CN108079292A - 一种抗pd-1抗体在制备治疗肝癌的药物中的用途 - Google Patents
一种抗pd-1抗体在制备治疗肝癌的药物中的用途 Download PDFInfo
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- CN108079292A CN108079292A CN201711173943.4A CN201711173943A CN108079292A CN 108079292 A CN108079292 A CN 108079292A CN 201711173943 A CN201711173943 A CN 201711173943A CN 108079292 A CN108079292 A CN 108079292A
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Abstract
本发明涉及一种抗PD‑1抗体在制备治疗肝癌的药物中的用途。
Description
技术领域
本发明涉及一种抗PD-1抗体在制备治疗肝癌的药物中的用途。
背景技术
原发性肝癌(Primary Hepatocellular Carcinoma)是全球性常见的恶性肿瘤，中国是肝癌高发区，发病人数约占全球的55％，死亡人数占50％；在肿瘤相关死亡中仅次于肺癌，位居第2。肝细胞癌(Hepatocellular Carcinoma,HCC)是原发性肝癌中最常见的类型，HCC大多在肝炎肝硬化基础上发生，大约出现于原始肝损害后的10～20年。大部分肝癌在早期是无症状的，多数患者在确诊时已达局部晚期或发生远处转移。晚期肝癌目前尚无标准的治疗方法，临床治疗面临着严峻的挑战。在中国晚期HCC患者的存活时间一般为3到6个月，全世界范围内来看最长也不超过1年，这与这些患者缺乏有效的***治疗有很大关系。HCC对常见的化疗抗拒，其治疗方法大致包括手术(肝切除术、肝移植和姑息治疗手术)、非手术治疗(局部治疗、动脉化学栓塞、化疗、放疗、生物治疗以及分子靶向治疗)以及其它治疗方法(包括参加临床研究)。
2007年12月索拉非尼成为美国FDA首个批准的用于治疗HCC的药物，但目前由于价格昂贵，限制了在我国患者中的使用。另外，多种正在开发的多激酶抑制剂在与索拉非尼头对头比较的研究中屡遭挫折：辉瑞公司的舒尼替尼与索拉非尼在晚期肝癌头对头比较的Ⅲ期临床试验于2010年4月被迫提前终止。雅培的多激酶抑制剂ABT-869与索拉非尼相比也无优势。罗氏公司的表皮生长因子受体酪氨酸激酶抑制剂特罗凯(厄洛替尼)与索拉非尼相比在增加额外益处方面同样遭遇了失败。Brivanib是靶向VEGF受体和碱性成纤维细胞生长因子受体的酪氨酸激酶抑制剂，在治疗不能接受手术切除、局部晚期或远处转移的晚期肝癌患者临床Ⅱ期试验中，6月无进展生存率达到18.2％，中位无进展生存时间为2.7月，中位生存时间10月，副作用比较弱，主要是疲倦、高血压和腹泻，但在与索拉非尼对比的Ⅲ期非劣效性临床试验中遭遇了失败，其总生存率并不令人满意。
PD-1抗体特异性识别并结合淋巴细胞表面PD-1，阻断PD-1/PD-L1信号通路，进而激活T细胞对肿瘤的免疫杀伤作用，调动机体免疫***而清除体内肿瘤细胞。
WO201508584公开了一种新的抗PD-1抗体，目前PD-1抗体正处于国内临床Ⅲ期，安全性良好，已经显示出一定的抗肿瘤作用。但是WO201508584中仅认为在乳腺癌、肺癌、胃癌、肠癌、肾癌、黑素瘤等特定的肿瘤中检测到高PD-L1的表达，可能通过其提供的PD-1抗体治疗，但未能研究PD-1抗体对于肝癌是否具有治疗作用。
发明内容
本发明提供了一种抗PD-1抗体在制备治疗肝癌的药物中的用途。优选所述肝癌是肝细胞癌，更优选所述肝癌是晚期肝细胞癌。
在本发明特别优选的实施方案中，所述肝癌的患者是***化疗(单药或联合用药的全身化疗)和/或靶向治疗失败或不可耐受的肝细胞癌患者，其中所述靶向治疗优选使用索拉非尼或阿帕替尼治疗。其中，所述肝癌患者的***化疗可以是使用一种或多种化疗药物进行的化疗，例如蒽环类抗肿瘤药物(包括但不限于多柔比星、表柔比星、伊达比星、吡柔比星、多柔比星脂质体)、铂类(顺铂、卡铂、奈达铂、奥沙利铂)、代谢拮抗剂(例如甲氨蝶呤、5-氟尿嘧啶、替加氟、吉西他滨、卡培他滨等)、亚叶酸或其盐，例如亚叶酸钙。优选的多种化疗药物进行的***化疗方案是使用FOLFOX(奥沙利铂、5-氟尿嘧啶、亚叶酸)方案进行化疗。
其中，治疗失败是指治疗过程中疾病进展或治疗结束后复发。
其中，化疗不可耐受是指在治疗过程中出现≥Ⅳ级的血液学毒性或≥Ⅲ级的非血液学毒性或≥Ⅱ级的心、肝、肾等主要脏器的损害。
其中，索拉非尼不可耐受是指在按当地标准采取充分的支持治疗，并在暂停用药至少7天且降低一个剂量水平用药后，CTCAE 2级的药物相关不良事件仍然持续或复发；在按机构标准采取充分的支持治疗，或在暂停用药至少7天且降低一个剂量水平用药后，CTCAE≥3级的药物相关不良事件仍持续或复发。
PD-1抗体是已知的，优选所述的PD-1抗体的轻链可变区包含分别如SEQ ID NO:4、SEQ ID NO:5和SEQ ID NO:6所示的LCDR1、LCDR2和LCDR3。
所述的PD-1抗体的重链可变区包含分别如SEQ ID NO:1、SEQ ID NO:2和SEQ IDNO:3所示的HCDR1、HCDR2和HCDR3。
其中，前面所述的各CDR序列如下表所示：
| 名称 | 序列 | 编号 |
| HCDR1 | SYMMS | SEQID NO：1 |
| HCDR2 | TISGGGANTYYPDSVKG | SEQID NO：2 |
| HCDR3 | QLYYFDY | SEQID NO：3 |
| LCDR1 | LASQTIGTWLT | SEQID NO：4 |
| LCDR2 | TATSLAD | SEQID NO：5 |
| LCDR3 | QQVYSIPWT | SEQID NO：6 |
优选的，所述的PD-1抗体为人源化抗体。
优选的优选的人源化抗体轻链可变区序列为如SEQ ID NO:10所示的序列或其变体；所述的变体优选在轻链可变区有0-10的氨基酸变化；更优选为A43S的氨基酸变化。所述人源化抗体重链可变区序列为如SEQ ID NO:9所示的序列或其变体；所述变体优选在重链可变区有0-10的氨基酸变化；更优选为G44R的氨基酸变化。
前述的人源化抗体重、轻链的可变区序列如下所示：
重链可变区
EVQLVESGGGLVQPGGSLRLSCAASGFTFSSYMMSWVRQAPGKGLEWVATISGGGANTYYPDSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARQLYYFDYWGQGTTVTVSS
SEQID NO：9轻链可变区
DIQMTQSPSSLSASVGDRVTITCLASQTIGTWLTWYQQKPGKAPKLLIYTATSLADGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQVYSIPWTFGGGTKVEIK
SEQID NO：10优选的人源化抗体轻链序列为如SEQ ID NO:8所示的序列或其变体；所述的变体优选在轻链可变区有0-10的氨基酸变化；更优选为A43S的氨基酸变化。
所述人源化抗体重链序列为如SEQ ID NO:7所示的序列或其变体；所述变体优选在重链可变区有0-10的氨基酸变化；更优选为G44R的氨基酸变化。
特别优选的所述的人源化抗体轻链序列为如SEQ ID NO:8所示的序列，重链序列为如SEQ ID NO:7所示的序列。
前述的人源化抗体重、轻链的序列如下所示：
重链
EVQLVESGGGLVQPGGSLRLSCAASGFTFSSYMMSWVRQAPGKGLEWVATISGGGANTYYPDSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARQLYYFDYWGQGTTVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK
SEQID NO：7
轻链
DIQMTQSPSSLSASVGDRVTITCLASQTIGTWLTWYQQKPGKAPKLLIYTATSLADGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQVYSIPWTFGGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC
SEQID NO：8
具体地，在给药时，其中所述的PD-1抗体的用量PD-1抗体的用量为1－10mg/kg，优选自1mg/kg、2mg/kg、3mg/kg、4mg/kg、5mg/kg、6mg/kg、7mg/kg、8mg/kg、9mg/kg、10mg/kg，更优选1mg/kg、3mg/kg、4mg/kg、5mg/kg、6mg/kg、10mg/kg。给药频次可以是一周一次、二周一次、三周一次、一月一次。
具体地，在给药时，其中所述的PD-1抗体或其抗原结合片段剂量选自50-600mg，优选自50mg、60mg、70mg、75mg、100mg、125mg、150mg、175mg、200mg、225mg、250mg、375mg、400mg、425mg、450mg、475mg、500mg、600mg，更优选自60mg、100mg、200mg、400mg、600mg。给药频次可以是一周一次、二周一次、三周一次、一月一次。
本发明中，所述的PD-1抗体可以单独给药，也可以联合其它化疗药物或靶向治疗药物联合给药，优选单独给药。
具体实施方式
以下结合实施例用于进一步描述本发明，但这些实施例并非限制本发明的范围。
实施例1：一项PD-1抗体在既往经过治疗的晚期肝细胞癌(HCC)患者中的随机、平行对照、多中心II/III期临床研究
一、研究目的
评价PD-1抗体在既往经过治疗的晚期肝细胞癌(HCC)患者中的有效性和安全性二、受试药物和给药方法
受试药物：
PD-1抗体其重、轻链的序列如本发明中SEQ ID NO：7和SEQ ID NO：8。生产厂家：上海恒瑞医药股份有限公司，制备成冻干粉剂形式。
给药方法：
第一阶段：A组：PD-1抗体，3mg/kg，静脉注射，每二周给药一次，42天为一个周期；B组：PD-1抗体，3mg/kg，静脉注射，每三周一次，42天为一个周期；
第二阶段：试验组：PD-1抗体，3mg/kg，静脉注射，每二周给药一次或者每三周给药一次+最佳支持治疗，42天为一个周期。注：根据第一阶段
三、入组标准
(1)经病理组织学或者细胞学检查确诊的晚期的HCC患者，不适合手术或局部治疗，且至少有一个可测量病灶。(2)***化疗(单药或联合用药的全身化疗)和/或索拉非尼靶向治疗失败或不可耐受的HCC患者。(3)入组前ECOG PS评分：0-1分。
四、临床实验结果
共入组210例受试者，观察到的安全性事件符合晚期肝细胞癌患者人群特征，未观察新的安全性信号。其中110例患者进行过至少一次治疗后肿瘤评估，17例患者病情部分缓解，34例患者疾病稳定，59例患者疾病发生进展。疾病控制率(DCR)为46.4％，客观缓解率(ORR)为15.5％。临床试验结果表明，PD1抗体显示出良好的抑瘤效果。
序列表
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江苏恒瑞医药股份有限公司
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Claims (11)
1.一种抗PD-1抗体在制备治疗肝癌的药物中的用途。
2.根据权利要求1所述的用途，其中所述肝癌是肝细胞癌。
3.根据权利要求1所述的用途，其中所述肝癌是晚期肝细胞癌。
4.根据权利要求1所述的用途，其中所述肝癌的患者是***化疗和/或靶向治疗失败或不可耐受的肝细胞癌患者，其中所述靶向治疗优选使用索拉非尼治疗。
5.根据权利要求1所述的用途，其中所述的PD-1抗体的轻链可变区包含分别如SEQ IDNO:4、SEQ ID NO:5和SEQ ID NO:6所示的LCDR1、LCDR2和LCDR3；重链可变区包含分别如SEQID NO:1、SEQ ID NO:2和SEQ ID NO:3所示的HCDR1、HCDR2和HCDR3。
6.根据权利要求5所述的用途，其中所述的PD-1抗体为人源化抗体。
7.权利要求6所述的用途，其中所述人源化抗体的轻链可变区序列为如SEQID NO:10所示的序列或其变体；所述的变体优选在轻链可变区有0-10的氨基酸变化；更优选为A43S的氨基酸变化。重链可变区序列为如SEQ ID NO:9所示的序列或其变体；所述变体优选在重链可变区有0-10的氨基酸变化；更优选为G44R的氨基酸变化。
8.根据权利要求6所述的用途，其中所述人源化抗体轻链序列为如SEQ IDNO:8所示的序列或其变体；所述的变体优选在轻链可变区有0-10的氨基酸变化；更优选为A43S的氨基酸变化；重链序列为如SEQ ID NO:7所示的序列或其变体；所述变体优选在重链可变区有0-10的氨基酸变化；更优选为G44R的氨基酸变化。
9.根据权利要求6所述的用途，其中所述的人源化抗体轻链序列为如SEQ IDNO:8所示的序列，重链序列为如SEQ ID NO:7所示的序列。
10.权利要求1-9任一项所述的用途，其中所述的PD-1抗体或其抗原结合片段剂量选自50-600mg，优选60mg、100mg、200mg、400mg、600mg，最优选200mg。
11.根据权利要求1-9任一项所述的用途，其中所述的PD-1抗体的用量为1－10mg/kg，优选1－5mg/kg，最优选3mg/kg。
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| CN114437204A (zh) * | 2020-10-30 | 2022-05-06 | 苏州盛迪亚生物医药有限公司 | 一种抗体或Fc融合蛋白的纯化方法 |
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| CN110812485A (zh) * | 2018-08-10 | 2020-02-21 | 江苏恒瑞医药股份有限公司 | 抗pd-1抗体联合化学疗法在制备***的药物中的用途 |
| WO2020093993A1 (zh) * | 2018-11-06 | 2020-05-14 | 江苏恒瑞医药股份有限公司 | 一种抗pd-1抗体和法米替尼联合在制备***的药物中的用途 |
| RU2783846C1 (ru) * | 2018-11-06 | 2022-11-21 | Цзянсу Хэнжуй Медсин Ко., Лтд. | Применение антитела к pd-1 в комбинации с фамитинибом для получения лекарственного средства для лечения опухолей |
| TWI822897B (zh) * | 2018-11-06 | 2023-11-21 | 大陸商江蘇恆瑞醫藥股份有限公司 | 一種抗pd-1抗體和法米替尼聯合在製備治療腫瘤的藥物中的用途 |
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| WO2021203769A1 (zh) * | 2020-04-10 | 2021-10-14 | 江苏恒瑞医药股份有限公司 | 一种抗pd-1抗体在制备治疗肢端黑色素瘤的药物中的用途 |
| CN114437204A (zh) * | 2020-10-30 | 2022-05-06 | 苏州盛迪亚生物医药有限公司 | 一种抗体或Fc融合蛋白的纯化方法 |
| CN116407629A (zh) * | 2022-12-28 | 2023-07-11 | 广州誉衡生物科技有限公司 | 抗-pd-1抗体及其在制备治疗肝癌患者的药物中的用途 |
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