WO1992010197A1 - Substances of polypeptide nature useful in human therapy - Google Patents
Substances of polypeptide nature useful in human therapy Download PDFInfo
- Publication number
- WO1992010197A1 WO1992010197A1 PCT/EP1991/002354 EP9102354W WO9210197A1 WO 1992010197 A1 WO1992010197 A1 WO 1992010197A1 EP 9102354 W EP9102354 W EP 9102354W WO 9210197 A1 WO9210197 A1 WO 9210197A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- substances
- lge
- obtainable
- patients
- administered
- Prior art date
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- C07K14/46—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
- C07K14/47—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals
- C07K14/4701—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals not used
- C07K14/4702—Regulators; Modulating activity
- C07K14/4703—Inhibitors; Suppressors
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
- C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
- C07K16/30—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants from tumour cells
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2/00—Peptides of undefined number of amino acids; Derivatives thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
Definitions
- the present invention concerns substances obtainable by extraction of animal tissues, particularly from goat or ovine tissues, which substances are useful in therapy and in diagnostics. More particularly, the invention refers to substances having surprising biological properties which make them useful in oncological therapy (or at least in supporting therapy of the neoplastic disease) and in diagnostic applications of the immunohistological and immunosero-logical kind.
- TNF tumor necrosis factor
- cytokines cytokines
- lymphokines such as interleukins
- immunotoxins deriving from conjugates of monoclonal antibodies with cytotoxic substances of different kind etc.
- AFC obtainable by extraction of sheep and lambs embryos, has been studied since 1940 but, apparently, without applicative results worth of further investigation (Schweiz-Rundsch-Med. Prax. 1990 79 (16): 498-502).
- compositions of polypeptide nature should be intended to comprise any kind of polypeptide compound, such as proteins, glycoproteins, mucoproteins, and the like.
- the substances of the present invention may be obtained by extracting, preferably in acidic conditions, homogenates of animal tissues, particularly of goats and sheeps.
- animal tissues particularly of goats and sheeps.
- the use of goat organs is particularly preferred; preliminary tests do not exclude the use of other animal species, for instance sharks.
- the extraction of the substances of the invention comprises the following steps:
- step b) 2N perchloric acid at a temperature of about 4 o C is preferably used.
- step d) a 3M KCl solution is preferably used and treatment is carried out for about 24 hours at 4°C.
- the dialysis, filtration cr centrifugation operations are carried out according to usual methods.
- the obtained substance may directly be used accordin ⁇ to the invention. It will accordingly be treated with usual methods to make it sterile and apyrogenic for the administration to patients or animals in form of suitable pharmaceutical compositions, such as those disclosed in Remington's Pharmaceutical Sciences Handbook, Mack Pub. Co., N.Y., USA.
- compositions comprise vials of lyophylized active principles which can be dissolved prior to the use with sterile saline solutions, solutions or suspensions in aqueous or oily sterile solvents and similar compositions suitable for the in vivo administration.
- the substances of the invention may be administered in a wide range of doses, for instance from 0,1 to 100 mg/day for more consecutive days or at different intervals (e.g. once a week, once a month or even longer periods).
- LGE substances extracted from goat liver, hereinafter referred to as LGE, a single administration of an amount of 1-3 mg of dry substance (1-3 ml of solution) can be sufficient to obtain surprising and very fast results in patients affected by tumor pathologies.
- a second administration after about 30 days may sometimes produce advantageous effects. It cannot however be ruled out that the ongoing tests could ask for changes in posology and treatment schedule, determined according to the pathology and the patient's conditions.
- the obtained solution (800 ml) has a mean protein concentration of 200 ⁇ g/ml according to the Lowry method.
- LGE The solution was concentrated by ultrafiltration to a concentration of 1 mg/ml, it was named LGE and directly used for the clinical tests, hereinbelow summarized, making always reference to the abbreviation LGE.
- a ion-exchange chromatography was used, according to the following method. About 20 ml of LGE were dialyzed against a phosphate buffer (Na-HPO.NaH 2 PO. 0.01 M, pH 6.5). After dialysis the sample was filtered through a 0.45 ⁇ m filter and then changed on a TSK DEAE SPW 7.5 ⁇ 75 mm column, equilibrated in the same dialysis buffer, with a flow of 30 ml/hour.
- a phosphate buffer Na-HPO.NaH 2 PO. 0.01 M, pH 6.5
- a linear gradient of phosphate buffer at pH 6.5 is started from an initial molarity of 0.01M to a final molarity of 0.1M, said gradient having a duration of
- Fig. 2 As it can be derived from the chromatogram (Fig. 2) various protein fractions were obtained which were singularly assayed in PAGE PAA4/30 to evaluate the components thereof.
- Those two samples, zones A and B were subsequently labelled with I 125 (Fig. 3 and 4) and used in
- zone A and zone B samples deriving from
- PAGE Plates LKB 3.5-9.5 were used according to the supplier's instructions.
- LGE zone A gave one marked band at pH 8.2, one marked band at pH 6.7 and some bands in acid zone with a certain prevalence of 3 particular bands at pH 5.6; 5 and 4.9.
- LGE zone B showed a remarkable intensity of staining of the zone in the acid zone at pH ⁇ 6 with a typical aspect of isoantigens.
- a second group of rabbits was immunized with LGE as described above (5 ml, corresponding to 5 mg of dry extract, emulsified with 2.5 ml of Freund's complete adjuvant).
- anti-LGE 1 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 which were tested in the same way as RF4.
- mice 10 week old were immunized for the production of monoclonal antibodies.
- LGE 1 mg/ml
- LGE zone A from DEAE 5PW (1 mg/ml)
- subcutaneous administration of 100 ⁇ l of antigen + 100 ⁇ l of Freund's Adjuvant 100 ⁇ l of antigen + 100 ⁇ l of Freund's Adjuvant.
- a first screening showed that many clones were directed towards the determinants expressed on the LGE low molecular weight components, whereas a lower number of clones recognized the 50.000 d protein.
- the 2 screening carried out after clone expansion, gave negative results for all the clones, therefore, it was decided to fuse the spleen from another immunized mouse. The fusion gave 400 clones (100%). In the first test, after approximately 10 days, 64 clones proved to be positive on LGE.
- the animals were sacrificed after 24, 48 and 72 hours and necropsied to calculate the antibody localization index.
- the antisera were tested on human tissue sections with the ABC immunoperoxydase and the immunogalactosidase procedures, and with RIA on human tissue extracts.
- Sections of formalin fixed - paraffin embedded carcinomas of stomach, large intestine, breast, lung, prostate and ovary, as well as tumoral explants (obtained in nude mice) of HT29 cells (from an intestinal carcinoma), breast cancer MCF7 and GTL16 cells were employed.
- tumoral explants obtained in nude mice
- HT29 cells from an intestinal carcinoma
- breast cancer MCF7 and GTL16 cells were employed.
- the LGE, the 125 I LGE, the rabbit anti-LGE and the rabbit 125I anti-LGE systems were tested in vivo, in nude mice and in nude mice xenografted with HT29 cells.
- 125 I-labelled anti-LGE immunoglobulins showed a significant LGE localization in the neoplastic mass 3-5 days after injection in nude mice xenografted with HT29 cells. The above results reproduced in vivo the immunocytochemical data.
- Neoplastic cell lines human (lines HMF7 and HT29) and rat (R3230Ac). 4) Basophil Degranulation Test.
- LGE acted as a strong LAK (Lymphokine-Activated Killer Cells) inducer on human lymphocytes.
- lymphocytes from different donors showed different cytotoxyc effects when treated with LGE.
- LGE was inactive in vitro on tumor cells and in vivo on tumor cells in "nude" mice model.
- LGE inhibited "in vitro" the proliferation of PBL. This could be related to a direct inhibitory effect on lymphocytes or it could be mediated through the induction of different inhibitory factors. The inhibitory effects appeared to be dose and time dependent.
- LGE was assayed in the basophil degranulation test. This test is used in order to recognize a specific antigen against basophils and/or attached antibodies which have acquired an immune memory. The test is considered positive for values over 30%. On blood samples of a pulmonary carcinoma patient, LGE produced in a very low concentration (1 ⁇ g - 0.1 ⁇ g/ml) the significant dose dependent basophil degranulation (>80%). Tests performed on further 5 cases showed that 50% patients suffering from neoplasia were positive to this test. No degranulation occurred on controls performed with non washed (i.e. in the presence of circulating antibodies and antigens and not only with factors attached to basophils) and without calcium samples (Tab. 1). Degranulation of basophils is not present using blood of healthy donors.
- mice and rabbits were daily subcutaneously injected (for 10 days) with an LGE solution, equivalent to 7.1 mg/kg dose.
- Chronic toxicity tests are ongoing in rabbits for six months with weekly doses of 1.2 mg/kg.
- 29 Terminal patients were treated on a compassionate basis and with the assent of patients.
- the treatment exerted highly favourable subactive effect, but no further analysis could be done because of the heterogeneicity of the pathologic, and clinical conditions, accordingly the patients were not submitted to instrumental or laboratory evaluation.
- LGE treatments ranged from the daily to the weekly administration (0.025 mg/kg). In this experience no anaphylactic reaction appeared.
- LGE induced an intense pain reduction with a better cenesthesis, appetite and bowel function improvement.
- the "N" patient collection represented 108 cases.
- the "U” experimentation was performed on 33 patients.
- the definition of responders was based only on subjective and objective general condition i.e. performance status, as the patients were all with a very low life expectance.
- Tab. 6 shows the results of this study on 82 patients which confirms the previous observation: in the remarkable percentage of cases, 37/82 (45.1%), the pain often resistant to the most important opioid and to the recent pain therapies, disappeared within 12/24 hours and in any case always within the first days.
- Tissues were embedded in paraffin and histologically examined. In addition, immunostaining with monoclonal antibodies against lymphocytes (common leucocyte antigen CLA), PAN P marker (L26 monoclonal), PAN T marker (UCHL1 monoclonal) were performed.
- monoclonal antibodies against lymphocytes common leucocyte antigen CLA
- PAN P marker L26 monoclonal
- PAN T marker UCHL1 monoclonal
- neoplastic tissues obtained before LGE treatment showed only a modest inflammatory infiltrate.
- the tissues examined 15 days after LGE treatment showed extensive areas of necrosis and prominent infiltrate of granulocytes.
- lymphocyte infiltration by eosinophilic granulocytes was quite obvious. Staining of different types of lymphocytes showed presence of CLA positive cells, mainly of B type lymphocytes, while UCHLl cells (T lymphocytes) were rare.
- the amount of responders after one month of observation was, respectively, of 48.2%, 45.4% and 45.1% although there was the difference in time, procedure and doctor culture.
- results of third trial show an intensive granulocytosis and perivascular necrosis in the neoplastic tissue after administration of single dose of LGE and confirm, from an histopathological point of view, the substance activity in inducing the lysis of neoplastic cells in man with a tumor specific mechanism and inducing immunogenic pattern in the host.
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- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Biophysics (AREA)
- Biochemistry (AREA)
- Genetics & Genomics (AREA)
- Molecular Biology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Immunology (AREA)
- Cell Biology (AREA)
- Toxicology (AREA)
- Zoology (AREA)
- Gastroenterology & Hepatology (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Peptides Or Proteins (AREA)
- Medicines Containing Material From Animals Or Micro-Organisms (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
Description
Claims
Priority Applications (11)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CA002098113A CA2098113C (en) | 1990-12-11 | 1991-12-09 | Substances of polypeptide nature useful in human therapy |
RU93042874A RU2113224C1 (en) | 1990-12-11 | 1991-12-09 | Polypeptide substance, method of its preparing and pharmaceutical composition showing antitumor and analgetic activity |
KR1019930701728A KR100196028B1 (en) | 1990-12-11 | 1991-12-09 | Substances of polypeptide nature useful in human therapy |
EP92900285A EP0574394B1 (en) | 1990-12-11 | 1991-12-09 | Substances of polypeptide nature useful in human therapy |
HU9301677A HU217615B (en) | 1990-12-11 | 1991-12-09 | Proteins of goat, process for producing them, and pharmaceutical compositions containing them |
DE69110060T DE69110060T2 (en) | 1990-12-11 | 1991-12-09 | SUBSTANCES OF PEPTIDIC NATURE USEFUL IN HUMAN THERAPY. |
AU90357/91A AU661287B2 (en) | 1990-12-11 | 1991-12-09 | Substances of polypeptide nature useful in human therapy |
JP50037392A JP3213942B2 (en) | 1990-12-11 | 1991-12-09 | Polypeptide substances useful for human therapy |
CS931116A CZ283037B6 (en) | 1990-12-11 | 1991-12-09 | Substances of polypeptidic nature, their use and pharmaceutical preparations in which they are comprised |
NO932101A NO308396B1 (en) | 1990-12-11 | 1993-06-09 | Process for the preparation of substances of a polypeptide nature |
US08/403,121 US5824640A (en) | 1990-12-11 | 1995-03-13 | Substances of polypeptide nature useful in human therapy |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
IT22341A/90 | 1990-12-11 | ||
IT02234190A IT1244879B (en) | 1990-12-11 | 1990-12-11 | EXTRACTS FROM ANIMAL TISSUES, USEFUL IN THERAPY AND DIAGNOSTICS. |
Publications (1)
Publication Number | Publication Date |
---|---|
WO1992010197A1 true WO1992010197A1 (en) | 1992-06-25 |
Family
ID=11194931
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/EP1991/002354 WO1992010197A1 (en) | 1990-12-11 | 1991-12-09 | Substances of polypeptide nature useful in human therapy |
Country Status (16)
Country | Link |
---|---|
US (1) | US5824640A (en) |
EP (1) | EP0574394B1 (en) |
JP (1) | JP3213942B2 (en) |
KR (1) | KR100196028B1 (en) |
AT (1) | ATE122890T1 (en) |
AU (1) | AU661287B2 (en) |
CA (1) | CA2098113C (en) |
CZ (1) | CZ283037B6 (en) |
DE (1) | DE69110060T2 (en) |
DK (1) | DK0574394T3 (en) |
ES (1) | ES2073277T3 (en) |
HU (1) | HU217615B (en) |
IT (1) | IT1244879B (en) |
NO (1) | NO308396B1 (en) |
RU (1) | RU2113224C1 (en) |
WO (1) | WO1992010197A1 (en) |
Cited By (13)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1995011659A2 (en) * | 1993-10-18 | 1995-05-04 | Tsentr Embrionalnych Tkanei 'emcell' | Pharmaceutical preparation with immuno-correcting properties based on a cell suspension, and a method of treating sugar diabetes using said preparation |
WO1996002567A1 (en) * | 1994-07-14 | 1996-02-01 | Zetesis S.P.A. | Proteins from mammalian liver and their use in oncology |
WO1996014340A1 (en) * | 1994-11-04 | 1996-05-17 | Zetesis S.P.A. | Antibodies against allogenic and xenogenic proteins, their use in diagnosis and therapy and methods for the determination thereof |
WO1996041641A1 (en) * | 1995-06-13 | 1996-12-27 | Zetesis S.P.A. | Pharmaceutical compositions with analgesic activity |
WO1997030154A1 (en) * | 1996-02-13 | 1997-08-21 | Zetesis S.P.A. | Nucleotide sequence from goat liver |
WO1998011137A1 (en) * | 1996-09-13 | 1998-03-19 | Zetesis S.P.A. | Use of proteins as anti-retroviral agents |
WO1998011909A1 (en) * | 1996-09-18 | 1998-03-26 | Zetesis S.P.A. | Use of proteins as agents against autoimmune diseases |
WO1999043340A1 (en) * | 1998-02-24 | 1999-09-02 | Zetesis S.P.A. | Oral compositions at low dosage of cytotoxic proteins |
WO2001093888A2 (en) * | 2000-06-08 | 2001-12-13 | Rakepoll Holding B.V. | A method of treatment of amyotrophic lateral sclerosis with a protein extractable from mammalian organs |
WO2001093896A2 (en) * | 2000-06-08 | 2001-12-13 | Rakepoll Holding B.V. | A method of treatment of alzheimer's disease with a protein extractable from mammalian organs |
WO2001093895A2 (en) * | 2000-06-08 | 2001-12-13 | Rakepoll Holding B.V. | A method of treatment of huntington's chorea with a protein extractable from mammalian organs |
WO2001093894A2 (en) * | 2000-06-08 | 2001-12-13 | Rakepoll Holding B.V. | A method of treatment of parkinson's disease with a protein extractable from mammalian organs |
WO2004039393A1 (en) * | 2002-10-30 | 2004-05-13 | Zetesis S.P.A. | Anti-tumor combinations comprising proteins and chemotherapeutics |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
ITMI20010762A1 (en) * | 2001-04-10 | 2002-10-10 | Zetesis Spa | USE OF UK114 PROTEIN OR ITS FRAGMENTS FOR THE TREATMENT AND PREVENTION OF ENDOTOXIC SHOCK |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0210588A2 (en) * | 1985-07-29 | 1987-02-04 | Mizuno, Den'Ichi | Antitumor polypeptide and a method of preparing the same |
Family Cites Families (2)
Publication number | Priority date | Publication date | Assignee | Title |
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GB1598811A (en) * | 1977-01-12 | 1981-09-23 | Hoffmann La Roche | Carcinoma-associated antigens |
US4818763A (en) * | 1984-01-12 | 1989-04-04 | Volker Rusch | Biologically active substance with hormonal properties, production process thereof and utilization of histones for medical purposes |
-
1990
- 1990-12-11 IT IT02234190A patent/IT1244879B/en active IP Right Grant
-
1991
- 1991-12-09 DE DE69110060T patent/DE69110060T2/en not_active Expired - Fee Related
- 1991-12-09 ES ES92900285T patent/ES2073277T3/en not_active Expired - Lifetime
- 1991-12-09 KR KR1019930701728A patent/KR100196028B1/en not_active IP Right Cessation
- 1991-12-09 AT AT92900285T patent/ATE122890T1/en not_active IP Right Cessation
- 1991-12-09 CZ CS931116A patent/CZ283037B6/en not_active IP Right Cessation
- 1991-12-09 HU HU9301677A patent/HU217615B/en not_active IP Right Cessation
- 1991-12-09 DK DK92900285.5T patent/DK0574394T3/en active
- 1991-12-09 AU AU90357/91A patent/AU661287B2/en not_active Ceased
- 1991-12-09 CA CA002098113A patent/CA2098113C/en not_active Expired - Fee Related
- 1991-12-09 EP EP92900285A patent/EP0574394B1/en not_active Expired - Lifetime
- 1991-12-09 WO PCT/EP1991/002354 patent/WO1992010197A1/en active IP Right Grant
- 1991-12-09 RU RU93042874A patent/RU2113224C1/en not_active IP Right Cessation
- 1991-12-09 JP JP50037392A patent/JP3213942B2/en not_active Expired - Fee Related
-
1993
- 1993-06-09 NO NO932101A patent/NO308396B1/en not_active IP Right Cessation
-
1995
- 1995-03-13 US US08/403,121 patent/US5824640A/en not_active Expired - Fee Related
Patent Citations (1)
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EP0210588A2 (en) * | 1985-07-29 | 1987-02-04 | Mizuno, Den'Ichi | Antitumor polypeptide and a method of preparing the same |
Non-Patent Citations (3)
Title |
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CHEMICAL ABSTRACTS, Vol. 102, No. 3, issued 21 January 1985, (Columbus, Ohio, USA), T. IKEDA et al., "General Methods for Isolation of Acetic Acid- and Heat-Stable Polypeptide Growth Factors for Mammary and Pituitary Tumor Cells", page 76, the Abstract No. 17760v; & CELL CULT. METHODS MOL. CELL BIOL., 1984, 2, 217-41. * |
CHEMICAL ABSTRACTS, Vol. 106, No. 23, issued 08 June 1987, (Columbus, Ohio, US), T. NISHIHARA et al., "Novel Antitumor Polypeptide Production by Human Macrophage-Like Cells", page 605, the Abstract No. 194775g; & JP,A,61 280 431. * |
SCHWEIZERISCHE RUNDSCHAU FUER MEDIZIN PRAXIS, Vol. 79, No. 16, 17 April 1990, A. KAST et al., "Faktor AF2 - die vierte Saeule in der Tumortherapie. Dokumentation Nr. 22", pages 498-502. * |
Cited By (31)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1995011659A3 (en) * | 1993-10-18 | 1995-06-01 | Ts Embrionalnych Tkanei Emcell | Pharmaceutical preparation with immuno-correcting properties based on a cell suspension, and a method of treating sugar diabetes using said preparation |
WO1995011659A2 (en) * | 1993-10-18 | 1995-05-04 | Tsentr Embrionalnych Tkanei 'emcell' | Pharmaceutical preparation with immuno-correcting properties based on a cell suspension, and a method of treating sugar diabetes using said preparation |
WO1996002567A1 (en) * | 1994-07-14 | 1996-02-01 | Zetesis S.P.A. | Proteins from mammalian liver and their use in oncology |
AU702294B2 (en) * | 1994-07-14 | 1999-02-18 | Zetesis S.P.A | Proteins from mammalian liver and their use in oncology |
US5792744A (en) * | 1994-07-14 | 1998-08-11 | Zetesis S.P.A. | Proteins from mammalian liver |
AU690756B2 (en) * | 1994-11-04 | 1998-04-30 | Zetesis S.P.A | Antibodies against allogenic and xenogenic proteins, their use in diagnosis and therapy and methods for the determination thereof |
WO1996014340A1 (en) * | 1994-11-04 | 1996-05-17 | Zetesis S.P.A. | Antibodies against allogenic and xenogenic proteins, their use in diagnosis and therapy and methods for the determination thereof |
CN1046737C (en) * | 1994-11-04 | 1999-11-24 | 泽特希斯有限公司 | Antibodies against allogenic and xenogenic proteins, their use in diagnosis and therapy and methods for determination thereof |
WO1996041641A1 (en) * | 1995-06-13 | 1996-12-27 | Zetesis S.P.A. | Pharmaceutical compositions with analgesic activity |
GB2325466A (en) * | 1996-02-13 | 1998-11-25 | Zetesis Spa | Nucleotide sequence from goat liver |
WO1997030154A1 (en) * | 1996-02-13 | 1997-08-21 | Zetesis S.P.A. | Nucleotide sequence from goat liver |
LT4481B (en) | 1996-02-13 | 1999-03-25 | Zetesis S.P.A. | Nucleotide sequence from goat liver |
US6107474A (en) * | 1996-02-13 | 2000-08-22 | Zetesis S.P.A | Nucleotide sequence encoding a 14 kDa protein from goat liver |
AU715178B2 (en) * | 1996-02-13 | 2000-01-20 | Zetesis S.P.A | Nucleotide sequence from goat liver |
GB2325466B (en) * | 1996-02-13 | 2000-03-22 | Zetesis Spa | Nucleotide sequence from goat liver |
WO1998011137A1 (en) * | 1996-09-13 | 1998-03-19 | Zetesis S.P.A. | Use of proteins as anti-retroviral agents |
US6207200B1 (en) * | 1996-09-13 | 2001-03-27 | Zetesis S.P.A. | Use of proteins as anti-retroviral agents |
AU719203B2 (en) * | 1996-09-13 | 2000-05-04 | Zetesis S.P.A | Use of proteins as anti-retroviral agents |
WO1998011909A1 (en) * | 1996-09-18 | 1998-03-26 | Zetesis S.P.A. | Use of proteins as agents against autoimmune diseases |
US6468536B1 (en) | 1996-09-18 | 2002-10-22 | Zetesis S.P.A. | Use of proteins as anti-diabetes agents |
WO1999043340A1 (en) * | 1998-02-24 | 1999-09-02 | Zetesis S.P.A. | Oral compositions at low dosage of cytotoxic proteins |
WO2001093888A2 (en) * | 2000-06-08 | 2001-12-13 | Rakepoll Holding B.V. | A method of treatment of amyotrophic lateral sclerosis with a protein extractable from mammalian organs |
WO2001093896A2 (en) * | 2000-06-08 | 2001-12-13 | Rakepoll Holding B.V. | A method of treatment of alzheimer's disease with a protein extractable from mammalian organs |
WO2001093895A2 (en) * | 2000-06-08 | 2001-12-13 | Rakepoll Holding B.V. | A method of treatment of huntington's chorea with a protein extractable from mammalian organs |
WO2001093894A2 (en) * | 2000-06-08 | 2001-12-13 | Rakepoll Holding B.V. | A method of treatment of parkinson's disease with a protein extractable from mammalian organs |
WO2001093896A3 (en) * | 2000-06-08 | 2002-10-31 | Rakepoll Holding B V | A method of treatment of alzheimer's disease with a protein extractable from mammalian organs |
WO2001093895A3 (en) * | 2000-06-08 | 2002-10-31 | Rakepoll Holding B V | A method of treatment of huntington's chorea with a protein extractable from mammalian organs |
WO2001093894A3 (en) * | 2000-06-08 | 2002-10-31 | Rakepoll Holding B V | A method of treatment of parkinson's disease with a protein extractable from mammalian organs |
WO2001093888A3 (en) * | 2000-06-08 | 2002-11-07 | Rakepoll Holding B V | A method of treatment of amyotrophic lateral sclerosis with a protein extractable from mammalian organs |
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Also Published As
Publication number | Publication date |
---|---|
IT9022341A1 (en) | 1992-06-11 |
IT9022341A0 (en) | 1990-12-11 |
CA2098113A1 (en) | 1992-06-11 |
HU217615B (en) | 2000-03-28 |
HUT64569A (en) | 1994-01-28 |
HU9301677D0 (en) | 1993-09-28 |
EP0574394A1 (en) | 1993-12-22 |
JPH06504039A (en) | 1994-05-12 |
ES2073277T3 (en) | 1995-08-01 |
NO932101D0 (en) | 1993-06-09 |
DE69110060T2 (en) | 1995-09-28 |
RU2113224C1 (en) | 1998-06-20 |
AU661287B2 (en) | 1995-07-20 |
JP3213942B2 (en) | 2001-10-02 |
ATE122890T1 (en) | 1995-06-15 |
CZ283037B6 (en) | 1997-12-17 |
AU9035791A (en) | 1992-07-08 |
KR100196028B1 (en) | 1999-06-15 |
NO932101L (en) | 1993-08-10 |
NO308396B1 (en) | 2000-09-11 |
IT1244879B (en) | 1994-09-12 |
CZ111693A3 (en) | 1994-04-13 |
US5824640A (en) | 1998-10-20 |
CA2098113C (en) | 2002-02-05 |
DE69110060D1 (en) | 1995-06-29 |
DK0574394T3 (en) | 1995-10-16 |
EP0574394B1 (en) | 1995-05-24 |
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