Antibodies useful in passive influenza immunization
Monoclonal antibodies and fragments thereof that are crossreactive with multiple clades of influenza virus including both Group 1 and Group 2 representatives are disclosed. These antibodies are useful in controlling influenza epidemics and pandemics as well as in providing prophylactic or therapeutic protection against seasonal influenza.
1. An isolated recombinant monoclonal antibody or an antigen binding fragment thereof that specifically binds the HA0 protein from influenza A viral clades H1, H5, H7 and H9 the monoclonal antibody or antigen binding fragment thereof comprising a heavy chain variable region comprising a CDR1 of the sequence GGIIRKYAIN (SEQ ID NO: 77), a CDR2 of the sequence GGIIAIFNTANYAQKFQG (SEQ ID NO: 78), and a CDR3 of the sequence ARGMNYYSDYFDY (SEQ ID NO: 79) and a light chain variable region comprising a CDR1 of the sequence RASQSVRSNNLA (SEQ ID NO: 80), a CDR2 of the sequence GASSRAT (SEQ ID NO: 81), and a CDR3 of the sequence QQYGSSPALT (SEQ ID NO: 82), said antibody or fragment being a single-chain antibody or fragment.
2. An isolated recombinant monoclonal antibody or an antigen binding fragment-thereof that specifically binds the HA0 and HA2 protein from influenza A viral clades H1, H5, H7 and H9; the monoclonal antibody or the antigen binding region comprising
a heavy chain variable region comprising the sequence QVQLVQSGAEVRK PGSSVKVSCKVSGGIIRKYAINWVRQAPGQGLEWMGGIIAIFNTANYAQKFQGRVTI TADESTSTVYMELSSLRSEDTALYYCARGMNYYSDYFDYWGQGSLVTVSP (amino acids 1-120 of SEQ ID NO:75), said antibody being a single chain antibody.
3. The monoclonal antibody of claim 2 , or an antigen binding fragment thereof, further comprising a light chain variable region comprising the sequence EIVLTQSPGTLSLSPGERATLSCRASQSVRSNNLAWYQHKPGQAPRLLIFGASSRA TGIP DRFSGSGSGTDFTLTISRLEPEDFAVYYCQQYGSSPALTFGGGTKVEIK (amino acids 1-109 of SEQ ID NO:76).
4. A pharmaceutical composition comprising the recombinant monoclonal antibody or antigen binding fragment thereof in accordance with claim 1 in an amount effective to confer passive immunity to a subject against influenza A viral clades H1, H5, H7 and H9 upon administration to the subject.
5. A recombinant monoclonal antibody of claim 1 , or an antigen binding fragment thereof that specifically binds the HA0 protein from influenza A viral clades H1, H5, H7 and H9 the monoclonal antibody or antigen binding fragment thereof comprising
a heavy chain variable region comprising a CDR1 of the sequence GGIIRKYAIN (SEQ ID NO: 77), a CDR2 of the sequence GGIIAIFNTANY AQKFQG (SEQ ID NO: 78), and a CDR3 of the sequence ARGMNYYSDYFDY (SEQ ID NO: 79) and
a light chain variable region comprising a CDR1 of the sequence RASQSVRSNNLA (SEQ ID NO: 80), a CDR2 of the sequence GASSRAT (SEQ ID NO: 81), and a CDR3 of the sequence QQYGSSPALT (SEQ ID NO: 82),
wherein the monoclonal antibody or antigen binding fragment is a bispecific antibody.
6. A pharmaceutical composition comprising the recombinant monoclonal antibody or the antigen binding fragment thereof in accordance with claim 5 .
7. A pharmaceutical composition comprising the recombinant monoclonal antibody or antigen binding fragment thereof in accordance with claim 2 or 3 in an amount effective to confer passive immunity to a subject against influenza A viral clades HI, H5, H7 and H9 upon administration to the subject.
8. A monoclonal antibody or an antigen binding fragment thereof that specifically binds the HA0 and HA2 protein from influenza A viral clades H1, H5, H7 and H9, comprising
a heavy chain variable region comprising the sequence QVQLVQSGAEVRKPGSSVKVSCKVSGGIIRKY AINWVRQAPGQGLEWMGGIIAIFNTANY AQKFQGRVTITADESTSTVYMELSS LRSEDTAL YYCARGMNYYSDYFDYWGQGSLVTVSP (amino acids 1-120 of SEQ ID NO:75), and optionally further comprising
a light chain variable region comprising the sequence EIVLTQSPGTLSLSPGERATLSCRASQSVRSNNLAWYQHKPGQAPRLLIFGASSRA TGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQQYGSSPALTFGGGTKVEIK (amino acids 1-109 of SEQ ID NO:76), wherein the monoclonal antibody or the antigen binding fragment thereof is a bispecific antibody.
9. A pharmaceutical composition comprising the monoclonal antibody or the antigen binding fragment thereof of claim 8 .
10. A monoclonal antibody produced recombinantly by a nonhuman host cell modified to contain a nucleotide sequence encoding
a heavy chain variable region comprising the sequence QVQL VQSGAEVRKPGSSVKVSCKVSGGIIRKY AINWVRQAPGQGLEWMGGIIAIFNTAN YAQKFQGRVTITADESTSTVYMELSSLRSEDTAL YYCARGMNYYSDYFDYWGQGSL VT VSP (amino acids 1-120 of SEQ ID NO:75) and
a light chain variable region comprising the sequence EIVLTQSPGTLSLSPGERATLSCRASQSVRSNNLAWYQHKPGQAPRLLIFGASSRA TGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQQYGSSPALTFGGGTKVEIK (amino acids 1-109 of SEQ ID NO:76) operably linked to control sequences for expression,
said antibody specifically binding to the HA0 protein from influenza A viral clades H1, H5, H7 and H9.
11. A monoclonal antibody produced recombinantly by a nonhuman host cell modified to contain a nucleotide sequence encoding a heavy chain variable region comprising a CDR1 of the sequence GGIIRKYAIN (SEQ ID NO: 77), a CDR2 of the sequence GGIIAIFNT ANY AQKFQG (SEQ ID NO: 78), and a CDR3 of the sequence ARGMNYYSDYFDY (SEQ ID NO: 79) and a light chain variable region comprising a CDR1 of the sequence RASQSVRSNNLA (SEQ ID NO: 80), a CDR2 of the sequence GASSRAT (SEQ ID NO: 81), and a CDR3 of the sequence QQYGSSPALT (SEQ ID NO: 82), aid nucleotide sequence operably linked to control sequences for expression, said antibody, specifically binding to the HA0 protein from influenza A viral clades H1, H5, H7 and H9.
12. An antibody or fragment thereof according to claim 1 wherein the fragment is selected from the group consisting of an Fab fragment, a F(ab′)2′ fragment and an Fv fragment.
13. An antibody or fragment thereof according to claim 2 wherein the fragment is selected from the group consisting of an Fab fragment, a F(ab′)2′ fragment and an Fv fragment.
14. A pharmaceutical composition comprising the recombinant monoclonal antibody or antigen binding fragment thereof in accordance with claim 1 .
15. A method for the treatment or prophylaxis of influenza infection in a subject at risk of infection by influenza A or exposed to or infected with influenza A which method comprises administering to the subject an effective amount for conferring passive immunity to said subject against influenza A viral clades H1, H5, H7 and H9 of the composition of claim 14 or 5 .