Anti-dengue virus antibodies and uses thereof

Abstract

The present invention provides, among other things, antibody agents (e.g., antibodies, and/or antigen-binding fragments thereof) that bind to DV epitopes, as well as compositions containing them and methods of designing, providing, formulating, using, identifying and/or characterizing them. In some embodiments, provided antibody agents show significant binding to a plurality of DV serotypes. In some embodiments, provided antibody agents show significant binding to all four DV serotypes. Such antibody agents are useful, for example, in the prophylaxis, treatment, diagnosis, and/or study of DV.

1 - 64 . (canceled) 
     
     
         65 . An antibody agent that:
 (a) has a heavy chain variable region that shows at least 95% substantial sequence homology with that of heavy chain variable region of 4E11 (SEQ ID NO. 1) and a light chain variable region that shows at least 95% substantial sequence homology with that of light chain variable region of 4E11 (SEQ ID NO. 2); and   (b) has a sequence variation from 4E11 at a position selected from those in one or more of Tables 4-8, and combinations thereof.   
     
     
         66 . The antibody agent of  claim 65 , wherein the antibody agent:
 (a) competes with 4E11 for binding to an epitope within each of SEQ ID NO. 17 (EDIII-DV1), SEQ ID NO. 18 (EDIII-DV2), SEQ ID NO. 19 (EDIII-DV3), SEQ ID NO. 20 (EDIII-DV4);   (b) shows enhanced affinity for the epitope within SEQ ID NO. 20 (EDIII-DV4) relative to that shown by 4E11; and/or   (c) shows comparable affinity to that shown by 4E11 for the epitopes within each of SEQ ID NO. 17 (EDIII-DV1), SEQ ID NO. 18 (EDIII-DV2), and SEQ ID NO. 19 (EDIII-DV3).   
     
     
         67 . A pharmaceutical composition comprising the antibody agent of  claim 65  and at least one pharmaceutically acceptable carrier or excipient. 
     
     
         68 . A method of providing an antibody composition, the method comprising steps of: providing an antibody agent that:
 (a) has a heavy chain variable region that shows at least 95% substantial sequence homology with that of heavy chain variable region of 4E11 (SEQ ID NO. 1) and a light chain variable region that shows at least 95% substantial sequence homology with that of light chain variable region of 4E11 (SEQ ID NO. 2);   (b) has a sequence variation from 4E11 at a position selected from those in one or more of Tables 4-8, and combinations thereof; and   formulating the antibody agent with at least one pharmaceutically acceptable carrier or excipient to provide the antibody composition.   
     
     
         69 . The method of  claim 68 , wherein the antibody agent:
 (a) competes with 4E11 for binding to an epitope within each of SEQ ID NO. 17 (EDIII-DV1), SEQ ID NO. 18 (EDIII-DV2), SEQ ID NO. 19 (EDIII-DV3), SEQ ID NO. 20 (EDIII-DV4);   (b) shows enhanced affinity for the epitope within SEQ ID NO. 20 (EDIII-DV4) relative to that shown by 4E11; and/or   (c) shows comparable affinity to that shown by 4E11 for the epitopes within each of SEQ ID NO. 17 (EDIII-DV1), SEQ ID NO. 18 (EDIII-DV2), and SEQ ID NO. 19 (EDIII-DV3).   
     
     
         70 . A method of treating a subject, the method comprising a step of:
 administering to a subject suffering from or susceptible to Dengue virus an antibody agent that:   (a) has a heavy chain variable region that shows at least 95% substantial sequence homology with that of heavy chain variable region of 4E11 (SEQ ID NO. 1) and a light chain variable region that shows at least 95% substantial sequence homology with that of light chain variable region of 4E11 (SEQ ID NO. 2); and   (b) has a sequence variation from 4E11 at a position selected from those in one or more of Tables 4-8, and combinations thereof.   
     
     
         71 . The method of  claim 70 , wherein the antibody agent:
 (a) competes with 4E11 for binding to an epitope within each of SEQ ID NO. 17 (EDIII-DV1), SEQ ID NO. 18 (EDIII-DV2), SEQ ID NO. 19 (EDIII-DV3), SEQ ID NO. 20 (EDIII-DV4);   (b) shows enhanced affinity for the epitope within SEQ ID NO. 20 (EDIII-DV4) relative to that shown by 4E11; and/or   (c) shows comparable affinity to that shown by 4E11 for the epitopes within each of SEQ ID NO. 17 (EDIII-DV1), SEQ ID NO. 18 (EDIII-DV2), and SEQ ID NO. 19 (EDIII-DV3).   
     
     
         72 . The method of  claim 70 , wherein the step of administering comprises administering a pharmaceutical composition comprising:
 the antibody agent; and   at least one pharmaceutically acceptable carrier or excipient, wherein the composition is formulated for administration by a route selected from the group consisting of: oral (PO), intravenous (IV), intramuscular (IM), intra-arterial, intramedullary, intrathecal, subcutaneous (SQ), intraventricular, transdermal, interdermal, intradermal, rectal (PR), vaginal, intraperitoneal (IP), intragastric (IG), topical, mucosal, intranasal, buccal, enteral, vitreal, sublingual, intratracheal instillation, bronchial instillation, oral spray, nasal spray, aerosol, or through a portal vein catheter.   
     
     
         73 . A method of  claim 72 , wherein:
 the pharmaceutical composition is formulated for IV administration; and   the step of administering involves administration by intravenous infusion.   
     
     
         74 . A method of  claim 72 , wherein:
 the pharmaceutical composition is formulated for IM administration; and   the step of administration is by intramuscular injection.   
     
     
         75 . A method of  claim 72 , wherein:
 the pharmaceutical composition is formulated for SQ administration;   and the step of administration is by subcutaneous injection.   
     
     
         76 . A method of treating a subject, the method comprising a step of:
 administering to a subject suffering from or susceptible to Dengue virus an antibody agent characterized in that multivariate logistic regression (MLR) analysis of features selected from the group consisting of: ZEPII value, main chain-main chain H-bonds, density of H-bonds, percentage of charged groups, density of cation-pi interactions, buried surface area, percentage of neutral polar groups, density of ionic bonds, and combinations thereof,   generates a predicted crystal structure for the antibody agent with its antigen that is characterized by an RMSD that is not greater than 3 angstroms.   
     
     
         77 . A method of treating a subject, the method comprising a step of:
 administering to a subject suffering from or susceptible to Dengue virus an antibody agent that:   (a) competes with 4E11 for binding in and ELISA assay;   (b) has at least a 450-fold affinity improvement to an epitope within EDIII-DV4 (SEQ ID NO. 20) compared to binding by 4E11 and maintains binding affinity to EDIII of DV1 (SEQ ID NO. 17), DV2 (SEQ ID NO. 18), and DV3 (SEQ ID NO. 19);   (c) has a heavy chain variable region that shows at least 95% substantial sequence homology with that of heavy chain variable region of 4E11 (SEQ ID NO. 1) and a light chain variable region that shows at least 95% substantial sequence homology with that of light chain variable region of 4E11 (SEQ ID NO. 2); and   (d) has a sequence variation from 4E11 at a position selected from those in one or more of Tables 4-8, and combinations thereof.   
     
     
         78 . A method of treating a subject, the method comprising a step of:
 administering to a subject suffering from or susceptible to Dengue virus an antibody agent that   (a) has at least a 75-fold increase in neutralizing potency towards DV4 compared to neutralizing potency by 4E11 in a focus reduction neutralization test (FRNT);   (b) maintains neutralizing potency to DV1-3 compared to neutralizing potency by 4E11 in a FRNT test;   (c) has a heavy chain variable region that shows at least 95% substantial sequence homology with that of heavy chain variable region of 4E11 (SEQ ID NO. 1) and a light chain variable region that shows at least 95% substantial sequence homology with that of light chain variable region of 4E11 (SEQ ID NO. 2); and   (d) has a sequence variation from 4E11 at a position selected from those in one or more of Tables 4-8, and combinations thereof.