ABSTRACT This proposal is focused on development of a novel non-immunosuppressive biologic therapy for RA by targeting fibroblast-like synoviocytes, local joint-lining cells that substantially contribute to joint destruction during rheumatoid arthritis (RA). The development of immunosuppressant disease-modifying anti-rheumatic agents (DMARDs) has dramatically improved the quality of life of RA patients; however a large proportion of patients still fail to reach sufficient control of disease activity on the currently available RA medications. There is a need for novel non-immunosuppressive therapies for RA that can be used alone or in combination with current DMARDs. To address this need, we are seeking to target fibroblast-like synoviocytes as a non- immunosuppressive option for RA. Here, we will demonstrate our biologic reduces FLS migration and invasion and reverses arthritis in mice. This project addresses a major unmet medical need in RA, the lack of non- immunosuppressive therapies for controlling disease activity. Once we obtain proof-of-concept data during this Phase I project, we will apply for Phase II funding to further develop the lead and characterize its preclinical efficacy and safety.