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WO2011036467A1 - Products useful in the treatment of haemophilia - Google Patents

Products useful in the treatment of haemophilia 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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WIPO (PCT)
Prior art keywords
lymphotoxin
haemophilia
product
bound
factor
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Ceased
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PCT/GB2010/051420
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French (fr)
Inventor
Russell David Keenan
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Individual
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Individual
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Publication of WO2011036467A1 publication Critical patent/WO2011036467A1/en
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    • 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.

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  • 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)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)

Abstract

Factor VIII bound to a lymphotoxin is useful in treating haemophilia A inhibitors. The lymphotoxin may be selected from corticosteroids, vincristine, rituxiMab, or any other agent which causes lymphocyte cell death. The lymphotoxin may be bound to Factor VIII directly, via a linker, via an antibody, or by other suitable methods. The invention allows targeted and safe treatment. Similarly, Factor IX bound to a lymphotoxin is useful in treating haemophilia B inhibitors.

Description

Products Useful in the Treatment of Haemophilia
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.
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") is an agent which in haemophilia A patients helps bring about blood clotting. This condition is usually inherited and affects males but can also be acquired in later life. 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.
The development of inhibitors is the most common serious complication of haemophilia therapy. Patients affected in this way either do not respond to their treatment, or respond poorly, and can experience very severe bleeding problems that are very difficult to treat.
Various methods have been used, or investigated, in attempts to overcome the problem of haemophilia inhibitors. Alternative blood clotting agents can be used, but these are only partially effective and are very expensive. Exposing the patients to factor VIII for a long time can help eradicate the inhibitor, but this is also very expensive and only partially effective. Immunosuppressive therapy can reduce the ability of the immune system to produce inhibitors but also affects the rest of the immune system and so has significant risks. For example, the present inventor has disclosed research in the area of immune therapy, in which 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).
Research is currently looking to develop targeted therapy to eradicate the anti factor VIII immune cells. The methods being explored currently are very elegant and complex. However, they would involve generating an individual therapy for every patient. This would be slow and therefore not suitable for emergencies, and would be very expensive. Through his work in haematology and immunology, and as a result of his experience as a physician, the applicant of the present application has found a simple, safe and effective solution to the problem of haemophilia inhibitors.
From a first aspect, the present invention provides a product comprising Factor VIII bound to a lyrnphotoxin.
From a second aspect, 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.
In accordance with the present invention, 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. For example, the binding may be direct, for example by covalent bonding, via a linker molecule, or via an antibody. For example, 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. Some non-limiting examples of suitable lymphotoxins are corticosteroids, cytotoxics and antibodies.
Examples of suitable corticosteroids 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. It is highly effective at eliminating factor VIII specific B cells, whilst at the same time it has a minimal effect on any other immune cells and so does not produce an immune-deficient state. 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. Thus 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. Thus the complex is directed to the inhibitor-producing cells, localising the lymphotoxin thereby killing the inhibitor- producing cells and leaving the normal cells unaffected.
With regard to the methods of treatment referred to herein, therapeutically effective amounts are administered to patients in need thereof. The skilled practitioner is well aware that required dosages depend on the mass and individual circumstances of a patient, and is able to adjust appropriate dosages accordingly. In further aspects 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. Thus, in a further aspect, the present invention provides a product comprising Factor IX bound to a lymphotoxin. In a yet further aspect the present invention provides the use of Factor IX bound to a lymphotoxin in treating haemophilia B inhibitors. Whereas this specification refers to haemophilia A and Factor VIII, it should also be understood as applicable to haemophilia B and Factor IX, mutatis mutandis.

Claims

1. A product comprising Factor VIII bound to a lymphotoxin.
2. A product as claimed in claim 1 wherein the Factor VIII is directly bound to the lymphotoxin.
3. A product as claimed in claim 1 wherein the Factor VIII is bound to the lymphotoxin via a linker molecule.
4. A product as claimed in claim 1 wherein the Factor VIII is bound to the lymphotoxin via an antibody.
5. A product as claimed in any preceding claim wherein the lymphotoxin is selected from corticosteroids, vincristine, rituxiMab, or any other agent which causes lymphocyte cell death.
6. A product as claimed in any preceding claim which is in the form of a pharmaceutical composition and further comprises a pharmaceutically acceptable diluent, carrier, excipient or additive.
7. A product as claimed in any preceding claim, for use in therapy.
8. A product as claimed in any preceding claim, for use in the treatment of haemophilia A inhibitors.
9. A product as claimed in any preceding claim, for use in the treatment of haemophilia A inhibitors, in combination with treatment of haemophilia A by Factor VIII.
10. Use of a product as claimed in any preceding claim in the manufacture of a medicament for the treatment of haemophilia A inhibitors.
11. A method of treating haemophilia A inhibitors comprising the administration of Factor VIII bound to a lympho toxin.
12. A method as claimed in claim 11 wherein the Factor VIII is directly bound to the lymphotoxin.
13. A method as claimed in claim 11 wherein the Factor VIII is bound to the lymphotoxin via a linker molecule.
14. A method as claimed in claim 11 wherein the Factor VIII is bound to the lymphotoxin via an antibody.
15. A method as claimed in any of claims 11 to 14 wherein the lymphotoxin is selected from corticosteroids, vincristine, ritirxiMab, or any other agent which causes lymphocyte cell death.
16. A method of treating haemophilia A comprising the administration of Factor VIII in combination with a method of treating haemophilia A inhibitors as claimed in any of claims 11 to 15.
17. A product comprising Factor IX bound to a lymphotoxin.
18. A product as claimed in claim 17 wherein the Factor IX is directly bound to the lymphotoxin.
19. A product as claimed in claim 17 wherein the Factor IX is bound to the lymphotoxin via a linker molecule.
20. A product as claimed in claim 17 wherein the Factor IX is bound to the lympho toxin via an antibody.
21. A product as claimed in any of claims 17 to 20 wherein the lymphotoxin is selected from corticosteroids, vincristine, rituxiMab, or any other agent which causes lymphocyte cell death.
22. A product as claimed in any of claims 17 to 21 which is in the form of a pharmaceutical composition and further comprises a pharmaceutically acceptable diluent, carrier, excipient or additive.
23. A product as claimed in any of claims 17 to 22, for use in therapy.
24. A product as claimed in any of claims 17 to 23, for use in the treatment of haemophilia B inhibitors.
25. A product as claimed in any of claims 17 to 24, for use in the treatment of haemophilia B inhibitors, in combination with treatment of haemophilia B by Factor IX.
26. Use of a product as claimed in any of claims 17 to 25 in the manufacture of a medicament for the treatment of haemophilia B inhibitors.
27. A method of treating haemophilia B inhibitors comprising the administration of Factor IX bound to a lymphotoxin.
28. A method as claimed in claim 27 wherein the Factor IX is directly bound to the lymphotoxin.
29. A method as claimed in claim 27 wherein the Factor IX is bound to the lymphotoxin via a linker molecule.
30. A method as claimed in claim 28 wherein the Factor IX is bound to the lymphotoxin via an antibody.
31. A method as claimed in any of claims 27 to 30 wherein the lymphotoxin is selected from corticosteroids, vincristine, rituxiMab, or any other agent which causes lymphocyte cell death.
32. A method of treating haemophilia B comprising the administration of Factor IX in combination with a method of treating haemophilia B inhibitors as claimed in any of claims 27 to 31.
PCT/GB2010/051420 2009-09-24 2010-08-26 Products useful in the treatment of haemophilia Ceased WO2011036467A1 (en)

Applications Claiming Priority (2)

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US24534109P 2009-09-24 2009-09-24
US61/245,341 2009-09-24

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1991008773A1 (en) * 1989-12-07 1991-06-27 The Center For Blood Research Tolerogenic immunoglobulin-protein conjugates
US20020039581A1 (en) * 2000-01-27 2002-04-04 Carreno Beatriz M. Antibodies against CTLA4 and uses therefor
WO2006079120A2 (en) * 2005-01-24 2006-07-27 Board Of Regents, The University Of Texas System Fc-fusion constructs binding to phosphatidylserine and their therapeutic use

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1991008773A1 (en) * 1989-12-07 1991-06-27 The Center For Blood Research Tolerogenic immunoglobulin-protein conjugates
US20020039581A1 (en) * 2000-01-27 2002-04-04 Carreno Beatriz M. Antibodies against CTLA4 and uses therefor
WO2006079120A2 (en) * 2005-01-24 2006-07-27 Board Of Regents, The University Of Texas System Fc-fusion constructs binding to phosphatidylserine and their therapeutic use

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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