A Mucin 16 bispecific T cell–engaging antibody for the treatment of ovarian cancer

Authors: Alison Crawford, Lauric Haber, Marcus P. Kelly, Kristin Vazzana, Lauren Canova, Priyanka Ram, Arpita Pawashe, Jennifer Finney, Sumreen Jalal, Danica Chiu, Curtis Colleton, Elena Garnova, Sosina Makonnen, Carlos Hickey, Pamela Krueger, Frank J. Delfino, Terra Potocky, Jessica Kuhnert, Stephen Godin, Marc W. Retter, Paurene Duramad, Douglas MacDonald, William C. Olson, Jeanette Fairhurst, Tammy Huang, Joel Martin, John Lin, Eric Smith, Gavin Thurston, Jessica R. Kirshner - Science Translational Medicine 2019 cited by 141

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.