A method of treating acute lung injury and the treatment of fibrosis, monoclonal antibody, hybridoma ads nv

 

The invention relates to medicine, in particular to the treatment and pulmonology, and for the treatment of acute lung injury and fibrosis. For this offer, enter the patient a therapeutic dose of antibodies that specifically bindv6. Also proposed hybridoma producing the indicated antibodies. The method provides suppression integranova receptorv6, which leads to the reduction processes of fibrosis and also phenomena of acute lung injury. 4 C. and 8 C.p. f-crystals, 3 ill.

The technical field to which the invention relates the Invention relates to medicine, in particular for the treatment of acute lung injury and fibrosis using antagonistsv6. This work was partially supported by grants from NIH (National Institute of health) HL47412 and HL53949. The U.S. government may have certain rights to this invention.

The prior art Integrins are heterodimeric receptors, cell adhesion, consisting of two subunits,and. Ina, expressed mainly in epithelial cells. In the healthy tissues of adult primates rarely determined mRNA and protein6, though6 is expressed during embryonic development, wound healing and in some epithelial tumors. When6-subunit is expressed in the cell line carcinoma of the colon in which it is absent in the norm, the expression of subunit leads to increased capacity for proliferation. Carboxyl terminal site of 11 amino acids that are unique to6-subunit is essential for the activity of integrinv6 in terms of increased proliferation (see Agrez et al., J. Cell Biol., 127: 547-556, 1994). Expression6 is induced in alveolar epithelial cells type II in injuries caused by injection of live bacteria, and expression6 see in local areas of subclinical inflammation, as well as in some clinical samples obtained from patients with chronic or acute inflammation of the lungs or kidneys (see Breuss et al., J. Cell Sci., 108:2241-2251, 1995).

Huang et al. (J. Cell Biol., Abyudaya, it was juvenile alopecia associated with infiltration of macrophages into the skin, and they had accumulated activated lymphocytes around the conducting Airways in the lungs.

Pulmonary fibrosis is a common violation, caused, as I believe, the destructive effects of products released from leukocytes (see , for example, article Marshall et al., Int. J. Biochem. Cell Bio., 29: 107-120, 1997). Induced by bleomycin lung injury and pulmonary fibrosis associated and may depend on the recruitment and activation of lymphocytes (see D. J. Schrier et al., Am. J. Pathol., 116:270-278, 1984). Among the proposed methods of treatment of damage to the lung parenchyma and pulmonary fibrosis is the use of "anticytokine" therapeutic approaches (see Coker et al., Thorax, 52(2):294-296, 1997).

However, modern methods of treatment of acute lung injury and pulmonary fibrosis are largely inadequate (see, for example, King et al. "Idiopathic pulmonary fibrosis and other interstitial lung diseases of unknown etiology" (Idiopathyic Pulmonary Fibrosis and other Interstitial Lung Diseases of Unknown Etiology) in Manual therapy of the respiratory system (Textbook of Respiratory Medicine) edited by Murray and Nadel, W. B. Saunders, Philadelphia, PA, PP 1827-1839, 1994). Thus, there is a mu is about the solution to this problem and other problems.

Summary of the invention One object of the invention is a method of treating acute lung injury in a patient, introducing a patient a therapeutic dose of antagonistv6. The invention also provides methods of inhibiting metastasis in the lungs, providing for the introduction to the patient a therapeutic dose of antagonistv6. The next object of the invention is a method of treating fibrosis in a patient, which comprises administration to the patient a therapeutic dose of antagonistv6. Another object of the invention is a monoclonal antibody produced by hybridomas ADS NV.

Another object of the invention is to hybridoma ADS NV.

List of drawings and other materials In Fig. 1.1 shows a graph of the comparison of the content of hydroxyproline in the lung in mice expressing a null mutation of the gene subunit of integrin6, with the control mice in the presence of bleomycin (blm) or saline (sal).

Fig. 1.2 is a photograph of a three-color staining of sections of the lungs at low took cennych by bleomycin wild-type mice (6+/+) but not in mice6-/- 30 days after treatment.

In Fig. 2 presents a graph comparing the increase of water content in the lungs of wild-type mice (6+/+) relative to mice6-/- in the presence of bleomycin (blm) or saline (sal).

In Fig. 3 presents a graph comparing the recruitment of lymphocytes from wild-type mice (6+/+) and mice6-/- after injection of bleomycin (blm) or saline (sal).

Information confirming the possibility of use of the invention the Present invention is methods and compositions for the treatment of acute lung injury, such as, but not limited to, damage to the lungs as the result of bacterial sepsis, hemorrhagic shock, inhalation of toxic substances and induced by bleomycin and other medicinal substances damage the lungs. In addition, the composition corresponding to the invention, used in the treatment of fibrosis epithelial organs, such as lungs, liver, kidneys, bladder and esophagus.

Song data can be prescribed as a prophylactic or therapeutic purposes for patients with sent the toxic aspirate (tools, used by inhalation), should likely be treated after this impact, whereas patients receiving bleomycin, may be prophylactic or therapeutic treatment. Usually the composition, corresponding to this invention, is administered daily for a period of 1-5 days, although patients with advanced pulmonary fibrosis, a progressive disease that can receive therapeutic doses during the periods from several months to several years. As used in this context, "therapeutic dose" is a dose that prevents, alleviates, reduces, or otherwise reduces the severity of the patient's symptoms.

In some embodiments, the invention presents antagonistsv6. These antagonists include, but are not limited to antibodies that specifically bind6; antibodies that specifically bind the ligandv6; ligands forv6; antimyeloma nucleic acids and peptide, ones and coworkers peptide analogs of such ligands.

Antibodies can be synthetic the preferred embodiment, the antagonist is an antibody, which specifically recognizes the cytoplasmic site of subunit6 (see, for example, article Weinacker et al., J. Cell Bio., 269:1-9, 1994). For therapeutic use of human monoclonal antibodies having human constant and variable parts, are often preferable in terms of minimizing the immune response of the patient against antibodies. These antibodies can be obtained by immunization of transgenic animals that carry the genes of the human immunoglobulin. Cm. article Jakobovits et al. , Ann. NY Acad. Sci., 764:525-535 (1995). In connection with synthetic and semi-synthetic antibodies, these terms are intended to encompass, but are not limited to, fragments of antibodies, antibodies with switched isotype, humanitarianism antibodies such as mouse-human, human-mouse, and so on), hybrid antibodies, with many specificdate, fully synthetic molecules such as antibodies, etc.,

As discussed below, the antibodies can be selected according to their ability to block the binding of ligand tov6 and/or other properties, such as the ability to protect in vivo induced from bleomycin the SS No HB12382, deposited on 6 August 1997).

In other embodiments of the invention use agonists presented peptides, polypeptides, proteins or peptidomimetics designed as ligands forv6 based on the presence of domain cell adhesion arginine-glycine-aspartic acid (RGD). Examples of the design of such molecules as ligands for integrins, are given, in particular, in the works Pierschbacher et al. , J. Cell. Biochem., 56:150-154 (1994); Ruoslahti, Ann. Rev. Cell. Dev. Biol., 12:697-715 (1996); Chorev et al., Biopolymers, 37: 367-375 (1995); Pasqualini et al. , J. Cell. Biol., 130:1189-1196 (1995), and Smith et al., J. Biol. Chem., 269:32788-32795 (1994).

In some embodiments the invention, the antisense molecule of nucleic acids used as antagonistsv6. Antimirova molecules of nucleic acids complementary oligonucleotide strands of nucleic acids designed to bind specific sequences of nucleotides in order to inhibit the formation of the protein target. The nucleotide sequence of6-integrin subunit was described in the application USSN 07/728215 filed July 11, 1991, included in this pin is the nation with the other antagonists. Antisense antagonist can be obtained as antisense oligonucleotide, such as RNA (see , for example, article Murayama et al., Antisense Nucleic Acid Drug Dev., 7: 109-114, 1997). Antisense genes can also be obtained in a viral vector, such as hepatitis b virus (see, for example, article Ji et al., J. Viral. Hepat., 4:167-173, 1997); adeno-associated virus (see , for example, article Xiao et al., Brain Res., 756:76-83, 1997) or in other systems, including but not limited to the delivery system genes HVJ virus(Sndai)-liposome (see, for example, article Kaneda et al., Ann. NY Acad. Sci., 811:299-308, 1997); "peptide vector (see, for example, article Vidal et al., CR Acad. Sci. III, 32:279-287, 1997); delivery to a gene in episomes or plasmid vector (see, for example, article Cooper et al., Proc. Natl. Acad. Sci. USA, 94:6450-6455, 1997), Yew et al., Hum. Gene Ther. , 8:575-584, 1997); delivery to a gene in the Assembly of the peptide-DNA (see, for example, article Niidome et al., J. Biol. Chem., 272:15307-15312, 1997), delivered in the form of deproteinizing DNA(see, for example, U.S. patents 5580859 and 5589466) and lipidic vector systems (see, for example, the article Lee et al., Crit. Rev. Ther. Drug Carrier Syst., 14:173-206, 1997).

Screening of candidate antagonistsv6 may be performed by functions in a number of ways known in UB and in mice, the inhibition of proliferation of tumor cells (see Agrez et al., J. Cell Bio., 127:547-556, 1994) and inhibition of cell migration and/or inhibition of cell adhesion (see Experimental examples).

Many suitable preparations antagonists corresponding to the invention, may be found in pharmaceutical formulary known to all pharmaceutical Pharmaceutical science" Remington (Remington''s Pharmaceutical Sciences, (15-e edition, Mack Publishing Company, Easton, Pennsylvania, 1975), in particular in Chapter 87 of the guide, written Blaug, Seymour. These drugs include, for example, powders, pastes, ointments, jellies, waxes, oils, lipids, anhydrous absorbent bases, emulsions of the type oil-in-water or water-in-oil emulsion type carbowax (polyethylene glycols of various molecular weights), semi-solid gels, and semi-solid mixtures containing carbowax.

The amount of the active ingredient necessary for effective therapy will depend on many different factors, including means of administration, site target site, physiological state of the patient and other medicines used. Thus, therapeutic dose should be determined to optimize safety and efficacy. Usually the doses used in vitro the investing animal an effective dose for the treatment of certain disorders will serve as a criterion for predicting the dose to humans. Different opinions are discussed, for example, in the monograph by Goodman and Gilman "the Pharmacological basis of therapeutics" (Pharmacological Basis of Therapeutics), 7th ed., MacMillan Publishing Company, New York, (1985) and in the directory "Pharmaceutical Sciences" Remington (Remington''s Pharmaceutical Sciences, (18th-oe edition, Mack Publishing Co, Easton, Penn., 1990). The techniques discussed in this context, including oral, intravenous, intraperitoneal, intramuscular, transcutaneous, nasal, ionophoretically introduction, etc.,

Compositions corresponding to the invention can be administered in various dosage forms depending on the method of introduction. For example, dosage forms suitable for oral administration include solid dosage forms such as powder, tablets, pills, capsules and tablets, and liquid dosage forms, such as elixirs, syrups and suspensions. The active ingredients can also be administered parenterally, in sterile liquid dosage forms. Gelatin capsules contain the active ingredient and as inactive ingredients of the media in the form of a powder, such as glucose, lactose, sucrose, mannitol, starch, cellulose or cellulose derivatives, magnesium stearate, stearic acid, sodium salt of saccharin, telepresencia desirable color, taste, stability, buffering capacity, dispersion or other known desirable characteristics are red iron oxide, silica gel, sodium lauryl sulfate, titanium dioxide, white food dye, etc., Such fillers can be used to obtain CT. As tablets and capsules can be produced as products with the delayed output to provide a continuous release of medicinal substance in a few hours. Compressed tablets can be sugar shell or shell from film to mask any unpleasant taste and protect the tablet from exposure to atmospheric conditions, or intersolubility membrane for selective destruction in the gastrointestinal kishechnom tract. Liquid dosage forms for oral administration may contain coloring and gives taste and odor component to increase the attractiveness for the patient.

The concentration of compositions corresponding to the invention, the pharmaceutical preparations can vary widely, i.e. from less than about 0.1%, usually about 2% or at least about 2% to high values, as 20-50% or more by weight, and should be selected primarily on the volume of testwuide the invention, may also be entered using liposomes. Liposomes include emulsions, foams, micelles, insoluble monolayers, liquid crystals, phospholipid dispersions, lamellar layers, etc. In these preparations intended for delivery of a composition corresponding to the invention, incorporate in the liposome as part of it, in the form of monocomponent or in combination with a molecule which binds to a desired target, such as an antibody or other therapeutic or immunoenzyme compositions. Thus, liposomes either filled or decorated with" the desired composition corresponding to the invention can be delivered systemically or may be directed to the tissue of interest, where the liposomes then deliver the selected therapeutic/ immunogenic peptide composition.

Liposomes for use in the invention are formed from standard forming vesicle lipids, which generally include neutral and negatively charged phospholipids and a Sterol, such as cholesterol. When choosing lipids mainly governed by considerations regarding, for example, the size of liposomes, acid lability and stability of liposomes in the bloodstream. There are several ways of cooking is, the prisoners in this context by reference.

The suspension of liposomes containing composition corresponding to the invention can be administered intravenously, locally, topically, etc. in a dose which varies in accordance inter alia with the method of administration, delivered a composition corresponding to the invention, and stage of disease that is being treated.

For solid compositions can be used in conventional non-toxic solid carriers include, for example, mannitol, lactose, starch, magnesium stearate, sodium salt of saccharin, talcum, cellulose, glucose, sucrose, magnesium carbonate, etc. of pharmaceutical quality. For oral administration of pharmaceutically acceptable non-toxic composition is obtained by incorporating any of the commonly used fillers such as the above media, and generally 10-95% of active ingredient, as in one or more tracks corresponding to the invention, and more preferably at a concentration of 25-75%.

For aerosol injection of the composition, corresponding to the invention, preferably used in finely powdered form together with surface-active substance and a gas displacer (propellants). Typical percentage of composio must be of course, non-toxic and soluble in propellant. Representatives of such agents are the esters or partial esters of fatty acids containing from 6 to 22 carbon atoms, such as Caproic, octanoic, lauric, palmitic, stearic, linoleic, linolenic, oleostearin and oleic acids with an aliphatic polyhydric alcohol or its cyclic anhydride. Can be used mixed esters, such as mixed or natural glycerides. Surface-active agent may be 0.1-20% by weight of the composition, preferably 0.25 to 5%. The balance of the composition typically provides propellant. It is also possible inclusion of media, if this is desirable, as, for example, when using lecithin for intranasal delivery.

Structures corresponding to the invention can additionally be delivered in the system depot-type encapsulated form or in the implant known in the prior art methods. Similar constructs can be delivered by a pump in the interest of the cloth.

Any of the above compositions may be suitable for treatment and therapeutic tools relevant to this invention, provided that Akti/p> The following examples are provided to illustrate certain aspects of the present invention and are not intended to limit its scope.

Experimental examples I. Introduction.

Pulmonary fibrosis is a common disorder which is believed due to the destructive action of the products secreted by leukocytes. Although respiratory epithelium is damaged by the development of fibrosis, not previously shown that epithelial cells are involved in this process. We investigate the effects of bleomycin, a drug which is known to cause fibrosis of the lungs in mice expressing a null mutation of one gene subunit of integrin (6), which is limited by the epithelial cells. Mouse6-/- clearly protected from bleomycin-induced fibrosis. Therapeutic tools with the focus on this integrin can, therefore, provide new approaches to the treatment of this in most cases incurable disorders.

Integrinv6 is expressed exclusively in the epithelial cells mainly during organogenesis and in response to damage. Mouse

II. The inactivation of the integrin subunit6 protects mice from bleomycin-induced fibrosis of the lungs.

Pulmonary toxicity of bleomycin (0.03 units (u) in 60 μl saline) or saline vehicle (60 μl), introduced by intratracheal injection, examine the corresponding age and gender of wild-type mice (6+/+) and mice6 -/ a - line 129SVEMS/ter. Pulmonary fibrosis assessed after 15, 30 and 60 days after treatment by examining the morphology of the lung and measurement of hydroxyproline content, the rate of deposition of collagen. Fibrosis is significant in treated with bleomycin wild-type mice to the 30-th day and develops to the 60-th day (Fig. 1.1 and 1.2). In contrast, in mice6-/- lung morphology remains almost normal during the experiment with only small areas of fibrosis, and the content of hydroxyproline in the lung not significantly different from that at a certain treated with saline animals at any point in time. This fact is not unique to mice of 129, since similar results were obtained for potom, the expression of integrinv6 is required for the induction of pulmonary fibrosis.

To determine the role ofv6 in the early stages of bleomycin-induced fibrosis measure the water content in the lungs, as an indicator of pulmonary edema caused by increased vascular permeability, at 1, 5 and 15 days after administration of bleomycin or saline. Mice wild-type and the water content in the lungs, the maximum increase on the 5th day and remains elevated for up to 15-th day after injection of bleomycin (Fig. 2). Regarding pulmonary fibrosis mouse6-/- largely protected from this early effect of bleomycin, which indicates the role of epithelialv6 in the development of bleomycin-induced discharge from vessels.

Previously we have shown that mouse6-/- demonstrated increased inflammatory response in mononuclear cells in the skin and the respiratory tract (see Huang X. Z. et al. , J. Cell Biol., 133:921-928, 1996). Induced by bleomycin lung injury and pulmonary fibrosis associated and may depend on the recruitment and activate the g src="https://img.russianpatents.com/chr/946.gif">6-/- bleomycin induced damage and fibrosis caused by recruitment or activation of lymphocytes, count lymphocytes CD4+ and CD8+ and assess the activation of lymphocytes by measuring the expression of the receptor for interleukin-2 (CD25) in cells obtained from crushed lungs of mice treated with saline or bleomycin 5 and 15 days after treatment. In the lungs of mice6-/- there are more CD4+, CD8+ and CD25+ than wild-type animals, consistent with our previous message. Bleomycin induces a significant increase in the number of lymphocytes expressing CD4 and CD8, and a noticeable increase in the percentage of lymphocytes expressing CD25 (Fig. 3), in mice as wild-type and6-/-. In mice as wild-type and6-/- recruitment and activation of pulmonary lymphocytes has a maximum of 5 days after injection of bleomycin and begins to decline after 15 days. Not limited to any one theory, these results assume that the unlikely is that the lack of recruitment and activation of lymphocytes in mice6-/- represent the basis for their protection from the effects of bleomycin in terms of lung damage.6-subunit described only that it forms the only heterodimer integrin,v6 and is limited to epithelial cells. In parallel with rapid induction of the expressionv6 after epithelial damage increase local concentrations of at least two ligands integrin (fibronectin and tenascin). Previously, we showed that the expressionv6 plays a role in the termination of inflammatory responses of mononuclear cells in the skin and the conducting Airways of the lungs (see Huang X. Z. et al., J. Cell Biol., 133:921-928, 1996). Published results show that integrin also plays a critical role in the induction of lung injury and pulmonary fibrosis in response to bleomycin.

Cells of the respiratory epithelium had long considered the main components of a passive barrier that separates the other cells of the lungs from the way are for the initiation and modulation of local reactions to injury. On the basis of recently obtained results suggest that cells of the respiratory epithelium have the ability to synthesize and secrete a number of proteins that can initiate and modulate the response to injury, including chemokines (e.g. interleukin-8, GROGRO, RANTES, GMCSF (colony-stimulating factor granulocyte-macrophage, GM-CSF), the WORLD-1(protein inhibition of migration 1) and MCP-1 (protein cytotoxicity of macrophages-1), other cytokines (eg, IL-6 (interleukin-6), IL-11 and IL-15) and growth factors (e.g., TGF(transforming growth factor-). Not limited to any one theory, one possible mechanism by which epithelialv6 may participate in the development of lung injury and fibrosis of the lungs, is modulation of expression of one or more of these proteins.

Modern methods of treatment of pulmonary fibrosis are largely inadequate. The results of this study show that the cells of the respiratory epithelium and the epithelial integrinv

III. Receiving a blocking antibodies.

A. Obtaining monoclonal antibodies.

To generate antibodies againstv6 mice6-/- subjected to immunization or keratinocytes derived from mice wild-type or recombinant secretively humanv6 (see Weinacker et al., J. Biol. Chem., 269:6940-6948, 1994) in Freund's adjuvant. Murine splenocytes are harvested and merge with cells of the mouse myeloma SP2/0 in accordance with standard procedures. Transfetsirovannyh6 and pseudotranslation SW480 cells used for screening the obtained supernatant using flow cytometry. Antibodies, which, as shown, recognize6-transfetsirovannyh, but not pseudotranslation SW480 cells, used in subsequent experiments.

C. Characterization of monoclonal antibodies.

To generate antibodies against murinev6 as immunogens use the Ah6-/- based on 129/S. Conduct screening received supernatants hybrid on differential staining of pseudo - and6-transfected SW480 cells. The resulting antibodies CS6 and 10D5 paint as6 person, expressed in SW480 cells, and6 click on the wild-type keratinocytes. CS6 further characterized by thus lysate (35S)-labeled murine keratinocytes. This antibody praecipitium heterodimer appropriate molecular weight, which is thev6, separating them from6+/+ keratinocytes, but not from6 -/ - keratinocytes, indicating that these antibodies are specific against integrinv6.
As Cs6, and 10D5 analyze also block the activity by conducting analyses of cell adhesion with6-transfitsirovannykh SW480 cells, and murine keratinocytes on fibronectin. However, only 10D5 exercises blocking activity on mouse �rc="https://img.russianpatents.com/chr/946.gif">6 -/ - keratinocytes.

C. Analysis of cell adhesion.

Treated polystyrene advance tablets for micrometrology not for tissue culture for 96 wells (Linbro/Titertek, Flow Laboratories, McLean, VA) coated with vitronectin, fibronectin, or collagen. 100 μl of a solution containing different amounts of matrix, contribute to the wells and incubated at 37oC for 1 hour. After incubation the wells are washed with PBS (phosphate buffered saline), then blocked with 1% BSA (bovine serum albumin) in serum-free DMEM (modified by way of Dulbecco Wednesday Needle) at 37oC for 30 minutes. Control wells fill with 1% BSA in DMEM. Cells collected in the same way as for the analysis of migration and resuspended in serum-free G, and then added to each coated with protein a hole in the presence or in the absence of PMA (formalparameterlist, FMA). For the experiments on the blocking cells incubated with antibodies for 5 minutes at 4oWith before placing in the hole. Tablets centrifuged (at the position of the upper side up) at 10 x g for 5 minutes before incubation for 1 hour at 34oWith in a humid atmosphere with a content of 7% CO2. Readhesion cell adalat 1% formaldehyde and stained with 0.5% crystal violet, then the wells are washed with PBS. The relative number of cells in each well is assessed by measuring the absorption at 595 nm in a microplate reader for (Bio-Rad).

D. analysis of the migration.

Analyses of cell migration, make use of a coated matrix tablets with connecting holes (pores 8 μm, Costar, Cambridge, MA). The inner surface of the membrane coated with collagen (10 μg/ml), fibronectin (10 μg/ml) or vitronectin (10 μg/ml) in PBS for 1 hour at 37oWith and blocked with 1% BSA. First of cultured keratinocytes harvested using trypsin/EDTA (ethylenediaminetetraacetic acid) and inactivate the trypsin inhibitor soybean trypsin. Cells suspended in serum-free G and placed in the upper chamber at a density of 3.6104/well in 100 μl medium in the presence or in the absence of formalparameterlist (PMA, 10 ng/ml). In experiments on the inhibition of antibody added to the upper and lower chambers in the presence of PMA. After 6 hours incubation, the cells fixed with 2% paraformaldehyde and stained with 0.5% crystal violet in 1% formaldehyde. Cells from the upper chamber were removed and the cells on the lower surface calculated using grid 10x at high magnification (40)/img.russianpatents.com/chr/946.gif">6-knocked out mice have reduced the frequency of metastases.

A line of transgenic mice, which spontaneously develop metastatic breast cancer (mouse MMTV-mTAg), cross-breed6-knocked out mice. In the offspring of mice with absence6 develop fast-growing primary tumor breast cancer at a much reduced frequency and degree of development of lung metastases compared with odnopolnymi animals, which Express6. Data immunohistochemistry show that6 is strongly expressed on the border of metastatic lesions. This implies that6 required for maximum metastasis in this model.

Since6-knocked out mice have chronic inflammation of the lungs, it is possible that the reduction of metastasis due to the presence of inflammation in the lungs, which disrupts the growth of metastases. To confirm this thesis conducted two experiments.

1. The line6-expressing cells isolated from primary tumors, injected syngeneic mice that are either ablauts eih groups, that suggests that the presence of inflammation at the knocked-out mice does not violate the growth of tumor cells in the lung.

2. Cell lines isolated from tumors or6-knocked out mice or wild-type mice, injected syngeneic mice wild type. Cell line wild-type invariably lead to lung tumors, while the lines knocked out of the cells does not lead. The results of this experiment suggest that tumor cells6 required for maximum metastasis in the system.

All references (including books, articles, theses, patents and patent applications) cited in this context, therefore, are specifically incorporated by reference in their entirety for all purposes.

Since the invention described in connection with specific variants of implementation, it will be understood that it may be further modified and this application is intended to cover any variations, uses or adaptations of the invention following in the main the principles of the invention and including such new directions, the exhaust from this description, both those that are within the boundaries of accepted practice in the prior art, to the th description and as those included in the scope of the invention and the scope of the attached claims.


Claims

1. A method of treating acute lung injury in a patient, wherein the patient is administered a therapeutic dose of antibodies that specifically bindv6.

2. The method according to p. 1, characterized in that as antibodies using monoclonal antibody.

3. The method according to p. 1, wherein the antibody is administered therapeutically.

4. The method according to p. 1, wherein the antibody is administered prophylactically.

5. A method of treating fibrosis in a patient, wherein the patient is administered a therapeutic dose of antibodies that specifically bindv6.

6. The method according to p. 5, wherein the fibrosis presents with pulmonary fibrosis.

7. The method according to p. 6, wherein the pulmonary fibrosis is the result of acute lung injury.

8. The method according to p. 1, characterized in that as antibodies using monoclonal antibody.

9. The method according to p. 5, wherein the antibody is administered therapeutically.

10. The method according to p. 5, wherein the antibody is administered r/945.gif">v6 produced by hybridomas ADS HB 12382.

12. Culture hybridoma ADS HB 12382 producing monoclonal antibodies against6 integrin subunitv6.

 

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