Single domain VHH antibodies directed to norovirus GI.1 and GII.4 and their use
Inventors
Bok, Karin • Garaicoechea, Lorena Laura • Parreno, Viviana • Aguilar, Andrea Pamela • Bok, Marina • Green, Lisbeth Kim • Sosnovtsev, Stanislav Vladimirovich
Assignees
Instituto Nacional de Tecnologia Agropecuaria INTA • US Department of Health and Human Services
Publication Number
US-10662238-B2
Publication Date
2020-05-26
Expiration Date
2034-05-09
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Abstract
Isolated VHH monoclonal antibodies are disclosed that specifically bind to a Norovirus polypeptide. In some embodiments, the Norovirus is a Genogroup I Norovirus or a Genogroup II Norovirus. In other embodiments, the Norovirus is Norwalk or MD2004 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. Also disclosed are methods of treating and/or preventing a NoV infection.
Core Innovation
The invention discloses isolated single-domain VHH monoclonal antibodies that specifically bind to Norovirus polypeptides, including those from Genogroup I and Genogroup II Noroviruses, such as Norwalk virus and MD2004 virus. These antibodies can specifically bind to the viral capsid protein VP1, including its P1 and P2 subdomains, and can be neutralizing. The antibodies may be derived from llamas, humanized, or chimeric, and include heavy chain variable domains with defined complementarity determining regions (CDRs). The invention also encompasses compositions including such antibodies, nucleic acids encoding them, expression vectors, and host cells expressing these nucleic acids.
The invention addresses the challenge of Norovirus infections, which are a leading cause of epidemic gastroenteritis and acute gastroenteritis in children, causing significant morbidity and mortality, especially in vulnerable populations like young children, the elderly, and immunocompromised individuals. Current limitations include the absence of cell culture systems to isolate and propagate Norovirus, limited antigenic characterization, lack of available vaccines or therapies, and the need for reagents capable of effective detection and neutralization of the virus.
The disclosed VHH monoclonal antibodies provide a novel source of high-affinity, thermostable, small molecular weight antibodies capable of binding to epitopes not readily accessible to conventional antibodies. Their stability, specificity, and ability to neutralize NoV by blocking viral capsid interactions with host ligands provide new opportunities for diagnostic detection, prophylaxis, and treatment of Norovirus infections. Methods using these antibodies for detecting Norovirus presence in biological samples and for treating or preventing Norovirus infections are also disclosed.
Claims Coverage
The patent includes one independent claim describing a method for treating Norovirus infection using specific isolated VHH monoclonal antibodies or encoding nucleic acids.
Use of isolated VHH monoclonal antibodies or antigen binding fragments
Administering a therapeutically effective amount of isolated VHH monoclonal antibody or an antigen binding fragment thereof, or nucleic acid molecule encoding the VHH or antigen binding fragment, to treat Norovirus infection.
Specific binding to Norovirus polypeptides with defined heavy chain variable domains
The antibodies specifically bind Norovirus polypeptides and comprise a heavy chain variable domain with complementarity determining regions (CDR1, CDR2, and CDR3) defined by amino acid sequences corresponding to SEQ ID NOs: 1 through 30, with respective CDR1, CDR2, and CDR3 sequences clearly delineated.
Treatment of Genogroup I or Genogroup II Norovirus infections
The method encompasses treatment of Norovirus infections from Genogroup I and/or Genogroup II using the disclosed antibodies.
Inclusion of antibody variants with at least 90% sequence identity
The antibodies used can have heavy chain variable domains at least 90% identical to the SEQ ID NOs specified, retaining the respective CDR sequences.
Option for humanized or chimeric antibodies
The antibodies can be humanized or chimeric monoclonal antibodies, including IgG isotypes.
Use in immunocompromised subjects and symptom amelioration
Methods include treatment in human subjects, including immunocompromised individuals, that reduce viral activity and ameliorate symptoms of Norovirus infection.
The claimed invention covers a therapeutic method for Norovirus infection using isolated VHH monoclonal antibodies or fragments having defined heavy chain variable region CDR sequences derived from SEQ ID NOs:1-30 and their nucleic acid encodings, including humanized or chimeric forms, specifically binding Genogroup I or II Norovirus polypeptides, to treat or ameliorate Norovirus infections.
Stated Advantages
The disclosed VHH antibodies have high affinity and specificity to Norovirus polypeptides, enabling effective detection and neutralization.
VHH antibodies are stable, small in size, and can access epitopes inaccessible to conventional antibodies, enhancing their therapeutic and diagnostic utility.
The antibodies can neutralize Norovirus by blocking viral capsid binding to host ligands, potentially reducing viral load and infection spread.
The invention provides antibodies that can be humanized or chimeric, reducing immunogenicity and improving clinical applicability.
The antibodies enable detection of different Norovirus genogroups and genotypes, improving diagnosis and surveillance.
Documented Applications
Use of VHH monoclonal antibodies for detecting Norovirus presence or infection in biological or environmental samples, including stool and tissue specimens.
Use in treatment and/or prevention of Norovirus infections, including GI.1 Norwalk virus and GII.4 MD2004 virus infections in humans, including immunocompromised subjects.
Use in neutralization assays and testing of vaccine efficacy by detecting antibody responses against Norovirus antigens.
Use in therapeutic methods to reduce noroviral infection or ameliorate gastroenteritis symptoms.
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