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Human monoclonal antibody against Hepatitis B virus surface antigen (HBVSAG)

Inactive Publication Date: 2007-04-24
YEDA RES & DEV CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0019]Further aspects of the present invention are various diagnostic prophylactic and therapeutic uses of the Ab 17.1.41 monoclonal antibodies and the Ag bound by these antibodies. In accordance with this aspect of the invention, pharmaceutical compositions comprising the Ab17.1.41 antibodies may be used for the treatment of chronic Hepatitis B patients by administering to such a patient a therapeutically effective amount of the antibodies or fragments thereof capable of binding to the HBVsAg being an amount effective in alleviating the symptoms of the HBV infection or reducing the number of circulating viral particles in an individual.
[0022]Such pharmaceutical compositions may also be used, for example, for immunization of new born babies against HBV infections or for immunization cfof liver transplantation patients to eliminate possible recurrent HBV infections in such patients.

Problems solved by technology

Hepatitis B virus (HBV) infection is a major worldwide health problem.
Approximately 5% of the world population is infected by HBV and chronically infected patients carry a high risk of developing cirrhosis and hepatocellular carcinoma.
Recombinant HBV vaccines provide a safe and effective means for active immunization against HBV, however, they do not always induce a sufficient and rapid antibody response.
These preparations are very expensive and available in relatively small amounts.
Furthermore, pooled plasma may contain contaminated blood samples and thus treatment with such antisera increases the patient's risk to contract other viral infections such as hepatitis C or HIV.

Method used

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  • Human monoclonal antibody against Hepatitis B virus surface antigen (HBVSAG)
  • Human monoclonal antibody against Hepatitis B virus surface antigen (HBVSAG)
  • Human monoclonal antibody against Hepatitis B virus surface antigen (HBVSAG)

Examples

Experimental program
Comparison scheme
Effect test

example 1

[0050]Human peripheral blood lymphocytes (PBL) from donors positive for anti HBVs antibodies were obtained and activated in vitro with PWM as described above. The cells were then fused with a human mouse heteromyeloto form hybridoma cell lines. One stable hybridoma clone secreting specific human anti HBVsAg designated 17.1.41 was characterized. The antibodies secreted by the above clone were purified on a protein A column as well as on an anti human Ig-agarose column and were found to be of the IgG1 Vκ type. The affinity constant of the antibodies to HBVsAg was 1.34×10−9. Specificity was tested by competitive inhibition assay using HBV surface antigen of the ad-ay (1:1).

example 2

[0051]The 17.1.41 antibodies were used for staining human liver fragments as described above. As seen in FIG. 1, the 17.1.41 antibodies were able to detect HBV particles present in the infected liver fragments.

[0052]The gene encoding the variable region of Ab 17.1.41 was isolated, fully sequenced, and its subgroups and CDRs were determined.

[0053]The antibody has a fully human Ig gene sequence as determined by alignment to Genebank sequences and Kabat protein sequences. FIG. 8 shows the nucleotide sequence of the cDNA encoding the light chain of the variable region of Ab 17.1.41 and its corresponding amino acid sequence (Sequence identification nos. I and 3). FIG. 9 shows the nucleotide sequence of the cDNA encoding the heavy chain of the variable region of Ab17.1.41 and its corresponding amino acid sequence (Sequence identification nos. 2 and 4).

[0054]The sequencing data revealed that the variable region of Ab 17.1.41 consists of the subgroups VH3, JH6, VK2 and JK2.

[0055]HBV genomes...

example 3

[0056]The biological activity of Ab 17.1.41 was characterized using the following HBV animal model: a mouse was treated so as to allow the stable engraftment of human liver fragments. The treatment included intensive irradiation followed by transplantation of scid (severe combined immunodeficient) mice bone marrow. Viral infection of human liver fragments was performed ex-vivo using HBV positive human serum (EP 699 235).

[0057]The animal model was used in three different modes representing various potential uses of the antibodies: treatment mode, combined prophylaxis / inhibition mode and combined inhibition / treatment.[0058]1. Treatment mode—This model demonstrates the ability to use the antibody to treat chronic HBV infection. Mice were transplanted with HBV infected human liver fragments. The mice were treated with Ab 17.1.41 at days 16, and 17 post liver transplantation. HBV DNA was tested on days 18 and 25. The number of HBV DNA copies (the viral load) in mouse sera was determined ...

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Abstract

Disclosed is a hybridoma cell line which produces human antibodies capable of binding to the hepatitis B virus surface antigen (HBVsAg), as well as antibodies produced by the cell line. Also disclosed are various uses of said antibodies in the prevention and treatment of HBV infection. Peripheral blood lymphocytes obtained from human donors having a high titer of anti HBVsAg antibodies are activated in vitro with pokeweed mitogen and then fused with heteromyeloma cells to generate hybridomas secreting human antibodies having a high affinity and specificity to HBVsAg.

Description

FIELD OF THE INVENTION[0001]The present invention concerns a hybridoma cell line producing human antibodies capable of binding to the hepatitis B virus surface antigen, antibodies produced by the cell lines, and various uses thereof.BACKGROUND OF THE INVENTION[0002]Hepatitis B virus (HBV) infection is a major worldwide health problem. Approximately 5% of the world population is infected by HBV and chronically infected patients carry a high risk of developing cirrhosis and hepatocellular carcinoma. (Progressive Hepatitis Research: Hepatitis B virus (HBV), Hepatitis C virus (HCV) and Hepatitis Delta virus (HDV) Ed. O. Crivelli, Sorina Biomedica, 1991).[0003]The immune response to HBV-encoded antigens includes both a cellular immune response which is active in the elimination of HBV infected cells, as well as a humoral antibody response to viral envelope antigens which contributes to the clearance of circulating virus particles. The dominant cause of viral persistence during HBV infect...

Claims

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Application Information

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IPC IPC(8): A61K39/42A61K39/395A61K38/00A61P31/12C07K16/08
CPCA61K38/00C07K16/082A61P31/12A61P31/20A61P43/00
Inventor DAGAN, SHLOMO
Owner YEDA RES & DEV CO LTD
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