A Bispecific Antibody for MUC16 and CD3 Has Preclinical Antitumor Activity

Ovarian cancer owes much of its lethality to recurrences after initially successful treatment. Immunotherapies have shown some promise, but the effectiveness of existing immunotherapies, such as programmed cell death 1 protein (PD-1) inhibitors, appears limited. Crawford and colleagues developed a bispecific antibody (REGN4018) that binds both the integral membrane glycoprotein Mucin 16 (MUC16), which is highly expressed in ovarian cancer cells, and the protein CD3, expressed by CD3⁺ T cells. In both human and cynomolgus monkey cell lines, REGN4018 bound CD3 and MUC16 T cells and tumor cells, respectively, and caused human and cynomolgus T cells to kill ovarian carcinoma cells. Demonstrating REGN4018's antitumor effects, mice injected intraperitoneally with ovarian carcinoma cells allowed to grow for six to seven days exhibited reduced tumor burden, measured via in vivo bioluminescence imaging, when treated with REGN4018 compared with nonbinding or CD3-binding control antibodies. This REGN4018 treatment also induced serum cytokines TNFα, IL2, IL6, IL8, and IL10 and CD25, PD-1, and granzyme B in T cells in the peritoneal cavity, indicating that the treatment activated T cells, a likely explanation for its antitumor efficacy. In immunocompetent MUC16 membrane-proximal region knockin mice expressing human CD3 on T cells, PET imaging with ⁸⁹Zr-labeled REGN4018 demonstrated that the bispecific antibody localized to the tumor, with some also appearing in the spleen, rather than to the MUC16-expressing tissues (trachea, ovary, and stomach). The tissues expressing MUC16 at low levels were not found to exhibit any cellular infiltration or necrosis after five days of REGN4018 treatment, demonstrating the treatment's targeted effects to the tumor rather than the normal tissues. Toxicology studies in cynomolgus monkeys also showed that the REGN4018 is tolerated well. The efficacy and tolerability of REGN4018 in mice and monkeys, respectively, indicate that clinical investigation of the treatment is warranted; to this end, a Phase I trial of REGN4018 as monotherapy and in combination with anti–PD-1 is under way.

Crawford A, Haber L, Kelly MP, Vazzana K, Canova L, Ram P, et al. A Mucin 16 bispecific T cell–engaging antibody for the treatment of ovarian cancer. Sci Transl Med 2019;11:eaau7534.

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