Targeting the CCR6-CCL20 pathway for treatment of psoriatic joint and entheseal inflammation

Project Summary/Abstract The goal of this project is to develop and validate a novel therapeutic lead compound for the treatment of psoriatic arthritis (PsA). Chemokines orchestrate the migration of inflammatory cells during normal immune responses and are required for immune tissue 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 development of psoriatic disease through the initiation and continuous recruitment of inflammatory Th17-expressing cells into skin and connective tissue. Our published biochemical, cell-based and in vivo studies prove that an engineered recombinant protein that mimics the dimeric version of the natural CCL20 molecule completely reverses its normal pro-inflammatory functional profile. In a Phase I SBIR project, the lead compound (CCL20LD) reduced the signs of established psoriatic dermatitis (PsD) in a preclinical mouse model that faithfully recapitulates human psoriasis. Unexpectedly, CCL20LD treatment also alleviated joint and tendon inflammation, demonstrating efficacy in a clinically relevant model of human psoriatic arthritis. The same project also yielded a favorable preliminary safety profile with no indication of liver or kidney toxicity and a validated manufacturing and quality control protocol. There is a significant need for new treatments for psoriatic arthritis because current options carry the risk of immunosuppression and loss of efficacy over time. This Direct-to-Phase II proposal builds on the completed Phase I milestones to complete preclinical testing and optimization of CCL20LD and assemble the necessary efficacy, safety, and manufacturing data for an IND application and clinical trials for psoriatic arthritis. XLock Biosciences, LLC (XL) will manufacture the CCL20LD protein and direct the studies proposed in three specific aims. In Aim 1, XLock will improve the in vivo stability of the first generation CCL20LD molecule with modifications known to extend the circulating half-life of biologic drugs. In Aim 2 XL and its academic collaborators at UC Davis will establish the therapeutic dose and schedule which produces the strongest anti-psoriatic effect in joint tissues in the shortest time period. Lastly, in Aim 3, XL’s collaborators at the Medical College of Wisconsin will measure CCL20LD’s immunomodulatory activity and its effect on rodent susceptibility to commensal fungal infection. Altering CCR6 signaling through the engineering of its native ligand is an innovative paradigm shift in clinical approaches for treating auto-inflammatory diseases. Development of engineered CCL20 variants as biological therapeutics will have significant positive impact for psoriatic arthritis patients by reducing side effects and providing a drug with extended therapeutic lifetimes. Moreover, the resultant method has the potential for treating other Th17–mediated diseases.