Clinical evaluation (phase I) of a combination of two human monoclonal antibodies to HBV: safety and antiviral properties.
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.
Galun
Eithan
E
Goldyne Savad Institute of Gene Therapy, Hadassah University Hospital, Jerusalem, Israel.
Eren
Rachel
R
Safadi
Rifaat
R
Ashour
Yaffa
Y
Terrault
Norah
N
Keeffe
Emmet B
EB
Matot
Edith
E
Mizrachi
Sara
S
Terkieltaub
Dov
D
Zohar
Merav
M
Lubin
Ido
I
Gopher
Judith
J
Shouval
Daniel
D
Dagan
Shlomo
S
D000328:Adult; D000368:Aged; D000911:Antibodies, Monoclonal / Q000008:administration & dosage* / Q000009:adverse effects; D004279:DNA, Viral / Q000032:analysis; D005260:Female; D006510:Hepatitis B Antibodies / Q000008:administration & dosage*; D006514:Hepatitis B Surface Antigens / Q000032:analysis / Q000276:immunology*; D019694:Hepatitis B, Chronic / Q000628:therapy* / Q000821:virology; D006801:Humans; D007136:Immunoglobulins / Q000627:therapeutic use; D008297:Male; D008875:Middle Aged
D000911:Antibodies, Monoclonal; D004279:DNA, Viral; D006510:Hepatitis B Antibodies; D006514:Hepatitis B Surface Antigens; D007136:Immunoglobulins; C045213:hepatitis B hyperimmune globulin