Potent anti-influenza A neuraminidase subtype N1 antibody
Inventors
WAN, Hongquan • Eichelberger, Maryna C. • Yang, Hua • Stevens, James • Shore, David A. • Garten, Rebecca J.
Assignees
US Department of Health and Human Services
Publication Number
US-10072070-B2
Publication Date
2018-09-11
Expiration Date
2035-12-03
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Abstract
Isolated monoclonal antibodies and antigen binding fragments thereof that specifically bind neuraminidase (NA) of an N1 subtype influenza virus are disclosed herein. These antibodies and antigen binding fragments can be used for the detection of an N1 subtype influenza virus and for determining the immunogenicity of vaccines. The antibodies and antigen binding fragments also can be used for the treatment of a subject to prevent or ameliorate an influenza infection.
Core Innovation
Isolated monoclonal antibodies and antigen binding fragments thereof specifically binding the neuraminidase (NA) of an N1 subtype influenza virus are disclosed. These antibodies bind an epitope bridging neighboring NA monomers of an N1 subtype influenza virus NA tetramer, a previously uncharacterized site, involving multiple amino acid contacts across adjacent monomers. An exemplary monoclonal antibody, CD6, comprises specific heavy and light chain complementarity determining regions (CDRs) with defined amino acid sequences (e.g., SEQ ID NOs: 1 and 2).
The disclosed antibodies and fragments can be used for detection of N1 subtype influenza virus, for assessing vaccine immunogenicity, and for treatment of subjects to prevent or ameliorate influenza infection. Methods include administering these antibodies or nucleic acids encoding them to subjects, contacting biological samples with the antibodies to detect infection, identifying proteins as vaccine candidates through immune complex formation, and quantifying NA in samples by immune complex detection.
The problem addressed is the need for effective antivirals against influenza viruses, especially given the emergence and circulation of oseltamivir-resistant A(H1N1)pdm09 (pH1N1) influenza viruses, which pose a public health threat. Conventional NA inhibitors can rapidly select resistant viruses, and thus there is an urgent need for new antivirals acting via distinct mechanisms. The disclosed monoclonal antibodies bind conserved NA epitopes, inhibiting enzyme activity by steric hindrance without inducing rapid selection of escape mutants, thereby offering potential therapeutics distinct from existing NA inhibitors.
Claims Coverage
The patent includes multiple claims covering isolated monoclonal antibodies or antigen binding fragments with defined heavy and light chain variable regions, nucleic acids encoding them, compositions, and methods of use.
Monoclonal antibodies specifically binding N1 subtype influenza virus neuraminidase
An isolated monoclonal antibody or antigen binding fragment comprising heavy chain variable domain with HCDR1, HCDR2, HCDR3 and light chain variable domain with LCDR1, LCDR2, LCDR3 as defined by SEQ ID NOs: 1 and 2, specifically binding NA of an N1 subtype influenza virus.
Defined complementarity determining regions and amino acid substitutions
The heavy chain variable domain includes HCDR1 (amino acids 26-33), HCDR2 (amino acids 51-60), HCDR3 (amino acids 99-113) and may include specific residues such as serine at 25, aspartic acid at 76, serine at 77 and 79. The light chain variable domain includes LCDR1 (amino acids 27-31), LCDR2 (amino acids 49-51), LCDR3 (amino acids 88-96) and may have specific residues like tyrosine at 48 and asparagine at 52.
Formats and labeling of antibodies
Antibodies may be IgG, IgM or IgA isotypes, humanized or chimeric, and may be intact antibodies or antigen binding fragments such as Fab, Fab’, F(ab’)2, scFv, and may be labeled with detectable markers including fluorescent, enzymatic, or radioactive labels.
Compositions and nucleic acids encoding antibodies
Pharmaceutical compositions containing the antibodies or fragments with pharmaceutically acceptable carriers, optionally combined with other antibodies targeting influenza proteins, and nucleic acid molecules encoding these antibodies operably linked to promoters, vectors, and host cells transformed therewith.
Methods of prevention, treatment, detection, and vaccine evaluation
Methods for inhibiting and/or treating influenza infection by administering antibodies or encoding nucleic acids, methods of detecting influenza infection by antibody binding to biological samples, methods of identifying vaccine candidates by immune complex formation, and methods for determining neuraminidase quantity using the antibodies.
The claims encompass isolated monoclonal antibodies and antigen binding fragments that specifically bind neuraminidase of N1 subtype influenza viruses with defined variable regions and CDRs, their nucleic acid sequences, pharmaceutical compositions, and methods of prophylaxis, therapy, detection, and vaccine candidate identification, highlighting the novel epitope bridging adjacent NA monomers as the inventive basis.
Stated Advantages
These antibodies inhibit influenza virus spread and growth effectively and protect against viral infection when administered prophylactically.
Their mechanism of action differs from conventional NA inhibitors, making them effective against oseltamivir- or zanamivir-resistant viruses.
By binding conserved epitopes bridging adjacent NA monomers, these antibodies reduce the likelihood of rapidly selecting escape mutants, supporting broad antiviral efficacy.
They offer potential as therapeutics distinct from existing drugs, including suitability for emergency prophylaxis and treatment of at-risk populations.
Documented Applications
Use of the isolated monoclonal antibodies and antigen binding fragments for prevention or treatment of influenza infection in subjects, including administering therapeutically effective amounts to reduce viral load and symptoms.
Methods for detecting influenza virus infections in biological samples by contacting samples with the antibodies and detecting immune complexes indicating infection.
Using the antibodies to identify proteins as vaccine candidates by evaluating immune complex formation between candidate proteins and the antibodies.
Quantifying neuraminidase enzyme levels in samples by immune complex formation with the antibodies and subsequent detection.
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