Abstract 1924: Rapid screening of anti-OX40 antibodies for cancer immunotherapy

Abstract

Abstract OX40, also known as CD134 or TNFRSF4, is a member of the TNFR superfamily. OX40 is a co-stimulatory receptor, and it interacts with its ligand to provide positive signal for T cell activation. OX40 is not expressed on naïve T cells, however its expression goes up after 24 to 72 hours following activation. Disruption of the OX40 pathway led to defective T cell responses, and overexpression of OX40 caused massive immune activation. Due to its importance in keeping immune homeostasis, strategies modulating the OX40 pathway hold great promise in efforts against cancer and autoimmune diseases. Based on the promising nature of this target, we focused on developing novel OX40 agonists that would effectively stimulate anti-tumor activity. Dozens of high-affinity candidate antibodies were generated using classic hybridoma technology. In order to directly screen for antibodies for anti-tumor effects in animals, we ranked these antibodies in vivo using the drug screening platform based on humanized mouse models. Specifically, we used B-hOX40 mice and implanted syngeneic tumors subcutaneously, followed by treating mice with purified candidate antibodies. We quickly identified several lead antibodies that effectively inhibited tumor growth using this approach, without prior knowledge of their in vitro activities. Their ability to stimulate T cells was confirmed by an engineered reporter line of Jurkat T cells in vitro. Furthermore, we showed that one clone works in concert with Keytruda in a double humanized model of h-OX40 and h-PD-1. We are currently investigating the mechanisms of action underlying these potentially valuable antibodies and carrying out more combination evaluation studies using other available humanized immune-checkpoint mouse models. Citation Format: Tian Gan, Yanan Li, Jian Ni, Benny(Yi) Yang. Rapid screening of anti-OX40 antibodies for cancer immunotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1924.