Crucell Holland BV, Leiden, The Netherlands.
PLoS One. 2010 Feb 8;5(2):e9106. doi: 10.1371/journal.pone.0009106.
The urgent medical need for innovative approaches to control influenza is emphasized by the widespread resistance of circulating subtype H1N1 viruses to the leading antiviral drug oseltamivir, the pandemic threat posed by the occurrences of human infections with highly pathogenic avian H5N1 viruses, and indeed the evolving swine-origin H1N1 influenza pandemic. A recently discovered class of human monoclonal antibodies with the ability to neutralize a broad spectrum of influenza viruses (including H1, H2, H5, H6 and H9 subtypes) has the potential to prevent and treat influenza in humans. Here we report the latest efficacy data for a representative antibody of this novel class.
METHODOLOGY/PRINCIPAL FINDINGS: We evaluated the prophylactic and therapeutic efficacy of the human monoclonal antibody CR6261 against lethal challenge with the highly pathogenic avian H5N1 virus in ferrets, the optimal model of human influenza infection. Survival rates, clinically relevant disease signs such as changes in body weight and temperature, virus replication in lungs and upper respiratory tract, as well as macro- and microscopic pathology were investigated. Prophylactic administration of 30 and 10 mg/kg CR6261 prior to viral challenge completely prevented mortality, weight loss and reduced the amount of infectious virus in the lungs by more than 99.9%, abolished shedding of virus in pharyngeal secretions and largely prevented H5N1-induced lung pathology. When administered therapeutically 1 day after challenge, 30 mg/kg CR6261 prevented death in all animals and blunted disease, as evidenced by decreased weight loss and temperature rise, reduced lung viral loads and shedding, and less lung damage.
CONCLUSIONS/SIGNIFICANCE: These data demonstrate the prophylactic and therapeutic efficacy of this new class of human monoclonal antibodies in a highly stringent and clinically relevant animal model of influenza and justify clinical development of this approach as intervention for both seasonal and pandemic influenza.
循环亚 H1N1 病毒对主要抗病毒药物奥司他韦的广泛耐药性、高致病性禽流感 H5N1 病毒感染人类的大流行威胁，以及实际上正在演变的猪源 H1N1 流感大流行，都强调了控制流感的创新方法的迫切医学需求。最近发现的一类具有中和广谱流感病毒（包括 H1、H2、H5、H6 和 H9 亚型）能力的人源单克隆抗体有可能预防和治疗人类流感。在这里，我们报告了该新型抗体的最新疗效数据。
方法/主要发现：我们评估了针对高致病性禽流感 H5N1 病毒在雪貂（人类流感感染的最佳模型）中致死性攻击的人源单克隆抗体 CR6261 的预防和治疗效果。研究了生存率、体重和体温等临床相关疾病迹象的变化、肺部和上呼吸道的病毒复制，以及宏观和微观病理学。在病毒攻击前预防性给予 30 和 10 mg/kg CR6261 可完全预防死亡率、体重减轻，并使肺部的传染性病毒减少 99.9%以上，消除了咽部分泌物中病毒的脱落，并在很大程度上预防了 H5N1 诱导的肺部病理学。在攻击后 1 天进行治疗性给药时，30 mg/kg CR6261 可预防所有动物的死亡，并减轻疾病，表现为体重减轻和体温升高减少、肺部病毒载量和脱落减少以及肺部损伤减少。
结论/意义：这些数据证明了在一种严格且具有临床相关性的流感动物模型中，这种新型人源单克隆抗体的预防和治疗效果，并证明了这种方法作为季节性和大流行性流感的干预措施的临床开发是合理的。
