一种半衰期延长的PD-1×VEGFA双特异性抗体在临床前模型中显示出强效的抗肿瘤活性

Background PD-1 blockade reactivates T-cell-mediated tumor killing but faces resistance in "cold" tumors with poor immune infiltration. VEGF-A inhibition (e.g., bevacizumab) normalizes tumor vasculature, enhancing immune cell delivery and synergizing with PD-1 inhibitors. Simultaneously disrupts immune evasion (via PD-1) and tumor blood supply (via VEGF-A), addressing microenvironmental barriers. Currently, several PD-1/L1×VEGF-A bispecific antibodies have been developed and demonstrated superior antitumor activity. Methods We developed a novel PD-1×VEGF-A bispecific antibody, BCG036, by fusing a fully human anti-VEGF-A VHH domain with an Fc-engineered IgG1 anti-PD-1 monoclonal antibody to extend its half-life. We used reporter cell lines to conduct blocking assays for PD-1 and VEGF-A. In vivo pharmacokinetic and efficacy studies were evaluated in FcRn humanized mice and xenograft mouse models bearing an established A375 tumor. Toxicology studies were conducted in cynomolgus monkeys to assess the safety and pharmacokinetic characteristics of the BCG036. Results BCG036 demonstrated high affinity and specificity for both human PD-1 and VEGF-A, with superior blocking activity for both PD-1/PD-L1 and VEGF/VEGFR signaling pathway than the benchmark. In vivo , BCG036 exhibited an extended half-life in humanized FcRn mice and demonstrated potent antitumor efficacy than the benchmark. Importantly, BCG036 displayed a favorable safety and PK profile in cynomolgus monkeys after repeated dosing at 100 mg/kg. Conclusions Our prolonged half-life version of the PD-1×VEGF-A bispecific antibody shows high affinity in vitro and has a strong ability to block the interactions of PD-1/PD-L1 and VEGFR2/VEGFA. It demonstrates strong antitumor activity in mouse models and has demonstrated good safety in cynomolgus monkeys, supporting a long-term dosing regimen.