Antibodies to Plasminogen Activator Inhibitor-1 (PAI-1) and Uses Thereof

Abstract

The invention provides antibodies that specifically bind to Plasminogen Activator inhibitor type-1 (PAI-1). The invention also provides pharmaceutical compositions, as well as nucleic acids encoding anti-PAI-1 antibodies, recombinant expression vectors and host cells for making such antibodies, or fragments thereof. Methods of using antibodies to modulate PAT-1 activity or detect PAI-1, either in vitro or in vivo, are also provided. The disclosure further provides methods of making antibodies that specifically bind to PAT-1 in the active conformational state.

1 - 15 . (canceled) 
     
     
         16 : An isolated monoclonal antibody that binds specifically to PAI-1, comprising:
 a heavy chain variable region that is at least 90% identical to the amino acid sequence of SEQ ID NO: 88 or 89 and comprises a CDR1 region comprising the amino acid sequence of SEQ ID NO: 34, a CDR2 region comprising the amino acid sequence of SEQ ID NO: 33, and a CDR3 region comprising the amino acid sequence of SEQ ID NO: 32; and   a light chain variable region that is at least 90% identical to the amino acid sequence of SEQ ID NO: 91, 93, 94, 95, 96, or 97 and comprises a CDR1 region comprising the amino acid sequence of SEQ ID NO: 37, a CDR2 region comprising the amino acid sequence of SEQ ID NO: 36 or SEQ ID NO: 145, and a CDR3 region comprising the amino acid sequence of SEQ ID NO: 35.   
     
     
         17 : An isolated monoclonal antibody that binds specifically to PAI-1, comprising:
 a heavy chain variable region that is at least 95% identical to the amino acid sequence of SEQ ID NO: 88 or 89 and comprises a CDR1 region comprising the amino acid sequence of SEQ ID NO: 34, a CDR2 region comprising the amino acid sequence of SEQ ID NO: 33, and a CDR3 region comprising the amino acid sequence of SEQ ID NO: 32; and   
       a light chain variable region that is at least 95% identical to the amino acid sequence of SEQ ID NO: 91, 93, 94, 95, 96, or 97 and comprises a CDR1 region comprising the amino acid sequence of SEQ ID NO: 37, a CDR2 region comprising the amino acid sequence of SEQ ID NO: 36 or SEQ ID NO: 145, and a CDR3 region comprising the amino acid sequence of SEQ ID NO: 35. 
     
     
         18 : An isolated monoclonal antibody that binds specifically to PAI-1, comprising:
 a heavy chain variable region that is at least 96% identical to the amino acid sequence of SEQ ID NO: 88 or 89 and comprises a CDR1 region comprising the amino acid sequence of SEQ ID NO: 34, a CDR2 region comprising the amino acid sequence of SEQ ID NO: 33, and a CDR3 region comprising the amino acid sequence of SEQ ID NO: 32; and   a light chain variable region that is at least 96% identical to the amino acid sequence of SEQ ID NO: 96 or 97 and comprises a CDR1 region comprising the amino acid sequence of SEQ ID NO: 37, a CDR2 region comprising the amino acid sequence of SEQ ID NO: 36 or SEQ ID NO: 145, and a CDR3 region comprising the amino acid sequence of SEQ ID NO: 35.   
     
     
         19 : The isolated monoclonal antibody of  claim 18 , wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 89 and the light chain variable region is at least 96% identical to the amino acid sequence of SEQ ID NO: 97 and comprises a CDR1 region comprising the amino acid sequence of SEQ ID NO: 37, a CDR2 region comprising the amino acid sequence of SEQ ID NO: 36 or SEQ ID NO: 145, and a CDR3 region comprising the amino acid sequence of SEQ ID NO: 35. 
     
     
         20 : A method of restoring plasmin generation comprising administering to a subject in need thereof a pharmaceutically effective amount of the isolated monoclonal antibody of  claim 19 . 
     
     
         21 : The method of  claim 20 , wherein the pharmaceutically effective amount of the isolated monoclonal antibody is administered orally, parenterally by a solution for injection, by inhalation, or topically. 
     
     
         22 : The method of  claim 20 , wherein the method treats a condition comprising increased levels of fibrotic tissue. 
     
     
         23 : The method of  claim 22 , wherein the condition is fibrosis, systemic sclerosis, interstitial lung disease, chronic lung disease, chronic kidney disease, peripheral limb ischemia, acute ischemic stroke with and without thrombolysis, or stent restenosis. 
     
     
         24 : The method of  claim 23 , wherein the method treats a condition comprising skin fibrosis, lung fibrosis, idiopathic pulmonary fibrosis, liver fibrosis, or kidney fibrosis. 
     
     
         25 : The method of  claim 23 , wherein the method treats a condition comprising venous and arterial thrombosis, deep vein thrombosis, or disseminated intravascular coagulation thrombosis. 
     
     
         26 : A container comprising the isolated monoclonal antibody of  claim 16 . 
     
     
         27 : The container of  claim 26 , wherein the container is a prefilled syringe, a vial, or an autoinjector. 
     
     
         28 : A kit, comprising the container of  claim 26  and a label or instructions for administration and/or use of the isolated monoclonal antibody. 
     
     
         29 : A method for restoring plasmin generation, treating increased levels of fibrotic tissue, fibrosis, systemic sclerosis, interstitial lung disease, chronic lung disease, chronic kidney disease, peripheral limb ischemia, acute ischemic stroke with and without thrombolysis, or stent restenosis, skin fibrosis, lung fibrosis, idiopathic pulmonary fibrosis, liver fibrosis, kidney fibrosis, venous and arterial thrombosis, deep vein thrombosis, or disseminated intravascular coagulation thrombosis, comprising administering a pharmaceutically effective amount of the isolated monoclonal antibody of  claim 16 .