Oral angiogenesis inhibitor LHbisD4 synergistically enhances anti-cancer therapy by combination with αPD-1 antibody

Abstract

Angiogenesis, the formation of new blood vessels from pre-existing ones, is a crucial process in tumor growth, thus tumoral angiogenesis is a key contributor to aggressive tumor growth. In this study, we have developed a novel strategy for using a potent anti-angiogenic drug to not only inhibit tumoral angiogenesis, but also transform the tumor microenvironment into an immunosupportive state. In this study we have successfully used LHbisD4, a previously developed heparin-based deoxycholic acid conjugate, as an orally active anti-angiogenic drug to induce potent anti-angiogenic and immunomodulatory effect in vitro and in vivo. By surface plasmon resonance (SPR) analysis we observed that LHbisD4 displays high binding affinity towards VEGF-A and treatment of LHbisD4 induced inhibition of VEGFR-2 phosphorylation in human umbilical vein endothelial cells (HUVECs), analyzed by western blot. LHbisD4 treatment in HUVECs also showed reduced proliferation by 82% compared to control and tubular formation was also reduced after treatment of LHbisD4. Their efficacy was successfully demonstrated in preclinical studies both as an anti-angiogenic and anti-tumor agent, and further its combination with αPD-1 antibody was evaluated to investigate the immunosupportive role of LHbisD4. The in vivo anti-tumor effect in mouse xenograft models showed 78.2% tumor growth inhibition compared to control. Through this study, we showed that LHbisD4 mediates a potent anti-angiogenic effect as well as an effective immunosupporting role, and potentiates the efficacy of immunotherapeutic agents in a synergistic manner.