卡瑞利珠单抗, 一种人源化抗PD-1 IgG4亚型单克隆抗体在临床前研究中表现出优异的抗肿瘤活性以及良好的安全性

doi:10.5246/jcps.2021.05.031

中国药学(英文版) ›› 2021, Vol. 30 ›› Issue (5): 393-408.DOI: 10.5246/jcps.2021.05.031

卡瑞利珠单抗, 一种人源化抗PD-1 IgG4亚型单克隆抗体在临床前研究中表现出优异的抗肿瘤活性以及良好的安全性

孙星¹, 杨昌永¹, 林侃¹, 周彩红¹, 廖成¹, 张利敏², 金薪盛², 毛浪勇², 应华², 陶维康², 张连山³^,^*()

1. 上海盛迪医药有限公司, 上海 200120
2. 上海恒瑞医药有限公司, 上海 200245
3. 江苏恒瑞医药股份有限公司, 江苏连云港 222047

收稿日期:2021-03-14 修回日期:2021-04-10 接受日期:2021-04-23 出版日期:2021-05-31 发布日期:2021-05-29
通讯作者: 张连山
作者简介:
+ Tel.: +86-18602190163, E-mail: zhanglianshan@hrs.com.cn

Camrelizumab (SHR-1210), a humanized anti-PD-1 IgG4 mAb, exhibits superior anti-tumor activity and a favorable safety profile in preclinical studies

Xing Sun¹, Changyong Yang¹, Kan Lin¹, Caihong Zhou¹, Chen Liao¹, Limin Zhang², Xinsheng Jin², Langyong Mao², Hua Ying², Weikang Tao², Lianshan Zhang³^,^*()

1 Shanghai Shengdi Pharmaceutical Co., Ltd., Shanghai 200120, China
2 Shanghai Hengrui Pharmaceutical Co., Ltd., Shanghai 200245, China
3 Jiangsu Hengrui Medicine Co., Ltd., Jiangsu 222047, China

Received:2021-03-14 Revised:2021-04-10 Accepted:2021-04-23 Online:2021-05-31 Published:2021-05-29
Contact: Lianshan Zhang

摘要/Abstract

摘要：

卡瑞利珠单抗是一种人源化的抗PD-1单克隆抗体。在体外与人和食蟹猴PD-1蛋白具有纳摩尔级别的高亲和力, 但不结合鼠源PD-1蛋白。它在体外有效阻断PD-1/PD-L1信号通路的同时还可以激活T细胞。卡瑞利珠单抗与PD-1独特的结合表位同PD-1和PD-L1结合表位有部分的重叠, 证明了卡瑞利珠单抗对PD-1/PD-L1具有很强的结合阻断活性。在PD-1转基因小鼠皮下移植瘤模型中, 卡瑞利珠单抗可以显著抑制MC-38和B16F10两种细胞在小鼠体内的生长, 抑瘤作用优于已上市的其它PD-1单抗。此外, 卡瑞利珠单抗在食蟹猴中表现出良好的药代动力学和安全性特征。并且, 我们发现了卡瑞利珠单抗具有很弱的VEGFR2结合活性, 但即使在很高的剂量下也不会激活VEGFR2信号通路。综上所述, 我们证明了卡瑞利珠单抗是优秀的肿瘤治疗药物, 现有数据也支持其在临床实践中进一步探索其有效性和安全性。

关键词: 卡瑞利珠单抗, PD-1, 结合表位, 药效, 安全性, VEGFR2

Abstract:

Camrelizumab is a humanized monoclonal antibody (mAb) against human PD-1. It demonstrated a single digit nanomolar binding affinity to human and cynomolgus monkey PD-1, but no cross-reactivity to murine PD-1. It exhibited potent PD-1/PD-L1 blocking activity as well as the T cell activation in vitro. The distinct binding sites of cameralizumab were perfectly overlapped with the PD-L1 binding sites, which supported its excellent ability in blocking PD-1/PD-L1 interaction. It also significantly inhibited the growth of murine MC-38 and B16F10 cell in humanized PD-1 transgenic mice with a superior inhibitory effect compared with the other marketed anti-PD-1 antibodies. Furthermore, camrelizumab also displayed a favorable pharmacokinetic (PK) and safety profile in cynomolgus monkeys. Besides, we showed that camrelizumab only bound to VEGFR2 with a very low affinity and did not activate VEGF pathways even at very high doses. Collectively, we provided evidence that cameralizumab was an ideal therapeutic candidate for cancer treatment, encouraging further evaluation of its efficacy/safety in the clinical setting.

Key words: Camrelizumab, PD-1, Binding epitope, Efficacy, Safety, VEGFR2

Supporting:

孙星, 杨昌永, 林侃, 周彩红, 廖成, 张利敏, 金薪盛, 毛浪勇, 应华, 陶维康, 张连山. 卡瑞利珠单抗, 一种人源化抗PD-1 IgG4亚型单克隆抗体在临床前研究中表现出优异的抗肿瘤活性以及良好的安全性[J]. 中国药学(英文版), 2021, 30(5): 393-408.

Xing Sun, Changyong Yang, Kan Lin, Caihong Zhou, Chen Liao, Limin Zhang, Xinsheng Jin, Langyong Mao, Hua Ying, Weikang Tao, Lianshan Zhang. Camrelizumab (SHR-1210), a humanized anti-PD-1 IgG4 mAb, exhibits superior anti-tumor activity and a favorable safety profile in preclinical studies[J]. Journal of Chinese Pharmaceutical Sciences, 2021, 30(5): 393-408.

图/表 17

Table 1. The binding affinity of camrelizumab with PD-1 antigen from different species.

Figure 1. The competitive binding ELISA of camrelizumab, HRP00339, and HRP00340. Camrelizumab inhibited the binding of itself to human PD-1, but did not inhibit either HRP00339 or HRP00340 for binding to human PD-1 (n = 2). Data were presented as mean ± SD.

Figure 2. (A) Overlay of the binding epitope structure for camrelizumab, human PD-L1, and human PD-1; (B) Overlay of the binding epitope structure for nivolumab, pembrolizumab, and human PD-1. The binding epitope structure of camrelizumab, nivolumab, pembrolizumab, human PD-L1, and human PD-1 is in magenta, yellow, green, cyan, and grey, respectively.

Figure 3. Antigen binding epitope mapping of camrelizumab, nivolumab, and pembrolizumab. SHR1210 denotes camrelizumab, Nivo denotes nivolumab, and Pembro denotes pembrolizumab. Pink: camrelizumab binding epitope amino acid residues; Yellow: nivolumab binding epitope amino acid residues; Green: pembrolizumab binding epitope amino acid residues; Blue: human PD-L1 binding epitope amino acid residues; Purple boxes: N-glycosylated residues; Brown boxes: disulfide-bonded residues.

Table 2. The binding affinity of camrelizumab with human Fc receptors.

Figure 4. The ability of camrelizumab and other PD-1 antibodies to block the interaction between PD-1 and PD-L1. Results were shown as mean ± SD of two representative experiments out of three.

Figure 5. Blocking activity evaluation of camrelizumab in a cell-based reporter assay. Results were shown as mean ± SD of one representative experiment out of three.

Figure 6. Stimulatory effect of camrelizumab on PBMC proliferation and IFN-γ secretion.

Figure 7. Human IFN-γ secretion induced by camrelizumab in an MLR assay.

Figure 8. Anti-tumor effect of camrelizumab in MC38 model in humanized PD-1 transgenic mice (n = 6). Data were presented as mean ± SEM. *Denoted P < 0.05, **denoted P < 0.01.

Table 3. Anti-tumor effect of camrelizumab in MC38 model in humanized PD-1 transgenic mice.

Figure 9. Anti-tumor effect of camrelizumab in B16F10 model in humanized PD-1 transgenic mice (n = 8). Data were presented as mean ± SEM. *Denoted P < 0.05.

Table 4. Anti-tumor effect of camrelizumab in B16F10 model in humanized PD-1 transgenic mice.

Table 5. PK parameters of camrelizumab in cynomolgus monkey after a single intravenous infusion at 1, 3 and 10 mg/kg (n = 6, half/sex). Data were presented as mean ± SD.

Table 6. The binding affinity of different anti-PD-1 antibodies to human VEGFR2.

Figure 10. Camrelizumab has no activation effect on VEGF signaling in VEGFR2-NFAT-REluc2P/KDR HEK293 cells. Data were presented as mean ± SD.

Figure 11. Camrelizumab has no activation effect on VEGF signaling in VEGFR2-NFAT-REluc2P/KDR HEK293 cells. Data were presented as mean ± SD.

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卡瑞利珠单抗, 一种人源化抗PD-1 IgG4亚型单克隆抗体在临床前研究中表现出优异的抗肿瘤活性以及良好的安全性

Camrelizumab (SHR-1210), a humanized anti-PD-1 IgG4 mAb, exhibits superior anti-tumor activity and a favorable safety profile in preclinical studies

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