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Hgf-sf monoclonal antibody combinations

a monoclonal antibody and sarcoma cell technology, applied in the field of hgfsf monoclonal antibody combinations, can solve the problems of abnormal tissue regeneration, high levels of human sarcoma cell lines, and abnormal development, and achieve the effect of increasing the binding of antigens and increasing the amount of hepatocyte growth factors

Inactive Publication Date: 2009-06-18
UNITED STATES OF AMERICA AS REPRESENTED BY THE SEC DHHS
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The present invention provides a combination of anti-HGF / SF antibodies that can inhibit the activity of HGF / SF. This combination can be used to treat cancer by inhibiting the growth of cancer cells. The invention also provides a method for screening for the presence of a developmental disorder or cancer by detecting the binding of the anti-HGF / SF antibodies to an antigen in a tissue sample. The amount of antigen in the sample can be measured and correlated with the clinical stage of cancer development or the presence of cancerous tissue.

Problems solved by technology

Decreased levels of HGF / SF could result in defective organogenesis resulting in developmental abnormalities.
Conversely, increased HGF / SF-Met signaling after tissue injury, such as hepatic injury, could lead to abnormal tissue regeneration which contributes to chronic hepatitis, cirrhosis, and / or liver cancer.
For example, although HGF / SF is synthesized by mesenchymal cells and acts predominantly on Met-expressing epithelial cells, it has been demonstrated that human sarcoma cell lines often inappropriately express high levels of Met and respond mitogenically to HGF / SF (Rong et al.

Method used

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  • Hgf-sf monoclonal antibody combinations
  • Hgf-sf monoclonal antibody combinations
  • Hgf-sf monoclonal antibody combinations

Examples

Experimental program
Comparison scheme
Effect test

example i

Anti-HGF / SF Antibody Production

[0093]Murine anti-HGF / SF monoclonal antibodies (Mab) were developed by fusion of the OUR-I myeloma cell line obtained from the American Type Culture Collection (ATCC) with spleen cells of a Balb / C mouse hyper-immunized with native HGF / SF. The fusion was performed when the mouse serum displayed positive neutralizing activity. ELISA positive hybridomas were re-cloned, and neutralizing activity was first screened in the MDCK cell scatter assay. Eight hybridoma cell lines were selected and ascites were produced and purified by FPLC protein-G column (Table 1).

MDCK Scattering Assay

[0094]No single Mab showed significant inhibition of HGF / SF mediated scattering activity in Madin-Darby canine kidney (MDCK) cells while pooled Mabs inhibited MDCK scattering. Whether or not it was possible for a specific sub-set of the Mabs to efficiently neutralize HGF / SF activity was determined. Combinations of two or three of the antibodies were tested and it was determined tha...

example ii

Cell Lines

[0099]MDCK cells were cultured in DMEM medium supplemented with 5% fetal bovine serum (FBS). S-114 cells (transformed with human HGF / SF and Met) (13) were grown in DMEM containing 8% of calf serum. ARZ-2 human renal carcinoma cell line (6) was maintained in DMEM containing 10% FBS. C-127 cell line is NIH 3T3 transformed with human HGF / SF and mouse Met (14), and U-118 cell line is established from human glioma that co-expresses HGF / SF and Met (11). Both cells were maintained in DMEM supplemented with 10% FBS. All cell lines were cultured at 37° C., 5% CO2.

Immunization for Mab Production

[0100]Rabbit polyclonal antibody to HGF / SF was used as positive control. HGF / SF was prepared from S114 cells (15), and mouse Mabs against the ligand were produced by injecting Balb / C mice IP with purified native and denatured (by boiling in sodium dodecyl sulfate (SDS) sample buffer) HGF / SF protein in complete Freund's adjuvant, followed by four additional injections in incomplete Fruend's ad...

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Abstract

The present invention provides a combination of anti-HGF / SF antibodies that specifically bind HGF / SF and inhibits HGF / SF activity. The present invention further provides a combination of anti-HGF / SF antibodies comprising three or more anti-HGF / SF antibodies selected from the group consisting of: antibody #1 produced from hybridoma 1C10-F1-A11, antibody #4 produced from hybridoma 8H2-F2-B10, antibody #5 produced from hybridoma 13B1-E4-E10, antibody #7 produced from hybridoma 15D7-B2, and antibody #10 produced from hybridoma 31D4-C9-D4. The invention also provides a method of treating cancer in a subject comprising administering to the subject a combination of anti-HGF / SF antibodies whereby the antibodies bind to a hepatocyte growth factor, whereby the binding of the antibodies to a hepatocyte growth factor results in an inhibition of hepatocyte growth factor binding to the hepatocyte growth factor receptor, whereby the inhibition of hepatocyte growth factor binding to receptor causes an inhibition of cancer growth, thereby treating the cancer.

Description

[0001]This application claims priority to U.S. provisional application Ser. No. 60 / 164,173 filed on Nov. 9, 1999. The 60 / 164,173 provisional patent application is herein incorporated by this reference in its entirety.BACKGROUND OF THE INVENTION[0002]1. Field of the Invention[0003]The present invention relates to combinations of monoclonal antibodies which specifically bind or recognize the antigen hepatocyte growth factor / scatter factor (HGF / SF) and inhibit HGF / SF activity. The application also relates to the use of the antibody in detection methods, in methods of identifying developmental disorders, and in therapy of particular conditions, such as cancer and liver disorders.[0004]2. Background Art[0005]HGF / SF is a heterodimeric molecule composed of an α-chain containing the N-terminal domain and four kringle domains (NK4), covalently disulfide linked to a serine protease-like β-chain. Acting through its receptor c-MET, HGF / SF initiates mitogenic, motogenic and morphogenic activitie...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K39/395C07K16/18G01N33/53G01N33/574A61P35/00C07K16/22
CPCC07K16/22A61K2039/505A61P35/00
Inventor CAO, BOLIANGWOUDE, GEORGE VANDE
Owner UNITED STATES OF AMERICA AS REPRESENTED BY THE SEC DHHS
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