An Anti-H5N1 Influenza Virus FcDART Antibody Is a Highly Efficacious Therapeutic Agent and Prophylactic against H5N1 Influenza Virus Infection

Abstract

Highly pathogenic H5N1 avian influenza viruses are associated with severe disease in humans and continue to be a pandemic threat. While 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 agent 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 IMPORTANCEHighly 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. In mice, these antibodies provided complete protection 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 provides a novel and effective therapeutic agent or prophylactic with activity against highly pathogenic H5N1 avian influenza viruses.

Bispecific VH/Fab antibodies targeting neutralizing and non-neutralizing Spike epitopes demonstrate enhanced potency against SARS-CoV-2

“…A parallel strategy to improve potency is to target multiple epitopes, either by engineering bispecific or multi-specific molecules or by combining multiple antibodies into a cocktail. 21 , 28 Targeting multiple epitopes has the added benefit of decreasing the likelihood of viral escape and resistance, 18 , 29 and has shown promise as a powerful viral immunotherapy against viruses, such as influenza 30 and HIV. 31 Indeed, several cocktails 12 , 29 and engineered multi-specific binders 19 , 32 have been shown to be effective against SARS-CoV-2.…”

Evaluation of multivalent H2 influenza pandemic vaccines in mice

“…Micronuetralization Assay (MN) MN titers were determined as described previously [50] using serum dilutions beginning 1:10, 100 TCID 50 units of each virus, and detection with erythrocytes as in the HAI assay.…”

Bispecific antibodies for viral immunotherapy

“…Zanin et al developed two neutralizing monoclonal antibodies against H5 influenza viruses of different clades, and combined them into a single bispecifc Fc-domain fusion protein (referred to as Fc-dual-affinity retargeting molecule, or FcDART). 17 The generated FcDART consist of 2 Fc-fusion protein chains that dimerize to form antibody derived binding sites. One polypeptide chain connects the light chain variable region (v L ) of the first antibody with the heavy chain variable region (v H ) of the second antibody via a Gly-Ser linker, and the second polypeptide contains the complementary variable regions.…”