Abstract
Abstract CTLA-4 (cytotoxic T-lymphocyte-associated protein 4), is a member of the immunoglobulin superfamily. It is expressed in T cells upon activation and transmits an inhibitory signal to T cells. It is also constitutively expressed in regulatory T cells (Tregs) which is associated with their immunosuppressive phenotype. CTLA-4 is homologous to the co-stimulatory protein CD28, and both receptors bind to the same ligands, CD80(B7-1) and CD86(B7-2). Importantly, cancer cells can be recognized and destroyed by the host’s immune system. In this setting, CTLA-4 functions as a brake to dampen anti-tumor T cell responses, which promote cancer progression. In this context, we are exploring antibodies that are as effective or exceed the effects of the approved CTLA-4 antibody. Antibodies blocking CTLA-4 are expected to subvert T cell inhibition. Moreover, regulatory T cells residing in the tumor microenvironment are sensitive to anti-CTLA-4 antibody since they have higher expression levels of CTLA-4 compared to activated T cells. Yervoy, the first FDA-approved CTLA-4 antibody, protects a fraction of cancer patients when used alone or in combination with other drugs. Here we report two humanized antibodies whose efficacy is equivalent or exceed that of Yervoy using the pharmacological efficacy evaluation platform established at Biocytogen. Potent inhibition and biological activity were further demonstrated by a series of tests in vitro. In conclusion, we successfully discovered two antibodies that exhibit superior anti-cancer activity in vivo with our humanized CTLA-4 mouse model. Downstream clinical evaluation of these novel antibodies is needed. Citation Format: Yuelei Shen, Jian Ni, Benny(Yi) Yang, Tian Gan, Chaoshe Guo. Novel CTLA-4 antibodies of potent antitumor activity were verified in humanized mouse models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3233.
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