US2013330352A1PendingUtilityA1

Treatment of myocardial infarction using tgf beta antagonists

37
Individually held — no corporate assignee on recordPriority: Sep 1, 2010Filed: Sep 1, 2011Published: Dec 12, 2013
Est. expirySep 1, 2030(~4.1 yrs left)· nominal 20-yr term from priority
Inventors:Geoffrey Y. AkitaRichard C. GregoryScott Michael LonningAmelia Kudel
A61P 43/00A61P 5/00A61P 9/10A61P 29/00C07K 14/495G01N 33/50C07K 2317/21A61K 39/3955A61K 45/06C07K 2317/56C07K 16/22A61K 2039/505A61K 2121/00A61K 39/395A61K 2039/545C07K 2317/76A61K 48/00
37
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Claims

Abstract

Disclosed herein is a method of treating a patient suffering a myocardial infarction, particularly an acute myocardial infarction, or of reducing an adverse consequence of a myocardial infarction in a patient comprising administering an antagonist of TGF-β to the patient during the acute stage of the myocardial infarction.

Claims

exact text as granted — not AI-modified
What is claimed is: 
     
         1 . A method of reducing an adverse consequence of a myocardial infarction in a patient comprising administering an antagonist of TGF-β to the patient during an acute stage of the myocardial infarction. 
     
     
         2 . The method of  claim 1 , wherein the myocardial infarction is an acute myocardial infarction. 
     
     
         3 . The method of  claim 1 , wherein administration of the antagonist of TGF-β is commenced within 120 hours of onset of myocardial ischemia. 
     
     
         4 . The method of  claim 1 , wherein administration of the antagonist of TGF-β is commenced within about 72 hours of onset of myocardial ischemia. 
     
     
         5 . The method of  claim 1 , wherein administration of the antagonist of TGF-β is commenced within about 48 hours of onset of myocardial ischemia. 
     
     
         6 . The method of  claim 1 , wherein administration of the antagonist of TGF-β is commenced within about 24 hours of onset of myocardial ischemia. 
     
     
         7 . The method of  claim 1 , wherein administration of the antagonist of TGF-β is commenced within about 12 hours of onset of myocardial ischemia. 
     
     
         8 . The method of  claim 1 , wherein administration of the antagonist of TGF-β is commenced prior to substantial macrophage and mononuclear infiltration of tissue affected by the myocardial infarction. 
     
     
         9 . The method of  claim 1 , wherein administration of the antagonist of TGF-β is commenced during a period characterized by neutrophilic infiltration of tissue affected by the myocardial infarction. 
     
     
         10 . The method of  claim 1 , wherein administration of the antagonist of TGF-β is commenced during a period characterized by necrosis of tissue affected by the myocardial infarction. 
     
     
         11 . The method of  claim 1 , wherein the patient is a human or a non-human mammal. 
     
     
         12 . The method of  claim 1 , wherein the method of reducing an adverse consequence of a myocardial infarction in a patient is a method of preserving myocardium. 
     
     
         13 . The method of  claim 1 , wherein the TGF-β antagonist is selected from the group consisting of:
 i) an antibody or antibody fragment that specifically binds to one or more isoforms of TGF-β; 
 ii) a TGF-β receptor or soluble fragment thereof; 
 iii) an antibody or antibody fragment that specifically binds to one or more TGF-β receptors; and 
 iv) an antisense or interfering RNA oligonucleotide. 
 
     
     
         14 . The method of  claim 1 , wherein the method further comprises administering a compound that is capable of selectively restoring a desirable function of TGF-β to the patient. 
     
     
         15 . The method of  claim 14 , wherein the compound capable of selectively restoring a desirable function of TGF-β is an anti-inflammatory drug. 
     
     
         16 . The method of  claim 14 , wherein the compound capable of selectively restoring a desirable function of TGF-β is an antagonist of TNF-α. 
     
     
         17 . The method of  claim 1 , wherein the method further comprises administering an ACE inhibitor to the patient. 
     
     
         18 . The method of  claim 17 , wherein the ACE inhibitor is selected from the group consisting of benazepril, captopril, fosinopril, moexipril, perindopril, quinapril, transdolapril, lisinopril, enalapril and ramparil. 
     
     
         19 . The method of  claim 1 , wherein the method further comprises administering an angiotensin II receptor antagonist to the patient. 
     
     
         20 . The method of  claim 19 , wherein the angiotensin II receptor antagonist is selected from the group consisting of eprosartan, telmisartan, losartan, irbesartan, olmesartan, candesartan, and valsartan. 
     
     
         21 . The method of  claim 1 , wherein the method further comprises administering a beta-adrenergic antagonist to the patient. 
     
     
         22 . The method of  claim 1 , wherein the beta-aderergic antagonist is selected from the group consisting of alprenolol, bucindolol, carteolol, carvedilol, labetalol, nadolol, oxprenolol, penbutolol, pindolol, propranolol, sotalol, timolol, atenolol, betaxolol, bisoprolol, celiprolol, esmolol, metoprolol, and nebivolol. 
     
     
         23 . The method of  claim 13 , wherein said TGF-β antagonist is an antibody or antibody fragment that specifically binds to one or more isoforms of TGF-β. 
     
     
         24 . The method of  claim 23 , wherein the antibody or antibody fragment neutralizes human TGF-β1, TGF-β2 and TGF-β3. 
     
     
         25 . The method of  claim 24 , wherein the antibody or antibody fragment comprises the PET1073G12 VH domain (SEQ ID NO: 2) with up to 5 mutations, or an antigen-binding portion thereof. 
     
     
         26 . The method of  claim 24 , wherein the antibody or antibody fragment comprises the PET1074B9 VH domain (SEQ ID NO: 12) with up to 5 mutations, or an antigen-binding portion thereof. 
     
     
         27 . The method of  claim 24 , wherein the antibody or antibody fragment comprises the PET1287A10 VH domain (SEQ ID NO: 22) with up to 5 mutations, or an antigen-binding portion thereof. 
     
     
         28 . The method of  claim 24 , wherein the antibody or antibody fragment comprises the PET1073G12 VL domain (SEQ ID NO: 7) with up to 5 mutations, or an antigen-binding portion thereof. 
     
     
         29 . The method of  claim 24 , wherein the antibody or antibody fragment comprises the PET1074B9 VL domain (SEQ ID NO: 17) with up to 5 mutations, or an antigen-binding portion thereof. 
     
     
         30 . The method of  claim 24 , wherein the antibody or antibody fragment comprises the PET1287A10 VL domain (SEQ ID NO: 27) with up to 5 mutations, or an antigen-binding portion thereof. 
     
     
         31 . The method of  claim 24 , wherein the antibody or antibody fragment comprises the PET 1073G12 VH domain (SEQ ID NO: 2) and the PET 1073G12 VL domain (SEQ ID NO: 7). 
     
     
         32 . The method of  claim 24 , wherein the antibody or antibody fragment comprises the PET 1074B9 VH domain (SEQ ID NO: 12) and the PET 1074B9 VL domain (SEQ ID NO: 17). 
     
     
         33 . The method of  claim 24 , wherein the antibody or antibody fragment comprises the PET 1287A10 VH domain (SEQ ID NO: 22) and the PET 1287A10 VL domain (SEQ ID NO: 27). 
     
     
         34 . The method of  claim 24 , wherein the antibody or antibody fragment comprises a set of CDRs HCDR1, HCDR2 and HCDR3, wherein said HCDR3 has an amino acid sequence selected from the group consisting of SEQ ID NO: 5, SEQ ID NO: 15 and SEQ ID NO: 25. 
     
     
         35 . The method of  claim 34 , wherein the HCDR1, HCDR2 and HCDR3 of the VH domain are within a germline heavy chain framework. 
     
     
         36 . The method of  claim 35 , wherein the HCDR1, HCDR2 and HCDR3 of the VH domain are within a framework that comprises up to 12 mutations from the germline amino acid sequence. 
     
     
         37 . The method of  claim 24 , wherein the antibody or antibody fragment comprises a set of CDRs LCDR1, LCDR2 and LCDR3, wherein said LCDR3 has an amino acid sequence selected from the group consisting of SEQ ID NO: 10, SEQ ID NO: 20 and SEQ ID NO: 30. 
     
     
         38 . The method of  claim 37 , wherein the LCDR1, LCDR2 and LCDR3 are within a germline heavy chain framework. 
     
     
         39 . The method of  claim 38 , wherein the LCDR1, LCDR2 and LCDR3 are within a framework that comprises up to 5 mutations from the germline amino acid sequence. 
     
     
         40 . The method of  claim 24 , wherein administering an antagonist of TGF-β to the patient during an acute stage of the myocardial infarction comprises administering a dose of about 1 mg per kilogram of patient body mass. 
     
     
         41 . The method of  claim 24 , wherein administering an antagonist of TGF-β to the patient during an acute stage of the myocardial infarction comprises administering a dose of about 5 mg per kilogram of patient body mass.

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