WO2000032223A2 - Traitement therapeutique a l'aide de medicaments immunogenes - Google Patents

Traitement therapeutique a l'aide de medicaments immunogenes Download PDF

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WO2000032223A2
WO2000032223A2 PCT/GB1999/004009 GB9904009W WO0032223A2 WO 2000032223 A2 WO2000032223 A2 WO 2000032223A2 GB 9904009 W GB9904009 W GB 9904009W WO 0032223 A2 WO0032223 A2 WO 0032223A2
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formulation
kit
use according
administration
drug
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PCT/GB1999/004009
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WO2000032223A3 (fr
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Michael Gerard Tovey
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Pharma Pacific Pty. Ltd.
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Publication of WO2000032223A3 publication Critical patent/WO2000032223A3/fr

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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
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/19—Cytokines; Lymphokines; Interferons
    • A61K38/21—Interferons [IFN]
    • 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
    • A61K38/177—Receptors; Cell surface antigens; Cell surface determinants
    • A61K38/1793—Receptors; Cell surface antigens; Cell surface determinants for cytokines; for lymphokines; for interferons
    • 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
    • A61K38/18—Growth factors; Growth regulators
    • A61K38/1816—Erythropoietin [EPO]
    • 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
    • A61K38/18—Growth factors; Growth regulators
    • A61K38/1841—Transforming growth factor [TGF]
    • 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
    • A61K38/19—Cytokines; Lymphokines; Interferons
    • A61K38/193—Colony stimulating factors [CSF]
    • 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
    • A61K38/19—Cytokines; Lymphokines; Interferons
    • A61K38/20—Interleukins [IL]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/04—Immunostimulants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/54—Medicinal preparations containing antigens or antibodies characterised by the route of administration
    • A61K2039/541—Mucosal route
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/545—Medicinal preparations containing antigens or antibodies characterised by the dose, timing or administration schedule
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K48/00—Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy

Definitions

  • the invention relates to therapeutic treatment with immunogenic drugs such as peptide drugs, including proteins.
  • an immunogenic drug such as a peptide drug elicits antibodies against the drug. This limits the effectiveness of the drug, particularly if injected repeatedly into a patient over a period of time.
  • immunogenic drugs include interferons (e.g. alpha, beta and gamma), interleukins (e.g. LL-2, IL-4, LL-10, IL-12, IL-15), growth factors (e.g. EPO, G-CSF, GM-CSF), monoclonal antibodies (e.g.OKT3, anti-TNF alpha, anti-IL2 R alpha, anti-IFN alpha Rl), and soluble receptors (e.g. TNF alpha SR p75 - Fc IgGl, IL-1 SR, IFN alpha SRI).
  • interferons e.g. alpha, beta and gamma
  • interleukins e.g. LL-2, IL-4, LL-10, IL-12, IL-15
  • growth factors
  • Oral administration of an antigen at appropriate dosage is known to induce "immunological tolerance", i.e suppression of the immune response to a subsequent systemic challenge by the antigen. Feeding of the antigen elicits a local immune response in the intestinal mucosa, but responses to the same antigen given subsequently by a systemic route are suppressed.
  • autoimmune diseases i.e. diseases in which a subject's immune system attacks its own tissues.
  • diseases include multiple sclerosis, rheumatoid arthritis, insulin-dependent diabetes, psoriasis and lupus erythematosus.
  • a number of studies have shown that oral administration of a protein such as myelin basic protein, a component of the myelin sheath of nerves, or Type II collagen, a constituent of cartilage, can induce tolerance to such proteins that are recognised as self-antigens by autoreactive T-cells in patients with multiple sclerosis and rheumatoid arthritis respectively.
  • a number of clinical trials are currently being conducted in which patients with multiple sclerosis and rheumatoid arthritis are treated with drugs based on oral formulations of native human peptides.
  • Active suppression is induced by oral administration of a relatively low dose of antigen and leads to immunological tolerance through inhibition of lymphocyte function.
  • Clonal anergy is induced by oral administration of a higher dose of antigen and leads to lymphocytes that are able to recognise antigen but not respond.
  • Clonal deletion is induced by oral administration of a very large dose of antigen and leads to elimination of reactive lymphocytes.
  • oral tolerance can be broadly defined as the inhibition of a Thl response in the periphery, either by large doses of antigen which induce anergy and/or clonal deletion, or by gut-mduced Th2 or Th3 type regulatory cells
  • the invention stems from a hypothesis of the inventor that oral administration of an immunogenic drug or a related compound may induce immunological tolerance to the drug, so that when the drug is subsequently administered its pharmacokmetics and/or clinical effectiveness are improved
  • This approach can be used in the therapeutic treatment of a subject with an immunogenic drug by
  • the administration of the first formulation enhances the pharmacokinetics and/or effectiveness of the second formulation by inducing immunological tolerance and reducing the immune response to the drug in the second formulation
  • the immunological tolerance is typically brought about by a mechanism of active suppression
  • the invention provides a kit that may be used to carry out the therapeutic treatment, which kit comp ⁇ ses
  • a first formulation comprising a compound in a dosage form for administration by an oromucosal route to induce immunological tolerance to the drug
  • a second formulation comprising the drug in a dosage form for administration to effect the therapeutic treatment
  • the invention provides:
  • an immunogenic drug for the manufacture of a second formulation for administration to effect therapeutic treatment of a disease of a human or animal, wherein the human or animal has become immunologically tolerant to the drug through administration by an oromucosal route of a first formulation comprising a compound that induces the immunological tolerance;
  • the immunogenic drug used in the invention may be any drug that, when administered to a subject, induces an immune response that reduces the pharmacokinetics and/or effectiveness of the drug.
  • the invention is particularly applicable to drugs that are administered in repeat doses over a period of time because the problem of rejection of such drugs by the immune system is greater than with dmgs that are only administered once.
  • the invention is also particularly applicable to expensive drugs because it reduces the amount of drug that needs to be administered to effect the therapeutic treatment; in conventional treatment regimes immunogenic dmgs often have to be administered in large doses to allow for the fact that the pharmacokinetics and/or effectiveness of the drug are reduced by the immune system.
  • the drug used in the invention is generally a peptide drug.
  • peptide as used herein means any molecule comprising a chain of six or more amino acids and includes full length proteins and polypeptides.
  • the peptide may, for example, be from 10 to 500 amino acids, from 20 to 300 amino acids or from 50 to 200 amino acids.
  • the peptide drugs that may be used in the invention include:
  • interferons e.g. IFN ⁇ , LFN ⁇ , IFN ⁇ , LFN ⁇ and IFN ⁇ cytokines - e.g. interleukin-1 (LL-1), LL-2, IL-4, LL-5, IL-12, LL-15, IL18 and
  • TGF- ⁇ growth factors e.g. granulocyte-macrophage stimulating factor (GM-CSF), granulocyte stimulating factor (G-CSF), erythropoietin (EPO) and LL-3 soluble receptors - e.g. tumour necrosis factor alpha soluble receptor (TNF ⁇ SR) and LL-1 SR antibodies - e.g. anti-IFN ⁇ , anti-IFN ⁇ , anti-TNF ⁇ , anti-IFN ⁇ R, anti-IFN ⁇ R and soluble receptor - IgG fusion proteins.
  • GM-CSF granulocyte-macrophage stimulating factor
  • G-CSF granulocyte stimulating factor
  • EPO erythropoietin
  • LL-3 soluble receptors e.g. tumour necrosis factor alpha soluble receptor (TNF ⁇ SR) and LL-1 SR antibodies - e.g. anti-IFN ⁇ , anti-IFN ⁇ , anti-TNF ⁇ , anti-IF
  • Interferons are anti-viral proteins produced by cells such as leukocytes and fibroblasts in response to viral infection.
  • Interferons such as IFN ⁇ are useful not only in the treatment of viral diseases, such as chronic hepatitis B and C, herpes and influenza, but also in the treatment of a variety of hematological malignancies including hairy cell leukemia, chronic myelogenous leukemia, low grade lymphomas, cutaneous T-cell lymphomas, and solid tumors such as renal cell carcinoma . , melanoma, carcinoid tumors, and AIDS-related Kaposi's sarcoma.
  • Recombinant IFN ⁇ is also useful for the treatment of remitting relapsing multiple sclerosis.
  • the invention can be applied to the treatment of viral diseases, cancers and multiple sclerosis.
  • Recombinant human LL-2 has been used extensively for the treatment of a number of neoplastic diseases including renal cell carcinoma (Rozenberg et al., 1989, Ann, Surg., 210:474) and malignant melanoma (Rozenberg et al, 1987, New Engl. J. Med., 316:889), and to a lesser extent for the treatment of certain vims diseases including chronic hepatitis B (Kakumu et al, 1988, Hepatology, 8:487-492).
  • G-CSF, GM-CSF and LL-3 are used principally to treat the neutropenia and leukopenia observed in cancer patients following chemotherapy.
  • the invention can therefore be used to treat these conditions.
  • Erythropoietin is a protein, normally produced in the liver of the fetus and in the kidneys of adults, which plays a role in the regulation of the oxygen level of the blood by stimulating the proliferation and differentiation of red blood cell precursor cells to mature red blood cells.
  • EPO can be administered to subjects for the treatment of diseases associated with inadequate red blood cell supply, e.g. anaemia and chronic renal failure. The invention can therefore be applied to the treatment of these diseases.
  • TNF ⁇ is a potent molecule which elicits a broad spectrum of biological responses.
  • the release of TNF ⁇ by macrophages induces local effects that participate in protection against infection.
  • TNF ⁇ can also have damaging effects; it induces septic shock when released systemically and is believed to play a role in autoimmune diseases such as rheumatoid arthritis.
  • antibodies against TNF ⁇ and soluble TNF ⁇ receptors that bind to and sequester TNF ⁇ are useful in the treatment of septic shock and rheumatoid arthritis.
  • a number of such antibodies and receptors are in development, for example antibody cA2 (Centocor), antibody cDP571 (Celltech).
  • the invention can be used to enhance the clinical effectiveness of such antibodies and receptors in the treatment of septic shock and autoimmune diseases such as rheumatoid arthritis.
  • the antibodies useable in the invention are generally monoclonal, and are preferably humanised or human.
  • one advantage of the invention is that it may allow the use of non-humanised antibodies that cannot normally be used for therapy because they are rejected by the immune system.
  • humanised antibodies the complementarity determining regions (CDRs) of a non-human antibody of a therapeutically useful specificity are grafted into the framework of a human antibody. This produces an antibody which has the therapeutically useful specificity but appears less foreign to the immune system than the donor non-human antibody.
  • Such humanised antibodies go some way to overcoming the problem of rejection by the immune system but, as mentioned above, they do not eliminate the problem but merely slow down the formation of anti-idiotype antibodies.
  • the drug may be a fusion protein.
  • fusion proteins are particularly prone to being rejected by the immune system because the process of fusing two proteins generates new epitopes, for example in the sequence around the fusion point.
  • fusion proteins useable in the invention are chimeric antibodies; bispecific antibodies; humanised antibodies; and antibodies linked to other peptides, for example antibodies linked to soluble receptors (e.g. TNF ⁇ soluble receptors).
  • the drug may be a nucleic acid (e.g. DNA) encoding a therapeutic peptide.
  • the nucleic acid is expressed in the subject, thereby producing the peptide.
  • the invention can be applied to diseases treatable by gene therapy, for example cystic fibrosis and Gaucher disease.
  • the nucleic acid is generally delivered in a vector. It is desirable to induce immunological tolerance not only to the therapeutic peptide encoded by the nucleic acid but also to the nucleic acid and/or the vector.
  • the compound administered in the first formulation may be a nucleic acid (e.g. DNA) encoding a peptide that induces tolerance.
  • the compound administered in the first formulation may be a peptide, in which case immunological tolerance is generated against the peptide only (not the nucleic acid).
  • nucleic acids used in the invention can, for example, be administered in naked DNA vectors, viral vectors or cellular vectors.
  • the vectors comprise a sequence encoding the therapeutic peptide linked to a control sequence which is capable of providing for the transcription of the coding sequence.
  • viral vecors useable in the invention include retrovirases, adenovimses and adeno-associated vims vectors.
  • cellular vectors include microorganisms that colonise the intestines, such as Salmonella and E.coli bacteria. Uptake of naked DNA constructs by mammalian cells is enhanced by several known transfection techniques, for example those including the use of transfection agents. Examples of such agents include cationic agents (for example calcium phosphate and DEAE-dextran) and lipofectants (for example lipofectamTM and trans fectamTM).
  • administration of the first formulation induces tolerance to the vector to prevent its elimination by the immune system and loss of the transducing gene. Furthermore, administration of the first formulation induces tolerence to recombinant protein expression systems for the production of peptides such as IL-2, LFN ⁇ and clotting factor IX, thereby allowing therapeutic or curative levels of the peptide to be attained in vivo.
  • peptides such as IL-2, LFN ⁇ and clotting factor IX
  • the compound in the first formulation does not have to be the same as the dmg in the second formulation in order for the compound to produce immunological tolerance against the dmg.
  • oral treatment with one interferon may induce immunological tolerance not only to the orally administered interferon but also to another interferon.
  • the compound in the first formulation may be the same or different to the drug in the second formulation.
  • the compound in the first formulation will normally be structurally related to the drug in the second formulation.
  • the dmg in the second formulation may be a full length protein and the compound in the first foimulation may comprise a partial sequence of the protein containing one or more epitopes of the protein.
  • a peptide in the first formulation may, for example, have at least 50%, at least 70%, at least 90%, at least 95% or at least 98% sequence identity to the peptide in the second formulation or to a part of the sequence of the peptide in the second formulation.
  • the two peptides may differ by, for example, from 1 to 100, from 1 to 50, from 1 to 20 or from 1 to 10 amino acids.
  • the compound in the first formulation and the drug in the second formulation will normally be from the same class of compounds.
  • the compound when the dmg is a cytokine (e.g. an interleukin) the compound will normally be a cytokine (e.g. an interleukin), when the dmg is a type I or type II interferon the compound will normally be a type I or type II interferon respectively, when the dmg is a growth factor the compound will normally be a growth factor, when the drug is a soluble receptor the compound will normally be a soluble receptor and when the drug is an antibody the compound will normally be an antibody.
  • cytokine e.g. an interleukin
  • the compound when the dmg is a type I or type II interferon the compound will normally be a type I or type II interferon respectively
  • the dmg when the dmg is a growth factor the compound will normally be a growth factor
  • the drug when the drug is a soluble
  • the basic treatment regimen according to the invention comprises administering a first formulation to a subject by an oromucosal route, e.g. orally comprising a compound in a dosage form which induces immunological tolerance to the drug, and administering a second formulation to the subject by a parenteral route comprising the dmg in a dosage form that effects the therapeutic treatment.
  • the dose of compound and drug administered in the first and second formulations will also vary according to factors such as the nature of the drug and the disease to be treated.
  • the dose of the compound in the first formulation is such that it induces immunological tolerance against the dmg to be administered in the second formulation.
  • the tolerance is preferably achieved through a mechanism of active suppression.
  • the dose of dmg administered in the second formulation is such that it is therapeutically effective.
  • a typical dose of the compound in the first formulation may be from 0.1 ⁇ g to 10 mg, for example from 1 ⁇ g to 5 mg or from 5 ⁇ g to 1 mg.
  • a typical dose of the dmg in the second formulation may be from 1 ⁇ g to 100 mg, for example from 5 ⁇ g to 100 mg.
  • test methods can be used to optimise the conditions for a particular course of treatment.
  • the dosages and timing of the doses will to a certain extent be up to the discretion of the physician, but can be optimised for each dmg.
  • the optimum doses and timing for each dmg will vary according to factors such as the disease to be treated, the route of administration and the condition and weight of the patient.
  • the first formulation is generally administered prior to administration of the second fo ⁇ nulation, but some benefit of immunological tolerance may be obtained if the two formulations are administered substantially simultaneously.
  • the first formulation is administered from 0 to 28 days, from 1 to 14 or from 4 to 7 days prior to the second formulation.
  • the relative timing of the administration of the two formulations is such that the subject exhibits oral tolerance to the drug in the second formulation.
  • the first formulation may, for example, be administered in from 1 to 14, from 1 to 7 or from 1 to 4 doses. It may be administered once a day for a number of days before administration of the second formulation. For example, the first formulation may be administered every day for from 1 to 4, 1 to 7 or 1 to 14 days.
  • the final dose of the first formulation may typically be given the day before the second formulation is administered, but it is also envisaged that there could be a delay before administration of the second formulation to allow immunological tolerance to build up; this delay could, for example, be from 1 to 7 or 1 to 4 days.
  • the number of doses of the second formulation and the frequency of the doses will vary according to factors such as the nature of the drug, the disease to be treated and how quickly the subject recovers from the disease. In some cases, only a single dose of the second formulation will be given, but the invention is particularly suited to treatment of diseases where it is necessary to give multiple doses of dmg.
  • the drag may be administered in multiple doses over a period of from 2 to 56 days or 4 to 28 days.
  • the number of doses may, for example, be from 1 to 14, from 1 to 7 or from 1 to 3. techniques, such as ELISA.
  • the first formulation is administered by an oromucosal route, i.e. the oral route or the nasal route.
  • the second formulation may be administered by any route such that a therapeutic effect is obtained.
  • the formulation is generally administered parenterally or systemically. The exact route of administration chosen will again depend on factors such as the nature of the dmg and the disease, but peripheral routes such as the intravenous, subcutaneous, intramuscular, intrathecal and intraperitoneal routes are appropriate.
  • the first and second formulations typically contain a pharmaceutically acceptable carrier or diluent.
  • the first formulation may take the form of a tablet, capsule, liquid solution, slow release formulation, liposome, aerosol or spray for oral administration.
  • the second formulation typically takes the form of a solution, for example in isotonic saline.
  • Figure 1 shows a standard curve for anti-human LFN ⁇ 2 in an ELISA for quantification of anti-LFN ⁇ antibodies in the sera of test animals .
  • Figure 2 shows the IgM antibody response to recombinant human LFN ⁇ 2 in Swiss mice at 4 days after i v injection of the IFN ⁇ 2.
  • the mice had been pre-treated with BSA alone or with various doses of the IFN ⁇ 2 in BSA by the oromucosal route.
  • Figure 3 shows the IgM antibody response to recombinant human LFN ⁇ in Swiss mice at 0, 7, 14, 21 and 28 days after i.v. injection of the IFN ⁇ .
  • the mice had been pre-treated by the oromucosal route with 10 3 , 10 4 , 10 5 , or 10 6 IU of the LFN ⁇ .
  • the first bar in each group of five is for excipient alone, the second is for 10 3 IU, the third is for 10 4 IU, the fourth is for 10 5 IU and the fifth is for 10 6 IU.
  • Figure 4 shows the IgM antibody response to recombinant human LFN ⁇ 2 in BALB/C mice at 21 days after subcutaneous injection of the IFN.
  • the mice had been pretreated with various doses of LFN ⁇ 2 by the oromucosal route once a day for four days prior to the injection.
  • Figure 5 shows the IgG antibody response to recombinant human IFN ⁇ 2 in BALB/c mice at 0, 7, 14 and 28 days after subcutaneous injection of 3 x 10 5 IU of human LFN ⁇ 2 without adjuvant three times a week for four weeks.
  • the mice had been pretreated once a day for 7 days by the oromucosal route with PBS alone (first base), BSA 100 ⁇ g/ml in PBS (second bar), 5 x 10 3 IU of LFN ⁇ 2 diluted in BSA/PBS (third bar), 10 6 (fourth bar) or 10 7 (fifth bar) IU of LFN ⁇ 2 alone.
  • Figure 6 shows the IgG antibody response of BALB/c mice to recombinant GM-CSF 21 days after subcutaneous injection of 3 ⁇ g of GM-CSF without adjuvant three times per week for four weeks.
  • the mice had been pre-treated by the oromucosal route with various doses of recombinant GM-CSF (0, l ⁇ g, 5 ⁇ g or 10 ⁇ g) or injected with 1.0 ⁇ g of human serum albumin alone in PBS once a day for 7 days.
  • This Example illustrates the induction of oral tolerance to interferons.
  • Carrier-free recombinant human interferon ⁇ 2 (RoferonTM A) at a concentration of 9 x 10 6 IU/ml and a specific activity of 2 x 10 8 LU/mg protein was obtained from Hoffmann-la-Roche, Basel, Switzerland.
  • the interferon was in aqueous isotonic solution in an acetate buffer at pH 5.0.
  • Bovine serum albumin/phosphate buffered saline excipient Bovine semm albumin fraction V RIA grade, immunoglobulin free (cat no.
  • microtiter plates (NUNC MaxisorbTM cat. no. 442406) were coated with 100 ⁇ l per well of a 2 ⁇ g/ml solution of RoferonTM LFN ⁇ 2 in 0.1 M solution of NaHCO 3 at pH 8.5 overnight at 4°C. The plates were then washed twice with 200 ⁇ l of PBS, and treated for 2 hrs with 100 ⁇ l per well of 2% gelatine (Sigma, cat. no. G7765) in PBS. The plates were then washed 3 times with 0.05% Tween 20TM (Biorad) in PBS, dried and stored at 4°C until use. Each semm sample was then tested at 10 "2 , 10 "3 , 10 "4 , and 10 "5 starting dilutions.
  • the plates were then washed 4 X with 200 ⁇ l per well of 0.05% TweenTM in PBS.
  • One hundred ⁇ l per well of a 400 ⁇ l/ml solution of o- phenylenediamine dihydrochloride (Sigma, cat. no. PI 526) in 44 mM citrate buffer pH 5.0 together with 0.03% H 2 O 2 was added per well.
  • the plates were then incubated for 30 minutes at 20°C and 50 ⁇ l per well of 0.5 ⁇ l H 2 SO 4 was added.
  • the optical density was then determined at 490 nM in a MetentechTM 960 spectrophotometer.
  • Results are expressed in arbitrary units determined from the reciprocal of the dilution obtained from a standard curve of serial two fold dilutions (1: 100 to 1 : 12,800) of a specific anti -interferon ⁇ 2 monoclonal antibody (mAb 1 18) ( Figure 1).
  • mice from a specific pathogen-free breeding colony were treated with various doses of recombinant human LFN ⁇ or IFN ⁇ or with excipient alone once a day for 4 or 7 days by the oromucosal route in a volume of 10 ⁇ l of BSA/PBS excipient. Animals were then injected intravenously or subcutaneously with 200 ⁇ l of interferon as indicated in the figure descriptions above. Two animals from each treatment group were then sacrificed at predetermined time points, e.g. 0, 7, 14, 21 and 28 days, and whole blood was recovered, pooled, and the semm was assayed for the presence of specific antibodies to the interferon.
  • mice were treated by the oromucosal route with various doses of recombinant human IFN ⁇ or IFN ⁇ in BSA/PBS, or with excipient alone for 4 days prior to intravenous injection of 9 x 10 5 IU of LFN ⁇ or IFN ⁇ respectively.
  • mice were treated by the oromucosal route with various doses of recombinant human LFN ⁇ in BSA/PBS, or with excipient alone once a day for 4 days prior to intravenous injection of 9 x 10 5 IU of IFN ⁇ .
  • mice were pretreated once a day for 7 days by the oromucosal route with 5x10 3 , 10 6 or 10 7 IU of recombinant IFN ⁇ 2 prior to subcutaneous injection of 3x10 5 IU of recombinant LFN ⁇ 2 without adjuvant three times a week for four weeks.
  • the IgG antibody response to recombinant human IFN ⁇ 2 in the mice was then determined using a specific ELISA for anti-IFN ⁇ 2 IgG at 0, 7, 14 and 28 days after subcutaneous injection of recombinant human IFN ⁇ 2.
  • EXAMPLE 2 This Example illustrates the induction of oral tolerance to recombinant GM- CSF.
  • Source of recombinant GM-CSF Source of recombinant GM-CSF
  • mice BALB/c mice were pretreated once a day for 7 days by the oromucosal route with 1.0, 5.0 or 10.0 ⁇ g of recombinant human GM-CSF prior to subcutaneous injection of 3.0 ⁇ g of recombinant GM-CSF without adjuvant three times a week for four weeks.
  • the IgG antibody response to recombinant human GM-CSF in the mice was then determined using a specific ELISA for anti-GM-CSF IgG at, for example, 21 days after subcutaneous injection of recombinant human GM-CSF.
  • the results at 21 days after subcutaneous injection shown in Figure 6 are expressed as the mean value for 6 animals per time point.

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

Abstract

L'invention concerne une trousse servant à administrer un traitement thérapeutique à un sujet à l'aide d'un médicament immunogène. Cette trousse comprend: a) une première préparation contenant un composé sous forme posologique à administrer par voie oro-muqueuse pour induire une tolérance immunologique au médicament; et b) une deuxième préparation contenant le médicament sous forme posologique à administrer pour effectuer le traitement thérapeutique. L'administration de la première préparation améliore l'efficacité de la deuxième préparation en réduisant la réponse immunitaire au médicament dans cette deuxième préparation. Le médicament peut être un médicament peptidique, tel qu'un interféron, une cytokine, un facteur de croissance, un récepteur soluble ou un anticorps.
PCT/GB1999/004009 1998-12-02 1999-12-01 Traitement therapeutique a l'aide de medicaments immunogenes WO2000032223A2 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU13991/00A AU1399100A (en) 1998-12-02 1999-12-01 Therapeutic treatment with immunogenic drugs

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
EP98403020.5 1998-12-02
EP98403020 1998-12-02

Publications (2)

Publication Number Publication Date
WO2000032223A2 true WO2000032223A2 (fr) 2000-06-08
WO2000032223A3 WO2000032223A3 (fr) 2000-10-19

Family

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Family Applications (1)

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PCT/GB1999/004009 WO2000032223A2 (fr) 1998-12-02 1999-12-01 Traitement therapeutique a l'aide de medicaments immunogenes

Country Status (2)

Country Link
AU (1) AU1399100A (fr)
WO (1) WO2000032223A2 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2013070362A1 (fr) * 2011-10-06 2013-05-16 The Research Foundation Of State University Of New York Compositions et méthodes d'induction d'une tolérance immunitaire
US20170209371A1 (en) * 2009-07-07 2017-07-27 The Research Foundation For The State University Of New York Phosphoserine containing compositions for immune tolerance induction

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997025862A1 (fr) * 1996-01-19 1997-07-24 Mcgill University Composition et methode de pretraitement de l'hepatite
WO1998041228A1 (fr) * 1997-03-19 1998-09-24 Shire Laboratories, Inc. Induction, par la voie des muqueuses, de tolerance a des polypeptides non-autologues administres de maniere parenterale

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997025862A1 (fr) * 1996-01-19 1997-07-24 Mcgill University Composition et methode de pretraitement de l'hepatite
WO1998041228A1 (fr) * 1997-03-19 1998-09-24 Shire Laboratories, Inc. Induction, par la voie des muqueuses, de tolerance a des polypeptides non-autologues administres de maniere parenterale

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20170209371A1 (en) * 2009-07-07 2017-07-27 The Research Foundation For The State University Of New York Phosphoserine containing compositions for immune tolerance induction
US10617640B2 (en) 2009-07-07 2020-04-14 The Research Foundation For The State University Of New York Phosphoserine containing compositions for immune tolerance induction
US11701328B2 (en) 2009-07-07 2023-07-18 The Research Foundation For The State University Of New York Phosphoserine containing compositions for immune tolerance induction
WO2013070362A1 (fr) * 2011-10-06 2013-05-16 The Research Foundation Of State University Of New York Compositions et méthodes d'induction d'une tolérance immunitaire
US10064922B2 (en) 2011-10-06 2018-09-04 The Research Foundation For The State University Of New York Compositions and methods for immune tolerance induction

Also Published As

Publication number Publication date
WO2000032223A3 (fr) 2000-10-19
AU1399100A (en) 2000-06-19

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