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Sci Rep
. 2025 Apr 8;15(1):10309.
doi: 10.1038/s41598-025-94314-5. Intranasal administration of a panreactive influenza antibody reveals Fc-independent mode of protection
Anna L Beukenhorst 1 2 , Keira L Rice 3 , Jacopo Frallicciardi 3 , Martin H Koldijk 3 , Carolyn M Boudreau 3 , Justin Crawford 3 , Lisette A H M Cornelissen 4 , Kelly A S da Costa 5 , Babette A de Jong 3 , Stephanie Fischinger 3 , Boris Julg 3 6 , Jaco M Klap 3 , Clarissa M Koch 3 , Zoltán Magyarics 3 , Faez A Nait Mohamed 6 , Vintus Okonkwo 6 , Lindsey Adams 6 , Caitlin M McCarthy 6 , Larance Ronsard 6 , Nigel Temperton 5 , Helene Vietsch 3 , Kanin Wichapong 7 8 , Bertjan Ziere 3 , Daniel Lingwood 6 , Jaap Goudsmit 9 10
Affiliations
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.
. 2025 Apr 8;15(1):10309.
doi: 10.1038/s41598-025-94314-5. Intranasal administration of a panreactive influenza antibody reveals Fc-independent mode of protection
Anna L Beukenhorst 1 2 , Keira L Rice 3 , Jacopo Frallicciardi 3 , Martin H Koldijk 3 , Carolyn M Boudreau 3 , Justin Crawford 3 , Lisette A H M Cornelissen 4 , Kelly A S da Costa 5 , Babette A de Jong 3 , Stephanie Fischinger 3 , Boris Julg 3 6 , Jaco M Klap 3 , Clarissa M Koch 3 , Zoltán Magyarics 3 , Faez A Nait Mohamed 6 , Vintus Okonkwo 6 , Lindsey Adams 6 , Caitlin M McCarthy 6 , Larance Ronsard 6 , Nigel Temperton 5 , Helene Vietsch 3 , Kanin Wichapong 7 8 , Bertjan Ziere 3 , Daniel Lingwood 6 , Jaap Goudsmit 9 10
Affiliations
- PMID: 40199998
- PMCID: PMC11978755
- DOI: 10.1038/s41598-025-94314-5
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.