IMM2510, a novel anti-PD-L1/VEGF bispecific antibody for cancer immunotherapy.

BACKGROUND: Dual inhibition of PD-1/PD-L1 and VEGF/VEGFR pathways is a promising strategy to overcome tumor immune evasion and inhibit angiogenesis. IMM2510 is a novel PD-L1 × VEGF bispecific antibody, constructed by fusing VEGFR1 domain 2 (VEGFR1D2) to each anti-PD-L1 heavy chain. In addition, IMM2510 incorporates an Fc region engineered for enhanced antibody-dependent cellular cytotoxicity (ADCC), enabling elimination of PD-L1-expressing tumor and stromal cells. METHODS: Binding and blocking activities were assessed using enzyme-linked immunosorbent assay, surface plasmon resonance, and flow cytometry. Functional assays included Jurkat-PD-1 and VEGFR2 reporter systems, HUVEC proliferation, mixed lymphocyte reaction, and NK cell-mediated cytotoxicity. Cooperative binding with VEGF165 was evaluated biochemically and in reporter assays. Antitumor efficacy was tested in MC38-hPD-L1 syngeneic tumors, HCC827 non-small cell lung cancer (NSCLC) xenografts, and MDA-MB-231 triple-negative breast cancer (TNBC) xenografts. RESULTS: IMM2510 bound PD-L1, VEGF-A, VEGF-B, and PlGF with high affinity, and blocked both PD-1/PD-L1 and VEGF/VEGFR interactions. It reversed PD-1-mediated T-cell inhibition, inhibited VEGF-driven endothelial proliferation, and induced potent ADCC and ADCP in killing PD-L1(+) tumor cells. Preincubation with VEGF165 enhanced PD-L1 binding and checkpoint blockade activity, indicating cooperative binding. In vivo, IMM2510 induced dose-dependent tumor growth inhibition, achieving superior efficacy to parental monotherapies and their combination. Consistent efficacy was observed across multiple tumor types, including NSCLC and TNBC. CONCLUSIONS: IMM2510 combines checkpoint blockade, anti-angiogenesis, Fc-mediated effector function, and cooperative binding, resulting in superior preclinical antitumor activity across diverse tumor settings. These findings position IMM2510 as a differentiated next-generation therapeutic candidate for clinical development.