On a mouse monoclonal antibody that neutralizes all four dengue virus serotypes.
The flavivirus envelope glycoprotein (E) is responsible for viral attachment and entry by membrane fusion. Its ectodomain is the primary target of the humoral immune response. In particular, the C-terminal Ig-like domain III of E, which is exposed at the surface of the viral particle, forms an attractive antigen for raising protective monoclonal antibodies (mAb). 9F12, a mouse mAb raised against a dengue virus (DENV) serotype 2 recombinant domain III, cross-reacts with corresponding domains from the other three DENV serotypes and also with West Nile virus. mAb 9F12 binds with nanomolar affinity to a conserved epitope that maps to the viral surface comprising residues 305, 307, 310 and 330 of the E protein. mAb 9F12 neutralizes all four DENV serotypes in plaque reduction assays. We expressed a single-chain Fv from 9F12 that retains the binding activity of the parent mAb. Adsorption and fusion inhibition assays indicate that mAb 9F12 prevents early steps of viral entry. Its virus inhibition activity and broad cross-reactivity makes mAb 9F12 a suitable candidate for optimization and humanization into a therapeutic antibody to treat severe infections by dengue.
Rajamanonmani
Ravikumar
R
Program in Emerging Infectious Diseases, Duke-NUS, Graduate Medical School, Singapore.|School of Biological Sciences, Nanyang Technological University, Biopolis, Singapore.
Nkenfou
Celine
C
Novartis Institute for Tropical Diseases, Biopolis, Singapore.
Clancy
Paula
P
Department of Biochemistry and Molecular Biology, James Cook University, Australia.
Yau
Yin Hoe
YH
School of Biological Sciences, Nanyang Technological University, Biopolis, Singapore.
Shochat
Susana Geifman
SG
School of Biological Sciences, Nanyang Technological University, Biopolis, Singapore.
Sukupolvi-Petty
Soila
S
Departments of Medicine, Molecular Microbiology, Pathology and Immunology, Washington University School of Medicine, St Louis, USA.
Schul
Wouter
W
Novartis Institute for Tropical Diseases, Biopolis, Singapore.
Diamond
Michael S
MS
Departments of Medicine, Molecular Microbiology, Pathology and Immunology, Washington University School of Medicine, St Louis, USA.
Vasudevan
Subhash G
SG
Program in Emerging Infectious Diseases, Duke-NUS, Graduate Medical School, Singapore.|Department of Biochemistry and Molecular Biology, James Cook University, Australia.
Lescar
Julien
J
AFMB CNRS UMR6098, Marseille, France.|School of Biological Sciences, Nanyang Technological University, Biopolis, Singapore.
D000595:Amino Acid Sequence; D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology*; D000914:Antibodies, Viral / Q000276:immunology*; D002460:Cell Line; D002522:Chlorocebus aethiops; D006224:Cricetinae; D003429:Cross Reactions; D003715:Dengue / Q000276:immunology; D003716:Dengue Virus / Q000145:classification* / Q000235:genetics / Q000276:immunology*; D018604:Epitope Mapping; D008561:Membrane Fusion / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D008969:Molecular Sequence Data; D009500:Neutralization Tests; D012703:Serotyping; D014709:Vero Cells; D014759:Viral Envelope Proteins / Q000737:chemistry / Q000235:genetics / Q000276:immunology*
D000911:Antibodies, Monoclonal; D000914:Antibodies, Viral; D014759:Viral Envelope Proteins