Bispecific biologic for rheumatoid arthritis therapy

ABSTRACT This proposal is focused on development of a novel bispecific biologic therapy for RA by targeting the transmembrane tyrosine phosphatase PTPRS through its extracellular region. The development of immunosuppressant disease-modifying anti-rheumatic agents (DMARDs) has dramatically improved the quality of life of rheumatoid arthritis (RA) patients, however a large proportion of patients fails to reach sufficient control of disease activity on the currently available RA medications. There is a need for therapies for RA that can enhance efficacy of current DMARDs. To address this need, we are seeking to target fibroblast-like synoviocytes, which are local joint-lining cells that substantially contribute to joint destruction during RA. Our company Knoubis Bio has identified the transmembrane phosphatase PTPRS as a novel target for synoviocyte-directed RA therapy. We have evidence that disrupting the interaction between PTPRS and its extracellular ligand syndecan- 4 reduces synoviocyte invasiveness and inflammatory arthritis in preclinical models without causing immunosuppression. Here, we will develop a bispecific biologic that dually targets PTPRS and acts as a DMARD as a novel biologic therapy for RA. We will pursue the following Specific Aims: 1) to perform pharmacokinetics studies of the biologic in mice and 2) to demonstrate the bispecific biologic displays superior efficacy compared to its single components in a mouse model of inflammatory arthritis. This project addresses a major unmet medical need in RA, the need for improved 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 bispecific biologic and characterize its preclinical efficacy and safety.