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WO2011036467A1 - Produits utiles dans le traitement de l'hémophilie - Google Patents

Produits utiles dans le traitement de l'hémophilie Download PDF

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Publication number
WO2011036467A1
WO2011036467A1 PCT/GB2010/051420 GB2010051420W WO2011036467A1 WO 2011036467 A1 WO2011036467 A1 WO 2011036467A1 GB 2010051420 W GB2010051420 W GB 2010051420W WO 2011036467 A1 WO2011036467 A1 WO 2011036467A1
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WO
WIPO (PCT)
Prior art keywords
lymphotoxin
haemophilia
product
bound
factor
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/GB2010/051420
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English (en)
Inventor
Russell David Keenan
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Individual
Original Assignee
Individual
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Individual filed Critical Individual
Publication of WO2011036467A1 publication Critical patent/WO2011036467A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/62—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being a protein, peptide or polyamino acid
    • A61K47/64—Drug-peptide, drug-protein or drug-polyamino acid conjugates, i.e. the modifying agent being a peptide, protein or polyamino acid which is covalently bonded or complexed to a therapeutically active agent
    • 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

Definitions

  • the present invention relates to the field of haemophilia treatment, and in particular to the treatment of haemophilia inhibitors.
  • Haemophilia is a group of bleeding disorders wherein the body's ability to control blood clotting or coagulation is impaired.
  • haemophilia A The commonest form of haemophilia is haemophilia A. Patients with haemophilia A have a factor VIII deficiency.
  • Factor VIII also known as "Coagulation Factor VIII”
  • Haemophilia A can be treated by administering replacement factor. This is administered intravenously and is very expensive.
  • Haemophilia inhibitors are a problem which can arise in some patients from the body's reaction to administration of the deficient clotting factor.
  • Inhibitors are agents produced by the immune system against the administered clotting factors. This is because the immune system recognises the administered clotting factor as a foreign entity and raises antibodies against it in a defence mechanism.
  • lymphotoxins are used as general non-specific immune suppressants
  • Hawkins SF, West S, Keenan R "A Novel Immunomodulatory Regime for the Eradication of Inhibitors to Factor VIII in Severe Haemophilia” Journal of Thrombosis and Haemostasis Aug 2005 volume 3, si page 1435; and Collins PW, Mathias M, Hanley J, Keeling D, Keenan R, Laffan M, Perry D, Liesner R, on behalf of UK Haemophilia Centre Doctors Organisation, "Rituximab and immune tolerance in severe haemophilia A: a consecutive national cohort" J Thromb Haemost 2009 Mar 5).
  • the present invention provides a product comprising Factor VIII bound to a lyrnphotoxin.
  • the present invention provides the use of Factor VIII bound to a lyrnphotoxin in treating haemophilia A inhibitors.
  • the present applicant has found that immune suppressants are effective in controlling this condition and eradicating inhibitors, and in his experience immune suppression has transformed the lives of patients. There is understandably great reluctance amongst those skilled in the art in the haemophilia community with respect to general systemic immune suppression and its risks.
  • the present invention addresses safety issues by targeting only the factor VIII specific immune response and leaving the rest of the immune system untouched.
  • factor VIII itself is used as a targeting molecule and is linked to a lymphotoxin which kills, or decreases the viability of, the factor VIII specific cells.
  • Factor VTII can be bound to lymphotoxin in a number of different ways.
  • the binding may be direct, for example by covalent bonding, via a linker molecule, or via an antibody.
  • Streptavidin can be used, to allow the biotinylation of Factor VIII.
  • the lymphotoxin is any agent known to cause lymphocyte cell death, or reduce the viability of such cells.
  • suitable lymphotoxins are corticosteroids, cytotoxics and antibodies.
  • corticosteroids examples include for example prednisolone and dexamethasone.
  • Suitable cytotoxics include, for example, vincristine, asparaginase and daunorubicin.
  • Suitable monoclonal antibodies include, for example, rituxiMab and campath.
  • the present invention relates to the general principle of targeting Factor VIII and accordingly any suitable lymphotoxin can be bound to it.
  • the efficacy of the present invention resides in the following principles.
  • Factor VIII specific B cells all express surface antibody with the exception of plasma cells.
  • the Factor VIII component of the product of the present invention binds to the specific B cells, thereby localising and targeting these cells with the lymphotoxin.
  • Plasma cells also produce the inhibitor, but although these do not express surface antibody and so are not targeted, they are end effector cells and cannot divide to repopulate and maintain the immune response.
  • the present invention thus provides a solution which is better than currently available treatments in several ways.
  • the present invention uses a combination of products each of which are known to have a long term excellent safety record.
  • the targeting of the present invention reduces the risk of side effects, allows efficacy at low dose, and is applicable to all patients with inhibitors including congenital and acquired haemophilia, rather than being an individualised therapy.
  • the present invention provides a practical solution to the problem.
  • the Factor VIII - Lymphotoxin complex of the present invention exhibits selective action against Factor VIII inhibitor - producing lymphocytes.
  • the VIII inhibitor lymphocytes are in a minority compared to normal lymphocytes.
  • the Factor VIII specific inhibitor B cells have antibody receptors specific for Factor VIII so selectively bind to the complex.
  • the complex is directed to the inhibitor-producing cells, localising the lymphotoxin thereby killing the inhibitor- producing cells and leaving the normal cells unaffected.
  • the present invention relates to the treatment of haemophilia inhibitors, wherein the haemophilia is not necessarily haemophilia A but could be other forms of haemophilia, for example haemophilia B. Patients with haemophilia B have a Factor IX deficiency.
  • the present invention provides a product comprising Factor IX bound to a lymphotoxin.
  • the present invention provides the use of Factor IX bound to a lymphotoxin in treating haemophilia B inhibitors.
  • this specification refers to haemophilia A and Factor VIII, it should also be understood as applicable to haemophilia B and Factor IX, mutatis mutandis.

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Public Health (AREA)
  • Animal Behavior & Ethology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Hematology (AREA)
  • Organic Chemistry (AREA)
  • Diabetes (AREA)
  • General Chemical & Material Sciences (AREA)
  • Molecular Biology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Epidemiology (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Selon l'invention, le facteur VIII lié à une lymphotoxine est utile pour traiter les inhibiteurs de l'hémophilie A. La lymphotoxine peut être choisie parmi les corticostéroïdes, la vincristine, le rituxiMab, ou tout autre agent susceptible d'induire la mort cellulaire des lymphocytes. La lymphotoxine peut être liée au Facteur VIII directement, par l'intermédiaire d'un lieur, par l'intermédiaire d'un anticorps, ou par tout autre procédé convenable. Cette invention permet un traitement ciblé et sans danger. De manière similaire, le Facteur IX lié à une lymphotoxine est utile pour traiter les inhibiteurs de l'hémophilie B.
PCT/GB2010/051420 2009-09-24 2010-08-26 Produits utiles dans le traitement de l'hémophilie Ceased WO2011036467A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US24534109P 2009-09-24 2009-09-24
US61/245,341 2009-09-24

Publications (1)

Publication Number Publication Date
WO2011036467A1 true WO2011036467A1 (fr) 2011-03-31

Family

ID=43480894

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/GB2010/051420 Ceased WO2011036467A1 (fr) 2009-09-24 2010-08-26 Produits utiles dans le traitement de l'hémophilie

Country Status (1)

Country Link
WO (1) WO2011036467A1 (fr)

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1991008773A1 (fr) * 1989-12-07 1991-06-27 The Center For Blood Research Conjugues immunoglobuline-proteine tolerogene
US20020039581A1 (en) * 2000-01-27 2002-04-04 Carreno Beatriz M. Antibodies against CTLA4 and uses therefor
WO2006079120A2 (fr) * 2005-01-24 2006-07-27 Board Of Regents, The University Of Texas System Constructions fixant la phosphatidylserine et leur utilisation pour le traitement de maladies

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1991008773A1 (fr) * 1989-12-07 1991-06-27 The Center For Blood Research Conjugues immunoglobuline-proteine tolerogene
US20020039581A1 (en) * 2000-01-27 2002-04-04 Carreno Beatriz M. Antibodies against CTLA4 and uses therefor
WO2006079120A2 (fr) * 2005-01-24 2006-07-27 Board Of Regents, The University Of Texas System Constructions fixant la phosphatidylserine et leur utilisation pour le traitement de maladies

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
ALEXANDER S ET AL: "Rituximab and desensitization for a patient with severe factor IX deficiency, inhibitors, and history of anaphylaxis", JOURNAL OF PEDIATRIC HEMATOLOGY/ONCOLOGY, vol. 30, no. 1, 1 January 2008 (2008-01-01), pages 93 - 95, XP009137375, ISSN: 1077-4114, DOI: 10.1097/MPH.0B013E31815CF742 *
COLLINS P W ET AL: "Rituximab and immune tolerance in severe hemophilia A: A consecutive national cohort", JOURNAL OF THROMBOSIS AND HAEMOSTASIS, vol. 7, no. 5, 3 May 2009 (2009-05-03), pages 787 - 794, XP002619265, ISSN: 1538-7933, DOI: 10.1111/J.1538-7836.2009.03332.X *
COLLINS PW; MATHIAS M; HANLEY J; KEELING D; KEENAN R; LAFFAN M; PERRY D; LIESNER R: "Rituximab and immune tolerance in severe haemophilia A: a consecutive national cohort", J THROMB HAEMOST., 5 March 2009 (2009-03-05)
HAWKINS SF; WEST S; KEENAN R: "A Novel Immunomodulatory Regime for the Eradication of Inhibitors to Factor VIII in Severe Haemophilia", JOURNAL OF THROMBOSIS AND HAEMOSTASIS, vol. 3, August 2005 (2005-08-01), pages 1435

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