Abstract 3824: Antitumor activity of REGN4659, a fully human anti-CTLA-4 monoclonal antibody, against MC38.Ova tumors grown in immunocompetent human CTLA-4 knock-in mice
Authors: Burova Elena , Allbritton Omaira , Brydges Susannah , Poueymirou William , Durso Robert , MacDonald Douglas , Ioffe Ella , Mohr Markus , Olson William , Thurston Gavin 
Published: August 2018

Cytotoxic T-lymphocyte associated antigen 4 (CTLA-4) is an inhibitory checkpoint receptor that is expressed by activated conventional T cells and regulatory T cells and negatively regulates T cell activation. CTLA-4 plays a key role in restraining the adaptive immune response of T cells against a variety of antigens, including self-antigens. However, in the tumor microenvironment, the co-inhibitory CTLA-4 receptor contributes to tumor immune escape. CTLA-4 shares its two ligands, CD80 and CD86, which are largely expressed on antigen-presenting cells, with CD28, a co-activator of T cells; however, CTLA-4 binds CD80 and CD86 with higher affinity than CD28. Blockade of CTLA-4 elicits an effective antitumor immunity in preclinical animal models and has demonstrated favorable clinical results in several solid malignancies. REGN4659 is a human IgG1 antibody that binds to the extracellular domain of human and monkey CTLA-4 with high affinity and specificity. REGN4659 blocks CTLA-4 interaction with CD80 and CD86 ligands and enhances the cytokine release of activated primary human T cells in vitro. The effects of treatment with REGN4659 on the subcutaneous growth of a mouse adenocarcinoma tumors expressing chicken ovalbumin (MC38.Ova) were evaluated in immunocompetent mice genetically engineered to express a human CTLA-4 chimeric protein from the endogenous mouse locus (CTLA-4 hum/hum knock-in). Prophylactic treatment with REGN4659 significantly suppressed MC38.Ova tumor growth in CTLA-4 knock-in mice in a dose dependent manner, and improved mouse survival. Because patients treated systemically with CTLA-4 blockade have suffered from immune-related adverse events, we investigated the efficacy of a peritumoral low-dose administration of a mouse-reactive surrogate anti-CTLA-4 antibody in an attempt to minimize systemic exposure. Peritumoral injection of anti-CTLA-4 antibody was as efficacious as intraperitoneal delivery at inducing anti-tumor immunity. Peritumoral anti-CTLA-4 antibody delivery was associated with lower circulating antibody levels but nonetheless caused systemic antitumor immunity as revealed by growth retardation of concomitantly implanted distant tumors. The mechanism of action and robust anti-tumor efficacy of REGN4659 supports its clinical development for the treatment of human cancers.

Citation Format: Elena Burova, Omaira Allbritton, Susannah Brydges, William Poueymirou, Robert Durso, Douglas MacDonald, Ella Ioffe, Markus Mohr, William Olson, Gavin Thurston. Antitumor activity of REGN4659, a fully human anti-CTLA-4 monoclonal antibody, against MC38.Ova tumors grown in immunocompetent human CTLA-4 knock-in mice [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 3824.