CN108368175A - Pd-1抗体及其用途 - Google Patents
Pd-1抗体及其用途 Download PDFInfo
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- CN108368175A CN108368175A CN201680069571.8A CN201680069571A CN108368175A CN 108368175 A CN108368175 A CN 108368175A CN 201680069571 A CN201680069571 A CN 201680069571A CN 108368175 A CN108368175 A CN 108368175A
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Abstract
本发明提供了以高亲和力与人PD‑1特异性结合的单克隆抗体。还提供了编码本发明抗体的核酸分子、表达载体、宿主细胞和用于表达本发明抗体的方法。本发明的PD‑1抗体抑制PD‑L1与PD‑1的结合,由此一般性地调节免疫应答,特别是由TcR和CD28介导的那些。本发明还提供了使用本发明的PD‑1抗体治疗各种疾病(包括传染性疾病和癌症)的方法。
Description
技术领域
本发明一般性地涉及治疗人疾病的免疫疗法。更具体地说,本发明涉及抗PD-1抗体治疗癌症的用途。
背景技术
适应性免疫应答涉及称为T细胞和B细胞的两类主要淋巴细胞的活化、选择和克隆增殖。遇到抗原后,T细胞增殖并分化成抗原特异性效应细胞,而B细胞增殖并分化成抗体分泌细胞。
T细胞活化是需要T细胞和抗原呈递细胞(APC)之间的若干信号传导事件的多步骤过程。为了发生T细胞活化,必须将两种类型的信号递送至休眠的T细胞。第一种类型由抗原特异性T细胞受体(TcR)介导,并赋予免疫应答特异性。第二种(共刺激)类型调节应答的大小,并通过T细胞上的辅助受体递送。
当其配体B7-1或B7-2接合时,通过活化CD28受体递送主要的共刺激信号。相比之下,相同的B7-1或B7-2配体与抑制性CTLA-4受体的接合导致T细胞应答的减弱。因此,CTLA-4信号拮抗由CD28介导的共刺激。在高抗原浓度下,CD28共刺激压倒了CTLA-4抑制效果。CD28和CTLA-4表达的时序调控在活化信号和抑制信号之间保持平衡并确保有效免疫应答的发展,同时防范自身免疫的发展。
最近已经鉴定出CD28和CTLA-4及其B-7样配体的分子同源物。ICOS是CD28样共刺激受体。PD-1(程序性死亡1)是CD28受体家族的抑制成员,该家族还包括CD28、CTLA-4、ICOS和BTLA。PD-1在活化的B细胞、T细胞和骨髓细胞上表达。该家族的最初成员CD28和ICOS通过在加入单克隆抗体后增加T细胞增殖的功能效应而被发现(Hutloff等(1999)Nature 397:263-266;Hansen等(1980)Immunogenics 10:247-260)。PD-1是通过筛选凋亡细胞中的差异表达而被发现的(Ishida等(1992)EMBO J11:3887-95)。该家族的其它成员CTLA-4和BTLA分别通过筛选细胞毒性T淋巴细胞和TH1细胞中的差异表达而被发现。CD28、ICOS和CTLA-4都具有允许同源二聚化的未配对的半胱氨酸残基。相比之下,PD-1被暗示作为单体存在,缺乏其它CD28家族成员特征性的未配对的半胱氨酸残基。
PD-1基因是作为Ig基因超家族的一部分的55kDa I型跨膜蛋白(Agata等(1996)Int Immunol 8:765-72)。PD-1含有膜近端免疫受体酪氨酸抑制基序(membrane proximalimmunoreceptor tyrosine inhibitory motif,ITIM)和膜远端基于酪氨酸的转换基序(membrane distal tyrosine-based switch motif,ITSM)。虽然在结构上与CTLA-4相似,但PD-1缺乏对B7-1和B7-2结合至关重要的MYPPPY基序。已经鉴定了PD-1的两种配体PD-L1和PD-L2,已经显示其在结合PD-1时下调T细胞活化(Freeman等(2000)J Exp Med 192:1027-34;Latchman等(2001)Nat Immunol 2:261-8;Carter等(2002)Eur J Immunol 32:634-43)。PD-L1和PD-L2都是B7同源物,其与PD-1结合,但不与其它CD28家族成员结合。PD-1是在活化的B细胞、T细胞和骨髓细胞上表达的CD28家族的抑制成员。PD-1的一种配体PD-L1在多种人癌症中丰富(Dong等(2002)Nat.Med.8:787-9)。PD-1和PD-L1之间的相互作用导致肿瘤浸润淋巴细胞的减少、T细胞受体介导的增殖的减少和癌细胞的免疫逃避(Dong等(2003)J.Mol.Med.81:281-7;Blank等(2005)Cancer Immunol.Immunother.54:307-314;Konishi等(2004)Clin.Cancer Res.10:5094-100)。通过抑制PD-1与PD-L1的局部相互作用可以逆转免疫抑制,并且当PD-1与PD-L2的相互作用也被阻断时该效果是相加的(Iwai等(2002)Proc.Nat'l.Acad.Sci.USA 99:12293-7;Brown等(2003)J.Immunol.170:1257-66).
发明内容
本发明提供了结合PD-1并展示许多合乎需要的性质的单克隆抗体。这些性质包括例如与人PD-1的高亲和力结合。
本发明提供了分离的单克隆抗体或其抗原结合片段,其中所述单克隆抗体以高亲和力结合人PD-1。本发明的单克隆抗体是小鼠抗体、嵌合抗体或人源化抗体。本发明的抗原结合片段是Fab、Fab'、F(ab)2或F(ab')2。
本发明还提供了编码抗PD-1单克隆抗体的分离的核酸分子。
本发明还提供了包含编码抗PD-1单克隆抗体的核酸分子的表达载体。
本发明还提供了包含含有编码抗PD-1单克隆抗体的核酸分子的表达载体的宿主细胞。
本发明还提供了使用抗PD-1抗体调节免疫应答的方法。特别地,本发明提供了使用抗PD-1抗体抑制肿瘤细胞生长的方法。
在一个方面,提供了抗PD-1单克隆抗体或其抗原结合片段,其中所述抗体包含含有SEQ ID NO:1(重链CDR1)、SEQ ID NO:2(重链CDR2)、SEQ ID NO:3(重链CDR3)的重链可变区和含有SEQ ID NO:4(轻链CDR1)、SEQ ID NO:5(轻链CDR2)和SEQ ID NO:6(轻链CDR3)的轻链可变区。
在另一方面,提供了包含如本文所述的单克隆抗体或其抗原结合片段和药学上可接受的载体的组合物。
在另一方面,提供了包含与治疗剂连接的如本文所述的单克隆抗体或其抗原结合片段的免疫缀合物。
在另一方面,提供了调节受试者中的免疫应答的方法,其包括向所述受试者施用如本文所述的抗体或其抗原结合部分,使得所述受试者中的免疫应答得到调节。
在另一方面,提供了抑制受试者中的肿瘤细胞生长的方法,其包括以有效抑制肿瘤细胞生长的量向所述受试者施用如本文所述的抗体或其抗原结合片段。
在另一方面,提供了治疗受试者中的传染性疾病的方法,其包括向所述受试者施用如本文所述的抗体或其抗原结合片段,使得所述受试者的所述传染性疾病被治疗。
附图简要说明
结合非限制性实施例和附图考虑时,参考详细描述将更好地理解本发明,其中:
图1A和1B显示PD-L1-Fc与PD-1转染的CHO细胞(CHO/PD-1)的结合。
图2显示PD-1-Fc-生物素与PD-L1-Fc的结合。
图3显示67D9和hu67D9的重链可变区(A)和轻(B)链可变区的氨基酸序列。67D9VH和67D9VL分别表示67D9的重链可变区和轻链可变区。选择humIII作为人源化重链的框架,选择humκIII用于人源化轻链。hu67D9VH和hu67D9VL分别表示hu67D9的重链可变区和轻链可变区。破折号表示与人抗体框架中的相应残基相同的氨基酸。CDR用括号括起来。
图4A-4D显示实验结果,其证明所有三种抗PD-1抗体67D9、c67D9和hu67D9都有效抑制PD-L1-Fc与在转染的CHO-K1细胞上表达的PD-1的结合。
图5A-5D显示实验结果,其证明每种抗PD-1抗体67D9(小鼠Ab)、c67D9(嵌合Ab)和hu67D9(人源化Ab)都与PD-I(A)结合,但不与ICOS(B)、CTLA-4(C)和CD28(D)结合。
图6A-6C显示实验结果,其证明三种抗PD-1抗体67D9(小鼠Ab)、c67D9(嵌合Ab)和hu67D9(人源化Ab)的每一种都在混合淋巴细胞反应测定中促进T细胞增殖(A)、IL-2(B)分泌和IFN-γ(C)分泌。
图7A-7C显示实验结果,其证明每种抗PD-1抗体67D9(小鼠Ab)、c67D9(嵌合Ab)和hu67D9(人源化Ab)都与人PD-1-Fc(A)和食蟹猴PD-1-Fc(B)结合,但不与小鼠PD-1-Fc(C)结合。
图8显示纳武单抗(Nivolumab)、派姆单抗(Pembrolizumab)和hu67D9(人源化67D9)在PBS中的DSC热分析图。
图9显示纳武单抗和hu67D9的动力学和亲和力测量结果。
图10显示纳武单抗和hu67D9与细胞表面表达的PD-1的结合。
图11显示纳武单抗和hu67D9与可溶性PD-1的结合。
图12显示在FITC标记的纳武单抗存在下纳武单抗和hu67D9与细胞表面上表达的PD-1的竞争结合。
图13显示在生物素标记的纳武单抗存在下纳武单抗和hu67D9与可溶性PD1的竞争结合。
图14显示在生物素标记的PDL1-Fc存在下纳武单抗和hu67D9与可溶性PD1的竞争结合。
具体实施方式
本发明涉及与人PD-1特异性结合的分离的单克隆抗体或其抗原结合片段。在某些实施方案中,本发明的抗体表现出一种或更多种合乎需要的功能特性,例如与PD-1的高亲和力结合,缺乏与其它CD28家族成员的交叉反应性,在混合淋巴细胞反应中刺激T细胞增殖以及IL-2和IFN-γ分泌的能力,抑制一种或更多种PD-1配体(例如PD-L1和/或PD-L2)结合的能力和/或与食蟹猴PD-1交叉反应的能力。在另一方面,本发明涉及特异性结合PD-1的单克隆抗体和特异性结合CTLA-4的单克隆抗体的组合应用。
本发明提供了与人PD-1特异性结合的分离的单克隆抗体或其抗原结合片段以及制备这样的抗体的方法。
在另一方面,本发明涉及使用抗PD-1抗体抑制受试者的肿瘤细胞生长的方法。如本文所证明的,抗PD-1抗体能够在体内抑制肿瘤细胞生长。本发明还涉及使用所述抗体改变免疫应答以及治疗诸如癌症或传染性疾病等疾病的方法。
为了使本发明可更容易理解,首先定义某些术语。在整个详细描述中阐述了额外的定义。
术语“程序性死亡1”、“程序性细胞死亡1”、“PD-1”、“PD1”、“PDCD1”、“hPD-1”和“hPD-I”可互换使用,并包括人PD-1的变体、同种型、种同源物以及与PD-1具有至少一个共同表位的类似物。
术语“细胞毒性T淋巴细胞相关抗原-4”、“CTLA-4”、“CTLA4”、“CTLA-4抗原”和“CD152”可互换使用,并包括人CTLA-4的变体、同种型、种同源物和与CTLA-4具有至少一个共同表位的类似物。
术语“免疫应答”是指例如淋巴细胞、抗原呈递细胞、吞噬细胞、粒细胞和由上述细胞或肝脏产生的可溶性大分子(包括抗体、细胞因子和补体)的作用,其导致选择性损坏、破坏或从人体中消除入侵的病原体、感染病原体的细胞或组织、癌细胞或在自身免疫或病理性炎症的情况下正常人细胞或组织。
如本文所提及的术语“抗体”包括完整抗体和任何抗原结合片段(即“抗原结合部分”)或其单链。“抗体”是指包含通过二硫键相互连接的至少两条重链(H)和两条轻链(L)的糖蛋白或其抗原结合部分。每条重链由重链可变区(本文缩写为VH)和重链恒定区构成。重链恒定区由三个结构域CH1、CH2和CH3构成。每条轻链由轻链可变区(本文缩写为VL)和轻链恒定区构成。轻链恒定区由一个结构域CL构成。VH和VL区可以进一步细分成称为互补决定区(CDR)的高变区,其散布有更保守的称为框架区(FR)的区域。每个VH和VL由三个CDR和四个FR构成,按照以下顺序从氨基末端到羧基末端排列:FR1、CDR1、FR2、CDR2、FR3、CDR3、FR4。重链和轻链的可变区含有与抗原相互作用的结合结构域。抗体的恒定区可介导免疫球蛋白与宿主组织或因子的结合,所述宿主组织或因子包括免疫系统的各种细胞(例如效应细胞)和经典补体系统的第一组分(Clq)。
如本文所用,抗体的术语“抗原结合片段”是指保留特异性结合抗原(例如PD-1)的能力的抗体的一个或更多个片段。已经显示抗体的抗原结合功能可以通过全长抗体的片段进行。囊括在抗体的术语“抗原结合片段”内的结合片段的实例包括(i)Fab片段,由VL、VH、CL和CH1结构域组成的单价片段;(ii)F(ab')2片段,包含在铰链区由二硫桥连接的两个Fab片段的二价片段;(iii)由VH和CH1结构域组成的Fd片段;(iv)由抗体单臂的VL和VH结构域组成的Fv片段,(v)dAb片段(Ward等,(1989)Nature 341:544-546),其由VH结构域组成;和(vi)分离的互补决定区(CDR)。
如本文所用的术语“单克隆抗体”或“单克隆抗体组合物”是指单分子组成的抗体分子的制备物。单克隆抗体组合物表现出对特定表位的单一结合特异性和亲和力。
术语“人源化抗体”旨在指其中来源于另一种哺乳动物物种例如小鼠的种系的CDR序列已被移植到人框架序列上的抗体。可以在人框架序列内进行额外的框架区修饰。
术语“嵌合抗体”旨在指其中可变区序列来源于一种物种并且恒定区序列来源于另一种物种的抗体,例如其中可变区序列来源于小鼠抗体并且恒定区序列来源于人抗体的抗体。
对于IgG抗体的术语“高亲和力”是指对靶抗原具有10-8M或更低、更优选10-9M或更低、甚至更优选10-10M或更低的KD的抗体。然而,对于其它抗体同种型而言,“高亲和力”结合可以不同。例如,对于IgM同种型的“高亲和力”结合是指具有10-7M或更低、更优选10-8M或更低、甚至更优选10-9M或更低的KD的抗体。
如本文所用,术语“受试者”包括任何人或非人动物。术语“非人动物”包括所有脊椎动物,例如哺乳动物和非哺乳动物,例如非人灵长类动物、绵羊、狗、猫、马、牛、鸡、两栖动物、爬行动物等。除注明时外,术语“患者”或“受试者”可互换使用。
在以下小节中进一步详细描述本发明的各个方面。
抗PD-1抗体
本发明的抗体的特征在于所述抗体的特定功能特征或性质。例如,所述抗体特异性结合PD-1(例如结合人PD-1并可与来自其它物种例如食蟹猴的PD-1交叉反应)。优选地,本发明的抗体以高亲和力结合PD-1,例如以1×10-7M或更低的KD结合PD-1。本发明的抗PD-1抗体优选表现出以下特征中的一个或更多个:
(a)基本不与人CD28、CTLA-4或ICOS结合;
(b)在混合淋巴细胞反应(MLR)测定中增加T细胞增殖;
(c)在MLR测定中增加IFN-γ和/或IL-2分泌;
(d)与人PD-1和食蟹猴PD-1结合;
(e)抑制PD-L1与PD-1的结合;
(f)以1×10-7M或更低的KD结合人PD-1,
优选地,所述抗体以1×10-8M或更低的KD结合人PD-1,以5×10-9M或更低的KD结合人PD-1,或以1×10-8M和1×10-12M之间或更小的KD结合人PD-1。更优选地,所述抗体以1×10-12M或更低的KD结合人PD-1。更优选地,所述抗体以3.209×10-12M的KD结合人PD-1。
本发明的抗体可以表现出上文所列特征的任何组合,例如上文所列特征中的两个、三个、四个、五个或更多个。
评估所述抗体对PD-1的结合能力的标准测定在本领域是已知的,包括例如ELISA、蛋白质印迹和RIA。也可以通过本领域已知的标准测定例如通过Biacore分析来评估所述抗体的结合动力学(例如结合亲和力)。在实施例中详细描述了用于评估任何上述特征的合适测定。
在一方面,本发明提供了分离的单克隆抗体或其抗原结合片段,其包含:
(a)包含SEQ ID NO:1(重链CDR1)、SEQ ID NO:2(重链CDR2)、SEQ ID NO:3(重链CDR3)的重链可变区;和
(b)包含SEQ ID NO:4(轻链CDR1)、SEQ ID NO:5(轻链CDR2)和SEQ ID NO:6(轻链CDR3)的轻链可变区;
其中所述抗体特异性结合PD-1,优选人PD-1。
优选的抗PD-1抗体包括:
(a)包含SEQ ID NO:8或SEQ ID NO:16的氨基酸序列的重链可变区;和
(b)包含SEQ ID NO:10或SEQ ID NO:18的氨基酸序列的轻链可变区。
同源抗体
本发明的抗体包含重链和轻链可变区,所述可变区包含与本文所述优选抗体的氨基酸序列同源的氨基酸序列,并且其中所述抗体保留本发明抗PD-1抗体的合乎需要的功能性质。
例如,本发明提供了包含重链可变区和轻链可变区的分离的单克隆抗体或其抗原结合部分,其中:
(a)所述重链可变区包含与选自由SEQ ID NO:8和16组成的组的氨基酸序列具有至少80%同源性的氨基酸序列;
(b)所述轻链可变区包含与选自由SEQ ID NO:10和18组成的组的氨基酸序列具有至少80%同源性的氨基酸序列;和
该抗体表现出一种或更多种以下性质:
(c)基本不与人CD28、CTLA-4或ICOS结合;
(d)在混合淋巴细胞反应(MLR)测定中增加T细胞增殖;
(e)在MLR测定中增加IFN-γ和/或IL-2分泌;
(f)与人PD-1和食蟹猴PD-1结合;
(g)抑制PD-L1与PD-1的结合;
(h)以1×10-7M或更低的KD结合人PD-1。
在其它实施方案中,VH和/或VL氨基酸序列可以与上述序列具有85%、90%、95%、96%、97%、98%或99%同源性。
如本文所用,两个氨基酸序列之间的同源性百分比等同于所述两个序列之间的同一性百分比。两个序列之间的同一性百分比是由序列共享的相同位置的数目的函数(即%同源性=相同位置的#/位置的总#×100),其考虑空位的数目以及各空位的长度,需要引入空位以便两个序列的最佳比对。如下面的非限制性实例中所述,序列的比较和两个序列之间的同一性百分比的确定可以使用数学算法来完成。
免疫缀合物
在另一方面,本发明的特征在于与治疗部分例如细胞毒素、药物(例如免疫抑制剂)或放射性毒素缀合的抗PD-1抗体或其片段。这种缀合物在本文中被称为“免疫缀合物”。包含一种或更多种细胞毒素的免疫缀合物被称为“免疫毒素”。细胞毒素或细胞毒性剂包括对细胞有害(例如杀死)的任何药剂。实例包括紫杉醇、细胞松弛素B、短杆菌肽D、溴化乙锭、依米丁、丝裂霉素、依托泊苷、替尼泊苷(tenoposide)、长春新碱、长春碱、秋水仙碱、阿霉素、柔红霉素、二羟基炭疽菌素二酮、米托蒽醌、光辉霉素、放线菌素D、1-去氢睾酮、糖皮质激素、普鲁卡因、丁卡因、利多卡因、普萘洛尔和嘌呤霉素及其类似物或同源物。治疗剂还包括例如抗代谢物(例如甲氨蝶呤、6-巯基嘌呤、6-硫鸟嘌呤、阿糖胞苷、5-氟尿嘧啶达卡巴嗪)、烷化剂(例如氮芥、thioepa苯丁酸氮芥(thioepa chlorambucil)、美法仑、卡莫司汀(BSNU)和洛莫司汀(CCNU)、环磷酰胺(cyclothosphamide)、白消安、二溴甘露醇、链脲佐菌素、丝裂霉素C和顺二氯二氨基铂(II)(DDP)顺铂)、蒽环类(例如柔红霉素(前称道诺霉素)和阿霉素)、抗生素(例如更生霉素(前称放线菌素)、博来霉素、光辉霉素和安曲霉素(AMC))和抗有丝分裂剂(例如长春新碱和长春碱)。
可以与本发明的抗体缀合的治疗性细胞毒素的其它优选实例包括倍癌霉素(duocarmycins)、卡利奇霉素、美登素和auristatin及其衍生物。
细胞毒素可以使用本领域可获得的接头技术与本发明的抗体缀合。已用于将细胞毒素缀合至抗体的接头类型的实例包括但不限于腙、硫醚、酯、二硫化物和含肽接头。
本发明的抗体还可以与放射性同位素缀合以产生细胞毒性放射性药物,也称为放射性免疫缀合物。可与诊断或治疗用抗体缀合的放射性同位素的实例包括但不限于碘131、铟111、钇90和镥177。本领域建立了制备放射性免疫缀合物的方法。放射性免疫缀合物的实例可商购,包括Zevalin.TM.(IDEC Pharmaceuticals)和Bexxar.TM.(CorixaPharmaceuticals),并且类似的方法可用于使用本发明的抗体制备放射性免疫缀合物。
本发明的抗体缀合物可以用于修饰给定的生物学反应,并且药物部分不被解释为限于经典的化学治疗剂。例如,药物部分可以是具有合乎需要的生物学活性的蛋白质或多肽。这样的蛋白质可以包括例如酶促活性毒素或其活性片段,例如相思豆毒蛋白、蓖麻毒蛋白A、假单胞菌外毒素或白喉毒素;蛋白质例如肿瘤坏死因子或干扰素-γ;或生物学反应修饰剂例如,举例来说,淋巴因子、白细胞介素-1(“IL-1”)、白细胞介素-2(“IL-2”)、白细胞介素-6(“IL-6”)、粒细胞巨噬细胞集落刺激因子(“GM-CSF”)、粒细胞集落刺激因子(“G-CSF”)或其它生长因子。
药物组合物
在另一方面,本发明提供了组合物,例如药物组合物,其包含与药学上可接受的载体一起配制的本发明的单克隆抗体或其抗原结合部分中的一种或组合。这样的组合物可以包含本发明的(例如两种或更多种不同)抗体或免疫缀合物或双特异性分子中的一种或组合。例如,本发明的药物组合物可以包含与靶抗原上的不同表位结合或具有互补活性的抗体(或免疫缀合物或双特异性物)的组合。
本发明的药物组合物也可以联合疗法施用,即与其它药剂组合。例如,联合疗法可以包括与至少一种其它抗炎剂或免疫抑制剂组合的本发明的抗PD-1抗体。下文在关于本发明的抗体的用途的章节中更详细地描述了可用于联合疗法的治疗剂的实例。
如本文所用,“药学上可接受的载体”包括生理学上相容的任何和所有溶剂、分散介质、包衣、抗菌剂和抗真菌剂、等渗剂和延迟吸收剂等。优选地,所述载体适合于静脉内、肌内、皮下、胃肠外、脊柱或表皮施用(例如通过注射或输注)。取决于施用途径,活性化合物即抗体、免疫缀合物或双特异性分子可以被包被在材料中以保护所述化合物免于可使化合物失活的酸和其它自然条件的作用。
本发明的药物化合物可包括一种或更多种药学上可接受的盐。“药学上可接受的盐”是指保留母体化合物的合乎需要的生物活性并且不会赋予任何不希望的毒理学作用的盐。这样的盐的实例包括酸加成盐和碱加成盐。酸加成盐包括衍生自无毒无机酸以及无毒有机酸的盐,所述无毒无机酸例如盐酸、硝酸、磷酸、硫酸、氢溴酸、氢碘酸、磷酸等,所述无毒有机酸例如脂族一元和二元羧酸、苯基取代的链烷酸、羟基链烷酸、芳族酸、脂肪族和芳族磺酸等。碱加成盐包括衍生自碱金属或碱土金属(例如钠、钾、镁、钙等)以及无毒有机胺(例如N,N'-二苄基乙二胺、N-甲基葡糖胺、氯普鲁卡因、胆碱、二乙醇胺、乙二胺、普鲁卡因等)的盐。
本发明的药物组合物还可以包含药学上可接受的抗氧化剂。药学上可接受的抗氧化剂的实例包括:(1)水溶性抗氧化剂,例如抗坏血酸、盐酸半胱氨酸、硫酸氢钠、焦亚硫酸钠、亚硫酸钠等;(2)油溶性抗氧化剂,例如棕榈酸抗坏血酸酯、丁基羟基茴香醚(BHA)、丁基羟基甲苯(BHT)、卵磷脂、没食子酸丙酯、α-生育酚等;和(3)金属螯合剂,例如柠檬酸、乙二胺四乙酸(EDTA)、山梨醇、酒石酸、磷酸等。
可用于本发明药物组合物中的合适的水性和非水性载体的实例包括水、乙醇、多元醇(例如甘油、丙二醇、聚乙二醇等)及其合适的混合物、植物油例如橄榄油和可注射的有机酯例如油酸乙酯。例如,通过使用包衣材料例如卵磷脂,通过在分散体的情况下保持所需的粒度和通过使用表面活性剂,可以保持适当的流动性。
这些组合物还可以含有佐剂,例如防腐剂、润湿剂、乳化剂和分散剂。可以通过上文的灭菌程序和通过包含各种抗菌剂和抗真菌剂(例如对羟基苯甲酸酯、氯丁醇、苯酚山梨酸等)来确保防止微生物的存在。将等渗剂例如糖、氯化钠等包含在所述组合物中也可为合乎需要的。另外,可通过包含延迟吸收的试剂例如单硬脂酸铝和明胶带来可注射药物形式的延长吸收。
药学上可接受的载体包括无菌水溶液或分散体和用于临时制备无菌可注射溶液或分散体的无菌粉末。此类介质和试剂用于药物活性物质的用途在本领域中是已知的。除非任何常规介质或试剂与所述活性化合物不相容,考虑将其在本发明的药物组合物中使用。补充活性化合物也可以掺入所述组合物中。
治疗组合物典型地必须在制造和储存条件下是无菌的和稳定的。该组合物可以配制成适合于高药物浓度的溶液剂、微乳剂、脂质体或其它有序结构。载体可以是含有例如水、乙醇、多元醇(例如甘油、丙二醇和液体聚乙二醇等)以及它们的合适混合物的溶剂或分散介质。例如,通过使用包衣材料例如卵磷脂,通过在分散体的情况下保持所需的粒度和通过使用表面活性剂,可以保持适当的流动性。在许多情况下,优选在组合物中包含等渗剂例如糖、多元醇例如甘露醇、山梨醇或氯化钠。可通过在组合物中包含延迟吸收的试剂例如单硬脂酸盐和明胶带来可注射组合物的延长吸收。
无菌可注射溶液可通过将所需量的活性化合物与上面列举的一种成分或成分的组合(根据需要)掺入合适的溶剂中,随后进行无菌微滤来制备。通常,通过将活性化合物掺入含有基础分散介质和来自上面列举的那些的所需其它成分的无菌媒介物中来制备分散体。在用于制备针对无菌可注射溶液的无菌粉末的情况下,优选的制备方法是真空干燥和冷冻干燥(冻干),其从它的先前的无菌过滤溶液产生活性成分加上任何另外的合乎需要的成分的粉末。
可以与载体材料组合以产生单一剂型的活性成分的量将根据待治疗的受试者和特定的施用模式而变化。可以与载体材料组合以产生单一剂型的活性成分的量通常是产生治疗效果的组合物的量。一般来说,在一百百分比中,该量的范围将为与药学上可接受的载体组合的约0.01%至约99%的活性成分,优选约0.1%至约70%,最优选约1%至约30%的活性成分。
调整剂量方案以提供最佳的合乎需要的反应(例如治疗反应)。例如,可以施用单次推注,可以随着时间推移施用几个分开的剂量,或者可以根据治疗情况的紧急情况所指示的按比例减少或增加剂量。以剂量单位形式配制胃肠外组合物以便于施用和剂量均匀性是特别有利的。本文所用的剂量单位形式是指适合作为待治疗受试者的单一剂量的物理离散单位;每个单位含有经计算产生合乎需要的治疗效果的预定量的活性化合物以及所需的药物载体。用于本发明的剂量单位形式的规格取决于并且直接依赖于(a)活性化合物的独特特征和待实现的特定治疗效果,以及(b)本领域配制这样的活性化合物用于治疗个体的敏感性所固有的限制。
对于所述抗体的施用,剂量范围为约0.0001至100mg/kg宿主体重,并且更通常为0.01至5mg/kg宿主体重。例如剂量可以是0.3mg/kg体重、1mg/kg体重、3mg/kg体重、5mg/kg体重或10mg/kg体重或在1-10mg/kg范围内。示例性的治疗方案需要每周施用一次,每两周施用一次,每三周施用一次,每四周施用一次,每月施用一次,每3个月施用一次或每3至6个月施用一次。本发明抗PD-1抗体的优选剂量方案包括通过静脉内施用的1mg/kg体重或3mg/kg体重,其中使用下列给药方案之一给予抗体:(i)每四周六个剂量,然后每三个月;(ii)每三周;(iii)3mg/kg体重一次,然后每3周1mg/kg体重。
或者,抗体可以作为持续释放制剂施用,在这种情况下需要较少频率的施用。剂量和频率根据患者体内抗体的半衰期而变化。通常,人抗体显示出最长的半衰期,接着是人源化抗体、嵌合抗体和非人抗体。施用的剂量和频率可以根据治疗是预防性还是治疗性而变化。在预防性应用中,相对低的剂量在长时间内以相对不频繁的间隔施用。一些患者在他们的余生中继续接受治疗。在治疗应用中,有时需要相对短的间隔的相对高的剂量直至疾病进展减少或终止,并且优选直至患者显示疾病症状的部分或完全缓解。之后,可以给患者施用预防性方案。
本发明药物组合物中活性成分的实际剂量水平可以变化,以获得有效实现特定患者、组合物和施用模式的合乎需要的治疗反应的活性成分的量,而不会对患者有毒。所选剂量水平将取决于多种药代动力学因素,包括所用本发明特定组合物或其酯、盐或酰胺的活性、施用途径、施用时间、使用的特定化合物的排出速率、治疗持续时间、与所用特定组合物组合使用的其它药物、化合物和/或材料、所治疗患者的年龄、性别、体重、状况、总体健康和既往病史以及医学领域众所周知的类似因素。
本发明的抗PD-1抗体的“治疗有效剂量”优选导致疾病症状的严重性的降低、无疾病症状期的频率和持续时间的增加或由于疾病折磨所致的损伤或残疾的预防。例如,对于肿瘤治疗,相对于未治疗的受试者,“治疗有效剂量”优选将细胞生长或肿瘤生长抑制至少约20%,更优选至少约40%,甚至更优选至少约60%,并且仍更优选至少约80%。化合物抑制肿瘤生长的能力可以在预测在人肿瘤中的功效的动物模型系统中评估。或者,可以通过检查化合物抑制的能力来评估组合物的这种性质,这种抑制通过技术从业人员已知的测定法体外进行。治疗有效量的治疗化合物可以减小肿瘤尺寸或以其它方式改善受试者的症状。本领域普通技术人员能够基于诸如受试者的尺寸、受试者症状的严重性以及所选择的特定组合物或施用途径等因素来确定这样的量。
在另一方面,本公开内容提供了包含如本文所述的抗PD-1抗体和抗CTLA-4抗体的套装药盒(pharmaceutical kit of parts)。所述药盒还可进一步包括用于治疗过度增殖性疾病(例如本文所述的癌症)的说明书。在另一个实施方案中,抗PD-1抗体和抗CTLA-4抗体可以以单位剂量形式共包装。
在某些实施方案中,同时施用具有不同结合特异性的两种或更多种单克隆抗体(例如抗PD-1和抗CTLA-4),在这种情况下,所施用的每种抗体的剂量落入所示范围内。抗体可以以单一剂量施用,或者更通常可以多次(occasions)施用。单个剂量之间的间隔可以是例如每周、每月、每三个月或每年。如通过测量患者中针对靶抗原的抗体的血液水平所指示的,间隔也可以是不规则的。在一些方法中,调整剂量以实现约1-1000μg/ml的血浆抗体浓度,并且在一些方法中约25-300μg/ml。
本发明的组合物可以通过一种或更多种施用途径使用本领域已知的多种方法中的一种或更多种来施用。如技术人员将理解的,施用的途径和/或模式将取决于合乎需要的结果而变化。本发明抗体的优选施用途径包括静脉内、肌内、皮内、腹膜内、皮下、脊柱或其它胃肠外施用途径,例如通过注射或输注。本文使用的短语“胃肠外施用”意指除肠内和局部施用之外的施用模式(通常通过注射),并且包括但不限于静脉内、肌内、动脉内、鞘内、囊内、眶内、心内、皮内、腹膜内、经气管、皮下、表皮下、关节内、囊下、蛛网膜下、脊柱内、硬膜外和胸骨内注射和输注。
或者,可以通过非胃肠外途径例如局部、表皮或粘膜施用途径(例如鼻内、经口、阴道、直肠、舌下或局部)施用本发明的抗体。
活性化合物可以用保护化合物免于快速释放的载体制备,例如控释制剂,其包括植入物,透皮贴剂和微囊化递送系统。可使用可生物降解的生物相容性聚合物,例如乙烯乙酸乙烯酯、聚酐类、聚乙醇酸、胶原、聚原酸酯和聚乳酸。用于制备这种制剂的许多方法是已被专利授权的或者是本领域技术人员通常已知的。参见例如,持续且受控释放的药物递送系统,J.R.Robinson,ed.,Marcel Dekker,Inc.,New York,1978。
治疗组合物可用本领域已知的医疗装置施用。
本发明的用途和方法
本发明的抗体、抗体组合物和方法具有许多体外和体内用途,其涉及例如检测PD-1或通过阻断PD-1增强免疫应答。在优选的实施方案中,本发明的抗体是人抗体。例如,可以将这些分子施用于培养中、体外或离体的细胞,或施用于人受试者(例如体内),以增强各种情况下的免疫力。因此,在一方面,本发明提供了改变受试者的免疫应答的方法,其包括向所述受试者施用本发明的抗体或其抗原结合部分,使得所述受试者中的免疫应答被改变。优选地,所述应答被增强、刺激或上调。
如本文所用,术语“受试者”旨在包括人和非人动物。非人动物包括所有脊椎动物,例如哺乳动物和非哺乳动物,例如非人灵长类动物、绵羊、狗、猫、牛、马、鸡、两栖动物和爬行动物,但优选哺乳动物,例如非人灵长类动物、绵羊、狗、猫、牛和马。优选的受试者包括需要增强免疫应答的人患者。所述方法特别适用于治疗患有可通过增强T细胞介导的免疫应答来治疗的病症的人患者。在一个具体的实施方案中,所述方法特别适用于体内治疗癌细胞。为了实现免疫力的抗原特异性增强,可以将所述抗PD-1抗体与目的抗原一起施用。当针对PD-1的抗体与另一种试剂一起施用时,可以以任一顺序或同时施用两者。
本发明还提供了检测样品中人PD-1抗原的存在情况或测量人PD-1抗原的量的方法,其包括使所述样品和对照样品与特异性结合人PD-1的人单克隆抗体或其抗原结合部分在允许所述抗体或其部分与人PD-1之间形成复合物的条件下接触。然后检测复合物的形成,其中所述样品与对照样品之间的复合物形成差异表明所述样品中存在人PD-1抗原。
鉴于与CD28、ICOS和CTLA-4相比,本发明的抗体对PD-1的特异性结合,本发明的抗体可以用于特异性检测细胞表面上的PD-1表达,并且可以用于通过免疫亲和纯化来纯化PD-1。
在另一方面,本发明提供了如本文所公开的抗体或其抗原结合部分在制备用于改变受试者中的免疫应答的药物中的用途。
癌症
通过抗体阻断PD-1可以增强患者对癌细胞的免疫应答。PD-1的配体PD-L1不在正常人细胞中表达,但在各种人癌症中丰富(Dong等(2002)Nat Med 8:787-9)。PD-1和PD-L1之间的相互作用导致肿瘤浸润淋巴细胞的减少、T细胞受体介导的增殖的减少和癌细胞的免疫逃避(Dong等(2003)J Mol Med 81:281-7;Blank等(2005)CancerImmunol.Immunother.54:307-314;Konishi等(2004)Clin.Cancer Res.10:5094-100)。通过抑制PD-1与PD-L1的局部相互作用可以逆转免疫抑制,并且当PD-1与PD-L2的相互作用也被阻断时,该效果是相加的。尽管先前的研究已经显示可以通过抑制PD-1与PD-L1的相互作用恢复T细胞增殖,但是没有关于通过阻断PD-1/PD-L1相互作用在体内直接影响癌肿瘤生长的报道。在一方面,本发明涉及使用抗PD-1抗体在体内治疗受试者,使得抑制癌性肿瘤的生长。可以单独使用抗PD-1抗体来抑制癌性肿瘤的生长。或者,如下所述,抗PD-1抗体可以与其它免疫原性试剂、标准癌症治疗或其它抗体联合使用。
因此,在一个实施方案中,本发明提供了抑制受试者的肿瘤细胞生长的方法,其包括向所述受试者施用治疗有效量的抗PD-1抗体或其抗原结合部分。
可使用本发明的抗体抑制其生长的优选癌症包括通常响应于免疫疗法的癌症。用于治疗的优选癌症的非限制性实例包括黑素瘤(例如转移性恶性黑素瘤)、肾癌(例如透明细胞癌)、前列腺癌(例如激素难治性前列腺腺癌)、乳腺癌、结肠癌和肺癌(例如非小细胞肺癌)。此外,本发明包括可使用本发明的抗体抑制其生长的难治性或复发性恶性肿瘤。
可以使用本发明的方法治疗的其它癌症的实例包括骨癌、胰腺癌、皮肤癌、头或颈癌、皮肤或眼内恶性黑素瘤、子宫癌、卵巢癌、直肠癌、肛门区域的癌症、胃癌、睾丸癌、子宫癌、输卵管癌、子宫内膜癌、宫颈癌、阴道癌、外阴癌、霍奇金病、非霍奇金淋巴瘤、食道癌、小肠癌、内分泌系统癌、甲状腺癌、甲状旁腺癌、肾上腺癌、软组织肉瘤、尿道癌、阴茎癌、慢性或急性白血病(包括急性骨髓性白血病、慢性骨髓性白血病、急性淋巴细胞性白血病、慢性淋巴细胞性白血病)、儿童实体瘤、淋巴细胞性淋巴瘤、膀胱癌、肾癌或输尿管癌、肾盂癌、中枢神经系统(CNS)肿瘤、原发性CNS淋巴瘤、肿瘤血管生成、脊柱肿瘤、脑干神经胶质瘤、垂体腺瘤、卡波西肉瘤、表皮样癌、鳞状细胞癌、T细胞淋巴瘤、环境诱发的癌症(包括由石棉诱发的癌症)以及所述癌症的组合。本发明还可用于治疗转移性癌症,特别是表达PD-L1的转移性癌症(Iwai等(2005)Int.Immunol.17:133-144)。
任选地,针对PD-1的抗体可以与免疫原性试剂例如癌细胞、纯化的肿瘤抗原(包括重组蛋白质、肽和碳水化合物分子)、细胞和用编码免疫刺激性细胞因子的基因转染的细胞组合(He等(2004)J.Immunol.173:4919-28)。可以使用的肿瘤疫苗的非限制性实例包括黑素瘤抗原的肽,例如gp100、MAGE抗原、Trp-2、MART1和/或酪氨酸酶的肽,或经转染以表达细胞因子GM-CSF的肿瘤细胞。
在人中,已显示一些肿瘤具有免疫原性,例如黑素瘤。预计通过经由PD-1阻断提高T细胞活化的阈值,我们可以预期在宿主中活化肿瘤反应。
可用于活化宿主免疫反应性的其它抗体可与抗PD-1组合使用。这些包括活化DC功能和抗原呈递的树突细胞表面上的分子。抗CD40抗体能够有效取代T细胞辅助活性(Ridge,J.等(1998)Nature 393:474-478)并且可以与PD-1抗体联合使用(Ito,N.等(2000)Immunobiology 201(5)527-40)。活化针对T细胞共刺激分子如CTLA-4、OX-40(Weinberg,A.等(2000)Immunol 164:2160-2169)、4-1BB(Melero,I.等(1997)Nature Medicine 3:682-685(1997)和ICOS(Hutloff,A.等(1999)Nature 397:262-266)的抗体也可以提供增加水平的T细胞活化。
在另一个实施方案中,本发明提供了治疗有效量的如本文所公开的抗PD-1抗体或其抗原结合部分在制备用于抑制受试者中的肿瘤细胞生长的药物中的用途。
传染性疾病
本发明的其它方法用于治疗已暴露于特定毒素或病原体的患者。因此,本发明的另一个方面提供了治疗受试者的传染性疾病的方法,其包括向所述受试者施用抗PD-1抗体或其抗原结合部分,使得所述受试者的所述传染性疾病被治疗。
介导PD-1阻断的抗体可单独使用或作为佐剂与疫苗联合使用,以刺激对病原体、毒素和自身抗原的免疫应答。这种治疗方法可特别有用的病原体的实例包括目前没有有效疫苗的病原体或常规疫苗不完全有效的病原体。这些包括但不限于HIV、肝炎(A、B和C)、流感、疱疹、贾第虫(Giardia)、疟疾、利什曼虫(Leishmania)、金黄色葡萄球菌(Staphylococcus aureus)、铜绿假单胞菌(Pseudomonas Aeruginosa)。针对由在感染过程中呈现改变的抗原的试剂例如HIV确立的感染,PD-1阻断尤其有用。这些新的表位在抗人PD-1施用时被认为是外来的,因此引起强烈的T细胞应答,其不被经PD-1的负信号抑制。
引起可通过本发明方法治疗的感染的病原性病毒的一些实例包括HIV、肝炎(A、B或C)、疱疹病毒(例如VZV、HSV-1、HAV-6、HSV-II和CMV、EB病毒)、腺病毒、流感病毒、黄病毒、埃可病毒、鼻病毒、柯萨奇病毒、玉米病毒、呼吸道合胞病毒、腮腺炎病毒、轮状病毒、麻疹病毒、风疹病毒、细小病毒、牛痘病毒、HTLV病毒、登革热病毒、乳头瘤病毒、软疣(molluscum)病毒、脊髓灰质炎病毒、狂犬病病毒、JC病毒和虫媒病毒脑炎病毒。
引起可通过本发明方法治疗的感染的病原性细菌的一些实例包括衣原体、立克次氏体细菌、分枝杆菌、葡萄球菌、链球菌、肺炎球菌、脑膜炎球菌和conococci、克雷伯氏菌、变形杆菌、沙雷菌、假单胞菌、军团菌、白喉、沙门氏菌、杆菌、霍乱、破伤风、肉毒中毒、炭疽、瘟疫、钩端螺旋体病和莱姆病细菌。
引起可通过本发明方法治疗的感染的病原性真菌的一些实例包括假丝酵母(Candida)(白色假丝酵母(albicans)、克柔假丝酵母(krusei)、光滑假丝酵母(glabrata)、热带假丝酵母(tropicalis)等)、新型隐球菌(Cryptococcus neoformans)、曲霉属(Aspergillus)(烟曲霉(fumigatus)、黑曲霉(niger)等)、毛霉属(Mucorales)(毛霉菌(mucor)、犁头霉(absidia)、根菌(rhizophus))、申克氏胞丝菌(Sporothrix schenkii)、皮炎芽生菌(Blastomyces dermatitidis)、巴西副球孢子菌(Paracoccidioidesbrasiliensis)、粗球孢子菌(Coccidioides immitis)和荚膜组织胞浆菌(Histoplasmacapsulatum)。
引起可通过本发明的方法治疗的感染的病原性寄生虫的一些实例包括溶组织内阿米巴(Entamoeba histolytica)、结肠小袋纤毛虫(Balantidium coli)、福氏耐格里变形虫(Naegleriafowleri)、棘变形虫属(Acanthamoeba sp.)、贾第鞭毛虫(Giardia lambia)、隐孢子虫属(Cryptosporidium sp.)、卡氏肺囊虫(Pneumocystis carinii)、间日疟原虫(Plasmodium vivax)、微小巴贝虫(Babesia microti)、布氏锥虫(Trypanosoma brucei)、克氏锥虫(Trypanosoma cruzi)、杜氏利什曼原虫(Leishmania donovani)、弓形虫(Toxoplasma gondi)和巴西日圆线虫(Nippostrongylus brasiliensis)。
在所有上述方法中,PD-1阻断可以与其它形式的免疫疗法例如细胞因子治疗(例如干扰素、GM-CSF、G-CSF、IL-2)或双特异性抗体疗法组合,双特异性抗体疗法提供增强的肿瘤抗原的呈递。
本发明的另一个实施方案提供了如本文所公开的抗PD-1抗体或其抗原结合部分在制备用于治疗受试者中的传染性疾病的药物中的用途。
本发明的试剂盒
在另一方面,本公开内容提供了包含本文公开的抗PD-1抗体或其抗原结合部分的试剂盒。该试剂盒还可以进一步包含使用说明书。在另一方面,该试剂盒可用于本文所述的任何一种方法或用途中。
本文中说明性描述的本发明可适当地在缺乏本文未具体公开的任何一个或多个要素、一个或多个限制的情况下实施。因此,例如,术语“包含”、“包括”、“含有”等应当被广义地理解并且没有限制。此外,本文使用的术语和表述已经被用作描述性术语而不是限制性术语,并且无意使用这样的术语和表述来排除所示出和描述的特征或其部分的任何等同物,但是认可的是,在要求保护的本发明的范围内各种修改是可能的。因此,应该理解的是,虽然已经通过优选实施方案和任选特征具体公开了本发明,但本领域技术人员可以采用本文公开的其中体现的本发明的修改和变化,并且这些修改和变化被认为在本发明的范围内。
本文已经广泛地和一般地描述了本发明。落入一般公开内容中的每个较窄种类和亚属群组也构成本发明的一部分。这包括本发明的一般性描述,其具有从该属中移除任何主题名称的附带条件或负面限定,而不管在本文中是否具体记载所移除的材料。
其它实施方案落入所附权利要求和非限制性实例内。另外,在根据马库什组描述本发明的特征或方面的情况下,本领域技术人员将认识到,也藉此根据马库什组的任何单个成员或成员亚组描述本发明。
实验部分
下面提供进一步说明本发明的不同特征的实施例。这些实施例还说明了实施本发明的有用方法。这些实施例不限制所要求保护的发明。
实施例1.PD-1-Fc和PD-L1-Fc的构建和表达
合成了含有编码与人Fc融合的人PD-1胞外区的cDNA的DNA(SEQ ID NO.11),其5’末端有Hind III位点,其3’末端有EcoRI位点。用Hind III和EcoRI消化该DNA,然后克隆到已用相同限制酶消化的pcDNA3.1(+)载体(Invitrogen)中,产生表达载体pcDNA3.1(+)-PD-1-Fc。使用Lipofectamine 2000试剂(Invitrogen)将合适的pcDNA3.1(+)-PD-1-Fc表达载体转染到CHO-K1细胞(ATCC)中。在500μg/ml G418存在下通过有限稀释分离稳定的转染子。选择产生最高量的PD-1-Fc蛋白的克隆并在无血清培养基中生长。最后,通过蛋白A亲和层析自无血清培养上清液纯化PD-1-Fc蛋白。通过在280nm处的吸光度确定蛋白质浓度。PD-1-Fc融合蛋白的氨基酸序列显示在SEQ ID NO:23中。
合成了含有编码与人Fc融合的人PD-L1胞外区的cDNA的DNA(SEQ ID NO.12),其5’末端有Hind III位点,其3’末端有EcoRI位点。用Hind III和EcoRI消化该DNA,然后克隆到已用相同限制酶消化的pcDNA3.1(+)载体(Invitrogen)中,产生表达载体pcDNA3.1(+)-PD-L1-Fc。使用Lipofectamine 2000试剂(Invitrogen)将合适的pcDNA3.1(+)-PD-L1-Fc表达载体转染到CHO-K1细胞(ATCC)中。在500μg/ml G418存在下通过有限稀释分离稳定的转染子。选择产生最高量的PD-L1-Fc蛋白的克隆并在无血清培养基中生长。最后,通过蛋白A亲和层析自无血清培养上清液纯化PD-L1-Fc蛋白。通过在280nm处的吸光度确定蛋白质浓度。PD-L1-Fc融合蛋白的氨基酸序列显示在SEQ ID NO:24中。
实施例2.PD-L1-Fc与CHO细胞上表达的PD-1结合的表征
开发了在细胞表面表达重组人PD-1的中国仓鼠卵巢(CHO)细胞系,并将其用于通过流式细胞术确定PD-L1与PD-1的结合。合成了含有编码全长人PD-1的cDNA的DNA(SEQ IDNO.13),其5’末端有Hind III位点,其3’末端有EcoRI位点。用Hind III和EcoRI消化该DNA,然后克隆到已用相同限制酶消化的pcDNA3.1(+)载体(Invitrogen)中,产生表达载体pcDNA3.1(+)-PD-1。使用Lipofectamine 2000试剂(Invitrogen)将合适的pcDNA3.1(+)-PD-1表达载体转染到CHO-K1细胞(ATCC)中。在500μg/ml G418存在下通过有限稀释分离稳定的转染子。全长人PD-1的氨基酸序列显示在SEQ ID NO:14中。用生物素蛋白标记试剂盒(Roche),使用生物素标记PD-L1-Fc重组蛋白。通过将PD-1转染的CHO细胞(CHO/PD-1)与不同浓度的生物素标记的PD-L1-Fc(生物素-PD-L1-Fc)一起孵育来评估PD-L1与PD-1的结合。洗涤细胞并用抗生物素蛋白-FITC检测结合。使用FACScan流式细胞术(Becton Dickinson)进行流式细胞术分析。图1A和1B中显示的结果表明生物素-PD-L1-Fc能够有效地结合CHO/PD-1细胞。
实施例3.PD-1-Fc与PD-L1-Fc结合的表征
用生物素蛋白质标记试剂盒(Roche),使用生物素标记PD-1-Fc重组蛋白。将不同浓度的生物素标记的PD-1-Fc(PD-1-Fc-生物素)加入到用PD-L1-Fc包被的96孔板中,随后在室温孵育1h。洗涤后,加入抗生物素蛋白-HRP并将平板进一步孵育1h。最后,加入3,3',5,5'-四甲基联苯胺(TMB)作为辣根过氧化物酶(HRP)的底物,并在450nm处测量吸光度。图2中显示的结果表明生物素-PD-1-Fc能够有效地结合PD-L1-Fc。
实施例4.针对PD-1的单克隆抗体的产生
为了产生针对PD-1的单克隆抗体,将6周龄的雌性BALB/c小鼠用完全弗氏佐剂(Sigma-Aldrich)中的重组PD-1-Fc蛋白皮下免疫三次。最后一次加强免疫四天后,将小鼠处死并将脾细胞与SP2/0细胞融合。将融合的细胞悬浮在次黄嘌呤/氨基蝶呤/胸苷(HAT)选择性培养基中并铺板于96孔微量滴定板中。12天后,选择产生抗PD-1抗体的杂交瘤克隆以特异性结合人PD-1。确立了一个分泌识别人PD-1的mAb的杂交瘤细胞系并将其命名为67D9。用小鼠Ab同种型分型试剂盒(Sigma)将67D9抗体同种型确定为(IgG2a,κ)。最后,通过蛋白G亲和层析自杂交瘤细胞培养上清液纯化67D9抗体。
实施例5.67D9重链和轻链可变区基因的克隆
用TRIzolReagent(Invitrogen)从67D9杂交瘤细胞中分离了RNA。根据制造商的说明书,通过5’RACE系统(Invitrogen)从杂交瘤细胞克隆67D9的轻链和重链的可变区cDNA。用于PCR扩增67D9重链的基因特异性引物(GSP)如下:GSP1-H,5’-AGC TGG GAA GGT GTGCAC ACC ACT-3’;GSP2-H,5’-CAG AGT TCC AGG TCA AGG TCA-3’;GSP3-H,5’-CTT GAC CAGGCA TCC TAG AGT-3’。用于PCR扩增67D9轻链可变区的GSP如下:GSP1-L,5’-TTG CTG TCCTGA TCA GTC CAA CT-3’;GSP2-L,5’-TGT CGT TCA CTG CCA TCA ATC TT-3’;GSP3-L,5’-TTG TTC AAG AAG CAC ACG ACT GA-3’。将最终的PCR产物克隆到pGEM-T载体(Promega)中进行序列测定。67D9的重链可变区的核苷酸和氨基酸序列分别显示在SEQ ID NO:15和16中。67D9轻链可变区的核苷酸和氨基酸序列分别显示于SEQ ID NO:17和18中。
实施例6.67D9嵌合抗体的构建与表达
合成了含有编码67D9嵌合抗体(c67D9)重链的cDNA的DNA(SEQ ID NO.19),其5’末端有Hind III位点,其3’末端有EcoRI位点。用Hind III和EcoRI消化该DNA,然后克隆到已用相同限制酶消化的pcDNA3.1(+)载体(Invitrogen)中,产生表达载体pcDNA3.1(+)-c67D9H。合成了含有编码c67D9轻链的cDNA的DNA(SEQ ID NO.20),其5’末端有Hind III位点,其3’末端有EcoRI位点。用Hind III和EcoRI消化该DNA,然后克隆到已用相同限制酶消化的pcDNA3.1(+)载体(Invitrogen)中,产生表达载体pcDNA3.1(+)-c67D9L。使用Lipofectamine 2000试剂将合适的pcDNA3.1(+)-c67D9H和pcDNA3.1(+)-c67D9L表达载体共转染到CHO-K1细胞中。在500μg/ml G418存在下通过有限稀释分离稳定的转染子。选择产生最高量的c67D9的克隆并在无血清培养基中生长。最后,通过蛋白A亲和层析自无血清培养上清液纯化c67D9。通过280nm处的吸光度确定抗体浓度。c67D9重链的氨基酸序列示于SEQ ID NO.21,c67D9轻链的氨基酸序列示于SEQ ID NO.22。
实施例7.抗PD-1单克隆抗体67D9的人源化
在蛋白质数据库(PDB)中搜索与67D9的可变片段(Fv)具有高度序列同一性的抗体序列。对67D9的轻链可变区(VL)和重链可变区(VH)进行了两次单独的BLASTP搜索。抗体1HOD(PDB No.1HOD)显示与67D9的VH具有83%同一性,与67D9的VL具有90%同一性。我们选择1HOD作为67D9的VH和VL的模板。为了通过同源建模(INSIGHT II 2003,Accelrys,SanDiego,CA)构建67D9Fv的三维结构,分别对67D9的VL和VH的序列和其模板进行了比对。自模板分配结构上保守的区域的坐标,由Insight II的Homology程序生成环区域。使新构建的结构进行分子动力学模拟,然后通过1000步的最速下降法进行能量最小化,然后使用Discover程序进行共轭梯度法。最后,通过Insight II分子建模软件获得67D9可变区的分子模型。
选择轻链亚组κIII(humκIII)和重链亚组III(humIII)的人共有序列分别作为67D9人源化形式的重链和轻链的人框架(图3)。选择人源化抗体中的互补决定区(CDR)为与小鼠抗体67D9中的那些CDR相同。67D9Fv的分子模型显示在67D9与人抗体模板之间不同的8个框架区(FR)残基位于CDR的内,并可能影响CDR的结构。因此,将人源化67D9抗体(hu67D9)中的这8个FR残基选择为鼠67D9残基而不是人抗体残基(图3)。hu67D9重链可变区的核苷酸和氨基酸序列分别示于SEQ ID NO.7和SEQ ID NO.8。hu67D9轻链可变区的核苷酸和氨基酸序列分别示于SEQ ID NO.9和SEQ ID NO.10。
实施例8.抗PD-1人源化抗体hu67D9的表达
合成了含有编码hu67D9重链的cDNA的DNA(SEQ ID NO.25),其5’末端有Hind III位点,其3’末端有EcoRI位点。用Hind III和EcoRI消化该DNA,然后克隆到已用相同限制酶消化的pcDNA3.1(+)载体(Invitrogen)中,产生表达载体pcDNA3.1(+)-hu67D9H。合成了含有编码hu67D9轻链的cDNA的DNA(SEQ ID NO.27),其5’末端有Hind III位点,其3’末端有EcoRI位点。用Hind III和EcoRI消化该DNA,然后克隆到已用相同限制酶消化的pcDNA3.1(+)载体(Invitrogen)中,产生表达载体pcDNA3.1(+)-hu67D9L。使用Lipofectamine 2000试剂将合适的pcDNA3.1(+)-hu67D9H和pcDNA3.1(+)-hu67D9L表达载体共转染到CHO-K1细胞中。在500μg/ml G418存在下通过有限稀释分离稳定的转染子。选择产生最高量的hu67D9的克隆并在无血清培养基中生长。最后,通过蛋白A亲和层析自无血清培养上清液纯化hu67D9。通过280nm处的吸光度确定抗体浓度。hu67D9重链的氨基酸序列示于SEQ IDNO.26,hu67D9轻链的氨基酸序列示于SEQ ID NO.28。
实施例9.结合亲和力测量
使用Holash及同事(Holash J,等Proc Natl Acad Sci U S A.2002;99(17):11393-8)描述的类似方法测定了67D9、c67D9和hu67D9的结合亲和力。简而言之,将固定浓度的抗PD-1抗体与不同浓度的PD-1-Fc孵育1小时。然后将混合物加入到用PD-1-Fc包被的96孔板中,然后孵育1h。洗涤后,加入HRP缀合的山羊抗人κ(用于检测c67D9或hu67D9)或HRP缀合的山羊抗小鼠κ(用于检测67D9),并将板进一步孵育1h。最后,添加TMB作为HRP的底物,并在450nm处测量吸光度。我们的结果表明,67D9、c67D9和hu67D9的结合亲和力(KD)分别为12.4pM、16.9pM和15.4pM。
实施例10.通过抗PD-1抗体阻断PD-L1与表达PD-1的CHO-K1细胞的结合
通过使用流式细胞术测定测试了抗PD-1抗体67D9、c67D9和hu67D9阻断PD-L1与被转染的CHO-K1(CHO/PD-1)细胞上表达的PD-1结合的能力。简而言之,将亚饱和浓度的生物素-PD-L1-Fc与10μg/ml的67D9、c67D9或hu67D9孵育1小时。然后将混合物加入到CHO/PD-1细胞中。1小时后,洗涤细胞并用抗生物素蛋白-PE检测结合。使用FACScan流式细胞术(Becton Dickinson)进行流式细胞术分析。图4A-4D中显示的结果表明全部三种抗PD-1抗体67D9、c67D9和hu67D9都有效地抑制了PD-L1-Fc与在被转染的CHO-K1细胞上表达的PD-1的结合。
实施例11.抗PD-1抗体与CD28家族成员的结合
抗PD-1抗体的特异性通过使用标准ELISA检测它们与CD28家族成员ICOS、CTLA-4和CD28(R&D System)的结合来检查。简而言之,将不同浓度的67D9、c67D9或hu67D9添加至用ICOS、CTLA-4、CD28或PD-1-Fc包被的96孔板,然后在室温孵育2h。洗涤后,加入HRP缀合的山羊抗人κ(用于检测c67D9或hu67D9)或HRP缀合的山羊抗小鼠κ(用于检测67D9),并将板进一步孵育1h。最后,添加TMB作为HRP的底物,并在450nm处测量吸光度。如图5A-5D所示,各抗PD-1抗体67D9、c67D9和hu67D9与PD-1结合,但不与其它CD28家族成员(ICOS、CTLA-4和CD28)结合。
实施例12.抗PD-1抗体在混合淋巴细胞反应中对细胞增殖和细胞因子产生的影响
使用混合淋巴细胞反应来证明阻断PD-1途径对淋巴细胞效应细胞的影响。在存在或不存在抗PD-1抗体的情况下,测试了测定中的T细胞的增殖、IFN-γ分泌和IL-2分泌。简而言之,通过Ficoll-Hypaque密度梯度离心从健康志愿者的肝素化血液分离人外周血单核细胞(PBMC)。将人PBMC在96孔平底板中培养过夜。将不同抗体浓度的抗PD-1抗体(67D9、c67D9或hu67D9)、PMA(10ng/ml)和离子霉素(ionomycin)(10ng/ml)加入到各培养物中。使用对照IgG4抗体作为阴性对照。将细胞在37℃培养3天。然后用3H-胸苷标记细胞,再培养6小时,并通过使用MicroBeta计数器(PerkinElmer)分析细胞增殖。图6A中显示的结果表明三种抗PD-1抗体67D9、c67D9和hu67D9中的每一种以浓度依赖性方式促进T细胞增殖。
将人PBMC在96孔平底板中培养过夜。将不同抗体浓度的抗PD-1抗体(67D9、c67D9或hu67D9)、PMA(10ng/ml)和离子霉素(10ng/ml)加入到各培养物中。使用对照IgG4抗体作为阴性对照。将细胞在37℃培养3天。然后从各培养物取出100μl培养基进行细胞因子测量。使用ELISA试剂盒(R&D System)测量IFN-γ和IL-2的水平。结果表明三种抗PD-1抗体67D9、c67D9和hu67D9中的每一种以浓度依赖性方式促进IL-2(图6B)和IFN-γ(图6C)分泌。
实施例13.与小鼠PD-1和食蟹猴PD-1结合的抗PD-1抗体的表征
使用与实施例1中用于人PD-1-Fc相同的方法将小鼠PD-1和食蟹猴PD-1制备为Fc融合蛋白。将不同浓度的67D9、c67D9或hu67D9添加到用人PD-1-Fc、小鼠PD-1-Fc或食蟹猴PD-1-Fc包被的96孔板中,然后在室温孵育1小时。洗涤后,加入HRP缀合的山羊抗人κ(用于检测c67D9或hu67D9)或HRP缀合的山羊抗小鼠κ(用于检测67D9),并将板进一步孵育1小时。最后,添加TMB作为HRP的底物,并在450nm处测量吸光度。如图7A-7C所示,各抗PD-1抗体67D9、c67D9和hu67D9都与人PD-1-Fc和食蟹猴PD-1-Fc结合,但不与小鼠PD-1-Fc结合。
实施例14.热稳定性测量
进行差示扫描量热法(DSC)测量以确定表观中点解折叠温度(Tm)。DSC也用于测量状态的热容和与可由温度变化诱导的转变相关的过剩热。过剩热容的积分是该过程的焓。主要的解折叠转变表现为显著的吸热峰。
使用VP-DSC(Microcal,Northhampton,MA)对PBS(pH 7.0)中的蛋白质浓度为0.5mg/mL的纳武单抗、派姆单抗和hu67D9溶液进行了DSC实验。以0.5mg/mL的蛋白质浓度分别测试了各mAb,并且使用不含蛋白质的缓冲液对照作为参照。在10℃最初的10min平衡之后以100℃/小时的速率从10℃至120℃扫描样品。进行了至少5次缓冲液-缓冲液扫描,以获得基线值并建立热史。使用Origin 7.0(Origin-Lab,Northampton,Massachusetts)分析数据。将所有热分析图进行基线校正(线性连接)并使用Origin中的非两态模型拟合以获得解折叠的表观中点温度(Tm)和解折叠的表观焓(ΔH)。如图8和表1所示,hu67D9的解折叠温度高于纳武单抗和派姆单抗,表明与纳武单抗和派姆单抗相比,hu67D9具有更好的热稳定性。
表1.由DSC确定的表观中点解折叠温度和解折叠焓
抗PD-1抗体 | Tm(℃) | ΔH(kcal) |
派姆单抗 | 72.3 | 829 |
纳武单抗 | 69.2 | 581 |
人源化67D9 | 83.5 | 929 |
实施例15.动力学和亲和力测量
Biacore系统使用的表面等离子体共振(SPR)的光学现象能够实时检测和测量蛋白质-蛋白质相互作用,而无需使用标记。可以通过测量该相互作用的结合动力学确定抗体对其抗原的亲和力。
在动力学和亲和常数的评估中,固定PD-1-Fc融合蛋白,并将hu67D9和纳武单抗稀释到运行缓冲液中并分析。
亲和常数由速率常数的比率计算。如图9所示,hu67D9的KD是3.209E-12M,而纳武单抗的KD是2.116E-11M。这些结果表明hu67D9以比纳武单抗更高的亲和力与PD-1结合。
实施例16与细胞表面PD-1的结合活性
使用标准流式细胞术测定测试了hu67D9结合在被转染的CHO-K1(CHO/PD-1)细胞上表达的PD-1的能力。
将系列稀释的hu67D9或纳武单抗分别与CHO/PD-1细胞一起孵育。孵育1小时后,洗涤细胞并将FITC标记的抗人抗体孵育1小时。然后洗涤细胞并使用FACScan流式细胞术进行流式细胞术分析。
如图10所示,hu67D9和纳武单抗都能够与细胞表面上表达的PD-1结合。hu67D9的EC50值远低于纳武单抗的EC50值,这表明hu67D9以比纳武单抗更高的亲和力结合细胞表面PD-1。
实施例17与可溶性PD-1的结合活性
抗PD-1抗体的特异性是使用标准ELISA技术通过检测它们与可溶性PD-1的结合来检查。
将不同浓度的hu67D9和纳武单抗加入到用PD-1-Fc包被的96孔板中,然后在室温孵育2小时。洗涤后,加入HRP缀合的山羊抗人κ,并将板进一步孵育1小时。最后,添加TMB作为HRP的底物,并在450nm处测量吸光度。
如图11所示,hu67D9和纳武单抗都能够与可溶性PD-1结合。hu67D9的EC50值远低于纳武单抗的EC50值,这表明hu67D9以比纳武单抗更高的亲和力结合可溶性PD-1。
实施例18与纳武单抗竞争结合细胞表面PD-1
使用流式细胞术测定测试了hu67D9竞争结合在被转染的CHO-K1(CHO/PD-1)细胞上表达的PD-1的能力。
将亚饱和浓度的FITC标记的纳武单抗分别与系列稀释的hu67D9或纳武单抗孵育。孵育1小时后,洗涤细胞并使用FACScan流式细胞术进行流式细胞术分析。
如图12所示,hu67D9和纳武单抗均与FITC标记的纳武单抗竞争结合细胞表面PD-1。hu67D9的IC50值远低于纳武单抗的IC50值,这表明hu67D9以比纳武单抗更高的亲和力竞争结合细胞表面PD-1。
实施例19与纳武单抗竞争结合可溶性PD1
使用标准ELISA技术检查抗PD-1抗体的竞争结合可溶性PD-1的活性。
将亚饱和浓度的生物素标记的纳武单抗和系列稀释的hu67D9或纳武单抗加入到用PD-1-Fc包被的96孔板中,然后在室温孵育2小时。洗涤后,加入HRP-抗生物素蛋白,将板进一步孵育1小时。最后,添加TMB作为HRP的底物,并在450nm处测量吸光度。
如图13所示,hu67D9和纳武单抗都与生物素标记的纳武单抗竞争并结合可溶性PD-1。hu67D9的EC50值远低于纳武单抗的EC50值,这表明hu67D9以比纳武单抗更高的亲和力竞争结合可溶性PD1。
实施例20与PD-L1竞争结合可溶性PD1
使用标准ELISA技术检查抗PD-1抗体与PD-L1竞争结合可溶性PD1。
将亚饱和浓度的生物素标记的PDL1-Fc和系列稀释的hu67D9或纳武单抗加入到用PD-1-Fc包被的96孔板中,随后在室温孵育2小时。洗涤后,加入HRP-抗生物素蛋白,将板进一步孵育1小时。最后,添加TMB作为HRP的底物,并在450nm处测量吸光度。
如图14所示,hu67D9和纳武单抗都与生物素标记的PDL1-Fc竞争并结合可溶性PD-1。hu67D9的EC50值远低于纳武单抗的EC50值,这表明hu67D9以比纳武单抗更高的亲和力竞争结合可溶性PD1。
序 列 表
<110> 亚洲生物技术私人有限公司
<120> PD-1抗体及其用途
<130> 31623SG1
<160> 28
<170> PatentIn版本3.5
<210> 1
<211> 5
<212> PRT
<213> 人工序列
<220>
<223> 重链CDR1
<400> 1
Thr Tyr Gly Met Ser
1 5
<210> 2
<211> 17
<212> PRT
<213> 人工序列
<220>
<223> 重链CDR2
<400> 2
Thr Ile Ser Gly Gly Gly Arg Asp Thr Tyr Tyr Pro Asp Thr Val Lys
1 5 10 15
Gly
<210> 3
<211> 11
<212> PRT
<213> 人工序列
<220>
<223> 重链CDR3
<400> 3
Gln Asp Tyr Gly Asn Tyr Val Trp Phe Ala Tyr
1 5 10
<210> 4
<211> 15
<212> PRT
<213> 人工序列
<220>
<223> 轻链CDR1
<400> 4
Arg Ala Ser Glu Ser Val Asp Ser Tyr Gly Ile Ser Phe Met His
1 5 10 15
<210> 5
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> 轻链CDR2
<400> 5
Ser Thr Ser Asn Arg Gly Ser
1 5
<210> 6
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> 轻链CDR3
<400> 6
Gln Gln Ser Gln Glu Val Pro Trp Thr
1 5
<210> 7
<211> 360
<212> DNA
<213> 人工序列
<220>
<223> hu67D9重链可变区的核苷酸序列
<400> 7
gaggtgcagc tcgtggaatc tgggggcgga ctggtgcagc ccggtggaag tctccggctg 60
agctgcgccg ctagtgggtt cactttttct acttacggga tgtcttgggt ccgacaggca 120
ccaggcaagg ggctggagtg ggtggctact atttctggag gaggccgaga cacctactac 180
cccgacaccg tcaagggacg ttttactatc agccgtgaca acagcaagaa taccctctac 240
cttcagatgt cttcactgcg agctgaagac accgctgtgt actattgtgc ccgtcaggac 300
tacggtaact acgtgtggtt cgcttactgg ggacagggaa ccctggtcac cgtctcctcg 360
<210> 8
<211> 120
<212> PRT
<213> 人工序列
<220>
<223> hu67D9重链可变区的氨基酸序列
<400> 8
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 Thr Tyr
20 25 30
Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Thr Ile Ser Gly Gly Gly Arg Asp Thr Tyr Tyr Pro Asp Thr 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 Ser Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gln Asp Tyr Gly Asn Tyr Val Trp Phe Ala Tyr Trp Gly Gln
100 105 110
Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 9
<211> 336
<212> DNA
<213> 人工序列
<220>
<223> hu67D9轻链可变区的核苷酸序列
<400> 9
gatattgttc tgacccagtc ccccgcttca ctggctgtga gtcctgggca gcgagctacc 60
atcagctgcc gggcttcaga gtccgtggat agctacggaa tttcatttat gcactggttc 120
cagcagaagc caggccaacc acctcagttg ctgatatatt cgacatctaa tcggggaagc 180
ggtgtgccag cccggtttag tggtagcggc tctggtacag atttctctct tacaattaac 240
ccagtggagg cggatgacac tgccaattac ttttgtcagc agagccagga agtgccttgg 300
acttttggtc agggcacgaa ggtagagatt aaacgg 336
<210> 10
<211> 112
<212> PRT
<213> 人工序列
<220>
<223> hu67D9轻链可变区的氨基酸序列
<400> 10
Asp Ile Val Leu Thr Gln Ser Pro Ala Ser Leu Ala Val Ser Pro Gly
1 5 10 15
Gln Arg Ala Thr Ile Ser Cys Arg Ala Ser Glu Ser Val Asp Ser Tyr
20 25 30
Gly Ile Ser Phe Met His Trp Phe Gln Gln Lys Pro Gly Gln Pro Pro
35 40 45
Gln Leu Leu Ile Tyr Ser Thr Ser Asn Arg Gly Ser Gly Val Pro Ala
50 55 60
Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Ser Leu Thr Ile Asn
65 70 75 80
Pro Val Glu Ala Asp Asp Thr Ala Asn Tyr Phe Cys Gln Gln Ser Gln
85 90 95
Glu Val Pro Trp Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg
100 105 110
<210> 11
<211> 1173
<212> DNA
<213> 人工序列
<220>
<223> 含有编码与人Fc融合的人PD-1胞外区的cDNA的DNA的核苷酸序列
<400> 11
aagcttcttg ccgccaccat gcagatccca caggcgccct ggccagtcgt ctgggcggtg 60
ctacaactgg gctggcggcc aggatggttc ttagactccc cagacaggcc ctggaacccc 120
cccaccttct ccccagccct gctcgtggtg accgaagggg acaacgccac cttcacctgc 180
agcttctcca acacatcgga gagcttcgtg ctaaactggt accgcatgag ccccagcaac 240
cagacggaca agctggccgc cttccccgag gaccgcagcc agcccggcca ggactgccgc 300
ttccgtgtca cacaactgcc caacgggcgt gacttccaca tgagcgtggt cagggcccgg 360
cgcaatgaca gcggcaccta cctctgtggg gccatctccc tggcccccaa ggcgcagatc 420
aaagagagcc tgcgggcaga gctcagggtg acagagagaa gggctagcga gcccaaatct 480
tgtgacaaaa ctcacacatg cccaccgtgc ccagcacctg aactcctggg gggaccgtca 540
gtcttcctct tccccccaaa acccaaggac accctcatga tctcccggac ccctgaggtc 600
acatgcgtgg tggtggacgt gagccacgaa gaccctgagg tcaagttcaa ctggtacgtg 660
gacggcgtgg aggtgcataa tgccaagaca aagccgcggg aggagcagta caacagcacg 720
taccgtgtgg tcagcgtcct caccgtcctg caccaggact ggctgaatgg caaggagtac 780
aagtgcaagg tctccaacaa agccctccca gcccccatcg agaaaaccat ctccaaagcc 840
aaagggcagc cccgagaacc acaggtgtac accctgcccc catctcggga ggagatgacc 900
aagaaccagg tcagcctgac ctgcctggtc aaaggcttct atcccagcga catcgccgtg 960
gagtgggaga gcaatgggca gccggagaac aactacaaga ccacgcctcc cgtgctggac 1020
tccgacggct ccttcttcct ctatagcaag ctcaccgtgg acaagagcag gtggcagcag 1080
gggaacgtct tctcatgctc cgtgatgcat gaggctctgc acaaccacta cacgcagaag 1140
agcctctccc tgtccccggg taaatgagaa ttc 1173
<210> 12
<211> 1443
<212> DNA
<213> 人工序列
<220>
<223> 含有编码与人Fc融合的人PD-L1胞外区的cDNA的DNA的核苷酸序列
<400> 12
aagcttgccg ccaccatgag gatatttgct gtctttatat tcatgaccta ctggcatttg 60
ctgaacgcat ttactgtcac ggttcccaag gacctatatg tggtagagta tggtagcaat 120
atgacaattg aatgcaaatt cccagtagaa aaacaattag acctggctgc actaattgtc 180
tattgggaaa tggaggataa gaacattatt caatttgtgc atggagagga agacctgaag 240
gttcagcata gtagctacag acagagggcc cggctgttga aggaccagct ctccctggga 300
aatgctgcac ttcagatcac agatgtgaaa ttgcaggatg caggggtgta ccgctgcatg 360
atcagctatg gtggtgccga ctacaagcga attactgtga aagtcaatgc cccatacaac 420
aaaatcaacc aaagaatttt ggttgtggat ccagtcacct ctgaacatga actgacatgt 480
caggctgagg gctaccccaa ggccgaagtc atctggacaa gcagtgacca tcaagtcctg 540
agtggtaaga ccaccaccac caattccaag agagaggaga aacttttcaa tgtgaccagc 600
acactgagaa tcaacacaac aactaatgag attttctact gcacttttag gagattagat 660
cctgaggaaa accatacagc tgaattggtc atcccagaac tacctctggc acatcctcca 720
aatgaaagga ctgctagcga gcccaaatct tgtgacaaaa ctcacacatg cccaccgtgc 780
ccagcacctg aactcctggg gggaccgtca gtcttcctct tccccccaaa acccaaggac 840
accctcatga tctcccggac ccctgaggtc acatgcgtgg tggtggacgt gagccacgaa 900
gaccctgagg tcaagttcaa ctggtacgtg gacggcgtgg aggtgcataa tgccaagaca 960
aagccgcggg aggagcagta caacagcacg taccgtgtgg tcagcgtcct caccgtcctg 1020
caccaggact ggctgaatgg caaggagtac aagtgcaagg tctccaacaa agccctccca 1080
gcccccatcg agaaaaccat ctccaaagcc aaagggcagc cccgagaacc acaggtgtac 1140
accctgcccc catcccggga tgagctgacc aagaaccagg tcagcctgac ctgcctggtc 1200
aaaggcttct atcccagcga catcgccgtg gagtgggaga gcaatgggca gccggagaac 1260
aactacaaga ccacgcctcc cgtgctggac tccgacggct ccttcttcct ctacagcaag 1320
ctcaccgtgg acaagagcag gtggcagcag gggaacgtct tctcatgctc cgtgatgcat 1380
gaggctctgc acaaccacta cacgcagaag agcctctccc tgtccccggg taaatgagaa 1440
ttc 1443
<210> 13
<211> 888
<212> DNA
<213> 智人
<400> 13
aagcttgccg ccaccatgca gatcccacag gcgccctggc cagtcgtctg ggcggtgcta 60
caactgggct ggcggccagg atggttctta gactccccag acaggccctg gaaccccccc 120
accttctccc cagccctgct cgtggtgacc gaaggggaca acgccacctt cacctgcagc 180
ttctccaaca catcggagag cttcgtgcta aactggtacc gcatgagccc cagcaaccag 240
acggacaagc tggccgcctt ccccgaggac cgcagccagc ccggccagga ctgccgcttc 300
cgtgtcacac aactgcccaa cgggcgtgac ttccacatga gcgtggtcag ggcccggcgc 360
aatgacagcg gcacctacct ctgtggggcc atctccctgg cccccaaggc gcagatcaaa 420
gagagcctgc gggcagagct cagggtgaca gagagaaggg cagaagtgcc cacagcccac 480
cccagcccct cacccaggcc agccggccag ttccaaaccc tggtggttgg tgtcgtgggc 540
ggcctgctgg gcagcctggt gctgctagtc tgggtcctgg ccgtcatctg ctcccgggcc 600
gcacgaggga caataggagc caggcgcacc ggccagcccc tgaaggagga cccctcagcc 660
gtgcctgtgt tctctgtgga ctatggggag ctggatttcc agtggcgaga gaagaccccg 720
gagccccccg tgccctgtgt ccctgagcag acggagtatg ccaccattgt ctttcctagc 780
ggaatgggca cctcatcccc cgcccgcagg ggctcagctg acggccctcg gagtgcccag 840
ccactgaggc ctgaggatgg acactgctct tggcccctct gagaattc 888
<210> 14
<211> 268
<212> PRT
<213> 智人
<400> 14
Pro Gly Trp Phe Leu Asp Ser Pro Asp Arg Pro Trp Asn Pro Pro Thr
1 5 10 15
Phe Ser Pro Ala Leu Leu Val Val Thr Glu Gly Asp Asn Ala Thr Phe
20 25 30
Thr Cys Ser Phe Ser Asn Thr Ser Glu Ser Phe Val Leu Asn Trp Tyr
35 40 45
Arg Met Ser Pro Ser Asn Gln Thr Asp Lys Leu Ala Ala Phe Pro Glu
50 55 60
Asp Arg Ser Gln Pro Gly Gln Asp Cys Arg Phe Arg Val Thr Gln Leu
65 70 75 80
Pro Asn Gly Arg Asp Phe His Met Ser Val Val Arg Ala Arg Arg Asn
85 90 95
Asp Ser Gly Thr Tyr Leu Cys Gly Ala Ile Ser Leu Ala Pro Lys Ala
100 105 110
Gln Ile Lys Glu Ser Leu Arg Ala Glu Leu Arg Val Thr Glu Arg Arg
115 120 125
Ala Glu Val Pro Thr Ala His Pro Ser Pro Ser Pro Arg Pro Ala Gly
130 135 140
Gln Phe Gln Thr Leu Val Val Gly Val Val Gly Gly Leu Leu Gly Ser
145 150 155 160
Leu Val Leu Leu Val Trp Val Leu Ala Val Ile Cys Ser Arg Ala Ala
165 170 175
Arg Gly Thr Ile Gly Ala Arg Arg Thr Gly Gln Pro Leu Lys Glu Asp
180 185 190
Pro Ser Ala Val Pro Val Phe Ser Val Asp Tyr Gly Glu Leu Asp Phe
195 200 205
Gln Trp Arg Glu Lys Thr Pro Glu Pro Pro Val Pro Cys Val Pro Glu
210 215 220
Gln Thr Glu Tyr Ala Thr Ile Val Phe Pro Ser Gly Met Gly Thr Ser
225 230 235 240
Ser Pro Ala Arg Arg Gly Ser Ala Asp Gly Pro Arg Ser Ala Gln Pro
245 250 255
Leu Arg Pro Glu Asp Gly His Cys Ser Trp Pro Leu
260 265
<210> 15
<211> 360
<212> DNA
<213> 人工序列
<220>
<223> 67D9重链可变区的核苷酸序列
<400> 15
gaagtgattc tggtggagtc tgggggaggc ttagtgaagc ctggagggtc cctgaaagtc 60
tcctgtgcgg cctctggatt cactttcagt acctatggca tgtcttgggt tcgccagact 120
ccggagaaga ggctggagtg ggtcgcaacc attagtggtg gtggtcgtga cacctactat 180
ccagacactg tgaaggggcg attcaccatc tccagagaca atgccaaaaa taccctgtat 240
ctacaaatga gcagtctgag gtctgaggac acggccttgt attattgtgc aagacaggac 300
tatggtaact acgtatggtt tgcttactgg ggccaaggga ctctggtcac tgtctctgca 360
<210> 16
<211> 120
<212> PRT
<213> 人工序列
<220>
<223> 67D9重链可变区的氨基酸序列
<400> 16
Glu Val Ile Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly
1 5 10 15
Ser Leu Lys Val Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Thr Tyr
20 25 30
Gly Met Ser Trp Val Arg Gln Thr Pro Glu Lys Arg Leu Glu Trp Val
35 40 45
Ala Thr Ile Ser Gly Gly Gly Arg Asp Thr Tyr Tyr Pro Asp Thr Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Ser Ser Leu Arg Ser Glu Asp Thr Ala Leu Tyr Tyr Cys
85 90 95
Ala Arg Gln Asp Tyr Gly Asn Tyr Val Trp Phe Ala Tyr Trp Gly Gln
100 105 110
Gly Thr Leu Val Thr Val Ser Ala
115 120
<210> 17
<211> 336
<212> DNA
<213> 人工序列
<220>
<223> 67D9轻链可变区的核苷酸序列
<400> 17
gacattgtgc tgacccaatc tccagcttct ttggctgtgt ctctagggca gagggccacc 60
atctcctgca gagccagcga aagtgttgat agttatggca ttagttttat gcactggttc 120
caacagaaac caggacagcc accccaactc ctcatctatt ctacatccaa ccgaggatcc 180
ggggtccctg ccaggtttag tggcagtggg tctgggacag acttcagcct caccatccat 240
cctatggagg aggatgatac tgcaatgtat ttctgtcagc aaagtcagga ggttccgtgg 300
acgttcggtg gaggcaccaa gctggaaatc aaacgg 336
<210> 18
<211> 112
<212> PRT
<213> 人工序列
<220>
<223> 67D9轻链可变区的氨基酸序列
<400> 18
Asp Ile Val Leu Thr Gln Ser Pro Ala Ser Leu Ala Val Ser Leu Gly
1 5 10 15
Gln Arg Ala Thr Ile Ser Cys Arg Ala Ser Glu Ser Val Asp Ser Tyr
20 25 30
Gly Ile Ser Phe Met His Trp Phe Gln Gln Lys Pro Gly Gln Pro Pro
35 40 45
Gln Leu Leu Ile Tyr Ser Thr Ser Asn Arg Gly Ser Gly Val Pro Ala
50 55 60
Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Ser Leu Thr Ile His
65 70 75 80
Pro Met Glu Glu Asp Asp Thr Ala Met Tyr Phe Cys Gln Gln Ser Gln
85 90 95
Glu Val Pro Trp Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys Arg
100 105 110
<210> 19
<211> 1422
<212> DNA
<213> 智人
<400> 19
aagcttgccg ccaccatgaa cttcggactc agcttgattt tccttgtcct aattttaaaa 60
ggtgtccagt gtgaagtgat tctggtggag tctgggggag gcttagtgaa gcctggaggg 120
tccctgaaag tctcctgtgc ggcctctgga ttcactttca gtacctatgg catgtcttgg 180
gttcgccaga ctccggagaa gaggctggag tgggtcgcaa ccattagtgg tggtggtcgt 240
gacacctact atccagacac tgtgaagggg cgattcacca tctccagaga caatgccaaa 300
aataccctgt atctacaaat gagcagtctg aggtctgagg acacggcctt gtattattgt 360
gcaagacagg actatggtaa ctacgtatgg tttgcttact ggggccaagg gactctggtc 420
actgtctctg cagctagcac caagggccca tccgtcttcc ccctggcgcc ctgctccagg 480
agcacctccg agagcacagc cgccctgggc tgcctggtca aggactactt ccccgaaccg 540
gtgacggtgt cgtggaactc aggcgccctg accagcggcg tgcacacctt cccggctgtc 600
ctacagtcct caggactcta ctccctcagc agcgtggtga ccgtgccctc cagcagcttg 660
ggcacgaaga cctacacctg caacgtagat cacaagccca gcaacaccaa ggtggacaag 720
agagttgagt ccaaatatgg tcccccatgc ccaccctgcc cagcacctga gttcctgggg 780
ggaccatcag tcttcctgtt ccccccaaaa cccaaggaca ctctcatgat ctcccggacc 840
cctgaggtca cgtgcgtggt ggtggacgtg agccaggaag accccgaggt ccagttcaac 900
tggtacgtgg atggcgtgga ggtgcataat gccaagacaa agccgcggga ggagcagttc 960
aacagcacgt accgtgtggt cagcgtcctc accgtcctgc accaggactg gctgaacggc 1020
aaggagtaca agtgcaaggt ctccaacaaa ggcctcccgt cctccatcga gaaaaccatc 1080
tccaaagcca aagggcagcc ccgagagcca caggtgtaca ccctgccccc atcccaggag 1140
gagatgacca agaaccaggt cagcctgacc tgcctggtca aaggcttcta ccccagcgac 1200
atcgccgtgg agtgggagag caatgggcag ccggagaaca actacaagac cacgcctccc 1260
gtgctggact ccgacggctc cttcttcctc tacagcaggc taaccgtgga caagagcagg 1320
tggcaggagg ggaatgtctt ctcatgctcc gtgatgcacg aggctctgca caaccactac 1380
acacagaaga gcctctccct gtctctgggt aaatgagaat tc 1422
<210> 20
<211> 738
<212> DNA
<213> 人工序列
<220>
<223> 含有编码c67D9轻链的cDNA的DNA的核苷酸序列
<400> 20
aagcttgccg ccaccatgga gaaagacaca ctcctgctat gggtcctgct tctctgggtt 60
ccaggttcca caggtgacat tgtgctgacc caatctccag cttctttggc tgtgtctcta 120
gggcagaggg ccaccatctc ctgcagagcc agcgaaagtg ttgatagtta tggcattagt 180
tttatgcact ggttccaaca gaaaccagga cagccacccc aactcctcat ctattctaca 240
tccaaccgag gatccggggt ccctgccagg tttagtggca gtgggtctgg gacagacttc 300
agcctcacca tccatcctat ggaggaggat gatactgcaa tgtatttctg tcagcaaagt 360
caggaggttc cgtggacgtt cggtggaggc accaagctgg aaatcaaacg gactgtggct 420
gcaccatctg tcttcatctt cccgccatct gatgagcagt tgaaatctgg aactgcctct 480
gttgtgtgcc tgctgaataa cttctatccc agagaggcca aagtacagtg gaaggtggat 540
aacgccctcc aatcgggtaa ctcccaggag agtgtcacag agcaggacag caaggacagc 600
acctacagcc tcagcagcac cctgacgctg agcaaagcag actacgagaa acacaaagtc 660
tacgcctgcg aagtcaccca tcagggcctg agctcgcccg tcacaaagag cttcaacagg 720
ggagagtgtt aggaattc 738
<210> 21
<211> 447
<212> PRT
<213> 人工序列
<220>
<223> c67D9重链的氨基酸序列
<400> 21
Glu Val Ile Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly
1 5 10 15
Ser Leu Lys Val Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Thr Tyr
20 25 30
Gly Met Ser Trp Val Arg Gln Thr Pro Glu Lys Arg Leu Glu Trp Val
35 40 45
Ala Thr Ile Ser Gly Gly Gly Arg Asp Thr Tyr Tyr Pro Asp Thr Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Ser Ser Leu Arg Ser Glu Asp Thr Ala Leu Tyr Tyr Cys
85 90 95
Ala Arg Gln Asp Tyr Gly Asn Tyr Val Trp Phe Ala Tyr Trp Gly Gln
100 105 110
Gly Thr Leu Val Thr Val Ser Ala Ala Ser Thr Lys Gly Pro Ser Val
115 120 125
Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala
130 135 140
Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser
145 150 155 160
Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val
165 170 175
Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro
180 185 190
Ser Ser Ser Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp His Lys
195 200 205
Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro
210 215 220
Pro Cys Pro Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val
225 230 235 240
Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr
245 250 255
Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu
260 265 270
Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys
275 280 285
Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser
290 295 300
Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys
305 310 315 320
Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile
325 330 335
Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro
340 345 350
Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu
355 360 365
Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn
370 375 380
Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser
385 390 395 400
Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg
405 410 415
Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu
420 425 430
His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys
435 440 445
<210> 22
<211> 218
<212> PRT
<213> 人工序列
<220>
<223> c67D9轻链的氨基酸序列
<400> 22
Asp Ile Val Leu Thr Gln Ser Pro Ala Ser Leu Ala Val Ser Leu Gly
1 5 10 15
Gln Arg Ala Thr Ile Ser Cys Arg Ala Ser Glu Ser Val Asp Ser Tyr
20 25 30
Gly Ile Ser Phe Met His Trp Phe Gln Gln Lys Pro Gly Gln Pro Pro
35 40 45
Gln Leu Leu Ile Tyr Ser Thr Ser Asn Arg Gly Ser Gly Val Pro Ala
50 55 60
Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Ser Leu Thr Ile His
65 70 75 80
Pro Met Glu Glu Asp Asp Thr Ala Met Tyr Phe Cys Gln Gln Ser Gln
85 90 95
Glu Val Pro Trp Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys Arg
100 105 110
Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln
115 120 125
Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr
130 135 140
Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser
145 150 155 160
Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr
165 170 175
Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys
180 185 190
His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro
195 200 205
Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
210 215
<210> 23
<211> 362
<212> PRT
<213> 人工序列
<220>
<223> PD-1-Fc融合蛋白的氨基酸序列
<400> 23
Pro Gly Trp Phe Leu Asp Ser Pro Asp Arg Pro Trp Asn Pro Pro Thr
1 5 10 15
Phe Ser Pro Ala Leu Leu Val Val Thr Glu Gly Asp Asn Ala Thr Phe
20 25 30
Thr Cys Ser Phe Ser Asn Thr Ser Glu Ser Phe Val Leu Asn Trp Tyr
35 40 45
Arg Met Ser Pro Ser Asn Gln Thr Asp Lys Leu Ala Ala Phe Pro Glu
50 55 60
Asp Arg Ser Gln Pro Gly Gln Asp Cys Arg Phe Arg Val Thr Gln Leu
65 70 75 80
Pro Asn Gly Arg Asp Phe His Met Ser Val Val Arg Ala Arg Arg Asn
85 90 95
Asp Ser Gly Thr Tyr Leu Cys Gly Ala Ile Ser Leu Ala Pro Lys Ala
100 105 110
Gln Ile Lys Glu Ser Leu Arg Ala Glu Leu Arg Val Thr Glu Arg Arg
115 120 125
Ala Ser Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys
130 135 140
Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro
145 150 155 160
Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys
165 170 175
Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp
180 185 190
Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu
195 200 205
Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu
210 215 220
His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn
225 230 235 240
Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly
245 250 255
Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu
260 265 270
Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr
275 280 285
Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn
290 295 300
Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe
305 310 315 320
Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn
325 330 335
Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr
340 345 350
Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
355 360
<210> 24
<211> 455
<212> PRT
<213> 人工序列
<220>
<223> PD-L1-Fc融合蛋白的氨基酸序列
<400> 24
Phe Thr Val Thr Val Pro Lys Asp Leu Tyr Val Val Glu Tyr Gly Ser
1 5 10 15
Asn Met Thr Ile Glu Cys Lys Phe Pro Val Glu Lys Gln Leu Asp Leu
20 25 30
Ala Ala Leu Ile Val Tyr Trp Glu Met Glu Asp Lys Asn Ile Ile Gln
35 40 45
Phe Val His Gly Glu Glu Asp Leu Lys Val Gln His Ser Ser Tyr Arg
50 55 60
Gln Arg Ala Arg Leu Leu Lys Asp Gln Leu Ser Leu Gly Asn Ala Ala
65 70 75 80
Leu Gln Ile Thr Asp Val Lys Leu Gln Asp Ala Gly Val Tyr Arg Cys
85 90 95
Met Ile Ser Tyr Gly Gly Ala Asp Tyr Lys Arg Ile Thr Val Lys Val
100 105 110
Asn Ala Pro Tyr Asn Lys Ile Asn Gln Arg Ile Leu Val Val Asp Pro
115 120 125
Val Thr Ser Glu His Glu Leu Thr Cys Gln Ala Glu Gly Tyr Pro Lys
130 135 140
Ala Glu Val Ile Trp Thr Ser Ser Asp His Gln Val Leu Ser Gly Lys
145 150 155 160
Thr Thr Thr Thr Asn Ser Lys Arg Glu Glu Lys Leu Phe Asn Val Thr
165 170 175
Ser Thr Leu Arg Ile Asn Thr Thr Thr Asn Glu Ile Phe Tyr Cys Thr
180 185 190
Phe Arg Arg Leu Asp Pro Glu Glu Asn His Thr Ala Glu Leu Val Ile
195 200 205
Pro Glu Leu Pro Leu Ala His Pro Pro Asn Glu Arg Thr Ala Ser Glu
210 215 220
Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro
225 230 235 240
Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys
245 250 255
Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val
260 265 270
Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp
275 280 285
Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr
290 295 300
Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp
305 310 315 320
Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu
325 330 335
Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg
340 345 350
Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys
355 360 365
Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp
370 375 380
Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys
385 390 395 400
Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser
405 410 415
Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser
420 425 430
Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser
435 440 445
Leu Ser Leu Ser Pro Gly Lys
450 455
<210> 25
<211> 1431
<212> DNA
<213> 人工序列
<220>
<223> 含有编码hu67D9重链的cDNA的DNA的核苷酸序列
<400> 25
aagcttgccg ccaccatgga ttttcaggtg cagattttca gcttcctgct aatcagtgcc 60
tcagtcataa tatccagagg agaggtgcag ctcgtggaat ctgggggcgg actggtgcag 120
cccggtggaa gtctccggct gagctgcgcc gctagtgggt tcactttttc tacttacggg 180
atgtcttggg tccgacaggc accaggcaag gggctggagt gggtggctac tatttctgga 240
ggaggccgag acacctacta ccccgacacc gtcaagggac gttttactat cagccgtgac 300
aacagcaaga ataccctcta ccttcagatg tcttcactgc gagctgaaga caccgctgtg 360
tactattgtg cccgtcagga ctacggtaac tacgtgtggt tcgcttactg gggacaggga 420
accctggtca ccgtctcctc ggctagcacc aagggcccat ccgtcttccc cctggcgccc 480
tgctccagga gcacctccga gagcacagcc gccctgggct gcctggtcaa ggactacttc 540
cccgaaccgg tgacggtgtc gtggaactca ggcgccctga ccagcggcgt gcacaccttc 600
ccggctgtcc tacagtcctc aggactctac tccctcagca gcgtggtgac cgtgccctcc 660
agcagcttgg gcacgaagac ctacacctgc aacgtagatc acaagcccag caacaccaag 720
gtggacaaga gagttgagtc caaatatggt cccccatgcc caccctgccc agcacctgag 780
ttcctggggg gaccatcagt cttcctgttc cccccaaaac ccaaggacac tctcatgatc 840
tcccggaccc ctgaggtcac gtgcgtggtg gtggacgtga gccaggaaga ccccgaggtc 900
cagttcaact ggtacgtgga tggcgtggag gtgcataatg ccaagacaaa gccgcgggag 960
gagcagttca acagcacgta ccgtgtggtc agcgtcctca ccgtcctgca ccaggactgg 1020
ctgaacggca aggagtacaa gtgcaaggtc tccaacaaag gcctcccgtc ctccatcgag 1080
aaaaccatct ccaaagccaa agggcagccc cgagagccac aggtgtacac cctgccccca 1140
tcccaggagg agatgaccaa gaaccaggtc agcctgacct gcctggtcaa aggcttctac 1200
cccagcgaca tcgccgtgga gtgggagagc aatgggcagc cggagaacaa ctacaagacc 1260
acgcctcccg tgctggactc cgacggctcc ttcttcctct acagcaggct aaccgtggac 1320
aagagcaggt ggcaggaggg gaatgtcttc tcatgctccg tgatgcacga ggctctgcac 1380
aaccactaca cacagaagag cctctccctg tctctgggta aatgagaatt c 1431
<210> 26
<211> 447
<212> PRT
<213> 人工序列
<220>
<223> hu67D9重链的氨基酸序列
<400> 26
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 Thr Tyr
20 25 30
Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Thr Ile Ser Gly Gly Gly Arg Asp Thr Tyr Tyr Pro Asp Thr 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 Ser Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gln Asp Tyr Gly Asn Tyr Val Trp Phe Ala Tyr Trp Gly Gln
100 105 110
Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val
115 120 125
Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala
130 135 140
Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser
145 150 155 160
Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val
165 170 175
Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro
180 185 190
Ser Ser Ser Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp His Lys
195 200 205
Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro
210 215 220
Pro Cys Pro Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val
225 230 235 240
Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr
245 250 255
Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu
260 265 270
Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys
275 280 285
Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser
290 295 300
Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys
305 310 315 320
Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile
325 330 335
Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro
340 345 350
Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu
355 360 365
Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn
370 375 380
Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser
385 390 395 400
Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg
405 410 415
Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu
420 425 430
His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys
435 440 445
<210> 27
<211> 742
<212> DNA
<213> 人工序列
<220>
<223> 含有编码hu67D9轻链的cDNA的DNA的核苷酸序列
<400> 27
aagcttgccg ccaccatgga ttttcaggtg cagattttca gcttcctgct aatcagtgcc 60
tcagtcataa tatccagagg agatattgtt ctgacccagt cccccgcttc actggctgtg 120
agtcctgggc agcgagctac catcagctgc cgggcttcag agtccgtgga tagctacgga 180
atttcattta tgcactggtt ccagcagaag ccaggccaac cacctcagtt gctgatatat 240
tcgacatcta atcggggaag cggtgtgcca gcccggttta gtggtagcgg ctctggtaca 300
gatttctctc ttacaattaa cccagtggag gcggatgaca ctgccaatta cttttgtcag 360
cagagccagg aagtgccttg gacttttggt cagggcacga aggtagagat taaacggact 420
gtggctgcac catctgtctt catcttcccg ccatctgatg agcagttgaa atctggaact 480
gcctctgttg tgtgcctgct gaataacttc tatcccagag aggccaaagt acagtggaag 540
gtggataacg ccctccaatc gggtaactcc caggagagtg tcacagagca ggacagcaag 600
gacagcacct acagcctcag cagcaccctg acgctgagca aagcagacta cgagaaacac 660
aaagtctacg cctgcgaagt cacccatcag ggcctgagct cgcccgtcac aaagagcttc 720
aacaggggag agtgttgaat tc 742
<210> 28
<211> 218
<212> PRT
<213> 人工序列
<220>
<223> hu67D9轻链的氨基酸序列
<400> 28
Asp Ile Val Leu Thr Gln Ser Pro Ala Ser Leu Ala Val Ser Pro Gly
1 5 10 15
Gln Arg Ala Thr Ile Ser Cys Arg Ala Ser Glu Ser Val Asp Ser Tyr
20 25 30
Gly Ile Ser Phe Met His Trp Phe Gln Gln Lys Pro Gly Gln Pro Pro
35 40 45
Gln Leu Leu Ile Tyr Ser Thr Ser Asn Arg Gly Ser Gly Val Pro Ala
50 55 60
Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Ser Leu Thr Ile Asn
65 70 75 80
Pro Val Glu Ala Asp Asp Thr Ala Asn Tyr Phe Cys Gln Gln Ser Gln
85 90 95
Glu Val Pro Trp Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg
100 105 110
Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln
115 120 125
Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr
130 135 140
Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser
145 150 155 160
Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr
165 170 175
Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys
180 185 190
His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro
195 200 205
Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
210 215
Claims (16)
1.一种抗PD-1单克隆抗体或其抗原结合片段,其中所述抗体包含含有SEQ ID NO:1(重链CDR1)、SEQ ID NO:2(重链CDR2)、SEQ ID NO:3(重链CDR3)的重链可变区和含有SEQ IDNO:4(轻链CDR1)、SEQ ID NO:5(轻链CDR2)和SEQ ID NO:6(轻链CDR3)的轻链可变区。
2.根据权利要求1所述的单克隆抗体,其中所述重链可变区包含SEQ ID NO:8或SEQ IDNO:16的氨基酸序列,并且所述轻链可变区包含SEQ ID NO:10或SEQ ID NO:18的氨基酸序列。
3.根据权利要求1所述的单克隆抗体,其中所述抗原结合片段是Fab、Fab'、F(ab)2或F(ab')2。
4.根据权利要求1所述的单克隆抗体,其中所述抗体是小鼠抗体、嵌合抗体或人源化抗体。
5.一种分离的核酸分子,其编码权利要求1-4中任一项所述的单克隆抗体。
6.一种表达载体,其包含权利要求5所述的核酸分子。
7.一种宿主细胞,其包含权利要求6所述的表达载体。
8.一种组合物,其包含权利要求1-4中任一项所述的单克隆抗体或其抗原结合片段和药学上可接受的载体。
9.一种免疫缀合物,其包含与治疗剂连接的权利要求1-4中任一项所述的单克隆抗体或其抗原结合片段。
10.根据权利要求9所述的免疫缀合物,其中所述治疗剂是细胞毒素或放射性同位素。
11.一种调节受试者中的免疫应答的方法,其包括向所述受试者施用权利要求1-4中任一项所述的抗体或其抗原结合部分,使得所述受试者中的免疫应答得到调节。
12.一种抑制受试者中的肿瘤细胞生长的方法,其包括以有效抑制肿瘤细胞生长的量向受试者施用权利要求1-4中任一项所述的抗体或其抗原结合片段。
13.一种治疗受试者中的传染性疾病的方法,其包括向所述受试者施用权利要求1-4中任一项所述的抗体或其抗原结合片段,使得所述受试者的所述传染性疾病被治疗。
14.权利要求1-4中任一项所述的抗体或其抗原结合部分在制备用于改变受试者中的免疫应答的药物中的用途。
15.权利要求1-4中任一项所述的抗体或其抗原结合部分在制备用于抑制受试者中的肿瘤细胞生长的药物中的用途。
16.权利要求1-4中任一项所述的抗体或其抗原结合部分在制备用于治疗受试者中的传染性疾病的药物中的用途。
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PCT/SG2016/050482 WO2017058115A1 (en) | 2015-09-29 | 2016-09-29 | Pd-1 antibodies and uses thereof |
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EP (1) | EP3356416B1 (zh) |
JP (1) | JP6952028B2 (zh) |
CN (1) | CN108368175B (zh) |
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KR20180040138A (ko) | 2015-07-13 | 2018-04-19 | 싸이톰스 테라퓨틱스, 인크. | 항pd-1 항체, 활성화 가능한 항pd-1 항체, 및 이들의 사용 방법 |
MX2018002315A (es) | 2015-09-01 | 2018-04-11 | Agenus Inc | Anticuerpos anti muerte programada 1 (pd 1) y metodos de uso de los mismos. |
AR106184A1 (es) | 2015-09-29 | 2017-12-20 | Celgene Corp | Proteínas de unión a pd-1 y sus métodos de uso |
KR20180069070A (ko) | 2015-11-03 | 2018-06-22 | 얀센 바이오테크 인코포레이티드 | Tim-3과 특이적으로 결합하는 항체 및 그의 용도 |
KR102379464B1 (ko) | 2016-06-20 | 2022-03-29 | 키맵 리미티드 | 항-pd-l1 항체 |
WO2018053401A1 (en) | 2016-09-19 | 2018-03-22 | Celgene Corporation | Methods of treating vitiligo using pd-1 binding proteins |
KR102257154B1 (ko) | 2016-09-19 | 2021-05-28 | 셀진 코포레이션 | Pd-1 결합 단백질을 사용하는 면역 질환의 치료 방법 |
JP7106538B2 (ja) | 2016-12-07 | 2022-07-26 | アジェナス インコーポレイテッド | 抗体およびその使用方法 |
WO2018133842A1 (zh) | 2017-01-20 | 2018-07-26 | 大有华夏生物医药集团有限公司 | 人程序性死亡受体pd-1的单克隆抗体及其片段 |
CN108341871A (zh) | 2017-01-24 | 2018-07-31 | 三生国健药业(上海)股份有限公司 | 抗pd-1单克隆抗体及其制备方法和应用 |
EP3512874A2 (en) | 2017-11-30 | 2019-07-24 | Grifols Diagnostic Solutions Inc. | Immunoassays and engineered proteins for monitoring antibody treatments to the immune checkpoint inhibitors pd1 and pd-l1 |
CA3091502A1 (en) | 2018-02-23 | 2019-08-29 | Eucure (Beijing) Biopharma Co., Ltd | Anti-pd-1 antibodies and uses thereof |
WO2019201169A1 (en) * | 2018-04-15 | 2019-10-24 | Salubris (Chengdu) Biotech Co., Ltd | Antibodies binding pd-1 and uses thereof |
EP3781202A4 (en) * | 2018-04-15 | 2022-01-05 | Immvira Co., Limited | PD-1 BINDING ANTIBODIES AND THEIR USES |
AU2019299555A1 (en) * | 2018-07-04 | 2021-02-25 | Cytoimmune Therapeutics, Inc. | Compositions and methods for immunotherapy targeting FLT3, PD-1, and/or PD-L1 |
WO2020015722A1 (en) * | 2018-07-19 | 2020-01-23 | Tayu Huaxia Biotech Medical Group Co., Ltd. | Anti-pd-1 antibodies, dosages and uses thereof |
EP3883969A4 (en) * | 2018-11-19 | 2022-11-16 | Biocytogen Pharmaceuticals (Beijing) Co., Ltd. | ANTI-PD-1 ANTIBODIES AND THEIR USES |
CN111423510B (zh) * | 2019-01-10 | 2024-02-06 | 迈威(上海)生物科技股份有限公司 | 重组抗人pd-1抗体及其应用 |
TWI809286B (zh) | 2019-07-05 | 2023-07-21 | 日商小野藥品工業股份有限公司 | 以pd-1/cd3雙特異性蛋白質所進行之血液性癌症治療 |
TW202120550A (zh) | 2019-08-08 | 2021-06-01 | 日商小野藥品工業股份有限公司 | 雙特異性蛋白質 |
WO2021063201A1 (zh) * | 2019-09-30 | 2021-04-08 | 四川科伦博泰生物医药股份有限公司 | 抗pd-1抗体及其用途 |
CA3211727A1 (en) | 2021-03-31 | 2022-10-06 | Merus N.V. | Novel pd-1 binding domains |
GB202107994D0 (en) | 2021-06-04 | 2021-07-21 | Kymab Ltd | Treatment of cancer |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN101213297A (zh) * | 2005-05-09 | 2008-07-02 | 小野药品工业株式会社 | 程序性死亡-1(pd-1)的人单克隆抗体及单独使用或与其它免疫治疗剂联合使用抗pd-1抗体来治疗癌症的方法 |
WO2014194302A3 (en) * | 2013-05-31 | 2015-02-26 | Sorrento Therapeutics, Inc. | Antigen binding proteins that bind pd-1 |
WO2015112800A1 (en) * | 2014-01-23 | 2015-07-30 | Regeneron Pharmaceuticals, Inc. | Human antibodies to pd-1 |
Family Cites Families (10)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
ES2654064T3 (es) * | 2002-07-03 | 2024-03-13 | Ono Pharmaceutical Co | Composiciones inmunopotenciadoras que comprenden anticuerpos anti-PD-L1 |
FR2906533B1 (fr) * | 2006-09-28 | 2013-02-22 | Pf Medicament | Procede de generation d'anticorps actifs contre un antigene de resistance,anticorps obtenus par ledit procede et leurs utilisations |
KR101586617B1 (ko) * | 2007-06-18 | 2016-01-20 | 머크 샤프 앤 도메 비.브이. | 사람 프로그램된 사멸 수용체 pd-1에 대한 항체 |
TW201134488A (en) * | 2010-03-11 | 2011-10-16 | Ucb Pharma Sa | PD-1 antibodies |
AR091649A1 (es) * | 2012-07-02 | 2015-02-18 | Bristol Myers Squibb Co | Optimizacion de anticuerpos que se fijan al gen de activacion de linfocitos 3 (lag-3) y sus usos |
LT2992017T (lt) * | 2013-05-02 | 2021-02-25 | Anaptysbio, Inc. | Antikūnai nukreipti prieš programuotos žūties baltymą-1 (pd-1) |
CN104250302B (zh) * | 2013-06-26 | 2017-11-14 | 上海君实生物医药科技股份有限公司 | 抗pd‑1抗体及其应用 |
MX2016003292A (es) * | 2013-09-13 | 2016-06-24 | Beigene Ltd | Anticuerpos anti-muerte programada 1 y su uso como terapeuticos y diagnosticos. |
LT3081576T (lt) * | 2013-12-12 | 2019-10-25 | Shanghai hengrui pharmaceutical co ltd | Pd-1 antikūnas, antigeną surišantis jo fragmentas ir jų medicininis pritaikomumas |
JOP20200094A1 (ar) * | 2014-01-24 | 2017-06-16 | Dana Farber Cancer Inst Inc | جزيئات جسم مضاد لـ pd-1 واستخداماتها |
-
2016
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Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN101213297A (zh) * | 2005-05-09 | 2008-07-02 | 小野药品工业株式会社 | 程序性死亡-1(pd-1)的人单克隆抗体及单独使用或与其它免疫治疗剂联合使用抗pd-1抗体来治疗癌症的方法 |
WO2014194302A3 (en) * | 2013-05-31 | 2015-02-26 | Sorrento Therapeutics, Inc. | Antigen binding proteins that bind pd-1 |
WO2015112800A1 (en) * | 2014-01-23 | 2015-07-30 | Regeneron Pharmaceuticals, Inc. | Human antibodies to pd-1 |
Non-Patent Citations (1)
Title |
---|
KATY K TSAI等: "PD-1 and PD-L1 antibodies for melanoma", 《HUMAN VACCINES & IMMUNOTHERAPEUTICS》 * |
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US10981991B2 (en) | 2021-04-20 |
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EP3356416B1 (en) | 2021-03-24 |
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RU2722451C1 (ru) | 2020-06-01 |
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