Abstract 6347: To develop a tumor selective INF-γ-Yervoy fusion antibody to increase the therapeutic effect and safety of current Yervoy therapy in cancer

Abstract

Abstract Introduction: Immune checkpoint inhibitor therapy is a highly promising strategy for clinical treatment of cancer. Among these inhibitors, yervoy stands out for its ability to induce cytotoxic T cell proliferation and activation by binding to CTLA-4. However, FDA has reported that yervoy would induce the over-activation of immune cells and cause the serious side effects. In additional, the therapeutic efficacy and application of Yervoy were still limited by the MHC expression of patient's tumor. Strategy: Therefore, we have developed a protease specific pro INF-γ-Yervoy to increase the therapeutic effect and safety of current immune checkpoint blockade therapy in cancer. We used the MMP-2/9 protease substrate as a linker between INF-γ and Yervoy. Using the concept of spatial shielding, IFNγ and Yervoy can block their functions from each other. Once the INF-γ-Yervoy arrives to the tumoral region, the INF-γ-Yervoy will be removed from Hinge Yervoy by the over-expressed MMPs protease locally so that the Yervoy will recruit its binding ability in order to increase the drug selectivity and improve the side effects. The INF-γ also can increase the MHC I expression in tumor to overcome the MHC-limitation of Yervoy. Result: On activation by MMP, IFNγ-yervoy not only restored yervoy’s binding ability but also released biologically active IFNγ. This finding confirms the reliability of IFNγ-yervoy’s functionality. In vivo studies demonstrated that IFNγ-yervoy enhances the therapeutic effect of yervoy against colorectal cancer by increasing CD8+ and CD4+ lymphocyte infiltration into the tumor area and inducing MHC-I expression in tumor cells. Mice treated with IFNγ-yervoy showed higher survival rates and body weight, as well as lower CD4+ and CD8+ lymphocyte activation rates in the blood and reduced organ damage. Conclusion: These results provide strong evidence that tumor-selective IFNγ-yervoy can improve the effectiveness of yervoy while reducing its side effects. It is likely that future immunotherapies would rely on such antibodies to activate local cancer cells or immune cells, thereby increasing the therapeutic effectiveness of cancer treatments and ensuring their safety. Keyword: Immune checkpoint inhibitor therapy, IFNγ, yervoy, rectal cancer, CTLA4 Citation Format: Chih-Hung Chuang. To develop a tumor selective INF-γ-Yervoy fusion antibody to increase the therapeutic effect and safety of current Yervoy therapy in cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6347.