A Novel Anti-Ctla-4 Antibody With Potent Anti-Tumor Activity Emerged Using Humanized Ctla-4 Mouse Model

CTLA-4 (Cytotoxic T-lymphocyte antigen 4), also known as CD152, belongs to immunoglobulin superfamily. It is an intracellular protein expressed in resting T cells; CTLA-4 translocates to the cell surface and transmits an inhibitory signal to T cells. In addition, CTLA-4 competes with its homologous T-cell co-stimulatory protein CD28 for ligands expressed on APC, namely CD80 (B7-1) and CD86 (B7-2), thereby antagonizing CD28 and inhibiting CD28 signaling, resulting in inhibition of IL-2, IFN-γ, IL-4 cytokines production, IL-2 receptor expression and cell cycle progression. Because Tregs constitutively express CTLA-4 at high levels, anti-CTLA-4 therapy would be expected to have the greatest effect on these cells. Ipilimumab, a fully human IgG1 monoclonal antibody, is the only commercially available CTLA-4 antagonist. It has been approved by FDA for treatment of metastatic melanoma, adjuvant melanoma and advanced renal cell carcinoma, based on its significant effect of tumor suppression demonstrated in clinical trials. We have interests in searching for potent CTLA-4 antagonists. We selected an antibody with the best efficacy, namely YH001, from the candidate molecules through Biocytoge9s in vivo drug screening platform. YH001 is a recombinant humanized anti-CTLA-4 IgG1 monoclonal antibody and it can bind with human CTLA-4 potently and specifically, without reactivity with other CD28 family receptors. YH001 was able to block the CTLA-4/CD80 and CTLA-4/CD86 interactions and potentiate CD28 signaling in the presence of cognate TCR stimulation. Moreover, YH001 also induced stronger bioluminescence than ipilimumab in the reporter assay. YH001 showed more potent ADCC activities than ipilimumab. YH001 showed dose-dependent in vivo anti-cancer efficacy, as well as Treg depletion and increased CD8+/Treg ratio in human CTLA-4 knock-in mice bearing MC38 tumors. Exposure to YH001 was dose proportional with a half-life of approximately 5 days in cynomolgus monkey. Our preclinical investigation of YH001 demonstrates Biocytogen9s capability in discovering clinical candidates using its robust antibody discovery platform. Citation Format: Chaoshe Guo, Yi Yang, Zhihong Li, Yanan Li, Yunyun Chen. A novel anti-CTLA-4 antibody with potent anti-tumor activity emerged using humanized CTLA-4 mouse model [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3368.