Abstract 6064: Multiomics preclinical characterization of SAR445877, an anti-PD-1 antibody-IL-15 mutein fusion protein with robust anti-tumor efficacy as monotherapy

Abstract Mechanism of action studies are imperative for translating oncology therapeutics into the clinic informing testable hypotheses and potential combination partners. One class of oncology therapeutics, immune-stimulatory cytokines can augment the antitumor efficacy of checkpoint blockade, but further translational work is required to understand beneficial treatment effects versus unwanted immunotoxicities. SAR445877 (SAR’877, formerly KD050), is a novel antibody-cytokine fusion protein consisting of an 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 effector T cells by biasing IL-15 stimulation to T cells expressing PD-1. Here we used immunohistochemistry (IHC), flow cytometry and spatial transcriptomics to characterize SAR’877 treatment effects on residual tumors in a B16-OVA mouse model. Mice were treated with isotype control, anti-mPD-1 (anti-murine PD-1), mntSAR’877 (mIgG2a-mutmIL15) or mSAR’877 (murine surrogate anti-mPD-1-mutmIL15). The mSAR’877 treated animals showed regression of tumors, decreased necrosis and increased tumor immune cell infiltration compared to isotype control, mntSAR’877, and anti-mPD-1. IHC performed on residual tumors treated with mSAR’877 displayed a further decrease of PD-L1+ cells compared to anti-mPD-1 or mntSAR’877. Spatial transcriptomic profiling using the GeoMx DSP instrument revealed significant infiltration of innate immune cells (NK, monocytes, and neutrophils) and adaptive immune cells (CD8 T and CTL cells) into the tumor leading-edge compartment when compared to anti-mPD-1. CD8 T cell and NK cell increases were orthogonally validated by IHC and flow cytometry. Pathway analyses showed these changes were also associated with an upregulation of cytotoxic pathways when compared to controls. Together, these data elucidated the mechanism of anti-PD-1/IL15 showing contributions of NK and CD8 T cells associated with anti-tumor activity observed in mice. These findings suggest that mSAR’877 shows superior efficacy to single agent PD-1 or untargeted IL-15 in mouse tumor models. Note: all authors are employed by Sanofi and may hold stock and/or stock options Citation Format: Julien Tessier, Joon Sang Lee, Ingeborg M. Langohr, Caroline Morel, Xiangming Li, Seth Garren, Virna Cortez-Retamozo, Dinesh Bangari, Donald Jackson, Donald Shaffer, Angela Hadjipanayis. Multiomics preclinical characterization of SAR445877, an anti-PD-1 antibody-IL-15 mutein fusion protein with robust anti-tumor efficacy as monotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 6064.