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Monoclonal antibodies that specifically block biological activity of a tumor antigen

a tumor antigen and monoclonal antibody technology, applied in the field of purified novel monoclonal antibodies, can solve the problems of affecting the antibody used to kill cancer cells also has a deleterious effect on normal cells, and the survival rate of cancer cells is still less than 40%

Inactive Publication Date: 2005-10-20
EISAI INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

"The invention provides antibodies that specifically bind to FR-α, a protein overexpressed in tumor cells. These antibodies can block the biological activity of FR-α and are useful for inhibiting the growth of dysplastic cells associated with increased expression of FR-α. The antibodies can be produced using various methods and may be used to treat cancer in humans. The technical effects of the invention include the development of improved methods for detecting and targeting FR-α, as well as the development of new cancer treatment strategies."

Problems solved by technology

Although chemotherapy is the recommended treatment and has enjoyed some success, the 5-year survival rate is still less than 40%.
A difficult problem in antibody therapy in cancer is that often the target of the antibody is expressed by normal tissues as well as cancerous tissues.
Thus, the antibodies that are used to kill cancer cells also have a deleterious effect on normal cells.
Finding unique targets or targets that are preferentially expressed in cancer tissues has proven difficult in many cancers.

Method used

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  • Monoclonal antibodies that specifically block biological activity of a tumor antigen
  • Monoclonal antibodies that specifically block biological activity of a tumor antigen
  • Monoclonal antibodies that specifically block biological activity of a tumor antigen

Examples

Experimental program
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Effect test

example 1

Generation of Anti-FR-α Antibody-Producing Cells

[0134] Murine antibody LK26 was raised against choriocarcinoma cell line Lu-75(c). LK26 was humanized by CDR grafting, yielding an IgG (IgG1 / κ subtype) expressed in NS0 cell lines, according to the method of U.S. Pat. No. 6,124,106. The NS0 cell line was transfected with a hPMS2-134 expression plasmid. The MMR gene was cloned into the pEF expression vector, which contains the elongation factor promoter upstream of the cloning site followed by a mammalian polyadenylation signal. This vector also contains the NEOr gene that allows for selection of cells retaining this plasmid. Briefly, cells were transfected with 1 μg of each vector using polyliposomes following the manufacturer's protocol (Life Technologies). Cells were then selected in 0.5 mg / ml of G418 for 10 days and G418 resistant cells were pooled together to analyze for gene expression. The pEF construct contains an intron that separates the exon 1 of the EF gene from exon 2, whi...

example 2

Screening Strategy to Identify Antibody-Producing Clones and Characterization of anti-FR-α Antibody

[0137] An application of the methods presented within this document is the use of MMR-deficient immunoglobulin-producing cells to create a cell that is substantially free of FR-α binding competitors or a cell that produces substantially only the target immunoglobulin, for example, a FR-α antibody of the invention, including but not limited to an antibody comprising a light chain comprising an amino acid sequence of SEQ ID NO:2 or 3 and a heavy chain comprising an amino acid sequence of SEQ ID NO:5 or 6. FIG. 4 outlines the screening procedure to identify clones that produce high affinity MAbs. The assay employs the use of a plate Enzyme Linked Immunosorbant Assay (ELISA) to screen for clones that produce high-affinity MAbs. 96-well plates containing single immunoglobulin-producing cells are grown in growth medium plus 0.5 mg / ml G418 to ensure clones retain the expression vector. Plate...

example 3

Binding of Antibody to Multimeric FR-α

[0143] Binding of a monoclonal antibody to the tetrameric form of FR-α was shown by Western blot. Briefly, SK-Ov-3 and IGROV tumor cells were grown in nude mice and excised. Tumor tissues were lysed in RIPA buffer with 15-20 strokes in a 2 ml Dounce tissue homogenizer. Insoluble material was removed by centrifugation and the total protein of the supernate was determined using a BioRad protein Assay. In different experiments, either 5 ug or 20 ug of protein was run on a 4-12% Bis-Tris gel (MES) under non-reducing conditions. The electrophoresed protein was transferred to a PVDF membrane. The membrane was blocked in Blotto (5% milk, 0.05% TBS-T). A 1:100 dilution of culture supernate from LK26 hybridoma cells and total concentration of 0.1% NaN3 was added directly to the Blotto blocking solution as the primary antibody, and the membrane was incubated overnight. The membrane was washed in 0.05% TBS-T and the secondary antibody (horseradish peroxida...

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Abstract

This invention relates to novel monoclonal antibodies that specifically bind to the alpha-folate receptor. In some embodiments, the antibodies inhibit a biological activity of folate receptor-α (FR-α). The antibodies are useful in the treatment of certain cancers, particularly cancers that have increased cell surface expression of the alpha-folate receptor (“FR-α”), such as ovarian, breast, renal, colorectal, lung, endometrial, or brain cancer. The invention also relates to cells expressing the monoclonal antibodies, antibody derivatives, such as chimeric and humanized monoclonal antibodies, antibody fragments, and methods of detecting and treating cancer using the antibodies, derivatives, and fragments.

Description

CROSS-REFERENCE TO RELATED APPLICATION [0001] This application claims benefit of U.S. Provisional Application No. 60 / 544,364, filed Feb. 12, 2004, the content of which is hereby incorporated by reference in its entirety.FIELD OF THE INVENTION [0002] This invention relates to purified novel monoclonal antibodies that specifically bind to the alpha-folate receptor (“FR-α”) and compositions thereof. In some embodiments, the antibodies of the invention block the biological activity of FR-α. The antibodies and compositions of the invention are useful in the treatment of certain cancers, particularly cancers that have increased cell surface expression of the alpha-folate receptor, such as ovarian, breast, renal, colorectal, lung, endometrial, or brain cancer. The invention also relates to hybridoma cells expressing the monoclonal antibodies, antibody derivatives, such as chimeric and humanized monoclonal antibodies, antibody fragments, mammalian cells expressing the monoclonal antibodies,...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K39/395C07H21/04C07K16/00C07K16/28C07K16/30C12N5/06C12N15/09
CPCA61K2039/505C07K16/28C07K16/30C07K2317/92C07K2317/24C07K2317/56C07K2317/732C07K16/3069A61P35/00A61P35/02A61P43/00A61K49/00C07K2317/51C07K2317/515G01N33/574G01N33/57492G01N2333/705
Inventor GRASSONICOLAIDES, NICHOLASSASS, PHILIP
Owner EISAI INC
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