Development of an engineered CCL20 protein as a lead therapeutic molecule for Psoriasis

Project Summary Abstract The goal of this project is to develop and validate a novel therapeutic lead compound for the treatment of psoriasisChemokines orchestrate the migration of inflammatory cells during normal immune function and are required for proper organ development and homeostasisWhen aberrant chemokine function occursimproper recruitment of immune cells can lead to a variety of inflammatory pathologies with devastating effects on a patientandapos s quality of lifeThe chemokine CCLand its G protein coupled receptor CCRdrive the development of psoriasis through the initiation and continuous recruitment of inflammatory Thcells into the dermisPreclinical studies by our team show that inhibiting CCLCCRsignaling can block the symptoms of psoriasisOur recently published biochemicalcell based and in vivo studies prove that an engineered recombinant protein that mimics the dimeric version of the natural CCLmolecule completely reverses its normal proinflammatory functional profileThis lead compoundCCLLDinvented by the PI at the Medical College of Wisconsinprevented the development of psoriatic dermatitisPsDin mice treated with ILGiven its efficacy in animalswe propose to develop CCLLD as a next generation treatment for psoriasisTo further validate CCLLD as a therapeutic lead compoundPF will conduct clinically relevant animal model testing and prepare for transfer of recombinant CCLLD protein production to a cGMP manufacturing environmentIn Aimof this applicationPF 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 Aimmilestone to show clearance of disease signs greater thanas compared to control animalsIn AimPF will establish a preliminary toxicology profile in one animal species with a milestone target that treated and control groups will not have greater thanvariation in serum biomarker levels of kidney and liver functionLastlyin AimPF will produce the engineered molecule in a commercial manufacturing setting and subsequently validate a Quality Control testing standard for additional preclinical testing in a plannedfollow on SBIR Phase II proposalSuccessful completion of Aimmilestones will result in the generation of threemg lots of the engineered molecule with purityandgtby HPLCand less thanvariance in biological assaysAltering CCRsignaling through the engineering of its native ligand is an innovative paradigm shift in clinical approaches for treating auto inflammatory diseasesDevelopment of engineered CCLvariants as biological therapeutics will have significant positive impact for PsD patients by reducing side effects and providing a drug with extended therapeutic lifetimesMoreoverthe resultant method has the potential for treating other Thmediated diseases PROJECT NARRATIVE Chemokines are soluble proteins that direct migrating immune cells to sites of foreign invasionAberrant chemokine function can lead to cancers and inflammatory diseasesIn particularCCLhas been linked to the pathophysiology of human psoriasisthe most common inflammatory skin diseaseThe goal of this Phase I SBIR project is to reverse CCLandapos s inflammatory properties through protein engineering and ultimately to develop potent anti psoriasis drugs with the potential of translating this research to other Thmediated diseases!