Howell Katie A, Brannan Jennifer M, Bryan Christopher, McNeal Andrew, Davidson Edgar, Turner Hannah L, Vu Hong, Shulenin Sergey, He Shihua, Kuehne Ana, Herbert Andrew S, Qiu Xiangguo, Doranz Benjamin J, Holtsberg Frederick W, Ward Andrew B, Dye John M, Aman M Javad
Integrated BioTherapeutics, Inc., Rockville, MD 20850, USA.
US Army Medical Research Institute of Infectious Diseases, Frederick, MD 21702-5011, USA.
Cell Rep. 2017 Apr 11;19(2):413-424. doi: 10.1016/j.celrep.2017.03.049.
Drug combinations are synergistic when their combined efficacy exceeds the sum of the individual actions, but they rarely include ineffective drugs that become effective only in combination. We identified several "enabling pairs" of neutralizing and non-neutralizing anti-ebolavirus monoclonal antibodies, whose combination exhibited new functional profiles, including transforming a non-neutralizing antibody to a neutralizer. Sub-neutralizing concentrations of antibodies 2G4 or m8C4 enabled non-neutralizing antibody FVM09 (IC >1 μM) to exhibit potent neutralization (IC 1-10 nM). While FVM09 or m8C4 alone failed to protect Ebola-virus-infected mice, a combination of the two antibodies provided 100% protection. Furthermore, non-neutralizers FVM09 and FVM02 exponentially enhanced the potency of two neutralizing antibodies against both Ebola and Sudan viruses. We identified a hotspot for the binding of these enabling antibody pairs near the interface of the glycan cap and GP2. Enabling cooperativity may be an underappreciated phenomenon for viruses, with implications for the design and development of immunotherapeutics and vaccines.
当药物组合的联合疗效超过各单药作用之和时，它们具有协同作用，但很少包含仅在联合使用时才有效的无效药物。我们鉴定出了几对具有中和作用和非中和作用的抗埃博拉病毒单克隆抗体的“增效组合”，其联合使用表现出了新的功能特性，包括将一种非中和抗体转变为中和抗体。亚中和浓度的抗体2G4或m8C4能使非中和抗体FVM09（IC>1 μM）表现出强效中和作用（IC 1 - 10 nM）。虽然单独的FVM09或m8C4无法保护感染埃博拉病毒的小鼠，但这两种抗体的组合提供了100%的保护。此外，非中和抗体FVM09和FVM02成倍增强了两种针对埃博拉病毒和苏丹病毒的中和抗体的效力。我们在聚糖帽和GP2的界面附近确定了这些增效抗体组合的结合热点。增效协同作用可能是病毒中一种未被充分认识的现象，对免疫治疗药物和疫苗的设计与开发具有启示意义。
