Negative Feedback Expansion of Tregs Caused by Endogenous IL-2 Limits the Activity of IL-2-based Therapies

Abstract

Stimulating effector T-cells (Teffs) without inducing regulatory T-cells (Tregs) has been the primary goal of IL-2-based therapies for cancer. Recently, modified IL-2 designed for differential T-cell expansion for the treatment of cancer has failed in the clinic. We propose that treatments based on exogenous administrations of modified IL-2 are inherently undermined by a negative feedback loop, caused by IL-2 secreted endogenously from activated effector T-cells. This endogenous IL-2 secretion subsequentially induces Treg expansion and inhibits the immune response that is essential for cancer clearance. Here, we demonstrate that treatments utilizing exogenous modified IL-2 indeed induce Treg expansion. To circumvent this negative feedback, we computationally designed a novel monoclonal humanized antibody (AU-007) that binds human IL-2 with pM affinity at a predefined epitope and completely blocks IL-2 binding to CD25 that is highly expressed on Tregs, without hindering IL-2 binding to CD122/CD132 dimer receptor expressed over effector cells. This epitope-specific, high-affinity antibody controls endogenous IL-2 and prevents it from expanding Tregs while allowing it to expand Teffs. We show that controlling endogenous IL-2 using AU-007 abrogates the negative feedback loop and replaces it with a positive feedback loop that enhances the expansion of NK cells and Teffs, an effect considered favorable for cancer immunotherapy.