Abstract 2236: A novel SIRPαxPD-L1 bispecific antibody remodels the innate and adaptive tumor microenvironment, and enhances tumor control

Checkpoint blockade immunotherapy has transformed cancer treatment. However, many patients fail to respond to these therapies, underscoring the urgent need for new therapeutic strategies. Targeting alternative pathways and immune cell subsets within the tumor microenvironment (TME) holds promise for improving outcomes in these patients. One key mechanism of anti-tumour immunity is the phagocytosis of tumor cells by myeloid cells, which can be suppressed by the interaction between the SIRPα receptor on myeloid cells and its ligand CD47, a "do not eat me" signal, on tumor cells. Inhibition of the SIRPα/CD47 axis restores myeloid cell activity, promotes antigen presentation and enables tumor cell elimination. In this study, we evaluated a novel bispecific antibody that simultaneously blocks SIRPα and PD-L1 (SIRPαxPDL1), critical immune checkpoint molecules frequently overexpressed in the TME. SIRPαxPDL1 demonstrated enhanced macrophage-mediated phagocytosis of tumour cells in vitro. Moreover, in the MC38 murine tumor model, SIRPαxPDL1 significantly improved tumor control and survival, compared to monotherapies targeting either PD-L1 or SIRPα alone or in combination. High-dimensional flow cytometry revealed the unique ability of SIRPαxPDL1 to promote monocyte-to-macrophage differentiation whilst enhancing CD8+ T cell infiltration and activation within the TME compared to the combination of SIRPα and PDL1 antibodies. Remarkably, SIRPαxPDL1 synergized with a tumour-targeting antibody, further augmenting tumor control and survival. These findings highlight, for the first time, the potential of SIRPαxPDL1 to remodel the myeloid compartment and activate antitumor immunity, offering a promising novel avenue in cancer immunotherapy and combination approaches. Citation Format: Mariela Navarrete, Cristobal Costoya, Erik van Buijtenen, Simone Wouters, Joost Kreijtz, Paul Vink, Hans van Eenennaam, Sergio A. Quezada. A novel SIRPαxPD-L1 bispecific antibody remodels the innate and adaptive tumor microenvironment, and enhances tumor control [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 2236.