Crawford et al. developed a bispecific antibody (REGN4018) that binds the membrane-proximal region of Mucin 16 (MUC16) on ovarian cells and T-cell CD3. In vitro studies showed that REGN4018 induced T cell activation and killed MUC16+ tumor cells with minimal interference from the shed form of MUC16. In immunodeficient mice, REGN4018 inhibited growth of human ovarian tumor cells in the presence of human T cells; in immunocompetent mice it blocked growth of MUC16+ tumors, which was enhanced by anti-PD-1. REGN4018 was well tolerated in cynomolgus monkeys with no overt toxicity, and a clinical trial in ovarian cancer has initiated.
Contributed by Katherine Turner
Advanced ovarian cancer is frequently treated with combination chemotherapy, but high recurrence rates show the need for therapies that can produce durable responses and extend overall survival. Bispecific antibodies that interact with tumor antigens on cancer cells and activating receptors on immune cells offer an innovative immunotherapy approach. Here, we describe a human bispecific antibody (REGN4018) 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. Binding and cytotoxicity of REGN4018 in vitro were minimally affected by high concentrations of CA-125, the shed form of MUC16, which is present in patients. 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.
Author Info: (1) Regeneron Pharmaceuticals Inc., Tarrytown, NY 10591, USA. alison.crawford@regeneron.com. (2) Regeneron Pharmaceuticals Inc., Tarrytown, NY 10591, USA. (3) Regeneron Pharmaceuti
Author Info: (1) Regeneron Pharmaceuticals Inc., Tarrytown, NY 10591, USA. alison.crawford@regeneron.com. (2) Regeneron Pharmaceuticals Inc., Tarrytown, NY 10591, USA. (3) Regeneron Pharmaceuticals Inc., Tarrytown, NY 10591, USA. (4) Regeneron Pharmaceuticals Inc., Tarrytown, NY 10591, USA. (5) Regeneron Pharmaceuticals Inc., Tarrytown, NY 10591, USA. (6) Regeneron Pharmaceuticals Inc., Tarrytown, NY 10591, USA. (7) Regeneron Pharmaceuticals Inc., Tarrytown, NY 10591, USA. (8) Regeneron Pharmaceuticals Inc., Tarrytown, NY 10591, USA. (9) Regeneron Pharmaceuticals Inc., Tarrytown, NY 10591, USA. (10) Regeneron Pharmaceuticals Inc., Tarrytown, NY 10591, USA. (11) Regeneron Pharmaceuticals Inc., Tarrytown, NY 10591, USA. (12) Regeneron Pharmaceuticals Inc., Tarrytown, NY 10591, USA. (13) Regeneron Pharmaceuticals Inc., Tarrytown, NY 10591, USA. (14) Regeneron Pharmaceuticals Inc., Tarrytown, NY 10591, USA. (15) Regeneron Pharmaceuticals Inc., Tarrytown, NY 10591, USA. (16) Regeneron Pharmaceuticals Inc., Tarrytown, NY 10591, USA. (17) Regeneron Pharmaceuticals Inc., Tarrytown, NY 10591, USA. (18) Regeneron Pharmaceuticals Inc., Tarrytown, NY 10591, USA. (19) Regeneron Pharmaceuticals Inc., Tarrytown, NY 10591, USA. (20) Regeneron Pharmaceuticals Inc., Tarrytown, NY 10591, USA. (21) Regeneron Pharmaceuticals Inc., Tarrytown, NY 10591, USA. (22) Regeneron Pharmaceuticals Inc., Tarrytown, NY 10591, USA. (23) Regeneron Pharmaceuticals Inc., Tarrytown, NY 10591, USA. (24) Regeneron Pharmaceuticals Inc., Tarrytown, NY 10591, USA. (25) Regeneron Pharmaceuticals Inc., Tarrytown, NY 10591, USA. (26) Regeneron Pharmaceuticals Inc., Tarrytown, NY 10591, USA. (27) Regeneron Pharmaceuticals Inc., Tarrytown, NY 10591, USA. (28) Regeneron Pharmaceuticals Inc., Tarrytown, NY 10591, USA. (29) Regeneron Pharmaceuticals Inc., Tarrytown, NY 10591, USA. (30) Regeneron Pharmaceuticals Inc., Tarrytown, NY 10591, USA.
