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, Julg Boris, Klap Jaco M, Koch Clarissa M, Magyarics Zoltán, Mohamed Faez A Nait, Okonkwo Vintus, Adams Lindsey, McCarthy Caitlin M, Ronsard Larance, Temperton Nigel, Vietsch Helene, Wichapong Kanin, Ziere Bertjan, Lingwood Daniel, Goudsmit Jaap
Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
Leyden Laboratories, Leiden, The Netherlands.
Sci Rep. 2025 Apr 8;15(1):10309. 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')), 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'), 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.
抗体的抗原结合片段（Fab）能结合并中和病毒病原体，其可结晶片段结构域（Fc）则催化效应功能。我们通过被动给予不同形式的全反应性抗流感抗体CR9114，研究了Fab介导与Fc介导的保护机制的相对贡献。我们证明，不依赖Fc（依赖Fab）与依赖Fc的保护机制的贡献取决于给药途径。我们使用了CR9114变体（野生型、两种Fc沉默变体或二价抗原结合片段F(ab')），通过静脉内或鼻内给药。我们发现，静脉内给予的CR9114需要Fc结构域来提供针对甲型和乙型流感病毒攻击的强效暴露前保护。相比之下，当CR9114局部给予鼻黏膜时，主要的保护模式由F(ab')提供，且在很大程度上不依赖Fc。重要的是，鼻内给药后的这种保护模式也适用于未被中和的乙型流感毒株。此外，与静脉内给药相比，鼻内给药对甲型H1N1、甲型H5N1、甲型H3N2、乙型Yam和乙型Vic流感的效力提高了50倍。这些结果为诸如CR9114等单克隆抗体在局部对抗病毒感染的应用提供了新的思路，并将有助于为暴露前预防的临床策略提供参考。更根本的是，这项研究揭示了全身给药与鼻内给药的预防性抗体的不同保护模式。
