Development of a humanized anti-CD47 antibody for treatment of tissue ischemia.

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DESCRIPTION (provided by applicant): Nitric oxide (NO) is a critical regulator of cardiovascular physiology, coordinating the activities of the endothelium, the vessel wall and circulating cells to optimize the flow of blood and oxygen to tissues. Increasing the bioavailability of NO should provide therapeutic benefit in the treatment of many diseases ascribed to insufficient NO bioavailability. All current approaches are limited by a heretofore unknown regulatory system, discovered by the founders of Vasculox, that limits the effects of NO signaling in all vascular cells. Thrombospondin-1 (TSP1) and its receptor, CD47, are present in all vascular tissues and limit NO signaling, thus worsening tissue ischemia, promoting thrombosis and inflammation and exacerbating the effects of aging on the cardiovascular system. Blocking the interaction of TSP-1 and CD47 with a monoclonal antibody (mAb) prevents these limiting effects on NO signaling in both mouse and porcine models of wound healing and tissue ischemia. Vasculox was founded to bring these discoveries to the healthcare market. Given the many roles of NO in cardiovascular regulation, we anticipate that a blocking anti-CD47 mAb will have therapeutic applications in many diseases such as peripheral artery disease (PAD), ischemia-reperfusion injury, sickle cell disease, myocardial infarction, stroke, thrombosis and others. Here we plan to develop for commercialization an anti-CD47 monoclonal antibody. This STTR proposal will provide a mechanism for Dr. Frazier's lab at Washington University School of Medicine to transfer to Vasculox, Inc. selected mAbs vs CD47 for subsequent testing and development as therapeutics. Most promising for future development is a panel of mAbs raised in the CD47-null mice to human CD47. These mAbs react with both human and mouse CD47 and will greatly facilitate development of a humanized anti-CD47 function-blocking mAb for use in clinical trials. In this phase I proposal, we plan to identify the most promising candidate mAbs for further development. In subsequent proposals, we will test these candidates in models of human cardiovascular diseases. The phase I specific aims are: 1. Determine the epitope specificity, species reactivity and effect on ligand binding of mAbs. 2. Identify those mAbs with efficacy in augmenting NO signaling in mouse and human smooth muscle cells in vitro. 3. Test active candidates in the MacFarlane skin flap mouse model of tissue ischemia, and determine effective dose, pharmacokinetic parameters and side effects of mAb administration. PUBLIC HEALTH RELEVANCE: The founder of Vasculox Inc, has discovered a regulatory receptor, CD47, that governs blood flow to all tissues of the body, blood pressure, thrombosis and other cardiovascular functions. Blocking this receptor improves wound healing, blood flow to dying tissues and other vascular parameters. Vasculox was founded to bring this new discovery to clinical practice by identifying antibodies vs CD47 to take forward into clinical development for treatment of peripheral vascular disease and other cardiovascular diseases in the future such as stroke and heart attack.