A broadly flavivirus cross-neutralizing monoclonal antibody that recognizes a novel epitope within the fusion loop of E protein.
Flaviviruses are a group of human pathogenic, enveloped RNA viruses that includes dengue (DENV), yellow fever (YFV), West Nile (WNV), and Japanese encephalitis (JEV) viruses. Cross-reactive antibodies against Flavivirus have been described, but most of them are generally weakly neutralizing. In this study, a novel monoclonal antibody, designated mAb 2A10G6, was determined to have broad cross-reactivity with DENV 1-4, YFV, WNV, JEV, and TBEV. Phage-display biopanning and structure modeling mapped 2A10G6 to a new epitope within the highly conserved flavivirus fusion loop peptide, the (98)DRXW(101) motif. Moreover, in vitro and in vivo experiments demonstrated that 2A10G6 potently neutralizes DENV 1-4, YFV, and WNV and confers protection from lethal challenge with DENV 1-4 and WNV in murine model. Furthermore, functional studies revealed that 2A10G6 blocks infection at a step after viral attachment. These results define a novel broadly flavivirus cross-reactive mAb with highly neutralizing activity that can be further developed as a therapeutic agent against severe flavivirus infections in humans.
State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Microbiology and Epidemiology, Beijing, China.
Yong-Qiang
YQ
Deng
Jian-Xin
JX
Dai
Guang-Hui
GH
Ji
Tao
T
Jiang
Hua-Jing
HJ
Wang
Hai-ou
HO
Yang
Weng-Long
WL
Tan
Ran
R
Liu
Man
M
Yu
Bao-Xue
BX
Ge
Qing-Yu
QY
Zhu
E-De
ED
Qin
Ya-Jun
YJ
Guo
Cheng-Feng
CF
Qin
D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology*; D057134:Antibodies, Neutralizing / Q000276:immunology; D003429:Cross Reactions / Q000276:immunology; D018604:Epitope Mapping; D000939:Epitopes / Q000276:immunology*; D005416:Flavivirus / Q000276:immunology*; D018177:Flavivirus Infections / Q000188:drug therapy / Q000517:prevention & control*; D051379:Mice; D014759:Viral Envelope Proteins / Q000276:immunology*; D053586:Virus Internalization
D000911:Antibodies, Monoclonal; D057134:Antibodies, Neutralizing; D000939:Epitopes; D014759:Viral Envelope Proteins
J Virol. 2003 Dec;77(24):12941-9
14645550
Nature. 2005 Sep 29;437(7059):764-9
16193056
Nat Med. 2004 Dec;10(12 Suppl):S98-109
15577938
J Virol. 2009 May;83(9):4338-44
19244332
J Clin Microbiol. 2005 Oct;43(10):4977-83
16207951
J Virol. 2004 Dec;78(23):12910-8
15542643
Expert Rev Mol Med. 2008 May 12;10:e12
18471342
Nat Med. 2005 May;11(5):522-30
15852016
J Virol. 2004 Dec;78(24):13975-86
15564505
Cell. 2002 Mar 8;108(5):717-25
11893341
Nature. 1975 Aug 7;256(5517):495-7
1172191
PLoS One. 2009;4(4):e4991
19337372
PLoS Pathog. 2008 May 09;4(5):e1000060
18464894
Nat Biotechnol. 2007 Dec;25(12):1421-34
18066039
Am J Trop Med Hyg. 1987 Mar;36(2):427-34
3826503
EMBO J. 2009 Oct 21;28(20):3269-76
19713934
J Gen Virol. 2003 Oct;84(Pt 10):2771-2779
13679612
J Immunol. 2009 Jul 1;183(1):650-60
19535627
J Virol. 2005 Dec;79(23):14606-13
16282460
J Virol. 2008 Sep;82(17):8828-37
18562544
Virology. 2005 Mar 15;333(2):239-50
15721358
Virology. 2008 Oct 25;380(2):296-303
18774583
J Gen Virol. 2001 Aug;82(Pt 8):1885-1892
11457994
Microbes Infect. 2007 Jan;9(1):1-6
17196419
J Virol. 2006 Dec;80(24):12149-59
17035317
J Virol. 2001 Aug;75(16):7769-73
11462053
Arch Virol. 1999;144(5):1035-9
10416385
J Virol. 2008 Jul;82(13):6631-43
18448542
Nat Struct Mol Biol. 2008 Mar;15(3):312-7
18264114
J Virol. 2004 Dec;78(23):12919-28
15542644
Adv Virus Res. 2003;59:141-75
14696329
Nature. 2004 Jan 22;427(6972):313-9
14737159
Expert Opin Biol Ther. 2007 Jun;7(6):885-92
17555373
Recent Pat Antiinfect Drug Discov. 2006 Jan;1(1):45-55
18221133
J Virol. 2006 Oct;80(19):9557-68
16973559
Lancet. 2008 Feb 9;371(9611):500-9
18262042
J Infect Dis. 2006 Nov 1;194(9):1300-8
17041857
Lancet Infect Dis. 2009 Nov;9(11):678-87
19850226
Ann N Y Acad Sci. 2001 Dec;951:286-97
11797785
Virology. 2003 Feb 1;306(1):170-80
12620809