Antibody Treatment of Ebola and Sudan Virus Infection via a Uniquely Exposed Epitope within the Glycoprotein Receptor-Binding Site

被引：80

作者：

Howell, Katie A. ^{[1
]}

Qiu, Xiangguo ^{[2
,3
,4
]}

Brannan, Jennifer M. ^{[5
]}

Bryan, Christopher ^{[6
]}

Davidson, Edgar ^{[6
]}

Holtsberg, Frederick W. ^{[1
]}

Wec, Anna Z. ^{[10
]}

Shulenin, Sergey ^{[1
]}

Biggins, Julia E. ^{[1
]}

Douglas, Robin ^{[1
]}

Enterlein, Sven G. ^{[1
]}

Turner, Hannah L. ^{[7
]}

Pallesen, Jesper ^{[7
]}

Murin, Charles D. ^{[7
,8
]}

He, Shihua ^{[2
,3
,4
]}

Kroeker, Andrea ^{[2
,3
,4
]}

Vu, Hong ^{[1
]}

Herbert, Andrew S. ^{[5
]}

Fusco, Marnie L. ^{[8
]}

Nyakatura, Elisabeth K. ^{[11
]}

Lai, Jonathan R. ^{[11
]}

Keck, Zhen-Yong ^{[12
]}

Foung, Steven K. H. ^{[12
]}

Saphire, Erica Ollmann ^{[8
,9
]}

Zeitlin, Larry ^{[13
]}

Ward, Andrew B. ^{[7
]}

Chandran, Kartik ^{[10
]}

Doranz, Benjamin J. ^{[6
]}

Kobinger, Gary P. ^{[2
,3
,4
]}

Dye, John M. ^{[5
]}

Aman, M. Javad ^{[1
]}

机构：

[1] Integrated BioTherapeut Inc, Gaithersburg, MD 20878 USA

[2] Publ Hlth Agcy Canada, Natl Microbiol Lab, Special Pathogens Program, Winnipeg, MB R3E 3R2, Canada

[3] Univ Manitoba, Dept Med Microbiol, Winnipeg, MB R3E 0J9, Canada

[4] Univ Manitoba, Dept Immunol, Winnipeg, MB R3E 0J9, Canada

[5] US Army Med Res Inst Infect Dis, Frederick, MD 21702 USA

[6] Integral Mol, Philadelphia, PA 19104 USA

[7] Scripps Res Inst, Dept Integrat Struct & Computat Biol, La Jolla, CA 92037 USA

[8] Scripps Res Inst, Dept Immunol & Microbial Sci, La Jolla, CA 92037 USA

[9] Scripps Res Inst, Skaggs Inst Chem Biol, La Jolla, CA 92037 USA

[10] Albert Einstein Coll Med, Dept Microbiol & Immunol, Bronx, NY 10461 USA

[11] Albert Einstein Coll Med, Dept Biochem, Bronx, NY 10461 USA

[12] Stanford Univ, Sch Med, Dept Pathol, Stanford, CA 94305 USA

[13] Mapp Biopharmaceut, San Diego, CA 92121 USA

来源：

CELL REPORTS | 2016年 / 15卷 / 07期

基金：

美国国家科学基金会;

关键词：

NIEMANN-PICK C1; MONOCLONAL-ANTIBODIES; NONHUMAN-PRIMATES; MOLECULAR CHARACTERIZATION; NEUTRALIZING ANTIBODY; FILOVIRUS ENTRY; MARBURG VIRUS; GUINEA-PIG; DISEASE; PROPHYLAXIS;

D O I：

10.1016/j.celrep.2016.04.026

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

Previous efforts to identify cross-neutralizing antibodies to the receptor-binding site (RBS) of ebolavirus glycoproteins have been unsuccessful, largely because the RBS is occluded on the viral surface. We report a monoclonal antibody (FVM04) that targets a uniquely exposed epitope within the RBS; cross-neutralizes Ebola (EBOV), Sudan (SUDV), and, to a lesser extent, Bundibugyo viruses; and shows protection against EBOV and SUDV in mice and guinea pigs. The antibody cocktail ZMapp (TM) is remarkably effective against EBOV (Zaire) but does not cross-neutralize other ebolaviruses. By replacing one of the ZMapp (TM) components with FVM04, we retained the anti-EBOV efficacy while extending the breadth of protection to SUDV, thereby generating a cross-protective antibody cocktail. In addition, we report several mutations at the base of the ebolavirus glycoprotein that enhance the binding of FVM04 and other cross-reactive antibodies. These findings have important implications for pan-ebolavirus vaccine development and defining broadly protective antibody cocktails.

引用

页码：1514 / 1526

页数：13

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