PROJECT SUMMARY (PI: YU) Since bones and cartilage (B&C) are common sites of serious degenerative diseases (e.g. cancer, arthritis, osteoporosis), a strategy to localize therapeutic agents to skeletal tissue (for high efficacy) with minimal distribution to other sites (for low side effects) could lead to significant improvement in treating a wide range of debilitating conditions. Recent advances in antibody therapy have produced promising drugs for rheumatoid arthritis (e.g. infliximab, abatacept); however they have off-site, target related side effects due to systemic immune suppression. Due to these side effects, mainly serious infection, patients need to be screened for therapy, and co- or concurrent administration of two types of immune modulatory drugs is not practiced although such approach may treat RA symptoms better. Based on a new understanding of RA biology and our recent findings that collagen hybridizing peptide (CHP) can bind to degraded collagen in skeletal tissues undergoing pathologic resorption, we propose to develop joint targeted antibody therapy that can seek and bind to collagens degraded by rheumatoid arthritis (RA). In aim 1, we will synthesize new CHP structures that have high affinity to denatured collagen. In aim 2, we plan to develop RA joint-targeted anti-TNF-a therapy by conjugating CHP to Fab that can neutralize mouse TNF-a. In aim 3, we will study the pharmacological properties, efficacy, and systemic immune suppression of the Fab-CHP conjugates in RA mouse models. Latest understanding of RA disease mechanism teaches that immune activations in RA take place locally at the disease site and most of TNF-a are produced by the inflamed tissue. Since off-site side effects are the major limitation of antibody therapy, the ability to localize immunomodulatory drugs could lead to high efficacy and low side effects. The success of this work may lead to an entirely new platform for antibody therapy for RA and other autoimmune diseases.