Evaluation and treatment of bradykinin-mediated disorders

Abstract

The present disclosure provides methods of evaluating a subject, e.g., a subject at risk for or suffering from a pKal-mediated or bradykinin-mediated disorder, based on values (e.g., percentages) of intact and/or cleaved kininogen in a sample of the subject. Provided methods permit analysis of patients with plasma kallikrein-mediated angioedema (KMA), or other diseases mediated by pKal useful in the evaluation and treatment. Such methods can involve the use of a detection agent that preferentially binds cleaved kininogen or intact kininogen.

1 - 50 . (canceled) 
     
     
         51 . A method for identifying a disorder as being associated with elevated contact system activation, the method comprising:
 measuring a level of a plasma kallikrein (pKal) marker in a sample from a subject having or suspected of having a disease associated with elevated contact system activation; and   identifying the disorder as being associated with elevated contact system activation if the value of the pKal marker is above a reference value.   
     
     
         52 . The method of  claim 51 , wherein the value of the pKal marker is the percentage of the pKal marker. 
     
     
         53 . The method of  claim 52 , wherein the percentage of the pKal marker is determined and the subject is identified as at risk for or having a disorder associated with elevated contact system activation if the percentage of the pKal marker is at or above a reference value. 
     
     
         54 . The method of  claim 51 , wherein the pKal marker is cleaved kininogen or cleaved kininogen and intact kininogen. 
     
     
         55 . The method of  claim 54 , wherein the levels of the cleaved kininogen and intact kininogen are measured by a detection agent, which specifically binds cleaved kininogen as compared to intact kininogen, or specifically binds intact kininogen as compared to cleaved kininogen. 
     
     
         56 . The method of  claim 55 , wherein the detection agent does not bind low molecular weight kininogen (LMWK). 
     
     
         57 . The method of  claim 51 , wherein the pKal marker is detected with an antibody. 
     
     
         58 . The method of  claim 57 , wherein the antibody specifically binds cleaved kininogen as compared to intact kininogen. 
     
     
         59 . The method of  claim 51 , wherein the levels of the pKal marker are measured by Western blot assay. 
     
     
         60 . The method of  claim 51 , wherein the sample is a blood sample or a plasma sample. 
     
     
         61 . The method of  claim 51 , wherein the disorder associated with elevated contact system activation is ulcerative colitis, rheumatoid arthritis, Crohn's disease, hereditary angioedema, cirrhosis, or sepsis. 
     
     
         62 . The method of  claim 51 , wherein the method further comprises administering an effective amount of a pKal inhibitor to the subject, if the subject is identified as having a disorder as being associated with elevated contact system activation. 
     
     
         63 . The method of  claim 62 , wherein the pKal inhibitor is DX-88, EPIKAL-2, or DX-2930.