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J Virol. 2015 Feb 11. pii: JVI.00078-15. [Epub ahead of print]
An anti-H5N1 influenza virus FcDART antibody is an highly efficacious therapeutic and prophylactic against H5N1 influenza virus infection.
Zanin M1, Keck ZY2, Rainey GJ3, Lam CY3, Boon AC1, Rubrum A1, Darnell D1, Wong SS1, Griffin Y1, Xia J2, Webster RG1, Webby R4, Johnson S3, Foung S2.
Author information
Abstract
Highly pathogenic H5N1 avian influenza viruses are associated with severe disease in humans and continue to be a pandemic threat. Whilst vaccines are available, other approaches are required for patients that typically respond poorly to vaccination, such as the elderly and the immunocompromised. To produce a therapeutic that is highly efficacious at low doses and is broadly specific against antigenically-drifted H5N1 influenza viruses, we developed two neutralizing monoclonal antibodies and combined them into a single bispecific-Fc fusion protein (FcDART). In mice, a single 2.5mg/kg therapeutic or prophylactic dose of either monoclonal antibody provided 100% protection against challenge with A/Vietnam/1203/04 (H5N1) or the antigenically-drifted strain A/Whooper swan/Mongolia/244/05 (H5N1). In ferrets, a single 1mg/kg prophylactic dose provided 100% protection against A/Vietnam/1203/04 challenge. FcDART was also effective, as a single 2.5mg/kg therapeutic or prophylactic dose in mice provided 100% protection against A/Vietnam/1203/04 challenge. Antibodies bound to conformational epitopes in antigenic sites on the globular head of the hemagglutinin protein, based on antibody escape mutations. Whilst it was possible to generate escape mutants in vitro, they were neutralized in vivo by the antibodies, as mice infected with escape mutants were 100% protected after only a single therapeutic dose of the antibody used to generate the escape mutant in vitro. In summary, we have combined the antigen specificities of two highly efficacious anti-H5N1 influenza virus antibodies into a bispecific FcDART, which represents a strategy to produce broadly neutralizing antibodies that are effective against antigenically diverse influenza viruses.
IMPORTANCE:
Highly pathogenic H5N1 avian influenza viruses are associated with severe disease in humans and are a pandemic threat. A vaccine is available but other approaches are required for patients that typically respond poorly to vaccination, such as the elderly and the immunocompromised. The variability of the virus means that such an approach must be broad spectrum. To achieve this, we developed two antibodies that neutralize H5N1 influenza viruses. These antibodies provided complete protection in mice against a spectrum of H5N1 influenza viruses at a single low dose. We then combined the two antibodies into a single molecule, FcDART, which combined the broad spectrum activity and protective efficacy of both antibodies. This treatment strategy represents a novel and effective therapeutic or prophylactic against highly pathogenic H5N1 avian influenza viruses.
Copyright ? 2015, American Society for Microbiology. All Rights Reserved.
PMID: 25673719 [PubMed - as supplied by publisher]
An anti-H5N1 influenza virus FcDART antibody is an highly efficacious therapeutic and prophylactic against H5N1 influenza virus infection.
Zanin M1, Keck ZY2, Rainey GJ3, Lam CY3, Boon AC1, Rubrum A1, Darnell D1, Wong SS1, Griffin Y1, Xia J2, Webster RG1, Webby R4, Johnson S3, Foung S2.
Author information
Abstract
Highly pathogenic H5N1 avian influenza viruses are associated with severe disease in humans and continue to be a pandemic threat. Whilst vaccines are available, other approaches are required for patients that typically respond poorly to vaccination, such as the elderly and the immunocompromised. To produce a therapeutic that is highly efficacious at low doses and is broadly specific against antigenically-drifted H5N1 influenza viruses, we developed two neutralizing monoclonal antibodies and combined them into a single bispecific-Fc fusion protein (FcDART). In mice, a single 2.5mg/kg therapeutic or prophylactic dose of either monoclonal antibody provided 100% protection against challenge with A/Vietnam/1203/04 (H5N1) or the antigenically-drifted strain A/Whooper swan/Mongolia/244/05 (H5N1). In ferrets, a single 1mg/kg prophylactic dose provided 100% protection against A/Vietnam/1203/04 challenge. FcDART was also effective, as a single 2.5mg/kg therapeutic or prophylactic dose in mice provided 100% protection against A/Vietnam/1203/04 challenge. Antibodies bound to conformational epitopes in antigenic sites on the globular head of the hemagglutinin protein, based on antibody escape mutations. Whilst it was possible to generate escape mutants in vitro, they were neutralized in vivo by the antibodies, as mice infected with escape mutants were 100% protected after only a single therapeutic dose of the antibody used to generate the escape mutant in vitro. In summary, we have combined the antigen specificities of two highly efficacious anti-H5N1 influenza virus antibodies into a bispecific FcDART, which represents a strategy to produce broadly neutralizing antibodies that are effective against antigenically diverse influenza viruses.
IMPORTANCE:
Highly pathogenic H5N1 avian influenza viruses are associated with severe disease in humans and are a pandemic threat. A vaccine is available but other approaches are required for patients that typically respond poorly to vaccination, such as the elderly and the immunocompromised. The variability of the virus means that such an approach must be broad spectrum. To achieve this, we developed two antibodies that neutralize H5N1 influenza viruses. These antibodies provided complete protection in mice against a spectrum of H5N1 influenza viruses at a single low dose. We then combined the two antibodies into a single molecule, FcDART, which combined the broad spectrum activity and protective efficacy of both antibodies. This treatment strategy represents a novel and effective therapeutic or prophylactic against highly pathogenic H5N1 avian influenza viruses.
Copyright ? 2015, American Society for Microbiology. All Rights Reserved.
PMID: 25673719 [PubMed - as supplied by publisher]