Methods of treatment with angiopoietin-2 antibodies

Abstract

The disclosure is directed to methods and uses of antibodies or antigen-binding fragments thereof against Angiopoietin-2 (Ang-2). Specifically, the disclosure is direct to the use of anti-Ang2 antibodies or antigen-binding fragments thereof for treating ischemia. The methods disclosed are useful for reducing microvascular permeability, increasing microvascular perfusion, reducing inflammation in a tissue, and treating or ameliorating diseases associated with ischemia and/or reperfusion injury. The disclosed methods are also useful for protecting solid organ transplant tissue and treating or preventing chronic tissue transplant rejection.

What is claimed is: 
     
         1 . A method for reducing microvascular permeability in a tissue, comprising administering a therapeutically effective amount of an anti-Ang2 antibody or antigen-binding fragment thereof to a tissue in need thereof. 
     
     
         2 . A method for increasing microvascular perfusion in a tissue, comprising administering a therapeutically effective amount of an anti-Ang2 antibody or antigen-binding fragment thereof to a tissue in need thereof. 
     
     
         3 . A method for reducing inflammation in a tissue, comprising administering a therapeutically effective amount of an anti-Ang2 antibody or antigen-binding fragment thereof to a tissue in need thereof. 
     
     
         4 . The method of any one of  claims 1  to  3 , wherein the tissue is selected from the group consisting of heart, kidney, brain, smooth muscle, and intestine tissue. 
     
     
         5 . The method of any one of  claims 1  to  4 , wherein the tissue is an allograft. 
     
     
         6 . A method for protecting a solid organ transplant tissue, comprising administering an effective amount of an anti-Ang2 antibody or antigen-binding fragment thereof to an allograft. 
     
     
         7 . A method for preventing chronic rejection, comprising administering a therapeutically effective amount of an anti-Ang2 antibody or antigen-binding fragment thereof to an allograft. 
     
     
         8 . A method for treating chronic allograft vasculopathy (CAV) in a subject comprising administering a therapeutically effective amount of an anti-Ang2 antibody or antigen-binding fragment thereof to an allograft. 
     
     
         9 . The method of any one of  claims 5  to  8 , wherein the allograft is a cardiac allograft. 
     
     
         10 . The method of any one of  claims 1  to  9 , wherein the tissue or allograft is at risk for or has suffered from ischemic reperfusion injury. 
     
     
         11 . The method of any one of  claims 5  to  10 , wherein the allograft is perfused with the anti-Ang2 antibody or antigen-binding fragment thereof. 
     
     
         12 . A method for treating or ameliorating myocardial ischemia, comprising administering a therapeutically effective amount of an anti-Ang2 antibody or antigen-binding fragment thereof to a subject in need thereof. 
     
     
         13 . A method for treating an IRI-induced inflammatory response in a subject comprising administering a therapeutically effective amount of an anti-Ang2 antibody or antigen-binding fragment thereof to the subject in need thereof. 
     
     
         14 . The method of  claim 13 , wherein administration of the anti-Ang2 antibody or antigen-binding fragment thereof reduces the immunoreactivity of VCAM-1. 
     
     
         15 . The method of any one of  claims 1  to  13 , wherein the anti-Ang2 antibody or antigen-binding fragment thereof neutralizes Ang-2. 
     
     
         16 . The method of any one of  claims 1  to  14 , wherein the anti-Ang2 antibody or antigen-binding fragment thereof preferentially bind Ang-2 over Ang-1. 
     
     
         17 . The method of any one of  claims 1  to  15 , wherein the anti-Ang2 antibody or antigen-binding fragment thereof is an antibody that binds to and neutralizes Ang-2, but does not bind to Ang-1. 
     
     
         18 . The method of any one of  claims 1  to  13 , wherein the anti-Ang2 antibody or antigen-binding fragment thereof comprises a variable light chain (VL) comprising CDRs 1-3 of SEQ ID NO: 3, 4, 5, 6, or 8 and a variable heavy chain (VH) comprising CDRs 1-3 of SEQ ID NO: 7. 
     
     
         19 . The method of  claim 18 , wherein the VL comprises the amino acid sequence of SEQ ID NO: 3, 4, 5, 6, or 8 and the VH comprises the amino acid sequence of SEQ ID NO: 7. 
     
     
         20 . The method of any one of  claims 1  to  19 , wherein the anti-Ang2 antibody or antigen-binding fragment thereof is Ang-2 antibody binds to the same epitope as MEDI1/5, MEDI2/5, MEDI3/5, MEDI4/5, or MEDI6/5. 
     
     
         21 . The method of any one of  claims 1  to  20 , wherein the anti-Ang2 antibody or antigen-binding fragment thereof is Ang-2 antibody competitively inhibits binding of MEDI1/5, MEDI2/5, MEDI3/5, MEDI4/5, or MEDI6/5 to Ang-2. 
     
     
         22 . The method of any one of  claims 1 - 21 , wherein the anti-Ang2 antibody or antigen-binding fragment thereof is Ang-2 antibody MEDI1/5, MEDI2/5, MEDI3/5, MEDI4/5, or MEDI6/5 or a derivative thereof. 
     
     
         23 . The method of any one of  claims 1  to  22 , wherein the anti-Ang2 antibody or antigen-binding fragment thereof is administered in a single dose. 
     
     
         24 . The method of any one of  claims 1  to  23 , wherein the anti-Ang2 antibody or antigen-binding fragment thereof is administered preoperatively. 
     
     
         25 . The method of  claim 23  or  24 , wherein the anti-Ang2 antibody or antigen-binding fragment thereof is administered to the allograft donor, to the allograft or to the allograft recipient. 
     
     
         26 . The method of any one of  claims 1 - 25 , wherein the anti-Ang2 antibody or antigen-binding fragment thereof reduces expression of VEGF, TGFβ, or both. 
     
     
         27 . The method of  claim 25 , wherein the anti-Ang2 antibody or antigen-binding fragment thereof is administered to allograft recipient. 
     
     
         28 . The method of  claim 27 , wherein the administration is systemic. 
     
     
         29 . The method of  claim 28 , wherein the administration is a multiple dose regimen. 
     
     
         30 . The method of  claim 29 , wherein the multiple dose regimen includes at least one dose to the recipient prior to transplant of the allograft. 
     
     
         31 . The method of  claim 29  or  31 , wherein the multiple dose regimen includes at least one dose to the recipient after transplant of the allograft. 
     
     
         32 . The method of  claim 31 , wherein at least 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 doses are given during the five days after transplant of the allograft to the recipient. 
     
     
         33 . The method of any one of  claims 27 - 32 , wherein the risk of allograft myocardial injury is reduced. 
     
     
         34 . The method of any one of  claims 27 - 33 , wherein the risk of microvascular endothelial cell activation is reduced 
     
     
         35 . The method of any one of  claims 27 - 34 , wherein the risk of inflammatory cell influx is reduced. 
     
     
         36 . The method of any one of  claims 27 - 35 , wherein allograft survival is prolonged. 
     
     
         37 . The method of any one of  claims 27 - 36 , wherein the risk of developing cardiac fibrosis or allograft vasculopathy is reduced.