An anti-H5N1 influenza virus FcDART antibody is a highly efficacious therapeutic agent and prophylactic against H5N1 influenza virus infection.
An anti-H5N1 influenza virus FcDART antibody is a highly efficacious therapeutic agent and prophylactic against H5N1 influenza virus infection.
复制标题
抗H5N1流感病毒FcDART抗体是针对H5N1流感病毒感染的高效治疗剂和预防剂。
DOI：
10.1128/jvi.00078-15
复制
发表时间：
2015
影响因子：
5.4
通讯作者：
Foung,Steven
中科院分区：
文献类型：
--
作者：
Zanin,Mark;Keck,Zhen-Yong;Rainey,GJonah;Lam,Chia-YingKao;Boon,AdrianusCM;Rubrum,Adam;Darnell,Daniel;Wong,Sook-San;Griffin,Yolanda;Xia,Jinming;Webster,RobertG;Webby,Richard;Johnson,Syd;Foung,Steven
高致病性H5 N1禽流感病毒与严重的人类疾病有关，并继续成为大流行的威胁。虽然疫苗是可用的，但对于通常对疫苗接种反应不佳的患者，如老年人和免疫功能低下的患者，需要其他方法。为了生产在低剂量下高度有效并且对抗原漂移的H5 N1流感病毒具有广泛特异性的治疗剂，我们开发了两种中和单克隆抗体，并将它们组合成单个双特异性Fc融合蛋白（Fc双亲和力重靶向[FcDART]分子）。在小鼠中，2.5 mg/kg体重单次治疗或预防剂量的单克隆抗体对A/Vietnam/1203/04（H5 N1）或抗原漂移株A/Whooper swan/Mongolia/244/05（H5 N1）的攻击提供了100%的保护。在雪貂中，单次1 mg/kg预防性给药对A/Vietnam/1203/04攻毒提供了100%的保护。FcDART也是有效的，因为小鼠单次给予2.5 mg/kg治疗或预防剂量可提供100%的抗A/Vietnam/1203/04攻击保护。基于对具有抗体逃逸突变的突变体的分析，抗体与血凝素蛋白球状头部抗原位点中的构象表位结合。虽然有可能在体外产生逃逸突变体，但它们在体内被抗体中和，因为感染逃逸突变体的小鼠在仅使用单一治疗剂量的抗体用于在体外产生逃逸突变体后100%受到保护。总之，我们将两种高效抗H5 N1流感病毒抗体的抗原特异性结合到双特异性FcDART分子中，这代表了一种生产有效对抗抗原多样性流感病毒的广泛中和抗体的策略。重要信息高致病性H5 N1禽流感病毒与人类严重疾病相关，是大流行的威胁。疫苗是可用的，但对于通常对疫苗接种反应不佳的患者，如老年人和免疫功能低下的患者，需要其他方法。病毒的变异性意味着这种方法必须是广谱的。为了实现这一目标，我们开发了两种中和H5 N1流感病毒的抗体。在小鼠中，这些抗体以单一低剂量提供了针对H5 N1流感病毒谱的完全保护。然后，我们将两种抗体组合成单一分子FcDART，其结合了两种抗体的广谱活性和保护功效。这种治疗提供了一种新的和有效的治疗剂或预防剂，其具有抗高致病性H5 N1禽流感病毒的活性。
Highly pathogenic H5N1 avian influenza viruses are associated with severe disease in humans and continue to be a pandemic threat. While vaccines are available, other approaches are required for patients that typically respond poorly to vaccination, such as the elderly and the immunocompromised. To produce a therapeutic agent that is highly efficacious at low doses and is broadly specific against antigenically drifted H5N1 influenza viruses, we developed two neutralizing monoclonal antibodies and combined them into a single bispecific Fc fusion protein (the Fc dual-affinity retargeting [FcDART] molecule). In mice, a single therapeutic or prophylactic dose of either monoclonal antibody at 2.5 mg/kg of body weight provided 100% protection against challenge with A/Vietnam/1203/04 (H5N1) or the antigenically drifted strain A/Whooper swan/Mongolia/244/05 (H5N1). In ferrets, a single 1-mg/kg prophylactic dose provided 100% protection against A/Vietnam/1203/04 challenge. FcDART was also effective, as a single 2.5-mg/kg therapeutic or prophylactic dose in mice provided 100% protection against A/Vietnam/1203/04 challenge. Antibodies bound to conformational epitopes in antigenic sites on the globular head of the hemagglutinin protein, on the basis of analysis of mutants with antibody escape mutations. While it was possible to generate escape mutantsin vitro, they were neutralized by the antibodiesin vivo, as mice infected with escape mutants were 100% protected after only a single therapeutic dose of the antibody used to generate the escape mutantin vitro. In summary, we have combined the antigen specificities of two highly efficacious anti-H5N1 influenza virus antibodies into a bispecific FcDART molecule, which represents a strategy to produce broadly neutralizing antibodies that are effective against antigenically diverse influenza viruses.IMPORTANCEHighly pathogenic H5N1 avian influenza viruses are associated with severe disease in humans and are a pandemic threat. A vaccine is available, but other approaches are required for patients that typically respond poorly to vaccination, such as the elderly and the immunocompromised. The variability of the virus means that such an approach must be broad spectrum. To achieve this, we developed two antibodies that neutralize H5N1 influenza viruses. In mice, these antibodies provided complete protection against a spectrum of H5N1 influenza viruses at a single low dose. We then combined the two antibodies into a single molecule, FcDART, which combined the broad-spectrum activity and protective efficacy of both antibodies. This treatment provides a novel and effective therapeutic agent or prophylactic with activity against highly pathogenic H5N1 avian influenza viruses.