Clinical evaluation (phase I) of a combination of two human monoclonal antibodies to HBV: Safety and antiviral properties

Eithan Galun; Rachel Eren; Rifaat Safadi; Yaffa Ashour; Norah Terrault; Emmet B. Keeffe; Edith Matot; Sara Mizrachi; Dov Terkieltaub; Merav Zohar; Ido Lubin; Judith Gopher; Daniel Shouval; Shlomo Dagan

doi:10.1053/jhep.2002.31867

Clinical evaluation (phase I) of a combination of two human monoclonal antibodies to HBV: Safety and antiviral properties

Eithan Galun, Rachel Eren, Rifaat Safadi, Yaffa Ashour, Norah Terrault, Emmet B. Keeffe, Edith Matot, Sara Mizrachi, Dov Terkieltaub, Merav Zohar, Ido Lubin, Judith Gopher, Daniel Shouval, Shlomo Dagan

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Abstract

Treatment of chronic hepatitis B virus (HBV) infection with interferon alfa and lamivudine is characterized by lack of viral clearance, loss of response, or emergence of drug-resistant mutants. Thus, new and multiple drug approaches are needed. We have developed two fully human monoclonal antibodies, directed against different epitopes of hepatitis B surface antigen (HBsAg) that bind to all major HBV subtypes. A phase I clinical study was conducted to evaluate the safety, tolerability, and efficacy of a mixture of these two monoclonal antibodies, HBV-AB^XTL. A total of 27 chronic HBV patients were enrolled. In part A of the study 15 patients in 5 cohorts received a single intravenous infusion of antibodies with doses ranging from 0.26 mg (260 IU) to 40 mg (40,000 IU). All patients completed 16 weeks of follow-up. In the second part of the study (part B), 12 patients in 4 cohorts received 4 weekly infusions of 10, 20, 40, or 80 mg each of HBV-AB^XTL and were followed for 4 additional weeks. Administration of antibodies was well tolerated. Patients administered doses at an Ab:Ag molar ratio of 1:2 to 1:20 showed a rapid and significant decrease in HBsAg to undetectable levels, with a corresponding reduction of HBV-DNA levels. In part B, HBV-AB^XTL induced a significant reduction in both HBsAg and HBV-DNA levels repeatedly after administration. In conclusion, these data suggest that HBV-AB^XTL binds HBV particles and reduces serum viral titers and HBsAg levels. HBV-AB^XTL could be combined with other monotherapies that are currently used to treat HBV carriers.

Original language	English
Pages (from-to)	673-679
Number of pages	7
Journal	Hepatology
Volume	35
Issue number	3
DOIs	https://doi.org/10.1053/jhep.2002.31867
State	Published - 2002
Externally published	Yes

Bibliographical note

Funding Information:
Abbreviations: HBV, hepatitis B virus; HBsAg, hepatitis B virus surface antigen; HBIG, hepatitis B immunoglobulin; mAb, monoclonal antibody. From the 1Goldyne Savad Institute of Gene Therapy, Hadassah University Hospital; 2XTL Biopharmaceuticals Ltd., Rehovot; 3Liver Unit, Hadassah University Hospital, Jerusalem, Israel; 4University of California at San Francisco, San Francisco, CA, and 5Stanford University Medical Center, Stanford, CA. Received August 1, 2001; accepted December 21, 2001. These studies were carried out in part in the General Clinical Research Center, Moffitt Hospital, University of California, San Francisco, with funds provided by the National Center for Research Resources, 5 M01RR-00079, U.S. Public Health Service. Address reprint requests to: Shlomo Dagan, Ph.D., XTL Biopharmaceuticals Ltd., P.O. Box 370, Kiryat Weizmann Science Park, Rehovot 76100, Israel. E-mail: [email protected]; fax: (972) 8-9405017. Copyright © 2002 by the American Association for the Study of Liver Diseases. 0270-9139/02/3503-0024$35.00/0 doi:10.1053/jhep.2002.31867

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Galun, E., Eren, R., Safadi, R., Ashour, Y., Terrault, N., Keeffe, E. B., Matot, E., Mizrachi, S., Terkieltaub, D., Zohar, M., Lubin, I., Gopher, J., Shouval, D., & Dagan, S. (2002). Clinical evaluation (phase I) of a combination of two human monoclonal antibodies to HBV: Safety and antiviral properties. Hepatology, 35(3), 673-679. https://doi.org/10.1053/jhep.2002.31867

@article{3a86bd6406b54717b88a3ef12acc383e,

title = "Clinical evaluation (phase I) of a combination of two human monoclonal antibodies to HBV: Safety and antiviral properties",

abstract = "Treatment of chronic hepatitis B virus (HBV) infection with interferon alfa and lamivudine is characterized by lack of viral clearance, loss of response, or emergence of drug-resistant mutants. Thus, new and multiple drug approaches are needed. We have developed two fully human monoclonal antibodies, directed against different epitopes of hepatitis B surface antigen (HBsAg) that bind to all major HBV subtypes. A phase I clinical study was conducted to evaluate the safety, tolerability, and efficacy of a mixture of these two monoclonal antibodies, HBV-ABXTL. A total of 27 chronic HBV patients were enrolled. In part A of the study 15 patients in 5 cohorts received a single intravenous infusion of antibodies with doses ranging from 0.26 mg (260 IU) to 40 mg (40,000 IU). All patients completed 16 weeks of follow-up. In the second part of the study (part B), 12 patients in 4 cohorts received 4 weekly infusions of 10, 20, 40, or 80 mg each of HBV-ABXTL and were followed for 4 additional weeks. Administration of antibodies was well tolerated. Patients administered doses at an Ab:Ag molar ratio of 1:2 to 1:20 showed a rapid and significant decrease in HBsAg to undetectable levels, with a corresponding reduction of HBV-DNA levels. In part B, HBV-ABXTL induced a significant reduction in both HBsAg and HBV-DNA levels repeatedly after administration. In conclusion, these data suggest that HBV-ABXTL binds HBV particles and reduces serum viral titers and HBsAg levels. HBV-ABXTL could be combined with other monotherapies that are currently used to treat HBV carriers.",

author = "Eithan Galun and Rachel Eren and Rifaat Safadi and Yaffa Ashour and Norah Terrault and Keeffe, {Emmet B.} and Edith Matot and Sara Mizrachi and Dov Terkieltaub and Merav Zohar and Ido Lubin and Judith Gopher and Daniel Shouval and Shlomo Dagan",

note = "Funding Information: Abbreviations: HBV, hepatitis B virus; HBsAg, hepatitis B virus surface antigen; HBIG, hepatitis B immunoglobulin; mAb, monoclonal antibody. From the 1Goldyne Savad Institute of Gene Therapy, Hadassah University Hospital; 2XTL Biopharmaceuticals Ltd., Rehovot; 3Liver Unit, Hadassah University Hospital, Jerusalem, Israel; 4University of California at San Francisco, San Francisco, CA, and 5Stanford University Medical Center, Stanford, CA. Received August 1, 2001; accepted December 21, 2001. These studies were carried out in part in the General Clinical Research Center, Moffitt Hospital, University of California, San Francisco, with funds provided by the National Center for Research Resources, 5 M01RR-00079, U.S. Public Health Service. Address reprint requests to: Shlomo Dagan, Ph.D., XTL Biopharmaceuticals Ltd., P.O. Box 370, Kiryat Weizmann Science Park, Rehovot 76100, Israel. E-mail: [email protected]; fax: (972) 8-9405017. Copyright {\textcopyright} 2002 by the American Association for the Study of Liver Diseases. 0270-9139/02/3503-0024$35.00/0 doi:10.1053/jhep.2002.31867",

year = "2002",

doi = "10.1053/jhep.2002.31867",

language = "אנגלית",

volume = "35",

pages = "673--679",

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T1 - Clinical evaluation (phase I) of a combination of two human monoclonal antibodies to HBV

T2 - Safety and antiviral properties

AU - Galun, Eithan

AU - Eren, Rachel

AU - Safadi, Rifaat

AU - Ashour, Yaffa

AU - Terrault, Norah

AU - Keeffe, Emmet B.

AU - Matot, Edith

AU - Mizrachi, Sara

AU - Terkieltaub, Dov

AU - Zohar, Merav

AU - Lubin, Ido

AU - Gopher, Judith

AU - Shouval, Daniel

AU - Dagan, Shlomo

N1 - Funding Information: Abbreviations: HBV, hepatitis B virus; HBsAg, hepatitis B virus surface antigen; HBIG, hepatitis B immunoglobulin; mAb, monoclonal antibody. From the 1Goldyne Savad Institute of Gene Therapy, Hadassah University Hospital; 2XTL Biopharmaceuticals Ltd., Rehovot; 3Liver Unit, Hadassah University Hospital, Jerusalem, Israel; 4University of California at San Francisco, San Francisco, CA, and 5Stanford University Medical Center, Stanford, CA. Received August 1, 2001; accepted December 21, 2001. These studies were carried out in part in the General Clinical Research Center, Moffitt Hospital, University of California, San Francisco, with funds provided by the National Center for Research Resources, 5 M01RR-00079, U.S. Public Health Service. Address reprint requests to: Shlomo Dagan, Ph.D., XTL Biopharmaceuticals Ltd., P.O. Box 370, Kiryat Weizmann Science Park, Rehovot 76100, Israel. E-mail: [email protected]; fax: (972) 8-9405017. Copyright © 2002 by the American Association for the Study of Liver Diseases. 0270-9139/02/3503-0024$35.00/0 doi:10.1053/jhep.2002.31867

PY - 2002

Y1 - 2002

N2 - Treatment of chronic hepatitis B virus (HBV) infection with interferon alfa and lamivudine is characterized by lack of viral clearance, loss of response, or emergence of drug-resistant mutants. Thus, new and multiple drug approaches are needed. We have developed two fully human monoclonal antibodies, directed against different epitopes of hepatitis B surface antigen (HBsAg) that bind to all major HBV subtypes. A phase I clinical study was conducted to evaluate the safety, tolerability, and efficacy of a mixture of these two monoclonal antibodies, HBV-ABXTL. A total of 27 chronic HBV patients were enrolled. In part A of the study 15 patients in 5 cohorts received a single intravenous infusion of antibodies with doses ranging from 0.26 mg (260 IU) to 40 mg (40,000 IU). All patients completed 16 weeks of follow-up. In the second part of the study (part B), 12 patients in 4 cohorts received 4 weekly infusions of 10, 20, 40, or 80 mg each of HBV-ABXTL and were followed for 4 additional weeks. Administration of antibodies was well tolerated. Patients administered doses at an Ab:Ag molar ratio of 1:2 to 1:20 showed a rapid and significant decrease in HBsAg to undetectable levels, with a corresponding reduction of HBV-DNA levels. In part B, HBV-ABXTL induced a significant reduction in both HBsAg and HBV-DNA levels repeatedly after administration. In conclusion, these data suggest that HBV-ABXTL binds HBV particles and reduces serum viral titers and HBsAg levels. HBV-ABXTL could be combined with other monotherapies that are currently used to treat HBV carriers.

AB - Treatment of chronic hepatitis B virus (HBV) infection with interferon alfa and lamivudine is characterized by lack of viral clearance, loss of response, or emergence of drug-resistant mutants. Thus, new and multiple drug approaches are needed. We have developed two fully human monoclonal antibodies, directed against different epitopes of hepatitis B surface antigen (HBsAg) that bind to all major HBV subtypes. A phase I clinical study was conducted to evaluate the safety, tolerability, and efficacy of a mixture of these two monoclonal antibodies, HBV-ABXTL. A total of 27 chronic HBV patients were enrolled. In part A of the study 15 patients in 5 cohorts received a single intravenous infusion of antibodies with doses ranging from 0.26 mg (260 IU) to 40 mg (40,000 IU). All patients completed 16 weeks of follow-up. In the second part of the study (part B), 12 patients in 4 cohorts received 4 weekly infusions of 10, 20, 40, or 80 mg each of HBV-ABXTL and were followed for 4 additional weeks. Administration of antibodies was well tolerated. Patients administered doses at an Ab:Ag molar ratio of 1:2 to 1:20 showed a rapid and significant decrease in HBsAg to undetectable levels, with a corresponding reduction of HBV-DNA levels. In part B, HBV-ABXTL induced a significant reduction in both HBsAg and HBV-DNA levels repeatedly after administration. In conclusion, these data suggest that HBV-ABXTL binds HBV particles and reduces serum viral titers and HBsAg levels. HBV-ABXTL could be combined with other monotherapies that are currently used to treat HBV carriers.

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Clinical evaluation (phase I) of a combination of two human monoclonal antibodies to HBV: Safety and antiviral properties

Abstract

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