Preclinical evaluation of the efficacy, pharmacokinetics and immunogenicity of JS-001, a programmed cell death protein-1 (PD-1) monoclonal antibody.
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 EC50of 21 nmol/L, and competently blocked the binding of PD-1 antigen to PD-L1 and PD-L2 with IC50of 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 Kdvalues 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 μg/mL) dose-dependently stimulated human T cell proliferation, as well as IFN-γ and TNF-α 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.
Department of Pharmacology and Toxicology, Beijing Institute of Radiation Medicine, Beijing 100850, China.
Jie
J
Fu
Department of Pharmacology and Toxicology, Beijing Institute of Radiation Medicine, Beijing 100850, China.
Fang
F
Wang
Department of Pharmacology and Toxicology, Beijing Institute of Radiation Medicine, Beijing 100850, China.
Li-Hou
LH
Dong
United-Power Pharma Tech Co, Ltd, Beijing 102206, China.
Jing
J
Zhang
United-Power Pharma Tech Co, Ltd, Beijing 102206, China.
Cheng-Lian
CL
Deng
United-Power Pharma Tech Co, Ltd, Beijing 102206, China.
Xue-Li
XL
Wang
United-Power Pharma Tech Co, Ltd, Beijing 102206, China.
Xin-Yao
XY
Xie
Shanghai Junshi Biosciences Inc, Shanghai 201203, China.
Jing
J
Zhang
Topalliance Biosciences Inc, Menlo Park, CA 94025, USA.
Ruo-Xian
RX
Deng
Shanghai Junshi Biosciences Inc, Shanghai 201203, China.
Li-Bo
LB
Zhang
Shanghai Junshi Biosciences Inc, Shanghai 201203, China.
Hai
H
Wu
Shanghai Junshi Biosciences Inc, Shanghai 201203, China.
Hui
H
Feng
Shanghai Junshi Biosciences Inc, Shanghai 201203, China.
Bo
B
Chen
Department of Pharmacology and Toxicology, Beijing Institute of Radiation Medicine, Beijing 100850, China.
Hai-Feng
HF
Song
D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000276:immunology* / Q000493:pharmacokinetics*; D060890:B7-H1 Antigen / Q000378:metabolism; D049109:Cell Proliferation; D006801:Humans; D008252:Macaca fascicularis; D008392:Marmota; D051379:Mice; D061027:Programmed Cell Death 1 Ligand 2 Protein / Q000378:metabolism; D061026:Programmed Cell Death 1 Receptor / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000276:immunology*; D011485:Protein Binding; D013601:T-Lymphocytes / Q000166:cytology / Q000187:drug effects
D000911:Antibodies, Monoclonal; D060890:B7-H1 Antigen; C423236:CD274 protein, human; C556977:PDCD1LG2 protein, human; D061027:Programmed Cell Death 1 Ligand 2 Protein; D061026:Programmed Cell Death 1 Receptor