Influenza a virus specific antibodies

Abstract

The invention relates to isolated, synthetic or recombinant antibodies and functional parts thereof specific for multiple influenza A virus subtypes. The invention further relates to the use of such antibodies for diagnosis of an influenza A virus infection and as a medicament and/or prophylactic agent for at least in part treating or alleviating symptoms of an influenza A virus infection.

What is claimed is: 
     
         1 . A synthetic or recombinant antibody or functional part thereof, or immunoglobulin chain or functional equivalent thereof:
 said synthetic or recombinant antibody or functional part thereof, or immunoglobulin chain or functional equivalent thereof having an in vitro H3N2 influenza A virus neutralizing activity with an IC50 value of less than 1 μg/ml; and   wherein said synthetic or recombinant antibody or functional part thereof or immunoglobulin chain or functional equivalent is capable of specifically binding at least one other influenza A virus subtype.   
     
     
         2 . The synthetic or recombinant antibody or functional part thereof, or immunoglobulin chain or functional equivalent thereof of  claim 1 , wherein said at least one other influenza A virus subtype is a group 2 influenza A virus subtype. 
     
     
         3 . The synthetic or recombinant antibody or functional part thereof, or immunoglobulin chain or functional equivalent thereof of  claim 1 , wherein said at least one other influenza A virus subtype is a group 1 influenza A virus subtype. 
     
     
         4 . The synthetic or recombinant antibody or functional part thereof, or immunoglobulin chain or functional equivalent thereof of  claim 1 , comprising:
 a heavy chain CDR1 sequence comprising a sequence which is at least 85% identical to a sequence selected from the group consisting of SEQ ID NO's:1-5, and/or   a heavy chain CDR2 sequence comprising a sequence which is at least 85% identical to a sequence selected from the group consisting of SEQ ID NO's:6-10, and/or   a heavy chain CDR3 sequence comprising a sequence which is at least 85% identical to a sequence selected from the group consisting of SEQ ID NO's:11-15, and/or   a light chain CDR1 sequence comprising a sequence which is at least 85% identical to a sequence selected from the group consisting of SEQ ID NO's:16-20, and/or   a light chain CDR2 sequence comprising a sequence which is at least 85% identical to a sequence selected from the group consisting of SEQ ID NO's:21-25, and/or   a light chain CDR3 sequence comprising a sequence which is at least 85% identical to a sequence selected from the group consisting of SEQ ID NO's:26-30.   
     
     
         5 . The synthetic or recombinant antibody or functional part thereof, or immunoglobulin chain or functional equivalent thereof of  claim 4 , having a heavy chain sequence comprising a sequence which is at least 85% identical to a sequence selected from the group consisting of SEQ ID NO's:31-35 and/or having a light chain sequence which is at least 85% identical to a sequence selected from the group consisting of SEQ ID NO's:36-40. 
     
     
         6 . The synthetic or recombinant antibody or functional part thereof, or immunoglobulin chain or functional equivalent thereof of  claim 4 , 
       wherein said synthetic or recombinant antibody or functional part thereof, or immunoglobulin chain or functional equivalent thereof is a nucleic acid molecule or a functional equivalent with a length of at least 15 nucleotides, or a functional equivalent thereof, encoding at least one CDR sequence of an antibody or functional part thereof or immunoglobulin chain or functional equivalent. 
     
     
         7 . The synthetic or recombinant antibody or functional part thereof, or immunoglobulin chain or functional equivalent thereof of  claim 6 , comprising a sequence which has at least 85% sequence identity to a sequence selected from the group consisting of:
 SEQ ID NO's:41-45, and   SEQ ID NO's:46-50, and   SEQ ID NO's:51-55, and   SEQ ID NO's:56-60, and   SEQ ID NO's:61-65, and   SEQ ID NO's:66-70.   
     
     
         8 . The synthetic or recombinant antibody or functional part thereof, or immunoglobulin chain or functional equivalent thereof of  claim 6 , comprising a sequence which has at least 85% sequence identity to a sequence selected from the group consisting of SEQ ID NO's:71-75 and/or comprising a sequence which has at least 85% sequence identity to a sequence selected from the group consisting of SEQ ID NO's:76-80. 
     
     
         9 . A vector comprising the nucleic acid molecule or functional equivalent of  claim 6 . 
     
     
         10 . An isolated or recombinant cell comprising the nucleic acid molecule or functional equivalent of  claim 6 , and/or a vector of  claim 9 . 
     
     
         11 . A pharmaceutical composition comprising: 
       at least one of:
 synthetic or recombinant antibody or functional part thereof, or immunoglobulin chain or functional equivalent thereof of  claim 4 ; 
 the nucleic acid molecule or functional equivalent of  claim 6 , or 
 the vector of  claim 9 ; 
 
       and a pharmaceutical acceptable carrier, diluent and/or excipient. 
     
     
         12 . The synthetic or recombinant antibody or functional part thereof, or immunoglobulin chain or functional equivalent thereof of  claim 4  or a vector thereof, for use as a medicament and/or prophylactic agent. 
     
     
         13 . The synthetic or recombinant antibody or functional part thereof, or immunoglobulin chain or functional equivalent thereof of  claim 12 , wherein said use is treating and/or inhibiting an influenza A virus infection. 
     
     
         14 . A method for producing the synthetic or recombinant antibody or functional part thereof, or immunoglobulin chain or functional equivalent thereof of  claim 1  comprising:
 providing a cell with the nucleic acid molecule or functional equivalent of  claim 6 , or 
 the vector of  claim 9 , and 
 allowing said cell to translate said nucleic acid molecule or functional equivalent or vector, thereby producing said antibody or functional part or immunoglobulin chain or functional equivalent; and 
 harvesting, purifying and/or isolating said antibody or functional part or immunoglobulin chain or functional equivalent. 
 
     
     
         15 . The synthetic or recombinant antibody or functional part thereof, or immunoglobulin chain or functional equivalent thereof of  claim 1  for use in diagnosis of an influenza A virus infection. 
     
     
         16 . A method for determining whether an influenza A virus is present in a sample comprising:
 contacting said sample with the synthetic or recombinant antibody or functional part thereof, or immunoglobulin chain or functional equivalent thereof of  claim 1 ,   allowing said synthetic or recombinant antibody or functional part thereof, or immunoglobulin chain or functional equivalent thereof to bind said influenza A virus, if present, and   determining whether influenza A virus is bound to said synthetic or recombinant antibody or functional part thereof, or immunoglobulin chain or functional equivalent thereof, thereby determining whether an influenza A virus is present in said sample.   
     
     
         17 . A synthetic or recombinant antibody or functional part thereof, or immunoglobulin chain or functional equivalent thereof, having an in vitro H7N1 influenza A virus neutralizing activity with an IC50 value of less than 5.0 μg/ml. 
     
     
         18 . A synthetic or recombinant antibody or functional part thereof, or immunoglobulin chain or functional equivalent thereof, having an in vitro H7N7 influenza A virus neutralizing activity with an IC50 value of less than 0.5 μg/ml. 
     
     
         19 . A synthetic or recombinant antibody or functional part thereof, or immunoglobulin chain or functional equivalent thereof, having an in vitro H1N1 influenza A virus neutralizing activity with an IC50 value of less than 5.0 μg/ml. 
     
     
         20 . A synthetic or recombinant antibody or functional part thereof, or immunoglobulin chain or functional equivalent thereof, having an in vitro H5N1 influenza A virus neutralizing activity with an IC50 value of less than 5.0 μg/ml. 
     
     
         21 . The synthetic or recombinant antibody or functional part thereof or  claim 17 , which is capable of specifically binding at least one other influenza A virus subtype. 
     
     
         22 . A synthetic or recombinant multimeric antibody, multimeric immunoglobulin or functional equivalent thereof, comprising:
 i) at least two different heavy chain CDR sequences and at least two different light chain CDR sequences of an antibody selected from the group consisting of AT10_001 and AT10_002 and AT10_003 and AT10_004 and AT10_005; and   ii) at least two different heavy chain CDR sequences and at least two different light chain CDR sequences of an antibody selected from the group consisting of AT10_001 and AT10_002 and AT10_003 and AT10_004 and AT10_005,   wherein said antibody selected in i) is different from said antibody selected in ii).   
     
     
         23 . The synthetic or recombinant multimeric antibody, multimeric immunoglobulin or functional equivalent thereof of  claim 22 , comprising:
 i) heavy chain CDR1, CDR2 and CDR3 and light chain CDR1, CDR2 and CDR3 sequences of an antibody selected from the group consisting of AT10_001 and AT10_002 and AT10_003 and AT10_004 and AT10_005; and   ii) heavy chain CDR1, CDR2 and CDR3 and light chain CDR1, CDR2 and CDR3 sequences of an antibody selected from the group consisting of AT10_001 and AT10_002 and AT10_003 and AT10_004 and AT10_005,   wherein said antibody selected in i) is different from said antibody selected in ii).   
     
     
         24 . The synthetic or recombinant multimeric antibody, multimeric immunoglobulin or functional equivalent thereof of  claim 22 , comprising:
 i) the heavy chain sequence and the light chain sequence of an antibody selected from the group consisting of AT10_001 and AT10_002 and AT10_003 and AT10_004 and AT10_005, or a sequences that is at least 85% identical thereto; and   ii) the heavy chain sequence and the light chain sequence of an antibody selected from the group consisting of AT10_001 and AT10_002 and AT10_003 and AT10_004 and AT10_005, or a sequence that is at least 85% identical thereto,   wherein said antibody selected in i) is different from said antibody selected in ii).   
     
     
         25 . The synthetic or recombinant multimeric antibody, multimeric immunoglobulin or functional equivalent thereof of  claim 22 , comprising:
 i) at least two different heavy chain CDR sequences and at least two different light chain CDR sequences of antibody AT10_002; and   ii) at least two different heavy chain CDR sequences and at least two different light chain CDR sequences of antibody AT10_005.   
     
     
         26 . The synthetic or recombinant multimeric antibody, multimeric immunoglobulin or functional equivalent thereof of  claim 22 , comprising:
 i) heavy chain CDR1, CDR2 and CDR3 and light chain CDR1, CDR2 and CDR3 sequences of antibody AT10_002; and   ii) heavy chain CDR1, CDR2 and CDR3 and light chain CDR1, CDR2 and CDR3 sequences of antibody AT10_005.   
     
     
         27 . The synthetic or recombinant multimeric antibody, multimeric immunoglobulin or functional equivalent thereof of  claim 22 , comprising:
 i) the heavy chain sequence and the light chain sequence of antibody AT10_002, or sequences that are at least 85% identical thereto; and   ii) the heavy chain sequence and the light chain sequence of antibody AT10_005, or sequences that are at least 85% identical thereto.   
     
     
         28 . The synthetic or recombinant multimeric antibody, multimeric immunoglobulin or functional equivalent thereof of  claim 22 , which is a dimeric antibody. 
     
     
         29 . An isolated or recombinant cell or a pharmaceutical composition comprising the synthetic or recombinant multimeric antibody, multimeric immunoglobulin or functional equivalent thereof of  claim 22 . 
     
     
         30 . The synthetic or recombinant multimeric antibody, multimeric immunoglobulin or functional equivalent thereof of  claim 22  for use as a medicament and/or prophylactic agent. 
     
     
         31 . The synthetic or recombinant multimeric antibody, multimeric immunoglobulin or functional equivalent thereof of  claim 22  for use as a medicament and/or prophylactic agent for at least in part treating and/or preventing and/or alleviating the symptoms of an influenza A infection. 
     
     
         32 . The synthetic or recombinant multimeric antibody, multimeric immunoglobulin or functional equivalent thereof of  claim 22  for use in diagnosis of an influenza A infection. 
     
     
         33 . A method for at least in part treating and/or preventing an influenza A virus infection, comprising administering to an individual in need thereof a therapeutically effective amount of the synthetic or recombinant multimeric antibody, multimeric immunoglobulin or functional equivalent thereof of  claim 22  and/or the cell or pharmaceutical composition of  claim 29 . 
     
     
         34 . A method for neutralizing a H1N1 influenza A virus and/or an H3N2 influenza A virus, comprising contacting said H1N1 influenza A virus and/or said H3N2 influenza A virus with The synthetic or recombinant multimeric antibody, multimeric immunoglobulin or functional equivalent thereof of  claim 22 , resulting in neutralization of said virus. 
     
     
         35 . A method for determining whether an influenza A virus is present in a sample comprising:
 contacting said sample with The synthetic or recombinant multimeric antibody, multimeric immunoglobulin or functional equivalent thereof of  claim 22 ,   allowing said multimeric antibody, multimeric immunoglobulin or functional equivalent to bind said influenza A virus, if present, and   determining whether influenza A virus is bound to said synthetic or recombinant multimeric antibody, multimeric immunoglobulin or functional equivalent thereof of, thereby determining whether an influenza A virus is present in said sample.   
     
     
         36 . A synthetic or recombinant antibody or functional part thereof, or immunoglobulin chain or functional equivalent thereof, capable of interacting with amino acids at positions A38, A40, A41, A42, A291, A292, A293, A318, B18, B19, B20, B21, B38, B41, B42, B45, B46, B48, B49, B52, B53, and B56 of influenza A virus group 1 hemagglutinin (H1/H5). 
     
     
         37 . A synthetic or recombinant antibody or functional part thereof, or immunoglobulin chain or functional equivalent thereof, capable of interacting with amino acids at positions A21, A324, A325, A327, B12, B14, B15, B16, B17, B18, B19, B25, B26, B30, B31, B32, B33, B34, B35, B36, B38, B146, B150, B153, and B154 of influenza A virus group 2 hemagglutinin (H3/H7). 
     
     
         38 . A synthetic or recombinant antibody or functional part thereof, or immunoglobulin chain or functional equivalent thereof, capable of interacting with amino acids at positions A38, A48, A275, A276, A277, A278, A289, A291, A318, B19, B20, B21, B36, B38, B39, B41, B42, B45, B46, B48, B49, B50, B52, B53, B56, B57, B58, B150 of influenza A virus group 2 hemagglutinin (H3/H7).