VEGF-Trap Platform

Introduction to Y-traps

Y-traps are comprised of an antibody that targets checkpoint inhibitors such as cytotoxic T-lymphocyte antigen-4 (CTLA-4) and programmed death-1 (PD-1)/PD-1 ligand (PD-L1) with traps that target transforming growth factor beta (TGF-β) fused to the C-terminus of the heavy chain. TGF-β is a protein secreted by tumor cells and inhibit anti-tumor T-cell responses. Binding between the trap and TGF-β can effectively neutralize its immunosuppressive effects.

Combining both checkpoint inhibitor and ligand binding has two key advantages. First, improved therapeutic potency: clinical trials using PD-L1/TGF-β traps (M7824) were able to elicit responses in patients who previously failed immune checkpoint therapy. Second, using a mono-therapy over combination therapy may aid in reducing the risk of adverse side effects commonly associated with immunotherapy.

Immunowake: VEGF-trap Platform

VEGF-traps are comprised on an antibody targeting checkpoint inhibitors (CTLA-4, PD-1, PD-L1) with traps targeting vascular endothelial growth factor (VEGF) fused to the C-terminus of the light chain. Mechanistically, the VEGF- and Y-traps work similarly: both serve as bifunctional fusion proteins and are more effective than an immune checkpoint inhibitors alone.

There are two key differences between the VEGF- and Y-traps. First, the traps are fused to the C-terminus of the light chain rather than the C-terminus of the heavy chain. Placing the VEGF trap on the C-terminus of the light chain had an additional benefit: ADCC effector functions were fully retained. No difference between antigen-binding and biological function were observed between the VEGF and Y configurations.

Second, the VEGF-traps target VEGF rather than TGF-β. VEGF is a protein expressed on vascular endothelial cells and is the key mediator of cancer angiogenesis. Angiogenesis is essential for cancer development and growth. As the tumor grows, it requires blood vessels for nutrients and oxygen. This central role of VEGF in cancer has made it an optimal therapeutic target. Recently, VEGF has been proven to be a valid clinical target with the FDA-approval of Avastin (inhibitor) and Zaltra (trap). In phase I to III studies, combination therapy with anti-PD-L1 and Avastin was found to double the response rate from 20% to 40% in patients and reduce the risk of disease progression and mortality. These findings suggest that there is a synergistic effect in targeting both PD-L1 and VEGF. Based on these clinical findings, Immunowake has developed a single molecule: PD-L1/VEGF trap.

Animal studies showed that PD-L1/VEGF trap was more effective than PD-L1 therapy alone and PD-L1/TGF-β trap. Mice retained long-term tumor regression even after dosing was stopped. Furthermore, all cured mice were protected from tumor re-challenge, suggesting the successful generation of anti-tumor memory.