Abstract 4578: Nonclinical safety assessment of VX15/2503: A humanized IgG4 monoclonal antibody to sema4D

Abstract

Abstract VX15/2503 is a humanized IgG4 monoclonal antibody that binds with approximately 3 nM affinity to Semaphorin 4D (SEMA4D, CD100). SEMA4D is an important mediator of axonal growth cone guidance, vascular development, angiogenesis, and T cell and B cell activation. SEMA4D is found predominantly as a 150 kDa transmembrane protein on lymphocytes and as a 240 kDa, homodimeric, soluble form of the protein. VX15/2503 or its murine progenitor (MAb 67-2) suppressed tumor growth and angiogenesis in syngeneic, xenograft and transgenic tumor models. Toxicology and pharmacology studies of VX15/2503 were performed in Sprague-Dawley rats and cynomolgus macaques using single or five weekly intravenous injections. Toxicology profiles were similar for both species in both studies. Single dose studies employed doses of between 0.01 and 100 mg/kg; repeat dose studies evaluated 10, 30 and 100 mg/kg. No adverse histopathologic or clinical effects were noted in either species injected with doses up to 100 mg/kg. Appetence, body weights, serum chemistry and ophthalmologic factors were also unaffected, as were primate ECG results. Thus the NOAEL was established at 100 mg/kg for both species. Partial to complete T cell associated SEMA4D saturation was observed in all animals across the dose ranges evaluated and SEMA4D saturation was dose dependent. Single dose animals that reached a VX15/2503 serum concentration of ≥2 µg/mL exhibited transient complete T cell saturation. Prolonged saturation occurred at the 100 mg/kg dose level. Repeat dose animals in the 100 mg/kg dose group were on average at least 20% saturated for 134 and 169 days in rats and cynomolgus macaques, respectively. Single dose VX15/2503 half-life values increased with dose and varied 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. Anti-VX15/2503 responses were detected in the sera of most animals in both studies. Human tissue arrays incubated with VX15/2503 showed diverse distribution of SEMA4D on resident or itinerant lymphocytes in lymphoid tissues as well as in sections of brain, lung and endometrium. Based on these results VX15/2503 was selected for clinical development in oncology. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4578. doi:10.1158/1538-7445.AM2011-4578