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

ABSTRACT 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 ELISA, 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 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.