CN111675763A - 抗met和ron双特异性抗体及其抗体-药物偶联物的制备和应用 - Google Patents
抗met和ron双特异性抗体及其抗体-药物偶联物的制备和应用 Download PDFInfo
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- Preparation Of Compounds By Using Micro-Organisms (AREA)
Abstract
本发明属于生物制药领域,更具体地说,涉及抗MET和RON双特异性抗体及其抗体‑药物偶联物的制备方法和应用。一种抗MET和RON的双特异性抗体,其包含抗MET的抗体片段和抗RON的抗体片段,抗MET的抗体片段和抗RON的抗体片段通过特定的化学“凸点‑嵌入‑凹穴”(knobs‑and‑holes)相连接。
Description
技术领域
本发明属于生物制药领域,更具体地说,涉及抗MET和RON双特异性抗体及其抗体-药物偶联物的制备方法和应用。
背景技术
肝细胞生长因子受体(MET)和巨嗜细胞刺激蛋白受体(RON)属于受体型酪氨酸激酶的一个独特的亚家族,他们具有相似的结构和功能。自从Met和RON分别在1987年和1993年被发现以来,他们在癌症中的作用已经在各种模型系统中被研究,包括遗传、转录组学、蛋白质组学和肿瘤微环境,这些研究表明了它们在肿瘤起始、进展、恶性和干性中的重要性。病理上,MET和/或RON的表达增加存在于各种类型的癌症中,包括结直肠癌、乳腺癌、肺癌和胰腺癌。MET和RON在原发性肿瘤中的过度表达也与病理生理参数相关,可作为预测患者生存和化疗反应的生物标志物。在细胞水平上,异常的MET和/或RON激活可以促进癌细胞侵袭生长、远处转移、化疗耐药和致瘤干性。这些活动通过不同的细胞内信号通路传导,如丝裂原活化蛋白激酶和磷脂酰肌醇3激酶通路。根据这些发现,MET和RON被认为是肿瘤发生的关键决定因素。此外,两种受体均已被证实可作为治疗具有MET和/或RON表达和信号改变的癌症的药物靶点。
MET和RON靶向治疗的临床应用一直在深入研究中。小分子激酶抑制剂(SMKIs)和治疗性单克隆抗体(TMAB)都已被开发出来。几种SMKI,如Cabozantinib和Crizotinib,已被FDA批准用于临床。由于MET和RON在结构上具有相似性,几乎所有靶向MET的SMKI也同样对RON有特异性。针对MET的TMAB,如ABT-700,SAIT301和Sym015,目前正在进行临床试验。同样还开发了针对RON的TMAB,例如IMC41A10、ZT/f2、6E6和narnatumab。Narnatumab进行了临床试验,但由于缺乏治疗效果而终止了。最近报道了一种使用针对MET和/或RON的抗体-药物偶联物(ADC)的策略。MET特异性ADC包括ABBV-399,TR1801-ADC和SHR-A1403等最近已进入临床试验(www.clinicaltrials.gov)。针对RON的ADC,如ZT/G4-单甲基瑞奥西汀E(ZT/G4-MMAE)和PCM5B14-DCM(PCM5B14-DCM)等也已被报道。累积结果表明,抗MET和抗RON ADC在灵长类动物体内均能有效地抑制和/或根除由不同类型的癌细胞株介导的异种移植瘤,并具有良好的药代动力学特征和可控的毒理活性。显然,这些发现奠定了抗MET和抗RON ADC作为癌症治疗新策略的基础。
近几年,国内在ADC药物的研发上有了长足的进步。多家科研单位和药物企业分别针对不同的药物靶点,采用特异性单克隆抗体积极地开展新型抗癌药物ADC的研发。抗体偶联药物的成功开发依赖于选择合适的抗原靶点,使该类药物的抗体部分可以与之特异性高活性结合,新靶点抗原应在肿瘤中的表达水平较高,在正常组织中的表达很少或不表达,或仅在特定组织类型中有表达,以提高药物的安全性和有效性。双特异性抗体又称为双功能抗体,是近年来肿瘤基因治疗的又一个研究热点。它有两个抗原结合部位,可分别结合两种不同的抗原表位。
本发明在罗氏公司的crossmab技术在Knobs-into-holes(KiH)方案的基础上,进一步解决了轻链错误联结的问题,简单的说,该技术首先在Fc区设计了特定的化学“凸点-嵌入-凹穴”(Knobs-into-holes)异源二聚体连结;同时将Fab区域的CH1和CL互换,以减少轻链错配。
本发明RON和MET的双重靶向优于单独抑制任一靶点。RON和MET是可以作为ADC药物合适的抗原靶点。通过CrossMab技术构建的抗MET和RON双特异性抗体将有助于肿瘤特异性靶向治疗。
发明内容
本发明提供一种双特异性抗体,其包含抗MET抗体片段和抗RON抗体片段。一种抗MET和RON的双特异性抗体,其包含抗MET的抗体片段和抗RON的抗体片段,抗MET的抗体片段和抗RON的抗体片段通过特定的化学“凸点-嵌入-凹穴”(knobs-and-holes)相连接。
抗RON抗体片段,氨基酸序列中393号氨基酸T突变为W;抗MET抗体片段,氨基酸序列中440号氨基酸Y突变为V,同时重链可变区中CH1与轻链可变区CL发生交换。
其中所述抗MET抗体片段PCM-C1D8,其重链可变区的氨基酸序列如SEQ ID NO:27所示;其轻链可变区的氨基酸序列如SEQ ID NO:28所示。其中所述抗RON抗体片段即PCM5B14,重链可变区的氨基酸序列如SEQ ID NO:31所示;其轻链可变区的氨基酸序列如SEQ ID NO:32所示。所述任一氨基酸序列至少95%同一性并保留相应生物活性的变体序列或经删除、替换和/或添加一个或多个氨基酸残基后获得的保留相应活性的变体序列。
免疫球蛋白重链可变区包括:
CDRH1,其包含SEQ ID NO:7的氨基酸序列;
CDRH2,其包含SEQ ID NO:8的氨基酸序列;
CDRH3,其包含SEQ ID NO:9的氨基酸序列;
免疫球蛋白轻链可变区包括:
CDRH1,其包含SEQ ID NO:10的氨基酸序列;
CDRH2,其包含SEQ ID NO:11的氨基酸序列;
CDRH3,其包含SEQ ID NO:12的氨基酸序列。
免疫球蛋白重链可变区包括:
CDRH1,其包含SEQ ID NO:19的氨基酸序列;
CDRH2,其包含SEQ ID NO:20的氨基酸序列;
CDRH3,其包含SEQ ID NO:21的氨基酸序列;
免疫球蛋白轻链可变区包括:
CDRH1,其包含SEQ ID NO:22的氨基酸序列;
CDRH2,其包含SEQ ID NO:23的氨基酸序列;
CDRH3,其包含SEQ ID NO:24的氨基酸序列。
本发明的另一个应用方案,一种抗体结合片段,其特征在于:包括SEQ ID NO:27,SEQ ID NO:28,SEQ ID NO:31或SEQ ID NO:32所示的抗原结合结构域中的任意一种或多种。
本发明还包括在制备的C1D8或PCM-C1D8的单克隆抗体中,纯化出能特异性识别人MET蛋白的单克隆抗体或其结合片段。首先,将单克隆抗体或其结合片段的基因序列插入人或人源化基序的互补决定区(CDR)序列,其中免疫球蛋白重链可变区CDRH1、CDRH2、CDRH3由选自SEQ ID NO:7-9的单克隆抗体序列分别或保守地进行替换;免疫球蛋白轻链可变区的CDRL1、CDRL2和CDRL3由SEQ ID NO:10-12的单克隆抗体序列分别或保守地进行替换。另一方面,将单克隆抗体或其结合片段与细胞毒性药物偶联,形成抗体-药物偶联物。偶联物中的抗体靶向结合到癌细胞上的MET受体时,通过内吞作用将抗MET抗体和细胞毒性药物一并内吞到细胞中,杀伤肿瘤细胞。此外,抗体或结合片段还可以与细胞毒性蛋白结合。将来,抗体及其结合片段也可与更多的细胞毒性或化疗药物结合。
本方案的另一个应用方案,包括在制备的H5B14或PCM5B14的单克隆抗体中,纯化出能特异性识别人RON蛋白的单克隆抗体或其结合片段。首先,将单克隆抗体或其结合片段的基因序列插入人或人源化基序的互补决定区(CDR)序列,其中免疫球蛋白重链可变区CDRH1、CDRH2、CDRH3由选自SEQ ID NO:19-21的单克隆抗体序列分别或保守地进行替换;免疫球蛋白轻链可变区的CDRL1、CDRL2和CDRL3由SEQ ID NO:22-24的单克隆抗体序列分别或保守地进行替换。另一方面,将单克隆抗体或其结合片段与细胞毒性药物偶联,形成抗体-药物偶联物。偶联物中的抗体靶向结合
到癌细胞上的RON受体时,通过内吞作用将抗RON抗体和细胞毒性药物一并内吞到细胞中,杀伤肿瘤细胞。此外,抗体或结合片段还可以与细胞毒性蛋白结合。将来,抗体及其结合片段也可与更多的细胞毒性或化疗药物结合。
本方案的另一个应用方案,所述双特异性抗体中抗MET和抗RON的抗体片段及PCMbs-MR之间通过CrossMab技术相连接。主要内容为,抗RON抗体片段,及氨基酸序列中393号氨基酸T突变为W;抗MET抗体片段,氨基酸序列中440号氨基酸Y突变为V,同时重链可变区中CH1与轻链可变区CL发生交换。
本方案的另一个应用方案,是在宿主细胞中制备能同时靶向MET和RON受体的双特异性抗体或结合片段的方法。其内容包括:在能表达免疫球蛋白重链可变区多肽或(和)免疫球蛋白轻链可变区多肽的宿主细胞中,表达特异性抗人MET和RON的受体结构域的免疫球蛋白重链可变区多肽或(和)疫球蛋白轻链可变区多肽,从而产生选自PCMbs-MR的抗体或其结合片段,并进行抗体或结合片段的纯化。所有的宿主细胞是PCMbs-MR的宿主细胞。
本方案的另一个应用方案,该方案将细胞毒性剂或化学治疗剂与抗体包括(PCM-C1D8,PCM5B14和PCMbs-MR)或其结合片段偶联或与细胞毒性蛋白质结合制备融合蛋白的步骤。另一方面,宿主细胞可以从细菌、酵母、昆虫、植物或哺乳动物细胞中筛选得到。
本方案的另一个应用方案,将抗MET和RON双特异性抗体或其结合片段与细胞毒性药物偶联,形成抗体-药物偶联物。偶联物中的抗体靶向结合到癌细胞上的MET和/或RON受体时,通过内吞作用将抗MET和/或RON抗体和细胞毒性药物一并内吞到细胞中,杀伤肿瘤细胞。此外,抗体或结合片段还可以与细胞毒性蛋白结合。将来,抗体及其结合片段也可与更多的细胞毒性或化疗药物结合。此外,肿瘤可以来自脑,乳腺,子宫颈,胰腺,皮肤、前列腺、肝脏,膀胱,结肠、头颈部,肾,肺,非小细胞肺癌,黑色素瘤,间皮瘤,卵巢,肉瘤、胃,子宫和神经管细胞瘤中。
抗MET和抗RON双特异性抗体PCMbs-MR通过蛋白酶敏感的二肽接头与MMAE按照1:4均匀标记合成抗体-药物偶联物(ADC)即PCMdt-MMAE。
本发明的另一个使用方案,包括纯化能表达特异性结合抗MET单克隆抗体的核酸,其表达的抗体的免疫球蛋白重链可变区和/或免疫球蛋白轻链可变区与单克隆抗体PCM-C1D8至少有95%同源性。一方面,免疫球蛋白重链可变区包含PCM-C1D8或PCM5BI4的重链可变区:编码CDRH1的核酸序列SEQ ID NO:1;编码CDRH2的核酸序列SEQ ID NO:2;编码CDRH3的核酸序列SEQ ID NO:3。免疫球蛋白轻链可变区包含PCM-C1D8的轻链可变区:编码CDRL1的核酸序列SEQ ID NO:4;编码CDRL2的核酸序列SEQ ID NO:5;编码CDRL3的核酸序列SEQIDNO:6。另一方面,免疫球蛋白重链可变区或(和)轻链可变区进一步添加编码细胞毒性蛋白并能与免疫球蛋白重链可变区或(和)轻链可变区形成融合蛋白的核酸序列。
本发明的另一个使用方案,包括纯化能表达特异性结合抗RON单克隆抗体的核酸,其表达的抗体的免疫球蛋白重链可变区和/或免疫球蛋白轻链可变区与单克隆抗体PCM-5B14至少有95%同源性。一方面,免疫球蛋白重链可变区包含PCM-C1D8或PCM5BI4的重链可变区:编码CDRH1的核酸序列SEQ ID NO:13;编码CDRH2的核酸序列SEQ ID NO:14;编码CDRH3的核酸序列SEQ ID NO:15。免疫球蛋白轻链可变区包含PCM-C1D8的轻链可变区:编码CDRL1的核酸序列SEQ ID NO:16;编码CDRL2的核酸序列SEQ ID NO:17;编码CDRL3的核酸序列SEQID NO:18。另一方面,免疫球蛋白重链可变区或(和)轻链可变区进一步添加编码细胞毒性蛋白并能与免疫球蛋白重链可变区或(和)轻链可变区形成融合蛋白的核酸序列。
本发明的另一个使用方案,包括产生免疫球蛋白重链可变区或免疫球蛋白轻链可变区多肽的方法,该方法包括:(a)培养宿主细胞,使之同时表达免疫球蛋白重链可变区或(和)轻链可变区以及编码细胞毒性蛋白的核酸序列,并在适当条件下使之形成融合蛋白,得到免疫球蛋白重链可变区或轻链可变区融合细胞毒性蛋白的多肽;(b)纯化包含免疫球蛋白重链可变区或免疫球蛋白轻链可变区的多肽。
本发明的另一个使用方案,包括纯化靶向人MET和RON受体结构域的双特异性抗体,该方法包括:(a)培养宿主细胞,使之同时表达免疫球蛋白重链可变区或(和)轻链可变区以及编码细胞毒性蛋白的核酸序列,并使两者形成融合蛋白,使得宿主细胞表达包含免疫球蛋白重链可变区和免疫球蛋白轻链可变区的多肽,从而产生抗体或抗体的抗原结合片段;(b)纯化抗体或抗体的抗原结合片段。
PCMdt-MMAE靶向递送MMAE在体外杀伤癌细胞和体内清除异种移植肿瘤中的疗效:证明PCMdt-MMAE在体内的高效的癌症治疗作用。
针对MET和RON受体产生的双特异性抗体,强烈诱导MET和RON内化:用抗MET抗体PCM-C1D8和抗RON抗体PCM-5B14产生的双特异性抗体,对其命名为PCMbs-MR,其能够强烈诱导癌细胞MET和RON蛋白的內吞。
双特异性抗体PCMbs-MR与药物偶联形成抗体-药物偶联物(ADC)的制备:对双特异性抗体PCMbs-MR进行药物偶联,偶联的药物包括多柔比星,美登素生物碱衍生物(DM1),单甲基奥瑞他汀E(MMAE)和多卡米星等化疗药物。将PCMbs-MR与MMAE偶联形成的ADC产物(PCMdt-MMAE),作为进一步研究的首选药物。
PCMdt-MMAE在体外杀伤癌细胞和体内清除异种移植瘤的治疗效果:使用乳腺癌、结肠癌、肺癌和胰腺癌等人类肿瘤细胞系,证实了PCMdt-MMAE在体外有效杀伤癌细胞的作用。通过人乳腺、结肠、肺和胰腺癌细胞系的异种移植瘤模型,验证了PCMdt-MMAE在体内的高效抗癌治疗作用。
本申请提供的特异性识别MET和/或RON结构域的抗MET和/或RON单克隆抗体的产生,为使用PCMdt-MMAE诱导肿瘤细胞MET和/或RON内吞导致靶向给药,提供了新型的药理基础。
附图说明
图1:抗MET和抗RON单克隆抗体制备流程及抗体示意图。
图2:显示了人源化的抗RON单克隆抗体PCM5B14和人源化的抗MET单克隆抗体PCM-C1D8示意图以及PCM5B14和PCM-C1D8组装成抗MET和RON双特异性抗体示意图。
图3:显示了抗MET和RON双特异性抗体PCMbs-MR与MET和RON不同表达情况的肿瘤细胞系的结合谱。
图4:显示了以HT-29为例抗MET和RON双特异性抗体PCMbs-MR在肿瘤细胞中的结合亲和力。
图5:显示了双特异性抗体PCMd-T02诱导肿瘤细胞表面MET和RON内吞效应。
图6:显示了双特异性抗体PCMd-T02与小分子药物MMAE偶联形成抗体药物偶联物(ADC)PCMdt-MMAE示意图。
图7:显示了PCMdt-MMAE在有或无移植瘤小鼠体内的药代动力学特征。
图8:显示了双靶向抗体药物偶联物PCMdt-MMAE对不同类型人癌细胞的体外杀伤作用。
图9:显示了双靶向抗体药物偶联物PCMdt-MMAE对不同类型癌细胞引起的小鼠移植瘤模型的治疗作用。
具体实施方式
本发明的详细说明
虽然下面详细讨论了本发明的各种使用方案的制订和使用,应当理解本发明提供了许多可以在各种具体环境中实施可应用的发明。这里讨论的具体实施案例仅是说明制造和使用本发明的具体方式,并不拓展本发明的范围。
为了便于理解本发明,下面定义了许多术语。本文定义术语的含义与本发明相关领域的熟练技术人员通常理解的含义一致。诸如“一个”之类的术语并非指在仅指单个实体,而是包括可用于说明特定示例的一般类别。本文中的术语用于描述具体使用方案,但是除了权利要求中所概述的之外,它们的使用不限制本发明。
本发明人开发了许多靶向MET和RON受体结构域的双特异性抗体,其在临床前模型中显示出生物学作用和肿瘤治疗效果。识别MET和RON受体结构域的双特异性抗体与化学药物偶联后,能高效地向肿瘤细胞递送细胞毒性药物,并靶向杀死癌细胞。
本文公开的抗MET和RON双特异性抗体用于治疗各种形式的癌症,例如非小细胞肺癌,乳腺癌,卵巢癌,前列腺癌,宫颈癌,结肠直肠癌,肺癌,胰腺癌,胃癌和头颈癌。将癌细胞暴露于有效治疗剂量的抗体中可以抑制或减少癌细胞的增殖。在一些使用方案,抗体抑制癌细胞增殖能力可达到40%、50%、60%、70%、80%、90%、95%、98%、99%或100%。
相对于核苷酸而言,术语“基本上如SEQ ID NO:(#)”中所述的序列,“与……类似的序列”,“核苷酸序列”和相似的术语是指基本上对应于本文中定义为SEQ ID NO:1的任何部分的序列。这些术语是指合成以及天然衍生的分子,并且具有生物学、免疫学、实验或其他功能上活性相同的序列,例如关于核酸片段的杂交,或编码全部或部分RONPSI抗体的能力。当然,这些术语旨在凸显其序列中的线性次序。
术语“同源性”是指两个核酸互补的程度。同源性分为部分同源与完全同源。部分互补序列是能部分地抑制完全互补序列与靶核酸杂交的序列,并且使用功能性术语“基本上同源”来指代。如本领域技术人员所知的,可以使用杂交或其他测定方法(例如竞争性PCR测定)来测定,当低同源性时也能特异性地测定杂交的程度。
与SEQ ID NO:#的抗MET抗体、抗RON抗体以及抗MET和RON双特异性抗体“基本上同源”的寡核苷酸序列,在本文中定义为当序列超过100bp时表现出与SEQ ID NO:#寡核苷酸序列有大于或等于75%,80%,85%,90%,91%,92%,93%,94%,95%,96%,97%,98%,99%或100%的同源性。通常,保守氨基酸取代将用于修饰所列百分比内的序列。保守氨基酸取代在本领域中是众所周知的。
术语“基因”指编码功能性蛋白质,多肽或寡肽的单位。如本领域所知的,该功能性术语至少包括部分基因组序列,cDNA序列或其片段或组合,以及基因产物,包括可能已被人工改变的基因产物。纯化的基因,核酸,蛋白质等用于指与至少一种通常与其相关的污染核酸或蛋白质分离后的产物。
术语“载体”是指将DNA片段从一个细胞转移到另一个细胞的核酸分子中。载体可以进一步分为设计用于复制特定序列载体,或者作为可与特定序列结合的启动子的表达载体,或者设计为用于引导这种启动子入核的载体。载体可以以独立于宿主细胞染色体的状态存在,或者可以整合到宿主细胞染色体中。
术语“宿主细胞”,“重组细胞”或“重组宿主”是指无论是原核或真核细胞,经过基因工程改造含有外源核酸片段或被修改片段的细胞。因此,基因工程细胞或重组细胞与不包含重组基因的天然细胞是不同的。
术语“融合蛋白”是指由包含至少两个基因核苷酸序列的核酸分子表达的杂合蛋白。例如,融合蛋白可包含与亲和基质结合的多肽和另一方面的多肽。
术语“抗体”包括多克隆和单克隆抗体制剂,以及包括杂合抗体、改造抗体、F(ab')2片段,F(ab)片段,Fv片段,单结构域抗体,嵌合抗体,人源化抗体制剂,及具有源抗体分子免疫结合特性的功能片段。
术语“单克隆抗体”是指具有同源抗体群的抗体组合物。该术语不限于抗体的种类或来源,也不限于其制作的方式。该术语包括完整的免疫球蛋白以及其片段,例如Fab,F(ab')2,Fv和具有源抗体分子免疫结合特性的功能片段。在本发明中,我们已经开发了许多杂交瘤,其与MET的受体结构区域具有独特的结合特性,例如,它们在MET表达细胞例如癌细胞中引发MET特异性内吞。如本文所用,杂交瘤PCM-C1D8及其产生的抗体PCM-C1D8。
制备单克隆抗体的方法是本领域已知的。合适的免疫载体通常是大的、代谢缓慢的大分子,例如蛋白质,多糖,聚乳酸,聚乙醇酸,聚合氨基酸,氨基酸共聚物,脂质聚集体(例如油滴或脂质体)和无活性的病毒颗粒。这些载体是本领域技术人员所熟知的。此外,抗原可以与细菌类毒素结合,例如来自白喉,破伤风,霍乱等的类毒素,以增强其免疫原性。
通常使用Kohler和Milstein的方法(Nature(1975)256:495-497)或其修改方法制备单克隆抗体。通常,免疫小鼠、仓鼠或大鼠。将脾脏和/或大淋巴结分离成单个细胞。然后诱导B细胞和/或分离的脾细胞与骨髓瘤细胞融合以形成杂交瘤(通常是不表达内源性抗体重链和/或轻链的细胞),并在选择性培养基中培养(例如,次黄嘌呤,氨基蝶呤,胸苷培养基,“HAT”)。通过有限稀释将得到的单克隆的杂交瘤,进而测定其产生与RON特异性结合的抗体的能力。然后在体外(例如,在组织培养瓶或中空纤维反应器中)或体内(例如,小鼠的腹水)培养筛选后的分泌单克隆抗体的杂交瘤细胞。
术语“抗体片段”是指抗体的一部分,例如F(ab')2,F(ab)2,Fab',Fab等。无论结构如何,抗体片段都能与相同的抗原结合。例如,抗RON单克隆抗体片段与RON的表位结合。
术语“抗体片段”是指能结合特定抗原的合成或基因工程多肽,例如包括轻链可变区的多肽,包括重链和轻链可变区的“Fv”片段,重组单链多肽分子,其中轻、重可变区域由肽链连接剂(“scFv蛋白”)和包括模拟高度可变区域的氨基酸残基在内的最小识别单元连接。
术语“嵌合抗体”是指含有可变结构域和源自啮齿动物抗体的互补决定区的重组蛋白,而抗体分子的其余部分源自人的抗体。
术语“人源化抗体”是指能够结合预定抗原的免疫球蛋白氨基酸序列变体或其片段,其包括基本上具有人免疫球蛋白的氨基酸序列的FR区和互补决定区(CDR)。基本上具有非人免疫球蛋白的氨基酸序列或工程化能结合预选抗原的序列。人源化抗体通常也被称为“镶嵌”抗体,其具有重链,轻链或两者的可变区中的CDR。
术语“抗体-药物偶联物”是指抗体或其抗体片段,包括能与MET和/或RON的蛋白结构域发生结合的抗体,与细胞毒性药物、细胞抑制剂和/或治疗剂偶联的抗体衍生物。术语“治疗剂”是指对癌细胞或活化的免疫细胞发挥细胞毒性、细胞抑制和/或免疫调节作用的药剂。治疗剂的非限制性实例包括细胞毒性制剂、化学治疗剂、细胞抑制剂和免疫调节剂。术语“化学治疗剂”是指可用于治疗癌症的化合物。术语“细胞毒性作用”是指使用本发明的耗竭、消除和/或杀死靶细胞。术语"细胞毒性剂"是指本发明的一种对靶细胞有细胞毒性和细胞静止效应的药剂。术语“细胞抑制作用”是指使用本发明的抑制细胞增殖。术语“细胞抑制剂”是指对细胞具有细胞抑制作用的本发明的试剂,能抑制特定细胞的生长和/或增殖。
正如本文所讨论的,考虑抗体或免疫球蛋白多肽的氨基酸序列的微小变化,例如,假设氨基酸序列中的变化保持至少75%,甚至80%,90%,95%,96%,97%,98%、99%和100%同源于重链可变域的人的框架区域。具体而言,在本发明中,如果人源化抗体与人可变结构域和恒定结构域的非CDR部分保持至少95%,96%,97%,98%,99%或100%的同源性,则人源化抗体被认为是完全人源化的。
氨基酸序列中的某些变化被认为是保守的氨基酸替代。保守替代是具有相似侧链的氨基酸之间的取代。氨基酸一般分为以下几类:(1)非极性:丙氨酸,缬氨酸,亮氨酸,异亮氨酸,脯氨酸,苯丙氨酸,蛋氨酸,色氨酸;(2)酸性:天冬氨酸,谷氨酸;(3)碱性:赖氨酸,精氨酸,组氨酸;(4)极性:赖氨酸,天冬酰胺,谷氨酰胺,半胱氨酸,丝氨酸,苏氨酸,酪氨酸。其他氨基酸家族包括:丝氨酸和苏氨酸是脂族-羟基家族;天冬酰胺和谷氨酰胺是一种含酰胺的家族;丙氨酸,缬氨酸,亮氨酸和异亮氨酸是脂肪族;苯丙氨酸,色氨酸和酪氨酸是一个芳香族。因此,可以合理地预期用异亮氨酸或缬氨酸单独替换亮氨酸,用谷氨酸取代天冬氨酸,用丝氨酸取代苏氨酸,或用结构相关氨基酸取代氨基酸将不具有对所得分子的结合或性质的主要影响,特别是如果置换不涉及框架区内的氨基酸。
通过测定多肽衍生物的比活性,可以容易地确定氨基酸变化是否导致功能性肽。本领域普通技术人员可以容易地制备抗体或免疫球蛋白分子的片段或类似物,包括在氨基和羧基末端的取代,包括用例如细胞毒性蛋白制备融合蛋白。还可以通过比较核苷酸和/或氨基酸序列数据(如本文所示)和/或序列数据库来鉴定结构域和功能域。计算机化的比较方法可用于鉴定在已知结构和/或功能的其他蛋白质中发生的序列基序或预测的蛋白质构象结构域。通常,保守氨基酸替代不会实质性的改变亲本序列的结构特征(例如,替代氨基酸不应倾向于破坏发生在亲本序列中的螺旋,或破坏其他类型的表示亲本序列的辅助结构)。
术语“细胞”和“细胞培养物”可互换使用,指大多数但不总是在单细胞悬浮液中或附着于板或组织的细胞,并包括它们的后代。术语“转化物”和“转化细胞”包括主要受试细胞和由其衍生的培养物,而不考虑转化的数量。此外,由于有意或无意的突变,所有后代的DNA含量可能不完全相同。包括具有与最初转化的细胞中筛选的相同功能或生物活性的突变后代。
术语“蛋白质”,“多肽”或“肽”是指包含通过肽键连接的氨基酸的化合物,并且可互换使用。
术语“内源性”是指其来源来自细胞内的物质。内源性物质是由细胞的代谢活动产生的。然而,内源性物质可能由于操纵细胞代谢而产生,例如,使细胞表达编码该物质的基因。
术语“外源性”是指其来源于细胞外部的物质。然而,外源物质可以通过本领域技术人员用已知的多种代谢或诱导手段中的任何一种方法而被细胞内化。
术语“基因”用于指功能性蛋白质,多肽或肽的编码单元。如本领域技术人员所理解的,该功能性术语包括基因组序列,cDNA序列或其片段或组合,以及基因产物,包括可能已被人工改变的基因产物。纯化的基因,核酸,蛋白质及类似物,在从通常与其相关的至少一种污染核酸或蛋白质中识别和分离时,用于指鉴这些实体。如本文所用的术语“序列”用于指核苷酸或氨基酸,无论是天然的还是人工的,例如修饰过的核酸或氨基酸。当描述“转录的核酸”时,那些位于编码区附近的序列区域5'和3'末端使得脱氧核糖核苷酸序列对应于所包括的蛋白质的全长mRNA的长度。术语“基因”包括基因的cDNA和基因组形式。基因可以产生多种RNA种类,其通过初级RNA转录物的差异剪接产生。作为同一基因的剪切体的cDNAs将包含序列同一性或完全同源性的区域(代表两个cDNA上相同外显子或相同外显子部分的存在)和完全非同一性的区域(例如,表示cDNA I上存在外显子"A",其中cDNA 2包含外显子"B")。因为这两个cDNA含有序列一致的区域,它们都将与从整个基因或含有两个cDNAs序列的部分基因中获得的探针杂交。因此,两种剪切体与这种探针基本上是同源的。
术语“载体”用于指将DNA片段从一个细胞转移到另一个细胞的核酸分子。本文所用的术语“载体”还包括表达载体,其涉及含有所需编码序列的重组DNA分子和在特定宿主生物中表达编码序列所必需的其他适当核酸序列。在原核生物中表达所必需的核酸序列通常包括启动子,操纵子(任选)和核糖体结合位点,通常与其他序列一起。已知真核细胞可利用启动子,增强子、终止和多聚腺核苷酸信号。
术语“药学上可接受”是指适合人和/或动物使用而没有与合理的益处/风险比相称的过度不良副作用(例如毒性,刺激和过敏反应)的组分。
术语“安全有效量”是指足以产生所需治疗反应的组分的量,而没有与使用时合理的益处/风险比相称的过度不良副作用(例如毒性,刺激或过敏反应)。“治疗有效量”是指有效产生所需治疗反应的本发明的药物的量。例如,有效延迟癌症或肉瘤或淋巴瘤的生长或导致癌症缩小或不转移的药物量。具体的安全有效量或治疗有效量将随着所治疗的具体病症、患者的身体状况、所治疗的哺乳动物类型、治疗的持续时间、并发症治疗的性质(如果有的话),以及所用的具体配方和化合物或其衍生物的结构等因素而变化。
术语“药用盐”是指用于制备化合物的酸或碱盐。药学上可接受的盐的例子包括但不限于矿物或有机酸盐的基本残留物,如胺;酸性残留物(如酚类)的碱盐或有机盐。最好是用有机或无机酸制成的盐。这些首选的酸性盐是氯化物溴、硫酸盐、硝酸盐、磷酸盐、磺酸盐、甲酸酯、马来酸盐、马来酸盐、柠檬酸、苯甲酸盐、盐酸盐、抗坏血酸等。首选的酚类盐是碱土金属盐、钠、钾或锂。
术语“药物载体”是指药学上可接受的溶剂,悬浮剂或载体,用于将抗MET和/或RON抗体,及其片段和/或抗体-药物偶联物(ADC),化合物递送至动物或人体内。载体可以是液体或固体,并按照计划的给药方式进行选择。蛋白和脂质体也是药物载体。
术语“癌症”是指在人和哺乳动物中发现的所有类型的癌症或恶性肿瘤,包括表达RON的癌和肉瘤。癌症比如脑癌,乳腺癌,子宫颈癌,胰腺癌,皮肤癌,前列腺癌,肝癌,膀胱癌,结肠癌,头颈癌,肾癌,肺癌,非小细胞肺癌,黑色素瘤,间皮瘤,卵巢癌,肉瘤,胃癌,子宫癌和髓母细胞瘤等。
特异性识别MET的单克隆抗体的产生:以MET蛋白用作小鼠免疫的免疫原。筛选识别MET受体结构域并且能够诱导癌细胞实施强烈的MET蛋白内吞作用的杂交瘤细胞和其产生的单克隆抗体。选择命名为PCM-C1D8的杂交瘤和其产生的抗体作为主要候选物。图1显示了识别MET的特异性单克隆抗体(MAB)的产生。
PCM-C1D8的人源化的产生:将人源化设计合成的包含来自PCM-C1D8的5条重链和5条轻链的互补决定区(CDR)序列,分别移植到人IgG1/k的框架中进行抗体人源化改造,以产生25种不同的人源化IgG1/k分子。分析各个人源化PCM-C1D8的特异性、灵敏度和亲和力。最终选择人源化PCM-C1D8为主要研发的抗体。
特异性识别RON的单克隆抗体的产生:以RON蛋白用作小鼠免疫的免疫原。筛选识别RON受体结构域并且能够诱导癌细胞实施强烈的RON蛋白内吞作用的杂交瘤细胞和其产生的单克隆抗体。选择命名为PCM-5B14的杂交瘤和其产生的抗体作为主要候选物。图1显示了识别RON的特异性单克隆抗体(MAB)的产生。
PCM-5B14的人源化的产生:将人源化设计合成的包含来自PCM-5B14的5条重链和5条轻链的互补决定区(CDR)序列,分别移植到人IgG1/k的框架中进行抗体人源化改造,以产生25种不同的人源化IgG1/k分子。分析各个人源化PCM5B14的特异性、灵敏度和亲和力。最终选择人源化PCM-5B14为主要研发的抗体。
抗MET和RON的双特异性抗体的产生:对抗MET和抗RON双特异性抗体进行改造主要包括:抗RON抗体片段,及氨基酸序列中393号氨基酸T突变为W;抗MET抗体片段,氨基酸序列中440号氨基酸Y突变为V,同时重链可变区中CH1与轻链可变区CL发生交换。合成后的双抗体即为PCMbs-MR。
PCMbs-MR诱导癌细胞表面MET和/或RON内吞中作用的实验证据:使用来自人乳腺癌,结肠癌,肺癌和胰腺癌等15种具有不同MET和/或RON表达水平的癌细胞系,分析PCMbs-MR诱导癌细胞表面MET和/或RON内吞的有效性。确认PCMbs-MR具有强烈诱导MET和/或RON内吞作用的代表性结果见图3。该结果证实PCMbs-MR在诱导RON和MET内吞作用方面非常有效,能够递送足够量的用于杀伤癌细胞的细胞毒性药物。
PCMbs-MR与多种细胞毒性药物偶联形成抗体-药物偶联物(ADC)和其偶联效应:选择人源化的PCMbs-MR用于药物偶联。使用的化学治疗剂包括阿霉素,美登素生物碱衍生物(DM1),单甲基奥瑞他汀E(MMAE)和多卡米星。最终选择与PCMbs-MR与MMAE偶联的产物即双特异性抗体PCMdt-MMAE作为用于进一步研究的ADC模型(图4)。如图4所示,PCMdt-MMAE通过人源化的PCMbs-MR与MMAE通过蛋白酶敏感性二肽接头以4:1的药物浓度与抗体比(DAR)偶联而成。形成的PCMdt-MMAE通过使用疏水相互作用色谱法,分析PCMdt与MMAE的偶联比例分配。图5的结果显示达到抗体分子与MMAE一比四的偶联比例分配,符合抗体药物一比四的比例.
PCMdt-MMAE在动物实验中的最大耐受剂量:将不同剂量的PCMdt-MMAE分别注射于小鼠体内,观察动物的体重和其他变化。图6的结果显示,PCMdt-MMAE在小鼠体内的最大耐受剂量为每公斤体重60毫克。远远高于正常的肿瘤治疗剂量。
PCMdt-MMAE靶向递送MMAE在体外杀伤癌细胞和体内清除异种移植肿瘤中的疗效:采用乳腺癌、结肠癌、肺癌和胰腺癌等多种人类癌细胞系,在体外实验中证实了PCMdt-MMAE对癌细胞的杀死作用(图7)。半数有效致死剂量为每毫升1-3微克。此外,通过人的乳腺、结肠、肺和胰腺癌细胞系的异种移植肿瘤模型,验证了PCMdt-MMAE在体内的高效的癌症治疗作用(图8和图9)。
针对MET和RON受体产生的双特异性抗体,强烈诱导MET和RON内化:用抗MET抗体PCM-C1D8和抗RON抗体PCM-5B14产生的双特异性抗体,对其命名为PCMbs-MR,其能够强烈诱导癌细胞MET和RON蛋白的內吞。
双特异性抗体PCMbs-MR与药物偶联形成抗体-药物偶联物(ADC)的制备:对双特异性抗体PCMbs-MR进行药物偶联,偶联的药物包括多柔比星,美登素生物碱衍生物(DM1),单甲基奥瑞他汀E(MMAE)和多卡米星等化疗药物。将PCMbs-MR与MMAE偶联形成的ADC产物(PCMdt-MMAE),作为进一步研究的首选药物。
PCMdt-MMAE在体外杀伤癌细胞和体内清除异种移植瘤的治疗效果:使用乳腺癌、结肠癌、肺癌和胰腺癌等人类肿瘤细胞系,证实了PCMdt-MMAE在体外有效杀伤癌细胞的作用。通过人乳腺、结肠、肺和胰腺癌细胞系的异种移植瘤模型,验证了PCMdt-MMAE在体内的高效抗癌治疗作用。
上述研究的结果表明:特异性识别MET和/或RON结构域的抗MET和/或RON单克隆抗体的产生,为使用PCMdt-MMAE诱导肿瘤细胞MET和/或RON内吞导致靶向给药,提供了新型的药理基础。
DNA序列:
CDRs from PCM-C1D8 VH(重链可变区):
CDR1:AACTTTGGTATACAC(15nt)SEQ ID NO:1
CDR2:GTGATATGGGGTGATGGAATCACAACCTATAATTCAGTTCTCAAATCC(48nt)SEQ ID NO:2
CDR3:TCTTATTTTTTGGGAGCTATGGTCTAC(27nt)SEQ ID NO:3
CDRs from PCM-C1D8 VL(轻链可变区):
CDR1:AAGGCCAGTCAGAGTGTGGGTACTGCTGTAGCC(33nt)SEQ ID NO:4
CDR2:TCGGCATCCACCCGGTACACT(21nt)SEQ ID NO:5
CDR3:CAACAATATAGCACTTCTCGGACG(24nt)SEQ ID NO:6
氨基酸序列:
CDRs from PCM5B14 VH(重链可变区):
CDR1:NFGIH(5aa)SEQ ID NO:7
CDR2:VIWGDGITTYNSVLKS(16aa)SEQ ID NO:8
CDR3:SYFLGAMVY(9aa)SEQ ID NO:9
CDRs from PCM5B14 VL(轻链可变区):
CDR1:KASQSVGTAVA(11aa)SEQ ID NO:10
CDR2:SASTRYT(7aa)SEQ ID NO:11
CDR3:QQYSTSRT(8aa)SEQ ID NO:12
DNA序列:
CDRs from PCM5B14 VH(重链可变区):
CDR1:GGCTACACCTTCACAGACTATCACATGGAT(30nt)SEQ ID NO:13
CDR2:GACATCAACCCAAACAATGGCGGCGCCATCTACAATCAGAAGTTTAAGGGC(51nt)SEQ IDNO:14
CDR3:TCTCACTACGATTATGCTGGAGGAGCTTGGTTCGCTTAC(39nt)SEQ ID NO:15
CDRs from PCM5B14 VL(轻链可变区):
CDR1:AAGAGCTCCCAGAGCCTGCTGTTCTCCGGCAACCAGAAGAATTACCTGGCT(51nt)SEQ IDNO:16
CDR2:TGGGCTTCTACCAGAGCTAGC(21nt)SEQ ID NO:17
CDR3:CAGCAGTACTATAGCTTCCCAAGAACC(27nt)SEQ ID NO:18
氨基酸序列:
CDRs from PCM5B14 VH(重链可变区):
CDR1:GYTFTDYHMD(10aa)SEQ ID NO:19
CDR2:DINPNNGGAIYNQKFKG(17aa)SEQ ID NO:20
CDR3:SHYDYAGGAWFAY(13aa)SEQ ID NO:21
CDRs from PCM5B14 VL(轻链可变区):
CDR1:KSSQSLLFSGNQKNYLA(17aa)SEQ ID NO:22
CDR2:WASTRAS(7aa)SEQ ID NO:23
CDR3:QQYYSFPRT(9aa)SEQ ID NO:24
PCM-C1D8重链可变区全长DNA序列SEQ ID NO:25:依次为Kozak—Leadingpeptide—VH(FR1-CDR1-FR2-CDR2-FR3-CDR3-FR4)-CHs(CH1-CH2-CH3)-Stop code
Kozak
GCCGCCACCATGGGTTGGTCATGTATTATTCTGTTTCTGGTGGCTACTGCTACCGGCGTGCATTCC
VH
CAGGTGCAGCTGGTCCAGTCTGGGGCTGAAGTGAAGAAGCCCGGCGCCACCGTGAAGATCAGCTGCAAGGTGTCCAACTTTGGTATACACTGGGTGCAGCAGGCTCCTGGCAAGGGCCTCGAGTGGATGGGCGTGATATGGGGTGATGGAATCACAACCTATAATTCAGTTCTCAAATCCCGGGTGACCATCACAGCTGACACCTCTACAGATACCGCCTATATGGAGCTGAGCTCCCTGAGATCCGAGGACACAGCCGTGTACTATTGCGCCCGGTCTTATTTTTTGGGAGCTATGGTCTACTGGGGACAGGGCACACTGGTGACCGTGAGCCGG(112aa)
CH1
GCTTCCACCAAGGGCCCTAGCGTGTTTCCACTGGCCCCCTCTTCCAAGTCTACAAGCGGAGGAACCGCCGCTCTGGGATGTCTGGTGAAGGATTACTTCCCAGAGCCCGTGACCGTGTCTTGGAACAGCGGCGCTCTGACAAGCGGCGTGCACACATTTCCTGCCGTGCTGCAGTCCTCTGGCCTGTACTCCCTGAGCTCCGTGGTGACAGTGCCATCTAGCTCCCTGGGCACACAGACCTATATCTGCAACGTGAATCACAAGCCAAGCAATACCAAGGTGGACAAGAAGGTG(98aa)
PCM-C1D8轻链可变区全长DNA序列SEQ ID NO:26:Kozak—leading peptide—VL(FR1-CDR1-FR2-CDR2-FR3-CDR3-FR4)—CL—Stop code
Kozak
GCCGCCACCATGGGCTGGTCATGTATTATTCTGTTTCTGGTCGCAACTGCTACTGGGGTGCATAGC
VL:
GAAATCGTGATGACTCAGTCTCCCGGAACCCTGTCCCTGTCTCCAGGCGAGCGGGCCACCCTGTCCTGCAAGGCCAGTCAGAGTGTGGGTACTGCTGTAGCCTGGTATCAGCAGAAGCCAGGCCAGGCTCCCAGGCTGCTGATCTACTCGGCATCCACCCGGTACACTGGCATCCCCGACAGGTTCAGCGGCTCCGGCTCTGGCACAGACTTCACCCTGACAATCTCTAGACTGGAGCCTGAGGACTTCGCCGTGTACTATTGCCAACAATATAGCACTTCTCGGACGTTTGGCCAGGGCACAAAGCTGGAGATCAAG(106aa)
CL:
CGGACCGTGGCCGCTCCCAGCGTGTTCATCTTTCCCCCTTCCGACGAGCAGCTGAAGTCCGGCACAGCTTCTGTGGTGTGCCTGCTGAACAACTTCTACCCCAGGGAGGCCAAGGTCCAGTGGAAGGTGGATAACGCTCTGCAGAGCGGCAATTCCCAGGAGTCTGTGACCGAGCAGGACAGCAAGGATTCCACATATTCTCTGTCTAGCACCCTGACACTGTCTAAGGCCGATTACGAGAAGCACAAGGTGTATGCTTGTGAAGTCACCCACCAGGGTCTGTCATCACCCGTCACTAAGTCTTTTAACCGAGGCGAATGCTGA(107aa)
PCM-C1D8重链可变区全长氨基酸序列SEQ ID NO:27:
AATMGWSCIILFLVATATGVHSQVQLVQSGAEVKKPGATVKISCKVSNFGIHWVQQAPGKGLEWMGVIWGDGITTYNSVLKSRVTITADTSTDTAYMELSSLRSEDT AVYYCARSYFLGAMVYWGQGTLVTVSR
PCM-C1D8轻链可变区全长氨基酸序列SEQ ID NO:28:
AATMGWSCIILFLVATATGVHSEIVMTQSPGTLSLSPGERATLSCKASQSVGTAVAWYQQKPGQAPRLLIYSASTRYTGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQQYSTSRTFGQGTKLEIK
PCM5B14重链可变区全长DNA序列SEQ ID NO:29:依次为Kozak—Leadingpeptide—VH(FR1-CDR1-FR2-CDR2-FR3-CDR3-FR4)-CHs(CH1-CH2-CH3)-Stop code
Kozak—Leading peptide—VH(FR1-CDR1-FR2-CDR2-FR3-CDR3-FR4)-CHs(CH1-CH2-CH3)-Stop code
Kozak
GCCGCCACCATGGGTTGGTCATGTATTATTCTGTTTCTGGTGGCTACTGCTACCGGCGTGCATTCC
VH
CAGGTGCAGCTGGTCCAGTCTGGGGCTGAAGTGAAGAAGCCCGGCGCCACCGTGAAGATCAGCTGCAAGGTGTCCGGCTACACCTTCACAGACTATCACATGGATTGGGTGCAGCAGGCTCCTGGCAAGGGCCTCGAGTGGATGGGCGACATCAACCCAAACAATGGCGGCGCCATCTACAATCAGAAGTTTAAGGGCCGGGTGACCATCACAGCTGACACCTCTACAGATACCGCCTATATGGAGCTGAGCTCCCTGAGATCCGAGGACACAGCCGTGTACTATTGCGCCCGGTCTCACTACGATTATGCTGGAGGAGCTTGGTTCGCTTACTGGGGACAGGGCACACTGGTGACCGTGAGCCGG(122aa)
CH1
GCTTCCACCAAGGGCCCTAGCGTGTTTCCACTGGCCCCCTCTTCCAAGTCTACAAGCGGAGGAACCGCCGCTCTGGGATGTCTGGTGAAGGATTACTTCCCAGAGCCCGTGACCGTGTCTTGGAACAGCGGCGCTCTGACAAGCGGCGTGCACACATTTCCTGCCGTGCTGCAGTCCTCTGGCCTGTACTCCCTGAGCTCCGTGGTGACAGTGCCATCTAGCTCCCTGGGCACACAGACCTATATCTGCAACGTGAATCACAAGCCAAGCAATACCAAGGTGGACAAGAAGGTG(98aa)
PCM5B14轻链可变区全长DNA序列SEQ ID NO:30:Kozak—leading peptide—VL(FR1-CDR1-FR2-CDR2-FR3-CDR3-FR4)—CL—Stop code
Kozak
GCCGCCACCATGGGCTGGTCATGTATTATTCTGTTTCTGGTCGCAACTGCTACTGGGGTGCATAGC
VL:
GAAATCGTGATGACTCAGTCTCCCGGAACCCTGTCCCTGTCTCCAGGCGAGCGGGCCACCCTGTCCTGCAAGAGCTCCCAGAGCCTGCTGTTCTCCGGCAACCAGAAGAATTACCTGGCTTGGTATCAGCAGAAGCCAGGCCAGGCTCCCAGGCTGCTGATCTACTGGGCTTCTACCAGAGCTAGCGGCATCCCCGACAGGTTCAGCGGCTCCGGCTCTGGCACAGACTTCACCCTGACAATCTCTAGACTGGAGCCTGAGGACTTCGCCGTGTACTATTGCCAGCAGTACTATAGCTTCCCAAGAACCTTTGGCCAGGGCACAAAGCTGGAGATCAAG
CL:
CGGACCGTGGCCGCTCCCAGCGTGTTCATCTTTCCCCCTTCCGACGAGCAGCTGAAGTCCGGCACAGCTTCTGTGGTGTGCCTGCTGAACAACTTCTACCCCAGGGAGGCCAAGGTCCAGTGGAAGGTGGATAACGCTCTGCAGAGCGGCAATTCCCAGGAGTCTGTGACCGAGCAGGACAGCAAGGATTCCACATATTCTCTGTCTAGCACCCTGACACTGTCTAAGGCCGATTACGAGAAGCACAAGGTGTATGCTTGTGAAGTCACCCACCAGGGTCTGTCATCACCCGTCACTAAGTCTTTTAACCGAGGCGAATGCTGA(107aa)
PCM5B14重链可变区全长氨基酸序列SEQ ID NO:31:
AATMGWSCIILFLVATATGVHSQVQLVQSGAEVKKPGATVKISCKVSGYTFTDYHMDWVQQAPGKGLEWMGDINPNNGGAIYNQKFKGRVTITADTSTDTAYMELSSLRSEDTAVYYCARSHYDYAGGAWFAYWGQGTLVTVSR
PCM5B14轻链可变区全长氨基酸序列SEQ ID NO:32:
AATMGWSCIILFLVATATGVHSEIVMTQSPGTLSLSPGERATLSCKSSQSLLFSGNQKNYLAWYQQKPGQAPRLLIYWASTRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQQYYSFPRTFGQGTKLEIK
图1抗MET和抗RON单克隆抗体制备流程及抗体示意图。以MET或RON的蛋白用作小鼠免疫的免疫原,取免疫后的小鼠脾细胞与小鼠骨髓瘤细胞SP2/0融合,筛选识别MET或RON受体结构域并且能够诱导癌细胞MET或RON蛋白内吞作用的杂交瘤细胞和其产生的单克隆抗体,之后保留抗体结构中重链可变区和轻链可变区的CDR,对其抗体骨架进行人源化序列替换,对抗MET和抗RON的人源化抗体分别命名为PCM-C1D8和PCM-5B14。
图2:显示了人源化的抗RON单克隆抗体PCM5B14和人源化的抗MET单克隆抗体PCM-C1D8示意图以及PCM5B14和PCM-C1D8组装成抗MET和RON双特异性抗体PCMbs-MR的示意图;对抗MET和抗RON双特异性抗体PCMbs-MR进行改造主要包括:抗RON抗体片段,及氨基酸序列中393号氨基酸T突变为W;抗MET抗体片段,氨基酸序列中440号氨基酸Y突变为V,同时重链可变区中CH1与轻链可变区CL发生交换。合成后的双抗体即为PCMbs-MR。
图3显示了抗MET和抗RON双特异性抗体PCMbs-MR与MET和RON表达情况不同的肿瘤细胞的结合谱。PCMbs-MR可以与MET和/或RON阳性的肿瘤细胞表面的MET和RON相互作用。
图4以MET和RON均阳性的结肠癌HT29细胞系用作测试模型发现双特异性抗体PCMbs-MR与这两个受体的综合亲和力Kd为0.84μg/ml。
图5测试了PCMbs-MR诱导细胞表面MET和/或RON的内吞效应。测试了MET和/或RON不同表达的单个细胞系T47-D、HCC1937、HCC2185、MDA-MB-486、MDA-MB-231、SUM52PE和HCC1806,其中以MET和RON均阴性的HCC1806位阴性对照,PCMbs-MR诱导细胞表面50%受体内吞(IE50)所需的时间为10.25h至22.86h。将细胞与5ug/ml的PCMbs-MR一起温育不同时间,在通过酸性缓冲液除去细胞表面结合的抗体后,通过FITC标记的山羊抗小鼠IgG1抗体和抗MET和抗RON抗体检测细胞表面剩余的RON分子。使用BD流式细胞仪分析来自各个样品的免疫荧光强度。将细胞表面RON减少50%所需的最短时间(小时)定义为EC50。
图6为抗MET和抗RON双特异性抗体PCMbs-MR通过蛋白酶敏感的二肽接头与MMAE按照1:4均匀标记合成抗体-药物偶联物(ADC)即PCMdt-MMAE。MMAE是一种高效的微管蛋白抑制剂,可阻断细胞有丝分裂导致细胞死亡。
图7为药物偶联物对小鼠体重和存活的毒理学作用。即PCMdt-MMAE在小鼠体内的药代动力学特征和毒性活性分析。在有或无BxPC-3肿瘤细胞介导的异种移植肿瘤的雌性Balb/c小鼠用作模型。所有小鼠均通过尾静脉注射10mg/kg PCMdt-MMAE。测量小鼠个体体重,以获得各组小鼠的平均体重。注射前小鼠体重(18-20g/只)设为100%。每天监测小鼠日常活动、体重和死亡情况。通过使用MMAE-ADC酶联免疫反应(ELISA)试剂盒,确定血浆中MMAE共轭PCMbs-MR的含量。研究结果表明,PCMdt-MMAE在治疗剂量下对受试小鼠没有毒性。此外,受试小鼠对60mg/kg的H5B14-MMAE具有良好的耐受性。
图8为PCMdt-MMAE体外对不同类型人癌细胞系的细胞毒性作用,包括结肠癌、乳腺癌和胰腺癌在内的8个人类癌细胞系。以不表达RON的癌细胞系作对照。同时,与鼠源的抗MET ADC即PCM-C1D8-MMAE和抗RON ADC即Zt/g4-MMAE进行比较。用不同剂量的PCMdt-MMAE处理癌细胞72小时,细胞存活率采用标准的MTS法测定。这些研究结果表明PCMdt-MMAE对表达MET和/或RON的癌细胞具有高度特异性,杀死50%的癌细胞(IC50)所需要的PCMdt-MMAE的最小量在1ug/ml到4ug/ml之间,这取决于不同的癌细胞系。
图9显示了PCMdt-MMAE在体内对4种小鼠移植瘤模型的治疗效果。对6周龄的雌性无胸腺裸鼠皮下注射来自各个细胞系的5×106个细胞。使用的癌细胞系是HCC1806,HT29,FG,T-47D,HCT116,BxPC-3和H358。将小鼠随机分为不同的组(每组五只小鼠)。当所有肿瘤均达到的平均肿瘤体积时开始治疗。通过小鼠尾静脉注射不同剂量的PCMdt-MMAE,PCM-C1D8-MMAE或PCM5B14-MMAE。通过按Q12 x 2时间表注射可变量的PCMdt-MMAE,在小鼠中进行剂量依赖性研究。每四天测量一次肿瘤体积。这些结果证明了PCMdt-MMAE在抑制异种移植肿瘤方面的有效性。PCMdt-MMAE平均减少了多达93%的肿瘤体积。其次,PCMdt-MMAE的抗癌活性是剂量依赖性的。1mg/kg的PCMdt-MMAE足以抑制肿瘤生长并在长达两周的时间内防止肿瘤再生长。高达7、10和15mg/kg的PCMdt-MMAE的增加可显着抑制肿瘤生长,并具有更高的治疗指数。第三,PCMdt-MMAE能够抑制多种来源的癌细胞介导的肿瘤生长,包括来自结肠,肺,胰腺和乳腺的癌细胞,而不论其转移和化学抗性状态如何。这表明PCMdt-MMAE具有广泛的抗癌活性,适用于治疗各种类型的癌症。最后,PCMdt-MMAE的作用是持久的。以单剂量注射10mg/kg时,PCMdt-MMAE抑制异种移植肿瘤的生长近四周。
可预期的是,本说明书中所讨论的任何实施方案可以通过本发明的任何方法、试剂盒、试剂或组合来实施,反之亦然。
必须明确指出的是,本文所述的具体实施方案是通过举例说明而不是限制本发明的方法来展示的。本发明的主要特征可以在不脱离本发明范围的情况下用于各种实施方案中。本领域技术人员将认识到,或者仅仅利用常规的实验即能够确定,本文所述具体步骤的许多等同物。这样的等同物被认为是在本发明的范围内,且被权利要求所涵盖。
本说明书中提到的所有出版物和专利申请反映了本发明所涉及领域的技术水平。所有的出版物和专利申请均引入本文作为参考,其引入的程度如同各个独立的出版物或专利申请与本专利的关联度。
词语“一个”或“一种”当与权利要求和/或说明书中的术语“包含”结合使用时,可以指“一种”,但其也与“一种或多种”、“至少一种”和“一种或多于一种”的意思相一致。在权利要求中所使用的术语“或者”是指“和/或”,除非明确指明仅仅是指供选择物,或供选择物为相互排斥的,尽管公开内容支持仅仅指供选择物及“和/或”的定义。在整个本申请中,术语“大约”用来说明这样的值,其包括装置和用来测定所述值的方法的误差的固有变化,或者研究受试者之间存在的变化。
如在本说明书和权利要求书中所使用的,词语“包含”(以及任何形式的“包含”),
“具有”(以及任何形式的“具有”),“包括”(以及任何形式的“包括”)或“含有”(以及任何形式的“含有”)是包括的或开放式的,且不排除额外的,未述及的元素或方法步骤。如本文所使用的,短语“大体上由..·组成”将权利要求的范围限定至指定的物质或步骤和未在实质上影响要求保护的发明的基本和新颖的特征。如本文所使用的,短语“由...组成”不包括在权利要求中指定的任何元素、步骤或者成分,除了例如通常与元素或限制有关的干扰。
本文所使用的术语“或其组合”是指在该术语之前所列举项目的全部排列和组合。例如,“A、B、C或其组合”意在包括A、B、C、AB、AC、BC或ABC中的至少一种,并且如果在特定的上下文中顺序是重要的,那么还包括BA、CA、CB、CBA、BCA、ACB、BAC或CAB。继续这个例子,明显包括的是包含一种或多种项目或术语的重复的组合,如BB、AAA、AB、BBC、AAABCC CC、CBBAAA,CABABB等等。本领域技术人员将理解的是,通常对任何组合中的项目或术语的数目没有限制,除非从上下文中有明显的显示。
如本文所使用的,表示近似的词语如但不限于“约”、“基本的”或者“基本上”指这样的情况,当这样修饰时理解为并非必须是绝对的或者精确的,而应认为是足够地接近本领域技术人员认为与当前的情况一样可以使用的情况。说明书可以变化的程度取决于进行多大的变化之后,仍然使得本领域技术人员认为经改变的特征仍然具有所需的性质和未经改变的特征所具有的能力。总地来说,与前面的讨论一致地,使用表示近似的词语如“约”修饰的数值可以从所宣称的数值变化至少±1、2、3、4、5、6、7、10、12或者15%。
根据本发明的公开内容,在适当的实验下可以制备和实施本文所公开和要求保护的全部组合物和/或方法。尽管已就优选的实施方案描述了本发明的组合物和方法,但是对于本领域技术人员来说明显的是,在不脱离本发明的构思、精神和范围的情况下,可以改变本文所述的组合物和/或方法以及方法的步骤或方法的步骤的顺序。所有这样相似的对本领域技术人员而言明显的取代和修饰被认为是在所附的权利要求所限定的本发明的精神、范围和构思内。
序列表
<110> 美国德州精准药靶有限公司
<120> 抗MET和RON双特异性抗体及其抗体-药物偶联物的制备和应用
<160> 32
<170> SIPOSequenceListing 1.0
<210> 1
<211> 15
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 1
aactttggta tacac 15
<210> 2
<211> 48
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 2
gtgatatggg gtgatggaat cacaacctat aattcagttc tcaaatcc 48
<210> 3
<211> 27
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 3
tcttattttt tgggagctat ggtctac 27
<210> 4
<211> 33
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 4
aaggccagtc agagtgtggg tactgctgta gcc 33
<210> 5
<211> 21
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 5
tcggcatcca cccggtacac t 21
<210> 6
<211> 24
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 6
caacaatata gcacttctcg gacg 24
<210> 7
<211> 5
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 7
Asn Phe Gly Ile His
1 5
<210> 8
<211> 16
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 8
Val Ile Trp Gly Asp Gly Ile Thr Thr Tyr Asn Ser Val Leu Lys Ser
1 5 10 15
<210> 9
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 9
Ser Tyr Phe Leu Gly Ala Met Val Tyr
1 5
<210> 10
<211> 11
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 10
Lys Ala Ser Gln Ser Val Gly Thr Ala Val Ala
1 5 10
<210> 11
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 11
Ser Ala Ser Thr Arg Tyr Thr
1 5
<210> 12
<211> 8
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 12
Gln Gln Tyr Ser Thr Ser Arg Thr
1 5
<210> 13
<211> 30
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 13
ggctacacct tcacagacta tcacatggat 30
<210> 14
<211> 51
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 14
gacatcaacc caaacaatgg cggcgccatc tacaatcaga agtttaaggg c 51
<210> 15
<211> 39
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 15
tctcactacg attatgctgg aggagcttgg ttcgcttac 39
<210> 16
<211> 50
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 16
aagagctccc agagcctgct gttctccggc aaccagaaga attacctggc 50
<210> 17
<211> 21
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 17
tgggcttcta ccagagctag c 21
<210> 18
<211> 27
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 18
cagcagtact atagcttccc aagaacc 27
<210> 19
<211> 10
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 19
Gly Tyr Thr Phe Thr Asp Tyr His Met Asp
1 5 10
<210> 20
<211> 17
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 20
Asp Ile Asn Pro Asn Asn Gly Gly Ala Ile Tyr Asn Gln Lys Phe Lys
1 5 10 15
Gly
<210> 21
<211> 13
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 21
Ser His Tyr Asp Tyr Ala Gly Gly Ala Trp Phe Ala Tyr
1 5 10
<210> 22
<211> 17
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 22
Lys Ser Ser Gln Ser Leu Leu Phe Ser Gly Asn Gln Lys Asn Tyr Leu
1 5 10 15
Ala
<210> 23
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 23
Trp Ala Ser Thr Arg Ala Ser
1 5
<210> 24
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 24
Gln Gln Tyr Tyr Ser Phe Pro Arg Thr
1 5
<210> 25
<211> 696
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 25
gccgccacca tgggttggtc atgtattatt ctgtttctgg tggctactgc taccggcgtg 60
cattcccagg tgcagctggt ccagtctggg gctgaagtga agaagcccgg cgccaccgtg 120
aagatcagct gcaaggtgtc caactttggt atacactggg tgcagcaggc tcctggcaag 180
ggcctcgagt ggatgggcgt gatatggggt gatggaatca caacctataa ttcagttctc 240
aaatcccggg tgaccatcac agctgacacc tctacagata ccgcctatat ggagctgagc 300
tccctgagat ccgaggacac agccgtgtac tattgcgccc ggtcttattt tttgggagct 360
atggtctact ggggacaggg cacactggtg accgtgagcc gggcttccac caagggccct 420
agcgtgtttc cactggcccc ctcttccaag tctacaagcg gaggaaccgc cgctctggga 480
tgtctggtga aggattactt cccagagccc gtgaccgtgt cttggaacag cggcgctctg 540
acaagcggcg tgcacacatt tcctgccgtg ctgcagtcct ctggcctgta ctccctgagc 600
tccgtggtga cagtgccatc tagctccctg ggcacacaga cctatatctg caacgtgaat 660
cacaagccaa gcaataccaa ggtggacaag aaggtg 696
<210> 26
<211> 708
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 26
gccgccacca tgggctggtc atgtattatt ctgtttctgg tcgcaactgc tactggggtg 60
catagcgaaa tcgtgatgac tcagtctccc ggaaccctgt ccctgtctcc aggcgagcgg 120
gccaccctgt cctgcaaggc cagtcagagt gtgggtactg ctgtagcctg gtatcagcag 180
aagccaggcc aggctcccag gctgctgatc tactcggcat ccacccggta cactggcatc 240
cccgacaggt tcagcggctc cggctctggc acagacttca ccctgacaat ctctagactg 300
gagcctgagg acttcgccgt gtactattgc caacaatata gcacttctcg gacgtttggc 360
cagggcacaa agctggagat caagcggacc gtggccgctc ccagcgtgtt catctttccc 420
ccttccgacg agcagctgaa gtccggcaca gcttctgtgg tgtgcctgct gaacaacttc 480
taccccaggg aggccaaggt ccagtggaag gtggataacg ctctgcagag cggcaattcc 540
caggagtctg tgaccgagca ggacagcaag gattccacat attctctgtc tagcaccctg 600
acactgtcta aggccgatta cgagaagcac aaggtgtatg cttgtgaagt cacccaccag 660
ggtctgtcat cacccgtcac taagtctttt aaccgaggcg aatgctga 708
<210> 27
<211> 134
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 27
Ala Ala Thr Met Gly Trp Ser Cys Ile Ile Leu Phe Leu Val Ala Thr
1 5 10 15
Ala Thr Gly Val His Ser Gln Val Gln Leu Val Gln Ser Gly Ala Glu
20 25 30
Val Lys Lys Pro Gly Ala Thr Val Lys Ile Ser Cys Lys Val Ser Asn
35 40 45
Phe Gly Ile His Trp Val Gln Gln Ala Pro Gly Lys Gly Leu Glu Trp
50 55 60
Met Gly Val Ile Trp Gly Asp Gly Ile Thr Thr Tyr Asn Ser Val Leu
65 70 75 80
Lys Ser Arg Val Thr Ile Thr Ala Asp Thr Ser Thr Asp Thr Ala Tyr
85 90 95
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
100 105 110
Ala Arg Ser Tyr Phe Leu Gly Ala Met Val Tyr Trp Gly Gln Gly Thr
115 120 125
Leu Val Thr Val Ser Arg
130
<210> 28
<211> 128
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 28
Ala Ala Thr Met Gly Trp Ser Cys Ile Ile Leu Phe Leu Val Ala Thr
1 5 10 15
Ala Thr Gly Val His Ser Glu Ile Val Met Thr Gln Ser Pro Gly Thr
20 25 30
Leu Ser Leu Ser Pro Gly Glu Arg Ala Thr Leu Ser Cys Lys Ala Ser
35 40 45
Gln Ser Val Gly Thr Ala Val Ala Trp Tyr Gln Gln Lys Pro Gly Gln
50 55 60
Ala Pro Arg Leu Leu Ile Tyr Ser Ala Ser Thr Arg Tyr Thr Gly Ile
65 70 75 80
Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr
85 90 95
Ile Ser Arg Leu Glu Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln
100 105 110
Tyr Ser Thr Ser Arg Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys
115 120 125
<210> 29
<211> 726
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 29
gccgccacca tgggttggtc atgtattatt ctgtttctgg tggctactgc taccggcgtg 60
cattcccagg tgcagctggt ccagtctggg gctgaagtga agaagcccgg cgccaccgtg 120
aagatcagct gcaaggtgtc cggctacacc ttcacagact atcacatgga ttgggtgcag 180
caggctcctg gcaagggcct cgagtggatg ggcgacatca acccaaacaa tggcggcgcc 240
atctacaatc agaagtttaa gggccgggtg accatcacag ctgacacctc tacagatacc 300
gcctatatgg agctgagctc cctgagatcc gaggacacag ccgtgtacta ttgcgcccgg 360
tctcactacg attatgctgg aggagcttgg ttcgcttact ggggacaggg cacactggtg 420
accgtgagcc gggcttccac caagggccct agcgtgtttc cactggcccc ctcttccaag 480
tctacaagcg gaggaaccgc cgctctggga tgtctggtga aggattactt cccagagccc 540
gtgaccgtgt cttggaacag cggcgctctg acaagcggcg tgcacacatt tcctgccgtg 600
ctgcagtcct ctggcctgta ctccctgagc tccgtggtga cagtgccatc tagctccctg 660
ggcacacaga cctatatctg caacgtgaat cacaagccaa gcaataccaa ggtggacaag 720
aaggtg 726
<210> 30
<211> 729
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 30
gccgccacca tgggctggtc atgtattatt ctgtttctgg tcgcaactgc tactggggtg 60
catagcgaaa tcgtgatgac tcagtctccc ggaaccctgt ccctgtctcc aggcgagcgg 120
gccaccctgt cctgcaagag ctcccagagc ctgctgttct ccggcaacca gaagaattac 180
ctggcttggt atcagcagaa gccaggccag gctcccaggc tgctgatcta ctgggcttct 240
accagagcta gcggcatccc cgacaggttc agcggctccg gctctggcac agacttcacc 300
ctgacaatct ctagactgga gcctgaggac ttcgccgtgt actattgcca gcagtactat 360
agcttcccaa gaacctttgg ccagggcaca aagctggaga tcaagcggac cgtggccgct 420
cccagcgtgt tcatctttcc cccttccgac gagcagctga agtccggcac agcttctgtg 480
gtgtgcctgc tgaacaactt ctaccccagg gaggccaagg tccagtggaa ggtggataac 540
gctctgcaga gcggcaattc ccaggagtct gtgaccgagc aggacagcaa ggattccaca 600
tattctctgt ctagcaccct gacactgtct aaggccgatt acgagaagca caaggtgtat 660
gcttgtgaag tcacccacca gggtctgtca tcacccgtca ctaagtcttt taaccgaggc 720
gaatgctga 729
<210> 31
<211> 144
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 31
Ala Ala Thr Met Gly Trp Ser Cys Ile Ile Leu Phe Leu Val Ala Thr
1 5 10 15
Ala Thr Gly Val His Ser Gln Val Gln Leu Val Gln Ser Gly Ala Glu
20 25 30
Val Lys Lys Pro Gly Ala Thr Val Lys Ile Ser Cys Lys Val Ser Gly
35 40 45
Tyr Thr Phe Thr Asp Tyr His Met Asp Trp Val Gln Gln Ala Pro Gly
50 55 60
Lys Gly Leu Glu Trp Met Gly Asp Ile Asn Pro Asn Asn Gly Gly Ala
65 70 75 80
Ile Tyr Asn Gln Lys Phe Lys Gly Arg Val Thr Ile Thr Ala Asp Thr
85 90 95
Ser Thr Asp Thr Ala Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp
100 105 110
Thr Ala Val Tyr Tyr Cys Ala Arg Ser His Tyr Asp Tyr Ala Gly Gly
115 120 125
Ala Trp Phe Ala Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Arg
130 135 140
<210> 32
<211> 135
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 32
Ala Ala Thr Met Gly Trp Ser Cys Ile Ile Leu Phe Leu Val Ala Thr
1 5 10 15
Ala Thr Gly Val His Ser Glu Ile Val Met Thr Gln Ser Pro Gly Thr
20 25 30
Leu Ser Leu Ser Pro Gly Glu Arg Ala Thr Leu Ser Cys Lys Ser Ser
35 40 45
Gln Ser Leu Leu Phe Ser Gly Asn Gln Lys Asn Tyr Leu Ala Trp Tyr
50 55 60
Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile Tyr Trp Ala Ser
65 70 75 80
Thr Arg Ala Ser Gly Ile Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly
85 90 95
Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu Pro Glu Asp Phe Ala
100 105 110
Val Tyr Tyr Cys Gln Gln Tyr Tyr Ser Phe Pro Arg Thr Phe Gly Gln
115 120 125
Gly Thr Lys Leu Glu Ile Lys
130 135
Claims (29)
1.一种抗MET和RON的双特异性抗体,其包含抗MET的抗体片段和抗RON的抗体片段,抗MET的抗体片段和抗RON的抗体片段通过化学“凸点-嵌入-凹穴”相连接。
2.根据权利要求1所述的双特异性抗体,其特征在于:抗RON抗体片段,氨基酸序列中393号氨基酸T突变为W;抗MET抗体片段,氨基酸序列中440号氨基酸Y突变为V,同时重链可变区中CH1与轻链可变区CL发生交换。
3.根据权利要求1所述的双特异性抗体,其特征在于:包含特异性识别和结合细胞表面抗原MET的结构域,其包括抗MET特异性抗体的重链可变区和轻链可变区,所述重链可变区的氨基酸序列如SEQ ID NO:27所示,轻链可变区的氨基酸序列如SEQ ID NO:28所示。
4.根据权利要求4所述的双特异性抗体,其特征在于:
其中
免疫球蛋白重链可变区包括:
CDRH1,其包含SEQ ID NO:7的氨基酸序列;
CDRH2,其包含SEQ ID NO:8的氨基酸序列;
CDRH3,其包含SEQ ID NO:9的氨基酸序列;
免疫球蛋白轻链可变区包括:
CDRH1,其包含SEQ ID NO:10的氨基酸序列;
CDRH2,其包含SEQ ID NO:11的氨基酸序列;
CDRH3,其包含SEQ ID NO:12的氨基酸序列。
5.根据权利要求1所述的双特异性抗体,其特征在于:特异性识别和结合细胞表面抗原RON的结构域,其包括抗RON特异性抗体的重链可变区和轻链可变区,所述重链可变区的氨基酸序列如SEQ ID NO:31所示,轻链可变区的氨基酸序列如SEQ ID NO:32所示。
6.根据权利要求5所述的双特异性抗体,其特征在于:
其中,
免疫球蛋白重链可变区包括:
CDRH1,其包含SEQ ID NO:19的氨基酸序列;
CDRH2,其包含SEQ ID NO:20的氨基酸序列;
CDRH3,其包含SEQ ID NO:21的氨基酸序列;
免疫球蛋白轻链可变区包括:
CDRH1,其包含SEQ ID NO:22的氨基酸序列;
CDRH2,其包含SEQ ID NO:23的氨基酸序列;
CDRH3,其包含SEQ ID NO:24的氨基酸序列。
7.根据权利要求2-6任一所述的双特异性抗体,其特征在于:所述任一氨基酸序列至少95%同一性并保留相应生物活性的变体序列或经删除、替换和/或添加一个或多个氨基酸残基后获得的保留相应活性的变体序列。
8.一种抗体结合片段,其特征在于:包括SEQ ID NO:27,SEQ ID NO:28,SEQ ID NO:31或SEQ ID NO:32所示的抗原结合结构域中的任意一种或多种。
9.一种制备权利要求1-7任一所述抗MET和RON双特异性抗体或权利要求8所述抗体结合片段的方法,该方法包括:表达在一定条件下能同时特异性结合人MET和RON受体结构域的免疫球蛋白重链可变区或免疫球蛋白轻链可变区或两者都有,在宿主细胞表达包含免疫球蛋白重链可变区或免疫球蛋白轻链可变区或两者都有的多肽序列,从而生产的抗体或其结合片段,以及纯化上述的抗体或其结合片段。
10.一种分离的多肽或其结合片段,其特征在于:能同时特异性结合人MET和RON受体结构域,其中包含免疫球蛋白重链可变区和/或免疫球蛋白轻链可变区,与PCMdt-02双特异性抗体的重链和轻链的互补决定区(CDRs)氨基酸序列至少具有至少95%同源性。
11.根据权利要求10所述的多肽或其结合片段,其特征在于:所述的CDRs序列之间插入人或人源化框架序列。
12.根据权利要求10所述的多肽或其结合片段,其特征在于:所述多肽具有SEQ ID NO:15和16序列特征。
13.一种分离的核酸,能表达特异性结合人MET和/或RON受体,其中包含与权利要求1-7任一所述抗MET和RON双特异性抗体或权利要求8所述抗体结合片段具有至少95%同源性的免疫球蛋白重链可变区和/或免疫球蛋白轻链可变区。
14.根据权利要求12所述分离的核酸,免疫球蛋白重链可变区和/或免疫球蛋白轻链可变区包含能编码细胞毒性蛋白核酸与免疫球蛋白重链可变区和/或免疫球蛋白轻链可变区或者两者融合表达形成融合蛋白。
15.一种表达载体,包含权利要求14所述的核酸。
16.一种宿主细胞,包含权利要求15所述的表达载体。
17.权利要求1-6任一所述的双特异性抗体或权利要求8所述抗体结合片段或权利要求10所述分离的多肽或其结合片段或权利要求12所述的分离的核酸或权利要求13所述的表达载体或权利要求14所述的宿主细胞在制备治疗抗癌药物中的应用。
18.一种双特异性抗体或抗体-药物偶联物,由权利要求1-6任一所述的双特异性抗体或权利要求8所述抗体结合片段与化学治疗药物结合得到,或者由权利要求1-6任一所述的双特异性抗体或权利要求8所述抗体结合片段与细胞毒性蛋白融合形成的融合蛋白;所述抗体-药物偶联物使得抗体靶向结合到靶细胞表面的MET和/或RON蛋白,并且使抗MET和RON双特异性抗体和药物一起被内吞到靶细胞内部。
19.权利要求18所述抗体-药物偶联物的制备方法:将细胞毒性或化学治疗药物与权利要求7中所得抗体或其结合片段进行偶联,或与细胞毒性蛋白质融合制备融合蛋白。
20.权利要求18所述抗体-药物偶联物在制备抗癌药物中的应用。
21.一种用于生产包含免疫球蛋白重链可变区或免疫球蛋白轻链可变区的多肽的方法,所述方法包括:(a)在一定条件下培养权利要求8的宿主细胞,使得宿主细胞表达包含免疫球蛋白重链可变区或免疫球蛋白轻链可变区的多肽,(b)纯化包含免疫球蛋白重链可变区或免疫球蛋白轻链可变区的多肽。
22.一种用于生产能结合人MET和RON的双特异性抗体或抗体结合片段的方法,所述方法包括:(a)在一定条件下培养权利要求8的宿主细胞,使得宿主细胞表达包含免疫球蛋白重链可变区或免疫球蛋白轻链可变区的多肽,进一步生产抗体或抗体结合片段,(b)纯化抗体或抗体结合片段。
23.一种抑制或减少癌细胞增殖的方法,包括将癌细胞暴露于单克隆抗体或其结合片段中,双特异性抗体PCMdt-02抗体药物偶联物特异性结合癌细胞MET和/或RON受体结构域,以有效抑制或减少癌细胞增殖。所述的癌细胞可以来自以下组织:乳腺,胰腺,肝脏,结肠,非小细胞肺等。
24.一种抗MET特异性抗体,特征在于:包含特异性识别和结合细胞表面抗原MET的结构域,其包括抗MET特异性抗体的重链可变区和轻链可变区,所述重链可变区的氨基酸序列如SEQ ID NO:27所示,轻链可变区的氨基酸序列如SEQ ID NO:28所示。
25.根据权利要求24所述的抗体,其特征在于:
其中,
免疫球蛋白重链可变区包括:
CDRH1,其包含SEQ ID NO:7的氨基酸序列;
CDRH2,其包含SEQ ID NO:8的氨基酸序列;
CDRH3,其包含SEQ ID NO:9的氨基酸序列;
免疫球蛋白轻链可变区包括:
CDRH1,其包含SEQ ID NO:10的氨基酸序列;
CDRH2,其包含SEQ ID NO:11的氨基酸序列;
CDRH3,其包含SEQ ID NO:12的氨基酸序列。
26.根据权利要求24所述的抗MET特异性抗体,特征在于:所述任一氨基酸序列至少95%同一性并保留相应生物活性的变体序列或经删除、替换和/或添加一个或多个氨基酸残基后获得的保留相应活性的变体序列。
27.一种在宿主细胞中制备权利要求24所述抗MET抗体的单克隆抗体或其结合片段的方法,该方法包括:表达在一定条件下特异性结合人MET的受体结构域的免疫球蛋白重链可变区或免疫球蛋白轻链可变区或两者都有,在宿主细胞表达包含免疫球蛋白重链可变区或免疫球蛋白轻链可变区或两者都有的多肽序列,从而生产源自C1D8或PCM-C1D8杂交瘤细胞的抗体或其结合片段,以及纯化上述的抗体或其结合片段。
28.根据权利要求27所述的方法,其中宿主细胞是C1D8或PCM-C1D8杂交瘤细胞。
29.根据权利要求27所述的方法,还包括将细胞毒性或化学治疗药物与抗体或其结合片段偶联,或与细胞毒性蛋白质融合制备融合蛋白的步骤。
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