US20090305966A1 - Use of histones for therapeutic purposes - Google Patents

Use of histones for therapeutic purposes Download PDF

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Publication number
US20090305966A1
US20090305966A1 US11/920,050 US92005006A US2009305966A1 US 20090305966 A1 US20090305966 A1 US 20090305966A1 US 92005006 A US92005006 A US 92005006A US 2009305966 A1 US2009305966 A1 US 2009305966A1
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Prior art keywords
histone
thrombocytopenia
therapeutically effective
set forth
treatment
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US11/920,050
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Michael Zeppezauer
Reiner Class
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Symbiotec GmbH Gesellschaft zur Forschung und Entwicklung der Biotechnologie
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Assigned to SYMBIOTEC GMBH GESELLSCHAFT FUR FORSCHUNG UND ENTWICKLUNG AUF DEM GEBIET DER BIOTECHNOLOGIE MBH reassignment SYMBIOTEC GMBH GESELLSCHAFT FUR FORSCHUNG UND ENTWICKLUNG AUF DEM GEBIET DER BIOTECHNOLOGIE MBH ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: CLASS, REINER, ZEPPEZAUER, MICHAEL
Publication of US20090305966A1 publication Critical patent/US20090305966A1/en
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; 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
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/1703—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
    • A61K38/1709—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/04—Antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic agents

Definitions

  • the invention relates to the use of at least one human recombinant histone of H1 subtype and/or of its therapeutically effective segment, especially histone H1.3 for therapeutic purposes.
  • thrombocytopenia In complex pathological conditions such as acute myeloid leukemia, there is frequently observed to be a thrombocytopenia which may even be enhanced by a chemotherapeutic treatment of the leukemia. Thrombocytopenia is, however, also observed with other etiology. Since thrombocytopenia may lead to life-threatening internal hemorrhages, therapies for various pathological symptoms which may be the cause of the thrombocytopenia are frequently made particularly difficult.
  • the active substance of the invention shows on the one hand a positive result in the treatment of a hematological disorder such as leukemia, but on the other hand also a positive result in the treatment of the thrombocytopenia associated with the hematological disorders.
  • the active substance used in this case based on human recombinant H1.3 concentrations 37.5 mg/qm 2 of body surface area etc., having been administered in a 0.9% NaCl solution intravenously 3 times a week over a period of about 4 hours.
  • the platelets in peripheral blood are on the ordinate in a number of from 0 to 40 ⁇ 10 9 .
  • Treatment with active substance of the invention for three weeks is shown on the abscissa, the platelet count measured for the patient before the first treatment being greatly reduced at about 8 ⁇ 10 9 .
  • three drip infusions take place per week with in each case 4 hours per infusion, with the 1st to 3rd infusion on the 1st, 3rd and 5th day in the first week, with the 4th to 6th infusion on the 8th, 10th and 12th day in the second week and finally with the 7th to 9th infusion on the 15th, 17th and 19th day in the 3rd week.
  • the appended diagram shows at the start of the second week up to conclusion of the treatment in the third week a jump in the platelet count after the 5th day of treatment and then a continuous rise in the platelet count from the 8th to the subsequent 19th day of treatment and a further slower rise in the platelet count at the first control examination on the 29th day and at a later discharge day FU1 of the patient without further addition of the active substance of the invention, the finally measured platelet count being, as already stated, about 32.5 ⁇ 10 9 .
  • the invention is not restricted to the use of human recombinant H1.3. Because of the close relationship of the H1 subtypes, it is obvious to a skilled worker also to employ as active substance other human recombinant H1 subtypes as basis for the active substance of the invention.
  • the active substance of the invention preferably consists of the complete unshortened subtypes of histone proteins.
  • the therapeutically effective segment of which he is capable directly on the basis of his expert knowledge and experience without outstanding innovative contributions being necessary in this case.
  • Such therapeutically effective histone segments therefore lie within the range of equivalents of the teaching of the invention disclosed herein.
  • the invention further discloses the therapeutic teaching of employing, when there is a threatening or incipient primary disorder which, experience has shown, may result in thrombocytopenia, the active substance of the invention prophylactically against a threatening thrombocytopenia even if, unlike leukemia, the active substance of the invention is not effective against the primary disorder.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Epidemiology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Immunology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Hematology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Diabetes (AREA)
  • Marine Sciences & Fisheries (AREA)
  • Zoology (AREA)
  • Oncology (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

The invention relates to the use of at least one human recombinant histone, especially at least one histone H1 subtype, and/or a therapeutic histone fraction as a basis for the treatment of thrombocytopenia.

Description

  • The invention relates to the use of at least one human recombinant histone of H1 subtype and/or of its therapeutically effective segment, especially histone H1.3 for therapeutic purposes.
  • The use of therapeutic active substances based on human recombinant histone H1 subtypes for the treatment of cancers, e.g. leukemia, are disclosed in the article by Reiner Class et al. in Am. J. Clin. Oncol. (CCT) vol. 19 No. 5 1996 and European patent application 98919254.7.
  • The effect of histone H1 and H2A/H2B fractions from calf thymus on hematological stem cells (CTU-S) in normal and radioactively irradiated rats was described in a Russian article by Semina O. V. et al. in Radiatsionnaia Biologiia, Radioccologiia 34 (4-5), 1994, Jul.-Oct.
  • In complex pathological conditions such as acute myeloid leukemia, there is frequently observed to be a thrombocytopenia which may even be enhanced by a chemotherapeutic treatment of the leukemia. Thrombocytopenia is, however, also observed with other etiology. Since thrombocytopenia may lead to life-threatening internal hemorrhages, therapies for various pathological symptoms which may be the cause of the thrombocytopenia are frequently made particularly difficult.
  • It was therefore an object of the invention to find an active substance which can be used therapeutically for thrombocytopenia in order thus also to improve substantially the success of curing the basic symptom as inducer of the thrombocytopenia.
  • It has been possible according to the invention to achieve the object by using for the therapy of thrombocytopenia inter alia as a result of faulty stem cell differentiation or weakened proliferation of megakaryocytes an active substance based on at least one human recombinant histone (especially at least one histone of H1 subtype) and/or its therapeutically effective segment.
  • This applies especially to a thrombocytopenia as concomitant manifestation of a hematological disorder.
  • It is moreover possible to employ the therapeutic method of the invention for the treatment of thrombocytopenia during or after chemotherapy for the treatment of a hematological disorder, especially acute myeloid leukemia.
  • It has surprisingly been possible to show that the active substance of the invention shows on the one hand a positive result in the treatment of a hematological disorder such as leukemia, but on the other hand also a positive result in the treatment of the thrombocytopenia associated with the hematological disorders.
  • It was thus possible with one and the same active substance to note both a regression in the leukemia and an increase in platelets.
  • It was possible to achieve therapeutic trial results also on patients with human recombinant histone H1.3, it having been possible to reduce markedly the number of pathological tumor cells in an AML patient and, at the same time, to increase substantially platelet production, whereby it was possible to improve substantially the prospects of curing the patient.
  • The trial results are reproduced in more detail below, the active substance used in this case, based on human recombinant H1.3 concentrations 37.5 mg/qm2 of body surface area etc., having been administered in a 0.9% NaCl solution intravenously 3 times a week over a period of about 4 hours.
  • The effect of the active substances of the invention in a 0.9% NaCl solution at, 37.5 mg/qm2 of body surface area on the thrombocytopenia of a patient is shown in the appended diagram.
  • The platelets in peripheral blood are on the ordinate in a number of from 0 to 40×109. Treatment with active substance of the invention for three weeks is shown on the abscissa, the platelet count measured for the patient before the first treatment being greatly reduced at about 8×109. Then in each case three drip infusions take place per week with in each case 4 hours per infusion, with the 1st to 3rd infusion on the 1st, 3rd and 5th day in the first week, with the 4th to 6th infusion on the 8th, 10th and 12th day in the second week and finally with the 7th to 9th infusion on the 15th, 17th and 19th day in the 3rd week. On the 29th day after the first infusion, a control measurement of the platelet count took place without a further infusion with the active substance of the invention. At a later time FU1, the patient was discharged with an almost normal platelet count of about 34×109, without an active substance of the invention having been supplied even once. This value lay outside the need to supply stored blood. The patient was asked to attend a follow-up examination with the possibility of resumption of treatment if the platelet count has not improved further on its own or had even deteriorated. The results of the follow-up examination are not shown here.
  • The appended diagram shows at the start of the second week up to conclusion of the treatment in the third week a jump in the platelet count after the 5th day of treatment and then a continuous rise in the platelet count from the 8th to the subsequent 19th day of treatment and a further slower rise in the platelet count at the first control examination on the 29th day and at a later discharge day FU1 of the patient without further addition of the active substance of the invention, the finally measured platelet count being, as already stated, about 32.5×109.
  • The invention is not restricted to the use of human recombinant H1.3. Because of the close relationship of the H1 subtypes, it is obvious to a skilled worker also to employ as active substance other human recombinant H1 subtypes as basis for the active substance of the invention.
  • Following the successful therapy of patients with a thrombocytopenia, here as concomitant syndrome of an AML leukemia, with human recombinant histone H1.3, it is particularly obvious to a skilled worker also to employ other recombinant H1 subtypes as alternative active substances singly or in combination according to the invention.
  • The active substance of the invention preferably consists of the complete unshortened subtypes of histone proteins. However, it is also obvious to a skilled worker to look for the therapeutically effective segment, of which he is capable directly on the basis of his expert knowledge and experience without outstanding innovative contributions being necessary in this case. Such therapeutically effective histone segments therefore lie within the range of equivalents of the teaching of the invention disclosed herein.
  • The invention further discloses the therapeutic teaching of employing, when there is a threatening or incipient primary disorder which, experience has shown, may result in thrombocytopenia, the active substance of the invention prophylactically against a threatening thrombocytopenia even if, unlike leukemia, the active substance of the invention is not effective against the primary disorder.

Claims (7)

1. The use of at least one human recombinant histone, especially at least one histone of the H1 subtype, and/or a therapeutically effective histone segment as basis for the therapeutic treatment of thrombocytopenia.
2. A histone and/or its therapeutically effective segment as set forth in claim 1 for the therapeutic treatment of thrombocytopenia as concomitant manifestation of hematological disorders.
3. A histone and/or its therapeutically effective segment as set forth in claim 1 for the therapeutic treatment of thrombocytopenia during or after a therapy for the treatment of hematological disorders, especially after chemotherapy.
4. A histone and/or its therapeutically effective segment as set forth in claim 1 for the therapeutic treatment of leukemia, especially acute myeloid leukemia with simultaneous therapeutic treatment of thrombocytopenia.
5. A histone and/or its therapeutically effective segment as set forth in claim 1 for therapy in the case of a thrombocytopenia resulting from a disorder of any etiology.
6. A histone and/or its therapeutically effective segment as set forth in claim 5 for prohylactic therapy in the case of a threatening thrombocytopenia resulting from a disorder of any etiology.
7. A histone and/or its therapeutically effective segment as set forth in claim 1, characterized in that it is recombinant human histone H1.3.
US11/920,050 2005-05-10 2006-05-04 Use of histones for therapeutic purposes Abandoned US20090305966A1 (en)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
DE102005022319.2 2005-05-10
DE102005022319A DE102005022319A1 (en) 2005-05-10 2005-05-10 Use of histones for therapeutic purposes
PCT/EP2006/004167 WO2006119912A2 (en) 2005-05-10 2006-05-04 Use of histones for therapeutic purposes

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PCT/EP2006/004167 A-371-Of-International WO2006119912A2 (en) 2005-05-10 2006-05-04 Use of histones for therapeutic purposes

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US13/758,950 Continuation US8962562B2 (en) 2005-05-10 2013-02-04 Use of histones for therapeutic purposes

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US11/920,050 Abandoned US20090305966A1 (en) 2005-05-10 2006-05-04 Use of histones for therapeutic purposes
US13/758,950 Expired - Fee Related US8962562B2 (en) 2005-05-10 2013-02-04 Use of histones for therapeutic purposes
US14/588,836 Abandoned US20150119331A1 (en) 2005-05-10 2015-01-02 Use of Histones for Therapeutic Purposes

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US (3) US20090305966A1 (en)
EP (1) EP1879609B1 (en)
JP (2) JP2008540473A (en)
KR (3) KR20140137462A (en)
CN (1) CN101171027A (en)
CA (2) CA2608019C (en)
DE (1) DE102005022319A1 (en)
ES (1) ES2461564T3 (en)
HU (1) HUE027070T2 (en)
PL (1) PL1879609T3 (en)
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DE102005022319A1 (en) * 2005-05-10 2006-11-23 Symbiotec Gesellschaft Zur Forschung Und Entwicklung Auf Dem Gebiet Der Biotechnologie Mbh Use of histones for therapeutic purposes

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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
US5571686A (en) * 1994-04-14 1996-11-05 Massachusetts Institute Of Technology Method of using megapoietin for prolonging the survival & viability of platlets
US5578571A (en) * 1990-01-04 1996-11-26 Symbiotec Gesellschaft Zur Forschung Und Entwicklung Auf Dem Gebiet Der Biotechnologie Mbh Cytostatic or cytotoxic combination of active substances for use in therapeutic procedures
US6468537B1 (en) * 1999-04-28 2002-10-22 The Board Of Trustees Of Northwestern University Localization of major peptide autoepitopes for nucleosome specific T cells of systemic lupus erythematosus
US20030017987A1 (en) * 1997-04-11 2003-01-23 Michael Zeppezauer Therapeutic, prophylactic, and diagnostic agent for cancer, useful for characterizing cancer cells with individual properties
US6884423B1 (en) * 1998-08-13 2005-04-26 Symbiotec Gmbh Antimicrobial histone H1 compositions, kits, and methods of use thereof

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EP0347057A1 (en) 1988-05-31 1989-12-20 Schering Biotech Corporation Method of treating myeloid leukemias
DE19715149A1 (en) 1997-04-11 1998-10-15 Symbiotec Gmbh Cancer therapeutic and diagnosis for the characterization of cancer cells with individual properties
DE10001113A1 (en) * 2000-01-13 2001-07-26 Strathmann Ag & Co Recombinant human histone protein, useful e.g. as anticancer or antibiotic agent, expressed in prokaryotic cells
US7931897B2 (en) 2001-02-07 2011-04-26 Chugai Seiyaku Kabushiki Kaisha Therapeutic agent for hematopoietic tumors
ATE481977T1 (en) 2001-02-22 2010-10-15 Philadelphia Health & Educatio COMPOSITIONS FOR PREVENTING THROMBOCYTE AGGREGATION
JP2002355048A (en) * 2001-05-31 2002-12-10 Communication Research Laboratory Ribonucleotide reductase r1 and peptide inhibiting the same
DE10230223A1 (en) * 2002-07-04 2004-01-22 Tegenero Ag Microparticles with CD28-specific monoclonal antibodies
US20040146585A1 (en) * 2002-10-31 2004-07-29 Oregon Health & Science University Use of thiol-based compositions in treating chemotherapeutic agent-induced thrombocytopenia
DE102005022319A1 (en) * 2005-05-10 2006-11-23 Symbiotec Gesellschaft Zur Forschung Und Entwicklung Auf Dem Gebiet Der Biotechnologie Mbh Use of histones for therapeutic purposes

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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
US5182257A (en) * 1984-01-12 1993-01-26 Volker Rusch Use of pure histones h1 and h2a:h2b dimers in therapeutic methods
US5578571A (en) * 1990-01-04 1996-11-26 Symbiotec Gesellschaft Zur Forschung Und Entwicklung Auf Dem Gebiet Der Biotechnologie Mbh Cytostatic or cytotoxic combination of active substances for use in therapeutic procedures
US5571686A (en) * 1994-04-14 1996-11-05 Massachusetts Institute Of Technology Method of using megapoietin for prolonging the survival & viability of platlets
US20030017987A1 (en) * 1997-04-11 2003-01-23 Michael Zeppezauer Therapeutic, prophylactic, and diagnostic agent for cancer, useful for characterizing cancer cells with individual properties
US6884423B1 (en) * 1998-08-13 2005-04-26 Symbiotec Gmbh Antimicrobial histone H1 compositions, kits, and methods of use thereof
US6468537B1 (en) * 1999-04-28 2002-10-22 The Board Of Trustees Of Northwestern University Localization of major peptide autoepitopes for nucleosome specific T cells of systemic lupus erythematosus

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PT1879609E (en) 2014-06-09
ES2461564T3 (en) 2014-05-20
JP2013151573A (en) 2013-08-08
CA2608019A1 (en) 2006-11-16
WO2006119912A3 (en) 2007-04-12
US8962562B2 (en) 2015-02-24
EP1879609B1 (en) 2014-03-12
JP2008540473A (en) 2008-11-20
KR20080007351A (en) 2008-01-18
KR20140137462A (en) 2014-12-02
DE102005022319A1 (en) 2006-11-23
WO2006119912A2 (en) 2006-11-16
PL1879609T3 (en) 2014-08-29
CA2608019C (en) 2013-07-02
US20140148391A1 (en) 2014-05-29
CA2811995A1 (en) 2006-11-16
US20150119331A1 (en) 2015-04-30
EP1879609A2 (en) 2008-01-23
JP5667238B2 (en) 2015-02-12
HUE027070T2 (en) 2016-08-29
KR20130099207A (en) 2013-09-05
CN101171027A (en) 2008-04-30

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