Abstract 1236: Pharmacokinetic evaluation and tolerability assessment of anti-PSMA x anti-CD3 SCORPIONTM molecule in humanized mice and non-human primates.

Abstract

Abstract Background: Treatment of metastatic, castrate-resistant prostate cancer (CRPC) remains a highly unmet medical need. We have developed a bispecific SCORPIONTM (multi-specific protein therapeutic) molecule that redirects T-cell cytotoxicity against cells expressing PSMA (Prostate Specific Membrane Antigen), a prostate cancer antigen. SCORPION molecules are antibody-like therapeutics containing two sets of binding domains linked to immunoglobulin Fc domains, which extend the half-life of the molecules in vivo. In these studies, we examine the pharmacokinetics and tolerability of our bispecific SCORPION molecule in humanized mice and non-human primates to assess the potential for clinical development. Materials and Methods: Cross-reactivity of the SCORPION molecule to cynomolgus antigens was first assessed by measuring binding to recombinant PSMA and primary cynomolgus T cells in vitro. Cross-reactivity was further assessed in redirected T-cell cytotoxicity assays using cynomolgus T cells. Pharmacokinetics of the SCORPION molecule were determined from single intravenous injections in BALB/c mice and cynomolgus monkeys. Serum draws at timepoints ranging from 15 minutes to 504 hours were used to determine the serum half-life in each species. Tolerability was assessed following single intravenous injections in both humanized NOD scid gamma (NSG) mice and cynomolgus monkeys. Cytokine release was measured using multiplex immunoassays; T-cell redistribution was followed using flow cytometry. Results: SCORPION molecules targeting PSMA and CD3 showed comparable in vitro binding and cytotoxic activity with human and cynomolgus T cells. Pharmacokinetic analysis showed an extended serum half-life in BALB/c mice and cynomolgus monkeys. Tolerability experiments in humanized NSG mice and cynomolgus monkeys showed a limited dose-dependent effect on cytokine release and T cell redistribution. Conclusions: These studies show that anti-PSMA x anti-CD3 SCORPION therapeutics possess suitable characteristics for further in vivo toxicology studies and merit further investigation as potential therapeutics in CRPC. Citation Format: Catherine J. McMahan, Gabriela Hernandez-Hoyos, Jeannette Bannink, Robert R. Bader, Padma Ravikumar, Toddy Sewell, Kenneth M. Bannink, Rebecca J. Gottschalk, Hang Fang, Starrla Johnson, Megan Aguilar, John Kumer, Paul A. Algate, David L. Bienvenue, John W. Blankenship. Pharmacokinetic evaluation and tolerability assessment of anti-PSMA x anti-CD3 SCORPIONTM molecule in humanized mice and non-human primates. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1236. doi:10.1158/1538-7445.AM2013-1236