JPH06172203A - Agent for inhibiting abnormal cell producing fibronectin receptor - Google Patents

Abstract

PURPOSE:To provide a medicine effective for treating diseases caused by the abnormal cell producing the fibronectin, and an agent for detecting the abnormal cell. CONSTITUTION:The fibronectin receptor-producing abnormal cell-inhibiting agent contains a substance having an affinity for the fibronectin receptor. The agent for detecting the fibronectin receptorproducing abnormal cell contains a substance having an affinity for the fibronectin receptor. Examples of the substance includes a polypeptide containing a RGD sequence, a fibronectin receptor-resistant antibody, and the substance combined with a cell-killing substance, The agent is used for a medicine for treating and diagnosing AIDS, cancers, etc.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a drug for treating and diagnosing diseases caused by abnormal cells producing fibronectin receptor, such as acquired immunodeficiency syndrome (AIDS) and cancer.

[0002]

AIDS is a human immunodeficiency virus (HI).
V) is a severe immunodeficiency caused by infection of T lymphocyte cells. Among the various AIDS symptoms caused by HIV, Kaposi's sarcoma, HIV-related nephritis, etc. are HI.
It is caused not only by immunodeficiency due to destruction of T cells by V, but also by interaction of HIV-infected T cells with the host and entry into normal tissues. Normally, T lymphocytes have only a small amount of fibronectin receptor on the cell surface in the normal state, but when infected with HIV, 2.5
The production of fibronectin receptor is increased about twice as much [J. Cell Biolo
gy), 114, 847-853 (199)
1)], HIV-infected T cells cause the abnormally produced fibronectin receptor to function and fuse with normal T cells to proliferate HIV or invade normal tissues to accelerate the progress of infection. Are believed to be present. As agents for treating AIDS, 3'-azido-2 ', 3'-dideoxythymidine, which acts on HIV-infected cells and inhibits viral reverse transcriptase, and 2', 3 '
-Only dideoxyinosine is domestically licensed. Outside of Japan, only a few drugs with similar mechanism of action are used. Naturally, these drugs show serious side effects, although they are natural from the viewpoint of the mechanism of action.
Its use is severely limited.

[0003]

SUMMARY OF THE INVENTION In consideration of the above situation, the present invention is a drug having a higher safety, which is effective in the treatment of diseases caused by abnormal fibronectin receptor-producing cells using new in-vivo substances, and diseases. It is an object of the present invention to provide a detecting agent for the abnormal cells, which is useful for the diagnosis of.

[0004]

Means for Solving the Problems To summarize the present invention, the first invention of the present invention relates to a fibronectin receptor production abnormal cell inhibitor, which is characterized by containing a substance having an affinity for fibronectin. The second invention of the present invention relates to an agent for detecting abnormal cells producing fibronectin receptor, which is characterized by containing a substance having an affinity for the fibronectin receptor.

In the present invention, the abnormal fibronectin receptor producing cell means a cell in which the fibronectin receptor is produced in an abnormally large amount than usual, and is, for example, T lymphocyte cells infected with HIV or some cancer cells. For example, T lymphocyte cells have only a small amount of fibronectin receptor on the cell surface in the normal state, but when infected with HIV, the production of fibronectin receptor is increased by about 2.5 times. Further, various cancer cells sometimes produce an abnormally large amount of fibronectin receptor during the processes such as proliferation and metastasis in the living body. Also, in vitro, these cancer cells produce several times as many fibronectin receptors stimulated by phorbol ester which is a carcinogenic promoter and Transforming growth factor (TGF) -β which is a transforming growth factor. Like

The inventors of the present invention have conducted extensive studies on substances related to fibronectin, which is an in-vivo substance, and as a result, substances having an affinity for the fibronectin receptor are more selectively and abundant in abnormal cells producing fibronectin receptor. Adherence to cells inhibits the adhesion and invasion of the cells to other normal cells and cells, and the cells to which many of these affinity substances adhere are dying in blood vessels, resulting in abnormal production of fibronectin receptor. The inventors have found that it is effective against diseases caused by cells and completed the first invention of the present invention. That is, in HIV-infected T lymphocyte cells, adhesion of the fibronectin receptor affinity substance prevents the cells from adhering and fusing with other cells, and suppresses HIV proliferation and invasion into normal tissues. Furthermore, HIV-infected T lymphocytes to which a fibronectin receptor affinity substance is attached become susceptible to the action of immunocompetent cells and disappear from blood vessels and tissues, and as a result, AIDS is treated. In addition, even in cancer cells with increased fibronectin receptor, invasion and metastasis of cancer cells are suppressed by the attachment of a fibronectin receptor affinity substance, and cancer cells free in tissues and blood,
It disappears from the blood vessels by the action of immunocompetent cells, and cancer is treated.

The present inventors have further found that by measuring the amount of fibronectin receptor affinity substance attached to these abnormal fibronectin receptor-producing cells, it is possible to carry out diagnosis such as detection and monitoring of diseases accompanied by the increase of the cells. Heading, the second invention of the present invention was completed.

The substance having an affinity for the fibronectin receptor that can be used in the present invention is, for example, RG in the molecule.
A polypeptide having a D sequence, for example, an anti-fibronectin receptor antibody. R in the polypeptide
At least one GD sequence may be provided, but a plurality of RGD sequences may be contained depending on the purpose. RG in the molecule
Examples of the polypeptide having the D sequence include the polypeptides represented by SEQ ID NOS: 1 to 5 in the sequence listing, and these are polypeptides derived from the cell adhesion active site in the human fibronectin molecule, and they are described in JP-A-1 (1998) -101, respectively. −
206998, 2-97397, 1-1809
No. 00 and No. 2-152990. Further, for example, a chimeric polypeptide in which a polypeptide derived from the cell adhesion active site in the human fibronectin molecule and a polypeptide derived from another active site in the human fibronectin molecule are bound to each other may be used. The chimeric polypeptides include, for example, the polypeptides represented by SEQ ID NOS: 6 to 13 of the sequence listing, and these are represented by SEQ ID NO: 14 of the sequence listing derived from the cell adhesion active site in human fibronectin molecule. The peptide is a polypeptide in which the heparin-binding active site-derived polypeptide in the human fibronectin molecule is bound directly or via a spacer. Regarding the polypeptides represented by SEQ ID NOS: 6 to 13, respectively, JP-A-2-311498,
Japanese Patent Application No. 3-238935 and Japanese Patent Application Laid-Open No. 3-28
4700. In addition, SEQ ID NO: 6
The polypeptides represented by 11 are multifunctional polypeptides that also have heparin-binding activity. Further, as chimeric polypeptides, there are disclosed in JP-A-1-261398 and 3-5.
It may be a polypeptide consisting of the polypeptide represented by SEQ ID NO: 14 derived from the cell adhesion active site in the human fibronectin molecule described in each of No. 9000 and the polypeptide derived from the fibrin binding active site in the human fibronectin molecule. Furthermore, a chimera-type polypeptide comprising a polypeptide derived from a cell adhesion active site in a human fibronectin molecule and a polypeptide derived from a protein of another species may be used. For example, the human fibronectin-derived polypeptide described in JP-A-4-54199, Or a chimeric polypeptide with a human collagen type XI-derived polypeptide, a chimeric polypeptide with a human collagen type V-derived polypeptide described in Japanese Patent Application No. 3-291958, and JP-A-3-232898. Chimeric polypeptide with human epidermal growth factor described in Japanese Patent Application No. 4-83
There are chimeric polypeptides with human fibroblast growth factor described in No. 220, and the like.

The polypeptide having an RGD sequence in the molecule may be a peptide having the RGD sequence grafted into another functional polypeptide molecule, and the grafted polypeptide is described in, for example, JP-A-3-34996. In the protein molecule described in Japanese Patent Application No. 3-16251, the RGD sequence was introduced into the protein A molecule described above and transplanted, the polypeptide inserted into the calpastatin molecule described in the same publication and transplanted. It may be a polypeptide inserted into or transplanted into.

Furthermore, a polypeptide having an RGD sequence in its molecule may be synthesized by a synthetic method, for example, Japanese Patent Laid-Open No.
Poly-RGDS having the RGD sequence represented by SEQ ID NO: 15 in the sequence listing described in JP-A-173828 as a repeating unit may be synthesized and used. The synthetic polypeptide may be a polypeptide having an RGD sequence in the molecule and having an affinity for the fibronectin receptor, which may be linear or branched, and may be a cyclic polypeptide. You may synthesize and use it as a peptide. These human fibronectin cell adhesion active site-derived polypeptides, chimeric polypeptides containing the polypeptides, RGD sequence-transplanted polypeptides, and synthetic polypeptides have a fibronectin receptor affinity and a characteristic of each polypeptide, and thus, the fibronectin It may be selected and used according to the type and severity of the disease caused by abnormal receptor-producing cells.

As an example, a polypeptide derived from human fibronectin cell adhesion active site (hereinafter referred to as C274) represented by SEQ ID NO: 3 in the sequence listing, and a human fibronectin cell adhesion active site polypeptide and heparin of the same fibronectin are shown. The polypeptide that is a chimeric polypeptide derived from the binding active site and is represented by SEQ ID NO: 7 in the sequence listing (hereinafter referred to as CH271) will be described in detail.

In the present specification, the shoulder numbers attached to amino acids indicate the number of amino acid residues from the N-terminus of the amino acid sequence obtained by translating the cDNA sequence of human fibronectin in the EMBL data bank.

The method for producing C274 represented by SEQ ID NO: 3 in the sequence listing is shown in the above-mentioned Japanese Patent Application Laid-Open No. 2-93797, and will be specifically described below. C274 (Pro ¹²³⁹ -A
sp ¹⁵¹² ) is a polypeptide represented by SEQ ID NO: 2 in the sequence listing (Pro ¹²³⁹ -Met ¹⁵¹⁷ ).
No. 8 publication, hereinafter referred to as C279) in which the C-terminal 5 amino acid residues are deleted. As a method for genetically preparing C274, it is convenient to use the above-mentioned plasmid pTFD707 encoding C279. C27
A plasmid encoding C274 can be prepared by converting the codon AAA of Lys ^{1513 at} the 5th residue from the C-terminus of 9 into the termination codon TAA. This base conversion can be performed by introducing a site-specific mutation.

Escherichia coli into which the plasmid expressing C274 has been introduced is designated as Escherichia coli JM109 / pTF7221 and has been deposited as Microtechnology Research Institute No. 1915 (FERM BP-1915).

Purification of C274 from the recombinant is carried out, for example, as follows. The cell pellet is suspended in a buffer solution and sonicated to separate a soluble fraction and an insoluble fraction. The latter is further solubilized with a buffer containing 7M urea. The soluble fraction was collected and applied to a column of Sepharose 4B bound with an antibody specific to the cell adhesion active site of human fibronectin,
Perform affinity purification. A buffer solution having a pH of about 2.3 is used for elution. C274 can be obtained by collecting the target fraction by immunoblotting. If necessary, it can be further purified by FPLC or HPLC.

CH271 represented by SEQ ID NO: 7 in the sequence listing
The manufacturing method is described in the above-mentioned Japanese Patent Laid-Open No. 2-311498, and will be specifically described below. CH271 (Pro
¹²³⁹ -Ser ¹⁵¹⁵ -Met-Ala ¹⁶⁹⁰ -Thr ¹⁹⁶⁰ ) is a polypeptide derived from the cell adhesion active site of human fibronectin (Pro
^1239- Ser ¹⁵¹⁵ ) is a polypeptide derived from the heparin-binding active site of fibronectin (Ala ¹⁶⁹⁰ -T) via Met.
It is a polypeptide bound to hr ¹⁹⁶⁰ ).

Plasmid pLF2435, which contains a cDNA fragment encoding the heparin-binding active site polypeptide of human fibronectin, was constructed in Biochemistr.
y), 25, 4936-4941 (1986).
It is a plasmid reconstructed by ligating the coding regions of pLF2, 4, 3 and 5 described in 1. The required cDNA fragment was excised from this plasmid pLF2435 with a restriction enzyme, and synthetic DNA containing a start codon at the 5'side was also prepared.
Synthetic DNA containing a stop codon on the 3'side is ligated with a DNA ligase, and then ligated to an expression vector.
A plasmid pHD101 expressing Ala ¹⁶⁹⁰ -Thr ¹⁹⁶⁰ in the heparin-binding active site can be constructed. 27 of Ala ¹⁶⁹⁰ -Thr ¹⁹⁶⁰
Plasmid pHD1 expressing a single amino acid residue polypeptide
E. coli introduced with 01 is Escherichia coli HB101 / pHD1
It is displayed as 01, and is based on Micro Engineering Research Article No. 2264 (FERM BP-226
4) has been deposited as

Next, the above-mentioned C279-encoding DNA is ligated to an expression vector to obtain the method described in JP-A-1-20699.
A plasmid which encodes Pro ¹²³⁹ -Ser ¹⁵¹⁵ -Met by introducing an NcoI site into the plasmid pTF7021 described in Japanese Patent No. 8
pTF7520 can be constructed. 3'of the translation region of the plasmid
CDNA extracted from the above-mentioned pHD101 at the terminal NcoI site
The recombinant plasmid pCH101 expressing CH271 in which the polypeptide derived from the cell adhesion active site of human fibronectin and the polypeptide derived from the heparin-binding active site of the same fibronectin were linked via Met derived from the NcoI site was obtained by connecting To be

Escherichia coli into which a plasmid expressing CH271 has been introduced is designated as Escherichia coli HB101 / pCH101 and has been deposited as Microtechnology Research Institute No. 2799 (FERM BP-2799).

By introducing the obtained plasmid into Escherichia coli and culturing it under appropriate conditions, the desired polypeptide is accumulated in E. coli. The polypeptide is purified, for example, as follows. After collecting the recombinant Escherichia coli cultivated in a medium such as L-broth, ultrasonic treatment is carried out to obtain a disrupted cell suspension, which is centrifuged to obtain a supernatant. After dialysis of the supernatant,
Pass through a column of DEAE ion exchanger, then CM
CH271 can be purified by performing chromatography on an ion exchanger, heparin-agarose or the like.

The anti-fibronectin receptor antibody used in the present invention may be any antibody that recognizes the fibronectin receptor, and may be a polyclonal antibody or a monoclonal antibody. Examples of the anti-fibronectin receptor monoclonal antibody include the antibody-producing strain Hybridom described in JP-A-2-245194.
a Monoclonal antibodies FNR-5 and FNR-31 produced by FNR-5 and Hybridoma FNR-31, respectively, may be used. Note that Hybridoma FNR-5 and Hybridoma FNR-31 have been deposited as Microtechnical Research Institute No. 10610 (FERM P-10610) and Microtechnical Research Institute No. 10611 (FERM P-10611), respectively. The monoclonal antibodies FNR-5 and FNR-3
From 1, the fragments possessing the recognition specificity to the fibronectin receptor, for example, the monovalent Fab fragment and the divalent (Fab ′) ₂ fragment may be prepared and used, and the recognition specificity is utilized. However, a mouse-human chimeric monoclonal antibody and a bispecific chimeric antibody may be prepared and used, and further, only an antigen recognition site may be used as an artificial antibody transplanted to a human antibody, and these are genetically engineered. You may produce.

The substance having an affinity for the fibronectin receptor used in the present invention can be modified with various substances before use. For example, a polypeptide having an RGD sequence and an anti-fibronectin receptor antibody are each modified with an antiviral agent, an anticancer agent, a cytotoxic agent, etc., whereby more selective toxicity can be imparted to cells with abnormal fibronectin receptor production. Antiviral agents include, for example, interferon, azidothymidine, sulfated curdlan, pokeweed antiviral protein, and the like, anticancer agents include, for example, mactinomycin D and mitomycin C, and cytotoxic agents include cytotoxic agents. Steroids, gelonin, abrin, lysine, etc.
It may be selected according to each disease. Further, by modifying with an activator of macrophages or lymphocytes such as cytokinin and lectin, immunocompetent cells can be activated and the effect as an inhibitor is enhanced. The therapeutic effect is also enhanced by using an antibody against the polypeptide of the present invention. In addition, by labeling the above-mentioned polypeptide or antibody with an enzyme, a fluorescent marker, a metal chelate, avidin, biotin, radioactivity, etc., it is possible to easily detect and monitor abnormal cells producing fibronectin receptor, which are caused by the cells. Easy diagnosis of diseases.

When the obtained substance having an affinity for the fibronectin receptor of the present invention is used as a medicine,
It may be orally or parenterally administered by formulating it with a pharmaceutical carrier according to need by a conventional method. As the excipient or carrier, a pharmacologically acceptable one is selected, and its type and composition differ depending on the administration route and administration method. For example, water, alcohols, animal or vegetable oils such as soybean oil, olive oil and mineral oil, or synthetic oil is used as the liquid carrier. As the solid carrier, sugars such as maltose and sucrose, amino acids, cellulose derivatives such as hydroxypropyl cellulose, organic acid salts such as magnesium stearate, etc. are used. In the case of an injection, the solution is preferably physiological saline, various buffer solutions, sugar solutions such as glucose, inositol, mannitol and lactose, and glycols such as ethylene glycol and polyethylene glycol. Also, inositol, mannitol, lactose,
A lyophilized preparation with saccharides such as sucrose and excipients such as amino acids such as phenylalanine, and a suitable solvent for injection at the time of administration, such as sterile water, physiological saline, glucose solution, electrolyte solution, amino acid solution intravenous administration It can also be administered by dissolving it in a working liquid. Although the content of the polypeptide of the present invention in the preparation varies depending on the preparation, it is usually 0.1.
% To 100% by weight, preferably 1 to 98% by weight. For example, in the case of an injectable solution, it is usually desirable to contain the active ingredient in an amount of 0.1 to 30% by weight, preferably 1 to 10% by weight. In the case of oral administration, it is used in the form of tablets, capsules, powders, granules, liquids, dry syrups, etc. together with the solid or liquid carrier. Capsules, granules and powders generally contain 5-100% by weight, preferably 25-98% by weight, of the active ingredient.

The dose is determined according to the age, weight, symptoms, treatment purpose, etc. of the patient, but the therapeutic dose is generally 1 to 100 mg / kg / day for parenteral administration and 5 to 500 mg / kg for oral administration.
/ Day.

The substance used in the formulation of the substance of the present invention as a detection agent for abnormal cells producing fibronectin receptor may be any substance as long as it can be used for ordinary polypeptide preparations and antibody preparations. The shape may be liquid or a freeze-dried product.

[0026]

Next, the physiological activity of the substance having an affinity for the fibronectin receptor of the present invention will be shown by experimental examples. As an example of the compound that can be used in the present invention, the results using a cell adhesion-active polypeptide derived from fibronectin and a chimeric polypeptide CH271 of heparin-binding activity polypeptide are shown, but the present invention is not limited to these experimental examples.

Experimental Example 1. Detection of abnormal cells producing fibronectin receptor Preparation of a substance having an affinity for a fluorescently labeled fibronectin receptor: Fluoresceinisothiocynate (fluoresceinisothiocyate) which is a fluorescent dye for CH271
anate) (FITC) combined with FITC-CH27
1 was prepared as follows. 2 ml of 1 mg / ml phosphate buffer of CH271 was placed in a dialysis tube (10,000 molecular weight cut) and dialyzed against about 1 liter of 0.01 M carbonate buffer (pH 9.2) at 4 ° C. overnight. Next, after dialysis, FIT
200 μl of a 1 mg / ml dimethyl sulfoxide solution of C was added, and the mixture was allowed to react overnight at 4 ° C. under conditions of light shielding. After the reaction was completed, this solution was put into a dialysis tube, and a phosphate buffer solution (p
H7.6) About 1 liter was dialyzed at 4 ° C. overnight, passed through a membrane filter (0.2 to 0.5 μm), and
ITC-CH271 was prepared. Induction of abnormal cells producing fibronectin receptor: Eagle's minimal medium (ME
Mouse T lymphoma cell EL-4 (5 x 10
⁵ cells / ml) with TGF-β at a concentration of 10 ng / ml, 37
It was allowed to act for 42 hours at 5 ° C. and 5% CO ₂ . Next 5 mM
After the cells were detached with EDTA and collected, they were thoroughly washed with a medium without fetal calf serum (FCS).

Detection of abnormal cells producing fibronectin receptor: FITC-CH271 was added to the above cells 1, 1
Add 0,100μg / ml, 37 ℃, 5%
It was cultured under CO ₂ condition for 1 hour. FCS-no additive MEM
After thorough washing with the medium, the cells were suspended in the same medium and analyzed with a flow cytometer. Cells similarly cultured and treated in the same medium containing no TGF-β were used as a control.

[0029]

[Table 1] Table 1 ──────────────────────────────────── TGF-β treatment FITC-CH271 action Concentration Fluorescence intensity (mean ± standard deviation) ──────────────────────────────────── None 0 20. 3 ± 11.0 〃 1 μg / ml 22.3 ± 12.9 〃 10 〃 39.2 ± 26.3 〃 100 〃 69.1 ± 29.8 10 ng / ml 0 20.2 ± 9.3 〃 1 μg / ml 30.7 ± 16.2 〃 10 〃 59.5 ± 29.7 〃 100 〃 93.1 ± 34.2 ───────────────────── ────────────────

As shown in FIGS. 1 and 2 and Table 1, the FIT
C-CH271 adheres more to TGF-β untreated cells than to control cells (TGF-β untreated cells), that is, EL-4 cells become abnormal cells producing fibronectin receptor by the action of TGF-β. Was confirmed. In addition, the detection of this abnormal cell is detected by FITC-CH271.
It was revealed that such a substance can be easily carried out by a substance having an affinity for a labeled fibronectin receptor.

Incidentally, FIG. 1 shows EL- which is not treated with TGF-β.
It is a figure which shows the binding property of FITC-CH271 to 4 cells, and the vertical axis | shaft has displayed the cell number and the horizontal axis has shown the fluorescence intensity in logarithm. In FIG. 1, the solid line represents cells by FITC-CH2710.
The number of cells of each fluorescence intensity when treated with μg / ml is shown, and the broken line shows the number of cells of each fluorescence intensity when the cells are not treated with FITC-CH271. In addition, FIG. 2 shows TG
FITC-CH27 on EL-4 cells treated with F-β
1 is a diagram showing the binding property of No. 1, in which the vertical axis represents the number of cells and the horizontal axis represents the fluorescence intensity in logarithm. In FIG. 2, the solid line indicates FI
The number of cells at each fluorescence intensity when treated with TC-CH27110 μg / ml is shown, and the broken line shows the cells as FITC-CH2.
The number of cells at each fluorescence intensity without treatment with 71 is shown.

Experimental Example 2. Removal of abnormal cells producing fibronectin receptor EL-4 cells 1 × 10 ⁶ cells / ml containing 20 ng of TGF-β
The mixture was added to the culture dish at 37 ° C. and 5% CO ₂ for 18 hours. The cells were collected by pipetting and centrifugation and washed thoroughly with MEM medium without FCS. For untreated EL-4, TGF
The same operation was performed without adding -β. CH271 was added to these cells at 10 μg / ml or 100 μg / ml, and after mixing well, 0.2 ml per mouse from the tail vein of C57BL / 6 (9-week-old female) mice, EL
⁴ -4 cells 6.0 × 10, and injected with CH271. After 9 days from the determination, the liver was removed and the liver weight was measured, and the liver weight / body weight conversion value (%) was calculated by the following formula (Equation 1).
The ability of CH271 to remove abnormal cells producing fibronectin receptor was calculated by the following formula (Equation 2) to determine the cancer metastasis inhibition rate (%), and the degree of liver metastasis of EL-4 cells was calculated by TG.
It was evaluated by comparing the F-β treated group and the untreated group.

[0033]

[Equation 1] Liver weight Body weight conversion value (%) = [{Liver weight of each mouse (g)} / {Weight of each mouse (g)} × 100

[0034]

[Equation 2] Cancer metastasis inhibition rate (%) = [1-{(AC) /
(BC)}] × 100

A: Liver weight / body weight conversion value (%) of each sample + EL-4 cell administration group B: Liver weight / body weight conversion value (%) of physiological saline + EL-4 cell administration group C: Liver weight of non-administration group Weight conversion value (%)

[0036]

[Table 2] Table 2 ──────────────────────────────────── Group TGF-β treatment CH271 dose Liver weight Body weight conversion value (%) Cancer metastasis suppression (number of animals) (mean ± standard deviation) Control rate (%) ──────────────────────── ───────────── 1 (9) None Saline 10.4 ± 0.8 −2 (5) 〃 2 μg 9.4 ± 0.5 17.5 3 (5) 〃 20 μg 8.8 ± 1.1 28.1 4 (5) 20 ng / ml saline 9.7 ± 0.4 12.3 5 (5) 〃 2 μg 8.0 ± 0.4 42.1 6 (5 ) 〃 20 μg 6.7 ± 0.8 64.9 7 (2) − − 4.7 ± 0.3 ^* − ────────────────────── ────────────── * Normal mouse control group liver weight body weight conversion value

As shown in FIG. 3 and Table 2, the inhibitory effect of CH271 on hepatic metastasis of EL-4 cells was TGF-β.
It strongly appeared in EL-4 cells treated with TGF-β as compared with EL-4 cells not treated with. That is, C
H271 showed a strong inhibitory effect on cells with abnormal fibronectin receptor production. Note that FIG. 3 is a diagram showing the liver weight / body weight conversion value (%) of each treatment group and the normal mouse group, the vertical axis represents the liver weight body weight conversion value (%), and the horizontal axis represents the group number of each mouse group. 1 is a TGF-β untreated EL-4 cell and saline administration group, 2 is a TGF-β untreated EL-4 cell and CH271 (2 μg) administration group, 3 is TGF-β untreated EL -4 cells and CH271 (20 μg) administration group, 4 TGF-β-treated EL-4 cells and physiological saline administration group, 5 TGF-β-treated EL-4 cells and CH
271 (2 μg) administration group, 6 is EL of TGF-β treatment
-4 cells and CH271 (20 μg) administration group, 7 is the respective group number of the control normal mouse group.

In FIG. 3, * indicates Student (Stud
ent) t-test revealed a significant difference at p <0.01,
** means that a significant difference was recognized at p <0.005, and *** means that a significant difference was recognized at P <0.001.

[0039]

EXAMPLES Next, the present invention will be specifically described with reference to examples, but the scope of the present invention is not limited to the examples. In addition, in each example, a part means a weight part.

Formulation Example 1 Phosphate buffer solution (PBS) was added to 30 parts of CH271 to make 2000 parts of the total amount, and this was dissolved, followed by sterilization filtration using Millipore filter GS type. This filtrate 2
g was placed in a 10 ml vial and lyophilized to obtain a lyophilized injection containing 30 mg of the polypeptide in 1 vial.

Formulation Example 2 CH271 50 parts, lactose 600 parts, crystalline cellulose 3
30 parts of hydroxypropyl cellulose and 20 parts of hydroxypropyl cellulose were mixed well, compressed using a roll type compressor (roller compactor), crushed and sieved so as to be between 16 and 60 mesh to obtain granules.

[0042]

INDUSTRIAL APPLICABILITY The present invention provides a fibronectin receptor production abnormal cell inhibitor useful as a therapeutic and diagnostic agent for diseases caused by fibronectin receptor production abnormal cells, such as AIDS and cancer.

[Sequence list]

 Sequence number: 1 Array length: 258 Array type: Number of amino acid chains: Single-stranded topology: Linear array type: Peptide sequence:  Pro Ser Ile Asp Leu Thr Asn Phe Leu Val Arg Tyr Ser Pro Val 1 5 10 15 Lys Asn Glu Glu Asp Val Ala Glu Leu Ser Ile Ser Pro Ser Asp 20 25 30 Asn Ala Val Val Leu Thr Asn Leu Leu Pro Gly Thr Glu Tyr Val 35 40 45 Val Ser Val Ser Ser Val Tyr Glu Gln His Glu Ser Thr Pro Leu 50 55 60 Arg Gly Arg Gln Lys Thr Gly Leu Asp Ser Pro Thr Gly Ile Asp 65 70 75 Phe Ser Asp Ile Thr Ala Asn Ser Phe Thr Val His Trp Ile Ala 80 85 90 Pro Arg Ala Thr Ile Thr Gly Tyr Arg Ile Arg His His Pro Glu 95 100 105 His Phe Ser Gly Arg Pro Arg Glu Asp Arg Val Pro His Ser Arg 110 115 120 Asn Ser Ile Thr Leu Thr Asn Leu Thr Pro Gly Thr Glu Tyr Val 125 130 135 Val Ser Ile Val Ala Leu Asn Gly Arg Glu Glu Ser Pro Leu Leu 140 145 150 Ile Gly Gln Gln Ser Thr Val Ser Asp Val Pro Arg Asp Leu Glu 155 160 165 Val Val Ala Ala Thr Pro Thr Ser Leu Leu Ile Ser Trp Asp Ala 170 175 180 Pro Ala Val Thr Val Arg Tyr Tyr Arg Ile Thr Tyr Gly Glu Thr 185 190 195 Gly Gly Asn Ser Pro Val Gln Glu Phe Thr Val Pro Gly Ser Lys 200 205 210 Ser Thr A la Thr Ile Ser Gly Leu Lys Pro Gly Val Asp Tyr Thr 215 220 225 Ile Thr Val Tyr Ala Val Thr Gly Arg Gly Asp Ser Pro Ala Ser 230 235 240 Ser Lys Pro Ile Ser Ile Asn Tyr Arg Thr Glu Ile Asp Lys Pro 245 250 255 Ser Gln Met SEQ ID NO: 2 Array length: 279 Array type: Number of amino acid chains: Single-stranded topology: Linear array type: Peptide sequence:  Pro Thr Asp Leu Arg Phe Thr Asn Ile Gly Pro Asp Thr Met Arg 1 5 10 15 Val Thr Trp Ala Pro Pro Pro Ser Ile Asp Leu Thr Asn Phe Leu 20 25 30 Val Arg Tyr Ser Pro Val Lys Asn Glu Glu Asp Val Ala Glu Leu 35 40 45 Ser Ile Ser Pro Ser Asp Asn Ala Val Val Leu Thr Asn Leu Leu 50 55 60 Pro Gly Thr Glu Tyr Val Val Ser Val Ser Ser Val Tyr Glu Gln 65 70 75 His Glu Ser Thr Pro Leu Arg Gly Arg Gln Lys Thr Gly Leu Asp 80 85 90 Ser Pro Thr Gly Ile Asp Phe Ser Asp Ile Thr Ala Asn Ser Phe 95 100 105 Thr Val His Trp Ile Ala Pro Arg Ala Thr Ile Thr Gly Tyr Arg 110 115 120 Ile Arg His His Pro Glu His Phe Ser Gly Arg Pro Arg Glu Asp 125 130 135 Arg Val Pro His Ser Arg Asn Ser Ile Thr Leu Thr Asn Leu Thr 140 145 150 Pro Gly Thr Glu Tyr Val Val Ser Ile Val Ala Leu Asn Gly Arg 155 160 165 Glu Glu Ser Pro Leu Leu Ile Gly Gln Gln Ser Thr Val Ser Asp 170 175 180 Val Pro Arg Asp Leu Glu Val Val Ala Ala Thr Pro Thr Ser Leu 185 190 195 Leu Ile Ser Trp Asp Ala Pro Ala Val Thr Val Arg Tyr Tyr Arg 200 205 210 Ile Thr T yr Gly Glu Thr Gly Gly Asn Ser Pro Val Gln Glu Phe 215 220 225 Thr Val Pro Gly Ser Lys Ser Thr Ala Thr Ile Ser Gly Leu Lys 230 235 240 Pro Gly Val Asp Tyr Thr Ile Thr Val Tyr Ala Val Thr Gly Arg 245 250 255 Gly Asp Ser Pro Ala Ser Ser Lys Pro Ile Ser Ile Asn Tyr Arg 260 265 270 Thr Glu Ile Asp Lys Pro Ser Gln Met 275 SEQ ID NO: 3 Array length: 274 Array type: Number of amino acid chains: Single-stranded topology: Linear array type: Peptide sequence:  Pro Thr Asp Leu Arg Phe Thr Asn Ile Gly Pro Asp Thr Met Arg 1 5 10 15 Val Thr Trp Ala Pro Pro Pro Ser Ile Asp Leu Thr Asn Phe Leu 20 25 30 Val Arg Tyr Ser Pro Val Lys Asn Glu Glu Asp Val Ala Glu Leu 35 40 45 Ser Ile Ser Pro Ser Asp Asn Ala Val Val Leu Thr Asn Leu Leu 50 55 60 Pro Gly Thr Glu Tyr Val Val Ser Val Ser Ser Val Tyr Glu Gln 65 70 75 His Glu Ser Thr Pro Leu Arg Gly Arg Gln Lys Thr Gly Leu Asp 80 85 90 Ser Pro Thr Gly Ile Asp Phe Ser Asp Ile Thr Ala Asn Ser Phe 95 100 105 Thr Val His Trp Ile Ala Pro Arg Ala Thr Ile Thr Gly Tyr Arg 110 115 120 Ile Arg His His Pro Glu His Phe Ser Gly Arg Pro Arg Glu Asp 125 130 135 Arg Val Pro His Ser Arg Asn Ser Ile Thr Leu Thr Asn Leu Thr 140 145 150 Pro Gly Thr Glu Tyr Val Val Ser Ile Val Ala Leu Asn Gly Arg 155 160 165 Glu Glu Ser Pro Leu Leu Ile Gly Gln Gln Ser Thr Val Ser Asp 170 175 180 Val Pro Arg Asp Leu Glu Val Val Ala Ala Thr Pro Thr Ser Leu 185 190 195 Leu Ile Ser Trp Asp Ala Pro Ala Val Thr Val Arg Tyr Tyr Arg 200 205 210 Ile Thr Ty r Gly Glu Thr Gly Gly Asn Ser Pro Val Gln Glu Phe 215 220 225 Thr Val Pro Gly Ser Lys Ser Thr Ala Thr Ile Ser Gly Leu Lys 230 235 240 Pro Gly Val Asp Tyr Thr Ile Thr Val Tyr Ala Val Thr Gly Arg 245 250 255 Gly Asp Ser Pro Ala Ser Ser Lys Pro Ile Ser Ile Asn Tyr Arg 260 265 270 Thr Glu Ile Asp SEQ ID NO: 4 Array length: 283 Array type: Number of amino acid chains: Single-stranded topology: Linear array type: Peptide sequence:  Ala Val Pro Pro Pro Thr Asp Leu Arg Phe Thr Asn Ile Gly Pro 1 5 10 15 Asp Thr Met Arg Val Thr Trp Ala Pro Pro Pro Ser Ile Asp Leu 20 25 30 Thr Asn Phe Leu Val Arg Tyr Ser Pro Val Lys Asn Glu Glu Asp 35 40 45 Val Ala Glu Leu Ser Ile Ser Pro Ser Asp Asn Ala Val Val Leu 50 55 60 Thr Asn Leu Leu Pro Gly Thr Glu Tyr Val Val Ser Val Ser Ser 65 70 75 Val Tyr Glu Gln His Glu Ser Thr Pro Leu Arg Gly Arg Gln Lys 80 85 90 Thr Gly Leu Asp Ser Pro Thr Gly Ile Asp Phe Ser Asp Ile Thr 95 100 105 Ala Asn Ser Phe Thr Val His Trp Ile Ala Pro Arg Ala Thr Ile 110 115 120 Thr Gly Tyr Arg Ile Arg His His Pro Glu His Phe Ser Gly Arg 125 130 135 Pro Arg Glu Asp Arg Val Pro His Ser Arg Asn Ser Ile Thr Leu 140 145 150 Thr Asn Leu Thr Pro Gly Thr Glu Tyr Val Val Ser Ile Val Ala 155 160 165 Leu Asn Gly Arg Glu Glu Ser Pro Leu Leu Ile Gly Gln Gln Ser 170 175 180 Thr Val Ser Asp Val Pro Arg Asp Leu Glu Val Val Ala Ala Thr 185 190 195 Pro Thr Ser Leu Leu Ile Ser Trp Asp Ala Pro Ala Val Thr Val 200 205 210 Arg Tyr Ty r Arg Ile Thr Tyr Gly Glu Thr Gly Gly Asn Ser Pro 215 220 225 Val Gln Glu Phe Thr Val Pro Gly Ser Lys Ser Thr Ala Thr Ile 230 235 240 Ser Gly Leu Lys Pro Gly Val Asp Tyr Thr Ile Thr Val Tyr Ala 245 250 255 Val Thr Gly Arg Gly Asp Ser Pro Ala Ser Ser Lys Pro Ile Ser 260 265 270 Ile Asn Tyr Arg Thr Glu Ile Asp Lys Pro Ser Gln Met 275 280 SEQ ID NO: 5 Array length: 385 Array type: Number of amino acid chains: Single-stranded topology: Linear array type: Peptide sequence:  Ala Pro Ile Val Asn Lys Val Val Thr Pro Leu Ser Pro Pro Thr 1 5 10 15 Asn Leu His Leu Glu Ala Asn Pro Asp Thr Gly Val Leu Thr Val 20 25 30 Ser Trp Glu Arg Ser Thr Thr Pro Asp Ile Thr Gly Tyr Arg Ile 35 40 45 Thr Thr Thr Pro Thr Asn Gly Gln Gln Gly Asn Ser Leu Glu Glu 50 55 60 Val Val His Ala Asp Gln Ser Ser Cys Thr Phe Asp Asn Leu Ser 65 70 75 Pro Gly Leu Glu Tyr Asn Val Ser Val Tyr Thr Val Lys Asp Asp 80 85 90 Lys Glu Ser Val Pro Ile Ser Asp Thr Ile Ile Pro Ala Val Pro 95 100 105 Pro Pro Thr Asp Leu Arg Phe Thr Asn Ile Gly Pro Asp Thr Met 110 115 120 Arg Val Thr Trp Ala Pro Pro Pro Ser Ile Asp Leu Thr Asn Phe 125 130 135 Leu Val Arg Tyr Ser Pro Val Lys Asn Glu Glu Asp Val Ala Glu 140 145 150 Leu Ser Ile Ser Pro Ser Asp Asn Ala Val Val Leu Thr Asn Leu 155 160 165 Leu Pro Gly Thr Glu Tyr Val Val Ser Val Ser Ser Val Tyr Glu 170 175 180 Gln His Glu Ser Thr Pro Leu Arg Gly Arg Gln Lys Thr Gly Leu 185 190 195 Asp Ser Pro Thr Gly Ile Asp Phe Ser Asp Ile Thr Ala Asn Ser 200 205 210 Phe Thr V al His Trp Ile Ala Pro Arg Ala Thr Ile Thr Gly Tyr 215 220 225 Arg Ile Arg His His Pro Glu His Phe Ser Gly Arg Pro Arg Glu 230 235 240 Asp Arg Val Pro His Ser Arg Asn Ser Ile Thr Leu Thr Asn Leu 245 250 255 Thr Pro Gly Thr Glu Tyr Val Val Ser Ile Val Ala Leu Asn Gly 260 265 270 Arg Glu Glu Ser Pro Leu Leu Ile Gly Gln Gln Ser Thr Val Ser 275 280 285 Asp Val Pro Arg Asp Leu Glu Val Val Ala Ala Thr Pro Thr Ser 290 295 300 Leu Leu Ile Ser Trp Asp Ala Pro Ala Val Thr Val Arg Tyr Tyr 305 310 315 Arg Ile Thr Tyr Gly Glu Thr Gly Gly Asn Ser Pro Val Gln Glu 320 325 330 Phe Thr Val Pro Gly Ser Lys Ser Thr Ala Thr Ile Ser Gly Leu 335 340 345 Lys Pro Gly Val Asp Tyr Thr Ile Thr Val Tyr Ala Val Thr Gly 350 355 360 Arg Gly Asp Ser Pro Ala Ser Ser Lys Pro Ile Ser Ile Asn Tyr 365 370 375 Arg Thr Glu Ile Asp Lys Pro Ser Gln Met 380 385 SEQ ID NO: 6 Array length: 548 Array type: Number of amino acid chains: Single-stranded topology: Linear array type: Peptide sequence:  Pro Thr Asp Leu Arg Phe Thr Asn Ile Gly Pro Asp Thr Met Arg 1 5 10 15 Val Thr Trp Ala Pro Pro Pro Ser Ile Asp Leu Thr Asn Phe Leu 20 25 30 Val Arg Tyr Ser Pro Val Lys Asn Glu Glu Asp Val Ala Glu Leu 35 40 45 Ser Ile Ser Pro Ser Asp Asn Ala Val Val Leu Thr Asn Leu Leu 50 55 60 Pro Gly Thr Glu Tyr Val Val Ser Val Ser Ser Val Tyr Glu Gln 65 70 75 His Glu Ser Thr Pro Leu Arg Gly Arg Gln Lys Thr Gly Leu Asp 80 85 90 Ser Pro Thr Gly Ile Asp Phe Ser Asp Ile Thr Ala Asn Ser Phe 95 100 105 Thr Val His Trp Ile Ala Pro Arg Ala Thr Ile Thr Gly Tyr Arg 110 115 120 Ile Arg His His Pro Glu His Phe Ser Gly Arg Pro Arg Glu Asp 125 130 135 Arg Val Pro His Ser Arg Asn Ser Ile Thr Leu Thr Asn Leu Thr 140 145 150 Pro Gly Thr Glu Tyr Val Val Ser Ile Val Ala Leu Asn Gly Arg 155 160 165 Glu Glu Ser Pro Leu Leu Ile Gly Gln Gln Ser Thr Val Ser Asp 170 175 180 Val Pro Arg Asp Leu Glu Val Val Ala Ala Thr Pro Thr Ser Leu 185 190 195 Leu Ile Ser Trp Asp Ala Pro Ala Val Thr Val Arg Tyr Tyr Arg 200 205 210 Ile Thr Ty r Gly Glu Thr Gly Gly Asn Ser Pro Val Gln Glu Phe 215 220 225 Thr Val Pro Gly Ser Lys Ser Thr Ala Thr Ile Ser Gly Leu Lys 230 235 240 Pro Gly Val Asp Tyr Thr Ile Thr Val Tyr Ala Val Thr Gly Arg 245 250 255 Gly Asp Ser Pro Ala Ser Ser Lys Pro Ile Ser Ile Asn Tyr Arg 260 265 270 Thr Glu Ile Asp Lys Pro Ser Ala Ile Pro Ala Pro Thr Asp Leu 275 280 285 Lys Phe Thr Gln Val Thr Pro Thr Ser Leu Ser Ala Gln Trp Thr 290 295 300 Pro Pro Asn Val Gln Leu Thr Gly Tyr Arg Val Arg Val Thr Pro 305 310 315 Lys Glu Lys Thr Gly Pro Met Lys Glu Ile Asn Leu Ala Pro Asp 320 325 330 Ser Ser Ser Val Val Val Ser Gly Leu Met Val Ala Thr Lys Tyr 335 340 345 Glu Val Ser Val Tyr Ala Leu Lys Asp Thr Leu Thr Ser Arg Pro 350 355 360 Ala Gln Gly Val Val Thr Thr Leu Glu Asn Val Ser Pro Pro Arg 365 370 375 Arg Ala Arg Val Thr Asp Ala Thr Glu Thr Thr Ile Thr Ile Ser 380 385 390 Trp Arg Thr Lys Thr Glu Thr Ile Thr Gly Phe Gln Val Asp Ala 395 400 405 Val Pro Ala Asn Gly Gln Thr Pro Ile Gln Arg Thr Ile Lys Pro 410 415 420 A sp Val Arg Ser Tyr Thr Ile Thr Gly Leu Gln Pro Gly Thr Asp 425 430 435 Tyr Lys Ile Tyr Leu Tyr Thr Leu Asn Asp Asn Ala Arg Ser Ser 440 445 450 Pro Val Val Ile Asp Ala Ser Thr Ala Ile Asp Ala Pro Ser Asn 455 460 465 Leu Arg Phe Leu Ala Thr Thr Pro Asn Ser Leu Leu Val Ser Trp 470 475 480 Gln Pro Pro Arg Ala Arg Ile Thr Gly Tyr Ile Ile Lys Tyr Glu 485 490 495 Lys Pro Gly Ser Pro Pro Arg Glu Val Val Pro Arg Pro Arg Pro 500 505 510 Gly Val Thr Glu Ala Thr Ile Thr Gly Leu Glu Pro Gly Thr Glu 515 520 525 Tyr Thr Ile Tyr Val Ile Ala Leu Lys Asn Asn Gln Lys Ser Glu 530 535 540 Pro Leu Ile Gly Arg Lys Lys Thr 545 SEQ ID NO: 7 Array length: 549 Array type: Number of amino acid chains: Single-stranded topology: Linear array type: Peptide sequence:  Pro Thr Asp Leu Arg Phe Thr Asn Ile Gly Pro Asp Thr Met Arg 1 5 10 15 Val Thr Trp Ala Pro Pro Pro Ser Ile Asp Leu Thr Asn Phe Leu 20 25 30 Val Arg Tyr Ser Pro Val Lys Asn Glu Glu Asp Val Ala Glu Leu 35 40 45 Ser Ile Ser Pro Ser Asp Asn Ala Val Val Leu Thr Asn Leu Leu 50 55 60 Pro Gly Thr Glu Tyr Val Val Ser Val Ser Ser Val Tyr Glu Gln 65 70 75 His Glu Ser Thr Pro Leu Arg Gly Arg Gln Lys Thr Gly Leu Asp 80 85 90 Ser Pro Thr Gly Ile Asp Phe Ser Asp Ile Thr Ala Asn Ser Phe 95 100 105 Thr Val His Trp Ile Ala Pro Arg Ala Thr Ile Thr Gly Tyr Arg 110 115 120 Ile Arg His His Pro Glu His Phe Ser Gly Arg Pro Arg Glu Asp 125 130 135 Arg Val Pro His Ser Arg Asn Ser Ile Thr Leu Thr Asn Leu Thr 140 145 150 Pro Gly Thr Glu Tyr Val Val Ser Ile Val Ala Leu Asn Gly Arg 155 160 165 Glu Glu Ser Pro Leu Leu Ile Gly Gln Gln Ser Thr Val Ser Asp 170 175 180 Val Pro Arg Asp Leu Glu Val Val Ala Ala Thr Pro Thr Ser Leu 185 190 195 Leu Ile Ser Trp Asp Ala Pro Ala Val Thr Val Arg Tyr Tyr Arg 200 205 210 Ile Thr T yr Gly Glu Thr Gly Gly Asn Ser Pro Val Gln Glu Phe 215 220 225 Thr Val Pro Gly Ser Lys Ser Thr Ala Thr Ile Ser Gly Leu Lys 230 235 240 Pro Gly Val Asp Tyr Thr Ile Thr Val Tyr Ala Val Thr Gly Arg 245 250 255 Gly Asp Ser Pro Ala Ser Ser Lys Pro Ile Ser Ile Asn Tyr Arg 260 265 270 Thr Glu Ile Asp Lys Pro Ser Met Ala Ile Pro Ala Pro Thr Asp 275 280 285 Leu Lys Phe Thr Gln Val Thr Pro Thr Ser Leu Ser Ala Gln Trp 290 295 300 Thr Pro Pro Asn Val Gln Leu Thr Gly Tyr Arg Val Arg Val Thr 305 310 315 Pro Lys Glu Lys Thr Gly Pro Met Lys Glu Ile Asn Leu Ala Pro 320 325 330 Asp Ser Ser Ser Val Val Val Ser Gly Leu Met Val Ala Thr Lys 335 340 345 Tyr Glu Val Ser Val Tyr Ala Leu Lys Asp Thr Leu Thr Ser Arg 350 355 360 Pro Ala Gln Gly Val Val Thr Thr Leu Glu Asn Val Ser Pro Pro 365 370 375 Arg Arg Ala Arg Val Thr Asp Ala Thr Glu Thr Thr Ile Thr Ile 380 385 390 Ser Trp Arg Thr Lys Thr Glu Thr Ile Thr Gly Phe Gln Val Asp 395 400 405 Ala Val Pro Ala Asn Gly Gln Thr Pro Ile Gln Arg Thr Ile Lys 410 415 420 P ro Asp Val Arg Ser Tyr Thr Ile Thr Gly Leu Gln Pro Gly Thr 425 430 435 Asp Tyr Lys Ile Tyr Leu Tyr Thr Leu Asn Asp Asn Ala Arg Ser 440 445 450 Ser Pro Val Val Ile Asp Ala Ser Thr Ala Ile Asp Ala Pro Ser 455 460 465 Asn Leu Arg Phe Leu Ala Thr Thr Pro Asn Ser Leu Leu Val Ser 470 475 480 Trp Gln Pro Pro Arg Ala Arg Ile Thr Gly Tyr Ile Ile Lys Tyr 485 490 495 Glu Lys Pro Gly Ser Pro Pro Arg Glu Val Val Pro Arg Pro Arg 500 505 510 Pro Gly Val Thr Glu Ala Thr Ile Thr Gly Leu Glu Pro Gly Thr 515 520 525 Glu Tyr Thr Ile Tyr Val Ile Ala Leu Lys Asn Asn Gln Lys Ser 530 535 540 Glu Pro Leu Ile Gly Arg Lys Lys Thr 545 SEQ ID NO: 8 Array length: 573 Array type: Number of amino acid chains: Single-stranded topology: Linear array type: Peptide sequence:  Pro Thr Asp Leu Arg Phe Thr Asn Ile Gly Pro Asp Thr Met Arg 1 5 10 15 Val Thr Trp Ala Pro Pro Pro Ser Ile Asp Leu Thr Asn Phe Leu 20 25 30 Val Arg Tyr Ser Pro Val Lys Asn Glu Glu Asp Val Ala Glu Leu 35 40 45 Ser Ile Ser Pro Ser Asp Asn Ala Val Val Leu Thr Asn Leu Leu 50 55 60 Pro Gly Thr Glu Tyr Val Val Ser Val Ser Ser Val Tyr Glu Gln 65 70 75 His Glu Ser Thr Pro Leu Arg Gly Arg Gln Lys Thr Gly Leu Asp 80 85 90 Ser Pro Thr Gly Ile Asp Phe Ser Asp Ile Thr Ala Asn Ser Phe 95 100 105 Thr Val His Trp Ile Ala Pro Arg Ala Thr Ile Thr Gly Tyr Arg 110 115 120 Ile Arg His His Pro Glu His Phe Ser Gly Arg Pro Arg Glu Asp 125 130 135 Arg Val Pro His Ser Arg Asn Ser Ile Thr Leu Thr Asn Leu Thr 140 145 150 Pro Gly Thr Glu Tyr Val Val Ser Ile Val Ala Leu Asn Gly Arg 155 160 165 Glu Glu Ser Pro Leu Leu Ile Gly Gln Gln Ser Thr Val Ser Asp 170 175 180 Val Pro Arg Asp Leu Glu Val Val Ala Ala Thr Pro Thr Ser Leu 185 190 195 Leu Ile Ser Trp Asp Ala Pro Ala Val Thr Val Arg Tyr Tyr Arg 200 205 210 Ile Thr Ty r Gly Glu Thr Gly Gly Asn Ser Pro Val Gln Glu Phe 215 220 225 Thr Val Pro Gly Ser Lys Ser Thr Ala Thr Ile Ser Gly Leu Lys 230 235 240 Pro Gly Val Asp Tyr Thr Ile Thr Val Tyr Ala Val Thr Gly Arg 245 250 255 Gly Asp Ser Pro Ala Ser Ser Lys Pro Ile Ser Ile Asn Tyr Arg 260 265 270 Thr Glu Ile Asp Lys Pro Ser Ala Ile Pro Ala Pro Thr Asp Leu 275 280 285 Lys Phe Thr Gln Val Thr Pro Thr Ser Leu Ser Ala Gln Trp Thr 290 295 300 Pro Pro Asn Val Gln Leu Thr Gly Tyr Arg Val Arg Val Thr Pro 305 310 315 Lys Glu Lys Thr Gly Pro Met Lys Glu Ile Asn Leu Ala Pro Asp 320 325 330 Ser Ser Ser Val Val Val Ser Gly Leu Met Val Ala Thr Lys Tyr 335 340 345 Glu Val Ser Val Tyr Ala Leu Lys Asp Thr Leu Thr Ser Arg Pro 350 355 360 Ala Gln Gly Val Val Thr Thr Leu Glu Asn Val Ser Pro Pro Arg 365 370 375 Arg Ala Arg Val Thr Asp Ala Thr Glu Thr Thr Ile Thr Ile Ser 380 385 390 Trp Arg Thr Lys Thr Glu Thr Ile Thr Gly Phe Gln Val Asp Ala 395 400 405 Val Pro Ala Asn Gly Gln Thr Pro Ile Gln Arg Thr Ile Lys Pro 410 415 420 A sp Val Arg Ser Tyr Thr Ile Thr Gly Leu Gln Pro Gly Thr Asp 425 430 435 Tyr Lys Ile Tyr Leu Tyr Thr Leu Asn Asp Asn Ala Arg Ser Ser 440 445 450 Pro Val Val Ile Asp Ala Ser Thr Ala Ile Asp Ala Pro Ser Asn 455 460 465 Leu Arg Phe Leu Ala Thr Thr Pro Asn Ser Leu Leu Val Ser Trp 470 475 480 Gln Pro Pro Arg Ala Arg Ile Thr Gly Tyr Ile Ile Lys Tyr Glu 485 490 495 Lys Pro Gly Ser Pro Pro Arg Glu Val Val Pro Arg Pro Arg Pro 500 505 510 Gly Val Thr Glu Ala Thr Ile Thr Gly Leu Glu Pro Gly Thr Glu 515 520 525 Tyr Thr Ile Tyr Val Ile Ala Leu Lys Asn Asn Gln Lys Ser Glu 530 535 540 Pro Leu Ile Gly Arg Lys Lys Thr Asp Glu Leu Pro Gln Leu Val 545 550 555 Thr Leu Pro His Pro Asn Leu His Gly Pro Glu Ile Leu Asp Val 560 565 570 Pro Ser Thr SEQ ID NO: 9 Array length: 574 Array Type: Number of amino acid chains: Single-stranded topology: Linear array type: Peptide sequence:  Pro Thr Asp Leu Arg Phe Thr Asn Ile Gly Pro Asp Thr Met Arg 1 5 10 15 Val Thr Trp Ala Pro Pro Pro Ser Ile Asp Leu Thr Asn Phe Leu 20 25 30 Val Arg Tyr Ser Pro Val Lys Asn Glu Glu Asp Val Ala Glu Leu 35 40 45 Ser Ile Ser Pro Ser Asp Asn Ala Val Val Leu Thr Asn Leu Leu 50 55 60 Pro Gly Thr Glu Tyr Val Val Ser Val Ser Ser Val Tyr Glu Gln 65 70 75 His Glu Ser Thr Pro Leu Arg Gly Arg Gln Lys Thr Gly Leu Asp 80 85 90 Ser Pro Thr Gly Ile Asp Phe Ser Asp Ile Thr Ala Asn Ser Phe 95 100 105 Thr Val His Trp Ile Ala Pro Arg Ala Thr Ile Thr Gly Tyr Arg 110 115 120 Ile Arg His His Pro Glu His Phe Ser Gly Arg Pro Arg Glu Asp 125 130 135 Arg Val Pro His Ser Arg Asn Ser Ile Thr Leu Thr Asn Leu Thr 140 145 150 Pro Gly Thr Glu Tyr Val Val Ser Ile Val Ala Leu Asn Gly Arg 155 160 165 Glu Glu Ser Pro Leu Leu Ile Gly Gln Gln Ser Thr Val Ser Asp 170 175 180 Val Pro Arg Asp Leu Glu Val Val Ala Ala Thr Pro Thr Ser Leu 185 190 195 Leu Ile Ser Trp Asp Ala Pro Ala Val Thr Val Arg Tyr Tyr Arg 200 205 210 Ile Thr T yr Gly Glu Thr Gly Gly Asn Ser Pro Val Gln Glu Phe 215 220 225 Thr Val Pro Gly Ser Lys Ser Thr Ala Thr Ile Ser Gly Leu Lys 230 235 240 Pro Gly Val Asp Tyr Thr Ile Thr Val Tyr Ala Val Thr Gly Arg 245 250 255 Gly Asp Ser Pro Ala Ser Ser Lys Pro Ile Ser Ile Asn Tyr Arg 260 265 270 Thr Glu Ile Asp Lys Pro Ser Met Ala Ile Pro Ala Pro Thr Asp 275 280 285 Leu Lys Phe Thr Gln Val Thr Pro Thr Ser Leu Ser Ala Gln Trp 290 295 300 Thr Pro Pro Asn Val Gln Leu Thr Gly Tyr Arg Val Arg Val Thr 305 310 315 Pro Lys Glu Lys Thr Gly Pro Met Lys Glu Ile Asn Leu Ala Pro 320 325 330 Asp Ser Ser Ser Val Val Val Ser Gly Leu Met Val Ala Thr Lys 335 340 345 Tyr Glu Val Ser Val Tyr Ala Leu Lys Asp Thr Leu Thr Ser Arg 350 355 360 Pro Ala Gln Gly Val Val Thr Thr Leu Glu Asn Val Ser Pro Pro 365 370 375 Arg Arg Ala Arg Val Thr Asp Ala Thr Glu Thr Thr Ile Thr Ile 380 385 390 Ser Trp Arg Thr Lys Thr Glu Thr Ile Thr Gly Phe Gln Val Asp 395 400 405 Ala Val Pro Ala Asn Gly Gln Thr Pro Ile Gln Arg Thr Ile Lys 410 415 420 P ro Asp Val Arg Ser Tyr Thr Ile Thr Gly Leu Gln Pro Gly Thr 425 430 435 Asp Tyr Lys Ile Tyr Leu Tyr Thr Leu Asn Asp Asn Ala Arg Ser 440 445 450 Ser Pro Val Val Ile Asp Ala Ser Thr Ala Ile Asp Ala Pro Ser 455 460 465 Asn Leu Arg Phe Leu Ala Thr Thr Pro Asn Ser Leu Leu Val Ser 470 475 480 Trp Gln Pro Pro Arg Ala Arg Ile Thr Gly Tyr Ile Ile Lys Tyr 485 490 495 Glu Lys Pro Gly Ser Pro Pro Arg Glu Val Val Pro Arg Pro Arg 500 505 510 Pro Gly Val Thr Glu Ala Thr Ile Thr Gly Leu Glu Pro Gly Thr 515 520 525 Glu Tyr Thr Ile Tyr Val Ile Ala Leu Lys Asn Asn Gln Lys Ser 530 535 540 Glu Pro Leu Ile Gly Arg Lys Lys Thr Asp Glu Leu Pro Gln Leu 545 550 555 Val Thr Leu Pro His Pro Asn Leu His Gly Pro Glu Ile Leu Asp 560 565 570 Val Pro Ser Thr SEQ ID NO: 10 Array length: 367 Array type: Number of amino acid chains: Single-stranded topology: Linear array type: Peptide sequence:  Pro Thr Asp Leu Arg Phe Thr Asn Ile Gly Pro Asp Thr Met Arg 1 5 10 15 Val Thr Trp Ala Pro Pro Pro Ser Ile Asp Leu Thr Asn Phe Leu 20 25 30 Val Arg Tyr Ser Pro Val Lys Asn Glu Glu Asp Val Ala Glu Leu 35 40 45 Ser Ile Ser Pro Ser Asp Asn Ala Val Val Leu Thr Asn Leu Leu 50 55 60 Pro Gly Thr Glu Tyr Val Val Ser Val Ser Ser Val Tyr Glu Gln 65 70 75 His Glu Ser Thr Pro Leu Arg Gly Arg Gln Lys Thr Gly Leu Asp 80 85 90 Ser Pro Thr Gly Ile Asp Phe Ser Asp Ile Thr Ala Asn Ser Phe 95 100 105 Thr Val His Trp Ile Ala Pro Arg Ala Thr Ile Thr Gly Tyr Arg 110 115 120 Ile Arg His His Pro Glu His Phe Ser Gly Arg Pro Arg Glu Asp 125 130 135 Arg Val Pro His Ser Arg Asn Ser Ile Thr Leu Thr Asn Leu Thr 140 145 150 Pro Gly Thr Glu Tyr Val Val Ser Ile Val Ala Leu Asn Gly Arg 155 160 165 Glu Glu Ser Pro Leu Leu Ile Gly Gln Gln Ser Thr Val Ser Asp 170 175 180 Val Pro Arg Asp Leu Glu Val Val Ala Ala Thr Pro Thr Ser Leu 185 190 195 Leu Ile Ser Trp Asp Ala Pro Ala Val Thr Val Arg Tyr Tyr Arg 200 205 210 Ile Thr T yr Gly Glu Thr Gly Gly Asn Ser Pro Val Gln Glu Phe 215 220 225 Thr Val Pro Gly Ser Lys Ser Thr Ala Thr Ile Ser Gly Leu Lys 230 235 240 Pro Gly Val Asp Tyr Thr Ile Thr Val Tyr Ala Val Thr Gly Arg 245 250 255 Gly Asp Ser Pro Ala Ser Ser Lys Pro Ile Ser Ile Asn Tyr Arg 260 265 270 Thr Glu Ile Asp Lys Pro Ser Met Asn Val Ser Pro Pro Arg Arg 275 280 285 Ala Arg Val Thr Asp Ala Thr Glu Thr Thr Ile Thr Ile Ser Trp 290 295 300 Arg Thr Lys Thr Glu Thr Ile Thr Gly Phe Gln Val Asp Ala Val 305 310 315 Pro Ala Asn Gly Gln Thr Pro Ile Gln Arg Thr Ile Lys Pro Asp 320 325 330 Val Arg Ser Tyr Thr Ile Thr Gly Leu Gln Pro Gly Thr Asp Tyr 335 340 345 Lys Ile Tyr Leu Tyr Thr Leu Asn Asp Asn Ala Arg Ser Ser Pro 350 355 360 Val Val Ile Asp Ala Ser Thr 365 SEQ ID NO: 11 Array length: 457 Array type: Number of amino acid chains: Single-stranded topology: Linear array type: Peptide sequence:  Pro Thr Asp Leu Arg Phe Thr Asn Ile Gly Pro Asp Thr Met Arg 1 5 10 15 Val Thr Trp Ala Pro Pro Pro Ser Ile Asp Leu Thr Asn Phe Leu 20 25 30 Val Arg Tyr Ser Pro Val Lys Asn Glu Glu Asp Val Ala Glu Leu 35 40 45 Ser Ile Ser Pro Ser Asp Asn Ala Val Val Leu Thr Asn Leu Leu 50 55 60 Pro Gly Thr Glu Tyr Val Val Ser Val Ser Ser Val Tyr Glu Gln 65 70 75 His Glu Ser Thr Pro Leu Arg Gly Arg Gln Lys Thr Gly Leu Asp 80 85 90 Ser Pro Thr Gly Ile Asp Phe Ser Asp Ile Thr Ala Asn Ser Phe 95 100 105 Thr Val His Trp Ile Ala Pro Arg Ala Thr Ile Thr Gly Tyr Arg 110 115 120 Ile Arg His His Pro Glu His Phe Ser Gly Arg Pro Arg Glu Asp 125 130 135 Arg Val Pro His Ser Arg Asn Ser Ile Thr Leu Thr Asn Leu Thr 140 145 150 Pro Gly Thr Glu Tyr Val Val Ser Ile Val Ala Leu Asn Gly Arg 155 160 165 Glu Glu Ser Pro Leu Leu Ile Gly Gln Gln Ser Thr Val Ser Asp 170 175 180 Val Pro Arg Asp Leu Glu Val Val Ala Ala Thr Pro Thr Ser Leu 185 190 195 Leu Ile Ser Trp Asp Ala Pro Ala Val Thr Val Arg Tyr Tyr Arg 200 205 210 Ile Thr T yr Gly Glu Thr Gly Gly Asn Ser Pro Val Gln Glu Phe 215 220 225 Thr Val Pro Gly Ser Lys Ser Thr Ala Thr Ile Ser Gly Leu Lys 230 235 240 Pro Gly Val Asp Tyr Thr Ile Thr Val Tyr Ala Val Thr Gly Arg 245 250 255 Gly Asp Ser Pro Ala Ser Ser Lys Pro Ile Ser Ile Asn Tyr Arg 260 265 270 Thr Glu Ile Asp Lys Pro Ser Met Asn Val Ser Pro Pro Arg Arg 275 280 285 Ala Arg Val Thr Asp Ala Thr Glu Thr Thr Ile Thr Ile Ser Trp 290 295 300 Arg Thr Lys Thr Glu Thr Ile Thr Gly Phe Gln Val Asp Ala Val 305 310 315 Pro Ala Asn Gly Gln Thr Pro Ile Gln Arg Thr Ile Lys Pro Asp 320 325 330 Val Arg Ser Tyr Thr Ile Thr Gly Leu Gln Pro Gly Thr Asp Tyr 335 340 345 Lys Ile Tyr Leu Tyr Thr Leu Asn Asp Asn Ala Arg Ser Ser Pro 350 355 360 Val Val Ile Asp Ala Ser Thr Ala Ile Asp Ala Pro Ser Asn Leu 365 370 375 Arg Phe Leu Ala Thr Thr Pro Asn Ser Leu Leu Val Ser Trp Gln 380 385 390 Pro Pro Arg Ala Arg Ile Thr Gly Tyr Ile Ile Lys Tyr Glu Lys 395 400 405 Pro Gly Ser Pro Pro Arg Glu Val Val Pro Arg Pro Arg Pro Gly 410 415 420 V al Thr Glu Ala Thr Ile Thr Gly Leu Glu Pro Gly Thr Glu Tyr 425 430 435 Thr Ile Tyr Val Ile Ala Leu Lys Asn Asn Gln Lys Ser Glu Pro 440 445 450 Leu Ile Gly Arg Lys Lys Thr 455 SEQ ID NO: 12 Array length: 368 Array type: Number of amino acid chains: Single-stranded topology: Linear array type: Peptide sequence:  Pro Thr Asp Leu Arg Phe Thr Asn Ile Gly Pro Asp Thr Met Arg 1 5 10 15 Val Thr Trp Ala Pro Pro Pro Ser Ile Asp Leu Thr Asn Phe Leu 20 25 30 Val Arg Tyr Ser Pro Val Lys Asn Glu Glu Asp Val Ala Glu Leu 35 40 45 Ser Ile Ser Pro Ser Asp Asn Ala Val Val Leu Thr Asn Leu Leu 50 55 60 Pro Gly Thr Glu Tyr Val Val Ser Val Ser Ser Val Tyr Glu Gln 65 70 75 His Glu Ser Thr Pro Leu Arg Gly Arg Gln Lys Thr Gly Leu Asp 80 85 90 Ser Pro Thr Gly Ile Asp Phe Ser Asp Ile Thr Ala Asn Ser Phe 95 100 105 Thr Val His Trp Ile Ala Pro Arg Ala Thr Ile Thr Gly Tyr Arg 110 115 120 Ile Arg His His Pro Glu His Phe Ser Gly Arg Pro Arg Glu Asp 125 130 135 Arg Val Pro His Ser Arg Asn Ser Ile Thr Leu Thr Asn Leu Thr 140 145 150 Pro Gly Thr Glu Tyr Val Val Ser Ile Val Ala Leu Asn Gly Arg 155 160 165 Glu Glu Ser Pro Leu Leu Ile Gly Gln Gln Ser Thr Val Ser Asp 170 175 180 Val Pro Arg Asp Leu Glu Val Val Ala Ala Thr Pro Thr Ser Leu 185 190 195 Leu Ile Ser Trp Asp Ala Pro Ala Val Thr Val Arg Tyr Tyr Arg 200 205 210 Ile Thr T yr Gly Glu Thr Gly Gly Asn Ser Pro Val Gln Glu Phe 215 220 225 Thr Val Pro Gly Ser Lys Ser Thr Ala Thr Ile Ser Gly Leu Lys 230 235 240 Pro Gly Val Asp Tyr Thr Ile Thr Val Tyr Ala Val Thr Gly Arg 245 250 255 Gly Asp Ser Pro Ala Ser Ser Lys Pro Ile Ser Ile Asn Tyr Arg 260 265 270 Thr Glu Ile Asp Lys Pro Ser Met Ala Ile Asp Ala Pro Ser Asn 275 280 285 Leu Arg Phe Leu Ala Thr Thr Pro Asn Ser Leu Leu Val Ser Trp 290 295 300 Gln Pro Pro Arg Ala Arg Ile Thr Gly Tyr Ile Ile Lys Tyr Glu 305 310 315 Lys Pro Gly Ser Pro Pro Arg Glu Val Val Pro Arg Pro Arg Pro 320 325 330 Gly Val Thr Glu Ala Thr Ile Thr Gly Leu Glu Pro Gly Thr Glu 335 340 345 Tyr Thr Ile Tyr Val Ile Ala Leu Lys Asn Asn Gln Lys Ser Glu 350 355 360 Pro Leu Ile Gly Arg Lys Lys Thr 365 SEQ ID NO: 13 Array length: 302 Array type: Number of amino acid chains: Single-stranded topology: Linear array type: Peptide sequence:  Pro Thr Asp Leu Arg Phe Thr Asn Ile Gly Pro Asp Thr Met Arg 1 5 10 15 Val Thr Trp Ala Pro Pro Pro Ser Ile Asp Leu Thr Asn Phe Leu 20 25 30 Val Arg Tyr Ser Pro Val Lys Asn Glu Glu Asp Val Ala Glu Leu 35 40 45 Ser Ile Ser Pro Ser Asp Asn Ala Val Val Leu Thr Asn Leu Leu 50 55 60 Pro Gly Thr Glu Tyr Val Val Ser Val Ser Ser Val Tyr Glu Gln 65 70 75 His Glu Ser Thr Pro Leu Arg Gly Arg Gln Lys Thr Gly Leu Asp 80 85 90 Ser Pro Thr Gly Ile Asp Phe Ser Asp Ile Thr Ala Asn Ser Phe 95 100 105 Thr Val His Trp Ile Ala Pro Arg Ala Thr Ile Thr Gly Tyr Arg 110 115 120 Ile Arg His His Pro Glu His Phe Ser Gly Arg Pro Arg Glu Asp 125 130 135 Arg Val Pro His Ser Arg Asn Ser Ile Thr Leu Thr Asn Leu Thr 140 145 150 Pro Gly Thr Glu Tyr Val Val Ser Ile Val Ala Leu Asn Gly Arg 155 160 165 Glu Glu Ser Pro Leu Leu Ile Gly Gln Gln Ser Thr Val Ser Asp 170 175 180 Val Pro Arg Asp Leu Glu Val Val Ala Ala Thr Pro Thr Ser Leu 185 190 195 Leu Ile Ser Trp Asp Ala Pro Ala Val Thr Val Arg Tyr Tyr Arg 200 205 210 Ile Thr T yr Gly Glu Thr Gly Gly Asn Ser Pro Val Gln Glu Phe 215 220 225 Thr Val Pro Gly Ser Lys Ser Thr Ala Thr Ile Ser Gly Leu Lys 230 235 240 Pro Gly Val Asp Tyr Thr Ile Thr Val Tyr Ala Val Thr Gly Arg 245 250 255 Gly Asp Ser Pro Ala Ser Ser Lys Pro Ile Ser Ile Asn Tyr Arg 260 265 270 Thr Glu Ile Asp Lys Pro Ser Asp Glu Leu Pro Gln Leu Val Thr 275 280 285 Leu Pro His Pro Asn Leu His Gly Pro Glu Ile Leu Asp Val Pro 290 295 300 Ser Thr SEQ ID NO: 14 Array length: 277 Array type: Number of amino acid chains: Single-stranded topology: Linear array type: Peptide sequence:  Pro Thr Asp Leu Arg Phe Thr Asn Ile Gly Pro Asp Thr Met Arg 1 5 10 15 Val Thr Trp Ala Pro Pro Pro Ser Ile Asp Leu Thr Asn Phe Leu 20 25 30 Val Arg Tyr Ser Pro Val Lys Asn Glu Glu Asp Val Ala Glu Leu 35 40 45 Ser Ile Ser Pro Ser Asp Asn Ala Val Val Leu Thr Asn Leu Leu 50 55 60 Pro Gly Thr Glu Tyr Val Val Ser Val Ser Ser Val Tyr Glu Gln 65 70 75 His Glu Ser Thr Pro Leu Arg Gly Arg Gln Lys Thr Gly Leu Asp 80 85 90 Ser Pro Thr Gly Ile Asp Phe Ser Asp Ile Thr Ala Asn Ser Phe 95 100 105 Thr Val His Trp Ile Ala Pro Arg Ala Thr Ile Thr Gly Tyr Arg 110 115 120 Ile Arg His His Pro Glu His Phe Ser Gly Arg Pro Arg Glu Asp 125 130 135 Arg Val Pro His Ser Arg Asn Ser Ile Thr Leu Thr Asn Leu Thr 140 145 150 Pro Gly Thr Glu Tyr Val Val Ser Ile Val Ala Leu Asn Gly Arg 155 160 165 Glu Glu Ser Pro Leu Leu Ile Gly Gln Gln Ser Thr Val Ser Asp 170 175 180 Val Pro Arg Asp Leu Glu Val Val Ala Ala Thr Pro Thr Ser Leu 185 190 195 Leu Ile Ser Trp Asp Ala Pro Ala Val Thr Val Arg Tyr Tyr Arg 200 205 210 Ile Thr T yr Gly Glu Thr Gly Gly Asn Ser Pro Val Gln Glu Phe 215 220 225 Thr Val Pro Gly Ser Lys Ser Thr Ala Thr Ile Ser Gly Leu Lys 230 235 240 Pro Gly Val Asp Tyr Thr Ile Thr Val Tyr Ala Val Thr Gly Arg 245 250 255 Gly Asp Ser Pro Ala Ser Ser Lys Pro Ile Ser Ile Asn Tyr Arg 260 265 270 Thr Glu Ile Asp Lys Pro Ser 275 SEQ ID NO: 15 Array length: 4 Array type: Number of amino acid chains: Single-stranded topology: Linear array type: Peptide sequence:  Arg Gly Asp Ser

[Brief description of drawings]

FIG. 1 shows the binding properties of fluorescent substances to TGF-β untreated cells.

FIG. 2 is a diagram showing the binding properties of fluorescent substances to TGF-β-treated cells.

FIG. 3 is a diagram showing liver weight / body weight conversion values in each group.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁵ Identification number Office reference number FI technical display location G01N 33/569 H 9015-2J

Claims (8)

[Claims] 1. A fibronectin receptor production abnormal cell inhibitor which comprises a substance having an affinity for a fibronectin receptor. 2. The fibronectin receptor production abnormal cell inhibitor according to claim 1, wherein the fibronectin receptor is of human origin. 3. The substance having an affinity for the fibronectin receptor is a linear, branched, or cyclic polypeptide containing an RGD sequence, an anti-fibronectin receptor antibody, or a substance having a cell-killing substance bound to these substances. The inhibitor of abnormal cell production of fibronectin receptor according to claim 1. 4. The inhibitor of abnormal fibronectin receptor production cells according to claim 3, wherein the substance having an affinity for the fibronectin receptor is a polypeptide containing one RGD sequence in its molecule. 5. A substance having an affinity for a fibronectin receptor is represented by the following general formula (Formula 1): embedded image Y- (Met) _n Z (wherein Y is a cell containing an RGD sequence derived from a fibronectin molecule). 5. The fibronectin receptor-producing abnormal cell according to claim 3, which is a polypeptide having an adhesive activity, n is 0 or 1, Z is -OH or a polypeptide having a heparin-binding activity derived from a fibronectin molecule). Inhibitor. 6. The abnormal fibronectin receptor production according to claim 4, wherein the substance having an affinity for the fibronectin receptor is a polypeptide selected from the group consisting of the polypeptides represented by SEQ ID NOS: 1 to 11 in the sequence listing. Cytostatic agent. 7. The inhibitor of abnormal fibronectin receptor production cells according to claim 1, wherein the abnormal fibronectin receptor production cells are human immunodeficiency virus-infected T lymphocyte cells. 8. A detection agent for abnormal cells producing fibronectin receptor, which comprises a substance having an affinity for fibronectin receptor.