt G2S;UPLC仪器类型:Waters Acquity I-CLASS;柱:Waters,HSST3,2.1×50mm,C18 1.8μm;洗脱液A:1l水+0.01%甲酸;洗脱液B:1l乙腈+0.01%甲酸;梯度:0.0min 2% B→2.0min 2% B→13.0min 90% B→15.0min 90% B;烘箱:50℃;流动速率:1.20ml/min;UV检测:210nm。
方法9:(LC-MS-制备纯化方法)
MS仪器:Waters,HPLC仪器:Waters(柱Waters X-Bridge C18,19mm×50mm,5μm,洗脱液A:水+0.05%氨,洗脱液B:具有梯度的乙腈(ULC);流动速率:40ml/min;UV检测:DAD;210-400nm)。
或:
MS仪器:Waters,HPLC仪器:Waters(柱Phenomenex Luna 5μ C18(2) 100A,AXIATech.50×21.2mm,洗脱液A:水+0.05%甲酸,洗脱液B:具有梯度的乙腈(ULC);流动速率:40ml/min;UV检测:DAD;210-400nm)。
方法10:(LC-MS分析方法)
MS仪器:Waters SQD;HPLC仪器:Waters UPLC;柱:Zorbax SB-Aq (Agilent),50mm×2.1mm,1.8μm;洗脱液A:水+0.025%甲酸,洗脱液B:乙腈(ULC)+0.025%甲酸;梯度:0.0min98%A-0.9min 25%A-1.0min 5%A-1.4min 5%A-1.41min 98%A-1.5min 98%A;烘箱:40℃;流动速率:0.600ml/min;UV检测:DAD;210nm。
方法11 (HPLC):
仪器:HP1100系列,柱:Merck Chromolith SpeedROD RP-18e, 50-4.6mm,目录号1.51450.0001,预柱Chromolith Guard Cartridge Kit, RP-18e,5-4.6mm,目录号1.51470.0001;梯度:流动速率5mL/Min;注射体积5μl;溶剂A:水中的HClO4(70%)(4mL/l),溶剂B:乙腈 起始20% B,0.50Min 20% B,3.00Min 90% B,3.50Min 90% B,3.51Min 20% B,4.00Min 20% B,柱温度:40℃,波长:210nm。
方法12 (LC-MS):
MS仪器类型:Thermo Scientific FT-MS;UHPLC+仪器类型:Thermo ScientificUltiMate 3000;柱:Waters,HSST3,2.1×75mm,C18 1.8μm;洗脱液A:1l水+0.01%甲酸;洗脱液B:1l乙腈+0.01%甲酸;梯度:0.0min 10% B→2.5min 95% B→3.5min 95% B;烘箱:50℃;流动速率:0.90ml/min;UV检测:210nm/最佳积分途径210-300nm。
方法13:(LC-MS):
MS仪器:Waters (Micromass) Quattro Micro;仪器Waters UPLC Acquity;柱:WatersBEH C18 1.7μ 50×2.1mm;洗脱液A:1l水+0.01mol甲酸铵,洗脱液B:1l乙腈;梯度:0.0min95% A→0.1min 95% A→2.0min 15% A→2.5min 15% A→2.51min 10% A→3.0min 10% A;烘箱:40℃;流动速率:0.5ml/min;UV检测:210nm。
方法14:(LC-MS):
MS仪器类型:ThermoFisherScientific LTQ-Orbitrap-XL;HPLC仪器类型:Agilent1200SL;柱:Agilent,POROSHELL 120,3×150mm,SB-C18 2.7μm;洗脱液A:1l水+0.1%三氟乙酸;洗脱液B:1l乙腈+0.1%三氟乙酸;梯度:0.0min 2% B→0.3min 2% B→5.0min 95% B→10.0min 95% B;烘箱:40℃;流动速率:0.75ml/min;UV检测:210nm。
下文没有明确描述其制备的所有反应物或试剂购自一般可得的来源。对于其制备同样没有描述在下文中并且不可购得或获自非一般可得的来源的所有其它反应物或试剂,参考描述了其制备的出版文献。
起始化合物和中间体:
中间体C52
(1R)-1-[1-苄基-4-(2,5-二氟苯基)-1H-吡咯-2-基]-2,2-二甲基丙-1-胺
将10.00g (49.01mmol) 4-溴-1H-吡咯-2-甲酸甲酯预先置入100.0mL DMF,并添加20.76g (63.72mmol)碳酸铯和9.22g (53.91mmol)苄基溴。将反应混合物在室温下搅拌过夜。将反应混合物分配于水和乙酸乙酯之间且水相用乙酸乙酯萃取。合并的有机相经硫酸镁干燥并在减压下蒸发溶剂。用90.0g 4-溴-1H-吡咯-2-甲酸甲酯重复反应。
合并的两组批料通过制备型RP-HPLC(柱:Daiso 300x100;10μ,流动速率:250mL/min,MeCN/水)纯化。在减压下蒸发溶剂且残余物在高真空下干燥。这得到125.15g (理论值的87%)化合物1-苄基-4-溴-1H-吡咯-2-甲酸甲酯。
LC-MS (方法1): Rt = 1.18 min; MS (ESIpos): m/z = 295 [M+H]+。
在氩气下,将4.80g (16.32mmol) 1-苄基-4-溴-1H-吡咯-2-甲酸甲酯预先置入DMF,并添加3.61g (22.85mmol)(2,5-二氟苯基)硼酸、19.20mL饱和碳酸钠溶液和1.33g(1.63mmol)[1,1'-双(二苯基膦基)二茂铁]-二氯钯(II):二氯甲烷。将反应混合物在85℃下搅拌过夜。将反应混合物通过硅藻土过滤且滤饼用乙酸乙酯洗涤。有机相用水萃取且然后用饱和NaCl溶液洗涤。有机相经硫酸镁干燥并在减压下蒸发溶剂。残余物借助硅胶纯化(流动相:环己烷/乙酸乙酯100:3)。在减压下蒸发溶剂且残余物在高真空下干燥。这得到3.60g (理论值的67%)化合物1-苄基-4-(2,5-二氟苯基)-1H-吡咯-2-甲酸甲酯。
LC-MS (方法7): Rt = 1.59 min; MS (ESIpos): m/z = 328 [M+H]+。
将3.60g (11.00mmol) 1-苄基-4-(2,5-二氟苯基)-1H-吡咯-2-甲酸甲酯预先置入90.0mL THF,并在0℃下添加1.04g (27.50mmol)氢化锂铝(2.4M,在THF中)。将反应混合物在0℃下搅拌30分钟。在0℃下,添加饱和酒石酸钾钠溶液,并将反应混合物与乙酸乙酯混合。有机相用饱和酒石酸钾钠溶液萃取三次。有机相用饱和NaCl溶液洗涤一次且经硫酸镁干燥。在减压下蒸发溶剂并将残余物溶解于30.0mL二氯甲烷中。添加3.38g (32.99mmol)氧化锰(IV),并在室温下搅拌48小时。添加另外2.20g (21.47mmol)氧化锰(IV),并在室温下搅拌过夜。将反应混合物通过硅藻土过滤且滤饼用二氯甲烷洗涤。在减压下蒸发溶剂且残余物2.80g (1-苄基-4-(2,5-二氟苯基)-1H-吡咯-2-甲醛)未经进一步纯化即用于合成下一步骤。
LC-MS (方法7): Rt = 1.48 min; MS (ESIpos): m/z = 298 [M+H]+。
将28.21g (94.88mmol) 1-苄基-4-(2,5-二氟苯基)-1H-吡咯-2-甲醛与23.00g(189.77mmol)(R)-2-甲基丙烷-2-亚磺酰胺一起预先置入403.0mL无水THF中,并添加67.42g (237.21mmol)异丙醇钛(IV)并将混合物在室温下搅拌过夜。添加500mL饱和NaCl溶液和1000.0mL乙酸乙酯,并在室温下搅拌1小时。将混合物通过硅藻土过滤且滤液用饱和NaCl溶液洗涤两次。有机相经硫酸镁干燥,在减压下蒸发溶剂且残余物使用BiotageIsolera(硅胶,柱1500+340g SNAP,流动速率200mL/min,乙酸乙酯/环己烷1:10)纯化。
LC-MS (方法7): Rt = 1.63 min; MS (ESIpos): m/z = 401 [M+H]+。
在氩气下将25.00g (62.42mmol)(R)-N-{(E/Z)-[1-苄基-4-(2,5-二氟苯基)-1H-吡咯-2-基]亚甲基}-2-甲基丙烷-2-亚磺酰胺预先置入无水THF中并冷却至-78℃。然后在-78℃下添加12.00g (187.27mmol)叔丁基锂(戊烷中的1.7M溶液)并将混合物在该温度下搅拌3小时。在-78℃下,然后相继添加71.4mL甲醇和214.3mL饱和氯化铵溶液,并使反应混合物升温至室温并在室温下搅拌1小时。将混合物用乙酸乙酯稀释并用水洗涤。有机相经硫酸镁干燥并在减压下蒸发溶剂。残余物(R)-N-{(1R)-1-[1-苄基-4-(2,5-二氟苯基)-1H-吡咯-2-基]-2,2-二甲基丙基}-2-甲基丙烷-2-亚磺酰胺未经进一步纯化即用于合成下一步骤。
LC-MS (方法6): Rt = 2.97 min; MS (ESIpos): m/z = 459 [M+H]+。
将28.00g (61.05mmol)(R)-N-{(1R)-1-[1-苄基-4-(2,5-二氟苯基)-1H-吡咯-2-基]-2,2-二甲基丙基}-2-甲基丙烷-2-亚磺酰胺预先置入186.7mL 1,4-二氧杂环己烷中,且然后添加45.8mL HCl的1,4-二氧杂环己烷溶液(4.0M)。将反应混合物在室温下搅拌2小时并在减压下蒸发溶剂。残余物通过制备型HPLC(柱:Kinetix 100x30;流动速率:60mL/min,MeCN/水)纯化。在减压下蒸发乙腈并将二氯甲烷添加至水性残余物。有机相用碳酸氢钠溶液洗涤且经硫酸镁干燥。在减压下蒸发溶剂且残余物在高真空下干燥。这得到16.2g(理论值的75%)标题化合物。
LC-MS (方法6): Rt = 2.10 min; MS (ESIpos): m/z = 338 [M-NH2]+, 709 [2M+H]+。
1H-NMR (400 MHz, DMSO-d6): δ[ppm] = 0.87 (s, 9H), 1.53 (s, 2H), 3.59(s, 1H), 5.24 (d, 2H), 6.56 (s, 1H), 6.94 (m, 1H), 7.10 (d, 2H), 7.20 (m,1H), 7.26 (m, 2H), 7.34 (m, 2H), 7.46 (m, 1H)。
中间体C58
(2S)-4-[{(1R)-1-[1-苄基-4-(2,5-二氟苯基)-1H-吡咯-2-基]-2,2-二甲基丙基}(乙醇酰基)氨基]-2-({[2-(三甲基甲硅烷基)乙氧基]羰基}氨基)丁酸
将4.3g (12.2mmol)的中间体C52溶解于525 mL DCM中,并添加3.63g (17.12mmol) 三乙酰氧基硼氢化钠和8.4 mL 乙酸。在室温下搅拌5 min之后,添加溶解于175 mL DCM中的8.99g (24.5mmol)中间体L57并将批料在室温下再搅拌45 min。然后用300 mL DCM稀释批料并用100 mL 碳酸氢钠溶液洗涤二次并用饱和的NaCl溶液洗涤一次。将有机相经硫酸镁干燥,在减压下蒸发溶剂并在高真空下干燥残余物。然后通过制备型RP-HPLC纯化残余物(柱:Chromatorex C18)。将相应的级分合并之后,在减压下蒸发溶剂并在高真空下干燥残余物。这得到4.6g (理论值的61%) (2S)-4-({(1R)-1-[1-苄基-4-(2,5-二氟苯基)-1H-吡咯-2-基]-2,2-二甲基丙基}氨基)-2-({[2-(三甲基甲硅烷基)乙氧基]羰基}氨基)丁酸甲酯。
LC-MS (方法12): Rt = 1.97 min; MS (ESIpos): m/z = 614 (M+H)+。
将2.06g (3.36mmol)此中间体首先装入76 mL DCM中并用0.81mL (7.17mmol) 乙酸2-氯-2-氧代乙酯在2.1 ml三乙胺存在的情况下酰化。在室温下搅拌20h之后,添加0.36mL 乙酸2-氯-2-氧代乙酯和0.94 ml 三乙胺并将批料在室温下再搅拌15 min。然后用500mL乙酸乙酯稀释混合物并相继用300 mL 5%柠檬酸振荡萃取二次,用300 mL饱和碳酸氢钠溶液振荡萃取两次并用100 mL饱和氯化钠溶液振荡萃取一次,且然后经硫酸镁干燥和浓缩。在高真空下干燥,得到2.17g (理论值的79%)保护的中间体。
LC-MS (方法1): Rt = 1.48 min; MS (ESIpos): m/z = 714 (M+H)+。
将2.17 mg (2.64mmol)的此中间体溶解于54 mL THF和27 mL 水,并添加26 mL 2摩尔浓度氢氧化锂溶液。将批料在室温下搅拌30 min且然后使用1.4 mL TFA将pH调节至3和4之间。在减压下浓缩批料。一旦大部分的THF已蒸发掉,则用DCM萃取水溶液两次且然后在减压下浓缩至干燥。通过制备型HPLC纯化残余物(柱:Chromatorex C18)。将相应的级分合并之后,在减压下蒸发溶剂并将残余物从乙腈/水冻干。这得到1.1 g (理论值的63%)的标题化合物。
LC-MS (方法1): Rt = 1.34 min; MS (ESIpos): m/z = 656 (M-H)-。
1H-NMR (400 MHz, DMSO-d6): δ[ppm] = 0.03 (s, 9H), 0.58 (m, 1H), 0.74-0.92 (m, 11H), 1.40 (m, 1H), 3.3 (m, 2H), 3.7 (m, 1H), 3.8-4.0 (m, 2H), 4.15(q, 2H), 4.9 and 5.2 (2d, 2H), 5.61 (s, 1H), 6.94 (m, 2H), 7.13-7.38 (m, 7H),7.48 (s, 1H), 7.60 (m, 1H), 12.35 (s, 1H)。
中间体C66
[(2S)-4-[{(1R)-1-[1-苄基-4-(2,5-二氟苯基)-1H-吡咯-2-基]-2,2-二甲基丙基}(乙醇酰基)氨基]-1-{[2-(甘氨酰基氨基)乙基]氨基}-1-氧代丁-2-基]氨基甲酸-2-(三甲基甲硅烷基)乙酯
首先,通过肽化学的经典方法(HATU偶联和Boc裂解),从N-[(苄基氧基)羰基]甘氨酸和(2-氨基乙基)氨基甲酸叔丁酯制备三氟乙酸{2-[(2-氨基乙基)氨基]-2-氧代乙基}氨基甲酸苄酯。
将13mg (0.036mmol)该中间体和25mg (0.033mmol)中间体C58溶于3mL DMF中,并添加19mg (0.05mmol) HATU和17μl N,N-二异丙基乙胺。在室温下搅拌10分钟后,浓缩混合物且残余物通过制备型HPLC纯化。这得到17.8mg (理论值的60%)中间体。
LC-MS (方法1): Rt = 1.36 min; MS (ESIpos): m/z = 891 (M+H)+。
将17mg (0.019mmol)该中间体溶解于10ml乙醇中,添加碳载钯(10%)且在室温下在标准压力下用氢气氢化2小时。滤出催化剂,在减压下蒸发溶剂且残余物在高真空下干燥。这得到9mg (理论值的62%)标题化合物。
LC-MS (方法1): Rt = 1.03 min; MS (ESIpos): m/z = 757 (M+H)+。
中间体C118
N-[(8S)-8-{2-[{(1R)-1-[1-苄基-4-(2,5-二氟苯基)-1H-吡咯-2-基]-2,2-二甲基丙基}(乙醇酰基)氨基]乙基}-2,2-二甲基-6,9-二氧代-5-氧杂-7,10-二氮杂-2-硅杂十二烷-12-基]-D-α-谷氨酰胺叔丁酯
标题化合物通过肽化学的经典方法通过使中间体L119和中间体C58在HATU存在的情况下偶联和后续氢化脱去Z保护基来制备。
LC-MS (方法1): Rt = 1.05 min; MS (ESIpos): m/z = 885 (M+H)+。
中间体C119
甘氨酰基-N-[(8S)-8-{2-[{(1R)-1-[1-苄基-4-(2,5-二氟苯基)-1H-吡咯-2-基]-2,2-二甲基丙基}(乙醇酰基)氨基]乙基}-2,2-二甲基-6,9-二氧代-5-氧杂-7,10-二氮杂-2-硅杂十二烷-12-基]-D-α-谷氨酰胺叔丁酯
中间体C119通过肽化学的经典方法通过使N-[(苄基氧基)羰基]甘氨酸2,5-二氧代吡咯烷-1-基酯和中间体C118在HATU存在的情况下偶联和后续通过经10%活性碳载钯在甲醇/二氯甲烷在室温下在氢气标准压力下氢化脱去Z保护基来制备。
LC-MS (方法1): Rt = 1.03 min; MS (ESIpos): m/z = 942 (M+H)+。
中间体L1
N-(2-氨基乙基)-2-(2,5-二氧代-2,5-二氢-1H-吡咯-1-基)乙酰胺三氟乙酸盐
标题化合物通过肽化学的经典方法从市售的(2,5-二氧代-2,5-二氢-1H-吡咯-1-基)乙酸和(2-氨基乙基)氨基甲酸叔丁酯制备。
LC-MS (方法1): Rt = 0.17 min; MS (ESIpos): m/z = 198 (M+H)+。
中间体L57
(2S)-4-氧代-2-({[2-(三甲基甲硅烷基)乙氧基]羰基}氨基)丁酸甲酯
将500.0mg (2.72mmol) L-天冬酰胺甲酯盐酸盐和706.3mg (2.72mmol) 2,5-二氧代吡咯烷-1-甲酸2-(三甲基甲硅烷基)乙酯预先置入5.0mL 1,4-二氧杂环己烷中,并添加826.8mg (8.17mmol)三乙胺。将反应混合物在室温下搅拌过夜。反应混合物直接通过制备型RP-HPLC(柱:Reprosil 250x40;10μ,流动速率:50mL/min,MeCN/水,0.1% TFA)纯化。然后在减压下蒸发溶剂并在高真空下干燥残余物。这得到583.9mg (理论值的74%)化合物(3S)-4-甲氧基-4-氧代-3-({[2-(三甲基甲硅烷基)乙氧基]羰基}氨基)丁酸。
LC-MS (方法1): Rt = 0.89 min; MS (ESIneg): m/z = 290 (M-H)-。
将592.9mg (3S)-4-甲氧基-4-氧代-3-({[2-(三甲基甲硅烷基)乙氧基]羰基}氨基)丁酸预先置入10.0mL 1,2-二甲氧基乙烷中,冷却至-15℃并添加205.8mg (2.04mmol)4-甲基吗啉和277.9mg (2.04mmol)氯甲酸异丁酯。15分钟后,以抽吸滤出沉淀并用每次10.0mL 1,2-二甲氧基乙烷处理两次。将滤液冷却至-10℃,并在强烈搅拌下添加溶解于10mL水中的115.5mg (3.05mmol)硼氢化钠。分离各相并将有机相用饱和碳酸氢钠溶液和饱和NaCl溶液洗涤各一次。有机相经硫酸镁干燥,在减压下蒸发溶剂并在高真空下干燥残余物。这得到515.9mg (理论值的91%)化合物N-{[2-(三甲基甲硅烷基)乙氧基]羰基}-L-高丝氨酸甲酯。
LC-MS (方法1): Rt = 0.87 min; MS (ESIpos): m/z = 278 (M+H)+。
将554.9mg (2.00mmol) N-{[2-(三甲基甲硅烷基)乙氧基]羰基}-L-高丝氨酸甲酯预先置入30.0mL二氯甲烷中,并添加1.27g (3.0mmol) Dess-Martin氧化剂和474.7mg(6.00mmol)吡啶。将混合物在室温下搅拌过夜。4小时后,将批料用二氯甲烷稀释并将有机相用10%Na2S2O3溶液、10%柠檬酸溶液和饱和碳酸氢钠溶液洗涤各三次。有机相经硫酸镁干燥并在减压下蒸发溶剂。这得到565.7mg (理论值的97%)标题化合物。
1H-NMR (400 MHz, DMSO-d6): δ [ppm] = 0.03 (s, 9H), 0.91 (m, 2H), 2.70-2.79 (m, 1H), 2.88 (dd, 1H), 3.63 (s, 3H), 4.04 (m, 2H), 4.55 (m, 1H), 7.54(d, 1H), 9.60 (t, 1H)。
中间体L119
N-(2-氨基乙基)-N2-[(苄基氧基)羰基]-D-α-谷氨酰胺叔丁酯三氟乙酸盐
中间体L119通过肽化学的经典方法通过使市售的(2R)-2-{[(苄基氧基)羰基]氨基}-5-叔丁氧基-5-氧代戊酸(1.00 g, 2.96 mmol)和(2-氨基乙基)氨基甲酸叔丁酯(560μl,3.6mmol)在HATU存在的情况下偶联和后续使用TFA在二氯甲烷中的10%溶液酸性脱去Boc保护基(其中基本上保留叔丁基酯保护基)来制备。通过制备型HPLC纯化后,得到标题化合物。
LC-MS (方法1): Rt = 0.62 min; MS (ESI-pos): m/z = 380 (M+H)+。
中间体L120
N-(2-氨基乙基)-N2-[(苄基氧基)羰基]-D-α-谷氨酰胺苄酯
中间体L120通过肽化学的经典方法通过使市售的(2R)-5-(苄基氧基)-2-{[(苄基氧基)羰基]氨基}-5-氧代戊酸(830 mg, 2.23 mmol)和(2-氨基乙基)氨基甲酸叔丁酯(420μl, 2.7mmol)在HATU存在的情况下偶联和后续使用TFA/二氯甲烷酸性脱去Boc保护基来制备。
中间体F104
(2S)-2-氨基-4-[{(1R)-1-[1-苄基-4-(2,5-二氟苯基)-1H-吡咯-2-基]-2,2-二甲基丙基}(乙醇酰基)氨基]-N-(2-{[(2,5-二氧代-2,5-二氢-1H-吡咯-1-基)乙酰基]氨基}乙基)丁酰胺三氟乙酸盐
将300 mg (0.456 mmol)中间体C58溶解于38mL DMF中,并添加142 mg (0.456 mmol)中间体L1和260 mg (0.684 mmol) HATU和318 µl N,N-二异丙基乙胺。将批料在室温下搅拌60分钟且然后浓缩。残余物通过制备型HPLC纯化,冻干后得到338 mg (理论值的87%)保护的中间体。
LC-MS (方法1): Rt = 1.30 min; MS (ESIpos): m/z = 837 (M+H)+。
在第二步骤中,将338 mg (0.404 mmol)该中间体溶解于40mL 2,2,2-三氟乙醇中。添加330.2 mg (2.42 mmol)氯化锌,并将批料在50℃下搅拌3小时。然后添加708 mg(2.42 mmol)乙二胺-N,N,N',N'-四乙酸和4mL 0.1%三氟乙酸水溶液。批料通过制备型HPLC纯化。浓缩相应级分并从乙腈/水冻干残余物,得到265mg (理论值的81%)标题化合物。
LC-MS (方法1): Rt = 0.82 min; MS (ESIpos): m/z = 693 (M+H)+。
中间体F325
N-[2-({(2S)-2-氨基-4-[{(1R)-1-[1-苄基-4-(2,5-二氟苯基)-1H-吡咯-2-基]-2,2-二甲基丙基}(乙醇酰基)氨基]丁酰基}氨基)乙基]-N2-[(2,5-二氧代-2,5-二氢-1H-吡咯-1-基)乙酰基]-D-α-谷氨酰胺三氟乙酸盐
在1.5当量HATU和3当量N,N-二异丙基乙胺存在的情况下将30mg (0.046mmol)中间体C58与29mg (0.055mmol) N-(2-氨基乙基)-N2-[(苄基氧基)羰基]-D-α-谷氨酰胺苄酯三氟乙酸盐(中间体L120)偶联。通过制备型HPLC纯化,得到39.5mg (理论值的82%)保护的中间体。首先从该中间体通过氢解裂解苄酯基。随后在DMF中在3当量N,N-二异丙基乙胺存在的情况下与1-{2-[(2,5-二氧代吡咯烷-1-基)氧基]-2-氧代乙基}-1H-吡咯-2,5-二酮偶联。在最后步骤中,将13.5 mg (0.012 mmol)的此中间体溶解于5 mL 2,2,2-三氟乙醇中。添加13 mg (0.096 mmol)氯化锌并将批料在50℃下搅拌3h。随后,添加28 mg (0.096 mmol)乙二胺-N,N,N',N'-四乙酸。通过制备型HPLC纯化批料。将相应的级分浓缩并从乙腈/水冻干残余物,得到9 mg (理论值的81%)的标题化合物。
LC-MS (方法12): Rt = 1.44 min; MS (ESIpos): m/z = 822 (M+H)+。
B:抗体-活性物质缀合物(ADC)的制备
B-1. 用于产生抗-CD123和抗-CXCR5抗体以及抗-CD123和抗-CXCR5抗体的嵌合和人源
化变体的一般方法
将所用的抗体,例如抗-CD123抗体TPP-8987、TPP-8988和TPP-9476,以及抗-CXCR5抗体TPP-9024、TPP-9574和TPP-9580的蛋白序列(氨基酸序列),通过本领域技术人员已知的方法转变成编码各蛋白的DNA序列并插入适用于瞬时哺乳动物细胞培养的表达载体中(如Tom等人,Methods Express的第12章:Expression Systems,由Micheal R.Dyson和YvesDurocher编辑,Scion Publishing Ltd, 2007中所述)。
B-2. 用于在哺乳动物细胞中表达抗体的一般方法
抗体,例如抗-CD123抗体TPP-8987、TPP-8988和TPP-9476,以及抗-CXCR5抗体TPP-9024、TPP-9574和TPP-9580在瞬时哺乳动物细胞培养物中产生,如Tom等人,MethodsExpress的第12章:Expression Systems,由Micheal R.Dyson和Yves Durocher编辑,ScionPublishing Ltd, 2007中所述。
B-3.从细胞上清液中纯化抗体的一般方法
抗体,例如抗-CD123抗体TPP-8987、TPP-8988和TPP-9476以及抗-CXCR5抗体TPP-9024、TPP-9574和TPP-9580,获自细胞培养上清液。该细胞上清液通过细胞离心来澄清化。该细胞上清液然后通过在MabSelect Sure (GE Healthcare)色谱柱上的亲和色谱法纯化。为此,该柱在DPBS pH 7.4(Sigma/Aldrich)中平衡,施加细胞上清液,且该柱用约10柱体积的DPBS pH 7.4 + 500 mM氯化钠洗涤。抗体在50 mM乙酸钠pH 3.5 + 500 mM氯化钠中洗脱,然后通过在Superdex 200柱(GE Healthcare)上在DPBS pH 7.4中的凝胶渗透色谱法进一步纯化。
市售抗体通过标准色谱法(蛋白A色谱,制备型凝胶过滤色谱(SEC-大小排阻色谱))从市售产品纯化。
B-4. 偶联至半胱氨酸侧链上的一般方法
下列抗体用于该偶联反应中:
抗-CD123 AK TPP-8987
抗-CD123 AK TPP-8988
抗-CD123 AK TPP-9476
抗-CXCR5 AK TPP-9024
抗-CXCR5 AK TPP-9574
抗-CXCR5 AK TPP-9580
小规模偶联:
将溶解在PBS缓冲液中的2至5当量的三(2-羧乙基)膦盐酸盐(TCEP)添加至在1 mg/ml至20 mg/ml浓度范围内,优选约5 mg/ml至15 mg/ml浓度范围内的2-5mg相应抗体在PBS缓冲液中的溶液中,并在室温下搅拌30分钟至1小时。随后,根据预期载量,作为在DMSO中的溶液添加2至12当量,优选约5-10当量的待偶联的马来酰亚胺前体化合物。在此,DMSO的量不应超过总体积的10%。 将批料在室温下搅拌60-240分钟,且随后用已预先调节至pH 8的PBS缓冲液稀释至2.5-7.5 ml的体积,且然后通过用PBS缓冲液pH 8平衡的PD-10柱(Sephadex®G-25, GE Healthcare),并用PBS缓冲液pH 8洗脱。将洗脱物在室温下在氩气下搅拌过夜。随后,溶液通过超速离心来浓缩并用PBS缓冲液(pH 7.2)再稀释。
中等规模偶联:
在氩气下,将2-5当量、优选3当量TCEP于PBS缓冲液中的溶液(c ~ 0.2-0.8 mg/ml,优选0.5 mg/ml)添加至PBS缓冲液中的20-200 mg所讨论抗体(c~5-15 mg/ml)中。将该批料在室温下搅拌30分钟,然后添加溶解于DMSO中的2-12、优选5-10当量马来酰亚胺前体化合物。在室温下搅拌另外1.5小时-2小时后,用已预先调节至pH 8的PBS缓冲液稀释该批料。
然后将该溶液施加至已用PBS缓冲液pH 8平衡的PD 10柱(Sephadex® G-25, GEHealthcare)并用PBS缓冲液pH 8洗脱。洗脱物用PBS缓冲液pH 8稀释至1-5mg/mL的浓度。将该溶液在室温下在氩气下搅拌过夜。如果需要,然后将溶液再缓冲至pH 7.2。该ADC溶液通过超速离心浓缩,用PBS缓冲液(pH 7.2)再稀释,然后如果需要再次浓缩至约10 mg/mL的浓度。
在所示结构式中,AK可具有取自根据实施例的表格的含义:
抗-CD123 AK TPP-8987 (部分还原)- S§1
抗-CD123 AK TPP-8988 (部分还原)- S§1
抗-CD123 AK TPP-9476 (部分还原)- S§1
抗-CXCR5 AK TPP-9024 (部分还原)- S§1
抗-CXCR5 AK TPP-9574 (部分还原)- S§1
抗-CXCR5 AK TPP-9580 (部分还原)- S§1
其中
§1代表与琥珀酰亚胺基团或与如果需要由其产生的异构水解开链琥珀酰胺或亚烷基残基的键合,
且
S代表部分还原抗体的半胱氨酸残基的硫原子。
根据本发明的缀合物的进一步纯化和表征
在反应后,在一些情况下,例如通过超滤浓缩反应混合物,且然后通过色谱法,例如使用Sephadex® G-25柱脱盐和纯化。例如用磷酸盐缓冲盐溶液(PBS)进行洗脱。然后将该溶液无菌过滤并冷冻。或者,可以将该缀合物冻干。
B-7. 抗体、毒簇载量和开放半胱氨酸加合物含量的测定
为了鉴定蛋白,除分子量测定外,在去糖基化和/或变性后进行胰蛋白酶消化,其在变性、还原和衍生化后通过发现的胰蛋白酶肽证实蛋白的身份。
如下测定实施例中描述的缀合物在PBS缓冲液中所得溶液的毒簇载量(在表中表示为DAR,药物/抗体比):
通过各缀合物物质的分子量的质谱测定,进行赖氨酸连接的ADC的毒簇载量的测定。在此,该抗体缀合物首先用PNGaseF去糖基化,并将样品酸化并在HPLC分离/脱盐后,使用ESI-MicroTofQ (Bruker Daltonik)通过质谱法分析。将TIC(总离子色谱图)中的信号上的所有波谱相加并基于MaxEnt去卷积计算不同缀合物物质的分子量。然后在不同物质的信号积分后计算DAR(= 药物/抗体比)。为此目的,将毒簇计数所加权的所有物质的积分结果的总和除以所有物质的简单加权积分结果的总和。
通过还原和变性的ADC的反相色谱法测定半胱氨酸连接的缀合物的毒簇载量。将盐酸胍(GuHCl)(28.6 mg)和DL-二硫苏糖醇(DTT)溶液(500 mM, 3 µl)添加至ADC溶液(1mg/mL, 50 µl)中。将该混合物在55℃下孵育1小时并通过HPLC分析。
在Agilent 1260 HPLC系统上用在220 nm的检测进行HPLC分析。在1 mL/min的流速下以下列梯度使用Polymer Laboratories PLRP-S聚合反相柱(目录号PL1912-3802)(2.1 x150 mm, 8微米粒度, 1000 Å):0 min, 25%B;3 min, 25%B;28 min, 50%B。洗脱液A由水中的0.05%三氟乙酸(TFA)组成,洗脱液B由乙腈中的0.05%三氟乙酸组成。
通过与非缀合抗体的轻链(L0)和重链(H0)的保留时间比较,分配检测的峰。将仅在缀合样品中检测到的峰分配给具有一个毒簇的轻链(L1)和具有一个、两个和三个毒簇的重链(H1、H2、H3)。
从通过积分测定为HC载量和LC载量的总和的两倍的峰面积确定具有毒簇的抗体的平均载量(所谓的DAR,药物/抗体比),其中从所有LC峰的毒簇计数加权积分结果的总和除以所有LC峰的简单加权积分结果的总和计算LC载量,且其中从所有HC峰的毒簇计数加权积分结果的总和除以所有LC峰的简单加权积分结果的总和计算HC载量。在个别情况下,由于一些峰的共洗脱,可能无法精确测定毒簇载量。
在通过HPLC无法充分分离轻链和重链的情况下,通过轻链和重链处的各缀合物物质的分子量的质谱测定进行半胱氨酸连接的缀合物的毒簇载量的测定。
为此目的,将盐酸胍(GuHCl)(28.6 mg)和DL-二硫苏糖醇(DTT)溶液(500 mM, 3 µl)添加至ADC溶液(1 mg/ml, 50 µl)中。将该混合物在55℃下孵育1小时并在使用ESI-MicroTofQ (Bruker Daltonik)在线脱盐后通过质谱法分析。
对于DAR测定,将TIC(总离子色谱图)中的信号上的所有波谱相加并基于MaxEnt去卷积计算轻链和重链处的不同缀合物物质的分子量。从通过积分测定为HC载量和LC载量的总和的两倍的峰面积测定具有毒簇的抗体的平均载量。在此,从通过所有LC峰的毒簇计数加权的积分结果的总和除以所有LC峰的简单加权积分结果的总和计算LC载量,且从通过所有HC峰的毒簇计数加权的积分结果的总和除以所有HC峰的简单加权积分结果的总和计算HC载量。
在开放构建体的情况下,为了测定开放半胱氨酸加合物的含量,测定所有单缀合的轻链和重链变体的封闭与开放半胱氨酸加合物(分子量Δ18道尔顿)的分子量面积比。所有变体的平均值得出开放半胱氨酸加合物的含量。
B-8. 验证ADC的抗原-结合
在已发生偶联后检查结合剂结合至靶分子上的能力。本领域技术人员熟悉可用于此目的的各种方法;例如,可以使用ELISA技术或表面等离子体共振分析(BIAcore™测量)检查缀合物的亲和力。本领域技术人员可以使用常用方法测量缀合物浓度,例如对抗体缀合物而言通过蛋白测定法(也参见Doronina等人; Nature Biotechnol. 2003; 21:778-784和Polson等人, Blood 2007; 1102:616-623)。
工作实施例ADC
经由马来酰亚胺残基偶联至抗体的半胱氨酸侧链的实施例和参考例的结构式所示的ADC,根据接头和偶联程序,主要以所示的开环形式存在。然而,制备物可包含小比例的闭环形式。
实施例1:
示例性程序A:
在氩气下,将0.029 mg TCEP于0.05 ml PBS缓冲液中的溶液添加至5 mg对应抗体于0.5 ml PBS中的溶液(c=10mg/mL)中。将批料在室温下搅拌30min,且然后添加溶解于50μlDMSO中的0.26 mg (0.00023 mmol)中间体F325。在室温下再搅拌90 min之后,批料用预先调节至pH 8的 PBS缓冲液稀释到2.5mL体积,且然后通过用PBS缓冲液pH 8平衡的PD 10柱(Sephadex® G-25, GE Healthcare),并用PBS缓冲液pH 8洗脱。然后将洗脱液在室温下在氩气下搅拌过夜。这随后通过超速离心浓缩并用PBS缓冲液(pH 7.2)再稀释。
示例性程序B:
在氩气下,将0.172 mg TCEP于0.3 ml PBS缓冲液中的溶液添加至30 mg相应抗体于3ml PBS中的溶液(c=10mg/mL)中。将批料在室温下搅拌30 min,且然后添加溶解于300μlDMSO中的1.57 mg (0.0014 mmol)中间体F325。在室温下再搅拌90 min之后,将批料用预先调节至pH 8的PBS缓冲液稀释至5mL体积,然后通过用PBS缓冲液pH 8平衡的PD 10柱(Sephadex® G-25, GE Healthcare),并用PBS缓冲液pH 8洗脱。然后将洗脱液在室温下氩气下搅拌过夜。然后将该溶液通过已用PBS缓冲液pH 7.2平衡的PD 10柱(Sephadex® G-25,GE Healthcare),并用PBS缓冲液pH 7.2洗脱。然后将洗脱液以超速离心浓缩,用PBS缓冲液(pH 7.2)再稀释,再浓缩和然后无菌过滤。
下列ADC类似于这些程序制备且如下表中所示表征:
。
代谢物的工作实施例
实施例M1
N-(3-{[(2R)-2-氨基-2-羧乙基]硫烷基}-3-羧基丙酰基)甘氨酰基-N-[2-({(2S)-2-氨基-4-[{(1R)-1-[1-苄基-4-(2,5-二氟苯基)-1H-吡咯-2-基]-2,2-二甲基丙基}(乙醇酰基)氨基]丁酰基}氨基)乙基]-D-α-谷氨酰胺三氟乙酸盐
位置异构体1,差向异构体混合物
将三乙胺(10 ml, 73 mmol)和然后1-({[2-(三甲基甲硅烷基)乙氧基]羰基}氧基)吡咯烷-2,5-二酮(8.31 g, 32.0 mmol)添加至L-半胱氨酸甲酯盐酸盐(1:1)(5.00 g, 29.1mmol)于1,4-二氧杂环己烷(200 ml)中的溶液中。将反应物在室温下搅拌20 h。然后将固体滤出并在高真空下浓缩滤液。通过制备型HPLC纯化残余物。
将210 µl (1.4 mmol) 1,8-二氮杂双环[5.4.0]十一碳-7-烯添加至所获得的N-{[2-(三甲基甲硅烷基)乙氧基]羰基}-L-半胱氨酸甲酯(130 mg, 465 μmol)和3-溴-4-甲氧基-4-氧代丁酸(393 mg, 1.86 mmol)于DMF(6.5 ml)中的溶液中并将反应物在室温下搅拌10 min。然后将反应物在减压下浓缩并通过制备型HPLC纯化残余物。在减压下蒸发溶剂并在高真空下干燥残余物。
将所得的中间体通过肽化学的经典方法在HATU存在的情况下与中间体C119偶联。然后通过用氢氧化锂于THF/水(1:1)中的溶液处理来将甲酯皂化。
在最后的步骤中,将获得的22 mg中间体溶解于10 mL 2,2,2-三氟乙醇中。添加34 mg (0.252 mmol)氯化锌并将批料在50℃下搅拌1h。然后添加74 mg (0.252 mmol)乙二胺-N,N,N',N'-四乙酸、10 mL水和500μL TFA。将混合物过滤并在减压下蒸发溶剂。通过制备型HPLC纯化残余物。将相应的级分浓缩并从乙腈/水将残余物冻干,得到13 mg (理论值的72%)的标题化合物。
LC-MS (方法5): Rt = 2.44 min; MS (ESIneg): m/z = 959 [M-H]-。
实施例M2
N-(2-{[(2R)-2-氨基-2-羧乙基]硫烷基}-3-羧基丙酰基)甘氨酰基-N-[2-({(2S)-2-氨基-4-[{(1R)-1-[1-苄基-4-(2,5-二氟苯基)-1H-吡咯-2-基]-2,2-二甲基丙基}(乙醇酰基)氨基]丁酰基}氨基)乙基]-D-α-谷氨酰胺三氟乙酸盐
位置异构体2,差向异构体混合物
标题化合物M2类似于实施例M1制备为差向异构体混合物:
将801μl (5.4mmol) 1,8-二氮杂双环[5.4.0]十一碳-7-烯添加至N-{[2-(三甲基甲硅烷基)乙氧基]羰基}-L-半胱氨酸甲酯(1000 mg, 3.58 mmol)和2-溴-4-乙氧基-4-氧代丁酸(926mg, 4.11mmol)于DMF(40 ml)中的溶液中并将反应物在室温下搅拌2 h。然后在减压下浓缩并通过制备型HPLC纯化残余物。
将所获得的中间体通过肽化学的经典方法在HATU和甲基吗啉存在的情况下与中间体C119偶联。然后通过用氢氧化锂于THF/水(1:1)中的溶液处理来将甲酯和乙酯皂化。
在最后的步骤中,将48 mg该中间体溶解于5 mL 2,2,2-三氟乙醇中。添加75 mg(0.550 mmol)氯化锌并将批料在50℃下搅拌3h。然后添加160 mg (0.550 mmol)乙二胺-N,N,N',N'-四乙酸、2 mL水和20μL TFA。将溶剂在减压下浓缩并通过制备型HPLC纯化残余物。将相应的级分浓缩并从乙腈/水将残余物冻干,得到14 mg (理论值的39%)的标题化合物。
LC-MS (方法5): Rt = 2.41 min; MS (ESIneg): m/z = 959 [M-H]-。
制备参考-ADC R1用于比较。在部分C中,来自实施例1的根据本发明的ADC相比于对应的参考-ADC R1的优势以示例性方式来显示。
参考实施例R1
示例性程序
在氩气下,将0.172 mg TCEP于300 µl PBS缓冲液中的溶液添加至30 mg对应AK于3mL PBS中的溶液(c=10mg/mL)中。将批料在室温下搅拌30 min,且然后添加溶解于300 μlDMSO中的1.291 mg (1.6 µmol)中间体F104。在室温下再搅拌90min之后,用预先调节至pH8的1.4ml PBS缓冲液将批料稀释。
然后将该溶液通过用PBS缓冲液pH 8平衡的PD 10柱(Sephadex® G-25, GEHealthcare),并用PBS缓冲液pH 8洗脱。将洗脱液用PBS缓冲液pH 8稀释至7.5 ml的总体积。将该溶液在室温下在氩气下搅拌过夜,且然后再次使用PD-10柱,再缓冲至pH 7.2。将洗脱液稀释至14 mL的总体积。然后通过超速离心浓缩至2 mL,用PBS缓冲液(pH 7.2)再稀释至14 mL并再浓缩至3 mL的体积。将样品通过离心管(Microsep Advance CentrifugalDevice 0.2 µm Supor Membrane/PALL公司)过滤。获得的ADC批次如下表征:
下列ADC类似于这些程序制备且如下表中所示表征:
。
还制备从参考实施例R1形成的代谢物Rm1和Rm2用于比较:
参考实施例Rm1
4-[(2-{[2-({(2S)-2-氨基-4-[{(1R)-1-[1-苄基-4-(2,5-二氟苯基)-1H-吡咯-2-基]-2,2-二甲基丙基}(乙醇酰基)氨基]丁酰基}氨基)乙基]氨基}-2-氧代乙基)氨基]-2-{[(2R)-2-氨基-2-羧基乙基]硫烷基}-4-氧代丁酸三氟乙酸盐
作为差向异构体混合物的位置异构体1:
首先,在N,N-二异丙基乙胺存在的情况下,使用1-({[2-(三甲基甲硅烷基)乙氧基]羰基}氧基)吡咯烷-2,5-二酮在DMF中将L-半胱氨酸甲酯盐酸盐(1:1)转变为N-{[2-(三甲基甲硅烷基)乙氧基]羰基}-L-半胱氨酸甲酯。
分份地将208 µl (1.4 mmol) 1,8-二氮杂双环[5.4.0]十一碳-7-烯添加至N-{[2-(三甲基甲硅烷基)乙氧基]羰基}-L-半胱氨酸甲酯(130 mg, 465 μmol)和3-溴-4-甲氧基-4-氧代丁酸(393 mg, 1.86 mmol)于DMF(6.5 ml)中的溶液中并将反应物在室温下搅拌10 min。然后在减压下浓缩并通过制备型HPLC纯化残余物。在减压下蒸发溶剂并在高真空下干燥残余物。
将所获得的中间体通过肽化学的经典方法在HATU存在的情况下与中间体C66偶联。然后通过用氢氧化锂于THF/水(1:1)中的溶液处理来将甲酯皂化。
在最后的步骤中,将18 mg该中间体溶解于10.6 mL 2,2,2-三氟乙醇中。添加22mg (0.16 mmol)氯化锌并将批料在50℃下搅拌2h。然后添加47 mg (0.16 mmol)乙二胺-N,N,N',N'-四乙酸和2 mL水和2-3滴TFA。将混合物过滤并在减压下蒸发溶剂。通过制备型HPLC纯化残余物。将相应的级分浓缩并从乙腈/水将残余物冻干,得到10.5 mg (理论值的78.5%)作为位置异构体混合物的标题化合物(异构体2)。
LC-MS (方法5): Rt = 2.43 min; MS (ESI-pos): m/z = 832 [M+H]+。
参考实施例Rm2
4-[(2-{[2-({(2S)-2-氨基-4-[{(1R)-1-[1-苄基-4-(2,5-二氟苯基)-1H-吡咯-2-基]-2,2-二甲基丙基}(乙醇酰基)氨基]丁酰基}氨基)乙基]氨基}-2-氧代乙基)氨基]-3-{[(2R)-2-氨基-2-羧基乙基]硫烷基}-4-氧代丁酸三氟乙酸盐
作为差向异构体混合物的异构体2:
首先,在N,N-二异丙基乙基胺存在的情况下,使用1-({[2-(三甲基甲硅烷基)乙氧基]羰基}氧基)吡咯烷-2,5-二酮于DMF中将L-半胱氨酸甲酯盐酸盐(1:1)转变为N-{[2-(三甲基甲硅烷基)乙氧基]羰基}-L-半胱氨酸甲酯。
将801μl (5.4mmol) 1,8-二氮杂双环[5.4.0]十一碳-7-烯添加至N-{[2-(三甲基甲硅烷基)乙氧基]羰基}-L-半胱氨酸甲酯(1000 mg, 3.58 mmol)和2-溴-4-乙氧基-4-氧代丁酸(926mg, 4.11mmol)于DMF(40 ml)中溶液中并将反应物在室温下搅拌2 h。然后在减压下浓缩并通过制备型HPLC纯化残余物。在减压下蒸发溶剂并在高真空下干燥残余物。
将所获得的中间体通过肽化学的经典方法在HATU存在的情况下与中间体C66偶联。然后通过用氢氧化锂于THF/水(1:1)中的溶液处理来将甲酯和乙酯皂化。
在最后的步骤中,将24 mg该中间体溶解于6.4 mL 2,2,2-三氟乙醇中。添加28.5mg (0.21 mmol)氯化锌并将批料在50℃下搅拌2h。然后添加61 mg (0.21 mmol)乙二胺-N,N,N',N'-四乙酸和2 mL水和2-3滴TFA。将混合物过滤并在减压下蒸发溶剂。通过制备型HPLC纯化残余物。将相应的级分浓缩并从乙腈/水将残余物冻干,得到14.5 mg (理论值的71%)的标题化合物。
LC-MS (方法5): Rt = 2.41 min; MS (ESI-pos): m/z = 832 [M+H]+。
C:生物学效果的评估
根据本发明的化合物的生物作用可显示于下述测定中:
C-1a: 针对CD123和CXCR5的ADC的细胞毒性作用的测定
用多种细胞系进行示例性ADC的细胞毒性作用的分析:
NCI-H292:人黏液表皮样肺癌细胞,ATCC-CRL-1848,标准培养基:RPMI 1640(Biochrom;#FG1215,稳定谷氨酰胺) + 10% FCS (Sigma; #F2442), TWEAKR-阳性;
KPL4:人乳腺癌细胞系,Bayer Pharma AG(在2012年7月19日在DSMZ身份检查和证实),标准培养基:RPMI 1640(来自Gibco公司;#21875-059,稳定的L-谷氨酰胺)+10%热失活的FBS (Gibco公司, No.10500-064);HER2-阳性。
SK-HEP-1:人肝癌细胞系,ATCC No. HTB-52,标准培养基:含有Earle氏盐+Glutamax I (Invitrogen 41090)+10%热失活的FCS (Gibco公司, No.10500-064)的MEM;TWEAKR-阳性
MOLM-13:人急性单核细胞白血病细胞(AML-M5a), DSMZ, No. ACC 554,标准培养基:RPMI 1640 (gibco公司;#21875-059,稳定的L-谷氨酰胺)+20%热失活的FCS (Gibco公司,No.10500-064);CD123-阳性。
MV-4-11:获得自外周血液的人双表型B骨髓单核细胞白血病细胞,ATCC-CRL-9591,标准培养基:IMDM (ATCC:30-2005)+10%热失活的FCS (Gibco, No.10500-064);CD123-阳性
NB4:获得自骨髓的人急性前骨髓细胞白血病细胞,DSMZ, No. ACC 207,标准培养基:RPMI 1640 + GlutaMAX I (Invitrogen 61870)+10%热失活的FCS(Gibco, No.10500-064)+2.5g的葡萄糖(20%葡萄糖溶液,Gibco, No.19002)+10mM Hepes (Invitrogen 15630)+1mM丙酮酸钠(Invitrogen 11360);CD123-阴性
Rec-1:人套细胞淋巴瘤细胞(B细胞非霍奇金氏淋巴瘤)ATCC CRL-3004,标准培养基:RPMI 1640+GlutaMAX I(Invitrogen 61870)+10%热失活的FCS(Gibco, No. 10500-064)CXCR5-阳性
细胞通过如美国组织培养物保藏中心(American Tissue Culture Collection;ATCC)或Leibniz-Institut DSMZ-Deutsche Sammlung von Mikroorganismen undZellkulturen GmbH (DSMZ)针对相关细胞系所述的标准方法进行培养。
MTT测定
用章节C-1下给出的生长培养基通过标准方法培养细胞。以如下方式执行:将细胞用Accutase于PBS中的溶液(Biochrom AG #L2143)分离,造粒,再悬浮于培养基中,计数且接种于具有白底的96孔培养板(Costar公司 #3610)(NCI H292:2500个细胞/孔,SK-HEP-1:1000个细胞/孔;KPL-4:1200个细胞/孔;在100μl的总体积中)中。然后将细胞在孵育箱中在37℃和5%二氧化碳下孵育。48小时之后,更换培养基。然后将浓度为10-5M至10-13M的10μl培养基中的抗体-活性物质缀合物移液至细胞(一式三份),然后将该批料在孵育箱中在37℃和5%二氧化碳下孵育。将悬浮液细胞计数并接种入具有白底的96孔培养板(Costar公司 #3610)(MOLM-13:2000个细胞/孔;NB4:7000个细胞/孔;MV-4-11:5000个细胞/孔,总体积100μl)。在37℃和5%二氧化碳下孵育6小时之后,更换培养基并通过移液10-5M至10-13M的浓度的10μl的培养基将抗体-活性物质缀合物或代谢物添加至90μl的细胞(一式三份)。将该批料在37℃和5%二氧化碳的孵育箱中孵育。96小时之后,使用MTT测定(ATCC, Manassas,Virginia, USA;目录号30-1010K)检测细胞增殖。为此,将MTT试剂与细胞一起孵育4小时,然后通过添加去垢剂来将细胞裂解过夜。在570nm下检测所形成的染料(Infinite M1000pro, Tecan公司)。使用DRC(剂量反应曲线)由测量的数据来计算生长抑制的IC50值。未用测试物质、但在其它方面相同处理的细胞的增殖被定义为100%的值。
下表1a列出来自该测定的代表性工作实施例的IC50值:
表1a
下表1b列出来自该测定的代表性参比实施例的IC50值。
表1b
给出的活性数据基于本实验部分中所述的具有给出药物/mAB比率的工作实施例。该值可能由于不同的药物/mAB比率而任选存在偏差。IC50值是几个独立实验的平均值或单个值。抗体-活性物质缀合物的作用对于包含各自相应接头和毒簇的各同种型对照是选择性的。此外,针对CD123的抗体-活性物质缀合物的靶标特异性通过用CD123-阴性细胞(NB4)测试来证明。
C-1b:所选实施例对驱动蛋白纺锤体蛋白KSP/Eg5的抑制的测定
在室温下,将人类驱动蛋白纺锤体蛋白KSP/Eg5的马达结构域(tebu-bio/Cytoskeleton Inc公司,编号027EG01-XL)在10nM的浓度下与用50μg/ml紫杉酚(Sigma公司,编号T7191-5MG)稳定化的微管(牛或猪,tebu-bio/Cytoskeleton Inc公司)一起在15mMPIPES pH 6.8 (5 mM MgCl2和10 mM DTT,Sigma公司)中孵育5分钟。将新鲜制备的混合物等分至384 MTP (来自Corning公司)中。然后添加浓度为1.0 x 10-6 M至1.0 x 10-13 M的待检查的抑制剂以及ATP (最终浓度500μM,Sigma公司)。在室温下孵育2小时。通过使用孔雀绿(Biomol公司)检测所形成的无机磷酸盐来检测ATP酶活性。添加试剂之后,在室温下孵育50分钟,然后在620nm的波长下检测吸收。所用的阳性对照是单星素(Monastrol)(Sigma公司,M8515-1mg)和伊斯平斯(Ispinesib)(AdooQ Bioscience公司A10486)。剂量-效应曲线的各个数据是八倍测定。IC50值是两次独立实验的平均值。100%对照是未用抑制剂处理的样品。
下表2列举来自所述测定的代表性工作实施例的IC50值并概述相应的细胞毒性数据(MTT测定)。
表2
所示的活性数据基于本实验部分中所述的工作实施例。
C-2a 内化测定
内化是能够经由抗体-活性物质缀合物(ADC)在表达抗原的癌细胞中特异性且有效提供细胞毒性有效负载的关键过程。经由特异性抗体和同种型对照抗体的荧光标记来监测该过程。为此,首先将荧光染料与抗体的赖氨酸缀合。使用两倍摩尔过量的CypHer 5E单NHS酯(批次357392,GE Healthcare)在pH 8.3下进行缀合。偶联之后,反应混合物通过凝胶色谱(Zeba旋转脱盐柱,40K,Thermo Scientific公司,编号87768;洗脱缓冲液:DULBECCO’SPBS,Sigma-Aldrich公司,编号D8537)纯化,以消除过量染料和调节pH值。使用VIVASPIN500柱(Sartorius stedim biotec公司)浓缩蛋白溶液。抗体的染料载量通过分光光度分析(NanoDrop公司)和随后计算(D/P =A染料ε蛋白: (A280-0.16A染料)ε染料)测定。
在此检查的抗体和同种型对照的染料载量具有可比拟的数量级。在细胞结合测定中测得偶联不会导致抗体亲和力的变化。
对于内化测定使用标记的抗体。在该处理开始前,100μl培养基中的细胞(2 x104/孔)接种于96-MTP (粗,黑色,透明底部,编号4308776,Applied Biosystems公司)中。在37℃/5% CO2下孵育18小时之后,更换培养基并以不同浓度(10、5、2.5、1、0.1μg/mL)添加标记的抗体。对标记的同种型对照(阴性对照)使用相同处理方案。选择的孵育时间为0小时、0.25小时、0.5小时、1小时、1.5小时、2小时、3小时、6小时和24小时。使用InCellAnalyzer 1000 (GE Healthcare公司)进行荧光测量。随后经由测量参数颗粒计数/细胞和总颗粒强度/细胞来进行动力学评估。
在结合受体之后,检查抗体的内化能力。为此目的,选择具有不同受体表达水平的肿瘤细胞。观察到靶标介导的高度特异性内化(用本发明的抗体),而同种型对照未显示内化。
C-2b:用悬浮细胞的内化测定
如C-2章节中所述实施荧光染剂的偶联。待检查的抗原由造血悬浮细胞表达;因此,在基于FACS的内化测定中检查内化。检测具有不同靶标表达水平的细胞。将细胞(5x104/孔)以100μl总体积接种于96-MTP中(Greiner bio-one,CELLSTAR,650 180,U型底)。以10μg/ml的最终浓度添加靶标特异性抗体之后,将批次在37℃下孵育不同的时间段(1h、2h、6h,一式三份)。在相同的条件下处理同种型对照。平行批次恒定在4℃下处理和孵育(阴性对照)。使用Guava流式细胞仪(Millipore)进行FACS分析。通过测量荧光强度进行动力学评估,并使用guavaSoft 2.6软件(Millipore)进行评估。对于此处所述的靶标和靶标特异性抗体,在各种细胞中检测到显著和特异性内化;同种型对照未显示内化。
C-2c:共定位:抗-CD123抗体的测定
由于接头,抗体-活性物质缀合物的活性代谢物通过溶酶体降解来产生。因此,内化后胞内运输的进行是至关重要的。关于使用对溶酶体细胞器特异性的标记(例如,表面分子或小GTP酶)的抗体的共定位的研究允许选择具有所需概况的抗体。为此,将总体积为100μl的靶标阳性细胞(5x104/孔)接种入96-MTP(Greiner bio-one, CELLSTAR, 650 180, U型底)。在添加CypHer5E-标记的抗-靶标抗体(最终浓度20μg/ml)后,将批次(每个时间点一式两份)在孵育箱(5% CO2)中在37℃下孵育30 min、2 h和6 h。在所选的孵育时间结束前30min,向待检查的批次中添加溶酶体特异性标记。将溶酶体用CytoPainter LysoGreen指示剂染色(最终浓度1:2000;abcam, ab176826)。在孵育后,添加200 μl冰冷的FACS缓冲液(DULBECCO'S PBS, Sigma-Aldrich, No.D8537+3%FBS热失活的FBS, Gibco, No.10500-064)并将细胞悬浮液在400 x g和4℃下离心5min。将细胞沉淀再悬浮于300μl冰冷的FACS缓冲液并再次离心(4 min, 400 x g,在4℃下)。在离心之后,将上清液丢弃并将细胞沉淀溶于30μl冰冷的FACS缓冲液中。然后立刻将样品进行FACS/成像分析(FlowSight amnis,Millipore)。使用特别的软件(共定位软件IDEAS Application v6.1)评估共定位。表3概述来自抗-CD123抗体的实施例的该测定的结果。
表3
实施例 | 共定位[%] |
TPP-9476 | 29 |
TPP-8997 | 28 |
TPP-8988 | 41 |
7G3 | 10 |
同种型对照 | 0.2 |
相比于亲本鼠抗体,抗体TPP-8987和TPP-9476展现显著改善的概况。
C-3 用于测定细胞渗透性的体外测试
物质的细胞渗透性可借助于体外测试在使用Caco-2细胞的通量测定中进行研究[M.D.Troutman和D.R. Thakker, Pharm. Res. 20 (8), 1210-1224 (2003)]。为此,将细胞在24孔过滤板上培养15-16天。为了测定渗透,将各种测试物质于HEPES缓冲液中施加至细胞顶端(A)或基底(B)上并孵育2小时。0小时之后和2小时之后,从顺式和反式隔室中获取样品。通过使用反相柱的HPLC (Agilent 1200, Böblingen, 德国)分离样品。HPLC系统经由Turbo离子喷雾界面与三重四极质谱仪API 4000 (AB SCIEX Deutschland GmbH,Darmstadt, 德国)联用。基于Papp值来评估渗透性,该值使用Schwab等人[D. Schwab等人,J. Med. Chem. 46, 1716-1725 (2003)]公开的公式计算。当Papp (B-A)与Papp (A-B)的比率(流出比率)>2或<0.5时,物质被分类为主动输送。
对于细胞内释放的毒簇至关重要的是B至A的渗透率[Papp (B-A)]和Papp (B-A)与Papp (A-B)的比率(流出比率):该渗透率越低,物质通过Caco-2细胞单层的主动和被动输送过程越慢。此外,如果流出比率未指示主动输送,则物质在细胞内释放之后可较长时间保留于细胞中。因此,可用于与生物化学靶标(在此:驱动蛋白纺锤体蛋白,KSP/Eg5)相互作用的时间也增加。
下表4记载来自该测定的代表性工作实施例的渗透率数据:
表4
相比于由参考实施例1中的ACD形成的参考代谢物RM1和RM2,可由根据本发明的实施例1中的ACD形成的代谢物M1和M2展现显著降低的从细胞的运输和降低的流出比率。
C-4 用于测定P-糖蛋白(P-gp)的底物特性的体外测试
许多肿瘤细胞表达用于活性物质的转运蛋白,这经常伴随着针对细胞抑制剂的抗性发展。不是此类转运蛋白(例如P-糖蛋白(P-gp)或BCRP)的底物的物质因此可展现改善的活性概况。
用于P-gp的物质(ABCB1)的底物特性借助于使用过表达P-gp(L-MDR1细胞)的LLC-PK1细胞的通量测定[A.H. Schinkel等人, J. Clin. Invest. 96, 1698-1705 (1995)]来测定。为此目的,将LLC-PK1细胞或L-MDR1细胞在96孔过滤板上培养3-4天。为了测定渗透,将单独或在抑制剂(例如伊维菌素(Ivermectin)或维拉帕米(Verapamil))存在的情况下的各自的测试物质于HEPES缓冲液中施加于细胞顶端(A)或基底(B)并孵育2小时。0小时之后和2小时之后,从顺式和反式隔室中获取样品。通过使用反相柱的HPLC分离样品。HPLC系统经由Turbo离子喷雾界面与API 3000三重四极质谱仪(Applied Biosystems Applera,Darmstadt, 德国)联用。基于Papp值来评估渗透性,该值使用Schwab等人 [D. Schwab等人,J. Med. Chem. 46, 1716-1725 (2003)]公开的公式计算。当Papp (B-A)与Papp (A-B)的流出比率>2时,物质被分类为P-gp底物。
作为评估P-gp底物特性的另外标准,可相互比较L-MDR1细胞和LLC-PK1细胞中的流出比率或在抑制剂存在或不存在的情况下的流出比率。如果这些值相差大于2倍,则所涉物质为P-gp底物。
C-5a:体外鉴定内化后的ADC代谢物
方法描述:
进行用免疫缀合物的内化研究以分析胞内形成的代谢物。为此,将人肺肿瘤细胞NCIH292 (3x105/孔)接种入6孔板中并孵育过夜(37℃, 5% CO2)。以10μg/mL (66nM)待检查的ADC处理细胞。内化在37℃和5% CO2下进行。在各个时间点(0、4、24、48、72h)取细胞样品用于进一步分析。首先,收获上清液(约5mL)和,在离心后(2 min, RT, 1000 rpm HeraeusVariofuge 3.0R),储存于-80℃。将细胞用PBS洗涤并用Accutase分离,并测定细胞数。再次洗涤后,将定义数量的细胞(2 x 105)与100 mL裂解缓冲液(哺乳动物细胞裂解试剂盒(Sigma MCL1)混合并在连续振荡下(Thermomixer, 15 min, 4℃, 650rpm)在蛋白LoBind管中(eppendorf目录号0030 108.116)孵育。孵育后,将裂解物离心(10 min, 4℃, 12000g, eppendorf 5415R)并收获上清液。将获得的上清液储存于-80℃。然后如下分析所有样品。
在用甲醇或乙腈沉淀蛋白后,通过高压液相色谱(HPLC)三重四极质谱仪(MS)联用来测定培养上清液或细胞裂解物中的化合物。
为了对50μL培养上清液/细胞裂解物进行后处理,添加150μL的沉淀试剂(甲醇)并将振荡10秒。沉淀试剂含有适合浓度(一般在20-100μg/L的范围内)的内标(ISTD)。以1881g离心10分钟之后,将上清液转移至由300μl与洗脱液匹配的缓冲剂填充的自动取样器小瓶中,并再次振荡并以1881 g离心10分钟。
最后使用来自AB SCIEX Deutschland GmbH的HPLC联用的三重四极质谱仪API4200,测定细胞裂解物和上清液样品。
对于校准,将空白裂解物或空白上清液以适当浓度(0.1-1000μg/l)混合。检测限值(LLOQ)为约0.2μg/L。
检测有效性的质量对照含有4和40μg/L。
C-5b:体内鉴定ADC代谢物
可能出现的代谢物的定量分析
将10mg/kg不同的本发明缀合物i.v.施用于异种移植小鼠后,可在施用这些缀合物24小时后测量抗体的血浆、肿瘤、肝、脾和肾浓度和可能出现的代谢物。关于异种移植模型的更详细的方法描述可见C-6。此处,仅涉及根据本发明的缀合物的代谢物浓度。在提及的基质中就代谢物测量值另外指出相比于肿瘤中的负荷,在血浆、肾、脾和肝脏中的代谢物负荷如何显著。
可能出现的代谢物的定量分析
血浆、肿瘤、肝、脾和肾中的化合物测定在通常用甲醇沉淀蛋白后借助高压液相色谱(HPLC)三重四极质谱仪(MS)联用进行。
为了对50μL血浆后处理,添加150μL的沉淀试剂(一般为甲醇)并振荡10秒。沉淀试剂含有适合浓度(一般在20-100μg/L的范围内)的内标(ISTD)。以1881g离心10分钟后,将上清液转移至由300μL与洗脱液匹配的缓冲剂填充的自动取样器小瓶中,并再次振荡。
在肿瘤或器官材料的后处理中,将各材料与3-20倍量的提取缓冲液混合。提取缓冲液含有50mL的组织蛋白提取试剂(Pierce, Rockford, IL)、两团完全-蛋白酶-抑制剂-混合物(Roche Diagnostics GmbH, Mannheim, Germany)和最终浓度为1mM的苯基甲基磺酰氟(Sigma, St.Louis, MO)。根据组织类型(硬:肿瘤;软:肝、肾、脾),选择Prescellys 24裂解的均质化程序和均质化仪器(Bertin Technologies)(www.prescellys.com)。让均质化的样品在4℃静置过夜。将50μL的均质化物转移至自动取样器小瓶并用150μl包括ISTD的甲醇填充,振荡10秒且然后静置5 min。添加300μL的乙酸铵缓冲液(pH 6.8)并短暂振荡,并将样品以1881g离心10分钟。
对于校准,将血浆样品的血浆和对应于组织样品的空白基质以0.6-1000μg/L的浓度混合。根据样品类型或组织类型,检测限值(LOQ)为1和20μg/L之间。
最后将血浆和基质样品使用来自AB SCIEX Deutschland GmbH的HPLC联用的三重四极柱质谱仪API4200测定。
检测有效性的质量对照组含有4、40和400μg/L。
表5:在REC-1异种移植nunu小鼠中单一10mg/kg i.v.施用实施例1x-9024 24小时后的肿瘤、肝、肾、脾和血浆中代谢物M1的浓度与同种型对照的比较
表5
C-6 体内效果测试
例如使用异种移植模型,可以体内测试根据本发明的缀合物的效果。本领域技术人员熟悉现有技术的允许测试根据本发明的化合物的效果的方法(参见例如WO 2005/081711;Polson等人, Cancer Res. 2009年3月15日;69(6):2358-64)。
将表达抗体-活性物质缀合物的抗原的人类肿瘤细胞皮下接种于免疫抑制小鼠(例如NMRi裸小鼠或SCID小鼠)的侧腹中。从细胞培养物中分离一百万到一千万个细胞,离心且再悬浮于培养基或培养基/基质胶中。将细胞悬浮液注射于小鼠的皮肤下。
在数天内,使肿瘤生长。在建立肿瘤后,肿瘤大小约40 mm²时开始治疗。为了检查对较大肿瘤的作用,也可以在肿瘤大小为50-100 mm²时才开始治疗。
用ADC的治疗经由静脉内(i.v.)途径进入小鼠尾静脉来进行。ADC以5mL/kg的体积来施用。
治疗方案取决于抗体缀合物的药代动力学。作为标准,治疗每七天连续进行三次。对于快速评估,用单次治疗的方案也可以是合适的。然而,治疗也可继续,或在以后的时间进行第二轮的另外治疗天数。
作为标准,每个治疗组使用8只动物。除了施用活性物质的组以外,一组作为对照组,根据相同的方案仅用缓冲剂或等张盐溶液治疗。
在实验期间,使用卡尺定期测量二维(长/宽)肿瘤面积。肿瘤面积借助长x宽测定。治疗组的平均肿瘤面积与对照组的肿瘤面积的比率以T/C面积比给出。
当治疗结束后所有的实验组同时停止时,可移取肿瘤并称重。治疗组与对照组的肿瘤平均重量的比率以T/C重量比给出。
C-6a.小鼠中实验肿瘤的生长抑制/消退
将肿瘤细胞(REC-1、MOLM-13或MV-4-11)以皮下接种至雌性NMRI-裸小鼠(Janvier)的侧腹。在肿瘤大小为40-50 mm²时,用抗体-活性物质缀合物每周一次进行静脉内治疗持续2或3周。
相比于对照组,用根据本发明的ADC治疗导致肿瘤生长的显著抑制。表6给出在实验结束的那天(从治疗开始时计算)对于肿瘤面积所测定的T/C值。
表6:
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<110> Bayer Pharma Aktiengesellschaft
<120> 具有KSP抑制剂的特异性抗体药物缀合物(ADC)
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<220>
<223> 抗体序列
<400> 4
Ser His Leu Leu Arg Ala Ser Trp Phe Ala Tyr
1 5 10
<210> 5
<211> 113
<212> PRT
<213> 人工序列
<220>
<223> 抗体序列
<400> 5
Asp Ile Val Met Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly
1 5 10 15
Glu Arg Ala Thr Ile Asn Cys Glu Ser Ser Gln Ser Val Leu Asn Ser
20 25 30
Gly Asn Gln Lys Asn Tyr Leu Thr Trp Tyr Gln Gln Lys Pro Gly Gln
35 40 45
Pro Pro Lys Leu Leu Ile Tyr Trp Ala Ser Thr Arg Glu Ser Gly Val
50 55 60
Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr
65 70 75 80
Ile Ser Ser Leu Gln Ala Glu Asp Val Ala Val Tyr Tyr Cys Gln Asn
85 90 95
Asp Tyr Ser Tyr Pro Tyr Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile
100 105 110
Lys
<210> 6
<211> 17
<212> PRT
<213> 人工序列
<220>
<223> 抗体序列
<400> 6
Glu Ser Ser Gln Ser Val Leu Asn Ser Gly Asn Gln Lys Asn Tyr Leu
1 5 10 15
Thr
<210> 7
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> 抗体序列
<400> 7
Trp Ala Ser Thr Arg Glu Ser
1 5
<210> 8
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> 抗体序列
<400> 8
Gln Asn Asp Tyr Ser Tyr Pro Tyr Thr
1 5
<210> 9
<211> 449
<212> PRT
<213> 人工序列
<220>
<223> 抗体序列
<400> 9
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Asp Tyr
20 25 30
Tyr Met Lys Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Asp Ile Ile Pro Ser Asn Gly Ala Thr Phe Tyr Asn Gln Lys Phe
50 55 60
Lys Gly Gln Val Thr Ile Thr Ala Asp Glu Ser Thr Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Ser His Leu Leu Arg Ala Ser Trp Phe Ala Tyr Trp Gly Gln
100 105 110
Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val
115 120 125
Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala
130 135 140
Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser
145 150 155 160
Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val
165 170 175
Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro
180 185 190
Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys
195 200 205
Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp
210 215 220
Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly
225 230 235 240
Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile
245 250 255
Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu
260 265 270
Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His
275 280 285
Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg
290 295 300
Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys
305 310 315 320
Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu
325 330 335
Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr
340 345 350
Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu
355 360 365
Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp
370 375 380
Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val
385 390 395 400
Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp
405 410 415
Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His
420 425 430
Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro
435 440 445
Gly
<210> 10
<211> 220
<212> PRT
<213> 人工序列
<220>
<223> 抗体序列
<400> 10
Asp Ile Val Met Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly
1 5 10 15
Glu Arg Ala Thr Ile Asn Cys Glu Ser Ser Gln Ser Val Leu Asn Ser
20 25 30
Gly Asn Gln Lys Asn Tyr Leu Thr Trp Tyr Gln Gln Lys Pro Gly Gln
35 40 45
Pro Pro Lys Leu Leu Ile Tyr Trp Ala Ser Thr Arg Glu Ser Gly Val
50 55 60
Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr
65 70 75 80
Ile Ser Ser Leu Gln Ala Glu Asp Val Ala Val Tyr Tyr Cys Gln Asn
85 90 95
Asp Tyr Ser Tyr Pro Tyr Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile
100 105 110
Lys Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp
115 120 125
Glu Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn
130 135 140
Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu
145 150 155 160
Gln Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp
165 170 175
Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr
180 185 190
Glu Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser
195 200 205
Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
210 215 220
<210> 11
<211> 118
<212> PRT
<213> 人工序列
<220>
<223> 抗体序列
<400> 11
Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Val Ser Asp Tyr Ser Ile Thr Ser Gly
20 25 30
Tyr Tyr Trp Asn Trp Ile Arg Gln Ala Pro Gly Lys Lys Leu Glu Trp
35 40 45
Met Gly Tyr Ile Ser Tyr Asp Gly Ser Asn Asn Tyr Asn Pro Ser Leu
50 55 60
Lys Asn Gly Arg Ile Thr Ile Ser Arg Asp Thr Ser Lys Asn Thr Phe
65 70 75 80
Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr
85 90 95
Cys Ala Arg Gly Glu Gly Phe Tyr Phe Asp Ser Trp Gly Gln Gly Thr
100 105 110
Leu Val Thr Val Ser Ser
115
<210> 12
<211> 6
<212> PRT
<213> 人工序列
<220>
<223> 抗体序列
<400> 12
Ser Gly Tyr Tyr Trp Asn
1 5
<210> 13
<211> 17
<212> PRT
<213> 人工序列
<220>
<223> 抗体序列
<400> 13
Tyr Ile Ser Tyr Asp Gly Ser Asn Asn Tyr Asn Pro Ser Leu Lys Asn
1 5 10 15
Gly
<210> 14
<211> 8
<212> PRT
<213> 人工序列
<220>
<223> 抗体序列
<400> 14
Gly Glu Gly Phe Tyr Phe Asp Ser
1 5
<210> 15
<211> 113
<212> PRT
<213> 人工序列
<220>
<223> 抗体序列
<400> 15
Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Lys Ser Ser Gln Ser Leu Phe Phe Gly
20 25 30
Ser Thr Gln Lys Asn Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln
35 40 45
Ala Pro Arg Leu Leu Ile Tyr Trp Ala Ser Thr Arg Glu Ser Gly Ile
50 55 60
Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr
65 70 75 80
Ile Ser Arg Leu Glu Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln
85 90 95
Tyr Tyr Asn Tyr Pro Trp Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile
100 105 110
Lys
<210> 16
<211> 17
<212> PRT
<213> 人工序列
<220>
<223> 抗体序列
<400> 16
Lys Ser Ser Gln Ser Leu Phe Phe Gly Ser Thr Gln Lys Asn Tyr Leu
1 5 10 15
Ala
<210> 17
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> 抗体序列
<400> 17
Trp Ala Ser Thr Arg Glu Ser
1 5
<210> 18
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> 抗体序列
<400> 18
Gln Gln Tyr Tyr Asn Tyr Pro Trp Thr
1 5
<210> 19
<211> 447
<212> PRT
<213> 人工序列
<220>
<223> 抗体序列
<400> 19
Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Val Ser Asp Tyr Ser Ile Thr Ser Gly
20 25 30
Tyr Tyr Trp Asn Trp Ile Arg Gln Ala Pro Gly Lys Lys Leu Glu Trp
35 40 45
Met Gly Tyr Ile Ser Tyr Asp Gly Ser Asn Asn Tyr Asn Pro Ser Leu
50 55 60
Lys Asn Gly Arg Ile Thr Ile Ser Arg Asp Thr Ser Lys Asn Thr Phe
65 70 75 80
Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr
85 90 95
Cys Ala Arg Gly Glu Gly Phe Tyr Phe Asp Ser Trp Gly Gln Gly Thr
100 105 110
Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro
115 120 125
Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly
130 135 140
Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn
145 150 155 160
Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln
165 170 175
Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser
180 185 190
Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser
195 200 205
Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr
210 215 220
His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser
225 230 235 240
Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg
245 250 255
Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro
260 265 270
Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala
275 280 285
Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val
290 295 300
Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr
305 310 315 320
Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr
325 330 335
Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu
340 345 350
Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys
355 360 365
Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser
370 375 380
Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp
385 390 395 400
Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser
405 410 415
Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala
420 425 430
Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly
435 440 445
<210> 20
<211> 220
<212> PRT
<213> 人工序列
<220>
<223> 抗体序列
<400> 20
Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Lys Ser Ser Gln Ser Leu Phe Phe Gly
20 25 30
Ser Thr Gln Lys Asn Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln
35 40 45
Ala Pro Arg Leu Leu Ile Tyr Trp Ala Ser Thr Arg Glu Ser Gly Ile
50 55 60
Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr
65 70 75 80
Ile Ser Arg Leu Glu Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln
85 90 95
Tyr Tyr Asn Tyr Pro Trp Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile
100 105 110
Lys Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp
115 120 125
Glu Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn
130 135 140
Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu
145 150 155 160
Gln Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp
165 170 175
Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr
180 185 190
Glu Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser
195 200 205
Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
210 215 220
<210> 21
<211> 113
<212> PRT
<213> 人工序列
<220>
<223> 抗体序列
<400> 21
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Lys
1 5 10 15
Ser Leu Lys Leu Ser Cys Ser Ala Ser Gly Phe Thr Phe Ser Thr Ser
20 25 30
Gly Met His Trp Phe Arg Gln Ala Pro Gly Lys Gly Leu Asp Trp Val
35 40 45
Ala Tyr Ile Ser Ser Ser Ser Gly Phe Val Tyr Ala Asp Ala Val Lys
50 55 60
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Gln Asn Thr Leu Tyr Leu
65 70 75 80
Gln Leu Asn Ser Leu Lys Ser Glu Asp Thr Ala Ile Tyr Tyr Cys Ala
85 90 95
Arg Ser Glu Ala Ala Phe Trp Gly Gln Gly Thr Leu Val Thr Val Ser
100 105 110
Ser
<210> 22
<211> 5
<212> PRT
<213> 人工序列
<220>
<223> 抗体序列
<400> 22
Thr Ser Gly Met His
1 5
<210> 23
<211> 16
<212> PRT
<213> 人工序列
<220>
<223> 抗体序列
<400> 23
Tyr Ile Ser Ser Ser Ser Gly Phe Val Tyr Ala Asp Ala Val Lys Gly
1 5 10 15
<210> 24
<211> 5
<212> PRT
<213> 人工序列
<220>
<223> 抗体序列
<400> 24
Ser Glu Ala Ala Phe
1 5
<210> 25
<211> 112
<212> PRT
<213> 人工序列
<220>
<223> 抗体序列
<400> 25
Asp Ile Val Leu Thr Gln Ala Pro Arg Ser Val Ser Val Thr Pro Gly
1 5 10 15
Glu Ser Ala Ser Ile Ser Cys Arg Ser Asn Lys Ser Arg Leu Ser Arg
20 25 30
Met Gly Ile Thr Pro Leu Asn Trp Tyr Leu Gln Lys Pro Gly Lys Ser
35 40 45
Pro Gln Leu Leu Ile Tyr Arg Met Ser Asn Leu Ala Ser Gly Val Pro
50 55 60
Asp Arg Phe Ser Gly Ser Gly Ser Glu Thr Asp Phe Thr Leu Lys Ile
65 70 75 80
Ser Lys Val Glu Thr Glu Asp Val Gly Val Tyr Tyr Cys Ala Gln Phe
85 90 95
Leu Glu Tyr Pro Pro Thr Phe Gly Ser Gly Thr Lys Leu Glu Ile Lys
100 105 110
<210> 26
<211> 16
<212> PRT
<213> 人工序列
<220>
<223> 抗体序列
<400> 26
Arg Ser Asn Lys Ser Arg Leu Ser Arg Met Gly Ile Thr Pro Leu Asn
1 5 10 15
<210> 27
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> 抗体序列
<400> 27
Arg Met Ser Asn Leu Ala Ser
1 5
<210> 28
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> 抗体序列
<400> 28
Ala Gln Phe Leu Glu Tyr Pro Pro Thr
1 5
<210> 29
<211> 442
<212> PRT
<213> 人工序列
<220>
<223> 抗体序列
<400> 29
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Lys
1 5 10 15
Ser Leu Lys Leu Ser Cys Ser Ala Ser Gly Phe Thr Phe Ser Thr Ser
20 25 30
Gly Met His Trp Phe Arg Gln Ala Pro Gly Lys Gly Leu Asp Trp Val
35 40 45
Ala Tyr Ile Ser Ser Ser Ser Gly Phe Val Tyr Ala Asp Ala Val Lys
50 55 60
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Gln Asn Thr Leu Tyr Leu
65 70 75 80
Gln Leu Asn Ser Leu Lys Ser Glu Asp Thr Ala Ile Tyr Tyr Cys Ala
85 90 95
Arg Ser Glu Ala Ala Phe Trp Gly Gln Gly Thr Leu Val Thr Val Ser
100 105 110
Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser
115 120 125
Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp
130 135 140
Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr
145 150 155 160
Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr
165 170 175
Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln
180 185 190
Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp
195 200 205
Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro
210 215 220
Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro
225 230 235 240
Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr
245 250 255
Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn
260 265 270
Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg
275 280 285
Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val
290 295 300
Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser
305 310 315 320
Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys
325 330 335
Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp
340 345 350
Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe
355 360 365
Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu
370 375 380
Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe
385 390 395 400
Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly
405 410 415
Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr
420 425 430
Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly
435 440
<210> 30
<211> 219
<212> PRT
<213> 人工序列
<220>
<223> 抗体序列
<400> 30
Asp Ile Val Leu Thr Gln Ala Pro Arg Ser Val Ser Val Thr Pro Gly
1 5 10 15
Glu Ser Ala Ser Ile Ser Cys Arg Ser Asn Lys Ser Arg Leu Ser Arg
20 25 30
Met Gly Ile Thr Pro Leu Asn Trp Tyr Leu Gln Lys Pro Gly Lys Ser
35 40 45
Pro Gln Leu Leu Ile Tyr Arg Met Ser Asn Leu Ala Ser Gly Val Pro
50 55 60
Asp Arg Phe Ser Gly Ser Gly Ser Glu Thr Asp Phe Thr Leu Lys Ile
65 70 75 80
Ser Lys Val Glu Thr Glu Asp Val Gly Val Tyr Tyr Cys Ala Gln Phe
85 90 95
Leu Glu Tyr Pro Pro Thr Phe Gly Ser Gly Thr Lys Leu Glu Ile Lys
100 105 110
Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu
115 120 125
Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe
130 135 140
Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln
145 150 155 160
Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser
165 170 175
Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu
180 185 190
Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser
195 200 205
Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
210 215
<210> 31
<211> 120
<212> PRT
<213> 人工序列
<220>
<223> 抗体序列
<400> 31
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Asp Tyr
20 25 30
Tyr Met Lys Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Asp Ile Ile Pro Ser Asn Gly Ala Thr Phe Tyr Asn Gln Lys Phe
50 55 60
Lys Gly Arg Val Thr Ile Thr Ala Asp Glu Ser Thr Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Ser His Leu Leu Arg Ala Ser Trp Phe Ala Tyr Trp Gly Gln
100 105 110
Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 32
<211> 5
<212> PRT
<213> 人工序列
<220>
<223> 抗体序列
<400> 32
Asp Tyr Tyr Met Lys
1 5
<210> 33
<211> 17
<212> PRT
<213> 人工序列
<220>
<223> 抗体序列
<400> 33
Asp Ile Ile Pro Ser Asn Gly Ala Thr Phe Tyr Asn Gln Lys Phe Lys
1 5 10 15
Gly
<210> 34
<211> 11
<212> PRT
<213> 人工序列
<220>
<223> 抗体序列
<400> 34
Ser His Leu Leu Arg Ala Ser Trp Phe Ala Tyr
1 5 10
<210> 35
<211> 113
<212> PRT
<213> 人工序列
<220>
<223> 抗体序列
<400> 35
Asp Ile Val Met Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly
1 5 10 15
Glu Arg Ala Thr Ile Asn Cys Glu Ser Ser Gln Ser Val Leu Asn Ser
20 25 30
Gly Asn Gln Lys Asn Tyr Leu Thr Trp Tyr Gln Gln Lys Pro Gly Gln
35 40 45
Pro Pro Lys Leu Leu Ile Tyr Trp Ala Ser Thr Arg Glu Ser Gly Val
50 55 60
Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr
65 70 75 80
Ile Ser Ser Leu Gln Ala Glu Asp Val Ala Val Tyr Tyr Cys Gln Asn
85 90 95
Asp Tyr Ser Tyr Pro Tyr Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile
100 105 110
Lys
<210> 36
<211> 17
<212> PRT
<213> 人工序列
<220>
<223> 抗体序列
<400> 36
Glu Ser Ser Gln Ser Val Leu Asn Ser Gly Asn Gln Lys Asn Tyr Leu
1 5 10 15
Thr
<210> 37
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> 抗体序列
<400> 37
Trp Ala Ser Thr Arg Glu Ser
1 5
<210> 38
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> 抗体序列
<400> 38
Gln Asn Asp Tyr Ser Tyr Pro Tyr Thr
1 5
<210> 39
<211> 449
<212> PRT
<213> 人工序列
<220>
<223> 抗体序列
<400> 39
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Asp Tyr
20 25 30
Tyr Met Lys Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Asp Ile Ile Pro Ser Asn Gly Ala Thr Phe Tyr Asn Gln Lys Phe
50 55 60
Lys Gly Arg Val Thr Ile Thr Ala Asp Glu Ser Thr Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Ser His Leu Leu Arg Ala Ser Trp Phe Ala Tyr Trp Gly Gln
100 105 110
Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val
115 120 125
Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala
130 135 140
Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser
145 150 155 160
Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val
165 170 175
Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro
180 185 190
Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys
195 200 205
Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp
210 215 220
Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly
225 230 235 240
Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile
245 250 255
Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu
260 265 270
Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His
275 280 285
Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg
290 295 300
Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys
305 310 315 320
Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu
325 330 335
Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr
340 345 350
Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu
355 360 365
Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp
370 375 380
Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val
385 390 395 400
Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp
405 410 415
Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His
420 425 430
Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro
435 440 445
Gly
<210> 40
<211> 220
<212> PRT
<213> 人工序列
<220>
<223> 抗体序列
<400> 40
Asp Ile Val Met Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly
1 5 10 15
Glu Arg Ala Thr Ile Asn Cys Glu Ser Ser Gln Ser Val Leu Asn Ser
20 25 30
Gly Asn Gln Lys Asn Tyr Leu Thr Trp Tyr Gln Gln Lys Pro Gly Gln
35 40 45
Pro Pro Lys Leu Leu Ile Tyr Trp Ala Ser Thr Arg Glu Ser Gly Val
50 55 60
Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr
65 70 75 80
Ile Ser Ser Leu Gln Ala Glu Asp Val Ala Val Tyr Tyr Cys Gln Asn
85 90 95
Asp Tyr Ser Tyr Pro Tyr Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile
100 105 110
Lys Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp
115 120 125
Glu Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn
130 135 140
Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu
145 150 155 160
Gln Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp
165 170 175
Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr
180 185 190
Glu Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser
195 200 205
Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
210 215 220
<210> 41
<211> 113
<212> PRT
<213> 人工序列
<220>
<223> 抗体序列
<400> 41
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Ile Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Thr Ser
20 25 30
Gly Met His Trp Phe Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Tyr Ile Ser Ser Ser Ser Gly Phe Val Tyr Ala Asp Ala Val Lys
50 55 60
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu
65 70 75 80
Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala
85 90 95
Arg Ser Glu Ala Ala Phe Trp Gly Gln Gly Thr Leu Val Thr Val Ser
100 105 110
Ser
<210> 42
<211> 5
<212> PRT
<213> 人工序列
<220>
<223> 抗体序列
<400> 42
Thr Ser Gly Met His
1 5
<210> 43
<211> 16
<212> PRT
<213> 人工序列
<220>
<223> 抗体序列
<400> 43
Tyr Ile Ser Ser Ser Ser Gly Phe Val Tyr Ala Asp Ala Val Lys Gly
1 5 10 15
<210> 44
<211> 5
<212> PRT
<213> 人工序列
<220>
<223> 抗体序列
<400> 44
Ser Glu Ala Ala Phe
1 5
<210> 45
<211> 112
<212> PRT
<213> 人工序列
<220>
<223> 抗体序列
<400> 45
Asp Ile Val Met Thr Gln Ser Pro Leu Ser Leu Pro Val Thr Pro Gly
1 5 10 15
Glu Pro Ala Ser Ile Ser Cys Arg Ser Gln Lys Ser Arg Leu Ser Arg
20 25 30
Met Gly Ile Thr Pro Leu Asn Trp Tyr Leu Gln Lys Pro Gly Gln Ser
35 40 45
Pro Gln Leu Leu Ile Tyr Arg Met Ser Asn Leu Ala Ser Gly Val Pro
50 55 60
Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile
65 70 75 80
Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Ala Gln Phe
85 90 95
Leu Glu Tyr Pro Pro Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys
100 105 110
<210> 46
<211> 16
<212> PRT
<213> 人工序列
<220>
<223> 抗体序列
<400> 46
Arg Ser Gln Lys Ser Arg Leu Ser Arg Met Gly Ile Thr Pro Leu Asn
1 5 10 15
<210> 47
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> 抗体序列
<400> 47
Arg Met Ser Asn Leu Ala Ser
1 5
<210> 48
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> 抗体序列
<400> 48
Ala Gln Phe Leu Glu Tyr Pro Pro Thr
1 5
<210> 49
<211> 442
<212> PRT
<213> 人工序列
<220>
<223> 抗体序列
<400> 49
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Ile Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Thr Ser
20 25 30
Gly Met His Trp Phe Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Tyr Ile Ser Ser Ser Ser Gly Phe Val Tyr Ala Asp Ala Val Lys
50 55 60
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu
65 70 75 80
Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala
85 90 95
Arg Ser Glu Ala Ala Phe Trp Gly Gln Gly Thr Leu Val Thr Val Ser
100 105 110
Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser
115 120 125
Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp
130 135 140
Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr
145 150 155 160
Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr
165 170 175
Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln
180 185 190
Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp
195 200 205
Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro
210 215 220
Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro
225 230 235 240
Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr
245 250 255
Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn
260 265 270
Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg
275 280 285
Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val
290 295 300
Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser
305 310 315 320
Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys
325 330 335
Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp
340 345 350
Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe
355 360 365
Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu
370 375 380
Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe
385 390 395 400
Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly
405 410 415
Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr
420 425 430
Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly
435 440
<210> 50
<211> 219
<212> PRT
<213> 人工序列
<220>
<223> 抗体序列
<400> 50
Asp Ile Val Met Thr Gln Ser Pro Leu Ser Leu Pro Val Thr Pro Gly
1 5 10 15
Glu Pro Ala Ser Ile Ser Cys Arg Ser Gln Lys Ser Arg Leu Ser Arg
20 25 30
Met Gly Ile Thr Pro Leu Asn Trp Tyr Leu Gln Lys Pro Gly Gln Ser
35 40 45
Pro Gln Leu Leu Ile Tyr Arg Met Ser Asn Leu Ala Ser Gly Val Pro
50 55 60
Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile
65 70 75 80
Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Ala Gln Phe
85 90 95
Leu Glu Tyr Pro Pro Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys
100 105 110
Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu
115 120 125
Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe
130 135 140
Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln
145 150 155 160
Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser
165 170 175
Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu
180 185 190
Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser
195 200 205
Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
210 215
<210> 51
<211> 113
<212> PRT
<213> 人工序列
<220>
<223> 抗体序列
<400> 51
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Ile Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Thr Ser
20 25 30
Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Tyr Ile Ser Ser Ser Ser Gly Phe Val Tyr Ala Asp Ala Val Lys
50 55 60
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu
65 70 75 80
Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala
85 90 95
Arg Ser Glu Ala Ala Phe Trp Gly Gln Gly Thr Leu Val Thr Val Ser
100 105 110
Ser
<210> 52
<211> 5
<212> PRT
<213> 人工序列
<220>
<223> 抗体序列
<400> 52
Thr Ser Gly Met His
1 5
<210> 53
<211> 16
<212> PRT
<213> 人工序列
<220>
<223> 抗体序列
<400> 53
Tyr Ile Ser Ser Ser Ser Gly Phe Val Tyr Ala Asp Ala Val Lys Gly
1 5 10 15
<210> 54
<211> 5
<212> PRT
<213> 人工序列
<220>
<223> 抗体序列
<400> 54
Ser Glu Ala Ala Phe
1 5
<210> 55
<211> 112
<212> PRT
<213> 人工序列
<220>
<223> 抗体序列
<400> 55
Asp Ile Val Met Thr Gln Ser Pro Leu Ser Leu Pro Val Thr Pro Gly
1 5 10 15
Glu Pro Ala Ser Ile Ser Cys Arg Ser Gln Lys Ser Arg Leu Ser Arg
20 25 30
Met Gly Ile Thr Pro Leu Asn Trp Tyr Leu Gln Lys Pro Gly Gln Ser
35 40 45
Pro Gln Leu Leu Ile Tyr Arg Met Ser Asn Leu Ala Ser Gly Val Pro
50 55 60
Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile
65 70 75 80
Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Ala Gln Phe
85 90 95
Leu Glu Tyr Pro Pro Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys
100 105 110
<210> 56
<211> 16
<212> PRT
<213> 人工序列
<220>
<223> 抗体序列
<400> 56
Arg Ser Gln Lys Ser Arg Leu Ser Arg Met Gly Ile Thr Pro Leu Asn
1 5 10 15
<210> 57
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> 抗体序列
<400> 57
Arg Met Ser Asn Leu Ala Ser
1 5
<210> 58
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> 抗体序列
<400> 58
Ala Gln Phe Leu Glu Tyr Pro Pro Thr
1 5
<210> 59
<211> 442
<212> PRT
<213> 人工序列
<220>
<223> 抗体序列
<400> 59
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Ile Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Thr Ser
20 25 30
Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Tyr Ile Ser Ser Ser Ser Gly Phe Val Tyr Ala Asp Ala Val Lys
50 55 60
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu
65 70 75 80
Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala
85 90 95
Arg Ser Glu Ala Ala Phe Trp Gly Gln Gly Thr Leu Val Thr Val Ser
100 105 110
Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser
115 120 125
Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp
130 135 140
Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr
145 150 155 160
Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr
165 170 175
Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln
180 185 190
Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp
195 200 205
Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro
210 215 220
Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro
225 230 235 240
Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr
245 250 255
Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn
260 265 270
Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg
275 280 285
Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val
290 295 300
Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser
305 310 315 320
Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys
325 330 335
Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp
340 345 350
Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe
355 360 365
Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu
370 375 380
Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe
385 390 395 400
Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly
405 410 415
Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr
420 425 430
Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly
435 440
<210> 60
<211> 219
<212> PRT
<213> 人工序列
<220>
<223> 抗体序列
<400> 60
Asp Ile Val Met Thr Gln Ser Pro Leu Ser Leu Pro Val Thr Pro Gly
1 5 10 15
Glu Pro Ala Ser Ile Ser Cys Arg Ser Gln Lys Ser Arg Leu Ser Arg
20 25 30
Met Gly Ile Thr Pro Leu Asn Trp Tyr Leu Gln Lys Pro Gly Gln Ser
35 40 45
Pro Gln Leu Leu Ile Tyr Arg Met Ser Asn Leu Ala Ser Gly Val Pro
50 55 60
Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile
65 70 75 80
Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Ala Gln Phe
85 90 95
Leu Glu Tyr Pro Pro Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys
100 105 110
Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu
115 120 125
Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe
130 135 140
Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln
145 150 155 160
Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser
165 170 175
Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu
180 185 190
Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser
195 200 205
Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
210 215
<210> 61
<211> 372
<212> PRT
<213> 智人
<400> 61
Met Asn Tyr Pro Leu Thr Leu Glu Met Asp Leu Glu Asn Leu Glu Asp
1 5 10 15
Leu Phe Trp Glu Leu Asp Arg Leu Asp Asn Tyr Asn Asp Thr Ser Leu
20 25 30
Val Glu Asn His Leu Cys Pro Ala Thr Glu Gly Pro Leu Met Ala Ser
35 40 45
Phe Lys Ala Val Phe Val Pro Val Ala Tyr Ser Leu Ile Phe Leu Leu
50 55 60
Gly Val Ile Gly Asn Val Leu Val Leu Val Ile Leu Glu Arg His Arg
65 70 75 80
Gln Thr Arg Ser Ser Thr Glu Thr Phe Leu Phe His Leu Ala Val Ala
85 90 95
Asp Leu Leu Leu Val Phe Ile Leu Pro Phe Ala Val Ala Glu Gly Ser
100 105 110
Val Gly Trp Val Leu Gly Thr Phe Leu Cys Lys Thr Val Ile Ala Leu
115 120 125
His Lys Val Asn Phe Tyr Cys Ser Ser Leu Leu Leu Ala Cys Ile Ala
130 135 140
Val Asp Arg Tyr Leu Ala Ile Val His Ala Val His Ala Tyr Arg His
145 150 155 160
Arg Arg Leu Leu Ser Ile His Ile Thr Cys Gly Thr Ile Trp Leu Val
165 170 175
Gly Phe Leu Leu Ala Leu Pro Glu Ile Leu Phe Ala Lys Val Ser Gln
180 185 190
Gly His His Asn Asn Ser Leu Pro Arg Cys Thr Phe Ser Gln Glu Asn
195 200 205
Gln Ala Glu Thr His Ala Trp Phe Thr Ser Arg Phe Leu Tyr His Val
210 215 220
Ala Gly Phe Leu Leu Pro Met Leu Val Met Gly Trp Cys Tyr Val Gly
225 230 235 240
Val Val His Arg Leu Arg Gln Ala Gln Arg Arg Pro Gln Arg Gln Lys
245 250 255
Ala Val Arg Val Ala Ile Leu Val Thr Ser Ile Phe Phe Leu Cys Trp
260 265 270
Ser Pro Tyr His Ile Val Ile Phe Leu Asp Thr Leu Ala Arg Leu Lys
275 280 285
Ala Val Asp Asn Thr Cys Lys Leu Asn Gly Ser Leu Pro Val Ala Ile
290 295 300
Thr Met Cys Glu Phe Leu Gly Leu Ala His Cys Cys Leu Asn Pro Met
305 310 315 320
Leu Tyr Thr Phe Ala Gly Val Lys Phe Arg Ser Asp Leu Ser Arg Leu
325 330 335
Leu Thr Lys Leu Gly Cys Thr Gly Pro Ala Ser Leu Cys Gln Leu Phe
340 345 350
Pro Ser Trp Arg Arg Ser Ser Leu Ser Glu Ser Glu Asn Ala Thr Ser
355 360 365
Leu Thr Thr Phe
370
<210> 62
<211> 378
<212> PRT
<213> 智人
<400> 62
Met Val Leu Leu Trp Leu Thr Leu Leu Leu Ile Ala Leu Pro Cys Leu
1 5 10 15
Leu Gln Thr Lys Glu Asp Pro Asn Pro Pro Ile Thr Asn Leu Arg Met
20 25 30
Lys Ala Lys Ala Gln Gln Leu Thr Trp Asp Leu Asn Arg Asn Val Thr
35 40 45
Asp Ile Glu Cys Val Lys Asp Ala Asp Tyr Ser Met Pro Ala Val Asn
50 55 60
Asn Ser Tyr Cys Gln Phe Gly Ala Ile Ser Leu Cys Glu Val Thr Asn
65 70 75 80
Tyr Thr Val Arg Val Ala Asn Pro Pro Phe Ser Thr Trp Ile Leu Phe
85 90 95
Pro Glu Asn Ser Gly Lys Pro Trp Ala Gly Ala Glu Asn Leu Thr Cys
100 105 110
Trp Ile His Asp Val Asp Phe Leu Ser Cys Ser Trp Ala Val Gly Pro
115 120 125
Gly Ala Pro Ala Asp Val Gln Tyr Asp Leu Tyr Leu Asn Val Ala Asn
130 135 140
Arg Arg Gln Gln Tyr Glu Cys Leu His Tyr Lys Thr Asp Ala Gln Gly
145 150 155 160
Thr Arg Ile Gly Cys Arg Phe Asp Asp Ile Ser Arg Leu Ser Ser Gly
165 170 175
Ser Gln Ser Ser His Ile Leu Val Arg Gly Arg Ser Ala Ala Phe Gly
180 185 190
Ile Pro Cys Thr Asp Lys Phe Val Val Phe Ser Gln Ile Glu Ile Leu
195 200 205
Thr Pro Pro Asn Met Thr Ala Lys Cys Asn Lys Thr His Ser Phe Met
210 215 220
His Trp Lys Met Arg Ser His Phe Asn Arg Lys Phe Arg Tyr Glu Leu
225 230 235 240
Gln Ile Gln Lys Arg Met Gln Pro Val Ile Thr Glu Gln Val Arg Asp
245 250 255
Arg Thr Ser Phe Gln Leu Leu Asn Pro Gly Thr Tyr Thr Val Gln Ile
260 265 270
Arg Ala Arg Glu Arg Val Tyr Glu Phe Leu Ser Ala Trp Ser Thr Pro
275 280 285
Gln Arg Phe Glu Cys Asp Gln Glu Glu Gly Ala Asn Thr Arg Ala Trp
290 295 300
Arg Thr Ser Leu Leu Ile Ala Leu Gly Thr Leu Leu Ala Leu Val Cys
305 310 315 320
Val Phe Val Ile Cys Arg Arg Tyr Leu Val Met Gln Arg Leu Phe Pro
325 330 335
Arg Ile Pro His Met Lys Asp Pro Ile Gly Asp Ser Phe Gln Asn Asp
340 345 350
Lys Leu Val Val Trp Glu Ala Gly Lys Ala Gly Leu Glu Glu Cys Leu
355 360 365
Val Thr Glu Val Gln Val Val Gln Lys Thr
370 375
Claims (11)
1.式(I)的抗体-活性物质缀合物(ADC)以及其盐、溶剂化物和这些溶剂化物的盐,
其中
n代表1至8,
AK 代表选自TPP-8987、TPP-9476和TPP-8988的抗-CD123抗体,
或
AK 代表抗-CXCR5抗体,其优选选自TPP-9574、TPP-9580和TPP-9024,
或
AK代表这些抗体的抗原结合片段,
其中所述抗体或抗原结合片段经由半胱氨酸侧基的硫原子连接。
2.根据权利要求1所述的式(I)的抗体-活性物质缀合物(ADC),其中n代表2至8。
3. 根据权利要求1所述的式(I)的抗体-活性物质缀合物(ADC),其中n代表4至8。
4.根据权利要求1至3之一所述的抗体-活性物质缀合物(ADC),其中AK
(i)代表包含重链可变区(VH)和轻链可变区(VL)的抗-CD123抗体,所述重链可变区包含如SEQ ID NO:2所示的重链可变CDR1序列(H-CDR1),如SEQ ID NO:3所示的重链可变CDR2序列(H-CDR2)和如SEQ ID NO:4所示的重链可变CDR3序列(H-CDR3),所述轻链可变区包含如SEQ ID NO:6所示的轻链可变CDR1序列(L-CDR1),如SEQ ID NO:7所示的轻链可变CDR2序列(L-CDR2)和如SEQ ID NO:8所示的轻链可变CDR3序列(L-CDR3),
(ii)代表包含重链可变区(VH)和轻链可变区(VL)的抗-CD123抗体,所述重链可变区包含如SEQ ID NO:12所示的重链可变CDR1序列(H-CDR1),如SEQ ID NO:13所示的重链可变CDR2序列(H-CDR2)和如SEQ ID NO:14所示的重链可变CDR3序列(H-CDR3),所述轻链可变区包含如SEQ ID NO:16所示的轻链可变CDR1序列(L-CDR1),如SEQ ID NO:17所示的轻链可变CDR2序列(L-CDR2)和如SEQ ID NO:18所示的轻链可变CDR3序列(L-CDR3),
(iii)代表包含重链可变区(VH)和轻链可变区(VL)的抗-CXCR5抗体,所述重链可变区包含如SEQ ID NO:22所示的重链可变CDR1序列(H-CDR1),如SEQ ID NO:23所示的重链可变CDR2序列(H-CDR2)和如SEQ ID NO:24所示的重链可变CDR3序列(H-CDR3),所述轻链可变区包含如SEQ ID NO:26所示的轻链可变CDR1序列(L-CDR1),如SEQ ID NO:27所示的轻链可变CDR2序列(L-CDR2)和如SEQ ID NO:28所示的轻链可变CDR3序列(L-CDR3),
(iv)代表包含重链可变区(VH)和轻链可变区(VL)的抗-CD123抗体,所述重链可变区包含如SEQ ID NO:32所示的重链可变CDR1序列(H-CDR1),如SEQ ID NO:33所示的重链可变CDR2序列(H-CDR2)和如SEQ ID NO:34所示的重链可变CDR3序列(H-CDR3),所述轻链可变区包含如SEQ ID NO:36所示的轻链可变CDR1序列(L-CDR1),如SEQ ID NO:37所示的轻链可变CDR2序列(L-CDR2)和如SEQ ID NO:38所示的轻链可变CDR3序列(L-CDR3),
(v)代表包含重链可变区(VH)和轻链可变区(VL)的抗-CXCR5抗体,所述重链可变区包含如SEQ ID NO:42所示的重链可变CDR1序列(H-CDR1),如SEQ ID NO:43所示的重链可变CDR2序列(H-CDR2)和如SEQ ID NO:44所示的重链可变CDR3序列(H-CDR3),所述轻链可变区包含如SEQ ID NO:46所示的轻链可变CDR1序列(L-CDR1),如SEQ ID NO:47所示的轻链可变CDR2序列(L-CDR2)和如SEQ ID NO:48所示的轻链可变CDR3序列(L-CDR3),或
(vi)代表包含重链可变区(VH)和轻链可变区(VL)的抗-CXCR5抗体,所述重链可变区包含如SEQ ID NO:52所示的重链可变CDR1序列(H-CDR1),如SEQ ID NO:53所示的重链可变CDR2序列(H-CDR2)和如SEQ ID NO:54所示的重链可变CDR3序列(H-CDR3),所述轻链可变区包含如SEQ ID NO:56所示的轻链可变CDR1序列(L-CDR1),如SEQ ID NO:57所示的轻链可变CDR2序列(L-CDR2)和如SEQ ID NO:58所示的轻链可变CDR3序列(L-CDR3),
或代表这些抗体的抗原结合片段。
5.根据权利要求1至4之一所述的抗体-活性物质缀合物(ADC),其中AK
(i)代表包含如SEQ ID NO:1所示的重链可变区(VH)和如SEQ ID NO:5所示的轻链可变区(VL)的抗-CD123抗体,
(ii)代表包含如SEQ ID NO:11所示的重链可变区(VH)和如SEQ ID NO:15所示的轻链可变区(VL)的抗-CD123抗体,
(iii)代表包含如SEQ ID NO:21所示的重链可变区(VH)和如SEQ ID NO:25所示的轻链可变区(VL)的抗-CXCR5抗体,
(iv)代表包含如SEQ ID NO:31所示的重链可变区(VH)和如SEQ ID NO:35所示的轻链可变区(VL)的抗-CD123抗体,
(v)代表包含如SEQ ID NO:41所示的重链可变区(VH)和如SEQ ID NO:45所示的轻链可变区(VL)的抗-CXCR5抗体,
(vi)代表包含如SEQ ID NO:51所示的重链可变区(VH)和如SEQ ID NO:55所示的轻链可变区(VL)的抗-CXCR5抗体,
或代表这些抗体的抗原结合片段。
6.根据权利要求1至5之一所述的抗体-活性物质缀合物(ADC),其中AK
(i)代表包含如SEQ ID NO:9所示的重链区和如SEQ ID NO:10所示的轻链区的抗-CD123抗体,
(ii)代表包含如SEQ ID NO:19所示的重链区和如SEQ ID NO:20所示的轻链区的抗-CD123抗体,
(iii)代表包含如SEQ ID NO:29所示的重链区和如SEQ ID NO:30所示的轻链区的抗-CXCR5抗体,
(iv)代表包含如SEQ ID NO:39所示的重链区和如SEQ ID NO:40所示的轻链区的抗-CD123抗体,
(v)代表包含如SEQ ID NO:49所示的重链区和如SEQ ID NO:50所示的轻链区的抗-CXCR5抗体,或
(vi)代表包含如SEQ ID NO:59所示的重链区和如SEQ ID NO:60所示的轻链区的抗-CXCR5抗体,
或代表这些抗体的抗原结合片段。
7.药物组合物,其包含至少一种根据前述权利要求中的一项或多项所述的抗体-活性物质缀合物(ADC)与惰性、无毒、药学上合适的助剂的组合。
8.根据前述权利要求中的一项或多项所述的抗体-活性物质缀合物(ADC),其用于治疗和/或预防疾病的方法中。
9.根据前述权利要求中的一项或多项所述的抗体-活性物质缀合物(ADC),其用于治疗过度增生和/或血管生成病症的方法中。
10.根据前述权利要求中的一项或多项所述的抗体-活性物质缀合物(ADC),其用于治疗癌症和肿瘤的方法中。
11.根据前述权利要求中的一项或多项所述的抗体-活性物质缀合物(ADC),其与一种或多种癌症免疫治疗的治疗配药,或与一种或多种针对癌症免疫治疗的分子靶标的活性物质组合,用于治疗癌症和肿瘤的方法中。
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- 2017-12-18 JP JP2019533393A patent/JP7030811B2/ja active Active
- 2017-12-18 US US16/472,682 patent/US11433140B2/en active Active
- 2017-12-18 WO PCT/EP2017/083313 patent/WO2018114804A1/de unknown
- 2017-12-18 CA CA3047522A patent/CA3047522A1/en not_active Abandoned
- 2017-12-18 EP EP17837872.5A patent/EP3558387B1/de active Active
- 2017-12-18 CN CN201780079147.6A patent/CN110072556B/zh active Active
- 2017-12-19 TW TW106144532A patent/TW201834694A/zh unknown
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JP7030811B2 (ja) | 2022-03-07 |
US20190365916A1 (en) | 2019-12-05 |
US11433140B2 (en) | 2022-09-06 |
WO2018114804A1 (de) | 2018-06-28 |
JP2020502205A (ja) | 2020-01-23 |
AR110567A1 (es) | 2019-04-10 |
EP3558387A1 (de) | 2019-10-30 |
CA3047522A1 (en) | 2018-06-28 |
CN110072556B (zh) | 2023-05-02 |
TW201834694A (zh) | 2018-10-01 |
US20220362392A1 (en) | 2022-11-17 |
EP3558387B1 (de) | 2021-10-20 |
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