Abstract 1777: REGN4018, a novel MUC16xCD3 bispecific T-cell engager for the treatment of ovarian cancer
Authors: Alison Crawford, Lauric Haber, Kristin Vazzana, Lauren Canova, Priyanka Ram, Jennifer Principio, Arpita Pawashe, Curtis Colleton, Marcus Kelly, Sosina Makkonen, Carlos Hickey, Paurene Duramad, Stephen Godin, John Lin, Eric Smith, Gavin Thurston, Jessica R. Kirshner
Journal: Cancer Research (2018)

Abstract Advanced ovarian cancer has a high rate of recurrence, thus there is a need for therapies that can produce durable responses and extend overall survival. Infiltrating CD3+ T cells are reported to correlate with improved clinical outcome in stage III/IV ovarian cancer. Bispecific antibodies that engage T cells via CD3 and a tumor antigen on ovarian tumor cells may be able to exploit these tumor-infiltrating T cells and have drawn interest as a novel strategy of antitumor immunotherapy. Mucin16 (MUC16) is a well described antigen highly expressed in ovarian cancer and several other tumors. We generated a human bispecific antibody (REGN4018) that binds MUC16 on tumor cells and CD3, bridging MUC16-expressing cells with CD3+ T cells. REGN4018 demonstrates MUC16-directed T cell activation and polyclonal T cell killing of MUC16-expressing tumor cells in vitro and in vivo. Binding and cytotoxicity are minimally affected by high concentrations of CA-125, the shed form of MUC16 that is used as a biomarker for ovarian cancer. Several murine tumor models were developed to determine the in vivo anti-tumor effects of REGN4018. As a xenogenic tumor model, human OVCAR-3 cells were grown as ascites in immunodeficient mice [NOD-SCID-IL2Rgamma deficient (NSG)] pre-implanted with human PBMC. Significant tumor inhibition by REGN4018 was observed at doses of ≥ 0.1 mg/kg. To enable investigation of clinical bispecific antibodies in tumor-bearing immune competent mice, mice were genetically engineered to humanize both CD3 and a part of MUC16 covering the antibody binding region. ImmunoPET imaging demonstrated localization of REGN4018 in both T cell-rich organs such as the spleen and lymph nodes as well as in MUC16-expressing tumors. REGN4018 inhibited growth of murine tumors transfected with human MUC16 in syngeneic tumor models at doses ≥ 0.05 mg/kg. The safety and tolerability of REGN4018 were evaluated in cynomolgous monkey studies. REGN4018 administration resulted in a minimal and transient increase in serum cytokines and C-reactive protein with no overt toxicity. Collectively, these data show the potent anti-tumor activity and tolerability of REGN4018 and provide strong support for the clinical testing of REGN4018 in patients with MUC16-expressing ovarian cancers. Citation Format: Alison Crawford, Lauric Haber, Kristin Vazzana, Lauren Canova, Priyanka Ram, Jennifer Principio, Arpita Pawashe, Curtis Colleton, Marcus Kelly, Sosina Makkonen, Carlos Hickey, Paurene Duramad, Stephen Godin, John Lin, Eric Smith, Gavin Thurston, Jessica R. Kirshner. REGN4018, a novel MUC16xCD3 bispecific T-cell engager for the treatment of ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1777.