Funded Projects

The Receptor for Advanced Glycation Endproducts (RAGE) is a single-transmembrane receptor with a large spectrum of ligands. Hyperactivation of RAGE leads to a wide range of diseases including cancer, atherosclerosis, Alzheimer disease, diabetes, sepsis, drug-induced liver injury and periodontitis. Ablating RAGE signaling in these conditions has resulted in greatly improved outcomes in murine models. Together, these studies establish RAGE as a highly attractive drug target. Due to the fact that under normal healthy condition the expression level of RAGE is extremely low in most cell types, the side effect of anti-RAGE therapy is expected to be very low. Dr. Ding Xu’s lab has shown that blocking heparan sulfate (HS)-RAGE interaction is a viable therapeutic approach. He has developed a novel monoclonal antibody that specifically targets part of the HS-binding site of RAGE. This mAb, name B2, was originally made in rabbit and reacts with both human and murine RAGE with low nanomolar affinity. We have cloned the variable region of B2 and have already generated chimeric rabbit-murine antibody and rabbit-human antibody to facilitate preclinical studies. Our studies have shown that B2 is highly effective in blocking RAGE signaling in endothelial cells, neutrophils and osteoclasts. To evaluate the therapeutic potential of anti-RAGE therapy in multiple human diseases, and to accelerate the development of our anti-RAGE technology, we request the Blue Sky funding to help us humanize the B2 antibody and discover novel anti-RAGE antibodies using yeast-display method. The 3 PIs involved in this project have never collaborated on this research before, and holds expertise in the field of RAGE, yeast-display, and antibody drug development. This unique team has combined expertise to discover and develop novel/better anti-RAGE antibodies that can help their labs with novel grants and patents.