Bispecific antibodies that interact with tumor antigens on cancer cells and activating receptors on immune cells offer an innovative immunotherapy approach. REGN4018 is a bispecific antibody that binds both Mucin 16 (MUC16), a glycoprotein that is highly expressed on ovarian cancer cells, and CD3, thus bridging MUC16-expressing cells with CD3+ T cells. REGN4018 induced T cell activation and killing of MUC16-expressing tumor cells in vitro. In preclinical studies with human ovarian cancer cells and human T cells in immunodeficient mice, REGN4018 potently inhibited growth of intraperitoneal ovarian tumors. Moreover, in a genetically engineered immunocompetent mouse expressing human CD3 and human MUC16 [humanized target (HuT) mice], REGN4018 inhibited growth of murine tumors expressing human MUC16, and combination with an anti– PD-1 antibody enhanced this efficacy. Immuno-PET imaging demonstrated localization of REGN4018 in MUC16-expressing tumors and in T cell–rich organs such as the spleen and lymph nodes. Toxicology studies in cynomolgus monkeys showed minimal and transient increases in serum cytokines and C-reactive protein after REGN4018 administration, with no overt toxicity. Collectively, these data demonstrate potent antitumor activity and good tolerability of REGN4018, supporting clinical evaluation of REGN4018 in patients with MUC16-expressing advanced ovarian cancer.
Dr.Alison Crawford is a Senior Staff Scientist in the department of Oncology and Angiogenesis at Regeneron Pharmaceuticals, Inc. She completed her BSc in Immunology from Glasgow University before being admitted to the Wellcome Trust Ph.D. program at Edinburgh University where she focused on T cell memory. Her post-doctoral work at the University of Pennsylvania examined T cell exhaustion during chronic viral infection and the role of checkpoint inhibition in alleviating T cell exhaustion. This piqued her interest in immunotherapies and she made the transition into industry at Regeneron Pharmaceuticals where her group uses pre-clinical models to examine bispecific antibodies targeting solid tumors. She led the in vivo pre-clinical research efforts on REGN4018 (MUC16xCD3) to advance the antibody through to IND submission.