CN1753912B - 抗pd-1抗体及其用途 - Google Patents
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Abstract
本发明公开内容提供了能够作为PD-1(程序性死亡1)激动剂和/或拮抗剂的抗体和抗原结合片段,由此总体调节免疫应答,特别是由TcR和CD28介导的那些免疫应答。所公开的组合物及方法可用于例如治疗自身免疫病、炎性疾病、***反应、移植物排斥、癌症以及其它免疫***紊乱。
Description
发明领域
技术领域涉及受程序性死亡1(PD-1)受体调控的免疫应答的调节。
发明背景
适应性免疫应答包括称为T细胞和B细胞的两大类淋巴细胞的激活、选择和克隆增殖。在遭遇抗原之后,T细胞增殖并分化为抗原特异性效应细胞,而B细胞增殖并分化为抗体分泌性细胞。
T细胞激活是需要T细胞和呈递抗原细胞(APC)之间的数个信号传导事件的多步过程。为使T细胞激活发生,必须将两类信号递送给静息T细胞。第一类是由抗原特异性T细胞受体(TcR)介导的,并赋予免疫应答特异性。第二种共刺激类型,调控着应答的量级并且是通过T细胞上的辅助受体递送的。
初级共刺激信号是通过活化CD28受体经与其配体B7-1或B7-2的接合而递送的。相反,抑制性CTLA-4受体与相同的B7-1或B7-2配体的接合,则导致T细胞应答的削弱。从而,CTLA-4信号拮抗由CD28所介导的共刺激。在高抗原浓度下,CD28共刺激胜过CTLA-4的抑制效应。CD28和CTLA-4表达的时序调节维持了激活和抑制信号之间的平衡,并确保了有效免疫应答的形成,而同时预防了自身免疫性的发展。
最近业已鉴定了CD28和CTLA-4及其B-7样配体的分子同系物。ICOS为CD28-样共刺激受体。PD-1(程序性死亡1)为抑制性受体和CTLA-4的相似物。本发明公开内容涉及由PD-1受体所介导的免疫应答的调节。
PD-1为50-55kDa的I型跨膜受体,其最初是在经历激活诱导的细胞凋亡的T细胞系中鉴定的。PD-1表达于T细胞、B细胞和巨噬细胞之上。PD-1的配体为B7家族成员PD-L1(B7-H1)和PD-L2(B7-DC)。
PD-1是免疫球蛋白(Ig)超家族成员,在其胞外区含有单个Ig V-样结构域。PD-1胞浆结构域含有两个酪氨酸,其中最接近于膜的酪氨酸(小鼠PD-1中的VAYEEL)位于ITIM(基于免疫受体酪氨酸的抑制基序)之内。PD-1上ITIM的存在预示着该分子通过募集胞浆磷酸酶发挥作用以削弱抗原受体的信号传导。人和鼠PD-1蛋白共有大约60%的氨基酸同一性,具有保守的四个潜在的N-糖基化位点以及限定Ig-V结构域的残基。胞浆区中的ITIM以及羧基末端酪氨酸(人和小鼠中的TEYATI)周围的ITIM-样基序在人和鼠直向同源物(orthologue)之间也是保守的。
PD-1表达于激活的T细胞、B细胞和单核细胞之上。实验数据暗示了PD-1与其配体在下调中央和外周免疫应答中的相互作用。特别是,野生型T细胞中而非PD-1缺陷型T细胞中的增殖在PD-L1的存在下受到抑制。另外,PD-1缺陷型小鼠表现出自身免疫表型。C57BL/6小鼠中的PD-1缺陷导致慢性进行性狼疮样肾小球肾炎和关节炎。在Balb/c小鼠中,PD-1缺陷由于心组织特异性自身反应性抗体的存在而引起严重的心肌病。
一般而言,存在着提供用于免疫紊乱的安全且有效的治疗方法的需要,所述免疫紊乱例如自身免疫病、炎性疾病、***反应、移植物排斥、癌症、免疫缺陷症以及其它免疫***相关紊乱。这些紊乱中所涉及的免疫应答的调节可通过操纵PD-1途径而实现。
发明概述
本发明公开内容提供了可作为PD-1激动剂和/或拮抗剂起作用,由此调节受PD-1调控的免疫应答的抗体。本发明公开内容还提供了包含新的抗原结合片段的抗-PD-1抗体。本发明的抗-PD-1抗体能够:(a)特异性结合于PD-1,包括人PD-1;(b)阻断PD-1与其天然配体的相互作用;或(c)发挥两种功能。此外,所述抗体可能拥有免疫调节性质,即,它们可能有效地调节与PD-1相关的免疫应答的下调。依赖于使用方法和期望效果,抗体可用于增强或者抑制免疫应答。
所述抗体的非限制性举例说明性实施方案有PD1-17、PD1-28、PD1-33、PD1-35和PD1-F2。其它实施方案包括PD1-17、PD1-28、PD1-33、PD1-35或PD1-F2中Fv片段的VH和/或VL结构域。更多的实施方案包括这些VH和VL结构域中任一个的一个或多个互补决定区(CDR)。其它实施方案包括PD1-17、PD1-28、PD1-33、PD1-35或PD1-F2中VH结构域的H3片段。
本发明公开内容也提供了包含PD-1抗体的组合物,及其在调节免疫应答的方法中的用途,包括治疗人或动物的方法。在特别的实施方案中,通过增强或减弱由TcR/CD28介导的T细胞应答,抗-PD-1抗体可用于治疗或预防免疫紊乱。对本发明组合物的治疗敏感的紊乱包括但不限于类风湿关节炎、多发性硬化、炎性肠病、Crohn氏病、***性红斑狼疮、I型糖尿病、移植物排斥、移植物抗宿主疾病、过度增生性免疫紊乱、癌症以及传染病。
另外,抗-PD-1抗体可在诊断上用于检测生物学样品中的PD-1或其片段。所检测的PD-1的量可能与PD-1的表达水平相关,其依次又与受试者中免疫细胞(如激活的T细胞、B细胞和单核细胞)的激活状态相关。
本发明公开内容也提供了分离的核酸,其包含编码来自PD1-17、PD1-28、PD1-33、PD1-35或PD1-F2的Fv片段的VH或VL结构域的序列。同样提供的有这样的分离核酸,其包含编码来自本发明公开的VH和VL结构域中任一个的一个或多个CDR的序列。本发明公开内容也提供了包含此类核酸的载体和宿主细胞。
本发明公开内容还提供了生产新的VH和VL结构域和/或功能性抗体的方法,所述功能性抗体包括衍生自PD1-17、PD1-28、PD1-33、PD1-35或PD1-F2的VH或VL结构域的此类结构域的全部或一部分。
本发明公开内容的另外方面将在下面的说明中部分阐明,并且部分地将会由于所述说明而显而易见,或者可通过实施本发明而了解。本发明示于所附的权利要求书中并在其中特别指出,且本发明公开内容不应当解释为以任何方式限制权利要求的范围。以下详述包括本发明多种实施方案的例示性代表,它们并非用于限制所请求保护的发明。附图构成本说明书的一部分,并且,连同所述说明,仅用于举例说明多种实施方案而非限制本发明。引述参考文献并非认可这些参考文献是本发明的现有技术。
附图简述
图1A和1B显示了如通过噬菌体ELISA所测定的scFv抗体与人PD-1的反应性。
图2A-2C显示了如通过ELISA所测定的IgG-转化的抗体与人或小鼠PD-1的反应性。
图3显示了ELISA结果,证明所选的PD-1抗体抑制PD-L1与PD-1的结合。
图4显示了ELISA结果,证明免疫调节性PD-1抗体与PD-1上的不同位点结合,如通过交叉阻断ELISA分析所测定的那样。
图5显示了T细胞增殖测定的结果,证明由TcR和抗-PD-1抗体PD1-17或PD-L1.Fc进行共接合使增殖下降。由TcR和抗-PD-1 J110进行共接合对增殖没有影响。
图6证明可溶形式的PD1-17促进的原代T细胞的增殖。
详述
定义
如本发明公开内容所用,术语“抗体”是指免疫球蛋白或其片段或衍生物,并且涵盖包含抗原结合位点的任何多肽,而不论其是在体外或是在体内生产的。该术语包括但不限于多克隆的、单克隆的、单特异性的、多特异性的、非特异性的、人源化的、单链的、嵌合的、合成的、重组的、杂交的、突变的以及移植的抗体。除非如“完整抗体”中那样由术语“完整”另行修饰,为了本发明公开内容的目的,术语“抗体”也包括抗体片段如Fab、F(ab′)2、Fv、scFv、Fd、dAb,以及保留抗原结合功能即特异性结合PD-1能力的其它抗体片段。一般地,此类片段将包含抗原结合结构域。
术语“抗原结合结构域”、“抗原结合片段”以及“结合片段”是指抗体分子的一部分,其包含负责抗体和抗原之间特异性结合的氨基酸。在抗原大的情况下,抗原结合结构域可能仅与抗原的一部分结合。抗原分子中负责与抗原结合结构域特异性相互作用的部分被称为“表位”或“抗原决定簇”。
抗原结合结构域一般地包含抗体轻链可变区(VL)和抗体重链可变区(VH),不过,它并非必需两者都包含。例如,所谓的Fd抗体片段仅由VH结构域组成,但仍保留了完整抗体的一些抗原结合功能。
术语“所有组成成分(repertoire)”是指遗传上多样性的核苷酸集合,其全部或部分地衍生自编码所表达的免疫球蛋白的序列。所述序列是通过例如H链的V、D和J区段以及例如L链的V和J区段的体内重排产生的。备选地,所述序列可通过体外刺激而由细胞系产生,响应于该刺激发生重排。备选地,部分或所有序列可通过核苷酸合成、随机诱变以及其它方法,如美国专利No.5,565,332中所公开的那样,通过将未重排的V区段与D和J区段组合而获得。
术语“特异性相互作用”和“特异性结合”是指两分子形成在生理条件下相对稳定的复合物。特异性结合以高亲和力以及低度到中度的结合量为特征,这有别于通常具有低亲和力与中度到高度的结合量的非特异性结合。一般地,当亲和常数KA高于106M-1或更优选高于108M-1时,认为结合是特异性的。如必要,可通过改变结合条件降低非特异性结合而基本上不影响特异性结合。熟练技术人员可利用常规技术优化合适的结合条件,如抗体的浓度、溶液的离子强度、温度、允许结合的时间、封闭剂(如血清清蛋白、乳酪蛋白)的浓度等。举例说明性的条件示于实施例1、2、4、6和7中。
短语“基本上如...中所示”意味着本发明相关的CDR、VH或VL结构域在指定区域(如CDR)上与所示序列完全相同或者仅具有不重要的区别。不重要的区别包括次要的氨基酸变化,例如在指定区域的序列中取代任意5个氨基酸中的1个或2个。
术语“PD-1活性”是指与PD-1相关的一种或多种免疫调节活性。例如,PD-1为TcR/CD28介导的免疫应答的负调节物。体内和体外评估PD-1活性的操作在实施例8、9和10中描述。
术语“调节”、“免疫调节的”及其同源词是指因与抗-PD-1抗体的相互作用所致的与T细胞应答下调相关的PD-1活性的下降或上升,其中所述下降或上升是相对于不存在相同抗体下的PD-1活性而言的。活性的下降或上升优选为至少大约10%、20%、30%、40%、50%、60%、70%、80%、90%或更多。当PD-1活性下降时,术语“调节的”及“调节”与术语“抑制的”及“抑制”是可互换的。当PD-1上升时,术语“调节的”及“调节”与术语“激活的”及“激活”是可互换的。PD-1的活性可利用如实施例8和9中所描述的T细胞增殖测定来定量确定。
术语“治疗”和“治疗方法”既指治疗性治疗又指预防/预防性措施。需要治疗的那些个体可包括早已患有特殊医学紊乱的个体,以及可能最终患有所述紊乱的那些个体(即需要预防性措施的那些个体)。
术语“有效量”是指足以降低PD-1活性的剂量或量,以实现患者症状的改善或达到期望的生物学结果,例如提高T细胞的溶细胞活性、诱导免疫耐受、降低或提高与T细胞介导的免疫应答的负调控相关的PD-1活性等。
术语“分离的”是指基本上脱离其天然环境的分子。例如,分离的蛋白基本上不含来自得到它的细胞或组织源的细胞材料或其它蛋白。术语“分离的”也指其中分离的蛋白足够纯以至于能够作为药物组合物施用的制剂,或者至少70-80%(w/w)纯,更优选至少80-90%(w/w)纯,甚至更优选90-95%纯,并且最优选至少95%、96%、97%、98%、99%或100%(w/w)纯。
抗-PD-1抗体
本发明公开内容提供了包含新型抗原结合片段的抗-PD-1抗体。
一般而言,例如,可利用传统的杂交瘤技术(Kohler和Milstein(1975)Nature,256:495-499)、重组DNA方法(美国专利No.4,816,567)或由抗体文库实施的噬菌体展示(Clackson等(1991)Nature,352:624-628;Marks等(1991)J.Mol.Biol.,222:581-597)制备抗体。关于其它抗体生产技术,也参见Antibodies:ALaboratory Manual,Harlow等编,Cold Spring Harbor Laboratory,1988。本发明不局限于任何特定的来源、起源物种、生产方法。
完整抗体,也称为免疫球蛋白,一般是四聚体糖基化蛋白,由两条大约各25kDa的轻(L)链以及两条大约各50kDa的重(H)链组成。抗体中发现了两类轻链,命名为λ链和κ链。依赖于重链恒定结构域的氨基酸序列,免疫球蛋白可分配为5大类:A、D、E、G和M,并且其中有数种可进一步划分为亚类(同种型),如IgG1、IgG2、IgG3、IgG4、IgA1和IgA2。
不同类型免疫球蛋白的亚基结构和三维构象是本领域众所周知的。关于抗体结构的综述,见Harlow等,同前。简言之,每条轻链由N-末端可变结构域(VL)和恒定结构域(CL)组成。每条重链由N-末端可变结构域(VH)、三或四个恒定结构域(CH)、以及铰链区组成。最接近于VH的CH结构域被命名为CH1。VH和VL结构域由四个具有相对保守序列的区域组成,称为构架区(FR1、FR2、FR3和FR4),它们构成三个高变序列区域的支架,所述高变序列区域称为互补决定区(CDR)。CDR含有大多数负责与抗原特异性相互作用的残基。三个CDR被称为CDR1、CDR2和CDR3。重链上的CDR组分被称为H1、H2和H3,而轻链上的CDR组分被相应地称为L1、L2和L3。CDR3,并且特别是H3,是抗原结合结构域内分子多样性的最大来源。例如,H3可短至2个氨基酸残基或者多于26个。
Fab片段(抗原结合片段)由通过恒定区之间的二硫键共价连接的VH-CH1和VL-CL结构域组成。为克服在宿主细胞中共表达时Fv中非共价连接的VH和VL结构域解离的倾向,可构建所谓的单链(sc)Fv片段(scFv)。在scFv中,柔性且足够长的多肽或者将VH的C-末端连接于VL的N-末端,或者将VL的C-末端连接于VH的N-末端。最常见地,利用15个残基的(Gly4Ser)3肽作为接头,但其它接头也是本领域公知的。
抗体多样性是编码可变区的多个种系基因组合装配以及多种体细胞事件的结果。体细胞事件包括V基因区段与D和J基因区段重组以制备完整VH区,以及V和J基因区段重组以制备完整VL区。重组过程本身是不精确的,导致V(D)J接合处氨基酸的丢失或添加。这些多样化机制出现在抗原暴露之前的发育B细胞之中。抗原刺激后,B细胞中表达的抗体基因经历体细胞突变。
根据种系基因区段的估计数、这些区段的随机重组以及随机VH-VL配对,可生产最多1.6×107个不同的抗体(FundamentalImmunology,第3版,Paul编,Raven Press,New York,NY,1993)。若考虑有助于抗体多样性的其它过程(如体细胞突变),则认为可潜在地产生1×1010以上的不同抗体(Immunoglobulin Genes,第2版,Jonio等编,Academic Press,San Diego,CA,1995)。由于这许多过程参与抗体的多样性,独立产生的抗体在CDR区将具有完全相同或者甚至基本上相似的氨基酸序列是非常不可能的。
本发明公开内容提供了新的来源于人免疫球蛋白基因文库的CDR。携带CDR的结构通常将是抗体重链或轻链或其部分,其中CDR位于对应于天然存在的VH及VL的CDR的位置上。例如,免疫球蛋白可变结构域的结构和定位可如Kabat等,Sequences of Proteins ofImmunological Interest,No.91-3242,National Institutes ofHealth Publications,Bethesda,MD,1991中所述确定。
抗-PD-1抗体、其scFv片段、VH和VL结构域及CDR的DNA和氨基酸序列示于序列表之中,并如表1中所列的那样列举。抗体特别的非限制性举例说明性的实施方案被称为PD1-17、PD1-28、PD1-33、PD1-35和PD1-F2。举例说明性实施方案的VH和VL结构域内每一个CDR的位置列于表2和3中。
表1:VH和VL结构域以及CDR的DNA和氨基酸(AA)序列
表2:重链CDR的位置
CDR | PD1-17SEQ IDNO:2 | PD1-28SEQ IDNO:6 | PD1-33SEQ IDNO:10 | PD1-35SEQ IDNO:14 | PD1-F2SEQ IDNO:47 |
H1 | 31-42 | 31-35 | 31-35 | 31-37 | 34-42 |
H2 | 57-72 | 50-66 | 50-66 | 52-67 | 57-73 |
H3 | 105-117 | 99-108 | 99-108 | 100-116 | 106-114 |
表3:轻链CDR的位置
CDR | PD1-17SEQ IDNO:4 | PD1-28SEQ IDNO:8 | PD1-33SEQ IDNO:12 | PD1-35SEQ IDNO:16 | PD1-F2SEQ IDNO:49 |
L1 | 23-35 | 23-33 | 23-36 | 23-35 | 28-35 |
L2 | 51-57 | 49-55 | 52-58 | 51-57 | 54-61 |
L3 | 92-100 | 88-98 | 91-102 | 90-100 | 94-101 |
抗-PD-1抗体也任选地包含抗体恒定区或其部分。例如,VL结构域可在其C末端附着有抗体轻链恒定结构域,包括人Cκ或Cλ链。类似地,基于VH结构域的特异性抗原结合结构域可附着有全部或部分免疫球蛋白重链,所述重链来源于任何抗体同种型如IgG、IgA、IgE和IgM以及任何同种型亚类,包括但不限于IgG1和IgG4。在例示性的实施方案中,PD1-17、PD1-28、PD1-33和PD1-35抗体包含人重链和轻链的C-末端片段,而PD1-F2包含人重链和轻链的C-末端片段。C-末端片段的DNA和氨基酸序列是本领域众所周知的(参见如Kabat等,Sequences of Proteins of Immunological Interest,No.91-3242,National Institutes of Health Publications,Bethesda,MD,1991)。非限制性的例示性序列示于表4。
表4
C-末端区 | DNA | 氨基酸 |
IgG1重链 | SEQ ID NO:44 | SEQ ID NO:45 |
λ轻链 | SEQ ID NO:42 | SEQ ID NO:43 |
κ轻链 | SEQ ID NO:57 | SEQ ID NO:58 |
某些实施方案包括来自PD1-17、PD1-28、PD1-33、PD1-35和PD1-F2的Fv片段的VH和/或VL结构域。另外的实施方案包括任何这些VH和VL结构域的至少一个CDR。包含SEQ ID NO:2、SEQ ID NO:4、SEQ ID NO:6、SEQ ID NO:8、SEQ ID NO:10、SEQ ID NO:12、SEQID NO:14、SEQ ID NOs:16-40、SEQ ID NO:47或SEQ ID NO:49中所示的至少一个CDR序列的抗体涵盖在本发明的范围之内。例如,一实施方案包括选自PD1-17、PD1-28、PD1-33、PD1-35和PD1-F2中至少之一的抗体的VH结构域的H3片段。
在某些实施方案中,VH和/或VL结构域可被种系化(germlined),也就是利用常规的分子生物学技术突变这些结构域的构架区(FRs),以匹配由种系细胞产生的那些结构域。在其它实施方案中,构架序列保持与共有的种系序列趋异。
在某些实施方案中,抗体特异性结合位于人PD-1胞外结构域内的表位。推定的胞外结构域由SEQ ID NO:41(Swissport登录号Q15116)中从大约氨基酸21到大约氨基酸170的序列组成。在某些其它实施方案中,抗体特异性结合位于小鼠PD-1胞外结构域内的表位,亲和力大于107M-1,并且优选大于108M-1。小鼠PD-1的氨基酸序列示于SEQ ID NO:56(登录号NM_008798),并且总体上与其人对应物有大约60%的同一性。在另一些实施方案中,本发明的抗体结合于PD-1的PD-L-结合结构域。
预期本发明的抗体也与其它蛋白结合,例如,包括包含全部或部分PD-1胞外结构域的重组蛋白。
本领域普通技术人员将会认识到本发明的抗体可用于检测、测量和抑制稍微不同于PD-1的蛋白。预期抗体将保留结合特异性,只要靶蛋白包含与SEQ ID NO:41所示序列中任何至少100、80、60、40或20个邻接氨基酸的序列具有至少大约60%、70%、80%、90%、95%或更高同一性的序列。同一性百分比是由标准比对算法确定的,例如Altshul等(1990)J.Mol.Biol.,215:403-410中所示的BasicLocal Alignment Tool(BLAST),Needleman等(1970)J.Mol.Biol.,48:444-453的算法或者Meyers等(1988)Comput.Appl.Biosci.,4:11-17的算法。
除了序列同源性分析之外,可进行表位作图(参见如EpitopeMapping Protocols,ed.Morris,Humana Press,1996)以及二级和三级结构分析,以鉴定所公开的抗体及其与抗原的复合物所采取的特定3D结构。此类方法包括但不限于X射线晶体学(Engstom(1974)Biochem.Exp.Biol.,11:7-13)以及本文所公开抗体的实际表现的计算机建模(Fletterick等(1986)Computer Graphics andMolecular Modeling,in Current Communications in MolecularBiology,Cold Spring Harbor Laboratory,Cold Spring Harbor,NY)。
衍生物
本发明公开内容也提供了用于获得特异于PD-1的抗体的方法。此类抗体中的CDR并不局限于表1中所鉴定的VH和VL的具体序列,并且可包括保留了特异性结合PD-1能力的这些序列的变体。此类变体可由熟练技术人员利用本领域众所周知的技术由表1中所列的序列得到。例如,可在FRs和/或CDRs中进行氨基酸取代、缺失或添加。尽管FRs中的变化通常被设计用于改善抗体的稳定性和免疫原性,但CDRs中的变化一般被设计用于提高抗体对其靶的亲和力。FRs变体也包括天然存在的免疫球蛋白同种异型。此类提高亲和力的变化可通过常规技术凭经验确定,所述技术包括改变CDR并测试抗体对其靶的亲和力。例如,可在所公开的任一CDR内进行保守氨基酸取代。可依据Antibody Engineering,第2版,0xford University Press,Borrebaeck编,1995中描述的方法进行各种改变。这些包括但不限于通过取代序列内编码功能上等同的氨基酸残基的不同密码子而改变了的核苷酸序列,由此产生“沉默”变化。例如,非极性氨基酸包括丙氨酸、亮氨酸、异亮氨酸、缬氨酸、脯氨酸、苯丙氨酸、色氨酸和甲硫氨酸。极性中性氨基酸包括甘氨酸、丝氨酸、苏氨酸、半胱氨酸、酪氨酸、天冬酰胺和谷氨酰胺。带正电荷的(碱性)氨基酸包括精氨酸、赖氨酸和组氨酸。带负电荷的(酸性)氨基酸包括天冬氨酸和谷氨酸。序列内的氨基酸取代可选自该氨基酸所属类别的其它成员(见表5)。此外,多肽中的任何天然残基也可用丙氨酸取代(参见如MacLennan等(1998)Acta Physiol.Scand.Suppl.643:55-67;Sasaki等(1998)Adv.Biophys.35:1-24)。
本发明抗体的衍生物和类似物可通过本领域众所周知的各种技术生产,包括重组及合成法(Maniatis(1990)Molecular Cloning,A Laboratory Manual,第二版,Cold Spring Harbor Laboratory,Cold Spring Harbor,NY,以及Bodansky等(1995)The Practiceof Peptide Synthesis,第二版,Spring Verlag,Berlin,德国)。
表5
原始残基 | 例示性取代 | 一般的取代 |
Ala(A) | Val,Leu,Ile | Val |
Arg(R) | Lys,Gln,Asn | Lys |
Asn(N) | Gln | Gln |
Asp(D) | Glu | Glu |
Cys(C) | Ser,Ala | Ser |
Gln(Q) | Asn | Asn |
Gly(G) | Pro,Ala | Ala |
His(H) | Asn,Gln,Lys,Arg | Arg |
Ile(I) | Leu,Val,Met,Ala,Phe,正亮氨酸 | Leu |
Leu(L) | 正亮氨酸,Ile,Val,Met,Ala,Phe | Ile |
Lys(K) | Arg,1,4-二氨基丁酸,Gln,Asn | Arg |
Met(M) | Leu,Phe,Ile | Leu |
Phe(F) | Leu,Val,Ile,Ala,Tyr | Leu |
Pro(P) | Ala | Gly |
Ser(S) | Thr,Ala,Cys | Thr |
Thr(T) | Ser | Ser |
Trp(W) | Tyr,Phe | Tyr |
Tyr(Y) | Trp,Phe,Thr,Ser | Phe |
Val(V) | Ile,Met,Leu,Phe,Ala,正亮氨酸 | Leu |
在一个实施方案中,用于制备作为本发明VH结构域的氨基酸序列变体的VH结构域的方法包括在本文所公开的VH结构域的氨基酸序列中添加、缺失、取代或***一个或多个氨基酸的步骤,任选地将如此提供的VH结构域与一个或多个VL结构域组合,并测试VH结构域或VH/VL组合或多个VH/VL组合对PD-1的特异性结合,或者,并任选地测试此抗原结合结构域调节PD-1活性的能力。VL结构域可具有完全相同于或基本上如根据表1所示的氨基酸序列。
可采用类似的方法,其中将本文公开的VL结构域的一个或多个序列变体与一个或多个VH结构域组合。
本发明公开内容的另一方面提供了制备与PD-1特异性结合的抗原结合片段的方法。所述方法包括:
(a)提供编码VH结构域的起始核酸所有组成成分,其中VH结构域包括将要被取代的CDR3或者缺失CDR3编码区;
(b)将所述所有组成成分与编码基本上如本文所示的VH CDR3(即H3)氨基酸序列的供体核酸组合,从而将供体核酸***到所述所有组成成分的CDR3区,以提供编码VH结构域的核酸的产物所有组成成分;
(c)表达产物所有组成成分的核酸;
(d)选择特异于PD-1的结合片段;和
(e)回收该特异性结合片段或编码它的核酸。
再次地,可采用类似的方法,其中将本发明的VL CDR3(即L3)与编码VL结构域的核酸所有组成成分组合,其中VL结构域包括将要被取代的CDR3或者缺失CDR3编码区。供体核酸可选自编码基本上如SEQ ID NO:17-40或SEQ ID NO:50-55中所示氨基酸序列的核酸。
可利用重组DNA技术将编码本发明CDR(如CDR3)的序列引入到缺失各自CDR(如CDR3)的可变结构域所有组成成分中,例如使用由Marks等(Bio/Technology(1992)10:779-783)描述的方法学。特别地,指向或邻近于可变结构域区域5′端的共有引物可与人VH基因的第三构架区的共有引物联合使用,以提供缺失CDR3的VH可变结构域所有组成成分。可将所述所有组成成分与特定抗体的CDR3组合。利用类似的技术,衍生自CDR3的序列可与缺失CDR3的VH或VL结构域所有组成成分改组,并将改组的完整VH或VL结构域与同源的VL或VH结构域组合,以制备本发明的PD-1特异性抗体。然后所述所有组成成分可在合适的宿主***如噬菌体展示***中展示,例如在WO92/01047中所描述的,从而可选择合适的抗原结合片段。
类似的改组或组合技术也由Stemmer(Nature(1994)370:389-391)公开,他描述了与β-内酰胺酶基因有关的技术,但评论说该途径可用于产生抗体。
在另一实施方案中,利用一个或多个所选VH和/或VL基因的随机诱变,人们可产生携带衍生自本文所公开的序列的一个或多个序列的新型VH或VL区。一种这样的技术即易错PCR由Gram等(Proc.Nat.Acad.Sci.U.S.A.(1992)89:3576-3580)描述。
可使用的另一种方法是直接诱变VH或VL基因的CDRs。此类技术由Barbas等(Proc.Nat.Acad.Sci.U.S.A.(1994)91:3809-3813)以及Schier等(J.Mol.Biol.(1996)263:551-567)公开。
类似地,可将一个或多个、或者所有三个CDRs移植到VH或VL结构域所有组成成分中,然后筛选特异于PD-1的抗原结合片段。
免疫球蛋白可变结构域的一部分将包含至少一个基本上如本文所示的CDRs,和任选地来自如本文所示的scFv片段的间插构架区。所述部分可包括FR1和FR4中任一或两者的至少大约50%,50%为FR1C-末端的50%和FR4 N-末端的50%。可变结构域基本部分N-末端或C-末端另外的残基可以是通常不与天然存在的可变结构域区结合的那些残基。例如,通过重组DNA技术构建抗体可能导致引入由接头编码的N-或C-末端残基,引入所述接头是为了易化克隆或其它操作步骤的。其它操作步骤包括引入接头以将可变结构域连接于另一蛋白序列,包括免疫球蛋白重链恒定区、其它可变结构域(例如,在微型双功能(diabody)抗体的生产中)、或者如下文更为详细讨论的蛋白标记。
尽管实施例中举例说明的实施方案包括VH和VL结构域的“匹配”配对,熟练技术人员将会认识到备选的实施方案可包括仅含来自VL或VH结构域的单个CDR的抗原结合片段。可利用两者中的任一单链特异性结合结构域筛选互补结构域,其能够形成能够与例如PD-1结合的两结构域特异性抗原结合片段。筛选可利用WO 92/01047中公开的所谓的等级双组合方法通过噬菌体展示筛选法完成,其中利用含H或L链克隆的个体菌落感染编码另一链(L或H)的完整克隆文库,并按照所述的噬菌体展示技术对所得的两链特异性结合结构域进行选择。
可将本文描述的抗-PD1抗体连接于另一个功能分子,如另一个肽或蛋白(清蛋白、另一个抗体等)、毒素、放射性同位素、细胞毒性剂或细胞抑制剂。例如,可通过化学交联或通过重组方法连接抗体。也可将抗体连接于多种非蛋白聚合物的一种,如聚乙二醇、聚丙二醇或聚氧化烯,其中以美国专利Nos.4,640,835;4,496,689;4,301,144;4,670,417;4,791,192或4,179,337中所示的方式进行。抗体可通过与聚合物共价缀合而化学修饰,例如,以提高其循环半衰期。例示性的聚合物以及附着它们的方法也显示在美国专利Nos.4,766,106;4,179,337;4,495,285和4,609,546中。
也可改变所公开的抗体以使之具有不同于天然模式的糖基化模式。例如,可缺失一个或多个碳水化合物部分和/或向原始抗体中添加一个或多个糖基化位点。向本文公开的抗体中添加糖基化位点可通过改变氨基酸序列,以使之含有本领域公知的糖基化位点共有序列来完成。增加抗体上的碳水化合物部分数目的另一种手段是通过将糖苷化学或酶促偶联于所述抗体的氨基酸残基。此类方法描述在WO87/05330和Aplin等(1981)CRC Crit.Rev.Biochem.,22:259-306中。从抗体中除去任何碳水化合物部分可化学或酶促完成,例如,如由Hakimuddin等(1987)Arch.Biochem.Biophys.,259:52;和Edge等(1981)Anal.Biochem.,118:131以及由Thotakura等(1987)Meth.Enzymol.,138:350所述的那样。抗体也可用可检测或功能性标记予以标记。可检测标记包括放射性标记如131I或99Tc,它们也可利用常规化学附着于抗体。可检测标记也包括酶标记如辣根过氧化物酶或碱性磷酸酶。可检测标记还包括化学部分如生物素,它可介由与特异性同源的可检测部分如标记的抗生物素蛋白予以检测。
其中CDR序列仅不显著地有别于SEQ ID NO:2、SEQ ID NO:4、SEQ ID NO:6、SEQ ID NO:8、SEQ ID NO:10、SEQ ID NO:12、SEQ ID NO:14、SEQ ID NOs:16-40、SEQ ID NO:47或SEQ ID NO:49中所示那些的抗体涵盖在本发明的范围之内。一般地,氨基酸由具有相似电荷、疏水性或立体化学特征的相关氨基酸取代。此类取代将落入技术人员的普通技术之内。与CDRs中不同,在FRs中可进行更多的基本变化,而不会不利地影响抗体的结合性质。FRs的变化包括但不限于:人源化非人来源的,或工程改造某些对于抗原接触或对于稳定结合位点重要的构架残基,例如,改变恒定区的类或亚类,改变可能变更效应子功能如Fc受体结合的特定氨基酸残基,例如美国专利Nos.5,624,821和5,648,260以及Lund等(1991)J.Immun.147:2657-2662和Morgan等(1995)Immunology 86:319-324中所描述的那样,或者改变可产生恒定区的物种。
本领域技术人员将会认识到上文所述的修饰并非是详尽无遗的,并且在本发明公开内容的教导下,许多其它修饰对熟练技术人员而言将会是显而易见的。
核酸、克隆和表达***
本发明公开内容还提供了编码所公开的抗体的分离的核酸。所述核酸可包括DNA或RNA,并且可以是全部或部分合成或重组的。提及的如本文所示的核苷酸序列涵盖了具有指定序列的DNA分子,并且涵盖了具有指定序列且其中U取代了T的RNA分子,除非上下文另有要求。
本文提供的核酸包括本文公开的CDR、VH结构域和/或VL结构域的编码序列。
本发明公开内容也提供了质粒、载体、噬菌粒、转录盒或表达盒形式的构建体,其包含编码本文公开的CDR、VH结构域和/或VL结构域的至少一种核酸。
本发明公开内容还提供了包含上述一种或多种构建体的宿主细胞。
同样提供的有编码任何CDR(H1、H2、H3、L1、L2或L3)、VH或VL结构域的核酸,以及制备所述编码产物的方法。所述方法包括由所述编码核酸表达所述编码产物。表达可通过在合适的条件下培养含所述核酸的重组宿主细胞实现。通过表达生产后,可利用任何合适的技术分离和/或纯化VH或VL结构域或特异性结合成员,然后适当地使用。
抗原结合片段、VH和/或VL结构域、以及编码核酸分子和载体可以以基本上纯或均质的形式,由其天然环境中分离和/或纯化,或者在核酸的情况下,除了编码具有所需功能的多肽的序列之外,不含或基本上不含其他来源的核酸或基因。
用于在多种不同宿主细胞中克隆和表达多肽的***是本领域众所周知的。有关适合于生产抗体的细胞,见Gene Expression Systems,Academic Press,Fernandez等编,1999。简言之,合适的宿主细胞包括细菌、植物细胞、哺乳动物细胞以及酵母和杆状病毒***。本领域可获得的用于表达异源多肽的哺乳动物细胞系包括中国仓鼠卵巢细胞、HeLa细胞、幼仓鼠肾细胞、NS0小鼠骨髓瘤细胞等等。常见的细菌宿主为大肠杆菌(E.coli)。可利用任何与本发明相容的蛋白表达***生产所公开的抗体。合适的表达***包括Gene ExpressionSystems,Academic Press,Fernandez等编,1999中所描述的转基因动物。
可选择或构建合适的载体,从而它们含有合适的调控序列,包括启动子序列、终止子序列、多腺苷酰化序列、增强子序列、标记基因以及其它适当的序列。载体可以是质粒或病毒,如适当的噬菌体或噬菌粒。有关更多细节,参见例如Sambrook等,Molecular Cloning:A Laboratory Manual,第二版,Cold Spring Harbor LaboratoryPress,1989。许多用于核酸操作的已知技术和方案在CurrentProtocols in Molecular Biology,第二版,Ausubel等编,JohnWiley & Sons,1992中有详细描述,例如,制备核酸构建体、诱变、测序、将DNA引入到细胞中和基因表达,以及蛋白分析。
本发明公开内容的另一方面提供了包含如此处所公开的核酸的宿主细胞。又在另一方面提供了包括将此核酸引入到宿主细胞中的方法。所述引入可采用任何可获得的技术。对于真核细胞,合适的技术可包括磷酸钙转染、DEAE-葡聚糖、电穿孔、脂质体介导的转染以及使用逆转录病毒或其它病毒转导,例如痘苗病毒,或者对昆虫细胞而言使用杆状病毒。对于细菌细胞,合适的技术可包括氯化钙转化、电穿孔以及使用噬菌体转染。在将核酸引入到细胞中之后,可通过例如在基因表达的条件下培养宿主细胞而使得或允许由所述核酸表达。
使用方法
所公开的抗-PD-1抗体能够调节与PD-1相关的免疫应答的下调。在特别的实施方案中,所述免疫应答是由TcR/CD28介导的。所公开的抗体可作为PD-1的激动剂或拮抗剂起作用,这依赖于其使用方法。抗体可用于预防、诊断或治疗哺乳动物尤其是人的医学紊乱。本发明的抗体也可用于分离PD-1或表达PD-1的细胞。此外,所述抗体可用于治疗处于紊乱危险之中或易感、或具有与异常PD-1表达或功能相关的紊乱的受试者。
本发明的抗体可用在用以诱导对特定抗原(如治疗蛋白)的耐受的方法之中。在一个实施方案中,耐受是针对特定抗原通过共施用抗原和本发明的抗-PD-1抗体诱导的。例如,频繁接受因子VIII的患者产生此蛋白的抗体;本发明的抗-PD-1抗体联合重组因子VIII的共施用预期将导致针对此凝血因子的免疫应答的下调。
本发明的抗体能够在可能期望免疫应答水平下降的情形下使用,例如,在某些类型的变应性或***反应(如通过抑制IgE生产),自身免疫病(如类风湿关节炎、I型糖尿病、多发性硬化、炎性肠病、Crohn氏病以及***性红斑狼疮),组织、皮肤和器官移植物排斥,以及移植物抗宿主疾病(GVHD)中。
当期望免疫应答减小时,本发明的抗-PD-1抗体可用作为PD-1激动剂,以增强与PD-1相关的免疫应答的弱化。在这些实施方案中,需要正信号(即由抗原受体如TcR或BcR介导的)和负信号(即PD-1)之间的共呈递和物理邻近性。优选的距离小于或与天然存在的呈递抗原细胞的大小相当,也就是小于大约100μm;更优选地,小于大约50μm;并且最优选地,小于大约20μm。
在有些实施方案中,正(激活)和负(抑制)信号是由固定于固体支持物基质或载体上的配体或抗体提供的。在多种不同的实施方案中,固体支持物基质可由聚合物组成,如活化琼脂糖、葡聚糖、纤维素、聚偏1,1-二氟乙烯(PVDF)。备选地,固体支持物基质可以是以硅石或塑料聚合物为基础,如尼龙、涤纶、聚苯乙烯、聚丙烯酸酯、聚乙烯、聚四氟乙烯等。
可将所述基质植入到患者脾中。备选地,所述基质可用于离体温育由患者获得的T细胞,然后分离T细胞并植回到患者之中。所述基质也可由可生物降解的材料制成,例如聚乙醇酸、聚羟基链烷酸酯、胶原或明胶,从而它们能够被注射到患者的腹膜腔中,并在注射后经过一段时间溶解。可对所述载体塑形以模拟细胞(如珠子或小球体)。
在有些实施方案中,正信号是由T细胞活化的结合TcR的抗-CD3抗体递送的。活化抗-CD3抗体是本领域公知的(参见例如美国专利Nos.6,405,696和5,316,763)。活化TcR信号和负PD-1信号之间的比率是利用本领域公知的常规操作、或如实施例8、9和10中所述通过实验确定的。
在某些情形下,可能期望引发或增强患者的免疫应答,以治疗免疫紊乱或癌症。由所公开的方法治疗或预防的紊乱包括但不限于微生物(如细菌)、病毒(如全身性病毒感染如流感、病毒性皮肤病如疱疹或带状疱疹)或寄生物感染;以及癌症(如黑素瘤和***癌)。
用抗-PD-1抗体刺激T细胞激活增强了T-T细胞应答。在此类情况下,所述抗体作为PD-1拮抗剂起作用。从而,在有些实施方案中,可利用所述抗体抑制或降低与PD-1相关的下调活性,也就是与TcR/CD28介导的免疫应答的下调相关的活性。在这些实施方案中,所述抗体并不偶联于正信号如TcR介导的刺激,例如所述抗体为其可溶、未结合支持物的形式。如实施例中所证明的那样,阻断PD-1/PD-L与拮抗性抗-PD-1抗体的相互作用导致增强的T细胞增殖应答,这与PD-1途径在T-T相互作用中的下调作用一致。在各种实施方案中,所述抗体抑制PD-L与PD-1的结合,IC50小于10nM,并且更优选小于5nM,并且最优选小于1nM。PD-L结合的抑制可如实施例6中所述或使用本领域公知的技术测量。
本发明的抗体或抗体组合物以治疗有效量施用。一般地,治疗有效量可能随受试者的年龄、状况和性别、以及受试者医学状况的严重度而不同。抗体的治疗有效量在从大约0.001到大约30mg/kg体重的范围内变动,优选从大约0.01到大约25mg/kg体重,从大约0.1到大约20mg/kg体重,或者从大约1到大约10mg/kg。所述剂量可根据需要调整,以满足所观察到的治疗效果。合适的剂量是由治疗医师根据临床指征选择的。
所述抗体可作为大丸剂施用,以便在施药后最大时间长度内使得抗体的循环水平最大化。在大丸剂施用后也可使用连续输注。
也可从患者中分离免疫细胞(如激活的T细胞、B细胞或单核细胞),并与本发明的抗体离体(ex vivo)温育。在有些实施方案中,免疫应答可通过从受试者中取出免疫细胞,将所述免疫细胞与本发明的抗-PD-1抗体体外接触,同时伴有免疫细胞的活化(如通过抗TcR和/或BcR抗原受体的抗体)进行抑制。在此类实施方案中,所述抗-PD-1抗体应当以多价的形式使用,从而免疫细胞表面上的PD-1分子经与此类抗体结合而成为“交联的”。例如,可将所述抗-PD-1抗体结合到固体支持物如珠子上,或者介由第二抗体交联。然后可利用本领域公知的方法分离免疫细胞并再植入到患者中。
在另一个方面,本发明的抗体可用作为靶向剂用于将另一种治疗剂或细胞毒性剂(如毒素)递送给表达PD-1的细胞。所述方法包括施用偶联于治疗剂或细胞毒性剂的抗-PD-1抗体,或在允许所述抗体与PD-1结合的条件下施用。
本发明的抗体也可用于检测生物学样品中PD-1的存在。所检测的PD-1的量可能与PD-1的表达水平相关,其依次又与受试者中免疫细胞(如激活的T细胞、B细胞和单核细胞)的激活状态相关。
采用抗体的检测法是本领域众所周知的,并且包括,例如,ELISA、放射免疫测定、免疫印迹、蛋白印迹、免疫荧光、免疫沉淀。所述抗体可在诊断试剂盒中提供,所述试剂盒合并了一种或多种这些技术以检测PD-1。此种试剂盒可含有其它组分、包装、说明书或其它材料,以辅助检测所述蛋白。
当抗体旨在用于诊断目的时,可能期望修饰它们,例如用配体基团(例如生物素)或可检测的标记基团(例如荧光基团、放射性同位素或酶)修饰。如果需要,可利用常规技术标记本发明的抗体。例如,合适的可检测标记包括例如荧光团、发色团、放射性原子、电子密试剂、酶以及具有特异性结合配偶体的配体。酶一般通过其活性予以检测。例如,辣根过氧化物酶可通过其将四甲联苯胺(TMB)转化为可由分光光度计定量的蓝色色素的能力予以检测。关于检测,合适的结合配偶体包括但不限于:生物素与抗生物素蛋白或链霉抗生物素蛋白,IgG与蛋白A,以及本领域公知的众多受体-配体对。其它改变和可能性对本领域普通技术人员将会是非常显而易见的,并认为是本发明范围内的等同物。
本发明的抗体可在筛选方法中用于鉴定能有效作为治疗剂的PD-1途径的抑制剂。在此筛选测定中,通过组合PD-1和本发明的抗体形成第一结合混合物;并测量所述第一结合混合物中的结合量(M0)。也通过组合PD-1、抗体、以及待筛选化合物或试剂形成第二结合混合物,并测量所述第二结合混合物中的结合量(M1)。待测化合物可以是另一种抗-PD-1抗体,如实施例中所举例说明的那样。然后比较所述第一及第二结合混合物中的结合量,例如,通过计算M1/M0比率进行比较。如果观察到第二结合混合物中的结合与第一结合混合物相比下降,则认为所述化合物或试剂能够调节与PD-1相关的免疫应答的下调。结合混合物的配制和优化落在本领域技术水平之内,此类结合混合物也可以含有必要的缓冲液和盐以增强或优化结合,并且另外的对照测定可包含在本发明的筛选测定中。这样可鉴定发现使PD-1抗体结合降低至少约10%(即,M1/M0<0.9)、优选大于约30%的化合物,然后,如果需要,如下文所述在其它测定或动物模型中对其进行改善紊乱能力的第二次筛选。PD-1与抗体之间的结合强度可利用以下技术测量,例如,酶联免疫吸附测定(ELISA),放射免疫测定(RIA),基于表面等离子体共振的技术(如Biacore),这些全部都是本领域众所周知的技术。
然后可如实施例中所述或在动物模型(一般地参见ImmunologicDefects in Laboratory Animals,Gershwin等编,Plenum Press,1981)中体外测试所述化合物,例如,如以下的动物模型:SWR×NZB(SNF1)转基因小鼠模型(Uner等(1998)J.Autoimmune.11(3):233-240),KRN转基因小鼠(K/BxN)模型(Ji等(1999)Immunol.Rev.169:139);SLE模型NZB×NZW(B/W)小鼠(Riemekasten等(2001)Arthritis Rheum.,44(10):2435-2445);多发性硬化模型小鼠实验性自身免疫性脑炎(EAE)(Tuohy等(1988)J.Immunol.141:1126-1130,Sobel等(1984)J.Immunol.132:2393-2401,以及Traugott,Cell Immunol.(1989)119:114-129);糖尿病NOD小鼠模型(Baxter等.(1991)Autoimmunity,9(1):61-67)等等)。
例如根据动物试验所确定的初步剂量以及用于人类施用的剂量比例换算是根据本领域公认的操作进行的。毒性和疗效可通过细胞培养物或实验动物中的标准药学操作确定。由细胞培养物测定或动物研究获得的数据可用于配制用于人的剂量范围。在一个实验动物模型中所达到的治疗有效剂量可利用本领域公知的换算因子予以换算以用于另一个动物,包括人(参见如Freireich等(1966)CancerChemother.Reports,50(4):219-244)。
药物组合物和施用方法
本发明公开内容提供了包含抗-PD-1抗体的组合物。此类组合物可能适合于制药用途以及向患者施用。所述组合物一般包括一种或多种本发明的抗体以及药学上可接受的赋形剂。短语“药学上可接受的赋形剂”包括与药物施用相容的任何及所有溶剂、分散介质、涂层、抗细菌剂和抗真菌剂、等渗剂以及吸收延迟剂等。此类介质和试剂对药学活性物质的用途是本领域众所周知的。所述组合物也可以含有其它提供补充的、附加的或增强的治疗功能的活性化合物。所述药物组合物也可连同施用说明书一起包含在容器、包装或分配器中。
本发明的药物组合物被配制为与其期望的施用途径相容。实现施用的方法是本领域普通技术人员公知的。例如,施用可以是静脉内、腹膜内、肌内、腔内、皮下或经皮。也有可能获得可局部或口服施用、或能够跨粘膜输送的组合物。
用于真皮内或皮下应用的溶液或悬浮液一般包括一种或多种如下成分:无菌稀释剂如注射用水、盐溶液、固定油、聚乙二醇、甘油、丙二醇或其它合成溶剂;抗细菌剂如苄醇或羟苯甲酸甲酯;抗氧化剂如抗坏血酸或亚硫酸氢钠;螯合剂如乙二胺四乙酸;缓冲液如乙酸盐、柠檬酸盐或磷酸盐;以及用于调整张力的试剂如氯化钠或葡萄糖。pH可用酸或碱调节,例如盐酸或氢氧化钠。此类制剂可封装在由玻璃或塑料制成的安瓿、一次性注射器或多剂量小瓶中。
适合于注射的药物组合物包括无菌水溶液或分散体,以及用于临时制备无菌可注射溶液或分散体的无菌粉末。对于静脉内施用,合适的载体包括生理盐水、制菌水、Cremophor EL(BASF,Parsippany,NJ)或磷酸缓冲盐溶液(PBS)。在所有情况下,所述组合物必需是无菌的,并且应当是存在容易的可注射性程度的流体。它在制造和贮藏条件下应当是稳定的,并且必需抗微生物如细菌和真菌的污染作用加以保存。微生物作用的预防可通过多种抗细菌剂和抗真菌剂实现,例如,对羟基苯甲酸酯、氯丁醇、苯酚、抗坏血酸、硫柳汞等。在许多情况下,组合物中将优选包括等渗剂,例如糖,多元醇如甘露糖醇、山梨糖醇以及氯化钠。载体可以是溶剂或分散介质,例如,含有水、乙醇、多羟基化合物(例如,甘油、丙二醇和液体聚乙二醇等)以及它们合适的混合物。例如,合适流动性可通过使用涂层如卵磷脂,在分散体的情况下通过维持所需的粒径和/或通过使用表面活性剂得以维持。可注射组合物的延迟吸收可通过将延迟吸收的试剂例如单硬脂酸铝和明胶包含到组合物中实现。
口服组合物一般包含惰性稀释剂或可食载体。可将它们封装到明胶胶囊中或压缩成片剂。为口服施用,可将抗体与赋形剂组合,并以片剂、锭剂或胶囊的形式使用。药学上相容的结合剂和/或佐剂材料可作为组合物的一部分包括在内。所述片剂、药丸、胶囊、锭剂等可含有如下任一成分或具有相似性质的化合物:粘合剂如微晶纤维素、黄蓍树胶或明胶;赋形剂如淀粉或乳糖;崩解剂如褐藻酸、Primogel或玉米淀粉;润滑剂如硬脂酸镁或Sterotes;助流剂如胶体二氧化硅;增甜剂如蔗糖或糖精;或调味剂如胡椒薄荷、水杨酸甲酯或橙味调味剂(orange Havoring)。
全身性施用也可以是通过跨粘膜或经皮手段。为了跨粘膜或经皮施用,制剂中使用与待穿过的屏障相称的渗透剂。此类渗透剂通常是本领域公知的,并且包括,例如去污剂、胆汁盐和梭链孢酸衍生物。例如,跨粘膜施用可通过使用糖锭、鼻腔喷雾、吸入剂或栓剂完成。例如,在抗体包含Fc部分的情况下,组合物可能(如美国专利No.6,030,613中所述介由FcRn受体介导的途径)能够跨肠、口或肺粘膜输送。对于经皮施用,可将活性化合物配制成如本领域普遍公知的软膏、油膏、凝胶或乳膏。为了通过吸入施用,可以气雾剂喷雾的形式由压缩容器或分配器递送抗体,所述容器或分配器含有合适的推进剂例如气体如二氧化碳或雾化器。
在某些实施方案中,本文公开的抗体与将会保护该化合物防止由体内迅速消除的载体一起制备,例如缓释制剂,包括植入物和微囊化递送***。可使用可生物降解的生物相容性聚合物如乙烯乙酸乙烯酯、聚酐、聚乙醇酸、胶原、聚原酸酯以及聚乳酸。用于制备此类制剂的方法对本领域技术人员将会是显而易见的。含有本文公开的抗体的脂质体悬浮液也可用作为药学上可接受的载体。这些可根据本领域技术人员公知的方法制备,例如,如美国专利No.4,522,811中所述的那样。
以剂量单位形式配制口服或肠胃外组合物可能是有利的,以易化施用和剂量的一致性。如本文所用的术语“剂量单位形式”是指适合作为待治疗受试者的单位剂量的物理上不连续的单位;每个单位含有预定量的经计算与所需药物载体相结合产生期望疗效的活性化合物。
本发明组合物的毒性和疗效可通过细胞培养物或实验动物中的标准药学方法确定,例如用以确定LD50(对50%群体致死的剂量)和ED50(在50%群体中治疗有效的剂量)的方法。毒性和疗效之间的剂量比率是治疗指数,且其可表达为LD50/ED50比率。优选呈现出大治疗指数的组合物。
对于本发明中所用的任何组合物,治疗有效剂量最初可由细胞培养物测定来估计。合适的生物测定的实例包括DNA复制测定、细胞因子释放测定、基于转录的测定、PD-1/PD-L1结合测定、肌酸激酶测定、基于前脂肪细胞(pre-adipocyte)分化的测定、基于脂肪细胞中葡萄糖吸收的测定、免疫学测定、其它例如实施例中所描述的测定。由细胞培养物测定和动物研究获得的数据可用于配制用于人的剂量范围。可在动物模型中配制剂量,以获得包括IC50(即实现半数最大症状抑制的抗体浓度)的循环血浆浓度范围。例如,可通过高效液相层析测量血浆中的循环水平。可通过合适的生物测定监控任何特定剂量的效力。剂量优选处于具有少许毒性或无毒性的循环浓度的范围内。剂量可依赖于所采用的剂型和所使用的施用途径而变。
以下实施例并非以任何方式限制本发明的范围。本领域普通技术人员将会认识到能够进行众多修改和变动而不会改变本发明的精神或范围。此类修改和变动涵盖在本发明的范围之内。特此将本申请通篇所引述的所有参考文献、专利和公开的专利申请的全部内容并入作为参考。
实施例
实施例1:结合PD-1的ScFv的选择
利用扩大形式的由Vaughan等(Nature Biotech.(1996)14:309-314)描述的1.38×1010文库的scFv噬菌粒文库选择特异于人PD-1的抗体。将可溶性PD-1融合蛋白(20μg/ml的磷酸缓冲盐水(PBS)溶液)或对照融合蛋白(50μg/ml的PBS溶液)涂覆到微量滴定板孔中,4℃过夜。孔在PBS中洗涤并在MPBS(3%奶粉的PBS溶液)中于37℃封闭1小时。将纯化的噬菌体(1012转导单位(tu))在终体积100μl的3%MPBS中封闭1小时。添加封闭的噬菌体到封闭的对照融合蛋白孔,并温育1小时。然后将封闭且去选择(deselect)的噬菌体转移到涂覆有PD-1融合蛋白的封闭的孔中,并温育另外一个小时。孔用PBST(含0.1%v/v Tween 20的PBS)洗涤5次,然后用PBS洗涤5次。洗脱结合的噬菌体颗粒,并用于感染10ml指数生长的大肠杆菌TG1。使感染的细胞在2TY液体培养基中于37℃生长1小时,然后涂布到2TYAG板上,并于30℃温育过夜。将菌落从板上刮到10ml2TY液体培养基中,并加入15%甘油于-70℃贮存。
用辅助噬菌体超感染来自第一轮淘选的甘油原种培养物,并进行拯救(rescue)以产生表达scFv抗体的噬菌体颗粒,用于第二轮淘选。以这种方式总共进行两轮淘选用于PD1-17的分离,除了在第二轮淘选中使用20μg/ml对照蛋白进行去选择。在三轮选择之后选到了克隆PD1-28、PD1-33和PD1-35。第二和第三轮的去选择是利用10μg/ml对照融合蛋白进行的。
鼠PD-1抗体是利用终浓度为100nM的生物素化鼠PD-1融合蛋白通过可溶性选择进行选择的。使用了如上文所述的scFv噬菌粒文库。对1ml 3%MPBS中的纯化的scFv噬菌体(1012tu)封闭30分钟,然后加入生物素化的抗原,并于室温下温育1小时。将噬菌体/抗原添加到250μl Dynal M280链霉抗生物素蛋白磁珠中,并室温下再温育15分钟,所述磁珠业已在1ml 3%MPBS中于37℃封闭1小时。珠子利用磁架捕获,并在1ml 3%MPBS/0.1%(v/v)Tween 20中洗涤4次,紧接着在PBS中洗涤3次。在末次PBS洗涤后,将珠子重悬于100μl PBS中,并用于感染5ml指数生长的大肠杆菌TG-1细胞。使感染的细胞于37℃温育1小时(30分钟静止,30分钟于250rpm振荡),然后涂布到2TYAG板上,并于30℃温育过夜。将长出的菌落从板上刮下,并如上文所述拯救噬菌体。如上所述进行第二轮可溶性选择。
实施例2:通过噬菌体ELISA确定抗体对PD-1的特异性
为确定抗体对PD-1的特异性,针对PD-1融合蛋白和对照蛋白进行了噬菌体ELISA。将来自选择产物的个体大肠杆菌菌落挑取到每孔含100μl 2TYAG培养基的96孔板中。向指数生长的培养物中添加感染复数(moi)为10的M13K07辅助噬菌体,并将板于37℃温育另外1小时。将板在台式离心机中以2000rpm离心10分钟。除去上清,并将细胞沉淀重悬于100μl 2TYAK中,并于30℃振荡温育过夜。第二天,将板以2000rpm离心10分钟,并将来自各孔的含噬菌体的上清液转移到新的96孔板中。在ELISA前,将噬菌体样品在终浓度为3%的MPBS中封闭。
将溶于PBS的0.5-2.5μg/ml人或小鼠PD-1融合蛋白和对照融合以及非融合蛋白于4℃过夜涂覆到96孔微量滴定板上。涂覆后,从孔中除去溶液,并使板在3%MPBS中封闭1小时。用PBS冲洗板,然后向各孔添加50μl预封闭的噬菌体。将板温育1小时,然后用PBST洗涤3次,紧接着用PBS洗涤3次。向各孔中加入50μl抗-M13-HRP缀合物(Pharmacia,Peapack,NJ)的1∶5000稀释液,并将板温育40-60分钟。各板用PBST洗涤3次,然后用PBS洗涤3次。向各孔添加50μl TMB底物,并温育样品直至显色。反应通过添加25μl 0.5M H2SO4终止。所产生的信号通过使用微量滴定板读数器在450nm处读取吸收度测量。表现出对PD-1融合蛋白而非对照融合蛋白的特异性结合的克隆从而得以鉴定和确认。
PD1-17scFv的特异性数据示于图1A。PD1-28、PD1-33和PD1-35scFv与人PD-1的反应性示于图1B(IgG1对照并不结合PD-1)。
实施例3:抗体克隆的鉴定
将结合PD-1的scFv的大肠杆菌克隆划线到2TYAG板上,并于30℃温育过夜。通过使用pCANTAB6载体序列寡核苷酸(oligos)扩增来自scFv克隆的VH和VL区对来自这些板的菌落进行测序。如实施例4中所述,测定了中和PD-L1与PD-1结合的独特的结合PD-1的克隆。scFv和IgG形式之间的序列差异归因于在由scFv转化为IgG期间由PCR引物所引入的变化。
实施例4:生化结合抑制测定和筛选
通过向指数生长的培养物中添加1mM IPTG并于30℃温育过夜来诱导ScFv生产。通过对来自过夜诱导的细菌沉淀进行渗透压休克获得粗制含scFv的周质提取物。将沉淀重悬于20%(w/v)蔗糖,50mMTris-HCl,pH 7.5,1mM EDTA,并在冰上冷却30分钟。通过离心除去细胞碎片,并通过层析纯化scFv,和将缓冲液交换成PBS。在96孔微量滴定板测定中测试了纯化的scFv(PD1-17、PD1-28、PD1-33和PD1-35)抑制生物素化的人PD-L1融合蛋白与固定在塑料上的人PD-1融合蛋白结合的能力。生物素化的PD-L1融合蛋白的结合是用AMDEX碱性磷酸酶检测的,并且所产生的信号是通过使用微量滴定板读数器在405nm处读取吸收度测量的。数据表达为总结合百分比,并试验了scFv浓度的滴定以建立作为计算的IC50值的克隆效价(clone potency)。scFv和IgG抗体的克隆效价数据示于表5。
PD1-F2scFv如上文所述生产和纯化。以105细胞/孔向聚-D-赖氨酸涂覆的96孔微量滴定板中加入终体积为100μl的表达鼠PD-1的细胞。将细胞离心,并在PBS中洗涤两次,然后用300μl溶于PBS的1%BSA室温下封闭1小时。封闭的细胞在PBST中洗涤三次,之后添加25μl/孔测定缓冲液(0.05%BSA,0.05%Tween 20,溶于Dulbecco氏PBS中)或样品,接着是25μl 300ng/ml的生物素化鼠PD-L1融合蛋白。生物素化的PD-L1融合蛋白的结合是用Amdex碱性磷酸酶检测的,并且信号如上所述进行读取。PD1-F2scFv和IgG的效价示于表6。
表6:抗-PD-1ScFv和IgG抗体的效价
克隆 | ScFv IC50(nM) | IgG IC50(nM) |
PD1-17 | 726 | 2.5 |
PD1-28 | 560 | 1.4 |
PD1-33 | 74 | 1.8 |
PD1-35 | 85 | 2.3 |
PD1-F2 | 28 | 1.0 |
实施例5:ScFv向IgG的转化
来自scFv克隆的重链和轻链V区是利用克隆特异性引物通过PCR扩增的。PCR产物用合适的限制酶消化并亚克隆到含人IgG1重链恒定结构域的载体中(Takahashi等(1982)Cell 29,671)或含人λ或κ轻链恒定结构域的载体中(Hieter等.(1982)Nature 294,536)。根据VH和VL区段的种系确定是否利用κ或λ轻链恒定结构域进行转化(表7)。
表7:PD-1抗体克隆VH和VL区的种系
克隆 | VH种系 | VL种系 |
PD1-17 | DP-70 | DPL-8 |
PD1-28 | DP-14 | DPL-23 |
PD1-33 | DP-7 | DPL-11 |
PD1-35 | DP-65 | DPL-2 |
PD1-F2 | DP-47 | L12(κ) |
质粒中V区结构域的***是通过来自个体大肠杆菌菌落的质粒DNA的测序验证的。通过标准技术由大肠杆菌培养物制备质粒,并利用标准技术将重链和轻链构建体共转染到真核细胞中。利用A蛋白琼脂糖凝胶(Pharmacia)纯化分泌的IgG,并将缓冲液交换成PBS。
抗-小鼠PD1抗体PD1-F2的结合亲和力是借助表面等离子体共振(SPR)***(BIAcore 3000)(Biacore,Piscataway,NJ)利用固定在CM5传感芯片上的鼠PD-1融合物确定的。流动细胞中PD1-F2的浓度范围从7.81到125nM变动,而抗-小鼠PD1抗体J43(eBioscience,San Diego,CA)的浓度范围从25nM到500nM变动。PD1-F2的平衡常数KD是6.7×10-9M(KA=1.5×108M-1),而J43的KD是3.8×10-7M(KA=2.6×106M-1)。
抗-PD-1 IgG结合人或鼠PD-1的能力测定如下。将ELISA板与2.5μg/ml人PD-1/IgG嵌合体温育过夜。用PBS/1%BSA洗涤板,并与测试抗体的系列稀释液在室温(RT)下温育2小时。洗涤后,添加饱和浓度的HRP缀合的山羊抗人抗体或HRP缀合的兔抗鼠抗体,并在室温下温育样品1小时。未结合的山羊和兔抗体利用PBS/1%BSA洗涤。测定利用TBM显色。结果表达为OD 405吸收度值,并示于图2A-2C。鼠抗人PD-1抗体J110是商业上可获得的(eBioscience,San Diego,CA),并包含在内用于比较。
实施例6:所选的PD-1抗体抑制PD-L1与PD-1的结合
进行抑制测定以评估抗体阻断PD-L1对PD-1的结合的能力。ELISA如实施例2中所述进行,并有改动。在与第一抗体抗-PD-1抗体室温下温育2小时后,添加固定浓度(1μg/ml)的生物素缀合的PD-L1-Ig,且样品于室温下再温育1小时。洗涤后,添加饱和浓度的抗生物素蛋白-HRP,并在室温下温育1小时。未结合的抗生物素蛋白-HRP利用PBS/1%BSA洗涤。测定利用TMB显色。
将结果与由J110获得的结果进行比较,如图3所示。抗人PD-1抗体J110和PD1-30并不抑制PD-L1与PD-1的结合。抗人抗体PD1-17、PD1-28、PD1-33和PD1-35以及抗小鼠抗体PD1-F2阻断PD-1/PD-L1相互作用。
实施例7:PD-1抗体识别PD-1上不同的位点
进行抑制测定以对由多种人抗人PD-1抗体所识别的位点进行作图。ELISA如实施例6中所述进行,并稍加改动。在与第一抗体室温下温育2小时后,添加固定浓度(0.25μg/ml)的生物素缀合的抗-PD-1抗体J110,且样品于室温下再温育1小时。洗涤后,添加饱和浓度的抗生物素蛋白-HRP,并在室温下温育1小时。未结合的抗生物素蛋白-HRP利用PBS/1%BSA洗涤。测定利用TMB显色。
如图4所示,抗人PD-1抗体(J110、J116、PD1-17、PD1-28、PD1-33和PD1-35)的结合限定了PD-1上至少两个不同的位点。交叉阻断结果显示J110和J116与完全相同或重叠的位点结合,而PD1-17、28、33和35与另一不同的位点结合。J116或J110对PD-1的结合阻断了J110的结合。相反,PD1-17、PD1-28、PD1-33和PD1-35的结合并不阻断J110的结合。这提示所测试的抗-PD-1抗体与至少两个不同的表位结合:一个被J110和J116识别,而另一个被PD1-17、PD1-28、PD1-33和PD1-35识别。
实施例8:PD-1接合导致T细胞应答下降
CD4+T细胞(5×104细胞/孔)用涂覆有抗hCD3+/-PD-L1-Fc或抗-PD-1(PD1-17或J110)的甲苯磺酰珠(Dynal,Great Neck,NY)刺激。融合蛋白的浓度或抗体效价如图5的X轴所示。72小时后,通过3H-胸苷掺入测定增殖。掺入的放射性利用LKB 1205板读数器测定。
如图5所示,抗-PD-1抗体PD1-17或PD-L1.Fc对PD-1的接合导致T细胞增殖下降。从而,PD1-17能够模拟PD-1配体并递送抑制信号。如下文所讨论的那样(实施例9),该抑制信号导致T细胞增殖和IL-2生产下降。抗体PD1-28、PD1-33和PD1-35具有与PD1-17相同的效应。所述效应是剂量依赖性的,因为在存在渐增浓度的PD1-17或PD-L1.Fc时细胞的激活导致T细胞增殖下降。对照抗-PD-1抗体J110(图5)或J116(数据未显示)并不抑制T细胞应答,并且提高J110的浓度对T细胞增殖具有极微的影响。为了比较,数值表示为抗-CD3应答的百分比。“100%”表示当细胞由抗-CD3/鼠IgG涂覆的小球体激活时所获得的CPMs。总而言之,这些结果表明有些但并非所有识别PD-1的抗体都可作为PD-1途径的激动剂起作用。
进行了更多的实验以弄清楚PD-1对T细胞应答的下调是否需要TcR/PD-1协同接合到单个(顺式(CIS))或不同(反式(TRANS))的细胞表面上。制备了两组小球体:一组含有抗-CD3和PD-L1.Fc(顺式),另一组含有抗-CD3或PD-L1.Fc(反式)。仅仅在PD-1和TcR两者都在相同表面(顺式)上被配体接合的条件下观察到通过PD-1的抑制。在测试的所有珠:细胞比率下,在TCR和PD-1信号被递送到不同的表面(反式)的条件下没有观察到抑制。
为排除反式实验中的空间位阻,利用抗-CD3抗体和B7.2.Fc设置了相似的测定。在这些测定中,在顺式和反式条件下都观察到T细胞应答的B7共刺激。总而言之,这些发现证明接近于TCR的PD-1是对T细胞激活的受体调节功能所必需的。因此,为调节T细胞应答,激活和抑制信号必须都由相同表面发出,无论所述表面是细胞的表面或是珠子的表面。
实施例9:抗体时PD-1接合的阻断导致增殖提高
为评估可溶性抗-PD-1抗体对增殖的影响,用抗-CD3/抗-CD28涂覆的珠子预活化CD4+T细胞48小时,收获,并在PD1-17、J110或对照IgG的存在下用所示浓度的PHA加10ng/ml IL-2再刺激。在开始培养时,以多种浓度添加各抗体。在72小时测量增殖。
结果证明PD1-17(图6)和PD1-35(数据未显示)促进了原代T细胞的增殖。对照抗体J110并不促进体外T细胞应答。所选的抗-PD1抗体,如由PD1-17和PD-35所例示的那样,抑制PD-1与其天然配体的相互作用,由此阻断负信号的递送。负信号的阻断也导致增殖和IL-2生产提高。
实施例10:紊乱的治疗
由PD-1调控的免疫应答的调节可用于期望免疫抑制效果或免疫应答增强的情形。本实施例描述了PD-1抗体作为PD-1激动剂或拮抗剂用于治疗分别处于疾病发作或具有确定的免疫紊乱或癌症的受试者的用途。
可能需要免疫应答增强的、处于癌症危险之中或患有癌症的受试者将会得益于PD-1拮抗剂的治疗,例如可溶形式的本发明的抗-PD-1抗体。最常见的,在门诊病人的环境下,以每周一次通过缓慢静脉内输注施用大约0.1-10mg/kg剂量的抗体。拮抗剂合适的治疗有效剂量是由治疗医师选择的,并且将在大约从1μg/kg到20mg/kg、从1μg/kg到10mg/kg、从1μg/kg到1mg/kg、从10μg/kg到1mg/kg、从10μg/kg到100μg/kg、从100μg到1mg/kg,以及从500μg/kg到5mg/kg的范围内变动。
也利用所述抗体预防和/或减轻涉及异常或不期望的免疫应答的疾病或状况的严重度和/或症状,例如在下文所例示的自身免疫紊乱中。
多发性硬化(MS)是中枢神经***疾病,它以髓鞘的炎症和丧失为特征。在用于多发性硬化的实验性自身免疫性脑炎(EAE)小鼠模型中(Tuohy等(J.Immunol.(1988)141:1126-1130),Sobel等(J.Immunol.(1984)132:2393-2401),以及Traugott(Cell Immunol.(1989)119:114-129),在诱发EAE之前(并且是连续地)用PD-1激动剂治疗小鼠预期将预防或延迟MS的发作。
关节炎是以关节中的炎症为特征的疾病。在用于类风湿关节炎的胶原诱发的关节炎(CIA)小鼠模型中(Courtenay等(Nature(1980)283:666-628)和Williams等(Immunol.(1995)84:433-439)),用PD-1激动剂治疗预期将预防或治疗类风湿关节炎(RA)或其它关节炎疾病。
***性红斑狼疮(SLE)是以自体抗体的存在为特征的自身免疫病。本发明的抗体和组合物可用作PD-1激动剂抑制自体反应性T细胞和B细胞的活性,并预防或治疗NZB×NZW小鼠(SLE小鼠模型)(Immunologic Defects in Laboratory Animals,Gershwin等编,Plenum Press,1981)或人的SLE或相关疾病。
预期本发明的PD-1抗体在离体治疗中将以每月一次或更低的频率作为PD-1激动剂施用。治疗持续时间将在一个月和数年之间的范围内变动。
为测试人体内所述抗体的临床功效,鉴定了患有黑素瘤、***癌、RA、SLE、MS、I型糖尿病的个体并随机化到治疗组中。治疗组包括安慰组和一到三个用PD-1激动剂(不同剂量)治疗的组。预期将对个体随访1至3年。预期接受治疗的个体将表现出改善。
根据本说明书内所引述的参考文献的教导,本说明书得到了最为彻底的理解,特此将它们全部全文并入作为参考。本说明书内的实施方案提供了本发明的实施方案的举例说明,而不应当解释为限制本发明的范围。熟练技术人员认识到许多其它实施方案为所请求保护的发明所涵盖,并期望本说明书和实施例仅仅被认为是例示性的,而本发明真正的范围和精神是由如下权利要求表示的。
Claims (13)
1.分离的抗体,其包含
包含3个CDRs的VH结构域,以及包含3个CDRs的VL结构域;
其中所述抗体包含
(a)SEQ I D NO:6的VH结构域和SEQ ID NO:8的VL结构域;或(b)SEQ ID NO:10的VH结构域和SEQ ID NO:12的VL结构域;或(c)SEQ ID NO:14的VH结构域和SEQ ID NO:16的VL结构域;且
其中所述抗体特异性结合位于人PD-1胞外结构域内的表位,且
其中抗体与PD-1的胞外结构域特异性结合,其亲和常数大于107M-1。
2.权利要求1的抗体,其中抗体抑制PD-L与PD-1的结合,其IC50低于10nM。
3.权利要求1的抗体,其是Fab、F(ab′)2、Fv、scFv、Fd或dAb。
4.权利要求1的抗体,其中抗体是人的。
5.权利要求1的抗体,其中抗体为IgG1或IgG4。
6.权利要求5的抗体,其中抗体为IgG1λ或IgG1κ。
7.药物组合物,其包含权利要求1的抗体。
8.有效剂量的权利要求7的药物组合物在制备用于治疗或预防选自自身免疫紊乱、针对移植物的免疫应答、***反应和癌症的紊乱的药物中的用途。
9.权利要求8的用途,其中受试者是人。
10.分离的核酸,其编码权利要求1的抗体。
11.表达载体,其包含权利要求10的核酸。
12.宿主细胞,其包含权利要求11的载体。
13.权利要求12的宿主细胞,其中宿主细胞选自:大肠杆菌、中国仓鼠卵巢细胞、HeLa细胞和NS0细胞。
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CN108530537B (zh) * | 2018-03-29 | 2019-07-02 | 中国人民解放军军事科学院军事医学研究院 | Pd-1/pd-l1信号通路抑制剂 |
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US7488802B2 (en) | 2009-02-10 |
US20060210567A1 (en) | 2006-09-21 |
ES2367430T3 (es) | 2011-11-03 |
BR0316880A (pt) | 2005-10-25 |
AU2003288675A8 (en) | 2004-07-14 |
AU2003288675A1 (en) | 2004-07-14 |
CN1753912A (zh) | 2006-03-29 |
JP4511943B2 (ja) | 2010-07-28 |
HK1083510A1 (en) | 2006-07-07 |
US20040213795A1 (en) | 2004-10-28 |
CA2508660A1 (en) | 2004-07-08 |
EP1576014A1 (en) | 2005-09-21 |
NO20053389L (no) | 2005-07-12 |
US20080311117A1 (en) | 2008-12-18 |
NO20053389D0 (no) | 2005-07-12 |
IL169152A0 (en) | 2007-07-04 |
WO2004056875A1 (en) | 2004-07-08 |
US7521051B2 (en) | 2009-04-21 |
IL169152A (en) | 2010-11-30 |
JP2006521783A (ja) | 2006-09-28 |
MXPA05006828A (es) | 2005-09-08 |
CA2508660C (en) | 2013-08-20 |
EP1576014B1 (en) | 2011-06-29 |
NO336442B1 (no) | 2015-08-17 |
AU2003288675B2 (en) | 2010-07-22 |
AU2010235966A1 (en) | 2010-11-11 |
ATE514713T1 (de) | 2011-07-15 |
JP2010189395A (ja) | 2010-09-02 |
US20100028330A1 (en) | 2010-02-04 |
US8088905B2 (en) | 2012-01-03 |
CN101899114A (zh) | 2010-12-01 |
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