Broadly neutralizing antibodies (
bnAbs) targeting the receptor binding site (RBS) of
hemagglutinin (HA) have potential for developing into powerful anti-
influenza agents. Several previously reported
influenza B
bnAbs are nevertheless unable to neutralize a portion of influenza B virus variants. HA-specific
bnAbs with hemagglutination inhibition (HI) activity may possess the ability to block virus entry directly.
Polymeric IgM antibodies are expected to more effectively inhibit virus attachment and entry into target cells due to their higher avidity and/or steric hindrance. We therefore hypothesized that certain RBS-targeted
IgM antibodies with strong cross-lineage HI activity might display broader and more potent
antiviral activity against rapidly evolving influenza B viruses. Methods: In this study, we generated
IgM and
IgG bnAbs targeting the RBS of influenza B virus using the murine hybridoma technique.
IgM and
IgG versions of the same
antibodies were then developed by isotype switching and characterized in subsequent in vitro and in vivo experiments. Results: Two
IgM and two
IgG bnAbs against influenza B virus HA were identified. Of these, one
IgM subtype antibody, C7G6-IgM, showed strong HI and neutralization activities against all 20 representative
influenza B strains tested, with higher potency and broader breadth of anti-
influenza activity in vitro than the
IgG subtype variant of itself, or other previously-reported
influenza B
bnAbs. Furthermore, C7G6-IgM conferred excellent cross-protection against distinct lineages of influenza B viruses in mice and ferrets, performing better than the anti-
influenza drug
oseltamivir, and showed an additive
antiviral effect when administered in combination with
oseltamivir. Mechanistically, C7G6-IgM potently inhibits
infection with influenza B virus strains from different lineages by blocking viral entry. Conclusion: In summary, our study highlights the potential of
IgM subtype
antibodies in combatting pathogenic microbes. Moreover, C7G6-IgM is a promising candidate for the development of prophylactics or
therapeutics against
influenza B
infection.