Abstract 4846: MM-401, a novel anti-TNFR2 antibody that induces T cell co-stimulation, robust anti-tumor activity and immune memory
Authors: Richards Jennifer , Wong Christina , Koshkaryev Alexander , Fulton Ross , Camblin Adam , Sampson James , Luus Lia , Suchy James , Grabow Stephanie , Kurella Vinodh , Kumar Sandeep , Lulo James , Qiu James , Jiao Yang , Xu Lihui , Paragas Violette , Razlog Maja , Muda Marco , Tam Eric , Raue Andreas , Drummond Daryl 
Published: August 2019

Abstract
TNFR2 has been implicated as a novel target for cancer immunotherapy. While TNFR2 has been linked to enhanced suppressive activity of regulatory T cells (Tregs) in auto-immune models, the effect of TNFR2-targeted therapy in cancer remains unclear. Here we present a novel monoclonal anti-TNFR2 antibody that provides T cell co-stimulation and yields robust anti-tumor activity in in vitro and in vivo models. In syngeneic murine tumor models, treatment with a murine surrogate anti-TNFR2 antibody results in robust anti-tumor activity both alone and in combination with checkpoint inhibitor antibodies targeting PD-1 and PDL-1. Complete responders exhibited immunological memory months after initial tumor clearance. Furthermore, significant anti-tumor activity was observed in anti-TNFR2-treated mice even in a model that proved resistant to PD1-targeted antibody treatment. Depletion studies suggest that CD8+ T and NK cells are required for activity, while TNFR2 knockout models suggest that TNFR2 expression on cancer cells is not required for activity. Using an antibody with a mutant-Fc, we show that activity is dependent on FcγR binding. Studies in FcγR knockout mice, complemented by studies using different antibody-Fc variants, confirm that enhanced agonism via FcγR binding is the dominant mechanism of action. Contrary to antibodies targeting other TNF superfamily receptors, treatment does not lead to strong depletion of TNFR2-expressing cell types such as Tregs. Consistent with its proposed mechanism, long-term dosing of the anti-TNFR2 antibody did not cause toxicity in two inbred mouse strains when compared to an anti-CTLA4 antibody, which caused weight loss, splenomegaly and elevated inflammatory cytokines in serum. Following anti-TNFR2 treatment, we observed a broad reversal of immunosuppression in the tumor characterized by downregulation of suppressive markers. A human anti-TNFR2 antibody (MM-401) with low nanomolar affinity and binding to the same epitope as the murine surrogate antibody has been developed. MM-401 is being developed as a potential novel treatment option for cancer patients.
Citation Format: Jennifer Richards, Christina Wong, Alexander Koshkaryev, Ross Fulton, Adam Camblin, James Sampson, Lia Luus, James Suchy, Stephanie Grabow, Vinodh Kurella, Sandeep Kumar, James Lulo, James Qiu, Yang Jiao, Lihui Xu, Violette Paragas, Maja Razlog, Marco Muda, Eric Tam, Andreas Raue, Daryl Drummond. MM-401, a novel anti-TNFR2 antibody that induces T cell co-stimulation, robust anti-tumor activity and immune memory [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 4846.