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Originally published as JGV in Press, 10.1099/vir.0.006874-0 on March 4, 2009 J Gen Virol 90 (2009), 799-809; DOI 10.1099/vir.0.006874-0

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On a mouse monoclonal antibody that neutralizes all four dengue virus serotypes

Ravikumar Rajamanonmani1,5, Celine Nkenfou2, Paula Clancy3, Yin Hoe Yau1, Susana Geifman Shochat1, Soila Sukupolvi-Petty4, Wouter Schul2, Michael S. Diamond4, Subhash G. Vasudevan3,5 and Julien Lescar1,6

1 School of Biological Sciences, Nanyang Technological University, Biopolis, Singapore
2 Novartis Institute for Tropical Diseases, Biopolis, Singapore
3 Department of Biochemistry and Molecular Biology, James Cook University, Australia
4 Departments of Medicine, Molecular Microbiology, Pathology and Immunology, Washington University School of Medicine, St Louis, USA
5 Program in Emerging Infectious Diseases, Duke-NUS, Graduate Medical School, Singapore
6 AFMB CNRS UMR6098, Marseille, France

Correspondence
Julien Lescar
julien{at}ntu.edu.sg
Subhash G. Vasudevan
subhash.vasudevan{at}duke-nus.edu.sg

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.






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