A novel TNFR2 antibody induces T cell co-stimulation and promotes durable anti-tumor immunity

Abstract

Abstract TNFR2, an emerging therapeutic target in immuno-oncology, is upregulated upon T cell activation and is expressed by tumor-infiltrating effector and regulatory T (Treg) cells. We generated a novel monoclonal antibody, Y9, specific to murine TNFR2 and investigated its mechanism of action. In vitro, Y9 stimulation of purified T cells increased proliferation and effector function, indicating that Y9 acts as an agonist and can provide co-stimulation. In vivo, Y9 treatment of mice with established tumors resulted in complete tumor clearance across a variety of models. The activity of Y9 on immune cells was confirmed by its decreased activity in mice depleted of NK or CD8+ T cells. Unlike the proposed Treg depletion mechanism of other therapeutic antibodies, depletion of Treg cells is not the primary mechanism of action of Y9 treatment. Instead, decreased TNFR2 and other co-inhibitory receptor surface expression was observed following treatment. Y9 activity depended on FcγR binding, which facilitated enhanced agonist activity. Based on this evidence, we developed MM-401, a human antibody targeting TNFR2. MM-401 has agonistic activity; upon incubation of MM-401 with human CD4+ and CD8+ T cells, we observed upregulation of activation markers and cytokine production comparable to MEDI6469 (anti-OX40). We also observed that MM-401 promotes antibody-dependent cellular cytotoxicity (ADCC) in an NK cell-mediated in vitro assay and a reduction in the number of Treg cells in human ovarian cancer ascites. These data suggest that MM-401 could also promote anti-tumor immunity by mediating ADCC, as well as by direct co-stimulation of T cell responses, and justifies the continued development of MM-401 as a novel cancer immunotherapy.