Humanized anti-claudin-1 antibodies and uses thereof

Abstract

The present invention relates to humanized anti-claudin-1 antibodies and uses thereof. Hepatitis C virus infection is a leading cause of chronic liver disease and a major indication for liver transplantation. The tight junction protein claudin-1 (CLDN1) is an essential entry factor for HCV and a promising target for therapy. For clinical development, the inventors have humanized a rat anti-CLDN1 antibody produced by genetic immunization that prevent HCV infection and also cure chronically infected human liver chimeric mice. The lead humanized anti-CLDN1 antibody (H3L3) pan-genotypically inhibited HCV pseudoparticle infection of primary human hepatocytes (PHH) without detectable escape. H3L3 efficiently inhibited infection by diverse HCV genotype 3 strains and exhibited marked synergy with direct-acting antivirals (DAAs). The inventors also demonstrate that anti-CLDN1 H3L3 cures persistent HCV infection in human-liver chimeric uPA-SCID mice in monotherapy. Thus, the present invention relates to humanized anti-claudin-1 antibodies and uses thereof, in particular for the prevention and treatment of hepatitis C virus infection, virus-induced liver diseases, hepatocellular carcinoma (HCC), nonalcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH).

1 - 15 . (canceled) 
     
     
         16 . An anti-Claudin-1 humanized antibody comprising all the Complementary Determining Regions (CDRs) of rat monoclonal antibody OM-7D3-B3, wherein the variable heavy chain of OM-7D3-B3 consists of amino acid sequence SEQ ID NO: 3 and the variable light chain of OM-7D3-B3 consists of amino acid sequence SEQ ID NO: 4, said anti-Claudin-1 humanized antibody further comprising an antibody variable heavy chain (VH) consisting of the amino acid sequence of SEQ ID NO: 9, and an antibody variable light chain (VL) consisting of the amino acid sequence of SEQ ID NO: 10. 
     
     
         17 . The anti-Claudin-1 humanized antibody according to  claim 16 , wherein said humanized antibody is a full antibody having an isotype selected from the group consisting of IgG1, IgG2, IgG3, and IgG4. 
     
     
         18 . The anti-Claudin-1 humanized antibody of  claim 16 , wherein said humanized antibody comprises an Fc region, wherein the Fc region contains a modification. 
     
     
         19 . The anti-Claudin-1 humanized antibody of  claim 18 , wherein the modification alters Fc receptor binding. 
     
     
         20 . The anti-Claudin-1 humanized antibody of  claim 18 , wherein the modification alters glycosylation of the Fc region. 
     
     
         21 . The anti-Claudin-1 humanized antibody of  claim 18 , wherein the modification alters C1q binding and/or reduced complement dependent cytotoxicity (CDC). 
     
     
         22 . A fragment of the anti-Claudin-1 humanized antibody according to  claim 16 , wherein said fragment is selected from the group consisting of Fv, Fab, F(ab′)2, Fab′, dsFv, scFv, sc(Fv)2 and diabodies. 
     
     
         23 . The anti-Claudin-1 humanized antibody according to  claim 16 , wherein said anti-Claudin-1 humanized antibody is conjugated to a cytotoxic moiety. 
     
     
         24 . A pharmaceutical composition comprising the humanized antibody according to  claim 16 , and a pharmaceutically acceptable carrier. 
     
     
         25 . A method of treating a viral infection in a patient in need thereof comprising a step of: administering to the patient a therapeutically effective amount of the humanized antibody according to  claim 16 . 
     
     
         26 . A method of treating a cancer in a patient in need thereof comprising a step of: administering to the patient a therapeutically effective amount of the humanized antibody according to  claim 16 . 
     
     
         27 . The method of  claim 26 , wherein the cancer is a colorectal cancer or a hepatocellular carcinoma. 
     
     
         28 . A method of treating a fatty liver disease (FLD) in a patient in need thereof comprising a step of: administering to the patient a therapeutically effective amount of the humanized antibody according to  claim 16 . 
     
     
         29 . The method of  claim 28 , wherein the fatty liver disease (FLD) is a nonalcoholic fatty liver disease (NAFLD) or a non-alcoholic steatohepatitis (NASH). 
     
     
         30 . An anti-Claudin-1 humanized antibody comprising all the Complementary Determining Regions (CDRs) of rat monoclonal antibody OM-7D3-B3, wherein the variable heavy chain of OM-7D3-B3 consists of amino acid sequence SEQ ID NO: 3 and the variable light chain of OM-7D3-B3 consists of amino acid sequence SEQ ID NO: 4, said anti-Claudin-1 humanized antibody further comprising an antibody variable heavy chain (VH) consisting of the amino acid sequence of SEQ ID NO: 1, and an antibody variable light chain (VL) consisting of the amino acid sequence of SEQ ID NO: 2. 
     
     
         31 . The anti-Claudin-1 humanized antibody according to  claim 30 , wherein said humanized antibody is a full antibody having an isotype selected from the group consisting of IgG1, IgG2, IgG3, and IgG4. 
     
     
         32 . The anti-Claudin-1 humanized antibody of  claim 30 , wherein said humanized antibody comprises an Fc region, wherein the Fc region contains a modification. 
     
     
         33 . The anti-Claudin-1 humanized antibody of  claim 32 , wherein the modification alters Fc receptor binding. 
     
     
         34 . The anti-Claudin-1 humanized antibody of  claim 32 , wherein the modification alters glycosylation of the Fc region. 
     
     
         35 . The anti-Claudin-1 humanized antibody of  claim 32 , wherein the modification alters C1q binding and/or reduced complement dependent cytotoxicity (CDC).