WO2019196309A1 - 抗pd-l1抗体及其用途 - Google Patents
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- WO2019196309A1 WO2019196309A1 PCT/CN2018/102584 CN2018102584W WO2019196309A1 WO 2019196309 A1 WO2019196309 A1 WO 2019196309A1 CN 2018102584 W CN2018102584 W CN 2018102584W WO 2019196309 A1 WO2019196309 A1 WO 2019196309A1
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Abstract
Description
小鼠PD-L1-Fc-Biotin |
抗体 | k on(1/Ms) | k off(1/s) | K D(M) |
YN007 | 8.1×10 5 | 1.09×10 -3 | 1.34×10 -9 |
Claims (72)
- 抗体、其抗原结合片段或变体,其以3×10 -9M或更低的K D值与PD-L1蛋白相结合。
- 根据权利要求1所述的抗体、其抗原结合片段或变体,所述抗体包含抗体轻链或其片段,所述抗体轻链或其片段包含LCDR1,且所述LCDR1包含SEQ ID NO:53所示的氨基酸序列TGTX 1SX 2VGGYX 3X 4VS;其中X 1是S、R或V;X 2是D、E或S;X 3是N或R;X 4是Y或E,且其中所述LCDR1根据抗体Kabat编号的索引确定。
- 根据权利要求2所述的抗体、其抗原结合片段或变体,所述LCDR1包含选自下组的氨基酸序列:SEQ ID NO:54-58。
- 根据权利要求1-3中任一项所述的抗体、其抗原结合片段或变体,所述抗体轻链或其片段包含LCDR2,且所述LCDR2包含SEQ ID NO:59所示的氨基酸序列X 1NSX 2RPS,其中X 1是G或E;X 2是N或I,且其中所述LCDR2根据抗体Kabat编号的索引确定。
- 根据权利要求4所述的抗体、其抗原结合片段或变体,所述LCDR2包含选自下组的氨基酸序列:SEQ ID NO:60-61。
- 根据权利要求1-5中任一项所述的抗体、其抗原结合片段或变体,所述抗体轻链或其片段包含LCDR3,且所述LCDR3包含SEQ ID NO:62所示的氨基酸序列:QSYDSSLSGX 1V,其中X 1是S或T,且其中所述LCDR3根据抗体Kabat编号的索引确定。
- 根据权利要求1-6中任一项所述的抗体、其抗原结合片段或变体,所述抗体轻链或其片段还包括框架区L-FR1,L-FR2,L-FR3,和L-FR4。
- 根据权利要求7所述的抗体、其抗原结合片段或变体,所述框架区选自以下组:人共有框架序列和人种系序列。
- 根据权利要求7-8中任一项所述的抗体、其抗原结合片段或变体,所述L-FR1的C末端与所述LCDR1的N末端直接或间接相连,所述L-FR1包含选自下组的氨基酸序列:SEQ ID NO:71。
- 根据权利要求7-9中任一项所述的抗体、其抗原结合片段或变体,所述L-FR2位于所述LCDR1与所述LCDR2之间,所述L-FR2包含选自下组的氨基酸序列:SEQ ID NO:72。
- 根据权利要求7-10中任一项所述的抗体、其抗原结合片段或变体,所述L-FR3位于所述LCDR2与所述LCDR3之间,所述L-FR3包含选自下组的氨基酸序列:SEQ ID NO:73-75。
- 根据权利要求7-11中任一项所述的抗体、其抗原结合片段或变体,所述L-FR4的N末端与所述LCDR3的C末端直接或间接相连,所述L-FR4包含选自下组的氨基酸序列:SEQ ID NO:76。
- 根据权利要求2-12中任一项所述的抗体、其抗原结合片段或变体,所述抗体轻链或 其片段包含轻链可变区VL,且所述轻链可变区VL包含选自以下组的氨基酸序列:SEQ ID NO:4、SEQ ID NO:11、SEQ ID NO:33、SEQ ID NO:37、SEQ ID NO:39和SEQ ID NO:41。
- 根据权利要求2-13中任一项所述的抗体、其抗原结合片段或变体,所述抗体轻链或其片段还包含人恒定区,且所述人恒定区包括人Igλ恒定区。
- 根据权利要求2-14中任一项所述的抗体、其抗原结合片段或变体,所述抗体轻链或其片段包含选自下组的氨基酸序列:SEQ ID NO:8、SEQ ID NO:15、SEQ ID NO:34、SEQ ID NO:38、SEQ ID NO:40和SEQ ID NO:42。
- 根据权利要求1-15中任一项所述的抗体、其抗原结合片段或变体,所述抗体包含抗体重链或其片段,所述抗体重链或其片段包含HCDR1,且所述HCDR1包含选自SEQ ID NO:45所示的氨基酸序列:X 1YAIS,其中X 1是S或T,且其中所述HCDR1根据抗体Kabat编号的索引确定。
- 根据权利要求16所述的抗体、其抗原结合片段或变体,所述抗体重链或其片段包含HCDR2,所述HCDR2包含SEQ ID NO:48所示的氨基酸序列,且其中所述HCDR2根据抗体Kabat编号的索引确定。
- 根据权利要求16-17中任一项所述的抗体、其抗原结合片段或变体,所述抗体重链或其片段包含HCDR3,且所述HCDR3包含选自SEQ ID NO:49所示的氨基酸序列:TMX 1X 2YX 3X 4GNX 5DY,其中X 1是D、E或G,X 2是G或E,X 3是S或G,X 4是Y或F,X 5是F或Y,且其中所述HCDR3根据抗体Kabat编号的索引确定。
- 根据权利要求18所述的抗体、其抗原结合片段或变体,所述HCDR3包含选自下组的氨基酸序列:SEQ ID NO:50-52。
- 根据权利要求16-19中任一项所述的抗体、其抗原结合片段或变体,所述抗体重链或其片段还包括框架区H-FR1,H-FR2,H-FR3,和H-FR4。
- 根据权利要求20所述的抗体、其抗原结合片段或变体,所述框架区选自以下组:人共有框架序列和人种系序列。
- 根据权利要求20-21中任一项所述的抗体、其抗原结合片段或变体,所述H-FR1的C末端与所述HCDR1的N末端直接或间接相连,所述H-FR1包含选自下组的氨基酸序列:SEQ ID NO:65-67。
- 根据权利要求20-22中任一项所述的抗体、其抗原结合片段或变体,所述H-FR2位于所述HCDR1与所述HCDR2之间,所述H-FR2包含选自下组的氨基酸序列:SEQ ID NO:68。
- 根据权利要求20-23中任一项所述的抗体、其抗原结合片段或变体,所述H-FR3位于 所述HCDR2与所述HCDR3之间,所述H-FR3包含选自下组的氨基酸序列:SEQ ID NO:69。
- 根据权利要求20-24中任一项所述的抗体、其抗原结合片段或变体,所述H-FR4的N末端与所述HCDR3的C末端直接或间接相连,所述H-FR4包含选自下组的氨基酸序列:SEQ ID NO:70。
- 根据权利要求16-25中任一项所述的抗体、其抗原结合片段或变体,所述抗体重链或其片段包含重链可变区VH,且所述重链可变区VH包含选自以下组的氨基酸序列:SEQ ID NO:2、SEQ ID NO:9、SEQ ID NO:31和SEQ ID NO:35。
- 根据权利要求16-26中任一项所述的抗体、其抗原结合片段或变体,所述抗体重链或其片段还包含人恒定区,且所述人恒定区包括人IgG1恒定区。
- 根据权利要求16-27中任一项所述的抗体、其抗原结合片段或变体,所述抗体重链或其片段包含选自下组的氨基酸序列:SEQ ID NO:6、SEQ ID NO:13、SEQ ID NO:32和SEQ ID NO:36。
- 根据权利要求1-28中任一项所述的抗体、其抗原结合片段或变体,所述PD-L1蛋白选自下组:人PD-L1蛋白和鼠PD-L1蛋白。
- 抗体、其抗原结合片段或变体,其以5×10 -9M或更低的K D与CD137蛋白相结合。
- 根据权利要求30所述的抗体、其抗原结合片段或变体,其以3×10 -9M或更低的K D与CD137蛋白相结合。
- 根据权利要求30-31中任一项所述的抗体、其抗原结合片段或变体,其可缓解或治疗肿瘤。
- 根据权利要求32所述的抗体、其抗原结合片段或变体,所述肿瘤包括结肠癌。
- 根据权利要求30-33中任一项所述的抗体、其抗原结合片段或变体,所述抗体包含抗体轻链或其片段。
- 根据权利要求34所述的抗体、其抗原结合片段或变体,所述轻链或其片段包含LCDR1-3,所述LCDR1-3的氨基酸序列依次如SEQ ID NO:80-82所示。
- 根据权利要求34-35中任一项所述的抗体、其抗原结合片段或变体,所述抗体轻链或其片段还包括框架区L-FR1、L-FR2、L-FR3和L-FR4。
- 根据权利要求36所述的抗体、其抗原结合片段或变体,所述框架区选自以下组:人共有框架序列和人种系序列。
- 根据权利要求36-37中任一项所述的抗体、其抗原结合片段或变体,所述L-FR1的C末端与所述LCDR1的N末端直接或间接相连,所述L-FR1包含以下的氨基酸序列:SEQ ID NO:89。
- 根据权利要求36-38中任一项所述的抗体、其抗原结合片段或变体,所述L-FR2位于所述LCDR1与所述LCDR2之间,所述L-FR2包含以下的氨基酸序列:SEQ ID NO:90。
- 根据权利要求38-39中任一项所述的抗体、其抗原结合片段或变体,所述L-FR3位于所述LCDR2与所述LCDR3之间,所述L-FR3包含以下的氨基酸序列:SEQ ID NO:91。
- 根据权利要求38-40中任一项所述的抗体、其抗原结合片段或变体,所述L-FR4的N末端与所述LCDR3的C末端直接或间接相连,所述L-FR4包含以下的氨基酸序列:SEQ ID NO:92。
- 根据权利要求34-41中任一项所述的抗体、其抗原结合片段或变体,所述抗体轻链或其片段包含轻链可变区VL,且所述轻链可变区VL包含以下的氨基酸序列:SEQ ID NO:20。
- 根据权利要求34-42中任一项所述的抗体、其抗原结合片段或变体,所述抗体轻链或其片段还包含人恒定区且所述人恒定区包括人Igλ恒定区。
- 根据权利要求34-43中任一项所述的抗体、其抗原结合片段或变体,所述抗体轻链或其片段包含以下的氨基酸序列:SEQ ID NO:23。
- 根据权利要求30-44中任一项所述的抗体、其抗原结合片段或变体,所述抗体包含抗体重链或其片段,所述重链或其片段包含HCDR1-3,所述HCDR1-3的氨基酸序列依次如SEQ ID NO:77-79所示。
- 根据权利要求45中任一项所述的抗体、其抗原结合片段或变体,所述抗体重链或其片段还包括框架区H-FR1、H-FR2、H-FR3和H-FR4。
- 根据权利要求46所述的抗体、其抗原结合片段或变体,所述框架区选自以下组:人共有框架序列和人种系序列。
- 根据权利要求46-47中任一项所述的抗体、其抗原结合片段或变体,所述H-FR1的C末端与所述HCDR1的N末端直接或间接相连,所述H-FR1包含以下的氨基酸序列:SEQ ID NO:84-85。
- 根据权利要求46-48中任一项所述的抗体、其抗原结合片段或变体,所述H-FR2位于所述HCDR1与所述HCDR2之间,所述H-FR2包含以下的氨基酸序列:SEQ ID NO:86。
- 根据权利要求46-49中任一项所述的抗体、其抗原结合片段或变体,所述H-FR3位于所述HCDR2与所述HCDR3之间,所述H-FR3包含以下的氨基酸序列:SEQ ID NO:87。
- 根据权利要求46-50中任一项所述的抗体、其抗原结合片段或变体,所述H-FR4的N末端与所述HCDR3的C末端直接或间接相连,所述H-FR4包含以下的氨基酸序列:SEQ ID NO:88。
- 根据权利要求46-51中任一项所述的抗体、其抗原结合片段或变体,所述抗体重链或其片段包含重链可变区VH,且所述重链可变区VH包含选自以下组的氨基酸序列:SEQ ID NO:18和SEQ ID NO:25。
- 根据权利要求45-52中任一项所述的抗体、其抗原结合片段或变体,所述抗体重链或其片段还包含人恒定区,且所述人恒定区包括人IgG恒定区。
- 根据权利要求45-53中任一项所述的抗体、其抗原结合片段或变体,所述抗体重链或其片段包含选自以下组的氨基酸序列:SEQ ID NO:21和SEQ ID NO:27。
- 根据权利要求30-54中任一项所述的抗体、其抗原结合片段或变体,所述CD137蛋白包括人CD137蛋白。
- 双特异性抗体,其以2×10 -9M或更低的K D值与PD-L1蛋白相结合,且以8×10 -9M或更低的K D值与CD137蛋白相结合。
- 根据权利要求56所述的双特异性抗体,其包含特异性结合所述PD-L1蛋白的第一靶向部分,其中所述第一靶向部分包含权利要求1-29中任一项所述的抗体、其抗原结合片段或变体。
- 根据权利要求56-57中任一项所述的双特异性抗体,其包含特异性结合所述CD137蛋白的第二靶向部分,其中所述第二靶向部分包含权利要求30-55中任一项所述的抗体、其抗原结合片段或变体。
- 根据权利要求57-58中任一项所述的双特异性抗体,其中所述结合CD137蛋白的抗体包含scFv,且所述scFv包含以下的氨基酸序列:SEQ ID NO:83。
- 根据权利要求56-59中任一项所述的双特异性抗体,其包含第一多肽链和第二多肽链,其中所述第一多肽链包含所述结合PD-L1蛋白的抗体的重链可变区,所述结合CD137蛋白的抗体的重链可变区,以及所述结合CD137蛋白的抗体的轻链可变区;且所述第二多肽链包含所述结合PD-L1蛋白的抗体的轻链可变区。
- 根据权利要求60所述的双特异性抗体,其中所述第一多肽链中,所述结合PD-L1蛋白的抗体的重链可变区位于所述结合CD137蛋白的抗体的重链可变区的N端,且所述结合CD137蛋白的抗体的重链可变区位于所述结合CD137蛋白的抗体的轻链可变区的N端;或者,所述结合PD-L1蛋白的抗体的重链可变区位于所述结合CD137蛋白的抗体的轻链可变区的N端,且所述结合CD137蛋白的抗体的轻链可变区位于所述结合CD137蛋白的抗体的重链可变区的N端。
- 根据权利要求60-61中任一项所述的双特异性抗体,所述第一多肽链中所述结合CD137蛋白的抗体的轻链可变区与所述结合CD137蛋白的抗体的重链可变区构成scFv。
- 根据权利要求60-62中任一项所述的双特异性抗体,其中所述第一多肽链中还包含人IgG恒定区,所述人IgG恒定区位于所述结合PD-L1蛋白的抗体的重链可变区的C端且位于所述结合CD137蛋白的抗体的轻链可变区的N端;或者,所述人IgG恒定区位于所述结合PD-L1蛋白的抗体的重链可变区的C端且位于所述结合CD137蛋白的抗体的重链可变区的N端。
- 根据权利要求60-63中任一项所述的双特异性抗体,其中所述第一多肽链包含选自下组的氨基酸序列:SEQ ID NO:30、SEQ ID NO:43和SEQ ID NO:44。
- 根据权利要求60-64中任一项所述的双特异性抗体,其中所述第二多肽链包括选自下组氨基酸序列:SEQ ID NO:15和SEQ ID NO:34。
- 分离的一种或多种核酸分子,其编码权利要求1-29中任一项所述的抗体、其抗原结合片段或变体,权利要求30-55中任一项所述的抗体、其抗原结合片段或变体,或权利要求56-65中任一项所述的双特异性抗体。
- 载体,其包含根据权利要求66所述的核酸分子。
- 细胞,其包含根据权利要求66所述的核酸分子或根据权利要求67所述的载体。
- 制备权利要求1-29中任一项所述的抗体、其抗原结合片段或变体,权利要求30-55中任一项所述的抗体、其抗原结合片段或变体,或权利要求56-65中任一项所述的双特异性抗体的方法,所述方法包括在使得权利要求1-29中任一项所述的抗体、其抗原结合片段或变体,权利要求30-55中任一项所述的抗体、其抗原结合片段或变体,或权利要求56-65中任一项所述的双特异性抗体表达的条件下,培养根据权利要求68所述的细胞。
- 药物组合物,其包含权利要求1-29中任一项所述的抗体、其抗原结合片段或变体,权利要求30-55中任一项所述的抗体、其抗原结合片段或变体,或权利要求56-65中任一项所述的双特异性抗体,权利要求66所述的核酸分子、权利要求67所述的载体和/或权利要求68所述的细胞,以及任选地药学上可接受的佐剂。
- 权利要求1-29中任一项所述的抗体、其抗原结合片段或变体,权利要求30-55中任一项所述的抗体、其抗原结合片段或变体,或权利要求56-65中任一项所述的双特异性抗体,权利要求66所述的核酸分子、权利要求67所述的载体、权利要求68所述的细胞和/或权利要求70所述的药物组合物在制备缓解或治疗肿瘤的药物中的应用。
- 抑制PD-L1蛋白和PD-1蛋白结合的方法,其包括施用权利要求1-29中任一项所述 的抗体、其抗原结合片段或变体,或权利要求56-65中任一项所述的双特异性抗体,权利要求66所述的核酸分子、权利要求67所述的载体、权利要求68所述的细胞和/或权利要求70所述的药物组合物。
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EA202092420A EA202092420A1 (ru) | 2018-04-09 | 2018-08-27 | Антитело против pd-l1 и его применение |
BR112020020637-7A BR112020020637A2 (pt) | 2018-04-09 | 2018-08-27 | anticorpo anti-pd-l1, fragmento de ligação ao antígeno ou variante do mesmo, anticorpo biespecífico, composição farmacêutica e uso dos mesmos para aliviar ou tratar tumores |
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US17/046,265 US20210380698A1 (en) | 2018-04-09 | 2018-08-27 | Anti-pd-l1 antibody and use thereof |
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CN202110431887.XA CN113121698B (zh) | 2018-04-09 | 2018-08-27 | 抗pd-l1抗体及其用途 |
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WO2022087458A1 (en) * | 2020-10-23 | 2022-04-28 | Asher Biotherapeutics, Inc. | Fusions with cd8 antigen binding molecules for modulating immune cell function |
WO2022148410A1 (zh) * | 2021-01-08 | 2022-07-14 | 北京韩美药品有限公司 | 抗pd-l1/抗4-1bb天然抗体结构样异源二聚体形式双特异抗体及其制备 |
CN116120461A (zh) * | 2022-04-29 | 2023-05-16 | 德琪(杭州)生物有限公司 | 新型抗药抗体以及其用途 |
WO2023138638A1 (zh) * | 2022-01-24 | 2023-07-27 | 原启生物科技(上海)有限责任公司 | 抗tigit和pd-l1的双特异性抗原结合蛋白及其用途 |
Families Citing this family (3)
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WO2023000675A1 (zh) * | 2021-07-23 | 2023-01-26 | 安徽安科生物工程(集团)股份有限公司 | 靶向pd-l1和4-1bb的双特异性抗体 |
WO2023134657A1 (zh) * | 2022-01-11 | 2023-07-20 | 原启生物科技(上海)有限责任公司 | 抗cldn18.2和4-1bb的双特异性抗原结合蛋白及其用途 |
CN114736303A (zh) * | 2022-03-17 | 2022-07-12 | 英诺湖医药(杭州)有限公司 | 抗pd-l1和4-1bb的双功能抗体及其医药用途 |
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Cited By (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2022087458A1 (en) * | 2020-10-23 | 2022-04-28 | Asher Biotherapeutics, Inc. | Fusions with cd8 antigen binding molecules for modulating immune cell function |
WO2022148410A1 (zh) * | 2021-01-08 | 2022-07-14 | 北京韩美药品有限公司 | 抗pd-l1/抗4-1bb天然抗体结构样异源二聚体形式双特异抗体及其制备 |
WO2023138638A1 (zh) * | 2022-01-24 | 2023-07-27 | 原启生物科技(上海)有限责任公司 | 抗tigit和pd-l1的双特异性抗原结合蛋白及其用途 |
CN116120461A (zh) * | 2022-04-29 | 2023-05-16 | 德琪(杭州)生物有限公司 | 新型抗药抗体以及其用途 |
CN116120461B (zh) * | 2022-04-29 | 2023-09-29 | 德琪(杭州)生物有限公司 | 新型抗药抗体以及其用途 |
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JP2021530430A (ja) | 2021-11-11 |
JP7360720B2 (ja) | 2023-10-13 |
IL297847A (en) | 2023-01-01 |
CN115991778A (zh) | 2023-04-21 |
MX2020010653A (es) | 2020-10-28 |
US20210380698A1 (en) | 2021-12-09 |
EA202092420A1 (ru) | 2021-01-28 |
PH12020551661A1 (en) | 2021-06-07 |
IL277893A (en) | 2020-11-30 |
ZA202006255B (en) | 2022-03-30 |
CA3095498A1 (en) | 2019-10-17 |
IL297847B2 (en) | 2024-02-01 |
CN113087799A (zh) | 2021-07-09 |
AU2018418224A1 (en) | 2020-11-26 |
CN110869390B (zh) | 2021-05-11 |
JP2023179558A (ja) | 2023-12-19 |
CN113121698A (zh) | 2021-07-16 |
KR20200140882A (ko) | 2020-12-16 |
BR112020020637A2 (pt) | 2021-03-23 |
CN113087799B (zh) | 2023-03-31 |
CO2020013833A2 (es) | 2020-12-21 |
EP3778635A1 (en) | 2021-02-17 |
SG11202009791VA (en) | 2020-11-27 |
CN113121698B (zh) | 2022-11-01 |
CN110869390A (zh) | 2020-03-06 |
IL297847B1 (en) | 2023-10-01 |
CL2020002600A1 (es) | 2021-01-29 |
EP3778635A4 (en) | 2022-01-26 |
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