Song Aihua, Myojo Kensuke, Laudenslager John, Harada Daisuke, Miura Toru, Suzuki Kazuo, Kuni-Kamochi Reiko, Soloff Rachel, Ohgami Kinya, Kanda Yutaka
Research Division, Kyowa Hakko Kirin, California, Inc., La Jolla, CA, USA.
R&D Division, Kyowa Hakko Kirin Co. Ltd., Tokyo, Japan.
Antiviral Res. 2014 Nov;111:60-8. doi: 10.1016/j.antiviral.2014.08.016. Epub 2014 Sep 16.
Influenza virus is a global health concern due to its unpredictable pandemic potential. Frequent mutations of surface molecules, hemagglutinin (HA) and neuraminidase (NA), contribute to low efficacy of the annual flu vaccine and therapeutic resistance to standard antiviral agents. The populations at high risk of influenza virus infection, such as the elderly and infants, generally mount low immune responses to vaccines, and develop severe disease after infection. Novel therapeutics with high effectiveness and mutation resistance are needed. Previously, we described the generation of a fully human influenza virus matrix protein 2 (M2) specific monoclonal antibody (mAb), Z3G1, which recognized the majority of M2 variants from natural viral isolates, including highly pathogenic avian strains. Passive immunotherapy with Z3G1 significantly protected mice from the infection when administered either prophylactically or 1-2days post infection. In the present study, we showed that Z3G1 significantly protected mice from lethal infection when treatment was initiated 3days post infection. In addition, therapeutic administration of Z3G1 reduced lung viral titers in mice infected with different viral strains, including amantadine and oseltamivir-resistant strains. Furthermore, prophylactic and therapeutic administration of Z3G1 sustained O2 saturation and reduced lung pathology in monkeys infected with a pandemic H1N1 strain. Finally, de-fucosylated Z3G1 with an IgG1/IgG3 chimeric Fc region was generated (AccretaMab® Z3G1), and showed increased ADCC and CDC in vitro. Our data suggest that the anti-M2 mAb Z3G1 has great potential as a novel anti-flu therapeutic agent.
由于流感病毒具有不可预测的大流行潜力，它一直是全球健康关注的焦点。其表面分子血凝素（HA）和神经氨酸酶（NA）频繁发生突变，导致年度流感疫苗效力低下以及对标准抗病毒药物产生治疗抗性。流感病毒感染的高危人群，如老年人和婴儿，通常对疫苗的免疫反应较弱，感染后会发展为严重疾病。因此需要高效且具有抗突变性的新型治疗方法。此前，我们描述了一种完全人源化的流感病毒基质蛋白2（M2）特异性单克隆抗体（mAb）Z3G1的产生，它能识别来自天然病毒分离株的大多数M2变体，包括高致病性禽流感毒株。当预防性给药或在感染后1 - 2天给药时，用Z3G1进行被动免疫疗法能显著保护小鼠免受感染。在本研究中，我们发现当在感染后3天开始治疗时，Z3G1能显著保护小鼠免受致命感染。此外，对感染不同病毒株（包括对金刚烷胺和奥司他韦耐药的毒株）的小鼠进行Z3G1治疗性给药可降低肺内病毒滴度。此外，对感染大流行H1N1毒株的猴子进行Z3G1预防性和治疗性给药可维持血氧饱和度并减轻肺部病理变化。最后，我们制备了具有IgG1/IgG3嵌合Fc区域的去岩藻糖基化Z3G1（AccretaMab® Z3G1），其在体外表现出增强的抗体依赖性细胞介导的细胞毒性（ADCC）和补体依赖性细胞毒性（CDC）。我们的数据表明，抗M2单克隆抗体Z3G1作为一种新型抗流感治疗药物具有巨大潜力。
