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 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 development of psoriasis through the initiation and continuous recruitment of inflammatory Th17 cells into the dermis. Pre- clinical studies by our team show that inhibiting CCL20/CCR6 signaling can block the symptoms of psoriasis. 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 of psoriatic dermatitis (PsD) in mice treated with IL-23. Given its efficacy in animals, we propose to develop CCL20LD as a next-generation treatment for psoriasis. To further validate CCL20LD as a therapeutic lead compound, PF will conduct clinically relevant animal model testing and prepare for transfer of recombinant CCL20LD protein production to a cGMP manufacturing environment.
In Aim 1 of this application, PF and its academic collaborators at UC Davis will test the therapeutic efficacy of the engineered protein in a preclinical animal model for PsD with an Aim 1 milestone to show clearance of disease signs greater than 50% as compared to control animals.
In Aim 2, PF will establish a preliminary toxicology profile in one animal species with a milestone target that treated and control groups will not have greater than 10% variation in serum biomarker levels of kidney and liver function. Lastly, in Aim 3, PF will produce the engineered molecule in a commercial manufacturing setting and subsequently validate a Quality Control testing standard for additional preclinical testing in a planned, follow-on SBIR Phase II proposal. Successful completion of Aim 3 milestones will result in the generation of three (3), 3-mg lots of the engineered molecule with purity (> 95% by HPLC) and less than 10% variance in biological assays. 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 PsD 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 I SBIR project is to reverse CCL20's inflammatory properties through protein engineering and ultimately to develop potent anti-psoriasis drugs with the potential of translating this research to other Th17-mediated diseases. !
