This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrowReprints and Permissions
Right arrow Copyright Information
Right arrow Books from ASM Press
Right arrow MicrobeWorld
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Goncalvez, A. P.
Right arrow Articles by Lai, C.-J.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Goncalvez, A. P.
Right arrow Articles by Lai, C.-J.

 Previous Article  |  Next Article 

Journal of Virology, July 2008, p. 7009-7021, Vol. 82, No. 14
0022-538X/08/$08.00+0     doi:10.1128/JVI.00291-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Humanized Monoclonal Antibodies Derived from Chimpanzee Fabs Protect against Japanese Encephalitis Virus In Vitro and In Vivo {triangledown}

Ana P. Goncalvez,1* Cheng-Hsin Chien,5 Kamolchanok Tubthong,4 Inna Gorshkova,3 Carrie Roll,1 Olivia Donau,1 Peter Schuck,3 Sutee Yoksan,4 Sy-Dar Wang,5 Robert H. Purcell,2 and Ching-Juh Lai1*

Molecular Viral Biology Section,1 Hepatitis Viruses Section, Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases,2 Protein Biophysics, National Institute of Biomedical Imaging and Bioengineering, NIH, Bethesda, Maryland 20892,3 Institute of Science and Technology for Research and Development, Mahidol University, Nakhonpathom, Thailand,4 Adimmune Corporation, Taichung, Taiwan5

Received 8 February 2008/ Accepted 6 May 2008

Japanese encephalitis virus (JEV)-specific Fab antibodies were recovered by repertoire cloning from chimpanzees initially immunized with inactivated JE-VAX and then boosted with attenuated JEV SA14-14-2. From a panel of 11 Fabs recovered by different panning strategies, three highly potent neutralizing antibodies, termed Fabs A3, B2, and E3, which recognized spatially separated regions on the virion, were identified. These antibodies reacted with epitopes in different domains: the major determinant for Fab A3 was Lys179 (domain I), that for Fab B2 was Ile126 (domain II), and that for Fab E3 was Gly302 (domain III) in the envelope protein, suggesting that these antibodies neutralize the virus by different mechanisms. Potent neutralizing antibodies reacted with a low number of binding sites available on the virion. These three Fabs and derived humanized monoclonal antibodies (MAbs) exhibited high neutralizing activities against a broad spectrum of JEV genotype strains. Demonstration of antibody-mediated protection of JEV infection in vivo is provided using the mouse encephalitis model. MAb B2 was most potent, with a 50% protective dose (ED50) of 0.84 µg, followed by MAb A3 (ED50 of 5.8 µg) and then MAb E3 (ED50 of 24.7 µg) for a 4-week-old mouse. Administration of 200 µg/mouse of MAb B2 1 day after otherwise lethal JEV infection protected 50% of mice and significantly prolonged the average survival time compared to that of mice in the unprotected group, suggesting a therapeutic potential for use of MAb B2 in humans.

* Corresponding author. Mailing address: 50 South Drive MSC 8005, Molecular Viral Biology Section, Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases, Bethesda, MD 20892. Phone for A. Goncalvez: (301) 594-2426. Fax: (301) 402-6413. E-mail: agoncalvez{at}niaid.nih.gov. Phone for C.-J. Lai: (301) 594-2422. Fax: (301) 402-6413. E-mail: clai{at}niaid.nih.gov

{triangledown} Published ahead of print on 14 May 2008.

Journal of Virology, July 2008, p. 7009-7021, Vol. 82, No. 14
0022-538X/08/$08.00+0     doi:10.1128/JVI.00291-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Vogt, M. R., Moesker, B., Goudsmit, J., Jongeneelen, M., Austin, S. K., Oliphant, T., Nelson, S., Pierson, T. C., Wilschut, J., Throsby, M., Diamond, M. S. (2009). Human Monoclonal Antibodies against West Nile Virus Induced by Natural Infection Neutralize at a Postattachment Step. J. Virol. 83: 6494-6507 [Abstract] [Full Text]  


Copyright © 2009 by the American Society for Microbiology.   For an alternate route to Journals.ASM.org, visit: http://intl-journals.asm.org | More Info»