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-9815887-B2
Publication Date
2017-11-14
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 Nowalk 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 isolated monoclonal neutralizing antibodies that specifically bind to Norovirus (NoV), including genogroup I and genogroup II NoVs, such as Norwalk virus (NV) and MD145-12. These antibodies can specifically bind to the viral capsid protein VP1, including its P1 and P2 subdomains, with high affinity (equilibrium constant Kd of 1 nM or less). The antibodies include chimpanzee monoclonal antibodies, humanized antibodies, and chimeric antibodies incorporating chimpanzee and human regions.
The antibodies are characterized by specific heavy and light chain variable regions and complementarity determining regions (CDRs), which confer specificity and neutralization ability against Norovirus. The antibodies and their antigen binding fragments can be used in compositions, including nucleic acids encoding these antibodies, expression vectors, and host cells expressing these nucleic acids. The disclosed antibodies can be labeled for detection purposes or linked to other molecules to enhance their functional utility.
The invention addresses the problem that Norovirus infections, a leading cause of epidemic gastroenteritis worldwide, currently lack vaccines or specific antiviral therapies due to challenges like the unavailability of permissive cell-culture systems and animal disease models. Moreover, immune correlates of protection remain poorly understood. There is a need for agents that can diagnose and treat NoV infections effectively.
The disclosed monoclonal antibodies provide a solution by specifically binding and neutralizing Norovirus, thus offering a tool for detecting viral presence in biological samples and methods for treating and preventing NoV infections in subjects, including vulnerable populations. These antibodies can reduce viral titers, inhibit hemagglutination, and block viral binding to histo-blood group antigens, offering direct prophylactic and therapeutic benefits against NoV infections.
Claims Coverage
The patent claims cover several inventive features related to monoclonal antibodies that specifically bind to Norovirus polypeptides, particularly focusing on their variable regions and therapeutic or diagnostic uses.
Monoclonal antibody variable region specificity
An isolated monoclonal antibody comprising heavy and light chain variable domains, where the heavy chain variable domain includes specific heavy chain complementarity determining regions (HCDR1, HCDR2, HCDR3) of defined amino acid sequences (SEQ ID NOs: 82, 84, 86 or variants thereof) and the light chain variable domain includes specific light chain complementarity determining regions (LCDR1, LCDR2, LCDR3) (SEQ ID NOs: 90, 92, 94 or variants thereof), conferring specific binding to a Norovirus antigen.
Heavy and light chain variable domain sequences
The antibody's heavy chain variable domain comprises one of the amino acid sequences set forth as SEQ ID NOs: 88, 104, 120, or 136 and the light chain variable domain comprises one of SEQ ID NOs: 96, 112, 128, or 144.
Combinations of heavy and light chain variable domains
Specific paired combinations of heavy chain variable domains with light chain variable domains are claimed, such as SEQ ID NO: 88 with SEQ ID NO: 96, SEQ ID NO: 104 with SEQ ID NO: 112, SEQ ID NO: 120 with SEQ ID NO: 128, or SEQ ID NO: 136 with SEQ ID NO: 144.
Antibody isotype and origin
The antibody can be of isotype IgG, IgM, or IgA and can be humanized or chimeric to suit therapeutic or diagnostic applications.
Antigen binding fragment
Isolated antigen binding fragments of the monoclonal antibody, including Fab, Fab', F(ab')2, single chain Fv (scFv), or disulfide stabilized Fv (dsFv) fragments, are claimed.
Labeling of antibodies and fragments
The antibodies or antigen binding fragments can be labeled with detectable labels such as fluorescent, enzymatic, or radioactive labels for use in detection or diagnostic assays.
Pharmaceutical compositions
Compositions comprising an effective amount of the antibody or antigen binding fragment and a pharmaceutically acceptable carrier for therapeutic use.
Nucleic acids encoding antibodies
Isolated nucleic acid molecules encoding the monoclonal antibody or antigen binding fragment, operably linked to promoters, vectors containing these nucleic acids, and host cells transformed with the vectors for expression of the antibody.
Methods of detecting Norovirus infection
Methods for detecting Norovirus infection in a subject by contacting a biological sample with the monoclonal antibody or fragment and detecting antibody binding as an indication of infection. This includes direct labeling or use of a secondary antibody for detection.
Methods of inhibiting Norovirus infection
Methods for inhibiting Norovirus infection in a subject by administering a therapeutically effective amount of the monoclonal antibody or fragment, optionally together with an antiviral agent, and monitoring viral titer.
The patent claims comprehensively cover monoclonal antibodies specific for Norovirus polypeptides with defined variable regions and CDR sequences, their fragments, labeled forms, nucleic acid encoding sequences, compositions including these antibodies, and their use in diagnostic and therapeutic methods to detect, prevent, and treat Norovirus infections.
Stated Advantages
The disclosed antibodies have neutralization ability against Norovirus infections, making them suitable for treatment and prevention.
The antibodies can be used for detecting the presence of Norovirus in biological samples, providing diagnostic utility.
Antibodies derived from chimpanzees may be administered to humans with minimal modification due to immunoglobulin similarities.
The use of antibodies provides immediate protection in high-risk populations as emergency prophylaxis.
Antibody treatments can help alleviate chronic NoV gastroenteritis in immunocompromised or debilitated individuals.
Documented Applications
Detecting the presence of Norovirus in biological or environmental samples using the disclosed antibodies.
Treating or preventing Norovirus infections, including those caused by genogroup I and II Noroviruses such as Norwalk virus and MD145-12 virus.
Using the antibodies in diagnostic kits and immunoassays to detect NoV polypeptides, especially VP1, in clinical samples.
Administering the antibodies as therapeutic agents to reduce viral titers and alleviate symptoms in infected subjects.
Using nucleic acids encoding the antibodies for recombinant expression in host cells for therapeutic antibody production.
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