The goal of this project is to develop and validate a novel therapeutic lead compound for the treatment of psoriasis. 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 psoriasis through the initiation and continuous recruitment of inflammatory Th17-expressing cells into the dermis. Our recently 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. This lead compound (CCL20LD), invented by the PI at the Medical College of Wisconsin, prevented the development and progression of psoriatic dermatitis (PsD) in a preclinical mouse model that faithfully recapitulates human psoriasis. During PF?s SBIR Phase I grant award period, we successfully completed all three milestones focused on the preclinical development of CCL20LD as a psoriatic therapy. First, using a new systemic, IL-23 minicircle model, Protein Foundry showed that CCL20LD alleviated signs of skin inflammation after disease establishment, demonstrating that CCL20LD is efficacious as a therapeutic treatment in a clinically relevant model of human psoriasis. Second, CCL20LD was shown in preliminary serological analyses to be relatively safe, with no accumulation of hepatic or nephrotic biomarkers of tissue damage. Third, PF validated a reproducible manufacturing and quality control protocol for the CCL20LD protein. Given the successful completion of the phase I work and the notable efficacy in animals, we propose to develop CCL20LD as a next-generation treatment for psoriasis. To perform the R/R&D necessary for an IND, this phase II application proposes to develop an optimized dosing schedule using clinically relevant animal models, and validate the safety profile in rodents to guide IND-enabling GLP toxicology studies in non-human primates.
In Aim 1 of this application, Protein Foundry and its academic collaborators at UC Davis will establish the therapeutic dose and schedule which produces the strongest anti- psoriatic effect in the shortest time period.
In Aim 2, Protein Foundry will use cytokine storm and anti-drug antibody assays to test immunogenicity and establish a toxicology profile in rodents to guide GLP toxicology studies in non-human primates. Lastly, in Aim 3, Protein Foundry will explore topical formulations for testing in animal models as a first key step in differentiating CCL20LD from current market therapeutics and fully establish CCL20LD?s targeted product profile. 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 psoriasis 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.
Chemokines are soluble proteins that direct migrating immune cells to sites of foreign invasion. Aberrant chemokine function can lead to cancers and inflammatory diseases. In particular, CCL20 has been linked to the pathophysiology of human psoriasis, the most common inflammatory skin disease. The goal of this Phase II SBIR project is to perform the necessary R/R&D activities to guide IND-enabling studies and the eventual first-in-man trials of CCL20LD as a psoriatic therapy. !
