tetano
Editor, Senior Moderator
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[SUP] 1 2 [/SUP], Keira L Rice[SUP] 3 [/SUP], Jacopo Frallicciardi[SUP] 3 [/SUP], Martin H Koldijk[SUP] 3 [/SUP], Carolyn M Boudreau[SUP] 3 [/SUP], Justin Crawford[SUP] 3 [/SUP], Lisette A H M Cornelissen[SUP] 4 [/SUP], Kelly A S da Costa[SUP] 5 [/SUP], Babette A de Jong[SUP] 3 [/SUP], Stephanie Fischinger[SUP] 3 [/SUP], Boris Julg[SUP] 3 6 [/SUP], Jaco M Klap[SUP] 3 [/SUP], Clarissa M Koch[SUP] 3 [/SUP], Zoltán Magyarics[SUP] 3 [/SUP], Faez A Nait Mohamed[SUP] 6 [/SUP], Vintus Okonkwo[SUP] 6 [/SUP], Lindsey Adams[SUP] 6 [/SUP], Caitlin M McCarthy[SUP] 6 [/SUP], Larance Ronsard[SUP] 6 [/SUP], Nigel Temperton[SUP] 5 [/SUP], Helene Vietsch[SUP] 3 [/SUP], Kanin Wichapong[SUP] 7 8 [/SUP], Bertjan Ziere[SUP] 3 [/SUP], Daniel Lingwood[SUP] 6 [/SUP], Jaap Goudsmit[SUP] 9 10 [/SUP]
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')[SUB]2[/SUB]), 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')[SUB]2[/SUB], 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[SUP] 1 2 [/SUP], Keira L Rice[SUP] 3 [/SUP], Jacopo Frallicciardi[SUP] 3 [/SUP], Martin H Koldijk[SUP] 3 [/SUP], Carolyn M Boudreau[SUP] 3 [/SUP], Justin Crawford[SUP] 3 [/SUP], Lisette A H M Cornelissen[SUP] 4 [/SUP], Kelly A S da Costa[SUP] 5 [/SUP], Babette A de Jong[SUP] 3 [/SUP], Stephanie Fischinger[SUP] 3 [/SUP], Boris Julg[SUP] 3 6 [/SUP], Jaco M Klap[SUP] 3 [/SUP], Clarissa M Koch[SUP] 3 [/SUP], Zoltán Magyarics[SUP] 3 [/SUP], Faez A Nait Mohamed[SUP] 6 [/SUP], Vintus Okonkwo[SUP] 6 [/SUP], Lindsey Adams[SUP] 6 [/SUP], Caitlin M McCarthy[SUP] 6 [/SUP], Larance Ronsard[SUP] 6 [/SUP], Nigel Temperton[SUP] 5 [/SUP], Helene Vietsch[SUP] 3 [/SUP], Kanin Wichapong[SUP] 7 8 [/SUP], Bertjan Ziere[SUP] 3 [/SUP], Daniel Lingwood[SUP] 6 [/SUP], Jaap Goudsmit[SUP] 9 10 [/SUP]
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')[SUB]2[/SUB]), 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')[SUB]2[/SUB], 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.