Developing dual VEGF/PDL1 inhibitor based high-affinity scFvs as a therapeutic strategy
2Department of Life Sciences, Ben Gurion University, Israel
3Department of Microbiology, Immunology and Genetics, Ben Gurion University, Israel
Both Programmed death-ligand 1 (PDL1) and Vascular endothelial growth factor (VEGF) cross interact to enhance cancer progression. PDL1 being associated with inhibition of the immune response against tumors and VEGF being an important factor in angiogenesis and migration of cancer cells as well as in immune cells inhibition activity; dual inhibition of PDL1 and VEGF could therefore have a synergistic therapeutic anti-cancer effect.
Here, we present a novel strategy for developing such a therapeutic, based on the simultaneous binding and inhibition of both PDL1 and VEGF. To this end, we generated a bi-specific protein (designated DuRan Bis), comprising single chain fragment variable (scFv)-based inhibitor of PDL1 fused to scFv-based inhibitor of VEGF, the latter attached to a Fc fragment. We found that the DuRan Bis binds to both ligands with high affinity in a concentration dependent manner.
We show that the engineered bi-specific fusion protein displayed superior inhibition activity of glioblastoma proliferation over each of the mono-specific treatments alone or when combined. When compared to immune cells given alone, the bi-specific inhibitor combined with immune cells decreased head and neck cancer cells viability and increased IFN-γ (cytokine released from activated T cells) supernatant levels probably due to an increased cytotoxicity of immune cells, a result of the PDL1 and VEGF inhibition. Our findings demonstrate that dual targeting of VEGF and PDL1 pathways may provide a novel useful therapeutic approach to cancer. Furthermore, this dual-specific protein platform may be utilized for generating bi-specific inhibitors for targets other than VEGF or PDL1.