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 . A method for developing a Dengue vaccine or therapeutic antibody, the method comprising steps of:
 determining that an antiviral agent, that is or comprises antibody heavy and light chain variable regions related to those of antibody 4E11 by mutation of one or more residues, shows comparable affinity to that shown by 4E5A to each of Dengue serotypes I, II, III, and IV when assessed by a method comprising one or more of competition ELISA with reference antibody 4E11, SPR, or combinations thereof.   
     
     
         66 . A method of assessing an antibody agent, the method comprising the steps of:
 (a) providing an antibody agent, wherein said antibody agent:   (i) has a heavy chain or light chain variable region that shows at least 90% overall sequence identity with that of antibody 4E11; and/or   (ii) shares at least one CDR with the reference antibody; and   (b) demonstrating that the antibody agent shows at least comparable activity to the activity of reference antibody 4E5A with respect to one or more of:   (i) binding affinity for an epitope that is or comprises an amino acid sequence selected from: EDIII-DV1 (SEQ ID NO: 17), EDIII-DV2 (SEQ ID NO: 18), EDIII-DV3 (SEQ ID NO: 19), and EDIII-DV4 (SEQ ID NO: 20);   (ii) neutralizing activity for a Dengue virus serotype selected from: EDIII-DV1 (SEQ ID NO: 17), EDIII-DV2 (SEQ ID NO: 18), EDIII-DV3 (SEQ ID NO: 19), and EDIII-DV4 (SEQ ID NO: 20).   
     
     
         67 . The method of  claim 65 , wherein the method of assessing comprises determining that the antibody agent shows a neutralization IC 50  between 1 ng/mL to 10 μg/mL for an epitope that is or comprises an amino acid sequence selected from: EDIII-DV1 (SEQ ID NO: 17), EDIII-DV2 (SEQ ID NO: 18), EDIII-DV3 (SEQ ID NO: 19), and EDIII-DV4 (SEQ ID NO: 20). 
     
     
         68 . The method of  claim 65 , wherein the method of assessing comprises determining that the antibody agent shows binding with a dissociation rate constant (K D ) less than 300 nM for an epitope that is or comprises an amino acid sequence selected from: EDIII-DV1 (SEQ ID NO: 17), EDIII-DV2 (SEQ ID NO: 18), EDIII-DV3 (SEQ ID NO: 19), and EDIII-DV4 (SEQ ID NO: 20). 
     
     
         69 . The method of  claim 65 , wherein the method of assessing comprises determining that the antibody agent competes with the reference antibody for binding to an epitope that is or comprises an amino acid sequence selected from: EDIII-DV1 (SEQ ID NO: 17), EDIII-DV2 (SEQ ID NO: 18), EDIII-DV3 (SEQ ID NO: 19), and EDIII-DV4 (SEQ ID NO: 20). 
     
     
         70 . The method of  claim 65 , wherein the method further comprises providing the antibody agent using a recombinant cell culture system, wherein the recombinant cell culture system is a mammalian cell line or hybridoma. 
     
     
         71 . The method of  claim 66 , wherein the method further comprises providing the antibody agent using a recombinant cell culture system, wherein the recombinant cell culture system is a mammalian cell line or hybridoma. 
     
     
         72 . The method of  claim 65 , wherein the method further comprises isolating the antibody agent from the serum of an animal. 
     
     
         73 . The method of  claim 66 , wherein the method further comprises isolating the antibody agent from the serum of an animal. 
     
     
         74 . 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 specific to Dengue virus,   which antibody agent comprises a heavy chain variable region and a light chain variable region, each of which includes complementarity determining regions (CDRs), wherein   the heavy chain variable region comprises CDRs whose amino acid sequences are set forth in SEQ ID NO: 23, SEQ ID NO: 24, SEQ ID NO: 25; and   the light chain variable region comprises CDRs whose amino acid sequences are set forth in SEQ ID NO: 26, SEQ ID NO: 27, and SEQ ID NO: 28.   
     
     
         75 . A method of  claim 70 , wherein:
 the pharmaceutical composition is formulated for IV administration; and   the step of administering involves administration by intravenous infusion.   
     
     
         76 . A method of  claim 70 , wherein:
 the pharmaceutical composition is formulated for IM administration; and   the step of administration is by intramuscular injection.   
     
     
         77 . A method of  claim 70 , wherein:
 the pharmaceutical composition is formulated for SQ administration;   and the step of administration is by subcutaneous injection.   
     
     
         78 . A method of  claim 71 , wherein:
 the pharmaceutical composition is formulated for IV administration; and   the step of administering involves administration by intravenous infusion.   
     
     
         79 . A method of  claim 71 , wherein:
 the pharmaceutical composition is formulated for IM administration; and   the step of administration is by intramuscular injection.   
     
     
         80 . A method of  claim 71 , wherein:
 the pharmaceutical composition is formulated for SQ administration;   and the step of administration is by subcutaneous injection.