SCR-M015, a PD-1/VEGF bispecific antibody exhibits potent anti-tumor efficacy in preclinical studies

Background: Combinations of PD-1 antibodies and anti-VEGF agents significantly improved clinical benefits over standards of care. The immune checkpoint and VEGF pathways has been demonstrated intrinsic mechanistic complementation, including VEGF effect on angiogenesis, immune cell infiltration, and dendritic cell maturation. We have developed a PD-1xVEGF bispecific antibody SCR-M015 and reported preclinical studies characterizing the functional activity. Method: Binding affinity was assessed using Surface Plasmon Resonance, and the EC50 were determined using ELISA and FACS. Bioluminescent cell-based reporter assays were explored to measure VEGF/VEGFR2 or PD-L1/PD-1 signaling blockage function. Mixed lymphocyte reaction (MLR) assay was applied to evaluate anti-PD1 functional activity. Anti-VEGF bioactivity was determined in HUVEC proliferation assay. In vivo efficacy studies were conducted in CDX models with human tumor cell lines. Result: SCR-M015 was constructed by fusing anti-PD-1 nanobody to the C-terminus of the heavy chain of an anti-VEGF-A antibody with a silent Fc, forming a 2+2 symmetrical structure. SCR-M015 exhibited specific and high-affinity binding to human PD-1 and VEGF. In vitro assays demonstrated that the anti-PD-L1/VEGF bispecific antibody exhibited more potent blockade activity against VEGF-A/VEGFR2 signaling and inhibition of HUVEC proliferation. In MLR assay, SCR-M015 showed dose-dependently increased IL-2 and IFN-gamma secretion, which was comparable to benchmark antibody. In vivo, SCR-M015 demonstrated more robust anti-tumor activity than benchmark antibody in different xenograft models. Furthermore, compared to the combination of anti-PD-1 monoclonal antibody and anti-VEGF monoclonal antibody, SCR-M015 showed more potent anti-tumor efficacy. Conclusions: SCR-M015 inhibits PD-1/PD-L1 signaling and VEGF-A/VEGFR2 signaling in vitro and shows potent and superior anti-tumor activity in vivo. These preclinical data demonstrates the promising potential for further clinical investigation in various types of tumors.