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.
Public Health Relevance Statement: 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.
Project Terms: 1D8 antigen; Acute; Adverse effects; Animals; Antibodies; Antigenic Determinants; Antigenic Surface Determinant Protein OA3; Antigenic Surface Determinant Protein OA3 Gene; Apoplexy; Area; Binding Determinants; Bioavailability; Biologic Availability; Biological Availability; Bizzozero's corpuscle/cell; Blood Platelets; Blood Pressure; Blood Vessels; Blood flow; Blood leukocyte; Body Tissues; CD47; CD47 Antigen; CD47 Antigen (Rh-Related Antigen, Integrin-Associated Signal Transducer); CD47 Antigen (Rh-Related Antigen, Integrin-Associated Signal Transducer) Gene; CD47 Glycoprotein; CD47 Glycoprotein Gene; CD47 gene; Cardiac infarction; Cardiovascular; Cardiovascular Body System; Cardiovascular Diseases; Cardiovascular Physiology; Cardiovascular system; Cardiovascular system (all sites); Cell Communication and Signaling; Cell Signaling; Cells; Cerebral Stroke; Cerebrovascular Apoplexy; Cerebrovascular Stroke; Cerebrovascular accident; Chimp; Chimpanzee; Clinical; Clinical Trials; Clinical Trials, Unspecified; Cyclic GMP; Deetjeen's body; Development; Diabetes Mellitus; Disease; Disorder; Dose; Drug Kinetics; EC 1.14.13.39; EDRF Synthase; Endogenous Nitrate Vasodilator; Endothelium; Endothelium-Derived Growth Factor Synthase; Endothelium-Derived Relaxing Factor; Epitopes; Erectile dysfunction; Family suidae; Flaps; Fruit; Future; Genetic; Guanosine Cyclic 3',5'-Monophosphate; Guanosine Cyclic Monophosphate; Guanosine, cyclic 3',5'-(hydrogen phosphate); Guanylyl Cyclase-Activating Factor Synthase; Hayem's elementary corpuscle; Hb SS disease; HbSS disease; Healthcare Market; Hemoglobin S Disease; Hemoglobin sickle cell disease; Hemoglobin sickle cell disorder; Human; Human, General; IAP Gene; IAP-50 antigen; INFLM; In Vitro; Inflammation; Integrin-Associated Protein; Integrin-Associated Protein Gene; Intracellular Communication and Signaling; Ischemia; Ischemia-Reperfusion Injury; Island Flaps; Knock-out; Knockout; Knockout Mice; L-Arginine,NADPH[{..}]oxygen oxidoreductase (nitric-oxide-forming); Laser-Doppler Flowmetry; Leiomyocyte; Leukocyte Surface Antigen CD47; Leukocyte Surface Antigen CD47 Gene; Leukocytes; Ligand Binding; Ligands; Literature; MER6; MER6 Gene; Mammals, Mice; Man (Taxonomy); Man, Modern; Markets, Health Care; Marrow leukocyte; Marrow platelet; Measurement; Mice; Mice, Knock-out; Mice, Knockout; Moab, Clinical Treatment; Modeling; Monoclonal Antibodies; Mononitrogen Monoxide; Murine; Mus; Myocardial Infarct; Myocardial Infarction; Myocytes, Smooth Muscle; NADPH-Diaphorase; NIH; NO Synthase; National Institutes of Health; National Institutes of Health (U.S.); Necrosis; Necrotic; Nitric Oxide; Nitric Oxide Signaling Pathway; Nitric Oxide Synthase; Nitric Oxide, Endothelium-Derived; Nitric-Oxide Synthetase; Nitrogen Monoxide; Nitrogen Protoxide; Nitrogen oxide; Null Mouse; O element; O2 element; OA3; OA3 Gene; OA3 antigen; OVTL3 protein, human; Organ System, Cardiovascular; Oxygen; Pan; Pan Genus; Pan Species; Patients; Peripheral Angiopathies; Peripheral Vascular Diseases; Peripheral Vascular Disorder; Peripheral arterial disease; Pharmacokinetics; Phase; Physiologic; Physiologic Availability; Physiological; Pigs; Platelets; Play; Pre-Clinical Model; Preclinical Models; Procedures; Process; Pulmonary Hypertension; Receptor Protein; Regulation; Reperfusion Damage; Reperfusion Injury; Reticuloendothelial System, Leukocytes; Reticuloendothelial System, Platelets; Role; STTR; Safety; Sickle Cell Anemia; Signal Transduction; Signal Transduction Systems; Signaling; Skin; Small Business Technology Transfer Research; Smooth Muscle Cells; Smooth Muscle Myocytes; Smooth Muscle Tissue Cell; Species Specificity; Stroke; Suidae; Surface Antigen Identified by Monoclonal Antibody 1D8; Surface Antigen Identified by Monoclonal Antibody 1D8 Gene; Surgical Flaps; Swine; System; System, LOINC Axis 4; THBS1; TSP; TSP-1; TSP1; Testing; Therapeutic; Thrombocytes; Thrombosis; Thrombospondin 1; Tissues; Treatment Side Effects; United States National Institutes of Health; Universities; Vascular Accident, Brain; Vascular, Heart; Vasodilatation; Vasodilation; Vasorelaxation; Washington; White Blood Cells; White Cell; Wound Healing; Wound Repair; age effect; aging effect; base; bioavailability of drug; biological signal transduction; brain attack; cGMP; cardiac infarct; cardiovascular disorder; cardiovascular function; cerebral vascular accident; circulatory system; clinical investigation; clinical practice; commercialization; coronary attack; coronary infarct; coronary infarction; diabetes; dietary fruit; disease/disorder; endothelial cell derived relaxing factor; experiment; experimental research; experimental study; guanosine 3'5' monophosphate; heart attack; heart infarct; heart infarction; improved; in vivo Model; integrin-associated protein IAP, human; integrin-associated protein p50; interest; intervention development; medical schools; mouse model; peripheral blood vessel disorder; porcine; preclinical study; prevent; preventing; public health relevance; receptor; research study; sickle cell disease; sickle disease; sicklemia; side effect; social role; stroke; suid; therapy adverse effect; therapy development; thrombocyte/platelet; thrombospondin-1 receptor CD47; tissue repair; treatment adverse effect; treatment development; vascular; white blood cell; white blood corpuscle
