Abstract 4063: SAR445877, an anti-PD-1 antibody-IL-15 mutein fusion protein restores function to exhausted T cells

Abstract During persistent viral infections and cancer, antigen-specific T cells become exhausted, express elevated levels of inhibitory receptors and gradually lose their functional potential. Immune checkpoint blockade can restore function of exhausted T cells to result in tumor clearance, however, only a minority of cancer patients see durable tumor control. Immune-stimulatory cytokines can augment the antitumor efficacy of checkpoint blockade, but their clinical use is marred by substantial toxicity. SAR445877 (SAR’877, formerly KD050), is a novel antibody-cytokine fusion protein consisting of Fc silenced human anti-PD-1 IgG1 fused to a mutated interleukin-15 (IL-15) /IL-15 receptor alpha sushi domain fusion, which can cis-activate direct cytokine stimulation to effector T cells and alleviate off target binding and the resultant toxicity. Here, we leveraged existing models of chronic antigen exposure to characterize the potential of SAR’877 to restore activity of exhausted T cells. C57BL/6 mice exposed to lymphocytic choriomeningitis virus (LCMV) Clone 13 develop persistent viral infection that results in development of dysfunctional, exhausted T cells. We tested the SAR’877 murine surrogate molecule (mKD050) using the LCMV Clone-13 (CL13) infection model for its ability to promote T cell function in vitro, in vivo, and to control viral infection. Treatment of exhausted T cells with mKD050 in vitro was able to increase expansion and cytokine production of antigen-specific CD8 T cells which was superior to anti-PD-1 antibody or non-targeting antibody-IL15/IL-15Ra fusion protein (mntKD050). Moreover, in vivo treatment of CL13 infected mice with mKD050 increased the numbers and functional output of antigen-specific CD4 and CD8 T cells compared to anti-PD-1 or mntKD050 treatments. Further, mKD050 increased the frequency of antigen-specific TCF1+TIM-3- stem-like CD8 T cells, which are critical to maintaining the T cell pool during chronic viral infection and cancer. The enhanced T cell function observed following treatment with mKD050 translated to hastened clearance of CL13. Finally, the hastened CL13 clearance observed following mKD050 treatment required an intact CD4 T cell compartment. Given the robust activity of mKD050 in reinvigorating dysfunctional T cells in a mouse model of chronic viral infection, we utilized the MIMIC CD8 T cell exhaustion model to explore whether SAR’877 could rescue the function of exhausted human T cells. SAR’877 stimulated proliferation and functional activity of exhausted human CD8 T cells in vitro. SAR’877 more potently induced proliferation and IFNγ and granzyme B production compared to anti-PD-1 and non-targeted IL15 mutein alone. Together, these results demonstrate that the PD-1 targeted IL15 mutein SAR’877 rescues the functional activity of chronically stimulated, exhausted T cells. Citation Format: Isaraphorn Pratumchai, Marie Bernardo, Kristi Lynn Marquardt, Chen Zhu, Fatima Menas, Roberto Carrio, Tony Byers, Donald Shaffer, Xiangming Li, John Ross Teijaro. SAR445877, an anti-PD-1 antibody-IL-15 mutein fusion protein restores function to exhausted T cells 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 (6Suppl): Abstract nr 4063.