Cooperativity Enables Non-neutralizing Antibodies to Neutralize Ebolavirus.
Cooperativity Enables Non-neutralizing Antibodies to Neutralize Ebolavirus.
复制标题
DOI：
10.1016/j.celrep.2017.03.049
复制
发表时间：
2017-04-11
期刊：
影响因子：
8.8
通讯作者：
Aman MJ
中科院分区：
文献类型：
--
作者：
Howell KA;Brannan JM;Bryan C;McNeal A;Davidson E;Turner HL;Vu H;Shulenin S;He S;Kuehne A;Herbert AS;Qiu X;Doranz BJ;Holtsberg FW;Ward AB;Dye JM;Aman MJ
当药物组合的联合功效超过单独作用的总和时，药物组合是协同的，但它们很少包括仅在组合中才有效的无效药物。我们鉴定了几种中和和非中和抗埃博拉病毒单克隆抗体的“使能对”，其组合表现出新的功能特征，包括将非中和抗体转化为中和剂。抗体2G 4或m8 C4的亚中和浓度使非中和抗体FVM 09（IC 50>1 μM）表现出强效中和作用（IC 50 1-10 nM）。虽然FVM 09或m8 C4单独不能保护埃博拉病毒感染的小鼠，但两种抗体的组合提供了100%的保护。此外，非中和剂FVM 09和FVM 02以指数方式增强了针对埃博拉病毒和苏丹病毒的两种中和抗体的效力。我们确定了这些使能抗体对在聚糖帽和GP 2的界面附近结合的热点。对于病毒来说，协同效应可能是一种未被充分认识的现象，这对免疫治疗药物和疫苗的设计和开发具有重要意义。我们描述了协同中和和体内保护协同性将非中和性埃博拉病毒抗体转化为有效的中和剂。描述了“使能的协同中和”现象，其中弱中和和/或非中和埃博拉病毒单克隆抗体在组合时表现出有效的中和作用。先前鉴定的抗体m8 C4和FVM 09单独无保护性，当组合时在小鼠中提供100%的针对埃博拉病毒和苏丹病毒攻击的保护。
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 (IC50 >1 μM) to exhibit potent neutralization (IC50 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. We describe cooperative neutralization and in vivo protection Cooperativity turns non-neutralizing ebolavirus antibodies into potent neutralizers A hotspot for antibody cooperativity identified on Ebola virus glycoprotein Howell et al. describe the phenomenon of “enabling, cooperative neutralization” where weakly neutralizing and/or non-neutralizing ebolavirus monoclonal antibodies exhibit potent neutralization when combined. The previously identified antibodies m8C4 and FVM09, which are non-protective alone, offer 100% protection against Ebola and Sudan virus challenge in mice when combined.
登录
查看更多内容
影响因子：
64.5
作者：
Flyak AI;Shen X;Murin CD;Turner HL;David JA;Fusco ML;Lampley R;Kose N;Ilinykh PA;Kuzmina N;Branchizio A;King H;Brown L;Bryan C;Davidson E;Doranz BJ;Slaughter JC;Sapparapu G;Klages C;Ksiazek TG;Saphire EO;Ward AB;Bukreyev A;Crowe JE Jr
通讯作者：
Crowe JE Jr
影响因子：
13.5
作者：
Carlsen, Thomas H. R.;Pedersen, Jannie;Prentoe, Jannick C.;Giang, Erick;Keck, Zhen-Yong;Mikkelsen, Lotte S.;Law, Mansun;Foung, Steven K. H.;Bukh, Jens
通讯作者：
Bukh, Jens
影响因子：
8.8
作者：
Howell KA;Qiu X;Brannan JM;Bryan C;Davidson E;Holtsberg FW;Wec AZ;Shulenin S;Biggins JE;Douglas R;Enterlein SG;Turner HL;Pallesen J;Murin CD;He S;Kroeker A;Vu H;Herbert AS;Fusco ML;Nyakatura EK;Lai JR;Keck ZY;Foung SKH;Saphire EO;Zeitlin L;Ward AB;Chandran K;Doranz BJ;Kobinger GP;Dye JM;Aman MJ
通讯作者：
Aman MJ
影响因子：
64.8
作者：
Qiu, Xiangguo;Wong, Gary;Audet, Jonathan;Bello, Alexander;Fernando, Lisa;Alimonti, Judie B.;Fausther-Bovendo, Hugues;Wei, Haiyan;Aviles, Jenna;Hiatt, Ernie;Johnson, Ashley;Morton, Josh;Swope, Kelsi;Bohorov, Ognian;Bohorova, Natasha;Goodman, Charles;Kim, Do;Pauly, Michael H.;Velasco, Jesus;Pettitt, James;Olinger, Gene G.;Whaley, Kevin;Xu, Bianli;Strong, James E.;Zeitlin, Larry;Kobinger, Gary P.
通讯作者：
Kobinger, Gary P.
影响因子：
5.4
作者：
Holtsberg, Frederick W.;Shulenin, Sergey;Aman, M. Javad
通讯作者：
Aman, M. Javad