Abstract 4318: Development of a novel SurrobodyTM that simultaneously activates both death receptors DR4 and DR5 and induces cancer cell death with high potency.

Abstract

Abstract Death receptors of the Tumor Necrosis Factor (TNF) family are found on surface of most cancer cells and their activation typically kills cancer cells through the stimulation of the extrinsic apoptotic pathway. The endogenous ligand for death receptors-4 and -5 (DR4 and DR5) is tumor necrosis factor-related apoptosis-inducing ligand, TRAIL (Apo2L). TRAIL is expressed by many cell types, including Natural Killer (NK) cells that are involved in the immune surveillance and elimination of cells in vivo. Given that most normal untransformed cells are not susceptible to TRAIL-induced apoptosis, activators of death receptors have emerged as promising cancer therapeutic agents. One strategy to stimulate death receptors in cancer patients has been to use soluble human recombinant TRAIL protein, but this agent has limitations of a short half-life and decoy receptor sequestration. An alternative strategy to evade decoy receptor sequestration and to have improved pharmacokinetic properties is to generate DR4 or DR5 agonist antibodies. To this end, several agonistic monoclonal antibodies have been reported that overcome the limitations of short half-life, but exhibited the limitation of activating only one of the two death receptors. The SurrobodyTM binding protein is a novel therapeutic protein structure based upon the pre-B cell antigen receptor common chain that is capable of being engineered to bind a diversity of targets with high affinity and specificity. We exploited a previously discovered SurrobodyTM that potently activates both DR4 and DR5 in vitro and in vivo. Here we show experimental results for a dual agonist SurrobodyTM that offers a powerful and likely more reliable strategy for cancer therapeutics based on simultaneous stimulation of both TRAIL receptors, DR4 and DR5. Citation Format: Snezana Milutinovic, Sihong Zhou, Carina Wimer, Paul W. Diaz, Arun K. Kashyap, Ramesh R. Bhatt, John C. Reed. Development of a novel SurrobodyTM that simultaneously activates both death receptors DR4 and DR5 and induces cancer cell death with high potency. [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 4318. doi:10.1158/1538-7445.AM2013-4318