There is a great need for new therapies for Crohn's disease (CD), which is a chronic, relapsing and tissue destructive inflammatory bowel disease (IBD). Estimates indicate that there are >1 million annual cases of IBD in the United States, 50% of which involve CD. Our primary objective is to develop a biologic that can be used to better treat and reduce the signs and symptoms of this devastating inflammatory disease. The current proposal stems from our findings that CXCR3 interactions enhance Th1 immune responses, and CXCR3 ligands (CXCL9, CXCL10, and CXCL11) are up regulated in CD patients. Fortunately, the clinical features of CD correlate with certain mouse models of colitis, including the spontaneous colitis observed in IL-10-/- mice. This model provides an excellent means to study IBD and develop therapies to treat this devastating disease. While there are small molecule antagonists that bind CXCR3, the use of these pharmaceuticals is limited by their relatively low bioavailability and hydrophobic nature, which are often associated with liver and cardiac toxicities. To solve this problem and to treat colitis that is mediated in large part b CXCR3 interactions, JYANT Technologies has developed a novel mutant CXCR3 ligand-immunoglobulin fusion protein (mut-CXCL11-Ig) that lacks immunogenic, glycosaminoglycan (connective tissues)-binding sites but retains the ability to tightly bind, but not activate CXCR3. Hence, this proposal will test the hypothesis that mut-CXCL11-Ig can inhibit CXCR3 interactions to reduce the signs and symptoms of colitis.
Two Specific Aims will be used to test this hypothesis for the development of our novel protein drug:
Aim 1 will ascertain the pharmacodynamics/pharmacokinetics (PK/PD) profile of mut-CXCL11-Ig.
Aim 2 will assess the efficacy of mut-CXCL11-Ig to treat and prevent spontaneous colitis as well as its immunogenicity and toxicity.
Aim 3 will characterize any off target chemokine receptor activity of mut-CXCL11-Ig using (18 different) human CCR1-10, CXCR1-7, and CX3CR1 whole cell PathHunter(r) ?-Arrestin activity assays and CXCR3 ligand-mediated human CD4+ T cell chemotaxis assays.
This proposal uses a novel chemokine receptor, CXCR3 (up regulated during IBD), protein antagonist to mitigate mouse colitis, which are similar to human IBD. Together, these studies serve as the proof-of-concept of this new protein drug to treat IBD and other inflammatory diseases.