Intranasal administration of a panreactive influenza antibody reveals Fc-independent mode of protection

Beukenhorst, Anna L., Rice, Keira L., Frallicciardi, Jacopo, Koldijk, Martin H., Boudreau, Carolyn M., Crawford, Justin, Cornelissen, Lisette A. H. M., da Costa, Kelly A. S., de Jong, Babette A., Fischinger, Stephanie, and others. (2025) Intranasal administration of a panreactive influenza antibody reveals Fc-independent mode of protection. Scientific Reports, 15 (1). Article Number 10309. ISSN 2045-2322. (doi:10.1038/s41598-025-94314-5) (KAR id:109851)

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Official URL: https://doi.org/10.1038/s41598-025-94314-5

Abstract

Monoclonal antibodies have two core mechanisms of protection: an antibody's antigen-binding fragment (Fab) can bind and neutralize viral pathogens and its fragment crystallizable domain (Fc) catalyzes effector functions. We investigated the relative contribution of Fab- versus Fc-mediated mechanisms of protection through passive administration of distinct forms of the pan-reactive anti-influenza antibody CR9114. We demonstrated that the contribution of Fc-independent (Fab-dependent) versus Fc-dependent mechanisms of protection is defined by the route of administration. We used CR9114 variants (wild-type, two Fc-silenced variants, or the bivalent antigen-binding fragment F(ab')2), administered either intravenously or intranasally. We found that intravenously-administered CR9114 requires the Fc domain to provide potent, pre-exposure protection against influenza A and B viral challenge. In contrast, when CR9114 was administered locally to the nasal mucosa, the main mode of protection was provided by F(ab')2, and was largely Fc-independent. Importantly, this mode of protection following intranasal administration also applied to non-neutralized influenza B strains. Moreover, intranasal administration resulted in an increase in potency against influenza A/H1N1, A/H5N1, A/H3N2, B/Yam and B/Vic compared to intravenous administration up to 50-fold. These results shed new light on the application of monoclonal antibodies such as CR9114 to combat viral infection locally, and will help inform clinical strategies of pre-exposure prophylaxis. More fundamentally, this study uncovers distinct modes of protection for systemic versus intranasally-administered prophylactic antibodies.

Item Type:	Article
DOI/Identification number:	10.1038/s41598-025-94314-5
Subjects:	Q Science > QR Microbiology > QR355 Virology
Institutional Unit:	Schools > Medway School of Pharmacy
Former Institutional Unit:	Divisions > Division of Natural Sciences > Medway School of Pharmacy
Depositing User:	Nigel Temperton
Date Deposited:	06 May 2025 19:50 UTC
Last Modified:	14 Aug 2025 14:13 UTC
Resource URI:	https://kar.kent.ac.uk/id/eprint/109851 (The current URI for this page, for reference purposes)

University of Kent Author Information

Temperton, Nigel J..

Creator's ORCID:	https://orcid.org/0000-0002-7978-3815
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