Monoclonal antibodies that bind or neutralize dengue virus

Abstract

The present invention relates to monoclonal antibodies that bind or neutralize dengue type 1, 2, 3, and/or 4 virus. The invention provides such antibodies, fragments of such antibodies retaining dengue virus-binding ability, fully human or humanized antibodies retaining dengue virus-binding ability, and pharmaceutical compositions including such antibodies. The invention further provides for isolated nucleic acids encoding the antibodies of the invention and host cells transformed therewith. Additionally, the invention provides for prophylactic, therapeutic, and diagnostic methods employing the antibodies and nucleic acids of the invention.

1 . A substantially pure polypeptide comprising
 a fully human or humanized chimpanzee monoclonal antibody that binds or neutralizes dengue type 1, 2, 3, and/or 4 virus,   or comprising   a monoclonal antibody that binds the antigen to which monoclonal antibody 5H2 (ATCC Accession No. PTA-5662) binds,   or comprising   a monoclonal antibody that binds the antigen to which monoclonal antibody 1A5 (ATCC Accession No. PTA-6265) binds.   
     
     
         2 . The substantially pure polypeptide of  claim 1  wherein said antibody fragment comprises an Fd fragment. 
     
     
         3 . The substantially pure polypeptide of  claim 1  wherein said antibody fragment comprises an Fab fragment. 
     
     
         4 . The substantially pure polypeptide of  claim 1  wherein said antibody includes a heavy chain CDR3 region having the amino acid sequence of SEQ ID NO: 7, 23, 39, 55, 71, 87, 103, 119, 135, 151, 167, or 183. 
     
     
         5 . The substantially pure polypeptide of  claim 4  wherein said antibody includes a heavy chain CDR2 region having the amino acid sequence of SEQ ID NO: 5 (when heavy chain CDR3 region is SEQ ID NO: 7), 21 (when heavy chain CDR3 region is SEQ ID NO: 23), 37 (when heavy chain CDR3 region is SEQ ID NO: 39), 53 (when heavy chain CDR3 region is SEQ ID NO: 55), 69 (when heavy chain CDR3 region is SEQ ID NO: 71), 85 (when heavy chain CDR3 region is SEQ ID NO: 87), 101 (when heavy chain CDR3 region is SEQ ID NO: 103), 117 (when heavy chain CDR3 region is SEQ ID NO: 119), 133 (when heavy chain CDR3 region is SEQ ID NO: 135), 149 (when heavy chain CDR3 region is SEQ ID NO: 151), 165 (when heavy chain CDR3 region is SEQ ID NO: 167), or 181 (when heavy chain CDR3 region is SEQ ID NO: 183). 
     
     
         6 . The substantially pure polypeptide of  claim 5  wherein said antibody includes a heavy chain CDR1 region having the amino acid sequence of SEQ ID NO: 3 (when heavy chain CDR3 region is SEQ ID NO: 7), 19 (when heavy chain CDR3 region is SEQ ID NO: 23), 35 (when heavy chain CDR3 region is SEQ ID NO: 39), 51 (when heavy chain CDR3 region is SEQ ID NO: 55), 67 (when heavy chain CDR3 region is SEQ ID NO: 71), 83 (when heavy chain CDR3 region is SEQ ID NO: 87), 99 (when heavy chain CDR3 region is SEQ ID NO: 103), 115 (when heavy chain CDR3 region is SEQ ID NO: 119), 131 (when heavy chain CDR3 region is SEQ ID NO: 135), 147 (when heavy chain CDR3 region is SEQ ID NO: 151), 163 (when heavy chain CDR3 region is SEQ ID NO: 167), or 179 (when heavy chain CDR3 region is SEQ ID NO: 183). 
     
     
         7 . The substantially pure polypeptide of  claim 4  wherein said antibody includes a heavy chain Fd region including the amino acid sequence of SEQ ID NO: 1 (when heavy chain CDR3 region is SEQ ID NO: 7), 17 (when heavy chain CDR3 region is SEQ ID NO: 23), 33 (when heavy chain CDR3 region is SEQ ID NO: 39), 49 (when heavy chain CDR3 region is SEQ ID NO: 55), 65 (when heavy chain CDR3 region is SEQ ID NO: 71), 81 (when heavy chain CDR3 region is SEQ ID NO: 87), 97 (when heavy chain CDR3 region is SEQ ID NO: 103), 113 (when heavy chain CDR3 region is SEQ ID NO: 119), 129 (when heavy chain CDR3 region is SEQ ID NO: 135), 145 (when heavy chain CDR3 region is SEQ ID NO: 151), 161 (when heavy chain CDR3 region is SEQ ID NO: 167), or 177 (when heavy chain CDR3 region is SEQ ID NO: 183). 
     
     
         8 . The substantially pure polypeptide of  claim 4  wherein said antibody includes a light chain CDR3 region having the amino acid sequence of SEQ ID NO: 15 (when heavy chain CDR3 region is SEQ ID NO: 7), 31 (when heavy chain CDR3 region is SEQ ID NO: 23), 47 (when heavy chain CDR3 region is SEQ ID NO: 39), 63 (when heavy chain CDR3 region is SEQ ID NO: 55), 79 (when heavy chain CDR3 region is SEQ ID NO: 71), 95 (when heavy chain CDR3 region is SEQ ID NO: 87), 111 (when heavy chain CDR3 region is SEQ ID NO: 103), 127 (when heavy chain CDR3 region is SEQ ID NO: 119), 143 (when heavy chain CDR3 region is SEQ ID NO: 135), 159 (when heavy chain CDR3 region is SEQ ID NO: 151), 175 (when heavy chain CDR3 region is SEQ ID NO: 167), or 191 (when heavy chain CDR3 region is SEQ ID NO: 183). 
     
     
         9 . The substantially pure polypeptide of  claim 8  wherein said antibody includes a light chain CDR2 region having the amino acid sequence of SEQ ID NO: 13 (when heavy chain CDR3 region is SEQ ID NO: 7), 29 (when heavy chain CDR3 region is SEQ ID NO: 23), 45 (when heavy chain CDR3 region is SEQ ID NO: 39), 61 (when heavy chain CDR3 region is SEQ ID NO: 55), 77 (when heavy chain CDR3 region is SEQ ID NO: 71), 93 (when heavy chain CDR3 region is SEQ ID NO: 87), 109 (when heavy chain CDR3 region is SEQ ID NO: 103), 125 (when heavy chain CDR3 region is SEQ ID NO: 119), 141 (when heavy chain CDR3 region is SEQ ID NO: 135), 157 (when heavy chain CDR3 region is SEQ ID NO: 151), 173 (when heavy chain CDR3 region is SEQ ID NO: 167), or 189 (when heavy chain CDR3 region is SEQ ID NO: 183). 
     
     
         10 . The substantially pure polypeptide of  claim 9  wherein said antibody includes a light chain CDR1 region having the amino acid sequence of SEQ ID NO: 11 (when heavy chain CDR3 region is SEQ ID NO: 7), 27 (when heavy chain CDR3 region is SEQ ID NO: 23), 43 (when heavy chain CDR3 region is SEQ ID NO: 39), 59 (when heavy chain CDR3 region is SEQ ID NO: 55), 75 (when heavy chain CDR3 region is SEQ ID NO: 71), 91 (when heavy chain CDR3 region is SEQ ID NO: 87), 107 (when heavy chain CDR3 region is SEQ ID NO: 103), 123 (when heavy chain CDR3 region is SEQ ID NO: 119), 139 (when heavy chain CDR3 region is SEQ ID NO: 135), 155 (when heavy chain CDR3 region is SEQ ID NO: 151), 171 (when heavy chain CDR3 region is SEQ ID NO: 167), or 187 (when heavy chain CDR3 region is SEQ ID NO: 183). 
     
     
         11 . The substantially pure polypeptide of  claim 4  wherein said antibody includes a light chain region including the amino acid sequence of SEQ ID NO: 9 (when heavy chain CDR3 region is SEQ ID NO: 7), 25 (when heavy chain CDR3 region is SEQ ID NO: 23), 41 (when heavy chain CDR3 region is SEQ ID NO: 39), 57 (when heavy chain CDR3 region is SEQ ID NO: 55), 73 (when heavy chain CDR3 region is SEQ ID NO: 71), 89 (when heavy chain CDR3 region is SEQ ID NO: 87), 105 (when heavy chain CDR3 region is SEQ ID NO: 103), 121 (when heavy chain CDR3 region is SEQ ID NO: 119), 137 (when heavy chain CDR3 region is SEQ ID NO: 135), 153 (when heavy chain CDR3 region is SEQ ID NO: 151), 169 (when heavy chain CDR3 region is SEQ ID NO: 167), or 185 (when heavy chain CDR3 region is SEQ ID NO: 183). 
     
     
         12 . The substantially pure polypeptide of  claim 4  wherein said antibody includes a heavy chain Fd region including the CDR amino acid sequences of SEQ ID NO: 1 (when heavy chain CDR3 region is SEQ ID NO: 7), 17 (when heavy chain CDR3 region is SEQ ID NO: 23), 33 (when heavy chain CDR3 region is SEQ ID NO: 39), 49 (when heavy chain CDR3 region is SEQ ID NO: 55), 65 (when heavy chain CDR3 region is SEQ ID NO: 71), 81 (when heavy chain CDR3 region is SEQ ID NO: 87), 97 (when heavy chain CDR3 region is SEQ ID NO: 103), 113 (when heavy chain CDR3 region is SEQ ID NO: 119), 129 (when heavy chain CDR3 region is SEQ ID NO: 135), 145 (when heavy chain CDR3 region is SEQ ID NO: 151), 161 (when heavy chain CDR3 region is SEQ ID NO: 167), or 177 (when heavy chain CDR3 region is SEQ ID NO: 183). 
     
     
         13 . The substantially pure polypeptide of  claim 12  wherein said antibody includes a light chain region including the CDR amino acid sequences of SEQ ID NO: 9 (when heavy chain CDR3 region is SEQ ID NO: 7), 25 (when heavy chain CDR3 region is SEQ ID NO: 23), 41 (when heavy chain CDR3 region is SEQ ID NO: 39), 57 (when heavy chain CDR3 region is SEQ ID NO: 55), 73 (when heavy chain CDR3 region is SEQ NO: 71), 89 (when heavy chain CDR3 region is SEQ ID NO: 87), 105 (when heavy chain CDR3 region is SEQ ID NO: 103), 121 (when heavy chain CDR3 region is SEQ ID NO: 119), 137 (when heavy chain CDR3 region is SEQ ID NO: 135), 153 (when heavy chain CDR3 region is SEQ ID NO: 151), 169 (when heavy chain CDR3 region is SEQ ID NO: 167), or 185 (when heavy chain CDR3 region is SEQ ID NO: 183). 
     
     
         14 . An isolated nucleic acid comprising a nucleotide sequence encoding a polypeptide of  claim 1 . 
     
     
         15 . An isolated nucleic acid as in  claim 14 , wherein said nucleic acid comprises a vector including a regulatory sequence operably joined to said nucleic acid. 
     
     
         16 . A host cell including a vector comprising a nucleic acid of  claim 14 . 
     
     
         17 . A pharmaceutical preparation comprising
 a pharmaceutically acceptable carrier; and   a substantially pure polypeptide.   
     
     
         18 . A diagnostic preparation comprising
 a pharmaceutically acceptable carrier; and   a substantially pure polypeptide selected polypeptide of  claim 1 .   
     
     
         19 . A method for the treatment of dengue virus disease comprising administering to a patient a therapeutically effective amount of the pharmaceutical preparation of  claim 17 . 
     
     
         20 . A method for prophylaxis against dengue virus disease comprising administering to a patient a prophylactically effective amount of the pharmaceutical preparation of  claim 17 . 
     
     
         21 . A method for the diagnosis of dengue virus disease comprising
 administering to a patient an effective amount of the diagnostic preparation of  claim 18 , and detecting binding of the substantially pure polypeptide as a determination of the presence of dengue virus disease.   
     
     
         22 . A method of detecting the presence of dengue virus in a biological sample comprising
 contacting said sample with the diagnostic preparation of  claim 18 , and   assaying binding of the substantially pure polypeptide as a determination of the presence of said dengue virus.   
     
     
         23 . Humanized IgG1 5H2 plasmid deposited with ATCC as ATCC Accession No. PTA-5662, or Humanized IgG1 1A5 plasmid deposited with ATCC as ATCC Accession No. PTA-6265, or Fab CMV-dhfr vector for expression of any full-length IgG1 deposited with ATCC as PTA-5662. 
     
     
         24 - 25 . (canceled)