Abstract 2972: Preclinical characterization of SAR445877, an anti-PD-1 antibody-IL-15 mutein fusion protein with robust anti-tumor efficacy as monotherapy and in combination with PD-L1 blockade

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Abstract Immune checkpoint blockade elicits durable anti-cancer responses in the clinic, however a large proportion of patients do not benefit from treatment. A major unmet medical need in immuno-oncology (IO) is extending the benefits of these therapies to patients who never experience tumor regression (primary resistance) or who derive initial benefit followed by tumor progression (acquired resistance). To improve clinical benefits of anti-PD-1 antibody, we generated SAR445877 (formerly KD050), which is an antibody cytokine fusion molecule that combines a human anti-PD-1 antibody with a mutated fusion of human IL15 and human IL15Rα sushi domain. SAR445877 binds to human PD-1 and inhibits immunosuppressive signaling through the PD-1/PD-L1 pathway. The IL15-IL15Rα fusion contains a single amino acid mutation that confers reduced potency of IL2/15Rβγ stimulation relative to wild type IL-15, reduces binding to IL-2Rβ expressing HEK 293 cells, (EC50: >108 nM vs 4.05nM) and decreases pSTAT5 activation in HEK blue IL-2 reporter assay by more than 5-fold. Through its IL15-IL15Rα fusion moiety, SAR445877 stimulates cells expressing IL2/15Rβγ with much weaker activity than wild type IL-15 when measured by CTLL-2 cell proliferation in vitro (EC50: 398.8nM vs 1.68nM). Fusion of IL-15 to anti-PD-1 antibody mediates cis-activation of human PD-1+ cells, including both PD-1+ HEK blue reporter cell line and human primary T cells, with higher potency compared to non-targeted IL-15. This cis-activation could result in expansion and activation of antigen-specific CD8+ T cells with improved activity in the tumor microenvironment compared to non-targeted IL-15. Antitumor efficacy of SAR445877 was explored in the CT26 colorectal cancer model using the clinical candidate. Transgenic mice expressing human PD-1 and PD-L1 were implanted with CT26 tumors expressing human PD-L1 and treated with SAR445877. SAR445877 displayed a more potent antitumor efficacy than pembrolizumab. Further, treatment with SAR445877 increased the CD8/CD4 T cell ratio and significantly increased the percentage of effector memory CD8 T cells in tumors. In anti-PD-L1 antibody resistant Pan02 syngeneic tumor model, a murine surrogate molecule produced a remarkable antitumor activity and was well tolerated. Combination treatment of murine surrogate with anti-mPD-L1 displayed greater antitumor activity than single agent treatment (TGI = 99.30% vs 78.78%). In summary, SAR445877 can target potency-reduced IL-15 to PD-1+ T cells and induce cis-activation of T cells. SAR445877 exhibited potent anti-tumor efficacy in PD-1 resistant preclinical model with good tolerability. These results support further evaluation of SAR445877 in a phase I clinical trial (ClinicalTrials.gov #NCT05584670). Citation Format: Marie Bernardo, Yu-an Zhang, Dan Lu, Stella Martomo, Fatima Menas, Chen Zhu, Raymond Perez, Jeegar Patel, Donald Shaffer, Xiangming Li. Preclinical characterization of SAR445877, an anti-PD-1 antibody-IL-15 mutein fusion protein with robust anti-tumor efficacy as monotherapy and in combination with PD-L1 blockade [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2972.