The objective of this project is to produce a genetically engineered monoclonal antibody appropriate for use as a therapeutic for diabetic nephropathy. Diabetes is the single largest cause of end-stage of renal disease in the U.S. and develops in 20-40% of patients. The dramatic results of the Diabetes Control and Complications Trial have established that hyperglycemia contributes to this problem. The direct relationships between hyperglycemia and non-enzymatic glycation of proteins has implicated excess protein glycation as a cause of diabetic complications. There is convincing experimental evidence that glycated as a cause of diabetic complications. There is convincing experimental evidence that glycated albumin adversely affects renal glomerular structure, function and metabolism, in ways that are analogous to diabetic nephropathy. Further, these effects are prevented by the A717 monoclonal antibody which is specific for glycated albumin. Pre-clinical studies have shown that murine A717 is therapeutically efficacious in preventing diabetic nephropathy. However, murine antibodies elicit a brisk human anti-murine antibody response in patients, severely limiting their therapeutic usefulness. An attractive and viable strategy to improve therapeutic effectiveness is to produce a totally "humanized" version of A717. The resulting antibody is essentially human with the affinity and specificity of the original A717 antibody. Given the magnitude of the problem and the fact that there is no treatment to prevent diabetic nephropathy, this project is eminently justified. PROPOSED COMMERCIAL APPLICATION: This research & development will lead to an immunocompatible (humanized) therapeutic monoclonal antibody for improved therapy of diabetic therapy of diabetic nephropathy. Use as a novel biological response modifier, it will also aid in preventing the occurrence of diabetic nephropathy.
NIH ExPorter
NIH ExPorter