Pharmacokinetics and safety in cynomolgus monkeys of a monoclonal antibody targeting human scavenger receptor class-B type-1 for hepatitis C treatment

Abstract

Scavenger receptor class B type-1 (SR-B1) is one of the many receptors used by HCV to infect hepatocytes. It is used by the virus not only to directly infect cells but also to facilitate cell-to-cell transmission of the virus. Agents such as anti-human SR-B1 (anti-hSR-B1) antibodies represent potential therapeutics for the treatment of HCV infections. The purpose of this study was to evaluate the safety and pharmacokinetics of an anti-hSR-B1 antibody (Seq2) in cynomolgus monkeys. The antibody was administered intravenously at 1, 10 and 100 mg/kg body weight; blood samples were taken pre- and post-dose to evaluate the pharmacokinetic profile and blood chemistry. Safety was assessed during treatment and the animals were sacrificed post-treatment for pathological assessment and liver antibody-receptor occupancy determination. Following administration of Seq2 antibody to cynomolgus monkeys a non-linear pharmacokinetic profile was observed. The clearance of the antibody decreased from 2 to 0.3 ml/h/kg with increasing doses from 1 to 100 mg/kg, respectively, and the antibody half-life varied from 62 to 218 h for the same doses. An increase in total cholesterol and high-density lipoprotein cholesterol levels after antibody administration was observed, with a good correlation between liver receptor occupancy and dose. The pharmacokinetics and toxicology results were in accordance with the pharmacology of the antibody mechanism. The elevation of total cholesterol was dose-dependent and did not exceed a twofold increase. The safety study indicated no adverse effects during the treatment or in the pathology analysis at any of the doses tested.