Abstract 2864: DXA023-G017, a bispecific PD-1/VEGF conjugate elicits potent anti-tumor efficacy in preclinical studies

Abstract Background: Programmed cell death protein 1 (PD-1) and vascular endothelial growth factor (VEGF) are often co-expressed in the tumor microenvironment. VEGF not only promotes tumor vessel normalization but also effectively alleviates immunosuppression, thereby enhancing the infiltration and activation of immune effector cells. The synergistic effect of combining immunotherapy with anti-angiogenic agents (anti-PD-1 in combined with anti-VEGF) has been validated in the clinical treatment of advanced non-small cell lung cancer (NSCLC). Although Ivonescimab, a PD-1/VEGF bispecific antibody, has exhibited a notable prolongation of progression-free survival (PFS) versus Keytruda in individuals with PD-L1-positive NSCLC, the impact on overall survival (OS) necessitates further validation. Furthermore, the combination of Ivonescimab with chemotherapy has demonstrated more extensive antitumor efficacy compared to Ivonescimab monotherapy. Consequently, a chemotherapeutic drug conjugates to the anti-PD-1/VEGF bispecific antibody with functional linker may represent a novel and promising strategy for enhancing clinical outcomes. DXA023, the bispecific antibody, possesses a tetravalent structure similar to Ivonescimab, demonstrated both efficacy and safety against both PD-L1 and VEGF targets. DXA023 was conjugated to a small molecule/functional linker complex, G017 to form a PD-1/VEGF conjugate (DXA023-G017), which holds promise for further enhancing antitumor activity. Methods: The antigen binding activities of DXA023 to PD-1 and VEGF were evaluated using ELISA and ForteBio assays. The protein binding affinities of both DXA023 and DXA023-G017 to PD-1 and VEGF were assessed by ELISA. The blockade of the PD-1/PD-L1 signaling pathway was determined using a luciferase reporter cell assay. Cell proliferation inhibitory assay was used to test in-vitro pharmacology of DXA023 and DXA023-G017. In vivo anti-tumor activities of DXA023 and DXA023-G017 were studied in an HCC827 tumor mouse model reconstituted with human peripheral blood mononuclear cells (PBMCs). Results: DXA023 exhibits specific and high-affinity binding to human PD-1 and VEGF. The AAS mutations introduced significantly reduces FcγR binding, thereby effectively diminishing the antibody’s ADCC effect, while still maintaining FcRn affinity. Both DXA023 and DXA023-G017 effectively block the PD-1/PD-L1 signaling pathway and demonstrate notable in-vitro antitumor activity. Furthermore, DXA023-G017 exhibits superior antitumor efficacy compared to DXA023 in the HCC827-PBMC mouse model. Conclusions: DXA023-G017, a dual-blocking anti-PD-1/VEGF bispecific conjugate, demonstrates impressive antitumor efficacy in a mouse tumor model, providing robust support for its clinical development as a treatment for various advanced solid tumors. Citation Format: Xiaobo Cai, Wei Zheng, Junxiang Jia, Shishan Hu, Hui Xia, Qingliang Yang, Zhixiang Guo, Wei Liu, Lu Bai, Jun Zheng, Wenjun Li, Yuanyuan Huang, Zhongliang Fan, Binbin Chen, Meng Dai, Robert ZHAO. DXA023-G017, a bispecific PD-1/VEGF conjugate elicits potent anti-tumor efficacy in preclinical studies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 2864.