A novel bispecific antibody CVL006 superior to AK112 for dual targeting of PD-L1 and VEGF in cancer therapy.

Background: Preclinical and clinical studies highlight the enhanced anticancer efficacy of combining anti-VEGF/VEGFR drugs with immune checkpoint inhibitors (ICIs). PD-L1/VEGF bispecific antibodies outperform monotherapy or combined PD-L1 inhibitors and anti-VEGF antibodies by simultaneously blocking the PD-1/PD-L1 immune pathway and VEGF-driven angiogenesis, providing a dual mechanism for superior antitumor activity. Methods: We developed CVL006, a novel bispecific antibody, by fusing an anti-PD-L1 VHH domain with a humanized IgG1 anti-VEGF monoclonal antibody. CVL006 retains antibody-dependent cellular cytotoxicity (ADCC) functionality. Preclinical evaluations included binding affinity and specificity assessments, dual-pathway blockade testing, and Results: CVL006 demonstrated high affinity and specificity for human PD-L1 and VEGF. It effectively inhibited VEGF/VEGFR signaling and the PD-L1/PD-1 axis, suppressing VEGF-induced angiogenesis and reactivating T cells. This reactivation led to increased cytokine secretion critical for immune response. Conclusions: CVL006 integrates immune checkpoint inhibition and tumor vascularization disruption, offering a comprehensive anticancer strategy. Its superior preclinical performance compared to atezolizumab and AK112 underscores its therapeutic potential, paving the way for further development and clinical translation.