Method of treating primary sclerosing cholangitis

Abstract

Disclosed is a method for treating a subject having primary sclerosing cholangitis, comprising administering to said subject an effective amount of a humanized antibody or antigen-binding fragment thereof having binding specificity for alpha 4 beta 7 integrin.

1 . A method for treating a human subject suffering from primary sclerosing cholangitis (PSC), wherein the method comprises the step of:
 administering to a subject suffering from PSC, an effective amount of an anti-α4β7 antibody,   further wherein the anti-α4β7 antibody has binding specificity for the α4β7 complex, wherein the antigen-binding region comprises the CDRs:   Light chain: CDR1 SEQ ID NO:11,
 CDR2 SEQ ID NO:12, 
 CDR3 SEQ ID NO:13, 
   Heavy chain: CDR1 SEQ ID NO:8,
 CDR2 SEQ ID NO:9, and 
 CDR3 SEQ ID NO:10. 
   
     
     
         2 . The method of  claim 1 , wherein said effective amount is an amount sufficient to normalize serum alkaline phosphatase (ALP) of said subject. 
     
     
         3 . The method of  claim 1 , wherein said effective amount is an amount sufficient to reduce serum alkaline phosphatase (ALP) of said subject by at least 35%. 
     
     
         4 . The method of  claim 1 , wherein said effective amount is an amount sufficient to improve Ishak necroinflammatory grading score by at least one point. 
     
     
         5 . The method of  claim 1 , wherein the anti-α4β7 antibody is administered to the subject according to the following dosing regimen:
 a. an initial dose of 300 mg of the anti-α4β7antibody as an intravenous infusion; 
 b. followed by a second subsequent dose of 300 mg of the anti-α4β7 antibody as an intravenous infusion at about two weeks after the initial dose; 
 c. followed by a third subsequent dose of 300 mg of the anti-α4β7 antibody as an intravenous infusion at about six weeks after the initial dose; 
 d. followed by a fourth and subsequent doses of 300 mg of the anti-α4β7 antibody as an intravenous infusion every four weeks or every eight weeks after the third subsequent dose of the anti-α4β7 antibody as needed. 
 
     
     
         6 . The method of  claim 1 , wherein said subject has chronic cholestatic liver disease with a subsequent diagnosis of PSC. 
     
     
         7 . The method of  claim 6 , wherein the subsequent diagnosis of PSC is based on cholangiographic findings of intrahepatic and/or extrahepatic bile duct irregularities consistent with PSC. 
     
     
         8 . The method of  claim 1 , wherein said subject further has diagnosis of IBD. 
     
     
         9 . The method of  claim 8 , wherein the diagnosis of IBD is based on clinical and endoscopic evidence and corroborated by a histopathology report. 
     
     
         10 . The method of  claim 1 , wherein said subject does not have a diagnosis of IBD. 
     
     
         11 . The method of  claim 1 , wherein said subject has alkaline phosphatase (ALP) elevation to at least 1.6 times the upper limit of normal (ULN) at the time of initial treatment. 
     
     
         12 . The method of  claim 1 , wherein said subject's Ishak fibrosis staging score is improved, maintained or normalized. 
     
     
         13 . The method of  claim 1 , wherein said subject's Amsterdam Cholestatic Complaints (ACCS) has improved, maintained or normalized, 5-D itch scale has improved, maintained or normalized, or said subject has a liver stiffness TE score of less than or equal to 14.3 kPa, as assessed by Transient Elastrography. 
     
     
         14 . The method of  claim 1 , wherein said anti-α4β7 antibody is administered to said subject intravenously or subcutaneously. 
     
     
         15 . The method of  claim 1 , wherein a PSC-related outcome selected from the group consisting of progression to cirrhosis, liver failure, death and liver transplantation is delayed or prevented. 
     
     
         16 . The method of  claim 1 , wherein a PSC-related complication selected from the group consisting of ascites, hepatic encephalopathy, development of varices, jaundice, variceal bleeding, cholangiocarcinoma, hepatocellular carcinoma, evidence of cirrhosis, and colorectal cancer is delayed or prevented. 
     
     
         17 . The method of  claim 1 , wherein said treatment does not cause one or more than one adverse event, wherein an adverse event is selected from the group consisting of, hepatoxicity, PML, cholangiocarcinoma, one or more complications due to portal hypertension, leucopenia, lymphopenia, colorectal cancer, infusion-related reactions, infection, acute respiratory failure, acute respiratory distress syndrome, Torsade de pointer, ventricular fibrillation, ventricular tachycardia, malignant hypertension, convulsive seizure, agranulocytosis, aplastic anemia, toxic epidermal necrolysis, Stevens-Johnson syndrome, hepatic necrosis, acute liver failure, anaphylactic shock, acute renal failure, pulmonary hypertension, pulmonary fibrosis, confirmed or suspected endotoxin shock, confirmed or suspected transmission of infectious agent by a medicinal product, neuroleptic malignant syndrome, malignant hyperthermia, spontaneous abortion, stillbirth, and fetal death. 
     
     
         18 . The method of  claim 1 , wherein said anti-α4β7 antibody is humanized. 
     
     
         19 . The method of  claim 1 , wherein said anti-α4β7 antibody is vedolizumab. 
     
     
         20 - 31 . (canceled)