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Journal of Virology, March 2006, p. 2654-2664, Vol. 80, No. 6
0022-538X/06/$08.00+0     doi:10.1128/JVI.80.6.2654-2664.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Preclinical Evaluation of Two Neutralizing Human Monoclonal Antibodies against Hepatitis C Virus (HCV): a Potential Treatment To Prevent HCV Reinfection in Liver Transplant Patients

Rachel Eren,¹ Dorit Landstein,¹ Dov Terkieltaub,¹ Ofer Nussbaum,¹ Arie Zauberman,¹ Judith Ben-Porath,¹ Judith Gopher,¹ Rachel Buchnick,¹ Riva Kovjazin,¹ Ziva Rosenthal-Galili,¹ Sigal Aviel,¹ Ehud Ilan,¹ Yariv Shoshany,¹ Lewis Neville,¹ Tal Waisman,¹ Ofer Ben-Moshe,¹ Alberto Kischitsky,¹ Steven K. H. Foung,² Zhen-Yong Keck,² Orit Pappo,³ Ahmed Eid,⁴ Oded Jurim,⁴ Gidi Zamir,⁴ Eithan Galun,⁵ and Shlomo Dagan^1*

XTL Biopharmaceuticals Ltd., Rehovot, Israel,¹ Department of Pathology, Stanford University School of Medicine, Stanford, California,² Department of Pathology, Hadassah University Medical Center, The Hebrew University of Jerusalem, Jerusalem, Israel,³ Department of Surgery, Hadassah University Medical Center, The Hebrew University of Jerusalem, Jerusalem, Israel,⁴ Goldyne Savad Institute of Gene Therapy, Hadassah University Hospital, Jerusalem, Israel⁵

Received 15 September 2005/ Accepted 2 December 2005

Passive immunotherapy is potentially effective in preventing reinfection of liver grafts in hepatitis C virus (HCV)-associated liver transplant patients. A combination of monoclonal antibodies directed against different epitopes may be advantageous against a highly mutating virus such as HCV. Two human monoclonal antibodies (HumAbs) against the E2 envelope protein of HCV were developed and tested for the ability to neutralize the virus and prevent human liver infection. These antibodies, designated HCV-AB 68 and HCV-AB 65, recognize different conformational epitopes on E2. They were characterized in vitro biochemically and functionally. Both HumAbs are immunoglobulin G1 and have affinity constants to recombinant E2 constructs in the range of 10^–10 M. They are able to immunoprecipitate HCV particles from infected patients' sera from diverse genotypes and to stain HCV-infected human liver tissue. Both antibodies can fix complement and form immune complexes, but they do not activate complement-dependent or antibody-dependent cytotoxicity. Upon complement fixation, the monoclonal antibodies induce phagocytosis of the immune complexes by neutrophils, suggesting that the mechanism of viral clearance includes endocytosis. In vivo, in the HCV-Trimera model, both HumAbs were capable of inhibiting HCV infection of human liver fragments and of reducing the mean viral load in HCV-positive animals. The demonstrated neutralizing activities of HCV-AB 68 and HCV-AB 65 suggest that they have the potential to prevent reinfection in liver transplant patients and to serve as prophylactic treatment in postexposure events.

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* Corresponding author. Mailing address: XTL Biopharmaceuticals Ltd., Rehovot, Israel. Phone: 972-89304443. Fax: 972-89304445. E-mail: sdagan{at}xtlbio.com.

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Journal of Virology, March 2006, p. 2654-2664, Vol. 80, No. 6
0022-538X/06/$08.00+0     doi:10.1128/JVI.80.6.2654-2664.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

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