Nonclinical safety assessment of a humanized IgG4 anti-SEMA4D antibody to support clinical development.

Abstract

e13071 Background: VX15/2503 is a humanized IgG4 monoclonal antibody binding with approximately 3 nM affinity to Semaphorin 4D (SEMA4D, CD100); an important mediator of axonal growth cone guidance, vascular development, angiogenesis, and T/ B cell activation. The pharmacology and toxicology of single and repeat doses of VX15/2503 was evaluated in rodents and primates. Methods: Toxicology and pharmacology studies of VX15/2503 were performed using Sprague-Dawley rats and cynomolgus macaques administered single or five weekly intravenous injections. Single dose studies employed doses of between 0.01 and 100 mg/kg; repeat dose studies evaluated 10, 30 and 100 mg/kg. Appetite, body weights, safety pharmacology, clinical pathology, anatomic pathology, and immunotoxicology data were collected in each study. Pharmacokinetics (PK), pharmacodynamics (T cell associated SEMA4D saturation; PD), and immunogenicity were also assessed. Results: Toxicology profiles were similar for both species in both studies; NOAEL = 100 mg/kg. No adverse effects were noted in any toxicology or safety pharmacology endpoint. Single dose VX15/2503 half-life values increased with dose and ranged from 27 to 246 hours in rats; similar results were obtained from the primate single dose study. Repeat dose Cmax and AUC (exposure) values were higher in both species than those from the single dose studies and steady-state was achieved after the fourth dose. PD was dose dependent for animals in both studies. Single dose animals that reached a VX15/2503 serum concentration of ≥2 µg/mL exhibited transient complete T cell SEMA4D saturation. Antigen saturation lasting longer than 130 days occurred in both species at the 100 mg/kg dose level. Anti-VX15/2503 responses were detected in the sera of most animals in both studies; however, anti-VX15/2503 antibodies showed modest effects on PK only at low MAb doses. Conclusions: VX15/2503 was well tolerated and safe over the course of five weekly injections in rats and cynomolgus macaques at doses up to 100 mg/kg. A phase 1 repeat dose, dose escalation study has been initiated to evaluate the safety, tolerability, pharmacokinetics and pharmacodynamics of VX15/2503 in adult patients with advanced solid tumors.