ABSTRACT
Rapidly evolving influenza A viruses (IAVs) and influenza B viruses (IBVs) are major causes of recurrent lower respiratory tract infections. Current influenza vaccines elicit antibodies predominantly to the highly variable head region of haemagglutinin and their effectiveness is limited by viral drift1 and suboptimal immune responses2. Here we describe a neuraminidase-targeting monoclonal antibody, FNI9, that potently inhibits the enzymatic activity of all group 1 and group 2 IAVs, as well as Victoria/2/87-like, Yamagata/16/88-like and ancestral IBVs. FNI9 broadly neutralizes seasonal IAVs and IBVs, including the immune-evading H3N2 strains bearing an N-glycan at position 245, and shows synergistic activity when combined with anti-haemagglutinin stem-directed antibodies. Structural analysis reveals that D107 in the FNI9 heavy chain complementarity-determinant region 3 mimics the interaction of the sialic acid carboxyl group with the three highly conserved arginine residues (R118, R292 and R371) of the neuraminidase catalytic site. FNI9 demonstrates potent prophylactic activity against lethal IAV and IBV infections in mice. The unprecedented breadth and potency of the FNI9 monoclonal antibody supports its development for the prevention of influenza illness by seasonal and pandemic viruses.
Subject(s)
Antibodies, Viral , Antibody Specificity , Influenza A virus , Influenza B virus , Influenza Vaccines , Influenza, Human , Molecular Mimicry , Neuraminidase , Animals , Humans , Mice , Antibodies, Monoclonal/chemistry , Antibodies, Monoclonal/immunology , Antibodies, Monoclonal/therapeutic use , Antibodies, Viral/chemistry , Antibodies, Viral/immunology , Antibodies, Viral/therapeutic use , Antibody Specificity/immunology , Arginine/chemistry , Catalytic Domain , Hemagglutinins, Viral/immunology , Influenza A virus/classification , Influenza A virus/enzymology , Influenza A virus/immunology , Influenza A Virus, H3N2 Subtype/enzymology , Influenza A Virus, H3N2 Subtype/immunology , Influenza B virus/classification , Influenza B virus/enzymology , Influenza B virus/immunology , Influenza Vaccines/chemistry , Influenza Vaccines/immunology , Influenza Vaccines/therapeutic use , Influenza, Human/immunology , Influenza, Human/prevention & control , Neuraminidase/antagonists & inhibitors , Neuraminidase/chemistry , Neuraminidase/immunology , Orthomyxoviridae Infections/immunology , Orthomyxoviridae Infections/prevention & control , Seasons , Sialic Acids/chemistryABSTRACT
In the aftermath of the COVID-19 pandemic, opportunities to modulate biological pathways common to the lifecycles of viruses need to be carefully considered. N-linked glycosylation in humans is mediated exclusively by the oligosaccharyltransferase complex and is frequently hijacked by viruses to facilitate infection. As such, STT3A/B, the catalytic domain of the OST complex, became an intriguing drug target with broad-spectrum antiviral potential. However, due to the critical role N-linked glycosylation plays in a number of fundamental human processes, the toxicological ramifications of STT3A/B inhibition required attention commensurate to that given to antiviral efficacy. Herein, we describe how known STT3A/B inhibitor NGI-1 inspired the discovery of superior tool compounds which were evaluated in in vitro efficacy and translational safety (e.g., CNS, cardiovascular, liver) studies. The described learnings will appeal to those interested in the therapeutic utility of modulating N-linked glycosylation as well as the broader scientific community.