Effective Combination Immunotherapy through Vessel Normalization Using a Cancer-Targeting Antiangiogenic Peptide-Antibody Hybrid

Abstract

Although cancer immunotherapy using immune checkpoint blockade (ICB) has changed the paradigm for treating patients with certain cancers, its therapeutic benefits are limited to approximately one-fourth of patients, highlighting the potential for combining immunotherapy with another therapeutic modality. Here, a treatment regimen that combines a cancer-targeting antiangiogenic agent that inhibits angiogenesis within the tumor and ICB to improve therapeutic outcome is reported. The cancer-targeting antiangiogenic modality is constructed as a hybrid complex, designated HyPEP(EDB-VEGF), comprising a cotinine-labeled bispecific peptide targeting both extra domain B of fibronectin (EDB) and vascular endothelial growth factor (VEGF) and an anticotinine antibody (Ab(cot)). The resulting HyPEP(EDB-VEGF) specifically bound to EDB-overexpressing CT26 murine colorectal cancer cells and inhibited VEGF-induced proliferation of human umbilical vascular endothelial cells. Upon intraperitoneal injection, HyPEP(EDB-VEGF) preferentially accumulates in CT26 syngeneic tumors and inhibits tumor growth in a dose-dependent manner. Furthermore, the combination of HyPEP(EDB-VEGF) with an anti-PD-1 antibody (alpha PD-1) in conjunction with dose optimization of the two modalities leads to substantial inhibition of tumor growth without loss of body weight due to vascular normalization within the tumor. These findings suggest that the combination of cancer-specific antiangiogenic therapy using HyPEP(EDB-VEGF) together with ICB may be a feasible approach for effective cancer therapy.