CN114507282A - 人单克隆抗-pd-l1抗体和使用方法 - Google Patents
人单克隆抗-pd-l1抗体和使用方法 Download PDFInfo
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Abstract
本发明包括结合至PD‑L1(也被称为程序化死亡配体1或B7H1)的人单克隆抗体。本发明的抗体与PD‑L1的结合抑制对它的受体PD1(程序化死亡1)的结合和配体‑介导的活性,并可用于治疗癌症和慢性病毒感染。
Description
本申请是申请日为2013年10月4日,中国国家申请号为201380063513.0,发明名称为“人单克隆抗-PD-L1抗体和使用方法”的发明申请的分案申请(中国国家申请号为201711156800.2)的继续分案申请。
相关申请
本申请要求提交于2012年10月4日的美国临时申请号61/709,731和提交于2013年3月13日的美国临时申请号61/779,969的优先权和利益,其内容通过引用各自以其整体结合到本文中。
发明领域
本发明主要涉及抗-PD-L1(也称为程序化细胞死亡1配体1或B7H1)抗体及其使用方法。
发明背景
免疫系统必须实现在有效应答以清除致病体和保持耐受以防止自身免疫疾病之间的平衡。T细胞对于保持这种平衡是关键的,并且它们的适当的调节主要通过B7-CD28家族的分子协调。B7家族成员(其行使配体的功能)和CD28家族成员(其行使受体的功能)之间的相互作用提供了关键的正信号,其不仅发起、提高和维持T细胞应答,而且在适当时还促进限制、终止和/或消弱T细胞应答的关键负信号。CD28家族的一个成员,称为PD-1(也称为程序化细胞死亡-1)在活化的T细胞、B细胞和单核细胞上被增量调节。PD-1在B7家族中有两个鉴定出的配体,PD-L1(也称为BH71或程序化细胞死亡-1配体1)和PD-L2。虽然主要在活化的抗原呈递细胞(APC)上发现PD-L2的表达倾向于为更受限的,但PD-L1的表达为更普遍的,包括造血谱系(其包括活化的T细胞、B细胞、单核细胞、树突细胞和巨噬细胞)和外周非淋巴组织(其包括心、骨骼、肌肉、胎盘、肺、肾和肝组织)的细胞。PD-L1的普遍表达暗示它在调节PD-1/PD-L1-介导外周耐受中的重要作用。
PD-L1和PD-1之间的结合对于T细胞应答的调节具有意义深远的作用。具体而言,PD-L1/PD-1相互作用抑制T细胞增殖和效应子细胞因子(其介导T细胞活性和免疫应答,例如IL-2和IFN-γ)的产生。此负调节功能对于阻止T细胞-介导的自身免疫和免疫病理学是重要的。然而,还已表明,PD-1/PD-L1轴在T细胞衰竭中发挥作用,由此负调节功能抑制T细胞对宿主的危害的应答。对T细胞的长期或慢性抗原刺激可诱导负免疫反馈机制,其抑制抗原特异性应答并导致病原体的免疫逃避。T细胞衰竭还可导致抗原-特异性T细胞自身的渐进性物理缺失(progressive physical deletion)。PD-1的T细胞表达在慢性抗原刺激期间被增量调节,并且其与PD-L1的结合导致在CD4+(T辅助细胞)和CD8+(细胞毒性T淋巴细胞或CTL)T细胞两者中效应子功能的阻断,因此暗示在T细胞衰竭的诱导中PD-1/PD-L1相互作用。
最近,已表明一些慢性病毒感染和癌症发展了免疫逃避策略,其通过引起PD-1/PD-L1-介导的T细胞衰竭而特别地利用PD-1/PD-L1轴。多种人肿瘤细胞和肿瘤相关抗原呈递细胞表达高水平的PD-L1,这暗示所述肿瘤诱导T细胞衰竭以逃避抗-肿瘤免疫应答。在慢性HIV感染期间,HIV-特异性CD8+ T细胞在功能上被损害,表现为产生细胞因子和效应子分子的能力降低和增殖能力降低。研究已表明PD-1在HIV感染个体的HIV-特异性CD8+ T细胞上高表达,这表明阻断PD-1/PD-L1通路对于HIV感染和AIDS患者的治疗可具有治疗潜能。综合在一起,阻断PD-1/PD-L1通路的作用剂将为多种癌症、HIV感染和/或与T-细胞衰竭相关的其它疾病和病况提供新的治疗方法。因此,对可阻断或阻止PD-1/PD-L1相互作用的作用剂存在迫切的需要。
发明简述
本发明基于结合PD-L1的单克隆抗体的发现。所述单克隆抗体为全人抗体。所述抗体结合PD-L1。所述抗体在本文中被称为huPD-L1抗体。
PD-L1也被称为程序化细胞死亡1配体1、程序化死亡配体1、PDCD1配体1、PDCD1L1、PDL1、B7同系物1、B7H1、B7-H、CD274和CD274抗原。
本发明提供分离的人源化单克隆抗体,其具有:具有三个CDR(其分别包含氨基酸序列SYGIS (SEQ ID NO:57)、WISAYNGNTNYAQKLED (SEQ ID NO:70)和ALPSGTILVGGWFDP(SEQ ID NO:86))的重链和具有三个CDR(其分别包含氨基酸序列TRSSGNIASNYVQ (SEQ IDNO:101)、EDNQRPS (SEQ ID NO:115)和QSYDSSNLWV (SEQ ID NO:127))的轻链;具有三个CDR(其分别包含氨基酸序列SYALS (SEQ ID NO:58)、AISGGGGSTYYADSVKD (SEQ ID NO:71)和DVFPETFSMNYGMDV (SEQ ID NO:87))的重链和具有三个CDR(其分别包含氨基酸序列QGDSLRSYYAS (SEQ ID NO:102)、GKNNRPS (SEQ ID NO:116)和NSRDSSGNHYV (SEQ ID NO:128))的轻链;具有三个CDR(其分别包含氨基酸序列DYAMH (SEQ ID NO:60)、LISGDGGSTYYADSVKD (SEQ ID NO:73)和VLLPCSSTSCYGSVGAFDI (SEQ ID NO:88))的重链和具有三个CDR(其分别包含氨基酸序列GGSDIGRKSVH (SEQ ID NO:103)、SDRDRPS (SEQ IDNO:117)和QVWDNNSDHYV (SEQ ID NO:129))的轻链;具有三个CDR(其包含氨基酸序列NYDMS(SEQ ID NO:61)、RVNWNGGSTTYADAVKD (SEQ ID NO:74)和EFVGAYDL (SEQ ID NO:89))的重链和具有三个CDR(其分别包含氨基酸序列 TGTSSDVGGYNYVS (SEQ ID NO:104)、DVSNRPS(SEQ ID NO:118)和SSYTSSTLP (SEQ ID NO:130))的轻链;具有三个CDR(其分别包含氨基酸序列GLYIH (SEQ ID NO:62)、WIIPIFGTANYAQKFED (SEQ ID NO:75)和GLRWGIWGWFDP(SEQ ID NO:90))的重链和具有三个CDR(其分别包含氨基酸序列RASQSIGNSLA (SEQ IDNO:105)、GASSRAT (SEQ ID NO:119)和QQHTIPTFS (SEQ ID NO:131))的轻链;具有三个CDR(其分别包含氨基酸序列DNAIS (SEQ ID NO:63)、WIIPIFGKPNYAQKFED (SEQ ID NO:76)和TMVRGFLGVMDV (SEQ ID NO:91))的重链和具有三个CDR(其分别包含氨基酸序列RASQGIGSYLA (SEQ ID NO:106)、AASTLQS (SEQ ID NO:120)和QQLNNYPIT (SEQ ID NO:132))的轻链;具有三个CDR(其分别包含氨基酸序列SYAMS (SEQ ID NO:64)、AISGSGGSTYYADSVKD (SEQ ID NO:77)和DQFVTIFGVPRYGMDV (SEQ ID NO:92))的重链和具有三个CDR(其分别包含氨基酸序列SGDKLGNKYAY (SEQ ID NO:107)、QDIKRPS (SEQ ID NO:121)和QTWDNSVV (SEQ ID NO:133))的轻链;具有三个CDR(其分别包含氨基酸序列SYAIS(SEQ ID NO:57)、WIIPIFGTANYAQKFED (SEQ ID NO:78)和GRQMFGAGIDF (SEQ ID NO:93))的重链和具有三个CDR(其分别包含氨基酸序列TRSSGSIDSNYVQ (SEQ ID NO:108)、EDNQRPS(SEQ ID NO:115)和QSYDSNNRHVI (SEQ ID NO:134))的轻链;具有三个CDR(其分别包含氨基酸序列TYALN (SEQ ID NO:65)、RIVPLIGLVNYAHNFED (SEQ ID NO:79)和EVYGGNSDY (SEQID NO:94))的重链和具有三个CDR(其分别包含氨基酸序列TRSSGNIGTNYVQ (SEQ ID NO:109)、EDYRRPS (SEQ ID NO:122)和QSYHSSGWE (SEQ ID NO:135))的轻链;具有三个CDR(其分别包含氨基酸序列SHGIT (SEQ ID NO:66)、WISAHNGHASNAQKVED (SEQ ID NO:80)和VHAALYYGMDV (SEQ ID NO:95))的重链和具有三个CDR(其分别包含氨基酸序列GGNNIGSKGVH (SEQ ID NO:110)、DDSDRPS (SEQ ID NO:123)和QVWDSSSDHWV (SEQ ID NO:136))的轻链;具有三个CDR(其分别包含氨基酸序列RHGMH (SEQ ID NO:67)、VISHDGSVKYYADSMKD (SEQ ID NO:81)和GLSYQVSGWFDP (SEQ ID NO:96))的重链和具有三个CDR(其分别包含氨基酸序列TRSSGSIASNYVQ (SEQ ID NO:111)、EDNQRPS (SEQ ID NO:115)和QSYDSTTPSV (SEQ ID NO:137))的轻链;具有三个CDR(其分别包含氨基酸序列SYGIS(SEQ ID NO:58)、WTSPHNGLTAFAQILED (SEQ ID NO:82)和VHPVFSYALDV (SEQ ID NO:97))的重链和具有三个CDR(其分别包含氨基酸序列TRSSGSIASNYVQ (SEQ ID NO:112)、EDNQRPS(SEQ ID NO:115)和QSYDGITVI (SEQ ID NO:138))的轻链;具有三个CDR(其分别包含氨基酸序列TYAFS (SEQ ID NO:68)、RIIPILGIANYAQKFED (SEQ ID NO:83)和DGYGSDPVL (SEQID NO:98))的重链和具有三个CDR(其分别包含氨基酸序列TRSSGSIASHYVQ (SEQ ID NO:113)、EDNKRPS (SEQ ID NO:124)和QSYDSSNRWV (SEQ ID NO:139))的轻链;或具有三个CDR(其分别包含氨基酸序列NYGIS (SEQ ID NO:69)、WISAYNGNTNYAQKVED (SEQ ID NO:84)和GDFRKPFDY (SEQ ID NO:99))的重链和具有三个CDR(其分别包含氨基酸序列TLRSGLNVGSYRIY (SEQ ID NO:114)、YKSDSNKQQAS (SEQ ID NO:125)和MIWYSSAVV (SEQ IDNO:140))的轻链;其中所述抗体结合人PD-L1。
在一个方面,抗体为单价的或二价的。在另一方面中,抗体为单链抗体。
本发明提供单链抗体,其包括:含SEQ ID NO: 1的VH核苷酸序列和含SEQ ID NO:3的VL核苷酸序列;含SEQ ID NO: 5的VH核苷酸序列和含SEQ ID NO: 7的VL核苷酸序列;含SEQ ID NO: 9的VH核苷酸序列和含SEQ ID NO: 11的VL核苷酸序列;含SEQ ID NO: 13的VH核苷酸序列和含SEQ ID NO: 15的VL核苷酸序列;含SEQ ID NO: 17的VH核苷酸序列和含SEQID NO: 19的VL核苷酸序列;含SEQ ID NO: 21的VH核苷酸序列和含SEQ ID NO: 23的VL核苷酸序列;含SEQ ID NO: 25的VH核苷酸序列和含SEQ ID NO: 27的VL核苷酸序列;含SEQ IDNO: 29的VH核苷酸序列和含SEQ ID NO: 31的VL核苷酸序列;含SEQ ID NO: 33的VH核苷酸序列和含SEQ ID NO: 35的VL核苷酸序列;含SEQ ID NO: 37的VH核苷酸序列和含SEQ IDNO: 39的VL核苷酸序列;含SEQ ID NO: 41的VH核苷酸序列和含SEQ ID NO: 43的VL核苷酸序列;含SEQ ID NO: 45的VH核苷酸序列和含SEQ ID NO: 47的VL核苷酸序列;含SEQ ID NO:49的VH核苷酸序列和含SEQ ID NO: 51的VL核苷酸序列;或含SEQ ID NO: 53的VH核苷酸序列和含SEQ ID NO: 55的VL核苷酸序列。
在另一个方面中,本发明提供单链抗体,其包括:含SEQ ID NO: 2的VH氨基酸序列和含SEQ ID NO: 4的VL氨基酸序列;含SEQ ID NO: 6的VH氨基酸序列和含SEQ ID NO: 8的VL氨基酸序列;含SEQ ID NO: 10的VH氨基酸序列和含SEQ ID NO: 12的VL氨基酸序列;含SEQ ID NO: 14的VH氨基酸序列和含SEQ ID NO: 16的VL氨基酸序列;含SEQ ID NO: 18的VH氨基酸序列和含SEQ ID NO: 20的VL氨基酸序列;含SEQ ID NO: 22的VH氨基酸序列和含SEQID NO: 24的VL氨基酸序列;含SEQ ID NO: 26的VH氨基酸序列和含SEQ ID NO: 28的VL氨基酸序列;含SEQ ID NO: 30的VH氨基酸序列和含SEQ ID NO: 32的VL氨基酸序列;含SEQ IDNO: 34的VH氨基酸序列和含SEQ ID NO: 36的VL氨基酸序列;含SEQ ID NO: 38的VH氨基酸序列和含SEQ ID NO: 40的VL氨基酸序列;含SEQ ID NO: 42的VH氨基酸序列和含SEQ IDNO: 44的VL氨基酸序列;含SEQ ID NO: 46的VH氨基酸序列和含SEQ ID NO: 48的VL氨基酸序列;含SEQ ID NO: 50的VH氨基酸序列和含SEQ ID NO: 52的VL氨基酸序列;或含SEQ IDNO: 54的VH氨基酸序列和含SEQ ID NO: 56的VL氨基酸序列。
在一些方面中,抗体具有在10-5 M-10-12 M的范围内的结合亲和力。
在另一方面中,抗体是双特异性抗体,其还结合至肿瘤-相关抗原、细胞因子或细胞表面受体。例如,所述肿瘤-相关抗原是CAIX。例如,所述细胞因子是IL-10。例如,所述细胞表面受体是CCR4、IL21R、BTLA、HVEM或TIM3。
本发明提供连接至治疗剂的抗体。例如,所述治疗剂是毒素、放射性标记、siRNA、小分子或细胞因子。
本发明提供产生任何上述抗体的细胞。
本发明还提供选择性杀伤肿瘤细胞的方法,其包括将所述细胞与任何上述抗体接触。在一方面中,通过抗体-依赖性细胞毒性(ADCC)、补体依赖性细胞毒性(CDC)、抗体依赖性细胞吞噬(ADCP)产生选择性杀伤。在另一方面中,所述肿瘤细胞表达PD-L1。
本发明还提供阻止或逆转T细胞衰竭的方法,其包括向有需要的受试者给予含任何上述抗体的组合物。
本发明还提供提高对抗原的免疫应答的方法,其包括向有需要的受试者给予含任何上述抗体的组合物。在一方面中,抗原是病毒抗原、细菌抗原或肿瘤相关抗原。在另一方面中,所述病毒抗原是HIV。在另外的方面中,所述肿瘤相关抗原是CAIX。在另一方面中,抗体在暴露于抗原之前或之后被给予。在另一方面中,所述抗体的给予引起抗原特异性T细胞活性增加。在另一方面中,T-细胞是效应子T细胞。
本发明还提供治疗或缓解癌症的症状的方法,其包括向有需要的受试者给予含任何上述抗体的组合物。例如,所述癌症是肾细胞癌或乳腺癌。例如,所述癌症是其中过量表达PD-L1的癌症。在另一实例中,所述癌症是诱导T细胞衰竭的癌症。
本发明还提供治疗或缓解慢性病毒感染的症状的方法,其包括向有需要的受试者给予含任何上述抗体的组合物。例如,所述慢性病毒感染是HIV感染。例如,所述慢性病毒感染是诱导T细胞衰竭的病毒感染。
本发明提供核酸序列,其包括SEQ ID NO: 1、3、5、7、9、11、13、15、17、19、21、23、25、27、29、31、33、35、37、39、41、43、45、47、49、51、53或55的核酸序列。
在另一方面中,本发明提供核酸序列,其编码SEQ ID NO: 2、4、6、8、10、12、14、16、18、20、22、24、26、28、30、32、34、36、38、40、42、44、46、48、50、52、54或56的多肽。
在另一方面中,本发明提供多肽,其包含SEQ ID NO: 2、4、6、8、10、12、14、16、18、20、22、24、26、28、30、32、34、36、38、40、42、44、46、48、50、52、54或56的氨基酸序列。
在另一方面中,本发明提供载体,其包含SEQ ID NO: 1、3、5、7、9、11、13、15、17、19、21、23、25、27、29、31、33、35、37、39、41、43、45、47、49、51、53或55的核酸序列。本发明提供载体,其包含SEQ ID NO: 2、4、6、8、10、12、14、16、18、20、22、24、26、28、30、32、34、36、38、40、42、44、46、48、50、52、54或56的核酸序列。本发明另外提供细胞,其包含上述载体的任一种。
本公开的任何方法中的给予途径包括但不限于肠胃外(例如,静脉内)、皮内、皮下、口服(例如,吸入)、经皮(即,局部)、经粘膜和直肠给予。
本公开的任何方法中的受试者是,例如,哺乳动物。所述哺乳动物是,例如,人。
本发明的其它特征和优势依据以下详述的说明书和权利要求将显而易见,并且包含在其中。
附图简述
图1. 抗-PD-L1 scFv-噬菌体克隆(14个克隆)的氨基酸序列。展示了对于IGHV和IGLV/IGKV两者的构架区1-4 (FW1-4)、互补决定区 1-3 (CDR1-3)和家族命名。使用Kabat编号。检索表:“.”与共有区匹配的AA、“X”非共有区AA和“-”为空白(即没有AA)。
图2. 通过FACS进行的huPD-L1抗体与人PD-L1 (hPD-L1)表达细胞的结合分析。测试四种类型的细胞,其包括亲本细胞系300.9和hPD-L1、hPD-L2或人C型凝集素结构域家族2成员(hCLEC2D)转染的300.9细胞。GF1538是抗hPD-L1的人源化抗体。GF1757是抗hPD-L2的人源化抗体。第二抗体是PE-山羊抗-人IgG。
图3. 在竞争性FACS分析中通过抗-PD-L1噬菌体-抗体对hPD-1结合至hPD-L1的抑制。测试呈噬菌体-scFv形式的所有抗-hPD-L1抗体对hPD1-hFc融合蛋白与hPD-L1表达293T细胞的结合的抑制。将1012 pfu的噬菌体-scFv与约0.25 μg/mL的可溶性hPD1-hFc混合并加入至hPD-L1表达质粒转染的293T细胞。在洗涤之后,将细胞与FITC-抗-人IgG抗体一起孵育以测量hPD1-hFc与细胞表面上的hPD-L1的结合。
图4. 在竞争性FACS分析中通过抗-PD-L1可溶性抗体对hPD-1结合至hPD-L1的抑制。将所有抗-hPD-L1抗体以所示浓度与hPD-L1表达质粒转染的300.9细胞预孵育30分钟,随后将0.125 μg的hPD-1-小鼠IgG2a加入各反应物中并孵育另外30分钟。在洗涤之后,将PE-山羊-抗-小鼠IgG2a Ab加入并接着洗涤和FACS分析。GF1538是抗hPD-L1的人源化Ab。GF1757为抗hPD-L2的人源化Ab。
图5. 双特异性抗体的设计和形成。
图6. 双特异性抗体(bsAb)构建体的确定。A)识别CAIX和PD-L1的双特异性抗体的图示和连接CH3结构域的“结进孔(knob into hole)”方法。B)三种类型的bsAb构建体的图示,其在CH2结构域中具有不同的突变以改变ADCC活性。
图7. 双特异性抗体的生成及其功能。A)展示与缀合的(非还原)对照IgG、亲本G37(WT)和双特异性(G37 KIHA + PD-L1 KIHB)抗体比较,在还原条件下工程改造的(G37KIHA)抗体的解离的蛋白凝胶。B)展示与对照IgG、亲本PDL-1 (WT)和双特异性(G37 KIHA +PD-L1 KIHB)抗体比较,在还原条件下工程改造的(PD-L1 KIHB)抗体的解离的蛋白凝胶。C)通过流式细胞术进行的双特异性抗体与CAIX+PDL-1- SKRC-52细胞的结合的分析。
图8. PD-L1特异性mAb42的功能表征。将来自四个健康供体(D1-D4)的PBMC在αPDL1 (mAb42)或对照同种型抗体的存在下培养,用0.1 μg/ml SEB刺激48小时,并通过MSD装置测量TNFα的生成。数据以一式三份的方式呈现*,p<0.0005。
详述
本发明提供特异性抗PD-L1的人源化单克隆抗体,也称为B7H1。所述抗体通过噬菌体展示抗体文库选择的方法通过使用脂蛋白体偶联的-PD-L1作为文库选择靶而鉴定。这些抗体代表新一类的抗PD-L1的人单克隆抗体。
这些抗-PD-L1人单克隆抗体在本文中被称为“huPD-L1抗体”。
PD-L1与PD-1的结合负调节T细胞抗原-特异性应答,这对自身免疫和免疫病理学的耐受和预防是极重要的。然而,过度的PD-L1/PD-1相互作用(其可由慢性抗原刺激引起)可导致T细胞抗原-特异性应答的抑制和T细胞的缺失(其为T细胞衰竭的特征)。T细胞衰竭是T细胞功能异常的状态,其可在慢性感染和癌症中产生。它定义为:弱效应子功能、抑制性受体的持续表达和不同于功能性效应子或记忆T细胞的转录状态的转录状态。衰竭阻止感染和肿瘤进展的管理。
已经在不同的癌症中检测到PD-L1过量表达。例如,在乳腺癌中,PD-L1被过量表达并与高风险预后因子相关。在肾细胞癌中,PD-L1被增量调节并且在肿瘤浸润的白细胞中也已发现PD-1表达增加。抗-PD-L1和抗-PD-1抗体在I期临床试验中对肾细胞癌已经表现出一些临床功效。可结合至PD-1或PD-L1的治疗剂可用于特异性靶向肿瘤细胞。能够阻断PD-1/PD-L1相互作用的作用剂在治疗已经诱导T细胞衰竭以逃避抗-肿瘤T细胞活性的癌症中可能甚至更有用。这类作用剂的使用(单独使用或与其它抗-癌症疗法组合使用)可有效靶向过量表达PD-L1的肿瘤细胞并增加抗-肿瘤T细胞活性,由此提高对靶肿瘤细胞的免疫应答。
在慢性抗原刺激(例如,通过慢性感染)后,PD-1和PD-L1还可被T细胞增量调节。在慢性HIV感染期间,HIV-特异性CD8+ T细胞功能上被损害,表现出降低的产生细胞因子和效应子分子的能力和减弱的增殖能力。PD-1在HIV感染个体的HIV-特异性CD8+ T细胞上高表达。因此,阻断此通路可增强HIV-特异性T细胞在响应用HIV肽刺激时增殖和产生细胞因子的能力,由此提高针对HIV的免疫应答。其它慢性感染也可从PD-1/PD-L1阻断剂的使用中受益,例如慢性病毒感染、细菌感染或寄生虫感染。
本发明提供特异性结合PD-L1蛋白的人单克隆抗体。本发明的抗体与PD-L1的结合干扰配体结合至它的受体PD1的能力。通过多种机制,huPD-L1抗体阻止抑制T细胞应答的负反馈机制。在一些情况下,huPD-L1抗体阻止、抑制或逆转T细胞衰竭。huPD-L1抗体的给予可导致T细胞增殖增加,抗原-特异性T细胞活性增加和效应子细胞因子的产生增加。在一些实例中,huPD-L1抗体促进或提高抗原-特异性免疫应答。此免疫应答可通过效应子T细胞介导。
huPD-L1抗体是单价的或二价的并包括单链或双链。功能上,huPD-L1抗体的结合亲和力在10-5 M-10-12 M的范围内。例如,huPD-L1抗体的结合亲和力为10-6 M-10-12 M、10-7M-10-12 M、10-8 M-10-12 M、10-9 M-10-12 M、10-5 M-10-11 M、10-6 M-10-11 M、10-7 M-10-11 M、10-8 M-10-11 M、10-9 M-10-11 M、10-10 M-10-11 M、10-5 M-10-10 M、10-6 M-10-10 M、10-7 M-10-10M、10-8 M-10-10 M、10-9 M-10-10 M、10-5 M-10-9 M、10-6 M-10-9 M、10-7 M-10-9 M、10-8 M-10-9M、10-5 M-10-8 M、10-6 M-10-8 M、10-7 M-10-8 M、10-5 M-10-7 M、10-6 M-10-7 M或10-5 M-10-6M。
此外,本发明的抗体包含治疗剂,其包括但不限于毒素、放射性标记、siRNA或细胞因子。
huPD-L1抗体能够诱导细胞死亡。细胞死亡通过直接或间接的机制诱导。例如,PD-L1通过huPD-L1抗体的结合可导致补体依赖性细胞毒性(CDC)。备选地,huPD-L1抗体结合PD-L1,并导致第二细胞类型的募集,其会杀伤PD-L14-表达的靶细胞。范例性机制(通过该机制huPD-L1抗体通过募集第二细胞类型介导细胞死亡)包括但不限于:抗体-依赖性细胞毒性(ADCC)和抗体依赖性细胞吞噬(ADCP)。靶PD-L1-表达细胞类型包括肿瘤细胞和T细胞(例如活化的T细胞)。
十四种独特的单克隆huPD-L1抗体被鉴定出。这些包括Ab-14、Ab-16、Ab-22、Ab-30、Ab-31、Ab-32、Ab-38、Ab-42、Ab-46、Ab-50、Ab-52、Ab-55、Ab-56和Ab-65。
单克隆huPD-L1抗体的核酸和氨基酸序列提供如下:
huPD-L1抗体的重链和轻链互补决定区的氨基酸序列在下表15A和15B中显示。
表15A.重链互补决定区的氨基酸序列。
抗体 | CDR1 | SEQ ID NO: | CDR2 | SEQ ID NO: | CDR3 | SEQ ID NO: |
共有区 | SYAIS | 57 | WISPIGGSTNYAQKVQG | 70 | GLXXXXXXXXXXXXXXXDV | 85 |
Ab-14 | SYGIS | 58 | WISAYNGNTNYAQKLED | 71 | ALPSGTILVGGWFDP | 86 |
Ab-16 | SYALS | 59 | AISGGGGSTYYADSVKD | 72 | DVFPETFSMNYGMDV | 87 |
Ab-22 | DYAMH | 60 | LISGDGGSTYYADSVKD | 73 | VLLPCSSTSCYGSVGAFDI | 88 |
Ab-30 | NYDMS | 61 | RVNWNGGSTTYADAVKD | 74 | EFVGAYDL | 89 |
Ab-31 | GLYIH | 62 | WIIPIFGTANYAQKFED | 75 | GLRWGIWGWFDP | 90 |
Ab-32 | DNAIS | 63 | WIIPIFGKPNYAQKFED | 76 | TMVRGFLGVMDV | 91 |
Ab-38 | SYAMS | 64 | AISGSGGSTYYADSVKD | 77 | DQFVTIFGVPRYGMDV | 92 |
Ab-42 | SYAIS | 57 | WIIPIFGTANYAQKFED | 78 | GRQMFGAGIDF | 93 |
Ab-46 | TYALN | 65 | RIVPLIGLVNYAHNFED | 79 | EVYGGNSDY | 94 |
Ab-50 | SHGIT | 66 | WISAHNGHASNAQKVED | 80 | VHAALYYGMDV | 95 |
Ab-52 | RHGMH | 67 | VISHDGSVKYYADSMKD | 81 | GLSYQVSGWFDP | 96 |
Ab-55 | SYGIS | 58 | WTSPHNGLTAFAQILED | 82 | VHPVFSYALDV | 97 |
Ab-56 | TYAFS | 68 | RIIPILGIANYAQKFED | 83 | DGYGSDPVL | 98 |
Ab-65 | NYGIS | 69 | WISAYNGNTNYAQKVED | 84 | GDFRKPFDY | 99 |
表15B.轻链互补决定区的氨基酸序列。
抗体 | CDR1 | SEQ ID NO: | CDR2 | SEQ ID NO: | CDR3 | SEQ ID NO: |
共有区 | TRSSGSIGSNYVQ | 100 | EDNQRPS | 115 | QSYDSSTWV | 126 |
Ab-14 | TRSSGNIASNYVQ | 101 | EDNQRPS | 115 | QSYDSSNLWV | 127 |
Ab-16 | QGDSLRSYYAS | 102 | GKNNRPS | 116 | NSRDSSGNHYV | 128 |
Ab-22 | GGSDIGRKSVH | 103 | SDRDRPS | 117 | QVWDNNSDHYV | 129 |
Ab-30 | TGTSSDVGGYNYVS | 104 | DVSNRPS | 118 | SSYTSSTLP | 130 |
Ab-31 | RASQSIGNSLA | 105 | GASSRAT | 119 | QQHTIPTFS | 131 |
Ab-32 | RASQGIGSYLA | 106 | AASTLQS | 120 | QQLNNYPIT | 132 |
Ab-38 | SGDKLGNKYAY | 107 | QDIKRPS | 121 | QTWDNSVV | 133 |
Ab-42 | TRSSGSIDSNYVQ | 108 | EDNQRPS | 115 | QSYDSNNRHVI | 134 |
Ab-46 | TRSSGNIGTNYVQ | 109 | EDYRRPS | 122 | QSYHSSGWE | 135 |
Ab-50 | GGNNIGSKGVH | 110 | DDSDRPS | 123 | QVWDSSSDHWV | 136 |
Ab-52 | TRSSGSIASNYVQ | 111 | EDNQRPS | 115 | QSYDSTTPSV | 137 |
Ab-55 | TRSSGSIASNYVQ | 112 | EDNQRPS | 115 | QSYDGITVI | 138 |
Ab-56 | TRSSGSIASHYVQ | 113 | EDNKRPS | 124 | QSYDSSNRWV | 139 |
Ab-65 | TLRSGLNVGSYRIY | 114 | YKSDSNKQQAS | 125 | MIWYSSAVV | 140 |
本文描述的huPD-L1抗体与PD-L1结合。在一方面中,huPD-L1抗体对PD-L1具有高亲和力和高特异性。在另一方面中,huPD-L1抗体可结合PD-1受体并阻止、抑制或阻断配体PD-L1结合其受体PD-1。在一些实例中,huPD-L1抗体可具有一些与PD-L2的交叉反应性。在一些实例中,huPD-L1抗体不显示任何与PD-L2的交叉反应性。在一些实例中,huPD-L1抗体以与结合至PD-L2相比更高的亲和力和/或更高的特异性结合至PD-L1。
本发明还描述以下抗体的特征,其与本文描述的huPD-L1抗体的氨基酸或核苷酸序列具有特定百分比的同一性或相似性。例如,当与本文描述的huPD-L1抗体的任一种的特定区域或全长作比较时,所述抗体可具有60%、70%、75%、80%、85%、90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或更高同一性。与本发明的核酸和蛋白的序列同一性或相似性可通过本领域已知的方法进行的序列比较和/或比对而确定。例如,可利用序列比较算法(即BLAST或BLAST 2.0)、手动比对或目测确定对本发明的核酸和蛋白的百分比序列同一性或相似性。
对于氨基酸序列,本领域技术人员将容易地认识到,对核酸、肽、多肽或蛋白序列的单个替代、缺失或添加(其在编码序列中变更、添加、缺失或替代单个氨基酸或小百分比的氨基酸)在本文中被统称为“保守性修饰变体”。在一些实施方案中,所述变更导致将氨基酸用化学上类似的氨基酸替代。提供功能上类似的氨基酸的保守性替代表在本领域为周知的。与未修饰的huPD-L1抗体相比,本文公开的huPD-L1抗体的这类保守性修饰变体可展示出增强的对PD-L2的交叉反应性。
抗体
本文使用的术语"抗体"是指免疫球蛋白分子和免疫球蛋白(Ig)分子的免疫活性部分,即,含特异性结合抗原(与抗原免疫反应)的抗原结合位点的分子。“特异性结合”或“与……免疫反应”意指抗体与所需抗原的一个或多个抗原决定簇反应和不与其它多肽反应。抗体包括但不限于多克隆抗体、单克隆抗体、嵌合抗体、dAb (结构域抗体)、单链抗体、Fab、Fab’和F(ab')2片段、scFv和Fab表达文库。
单链Fv ("scFv")多肽分子是共价连接的VH:VL杂二聚体,其可自包含通过肽编码的接头连接的VH-和VL-编码基因的基因融合物表达(参见Huston等人(1988) Proc NatAcad Sci USA 85(16):5879-5883)。许多方法已被描述以分辨化学结构,用于将天然聚集的、但化学上分隔开的来自抗体V区的轻多肽链和重多肽链转变成scFv分子(其可折叠成与抗原-结合位点的结构大体上类似的三维结构)。参见,例如,美国专利号5,091,513、5,132,405和4,946,778。
已经并且可以创建非常大的天然人scFv文库以提供抗大量靶分子的重排抗体基因的大来源。可从患有传染性疾病的个体中构建较小的文库以便分离疾病-特异性抗体。(参见Barbas等人, Proc. Natl. Acad. Sci. USA 89:9339-43 (1992); Zebedee等人,Proc. Natl. Acad. Sci. USA 89:3175-79 (1992))。
通常,从人获得的抗体分子涉及种类IgG、IgM、IgA、IgE和IgD的任一种,它们在分子中存在的重链的性质上彼此不同。某些种类还具有亚类,例如IgG1、IgG2以及其它。此外,在人中,轻链可为κ链或λ链。术语"抗原-结合位点"或"结合部分"是指免疫球蛋白分子的一部分,该部分参与抗原结合。抗原结合位点由重("H")链和轻("L")链的N-末端可变("V")区的氨基酸残基形成。在重链和轻链的V区内被称为"高变区"的三个高度差异的伸展区(stretch)被插入在被称为"构架区"或"FR"的更保守的侧翼伸展区之间。因此,术语"FR"是指天然存在于免疫球蛋白中的高变区之间并邻接于免疫球蛋白中的高变区的氨基酸序列。在抗体分子中,轻链的三个高变区和重链的三个高变区在三维空间中相对于彼此排列以形成抗原-结合表面。抗原-结合表面与结合的抗原的三维表面互补,并且重链和轻链的每一个的三个高变区被称为"互补决定区"或"CDR"。在图2中显示了scFv抗体的VH和VL区的CDR。
本文使用的术语“表位”包括能够特异性结合至免疫球蛋白、scFv或T-细胞受体的任何蛋白决定簇。表位决定簇通常由分子(例如氨基酸或糖侧链)的化学上有活性的表面集簇组成,且通常具有特定的三维结构特征,和特定的电荷特征。例如,抗体可针对多肽的N-末端或C-末端肽而产生。
本文使用的术语"免疫结合"和"免疫结合性质"是指这样类型的非共价相互作用,其发生在免疫球蛋白分子和抗原(对于该抗原而言免疫球蛋白为特异性的)之间。免疫结合相互作用的强度或亲和力可以相互作用的解离常数(Kd)表示,其中较小的Kd表示较大的亲和力。所选多肽的免疫结合性质可使用本领域中周知的方法定量。一种这类方法牵涉测量抗原-结合位点/抗原复合物形成和解离的速度,其中那些速度取决于复合物配偶体的浓度、相互作用的亲和力和几何参数,所述参数同等地在两个方向上影响速度。因此,"结合速率常数"(Kon)和"解离速率常数"(Koff)两者都可通过浓度与缔合和解离的实际速度的计算而确定。(参见Nature 361:186-87 (1993))。Koff /Kon的比率使得与亲和力不相关的所有参数的删除成为可能,并且等于解离常数Kd (通常参见Davies等人(1990) Annual RevBiochem 59:439-473)。当平衡结合常数(Kd)为≤10 μM,优选为≤ 10 nM,更优选为≤ 10nM,和最优选为≤ 100 pM - 约1 pM时(如通过测定例如放射配体结合测定或本领域技术人员已知的类似测定所测量),本发明的抗体被认为特异性地结合至PD-L1表位。
可将本发明的PD-L1蛋白或其衍生物、片段、类似物、同系物或直系同源物用作抗体(其免疫上特异性结合这些蛋白组分)的产生中的免疫源。可将与脂蛋白体偶联的PD-L1蛋白或其衍生物、片段、类似物、同系物或直系同源物用作抗体(其免疫上特异性结合这些蛋白组分)的产生中的免疫源。
本领域技术人员将认识到,通过弄清是否一种人单克隆抗体阻止本发明的人单克隆抗体结合至PD-L1,有可能确定(不需要过度的实验)是否前者具有与后者一样的特异性。如果所述受测试的人单克隆抗体与本发明的人单克隆抗体竞争(如通过由本发明的人单克隆抗体产生的结合中的减少所示),那么有可能两种单克隆抗体结合至相同的或密切相关的表位。
确定是否一种人单克隆抗体具有本发明的人单克隆抗体的特异性的另一方法是将本发明的人单克隆抗体与PD-L1蛋白(它通常是与PD-L1蛋白有反应的)预孵育,并随后加入受测试的人单克隆抗体以确定是否受测试的人单克隆抗体在其结合PD-L1的能力上被抑制。如果所述受测试的人单克隆抗体被抑制,那么很有可能,它具有与本发明的单克隆抗体相同或功能上同等的表位特异性。本发明的人单克隆抗体的筛选还可通过使用PD-L1并确定是否该测试单克隆抗体能够中和PD-L1而实施。
本领域内已知的多种方法可用于制备定向抗本发明的蛋白或抗其衍生物、片段、类似物、同系物或直系同源物的多克隆或单克隆抗体。(参见,例如,Antibody:ALaboratory Manual(抗体:实验室手册), Harlow E, and Lane D, 1988, Cold SpringHarbor Laboratory Press, Cold Spring Harbor, NY, 通过引用并入本文)。
抗体可通过周知的技术,例如使用蛋白A或蛋白G的亲和层析(其主要提供免疫血清的IgG流分)纯化。随后或备选地,可将特异性抗原(其为寻求的免疫球蛋白的靶)或其表位固定在柱上以通过免疫亲和层析而纯化免疫特异性抗体。免疫球蛋白的纯化例如由D.Wilkinson论述(The Scientist, 由The Scientist, Inc., Philadelphia PA, Vol. 14,No. 8 (2000年4月17日), 25-28页公布)。
本文使用的术语"单克隆抗体"或“MAb”或"单克隆抗体组合物"是指含有仅一种分子种类的抗体分子的抗体分子群体,所述抗体分子由独特的轻链基因产物和独特的重链基因产物组成。尤其地,单克隆抗体的互补决定区(CDR)在该群体的所有分子中为一致的。MAb含有能够与特定抗原表位免疫反应的抗原结合位点(其表征为对抗原表位独特的结合亲和性)。
单克隆抗体可使用杂交瘤法,例如由Kohler和Milstein, Nature, 256:495(1975)描述的那些杂交瘤法而制备。在杂交瘤法中,通常将小鼠、仓鼠或其它合适的宿主动物用免疫剂免疫以引出产生或能够产生抗体的淋巴细胞,所述抗体与免疫剂特异性结合。备选地,淋巴细胞可在体外被免疫。
免疫剂通常包括蛋白抗原、其片段或其融合蛋白。通常,如果需要人源细胞则使用外周血淋巴细胞,或如果需要非人哺乳动物源则使用脾细胞或淋巴结细胞。随后使用合适的融合剂,例如聚乙二醇将淋巴细胞与永生化的细胞系融合以形成杂交瘤细胞(Goding,Monoclonal Antibodies:principles and Practice(单克隆抗体:原理和实施),Academic Press, (1986年) 59-103页)。永生化的细胞系通常为转化的哺乳动物细胞,特别是啮齿动物、牛和人源的骨髓瘤细胞。通常,使用大鼠或小鼠骨髓瘤细胞系。可将杂交瘤细胞在合适的培养基中培养,所述培养基优选含有一种或多种抑制未融合的永生化细胞的生长或存活的物质。例如,如果亲本细胞缺乏酶——次黄嘌呤鸟嘌呤磷酸核糖基转移酶(HGPRT或HPRT),则杂交瘤的培养基通常包含次黄嘌呤、氨基蝶呤和胸苷("HAT培养基"),所述物质防止HGPRT-缺陷型细胞的生长。
优选的永生化的细胞系是有效地融合、支持由选定的抗体产生细胞产生的抗体的稳定高水平表达和对诸如HAT培养基等培养基敏感的那些细胞系。更优选的永生化的细胞系为鼠骨髓瘤系,其可例如从Salk Institute cell Distribution Center,圣地亚哥,加利福利亚和American Type Culture Collection,马纳萨斯,维吉尼亚获得。人骨髓瘤和小鼠-人杂骨髓瘤细胞系也已被描述用于人单克隆抗体的产生。(参见Kozbor, J. Immunol.,133:3001 (1984); Brodeur等人, Monoclonal Antibody Production Techniques andApplications(单克隆抗体的产生技术和应用), Marcel Dekker, Inc., New York,(1987) 51-63页))。
杂交瘤细胞在其中培养的培养基可随后针对定向抗抗原的单克隆抗体的存在而测定。优选地,由杂交瘤细胞产生的单克隆抗体的结合特异性通过免疫沉淀或通过体外结合测定,例如放射免疫测定(RIA)或酶联免疫吸附测定(ELISA)而确定。这类技术和测定在本领域中是已知的。单克隆抗体的结合亲和力可例如通过Munson和Pollard, Anal.Biochem., 107:220 (1980)的Scatchard分析而确定。此外,在单克隆抗体的治疗应用中,重要的是鉴定出对靶抗原具有高度特异性和高结合亲和力的抗体。
在所需杂交瘤细胞被鉴定出之后,可通过有限稀释步骤将克隆亚克隆并通过标准方法让其生长。(参见Goding, 单克隆抗体:原理和实施(Monoclonal Antibodies: principles and Practice), Academic Press, (1986) 59-103页)。为此目的的合适的培养基包括,例如,Dulbecco's Modified Eagle's Medium和RPMI-1640培养基。备选地,可让杂交瘤细胞作为哺乳动物的腹水在体内生长。
由亚克隆分泌的单克隆抗体可通过常规免疫球蛋白纯化方法例如,A蛋白琼脂糖、羟基磷灰石层析、凝胶电泳、透析或亲和层析从培养基或腹水流体中分离或纯化。
单克隆抗体也可通过重组DNA法(例如在美国专利号4,816,567中描述的那些)而进行。编码本发明的单克隆抗体的DNA可容易地使用常规方法(例如,通过使用能够特异性地结合至编码鼠抗体的重链和轻链的基因的寡聚核苷酸探针)分离并测序。本发明的杂交瘤细胞作为这类DNA的优选来源。一旦被分离出来,该DNA就可被放入表达载体,其随后被转染入宿主细胞例如猿猴COS细胞、中国仓鼠卵巢(CHO)细胞或骨髓瘤细胞(其不另外产生免疫球蛋白),以获得在重组宿主细胞中的单克隆抗体的合成。DNA也可例如,通过用人重链和轻链恒定结构域的编码序列代替同源鼠序列(参见美国专利号4,816,567; Morrison,Nature 368, 812-13(1994))或通过将非免疫球蛋白多肽的编码序列的全部或一部分共价连接至免疫球蛋白编码序列而修饰。这类非免疫球蛋白多肽可取代本发明的抗体的恒定结构域,或可取代本发明的抗体的抗原-结合位点的可变结构域,以产生嵌合二价抗体。
全人抗体是抗体分子,其中轻链和重链二者的整个序列(包含CDR)由人基因产生。本文中这类抗体被称为“人源化抗体”、“人抗体”或“全人抗体”。人单克隆抗体可通过使用三源杂交瘤技术、人B细胞杂交瘤技术(参见Kozbor等人, 1983 Immunol Today 4: 72)和用以制备人单克隆抗体的EBV杂交瘤技术(参见Cole等人, 1985 In: 单克隆抗体和癌治疗(Monoclonal Antibodies and Cancer Therapy), Alan R. Liss, Inc.,77-96页)而制备。人单克隆抗体通过使用人杂交瘤(参见Cote等人, 1983. Proc Natl Acad Sci USA80: 2026-2030)或通过在体外用Epstein Barr病毒转化人B细胞(参见Cole等人, 1985In: 单克隆抗体和癌治疗(Monoclonal Antibodies and Cancer Therapy), Alan R.Liss, Inc.,77-96页)可被利用和可被制备。
此外,人抗体也可使用另外的技术(其包括噬菌体展示文库)而制备。(参见Hoogenboom和Winter, J. Mol. Biol., 227:381 (1991);Marks等人, J. Mol. Biol.,222:581 (1991))。类似地,人抗体可通过将人免疫球蛋白基因座引入转基因动物(例如,其中内源免疫球蛋白基因被部分地或完全地失活的小鼠)制得。在激发时,观察到人抗体产生,其与在人中包括基因重排、装配和抗体库(antibody repertoire)的所有方面中观察到的密切相似。此方法在例如,美国专利号5,545,807、5,545,806、5,569,825、5,625,126、5,633,425、5,661,016和Marks等人,Bio/Technology 10, 779-783 (1992);Lonberg等人,Nature 368 856-859(1994);Morrison, Nature 368, 812-13(1994);Fishwild等人,Nature Biotechnology 14, 845-51(1996);Neuberger, Nature Biotechnology 14, 826(1996);以及Lonberg和Huszar, Intern. Rev. Immunol. 13 65-93(1995)中描述。
人抗体可另外使用转基因非人动物而制备,所述动物被修饰以便在响应抗原的激发时产生全人抗体而非该动物的内源抗体。(参见PCT公开WO94/02602)。在非人宿主中编码重和轻免疫球蛋白链的内源基因已经被失能,并且编码人重链和轻链免疫球蛋白的活性的基因座被插入宿主的基因组。人基因例如使用含所需人DNA片段的酵母人工染色体而被掺入。随后通过将中间转基因动物(其含有少于全部修饰补充)杂交作为子代获得提供全部所需修饰的动物。这类非人动物的优选实施方案是小鼠,并被称为XenomouseTM (如在PCT公布WO 96/33735和WO 96/34096中公开)。此动物产生分泌全人免疫球蛋白的B细胞。抗体可在用目的免疫源免疫之后直接从动物(例如,作为多克隆抗体的制备)或备选地从来源于该动物的永生化的B细胞(例如产生单克隆抗体的杂交瘤)获得。另外,编码具有人可变区的免疫球蛋白的基因可被回收并表达以直接获得抗体,或可被进一步修饰以获得抗体的类似物,例如,单链Fv (scFv)分子。
产生缺乏内源免疫球蛋白重链的表达的非人宿主(例如小鼠)的方法的实例在美国专利号5,939,598中公开。它可以通过以下方法获得,所述方法包括:从胚胎干细胞中的至少一个内源重链基因座中删除J片段基因以阻止基因座的重排和阻止重排的免疫球蛋白重链基因座的转录物的形成,所述删除通过含编码可选择标志物的基因的靶向载体而实现;和从胚胎干细胞产生转基因小鼠,其体细胞和生殖细胞含有编码可选择标志物的基因。
用于制备目的抗体(例如人抗体)的一种方法在美国专利号5,916,771中公开。此方法包括将含有编码重链的核苷酸序列的表达载体引入培养中的一种哺乳动物宿主细胞中,将含编码轻链的核苷酸序列的表达载体引入另一哺乳动物宿主细胞,并将两种细胞融合以形成杂交细胞。该杂交细胞表达含重链和轻链的抗体。
在对此方法的进一步改进中,用于鉴定免疫源上的临床相关表位的方法和用于选择以高亲和力免疫特异性地结合至相关表位的抗体的相关方法在PCT公布WO 99/53049中公开。
抗体可通过含编码上面描述的单链抗体的DNA片段的载体表达。
这些可包括载体、脂质体、裸DNA、佐剂-辅助的DNA、基因枪、导管等。载体包括例如在WO 93/64701中描述的化学缀合物(其具有靶向部分(例如,细胞表面受体的配体)和核酸结合部分(例如,多聚赖氨酸))、病毒载体(例如DNA或RNA病毒载体)、在例如PCT/US 95/02140 (WO 95/22618)中描述的融合蛋白(其为含靶向部分(例如对靶细胞特异的抗体)和核酸结合部分(例如鱼精蛋白))、质粒、噬菌体等。所述载体可为染色体的、非染色体的或人造的。
优选的载体包括病毒载体、融合蛋白和化学缀合物。逆转录病毒载体包括莫洛尼氏鼠白血病病毒。DNA病毒载体是优选的。这些载体包括痘载体例如正痘或禽痘载体、疱疹病毒载体例如单纯疱疹病毒I (HSV)载体(参见Geller, A. I. 等人, J. Neurochem, 64:487 (1995);Lim, F. 等人, in DNA Cloning: Mammalian Systems(在DNA克隆中:哺乳动物系统), D. Glover编辑(Oxford Univ. Press, Oxford England) (1995); Geller, A.I. 等人, Proc Natl. Acad. Sci.: U.S.A. 90:7603 (1993); Geller, A. I.等人,Proc Natl. Acad. Sci USA 87:1149 (1990))、腺病毒载体(参见LeGal LaSalle等人,Science, 259:988 (1993); Davidson等人, Nat. Genet 3:219 (1993); Yang等人, J.Virol. 69:2004 (1995))和腺相关病毒载体(参见Kaplitt, M. G. 等人, Nat. Genet.8:148 (1994))。
痘病毒载体将基因引入细胞胞质。禽痘病毒载体仅导致核酸的短期表达。腺病毒载体、腺相关病毒载体和单纯疱疹病毒(HSV)载体对于将核酸引入神经细胞是优选的。腺病毒载体(约2个月)导致与腺相关病毒(约4个月)相比更短期限的表达,所述腺相关病毒又比HSV载体的表达期限更短。选择的具体载体将取决于靶细胞和被处理的条件。所述引入可通过标准技术,例如感染、转染、转导或转化进行。基因转移的模式的实例包括例如,裸DNA、CaPO4沉淀、DEAE葡聚糖、电穿孔、原生质体融合、脂质转染法、细胞显微注射和病毒载体。
可使用载体以靶向基本上任何所需的靶细胞。例如,立体定位注射可用于将载体(例如腺病毒,HSV)指引至所需位置。另外,颗粒可通过脑室内(icv)灌注使用微泵灌注系统(例如SynchroMed灌注系统)递送。基于总体流动(bulk flow)的方法(被称为对流(convection))也被证明在递送大分子至脑的扩展区域的情况下是有效的,并可在递送载体至靶细胞中是有用的。(参见Bobo等人, Proc. Natl. Acad. Sci. USA 91:2076-2080(1994); Morrison等人, Am. J. Physiol. 266:292-305 (1994))。可使用的其它方法包括导管、静脉内、肠胃外、腹膜内和皮下注射,以及口服或其它已知的给予途径。
这些载体可用于表达大量的抗体,其可以多种方式使用。例如,在样品中检测PD-L1的存在。抗体也可用于尝试结合并干扰PD-L1活性。
可修改技术以制备对本发明的抗原蛋白特异的单链抗体(参见例如,美国专利号4,946,778)。此外,可修改方法以构建Fab表达文库(参见例如,Huse等人, 1989 Science246: 1275-1281),以允许快速和有效鉴定对蛋白或其衍生物、片段、类似物或同系物具有所需特异性的单克隆Fab片段。含针对蛋白抗原的独特型的抗体片段可通过本领域已知的技术制备,其包括但不限于:(i)通过胃蛋白酶消化抗体分子制备的F(ab')2片段;(ii)通过将F(ab')2片段的二硫键还原产生的Fab片段;(iii)通过用木瓜蛋白酶和还原剂处理抗体分子而产生的Fab片段和(iv) Fv片段。
杂缀合物抗体也在本发明的范围内。杂缀合物抗体由两个共价连接的抗体组成。这类抗体已例如被提议将免疫系统细胞靶向至不需要的细胞(参见美国专利号4,676,980)和用于HIV感染的治疗(参见WO 91/00360;WO 92/200373;EP 03089)。预期所述抗体可使用合成蛋白化学中的已知方法(包括包含交联剂的那些)在体外制备。例如,免疫毒素可使用二硫化物交换反应(disulfide exchange reaction)或通过形成硫醚键而构建。针对此目的的合适试剂的实例包括亚氨基硫醇酯(iminothiolate)和甲基-4-巯基丁酰亚胺酸酯和例如在美国专利号4,676,980中公开的那些。
对于效应子功能,为了增强例如抗体在治疗癌症中的效果,修饰本发明的抗体可能为合乎需要的。例如,可将半胱氨酸残基引入Fc区,由此允许在此区中链间二硫键的形成。由此生成的同源二聚抗体可增强内化能力和/或增加补体-介导的细胞杀伤和抗体-依赖性细胞的细胞毒性(ADCC)。(参见Caron等人, J. Exp Med., 176: 1191-1195 (1992)和Shopes, J. Immunol., 148: 2918-2922 (1992))。备选地,抗体可经工程改造以具有双Fc区,并且可由此具有增强的补体裂解和ADCC能力。(参见Stevenson等人, Anti-Caner DrugDesign(抗癌药物设计), 3: 219-230 (1989))。
本发明还涉及免疫缀合物,其包含与细胞毒性剂例如毒素(例如,细菌、真菌、植物或动物源的酶活性毒素,或其片段)或放射性同位素(即,放射性缀合物)缀合的抗体。
可使用的酶活性毒素及其片段包括白喉A链、白喉毒素的非结合活性片段、外毒素A链(来自铜绿假单胞菌(Pseudomonas aeruginosa))、蓖麻毒素A链、相思豆毒蛋白A链、蒴莲根毒素A链、α-八叠球菌(α-sarcin)、油桐(Aleurites fordii)蛋白、石竹素蛋白、美国商陆蛋白(Phytolaca americana proteins)(PAPI、PAPII和PAP-S)、苦瓜抑制因子、泻果素、巴豆毒素、石碱草抑制因子、白树毒素、丝林霉素、局限曲霉素(restrictocin)、酚霉素(phenomycin)、依诺霉素(neomycin)和单端孢霉烯族毒素类(tricothecenes)。多种放射性核素对于制备放射性缀合抗体是可利用的。实例包括212Bi、131I、131In、90Y和186Re。
抗体和细胞毒性剂的缀合物使用多种双功能蛋白-偶联剂例如N-琥珀酰亚胺基-3-(2-吡啶基二硫醇)丙酸酯(SPDP)、亚胺基硫代环戊烷(IT)、亚胺酯的双功能衍生物(例如己二亚胺酸二甲酯盐酸盐)、活性酯(例如辛二酸二琥珀酰亚胺酯)、醛(例如戊二醛)、双叠氮化合物(例如双(对-叠氮苯甲酰)己二胺)、双-重氮衍生物(例如双-(对-重氮苯甲酰)-乙二胺)、二异氰酸酯(例如甲苯基2,6-二异氰酸酯)和双-活性氟化合物(例如1,5-二氟代-2,4-二硝基苯)制造。例如,蓖麻毒素免疫毒素可按在Vitetta等人, Science 238: 1098(1987)中描述而制备。碳-14-标记的1-异硫氰酰基苄基-3-甲基二乙烯三胺五乙酸(MX-DTPA)是用于将放射核苷酸缀合至抗体的范例性的螯合剂。(参见WO94/11026)。
本领域的普通技术人员将认识到,种类繁多的可能的部分可偶联至所得抗体或本发明的其它分子。(参见,例如,"Conjugate Vaccins", Contributions to Microbiologyand Immunology(“缀合物疫苗”,对微生物和免疫学的贡献), J. M. Cruse和R. E.Lewis, Jr (编辑), Carger Press, New York, (1989), 其全部内容通过引用并入本文)。
偶联可通过任何化学反应实施,所述化学反应结合两个分子,只要抗体和其它部分保持它们各自的活性。此连接可包括许多化学机制,例如共价结合、亲和结合、插层、配位结合和络合。然而,优选的结合是共价结合。共价结合可通过存在的侧链的直接缩合或通过外部的桥接分子的掺入而完成。许多二价的或多价的连接剂在将蛋白分子(例如本发明的抗体)偶联至其它分子中是有用的。例如,代表性的偶联剂可包括有机化合物例如硫酯、碳二亚胺、琥珀酰亚胺酯、二异氰酸酯、戊二醛、重氮苯和环己二胺(hexamethylenediamines)。该列表不意图为本领域已知多种种类的偶联剂的穷举,而是较常见的偶联剂的范例。(参见Killen和Lindstrom, Jour. Immun. 133:1335-2549 (1984);Jansen等人,Immunological Reviews 62:185-216 (1982);和Vitetta等人, Science 238:1098(1987))。优选的连接物在以下文献中描述(参见,例如, Ramakrishnan, S.等人, CancerRes. 44:201-208 (1984),其描述MBS (M-马来亚胺基苯甲酰-N-羟基琥珀酰亚胺酯)的使用)。还参见,美国专利号5,030,719,其描述通过寡肽连接物的方式偶联至抗体的卤化乙酰基酰肼衍生物的使用。特别优选的连接物包括:(i) EDC (1-乙基-3-(3-二甲氨基-丙基)碳二亚胺盐酸盐;(ii) SMPT (4-琥珀酰亚胺基氧基羰基-α-甲基-α-(2-吡啶基二硫代)-甲苯(Pierce Chem. Co., Cat. (21558G);(iii) SPDP (琥珀酰亚胺基-6 [3-(2-吡啶基二硫代)丙酰氨基]己酸酯(Pierce Chem. Co., Cat #21651G);(iv)磺基-LC-SPDP (磺基琥珀酰亚胺基6 [3-(2-吡啶基二硫代)-丙酰胺]己酸酯(Pierce Chem. Co. Cat. #2165-G);和(v)缀合至EDC的磺基-NHS (N-羟基磺基-琥珀酰亚胺: Pierce Chem. Co., Cat. #24510)。
上面描述的连接物含有具有不同性质的组分,由此导致具有不同生理化学特性的缀合物。例如,烷基羧酸酯的磺基-NHS酯与芳香羧酸酯的磺基-NHS酯相比为更稳定的。含连接物的NHS-酯与磺基-NHS酯相比为更不可溶的。另外,连接物SMPT含空间阻碍性二硫键并可形成具有增加的稳定性的缀合物。二硫键通常与其它键相比更不稳定,因为二硫键在体外被裂解开,导致可获得较少的缀合物。磺基-NHS尤其可增强碳二亚胺偶联的稳定性。碳二亚胺偶联(例如EDC),当联合磺基-NHS使用时,比单独的碳二亚胺偶联反应,形成对水解更有抗性的酯。
本文公开的抗体还可配制为免疫脂质体。含抗体的脂质体通过本领域已知的方法(例如在Epstein等人, Proc. Natl. Acad. Sci. USA, 82: 3688 (1985);Hwang等人,Proc. Natl Acad. Sci. USA, 77: 4030 (1980);和美国专利号4,485,045和4,544,545中描述)制备。具有增加的循环时间的脂质体在美国专利号5,013,556中公开。
特别有用的脂质体可通过反相蒸发法用包含磷脂酰胆碱、胆固醇和PEG-衍生的磷酯酰乙醇胺(PEG-PE)的脂质组合物生成。将脂质体挤压通过确定的孔径的滤器以产生具有所需直径的脂质体。本发明抗体的Fab'片段可如在Martin等人, J. Biol. Chem., 257:286-288 (1982)中描述通过二硫互换反应缀合至脂质体。
抗PD-L1的抗体的用途
本发明的特异性结合PD-L1蛋白的抗体或其片段可被给予用于癌症或其它增殖性病症的治疗。许多癌症过量表达PD-L1和PD-L1的增量调节与高风险预后因子相关。在肿瘤细胞中PD-L1的过量表达也可指示肿瘤细胞逃避抗-肿瘤免疫的机制,例如通过诱导T细胞衰竭。这类癌症包括肾细胞癌和乳腺癌。其它范例性的癌症是与T细胞衰竭相关或利用T细胞衰竭以逃避抗-肿瘤T细胞活性的那些癌症。本发明抗体的使用可增强在响应用肿瘤抗原肽刺激时肿瘤抗原-特异性T细胞增殖和产生细胞因子的能力,由此提高T细胞活性或抗-肿瘤免疫应答。
本发明的特异性结合PD-L1蛋白的抗体或其片段可被给予用于慢性感染的治疗。这类慢性感染包括,例如,病毒感染、细菌感染和寄生虫感染。范例性的慢性病毒感染是HIV。在慢性HIV感染期间,HIV-特异性CD8+ T细胞功能上被损害,表现出产生细胞因子和效应子分子的能力降低和增殖能力减弱。PD-1在HIV感染个体的HIV-特异性CD8+ T细胞上高表达。本发明抗体的使用可增强在响应用HIV肽刺激时HIV-特异性T细胞增殖和产生细胞因子的能力,由此提高T细胞活性或抗-病毒免疫应答。
可将本发明的抗体(其包括双特异性、多克隆、单克隆、人源化和全人抗体)用作治疗剂。这些药剂可通常用于在受试者中治疗或预防癌症,增加疫苗功效或提高天然免疫应答。将抗体制剂(优选地对其靶抗原具有高特异性和高亲和力的抗体制剂)给予受试者并且通常因其与靶标的结合而具有效果。抗体的给予可消除或抑制或干扰PD-L1蛋白的活性。
本发明的抗体能够诱导细胞死亡。细胞死亡通过直接或间接的机制诱导。例如,PD-L1被huPD-L1抗体结合可导致补体依赖性细胞毒性(CDC)。备选地,huPD-L1抗体结合PD-L1,并导致第二细胞类型的募集,其会杀伤PD-L14-表达的靶细胞。范例性的机制(依据该机制huPD-L1抗体通过第二细胞类型的募集介导细胞死亡)包括但不限于抗体-依赖性细胞毒性(ADCC)和抗体依赖性细胞吞噬(ADCP)。靶PD-L1-表达的细胞类型包括肿瘤细胞和T细胞,例如,活化的T细胞。
本发明的特异性结合PD-L1蛋白的抗体或其片段可以药物组合物的形式给予用于癌症或慢性感染的治疗。涉及制备治疗组合物(其包含抗体)的原理和考虑,以及选择组分的指南提供于例如Remington: The Science And Practice Of Pharmacy第19版(AlfonsoR. Gennaro等人编著) Mack Pub. Co., Easton, Pa., 1995; Drug AbsorptionEnhancement: Concepts, Possibilities, Limitations, And Trends(药物吸收促进:概念、可能性、限制和趋势), Harwood Academic Publishers, Langhorne, Pa., 1994;和Peptide And protein Drug Delivery (肽和蛋白药物递送)(Advances In ParenteralSciences, Vol. 4), 1991, M. Dekker, New York中。
本发明抗体的治疗上有效的量通常涉及实现治疗目标所需的量。如上指出,这可以是抗体和它的靶抗原之间的结合相互作用,在某些情况下,这干扰靶的机能。此外,给予所需量取决于抗体对它的特异性抗原的结合亲和力,并也取决于给予的抗体从给予了该抗体的自由体积的其它受试者中耗尽的速率。本发明抗体或抗体片段的治疗上有效的剂量给药的常用范围(以非限制实例的方式)可为约0.1 mg/kg体重-约50 mg/kg体重。常用给药频率可在例如从每天两次至一周一次的范围内。
在使用抗体片段的情况下,特异性结合至靶蛋白的结合结构域的最小的抑制性片段是优选的。例如,基于抗体的可变区序列,可设计肽分子,其保持结合靶蛋白序列的能力。这类肽可化学合成和/或通过重组DNA技术制备。(参见,例如,Marasco等人, Proc. Natl.Acad. Sci. USA, 90: 7889-7893 (1993))。制剂还可根据治疗的特定适应症的需要而含有超过一种活性化合物,优选相互间无不利影响的具有互补活性的那些。备选地或另外,组合物可包含增强它的功能的作用剂,例如,细胞毒性剂、细胞因子、化学治疗剂或生长抑制剂。这类分子合适以对于意图目的有效的量组合存在。
活性成分也可截留在微胶囊(例如通过凝聚技术或通过界面聚合而制备,分别例如,羟甲基纤维素或明胶-微胶囊和聚(异丁烯酸甲酯)微胶囊)中、胶质药物递送系统(例如,脂质体、白蛋白微球、微乳剂、纳米-颗粒和纳米胶囊)中或大乳剂(macroemulsions)中。
用于体内给予的制剂必须是无菌的。这通过穿过无菌过滤膜过滤容易地实现。
可制备持续释放的制剂。持续释放的制剂的合适实例包括含抗体的固体疏水聚合物的半透性基质,所述基质呈成形制品的形式,例如,薄膜或微胶囊。持续释放基质的实例包括多元酯、水凝胶(例如,聚(2-羟乙基-异丁烯酸酯)或聚(乙烯醇))、聚交酯(美国专利号3,773,919)、L-谷氨酸和γ乙基-L-谷氨酸酯的共聚物、不可降解的乙烯乙酸乙烯酯、可降解乳酸-乙醇酸共聚物例如LUPRON DEPOT TM (可注射微球体,其由乳酸-乙醇酸共聚物和乙酸亮丙瑞林组成)和聚-D-(-)-3-羟基丁酸。虽然聚合物(例如乙烯乙酸乙烯酯和乳酸-乙醇酸)使分子的释放能够持续超过100天,但某些水凝胶释放蛋白持续较短时间。
可将本发明的抗体用作在样品中检测PD-L1 (或蛋白或其蛋白片段)的存在的作用剂。优选地,抗体含可检测的标记。抗体可为多克隆的或更优选为单克隆的。可使用完整抗体或其片段(例如,Fab、scFv或F(ab)2)。关于探针或抗体的术语"标记的",意图包括通过偶联(即,物理连接)可检测的物质至探针或抗体直接标记探针或抗体,以及通过与另一直接标记的试剂的反应性间接标记探针或抗体。间接标记的实例包括使用荧光标记的第二抗体检测第一抗体和用生物素末端标记DNA探针使得它可用荧光标记的链霉亲和素检测。术语"生物样品"意图包括从受试者分离的组织、细胞和生物流体,以及存在于受试者中组织、细胞和流体。因此,血液和血液的流分或组分(其包含血清、血浆或淋巴)包含于术语“生物样品”的使用中。即,本发明的检测方法可用于在体外的生物样品中或在体内检测分析物mRNA、蛋白或基因组DNA。例如,用于检测分析物mRNA的体外技术包括Northern杂交和原位杂交。用于检测分析物蛋白的体外技术包括酶联免疫吸附测定(ELISA)、蛋白质印迹、免疫沉淀和免疫荧光。用于检测分析物基因组DNA的体外技术包括Southern杂交。用于指导免疫测定的方法描述于例如“ELISA: Theory and Practice: methods in Molecular Biology(ELISA:理论与实践:分子生物学方法)”, Vol. 42, J. R. Crowther (主编) HumanPress, Totowa, NJ, 1995;“Immunoassay(免疫测定)”, E. Diamandis和T.Christopoulus, Academic Press, Inc., San Diego, CA, 1996;和“Practice andTheory of Enzyme Immunoassay(酶免疫测定的实践与理论)”, P. Tijssen, ElsevierScience Publishers, Amsterdam, 1985。此外,用于检测分析物蛋白的体内技术包括向受试者引入标记的抗-分析物蛋白抗体。例如,所述抗体可用放射性标记物标记,所述放射性标记物在受试者中的存在和位置可通过标准成像技术检测。
定向抗PD-L1蛋白的抗体(或其片段)可用于本领域已知的方法,其涉及PD-L1蛋白的定位和/或定量(例如,用于测量在合适的生理学样品中PD-L1蛋白的水平、用于诊断方法、用于蛋白成像等)。在给定的实施方案中,对PD-L1蛋白特异的抗体或其衍生物、片段、类似物或同系物(其含抗体衍生的抗原结合结构域)被利用作为药理活性化合物(在下文中被称为"治疗药")。
本发明的对PD-L1蛋白特异的抗体可用于通过标准技术,例如免疫亲和、层析或免疫沉淀分离PD-L1多肽。定向抗PD-L1蛋白的抗体(或其片段)可作为临床试验程序的一部分诊断性地用于监测组织中蛋白的水平,例如,确定给定治疗方案的功效。检测可通过将所述抗体偶联(即,物理连接)至可检测的物质而促进。可检测的物质的实例包括多种酶、辅基、荧光材料、发光材料、生物发光材料和放射性材料。合适的酶的实例包括辣根过氧化物酶、碱性磷酸酶、β-半乳糖苷酶或乙酰胆碱酯酶;合适的辅基复合物的实例包括链霉亲和素/生物素和抗生物素/生物素;合适的荧光材料的实例包括伞形酮、荧光素、异硫氰酸荧光素、若丹明、二氯三嗪基胺荧光素、氯化丹酰或藻红素;发光材料的实例包括鲁米诺;生物发光材料的实例包括萤光素酶、萤光素和水母素;以及合适的放射性材料的实例包括125I、131I、35S或3H。
治疗组合物
本发明的抗体或作用剂(本文也称为"活性化合物"),及其衍生物、片段、类似物和同系物可被掺入适合于给予的药物组合物。这类组合物通常包括抗体或作用剂和药学上可接受的载体。本文使用的术语"药学上可接受的载体"意图包括任何和所有与药物给予相容的溶剂、分散介质、包衣、抗细菌和抗真菌剂、等渗和吸收延迟剂等。合适的载体描述于最新版的Remington’s Pharmaceutial Sciences,其为本领域中标准参考文本,其通过引用并入本文。这类载体或稀释剂的优选实例包括但不限于水、盐水、林格氏溶液、葡萄糖溶液和5%人血清白蛋白。也可使用脂质体和非水性媒介(例如固定油)。药物活性物质的这样的媒介和作用剂的使用在本领域是周知的。除了任何常规媒介或作用剂与活性化合物不相容的情况之外,其在组合物中的使用为预期的。补充活性化合物也可掺入该组合物。
本发明的药物组合物被配制为与其意图的给予途径相容。给予途径的实例包括肠胃外(例如,静脉内、皮内、皮下)、口服(例如,吸入)、透皮(即,表面)、透粘膜和直肠给予。用于肠胃外、皮内或皮下应用的溶液或混悬液可包括以下组分:无菌稀释剂(例如注射用水、盐水溶液、固定油、聚乙二醇、甘油、丙二醇或其它合成的溶剂);抗细菌剂(例如苯甲醇或对羟基苯甲酸甲酯);抗氧化剂(例如抗坏血酸或亚硫酸氢钠);螯合剂(例如乙二胺四乙酸(EDTA));缓冲液(例如乙酸盐、柠檬酸盐或磷酸盐),以及用于调节张力的作用剂(例如氯化钠或葡萄糖)。可用酸或碱(例如盐酸或氢氧化钠)调节pH。可将肠胃外制剂封装在安瓿、一次性注射器或玻璃或塑料制成的多剂量小瓶中。
适合于可注射用途的药物组合物包括无菌水性溶液(在水溶的情况下)或分散液和用于无菌可注射溶液或分散液的临时配制的无菌粉末。对于静脉内给予,合适的载体包括生理盐水、抑菌水、Cremophor ELTM(BASF, Parsippany, N.J.)或磷酸盐缓冲盐水(PBS)。在所有情况下,组合物必须为无菌的且应该为流动性的,达到容易可注射性存在的程度。它必须在制造和储存条件下稳定并且必须保持抗微生物(例如细菌和真菌)的污染活动。载体可为溶剂或分散介质,其包含例如,水、乙醇、多元醇(例如,甘油、丙二醇和液体聚乙二醇等)及其合适的混合物。合适的流动性可例如通过使用包衣(例如卵磷脂)、通过在分散液的情况下保持所需粒度和通过使用表面活性剂而保持。预防微生物的活动可通过多种抗细菌和抗真菌剂(例如,对羟基苯甲酸酯、氯代丁醇、苯酚、抗坏血酸、硫柳汞等)而实现。在许多情况下,优选在组合物中包括等渗剂(例如,糖、多元醇例如甘露糖醇、山梨糖醇、氯化钠)。可注射组合物的延长吸收可通过将延迟吸收的作用剂(例如,单硬脂酸铝和明胶)包含入组合物而发生。
无菌可注射溶液可通过将活性化合物以所需量掺入带有上面列举的一种成分或成分的组合的合适溶剂,根据需要,随后过滤灭菌而制备。通常,分散液通过将活性化合物掺入含有基础分散介质和来自上述列举的那些的所需其它成分的无菌媒介而制备。在用于制备无菌可注射溶液的无菌粉末的情况下,制备的方法为真空干燥和冻干,其产生来自其先前无菌过滤溶液的活性成分加上任何另外所需成分的粉末。
口服组合物通常包括惰性稀释剂或可食用载体。它们可以被封装于明胶胶囊中或压制成片剂。为了口服治疗给予的目的,活性化合物可与赋形剂掺合并以片剂、锭剂或胶囊的形式使用。口服组合物也可使用流体载体制备以用作漱口剂,其中在流体载体中的化合物被口腔施用和漱口并吐出或吞下。药学上相容的结合剂和/或佐药材料可被包括作为组合物的一部分。片剂、丸剂、胶囊、锭剂等可含有任何以下成分或类似性质的化合物:粘合剂(例如微晶纤维素、黄芪树胶或明胶);赋形剂(例如淀粉或乳糖);崩解剂(例如藻酸、Primogel或玉米淀粉);润滑剂(例如硬脂酸镁或Sterotes);助流剂(例如胶质二氧化硅);甜味剂(例如蔗糖或糖精);或矫味剂(例如薄荷、水杨酸甲酯或桔子调味料)。
对于通过吸入给予,化合物以来自压力容器或分配器(其含有合适的推进剂,例如,诸如二氧化碳等气体)或喷雾器的气雾剂喷雾的形式递送。
全身给予也可通过透粘膜的或透皮的方式。对于透粘膜的或透皮的给予,适合于待渗透的屏障的渗透剂被用于制剂。这类渗透剂在本领域中为普遍已知的,并对于透粘膜给予,包括例如去垢剂、胆汁盐和夫西地酸衍生物。透粘膜的给予可通过使用鼻喷雾或栓剂完成。对于透皮的给予,活性化合物被配制成如本领域普遍已知的软膏、油膏、凝胶或乳膏。
化合物也可以栓剂(例如,用常规栓剂基例如可可脂和其它甘油酯)或用于直肠递送的滞留型灌肠剂的形式制备。
在一个实施方案中,活性化合物用保护化合物以防从体内快速消除的载体(例如控释制剂,其包括植入物和微囊包封递送系统)制备。可使用生物可降解的、生物相容的聚合物例如乙烯乙酸乙烯酯、聚酐、聚乙醇酸、胶原、聚原酸酯和聚乳酸。用于制备这类制剂的方法对于本领域技术人员是显而易见的。所述材料也可从Alza Corporation和NovaPharmaceuticals,Inc.商购获得。脂质体混悬液(其包括用针对病毒抗原的单克隆抗体靶向至被感染的细胞的脂质体)也可用作药学上可接受的载体。这些可根据本领域技术人员已知的方法(例如,描述于美国专利号4,522,811中的方法)而制备。
特别有利的是,以容易给予和剂量均匀的剂量单位形式配制口服或肠胃外组合物。本文使用的剂量单位形式是指适合作为待治疗的受试者的单一剂量(unitarydosages)的生理上分离单位;各单位含有预定量的活性化合物(其经计算以与所需的药物载体联合产生所需治疗效果)。本发明的剂量单位形式的规格受控于并直接取决于活性化合物的独特的特征和待达到的特定治疗效果,以及在配制这类活性化合物用于个体治疗的领域中固有的限制。
药物组合物可与用于给予的使用说明书一起包含于容器、包装或分配器中。
诊断测定
本发明的huPD-L1抗体,当连接至可检测的部分时,提供用于检测“癌性组织”或趋向于异常的细胞增殖并由此处于癌风险中的组织的方法。除因原位新生物所致而变为癌性的组织之外,例如,抗体-可检测部分缀合物还提供检测存在于远端器官和/或组织中的癌性转移组织的方法。因此这类组织可通过如下检测:将怀疑为癌性的组织与抗体-可检测部分在合适的条件下接触以引起可检测部分在癌性组织中被检测,由此检测癌性组织的存在。
本发明的huPD-L1抗体,当连接至可检测部分时,提供在罹患癌症或慢性感染的受试者中检测T细胞衰竭的方法。例如,huPD-L1抗体可用于在受试者中检测PD-L1的水平,其中与参考水平相比该水平可表明是否受试者正罹患T细胞衰竭。因此,此方法也可用于确定是否治疗(其使用huPD-L1抗体通过逆转或抑制T细胞衰竭以提高免疫应答)会对受试者有益。
可检测部分可直接缀合至抗体或片段,或间接地通过使用例如荧光第二抗体而缀合。直接缀合可通过例如荧光团至抗体或抗体片段的标准化学偶联或通过遗传工程改造完成。可构建嵌合体或融合蛋白,其含有偶联至荧光或生物发光蛋白的抗体或抗体片段。例如,Casadei等人描述了制备能够在哺乳动物细胞中表达水母素和抗体基因的融合蛋白的载体构建体的方法。
本文使用的关于探针或抗体的术语"标记的",意图包括通过将可检测的物质偶联(即,物理连接)至探针或抗体而直接标记探针或抗体,以及通过与直接标记的另一试剂的反应性而间接标记探针或抗体。间接标记的实例包括使用荧光标记的第二抗体检测第一抗体和用生物素末端标记DNA探针使得它可用荧光标记的链霉亲和素检测。术语"生物样品"意图包括从受试者分离的组织、细胞和生物流体(例如活检样品),以及存在于受试者中的组织、细胞和流体。即,本发明的检测方法可用于在体外的生物样品中和在体内检测癌症、癌细胞或癌-相关细胞(例如与肿瘤或癌细胞相关的基质细胞)。例如,用于检测PD-L1的体外技术包括酶联免疫吸附测定(ELISA)、蛋白质印迹、免疫沉淀和免疫荧光。此外,用于检测PD-L1的体内技术包括向受试者引入标记的抗-PD-L1抗体。例如,抗体可用放射性标记物标记,所述放射性标记物在受试者中的存在和位置可通过标准成像技术检测。在实施方案中,本发明提供在受试者中检测肿瘤或癌细胞的非侵入式方法。受试者被给予本发明的抗体或scFv抗体,在将所述抗体连接至可检测部分(即,任何能够通过例如,荧光、化学、化学发光、放射性或本领域已知的其它方法检测的部分)时,抗体被允许定位于肿瘤,随后通过观察可检测部分而检测。
在“靶向的”缀合物,即,含有靶向部分(设计用以在受试者或动物中在一个或多个特定位点位点上定位缀合物的分子或特征)的缀合物的情况下,定位是指当在受试者内结合的“定位的”实体和未结合的“自由”实体之间的平衡已经基本上达到时的状态。这类平衡达到的速率取决于给予途径。例如,通过静脉内注射给予以定位血栓的缀合物在注射几分钟内可实现定位或累积于血栓。另一方面,口服给予以定位肠内的感染的缀合物可花费数小时以实现定位。备选地,定位可仅仅指在给予实体之后在选定的时间期限中该实体在受试者或动物中的位置。通过另一实例的方式,当部分在给予之后变得分散时实现定位。
在所有以上情况下,对实现定位的时间的合理估计可由本领域技术人员作出。此外,作为时间函数的定位状态可根据本发明的方法(例如用光检测设备)通过对可检测部分(例如,光-发射缀合物)成像而追踪(follow)。使用的“光检测设备”应该具有足够高的灵敏性以能够在合理数量的时间内对来自哺乳动物内的微弱的光成像,并且使用来自这类设备的信号构建图像。
在其中有可能使用特别亮的光-产生部分和/或检测定位在被成像的受试者或动物的表面附近的光-产生融合蛋白的情况下,可使用一副“夜视”护目镜或标准高灵敏性视频照相机,例如Silicon Intensified Tube (SIT)照相机(例如,来自HammamatsuPhotonic Systems, Bridgewater, N.J.)。然而,更通常,需要更灵敏的光检测方法。
在极低的光水平下,每单位面积的光子通量变得低,以至于成像得到的景物不再表现为连续的。替代地,它表示为时间上和空间上都相距很远的单独的光子。在显示器上观看,这类图像看起来和闪烁的光点一样,各自代表单个检测出的光子。通过这些检测出的光子随时间推移在数字图像处理器中被积累,可获得和构建图像。与其中每一个像点的信号都被赋予了强度值的传统相机相反,在光子计数成像中信号的振幅不带有任何意义。目标在于仅检测信号(光子)的存在并计数随时间推移关于它的位置的信号的出现。
至少两种类型的光检测设备(下面描述)可检测单独的光子并产生可由图像处理器分析的信号。降噪光子检测设备通过降低光子检测器中的背景噪声,而不是放大光子信号实现灵敏性。噪音主要通过冷却检测器阵列而降低。设备包括电荷耦合设备(CCD)照相机,其被称为“后薄化的”、冷却的CCD照相机。在更灵敏的装置中,冷却使用例如,液氮(其将CCD阵列的温度带到约–120℃)而实现。“后薄化的”是指超薄的后板,其缩短了路径长度(光子沿其前进而被检测),由此增强量子效率。特别灵敏的后薄化的低温CCD照相机为“TECH512”,从Photometrics, Ltd. (Tucson, Ariz.)可得的系列200照相机。
“光子放大设备”在光子撞击检测屏之前放大光子。这类包括带有增强仪的CCD照相机,例如微通道增强仪。微通道增强仪通常含有与照相机检测屏垂直的和同延的金属通道阵列。将微通道阵列放在待成像的样品、受试者或动物与照相机之间。进入该阵列的通道的大多数光子在离开之前接触通道的一侧。横跨阵列施用的电压导致来自光子碰撞的许多电子的释放。来自这类碰撞的电子以“散弹枪”的方式离开它们起点的通道,并通过照相机检测。
甚至更强的灵敏性可通过如下实现:增强型微通道阵列串联放置,使得在第一阶段产生的电子依次在第二阶段中导致电子的放大信号。然而,灵敏性的增强以空间解析度(其随着每一级额外放大而降低)为代价实现。范例性的基于微通道增强器的单光子检测设备为从Hamamatsu可得的C2400系列。
图像处理器处理由光检测设备产生的信号,所述光检测设备计数光子以构建图像(其可例如在显示器上展示或在图像打印机上打印)。这类图像处理器通常作为系统(其包括上面描述的灵敏光子计数照相机)的一部分出售,并因此从相同来源可得。所述图像处理器通常连接至个人电脑(例如IBM-兼容PC或Apple Macintosh (Apple Computer,Cupertino, Calif.)),其可以或可以不被包括作为购买的成像系统的一部分。一旦图像呈数字文件的形式,它们就可通过多种图像处理程序操作(例如“ADOBE PHOTOSHOP”, AdobeSystems, Adobe Systems, Mt. View, Calif.)和打印。
在一个实施方案中,生物样品含有来自测试受试者的蛋白分子。一种优选的生物样品是外周血白细胞样品,其通过常规方法从受试者分离。
本发明还包括用于在生物样品中检测PD-L1或PD-L1-表达的细胞的存在的试剂盒。例如,试剂盒可包括:能够在生物样品中检测癌或肿瘤细胞的标记的化合物或作用剂(例如,抗-PD-L1 scFv或单克隆抗体)、用于在样品中检测PD-L1的量的工具和用于将样品中PD-L1的量与标准作比较的方法。在一些实施方案中,所述标准是非癌细胞或其细胞提取物。化合物或作用剂可包装在合适的容器中。试剂盒可进一步包括使用试剂盒以在样品中检测癌症的说明书。
双特异性抗体
双特异性抗体(bsAb)是抗体,其包含两个可变结构域或scFv单位使得所得抗体识别两种不同抗原。本发明提供识别PD-L1和第二抗原的双特异性抗体。范例性的第二抗原包括肿瘤相关抗原、细胞因子和细胞表面受体。在一些实施方案中,所述第二抗原可以是CAIX(碳酸酐酶IX或G250)、IL-10或CCR4。在一些实施方案中,所述第二抗原可以是细胞表面受体,其中所述细胞表面受体是CCR4、IL21R、BTLA、HVEM或TIM3。
本发明的双特异性抗体包括本文公开的huPD-L1抗体的重链和轻链组合或scFv。
双特异性抗体的构建
本发明的双特异性抗体可使用本领域已知方法构建。在一些实施方案中,所述双特异性抗体是单个多肽,其中两个scFv片段通过长接头多肽(其长度足以允许两个scFv单位之间的分子内缔合)连接以形成抗体。在其它实施方案中,双特异性抗体是通过共价或非共价键连接的一个以上的多肽。
在另一实施方案中,双特异性抗体使用“结进孔”法(Ridgway等人, Protein Eng7:617-621 (1996))构建。在此方法中,将两个不同可变结构域的Ig重链还原以选择性地破坏重链配对同时保留重链-轻链配对。将识别两个不同抗原的两个重链-轻链杂二聚体混合以促进杂连接配对,所述杂连接配对通过CH3结构域的工程改造的“结进孔”介导(如在图5和6A中所示)。
在另一实施方案中,双特异性抗体可通过如下构建:交换来自两个或更多个不同抗体的重链-轻链二聚体以产生杂交抗体,其中第一重链-轻链二聚体识别PD-L1和第二重链-轻链二聚体识别第二抗原。重链-轻链二聚体的机制与人IgG4(其也发挥双特异性分子的功能)的形成类似。IgG重链的二聚化受分子内的力(例如配对每条重链的CH3结构域和二硫桥的分子内的力)的驱动。在CH3结构域中特定氨基酸的存在(R409)已经表现出促进IgG4分子的构建和二聚体交换。重链配对也通过在抗体的铰链区中的重链间的二硫桥而进一步稳定。具体地,在IgG4中,铰链区在氨基酸226-230含有氨基酸序列Cys-Pro-Ser-Cys (与含有序列Cys-Pro-Pro-Cys的稳定的IgG1铰链区相比)。此229位的丝氨酸的序列差异已经与IgG4在铰链区形成新链内二硫键的倾向关联起来(Van der Neut Kolfschoten, M. 等人,2007, Science 317:1554-1557和Labrijn, A.F. 等人, 2011, Journal of immunol187:3238-3246)。
因此,本发明的双特异性抗体可通过如下产生:在识别PD-L1或第二抗原的抗体的CH3结构域中引入R409残基和铰链区中引入Cys-Pro-Ser-Cys序列,使得重链-轻链二聚体交换以产生抗体分子,所述抗体分子具有识别PD-L1的一个重链-轻链二聚体和识别第二抗原的第二重链-轻链二聚体,其中所述第二抗原是本文公开的任何抗原。优选地,双特异性抗体含有与一个抗-CAIX (碳酸酐酶IX或250)重链-轻链二聚体缀合的一个抗-PD-L1重链-轻链二聚体,如实施例3和4中讨论。重链-轻链二聚体交换也可用还原剂(例如还原型谷胱甘肽)的加入而增强,以促进。还可改变已知的IgG4分子使得重链和轻链如本文公开识别PD-L1或第二抗原。将此方法用于构建本发明的双特异性抗体可为有利的,原因是IgG4分子的内在特性,其中Fc区与其它IgG亚型不同之处在于:它与免疫应答的效应子系统(例如由某种白血细胞所表达的Fc受体和补体)相互作用差。此特性使得这些基于IgG4的双特异性抗体对于治疗应用(其中需要抗体结合靶并功能上改变与靶相关的信号转导通路,但不触发效应子的活性)而言为吸引人的。
在一些实施方案中,将突变引入bsAb的恒定区以便改变bsAb的抗体依赖性细胞-介导的细胞毒性(ADCC)活性。这类实例描述于图6B中。例如,突变是在CH2结构域中的LALA突变。在一方面中,bsAb含有在杂二聚体型bsAb的一个scFv单位上的突变,其降低ADCC活性。在另一方面中,bsAb在杂二聚体型bsAb的两条链上都含有突变,其完全消除ADCC活性。例如,bsAb的一个或两个scFv单位引入的突变是在CH2结构域中的LALA突变。可将具有可变ADCC活性的这些bsAb优化使得所述bsAb对表达被bsAb识别的一个抗原的细胞展示出最大的选择性杀伤,但对被bsAb识别的第二抗原展示出最小的杀伤。
范例性的第二抗原
本发明提供识别PD-L1和第二抗原的双特异性抗体。
在一些实施方案中,第二抗原为肿瘤相关抗原。在一些实施方案中,肿瘤相关抗原是碳酸酐酶IX(CAIX)。例如,可构建CAIX/PD-L1双特异性抗体,其包含本文描述的huPD-L1抗体的一条重链和一条轻链的组合和识别CAIX的一条重链和一条轻链的组合(图6A)。CAIX已经被描述为针对疾病进展的预后标志物和使用IL-2的免疫疗法的靶。CAIX为在癌症(例如肾细胞癌)中高表达的肿瘤-相关抗原。在一些情况下,通过肿瘤细胞的PD1/PD-L1轴的活化可诱导针对某些肿瘤-特异性抗原(例如CAIX)的T细胞衰竭,由此表达CAIX的肿瘤细胞逃避通过免疫系统的识别。靶向CAIX和PD-L1两者的bsAb作为新的癌治疗剂。使用CAIX/PD-L1bsAb的治疗会抑制或逆转针对CAIX的PD-1/PD-L1-介导的T-细胞衰竭,并促进肿瘤监测和抗CAIX-表达肿瘤细胞的免疫应答。例如,用CAIX/PD-L1 bsAb的治疗会促进抗肿瘤细胞的抗原-特异性免疫应答,其中所靶向的抗原是CAIX。
在一些实例中,可将突变引入至CAIX或PD-L1链恒定区中(例如,CH2结构域)以降低ADCC活性(图6B)。在一些实例中,可将突变同时引入至CAIX和PD-L1链恒定区中以完全消除ADCC活性。具有可变ADCC活性的突变的bsAb可针对它们杀伤肿瘤细胞的特异性通过本领域已知的方法测定。优选地,CAIX/PD-L1 bsAb展现出对CAIX-表达肿瘤细胞的最大选择性杀伤,但仅展现出对PD-L1-表达内源外周血单核细胞(PBMC)的最小杀伤。
在一些实施方案中,第二抗原是细胞表面受体,其中所述细胞表面受体是白介素21受体(IL21R)。例如,可构建IL21R/PD-L1双特异性抗体,其包括本文描述的huPD-L1抗体的一条重链和一条轻链的组合和以竞争的方式结合IL21R的一条重链和一条轻链的组合。细胞因子IL21由CD4+ T辅助细胞分泌并结合至IL21R以促进多种免疫活化通路,特别是,促进CTL的抗原-特异性细胞毒性和NK细胞的成熟、增殖和细胞毒性(Sondergaard, H 等人,2009 Tissue antigens 74:467-479;Kasaian, M. T.等人, 2002 Immunity 16:559-569;和Coquet, J. M. 等人, 2008 J Immunol 178:2827-2834)。特别地,IL21已被显示促进抗黑色素瘤抗原的活化和细胞毒性能力(Li, Y. 等人, 2005, J Immunol 175:2261-2269)。全身给予IL21已被探究用于治疗癌症并已经显示一些功效(Schmidt, H. 等人, 2010Clinical cancer research, 16: 5312-5319),但是,一些数据也已显示有害的和不期望的副作用(Grunwald, V. 等人, 2011, Acta Oncol 50:121-126)。
本发明的IL21R/PD-L1 bsAb以竞争的方式结合至IL21R,由此作为细胞因子IL21的模拟物或替代物起作用。通过IL21R/PD-L1 bsAb的结合可导致IL21R-介导的通路的活化和随后的对抗肿瘤细胞(其已诱导PD-L1-介导的T-细胞衰竭)的抗原-特异性细胞毒性免疫应答的促进。用本发明的双特异性抗体治疗的一个具体的益处是将IL21R活化定位至其中已经发生PD-1/PD-L1-介导的T细胞衰竭的区域(例如,在肿瘤微环境中,例如在已经诱导T细胞衰竭以逃避抗-肿瘤免疫应答的肿瘤附近或之内)。以此方式,ILR/PD-L1 bsAb以以下双重机制促进抗-肿瘤免疫应答:1) 通过逆转或抑制PD-1/PD-L1-介导的T细胞衰竭,和2)通过促进IL21/IL21R-介导的细胞毒性免疫应答的活化,由此诱导抗原-特异性或抗-肿瘤免疫应答和细胞毒性。
IL21R/PD-L1双特异性抗体也可用于对受试者免疫接种的疫苗中,或用作疫苗佐剂。在生发中心反应(GCR)(其中产生高-亲和性抗体-分泌浆细胞和记忆B细胞,其确保持续的免疫保护和抗先前遇到的外来抗原的快速记忆应答)中,PD1由滤泡T辅助细胞(TFH)表达同时PDL1由生发中心B细胞表达(Crotty, S.等人, 2011, Annual review ofImmunology, 29:621-623)。PD1或PD-L1的过量表达抑制抗体-产生B细胞的扩充。IL21R/PD-L1双特异性抗体(其中所述抗体的PD-L1部分抑制PD1/PD-L1轴)的使用会导致仅高亲和性抗体的优先扩充。由于IL-21强烈地促进抗原-特异性B细胞至抗体-分泌浆细胞的转变,和TFH活性的形成和持续(Crotty, S. 等人, 2011, Annual review of Immunology, 29:621-623),抗PDL1具有IL21替代或竞争活性的bsAb可充当关于促进抗特定抗原(例如通过疫苗给予的抗原或感染物质的抗原)的高亲和性抗体产生的GCR-特异性佐剂。
在一些实施方案中,第二抗原是BTLA (B和T淋巴细胞弱化子蛋白)或HVEM (疱疹病毒进入中介体,也称为TNFRSF14)。例如,可构建BTLA/PD-L1双特异性抗体,其包括本文描述的huPD-L1抗体的一条重链和一条轻链的组合和结合BTLA的一条重链和一条轻链的组合。例如,可构建HVEM/PD-L1双特异性抗体,其包括本文描述的huPD-L1抗体的一条重链和一条轻链的组合和结合HVEM(优选地,结合至介导与BTLA的结合的HVEM的那些区域)的一条重链和一条轻链的组合。BTLA至HVEM的结合导致T细胞抑制,这类似于PD1/PD-L1相互作用。本发明的BTLA/PD-L1或HVEM/PD-L1双特异性抗体会抑制或阻止BTLA与HVEM之间的缔合,和阻止BTLA/HVE-介导的T细胞抑制。BTLA抑制促进肿瘤-特异性T细胞应答。因此,使用本发明的双特异性抗体的治疗导致限制T细胞活性的两条不同的抑制因子通路的同时阻断。
在一些实例中,HVEM/PD-L1 bsAb抗体还阻止HVEM与另一HVEM配体,CD160(其已被表明是针对B细胞慢性淋巴细胞白血病(BCLL)细胞的存活的激动剂,并且强烈地抑制CD4+T-细胞活化和功能)之间的缔合。使用本发明的HVEM/PD-L1双特异性抗体(其也阻止HVEM/CD160结合)的治疗导致两条抑制因子通路(其限制T细胞活性和抑制CD160-介导的肿瘤存活通路)的同时阻断。
在一些实施方案中,第二抗原为TIM3(T-细胞免疫球蛋白和粘蛋白结构域3)。例如,可构建TIM3/PD-L1双特异性抗体,其包括本文描述的huPD-L1抗体的一条重链和一条轻链的组合和结合TIM3的一条重链和一条轻链的组合。在一方面中,本发明的抗体阻止或抑制TIM3与半乳凝素-9 (GAL9)的结合。TIM3与GAL9之间的相互作用导致巨噬细胞的活化和T细胞功能的抑制(Sakuishi, K.等人, 2010, The Journal of experimental medicine,207:2187-2194和Zhang, Y.等人, 2012, Journal of leukocyte biology, 91: 189-196)。TIM3也已被表明促进骨髓衍生的抑制因子细胞(MDSC)的活性(Dardalhon, V.等人,2012 Journal of leukocyte biology, 185:1383-1392)。因此,使用本发明的双特异性抗体(例如TIM3/PD-L1 bsAb)的治疗会逆转和阻止T-细胞衰竭,促进肿瘤监测和抑制MDSC的生成。TIM3/PD-L1 bsAb的使用可特别有益于罹患具有TIM3多态性的癌症(例如肾细胞癌和转移性肾细胞癌)的受试者的治疗。
本文公开的双特异性抗体可在疾病或医学病况(例如,癌症)的治疗中是有用的。本发明的双特异性抗体可在与T细胞衰竭相关的疾病或医学病况中是特别有用的。在一些情况下,可将本文公开的双特异性抗体用作用于促进抗原-特异性免疫应答的疫苗。本发明的双特异性抗体靶向抑制T-细胞衰竭的肿瘤。
治疗方法
本发明提供治疗处于(或易感于)癌症或其它细胞增殖-相关疾病或病症的风险中的受试者的预防和治疗方法。这类疾病或病症包括但不限于,例如,与PD-L1的异常表达相关的那些疾病或病症。例如,所述方法被用于治疗、预防或缓解肾细胞癌或乳腺癌的症状。备选地,所述方法被用于治疗、预防或缓解癌症(其中PD-L1在T细胞应答中发挥负调节作用)的症状。备选地,所述方法被用于治疗、预防或缓解实体肿瘤(例如乳腺癌、肺癌、卵巢癌、前列腺癌、结肠癌、宫颈癌、脑癌、肝癌、胰腺癌或胃癌)的症状。备选地,所述方法被用于治疗、预防或缓解已转移的癌症的症状。
本发明提供治疗处于(或易感于)慢性病毒感染、细菌感染或寄生虫感染风险中的受试者的预防和治疗方法。特别是,本发明提供治疗处于(或易感于)HIV感染或AIDS的风险中的受试者的预防和治疗方法。
本发明还提供用于治疗处于与T-细胞衰竭相关的疾病或病症或病况的风险中的或发展T-细胞衰竭的风险中的受试者的预防和治疗方法的治疗方法。本发明还提供用于治疗处于与T-细胞衰竭相关的疾病或病症或病况的风险中或发展T-细胞衰竭的风险中的受试者的预防和治疗方法的治疗方法。这类疾病或病症包括但不限于HIV、AIDS和慢性的细菌感染、病毒感染或寄生虫感染。其它这类慢性感染包括由例如,乙肝病毒(HBV)、丙肝病毒(HCV)、单纯疱疹病毒1 (HSV-1)、幽门螺杆菌(H. pylori)或弓形虫(Toxoplasma gondii)引起的那些。
因此,在一方面中,本发明提供通过将本发明的单克隆抗体或scFv抗体给予受试者用于在受试者中预防、治疗或缓解癌症或细胞增殖性疾病或病症的症状的方法。例如,huPD-L1抗体可以治疗上有效的量给予。
处于癌症或细胞增殖-相关疾病或病症风险中的受试者包括具有癌症家族史的患者或暴露于已知或怀疑致癌的物质的受试者。预防药物的给予可发生在癌症的表现之前,使得疾病被预防或,备选地,在其进展中被延缓。
在另一方面中,通过将细胞与本发明的PD-L1抗体接触而抑制肿瘤细胞的生长或减弱抑制因子T细胞活性。所述细胞是表达PD-L1的任何细胞。例如所述细胞是T细胞。
增加或增强对抗原的免疫应答的方法也包含在本发明中。免疫应答通过对受试者给予本发明的单克隆抗体或scFv抗体而增加或增强。免疫应答例如通过提高抗原特异性T效应子功能而被提高。抗原是病毒(例如HIV)抗原、细菌抗原、寄生虫抗原或肿瘤抗原。免疫应答是天然免疫应答。天然免疫应答是指其为感染的结果的免疫应答。感染是慢性感染。增加或增强对抗原的免疫应答可通过本领域已知的多种方法测量。例如,免疫应答可通过测量以下任一项而测量:T细胞活性、T细胞增殖、T细胞活化、效应子细胞因子的产生和T细胞转录特征。
备选地,免疫应答是由于接种疫苗诱导的应答。因此,在另一方面中,本发明提供通过对受试者给予本发明的单克隆抗体或scFv抗体和疫苗而增加疫苗功效的方法。所述抗体和所述疫苗被序贯或同时给予。所述疫苗是肿瘤疫苗、细菌疫苗或病毒疫苗。
组合方法
本发明提供通过给予两种抗体在患者中治疗癌症,所述两种抗体结合至PD-L1蛋白的相同表位或,备选地,PD-L1蛋白的两个不同表位。备选地,癌症通过给予结合至PD-L1的第一抗体和结合至除PD-L1之外的蛋白的第二抗体而治疗。例如,除PD-L1之外的其它蛋白可包括但不限于CAIX、CCR4和IL-10。例如,所述除PD-L1之外的其它蛋白是肿瘤-相关抗原。
在一些实施方案中,本发明提供huPD-L1抗体单独或与另外的抗体(其识别除PD-L1之外的另一蛋白)一起给予,其中细胞能够实现或提高免疫应答。例如,这些细胞可为外周血单核细胞(PBMC)或存在于PBMC中的任何细胞类型,例如,细胞毒性T细胞、巨噬细胞和天然杀伤(NK)细胞。
另外,本发明提供结合至PD-L1蛋白的抗体和抗-肿瘤剂,例如小分子、生长因子、细胞因子或其它治疗剂(其包括生物分子例如肽、肽模拟物、类肽、聚核苷酸、脂质-衍生的介质、小生物来源的胺、激素、神经肽和蛋白酶)的给予。小分子包括但不限于无机分子和小有机分子。合适的生长因子或细胞因子包括IL-2、GM-CSF、IL-12和TNF-α。小分子文库是本领域已知的。(参见Lam, Anticancer Drug Des., 12:145, 1997.)。
本发明将在以下实施例中进一步描述,所述实施例不限制描述于权利要求中的本发明的范围。
实施例
实施例1:抗PD-L1的人mAb的产生
抗人PD-L1的人mAb通过对270亿个成分的人scFv噬菌体展示文库淘选而产生。使用呈顺磁性的脂蛋白体(PMPL)形式的全长PD-L1(这确保用于展示于文库的PD-L1的细胞外结构域的正确定向),鉴定出14个独特的结合PD-L1的scFv-噬菌体。针对这些14个独特的scFv-噬菌体构建人IgG构建体:Ab-14、Ab-16、Ab-22、Ab-30、Ab-31、Ab-32、Ab-38、Ab-42、Ab-46、Ab-50、Ab-52、Ab-5、Ab-56和Ab-65。
实施例2:结合至PD-L1的huPD-L1 mAb的表征
huPD-L1抗体的结合分析使用PD-L1-表达细胞进行。测试了四种类型的细胞,其包括亲本细胞系300.19和经转染表达人PD-L1(hPD-L1)、人PD-L2 (HPD-L2)和人C-型凝集素结构域家族2成员(hCLEC2D)的细胞系。结合测定一式两份进行,结果概述在下表16-19和图2中。通过使用四种抗体浓度:10 μg/ml、1 μg/ml、0.1 μg/ml和0.01 μg/ml测试抗体亲和力。将GF1538和GF1757抗体用作对照:GF1538是抗hPD-L1的人源化Ab和GF1757是抗hPD-L2的人源化Ab。使用的第二抗体是PE-山羊抗-人IgG。所有值显示平均荧光强度(GMFI)(如通过FAC分析所检测)。
来自结合测定的结果表明受测试的huPD-L1抗体表现出对于结合PD-L1的高亲和性和特异性。使用亲本细胞系300.19(其不表达人PD-L1)作为对照,建立了基础的或非特异性的荧光(表16和图2,左上)。通过用huPD-L1抗体转染对表达人PD-L1的300.19细胞的染色显示出明显较高的平均荧光强度(MFI),这证明该抗体可结合至PD-L1。明显的FMI值(甚至在抗体的0.01 μg/ml的最低稀释度下)证明huPD-L1对结合PD-L1蛋白的高亲和力(表17A、17B和图2,右上)。当HuPD-L1抗体当在300.19细胞中表达时展示出一些结合人PD-L2或CLEC2D的能力(如由表18A、18B、19A、19B和图2,下部两张图所展示)。不过,染色PD-L2和CLE2D所得的MFI值不如PD-L1获得的值高。此外,在较低稀释度下,所述MFI值并不明显高于基础水平,这表明huPD-L1抗体不具有对PD-L2或CLE2D的高亲和力或特异性。尽管少数huPD-L1抗体(例如Ab-42)展示了和PD-L2的一些交叉反应性,但是该抗体具有明显更高的对PD-L1的亲和力和特异性。
表16. 使用huPD-L1在未转染的300.19细胞上染色
表17A.使用huPD-L1在hPD-L1-转染的300.19细胞上染色,测定1结果。
表17B.使用huPD-L1在hPD-L1-转染的300.19细胞上染色,测定2结果。
表18A.使用huPD-L1在hPD-L2-转染的300.19细胞上染色,测定1结果。
表18B.使用huPD-L1在hPD-L2-转染的300.19细胞上染色,测定2结果。
表19A.使用huPD-L1在hCLEC2D-转染的300.19细胞上染色,测定1。
表19B.使用huPD-L1在hCLEC2-转染的300.19细胞上染色,测定2。
实施例2:阻断PD/PD-L1结合的抗-PD-L1的噬菌体-抗体的表征
进行竞争性FACS分析以表征通过抗-PD-L1的噬菌体抗体对hPD1结合至hPD-L1的抑制。所有抗-hPD-L1抗体呈噬菌体-scFv形式。用编码融合至人Fc区的人PD-L1的载体(用于hPD-L1-Fc的表达)转染293T细胞。在此测定中,将1012个噬斑形成单位(pfu)的噬菌体-scFv与大约0.25 mg/ml的可溶性hPD-1-hFc融合蛋白混合并随后加入至hPD-L1-表达的293T细胞。在洗涤之后,将细胞与FITC-抗-人IgG抗体一起孵育并通过FACS分析以测量在细胞表面上hPD1-hFc与hPD-L1的结合。
荧光值通过FACS分析获得并用于生成对hPD-1结合至hPD-L1+细胞的抑制百分比。这些值展示于图3中。几乎所有的抗-PD-L1噬菌体scFvs都表现出一些对hPD-1至hPD-L1的结合的抑制能力。尤其,Ab-14、Ab-16、Ab-30、Ab-31、Ab-42、Ab-50、Ab-52和Ab-55噬菌体-scFvs表现出对hPD-1/hPD-L1结合的明显抑制。
实施例3:阻断PD/PD-L1结合的huPD-L1可溶性mAb的表征
进行竞争性FACS分析以表征通过本发明的可溶性huPD-L1抗体对hPD1结合至hPD-L1的抑制。针对它们抑制hPD1-IgG融合蛋白与hPD-L1-表达300.19细胞的结合的能力,测试所有huPD-L1抗体。在此测定中,50,000个表达hPD-L1的细胞与以下浓度的huPD-L1或对照抗体一起预孵育30分钟:10 μg/ml、1 μg/ml、0.1 μg/ml和0.01 μg/ml。在预孵育之后,将0.125 μg的融合至小鼠IgG2的人PD1加入细胞并孵育另外30分钟。将该细胞洗涤两次,并随后将0.125 μg的山羊抗-小鼠IgG2-PE抗体加入细胞中。在孵育30分钟之后,将细胞洗涤两次并随后通过FACS分析。将由FACS分析获得的值表示为平均荧光强度单位(MFI)并概述在表20中。来自表20的MFI值被用于生成图4的对hPD1与hPD-L1+细胞的结合的抑制百分比。如本文所示,所有受测试的huPD-L1可溶性抗体在10 μg/ml下表现出对hPD1与hPD-L1的结合的几乎完全抑制。在连续更低的浓度下,多数可溶性抗体仍然表现出对PD1/PD-L1结合的非常良好抑制,特别是Ab-42和Ab-50。
表20.使用huPD-L1阻断PD-1结合的结果
实施例4:双特异性抗体的形成
基于铰链在产生IgG4分子的半单体中的作用,假设在人IgG1的铰链区引入带电荷的突变可不仅促进半单体交换而且也潜在性地稳定双特异性分子。此实施例表明铰链突变和CH3突变的组合增加双特异性抗体的形成。
为进一步稳定杂二聚体的形成,将带相反电荷的突变进一步替换在CH3结构域中,这是“结进孔”的概念。双特异性抗体的形成按以下步骤实现:第一,分别表达并纯化携带有双特异性突变的两种亲本抗体。随后将所述抗体在温和的还原剂存在下混合。所述对抗体的温和还原引起将抗体解离为各自具有可变的重链和轻链的两个单体。随后将单体混合在一起,接着进行氧化步骤,其引起双特异性抗体分子的形成。
生成识别PD-L1和G250(碳酸酐酶IX)的双特异性抗体。通过两个独立的载体产生和纯化抗-G250亲本的(G37野生型,G37WT)和工程改造的(G37 KIHA)抗体。G37 KIHA(其遵循“结进孔”概念并携带双特异性突变)在免疫球蛋白铰链区的序列中被改变。
为了解G37 KIHA的解离活性,通过处于不同浓度的谷胱甘肽(GSH)使抗体在温和的还原剂存在下混合以干扰形成抗体单体(图7A)。加入渐增浓度的还原剂(GSH)引起抗体解离成单体(如在图7A中,通过低分子重量物类的水平增加所示)。
类似地,通过两个独立的载体表达和纯化抗-PD-L1亲本(PD-L1野生型,PDL-1WT)和工程改造的(PD-L1 KIHB)抗体。使用不同浓度的GSH验证用以获得抗-PD-L1单体的合适条件(图7B)。选出GSH浓度的最优条件并且将所得抗-PD-L1单体与G37 KIHA单体一起孵育。双特异性抗体的形成在野生型IgG的相同大小处被观察到,这说明生成了含有两个重链-轻链的单体(一个PD-L1-特异性单体和一个G250-特异性单体)的抗体。
实施例 5:双特异性抗体功能
实施例3中生成的双特异性抗体随后被针对它们识别两种抗原(例如,PD-L1和G250)的能力进行测试。PD-L1和G250双特异性抗体的功能使用流式细胞术测试。CAIX+PD-L1- SKRC-52表达CAIX (250)而非PD-L1,并因此预期细胞可仅被抗-CAIX抗体G37识别,而非抗PD-L1抗体识别。为避免抗体结合的饱和,抗体的浓度是低的并呈减少剂量的方式。事实上,亲本抗-G37识别SKRC-52细胞,而亲本抗-PD-L1不是如此(水平与对照相同)。含缀合的抗-G37和抗-PD-L1单体的双特异性抗体以相对于亲本G37抗体减少一半的浓度识别SKRC-52细胞,由此证明了使用本文描述的方法和抗体生成的双特异性抗体的功能性。
实施例6:对mAb42的功能表征
进行对抗PD-L1的单克隆抗体(mAb42)的进一步功能表征。培养来自4个不同健康供体(D1-D4)的外周血单核细胞(PBMC)。PBMC在mAb42存在下或在对照同种型IgG抗体的存在下培养。将PMBC用0.1 μg/ml SEB (葡萄球菌肠毒素B)刺激并使用MSD (Meso ScaleDelivery)测量TNFα的产生。样品分析以一式三份的方式进行。
如在图8中所示,与对照抗体相比,在全部四个供体样品中当在抗-PD-L1抗体(mAb42)的存在下培养时,在mAb42的存在下培养PBMC引起在响应SEB时TNFα的产生增加。此外,TNFα产生的增加是统计上显著的,p<0.0005。因此,使用抗-PD-L1抗体的治疗提高在响应人中的抗原或感染时的免疫应答。
其它实施方案
尽管本发明已经结合其详述进行了描述,但上述描述意图阐明而非限制本发明的范围,本发明的范围通过随附的权利要求的范围定义。其它方面、优点和修改在随附权利要求的范围内。
序列表
<110> Dana-Farber Cancer Institute, Inc.
Marasco, Wayne A.
Sui, Jianhua
<120> 人单克隆抗-PD-L1抗体和使用方法
<130> 20363-068001WO
<140> PCT/US13/63509
<141> 2013-10-04
<150> US 61/709,731
<151> 2012-10-04
<150> US 61/779,969
<151> 2013-03-13
<160> 140
<170> PatentIn version 3.5
<210> 1
<211> 372
<212> DNA
<213> 人工序列
<220>
<223> Ab-14的可变重链
<400> 1
caggtgcagc tggtgcagtc tggagctgag gtgaagaagc ctggggcctc agtgaaggtc 60
tcctgcaagg cttctggtta cacctttacc agctatggta tcagctgggt gcgacaggcc 120
cctggacaag ggcttgagtg gatgggatgg atcagcgctt acaatggtaa cacaaactat 180
gcacagaagc tccagggcag agtcaccatg accacagaca catccacgag cacagcctac 240
atggagctga ggagcctgag atctgacgac acggccgtgt attactgtgc gagagctcta 300
cctagtggga ctatactggt cggaggttgg ttcgacccct ggggccaggg aaccctggtc 360
accgtctcct ca 372
<210> 2
<211> 124
<212> PRT
<213> 人工序列
<220>
<223> Ab-14的可变重链
<400> 2
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr
20 25 30
Gly Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Trp Ile Ser Ala Tyr Asn Gly Asn Thr Asn Tyr Ala Gln Lys Leu
50 55 60
Gln Gly Arg Val Thr Met Thr Thr Asp Thr Ser Thr Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Arg Ser Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Ala Leu Pro Ser Gly Thr Ile Leu Val Gly Gly Trp Phe Asp
100 105 110
Pro Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 3
<211> 333
<212> DNA
<213> 人工序列
<220>
<223> Ab-14的可变轻链
<400> 3
aattttatgc tgactcagcc ccactctgtg tcggagtctc cggggaagac ggtaaccatc 60
tcctgcaccc gcagcagtgg caacattgcc agcaattatg tgcagtggta ccaacagcgc 120
ccgggcagtg cccccaccac tgtgatctat gaggataacc aaagaccctc tggggtccct 180
gatcggttct ctggctccat cgacagctcc tccaactctg cctccctcac catctctgga 240
ctgaagactg aggacgaggc tgactactac tgtcagtctt atgatagcag caatctttgg 300
gtgttcggcg gagggaccaa gctgaccgtc cta 333
<210> 4
<211> 111
<212> PRT
<213> 人工序列
<220>
<223> Ab-14的可变轻链
<400> 4
Asn Phe Met Leu Thr Gln Pro His Ser Val Ser Glu Ser Pro Gly Lys
1 5 10 15
Thr Val Thr Ile Ser Cys Thr Arg Ser Ser Gly Asn Ile Ala Ser Asn
20 25 30
Tyr Val Gln Trp Tyr Gln Gln Arg Pro Gly Ser Ala Pro Thr Thr Val
35 40 45
Ile Tyr Glu Asp Asn Gln Arg Pro Ser Gly Val Pro Asp Arg Phe Ser
50 55 60
Gly Ser Ile Asp Ser Ser Ser Asn Ser Ala Ser Leu Thr Ile Ser Gly
65 70 75 80
Leu Lys Thr Glu Asp Glu Ala Asp Tyr Tyr Cys Gln Ser Tyr Asp Ser
85 90 95
Ser Asn Leu Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu
100 105 110
<210> 5
<211> 372
<212> DNA
<213> 人工序列
<220>
<223> Ab-16的可变重链
<400> 5
gaggtgcagc tggtgcagtc tgggggaggc gtggtccagc ctgggaggtc cctgagactc 60
tcctgtgcag cctctggatt cacctttagc agctatgccc tgagctgggt ccgccaggct 120
ccagggaagg ggctggagtg ggtctcagct attagtggtg gtggtggtag cacatactac 180
gcagactccg tgaagggccg gttcaccatc tccagagaca attccaagaa cacgctgtat 240
ctgcaaatga acagcctgag agccgaggac acggccgtat attactgtgc gaaagacgtg 300
tttccagaga ctttttcgat gaactacggt atggacgtct ggggccaagg aaccctggtc 360
accgtctcct ca 372
<210> 6
<211> 124
<212> PRT
<213> 人工序列
<220>
<223> Ab-16的可变重链
<400> 6
Glu Val Gln Leu Val Gln Ser Gly Gly Gly Val Val Gln Pro Gly Arg
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30
Ala Leu Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Ala Ile Ser Gly Gly Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Lys Asp Val Phe Pro Glu Thr Phe Ser Met Asn Tyr Gly Met Asp
100 105 110
Val Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 7
<211> 324
<212> DNA
<213> 人工序列
<220>
<223> Ab-16的可变轻链
<400> 7
tcttctgagc tgactcagga ccctgctgtg tctgtggcct tgggacagac agtcaggatc 60
acatgccaag gagacagcct cagaagctat tatgcaagct ggtaccagca gaagccagga 120
caggcccctg tacttgtcat ctatggtaaa aacaaccggc cctcagggat cccagaccga 180
ttctctggct ccagctcagg aaacacagct tccttgacca tcactggggc tcaggcggaa 240
gatgaggctg actattactg taactcccgg gacagcagtg gtaaccatta tgtcttcgga 300
actgggacca aggtcaccgt ccta 324
<210> 8
<211> 108
<212> PRT
<213> 人工序列
<220>
<223> Ab-16的可变轻链
<400> 8
Ser Ser Glu Leu Thr Gln Asp Pro Ala Val Ser Val Ala Leu Gly Gln
1 5 10 15
Thr Val Arg Ile Thr Cys Gln Gly Asp Ser Leu Arg Ser Tyr Tyr Ala
20 25 30
Ser Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Val Leu Val Ile Tyr
35 40 45
Gly Lys Asn Asn Arg Pro Ser Gly Ile Pro Asp Arg Phe Ser Gly Ser
50 55 60
Ser Ser Gly Asn Thr Ala Ser Leu Thr Ile Thr Gly Ala Gln Ala Glu
65 70 75 80
Asp Glu Ala Asp Tyr Tyr Cys Asn Ser Arg Asp Ser Ser Gly Asn His
85 90 95
Tyr Val Phe Gly Thr Gly Thr Lys Val Thr Val Leu
100 105
<210> 9
<211> 384
<212> DNA
<213> 人工序列
<220>
<223> Ab-22的可变重链
<400> 9
caggtgcagc tggtgcagtc tgggggaggc gtggtacagc ctggggggtc cctgagactc 60
tcctgtgcag cctctggatt cacctttgat gattatgcca tgcactgggt ccgtcaagct 120
ccagggaagg gtctggagtg ggtctctctt attagtgggg atggtggtag cacatactat 180
gcagactctg tgaagggccg attcaccatc tccagagaca acagcaaaaa ctccctgtat 240
ctgcaaatga acagtctgag aactgaggac accgccttgt attactgtgc aaaagtgctc 300
ctcccctgta gtagtaccag ctgctatgga agcgtcggtg cttttgatat ctggggccaa 360
gggaccacgg tcaccgtctc ctca 384
<210> 10
<211> 128
<212> PRT
<213> 人工序列
<220>
<223> Ab-22的可变重链
<400> 10
Gln Val Gln Leu Val Gln Ser Gly Gly Gly Val Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asp Asp Tyr
20 25 30
Ala Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Leu Ile Ser Gly Asp Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Ser Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Thr Glu Asp Thr Ala Leu Tyr Tyr Cys
85 90 95
Ala Lys Val Leu Leu Pro Cys Ser Ser Thr Ser Cys Tyr Gly Ser Val
100 105 110
Gly Ala Phe Asp Ile Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser
115 120 125
<210> 11
<211> 324
<212> DNA
<213> 人工序列
<220>
<223> Ab-22的可变轻链
<400> 11
taggacgatg agctcggtcc cagctccgaa gacataatga tcactattat tatcccacac 60
ctgacagtaa taatcggcct catcaccggc ttcgaccctg ctgatggtca gggtggccgt 120
gttcccagag ttggagccag agaatcgctc agagatccct gagggccggt ccctatcaga 180
gtagatgacc aacgcagggg cctggcctgg cttctgctgg taccagtgca cactcttcct 240
tccaatgtcg cttcccccac aggtaatcct ggccgtcttt cctggggcca ctgacactga 300
gggtgcctga gtcagcacag gcag 324
<210> 12
<211> 108
<212> PRT
<213> 人工序列
<220>
<223> Ab-22的可变轻链
<400> 12
Leu Pro Val Leu Thr Gln Ala Pro Ser Val Ser Val Ala Pro Gly Lys
1 5 10 15
Thr Ala Arg Ile Thr Cys Gly Gly Ser Asp Ile Gly Arg Lys Ser Val
20 25 30
His Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Ala Leu Val Ile Tyr
35 40 45
Ser Asp Arg Asp Arg Pro Ser Gly Ile Ser Glu Arg Phe Ser Gly Ser
50 55 60
Asn Ser Gly Asn Thr Ala Thr Leu Thr Ile Ser Arg Val Glu Ala Gly
65 70 75 80
Asp Glu Ala Asp Tyr Tyr Cys Gln Val Trp Asp Asn Asn Ser Asp His
85 90 95
Tyr Val Phe Gly Ala Gly Thr Glu Leu Ile Val Leu
100 105
<210> 13
<211> 351
<212> DNA
<213> 人工序列
<220>
<223> Ab-30的可变重链
<400> 13
caggtgcagc tggtgcagtc tgggggaagt gtggtacggc ctggggaatc cctcagactc 60
tcctgtgtag cctctggatt catctttgat aattatgaca tgagttgggt ccgccaagtt 120
ccagggaagg ggctggagtg ggtctctcgt gttaattgga atggtggtag cacaacttat 180
gcagacgctg tgaagggccg attcaccatc tccagagaca acaccaagaa ctccctgtat 240
ctacaaatga acaacctgag agccgaagac acggccgtgt attactgtgt gcgcgagttt 300
gtcggtgctt atgatctctg gggccagggg accacggtca ccgtctcctc a 351
<210> 14
<211> 117
<212> PRT
<213> 人工序列
<220>
<223> Ab-30的可变重链
<400> 14
Gln Val Gln Leu Val Gln Ser Gly Gly Ser Val Val Arg Pro Gly Glu
1 5 10 15
Ser Leu Arg Leu Ser Cys Val Ala Ser Gly Phe Ile Phe Asp Asn Tyr
20 25 30
Asp Met Ser Trp Val Arg Gln Val Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Arg Val Asn Trp Asn Gly Gly Ser Thr Thr Tyr Ala Asp Ala Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Thr Lys Asn Ser Leu Tyr
65 70 75 80
Leu Gln Met Asn Asn Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Val Arg Glu Phe Val Gly Ala Tyr Asp Leu Trp Gly Gln Gly Thr Thr
100 105 110
Val Thr Val Ser Ser
115
<210> 15
<211> 327
<212> DNA
<213> 人工序列
<220>
<223> Ab-30的可变轻链
<400> 15
cagtctgccc tgactcagcc tgcctccgtg tctgggtctc ctggacagtc gatcaccatc 60
tcctgcactg gaaccagcag tgacgttggt ggttataact atgtctcctg gtaccaacaa 120
cacccaggca aagcccccaa actcatgatt tatgatgtca gtaatcggcc ctcaggggtt 180
tctaatcgct tctctggctc caagtctggc aacacggcct ccctgaccat ctctgggctc 240
caggctgagg acgaggctga ttattactgc agctcatata caagcagcac tctgccgttc 300
ggcggaggga ccaagctgac cgtccta 327
<210> 16
<211> 109
<212> PRT
<213> 人工序列
<220>
<223> Ab-30的可变轻链
<400> 16
Gln Ser Ala Leu Thr Gln Pro Ala Ser Val Ser Gly Ser Pro Gly Gln
1 5 10 15
Ser Ile Thr Ile Ser Cys Thr Gly Thr Ser Ser Asp Val Gly Gly Tyr
20 25 30
Asn Tyr Val Ser Trp Tyr Gln Gln His Pro Gly Lys Ala Pro Lys Leu
35 40 45
Met Ile Tyr Asp Val Ser Asn Arg Pro Ser Gly Val Ser Asn Arg Phe
50 55 60
Ser Gly Ser Lys Ser Gly Asn Thr Ala Ser Leu Thr Ile Ser Gly Leu
65 70 75 80
Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Ser Ser Tyr Thr Ser Ser
85 90 95
Thr Leu Pro Phe Gly Gly Gly Thr Lys Leu Thr Val Leu
100 105
<210> 17
<211> 363
<212> DNA
<213> 人工序列
<220>
<223> Ab-31的可变重链
<400> 17
caggtgcagc tggtgcagtc tggggctgag gtgaagaagc caggggccac agtgaaggtc 60
tcctgcaagg tttttggaga caccttccgc ggcctctata tacactgggt gcgacaggcc 120
cctggacaag ggcttgagtg gatgggaggg atcatcccta tctttggtac agcaaactac 180
gcacagaagt tccagggcag agtcacgatt accacggacg aatccacgag cacagcctac 240
atggagctga gcagcctgag atctgaggac acggccgtgt attactgtgc gagcggacta 300
cgttggggga tctggggctg gttcgacccc tggggccagg gcaccctggt caccgtctcc 360
tca 363
<210> 18
<211> 121
<212> PRT
<213> 人工序列
<220>
<223> Ab-31的可变重链
<400> 18
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Thr Val Lys Val Ser Cys Lys Val Phe Gly Asp Thr Phe Arg Gly Leu
20 25 30
Tyr Ile His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Gly Ile Ile Pro Ile Phe Gly Thr Ala Asn Tyr Ala Gln Lys Phe
50 55 60
Gln Gly Arg Val Thr Ile Thr Thr Asp Glu Ser Thr Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Ser Gly Leu Arg Trp Gly Ile Trp Gly Trp Phe Asp Pro Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 19
<211> 321
<212> DNA
<213> 人工序列
<220>
<223> Ab-31的可变轻链
<400> 19
gaaattgtgt tgacgcagtc tccagccacc ctgtctttgt ctccagggga aagagccacc 60
ctctcctgca gggccagtca gagtattggc aacagcttag cctggtacca gcagaaacct 120
ggccaggctc ccaggctcct catgtatggt gcatccagca gggccactgg catcccagac 180
aggttcagtg gcagtggggc tgggacagac ttcactctca ccatcagcag cctagagcct 240
gaagattttg caacgtatta ctgtcagcag catactatcc caacattctc tttcggccct 300
gggaccaaag tggaagtcaa a 321
<210> 20
<211> 107
<212> PRT
<213> 人工序列
<220>
<223> Ab-31的可变轻链
<400> 20
Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Ile Gly Asn Ser
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Met
35 40 45
Tyr Gly Ala Ser Ser Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser Gly
50 55 60
Ser Gly Ala Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Glu Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln His Thr Ile Pro Thr Phe
85 90 95
Ser Phe Gly Pro Gly Thr Lys Val Glu Val Lys
100 105
<210> 21
<211> 363
<212> DNA
<213> 人工序列
<220>
<223> Ab-32的可变重链
<400> 21
gaggtgcagc tggtgcagtc tggggctgag ctgaagaagc ctgggtcctc ggtgaaggtc 60
tcctgcaagg cttttggagg caccttcagt gacaatgcta tcagctgggt gcgacaggcc 120
cctggacaag ggcctgagtg gatggggggc atcattccta tctttggaaa accaaactac 180
gcacagaagt tccagggcag agtcacgatt accgcggacg aatccacgag cactgcctac 240
atggtcctga gcagcctgag atctgaggac acggccgtat attactgtgc gagaactatg 300
gttcggggct ttcttggggt tatggacgtc tggggccaag ggaccacggt caccgtctcc 360
tca 363
<210> 22
<211> 121
<212> PRT
<213> 人工序列
<220>
<223> Ab-32的可变重链
<400> 22
Glu Val Gln Leu Val Gln Ser Gly Ala Glu Leu Lys Lys Pro Gly Ser
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Phe Gly Gly Thr Phe Ser Asp Asn
20 25 30
Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Pro Glu Trp Met
35 40 45
Gly Gly Ile Ile Pro Ile Phe Gly Lys Pro Asn Tyr Ala Gln Lys Phe
50 55 60
Gln Gly Arg Val Thr Ile Thr Ala Asp Glu Ser Thr Ser Thr Ala Tyr
65 70 75 80
Met Val Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Thr Met Val Arg Gly Phe Leu Gly Val Met Asp Val Trp Gly
100 105 110
Gln Gly Thr Thr Val Thr Val Ser Ser
115 120
<210> 23
<211> 321
<212> DNA
<213> 人工序列
<220>
<223> Ab-32的可变轻链
<400> 23
gatattgtga tgacccagac tccatccttc ctgtccgcat ccataggaga cagagtcacc 60
atcacttgcc gggccagtca gggcattggc agttatttag cctggtatca gcaaagacca 120
ggggaagccc ctaagctcct gatctatgct gcatcgactt tgcaaagtgg agtcccatca 180
aggttcagcg gcagtggatc tgggacggac ttcactctca caatcagcaa cctgcagcct 240
gaagattttg caacttatta ctgtcaacag cttaataatt acccgatcac cttcggccaa 300
gggacacgac tggagattaa a 321
<210> 24
<211> 107
<212> PRT
<213> 人工序列
<220>
<223> Ab-32的可变轻链
<400> 24
Asp Ile Val Met Thr Gln Thr Pro Ser Phe Leu Ser Ala Ser Ile Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Gly Ser Tyr
20 25 30
Leu Ala Trp Tyr Gln Gln Arg Pro Gly Glu Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Ala Ala Ser Thr Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Asn Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Leu Asn Asn Tyr Pro Ile
85 90 95
Thr Phe Gly Gln Gly Thr Arg Leu Glu Ile Lys
100 105
<210> 25
<211> 375
<212> DNA
<213> 人工序列
<220>
<223> Ab-38的可变重链
<400> 25
caggtgcagc tggtgcagtc tgggggaggc ttggtacagc ctggggggtc cctgagactc 60
tcctgtgcag cctctggatt cacctttagc agctatgcca tgagctgggt ccgccaggct 120
ccagggaagg ggctggagtg ggtctcagct attagtggta gtggtggtag cacatactac 180
gcagactccg tgaagggccg gttcaccatc tccagagaca attccaagaa cacgctgtat 240
ctgcaaatga acagcctgag agccgaggac acggccgtat attactgtgc gaaagatcag 300
ttcgttacga tttttggagt gccaagatac ggtatggacg tctggggcca agggaccacg 360
gtcaccgtct cctca 375
<210> 26
<211> 125
<212> PRT
<213> 人工序列
<220>
<223> Ab-38的可变重链
<400> 26
Gln Val Gln Leu Val Gln Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30
Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Ala Ile Ser Gly Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Lys Asp Gln Phe Val Thr Ile Phe Gly Val Pro Arg Tyr Gly Met
100 105 110
Asp Val Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser
115 120 125
<210> 27
<211> 315
<212> DNA
<213> 人工序列
<220>
<223> Ab-38的可变轻链
<400> 27
cagtctgccc tgactcagcc accctcagtg tccgtgtccc caggacagac agccaacatc 60
ccctgctctg gagataaatt ggggaataaa tatgcttact ggtatcagca gaagccaggc 120
cagtcccctg tactgctcat ctatcaagat atcaagcggc cctcaaggat ccctgagcga 180
ttctctggct ccaactctgc ggacacagcc actctgacca tcagcgggac ccaggctatg 240
gatgaggctg actattactg tcagacgtgg gacaacagcg tggtcttcgg cggcgggacc 300
aagctgaccg tcctc 315
<210> 28
<211> 105
<212> PRT
<213> 人工序列
<220>
<223> Ab-38的可变轻链
<400> 28
Gln Ser Ala Leu Thr Gln Pro Pro Ser Val Ser Val Ser Pro Gly Gln
1 5 10 15
Thr Ala Asn Ile Pro Cys Ser Gly Asp Lys Leu Gly Asn Lys Tyr Ala
20 25 30
Tyr Trp Tyr Gln Gln Lys Pro Gly Gln Ser Pro Val Leu Leu Ile Tyr
35 40 45
Gln Asp Ile Lys Arg Pro Ser Arg Ile Pro Glu Arg Phe Ser Gly Ser
50 55 60
Asn Ser Ala Asp Thr Ala Thr Leu Thr Ile Ser Gly Thr Gln Ala Met
65 70 75 80
Asp Glu Ala Asp Tyr Tyr Cys Gln Thr Trp Asp Asn Ser Val Val Phe
85 90 95
Gly Gly Gly Thr Lys Leu Thr Val Leu
100 105
<210> 29
<211> 360
<212> DNA
<213> 人工序列
<220>
<223> Ab-42的可变重链
<400> 29
caggtgcagc tggtgcagtc tggggctgag gtgaagaagc ctgggtcctc ggtgaaggtc 60
tcctgcaagg cttctggagg caccttcagc agctatgcta tcagctgggt gcgacaggcc 120
cctggacaag ggcttgagtg gatgggaggg atcatcccta tctttggtac agcaaactac 180
gcacagaagt tccagggcag agtcacgatt accgcggaca aatccacgag cacagcctac 240
atggagctga gcagcctgag atctgaggac acggccgtct attactgtgc gagagggcgt 300
caaatgttcg gtgcgggaat tgatttctgg ggcccgggca ccctggtcac cgtctcctca 360
<210> 30
<211> 120
<212> PRT
<213> 人工序列
<220>
<223> Ab-42的可变重链
<400> 30
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Ser Tyr
20 25 30
Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Gly Ile Ile Pro Ile Phe Gly Thr Ala Asn Tyr Ala Gln Lys Phe
50 55 60
Gln Gly Arg Val Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Arg Gln Met Phe Gly Ala Gly Ile Asp Phe Trp Gly Pro
100 105 110
Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 31
<211> 336
<212> DNA
<213> 人工序列
<220>
<223> Ab-42的可变轻链
<400> 31
aattttatgc tgactcagcc ccactctgtg tcggagtctc cggggaagac ggtaaccatc 60
tcctgcaccc gcagcagtgg cagcattgac agcaactatg tgcagtggta ccagcagcgc 120
ccgggcagcg cccccaccac tgtgatctat gaggataacc aaagaccctc tggggtccct 180
gatcggttct ctggctccat cgacagctcc tccaactctg cctccctcac catctctgga 240
ctgaagactg aggacgaggc tgactactac tgtcagtctt atgatagcaa caatcgtcat 300
gtgatattcg gcggagggac caagctgacc gtccta 336
<210> 32
<211> 112
<212> PRT
<213> 人工序列
<220>
<223> Ab-42的可变轻链
<400> 32
Asn Phe Met Leu Thr Gln Pro His Ser Val Ser Glu Ser Pro Gly Lys
1 5 10 15
Thr Val Thr Ile Ser Cys Thr Arg Ser Ser Gly Ser Ile Asp Ser Asn
20 25 30
Tyr Val Gln Trp Tyr Gln Gln Arg Pro Gly Ser Ala Pro Thr Thr Val
35 40 45
Ile Tyr Glu Asp Asn Gln Arg Pro Ser Gly Val Pro Asp Arg Phe Ser
50 55 60
Gly Ser Ile Asp Ser Ser Ser Asn Ser Ala Ser Leu Thr Ile Ser Gly
65 70 75 80
Leu Lys Thr Glu Asp Glu Ala Asp Tyr Tyr Cys Gln Ser Tyr Asp Ser
85 90 95
Asn Asn Arg His Val Ile Phe Gly Gly Gly Thr Lys Leu Thr Val Leu
100 105 110
<210> 33
<211> 354
<212> DNA
<213> 人工序列
<220>
<223> Ab-46的可变重链
<400> 33
gaggtgcagc tggtggagtc tggggctgaa gtaaagaagc ctgggtcctc ggtgaaagtc 60
tcctgcaagg tttcaggagg cacattcggc acctatgctc tcaactgggt gcgccaggcc 120
cctggacaag ggcttgagtg gatgggaagg atcgtccctc tcattggtct agtaaactac 180
gcacataact ttgagggcag aatctcgatt accgcggaca agtccacggg cacagcctac 240
atggaactga gcaacctgag atctgacgac acggccgtgt attactgtgc gagagaggtc 300
tacggtggta actccgacta ctggggccag ggaaccctgg tcaccgtctc ctca 354
<210> 34
<211> 118
<212> PRT
<213> 人工序列
<220>
<223> Ab-46的可变重链
<400> 34
Glu Val Gln Leu Val Glu Ser Gly Ala Glu Val Lys Lys Pro Gly Ser
1 5 10 15
Ser Val Lys Val Ser Cys Lys Val Ser Gly Gly Thr Phe Gly Thr Tyr
20 25 30
Ala Leu Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Arg Ile Val Pro Leu Ile Gly Leu Val Asn Tyr Ala His Asn Phe
50 55 60
Glu Gly Arg Ile Ser Ile Thr Ala Asp Lys Ser Thr Gly Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Asn Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Glu Val Tyr Gly Gly Asn Ser Asp Tyr Trp Gly Gln Gly Thr
100 105 110
Leu Val Thr Val Ser Ser
115
<210> 35
<211> 330
<212> DNA
<213> 人工序列
<220>
<223> Ab-46的可变轻链
<400> 35
aattttatgc tgactcagcc ccactcagtg tcggagtctc cggggaagac ggtaaccatc 60
tcctgcactc gcagtagtgg caacattggc accaactatg tgcagtggta ccagcagcgc 120
ccgggcagtg cccccgtcgc tttgatctac gaggattatc gaagaccctc tggggtccct 180
gatcggttct ctggctccat cgacagctcc tccaactctg cctccctcat catctctgga 240
ctgaagcctg aggacgaggc tgactactac tgtcagtctt atcatagcag cggttgggaa 300
ttcggcggag ggaccaagct gaccgtcctc 330
<210> 36
<211> 110
<212> PRT
<213> 人工序列
<220>
<223> Ab-46的可变轻链
<400> 36
Asn Phe Met Leu Thr Gln Pro His Ser Val Ser Glu Ser Pro Gly Lys
1 5 10 15
Thr Val Thr Ile Ser Cys Thr Arg Ser Ser Gly Asn Ile Gly Thr Asn
20 25 30
Tyr Val Gln Trp Tyr Gln Gln Arg Pro Gly Ser Ala Pro Val Ala Leu
35 40 45
Ile Tyr Glu Asp Tyr Arg Arg Pro Ser Gly Val Pro Asp Arg Phe Ser
50 55 60
Gly Ser Ile Asp Ser Ser Ser Asn Ser Ala Ser Leu Ile Ile Ser Gly
65 70 75 80
Leu Lys Pro Glu Asp Glu Ala Asp Tyr Tyr Cys Gln Ser Tyr His Ser
85 90 95
Ser Gly Trp Glu Phe Gly Gly Gly Thr Lys Leu Thr Val Leu
100 105 110
<210> 37
<211> 360
<212> DNA
<213> 人工序列
<220>
<223> Ab-50的可变重链
<400> 37
caggtgcagc tggtgcagtc tggaggtgag gtgaagaagc cgggggcctc agtgaaggtc 60
tcctgcaagg cttctggtta caccttgagc agtcatggta taacctgggt gcgacaggcc 120
cctggacaag ggcttgagtg gatgggatgg atcagcgctc acaatggtca cgctagcaat 180
gcacagaagg tggaggacag agtcactatg actactgaca catccacgaa cacagcctac 240
atggaactga ggagcctgac agctgacgac acggccgtgt attactgtgc gagagtacat 300
gctgccctct actatggtat ggacgtctgg ggccaaggaa ccctggtcac cgtctcctca 360
<210> 38
<211> 120
<212> PRT
<213> 人工序列
<220>
<223> Ab-50的可变重链
<400> 38
Gln Val Gln Leu Val Gln Ser Gly Gly Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Leu Ser Ser His
20 25 30
Gly Ile Thr Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Trp Ile Ser Ala His Asn Gly His Ala Ser Asn Ala Gln Lys Val
50 55 60
Glu Asp Arg Val Thr Met Thr Thr Asp Thr Ser Thr Asn Thr Ala Tyr
65 70 75 80
Met Glu Leu Arg Ser Leu Thr Ala Asp Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Val His Ala Ala Leu Tyr Tyr Gly Met Asp Val Trp Gly Gln
100 105 110
Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 39
<211> 324
<212> DNA
<213> 人工序列
<220>
<223> Ab-50的可变轻链
<400> 39
cagtctgtgc tgactcagcc accctcggtg tcagtggccc caggacagac ggccaggatt 60
acctgtgggg gaaacaacat tggaagtaaa ggtgtgcact ggtatcagca gaagccaggc 120
caggcccctg tactggtcgt ctatgatgat agtgaccggc cctcagggat ccctgagcga 180
ttctctggct ccaactctgg gaacacggcc accctgacca tcagcagggt cgaagccggg 240
gatgaggccg actattactg tcaggtgtgg gatagtagta gtgatcattg ggtgttcggc 300
ggagggacca agctgaccgt ccta 324
<210> 40
<211> 108
<212> PRT
<213> 人工序列
<220>
<223> Ab-50的可变轻链
<400> 40
Gln Ser Val Leu Thr Gln Pro Pro Ser Val Ser Val Ala Pro Gly Gln
1 5 10 15
Thr Ala Arg Ile Thr Cys Gly Gly Asn Asn Ile Gly Ser Lys Gly Val
20 25 30
His Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Val Leu Val Val Tyr
35 40 45
Asp Asp Ser Asp Arg Pro Ser Gly Ile Pro Glu Arg Phe Ser Gly Ser
50 55 60
Asn Ser Gly Asn Thr Ala Thr Leu Thr Ile Ser Arg Val Glu Ala Gly
65 70 75 80
Asp Glu Ala Asp Tyr Tyr Cys Gln Val Trp Asp Ser Ser Ser Asp His
85 90 95
Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu
100 105
<210> 41
<211> 363
<212> DNA
<213> 人工序列
<220>
<223> Ab-52的可变重链
<400> 41
caggtgcagc tgcaggagtc ggggggaggc gtggtgcagc ctgggaggtc cctgagactc 60
tcctgttcag cctctggatt caccttcagc agacatggca tgcactgggt ccgccaggct 120
ccaggcaagg ggctggagtg ggtggcagtg atatcacatg atggaagtgt aaaatactat 180
gcagactcca tgaagggccg attcagcatc tccagagaca attccaacaa cacactgtat 240
ctccaaatgg acagcctgag agctgacgac acggccgttt attactgtgc gagaggactg 300
tcgtaccagg tgtcggggtg gttcgacccc tggggccagg gcaccctggt caccgtctcc 360
tca 363
<210> 42
<211> 121
<212> PRT
<213> 人工序列
<220>
<223> Ab-52的可变重链
<400> 42
Gln Val Gln Leu Gln Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg
1 5 10 15
Ser Leu Arg Leu Ser Cys Ser Ala Ser Gly Phe Thr Phe Ser Arg His
20 25 30
Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Val Ile Ser His Asp Gly Ser Val Lys Tyr Tyr Ala Asp Ser Met
50 55 60
Lys Gly Arg Phe Ser Ile Ser Arg Asp Asn Ser Asn Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asp Ser Leu Arg Ala Asp Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Leu Ser Tyr Gln Val Ser Gly Trp Phe Asp Pro Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 43
<211> 333
<212> DNA
<213> 人工序列
<220>
<223> Ab-52的可变轻链
<400> 43
aattttatgc tgactcagcc ccactctgtg tcggagtctc cggggaagac ggtaaccatc 60
tcctgcaccc gcagcagtgg cagcattgcc agcaactatg tgcagtggta ccagcagcgc 120
ccgggcagtg cccccaccac tgtgatctat gaggataacc aaagaccctc tggggtccct 180
gatcggttct ctggctccat cgacagctcc tccaactctg cctccctcac catctctgga 240
ctgaagactg aggacgaggc tgactactac tgtcagtctt atgatagcac caccccttcg 300
gtgttcggcg gcgggaccaa gctgaccgtc cta 333
<210> 44
<211> 111
<212> PRT
<213> 人工序列
<220>
<223> Ab-52的可变轻链
<400> 44
Asn Phe Met Leu Thr Gln Pro His Ser Val Ser Glu Ser Pro Gly Lys
1 5 10 15
Thr Val Thr Ile Ser Cys Thr Arg Ser Ser Gly Ser Ile Ala Ser Asn
20 25 30
Tyr Val Gln Trp Tyr Gln Gln Arg Pro Gly Ser Ala Pro Thr Thr Val
35 40 45
Ile Tyr Glu Asp Asn Gln Arg Pro Ser Gly Val Pro Asp Arg Phe Ser
50 55 60
Gly Ser Ile Asp Ser Ser Ser Asn Ser Ala Ser Leu Thr Ile Ser Gly
65 70 75 80
Leu Lys Thr Glu Asp Glu Ala Asp Tyr Tyr Cys Gln Ser Tyr Asp Ser
85 90 95
Thr Thr Pro Ser Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu
100 105 110
<210> 45
<211> 360
<212> DNA
<213> 人工序列
<220>
<223> Ab-55的可变重链
<400> 45
caggtgcagc tggtgcagtc tggagctgag gtgaagaagc ctggggcctc agtgaaggtc 60
tcctgcaagg cttctggtta cacctttacc agctatggta tcagctgggt gcgacaggcc 120
cctggacaag ggcttgagtg gatgggatgg accagccctc ataatggtct cacagcattt 180
gcacagatcc tagagggccg agtcaccatg accacagaca catccacgaa cacagcctac 240
atggaattga ggaacctgac atttgatgac acggccgttt atttctgtgc gaaagtacat 300
cctgtcttct cttatgcgtt ggacgtctgg ggccaaggca ccctggtcac cgtctcctca 360
<210> 46
<211> 120
<212> PRT
<213> 人工序列
<220>
<223> Ab-55的可变重链
<400> 46
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr
20 25 30
Gly Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Trp Thr Ser Pro His Asn Gly Leu Thr Ala Phe Ala Gln Ile Leu
50 55 60
Glu Gly Arg Val Thr Met Thr Thr Asp Thr Ser Thr Asn Thr Ala Tyr
65 70 75 80
Met Glu Leu Arg Asn Leu Thr Phe Asp Asp Thr Ala Val Tyr Phe Cys
85 90 95
Ala Lys Val His Pro Val Phe Ser Tyr Ala Leu Asp Val Trp Gly Gln
100 105 110
Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 47
<211> 330
<212> DNA
<213> 人工序列
<220>
<223> Ab-55的可变轻链
<400> 47
aattttatgc tgactcagcc ccactctgtg tcggagtccc cggggaagac ggtaaccatc 60
tcctgcaccc gcagcagtgg cagcattgcc agcaactatg tacagtggta ccagcagcgc 120
ccgggcagtt cccccaccac tgtgatctat gaagataacc aaagaccctc tggggtccct 180
gatcggttct ctggctccat cgacacctcc tccaactctg cctccctcac catctctgga 240
ctgaagacta aggacgaggc ggactactac tgtcagtctt atgatggcat cactgtgatt 300
ttcggcggag ggaccaagtt gaccgtccta 330
<210> 48
<211> 110
<212> PRT
<213> 人工序列
<220>
<223> Ab-55的可变轻链
<400> 48
Asn Phe Met Leu Thr Gln Pro His Ser Val Ser Glu Ser Pro Gly Lys
1 5 10 15
Thr Val Thr Ile Ser Cys Thr Arg Ser Ser Gly Ser Ile Ala Ser Asn
20 25 30
Tyr Val Gln Trp Tyr Gln Gln Arg Pro Gly Ser Ser Pro Thr Thr Val
35 40 45
Ile Tyr Glu Asp Asn Gln Arg Pro Ser Gly Val Pro Asp Arg Phe Ser
50 55 60
Gly Ser Ile Asp Thr Ser Ser Asn Ser Ala Ser Leu Thr Ile Ser Gly
65 70 75 80
Leu Lys Thr Lys Asp Glu Ala Asp Tyr Tyr Cys Gln Ser Tyr Asp Gly
85 90 95
Ile Thr Val Ile Phe Gly Gly Gly Thr Lys Leu Thr Val Leu
100 105 110
<210> 49
<211> 354
<212> DNA
<213> 人工序列
<220>
<223> Ab-56的可变重链
<400> 49
gaggtgcagc tggtggagtc tggagctgag gtgatgaacc ctgggtcctc ggtgagggtc 60
tcctgcaggg gttctggagg cgacttcagt acctatgctt tcagctgggt gcgacaggcc 120
cctggacaag ggcttgagtg gatgggaagg atcatcccta tccttggtat agcaaactac 180
gcacagaagt tccagggcag ggtcacgatt accgcggaca aatccacgag cacagcctac 240
atggagctga gcagcctgag atctgacgat acggccgtgt attactgtgc gagagatggc 300
tatggttcgg acccggtgct atggggccag ggcaccctgg tcaccgtctc ctca 354
<210> 50
<211> 118
<212> PRT
<213> 人工序列
<220>
<223> Ab-56的可变重链
<400> 50
Glu Val Gln Leu Val Glu Ser Gly Ala Glu Val Met Asn Pro Gly Ser
1 5 10 15
Ser Val Arg Val Ser Cys Arg Gly Ser Gly Gly Asp Phe Ser Thr Tyr
20 25 30
Ala Phe Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Arg Ile Ile Pro Ile Leu Gly Ile Ala Asn Tyr Ala Gln Lys Phe
50 55 60
Gln Gly Arg Val Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Asp Gly Tyr Gly Ser Asp Pro Val Leu Trp Gly Gln Gly Thr
100 105 110
Leu Val Thr Val Ser Ser
115
<210> 51
<211> 333
<212> DNA
<213> 人工序列
<220>
<223> Ab-56的可变轻链
<400> 51
aattttatgc tgactcagcc ccactctgtg tcggggtctc cggggaagac ggtaaccctc 60
ccctgcaccc gcagcagtgg cagcattgcc agccactatg tccagtggta ccagcagcgc 120
ccgggcagtg cccccaccac tgtgatctat gaggataaca agagaccctc tggggtccct 180
gatcggttct ctggctccat cgacagctcc tccaactctg cctccctcag catctctgga 240
ctgaagactg aggacgaggc tgactactac tgtcagtctt atgatagcag caatcgttgg 300
gtgttcggcg gagggaccaa gctgaccgtc cta 333
<210> 52
<211> 111
<212> PRT
<213> 人工序列
<220>
<223> Ab-56的可变轻链
<400> 52
Asn Phe Met Leu Thr Gln Pro His Ser Val Ser Gly Ser Pro Gly Lys
1 5 10 15
Thr Val Thr Leu Pro Cys Thr Arg Ser Ser Gly Ser Ile Ala Ser His
20 25 30
Tyr Val Gln Trp Tyr Gln Gln Arg Pro Gly Ser Ala Pro Thr Thr Val
35 40 45
Ile Tyr Glu Asp Asn Lys Arg Pro Ser Gly Val Pro Asp Arg Phe Ser
50 55 60
Gly Ser Ile Asp Ser Ser Ser Asn Ser Ala Ser Leu Ser Ile Ser Gly
65 70 75 80
Leu Lys Thr Glu Asp Glu Ala Asp Tyr Tyr Cys Gln Ser Tyr Asp Ser
85 90 95
Ser Asn Arg Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu
100 105 110
<210> 53
<211> 354
<212> DNA
<213> 人工序列
<220>
<223> Ab-65的可变重链
<400> 53
gaggtgcagc tggtgcagtc tggagctgag gtgaagaagc ctggggcctc agtgaaggtc 60
tcctgcaagg cttctggtta cacctttacc aactatggta tcagctgggt gcgacaggcc 120
cctggacaag ggcttgagtg gatgggatgg atcagcgctt acaatggtaa cacaaactat 180
gcacagaagg tccagggcag agtcaccatg accacagaca catccacgag cacaggctac 240
atggagctga ggagcctgag atctgacgac acggccgtgt attactgtgc gagaggagat 300
tttcggaaac cctttgacta ctggggccag ggaaccctgg tcaccgtctc ctca 354
<210> 54
<211> 118
<212> PRT
<213> 人工序列
<220>
<223> Ab-65的可变重链
<400> 54
Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Tyr
20 25 30
Gly Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Trp Ile Ser Ala Tyr Asn Gly Asn Thr Asn Tyr Ala Gln Lys Val
50 55 60
Gln Gly Arg Val Thr Met Thr Thr Asp Thr Ser Thr Ser Thr Gly Tyr
65 70 75 80
Met Glu Leu Arg Ser Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Asp Phe Arg Lys Pro Phe Asp Tyr Trp Gly Gln Gly Thr
100 105 110
Leu Val Thr Val Ser Ser
115
<210> 55
<211> 345
<212> DNA
<213> 人工序列
<220>
<223> Ab-65的可变轻链
<400> 55
ctgcctgtgc tgactcagcc ggcttccctc tctgcatccc ccggagcatc agccagtctc 60
acctgcacct tacgcagtgg cctcaatgtt ggttcctaca ggatatactg gtaccagcag 120
aagccaggga gtcgtcccca gtatctcctg aactacaaat cagactcaaa taaacagcag 180
gcctctggag tccccagccg cttctctgga tccaaggatg cttcggccaa tgcagggatt 240
ttactcatct ccgggctcca gtctgaggat gaggctgact attactgtat gatttggtac 300
agcagcgctg tggtattcgg cggagggacc aagctgaccg tccta 345
<210> 56
<211> 115
<212> PRT
<213> 人工序列
<220>
<223> Ab-65的可变轻链
<400> 56
Leu Pro Val Leu Thr Gln Pro Ala Ser Leu Ser Ala Ser Pro Gly Ala
1 5 10 15
Ser Ala Ser Leu Thr Cys Thr Leu Arg Ser Gly Leu Asn Val Gly Ser
20 25 30
Tyr Arg Ile Tyr Trp Tyr Gln Gln Lys Pro Gly Ser Arg Pro Gln Tyr
35 40 45
Leu Leu Asn Tyr Lys Ser Asp Ser Asn Lys Gln Gln Ala Ser Gly Val
50 55 60
Pro Ser Arg Phe Ser Gly Ser Lys Asp Ala Ser Ala Asn Ala Gly Ile
65 70 75 80
Leu Leu Ile Ser Gly Leu Gln Ser Glu Asp Glu Ala Asp Tyr Tyr Cys
85 90 95
Met Ile Trp Tyr Ser Ser Ala Val Val Phe Gly Gly Gly Thr Lys Leu
100 105 110
Thr Val Leu
115
<210> 57
<211> 5
<212> PRT
<213> 人工序列
<220>
<223> 重链CDR1共有区, Ab-42
<400> 57
Ser Tyr Ala Ile Ser
1 5
<210> 58
<211> 5
<212> PRT
<213> 人工序列
<220>
<223> Ab-14, Ab-55的重链CDR1
<400> 58
Ser Tyr Gly Ile Ser
1 5
<210> 59
<211> 5
<212> PRT
<213> 人工序列
<220>
<223> Ab-16的重链CDR1
<400> 59
Ser Tyr Ala Leu Ser
1 5
<210> 60
<211> 5
<212> PRT
<213> 人工序列
<220>
<223> Ab-22非人重链CDR1
<400> 60
Asp Tyr Ala Met His
1 5
<210> 61
<211> 5
<212> PRT
<213> 人工序列
<220>
<223> Ab-30的重链CDR1
<400> 61
Asn Tyr Asp Met Ser
1 5
<210> 62
<211> 5
<212> PRT
<213> 人工序列
<220>
<223> Ab-31的重链CDR1
<400> 62
Gly Leu Tyr Ile His
1 5
<210> 63
<211> 5
<212> PRT
<213> 人工序列
<220>
<223> Ab-32的重链CDR1
<400> 63
Asp Asn Ala Ile Ser
1 5
<210> 64
<211> 5
<212> PRT
<213> 人工序列
<220>
<223> Ab-38的重链CDR1
<400> 64
Ser Tyr Ala Met Ser
1 5
<210> 65
<211> 5
<212> PRT
<213> 人工序列
<220>
<223> Ab-46的重链CDR1
<400> 65
Thr Tyr Ala Leu Asn
1 5
<210> 66
<211> 5
<212> PRT
<213> 人工序列
<220>
<223> Ab-50的重链CDR1
<400> 66
Ser His Gly Ile Thr
1 5
<210> 67
<211> 5
<212> PRT
<213> 人工序列
<220>
<223> Ab-52的重链CDR1
<400> 67
Arg His Gly Met His
1 5
<210> 68
<211> 5
<212> PRT
<213> 人工序列
<220>
<223> Ab-56的重链CDR1
<400> 68
Thr Tyr Ala Phe Ser
1 5
<210> 69
<211> 5
<212> PRT
<213> 人工序列
<220>
<223> Ab-65的重链CDR1
<400> 69
Asn Tyr Gly Ile Ser
1 5
<210> 70
<211> 17
<212> PRT
<213> 人工序列
<220>
<223> 重链CDR2共有区
<400> 70
Trp Ile Ser Pro Ile Gly Gly Ser Thr Asn Tyr Ala Gln Lys Val Gln
1 5 10 15
Gly
<210> 71
<211> 17
<212> PRT
<213> 人工序列
<220>
<223> Ab-14的重链CDR2
<400> 71
Trp Ile Ser Ala Tyr Asn Gly Asn Thr Asn Tyr Ala Gln Lys Leu Glu
1 5 10 15
Asp
<210> 72
<211> 17
<212> PRT
<213> 人工序列
<220>
<223> Ab-16的重链CDR2
<400> 72
Ala Ile Ser Gly Gly Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val Lys
1 5 10 15
Asp
<210> 73
<211> 17
<212> PRT
<213> 人工序列
<220>
<223> Ab-22的重链CDR2
<400> 73
Leu Ile Ser Gly Asp Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val Lys
1 5 10 15
Asp
<210> 74
<211> 17
<212> PRT
<213> 人工序列
<220>
<223> Ab-30的重链CDR2
<400> 74
Arg Val Asn Trp Asn Gly Gly Ser Thr Thr Tyr Ala Asp Ala Val Lys
1 5 10 15
Asp
<210> 75
<211> 17
<212> PRT
<213> 人工序列
<220>
<223> Ab-31的重链CDR2
<400> 75
Trp Ile Ile Pro Ile Phe Gly Thr Ala Asn Tyr Ala Gln Lys Phe Glu
1 5 10 15
Asp
<210> 76
<211> 17
<212> PRT
<213> 人工序列
<220>
<223> Ab-32的重链CDR2
<400> 76
Trp Ile Ile Pro Ile Phe Gly Lys Pro Asn Tyr Ala Gln Lys Phe Glu
1 5 10 15
Asp
<210> 77
<211> 17
<212> PRT
<213> 人工序列
<220>
<223> Ab-38的重链CDR2
<400> 77
Ala Ile Ser Gly Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val Lys
1 5 10 15
Asp
<210> 78
<211> 17
<212> PRT
<213> 人工序列
<220>
<223> Ab-42的重链CDR2
<400> 78
Trp Ile Ile Pro Ile Phe Gly Thr Ala Asn Tyr Ala Gln Lys Phe Glu
1 5 10 15
Asp
<210> 79
<211> 17
<212> PRT
<213> 人工序列
<220>
<223> Ab-46的重链CDR2
<400> 79
Arg Ile Val Pro Leu Ile Gly Leu Val Asn Tyr Ala His Asn Phe Glu
1 5 10 15
Asp
<210> 80
<211> 17
<212> PRT
<213> 人工序列
<220>
<223> Ab-50的重链CDR2
<400> 80
Trp Ile Ser Ala His Asn Gly His Ala Ser Asn Ala Gln Lys Val Glu
1 5 10 15
Asp
<210> 81
<211> 17
<212> PRT
<213> 人工序列
<220>
<223> Ab-52的重链CDR2
<400> 81
Val Ile Ser His Asp Gly Ser Val Lys Tyr Tyr Ala Asp Ser Met Lys
1 5 10 15
Asp
<210> 82
<211> 17
<212> PRT
<213> 人工序列
<220>
<223> Ab-55的重链CDR2
<400> 82
Trp Thr Ser Pro His Asn Gly Leu Thr Ala Phe Ala Gln Ile Leu Glu
1 5 10 15
Asp
<210> 83
<211> 17
<212> PRT
<213> 人工序列
<220>
<223> Ab-56的重链CDR2
<400> 83
Arg Ile Ile Pro Ile Leu Gly Ile Ala Asn Tyr Ala Gln Lys Phe Glu
1 5 10 15
Asp
<210> 84
<211> 17
<212> PRT
<213> 人工序列
<220>
<223> Ab-65的重链CDR2
<400> 84
Trp Ile Ser Ala Tyr Asn Gly Asn Thr Asn Tyr Ala Gln Lys Val Glu
1 5 10 15
Asp
<210> 85
<211> 19
<212> PRT
<213> 人工序列
<220>
<223> 重链CDR3共有区
<220>
<221> 其它特征
<222> (3)..(17)
<223> Xaa可以是任何天然存在的氨基酸
<400> 85
Gly Leu Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
1 5 10 15
Xaa Asp Val
<210> 86
<211> 15
<212> PRT
<213> 人工序列
<220>
<223> Ab-14的重链CDR3
<400> 86
Ala Leu Pro Ser Gly Thr Ile Leu Val Gly Gly Trp Phe Asp Pro
1 5 10 15
<210> 87
<211> 15
<212> PRT
<213> 人工序列
<220>
<223> Ab-16的重链CDR3
<400> 87
Asp Val Phe Pro Glu Thr Phe Ser Met Asn Tyr Gly Met Asp Val
1 5 10 15
<210> 88
<211> 19
<212> PRT
<213> 人工序列
<220>
<223> Ab-22的重链CDR3
<400> 88
Val Leu Leu Pro Cys Ser Ser Thr Ser Cys Tyr Gly Ser Val Gly Ala
1 5 10 15
Phe Asp Ile
<210> 89
<211> 8
<212> PRT
<213> 人工序列
<220>
<223> Ab-30的重链CDR3
<400> 89
Glu Phe Val Gly Ala Tyr Asp Leu
1 5
<210> 90
<211> 12
<212> PRT
<213> 人工序列
<220>
<223> Ab-31的重链CDR3
<400> 90
Gly Leu Arg Trp Gly Ile Trp Gly Trp Phe Asp Pro
1 5 10
<210> 91
<211> 12
<212> PRT
<213> 人工序列
<220>
<223> Ab-32的重链CDR3
<400> 91
Thr Met Val Arg Gly Phe Leu Gly Val Met Asp Val
1 5 10
<210> 92
<211> 16
<212> PRT
<213> 人工序列
<220>
<223> Ab-38的重链CDR3
<400> 92
Asp Gln Phe Val Thr Ile Phe Gly Val Pro Arg Tyr Gly Met Asp Val
1 5 10 15
<210> 93
<211> 11
<212> PRT
<213> 人工序列
<220>
<223> Ab-42的重链CDR3
<400> 93
Gly Arg Gln Met Phe Gly Ala Gly Ile Asp Phe
1 5 10
<210> 94
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> Ab-46的重链CDR3
<400> 94
Glu Val Tyr Gly Gly Asn Ser Asp Tyr
1 5
<210> 95
<211> 11
<212> PRT
<213> 人工序列
<220>
<223> Ab-50的重链CDR3
<400> 95
Val His Ala Ala Leu Tyr Tyr Gly Met Asp Val
1 5 10
<210> 96
<211> 12
<212> PRT
<213> 人工序列
<220>
<223> Ab-52的重链CDR3
<400> 96
Gly Leu Ser Tyr Gln Val Ser Gly Trp Phe Asp Pro
1 5 10
<210> 97
<211> 11
<212> PRT
<213> 人工序列
<220>
<223> Ab-55的重链CDR3
<400> 97
Val His Pro Val Phe Ser Tyr Ala Leu Asp Val
1 5 10
<210> 98
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> Ab-56的重链CDR3
<400> 98
Asp Gly Tyr Gly Ser Asp Pro Val Leu
1 5
<210> 99
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> Ab-65的重链CDR3
<400> 99
Gly Asp Phe Arg Lys Pro Phe Asp Tyr
1 5
<210> 100
<211> 13
<212> PRT
<213> 人工序列
<220>
<223> 轻链CDR1共有区
<400> 100
Thr Arg Ser Ser Gly Ser Ile Gly Ser Asn Tyr Val Gln
1 5 10
<210> 101
<211> 13
<212> PRT
<213> 人工序列
<220>
<223> Ab-14的轻链CDR1
<400> 101
Thr Arg Ser Ser Gly Asn Ile Ala Ser Asn Tyr Val Gln
1 5 10
<210> 102
<211> 11
<212> PRT
<213> 人工序列
<220>
<223> Ab-16的轻链CDR1
<400> 102
Gln Gly Asp Ser Leu Arg Ser Tyr Tyr Ala Ser
1 5 10
<210> 103
<211> 11
<212> PRT
<213> 人工序列
<220>
<223> Ab-22的轻链CDR1
<400> 103
Gly Gly Ser Asp Ile Gly Arg Lys Ser Val His
1 5 10
<210> 104
<211> 14
<212> PRT
<213> 人工序列
<220>
<223> Ab-30的轻链CDR1
<400> 104
Thr Gly Thr Ser Ser Asp Val Gly Gly Tyr Asn Tyr Val Ser
1 5 10
<210> 105
<211> 11
<212> PRT
<213> 人工序列
<220>
<223> Ab-31的轻链CDR1
<400> 105
Arg Ala Ser Gln Ser Ile Gly Asn Ser Leu Ala
1 5 10
<210> 106
<211> 11
<212> PRT
<213> 人工序列
<220>
<223> Ab-32的轻链CDR1
<400> 106
Arg Ala Ser Gln Gly Ile Gly Ser Tyr Leu Ala
1 5 10
<210> 107
<211> 11
<212> PRT
<213> 人工序列
<220>
<223> Ab-38的轻链CDR1
<400> 107
Ser Gly Asp Lys Leu Gly Asn Lys Tyr Ala Tyr
1 5 10
<210> 108
<211> 13
<212> PRT
<213> 人工序列
<220>
<223> Ab-42的轻链CDR1
<400> 108
Thr Arg Ser Ser Gly Ser Ile Asp Ser Asn Tyr Val Gln
1 5 10
<210> 109
<211> 13
<212> PRT
<213> 人工序列
<220>
<223> Ab-46的轻链CDR1
<400> 109
Thr Arg Ser Ser Gly Asn Ile Gly Thr Asn Tyr Val Gln
1 5 10
<210> 110
<211> 11
<212> PRT
<213> 人工序列
<220>
<223> Ab-50的轻链CDR1
<400> 110
Gly Gly Asn Asn Ile Gly Ser Lys Gly Val His
1 5 10
<210> 111
<211> 13
<212> PRT
<213> 人工序列
<220>
<223> Ab-52的轻链CDR1
<400> 111
Thr Arg Ser Ser Gly Ser Ile Ala Ser Asn Tyr Val Gln
1 5 10
<210> 112
<211> 13
<212> PRT
<213> 人工序列
<220>
<223> Ab-55的轻链CDR1
<400> 112
Thr Arg Ser Ser Gly Ser Ile Ala Ser Asn Tyr Val Gln
1 5 10
<210> 113
<211> 13
<212> PRT
<213> 人工序列
<220>
<223> Ab-56的轻链CDR1
<400> 113
Thr Arg Ser Ser Gly Ser Ile Ala Ser His Tyr Val Gln
1 5 10
<210> 114
<211> 14
<212> PRT
<213> 人工序列
<220>
<223> Ab-65的轻链CDR1
<400> 114
Thr Leu Arg Ser Gly Leu Asn Val Gly Ser Tyr Arg Ile Tyr
1 5 10
<210> 115
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> Ab-14, Ab-42, Ab-52, Ab-55的轻链CDR2共有区
<400> 115
Glu Asp Asn Gln Arg Pro Ser
1 5
<210> 116
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> Ab-16的轻链CDR2
<400> 116
Gly Lys Asn Asn Arg Pro Ser
1 5
<210> 117
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> Ab-22的轻链CDR2
<400> 117
Ser Asp Arg Asp Arg Pro Ser
1 5
<210> 118
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> Ab-30的轻链CDR2
<400> 118
Asp Val Ser Asn Arg Pro Ser
1 5
<210> 119
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> Ab-31的轻链CDR2
<400> 119
Gly Ala Ser Ser Arg Ala Thr
1 5
<210> 120
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> Ab-32的轻链CDR2
<400> 120
Ala Ala Ser Thr Leu Gln Ser
1 5
<210> 121
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> Ab-38的轻链CDR2
<400> 121
Gln Asp Ile Lys Arg Pro Ser
1 5
<210> 122
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> Ab-46的轻链CDR2
<400> 122
Glu Asp Tyr Arg Arg Pro Ser
1 5
<210> 123
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> Ab-50的轻链CDR2
<400> 123
Asp Asp Ser Asp Arg Pro Ser
1 5
<210> 124
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> Ab-56的轻链CDR2
<400> 124
Glu Asp Asn Lys Arg Pro Ser
1 5
<210> 125
<211> 11
<212> PRT
<213> 人工序列
<220>
<223> Ab-65的轻链CDR2
<400> 125
Tyr Lys Ser Asp Ser Asn Lys Gln Gln Ala Ser
1 5 10
<210> 126
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> 轻链CDR3共有区
<400> 126
Gln Ser Tyr Asp Ser Ser Thr Trp Val
1 5
<210> 127
<211> 10
<212> PRT
<213> 人工序列
<220>
<223> Ab-14的轻链CDR3
<400> 127
Gln Ser Tyr Asp Ser Ser Asn Leu Trp Val
1 5 10
<210> 128
<211> 11
<212> PRT
<213> 人工序列
<220>
<223> Ab-16的轻链CDR3
<400> 128
Asn Ser Arg Asp Ser Ser Gly Asn His Tyr Val
1 5 10
<210> 129
<211> 11
<212> PRT
<213> 人工序列
<220>
<223> Ab-22的轻链CDR3
<400> 129
Gln Val Trp Asp Asn Asn Ser Asp His Tyr Val
1 5 10
<210> 130
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> Ab-30的轻链CDR3
<400> 130
Ser Ser Tyr Thr Ser Ser Thr Leu Pro
1 5
<210> 131
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> Ab-31的轻链CDR3
<400> 131
Gln Gln His Thr Ile Pro Thr Phe Ser
1 5
<210> 132
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> Ab-32的轻链CDR3
<400> 132
Gln Gln Leu Asn Asn Tyr Pro Ile Thr
1 5
<210> 133
<211> 8
<212> PRT
<213> 人工序列
<220>
<223> Ab-38的轻链CDR3
<400> 133
Gln Thr Trp Asp Asn Ser Val Val
1 5
<210> 134
<211> 11
<212> PRT
<213> 人工序列
<220>
<223> Ab-42的轻链CDR3
<400> 134
Gln Ser Tyr Asp Ser Asn Asn Arg His Val Ile
1 5 10
<210> 135
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> Ab-46的轻链CDR3
<400> 135
Gln Ser Tyr His Ser Ser Gly Trp Glu
1 5
<210> 136
<211> 11
<212> PRT
<213> 人工序列
<220>
<223> Ab-50的轻链CDR3
<400> 136
Gln Val Trp Asp Ser Ser Ser Asp His Trp Val
1 5 10
<210> 137
<211> 10
<212> PRT
<213> 人工序列
<220>
<223> Ab-52的轻链CDR3
<400> 137
Gln Ser Tyr Asp Ser Thr Thr Pro Ser Val
1 5 10
<210> 138
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> Ab-55的轻链CDR3
<400> 138
Gln Ser Tyr Asp Gly Ile Thr Val Ile
1 5
<210> 139
<211> 10
<212> PRT
<213> 人工序列
<220>
<223> Ab-56的轻链CDR3
<400> 139
Gln Ser Tyr Asp Ser Ser Asn Arg Trp Val
1 5 10
<210> 140
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> Ab-65的轻链CDR3
<400> 140
Met Ile Trp Tyr Ser Ser Ala Val Val
1 5
Claims (10)
1.一种分离的人源化单克隆抗体,其具有:
a. 具有三个CDR的重链,所述CDR分别包括氨基酸序列SYGIS (SEQ ID NO:57)、WISAYNGNTNYAQKLED (SEQ ID NO:70)和ALPSGTILVGGWFDP (SEQ ID NO:86);和具有三个CDR的轻链,所述CDR分别包括氨基酸序列TRSSGNIASNYVQ (SEQ ID NO:101)、EDNQRPS (SEQID NO:115)和QSYDSSNLWV (SEQ ID NO:127);
b. 具有三个CDR的重链,所述CDR分别包括氨基酸序SYALS (SEQ ID NO:58)、AISGGGGSTYYADSVKD (SEQ ID NO:71)和DVFPETFSMNYGMDV (SEQ ID NO:87);和具有三个CDR的轻链,所述CDR分别包括氨基酸序列QGDSLRSYYAS (SEQ ID NO:102)、GKNNRPS (SEQID NO:116)和NSRDSSGNHYV (SEQ ID NO:128);
c. 具有三个CDR的重链,所述CDR分别包括氨基酸序列DYAMH (SEQ ID NO:60)、LISGDGGSTYYADSVKD (SEQ ID NO:73)和VLLPCSSTSCYGSVGAFDI (SEQ ID NO:88);和具有三个CDR的轻链,所述CDR分别包括氨基酸序列GGSDIGRKSVH (SEQ ID NO:103)、SDRDRPS (SEQID NO:117)和QVWDNNSDHYV (SEQ ID NO:129);
d. 具有三个CDR的重链,所述CDR分别包括氨基酸序列NYDMS (SEQ ID NO:61)、RVNWNGGSTTYADAVKD (SEQ ID NO:74)和EFVGAYDL (SEQ ID NO:89);和具有三个CDR的轻链,所述CDR分别包括氨基酸序列TGTSSDVGGYNYVS (SEQ ID NO:104)、DVSNRPS (SEQ IDNO:118)和SSYTSSTLP (SEQ ID NO:130);
e. 具有三个CDR的重链,所述CDR分别包括氨基酸序列GLYIH (SEQ ID NO:62)、WIIPIFGTANYAQKFED (SEQ ID NO:75)和GLRWGIWGWFDP (SEQ ID NO:90);和具有三个CDR的轻链,所述CDR分别包括氨基酸序列RASQSIGNSLA (SEQ ID NO:105)、GASSRAT (SEQ ID NO:119)和QQHTIPTFS (SEQ ID NO:131);
f. 具有三个CDR的重链,所述CDR分别包括氨基酸序列DNAIS (SEQ ID NO:63)、WIIPIFGKPNYAQKFED (SEQ ID NO:76)和TMVRGFLGVMDV (SEQ ID NO:91);和具有三个CDR的轻链,所述CDR分别包括氨基酸序列RASQGIGSYLA (SEQ ID NO:106)、AASTLQS (SEQ ID NO:120)和QQLNNYPIT (SEQ ID NO:132);
g. 具有三个CDR的重链,所述CDR分别包括氨基酸序列SYAMS (SEQ ID NO:64)、AISGSGGSTYYADSVKD (SEQ ID NO:77)和DQFVTIFGVPRYGMDV (SEQ ID NO:92);和具有三个CDR的轻链,所述CDR分别包括氨基酸序列SGDKLGNKYAY (SEQ ID NO:107)、QDIKRPS (SEQID NO:121)和QTWDNSVV (SEQ ID NO:133);
h. 具有三个CDR的重链,所述CDR分别包括氨基酸序列SYAIS (SEQ ID NO:57)、WIIPIFGTANYAQKFED (SEQ ID NO:78)和GRQMFGAGIDF (SEQ ID NO:93);和具有三个CDR的轻链,所述CDR分别包括氨基酸序列TRSSGSIDSNYVQ (SEQ ID NO:108)、EDNQRPS (SEQ IDNO:115)和QSYDSNNRHVI (SEQ ID NO:134);
i. 具有三个CDR的重链,所述CDR分别包括氨基酸序列TYALN (SEQ ID NO:65)、RIVPLIGLVNYAHNFED (SEQ ID NO:79)和EVYGGNSDY (SEQ ID NO:94);和具有三个CDR的轻链,所述CDR分别包括氨基酸序列TRSSGNIGTNYVQ (SEQ ID NO:109)、EDYRRPS (SEQ ID NO:122)和QSYHSSGWE (SEQ ID NO:135);
j. 具有三个CDR的重链,所述CDR分别包括氨基酸序列SHGIT (SEQ ID NO:66)、WISAHNGHASNAQKVED (SEQ ID NO:80)和VHAALYYGMDV (SEQ ID NO:95);和具有三个CDR的轻链,所述CDR分别包括氨基酸序列GGNNIGSKGVH (SEQ ID NO:110)、DDSDRPS (SEQ ID NO:123)和QVWDSSSDHWV (SEQ ID NO:136);
k. 具有三个CDR的重链,所述CDR分别包括氨基酸序列RHGMH (SEQ ID NO:67)、VISHDGSVKYYADSMKD (SEQ ID NO:81)和GLSYQVSGWFDP (SEQ ID NO:96);和具有三个CDR的轻链,所述CDR分别包括氨基酸序列TRSSGSIASNYVQ (SEQ ID NO:111)、EDNQRPS (SEQ IDNO:115)和QSYDSTTPSV (SEQ ID NO:137);
l. 具有三个CDR的重链,所述CDR分别包括氨基酸序列SYGIS (SEQ ID NO:58)、WTSPHNGLTAFAQILED (SEQ ID NO:82)和VHPVFSYALDV (SEQ ID NO:97);和具有三个CDR的轻链,所述CDR分别包括氨基酸序列TRSSGSIASNYVQ (SEQ ID NO:112)、EDNQRPS (SEQ IDNO:115)和QSYDGITVI (SEQ ID NO:138);
m. 具有三个CDR的重链,所述CDR分别包括氨基酸序列TYAFS (SEQ ID NO:68)、RIIPILGIANYAQKFED (SEQ ID NO:83)和DGYGSDPVL (SEQ ID NO:98);和具有三个CDR的轻链,所述CDR分别包括氨基酸序列TRSSGSIASHYVQ (SEQ ID NO:113)、EDNKRPS (SEQ ID NO:124)和QSYDSSNRWV (SEQ ID NO:139);或
n. 具有三个CDR的重链,所述CDR分别包括氨基酸序列NYGIS (SEQ ID NO:69)、WISAYNGNTNYAQKVED (SEQ ID NO:84)和GDFRKPFDY (SEQ ID NO:99);和具有三个CDR的轻链,所述CDR分别包括氨基酸序列TLRSGLNVGSYRIY (SEQ ID NO:114)、YKSDSNKQQAS (SEQID NO:125)和MIWYSSAVV (SEQ ID NO:140);
其中所述抗体结合人PD-L1。
2.权利要求1的抗体,其中所述抗体是单价的或二价的。
3.权利要求1的抗体,其中所述抗体为单链抗体。
4.单链抗体,其包含:
a. 含SEQ ID NO: 1的VH核苷酸序列和含SEQ ID NO: 3的VL核苷酸序列;
b. 含SEQ ID NO: 5的VH核苷酸序列和含SEQ ID NO: 7的VL核苷酸序列;
c. 含SEQ ID NO: 9的VH核苷酸序列和含SEQ ID NO: 11的VL核苷酸序列;
d. 含SEQ ID NO: 13的VH核苷酸序列和含SEQ ID NO: 15 的VL核苷酸序列;
e. 含SEQ ID NO: 17的VH核苷酸序列和含SEQ ID NO: 19 的VL核苷酸序列;
f. 含SEQ ID NO: 21的VH核苷酸序列和含SEQ ID NO: 23的VL核苷酸序列;
g. 含SEQ ID NO: 25的VH核苷酸序列和含SEQ ID NO: 27的VL核苷酸序列;
h. 含SEQ ID NO: 29的VH核苷酸序列和含SEQ ID NO: 31的VL核苷酸序列;
i. 含SEQ ID NO: 33的VH核苷酸序列和含SEQ ID NO: 35的VL核苷酸序列;
j. 含SEQ ID NO: 37的VH核苷酸序列和含SEQ ID NO: 39的VL核苷酸序列;
k. 含SEQ ID NO: 41的VH核苷酸序列和含SEQ ID NO: 43的VL核苷酸序列;
l. 含SEQ ID NO: 45的VH核苷酸序列和含SEQ ID NO: 47的VL核苷酸序列;
m. 含SEQ ID NO: 49的VH核苷酸序列和含SEQ ID NO: 51的VL核苷酸序列;或
n. 含SEQ ID NO: 53的VH核苷酸序列和含SEQ ID NO: 55的VL核苷酸序列。
5.单链抗体,其包含:
a. 含SEQ ID NO: 2的VH氨基酸序列和含SEQ ID NO: 4的VL氨基酸序列;
b. 含SEQ ID NO: 6的VH氨基酸序列和含SEQ ID NO: 8的VL氨基酸序列;
c. 含SEQ ID NO: 10的VH氨基酸序列和含SEQ ID NO: 12的VL氨基酸序列;
d. 含SEQ ID NO: 14的VH氨基酸序列和含SEQ ID NO: 16的VL氨基酸序列;
e. 含SEQ ID NO: 18的VH氨基酸序列和含SEQ ID NO: 20的VL氨基酸序列;
f. 含SEQ ID NO: 22的VH氨基酸序列和含SEQ ID NO: 24的VL氨基酸序列;
g. 含SEQ ID NO: 26的VH氨基酸序列和含SEQ ID NO: 28的VL氨基酸序列;
h. 含SEQ ID NO: 30的VH氨基酸序列和含SEQ ID NO: 32的VL氨基酸序列;
i. 含SEQ ID NO: 34的VH氨基酸序列和含SEQ ID NO: 36的VL氨基酸序列;
j. 含SEQ ID NO: 38的VH氨基酸序列和含SEQ ID NO: 40的VL氨基酸序列;
k. 含SEQ ID NO: 42的VH氨基酸序列和含SEQ ID NO: 44的VL氨基酸序列;
l. 含SEQ ID NO: 46的VH氨基酸序列和含SEQ ID NO: 48的VL氨基酸序列;
m. 含SEQ ID NO: 50的VH氨基酸序列和含SEQ ID NO: 52的VL氨基酸序列;或
n. 含SEQ ID NO: 54的VH氨基酸序列和含SEQ ID NO: 56的VL氨基酸序列。
6.权利要求1的抗体,其中所述抗体具有在10-5 M-10-12 M的范围内的结合亲和力。
7.权利要求1的抗体,其中所述抗体是双特异性抗体,其还结合至肿瘤-相关抗原、细胞因子或细胞表面受体。
8.权利要求7的抗体,其中所述肿瘤-相关抗原是CAIX。
9.权利要求7的抗体,其中所述细胞因子是IL-10。
10.权利要求7的抗体,其中所述细胞表面受体是CCR4、IL21R、BTLA、HVEM或TIM3。
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CN201380063513.0A CN104994873B (zh) | 2012-10-04 | 2013-10-04 | 人单克隆抗‑pd‑l1抗体和使用方法 |
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Families Citing this family (268)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
ES2834093T3 (es) | 2011-07-21 | 2021-06-16 | Sumitomo Dainippon Pharma Oncology Inc | Inhibidores de proteína quinasa heterocíclicos |
CN110981964B (zh) | 2013-01-14 | 2023-09-15 | Xencor股份有限公司 | 新型异二聚体蛋白 |
US10858417B2 (en) | 2013-03-15 | 2020-12-08 | Xencor, Inc. | Heterodimeric proteins |
RS57559B1 (sr) | 2013-09-06 | 2018-10-31 | Aurigene Discovery Tech Ltd | 1,3,4-oksadiazol i 1,3,4-tiadiazol derivativi kao imunomodulatori |
SG11201601682RA (en) | 2013-09-06 | 2016-04-28 | Aurigene Discovery Tech Ltd | 1,2,4-oxadiazole derivatives as immunomodulators |
CA2922982A1 (en) | 2013-09-06 | 2015-03-12 | Aurigene Discovery Technologies Limited | Cyclic peptidomimetic compounds as immunomodulators |
AU2013400609B9 (en) | 2013-09-13 | 2020-03-05 | Beigene Switzerland Gmbh | Anti-PD1 antibodies and their use as therapeutics and diagnostics |
WO2015048312A1 (en) | 2013-09-26 | 2015-04-02 | Costim Pharmaceuticals Inc. | Methods for treating hematologic cancers |
JOP20200094A1 (ar) | 2014-01-24 | 2017-06-16 | Dana Farber Cancer Inst Inc | جزيئات جسم مضاد لـ pd-1 واستخداماتها |
JOP20200096A1 (ar) | 2014-01-31 | 2017-06-16 | Children’S Medical Center Corp | جزيئات جسم مضاد لـ tim-3 واستخداماتها |
GB201403775D0 (en) | 2014-03-04 | 2014-04-16 | Kymab Ltd | Antibodies, uses & methods |
RU2717641C2 (ru) | 2014-04-21 | 2020-03-24 | Натера, Инк. | Обнаружение мутаций и плоидности в хромосомных сегментах |
CN106795502B (zh) * | 2014-06-12 | 2021-12-14 | 波尔图大学 | 用于免疫受损宿主的疫苗 |
WO2016000619A1 (en) * | 2014-07-03 | 2016-01-07 | Beigene, Ltd. | Anti-pd-l1 antibodies and their use as therapeutics and diagnostics |
NZ728688A (en) | 2014-07-22 | 2023-06-30 | Cb Therapeutics Inc | Anti-pd-1 antibodies |
RU2722212C9 (ru) | 2014-08-05 | 2020-07-23 | СиБи ТЕРЕПЬЮТИКС, ИНК. | Анти-pd-l1 антитела |
EP3191126B1 (en) | 2014-09-13 | 2020-05-13 | Novartis AG | Combination therapies of alk inhibitors |
CU20170052A7 (es) * | 2014-10-14 | 2017-11-07 | Dana Farber Cancer Inst Inc | Moléculas de anticuerpo que se unen a pd-l1 |
WO2016070051A2 (en) | 2014-10-31 | 2016-05-06 | Oncomed Pharmaceuticals, Inc. | Combination therapy for treatment of disease |
US10259887B2 (en) | 2014-11-26 | 2019-04-16 | Xencor, Inc. | Heterodimeric antibodies that bind CD3 and tumor antigens |
CA2967426A1 (en) | 2014-11-26 | 2016-06-02 | Xencor, Inc. | Heterodimeric antibodies that bind cd3 and tumor antigens |
KR20170090506A (ko) * | 2014-12-19 | 2017-08-07 | 다나-파버 캔서 인스티튜트 인크. | 키메라 항원 수용체 및 이의 사용 방법 |
GB201500319D0 (en) | 2015-01-09 | 2015-02-25 | Agency Science Tech & Res | Anti-PD-L1 antibodies |
MA41414A (fr) | 2015-01-28 | 2017-12-05 | Centre Nat Rech Scient | Protéines de liaison agonistes d' icos |
MY196130A (en) | 2015-03-10 | 2023-03-16 | Aurigene Discovery Tech Ltd | 1,2,4-Oxadiazole and Thiadiazole Compounds as Immunomodulators |
CA2978942A1 (en) | 2015-03-13 | 2016-09-22 | Cytomx Therapeutics, Inc. | Anti-pdl1 antibodies, activatable anti-pdl1 antibodies, and methods of use thereof |
US10836827B2 (en) | 2015-03-30 | 2020-11-17 | Stcube, Inc. | Antibodies specific to glycosylated PD-L1 and methods of use thereof |
US11933786B2 (en) | 2015-03-30 | 2024-03-19 | Stcube, Inc. | Antibodies specific to glycosylated PD-L1 and methods of use thereof |
DK3303394T3 (da) | 2015-05-29 | 2020-07-06 | Agenus Inc | Anti-ctla-4-antistoffer og fremgangsmåder til anvendelse deraf |
WO2016197367A1 (en) | 2015-06-11 | 2016-12-15 | Wuxi Biologics (Shanghai) Co. Ltd. | Novel anti-pd-l1 antibodies |
WO2017020291A1 (en) * | 2015-08-06 | 2017-02-09 | Wuxi Biologics (Shanghai) Co. Ltd. | Novel anti-pd-l1 antibodies |
EP3331919A1 (en) | 2015-08-07 | 2018-06-13 | GlaxoSmithKline Intellectual Property Development Limited | Combination therapy comprising anti ctla-4 antibodies |
AR105654A1 (es) | 2015-08-24 | 2017-10-25 | Lilly Co Eli | Anticuerpos pd-l1 (ligando 1 de muerte celular programada) |
ES2839212T3 (es) | 2015-09-29 | 2021-07-05 | Inst Nat Sante Rech Med | Métodos para determinar el estado metabólico de linfomas B |
JP6983371B2 (ja) | 2015-11-17 | 2021-12-17 | スーヂョウ サンケイディア バイオファーマスーティカルズ カンパニー リミテッド | 抗pd−l1抗体、その抗原結合フラグメントおよびその医療用途 |
EP4015537A1 (en) | 2015-12-01 | 2022-06-22 | GlaxoSmithKline Intellectual Property Development Limited | Combination treatments and uses and methods thereof |
KR20180085793A (ko) | 2015-12-02 | 2018-07-27 | 주식회사 에스티큐브 | 글리코실화된 pd-1에 대해 특이적인 항체 및 이의 사용 방법 |
MA52157A (fr) | 2015-12-03 | 2021-02-17 | Glaxosmithkline Ip Dev Ltd | Dinucléotides cycliques de purine utilisés comme modulateurs de sting |
WO2017098421A1 (en) | 2015-12-08 | 2017-06-15 | Glaxosmithkline Intellectual Property Development Limited | Benzothiadiazine compounds |
CN106939047B (zh) * | 2016-01-04 | 2021-08-31 | 江苏怀瑜药业有限公司 | 一种pd-l1抗体及其制备方法 |
EP3400443B1 (en) | 2016-01-04 | 2020-09-16 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Use of pd-1 and tim-3 as a measure for cd8+ cells in predicting and treating renal cell carcinoma |
US20190178888A1 (en) | 2016-01-11 | 2019-06-13 | Technion Research & Development Foundation Limited | Methods of determining prognosis of sepsis and treating same |
CN109715821B (zh) | 2016-01-29 | 2022-09-06 | 索伦托药业有限公司 | 与pd-l1结合的抗原结合蛋白 |
MX2017016851A (es) | 2016-03-04 | 2018-04-30 | Sichuan Kelun Biotech Biopharmaceutical Co Ltd | Anticuerpo para el ligando del factor 1 de muerte celular programada (pdl-1), composicion farmaceutica del mismo y uso de los mismos. |
WO2017153952A1 (en) | 2016-03-10 | 2017-09-14 | Glaxosmithkline Intellectual Property Development Limited | 5-sulfamoyl-2-hydroxybenzamide derivatives |
WO2017161976A1 (en) * | 2016-03-23 | 2017-09-28 | Mabspace Biosciences (Suzhou) Co., Ltd | Novel anti-pd-l1 antibodies |
US11660352B2 (en) | 2016-03-29 | 2023-05-30 | Stcube, Inc. | Dual function antibodies specific to glycosylated PD-L1 and methods of use thereof |
CR20200045A (es) | 2016-04-07 | 2020-03-11 | Glaxosmithkline Ip Dev Ltd | AMIDAS HETEROCÍCLICAS ÚTILES COMO MODULADORES DE PROTEÍNAS (Divisional 2018-0472) |
EP3440072B1 (en) | 2016-04-07 | 2020-01-29 | GlaxoSmithKline Intellectual Property Development Ltd | Heterocyclic amides useful as protein modulators |
EP3452483B1 (en) | 2016-05-05 | 2020-04-01 | GlaxoSmithKline Intellectual Property (No. 2) Limited | Enhancer of zeste homolog 2 inhibitors |
CN105968200B (zh) * | 2016-05-20 | 2019-03-15 | 瑞阳(苏州)生物科技有限公司 | 抗人pd-l1人源化单克隆抗体及其应用 |
CN106008714B (zh) | 2016-05-24 | 2019-03-15 | 瑞阳(苏州)生物科技有限公司 | 抗人pd-1人源化单克隆抗体及其应用 |
SG11201810023QA (en) | 2016-05-27 | 2018-12-28 | Agenus Inc | Anti-tim-3 antibodies and methods of use thereof |
CN109563034A (zh) | 2016-06-08 | 2019-04-02 | 葛兰素史密斯克莱知识产权发展有限公司 | 化学化合物 |
ES2913929T3 (es) | 2016-06-08 | 2022-06-06 | Glaxosmithkline Ip Dev Ltd | Compuestos químicos como inhibidores de la ruta de ATF4 |
AU2017283480A1 (en) | 2016-06-13 | 2019-01-24 | Torque Therapeutics, Inc. | Methods and compositions for promoting immune cell function |
US9567399B1 (en) | 2016-06-20 | 2017-02-14 | Kymab Limited | Antibodies and immunocytokines |
JP7461741B2 (ja) | 2016-06-20 | 2024-04-04 | カイマブ・リミテッド | 抗pd-l1およびil-2サイトカイン |
WO2018029474A2 (en) | 2016-08-09 | 2018-02-15 | Kymab Limited | Anti-icos antibodies |
US10590199B2 (en) * | 2016-06-29 | 2020-03-17 | Checkpoint Therapeutics, Inc. | PD-L1-specific antibodies and methods of using the same |
CN109475536B (zh) | 2016-07-05 | 2022-05-27 | 百济神州有限公司 | 用于治疗癌症的PD-l拮抗剂和RAF抑制剂的组合 |
CN109789135A (zh) | 2016-07-20 | 2019-05-21 | 葛兰素史密斯克莱知识产权发展有限公司 | 作为perk抑制剂的异喹啉衍生物 |
KR20190031299A (ko) | 2016-07-20 | 2019-03-25 | 주식회사 에스티큐브 | 글리코실화된 pd-l1에 결합하는 항체의 조합을 사용하는 암 치료 방법 |
CN106243223B (zh) * | 2016-07-28 | 2019-03-05 | 北京百特美博生物科技有限公司 | 抗人pdl1抗体及其用途 |
EP3490676A1 (en) * | 2016-07-29 | 2019-06-05 | Eli Lilly and Company | Combination therapy with merestinib and anti-pd-l1 or anti-pd-1 inhibitors for use in the treatment of cancer |
CN109689688B (zh) | 2016-08-09 | 2023-06-13 | 科马布有限公司 | 抗icos抗体 |
EP4353747A2 (en) | 2016-08-19 | 2024-04-17 | BeiGene Switzerland GmbH | Combination of zanubrutinib with an anti-cd20 or an anti-pd-1 antibody for use in treating cancer |
CN110191720A (zh) | 2016-09-09 | 2019-08-30 | Tg治疗有限公司 | 用于治疗血液学癌症的抗-CD20抗体、PI 3激酶-δ抑制剂以及抗-PD-1或抗-PD-L1抗体的组合 |
CN117586403A (zh) | 2016-10-11 | 2024-02-23 | 艾吉纳斯公司 | 抗lag-3抗体及其使用方法 |
WO2018071913A2 (en) | 2016-10-14 | 2018-04-19 | Dana-Farber Cancer Institute, Inc. | Modular tetrameric bispecific antibody platform |
WO2018083248A1 (en) | 2016-11-03 | 2018-05-11 | Kymab Limited | Antibodies, combinations comprising antibodies, biomarkers, uses & methods |
CN106496327B (zh) * | 2016-11-18 | 2019-01-15 | 昆山百尔泰生物科技有限公司 | 针对pd-l1胞外段的人源抗体或抗体片段和用途、核苷酸序列和载体 |
US11279694B2 (en) | 2016-11-18 | 2022-03-22 | Sumitomo Dainippon Pharma Oncology, Inc. | Alvocidib prodrugs and their use as protein kinase inhibitors |
AU2017369994A1 (en) | 2016-12-01 | 2019-06-13 | Glaxosmithkline Intellectual Property Development Limited | Combination therapy |
KR20190090822A (ko) | 2016-12-01 | 2019-08-02 | 글락소스미스클라인 인털렉츄얼 프로퍼티 디벨로프먼트 리미티드 | 조합 요법 |
MA50948A (fr) | 2016-12-07 | 2020-10-14 | Agenus Inc | Anticorps et procédés d'utilisation de ceux-ci |
EA201991383A1 (ru) | 2016-12-07 | 2019-12-30 | Эйдженус Инк. | Антитела против ctla-4 и способы их применения |
EP3554535A4 (en) | 2016-12-14 | 2020-10-21 | Janssen Biotech, Inc. | PD-L1 BINDING FIBRONECTIN TYPE III DOMAINS |
WO2018111978A1 (en) | 2016-12-14 | 2018-06-21 | Janssen Biotech, Inc. | Cd137 binding fibronectin type iii domains |
US10626165B2 (en) | 2016-12-14 | 2020-04-21 | Janssen Biotech, Inc. | CD8a-binding fibronectin type III domains |
CN110198954A (zh) | 2017-01-13 | 2019-09-03 | 艾吉纳斯公司 | 与ny-eso-1结合的t细胞受体和其使用方法 |
WO2018137681A1 (en) | 2017-01-25 | 2018-08-02 | Beigene, Ltd. | Crystalline forms of (s) -7- (1- (but-2-ynoyl) piperidin-4-yl) -2- (4-phenoxyphenyl) -4, 5, 6, 7-tetrahy dropyrazolo [1, 5-a] pyrimidine-3-carboxamide, preparation, and uses thereof |
CN106699891B (zh) * | 2017-01-25 | 2019-04-09 | 北京天广实生物技术股份有限公司 | 一种抗pd-l1抗体、其药物组合物及其用途 |
AU2018224094A1 (en) | 2017-02-24 | 2019-09-19 | Macrogenics, Inc. | Bispecific binding molecules that are capable of binding CD137 and tumor antigens, and uses thereof |
CA3052767A1 (en) | 2017-02-27 | 2018-08-30 | Glaxosmithkline Intellectual Property Development Limited | Heterocyclic amides as kinase inhibitors |
US20200239579A1 (en) * | 2017-03-09 | 2020-07-30 | Genmab A/S | Antibodies against pd-l1 |
US20210186982A1 (en) | 2017-03-24 | 2021-06-24 | Universite Nice Sophia Antipolis | Methods and compositions for treating melanoma |
JOP20190222A1 (ar) * | 2017-04-11 | 2019-09-24 | Zymeworks Inc | الأجسام المضادة ثنائية النوعية المضادة لـ pd-l1 والمضادة لـ tim-3 |
EP3609921A2 (en) | 2017-04-13 | 2020-02-19 | Agenus Inc. | Anti-cd137 antibodies and methods of use thereof |
MX2019012295A (es) | 2017-04-14 | 2020-02-07 | Tollnine Inc | Polinucleotidos inmunomoduladores, conjugados de anticuerpos de los mismos y metodos para su uso. |
RU2665790C1 (ru) * | 2017-04-17 | 2018-09-04 | Закрытое Акционерное Общество "Биокад" | Моноклональное антитело к pd-l1 |
JOP20190248A1 (ar) | 2017-04-21 | 2019-10-20 | Amgen Inc | بروتينات ربط مولد ضد trem2 واستخداماته |
AR111651A1 (es) | 2017-04-28 | 2019-08-07 | Novartis Ag | Conjugados de anticuerpos que comprenden agonistas del receptor de tipo toll y terapias de combinación |
EP3618863B1 (en) | 2017-05-01 | 2023-07-26 | Agenus Inc. | Anti-tigit antibodies and methods of use thereof |
EP3630148A4 (en) * | 2017-05-26 | 2021-06-16 | The Johns Hopkins University | MULTIFUNCTIONAL ANTIBODY LIGAND TRAPS FOR THE MODULATION OF IMMUNTOLERANCE |
WO2018222949A1 (en) | 2017-06-01 | 2018-12-06 | Cytomx Therapeutics, Inc. | Activatable anti-pdl1 antibodies, and methods of use thereof |
CA3065447A1 (en) | 2017-06-05 | 2018-12-13 | Janssen Biotech, Inc. | Methods of engineering surface charge for bispecific antibody production |
WO2018225093A1 (en) | 2017-06-07 | 2018-12-13 | Glaxosmithkline Intellectual Property Development Limited | Chemical compounds as atf4 pathway inhibitors |
CA3066048A1 (en) | 2017-06-09 | 2018-12-13 | Glaxosmithkline Intellectual Property Development Limited | Combination therapy |
WO2018229715A1 (en) | 2017-06-16 | 2018-12-20 | Novartis Ag | Compositions comprising anti-cd32b antibodies and methods of use thereof |
GB201709808D0 (en) | 2017-06-20 | 2017-08-02 | Kymab Ltd | Antibodies |
WO2018234879A1 (en) | 2017-06-22 | 2018-12-27 | Novartis Ag | USE OF IL-1β BINDING ANTIBODIES IN THE TREATMENT OF CANCER |
US20200172628A1 (en) | 2017-06-22 | 2020-06-04 | Novartis Ag | Antibody molecules to cd73 and uses thereof |
WO2018235056A1 (en) | 2017-06-22 | 2018-12-27 | Novartis Ag | IL-1BETA BINDING ANTIBODIES FOR USE IN THE TREATMENT OF CANCER |
WO2018237157A1 (en) | 2017-06-22 | 2018-12-27 | Novartis Ag | CD73 BINDING ANTIBODY MOLECULES AND USES THEREOF |
US11597768B2 (en) | 2017-06-26 | 2023-03-07 | Beigene, Ltd. | Immunotherapy for hepatocellular carcinoma |
CA3066747A1 (en) | 2017-06-27 | 2019-01-03 | Novartis Ag | Dosage regimens for anti-tim-3 antibodies and uses thereof |
BR112020000086A2 (pt) | 2017-07-03 | 2020-07-07 | Glaxosmithkline Intellectual Property Development Limited | derivados de 2-(4-clorofenóxi)-n-((1-(2-(4-clorofenóxi) etinazetidin-3-il) metil) acetamida e compostos relacionados como inibidores de atf4 para tratamento de câncer e outras doenças |
BR112020000122A2 (pt) | 2017-07-03 | 2020-07-07 | Glaxosmithkline Intellectual Property Development Limited | derivados da n-(3-(2-(4-clorofenóxi)acetamido)biciclo[1.1.1] pentan-1-il)-2-ciclobutano-1-carboxamida e compostos relacionados como inibidores do atf4 para tratamento contra o câncer e outras doenças |
CN111163798A (zh) | 2017-07-20 | 2020-05-15 | 诺华股份有限公司 | 用于抗lag-3抗体的给药方案及其用途 |
WO2019021208A1 (en) | 2017-07-27 | 2019-01-31 | Glaxosmithkline Intellectual Property Development Limited | USEFUL INDAZOLE DERIVATIVES AS PERK INHIBITORS |
JP7387585B2 (ja) | 2017-09-04 | 2023-11-28 | アジェナス インコーポレイテッド | 混合系統白血病(mll)特異的ホスホペプチドに結合するt細胞受容体およびその使用方法 |
UY37866A (es) | 2017-09-07 | 2019-03-29 | Glaxosmithkline Ip Dev Ltd | Nuevos compuestos derivados de benzoimidazol sustituidos que reducen la proteína myc (c-myc) en las células e inhiben la histona acetiltransferasa de p300/cbp. |
WO2019053617A1 (en) | 2017-09-12 | 2019-03-21 | Glaxosmithkline Intellectual Property Development Limited | CHEMICAL COMPOUNDS |
JP7196160B2 (ja) | 2017-09-12 | 2022-12-26 | スミトモ ファーマ オンコロジー, インコーポレイテッド | Mcl-1阻害剤アルボシジブを用いた、bcl-2阻害剤に対して非感受性である癌の治療レジメン |
WO2019061324A1 (en) | 2017-09-29 | 2019-04-04 | Curis Inc. | CRYSTALLINE FORMS OF IMMUNOMODULATORS |
WO2019069270A1 (en) | 2017-10-05 | 2019-04-11 | Glaxosmithkline Intellectual Property Development Limited | GENERATOR STIMULATOR MODULATORS (STING) INTERFERON |
AU2018344902B2 (en) | 2017-10-05 | 2021-06-03 | Glaxosmithkline Intellectual Property Development Limited | Modulators of stimulator of interferon genes (STING) useful in treating HIV |
KR20200068659A (ko) | 2017-10-11 | 2020-06-15 | 오리진 디스커버리 테크놀로지스 리미티드 | 3-치환된 1,2,4-옥사다이아졸의 결정질 형태 |
US20210040205A1 (en) | 2017-10-25 | 2021-02-11 | Novartis Ag | Antibodies targeting cd32b and methods of use thereof |
DE102017125019B4 (de) * | 2017-10-25 | 2019-10-17 | Epiontis Gmbh | PDCD1 als epigenetischer Marker zur Identifizierung von Immunzellen, insbesondere PD1+ Zellen |
JP7378394B2 (ja) | 2017-11-03 | 2023-11-13 | オーリジーン オンコロジー リミテッド | Tim-3およびpd-1経路の二重阻害剤 |
EP3706798A1 (en) | 2017-11-06 | 2020-09-16 | Aurigene Discovery Technologies Limited | Conjoint therapies for immunomodulation |
CN111801334B (zh) | 2017-11-29 | 2023-06-09 | 百济神州瑞士有限责任公司 | 使用包含btk抑制剂的组合治疗惰性或侵袭性b-细胞淋巴瘤 |
EP3717907A1 (en) | 2017-11-30 | 2020-10-07 | Novartis AG | Bcma-targeting chimeric antigen receptor, and uses thereof |
CN107973854B (zh) * | 2017-12-11 | 2021-05-04 | 苏州银河生物医药有限公司 | Pdl1单克隆抗体及其应用 |
GB201721338D0 (en) | 2017-12-19 | 2018-01-31 | Kymab Ltd | Anti-icos Antibodies |
WO2019122882A1 (en) | 2017-12-19 | 2019-06-27 | Kymab Limited | Bispecific antibody for icos and pd-l1 |
KR102311838B1 (ko) * | 2017-12-27 | 2021-10-14 | 주식회사 파멥신 | 항-pd-l1 항체 및 이의 용도 |
WO2019134946A1 (en) | 2018-01-04 | 2019-07-11 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Methods and compositions for treating melanoma resistant |
CN112218651A (zh) | 2018-01-08 | 2021-01-12 | 诺华公司 | 用于与嵌合抗原受体疗法组合的免疫增强rna |
MX2020007406A (es) | 2018-01-10 | 2020-09-14 | Jiangsu Hengrui Medicine Co | Anticuerpo pd-l1, fragmento de union al antigeno del mismo y uso farmaceutico del mismo. |
US11673897B2 (en) | 2018-01-26 | 2023-06-13 | Exelixis, Inc. | Compounds for the treatment of kinase-dependent disorders |
CR20200355A (es) | 2018-01-26 | 2021-02-22 | Exelixis Inc | Compuestos para el tratamiento de trastornos dependientes de cinasas |
CR20230287A (es) | 2018-01-26 | 2023-07-26 | Exelixis Inc | COMPUESTOS PARA EL TRATAMIENTO DE TRASTORNOS DEPENDIENTES DE CINASAS (Divisional 2020-358) |
CA3090249A1 (en) | 2018-01-31 | 2019-08-08 | Novartis Ag | Combination therapy using a chimeric antigen receptor |
EP3752203A1 (en) | 2018-02-13 | 2020-12-23 | Novartis AG | Chimeric antigen receptor therapy in combination with il-15r and il15 |
US20210080467A1 (en) | 2018-02-21 | 2021-03-18 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Use of sk1 as biomarker for predicting response to immunecheckpoint inhibitors |
WO2019193541A1 (en) | 2018-04-06 | 2019-10-10 | Glaxosmithkline Intellectual Property Development Limited | Bicyclic aromatic ring derivatives of formula (i) as atf4 inhibitors |
WO2019193540A1 (en) | 2018-04-06 | 2019-10-10 | Glaxosmithkline Intellectual Property Development Limited | Heteroaryl derivatives of formula (i) as atf4 inhibitors |
CN113121698B (zh) * | 2018-04-09 | 2022-11-01 | 原启生物科技(上海)有限责任公司 | 抗pd-l1抗体及其用途 |
US20210147547A1 (en) | 2018-04-13 | 2021-05-20 | Novartis Ag | Dosage Regimens For Anti-Pd-L1 Antibodies And Uses Thereof |
AU2019261451A1 (en) | 2018-04-26 | 2020-12-03 | Agenus Inc. | Heat shock protein-binding peptide compositions and methods of use thereof |
GB201807924D0 (en) | 2018-05-16 | 2018-06-27 | Ctxt Pty Ltd | Compounds |
AR126019A1 (es) | 2018-05-30 | 2023-09-06 | Novartis Ag | Anticuerpos frente a entpd2, terapias de combinación y métodos de uso de los anticuerpos y las terapias de combinación |
WO2019232244A2 (en) | 2018-05-31 | 2019-12-05 | Novartis Ag | Antibody molecules to cd73 and uses thereof |
CA3098420A1 (en) | 2018-06-01 | 2019-12-05 | Novartis Ag | Binding molecules against bcma and uses thereof |
EP3820843A1 (en) | 2018-07-09 | 2021-05-19 | GlaxoSmithKline Intellectual Property Development Limited | Chemical compounds |
AR116109A1 (es) | 2018-07-10 | 2021-03-31 | Novartis Ag | Derivados de 3-(5-amino-1-oxoisoindolin-2-il)piperidina-2,6-diona y usos de los mismos |
SG11202011872QA (en) | 2018-07-10 | 2021-01-28 | Novartis Ag | 3-(5-hydroxy-1-oxoisoindolin-2-yl)piperidine-2,6-dione derivatives and their use in the treatment of ikaros family zinc finger 2 (ikzf2)-dependent diseases |
WO2020031107A1 (en) | 2018-08-08 | 2020-02-13 | Glaxosmithkline Intellectual Property Development Limited | Chemical compounds |
WO2020044206A1 (en) | 2018-08-29 | 2020-03-05 | Glaxosmithkline Intellectual Property Development Limited | Heterocyclic amides as kinase inhibitors for use in the treatment cancer |
JP2022513374A (ja) | 2018-10-22 | 2022-02-07 | グラクソスミスクライン、インテレクチュアル、プロパティー、ディベロップメント、リミテッド | 投薬 |
EP3873532A1 (en) | 2018-10-31 | 2021-09-08 | Novartis AG | Dc-sign antibody drug conjugates |
EP3880202A2 (en) | 2018-11-16 | 2021-09-22 | ArQule, Inc. | Pharmaceutical combination for treatment of cancer |
WO2020104479A1 (en) | 2018-11-20 | 2020-05-28 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Methods and compositions for treating cancers and resistant cancers with anti transferrin receptor 1 antibodies |
WO2020104496A1 (en) | 2018-11-20 | 2020-05-28 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Bispecific antibody targeting transferrin receptor 1 and soluble antigen |
AU2019390729B2 (en) | 2018-11-30 | 2022-08-11 | Glaxosmithkline Intellectual Property Development Limited | Compounds useful in HIV therapy |
MX2021006544A (es) | 2018-12-04 | 2021-07-07 | Sumitomo Pharma Oncology Inc | Inhibidores de cinasa dependiente de ciclina 9 (cdk9) y polimorfos de los mismos para uso como agentes para el tratamiento de cancer. |
WO2020115261A1 (en) | 2018-12-07 | 2020-06-11 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Methods and compositions for treating melanoma |
WO2020120592A1 (en) | 2018-12-12 | 2020-06-18 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Methods and compositions for predicting and treating melanoma |
JP2022512399A (ja) | 2018-12-13 | 2022-02-03 | エグゼリクシス, インコーポレイテッド | キナーゼ阻害剤の結晶性形態及び塩形態 |
US20220064332A1 (en) | 2018-12-19 | 2022-03-03 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Methods and compositions for treating cancers by immuno-modulation using antibodies against cathespin-d |
JP2022514315A (ja) | 2018-12-20 | 2022-02-10 | ノバルティス アーゲー | 3-(1-オキソイソインドリン-2-イル)ピペリジン-2,6-ジオン誘導体を含む投与計画及び薬剤組み合わせ |
EP3898974A1 (en) | 2018-12-21 | 2021-10-27 | Onxeo | New conjugated nucleic acid molecules and their uses |
AU2019406840A1 (en) | 2018-12-21 | 2021-06-03 | Novartis Ag | Use of IL-1 beta antibodies in the treatment or prevention of myelodysplastic syndrome |
WO2020132560A2 (en) | 2018-12-21 | 2020-06-25 | Aim Immunotech Inc. | Compositions and methods for cancer therapy |
WO2020128620A1 (en) | 2018-12-21 | 2020-06-25 | Novartis Ag | Use of il-1beta binding antibodies |
WO2020127885A1 (en) | 2018-12-21 | 2020-06-25 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Compositions for treating cancers and resistant cancers |
WO2020128637A1 (en) | 2018-12-21 | 2020-06-25 | Novartis Ag | Use of il-1 binding antibodies in the treatment of a msi-h cancer |
EP3897613A1 (en) | 2018-12-21 | 2021-10-27 | Novartis AG | Use of il-1beta binding antibodies |
EP3914356A1 (en) | 2019-01-25 | 2021-12-01 | Exelixis, Inc. | Compounds for the treatment of kinase-dependent disorders |
WO2020157131A1 (en) | 2019-01-30 | 2020-08-06 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Methods and compositions for identifying whether a subject suffering from a cancer will achieve a response with an immune-checkpoint inhibitor |
AU2020214412A1 (en) | 2019-02-01 | 2021-08-12 | Glaxosmithkline Intellectual Property Development Limited | Belantamab mafodotin in combination with pembrolizumab for treating cancer |
WO2020161083A1 (en) | 2019-02-04 | 2020-08-13 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Methods and compositions for modulating blood-brain barrier |
CN113412262A (zh) | 2019-02-12 | 2021-09-17 | 大日本住友制药肿瘤公司 | 包含杂环蛋白激酶抑制剂的制剂 |
EP3924520A1 (en) | 2019-02-13 | 2021-12-22 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Methods and compositions for selecting a cancer treatment in a subject suffering from cancer |
CA3124935A1 (en) | 2019-02-15 | 2020-08-20 | Novartis Ag | 3-(1-oxo-5-(piperidin-4-yl)isoindolin-2-yl)piperidine-2,6-dione derivatives and uses thereof |
KR20210129672A (ko) | 2019-02-15 | 2021-10-28 | 노파르티스 아게 | 치환된 3-(1-옥소이소인돌린-2-일)피페리딘-2,6-디온 유도체 및 이의 용도 |
WO2020191326A1 (en) | 2019-03-20 | 2020-09-24 | Sumitomo Dainippon Pharma Oncology, Inc. | Treatment of acute myeloid leukemia (aml) with venetoclax failure |
WO2020198077A1 (en) | 2019-03-22 | 2020-10-01 | Sumitomo Dainippon Pharma Oncology, Inc. | Compositions comprising pkm2 modulators and methods of treatment using the same |
CN109929037B (zh) * | 2019-04-01 | 2023-03-17 | 华博生物医药技术(上海)有限公司 | 针对程序性死亡配体的结合物及其应用 |
JP7212990B2 (ja) | 2019-04-26 | 2023-01-26 | アイ-エムエービー バイオファーマ ユーエス リミテッド | ヒトpd‐l1抗体 |
WO2020221796A1 (en) | 2019-04-30 | 2020-11-05 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Methods and compositions for treating melanoma |
US20220251079A1 (en) | 2019-05-16 | 2022-08-11 | Stingthera, Inc. | Benzo[b][1,8]naphthyridine acetic acid derivatives and methods of use |
EP3969438A1 (en) | 2019-05-16 | 2022-03-23 | Stingthera, Inc. | Oxoacridinyl acetic acid derivatives and methods of use |
CA3139148A1 (en) | 2019-06-03 | 2020-12-10 | Exelixis, Inc. | Crystalline salt forms of a kinase inhibitor |
AR119069A1 (es) | 2019-06-04 | 2021-11-24 | Exelixis Inc | Compuestos para el tratamiento de trastornos dependientes de quinasas |
CN114222760A (zh) | 2019-06-26 | 2022-03-22 | 葛兰素史密斯克莱知识产权发展有限公司 | Il1rap结合蛋白 |
CN114302878A (zh) | 2019-07-03 | 2022-04-08 | 大日本住友制药肿瘤公司 | 酪氨酸激酶非受体1(tnk1)抑制剂及其用途 |
US20220356255A1 (en) | 2019-07-15 | 2022-11-10 | Capella Bioscience Ltd | Anti-pd-l1 antibodies |
GB201910305D0 (en) | 2019-07-18 | 2019-09-04 | Ctxt Pty Ltd | Compounds |
GB201910304D0 (en) | 2019-07-18 | 2019-09-04 | Ctxt Pty Ltd | Compounds |
CN112300279A (zh) * | 2019-07-26 | 2021-02-02 | 上海复宏汉霖生物技术股份有限公司 | 针对抗cd73抗体和变体的方法和组合物 |
BR112022003740A2 (pt) | 2019-08-30 | 2022-05-31 | Agenus Inc | Anticorpos anti-cd96 e métodos de uso dos mesmos |
WO2021043961A1 (en) | 2019-09-06 | 2021-03-11 | Glaxosmithkline Intellectual Property Development Limited | Dosing regimen for the treatment of cancer with an anti icos agonistic antibody and chemotherapy |
WO2021048292A1 (en) | 2019-09-11 | 2021-03-18 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Methods and compositions for treating melanoma |
EP4031578A1 (en) | 2019-09-18 | 2022-07-27 | Novartis AG | Entpd2 antibodies, combination therapies, and methods of using the antibodies and combination therapies |
TW202124446A (zh) | 2019-09-18 | 2021-07-01 | 瑞士商諾華公司 | 與entpd2抗體之組合療法 |
CN114729049A (zh) | 2019-09-27 | 2022-07-08 | 葛兰素史密斯克莱知识产权发展有限公司 | 抗原结合蛋白 |
JP2022550420A (ja) * | 2019-09-30 | 2022-12-01 | ハーバー・バイオメド・(シャンハイ)・カンパニー・リミテッド | 抗pd-l1抗原結合タンパク質及びその応用 |
EP4037714A1 (en) | 2019-10-03 | 2022-08-10 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Methods and compositions for modulating macrophages polarization |
WO2021076574A2 (en) | 2019-10-14 | 2021-04-22 | Aro Biotherapeutics Company | Fn3 domain-sirna conjugates and uses thereof |
US11628222B2 (en) | 2019-10-14 | 2023-04-18 | Aro Biotherapeutics Company | CD71 binding fibronectin type III domains |
EP4045686A1 (en) | 2019-10-17 | 2022-08-24 | Institut National de la Santé et de la Recherche Médicale (INSERM) | Methods for diagnosing nasal intestinal type adenocarcinomas |
KR20220103947A (ko) | 2019-10-21 | 2022-07-25 | 노파르티스 아게 | 베네토클락스 및 tim-3 억제제를 사용한 조합 요법 |
BR112022007179A2 (pt) | 2019-10-21 | 2022-08-23 | Novartis Ag | Inibidores de tim-3 e usos dos mesmos |
US20240122938A1 (en) | 2019-10-29 | 2024-04-18 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Methods and compositions for treating uveal melanoma |
WO2021102343A1 (en) | 2019-11-22 | 2021-05-27 | Sumitomo Dainippon Pharma Oncology, Inc. | Solid dose pharmaceutical composition |
WO2021113307A2 (en) * | 2019-12-02 | 2021-06-10 | Dana-Farber Cancer Institute, Inc. | Antibodies against pd-l1 and methods of use thereof |
CA3164754A1 (en) | 2019-12-19 | 2021-06-24 | Inserm (Institut National De La Sante Et De La Recherche Medicale) | Methods and vaccine compositions to treat cancers |
CA3164642A1 (en) | 2019-12-19 | 2021-06-24 | Ngm Biopharmaceuticals, Inc. | Ilt3-binding agents and methods of use thereof |
CN115052662A (zh) | 2019-12-20 | 2022-09-13 | 诺华股份有限公司 | 抗TGFβ抗体和检查点抑制剂用于治疗增殖性疾病的用途 |
CN111378042A (zh) * | 2020-01-15 | 2020-07-07 | 哈尔滨医科大学 | 一种切伦科夫荧光成像探针及其制备方法与应用 |
US20230076415A1 (en) | 2020-01-17 | 2023-03-09 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Methods and compositions for treating melanoma |
MX2022008763A (es) | 2020-01-17 | 2022-07-27 | Novartis Ag | Combinacion que comprende un inhibidor de tim-3 y un agente hipometilante para usarse en el tratamiento del sindrome mielodisplasico o leucemia mielomonocitica cronica. |
WO2021152495A1 (en) | 2020-01-28 | 2021-08-05 | Glaxosmithkline Intellectual Property Development Limited | Combination treatments and uses and methods thereof |
US20230090446A1 (en) | 2020-01-28 | 2023-03-23 | Universite De Strasbourg | Antisense oligonucleotide targeting linc00518 for treating melanoma |
WO2021156360A1 (en) | 2020-02-05 | 2021-08-12 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Methods for discontinuing a treatment with a tyrosine kinase inhibitor (tki) |
MX2022010515A (es) | 2020-02-28 | 2022-11-14 | Tallac Therapeutics Inc | Conjugacion mediada por transglutaminasa. |
WO2021170777A1 (en) | 2020-02-28 | 2021-09-02 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Methods for diagnosing, prognosing and managing treatment of breast cancer |
EP4136105A1 (en) | 2020-04-14 | 2023-02-22 | GlaxoSmithKline Intellectual Property Development Limited | Combination treatment for cancer based upon an icos antibody and a pd-l1 antibody tgf-beta-receptor fusion protein |
CN116589581A (zh) | 2020-05-01 | 2023-08-15 | 恩格姆生物制药公司 | Ilt结合剂和其使用方法 |
US11919956B2 (en) | 2020-05-14 | 2024-03-05 | Xencor, Inc. | Heterodimeric antibodies that bind prostate specific membrane antigen (PSMA) and CD3 |
AR122644A1 (es) | 2020-06-19 | 2022-09-28 | Onxeo | Nuevas moléculas de ácido nucleico conjugado y sus usos |
WO2021262597A2 (en) | 2020-06-22 | 2021-12-30 | Ngm Biopharmaceuticals, Inc. | Lair-1-binding agents and methods of use thereof |
JP2023531676A (ja) | 2020-06-23 | 2023-07-25 | ノバルティス アーゲー | 3-(1-オキソイソインドリン-2-イル)ピぺリジン-2,6-ジオン誘導体を含む投与レジメン |
US20230266332A1 (en) | 2020-07-28 | 2023-08-24 | Inserm (Institut National De La Santè Et De La Recherch Médicale) | Methods and compositions for preventing and treating a cancer |
US20230301979A1 (en) | 2020-07-31 | 2023-09-28 | Exelixis, Inc. | Combinations for the treatment of cancer |
CN116134027A (zh) | 2020-08-03 | 2023-05-16 | 诺华股份有限公司 | 杂芳基取代的3-(1-氧代异吲哚啉-2-基)哌啶-2,6-二酮衍生物及其用途 |
KR102607909B1 (ko) | 2020-08-19 | 2023-12-01 | 젠코어 인코포레이티드 | 항-cd28 조성물 |
US20230314440A1 (en) | 2020-08-21 | 2023-10-05 | Exelixis, Inc. | Method of treating cancer |
CA3187272A1 (en) | 2020-10-08 | 2022-04-14 | Thorsten Ross | Trispecific binders |
WO2022081886A1 (en) * | 2020-10-14 | 2022-04-21 | Xencor, Inc. | Bispecific antibodies that bind pd-l1 and cd28 |
WO2022084531A1 (en) | 2020-10-23 | 2022-04-28 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Methods and compositions for treating glioma |
KR20230104651A (ko) | 2020-11-06 | 2023-07-10 | 노파르티스 아게 | Cd19 결합 분자 및 이의 용도 |
WO2022101481A1 (en) | 2020-11-16 | 2022-05-19 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Methods and compositions for predicting and treating uveal melanoma |
EP4244392A1 (en) | 2020-11-16 | 2023-09-20 | Inserm (Institut National De La Sante Et De La Recherche Medicale) | Methods and compositions for predicting and treating uveal melanoma |
TW202237119A (zh) | 2020-12-10 | 2022-10-01 | 美商住友製藥腫瘤公司 | Alk﹘5抑制劑和彼之用途 |
WO2022162569A1 (en) | 2021-01-29 | 2022-08-04 | Novartis Ag | Dosage regimes for anti-cd73 and anti-entpd2 antibodies and uses thereof |
AU2022230795A1 (en) | 2021-03-02 | 2023-09-21 | Glaxosmithkline Intellectual Property Development Limited | Substituted pyridines as dnmt1 inhibitors |
CA3212665A1 (en) | 2021-03-09 | 2022-09-15 | Xencor, Inc. | Heterodimeric antibodies that bind cd3 and cldn6 |
KR20230154311A (ko) | 2021-03-10 | 2023-11-07 | 젠코어 인코포레이티드 | Cd3 및 gpc3에 결합하는 이종이량체 항체 |
EP4308118A1 (en) | 2021-03-17 | 2024-01-24 | Institut National de la Santé et de la Recherche Médicale (INSERM) | Methods and compositions for treating melanoma |
WO2022195551A1 (en) | 2021-03-18 | 2022-09-22 | Novartis Ag | Biomarkers for cancer and methods of use thereof |
EP4314060A1 (en) | 2021-03-31 | 2024-02-07 | GlaxoSmithKline Intellectual Property Development Limited | Antigen binding proteins and combinations thereof |
TW202304979A (zh) | 2021-04-07 | 2023-02-01 | 瑞士商諾華公司 | 抗TGFβ抗體及其他治療劑用於治療增殖性疾病之用途 |
PE20240327A1 (es) | 2021-04-13 | 2024-02-22 | Nuvalent Inc | Heterociclos con sustitucion amino para tratar canceres con mutaciones de egfr |
WO2022219080A1 (en) | 2021-04-14 | 2022-10-20 | INSERM (Institut National de la Santé et de la Recherche Médicale) | New method to improve nk cells cytotoxicity |
WO2022223791A1 (en) | 2021-04-23 | 2022-10-27 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Methods and compositions for treating cell senescence accumulation related disease |
US20220396623A1 (en) | 2021-05-18 | 2022-12-15 | Kymab Limited | Uses of anti-icos antibodies |
AR125874A1 (es) | 2021-05-18 | 2023-08-23 | Novartis Ag | Terapias de combinación |
GB202107994D0 (en) | 2021-06-04 | 2021-07-21 | Kymab Ltd | Treatment of cancer |
CA3216098A1 (en) | 2021-07-30 | 2023-02-02 | Uwe Reusch | Duplexbodies |
WO2023078900A1 (en) | 2021-11-03 | 2023-05-11 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Methods and compositions for treating triple negative breast cancer (tnbc) |
WO2023111203A1 (en) | 2021-12-16 | 2023-06-22 | Onxeo | New conjugated nucleic acid molecules and their uses |
WO2023118165A1 (en) | 2021-12-21 | 2023-06-29 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Methods and compositions for treating melanoma |
WO2023122739A1 (en) | 2021-12-22 | 2023-06-29 | Exelixis, Inc. | Crystalline forms and salt forms of a kinase inhibitor |
WO2023173091A1 (en) | 2022-03-11 | 2023-09-14 | Ngm Biopharmaceuticals, Inc. | Osteoclast-associated ig-like receptor (oscar) and methods of use thereof |
WO2023174210A1 (en) | 2022-03-14 | 2023-09-21 | Laekna Limited | Combination treatment for cancer |
WO2023194656A1 (en) | 2022-04-08 | 2023-10-12 | Tilt Biotherapeutics Oy | Monoclonal pd-l1 antibodies |
WO2023214325A1 (en) | 2022-05-05 | 2023-11-09 | Novartis Ag | Pyrazolopyrimidine derivatives and uses thereof as tet2 inhibitors |
WO2023222854A1 (en) | 2022-05-18 | 2023-11-23 | Kymab Limited | Uses of anti-icos antibodies |
WO2023230541A1 (en) | 2022-05-27 | 2023-11-30 | Viiv Healthcare Company | Piperazine derivatives useful in hiv therapy |
WO2024033400A1 (en) | 2022-08-10 | 2024-02-15 | Institut National de la Santé et de la Recherche Médicale | Sk2 inhibitor for the treatment of pancreatic cancer |
WO2024033399A1 (en) | 2022-08-10 | 2024-02-15 | Institut National de la Santé et de la Recherche Médicale | Sigmar1 ligand for the treatment of pancreatic cancer |
WO2024056716A1 (en) | 2022-09-14 | 2024-03-21 | Institut National de la Santé et de la Recherche Médicale | Methods and pharmaceutical compositions for the treatment of dilated cardiomyopathy |
WO2024084034A1 (en) | 2022-10-21 | 2024-04-25 | Institut National de la Santé et de la Recherche Médicale | Methods and pharmaceutical compositions for the treatment of osteoarthritis |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN101248089A (zh) * | 2005-07-01 | 2008-08-20 | 米德列斯公司 | 抗程序性死亡配体1(pd-l1)的人单克隆抗体 |
Family Cites Families (39)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3773919A (en) | 1969-10-23 | 1973-11-20 | Du Pont | Polylactide-drug mixtures |
FR2413974A1 (fr) | 1978-01-06 | 1979-08-03 | David Bernard | Sechoir pour feuilles imprimees par serigraphie |
US4485045A (en) | 1981-07-06 | 1984-11-27 | Research Corporation | Synthetic phosphatidyl cholines useful in forming liposomes |
US4522811A (en) | 1982-07-08 | 1985-06-11 | Syntex (U.S.A.) Inc. | Serial injection of muramyldipeptides and liposomes enhances the anti-infective activity of muramyldipeptides |
US4816567A (en) | 1983-04-08 | 1989-03-28 | Genentech, Inc. | Recombinant immunoglobin preparations |
US4544545A (en) | 1983-06-20 | 1985-10-01 | Trustees University Of Massachusetts | Liposomes containing modified cholesterol for organ targeting |
US4676980A (en) | 1985-09-23 | 1987-06-30 | The United States Of America As Represented By The Secretary Of The Department Of Health And Human Services | Target specific cross-linked heteroantibodies |
WO1988001513A1 (en) | 1986-08-28 | 1988-03-10 | Teijin Limited | Cytocidal antibody complex and process for its preparation |
US4946778A (en) | 1987-09-21 | 1990-08-07 | Genex Corporation | Single polypeptide chain binding molecules |
US5091513A (en) | 1987-05-21 | 1992-02-25 | Creative Biomolecules, Inc. | Biosynthetic antibody binding sites |
US5132405A (en) | 1987-05-21 | 1992-07-21 | Creative Biomolecules, Inc. | Biosynthetic antibody binding sites |
GB8823869D0 (en) | 1988-10-12 | 1988-11-16 | Medical Res Council | Production of antibodies |
WO1991000360A1 (en) | 1989-06-29 | 1991-01-10 | Medarex, Inc. | Bispecific reagents for aids therapy |
US5013556A (en) | 1989-10-20 | 1991-05-07 | Liposome Technology, Inc. | Liposomes with enhanced circulation time |
WO1991010741A1 (en) | 1990-01-12 | 1991-07-25 | Cell Genesys, Inc. | Generation of xenogeneic antibodies |
US5545806A (en) | 1990-08-29 | 1996-08-13 | Genpharm International, Inc. | Ransgenic non-human animals for producing heterologous antibodies |
US5633425A (en) | 1990-08-29 | 1997-05-27 | Genpharm International, Inc. | Transgenic non-human animals capable of producing heterologous antibodies |
US5625126A (en) | 1990-08-29 | 1997-04-29 | Genpharm International, Inc. | Transgenic non-human animals for producing heterologous antibodies |
ES2108048T3 (es) | 1990-08-29 | 1997-12-16 | Genpharm Int | Produccion y utilizacion de animales inferiores transgenicos capaces de producir anticuerpos heterologos. |
US5661016A (en) | 1990-08-29 | 1997-08-26 | Genpharm International Inc. | Transgenic non-human animals capable of producing heterologous antibodies of various isotypes |
JPH06507398A (ja) | 1991-05-14 | 1994-08-25 | リプリジェン コーポレーション | Hiv感染治療のための異種複合抗体 |
KR100252547B1 (ko) | 1991-09-05 | 2000-09-01 | 프레드 마리얀스키 | 폴리-또는 올리고누클레오티드의 세포로의 표적화된 전달 |
CA2140638C (en) | 1992-07-24 | 2010-05-04 | Raju Kucherlapati | Generation of xenogeneic antibodies |
EP0752248B1 (en) | 1992-11-13 | 2000-09-27 | Idec Pharmaceuticals Corporation | Therapeutic application of chimeric and radiolabeled antibodies to human B lymphocyte restricted differentiation antigen for treatment of B cell lymphoma |
EP0745134A1 (en) | 1994-02-22 | 1996-12-04 | Danafarber Cancer Institute | Nucleic acid delivery system, method of synthesis and uses thereof |
CA2219361C (en) | 1995-04-27 | 2012-02-28 | Abgenix, Inc. | Human antibodies derived from immunized xenomice |
EP0823941A4 (en) | 1995-04-28 | 2001-09-19 | Abgenix Inc | HUMAN ANTIBODIES DERIVED FROM IMMUNIZED XENO MOUSES |
US5916771A (en) | 1996-10-11 | 1999-06-29 | Abgenix, Inc. | Production of a multimeric protein by cell fusion method |
US20020029391A1 (en) | 1998-04-15 | 2002-03-07 | Claude Geoffrey Davis | Epitope-driven human antibody production and gene expression profiling |
JP2009055928A (ja) | 2005-12-19 | 2009-03-19 | T S Tec Kk | 車両用表皮一体発泡成形シート |
CN101104640A (zh) | 2006-07-10 | 2008-01-16 | 苏州大学 | 抗人pd-l1单克隆抗体制备及应用 |
EP2133365B1 (en) | 2006-12-27 | 2017-05-17 | Emory University | Compositions and methods for the treatment of infections and tumors |
AU2009296392B2 (en) * | 2008-09-26 | 2016-06-02 | Dana-Farber Cancer Institute, Inc. | Human anti-PD-1, PD-L1, and PD-L2 antibodies and uses therefor |
KR101573109B1 (ko) | 2009-11-24 | 2015-12-01 | 메디뮨 리미티드 | B7―h1에 대한 표적화된 결합 물질 |
AU2015327781A1 (en) * | 2014-10-03 | 2017-04-20 | Dana-Farber Cancer Institute, Inc. | Glucocorticoid-induced tumor necrosis factor receptor (GITR) antibodies and methods of use thereof |
WO2016070051A2 (en) * | 2014-10-31 | 2016-05-06 | Oncomed Pharmaceuticals, Inc. | Combination therapy for treatment of disease |
KR20170090506A (ko) * | 2014-12-19 | 2017-08-07 | 다나-파버 캔서 인스티튜트 인크. | 키메라 항원 수용체 및 이의 사용 방법 |
MA41460A (fr) * | 2015-02-03 | 2017-12-12 | Oncomed Pharm Inc | Agents de liaison à la tnfrsf et leurs utilisations |
CA2978942A1 (en) * | 2015-03-13 | 2016-09-22 | Cytomx Therapeutics, Inc. | Anti-pdl1 antibodies, activatable anti-pdl1 antibodies, and methods of use thereof |
-
2013
- 2013-10-04 WO PCT/US2013/063509 patent/WO2014055897A2/en active Application Filing
- 2013-10-04 CN CN202111595551.3A patent/CN114507282A/zh active Pending
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-
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- 2020-03-30 US US16/834,901 patent/US20200385482A1/en not_active Abandoned
Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN101248089A (zh) * | 2005-07-01 | 2008-08-20 | 米德列斯公司 | 抗程序性死亡配体1(pd-l1)的人单克隆抗体 |
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