Monoclonal antibodies that neutralize a norovirus
Inventors
Chen, Zhaochun • Purcell, Robert H. • Green, Lisbeth Kim • Sosnovtsev, Stanislav • Bok, Karin
Assignees
US Department of Health and Human Services
Publication Number
US-9534041-B2
Publication Date
2017-01-03
Expiration Date
2034-02-11
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Abstract
Monoclonal neutralizing antibodies are disclosed that specifically bind to a Norovirus. In some embodiments, the Norovirus is a genogroup II Norovirus or a Genogroup II Norovirus. In some embodiments, the Norovirus is Norwalk virus. In some embodiments, the monoclonal antibodies specifically bind VP1. Also disclosed are compositions including the disclosed antibodies, nucleic acids encoding these antibodies, expression vectors including the nucleic acids, and isolated host cells that express the nucleic acids. The antibodies and compositions disclosed herein can be used for detecting the presence of a Norovirus in a biological sample, or detecting a Norovirus infection. In addition, the neutralization ability of the disclosed antibodies makes them ideal for treating a subject with a Norovirus infection. Thus, disclosed are methods of treating and/or preventing these infections.
Core Innovation
The invention discloses monoclonal neutralizing antibodies that specifically bind to Norovirus (NoV), including genogroup I and genogroup II NoVs such as Norwalk virus. These antibodies can specifically bind viral protein VP1, including its P1 or P2 subdomains, with high affinity (Kd of 1 nM or less). The antibodies may be chimpanzee-derived, humanized, or chimeric, and can be provided as full antibodies or antigen binding fragments like Fabs or scFvs.
The disclosed antibodies and compositions including nucleic acids encoding them, expression vectors, and host cells expressing the antibodies, are useful for detecting the presence of Norovirus in biological samples and diagnosing infections. Further, the neutralizing ability of the antibodies enables their use in treating or preventing Norovirus infections by administering therapeutically effective amounts to subjects to reduce viral titers and disease symptoms.
The problem solved arises from the significant disease burden caused by NoVs worldwide, especially gastroenteritis outbreaks without specific antiviral therapies or vaccines available. Existing challenges include rapid virus evolution, lack of long-term immunity, and poorly understood immune correlates. The invention addresses the need for agents for treatment and diagnosis by providing specific monoclonal antibodies capable of neutralizing NoV, including probes to detect infections and therapeutic agents to treat or prevent infections.
Claims Coverage
The patent contains one primary independent claim directed to an isolated monoclonal antibody with defined complementarity determining regions (CDRs) that specifically binds Norwalk Virus VP1 with high affinity. Additional claims cover variants, fragments, labeled antibodies, compositions, nucleic acids, host cells, and methods of detection and treatment.
Monoclonal antibody with specific complementarity determining regions
An isolated monoclonal antibody comprising heavy and light chain variable domains, where the heavy chain CDR1, CDR2, and CDR3 and the light chain CDR1, CDR2, and CDR3 sequences are specifically defined by SEQ ID NOs selected among listed sequences (e.g., SEQ ID NO: 18, 20, 22 for HCDRs and SEQ ID NO: 26, 28, 30 for LCDRs) and that binds Norwalk Virus VP1 with a dissociation constant (Kd) of 1 nM or less.
Antibody variable domain sequence identities
The heavy chain variable domain comprises amino acid sequences of SEQ ID NOs: 8, 24, 40, 56, or 72 and the light chain variable domain comprises SEQ ID NOs: 16, 32, 48, 64, or 80, ensuring specificity to Norwalk Virus VP1.
Pairs of heavy and light chain variable domains
Specific pairs of heavy and light chain variable domain sequences are claimed, including combinations such as heavy chain SEQ ID NO: 8 with light chain SEQ ID NO: 16, heavy chain SEQ ID NO: 24 with light chain SEQ ID NO: 32, among others, defining particular monoclonal antibodies.
Isotypes and formats of antibodies
The monoclonal antibody can be of various isotypes such as IgG, IgM or IgA, and include humanized or chimeric forms. Antigen binding fragments like Fab, Fab', F(ab')2, scFv, or disulfide stabilized Fv are also covered.
Labeled antibodies and compositions
Antibodies or antigen binding fragments can be labeled with fluorescent, enzymatic or radioactive markers and formulated in pharmaceutical compositions with acceptable carriers.
Nucleic acids and expression systems
Isolated nucleic acid molecules encoding the claimed antibodies or fragments, operably linked to promoters and included in expression vectors, as well as host cells transformed with such vectors, are part of the claimed subject matter.
Diagnostic methods using antibodies
Methods for detecting Norwalk virus infection by contacting a biological sample with the isolated monoclonal antibody or fragment and detecting antibody binding indicative of infection are claimed, including use of directly labeled antibodies or secondary antibodies for detection.
Therapeutic methods for treatment of Norwalk infection
Methods of treating Norwalk virus infection by administering therapeutically effective amounts of the antibody, antigen binding fragment, or nucleic acid encoding them, optionally combined with an antiviral agent, with possible monitoring of viral titer.
The claims encompass isolated monoclonal antibodies with specified CDR sequences and variable domains that specifically bind Norwalk Virus VP1 with high affinity, antibody fragments, labeled antibodies, nucleic acids, expression vectors and host cells, as well as diagnostic and therapeutic methods employing these antibodies or encoding nucleic acids.
Stated Advantages
The antibodies disclosed have neutralization ability reducing infectious titers of Norovirus, making them ideal for treatment.
Use of these antibodies enables detection and diagnosis of Norovirus infection with high specificity.
The antibodies can be used for emergency prophylaxis to protect individuals at risk or exposed to NoV outbreaks.
Such antibodies may alleviate chronic NoV gastroenteritis in vulnerable populations such as immunocompromised individuals or elderly patients.
Documented Applications
Detecting the presence of a Norovirus in biological samples including stool, environmental and clinical specimens.
Treating and preventing Norovirus infections in subjects, including vulnerable populations like infants, elderly, and immunocompromised.
Using monoclonal antibodies or their nucleic acids as emergency prophylaxis during Norovirus outbreaks.
Testing vaccine compositions for efficacy by detecting conformational Norovirus antigens that elicit neutralizing immune responses.
Administering antibodies in therapeutic regimens, including co-administration with antiviral agents and electrolyte support.
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