Development of an engineered CCL20 as a therapeutic molecule for chronic graft-versus-host disease

Project Summary/Abstract The goal of this project is to validate a novel therapeutic lead compound for the treatment of chronic graft versus host disease (cGVHD). Chronic graft versus host disease (cGVHD), the leading cause of long-term morbidity and mortality following allogeneic hematopoietic stem cell transplantation, affects up to 25,000 new patients each year in the U.S. It is now widely accepted that dysregulated T helper 17 (Th17) cells contribute to the development and progression of cGVHD, which can damage virtually any organ system. Up to 40% of cGVHD patients die within seven years during treatment and half of cGVHD patients become unresponsive to corticosteroid therapy with few alternatives. This dismal clinical outlook highlights a clear unmet need for a safe and effective treatment for cGVHD. Chemokines orchestrate the migration of inflammatory cells during normal immune function and are required for proper organ development and homeostasis. When aberrant chemokine function occurs, improper recruitment of immune cells can lead to a variety of inflammatory pathologies with devastating effects on a patient’s quality of life. The chemokine CCL20 and its G protein- coupled receptor CCR6 drive the continuous recruitment of Th17 cells in several autoimmune and chronic inflammatory diseases (e.g. psoriasis, psoriatic arthritis and rheumatoid arthritis) and are likely to participate in the pathogenesis of cGVHD. Our published biochemical, cell-based and in vivo studies prove that an engineered dimeric form of CCL20 molecule (CCL20LD) completely reverses its normal pro-inflammatory functional profile. This lead molecule was therapeutically efficacious in mouse models of psoriasis and psoriatic arthritis and has the potential to treat other Th17-mediated diseases. We propose to validate CCL20LD as a next-generation biologic treatment for cGVHD. In Aim 1, XLock Biosciences and its academic collaborators at City of Hope will test the therapeutic efficacy of the engineered protein in an established murine model of cGVHD with an Aim 1 milestone to show statistically significant reductions in multiple disease signs as compared to control animals. In Aim 2, our company will produce a 2nd–generation XTEN extended version of CCL20LD that maintains the in vitro inhibition of cell migration at levels comparable to the 1st–generation molecule. Successful completion of Aim 2 milestones will result in at least two version of CCL20LD with varying lengths of XTEN sequence that preserve the inhibitory potency of CCL20LD and prolong its circulating lifeteim in vivo. Altering CCR6 signaling through the engineering of its native ligand is an innovative paradigm shift in clinical approaches for treating auto-inflammatory diseases. Validation of engineered CCL20 variants as biological therapeutic for cGVHD will have significant positive impact for patients by reducing side effects associated with prolonged administration of prednisone, the standard treatment for over 30 years, and providing a drug with extended therapeutic lifetimes.