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Journal of Virology, December 2009, p. 12473-12482, Vol. 83, No. 23
0022-538X/09/$08.00+0     doi:10.1128/JVI.01138-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Identification and Characterization of Broadly Neutralizing Human Monoclonal Antibodies Directed against the E2 Envelope Glycoprotein of Hepatitis C Virus{triangledown}

Teresa J. Broering,1 Kerry A. Garrity,1 Naomi K. Boatright,1 Susan E. Sloan,1 Frantisek Sandor,2 William D. Thomas Jr.,1 Gyongyi Szabo,2 Robert W. Finberg,2 Donna M. Ambrosino,1 and Gregory J. Babcock1*

MassBiologics, University of Massachusetts Medical School, Boston, Massachusetts,1 Department of Medicine, University of Massachusetts Medical School, Worcester, Massachusetts2

Received 3 June 2009/ Accepted 8 September 2009

Nearly all livers transplanted into hepatitis C virus (HCV)-positive patients become infected with HCV, and 10 to 25% of reinfected livers develop cirrhosis within 5 years. Neutralizing monoclonal antibody could be an effective therapy for the prevention of infection in a transplant setting. To pursue this treatment modality, we developed human monoclonal antibodies (HuMAbs) directed against the HCV E2 envelope glycoprotein and assessed the capacity of these HuMAbs to neutralize a broad panel of HCV genotypes. HuMAb antibodies were generated by immunizing transgenic mice containing human antibody genes (HuMAb mice; Medarex Inc.) with soluble E2 envelope glycoprotein derived from a genotype 1a virus (H77). Two HuMAbs, HCV1 and 95-2, were selected for further study based on initial cross-reactivity with soluble E2 glycoproteins derived from genotypes 1a and 1b, as well as neutralization of lentivirus pseudotyped with HCV 1a and 1b envelope glycoproteins. Additionally, HuMAbs HCV1 and 95-2 potently neutralized pseudoviruses from all genotypes tested (1a, 1b, 2b, 3a, and 4a). Epitope mapping with mammalian and bacterially expressed proteins, as well as synthetic peptides, revealed that HuMAbs HCV1 and 95-2 recognize a highly conserved linear epitope spanning amino acids 412 to 423 of the E2 glycoprotein. The capacity to recognize and neutralize a broad range of genotypes, the highly conserved E2 epitope, and the fully human nature of the antibodies make HuMAbs HCV1 and 95-2 excellent candidates for treatment of HCV-positive individuals undergoing liver transplantation.

* Corresponding author. Mailing address: MassBiologics, University of Massachusetts Medical School, Boston, MA 02130. Phone: (617) 983-6415. Fax: (617) 983-6477. E-mail: greg.babcock{at}umassmed.edu

{triangledown} Published ahead of print on 16 September 2009.

Journal of Virology, December 2009, p. 12473-12482, Vol. 83, No. 23
0022-538X/09/$08.00+0     doi:10.1128/JVI.01138-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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