Broadly neutralizing hemagglutinin stalk-specific antibodies require FcγR interactions for protection against influenza virus in vivo.
Broadly neutralizing hemagglutinin stalk-specific antibodies require FcγR interactions for protection against influenza virus in vivo.
复制标题
作者：
抗流感病毒的中和抗体传统上被认为仅通过其可变区提供保护; Fc结构域赋予的机制的贡献仍然存在争议。我们研究了Fc与其同源受体相互作用对中和抗流感抗体集合的体内贡献。靶向血凝素（HA）保守茎区的5种广泛中和单克隆抗体（bNAb）需要抗体Fc和IgG Fc受体（Fcγ R）之间的相互作用，以提供对致死性H1N1攻击的保护，而针对HA可变头部结构域的3种毒株特异性单克隆抗体（mAb）在存在或不存在FcγR相互作用的情况下具有同等保护性。尽管所有抗体都能阻断感染，但只有抗茎bNAb能够介导感染细胞的细胞毒性，这解释了它们对FcγR的依赖性。用抗HA茎mAb产生的免疫复合物有效地与Fcγ R相互作用，但抗HA头部免疫复合物不与Fc γ R相互作用。这些结果表明，抗HA抗体的FcγR结合能力取决于同源Fab与抗原的相互作用。我们利用这些不同的mAb介导的保护机制来重新设计抗茎bNAb，以选择性地增强FcγR结合，从而增强其保护活性。这些发现揭示了bNAb以前未表征的性质，并指导了增强mAb介导的抗病毒治疗的方法。
Neutralizing antibodies against influenza viruses have traditionally been thought to provide protection exclusively through their variable region; the contributions of mechanisms conferred by the Fc domain remain controversial. We investigated the in vivo contributions of Fc interactions with their cognate receptors for a collection of neutralizing anti-influenza antibodies. Whereas five broadly neutralizing monoclonal antibodies (bNAbs) targeting the conserved stalk region of hemagglutinin (HA) required interactions between the antibody Fc and Fc receptors for IgG (FcγRs) to confer protection from lethal H1N1 challenge, three strain-specific monoclonal Abs (mAbs) against the variable head domain of HA were equally protective in the presence or absence of FcγR interactions. Although all antibodies blocked infection, only anti-stalk bNAbs were capable of mediating cytotoxicity of infected cells, which accounts for their FcγR dependence. Immune complexes generated with anti–HA stalk mAb efficiently interacted with FcγRs, but anti–HA head immune complexes did not. These results suggest that FcγR binding capacity by anti-HA antibodies was dependent on the interaction of the cognate Fab with antigen. We exploited these disparate mechanisms of mAb-mediated protection to reengineer an anti-stalk bNAb to selectively enhance FcγR engagement to augment its protective activity. These findings reveal a previously uncharacterized property of bNAbs and guide an approach toward enhancing mAb-mediated antiviral therapeutics.
登录
查看更多内容
DOI：
10.1111/j.1432-1033.1987.tb10541.x
发表时间：
1987-01-02
期刊：
EUROPEAN JOURNAL OF BIOCHEMISTRY
影响因子：
--
作者：
KILAR, F;ZAVODSZKY, P
通讯作者：
ZAVODSZKY, P
影响因子：
4.4
作者：
El Bakkouri, Karim;Descamps, Francis;Saelens, Xavier
通讯作者：
Saelens, Xavier
影响因子：
4.3
作者：
Belser JA;Katz JM;Tumpey TM
通讯作者：
Tumpey TM
DOI：
10.1084/jem.20100995
发表时间：
2010-10-25
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Abboud N;Chow SK;Saylor C;Janda A;Ravetch JV;Scharff MD;Casadevall A
通讯作者：
Casadevall A
影响因子：
5.4
作者：
Jegaskanda, Sinthujan;Weinfurter, Jason T.;Kent, Stephen J.
通讯作者：
Kent, Stephen J.