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Diagnosis and Treatment of Cancer Using Anti-Desmoglein-3 Antibodies

a technology of desmoglein-3 and cancer, which is applied in the field of cancer diagnosis and treatment, cell proliferation inhibitors, and anticancer agents, can solve the problems of insufficient response to chemotherapy and radiation therapy, slow progression, and inability to fully express anti-dsg3 antibodies, etc., and achieves the effect of high expression

Inactive Publication Date: 2010-04-15
CHUGAI PHARMA CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0014]The present inventors discovered that DSG3 is highly expressed in cancer cells such as lung cancer cells. Furthermore, when complement-dependent cytotoxicity (CDC) activity and antibody-dependent cellular cytotoxicity (ADCC) activity of anti-DSG3 antibodies were measured, the anti-DSG3 antibodies were found to have CDC activity and ADCC activity towards DSG3-expressing cells. Furthermore, from the above-mentioned findings, the present inventors discovered that the anti-DSG3 antibodies were effective for diagnosing, preventing, and treating cancers in which the DSG3 expression is elevated, including lung cancer, and thereby completed the present invention.

Problems solved by technology

However, involvement of the DSG3 protein in other diseases, or functions of anti-DSG3 antibodies other than the cell-dissociating activity have not been elucidated.
Examples of the characteristics of non-small cell lung cancer are slow progression compared to small-cell cancers, and insufficient response to chemotherapy and radiation therapy.
Therefore, when the tumor is localized, surgical resection is the number one choice, but the treatment outcome is very poor compared to other carcinomas such as stomach cancer at the same disease stage by TNM classification.
While recent attempts have been actively pursued to improve the outcome by multimodal treatment, effective therapeutic methods that lead to complete remission have not been established.

Method used

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  • Diagnosis and Treatment of Cancer Using Anti-Desmoglein-3 Antibodies
  • Diagnosis and Treatment of Cancer Using Anti-Desmoglein-3 Antibodies
  • Diagnosis and Treatment of Cancer Using Anti-Desmoglein-3 Antibodies

Examples

Experimental program
Comparison scheme
Effect test

example 1

DSG3 mRNA Expression Analysis in Various Types of Cancers

[0400]Gene chip was used to perform DSG3 gene expression analysis. To search for a gene whose expression is enhanced in cancer cells, various RNAs and total RNAs prepared from various extracted tissues by conventional methods using ISOGEN (manufactured by Nippon Gene) shown in Tables 1 and 2 were used. More specifically, gene expression analysis was carried out using 10 μg each of total RNAs, and subjecting them to GeneChip U-133A (manufactured by Affymetrix) according to the Expression Analysis Technical Manual (manufactured by Affymetrix). When analyzing lung adenocarcinoma and hepatocellular carcinoma, a total of 10 μg was obtained by combining total RNAs of twelve lung adenocarcinoma cases and three hepatocellular carcinoma cases to perform the analysis (Table 1).

TABLE 1TissueSourceWhole brainClontech 64020-1LungClinical sample, 1 caseTracheaClontech 64091-1HeartAmbion 7966KidneyAmbion 7976LiverClinical sample (Surgery)Pan...

example 2

Immunohistological Staining of DSG3 in Lung Squamous Cell Carcinoma

[0404]Since transcription of the DSG3 gene is enhanced in cancer cells, in particular, lung squamous cell carcinoma cells, immunohistological staining analysis was performed to confirm expression of the DSG3 protein.

[0405]Each sample was prepared as a fixed paraffin embedded preparation, and a section sliced to a thickness of 4 μm was mounted on a slide glass and then left at 37° C. for about 16 hours to dry sufficiently. The section was deparaffinized by soaking three times in 100% xylene for five minutes each, and then hydrophilized by soaking three times in 100% ethanol for five minutes each and further soaking in 70% ethanol for five minutes. Then, after washing three times in a 50 mM TBS buffer solution for five minutes, the antigen in the section was activated by treating the section with a citrate buffer (10 mM, pH 7.0) at 120° C. for ten minutes. The section in which the antigen had been activated was washed ...

example 3

Preparation of Anti-DSG3 Antibody

[0407]3-1) Cloning of a Full-Length cDNA Encoding Human DSG3

[0408]A full-length cDNA encoding human DSG3 was obtained by PCR amplification using Human Small Intestine Marathon-Ready cDNA (CLONTECH) as a template. Specifically, 50 μL of a reaction solution containing 2 μL of cDNA, 1 μL of sense primer (SEQ ID NO: 37), 1 μL of antisense primer (SEQ ID NO: 38), 5 μL of 10×KOD-Plus buffer, 5 μL of 2 mM dNTPs, 2 μL of 25 mM MgSO4, and 1 μL of KOD-Plus was subjected to a PCR reaction performed by five cycles of a reaction cycle consisting of reactions at 94° C. for 15 seconds and 70° C. for two minutes, five cycles of a reaction cycle consisting of reactions at 94° C. for 15 seconds and 68° C. for two minutes, and 28 cycles of a reaction cycle consisting of reactions at 94° C. for 15 seconds and 66° C. for two minutes. The amplified product obtained by the above-mentioned PCR reaction was inserted into pGEM-T easy using a pGEM-T Easy Vector System I (Prome...

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Abstract

Methods that involve detection of a DSG3 protein for diagnosing cancer are disclosed. In lung cancer, the expression of DSG3 was found to be enhanced at very high frequency at the gene level and protein level. Methods of the present invention can be carried out using an antibody that recognizes a DSG3 protein. Pharmaceutical compositions, cell growth inhibitors, and anticancer agents containing a DSG3-binding antibody as an active ingredient are also disclosed. Methods of inducing cell damage in DSG3-expressing cells and methods of suppressing proliferation of DSG3-expressing cells by contacting the DSG3-expressing cells with DSG3-binding antibodies are also disclosed.

Description

TECHNICAL FIELD[0001]The present invention relates to methods for diagnosing and treating cancer, cell proliferation inhibitors, and anticancer agents.BACKGROUND ART[0002]Desmoglein 3 (hereinafter referred to as DSG3) was first identified as a glycoprotein having a molecular weight of 130 kDa by immunoprecipitation of keratinocyte extracts with an autoantibody obtained from the serum of patients affected by pemphigus vulgaris (hereinafter referred to as PV), which is an autoimmune blister-forming disease of the skin and mucosa, and was named the PV antigen (hereinafter referred to as PVA) (Non-patent Document 1 and J. Clin. Invest. 74, 313-320, 1984). Then, antibody molecules that react with the above-mentioned 130-kDa protein were isolated from the serum of PV patients by affinity purification. Next, an expression library was constructed using poly(A) RNA isolated from human keratinocytes and was screened using the isolated antibodies, and a cDNA encoding PVA was isolated. Based on...

Claims

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Application Information

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IPC IPC(8): A61K39/395C07K16/18C12N5/00C12Q1/68A61P35/00
CPCC07K16/28C07K2316/96C07K2317/565G01N33/57423C07K2317/734C07K2319/30C07K2317/732C07K2317/73A61P1/04A61P1/18A61P11/00A61P35/00A61P43/00C07K2319/035C07K2317/24G01N2333/705
Inventor ABURATANI, HIROYUKIISHIKAWA, SHUNPEIITO, HIROTAKANAKANO, KIYOTAKAKAWAI, SHIGETO
Owner CHUGAI PHARMA CO LTD
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