CN116981694A - 抗pd-1多肽及其用途 - Google Patents
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Abstract
本申请提供了抗PD‑1多肽或其片段。进一步提供了使用所述抗体或其片段来治疗和诊断疾病,诸如癌症、感染或免疫疾病的方法。
Description
技术领域
本申请涉及抗PD-1多肽(包括抗PD-1抗体及其免疫活性片段),编码抗PD-1抗体或其免疫活性片段的分离的核酸,尤其是将它用于治疗疾病时,所述疾病的患病细胞利用PD-1/PD-L1检查点进行免疫逃逸的疾病。本申请尤其涉及人源化抗PD-1抗体及其抗原结合片段,其能够增强免疫系统针对患病组织(包括表达PD-L1和/或PD-L2的癌细胞和感染细胞)的激活。
背景技术
程序性细胞死亡蛋白1(PD-1)的cDNA于1992年从小鼠T细胞杂交瘤和发生凋亡的造血祖细胞系中分离出来。研究表明,PD-1的缺乏会导致在多个品系的小鼠中出现不同的自身免疫表型。带有转基因T细胞受体(TCR)的PD-1缺陷型异体T细胞表现出对异体抗原的应答增强,这表明T细胞上的PD-1在对抗原的应答中起着负调节作用。
一些研究促进了与PD-1相互作用的分子的发现。1999年,PD-1的B7同源物1(B7-H1,也被称为程序性死亡配体1[PD-L1])被确定,并在体外被证明是人类T细胞反应的抑制剂。后来B7-H1(以下简称PD-L1)被证明是PD-1的一个结合和功能伴侣。其后,人们确定PD-L1缺陷的小鼠(PD-L1敲除小鼠)易于罹患自身免疫性疾病,尽管这些小鼠不会自发患病。随后明确,PD-L1/PD-1在体内的相互作用,对T细胞应答的抑制(尤其是在肿瘤微环境中)起着重要作用。
此外,研究还表明,肿瘤相关的PD-L1促进活化的T细胞凋亡((Dong H.等,Tumor-associatedB7-H1 promotes T-cell apoptosis:apotential mechanism of immuneevasion.Nature medicine.2002;8(8):793-800),并刺激人类外周血T细胞产生IL-10((Dong H等,B7-H1,athirdmember ofthe B7 family,co-stimulates T-cellproliferation and interleukin-10secretion.Nature medicine.1999;5(12):1365-9)来介导免疫抑制。众所周知,PD-L1对免疫抑制的影响更为复杂。除了T细胞凋亡和IL-10诱导外,PD-L1还可以通过各种机制诱导T细胞功能失调。PD通路也被证明可以在体外和体内促进T细胞的失能。
近年来,FDA批准了两个PD-1单抗(PD-1单克隆抗体)用于治疗人类癌症,其中一个来自百时美施贵宝(Opdivo、纳武利尤单抗、MDX-1106、BMS-936558、ONO-4538),另一个来自默克(Keytruda、派姆单抗、lambrolizumab、MK-3475)。此外,在涉及数千名患者的数百项临床试验中,针对PD-1或PD-L1的多种单克隆抗体正在积极开发。迄今为止,抗PD疗法通过诱导晚期和转移性肿瘤的消退和提高生存率带来了巨大的临床效益。更重要的是,抗PD疗法具有持久的效果,可耐受的毒性,并被证明适用于多种癌症类型,尤其是实体瘤。由于其相对于其他癌症疗法的非重叠机制,抗PD疗法正在与几乎所有的癌症治疗方法相结合,试图进一步扩大治疗效果。除了与各种癌症免疫疗法(如癌症疫苗、共刺激和共同抑制抗体、以及过继细胞疗法)相结合外,各种临床试验也开始将抗PD-1疗法与化疗、放疗和靶向疗法相结合。
尽管已经开发出了针对PD-1的抗体,但针对作为治疗剂的PD-1抗体仍有改进的空间。因此,本领域需要开发具有更高特异性和效率的新型抗PD-1抗体。
发明内容
本申请提供了抗体及其免疫反应性片段,其以高亲和力结合细胞(例如,癌细胞)上表达的PD-1分子,并促进针对癌细胞的有效免疫应答。本文提供的抗体及其免疫反应性片段能够增强免疫系统的活化,因此提供了重要的治疗剂和诊断剂,用于靶向与PD-1分子表达和/或活性相关的病理状况。在一方面,本申请提供一种分离的抗体或其抗原结合片段,包括一个重链(HC)可变区序列和一个轻链(LC)可变区序列,其中,所述抗体与PD-1的胞外结构域结合,其结合亲和力优于10nM或约10nM,优于8nM或约8nM,优于6nM或约6nM,优于4nM或约4nM,优于2nM或约2nM,优于1nM或约1nM,所述亲和力通过SPR分析确定,例如约0.5-4nM,约0.8-4.0nM,约1.0-4.0nM,约2.0-4.0nM,约3.0-4.0nM,约0.6-3.5nM,约1.4-3.5nM,约2.5-3.5nM、约0.7-2.5nM、约0.8-2.0nM、约1.0-2.0nM、约0.4nM、0.3nM、0.2nM、0.1nM,或更优,所述亲和力通过SPR分析确定。
在某些实施方案中,本申请提供了一种抗体或其抗原结合片段,其包含下述的至少一项:
(a)包含GFTFSSYGMS的CDR1H序列(SEQ ID NO:1)。
(b)包含IISGGGRDIYYLDSVKG的CDR2H序列(SEQ ID NO:2)。
(c)包含PIYDAYSFAY的CDR3H序列(SEQ ID NO:3)。
(d)包含RASQTISNNLH的CDR1L序列(SEQ ID NO:4)。
(e)包含YASQSIS的CDR2L序列(SEQ ID NO:5),和
(f)包含QQSYSWPLT的CDR3L序列(SEQ ID NO:6)。
在某些实施方案中,本申请提供一种抗体或其抗原结合片段,其中
(a)所述HC包含:
包含GFTFSSYGMS的CDR1H序列(SEQ ID NO:1)。
包含IISGGGRDIYYLDSVKG的CDR2H序列(SEQ ID NO:2),和
包含PIYDAYSFAY的CDR3H序列(SEQ ID NO:3)。
(b)所述LC包含:
包含RASQTISNNLH的CDR1L序列(SEQ ID NO:4)。
包含YASQSIS的CDR2L序列(SEQ ID NO:5),和
包含QQSYSWPLT的CDR3L序列(SEQ ID NO:6)。
所述CDR序列是根据Kabat等人,Sequences ofProteins ofImmunologicalInterest,Fifth Edition,NIH Publication 91-3242,Bethesda MD(1991),vols.1-3确定的。
在某些实施方案中,所述抗体是嵌合抗体、人源化抗体或人抗体。在某些实施方案中,本发明的抗体或其抗原结合片段进一步包含人受体框架。在某些实施方案中,所述人受体框架源自人免疫球蛋白框架或人共有框架。在某些实施方案中,所述人受体框架包含用于VL的κI亚型框架序列,和用于VH的III亚型框架序列。一般而言,序列的亚型是如Kabat等,Sequences of Proteins ofImmunological Interest,第5版,NIH Publication 91-3242,Bethesda MD(1991),1-3卷中所述的亚型。在某些实施方案中,对于VL,所述亚型是如Kabat等(同上)所述的κI亚型。在某些实施方案中,对于VH,所述亚型是如Kabat等(同上)所述的III亚型。
在某些实施方案中,所述抗体或其抗原结合片段包含人共有框架。在一些实施方案中,所述抗体或其抗原结合片段包含具有氨基酸序列的改变的人共有框架,所述变化例如,1-15、1-10、2-9、3-8、4-7或5-6个氨基酸的改变。
在某些实施方案中,本申请的抗体或其抗原结合片段包含HC可变区序列,所述HC可变区序列包含由SEQ ID NO:7或8所示的氨基酸序列,或与SEQ ID NO:7或8具有高于80%、85%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%同一性的氨基酸序列。在某些实施方案中,本申请的抗体或其抗原结合片段包含LC可变区序列,所述LC可变区序列包含由SEQ ID NO:9或SEQ ID NO:10所示的氨基酸序列,或与SEQ ID NO:9或10具有高于80%、85%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%同一性的氨基酸序列。在某些实施方案中,所述HC可变区序列包含SEQ ID NO:7的氨基酸序列,并且所述LC可变区序列包含SEQ ID NO:9或SEQ ID NO:10的氨基酸序列。在某些实施方案中,所述HC可变区序列包含SEQ ID NO:8的氨基酸序列,并且所述LC可变区序列包含SEQ ID NO:9或SEQID NO:10的氨基酸序列。在某些实施方案中,所述抗体或其抗原结合片段包含下述HC序列,其包含SEQ ID NO:11或12所示的氨基酸序列,或者与SEQ ID NO:11或12具有高于80%、85%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%同一性的氨基酸序列。在某些实施方案中,本申请的抗体或其抗原结合片段包含下述LC序列,其包含SEQ ID NO:13或14所示的氨基酸序列,或者与SEQ ID NO:13或14具有高于80%、85%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%同一性的氨基酸序列。在某些实施方案中,所述HC序列包含SEQ ID NO:11的氨基酸序列,而所述LC序列包含SEQ ID NO:13或SEQ ID NO:14的氨基酸序列。在某些实施方案中,所述HC序列包含SEQ ID NO:12的氨基酸序列,而所述LC可变区序列包含SEQ ID NO:13或SEQ ID NO:14的氨基酸序列。在某些实施方案中,所述抗体是IgG1、IgG2或IgG4的同种型。在某些实施方案中,所述抗原结合片段包含选自下组中的任一项:Fab、F(ab')2、Fab'、scFv和Fv。在某些实施方案中,本申请的抗体或其抗原结合片段为阻断抗体(blocking antibody)或拮抗剂抗体,其抑制或降低其结合的PD-1分子的生物学活性。优选的阻断抗体或拮抗剂抗体基本或完全抑制PD-1分子的生物学活性。
在一方面,本申请提供了一种双特异性抗体,其包含本申请的抗体或其抗原结合片段以及第二抗体或其抗原结合片段。在某些实施方案中,所述第二抗体或其抗原结合片段特异性地结合肿瘤细胞表面表达的肿瘤抗原,其中所述肿瘤抗原包含选自下组的任一项:A33;ADAM-9;ALCAM;BAGE;β-连环蛋白;CA125;羧肽酶M;CD103;CD19;CD20;CD22;CD23;CD25;CD27;CD28;CD36;CD40/CD154;CD45;CD46;CD5;CD56;CD79a/CD79b;CDK4;CEA;CTLA4;细胞角蛋白8;EGF-R;EphA2;ErbB1;ErbB3;ErbB4;GAGE-1;GAGE-2;GD2/GD3/GM2;HER-2/neu;人乳头瘤病毒-E6;人乳头瘤病毒-E7;JAM-3;KID3;KID31;KSA(17-1A);LUCA-2;MAGE-1;MAGE-3;MART;MUC-1;MUM-1;N-乙酰氨基葡萄糖基转移酶;抑瘤素M;pl5;PIPA;PSA;PSMA;ROR1;TNF-β受体;TNF-α受体;TNF-γ受体;转铁蛋白受体;和VEGF受体。在一些实施方案中,所述第二抗体或其抗原结合片段特异性地结合异常细胞或免疫细胞表面表达的检查点蛋白,其中所述免疫检查点蛋白包含选自下组的任一项:2B4;4-1BB;4-1BB配体;B7-1;B7-2;B7H2;B7H3;B7H4;B7H6;BTLA;CD155;CD160;CD19;CD200;CD27;CD27配体;CD28;CD40;CD40配体;CD47;CD48;CTLA-4;DNAM-1;半乳糖凝集素-9。GITR;GITR配体;HVEM;ICOS;ICOS配体;IDOI;KIR;3DL3;LAG-3;OX40;OX40配体;PD-L1;PD-1;PD-L2;LAG3;PGK;SIRPα;TIM-3;TIGIT;VSIG8。
在一方面,本申请提供了一种多肽,其包含本申请的抗体或其抗原结合片段。
在一方面,本申请提供了一种多肽,其包含本申请的抗体或其抗原结合片段的HC可变区和/或LC可变区。
在一方面,本申请提供了包含本申请的抗体或其抗原结合片段的缀合物。在某些实施方案中,本申请提供了由本申请的抗体或其抗原结合片段组成的缀合物,其连接有治疗剂。在某些实施方案中,所述治疗剂是细胞毒素或放射性同位素。
在一方面,本申请提供一种组合物,包含本申请的抗体或其抗原结合片段、双特异性抗体、多肽、缀合物和药学上可接受的载体。在某些实施方案中,所述组合物进一步包含抗癌剂。在某些实施方案中,所述剂是抗体、化学治疗剂、放射治疗剂、激素治疗剂、毒素或免疫治疗剂。在某些实施方案中,所述组合物进一步包含抑制检查点的抗体或剂。
在一方面,本申请提供了一种用于治疗癌症的制品或试剂盒,其包含本申请的抗体或其抗原结合片段、双特异性抗体、多肽、缀合物或组合物,以及包装插页,其包含关于使用本申请相关的抗体或其抗原结合片段、双特异性抗体、多肽、缀合物或组合物的必要信息。
在一方面,本申请提供了一种用于诊断癌症或确定PD-1的存在和/或量的制品或试剂盒,其包含本申请的抗体或其抗原结合片段,以及包装插页,其包含关于使用本申请的抗体或其抗原结合片段的必要信息。
在一方面,本申请提供了编码本申请的抗体或其抗原结合片段的分离的核酸。在某些实施方案中,本申请提供了编码本申请的抗体或其抗原结合片段的HC可变区和/或LC可变区的分离的核酸。在某些实施方案中,本申请提供了包含所述核酸的表达载体,或包含所述表达载体的宿主细胞。
在一方面,本申请提供了一种用于制备抗体或其抗原结合片段的方法,其包括在上述宿主细胞中表达所述抗体或其抗原结合片段,并且从所述宿主细胞中分离所述抗体或其抗原结合片段。
在一方面,本申请提供了一种治疗癌症的方法,其包括向患有癌症疾病的患者施用有效量的本申请的上述抗体或其抗原结合片段、双特异性抗体、多肽、缀合物、组合物、制品或试剂盒。在某些实施方案中,所述癌症包含选自下组的任一项:淋巴瘤、黑素瘤、结直肠腺癌、前列腺癌、乳腺癌、结肠癌、肺癌、肝癌、胃癌和肾透明细胞癌。
在一个实施方案中,有效量的本申请的上述抗体或其抗原结合片段、双特异性抗体、多肽、缀合物、组合物、制品或试剂盒是向患者施用的唯一的治疗性抗癌药剂。在另一个实施方案中,它们可以与另一种抗体或抗体片段或抗癌药剂组合施用,所述抗体或抗体片段或抗癌药剂包括但不限于,针对检查点分子或其受体的抗体(例如,抗CTLA-4抗体、抗B7S1抗体、抗PD-L1抗体,抗B7H3抗体,等);抗表皮生长因子受体(EGFR)药剂,诸如帕尼单抗(panitumumab),抗EGFR抗体西妥昔单抗(cetuximab,),和EGFR酪氨酸激酶(TK)抑制剂吉非替尼(gefitinib,/>)和埃罗替尼(erlotinib,/>);烷基化剂,诸如顺铂(cisplatin)、卡铂(carboplatin)、奥沙利铂(oxaliplatin)、奈达铂(nedaplatin)、赛特铂(satraplatin)、四硝酸三核铂(triplatin tetranitrate)、氮芥、环磷酰胺、苯丁酸氮芥和异环磷酰胺;紫杉醇(paclitaxel)和多西他赛(docetaxel);和拓扑异构酶抑制剂,诸如,例如,伊立替康(irinotecan)、托泊替康(topotecan)、安吖啶(amsacrine)、依托泊苷(etoposide)、磷酸依托泊苷(etoposide phosphate)和替尼泊苷(teniposide)。
在某些实施方案中,如上所述的本申请的抗体或其抗原结合片段、双特异性抗体、多肽、缀合物、组合物、制品或试剂盒与另一种抗PD-1抗体或抗PD-L1抗体组合施用以在癌症治疗中实现协同作用。
在一方面,本申请提供了一种治疗癌症的方法,包括向患有癌症疾病的受试者施用有效量的本申请的抗体或其抗原结合片段、双特异性抗体、多肽、缀合物、组合物、制品或试剂盒。在某些实施方案中,所述癌症包含选自下组的任一项:前列腺癌、乳腺癌、结肠癌、肺癌、肝癌、胃癌和肾透明细胞癌、膀胱癌、乳腺癌、结直肠癌、子宫内膜癌、食道癌、头颈癌、肾癌、白血病、肝癌、肺癌、淋巴瘤、黑色素瘤、胰腺癌、前列腺癌和甲状腺癌。在某些实施方案中,所述癌症包含选自下组的任一项:微卫星不稳定性高的结直肠癌、微卫星稳定的结直肠癌、三阴乳腺癌、梅克尔细胞癌、子宫内膜癌或食道癌。
在一方面,本申请提供一种治疗癌症的方法,包括a)用本申请的上述抗体或其抗原结合片段、双特异性抗体、多肽、缀合物、组合物、制品或试剂盒在体外处理活化的T细胞、B细胞、NK细胞、树突状细胞、单核细胞或它们的组合,或外周血单核细胞(PBMC);和b)将处理的T细胞、B细胞、NK细胞、树突状细胞、单核细胞或它们的组合,或外周血单核细胞(PBMC)施用于所述患者。在一些实施方案中,所述方法进一步包括,在步骤a)之前,从个体中分离出T细胞、B细胞、NK细胞、树突状细胞或单核细胞。在一些实施方案中,所述T细胞和/或NK细胞来自待治疗的患者。在一些实施方案中,所述T细胞是肿瘤浸润性T淋巴细胞、CD4+T细胞、CD8+T细胞,或其组合。
因此,在一方面,本申请还提供了淋巴细胞组,包含来自受试者的T细胞和/或NK细胞,并在体外用本申请的上述抗体或其抗原结合片段、双特异性抗体、多肽、缀合物、组合物、制品或试剂盒进行处理。在一些实施方案中,所述T细胞和/或NK细胞来自待治疗的患者。在一些实施方案中,所述T细胞是肿瘤浸润性T淋巴细胞、CD4+T细胞、CD8+T细胞,或其组合。
在一方面,本申请提供了一种治疗或抑制有需要的患者的感染的方法,包括向患者施用有效量的本申请的上述抗体或其抗原结合片段、双特异性抗体、多肽、缀合物、组合物、制品或试剂盒。在某些实施方案中,所述感染是病毒、细菌、真菌或寄生虫感染。在某些特定的实施方案中,所述感染是HIV感染。
在一方面,本申请提供了一种用于检测或定量PD-1多肽的表达或活性的方法,其包括使本申请的抗体或其抗原结合片段与来自受试者的样本接触。在某些实施方案中,所述抗体或其抗原结合片段用可检测的物质标记。在某些实施方案中,所述抗体或其抗原结合片段是放射性标记的、荧光标记的或酶标记的。
在一方面,本申请提供了一种预测受试者患癌风险的方法,所述方法包括通过使用本申请的抗体或其抗原结合片段来检测、定量或监测PD-1多肽的表达或活性。
在一方面,本申请提供了一种用于监测药剂治疗癌症的有效性的方法,所述癌症显示出PD-1表达量或活性的升高,所述方法包括通过使用本申请的抗体或其抗原结合片段来检测或定量PD-1多肽的表达或活性。
在一个实施方案中,本申请提供了一种编码人抗PD-1抗体或其片段的分离的多核苷酸,其中所述抗体包含选自SEQ ID NO:7-14,优选选自SEQ ID NO:11-14的氨基酸序列。在某些实施方案中,人PD-1抗体包含重链和轻链,其中所述重链包含SEQ ID NO:7,而所述轻链包含SEQ ID NO:9或SEQ ID NO:10。在某些实施方案中,所述人PD-1抗体包含重链和轻链,其中所述重链包含SEQ ID NO:8,所述轻链包含SEQ ID NO:9或SEQ ID NO:10。在某些实施方案中,所述抗体包含重链和轻链,其中所述重链包含SEQ ID NO:11,所述轻链包含SEQID NO:13或SEQ ID NO:14。在某些实施方案中,所述抗体包含重链和轻链,其中所述重链包含SEQ ID NO:12,所述轻链包含SEQ ID NO:13或SEQ ID NO:14。更优选地,所述抗体包含重链和轻链,其中所述轻链包含SEQ ID NO:10或SEQ ID NO:14,且所述重链包含SEQ ID NO:7、SEQ ID NO:8、SEQ ID NO:11或SEQ ID NO:12。在一些实施方案中,所述抗体或抗体片段包含单链抗体片段的VH和VL结构域。在一些实施方案中,所述VH结构域包含选自SEQ IDNO:1、SEQ ID NO:2和SEQ ID NO:3的序列。在一些实施方案中,所述VH结构域包含三个CDR,其中所述三个CDR中的每一个包括选自SEQ ID NO:1、SEQ ID NO:2和SEQ ID NO:3的序列。在一些实施方案中,所述VH结构域包含SEQ ID NO:7或SEQ ID NO:8。在一些实施方案中,所述VL结构域包含选自SEQ ID NO:4、SEQ ID NO:5和SEQ ID NO:6的序列。在一些实施方案中,所述VL结构域包含三个CDR,其中所述三个CDR中的每一个都包含选自SEQ ID NO:4、SEQID NO:5和SEQ ID NO:6的序列。在一些实施方案中,所述VL结构域包含SEQ ID NO:9或SEQID NO:10。
在一个实施方案中,本申请提供了一种诊断与细胞上PD-1的表达有关的疾病、失调或病症,或确定PD-1的存在和/或量的方法,其中所述方法包括a)使细胞与人抗PD-1抗体或其片段接触,其中所述抗体或其片段包含选自SEQ ID NO:7-14的氨基酸序列;和b)检测PD-1的存在,其中PD-1的存在可诊断出与PD-1的表达相关的疾病、不调或病症。在某些实施方案中,与PD-1的表达相关的疾病、失调或病症是癌症。
在一个实施方案中,本申请提供了一种在哺乳动物中诊断、预后或确定PD-1相关疾病风险的方法,其中所述方法包括检测来自所述哺乳动物的样本中PD-1的表达,包括a)将样品与人抗PD-1抗体或其片段接触,其中所述抗体或其片段包含选自SEQ ID NO:7-14的氨基酸序列;和b)检测PD-1的存在,其中PD-1的存在可诊断哺乳动物中的PD-1相关疾病。在某些实施方案中,所述PD-1相关的疾病是癌症。
在一个实施方案中,本申请提供了一种阻断PD-1依赖性T细胞、B细胞、NK细胞、树突状细胞或单核细胞抑制的方法,其中所述方法包括使细胞与人抗PD-1抗体或其片段接触,其中所述抗体或其片段包含选自SEQ ID NO:7-14的氨基酸序列。在一些实施方案中,所述细胞选自B细胞、T细胞或NK细胞。在一个实施方案中,本申请提供了一种阻断哺乳动物中PD-1依赖性免疫抑制的方法,其中所述方法包括向哺乳动物施用有效量的上述抗PD-1抗体或其片段。在某些实施方案中,所述哺乳动物包含异常细胞,所述异常细胞选自表达PD-1的T细胞、B细胞、NK细胞、树突状细胞或单核细胞以及表达PD-L1和/或PD-L2的异常细胞。
在一个实施方案中,本申请提供了一种在哺乳动物中提供抗肿瘤免疫的方法,其中所述方法包括向哺乳动物施用有效量的编码和表达抗PD-1抗体或其片段的基因修饰的细胞,其中所述抗PD-1抗体或其片段包含选自SEQ ID NO:7-14的氨基酸序列。
附图说明
图1.纯化的抗体的SDS-PAGE分析结果。
图2A-2B.确定抗体与人(2A)和猕猴(2B)PD-1的结合亲和力的ELISA结果。
图3.抗体与表达人PD-1的Jurkat细胞的结合亲和力的流式细胞分析。
图4.显示在基于细胞的测试中,人源化抗PD-1抗体有效地阻断了PD-1和PD-L1的相互作用。
图5A-5C.显示在细胞因子释放测试中,与抗PD-1抗体相互作用的人外周血单核细胞(PBMC)分泌的IL-2(5A)、IFN-γ(5B)和TNF-α(5C)增多。
图6A-6C.显示抗体VH7+VL6在体内对肿瘤生长的抑制。图6A是对各小鼠组的肿瘤大小的分析结果。图6B和6C分别显示每只小鼠的肿瘤大小变化。
具体实施方式
本申请在此提供与PD-1蛋白,尤其是人PD-1蛋白或多肽结合的抗体及其片段。本申请还涉及所述抗体及其片段用于增强免疫系统针对例如癌细胞的激活。
本申请进一步提供了制造抗PD-1抗体的方法、编码抗PD-1抗体的多核苷酸以及包含编码抗PD-1抗体的多核苷酸的细胞。
1.定义
应当理解,本申请不限于本文描述的方面,其本身当然可以变化。还应理解,如本文所用,术语仅用于描述特定方面,而不意图进行限制,因为本申请的范围仅会由所附权利要求限制。
除非另有定义,否则本文使用的所有技术和科学术语具有与所述技术所属领域的普通技术人员通常所理解的相同的含义。本文引用的所有技术和专利公开通过引用以其整体并入本文。除非另有说明,本领域技术人员将采用本领域技术范围内的组织培养、免疫学、分子生物学、微生物学、细胞生物学和重组DNA的常规技术。参见例如,Sambrook和Russell编(2001)Molecular Cloning:A Laboratory Manual,第3版;Harlow和Lane编(1999)Antibodies,ALaboratory Manual.MONOCLONAL ANTIBODIES:A PRACTICALAPPROACH(Shepherd,P.等编,2000)Oxford UniversityPress,USA,NewYork N.Y.。
如本文所用,术语"PD-1"是指程序性细胞死亡蛋白,它属于免疫球蛋白超家族,其功能是作为共抑制受体对免疫系统进行负向调节。PD-1是CD28/CTLA-4家族的一个成员,有两个已知的配体,包括PD-L1和PD-L2。PD-1的替代名称或同义词包括PDCD1、PD1、CD279和SLEB2等。人PD-1的代表性氨基酸序列公开于NCBI登录号NP 005009.2下。而编码人PD-1的代表性核酸序列显示于NCBI登录号NM 005018.2下。PD-1蛋白由循环淋巴细胞(如T细胞、B细胞、单核细胞、自然杀伤性T细胞、NK细胞和巨噬细胞)表达,是一种活化和耗竭的标志物。
如本文所用,术语"PD-L1"是指程序性细胞死亡配体1(PD-L1,例如,Freeman等,Freeman et al.(2000)J.Exp.Med.192:1027).PD-L1的替代名称或同义词包括PDCDIL1、PDL1、B7Hl、CD274和B7-H等。人PD-L1的代表性氨基酸序列公布于NCBI登录号NP 054862.1下。而编码人PD-L1的代表性核酸序列显示于NCBI登录号NM 014143.3下。PD-L1在胎盘、脾脏、淋巴结、胸腺、心脏、胎儿肝脏中表达,也在许多肿瘤或癌症细胞上发现。PD-L1与其受体PD-1或B7-1结合,后者在活化的T细胞、B细胞和骨髓细胞上表达。PD-L1和其受体的结合诱导信号转导,以抑制TCR介导的细胞因子生产和T细胞增殖的活化。因此,PD-L1在特定事件(诸如怀孕、自身免疫性疾病、组织异体移植)中发挥了抑制免疫系统的主要作用,并被认为允许肿瘤或癌细胞规避免疫检查点和逃避免疫反应。据报道,与常驻腹膜的巨噬细胞相比,PD-L1也在炎症巨噬细胞上高度表达,但可以通过经典的活化刺激物,诸如脂多糖、IFN-γ和聚肌胞苷酸(polyinosinic-polycytidylic acid)诱导常驻巨噬细胞表达。
如本文所用,术语"PD-L2"是指程序性细胞死亡配体2。PD-L2的替代名称或同义词包括PDCDIL2、PDL2、B7-DC、Btdc和CD273等。人PD-L2的代表性氨基酸序列在NCBI登录号NP079515.2下公开。
如本文所用,术语"抗PD-1抗体"是指能够与PD-1(如人、猴或猴子PD-1)特异性结合的抗体。其优点是,抗PD-1抗体与PD-1特异性结合,其亲和力足以用于诊断和/或治疗。优选所述抗PD-1抗体与PD-L1、PD-L2和/或PD-1的其他配体竞争结合PD-1。
如本申请所用,术语“抗体”,也称为“免疫球蛋白”,涵盖具有天然抗体结构特征的抗体和具有与天然抗体不同的结构特征但表现出对PD-1分子的结合特异性的抗体样分子。术语抗体意图涵盖免疫球蛋白分子和免疫球蛋白分子的免疫学活性片段,即,含有抗原结合位点的分子。免疫球蛋白分子可以是任意类型(例如,IgG、IgE、IgM、IgD、IgA和IgY),类别(例如,IgG1、IgG2、IgG3、IgG4、IgA1和IgA2)或亚类。
术语“重链”(“HC”)、“轻链”(“LC”)、“轻链可变区”(“VL”)、“重链可变区”(“VH”)、“框架区”(“FR”)指天然存在的免疫球蛋白中的结构域和合成(例如,重组)结合蛋白(例如,人源化抗体)的相应结构域。天然存在的免疫球蛋白(例如,IgG)的基本结构单元是具有两条轻链和两条重链的四聚体。每条链的氨基末端(“N”)部分包括约100至110或更多个氨基酸的可变区,主要负责抗原识别。每条链的羧基末端(“C”部分定义为恒定区,轻链具有单个恒定结构域,且重链通常具有三个恒定结构域和铰链区。因此,天然存在的IgG分子的轻链的结构为N-VL-CL-C,且IgG重链的结构为N-VH-CH1-H-CH2-CH3-C(其中H为铰链区)。IgG分子的可变区由互补决定区(CDR)(包含有与抗原接触的残基)和非CDR节段(称为框架节段,其维持结构并确定CDR环的位置)组成。因此,VL和VH结构域具有N-FR1-CDR1-FR2-CDR2-FR3-CDR3-FR4-C结构。
在天然抗体中,可变性在抗体的可变区分布不均匀。其集中于轻链和重链可变区中被称为互补决定区(CDR)或高变区的三个节段中。重链上的CDR可以被称为CDRnH,"n"是一个整数,并不表示重链上CDR的顺序。同样,轻链上的CDR可以被称为CDRnL,"n"是一个标记CDR的整数,并不表示轻链上CDR的顺序。可变结构域中更加高保守的部分称为框架(FR)。天然重链和轻链的可变区各自包含通过三个CDR连接的四个FR区。每条链中的CDR由FR区紧连在一起,并与来自另一条链的CDR共同促成抗体的抗原结合位点的形成[参见Kabat,E.A.等,Sequences ofProteins ofImmunological Interest National Institute ofHealth,Bethesda,MD(1987)]。恒定区不直接参与抗体与抗原的结合,但表现出多种效应子功能,诸如抗体参与到抗体依赖性细胞毒性(ADCC)中。
如本文所使用的,术语抗体的“抗原结合片段”(或简称“抗体片段”)指抗体的一个或多个片段,其保留与抗原(例如,PD-1分子,诸如人PD-1)特异性结合的能力。所述抗体片段仅包含完整抗体的一部分,其中所述部分优选地保留当其存在于完整抗体中时与所述部分通常相关的至少一个,优选大部分或全部功能。抗体片段的实例包括Fab、Fab'、F(ab')2和Fv片段;双体抗体(diabody);线性抗体;单链抗体分子;和由抗体片段形成的多特异性抗体。
木瓜蛋白酶消化抗体产生两个相同的抗原结合片段,称为“Fab”片段,每个具有单个抗原结合位点,和一个残余Fc片段,其名称反映了其易于结晶的能力。“Fab”片段还含有轻链的恒定结构域和重链的第一恒定结构域(CH1)。“Fab'”片段与Fab片段的区别在于在重链CH1结构域的羧基末端添加了几个残基,包括来自抗体铰链区的一个或多个半胱氨酸。“Fab'-SH”指代的是恒定结构域的半胱氨酸残基具有游离硫醇基团的Fab'。“F(ab')”片段是由胃蛋白酶消化产物“F(ab')2”的铰链半胱氨酸二硫键断裂产生。
“Fd”片段由VH和CH1结构域组成。“dAb”片段(Ward等,(1989)Nature341:544-546)由VH结构域组成。分离的互补决定区(CDR)和两个或更多个分离的CDR的组合,其可选通过合成接头连接。
“Fv”片段由抗体单臂的VL和VH结构域组成。单链Fv(scFv)由一个重链可变区和一个轻链可变区组成,其通过柔性肽接头共价地连接为一条单链多肽链。
术语“双体抗体”指具有两个抗原结合位点的小抗体片段,所述片段在同一条多肽链(VH-VL)中包含与轻链可变结构域(VL)连接的重链可变结构域(VH)。通过使用接头(因为太短而无法容许同一条链上的两个结构域之间配对),所述结构域被迫与另一条链的互补结构域配对并产生两个抗原结合位点。双体抗体在例如EP 404,097;WO 93/11161;和Hollinger等,Proc.Natl.Acad.Sci.USA,90:6444-48(1993)中有更全面的描述。
使用本领域技术人员已知的常规技术,例如通过重组DNA技术,或通过完整免疫球蛋白的酶促或化学切割,获得这些抗体片段。
如本文所使用的,术语“单克隆抗体”指从基本均质的抗体群体中获得的抗体,即,除了可能的变体抗体(例如,含有天然存在的突变或在单克隆抗体制备中出现的突变,这样的变体通常以少量存在),构成群体的单个抗体是相同的和/或结合相同的表位。
如本文所使用的,术语“嵌合抗体”意指某种抗体,其中使用重组DNA技术,把来自一个物种的单克隆抗体的Fc恒定区(例如,小鼠Fc恒定区)替换为来自另一物种的抗体的Fc恒定区(例如,人Fc恒定区)。参见,例如,Robinson等,PCT/US86/02269;Morrison等,欧洲专利申请173,494。
如本文所使用的,术语“人源化抗体”指包括人框架区和来自非人(例如小鼠、大鼠、兔或合成)免疫球蛋白的一个或多个CDR的抗体。提供CDR的非人免疫球蛋白称为“供体”,而提供框架的人免疫球蛋白称为“受体(acceptor)”。在一方面,所有CDR来自人源化免疫球蛋白中的供体免疫球蛋白。因此,除可能的CDR外,人源化免疫球蛋白的所有部分与天然人免疫球蛋白序列的相应部分基本相同。可以通过基因工程的手段构建人源化抗体(参见例如,美国专利号5,585,089)。
“受体人框架”意指包含源自人免疫球蛋白框架或人共有框架的轻链可变结构域(VL)框架或重链可变结构域(VH)框架的氨基酸序列的框架。“源自”人免疫球蛋白框架或人共有框架的受体人框架可包含其相同的氨基酸序列,或者其可含有氨基酸序列变化。在一些实施方案中,氨基酸变化的数目是1-10、2-9、3-8、4-7或5-6个。
“人共有框架”是代表在人免疫球蛋白VL或VH框架序列的选择中最常见的氨基酸残基的框架。一般而言,人免疫球蛋白VL或VH序列的选择来自可变结构域序列的亚型。一般而言,所述序列的亚型是如Kabat等,Sequences of Proteins of ImmunologicalInterest,第五版,NIH Publication 91-3242,BethesdaMD(1991),1-3卷中的亚型。在某些实施方案中,对于VL,所述亚型是如Kabat等(同上)中的亚型κI。在某些实施方案中,对于VH,所述亚型是如Kabat等(同上)中的亚型III。
如本文所使用的,术语“人抗体”意图包括具有源自人种系免疫球蛋白序列可变区和恒定区的抗体。本技术的人抗体可包括不由人种系免疫球蛋白序列编码的氨基酸残基(例如,由随机或位点特异性体外诱变或由体内体细胞突变引入的突变)。然而,本文所使用的术语“人抗体”不意图包括这种抗体,其中源自另一哺乳动物物种的种系(诸如兔)的CDR序列已移植入人框架序列。因此,如本文所使用的,术语“人抗体”指一种抗体,其中基本上所述蛋白的每个部分(例如,CDR、框架、CL、CH结构域(例如,CH1、CH2、CH3)、铰链、VL、VH)在人类中基本上无免疫原性,仅有微小的序列变化或变异。因此,人抗体不同于嵌合或人源化抗体。应当指出,人抗体可以由能够表达功能性重排的人免疫球蛋白(例如,重链和/或轻链)基因的非人动物或原核或真核细胞产生。
如本文所使用的,短语“双特异性抗体”或“双特异性抗原结合抗体”或“双功能抗体”是具有两个不同的重链/轻链对和两个不同的结合位点的人工杂交抗体。就本申请而言,“双特异性抗体”特异性结合PD-1和另一种抗原,例如,在肿瘤细胞上表达的肿瘤抗原。
“缀合物”是缀合至一个或多个异源分子的抗体,所述异源分子包括但不限于细胞毒性剂。
“阻断”抗体或“拮抗剂”抗体是抑制或降低其结合的抗原的生物学活性的抗体。优选的阻断抗体或拮抗剂抗体基本或完全抑制抗原的生物学活性。
如本文所使用的,术语“分离的”指基本上不含其他材料的分子或生物学或细胞材料。例如,当通过重组DNA技术产生时,基本上不含细胞材料、病毒材料或培养基的核酸或肽,或者在化学合成时,基本上不含化学前体或其他化学物质。此外,“分离的核酸”意在包括不天然以片段存在并且不会在天然状态下发现的核酸片段。术语“分离的”在本文中还用于指从其他细胞蛋白分离的多肽,并且意在涵盖纯化的和重组的多肽。
如本文所使用的,在两个或更多个核酸或多肽序列的上下文中使用的“同源性”或“同一性”的百分比,指两个或更多个序列或亚序列是相同的或具有指定百分比的相同核苷酸或氨基酸残基,例如在指定的区域上(例如,编码本文所述抗体的核苷酸序列或本文所述抗体的氨基酸序列)具有,至少80%同一性,优选地至少85%、90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或更高同一性。同源性可以通过比较各序列中的位置来确定,可以为了比较的目的对所述位置进行比对。当经比较的序列中的一个位置由相同的碱基或氨基酸占据时,则所述分子在所述位置是同源的。序列之间的同源性的程度是匹配数或序列共享的同源位置数的函数。可以使用本领域已知的软件程序做比对和确定同源性百分比或序列的同一性。优选地,使用默认参数用于比对。优选的比对程序是使用默认参数的BLAST。优选的程序是BLASTN和BLASTP。这些程序的细节可以在以下因特网地址找到:ncbi.nlm.nih.gov/cgi-bin/BLAST。
“亲和力”指分子(例如,抗体)的单个结合位点与其结合伴侣(例如,抗原)之间非共价相互作用的总强度。除非另有说明,否则如本文所使用的,“结合亲和力”指固有的结合亲和力,其反映结合对的成员(例如,抗体和抗原)之间的1:1相互作用。亲和力可以通过本领域已知的常规方法测量,包括,例如,Biacore,放射免疫测定(RIA)和ELISA。
分子X对其伴侣Y的亲和力通常可以通过平衡解离常数(KD)来表示,所述常数以比率koff/kon(kd/ka)计算。参见,例如,Chen,Y.,等,(1999)J.MoI Biol293:865-881。低亲和力抗体通常结合抗原缓慢并趋向于易于解离,而高亲和力抗体通常更快地结合抗原并趋向于保持更长时间的结合。在本申请的一个实施方案中,“解离速率(kd)”通过使用表面等离子体共振测定来测量。根据本申请,“合速率”或“缔合的速率”或“缔合速率(ka)”或“kon”也可以使用相同的表面等离子体共振技术确定,并且通过同时拟合缔合和解离传感图,使用简单的一对一Langmuir结合模型(BIAcore评价软件)计算。
如本文所使用的,术语“EC50”指在体外或体内测定中,结合PD-1和/或诱导应答的抗体或其抗原结合片段的浓度,其为最大结合或应答的50%,即最大结合或应答至基线的一半。
术语“癌症”、“赘生物(neoplasm)”和“肿瘤(tumor)”在本申请中可以互换使用,是指由细胞的异常不受控制的生长导致的赘生物或肿瘤,所述异常不受控制的生长使其对宿主生物体致病。在一些实施方案中,癌症指已局限于局部的良性肿瘤。在其他实施方案中,癌症指已经侵入并破坏了邻近身体结构并扩散到远端的恶性肿瘤。在一些实施方案中,所述癌症与特异性癌症抗原相关。
如本文所使用的,受试者的疾病“治(treating)”或“治疗(treatment)”指用于获得有益或所需结果的方法,所述结果包括但不限于以下的一种或多种:一种或多种症状的减轻或改善,病况(包括疾病)范围的缩小,病况(包括疾病)的稳定(即,不恶化)状态,病况(包括疾病)的延缓或减慢,病况(包括疾病)的进展、改善或缓和,状态和缓解(无论是部分还是全部),无论是可检测的还是不可检测的。
“药学上可接受的载体”是与活性成分构成药物制剂的载体。药学上可接受的载体包括但不限于,缓冲剂、赋形剂、稳定剂或防腐剂。
术语“包装插页”用于指代通常包括在治疗产品商业包装中的说明书。一般而言,在包装插页上有关于治疗产品的使用信息,诸如适应症、用法、剂量、施用、联合疗法、禁忌症和/或警告。
本申请将针对特定实施方案并参考某些附图进行描述,但是本申请不限于此,而是仅由权利要求来限定。如本说明书和权利要求中所使用的术语“包含”不排除其他元件或步骤。当提及单数名词时使用不定冠词或定冠词,例如,“一”或“一个”,“所述”,除非另有特别说明,否则其包括所述名词的复数形式。
2.抗PD-1抗体及其制备的方法
本申请涵盖分离的抗PD-1抗体或其片段,包含编码抗PD-1抗体或其片段的序列的多核苷酸。
分离的抗PD-1抗体或其片段与细胞(例如,癌细胞)上表达的PD-1分子高亲和力地结合,促进对癌细胞的有效免疫反应。本申请提供的抗体及其免疫活性片段能够增强免疫系统的活性,从而提供重要的治疗和诊断制剂,用于针对与PD-1分子的表达和/或活性相关的病理状况。在一方面,本申请提供一种分离的抗体或其抗原结合片段,包括一个重链(HC)可变区序列和一个轻链(LC)可变区序列。其中,所述抗体与PD-1的胞外结构域结合,其结合亲和力优于10nM或约10nM,优于8nM或约8nM,优于6nM或约6nM,优于4nM或约4nM,优于2nM或约2nM,优于1nM或约1nM,其通过SPR分析确定;例如约0.5-4nM,约0.8-4.0nM,约1.0-4.0nM,约2.0-4.0nM,约3.0-4.0nM,约0.6-3.5nM,约1.4-3.5nM,约2.5-3.5nM、约0.7-2.5nM、约0.8-2.0nM、约1.0-2.0nM、约0.4nM、0.3nM、0.2nM、0.1nM或更好,其通过SPR分析确定。
在某些实施方案中,本申请提供了一种抗体或其抗原结合片段,包含下述的至少一项:
(a)包含GFTFSSYGMS的CDR1H序列(SEQ ID NO:1)。
(b)包含IISGGGRDIYYLDSVKG的CDR2H序列(SEQ ID NO:2)。
(c)包含PIYDAYSFAY的CDR3H序列(SEQ ID NO:3)。
(d)包含RASQTISNNLH的CDR1L序列(SEQ ID NO:4)。
(e)包含YASQSIS的CDR2L序列(SEQ ID NO:5),和
(f)包含QQSYSWPLT的CDR3L序列(SEQ ID NO:6)。
在某些实施方案中,本申请提供一种抗体或其抗原结合片段,其中
(a)所述HC包含
包含GFTFSSYGMS的CDR1H序列(SEQ ID NO:1)。
包含IISGGGRDIYYLDSVKG的CDR2H序列(SEQ ID NO:2),和
包含PIYDAYSFAY的CDR3H序列(SEQ ID NO:3)。
(b)所述LC包含
包含RASQTISNNLH的CDR1L序列(SEQ ID NO:4)。
包含YASQSIS的CDR2L序列(SEQ ID NO:5),和
包含QQSYSWPLT的CDR3L序列(SEQ ID NO:6)。
在某些实施方案中,所述抗体是嵌合抗体、人源化抗体或人抗体。在某些实施方案中,本申请的抗体或其抗原结合片段进一步包含人受体框架。在某些实施方案中,所述人受体框架来自人免疫球蛋白框架或人共有框架。在某些实施方案中,所述人受体框架包含VL的亚型κI框架序列,以及VH的亚型III框架序列。通常,所述亚型序列是如Kabat等,Sequences ofProteins of Immunological Interest,Fifth Edition,NIH Publication91-3242,Bethesda MD(1991),vols.1-3中所述的亚型。在某些实施方案中,对于VL,所述亚群是如上所述的Kabat等所述的亚型κI。在某些实施方案中,对于VH,所述亚群是如上所述的Kabat等所述的亚型III。
在某些实施方案中,所述抗体或其抗原结合片段包含人共有框架。在某些实施方案中,所述抗体或其抗原结合片段包含具有氨基酸序列变化的人共有框架,例如,1-15、1-10、2-9、3-8、4-7或5-6个氨基酸变化。
在某些实施方案中,本申请的抗体或其抗原结合片段包含由SEQ ID NO:7或8所示的氨基酸序列组成的HC可变区序列,或与SEQ ID NO:7或8具有高于80%、85%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%同一性的氨基酸序列。在某些实施方案中,本申请的抗体或其抗原结合片段包含由SEQ ID NO:9或SEQ ID NO:10所示的氨基酸序列组成的LC可变区序列,或与SEQ ID NO:9或10具有高于80%、85%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%同一性的氨基酸序列。在某些实施方案中,HC可变区域序列包含SEQ ID NO:7的氨基酸序列,LC可变区域序列包含SEQ ID NO:9或SEQ ID NO:10的氨基酸序列。在某些实施方案中,HC可变区域序列包含SEQ ID NO:8的氨基酸序列,LC可变区域序列包含SEQ ID NO:9或SEQ ID NO:10的氨基酸序列。在某些实施方案中,本申请的抗体或其抗原结合片段包含由SEQ ID NO:11或12所示的氨基酸序列组成的HC序列,或与SEQID NO:11或12具有高于80%、85%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%同一性的氨基酸序列。在某些实施方案中,本申请的抗体或其抗原结合片段包含由SEQID NO:13或SEQ ID NO:14所示的氨基酸序列组成的LC序列,或与SEQ ID NO:13或14具有高于80%、85%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%同一性的氨基酸序列。在某些实施方案中,HC序列包含SEQ ID NO:11的氨基酸序列,LC序列包含SEQ ID NO:13或SEQ ID NO:14的氨基酸序列。在某些实施方案中,HC序列包含SEQ ID NO:12的氨基酸序列,LC可变区序列包含SEQ ID NO:13或SEQ ID NO:14的氨基酸序列。
在某些实施方案中,所述抗体是IgG同型,例如IgG1、IgG2或IgG4同型。在某些实施方案中,抗原结合片段包含选自下组的任一项:Fab、F(ab')2、Fab'、scFv和Fv。在某些实施方案中,本申请的抗体或其抗原结合片段是阻断抗体或拮抗剂抗体,它能抑制或降低其结合的PD-1分子的生物活性。优选所述阻断抗体或拮抗剂抗体基本上或完全抑制PD-1分子的生物活性。
本申请的抗PD-1抗体优选地为单克隆的。在本申请的范围内还涵盖的是本文提供的抗PD-1抗体的Fab、Fab'、Fab'-SH和F(ab')2片段。这些抗体片段可以通过诸如酶促消化的传统手段产生,或者可以通过重组技术生成。所述抗PD-1抗体及其片段可用于诊断和治疗目的,包括癌症的诊断和治疗。
单克隆抗体是从基本上均质的抗体群中获得的,即,除了可能天然存在的突变可少量存在以外,包含所述群的单个抗体是相同的。因此,修饰语“单克隆”表明所述抗体的特征不是不同抗体的混合物。可以使用杂交瘤方法或重组DNA方法(美国专利号4,816,567)制作本申请的单克隆抗PD-1抗体。
在杂交瘤方法中,通过整个PD-1分子或所述分子的部分(例如,包含PD-1的胞外结构域的多肽),与佐剂一起,免疫小鼠或其他适当的宿主动物,诸如仓鼠。可以使用本领域公知的方法制备PD-1分子或包含PD-1分子的胞外结构域的多肽。在一个实施方案中,使用含有PD-1的胞外区(ECD)的多肽免疫动物,所述胞外区与免疫球蛋白重链的Fc部分融合。在一个实施方案中,使用PD-1-IgG1融合蛋白免疫动物。两周后,对动物进行加强免疫。7至14天后,对动物采血,并测定血清的抗PD-1效价。对动物加强免疫直至效价平稳。或者,可以在体外免疫淋巴细胞。然后使用合适的融合剂(诸如,聚乙二醇)使淋巴细胞与骨髓瘤细胞融合以形成杂交瘤细胞(Goding,Monoclonal Antibodies:Principles andPractice,59-103页(Academic Press,1986))。
将由此制备的杂交瘤细胞接种并培养于合适的培养基中,所述培养基优选含有一种或多种抑制未融合亲代骨髓瘤细胞的生长或存活的物质。优选的骨髓瘤细胞是有效融合的,支持通过所选的产生抗体的细胞稳定高水平地产生抗体,并对培养基(诸如HAT培养基)敏感的那些骨髓瘤细胞。其中,优选的骨髓瘤细胞系是鼠源骨髓瘤细胞系,诸如SP-2或X63-Ag8-653细胞。(Kozbor,J.Immunol,133:3001(1984);Brodeur等,Monoclonal抗体Production Techniques and Applications,51-63页(Marcel Dekker,Inc.,New York,1987))还描述了把人骨髓瘤和小鼠人异源骨髓瘤细胞系用于生产人单克隆抗体。
在培养杂交瘤细胞的培养基中测定针对PD-1的单克隆抗体的产生。优选地,杂交瘤细胞产生的单克隆抗体的结合特异性通过免疫沉淀或通过体外结合测定,诸如放射免疫测定(RIA)或酶联免疫吸附测定(ELISA)来确定。
然后可以通过本领域的常规方法确定单克隆抗体的结合亲和力。鉴定出产生具有所需的特异性、亲和力和/或活性的抗体的杂交瘤细胞后,可通过有限的稀释程序来亚克隆并通过标准方法培养所述克隆(Goding,Monoclonal Antibodies:PrinciplesandPractice,59-103页(Academic Press,1986))。
用于所述目的的合适的培养基包括,例如,D-MEM或RPMI-1640培养基。另外,杂交瘤细胞可以作为腹水肿瘤在动物体内生长。通过常规免疫球蛋白纯化程序,将经亚克隆分泌的单克隆抗体从培养基、腹水液体或血清中适当地分离。
本申请的抗PD-1抗体可以通过使用组合文库针对具有所需的一种或多种活性的合成抗体克隆进行筛选来制作。大体上,合成抗体克隆通过筛选噬菌体文库来挑选,所述噬菌体文库含有展示抗体可变区(Fv)不同片段的噬菌体,所述Fv片段与噬菌体外壳蛋白融合。这种噬菌体文库通过针对目的抗原的亲和色谱淘选。表达的Fv片段的克隆可结合目的抗原,其吸附至抗原,由此从文库中的非结合克隆中分离出来。然后从抗原上洗脱结合的克隆,并且可以通过抗原吸附/洗脱的额外循环进一步富集。本申请的任何抗PD-1抗体均可通过以下方法获得:设计合适的抗原筛选程序,选择目的噬菌体克隆,然后使用来自目的噬菌体克隆的Fv序列和Kabat等在,Sequences ofProteins of Immunological Interest,第5版,NIH Publication 91-3242,Bethesda MD(1991),1-3卷中描述的合适的恒定区(Fc)序列构建全长抗PD-1抗体克隆。
VH和VL基因的组库(repertoire)可以通过聚合酶链反应(PCR)分别克隆,并在噬菌体文库中随机重组,然后可以搜索其中的抗原结合克隆,如Winter等,Ann.Rev.Immunol,12:433-455(1994)中所述。来自免疫来源的文库向免疫原提供高亲和力抗体,而无需构建杂交瘤。或者,可以克隆幼稚(naive)组库以向广泛的非自身和自身抗原提供单一来源的人抗体,而无需任何免疫,如Griffiths等,EMBO J,12:725-734(1993)所述。最后,幼稚文库还可以通过克隆来自干细胞的未重排的V基因节段,并使用含有随机序列的PCR引物以编码高度可变的CDR3区并在体外完成重排来合成制作,如Hoogenboom和Winter,J.MoI Biol,227:381-388(1992)中所述。
由幼稚文库(天然的或合成的)产生的抗体可以具有中等亲和力,但是亲和力成熟也可以通过构建二级文库并从中重新选择而在体外进行模拟。例如,可以通过在Hawkins等,J.MoLBiol.,226:889-896(1992)的方法中或Gram等,Proc.Natl.Acad.Sci USA,89:3576-3580(1992)的方法中使用易错聚合酶(在Leung等,Technique,1:11-15(1989)中报道的)在体外随机引入突变。另外,亲和力成熟可以在所选的单个Fv克隆中,通过随机突变一个或多个CDR来进行(例如,使用PCR和携带涵盖目的CDR的随机序列的引物),并筛选更高亲和力的克隆。另一种有效的方法是把通过噬菌体展示的所选VH或VL结构域与获得自未经免疫的供体的天然存在的V结构域变体组库重组,并在几轮链改组(chainreshuffling)中筛选更高的亲和力,如Marks等,Biotechnol,10:779-783(1992)中所述。
对于PD-1,即使亲和力略有不同,也可以在具有不同亲和力的噬菌体抗体之间挑选。然而,所选抗体的随机突变(例如,如在上述的一些亲和力成熟技术中所进行的)可能会产生许多突变体,大多数与抗原结合,少数几个具有更高的亲和力。为了保留所有更高亲和力的突变体,噬菌体可以与过量的生物素化的PD-1一起孵育,但是生物素化的PD-1的摩尔浓度低于针对PD-1的目标摩尔亲和常数。然后,高亲和力结合噬菌体可通过链霉亲和素包被的顺磁珠捕获。这样的“平衡捕获”容许根据抗体的结合亲和力来选择抗体,其敏感性容许从具有低亲和力的大量过量噬菌体中分离具有低至两倍高亲和力的突变体克隆。
可以基于活性的性能来挑选抗PD-1克隆。在一个实施方案中,本申请提供了阻断PD-1受体与其配体之间结合的抗PD-1抗体。具有本文所述的特性的本申请的抗PD-1抗体可以通过任何方便的方法针对所需特性通过筛选抗PD-1杂交瘤克隆来获得。例如,如果所需的抗体为阻断或不阻断PD-1受体与PD-1配体结合的抗PD-1单克隆抗体,则可以在结合竞争测定中测试候选抗体,诸如竞争性结合ELISA,其中板孔用PD-1包被,具有过量PD-1受体的抗体的溶液铺在经包被的板上,并通过酶促反应检测结合的抗体,例如使结合的抗体与缀合有HRP的抗Ig抗体或生物素化的抗Ig抗体接触,并进行HRP显色反应(例如通过用链霉亲和素-HRP和/或过氧化氢使板子显色,并使用ELISA酶标仪在490nm处通过分光光度法检测HRP显色反应)。
3.分离的多核苷酸、载体、宿主细胞和重组方法
本申请提供了分离的多核苷酸、载体或宿主细胞,包括本申请的上述抗PD-1抗体或其片段的编码序列。在一些实施方案中,所述抗PD-1抗体是本申请的杂交瘤来源的单克隆抗体或噬菌体展示Fv克隆。在一些实施方案中,编码本申请杂交瘤来源的单克隆抗体或噬菌体展示Fv克隆的DNA易于使用常规程序分离和测序(例如,通过使用寡核苷酸引物,其经设计以从杂交瘤或噬菌体DNA模板中特异性扩增目的重链和轻链编码区)。一经分离,所述DNA可置于表达载体中,然后转染到宿主细胞中(诸如大肠杆菌细胞、猿猴COS细胞、中国仓鼠卵巢(CHO)细胞,或不另外产生免疫球蛋白的骨髓瘤细胞),以在重组宿主细胞中获得所需的单克隆抗体的合成。
编码本申请的Fv克隆的DNA可以与编码重链和/或轻链恒定区的已知DNA序列(例如,合适的DNA序列可以从Kabat等(同上)获得)结合以形成编码全长或部分长度的重链和/或轻链的克隆。应当理解,任意同种型的恒定区可以用于所述目的,包括IgG、IgM、IgA、IgD和IgE恒定区,并且这样的恒定区可以从任意人类或动物物种获得。Fv克隆,其源自一个动物(诸如人)物种的可变结构域DNA,然后与另一动物物种的恒定区DNA融合以形成“杂交”,如本文所用的“嵌合”和“杂交”抗体的定义中包括全长重链和/或轻链的编码序列。在一个优选的实施方案中,源自人可变DNA的Fv克隆与人恒定区DNA融合以形成针对全人的、全长的或部分长度的重链和/或轻链的编码序列。
编码源自本申请的杂交瘤的抗PD-1抗体的DNA还可以经过修饰,例如,用人重链和轻链恒定结构域的编码序列替换源自杂交瘤克隆的同源鼠源序列(例如,如Morrison等,Proc.NatlAcad.Sci.USA,81:6851-6855(1984)中的方法)。编码杂交瘤或Fv克隆来源的抗体或片段的DNA可以通过将非免疫球蛋白多肽的全部或部分编码序列共价连接至免疫球蛋白编码序列来进一步修饰。以这种方式,制备具有本申请的Fv克隆或杂交瘤克隆来源的抗体的结合特异性的“嵌合”或“杂交”抗体。
为了重组生产本申请的抗体,编码它的核酸经分离并插入可复制的载体中以用于进一步克隆(DNA的扩增)或用于表达。编码抗体的DNA使用常规程序(例如,通过使用能够与编码抗体的重链和轻链的基因特异性结合的寡核苷酸探针)易于分离和测序。许多种载体可用。载体的选择部分取决于要使用的宿主细胞。一般而言,优选的宿主细胞是原核或真核(通常是哺乳动物)来源的。应当理解,任何同种型的恒定区可以用于所述目的,包括IgG、IgM、IgA、IgD和IgE恒定区,并且这样的恒定区可以从任意人类或动物物种获得。
4.缀合物及其制备方法
本申请的抗PD-1抗体或其片段与一种或多种其他分子(诸如毒素,例如卡奇霉素(calicheamicin)、美登木素生物碱类(maytansinoids)、海兔毒素类(dolastatins)、aurostatins、单端孢霉烯(trichothecene)和CC1065),以及这些毒素具有毒素活性的衍生物)、放射性同位素和免疫调节剂,在本申请中考虑。
在一些实施方案中,所述缀合物用于治疗T细胞淋巴瘤、B细胞淋巴瘤或淋巴细胞白血病,包括缀合了一个或多个美登木素生物碱分子的本申请的抗体(全长或片段)。美登木素生物碱类是通过抑制微管蛋白聚合起作用的有丝分裂抑制剂。美登木素(maytansine)最初是从东非灌木齿叶美登木(Maytenus serrate)中分离的(美国专利号3,896,111)。随后,发现某些微生物也生产美登木素生物碱类,诸如美登醇和C-3美登醇酯(美国专利号4,151,042)。含有美登木素生物碱类的免疫缀合物,其制备方法及其治疗用途在例如美国专利5,208,020、5,416,064号和欧洲专利EP 0425235 B1(其公开内容在此通过引用明确地并入)中公开。抗体和美登木素生物碱的缀合物可以使用多种双功能蛋白偶联剂制作,诸如N-琥珀酰亚胺基-3-(2-吡啶基二硫代)丙酸酯(SPDP),琥珀酰亚胺基-4-(N-马来酰亚胺基甲基)环己烷-1-羧酸酯(SMCC),亚氨基硫杂环戊烷(IT),亚氨酸酯的双功能衍生物。在一些实施方案中,所述缀合物包含本申请的抗体,其缀合至海兔毒素类或海兔毒素肽类似物和衍生物,奥瑞他汀(auristatin)(美国专利号5635483;5780588)。为了选择性地破坏肿瘤,所述抗体可包含高放射性原子。多种放射性同位素可用于生产放射性缀合的抗体。放射性或其他标记可以已知方式掺入所述缀合物。例如,所述肽可以是生物合成的,或者可以使用合适的氨基酸前体通过化学氨基酸合成来合成,包括例如用氟-9代替氢。"MonoclonalAntibodies in Immunoscintigraphy"(Chatal,CRC Press 1989)详细描述了其他方法。
在一些实施方案中,所述缀合物用于治疗T细胞淋巴瘤、B细胞淋巴瘤或淋巴细胞白血病,其包括结合一种或多种免疫调节剂的本申请的抗体(全长或片段),其中所述免疫调节剂可与抗体(全长或片段)协同工作,以增强针对抗原和异常细胞(包括肿瘤细胞)的免疫反应。在一些实施方案中,所述免疫调节剂选自下组的任一种:检查点抑制剂(诸如阿特珠单抗(Atezolizumab)、阿维单抗(Avelumab)、西米普利单抗(Cemiplimab)、度伐鲁单抗(Durvalumab)、伊匹单抗(Ipilimumab)、纳武单抗(Nivolumab)、派姆单抗(Pembrolizumab))、细胞因子(诸如阿地白介素(Aldesleukin)、粒细胞-巨噬细胞集落刺激因子、IFNα-2a、IFNα-2B、Pre-IFNα-2B)、激动剂和佐剂(诸如咪喹莫特(Imiquimod)或多聚ICLC),或与其作用相同的分子。
通常,基于肽的药物部分可以通过在两个或更多个氨基酸和/或肽片段之间形成肽键来制备。这样的肽键可以例如根据肽化学领域中公知的液相合成方法来制备。奥瑞他汀/海兔毒素药物部分可根据以下的方法制备:US 5635483;US 5780588。还可参见Doronina(2003)NatBiotechnol 21(7):778-784。
本申请进一步考虑了抗体和具有溶核活性的化合物(例如,核糖核酸酶或DNA核酸内切酶诸如脱氧核糖核酸酶;DNase)之间形成的免疫缀合物。
5.抗体片段和其制备方法
本申请包括了抗体片段。所述抗体片段是本申请的抗PD-1抗体的免疫活性片段。在某些情况下,使用抗体片段而不是整个抗体是有优势的。片段的尺寸较小,可以快速清除,并可使其更易于进入实体瘤。
已经开发了用于生产抗体片段的多种技术。传统上,这些片段经由完整抗体的蛋白水解消化而获得(参见,例如,Morimoto等,Journal ofBiochemical and BiophysicalMethods 24:107-117(1992);和Brennan等,Science,229:81(1985))。然而,这些片段现在可以直接由重组宿主细胞生产。Fab、Fv和ScFv抗体片段可在大肠杆菌中表达并从大肠杆菌中分泌,因此容许这些片段便利地大量生产。抗体片段可以从上述抗体噬菌体文库中分离。或者,Fab'-SH片段可以直接从大肠杆菌中回收并经化学偶联以形成F(ab')2片段(Carter等,Bio/Technology 10:163-167(1992))。根据另一种方法,F(ab')2片段可以直接从重组宿主细胞培养物中分离。美国专利5,869,046号中描述了体内半衰期增加的Fab和F(ab')2片段,其包含挽救受体(salvage receptor)结合表位残基。其他生产抗体片段的技术对本领域技术人员会是显而易见的。
在其他实施方案中,所选抗体是单链Fv片段(scFv)。参见WO 93/16185;美国专利5,571,894;和5,587,458号。Fv和scFv是现已知唯有的具有完整结合位点而没有恒定区的类型;因此,它们适合于在体内使用期间减少非特异性结合。可以构建scFv融合蛋白以在scFv的氨基或羧基末端产生效应蛋白的融合。参见抗体工程,Borrebaeck编,同上。所述抗体片段也可以是“线性抗体”,例如,如美国专利US 5,641,870号中所述的。这样的线性抗体片段可以是单特异性的或双特异性的。
6.人源化抗体和人抗体
本申请的抗PD-1抗体在一些实施方案中是人源化的抗体。各种使非人抗体人源化的方法在本领域是已知的。例如,人源化抗体可以具有从非人来源引入其的一个或多个氨基酸残基。这些非人氨基酸残基通常被称为“引进”残基,其通常取自“引进”的可变结构域。基本上可以按照Winter和同事的方法进行人源化(Jones等(1986)Nature 321:522-525;Riechmann等(1988)Nature 332:323-327;Verhoeyen等(1988)Science 239:1534-1536),通过用高变区序列取代人抗体的相应序列。因此,这样的“人源化”抗体是嵌合抗体(美国专利4,816,567号),其中基本上小于完整的人可变结构域的部分经由来自非人物种的相应序列取代。在实践中,人源化抗体通常是其中一些高变区残基和可能的一些FR残基经来自啮齿动物抗体中类似位点残基取代的人抗体。用于制作人源化抗体的人可变结构域(轻链和重链)的选择对于降低抗原性非常重要。根据所谓的“最佳-拟合”方法,针对已知的人可变结构域序列的整个文库筛选啮齿动物抗体的可变结构域序列。然后,把最接近啮齿动物的人序列作为人源化抗体的人框架(Sims等(1993)J.Immunol.151:2296;Chothia等(1987)J.MoI.Biol.196:901。另一种方法使用特定框架,所述框架源自轻链或重链的特定亚型的全人抗体的共有序列。
进一步重要的是将抗体人源化并保留对抗原的高亲和力和其他有利的生物学特性。为了达到所述目标,根据一个方法,通过使用亲本和人源化序列的三维模型对亲本序列和多种概念性人源化产物进行分析的过程来制备人源化抗体。三维免疫球蛋白模型是普遍可获得的并且对本领域技术人员是熟悉的。说明并显示所选候选免疫球蛋白序列可能的三维构象结构的计算机程序是可获得的。对这些展示内容进行检视,可分析残基在候选免疫球蛋白序列功能中可能作用,即,分析影响候选免疫球蛋白结合其抗原的能力的残基。通过这种方式,可以从受体和输入序列中选择并结合FR残基,以获得所需的抗体特性,诸如PD-1的增加的亲和力。
转基因动物(例如小鼠),其在没有内源性免疫球蛋白产生的情况下,免疫后也能够产生一整个组库的人抗体。例如,已有描述显示在嵌合和种系突变小鼠中抗体重链连接区(JH)基因的纯合缺失完全抑制了内源性抗体的产生。向这样的种系突变小鼠中导入人种系免疫球蛋白基因阵列会在抗原刺激后生产出人抗体。参见,例如,Jakobovits等,Nature,362:255(1993);Bruggermann等,Year inImmunol,7:33(1993)。
基因改组(Gene shuffling)也可用于从非人(例如啮齿动物)抗体中得到人抗体,其中所述人抗体与起始非人抗体具有相似的亲和力和特异性。根据所述方法(也称为“表位印迹”),将通过上述噬菌体展示技术获得的非人抗体片段的重链或轻链可变区替换为一组库的人V结构域基因,创建非人链/人链scFv或Fab嵌合体群。用抗原进行选择可分离非人链/人链嵌合scFv或Fab,其中人链恢复了去除初始噬菌体展示克隆中相应的非人链时被破坏的抗原结合位点,即,所述表位控制了(印记了)对人链伴侣的选择。当重复所述过程以替换剩余的非人链时,则获得人抗体(参见1993年4月1日公开的PCT WO 93/06213)。与通过CDR移植的传统非人抗体的人源化不同,所述技术提供了完全的人抗体,其没有非人来源的FR或CDR残基。
7.双特异性抗体及其制备方法
双特异性抗体是对至少两种不同抗原具有结合特异性的单克隆抗体,优选为人或人源化抗体。在本申请中,一个结合特异性是针对PD-1的,另一个是针对任意其他抗原的。示例性的双特异性抗体可结合PD-1蛋白的两个不同表位。双特异性抗体也可用于将细胞毒性剂定位于表达PD-1的细胞,在这种情况下,抗体拥有一个PD-1结合臂和一个细胞毒剂结合臂。
在一些实施方案中,所述双特异性抗体拥有PD-1结合臂,其包含本申请的抗PD-1抗体或其片段,以及与肿瘤抗原或免疫检查点蛋白结合的臂。在一些实施方案中,所述肿瘤抗原包含选自下组的任一项:A33;ADAM-9;ALCAM;BAGE;β-连环蛋白;CA125;羧肽酶M;CD103;CD19;CD20。CD22;CD23;CD25;CD27;CD28;CD36;CD40/CD154;CD45;CD46;CD5;CD56;CD79a/CD79b;CDK4;CEA;CTLA4;细胞角蛋白8;EGF-R;EphA2;ErbB1;ErbB3;ErbB4;GAGE-1;GAGE-2;GD2/GD3/GM2;HER-2/neu;人乳头瘤病毒-E6;人乳头瘤病毒-E7;JAM-3;KID3;KID31;KSA(17-1A);LUCA-2;MAGE-1;MAGE-3;MART;MUC-1;MUM-1;N-乙酰葡糖胺转移酶;抑瘤素M;pl5;PIPA;PSA;PSMA;ROR1;TNF-β受体;TNF-a受体;TNF-γ受体;转铁蛋白受体和VEGF受体。在一些实施方案中,所述免疫检查点蛋白包含选自下组的任一项:2B4;4-1BB;4-1BB配体,B7-1;B7-2;B7H2;B7H3;B7H4;B7H6;BTLA;CD155;CD160;CD19;CD200;CD27;CD27配体;CD28。CD40;CD40配体;CD47;CD48;CTLA-4;DNAM-1;半乳糖凝集素9;GITR;GITR配体;HVEM;ICOS;ICOS配体;IDOI;KIR;3DL3;LAG-3;OX40;OX40配体;PD-L1;PD-1;PD-L2;LAG3;PGK;SIRPα;TIM-3;TIGIT;VSIG8。
双特异性抗体可以制备为全长抗体或抗体片段(例如F(ab')2双特异性抗体)。制作双特异性抗体的方法是本领域已知的。通常,双特异性抗体的重组生产基于两个免疫球蛋白重链-轻链对的共表达,其中两个重链具有不同的特异性。由于免疫球蛋白重链和轻链的随机组合,这些杂交瘤(四源杂交瘤)产生可能具有10种不同抗体分子的混合物,其中只有一种具有正确的双特异性结构。对正确分子的纯化,其通常通过亲和色谱步骤完成,相当麻烦,并且产率低。根据不同且更优选的方法,将具有需的结合特异性(抗体-抗原结合位点)的抗体可变结构域与免疫球蛋白恒定结构域序列融合。融合物优选地与免疫球蛋白重链恒定结构域融合,所述结构域包含铰链、CH2和CH3区的至少一部分。优选的在至少一个融合物中具有第一重链恒定区(CH1),所述CH1含有轻链结合所必需的位点。将编码免疫球蛋白重链融合物和(如果需要)免疫球蛋白轻链的DNA插入单独的表达载体中,并共转染到合适的宿主生物体中。当在构建体中使用比例不等的三个多肽链提供最佳产率时,其为实施方案中调节三个多肽片段的相互比例提供了极大灵活性。然而,当至少两条多肽链以相等比例表达导致高产率或当比例没有特别意义时,则可以在一个表达载体中插入两个或全部三个多肽链的编码序列。
在所述方法的优选实施方案中,所述双特异性抗体由在一个臂中具有第一结合特异性的杂交免疫球蛋白重链和在另一个臂中的杂交免疫球蛋白重链-轻链对(提供第二结合特异性)组成。已经发现,所述不对称结构有助于将所需的双特异性化合物从不需要的免疫球蛋白链组合中分离,因为仅在双特异性抗体的一半中存在免疫球蛋白轻链提供了一种便利的分离方式。所述方法在WO 94/04690中公开。生成双特异性抗体的进一步细节参见,例如,Suresh等,Methods in Enzymology,121:210(1986)。
8.药物组合物
包含本申请的抗PD-1抗体片段、多核苷酸、载体、宿主细胞、缀合物或双特异性抗体的治疗剂,其通过将具有所需纯度的本申请的抗PD-1抗体、片段、多核苷酸、载体、宿主细胞、缀合物或双特异性抗体与可选的生理学上可接受的载体、辅料或稳定剂(Remington:The Science and Practice of Pharmacy 20th edition(2000)),以水溶液、冻干或其他干燥剂的形式制备以用于储存。所述可接受的载体、赋形剂或稳定剂在采用的剂量和浓度下对受试者无毒,并且包括缓冲剂,诸如磷酸盐、柠檬酸盐、组氨酸和其他有机酸;抗氧化剂,包括抗坏血酸和蛋氨酸;防腐剂;低分子量(少于约10个残基)多肽;蛋白质,诸如血清白蛋白、明胶或免疫球蛋白;亲水聚合物,诸如聚乙烯吡咯烷酮;氨基酸,诸如甘氨酸、谷氨酰胺、天冬酰胺、组氨酸、精氨酸或赖氨酸;单糖、二糖和其他碳水化合物,包括葡萄糖、甘露糖或糊精;螯合剂,诸如EDTA;糖类,诸如蔗糖、甘露醇、海藻糖或山梨糖醇;成盐的反荷离子,诸如钠;金属络合物;和/或非离子表面活性剂,诸如TWEENTM、PLURONICSTM或聚乙二醇(PEG)。
如所治疗的特定适应症所需要的,本文的制剂还可含有一种以上的活性化合物,优选地为具有互补活性而不对彼此造成不利影响的那些化合物。这样的分子适于以对预期目的有效的量存在于组合中。
在胶体药物递送系统(例如,脂质体、白蛋白微球、微乳剂、纳米颗粒和纳米胶囊)中或粗乳状液中,所述活性成分也可包裹在例如通过凝聚技术或通过界面聚合制备的微胶囊中,例如分别为羟甲基纤维素或明胶-微胶囊和聚(甲基丙烯酸甲酯)微胶囊。
可以制备缓释制剂。缓释制剂的合适实例包括含有本申请的免疫球蛋白的固体疏水性聚合物的半透性基质,所述基质为成型制品的形式,例如,薄膜或微胶囊。
9.抗PD-1抗体的诊断和治疗用途
在一方面,基于本文公开的抗体和PD-1的特异性结合,本申请的抗体可以用于检测和定量生理样本,诸如尿液、血浆、细胞裂解液和活检样本中的PD-1多肽。因此,本文公开的抗PD-1抗体可用于在诊断上监测组织中的PD-1水平,例如,以确定癌症的进展和/或给定治疗方案的功效。本领域技术人员知道,本文公开的PD-1抗体可以与可检测材料偶联以促进检测。在某些实施方案中,本文公开的抗PD-1抗体或其片段连接至固相支承体以促进检测。
在另一方面,基于本文公开的抗体和PD-1的特异性结合,本申请的抗体可以用于,例如,通过亲和色谱法或免疫沉淀法分离,通过流式细胞术方法分析或分选细胞,以及通过免疫组织化学、细胞学分析、ELISA或免疫沉淀法检测固定的组织样本或细胞涂片样本中的PD-1多肽。
在某些实施方案中,要检测、定量或分析的PD-1分子是人PD-1蛋白或其片段。在某些实施方案中,将PD-1蛋白或其片段置于溶液中,诸如裂解溶液或含有破碎细胞的亚细胞级分的溶液,或存在于PD-1阳性细胞的表面上,或含有PD-1和其他细胞成分的复合物中。
本申请的检测方法可以用于在体外以及体内检测生物样本中PD-1多肽的表达水平。用于检测PD-1多肽的体外技术包括酶联免疫吸附测定(ELISA)、蛋白质印迹、流式细胞术、免疫沉淀、放射免疫测定和免疫荧光(例如,IHC)。此外,用于检测PD-1多肽的体内技术包括将标记的抗PD-1抗体引入受试者。仅作为示例,可以用放射性标志物标记抗体,所述放射性标志物在受试者中的存在和位置可以通过标准成像技术检测。
用于检测蛋白质基因表达的其他基于抗体的方法包括免疫测定,诸如酶联免疫吸附测定(ELISA)和放射免疫测定(RIA)。合适的抗体测定标记是本领域已知的,并且包括酶标记(诸如葡萄糖氧化酶)和放射性同位素或其他放射性试剂,以及荧光标记(诸如荧光素和若丹明(rhodamine)),以及生物素。
本文公开的PD-1抗体或其片段可以用作任意种类的生物样本的诊断试剂。在一方面,本文公开的PD-1抗体可用作人类生物样本的诊断试剂。PD-1抗体可以用于以多种标准测定形式测定PD-1多肽。此种形式包括免疫沉淀、蛋白质印迹、ELISA、放射免疫测定、流式细胞术、IHC和免疫计量测定。
本申请还提供了抗PD-1抗体及其片段的预后(或预测)用途,用于确定受试者是否处于患有与增加的PD-1多肽表达或活性相关的内科疾病或病况的风险中(例如,检测癌前细胞)。因此,本文公开的抗PD-1抗体及其片段可以用于预后或预测目的,以在内科疾病或病况(例如癌症)的发作前预防性治疗个体,所述内科疾病或病况(例如癌症)特征在于PD-1多肽表达或活性的增加,或与PD-1多肽表达或活性的增加相关。
本申请的另一方面提供了用于确定受试者中PD-1表达的方法,以由此筛选内科疾病或病况(例如癌症)的治疗或预防化合物,所述内科疾病或病况(例如癌症)特征在于PD-1多肽表达或活性的增加,或与PD-1多肽表达或活性的增加相关。
在某些实施方案中,上述内科疾病或病况为癌前病况或癌症,所述内科疾病或病况特征在于PD-1多肽的表达或活性或PD-1多肽表达或活性的增加,或与PD-1多肽表达或活性的增加相关。在某些实施方案中,可以使用预后测定来鉴定患有癌症或处于患癌风险的受试者。因此,本申请提供了一种方法,其用于鉴定与PD-1多肽表达水平增加相关的疾病或病况(例如癌症),其中测试样本获取自受试者并可检测到PD-1多肽,其中,若与对照样本相比存在PD-1多肽水平的增加,则预测受试者患有与增加的PD-1多肽表达水平相关的疾病或病况(例如癌症)或处于患所述病或病况(例如癌症)的风险中。
在另一方面,本申请提供了用于确定受试者是否可以用治疗剂进行有效治疗的方法,所述治疗剂针对与PD-1多肽表达的增加相关的病症或病况(例如癌症),其中生物学样本获自受试者并且使用PD-1抗体检测PD-1多肽。确定从受试者获得的生物样本中PD-1多肽的表达水平,并将其与在从无疾病的受试者获得的生物样本中发现的PD-1表达水平比较。与从健康受试者获得的样本相比,从疑似患有疾病或病况的受试者获得的样本中PD-1多肽水平升高指示待测试的受试者中PD-1相关的疾病或病况(例如癌症)。
在一方面,本申请提供了监测药剂对PD-1多肽表达的治疗功效的方法。这样的测定可以应用于药物筛选和临床试验。例如,可以在表现出升高的PD-1表达的受试者例如被诊断有癌症的患者的临床试验中监测药剂降低PD-1多肽水平的有效性。可以通过施用药剂并观察反应来鉴定影响PD-1多肽表达的药剂。以此方式,PD-1多肽的表达模式可以用作标志物来指示受试者对药剂的生理反应。
前述仅仅是使用本申请的抗PD-1抗体及其片段的示例性测定。现在或以后开发的使用抗体或其片段用于测定PD-1的其他方法也包括在本申请的范围内。
在一方面,本申请提供了用于治疗癌症的方法,所述方法包括向需要这样的治疗的受试者施用有效量的特异性结合PD-1的抗PD-1抗体或其片段。本申请的抗体可以用于治疗、抑制与包括PD-1分子的一种或多种抗原分子的表达和/或活性有关,或对与包括PD-1分子的一种或多种抗原分子的表达和/或活性增加有关的疾病、病症或病况,延迟其进展,预防/延迟其复发,改善或预防所述疾病、病症或病况。
对于本申请的抗PD-1抗体或其片段的治疗用途,本申请的抗体的适当剂量(当单独使用或与其他药剂组合使用时,会取决于要治疗的疾病的类型、抗体的类型、疾病的严重程度和病程、是否为预防或治疗目的而施用抗体、既往治疗、患者的临床病史和对所述抗体的应答,以及主治医师的判断。所述抗体适合一次或多次施用于患者。取决于疾病的类型和严重程度,约1μg/kg至15mg/kg(例如0.1mg/kg-10mg/kg)的抗体是向患者施用的合适剂量,无论是例如通过一次或多次单独施用,还是通过连续输注。
本申请的抗体可以单独使用或与其他组合物联合用于治疗。例如,本申请的抗体可以与另一种抗体、类固醇(诸如可吸入的、全身或皮肤类固醇)、化学治疗剂(包括化学治疗剂的混合物)、其他细胞毒性剂、抗血管生成剂、细胞因子和/或生长抑制剂共施用。上述这样的联合疗法包括联合施用(其中两种或更多种药剂包括在相同或分开的制剂中)和分开施用,在这种情况下,在施用一种或多种其他药剂之前、期间和/或之后,可以施用本申请的抗PD-1抗体或其片段。联合施用的治疗剂的有效量取决于诸如以下因素:要使用的治疗剂的类型和要治疗的特定患者。并且通常会由医生或兽医决定。
10.试剂盒和制品
本申请提供了用于确定PD-1的表达水平的诊断方法。在一个具体的方面,本申请提供了用于确定PD-1的表达水平的试剂盒。所述试剂盒包含本文公开的抗PD-1抗体或其片段以及关于如何使用试剂盒的说明书,例如,用于收集样本和/或进行检测和/或分析结果的说明书。所述试剂盒可用于检测生物样本例如任意体液中PD-1多肽的存在,所述体液包括但不限于,例如,痰、血清、血浆、淋巴液、囊肿液、尿液、粪便、脑脊髓液、腹水或血液,包括人体组织的活检样本。所述测试样本还可以是肿瘤细胞、与肿瘤相邻的正常细胞、与肿瘤组织类型相对应的正常细胞、血细胞、外周血淋巴细胞,或它们的组合。
在某些实施方案中,所述试剂盒可进一步包含本申请的抗PD-1抗体之外的一种或多种其他PD-1抗体,其能够结合生物样本中的PD-1多肽。所述一种或多种PD-1抗体可以带标记。在某些实施方案中,所述试剂盒包含例如附接至固相支承物的第一抗体,其结合PD-1多肽;以及可选:2)第二、不同的抗体,其与PD-1多肽或第一抗体结合并缀合有可检测标记。
所述试剂盒还可以包含,例如,缓冲剂、防腐剂或蛋白稳定剂。所述试剂盒还可包含检测可检测标记所必需的组分,例如酶或底物。试剂盒还可以含有一种对照样本或一系列对照样本,其可以经测定并与所述测试样本进行比较。所述试剂盒的每个组分可以装在一个单独的容器中,所有多个容器可以放在单个包装中,同时在包装插页写上有关如何使用试剂盒的说明,例如,用于收集样本和/或进行检测和/或分析结果的说明。
在另一方面,本申请提供了一种制品,其包含用于治疗、预防和/或诊断上述病症的材料。所述制品包含容器和容器上或与容器相连的标签或包装插页,所述标签或包装插页上具有例如治疗适应症、施用方案和警告的书面说明。合适的容器包括例如瓶子、小瓶、注射器等。所述容器可以由多种材料形成,诸如玻璃或塑料。所述容器容纳包含本申请的抗PD-1抗体或其片段的组合物,所述组合物本身或与另一种组合物联合时,对治疗、预防和/或诊断内科疾病或病况(例如,癌症)有效,所述内科疾病或病况(例如,癌症)的特征在于包括PD-1多肽的一种或多种分子的表达和/或活性的增加,或与一种或多种分子的表达和/或活性的增加相关。
所述制品可包含:(a)第一容器,其中含有组合物,其中所述组合物包含本申请的抗体;和(b)第二、第三或第四容器,其具有包含另一种活性成分的组合物。另外,所述制品可进一步包含含有药学上可接受的缓冲液(诸如抑菌注射用水(BWFI)、磷酸盐缓冲盐水、林格氏溶液(Ringer's solution)和葡萄糖溶液)的容器。其可进一步包括从商业和用户角度来看所需的其他材料,包括其他缓冲液、稀释剂、过滤器、针头和注射器。
11.治疗方法
本申请的抗PD-1抗体或其片段可用于特定治疗方法。本申请进一步包含基于抗体的疗法,其涉及将有效量的本申请的抗体或其抗原结合片段、双特异性抗体、多肽、缀合物、组合物、制品或试剂盒施用于患者,例如人类患者或非人灵长类动物,以治疗本文所述的一种或多种疾病或病况。
在一些实施方案中,所述患者是患有肿瘤的患者。在一些实施方案中,所述患者是患有感染的。在一个实施方案中,所述患者带有肿瘤细胞或感染的细胞,其过表达PD-1配体,例如过表达PD-L1和/或PD-L2。
癌症的非限制性实例包括结肠直肠癌、子宫内膜癌、食道癌、头颈癌、甲状腺癌、白血病(包括急性白血病(例如,急性淋巴细胞白血病、急性骨髓细胞(包括成髓细胞、早幼粒细胞、髓单核细胞、单核细胞的和红白血病)白血病和慢性白血病(例如,慢性髓细胞(粒细胞)白血病和慢性淋巴细胞白血病))、真性红细胞增多、淋巴瘤(例如,霍奇金病和非霍奇金病)、多发性骨髓瘤、华氏巨球蛋白血症、重链病和实体瘤(包括但不限于肉瘤和恶性上皮肿瘤,诸如纤维肉瘤、肌肉瘤、脂肪肉瘤、软骨肉瘤、成骨肉瘤、脊索瘤、血管肉瘤、内皮肉瘤、淋巴管肉瘤、淋巴管内皮肉瘤、滑膜瘤、间皮瘤、尤文氏瘤、平滑肌肉瘤、横纹肌肉瘤、结肠癌、胰腺癌、乳腺癌、卵巢癌、前列腺癌、鳞状细胞癌、基底细胞癌、腺癌、汗腺癌、皮脂腺癌、乳头状上皮癌、乳头状腺癌、囊腺癌、髓样癌、支气管癌、肾细胞癌、肝癌、胆管癌、绒毛癌、精原细胞癌、胚胎癌、威尔姆氏肿瘤、宫颈癌、睾丸肿瘤、肺癌、小细胞肺癌、膀胱癌、上皮癌、胶质瘤、星形细胞瘤、髓母细胞瘤、颅咽管瘤、室管膜瘤、松果体瘤、血管母细胞瘤、听神经瘤、少突胶质细胞瘤、脑膜瘤、黑色素瘤、神经母细胞瘤和视网膜母细胞瘤。而在某些实施方案中,所述感染是病毒、细菌、真菌或寄生虫感染。在某些特定的实施方案中,所述感染是HIV感染。
本申请还提供了细胞疗法,以及在某些实施方案中的嵌合抗原受体(CAR)T细胞疗法。可以使用合适的T细胞,所述T细胞与本申请的抗PD-1抗体或其片段接触(或可选地被工程化以表达本申请的抗PD-1抗体或其结合片段)。在这种接触或工程化后,所述T细胞可以被引入至需要治疗的癌症患者。所述癌症患者可患有本文所披露的任何类型的癌症。所述T细胞可以是,例如,肿瘤浸润性T淋巴细胞,CD4+T细胞,CD8+T细胞,或其组合,没有限制。在一些实施方案中,所述T细胞是从癌症患者身上分离出来的。在一些实施方案中,所述T细胞是由供者或从细胞库中提供的。当所述T细胞从癌症患者身上分离出来时,可以最大限度地减少不希望发生的免疫反应。当T细胞由患者本人以外的供者提供或来自细胞库时,编码T细胞受体和HLA基因的一个或多个基因会被敲除。
任何特定患者的具体剂量和治疗方案将取决于各种因素,包括所使用的本申请的抗PD-1抗体或其片段、患者的年龄、体重、一般健康状况、性别和饮食,以及给药时间、排泄率、药物联用和所治疗的特定疾病的严重程度。医疗护理人员对这些因素的判断属于本领域的常规技术。用药量还取决于要治疗的患者个体、给药途径、药剂类型、所用化合物的特性、疾病的严重程度和所需效果。使用量可以通过本领域众所周知的药理学和药代动力学原理来确定。
在一些实施方案中,本申请的抗体或其抗原结合片段、双特异性抗体、多肽、缀合物、组合物、制品或试剂盒与抗肿瘤剂、抗病毒剂、抗菌或抗生素剂或抗真菌剂联合施用。本领域已知的这些药剂中的任何一种都可以以目前披露的组合物施用。
在另一个实施方案中,本申请的抗体或其抗原结合片段、双特异性抗体、多肽、缀合物、组合物、制品或试剂盒与化疗剂联合施用。可与本申请的组合物一起施用的化学治疗剂包括但不限于抗生素衍生物(如多柔比星、博莱霉素、柔红霉素和放线菌素D);抗雌激素(例如,他莫昔芬);抗代谢物(例如,氟尿嘧啶、5-FU、甲氨蝶呤、氟尿嘧啶、干扰素α-2b、谷氨酸、普利卡霉素、巯嘌呤和6-硫代鸟嘌呤);细胞毒剂(例如,卡莫司汀、BCNU、洛莫司汀、CCNU、阿糖胞苷、环磷酰胺、雌莫司汀、羟基脲、甲基苄肼、丝裂霉素、白消安、顺铂和硫酸长春新碱);激素(例如,甲羟孕酮、雌莫司汀磷酸钠、炔雌醇、雌二醇、醋酸甲地孕酮、甲基睾酮、己烯雌酚磷酸酯(diethylstilbestrol diphosphate)、氯烯雌醚和睾内酯);氮芥衍生物(例如,美法仑,苯丁酸氮芥,二氯甲基二乙胺(氮芥)以及塞替派);类固醇及其组合物(例如,倍他米松磷酸钠);以及其他(例如,达卡巴嗪,门冬酰胺酶,米托坦,硫酸长春新碱,硫酸长春碱,以及依托泊苷)。
在另一个实施方案中,本申请的抗体或其抗原结合片段、双特异性抗体、多肽、缀合物、组合物、制品或试剂盒与细胞因子联合施用,其中所述细胞因子包括但不限于IL-2、IL-3、IL-4、IL-5、IL-6、IL-7、IL-l0、IL-12、IL-13、IL-15、抗CD40、CD40L、和TNF-α。在另外的实施方案中,本申请的组合物与其他治疗或预防方案(例如放射疗法)联合施用。
本申请的抗体或其抗原结合片段、双特异性抗体、多肽、缀合物、组合物、制品或试剂盒在一些实施方案中可与免疫检查点抑制剂一起使用。免疫检查点是免疫系统中的下述分子,它们要么调高信号(共刺激分子),要么调低信号。许多癌症通过抑制T细胞信号来保护自己免受免疫系统的伤害。免疫检查点抑制剂可以帮助阻止这种保护机制。免疫检查点抑制剂可以针对以下检查点分子中的任何一个或多个:2B4;4-1BB;4-1BB配体,B7-1;B7-2;B7H2;B7H3;B7H4;B7H6;BTLA;CD155;CD160;CD19;CD200;CD27;CD27配体。CD28;CD40;CD40配体;CD47;CD48;CTLA-4;DNAM-1;Galectin-9;GITR;GITR配体;HVEM;ICOS;ICOS配体;IDOI;KIR;3DL3;LAG-3;OX40;OX40配体;PD-L1;PD-1;PD-L2;LAG3;PGK;SIRPα;TIM-3;PD-1;VSIG8。
程序性T细胞死亡1蛋白(PD-1)是一种在T细胞表面发现的跨膜蛋白,当它与肿瘤细胞上的程序性T细胞死亡配体1(PD-L1)结合时,会导致T细胞活性的抑制和T细胞介导的细胞毒性的降低。因此,PD-1和PD-L1是免疫下调因子或免疫检查点"关闭开关"。PD-1抑制剂的示例包括但不限于:纳武单抗(Opdivo)(BMS-936558),派姆单抗(Keytruda,匹地利珠单抗,AMP-224,MEDI0680(AMP-514,PDR001,MPDL3280A,MEDI4736,BMS-936559和MSB0010718C。程序性死亡配体1(PD-L1),也被称为分化簇274(CD274)或B7同源物1(B7-H1),是一种蛋白质,在人类中由CD274基因编码。PD-L1抑制剂的非限制性示例包括:阿特珠单抗(Tecentriq)、度伐鲁单抗(MEDI4736)、阿维单抗(MSB0010718C)、MPDL3280A、BMS935559(MDX-l05)和AMP-224。CTLA-4是一种下调免疫系统的蛋白受体。CTLA-4抑制剂的非限制性示例包括伊匹单抗(Yervoy)(也被称为BMS-734016、MDX-0l0、MDX-l0l)和曲美木单抗(tremelimumab)(原为替西利姆单抗(ticilimumab),CP-675,206)。淋巴细胞激活基因3(LAG-3)是细胞表面的一种免疫检查点受体,通过对Tregs的作用以及对CD8+T细胞的直接作用来抑制免疫反应。LAG-3抑制剂包括但不限于LAG525和BMS-986016。CD28在几乎所有的人类CD4+T细胞和大约一半的CD8 T细胞上组成性表达。促使T细胞扩增。CD28抑制剂的非限制性示例包括TGN1412。CD122增加CD8+效应T细胞的增殖。非限制性示例包括NKTR-214。4-IBB(也被称为CD137)参与T细胞增殖。已知CD137介导的信号传导也可保护T细胞,尤其是CD8+T细胞免受活化诱导的细胞死亡。PF-05082566、乌瑞芦单抗(Urelumab)(BMS-663513)和脂质运载蛋白是CD137抑制剂的示例。
对于上述任何一种的联合治疗,本申请的抗体或其抗原结合片段、双特异性抗体、多肽、缀合物、组合物、制品或试剂盒可以与其他抗癌剂同时或分开给药。
在一个实施方案中,提供了一种治疗或抑制有需要的患者的感染的方法,包括向患者施用有效量的本申请的抗体或其抗原结合片段、双特异性抗体、多肽、缀合物、组合物、制品或试剂盒。
实施例
实施例1.抗PD-1抗体的产生
BALB/c小鼠(6周龄,购自北京维通利华实验动物技术有限公司)通过皮下注射his-标记的人PD-1重组蛋白(PD-1/6His,自产,NCBI登记号:NP_005009.2,胞外结构域Pro21-Gln167)和完全弗氏佐剂(SigmaAldrich#F5881)进行免疫。重复免疫4次,每次间隔3天。用蛋白质免疫后,用辐照的表达人PD-1的Jurkat细胞(在实施例6中生成)对小鼠进行2次免疫。末次免疫3天后,仔细剖析靠近注射部位的淋巴结。淋巴细胞与P3X63Ag8.653骨髓瘤细胞(细胞库,中国科学院,#TCM10)用PEG1500(聚乙二醇1500,罗氏#783641,10x 4mL,溶于75mM Hepes,PEG 50%W/V)融合,并用HAT选择法(Sigma#H0262)和HFCS(杂交瘤融合和克隆补充剂,50x,罗氏#11-363-735-001)克隆。通过ELISA和细胞基质测定对杂交瘤上清液进行筛选,以获得能与人PD-1结合的抗体。使用CDR移植法和反向突变对选定的小鼠抗PD-1克隆进行人源化。
通过CDR移植法实现抗体的人源化:对受体框架(acceptor framework)进行选择。使用NCBI Ig-Blast(http://www.ncbi.nlm.nih.gov/projects/igblast)在人类种系数据库中搜索亲代抗体的可变区序列。为每个重链和轻链选择五个不同的人受体(即与亲本抗体具有高度同源性的人类可变区)。将人受体的CDR替换为小鼠的CDR,从而形成人源化的可变区序列。然后,进行反向突变,产生了4条重链和轻链。重链和轻链的鼠源CDR序列(SEQ IDNO:1-6)分别如下所示。设计、合成了9条人源化重链和9条人源化轻链的编码基因,并将其插入表达载体中。表达人源化抗体,然后用于测试亲和力排名。
实施例2:抗PD-1抗体的表达和纯化
合成编码人源化IgG重链和轻链的DNA序列并将其插入pTT5载体(GenscriptBiotech公司有售)以构建全长IgG的表达质粒。嵌合抗体的表达在HEK293细胞培养物(ThermoFisher Scientific公司有售)中进行,上清液用蛋白A亲和柱(Yeasen#36410ES08)纯化。使用PD-10脱盐柱(ThermoFisher Scientific有售)将纯化的抗体通过缓冲液交换至PBS中。纯化的抗体的浓度和纯度分别通过OD280和SDS-PAGE测定。人源化抗体在HEK 293细胞培养物中表达。离心沉淀细胞。过滤上清液并进行SDS-PAGE分析(图1)。将人IgG随机混合物(可从Genscript生物技术公司购买)用作对照。结果表明,人源化抗体被成功地表达和纯化了。
实施例3.SPR分析抗PD-1抗体与人PD-1的结合亲和力
使用胺偶联法将抗人Fc gamma特异性抗体(Jackson ImmunoResearch#109-005-098)固定在传感器芯片上。将分泌到培养基中的人源化抗体加上嵌合VH+VL(亲代小鼠VH+VL与人Fc结合)分别注入并用抗人Fc抗体通过Fc(捕获阶段)进行捕获。平衡后,注入PD-1200秒(结合阶段),然后注入电泳缓冲液600秒(解离阶段)。从每个循环的人源化抗体流通池的响应值中减去参比流动池(流动池1)的响应值。在注入其他人源化抗体之前,使表面再生。重复进行所述过程,直到分析完所有抗体。人源化抗体的脱落率是通过使用Biacore8K评估软件将试验数据局部拟合为1:1的相互作用模型得到的。抗体按其解离率常数(脱落率,kd)进行排序。挑选出与PD-1亲和力类似于亲本抗体的结合剂(表1)。
表1.亲和力测量数据
因此,选择了VH6+VL1、VH6+VL6、VH7+VL1和VH7+VL6进行进一步鉴定。表2中的抗体或其片段的序列如下所示。
CDR1H氨基酸序列(SEQ ID NO:1)
GFTFSSYGMS
CDR2H氨基酸序列(SEQ ID NO:2)
IISGGGRDIYYLDSVKG
CDR3H氨基酸序列(SEQ ID NO:3)
PIYDAYSFAY
CDR1L氨基酸序列(SEQ ID NO:4)
RASQTISNNLH
CDR2L氨基酸序列(SEQ ID NO:5)
YASQSIS
CDR3L氨基酸序列(SEQ ID NO:6)
QQSYSWPLT
重链可变区(VH6)氨基酸序列(SEQ ID NO:7)
EVQLVESGGGLVQPGGSLRLSCAASGFTFSSYGMSWVRQAPGKRLEWAIISGGGRDIYYLDSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCSSPIYDAYSFAYWGQGTLVTVSS
重链可变区(VH7)氨基酸序列(SEQ ID NO:8)
EVQLVESGGGLVQPGGSLRLSCAASGFTFSSYGMSWVRQAPGKGLEWAIISGGGRDIYYLDSVKGRFTISRDNSKNNLYLQMNSLRAEDTAVYYCSSPIYDAYSFAYWGQGTLVTVSS
轻链可变区(VL1)氨基酸序列(SEQ ID NO:9)。
EIVMTQSPATLSVSPGERATLSCRASQTISNNLHWYQQKPGQAPRLLIYYASQSISGIPARFSGSGTEFTLTISSLQSEDFAVYYCQQSYSWPLTFGGGTKLEIK
轻链可变区(VL6)氨基酸序列(SEQ ID NO:10)
EIVLTQSPATLSVSPGERATLSCRASQTISNNLHWYHQKPGQAPRLLIKYASQSISGIPSRFSGSGTDFTLTISSLQSEDFAVYFCQQSYSWPLTFGGGTKLEIK
包含VH6的重链氨基酸序列1(HC1)(SEQ ID NO:11,全长序列)。
EVQLVESGGGLVQPGGSLRLSCAASGFTFSSYGMSWVRQAPGKRLEWVAIISGGGRDIYYLDSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCSSPIYDAYSFAYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK
包含VH7的重链氨基酸序列2(HC2)(SEQ ID NO:12,全长序列)。
EVQLVESGGGLVQPGGSLRLSCAASGFTFSSYGMSWVRQAPGKGLEWVAIISGGGRDIYYLDSVKGRFTISRDNSKNNLYLQMNSLRAEDTAVYYCSSPIYDAYSFAYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK
包含VL1的轻链氨基酸序列1(LC1)(SEQ ID NO:13,全长序列)。
EIVMTQSPATLSVSPGERATLSCRASQTISNNLHWYQQKPGQAPRLLIYYASQSISGIPARFSGSGTEFTLTISSLQSEDFAVYYCQQSYSWPLTFGGGTKLEIKRTVAAPSVFPPSDEQLKSGTASVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC
包含VL6的轻链氨基酸序列2(LC2)(SEQ ID NO:14,全长序列)。
EIVLTQSPATLSVSPGERATLSCRASQTISNNLHWYHQKPGQAPRLLIKYASQSISGIPSRFSGSGTDFTLTISSLQSEDFAVYFCQQSYSWPLTFGGGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC
包含嵌合VH的重链氨基酸序列(SEQ ID NO:15,全长序列)
EVKLVESGGGLVKPGGSLKLSCAASGFTFSSYGMSWVRQTPEKRLEWVAIISGGGRDIYYLDSVKGRFTISRDNAKNNLYLQMSSLRSEDTAFYYCSSPIYDAYSFAYWGQGTLVTVSAASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK
包含嵌合VL的轻链氨基酸序列(SEQ ID NO:16,全长序列)。
DIVLVQSPATLSVTPGDSVSLSCRASQTISNNLHWYHQKSHESPRLLIKYASQSISGIPSRFSGSGTDFTLSINSVETEDFGMYFCQQSYSWPLTFGAGTNLELKRTVAAPSVFIFPPSDEQLKSGTASVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC
为进一步解释,上述序列之间的包含关系见表2。右边的序列包含在同一行左边的序列中。
表2:
实施例4.通过ELISA测量与人和猕猴PD-1的结合情况
用2μg/mL人PD-1/His(自产)或溶于1x PBS的猕猴PD-1/His蛋白(ACROBiosystems#PD1-C5223)(50μL/孔)包被MaxiSorp 96孔板(NUNC#449824)。使板子在4℃下孵育过夜。去除包被液,用200μL/孔PBST(含0.05%吐温-20的1x PBS)洗板一次。然后加入200μL/孔阻断缓冲液(1x PBS含0.05%吐温-20,3%BSA)并在室温下孵育1小时。去除阻断缓冲液,用200μL/孔的PBST洗板三次。将抗体VH7+VL6(在实施例2中生成)和人IgG1同型对照(hIgG1,Sigma#I5154-1MG)用1x PBS稀释并加入板中(50μL/孔)。将板子在室温下孵育2小时。移除孔中的抗体,用200μL/孔的PBST洗板三次。将山羊抗人IgG(H&L)-HRP二抗(Jackson Immuno Research#109-035-088)在1x PBS中以1:5000稀释,并加入到每个孔中(50μL/孔)。将板子在室温下孵育1小时。去除二抗,用200μL/孔的PBST洗板5次。加入50μL/孔TMB(eBioscience#85-00-4201-56),在室温下孵育数分钟。然后加入50μL/孔的2N H2SO4以停止反应。在450nm处测量光密度。
抗PD-1抗体VH7+VL6与人和猕猴的PD-1结合,EC50分别为0.10nM和0.40nM(表3)。这些结果表明,抗PD-1抗体可以与人和猕猴的PD-1高亲和力地结合(图2A和2B)。
表3.与人和猕猴PD-1的结合情况
实施例5.与Jurkat细胞上的人PD-1的结合
将表达人PD-1的Jurkat细胞(在实施例6中生成)与不同浓度的抗PD-1抗体VH7+VL6或人IgG1同型对照(Sigma#I5154-MG)在4℃下孵育30分钟。然后用FACS缓冲液(PBS加2%FBS)清洗细胞一次,用AlexaFluor 594AffiniPure山羊抗人IgG二抗(JacksonImmunoResearch#109-585-088)在4℃下孵育30分钟。用FACS缓冲液洗涤一次后,将细胞重新悬浮于200μLFACS缓冲液中。染色后的细胞用BD LSRFortessa流式细胞仪进行分析。
如图3所示,抗PD-1抗体VH7+VL6与Jurkat上表达的人PD-1结合,EC50为2.16nM。
实施例6.在基于细胞的测定中抗PD-1抗体对PD-1和PD-L1之间相互作用的阻断作用
为了进行所述试验,首先生成了两个稳定的细胞系。编码嵌合PD-1受体的DNA(人PD-1的胞外和跨膜结构域与人CD3ζ链的细胞质结构域融合(NCBI登录号:NP_932170.1))和编码NFAT-荧光素酶的DNA(从pGL4.30[luc2P/NFAT-RE/Hygro]扩增,Sigma#E8481)克隆到pcDNA3.4载体(Invitrogen#A14697)并通过电穿孔转染到Jurkat细胞(细胞库,中国科学院,#TCHU123)。通过G418选择和限制稀释产生稳定的细胞系,并命名为Jurkat/PD-1-CD3z/NF-luci细胞。用同样的方法,在CHO-K1细胞(细胞库,中国科学院,#GNHa7)上产生一个表达全长人PD-L1(NCBI登录号:NP_054862.1)的稳定细胞系,命名为CHO/PD-L1细胞。
在共培养的前一天,将CHO/PD-L1细胞接种于96孔平底板中(NUNC#167008)(5×104细胞/孔),其含有10%FBS(Gibco#16000-044)和1%青霉素-链霉素(Corning#30-002-CI)的完全RPMI1640培养基(Thermo Fisher#C11875500BT),并在CO2培养箱中培养过夜。Jurkat/PD-1-CD3z/NF-luci细胞在与CHO/PD-L1细胞共培养之前,用抗PD-1抗体或人IgG1同型对照(Sigma#I5154-1MG)预培养30分钟。然后除去CHO/PD-L1细胞的培养液,将带有抗体的Jurkat/PD-1-CD3z/NF-luci细胞接种于孔中(1×105个细胞/孔)。6小时后,使用LuciferaseAssay System试剂盒(Promega#E1500)检测荧光信号。
结果见表4和图4,抗体VH7+VL6完全抑制了CHO/PD-L1细胞诱导的荧光信号,这表明抗体VH7+VL6可以有效阻断PD-1和PD-L1的相互作用。纳武单抗(CAS#946414-94-4,上海凯博特公司生产)和派姆单抗(CAS#1374853-91-4,上海凯博特公司生产)对荧光信号的抑制率为75%和71%。
表4.抗PD-1抗体对荧光素酶信号的抑制情况
抗体 | EC50(nM) | 最大抑制(%) |
VH7+VL6 | 0.38 | 100 |
纳武单抗 | 0.04 | 75 |
派姆单抗 | 0.16 | 71 |
实施例7.增强人PBMC上IL-2、IFN-γ和TNF-α的产生
IL-2释放试验
用葡萄球菌肠毒素B(SEB,0.1μg/mL,溶于PBS中,100μL/孔)(由中国军事医学科学院提供)包被96孔平底板(NUNC#167008),在4℃下过夜。第二天,将分离自健康供者的人外周血单核细胞(PBMC)悬浮于含有10%FBS(Gibco#16000-044)和1%青霉素-链霉素(Corning#30-002-CI)的完整RPMI 1640培养基中(Thermo Fisher#C11875500BT)。然后将PBMC接种到预先包被的板子上(3×105个细胞/孔),并与不同浓度的抗PD-1抗体或人IgG1同型对照(Sigma#I5154-1MG)在CO2培养箱中培养72小时。收集培养物上清液,根据制造商的说明,用人IL-2DuoSet ELISA试剂盒(R&D systems#DY202)评估IL-2水平。
图5A显示,抗体VH7+VL6、纳武单抗和派姆单抗以同等水平增加PBMC的IL-2分泌。
IFN-γ和TNF-α释放试验
用SEB(40ng/ml,溶于17mlPBS中)包被100mm TC处理的细胞培养皿(BD Falcon#353003),在4℃下过夜。第二天,将5×107个人PBMC细胞悬浮于20mL含有10%FBS和1%青霉素-链霉素的完全RPMI1640培养基中,并接种于预包被的皿中。将皿放在CO2培养箱中培养。用SEB(4ng/ml,溶于PBS中,100μL/孔)包被96孔平底板,在4℃下过夜。培养72小时后,离心收集PBMC,用完全RPMI1640培养基清洗一次。然后将PBMC与不同浓度的抗PD-1抗体或人IgG1同型对照(Sigma#I5154-1MG)预孵育30分钟,并接种于预包被有SEB的平板(3×105个细胞/孔)。在二氧化碳培养箱中培养24小时后,收集培养物上清液,根据制造商的说明,用人IFN-γDuoSet ELISA(R&D systems#DY285B)和人TNF-αDuoSet ELISA(R&D systems#DY210)试剂盒评估IFN-γ和TNF-α水平。
与IL-2释放试验的结果一致,所有的抗PD-1抗体都明显增加了IFN-γ和TNF-α的分泌。由抗体VH7+VL6引发的IFN-γ和TNF-α分泌的增加多于由纳武单抗和派姆单抗引发的增加(图5B和5C)。
实施例8.抗肿瘤活性的动物体内研究
用于动物研究的抗体表达和纯化
将编码VH7(SEQ ID NO:8)和VL6(SEQ ID NO:10)的DNA序列亚克隆到pcDNA3.4载体(Invitrogen#A14697)中,构建两个质粒,pcDNA3.4-VH7和pcDNA3.4-VL6。使用无内毒素Plasmid DNA Maxiprep试剂盒(TIANGEN#DP117)制备pcDNA3.4-VH7和pcDNA3.4-VL6。在293-F(Invitrogen#R79007)中进行抗体表达。培养物上清液中的抗体通过蛋白A亲和柱(Yeasen#36410ES08)纯化。通过透析,纯化的抗体经缓冲液交换至组氨酸缓冲液中(20mM组氨酸,5%蔗糖,0.02%吐温80,pH5.5)。纯化的抗体的浓度和纯度分别通过OD280和SDS-PAGE确定。
动物研究
在这项研究中,使用了携带CT26的人PD-1敲除小鼠肿瘤模型来研究抗体VH7+VL6的抗肿瘤活性。
小鼠结肠癌细胞CT26(细胞库,中国科学院,#TCM37)在RPMI1640培养基中培养,加入10%FBS和1%青霉素-链霉素。将100μL的PBS中的5×105个CT26细胞通过右背侧皮下注射每只人PD-1基因敲除小鼠(BALB/c,雌性,6-8周龄,GemPharmatech)。当平均肿瘤体积达到约63mm3时,将小鼠随机分组,每组8只,并施用抗体。在第5、8、11、14和17天腹腔注射抗PD-1抗体VH7+VL6,剂量为5mg/kg。对照组的小鼠注射人IgG1同种型对照(Bioxcell#BP0085)。每两天用卡尺测量一次肿瘤。肿瘤体积根据以下公式计算:宽2×长/2(mm3)。当任何一组的平均肿瘤体积达到2000mm3时,小鼠被安乐死。
图6A显示的结果表明,抗体VH7+VL6强烈抑制了体内的肿瘤生长,50%的肿瘤在第20天完全消退(图6B和6C)。在用人IgG1同种型抗体治疗的对照组中,肿瘤生长得显著更快、且更大。没有与施用抗体显著相关的体重变化。
序列表
<110> 苏州鑫康合生物医药科技有限公司
北京鑫康合生物医药科技有限公司
<120> 抗PD-1多肽及其用途
<130> PG03155A-FF00564CN
<150> PCT/CN2021/094422
<151> 2021-05-18
<160> 16
<170> PatentIn version 3.5
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<212> PRT
<213> 人工序列
<220>
<223> VL1
<400> 9
Glu Ile Val Met Thr Gln Ser Pro Ala Thr Leu Ser Val Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Thr Ile Ser Asn Asn
20 25 30
Leu His Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile
35 40 45
Tyr Tyr Ala Ser Gln Ser Ile Ser Gly Ile Pro Ala Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Ser
65 70 75 80
Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Ser Tyr Ser Trp Pro Leu
85 90 95
Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
100 105
<210> 10
<211> 107
<212> PRT
<213> 人工序列
<220>
<223> VL6
<400> 10
Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Val Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Thr Ile Ser Asn Asn
20 25 30
Leu His Trp Tyr His Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile
35 40 45
Lys Tyr Ala Ser Gln Ser Ile Ser Gly Ile Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Ser
65 70 75 80
Glu Asp Phe Ala Val Tyr Phe Cys Gln Gln Ser Tyr Ser Trp Pro Leu
85 90 95
Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
100 105
<210> 11
<211> 449
<212> PRT
<213> 人工序列
<220>
<223> HC1
<400> 11
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30
Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Arg Leu Glu Trp Val
35 40 45
Ala Ile Ile Ser Gly Gly Gly Arg Asp Ile Tyr Tyr Leu Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ser Ser Pro Ile Tyr Asp Ala Tyr Ser Phe Ala Tyr Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe
115 120 125
Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu
130 135 140
Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp
145 150 155 160
Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu
165 170 175
Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser
180 185 190
Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro
195 200 205
Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys
210 215 220
Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro
225 230 235 240
Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser
245 250 255
Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp
260 265 270
Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn
275 280 285
Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val
290 295 300
Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu
305 310 315 320
Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys
325 330 335
Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr
340 345 350
Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr
355 360 365
Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu
370 375 380
Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu
385 390 395 400
Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys
405 410 415
Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu
420 425 430
Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly
435 440 445
Lys
<210> 12
<211> 449
<212> PRT
<213> 人工序列
<220>
<223> HC2
<400> 12
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30
Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Ile Ile Ser Gly Gly Gly Arg Asp Ile Tyr Tyr Leu Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Asn Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ser Ser Pro Ile Tyr Asp Ala Tyr Ser Phe Ala Tyr Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe
115 120 125
Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu
130 135 140
Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp
145 150 155 160
Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu
165 170 175
Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser
180 185 190
Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro
195 200 205
Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys
210 215 220
Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro
225 230 235 240
Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser
245 250 255
Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp
260 265 270
Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn
275 280 285
Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val
290 295 300
Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu
305 310 315 320
Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys
325 330 335
Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr
340 345 350
Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr
355 360 365
Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu
370 375 380
Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu
385 390 395 400
Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys
405 410 415
Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu
420 425 430
Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly
435 440 445
Lys
<210> 13
<211> 214
<212> PRT
<213> 人工序列
<220>
<223> LC1
<400> 13
Glu Ile Val Met Thr Gln Ser Pro Ala Thr Leu Ser Val Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Thr Ile Ser Asn Asn
20 25 30
Leu His Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile
35 40 45
Tyr Tyr Ala Ser Gln Ser Ile Ser Gly Ile Pro Ala Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Ser
65 70 75 80
Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Ser Tyr Ser Trp Pro Leu
85 90 95
Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys Arg Thr Val Ala Ala
100 105 110
Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly
115 120 125
Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala
130 135 140
Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln
145 150 155 160
Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser
165 170 175
Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr
180 185 190
Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser
195 200 205
Phe Asn Arg Gly Glu Cys
210
<210> 14
<211> 214
<212> PRT
<213> 人工序列
<220>
<223> LC2
<400> 14
Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Val Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Thr Ile Ser Asn Asn
20 25 30
Leu His Trp Tyr His Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile
35 40 45
Lys Tyr Ala Ser Gln Ser Ile Ser Gly Ile Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Ser
65 70 75 80
Glu Asp Phe Ala Val Tyr Phe Cys Gln Gln Ser Tyr Ser Trp Pro Leu
85 90 95
Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys Arg Thr Val Ala Ala
100 105 110
Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly
115 120 125
Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala
130 135 140
Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln
145 150 155 160
Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser
165 170 175
Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr
180 185 190
Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser
195 200 205
Phe Asn Arg Gly Glu Cys
210
<210> 15
<211> 449
<212> PRT
<213> 人工序列
<220>
<223> 包含嵌合VH的HC
<400> 15
Glu Val Lys Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly
1 5 10 15
Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30
Gly Met Ser Trp Val Arg Gln Thr Pro Glu Lys Arg Leu Glu Trp Val
35 40 45
Ala Ile Ile Ser Gly Gly Gly Arg Asp Ile Tyr Tyr Leu Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Asn Leu Tyr
65 70 75 80
Leu Gln Met Ser Ser Leu Arg Ser Glu Asp Thr Ala Phe Tyr Tyr Cys
85 90 95
Ser Ser Pro Ile Tyr Asp Ala Tyr Ser Phe Ala Tyr Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ala Ala Ser Thr Lys Gly Pro Ser Val Phe
115 120 125
Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu
130 135 140
Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp
145 150 155 160
Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu
165 170 175
Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser
180 185 190
Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro
195 200 205
Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys
210 215 220
Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro
225 230 235 240
Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser
245 250 255
Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp
260 265 270
Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn
275 280 285
Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val
290 295 300
Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu
305 310 315 320
Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys
325 330 335
Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr
340 345 350
Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr
355 360 365
Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu
370 375 380
Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu
385 390 395 400
Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys
405 410 415
Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu
420 425 430
Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly
435 440 445
Lys
<210> 16
<211> 214
<212> PRT
<213> 人工序列
<220>
<223> 包含嵌合VL的LC
<400> 16
Asp Ile Val Leu Val Gln Ser Pro Ala Thr Leu Ser Val Thr Pro Gly
1 5 10 15
Asp Ser Val Ser Leu Ser Cys Arg Ala Ser Gln Thr Ile Ser Asn Asn
20 25 30
Leu His Trp Tyr His Gln Lys Ser His Glu Ser Pro Arg Leu Leu Ile
35 40 45
Lys Tyr Ala Ser Gln Ser Ile Ser Gly Ile Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Ser Ile Asn Ser Val Glu Thr
65 70 75 80
Glu Asp Phe Gly Met Tyr Phe Cys Gln Gln Ser Tyr Ser Trp Pro Leu
85 90 95
Thr Phe Gly Ala Gly Thr Asn Leu Glu Leu Lys Arg Thr Val Ala Ala
100 105 110
Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly
115 120 125
Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala
130 135 140
Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln
145 150 155 160
Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser
165 170 175
Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr
180 185 190
Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser
195 200 205
Phe Asn Arg Gly Glu Cys
210
Claims (21)
1.一种分离的抗体或其抗原结合片段,包含重链(HC)可变区序列和轻链(LC)可变区序列,其中所述抗体与PD-1的胞外结构域结合,通过SPR分析确定的结合亲和力优于10nM,其中
(a)所述HC包含
CDR1H,所述CDR1H含有GFTFSSYGMS(SEQ ID NO:1)所示氨基酸序列,
CDR2H,所述CDR2H含有IISGGGRDIYYLDSVKG(SEQ ID NO:2)所示氨基酸序列,和
CDR3H,所述CDR3H含有PIYDAYSFAY(SEQ ID NO:3)所示氨基酸序列。
(b)所述LC包含
CDR1L,所述CDR1L含有RASQTISNNLH(SEQ ID NO:4)所示氨基酸序列,
CDR2L,所述CDR2L含有YASQSIS(SEQ ID NO:5)所示氨基酸序列,和
CDR3L,所述CDR3L含有QQSYSWPLT(SEQ ID NO:6)所示氨基酸序列。
2.如权利要求1所述的抗体或其抗原结合片段,其中所述抗体是嵌合抗体、人源化抗体或人抗体。
3.如权利要求1或2所述的抗体或其抗原结合片段,其进一步包含人受体框架。
4.如权利要求1-3中任一项所述的抗体或其抗原结合片段,其中所述HC可变区序列包含SEQ ID NO:7所示的氨基酸序列或与SEQ ID NO:7具有高于80%、85%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%同一性的氨基酸序列。
5.如权利要求1-3中任一项所述的抗体或其抗原结合片段,其中所述HC可变区序列包含SEQ ID NO:8所示的氨基酸序列或与SEQ ID NO:8具有高于80%、85%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%同一性的氨基酸序列。
6.如权利要求4或5所述的抗体或其抗原结合片段,其中所述LC可变区序列包含SEQ IDNO:9所示的氨基酸序列或与SEQ ID NO:9具有高于80%、85%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%同一性的氨基酸序列。
7.如权利要求4或5所述的抗体或其抗原结合片段,其中所述LC可变区序列包含SEQ IDNO:10所示的氨基酸序列或与SEQ ID NO:10具有高于80%、85%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%同一性的氨基酸序列。
8.如权利要求1-7中任一项所述的抗体或其抗原结合片段,其中所述HC可变区序列包含SEQ ID NO:7或SEQ ID NO:8的氨基酸序列,或与SEQ ID NO.7或8具有高于80%、85%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%同一性的氨基酸序列,并且,所述LC可变区序列包含SEQ ID NO:9或SEQ ID NO:10的氨基酸序列,或与SEQ ID NO:9或10具有高于80%、85%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%同一性的氨基酸序列。
9.如权利要求1-8中任一项所述的抗体或其抗原结合片段,其中
1)所述HC可变区序列包含SEQ ID NO:7的氨基酸序列或与SEQ ID NO:7具有高于80%、85%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%同一性的氨基酸序列,并且,所述LC可变区域序列包含SEQ ID NO:10的氨基酸序列或与SEQ ID NO:10具有高于80%、85%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%同一性的氨基酸序列,或
2)所述HC可变区序列包含SEQ ID NO:8的氨基酸序列或与SEQ ID NO:8具有高于80%、85%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%同一性的氨基酸序列,并且,所述LC可变区序列包含SEQ ID NO:10的氨基酸序列或与SEQ ID NO:10具有高于80%、85%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%同一性的氨基酸序列。
10.如权利要求1-9中任一项所述的抗体或其抗原结合片段,其中所述抗体是IgG同种型。
11.如权利要求1-10中任一项所述的抗体或其抗原结合片段,其中所述抗原结合片段包含选自下组的任一项:Fab、F(ab')2、Fab'、scFv、Fv、Fd、dAb和双体抗体(diabody)。
12.一种双特异性抗体,包含如权利要求1-11中任一项所述的抗体或其抗原结合片段以及第二抗体或其抗原结合片段。
13.根据权利要求12的双特异性抗体,其中所述第二抗体或其抗原结合片段特异性地与肿瘤细胞表面表达的肿瘤抗原结合,其中所述肿瘤抗原包含选自下组的任一项:A33;ADAM-9;ALCAM;BAGE;β-连环蛋白;CA125;羧肽酶M;CD103;CD19;CD20;CD22;CD23;CD25;CD27;CD28;CD36;CD40/CD154;CD45;CD46;CD5;CD56;CD79a/CD79b;CDK4;CEA;CTLA4;细胞角蛋白8;EGF-R;EphA2;ErbB1;ErbB3;ErbB4;GAGE-1;GAGE-2;GD2/GD3/GM2;HER-2/neu;人乳头瘤病毒-E6;人乳头瘤病毒-E7;JAM-3;KID3;KID31;KSA(17-1A);LUCA-2;MAGE-1;MAGE-3;MART;MUC-1;MUM-1;N-乙酰氨基葡萄糖基转移酶;抑瘤素M;pl5;PIPA;PSA;PSMA;ROR1;TNF-β受体;TNF-α受体;TNF-γ受体;转铁蛋白受体;和VEGF受体。
14.一种缀合物,包含如权利要求1-11中任一项所述的抗体或其抗原结合片段,其连接有治疗剂。
15.如权利要求14所述的缀合物,其中所述治疗剂是细胞毒素或放射性同位素。
16.一种组合物,其包含如权利要求1-11中任一项所述的抗体或其抗原结合片段、如权利要求12或13所述的双特异性抗体、或如权利要求14或15所述的缀合物,以及药学上可接受的赋形剂。
17.一种淋巴细胞,包括来自受试者的T细胞和/或NK细胞,并经由权利要求1-11中任一项所述的抗体或其抗原结合片段的体外处理。
18.编码如权利要求1-11中任一项所述的抗体或其抗原结合片段的分离的核酸。
19.一种包含如权利要求18所述的核酸的表达载体。
20.如权利要求1-11中任一项所述的抗体或其抗原结合片段、如权利要求12或13所述的双特异性抗体、如权利要求16所述的组合物或如权利要求17所述的淋巴细胞在制备治疗受试者癌症的药物中的用途。
21.如权利要求20所述的用途,其中所述癌症选自下组的任一项或多项:淋巴瘤、黑色素瘤、结肠直肠腺癌、前列腺癌、乳腺癌、结肠癌、肺癌、肝癌、胃癌、和肾透明细胞癌。
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