Developing a dual VEGF/PDL1 inhibitor based on high-affinity scFv heterodimers as an anti-cancer therapeutic strategy

Area of Science:

• Immunology
• Oncology
• Biotechnology

Background:

• Programmed death-ligand 1 (PDL1) interaction inhibits anti-tumor immune responses.
• Vascular Endothelial Growth Factor (VEGF) promotes tumor angiogenesis and proliferation while suppressing immune cells.
• Simultaneous inhibition of PDL1 and VEGF offers a potential synergistic anti-cancer therapy.

Purpose of the Study:

• To develop a novel therapeutic agent that simultaneously binds and inhibits both PDL1 and VEGF.
• To engineer a bispecific protein using a single polypeptide chain scaffold for high-affinity dual inhibition.

Main Methods:

• Generation of a bispecific protein, DuRan-Bis, composed of anti-PDL1 and anti-VEGF single chain variable fragments (scFv) fused to an Fc fragment.
• Assessment of DuRan-Bis binding affinity to both PDL1 and VEGF.
• Evaluation of DuRan-Bis efficacy in inhibiting glioblastoma cell proliferation and enhancing immune cell-mediated killing of head and neck cancer cells.

Main Results:

• DuRan-Bis demonstrated high-affinity binding to both PDL1 and VEGF.
• The DuRan-Bis chimera exhibited superior inhibition of glioblastoma cell proliferation compared to mono-specific inhibitors.
• Combination therapy with DuRan-Bis and immune cells reduced head and neck cancer cell viability more effectively than immune cells alone.

Conclusions:

• The study presents the first single polypeptide chain scFv-scFv-Fc scaffold for engineering a high-affinity bispecific PDL1 and VEGF inhibitor.
• DuRan-Bis represents a promising novel therapeutic strategy for synergistic anti-cancer treatment by targeting both immune evasion and tumor growth pathways.
• This approach holds potential for enhancing cancer immunotherapy efficacy.