论文部分内容阅读
鉴于人H5N1亚型流感可能大规模流行及目前H5N1亚型流感病毒对抗病毒药物具有抵抗性,现急需一种新的有效的治疗方法。先前的研究结果显示,免疫单一的单克隆抗体可以防止H5N1亚型流感的感染,但其不能有效中和大范围的不同的H5N1亚型流感病毒毒株,也不能有效中和潜在的逃逸突变体。作者选择两株能识别H5N1亚型流感病毒血凝素分子上不同表位的单克隆抗体,在体外培养时,这两株单克隆抗体中的一株单抗能中和另一株单抗的逃逸突变体,两者结合在一起能有效中和A型流感病毒H5N1亚型的0、1、2.1、2.2、2.3、4、7和8分支体。这种嵌合的单克隆抗体被结合在一起后,在用10 MLD50(半数致死量)高致病性A型流感病毒H5N1亚型对小鼠进行攻毒前后,能使所有小鼠免受两种不同分支体病毒(分支体1和2.1)的感染。同时还检测了单剂量和双剂量的单抗混合物的有效性。使用两倍剂量的混合物进行治疗,不仅能使病毒尽早从肺中清除,而且能完全阻止肺源H5N1对小鼠的感染。治疗后也未检测到逃逸突变体的存在。本研究为两种或更多的单克隆抗体按需混合以防止逃逸突变体的产生及提高抗H5N1感染的被动治疗的效果提供了理论依据。混合治疗法使低剂量抗体用于流感病毒感染的被动治疗成为可能,从而减少流感暴发期间的经济损失。
In view of the possible pandemic of human H5N1 subtype influenza and the current resistance of H5N1 subtype influenza viruses to antiviral drugs, a new and effective treatment is urgently needed. Previous studies have shown that immunization with monoclonal antibodies can prevent H5N1 subtype influenza infection, but it can not effectively neutralize a wide range of different H5N1 subtype influenza virus strains, nor can it effectively neutralize potential escape mutants . The authors chose two monoclonal antibodies that recognize different epitopes on the hemagglutinin molecule of the H5N1 influenza virus. In vitro culture, one of the two monoclonal antibodies was able to neutralize the other mAb Escape mutants, both together effectively neutralize the 0, 1, 2.1, 2.2, 2.3, 4, 7 and 8 branches of the H5N1 subtype of influenza A virus. After the chimeric monoclonal antibodies were bound together, mice were challenged with 10 MLD50 (median lethal dose) of the highly pathogenic influenza A virus H5N1 subtype before and after they were immunized against all Infection with different branch viruses (Branches 1 and 2.1). The effectiveness of single and dual doses of the mAb mixture was also tested. Treating with a mixture of two doses not only cleared the virus from the lungs as soon as possible, but also completely prevented lung-derived H5N1 infection in mice. No escape mutants were detected after treatment. This study provides a theoretical basis for the combination of two or more monoclonal antibodies on an as-needed basis to prevent escape mutants and improve passive therapy against H5N1 infection. Hybrid therapy makes it possible to use low-dose antibodies for passive treatment of influenza virus infections, thereby reducing the economic loss during flu outbreaks.