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Background Inhibition of PD-L1 and VEGF – individually and in combination – has activity across multiple solid tumors. However, not all patients respond, responses can be of short duration, and treatment is limited by toxicity. Novel approaches targeting both pathways with one bispecific have shown promising activity.IMM-2510 is a novel bispecific antibody targeting VEGF and PD-L1. Each PD-L1 antibody heavy chain is fused at the N-terminus to a VEGFR1D2 domain. The Fc region is engineered for enhanced effector function. This design achieves angiogenic inhibition, relief from VEGF-induced immune suppression, immune checkpoint blockade and PD-L1-directed ADCC in the tumor microenvironment.Methods In vitro binding was assessed using plate-based ELISA and cell-based flow cytometry, as well as binding to PD-L1-expressing cell lines and endogenous binding to human PBMCs. ELISA was also used to demonstrate AXN-2510’s blockade of binding of VEGF to VEGFR. IMM-2510 inhibition of PD-1/PD-L1 binding was performed using a PD-L1 expressing cell line and biotin-labelled PD-1-Fc.VEGF/VEGFR signaling blockade by IMM-2510 was assessed by a functional assay and HUVEC proliferation. Functional inhibition of PD-1/PD-L1 signaling and cooperativity with VEGF were tested using a similar assay. Jurkat-PD-1 reporter assays with Raji-PD-L1 cells were performed to measure release of immune checkpoint inhibition by IMM-2510. ADCC and ADCP were measured in vitro and in vivo.In vivo efficacy of IMM-2510 was tested in three murine models, including a humanized CRC model and lung and breast xenograft models.Results IMM-2510 exhibits high binding affinity for both PD-L1 and VEGF individually and simultaneously. IMM-2510 bound to human PD-L1, VEGF-A, VEGF-B, and PlGF. PD-L1 binding was demonstrated in cell lines and human donor-derived PBMCs. Additionally, IMM-2510 blocked ligand-receptor interaction of both pathways. Cooperativity was noted as VEGF-enhanced binding and anti-PD-L1 function.Functional inhibition of T cell immune suppression was achieved with IMM-2510 treatment. Angiogenesis inhibition was shown via endothelial proliferation reduction and decrease in VEGF/VEGFR signaling. Modifications in the Fc domain led to enhanced ADCC and ADCP in both in vitro and mouse tumor studies. In three murine models, IMM-2510 treatment resulted in 70-95% tumor growth inhibition.Conclusions IMM-2510 is an anti-PD-L1xVEGF bispecific antibody designed to have immune stimulatory, antiangiogenic, and anti-tumor activity in the TME. This agent has unique capabilities to target multiple tumorigenic pathways, improving upon the class-specific functions of this drug class, with added anti-tumor effects. IMM-2510 is currently in clinical trials for multiple solid tumor indications, including front-line NSCLC. 1 Reference ASCO 2023, Journal of Clinical Oncology 41(16_suppl).