Preclinical evaluation of the efficacy, pharmacokinetics and immunogenicity of JS-001, a programmed cell death protein-1 (PD-1) monoclonal antibody
Preclinical evaluation of the efficacy, pharmacokinetics and immunogenicity of JS-001, a programmed cell death protein-1 (PD-1) monoclonal antibody
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DOI：
10.1038/aps.2016.161
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发表时间：
2017-05-01
影响因子：
8.2
通讯作者：
Song, Hai-feng
中科院分区：
文献类型：
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作者：
Fu, Jie;Wang, Fang;Song, Hai-feng
JS-001是中国食品药品监督管理局批准的第一个进入临床试验的抗程序性细胞死亡蛋白-1(PD-1)的单抗。然而，到目前为止，还没有可用的临床前药理学和药代动力学(PK)数据。在这项研究中，我们研究了JS-001的疗效并进行了临床前PK研究，包括监测抗药物抗体(ADA)。我们发现JS-001能与PD-1抗原特异性结合，其EC50为21nmol/L，能有效阻断PD-1抗原与PD-L1和PD-L2的结合，IC50值分别为3.0和3.1nmol/L。此外，JS-001还表现出明显的种间交叉反应：它能与人和食蟹猴外周血单个核细胞上的PD-1抗原结合，但不能与小鼠和土拨鼠的外周血单个核细胞上的PD-1抗原结合，JS-001与PD-1抗原相互作用的K-d值分别为2.1nmol/L和1.2nmol/L。在体外，JS-001(0.01-10微克/毫升)剂量依赖性地刺激人T细胞增殖，以及干扰素-γ和肿瘤坏死因子-α的分泌。在乙肝表面抗原免疫的食蟹猴中，PD-1(+)/CD4(+)和PD-1(+)/CD8(+)的表达显著升高，肌肉注射JS-001(1和10 mg/kg)可显著降低PD-1(+)/CD4(+)和PD-1(+)/CD8(+)的表达，这与PD-1受体占有率(RO)的结果相一致。在PK研究中，18只食蟹猴以1、10和75 mg/kg的单次递增剂量给药，另外6只食蟹猴连续给药10 mg/kg。JS-001单次给药1和10 mg/kg组的血浆清除率符合线性PK曲线，而75 mg/kg组符合非线性PK曲线。连续给药10 mg/kg组未见药物蓄积。但免疫原性研究表明，上一次接触的AUC低于第一次，这可能是由于ADAs的产生所致。这些非临床数据令人鼓舞，为JS-001在临床试验中的疗效和安全性提供了依据。
JS-001 is the first monoclonal antibody (mAb) against programmed cell death protein-1 (PD-1) approved by the China Food and Drug Administration (CFDA) into the clinical trails. To date, however, no pre-clinical pharmacological and pharmacokinetic (PK) data are available. In this study, we investigated the efficacy of JS-001 and conducted a preclinical PK study, including the monitoring of anti-drug antibodies (ADAs). We found that JS-001 specifically bound to PD-1 antigen with an EC50 of 21 nmol/L, and competently blocked the binding of PD-1 antigen to PD-L1 and PD-L2 with IC50 of 3.0 and 3.1 nmol/L, respectively. Furthermore, JS-001 displayed distinct species cross-reactivity: it could bind to the PD-1 antigen on the peripheral blood mononuclear cells (PBMCs) of humans and cynomolgus monkeys, but not to those of mice and woodchucks; the K-d values for the interaction between JS-001 and PD-1 antigens on CD8(+) T cells of human and cynomolgus monkey were 2.1 nmol/L and 1.2 nmol/L, respectively. In vitro, treatment with JS-001 (0.01-10 mu g/mL) dose-dependently stimulated human T cell proliferation, as well as IFN-gamma and TNF-alpha secretion. In HBsAg-vaccinated cynomolgus monkeys, the expression of PD-1(+)/CD4(+) and PD-1(+)/CD8(+) was significantly elevated, intramuscular injection of JS-001 (1 and 10 mg/kg) resulted in dramatic decreases in PD-1(+)/CD4(+) and PD-1(+)/CD8(+) expression in a dose-dependent manner, which was supported by PD-1 receptor occupancy (RO) results. In the PK study, 18 cynomolgus monkeys treated with single, ascending doses of 1, 10, and 75 mg/kg, and another 6 cynomolgus monkeys received 10 mg/kg successive administration. The plasma clearance of JS-001 followed a linear PK profile with single administration in the 1 and 10 mg/kg groups and a non-linear PK profile in the 75 mg/kg group. In the successive 10 mg/kg administration group, no drug accumulation was observed. But the AUC from the last exposure was lower than that of the first administration, which was probably due to the production of ADAs, as demonstrated in immunogenicity study. These non-clinical data are encouraging and provide a basis for the efficacy and safety of JS-001 in clinical trials.