# US 10,370,439 B2 · Prevention of tissue ischemia and related methods > Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt - Number: US 10,370,439 B2 - Document ID: US10370439B2 - Status: Granted - Kind: B2 - Application number: 14/500,861 - Filed: 2014-09-29 - Published: 2016-08-04 - Granted: 2019-08-06 - Earliest claimed: 2006-10-06 - Assignees: The United States of America, as represented by the Secretary, Department of Health and Human Services - Applicants: The United States of America, as represented by the Secretary, Department of Health and Human Services - Inventors: Jeffrey S. Isenberg; David D. Roberts - Web page: https://patentgrep.com/patent/US10370439B2 ## CPC - C07K 16/18: against material from animals or humans - A61K 39/3955: {against proteinaceous materials, e.g. enzymes, hormones, lymphokines} - A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca - A61K 48/00: Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy - A61P 7/06: Antianaemics - A61P 9/00: Drugs for disorders of the cardiovascular system - A61P 9/08: Vasodilators for multiple indications - A61P 9/10: for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis - A61P 9/12: Antihypertensives - A61P 17/00: Drugs for dermatological disorders - A61P 17/02: for treating wounds, ulcers, burns, scars, keloids, or the like - A61P 19/02: for joint disorders, e.g. arthritis, arthrosis - A61P 19/08: for bone diseases, e.g. rachitism, Paget's disease - A61P 37/06: Immunosuppressants, e.g. drugs for graft rejection - A61P 41/00: Drugs used in surgical methods, e.g. surgery adjuvants for preventing adhesion or for vitreum substitution - B01J 21/063: {Titanium; Oxides or hydroxides thereof} - B01J 21/12: Silica and alumina - B01J 23/002: {Mixed oxides other than spinels, e.g. perovskite} - B01J 23/30: Tungsten - B01J 27/188: with chromium, molybdenum, tungsten or polonium - B01J 37/0205: {in several steps} - C07C 45/002: {by dehydrogenation} - C07C 45/52: by dehydration and rearrangement involving two hydroxy groups in the same molecule - C07C 51/235: of —CHO groups or primary alcohol groups - C07C 51/252: {of propene, butenes, acrolein or methacrolein} - C07C 253/26: containing carbon-to-carbon multiple bonds, e.g. unsaturated aldehydes - C07K 7/06: having 5 to 11 amino acids - C07K 9/001: {the peptide sequence having less than 12 amino acids and not being part of a ring structure} - C07K 14/475: Growth factors; Growth regulators - C07K 14/78: Connective tissue peptides, e.g. collagen, elastin, laminin, fibronectin, vitronectin or cold insoluble globulin [CIG] - G01N 33/6887: {from muscle, cartilage or connective tissue} - G01N 33/6893: {related to diseases not provided for elsewhere} - A61K 2039/505: {comprising antibodies} - A61P 7/04: Antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic agents - B01J 2523/00: Constitutive chemical elements of heterogeneous catalysts - C07K 2317/76: Antagonist effect on antigen, e.g. neutralization or inhibition of binding - G01N 2333/705: Assays involving receptors, cell surface antigens or cell surface determinants - C07K: PEPTIDES (peptides in foodstuffs A23; obtaining protein compositions for foodstuffs, working-up proteins for foodstuffs A23J; preparations for medicinal purposes A61K; peptides containing beta-lactam rings C07D; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, C07D; ergot alkaloids of the cyclic peptide type C07D519/02; macromolecular compounds having statistically distributed amino acid units in their molecules, i.e. when the preparation does not provide for a specific; but for a random sequence of the amino acid units, homopolyamides and block copolyamides derived from amino acids C08G69/00; macromolecular products derived from proteins C08H1/00; preparation of glue or gelatine C09H; single cell proteins, enzymes C12N; genetic engineering processes for obtaining peptides C12N15/00; compositions for measuring or testing processes involving enzymes C12Q; investigation or analysis of biological material G01N33/00) - A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D) - A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS - B01J: CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS - C07C: ACYCLIC OR CARBOCYCLIC COMPOUNDS - G01N: INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES (measuring or testing apparatus or processes other than immunoassay, involving enzymes or microorganisms C12M, C12Q) ## Abstract Provided herein are compositions for preventing, ameliorating, and/or reducing tissue ischemia and/or tissue damage due to ischemia, increasing blood vessel diameter, blood flow and tissue perfusion in the presence of vascular disease including peripheral vascular disease, atherosclerotic vascular disease, coronary artery disease, stroke and influencing other conditions, by suppressing CD47 and/or blocking TSP1 and/or CD47 activity or interaction. Influencing the interaction of CD47-TSP1 in blood vessels allows for control of blood vessel diameter and blood flow, and permits modification of blood pressure and cardiac function. Under conditions of decreased blood flow, for instance through injury or atherosclerosis, blocking TSP1-CD47 interaction allows blood vessels to dilate and increases blood flow, tissue perfusion and tissue survival. ## Claims ### Claim 1 A method of increasing tissue perfusion in a subject, comprising: selecting a subject in need of increased tissue perfusion; and administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising a humanized antibody to thrombospondin-1 (TSP1), wherein the humanized antibody is a humanized version of antibody A6.1 or a humanized version of antibody C6.7, thereby increasing tissue perfusion in the subject. ### Claim 2 (depends on 1) The method of claim 1, wherein the subject has or is at risk of developing at least one disease or condition selected from the group consisting of: ischemia/reperfusion injury, myocardial infarction, myocardial ischemia, stroke, cerebral ischemia, sickle cell anemia, and pulmonary hypertension. ### Claim 3 (depends on 1) The method of claim 1, wherein the subject is a human of about 65 or more years of age. ### Claim 4 (depends on 1) The method of claim 1, further comprising administering a therapeutically effective amount of a nitric oxide donor or precursor, nitrovasodilator, activator of soluble guanylyl cyclase, or cGMP phosphodiesterase inhibitor to the subject. ### Claim 5 (depends on 1) The method of claim 1, wherein the subject has or is at risk of developing at least one disease or condition selected from the group consisting of: hypertension, atherosclerosis, vasculopathy, ischemia secondary to diabetes, and peripheral vascular disease. ### Claim 6 (depends on 1) The method of claim 1, wherein the need for increased tissue perfusion arises because the subject has had, is having, or will have a surgery selected from the group consisting of: integument surgery, soft tissue surgery, composite tissue surgery, skin graft surgery, and surgery for reattachment of severed body parts. ### Claim 7 (depends on 1) The method of claim 1, wherein the need for increased tissue perfusion arises because the subject has had, is having, or will have organ transplant surgery. ### Claim 8 A method comprising: selecting a subject to be subjected to ischemia; and administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising a humanized antibody to thrombospondin-1 (TSP1), wherein the humanized antibody is a humanized version of antibody A6.1 or a humanized version of antibody C6.7, thereby reducing direct ischemic injury and/or ischemia/reperfusion injury in the subject when the subject is subjected to ischemia. ### Claim 9 (depends on 8) The method of claim 8, wherein the ischemia arises because the subject will have or is having a surgery selected from the group consisting of: integument surgery, soft tissue surgery, composite tissue surgery, skin graft surgery, and surgery for reattachment of severed body parts. ### Claim 10 (depends on 9) The method of claim 9, wherein the skin graft is an autograft. ### Claim 11 (depends on 8) The method of claim 8, wherein the ischemia arises because the subject will have or is having organ transplant surgery. ### Claim 12 (depends on 8) The method of claim 8, wherein the subject is a human of about 65 or more years of age. ### Claim 13 (depends on 8) The method of claim 8, further comprising administering a therapeutically effective amount of a nitric oxide donor or precursor, nitrovasodilator, activator of soluble guanylyl cyclase, or cGMP phosphodiesterase inhibitor to the subject. ### Claim 14 A method of treating a subject, comprising: selecting a subject that has or is at risk of direct ischemic injury or ischemia/reperfusion injury; and administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising a humanized antibody to thrombospondin-1 (TSP1), wherein the humanized antibody is a humanized version of antibody A6.1 or a humanized version of antibody C6.7, thereby treating the direct ischemic injury and/or ischemia/reperfusion injury in the subject. ### Claim 15 (depends on 14) The method of claim 14, wherein the subject has or is at risk of a disease or condition selected from the group consisting of: myocardial infarction, myocardial ischemia, stroke, cerebral ischemia, sickle cell anemia, and pulmonary hypertension. ### Claim 16 (depends on 14) The method of claim 14, wherein the subject has or is at risk of a disease or condition selected from the group consisting of: hypertension, atherosclerosis, vasculopathy, ischemia secondary to diabetes, and peripheral vascular disease. ### Claim 17 (depends on 14) The method of claim 14, wherein the pharmaceutical composition is administered before, during, or after the subject undergoes surgery. ### Claim 18 (depends on 17) The method of claim 17, wherein the surgery is selected from the group consisting of: integument surgery, soft tissue surgery, composite tissue surgery, skin graft surgery and surgery for reattachment of severed body parts. ### Claim 19 (depends on 17) The method of claim 17, wherein the surgery is organ transplant surgery. ### Claim 20 (depends on 14) The method of claim 14, wherein the subject is a human of about 65 or more years of age. ### Claim 21 (depends on 14) The method of claim 14, further comprising administering a therapeutically effective amount of a nitric oxide donor or precursor, nitrovasodilator, activator of soluble guanylyl cyclase, or cGMP phosphodiesterase inhibitor to the subject. ### Claim 22 A method, comprising: selecting a donor organ; and administering to the donor organ, prior to its transplantation into the recipient, a therapeutically effective amount of a pharmaceutical composition comprising a humanized antibody to thrombospondin-1 (TSP1), wherein the humanized antibody is a humanized version of antibody A6.1 or a humanized version of antibody C6.7, thereby reducing direct ischemic injury and/or ischemia/reperfusion injury in the donor organ. ### Claim 23 (depends on 22) The method of claim 22, further comprising administering a therapeutically effective amount of a nitric oxide donor or precursor, nitrovasodilator, activator of soluble guanylyl cyclase, or cGMP phosphodiesterase inhibitor to the subject. ### Claim 24 (depends on 1) The method of claim 1, wherein the increased tissue perfusion occurs within 24 hours of administration of the composition. ### Claim 25 (depends on 14) The method of claim 14, wherein treating the direct ischemic injury and/or ischemia reperfusion injury occurs within 24 hours of administration of the composition.