Fully human influenza m2 specific antibodies

Abstract

The present invention relates to human antibodies, preferably to fully human antibodies, which are specifically binding to influenza M2e antigen. The invention further relates to individual light- and/or heavy chains of such antibodies, to nucleic acids encoding said antibodies or their light- and/or heavy chain, and to expression vectors for the expression of said antibodies. Furthermore, the invention relates to the use of said antibodies in the treatment and/or prevention of influenza A virus infection, preferably in humans.

1 . A method of producing an isolated monoclonal antibody, wherein said monoclonal antibody is specifically binding influenza M2e antigen, and wherein said monoclonal antibody is a human monoclonal antibody, and wherein said antibody comprises at least one antigen binding site, wherein said antigen binding site comprises:
 (a) one light chain variable region (LCVR), wherein said LCVR comprises: (i) one light chain complementarity determining region 1 (LC CDR1), wherein said LC CDR1 consists of the peptide of any one of SEQ ID NOs 1, 2, 3, 4, 5, and 6; (ii) one LC CDR2, wherein said LC CDR2 consists of the peptide of SEQ ID NO: 7; and (iii) one LC CDR3, wherein said LC CDR3 consists of the peptide of any one of SEQ ID NOs 8, 9, 10, and 11; and   (b) one heavy chain variable region (HCVR), wherein said HCVR comprises: (i) one heavy chain complementarity determining region 1 (HC CDR1), wherein said HC CDR1 consists of the peptide of SEQ ID NO: 12; (ii) one HC CDR2, wherein said HC CDR2 consists of the peptide of any one of SEQ ID NOs 13 and 14; and (iii) one HC CDR3, wherein said HC CDR3 consists of the peptide of any one of SEQ ID NOs 15, 16, 17, 18, and 19.   
     
     
         2 . The method of  claim 1 , wherein said at least one antigen binding site recognizes an epitope comprised by the amino acid sequence LLTEVETP (SEQ ID NO: 93). 
     
     
         3 . The method of  claim 1 , wherein
 said LC CDR1 consists of the peptide of any one of SEQ ID NOs 1, 4 and 6,   said LC CDR2 consists of the peptide of SEQ ID NO: 7,   said LC CDR3 consists of the peptide of SEQ ID NO: 8,   said HC CDR1 consists of the peptide of SEQ ID NO: 12,   said HC CDR2 consists of the peptide of SEQ ID NO: 13, and   said HC CDR3 consists of the peptide of SEQ ID NO: 15.   
     
     
         4 . The method of  claim 3 , wherein
 said LC CDR1 consists of the peptide of SEQ ID NO: 1,   said LC CDR2 consists of the peptide of SEQ ID NO: 7,   said LC CDR3 consists of the peptide of SEQ ID NO: 8,   said HC CDR1 consists of the peptide of SEQ ID NO: 12,   said HC CDR2 consists of the peptide of SEQ ID NO: 13, and   said HC CDR3 consists of the peptide of SEQ ID NO: 15.   
     
     
         5 . The method of  claim 1 , wherein position 5 to 113 of said LCVR consists of the peptide of any one of SEQ ID NOs 20, 21 and 22. 
     
     
         6 . The method of  claim 1 , wherein position 5 to 113 of said LCVR consists of the peptide of any one of SEQ ID NOs 20, 21 and 22, and wherein position 1 to 4 of said LCVR consists of the peptide of SEQ ID NO: 24. 
     
     
         7 . The method of  claim 1 , wherein position 7 to 121 of said HCVR consists of the peptide of SEQ ID NO: 23. 
     
     
         8 . The method of  claim 1 , wherein position 7 to 121 of said HCVR consists of the peptide of SEQ ID NO: 23, and wherein position 1 to 6 of said HCVR consists of the peptide of SEQ ID NO: 25. 
     
     
         9 . The method of  claim 1 , wherein position 5 to 113 of said LCVR consists of the peptide of any one of SEQ ID NOs 20, 21 and 22, and wherein position 7 to 121 of said HCVR consists of the peptide of SEQ ID NO: 23. 
     
     
         10 . The method of  claim 1 , wherein position 5 to 113 of said LCVR consists of the peptide of SEQ ID NO: 20, and wherein position 7 to 121 of said HCVR consists of the peptide of SEQ ID NO: 23, and wherein position 1 to 4 of said LCVR consists of the peptide of SEQ ID NO: 24, and wherein position 1 to 6 of said HCVR consists of the peptide of SEQ ID NO: 25. 
     
     
         11 . The method of  claim 1 , wherein said monoclonal antibody comprises at least one light chain, and wherein said monoclonal antibody further comprises at least one heavy chain, wherein said light chain comprises the amino acid sequence of any one of SEQ ID NOs 26, 27, and 28, and wherein said heavy chain comprises of the amino acid of SEQ ID NO: 29. 
     
     
         12 . The method of  claim 1 , wherein said monoclonal antibody comprises at least one light chain, and wherein said monoclonal antibody further comprises at least one heavy chain, wherein said light chain consists of the amino acid sequence of any one of SEQ ID NOs 26, 27, and 28, and wherein said heavy chain consists of the amino acid of SEQ ID NO: 29. 
     
     
         13 . The method of  claim 1 , wherein said influenza M2e antigen is the extracellular domain of the influenza A M2 protein, and wherein said influenza M2e antigen is the peptide of any one of SEQ ID NOs 48 to 83 and 90 to 92. 
     
     
         14 . The method of  claim 1 , wherein said influenza M2e antigen is the extracellular domain of the influenza A M2 protein, and wherein said influenza M2e antigen is the peptide of any one of SEQ ID NO: 48. 
     
     
         15 . The method of  claim 11 , wherein the dissociation constant (Kd) of said monoclonal antibody and said influenza M2e antigen is at most 100 nM or less. 
     
     
         16 . The method of  claim 11 , wherein the dissociation constant (Kd) of said monoclonal antibody and said influenza M2e antigen is at most 10 nM or less. 
     
     
         17 . A method of producing an isolated polynucleotide comprising a nucleic acid encoding the monoclonal antibody of the method of  claim 1 . 
     
     
         18 . A method of producing an expression vector comprising a nucleic acid encoding the monoclonal antibody of the method of  claim 1 . 
     
     
         19 . A method of producing an isolated host cell comprising at least one expression vector comprising a nucleic acid encoding the monoclonal antibody of the method of  claim 1 .