评估靶向PD-1和VEGF双特异性抗体的临床前模型

Immune checkpoint inhibitors have transformed oncology treatment, yet primary and acquired resistance remain a significant clinical challenge. Bispecific antibodies targeting both PD-1 and VEGF have achieved remarkable success in clinical trials and have attracted widespread attention by concurrently modulating T-cell immunity while remodeling vasculature within the tumor microenvironment. Physiologically relevant preclinical models that accurately recapitulate human immune and target interactions are essential for evaluating novel therapeutics targeting PD-1 and VEGF. We established an integrated preclinical platform utilizing complementary humanized models. First, we developed BALB/c-hPD1/hPDL1 dual-humanized mice using CRISPR/Cas9 technology and engineered a CT26-hPDL1-hVEGFA dual-humanized colon carcinoma cell line. Implantation of these cells into BALB/c-hPD1/hPDL1 mice created an in vivo system simultaneously modeling the human PD-1/PD-L1 checkpoint and VEGFA signaling pathways. In this target-humanized model, the PD-1/VEGF bispecific antibody Ivonescimab demonstrated significant tumor growth inhibition, and showed superior efficacy compared to combination therapy with anti-PD-1 and anti-VEGFA antibodies, thereby validating the model's capability for assessing the synergistic effects of bispecific antibodies. To assess human T-cell-mediated responses to PD-1/VEGF bispecific antibody treatment, we established a dual-humanized model by engrafting the human tumor cell line LS174T into human peripheral blood mononuclear cell (PBMC) immune system humanized NCG mice. This model demonstrated robust human T-cell reconstitution suitable for evaluating mono- and combination therapies. In efficacy experiments using this model, Ivonescimab similarly exhibited potent antitumor activity with no observed treatment-related hemorrhagic complications, providing preliminary evidence for the safety profile of this combination strategy. These two models used together provide an integrated and translationally relevant preclinical platform for assessing efficacy and potential safety liabilities of PD-1/VEGF-targeted therapies. Using this comprehensive platform will effectively support the discovery and development of novel immunotherapies for complex indications, enabling preclinical risk assessment and accelerating candidate drug translation.