Humanized antibodies against west nile virus and therapeutic and prophylactic uses thereof

Abstract

The present invention relates to compositions comprising humanized antibodies or fragments thereof that immunospecifically bind to one or more antigens of a flavivirus, particularly of West Nile Virus (WNV) and methods for preventing, treating or ameliorating symptoms associated with a flavivirus, particularly of West Nile Virus (WNV) infection utilizing said compositions. In particular, the present invention relates to methods for preventing, treating or ameliorating symptoms associated with WNV infection, said methods comprising administering to a human subject an effective amount of one or more humanized antibodies or fragments thereof that immunospecifically bind to a WNV antigen. The present invention also relates to detectable or diagnostic compositions comprising humanized antibodies or fragments thereof that immunospecifically bind to a WNV antigen and methods for detecting or diagnosing WNV infection utilizing said compositions.

1 .- 16 . (canceled) 
     
     
         17 . A method for prophylactic treatment of a West Nile Virus (WNV) infection in a patient, said method comprising administering to said patient a prophylactically effective amount of a humanized antibody or an epitope binding fragment thereof comprising three VH complementary determining regions (CDRs) and three VL CDRs,
 wherein the CDRs are from monoclonal antibody E16, E24, or E34,   wherein one or more of said CDRs optionally differs by one amino acid substitution from a CDR from monoclonal antibody E16, E24, or E34, and   wherein the antibody or epitope binding fragment thereof specifically binds a WNV epitope defined by monoclonal antibody E16, E24, or E34.   
     
     
         18 . The method of  claim 17  wherein said humanized antibody comprises a humanized variable region having a heavy chain and a light chain, said heavy chain comprising the amino acid sequence of SEQ ID NO: 21, SEQ ID NO: 22 or SEQ ID NO: 23 and said light chain region comprising the amino acid sequence of SEQ ID NO: 25 or SEQ ID NO: 26. 
     
     
         19 . The method of  claim 17  wherein the CDRs are from monoclonal antibody E16. 
     
     
         20 . The method of  claim 17  wherein said humanized antibody comprises a VH CDR1 comprising the amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 27, a VH CDR2 comprising the amino acid sequence of SEQ ID NO: 2, SEQ ID NO: 28, or SEQ ID NO: 39, and a VH CDR3 comprising the amino acid sequence of SEQ ID NO: 3, SEQ ID NO: 29, or SEQ ID NO: 40. 
     
     
         21 . The method of  claim 17  wherein said humanized antibody comprises a VL CDR1 having the amino acid sequence of SEQ ID NO: 11, a VL CDR2 comprising the amino acid sequence of SEQ ID NO: 12, and a VL CDR3 comprising the amino acid sequence of SEQ ID NO: 13 or SEQ ID NO: 34. 
     
     
         22 . The method of  claim 17  wherein said humanized antibody comprises a framework region comprising at least one amino acid modification in heavy chain FR3 or light chain FR2. 
     
     
         23 . The method of  claim 22  wherein the at least one amino acid modification in heavy chain FR3 comprises a substitution at position 66, 67, 69, 71, 75, 76, 79, 81, 82A, 83, 85 or 87. 
     
     
         24 . The method of  claim 22  wherein the at least one amino acid modification in light chain FR2 comprises a substitution at position 43 or 49. 
     
     
         25 . The humanized antibody of  claim 17 , wherein the humanized antibody is an epitope-binding antibody fragment. 
     
     
         26 . The humanized antibody of  claim 25 , wherein the epitope-binding fragment is a Fab, F(ab′) 2 , or scFv fragment. 
     
     
         27 . A pharmaceutical composition comprising (i) a prophylactically effective amount of the humanized antibody of  claim 17 ; and (ii) a pharmaceutically acceptable carrier. 
     
     
         28 . The method of  claim 17  further comprising administering an anti-viral agent. 
     
     
         29 . The method of  claim 28 , wherein the anti-viral agent is selected from the group consisting of protease inhibitors, nucleoside reverse transcriptase inhibitors, non-nucleoside reverse transcriptase inhibitors, nucleoside analogs, and alpha-interferons. 
     
     
         30 . The method of  claim 28 , wherein the anti-viral agent is selected from the group consisting of zidovudine, acyclovir, gancyclovir, vidarabine, idoxuridine, trifluridine and ribavirin, foscarnet, amantadine, rimantadine, saquinavir, indinavir, amprenavir, lopinavir, ritonavir, adefovir, clevadine, entecavir, and pleconaril. 
     
     
         31 . The method of  claim 17  wherein said patient is human.