Targeted Molecular Radiotherapy for Rheumatoid Arthritis

The progression of rheumatoid arthritis (RA), specifically, the growth of the bone-destroying pannus in RA joints, depends on the formation of new blood vessels, whose growth is mediated primarily by vascular endothelial growth factor (VEGF) and its cognate receptors. VEGF and its receptors are highly expressed at the RA joints and therapeutic strategies that target RA-associated VEGF signaling are under intense pre-clinical and clinical testing. However, the fundamental shortcoming of these strategies is that they target only endothelial cells and thereby provide, at best, only cytostatic effects that would require continuous therapy. Thus, there is an unmet need for more effective targeted therapies. This project will develop a radiopharmaceutical that will destroy endothelial and other pannus cells involved in pathology of RA joints. The approach is based on the hypothesis that therapeutically significant doses of Lu-177 radiopharmaceutic can be selectively delivered to RA joints by targeting overexpressed VEGF receptors in RA angiogenic vasculature. This approach is designed to destroy both angiogenic vasculature and destructive inflammatory cells within the pannus of a diseased joint. In Phase I, the hypothesis will be tested in a mouse model of collagen-induced immune mediated arthritis, with the goal of establishing a regimen for the delivery of a safe but therapeutically significant dose of Lu-177 to RA joints. Commercial Applications and other Benefits as described by the awardee: The targeted radiopharmaceutical should reduce the disease burden for the two percent of the population that already suffers from rheumatoid arthritis, and potentially for many more among rapidly aging baby boomers.