Preclinical evaluation of the efficacy, pharmacokinetics and immunogenicity of JS-001, a programmed cell death protein-1 （PD-1） monoclonal antibody

• Published in: 中国药理学报：英文版 2017, Vol.38 (5), p.710-718
• Main Author: Jie FU Fang WANG Li-hou DONG Jing ZHANG Cheng-lian DENG Xue-li WANG Xin-yao XIE Ruo-xian DENG Li-bo ZHANG Hai WU Hui FENG Bo CHEN Hai-feng SONG
• Format: Article
• Language: English
• ISSN: 1671-4083; 1745-7254

JS-O01 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-c~inical pharmacological and pharmacokinetic （PK） data are available. In this study, we investigated the efficacy of JS-O01 and conducted a preclinical PK study, including the monitoring of anti-drug antibodies （ADAs）. We found that JS-O01 specifically bound to PD-1 antigen with an ECso of 21 nmoVL, and competently blocked the binding of PD-1 antigen to PD-L1 and PD-L2 with IC~o of 3.0 and 3.1 nmol/L, respectively. Furthermore, JS-O01 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 Kd values for the interaction between JS-O01 and PD-1 antigens on CDS＊ T cells of human and cynomolgus monkey were 2.1 nmol/L and 1.2 nmoVL, respectively. In vitro, treatment with JS-O01 （0.01-10 pg/mL） dose-dependently stimulated human T cell proliferation, as well as IFN-y and TNF-a secretion. In HBsAg-vaccinated cynomolgus monkeys, the expression of PD-I＋/CD4~ and PD-I＋/CD8~ was significantly elevated, intramuscular injection of JS-O01 （1 and 10 mg/kg） resulted in dramatic decreases in PD-I＋/CD4＋ and PD-I＋/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-O01 followed a linear PK profile with single administration in the I 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-O01 in clinical trials.