Peter Brams

Abstract 2587: In vitro plasma stability of human anti-CD70 antibody drug conjugate, MDX-1203

Proceedings: AACR 101st Annual Meeting 2010‐‐ Apr 17‐21, 2010; Washington, DC MDX-1203 is a human anti-CD70 antibody conjugated to a pro-drug containing DNA alkylating cytotoxic Drug A. Drug A is composed of the anti-tumor compound Drug B, containing an ester linked protecting group, and a maleimide containing cleavable peptide linker designed to facilitate conjugation to the antibody. Mechanism of action of ADCs involve antibody mediated tumor specific delivery, cellular uptake, and intracellular pro-drug release and activation. Understanding the stability of the peptide linker as well as the pro-drug in various plasma matrices is critical for the development of successful ADC therapeutic. We have generated mouse monoclonal antibodies that specifically recognize either the intact Drug A or Drug A without the protecting group. Using these antibodies, an ELISA method was developed to study in vitro plasma stability of pro-drug in MDX-1203. Our results indicate that the plasma stability of ester linked protecting group varies significantly depending on the animal species probably due to variation in the level of plasma esterase activity. In order to determine the peptide linker stability, a radiolabeled MDX-1203 with 14C radiolabel on Drug A was made. A Thin Layer Chromatography method was developed to determine the in vitro plasma stability of the peptide linker in different plasma matrices. Our results indicate that the peptide linker in MDX-1203 is stable at 37o C up to 6 days. Based on these experimental data, we propose a model for stability of the peptide linker as well as the pro-drug in MDX-1203 in various plasma matrices. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2587.