WO2000067777A1 - Procede de prophylaxie et de traitement et agents utilisables dans ce procede - Google Patents

Procede de prophylaxie et de traitement et agents utilisables dans ce procede Download PDF

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Publication number
WO2000067777A1
WO2000067777A1 PCT/AU2000/000424 AU0000424W WO0067777A1 WO 2000067777 A1 WO2000067777 A1 WO 2000067777A1 AU 0000424 W AU0000424 W AU 0000424W WO 0067777 A1 WO0067777 A1 WO 0067777A1
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Prior art keywords
cell epitope
molecule
agent
cytokine
subject
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PCT/AU2000/000424
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English (en)
Inventor
George Harris
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Biofan Pty Ltd
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Publication date
Priority claimed from AUPQ0219A external-priority patent/AUPQ021999A0/en
Priority claimed from AUPQ0220A external-priority patent/AUPQ022099A0/en
Application filed by Biofan Pty Ltd filed Critical Biofan Pty Ltd
Priority to AU43852/00A priority Critical patent/AU4385200A/en
Publication of WO2000067777A1 publication Critical patent/WO2000067777A1/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
    • A61K38/193—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
    • A61K38/1703—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
    • 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
    • A61K38/191—Tumor necrosis factors [TNF], e.g. lymphotoxin [LT], i.e. TNF-beta
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • 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

Definitions

  • the present invention relates generally to a method of down-regulating or otherwise reducing the functional levels of an endogenously produced molecule in a subject and agents useful for same. More particularly, the present invention relates to a method of reducing the functional levels of one or more complement components, a cytokine or an adhesion molecule in a subject and agents useful for same. Still more particularly, the present invention contemplates a method of down-regulating or otherwise reducing the functional levels of a cytokine by administering to said subject a cytokine and/or cytokine receptor, or a derivative, homologue, analogue, chemical equivalent thereof, immunogenic composition. The method of the present invention is useful, inter alia, in a range of therapeutic and prophylactic applications.
  • Cytokines are pleiotropic molecules which, inter alia, impart signals to cells to regulate the immune response, control cell proliferation and differentiation and to regulate the operation of the cytokine network.
  • cytokines also induce adverse side effects such as inhibition of normal cell growth, undesirable modulation of the functional activity of other cytokines or other unwanted immune effects such as severe inflammation, fever, malaise, nausea or leukopenia.
  • chronic inflammation is facilitated by the presence of GM-CSF and/or M-CSF and/or TNF- .
  • methods for therapeutically or prophylactically reducing unwanted cytokine effects have centred on the administration of antibodies directed to cytokines which have been raised in mice.
  • the inventors have developed a method of reducing the level of unwanted endogenously produced molecules by inducing, in the subject to be treated, an immune response specifically directed to said molecule.
  • the subject specification contains amino acid sequence information prepared using the programme Patentln Version 2.0, presented herein after the bibliography.
  • Each amino acid sequence is identified in the sequence listing by the numeric indicator ⁇ 210> followed by the sequence identifier (e.g. ⁇ 210> 1, ⁇ 210> 2, etc).
  • the length, type of sequence (protein (PRT), etc) and source organism for each amino acid sequence is indicated by information provided in the numeric indicator fields ⁇ 211 > , ⁇ 212 > and ⁇ 213 > , respectively.
  • Amino acid sequences referred to in the specification are defined by the information provided in numeric indicator field ⁇ 400 > followed by the sequence identifier (e.g. ⁇ 400> 1, ⁇ 400 > 2, etc).
  • One aspect of the present invention provides a method of down regulating or otherwise reducing the functional level of an endogenously-produced molecule in a subject said method comprising administering to said subject an effective amount of an agent, the agent comprising said molecule or the ligand of said molecule or a derivative, homologue, analogue, chemical equivalent or mimetic thereof for a time and under conditions sufficient to induce, upregulate or otherwise elicit an immune response directed to said molecule and/or said ligand.
  • Another aspect of the present invention provides a method of down-regulating or otherwise reducing the functional level of a complement component in a subject said method comprising administering to said subject an effective amount of an agent, the agent comprising said complement component or the ligand of said complement component or a derivative, homologue, analogue, chemical equivalent or mimetic thereof for a time and under conditions sufficient to induce, upregulate or otherwise elicit an immune response directed to said complement component and/or said ligand.
  • Still another aspect of the present invention provides a method of down-regulating or otherwise reducing the functional level of a cytokine in a subject said method comprising administering to said subject an effective amount of an agent, the agent comprising said cytokine and/or said cytokine receptor or a derivative, homologue, analogue, chemical equivalent or mimetic thereof for a time and under conditions sufficient to induce, up- regulate or otherwise elicit an immune response directed to said cytokine and/or said cytokine receptor.
  • Still yet another aspect of the present invention provides a method of down-regulating or otherwise reducing the functional level of GM-CSF in a subject said method comprising administered to said subject an effective amount of an agent, the agent comprising GM- CSF and/ or GM-CSF receptor or a derivative, homologue, analogue, chemical equivalent or mimetic thereof for a time and under conditions sufficient to induce, up-regulate or otherwise elicit an immune response directed to GM-CSF and/or GM-CSF receptor.
  • an agent comprising GM- CSF and/ or GM-CSF receptor or a derivative, homologue, analogue, chemical equivalent or mimetic thereof for a time and under conditions sufficient to induce, up-regulate or otherwise elicit an immune response directed to GM-CSF and/or GM-CSF receptor.
  • Yet another aspect of the present invention provides a method of down-regulating or otherwise reducing the functional level of M-CSF in a subject said method comprising administering to said subject an effective amount of an agent, the agent comprising M-CSF and/or M-CSF receptor or a derivative, homologue, analogue, chemical equivalent or mimetic thereof for a time and under conditions sufficient to induce, up-regulate or otherwise elicit an immune response directed to said M-CSF and/or M-CSF receptor.
  • a further aspect of the present invention provides a method of down-regulating or otherwise reducing the functional level of an adhesion molecule in a subject said method comprising administering to said subject an effective amount of an agent, the agent comprising said adhesion molecule and/or adhesion molecule ligand or a derivative, homologue, analogue, chemical equivalent or mimetic thereof for a time and under conditions sufficient to induce, up-regulate or otherwise elicit an immune response directed to said adhesion molecule and/or adhesion molecule ligand.
  • Another further aspect of the present invention provides a method of down-regulating or otherwise reducing the functional level of TNF- ⁇ in a subject said method comprising administering to said subject an effective amount of an agent, the agent comprising TNF- ⁇ and/or TNF- ⁇ receptor or a derivative, homologue, analogue, chemical equivalent or mimetic thereof for a time and under conditions sufficient to induce, up-regulate or otherwise elicit an immune response directed to said TNF- ⁇ and/or TNF- ⁇ receptor.
  • Yet another further aspect of the present invention provides a method of down-regulating or otherwise reducing the functional level of Integrin ⁇ 4 ⁇ j in a subject said method comprising administering to said subject an effective amount of an agent comprising said Integrin ⁇ 4 ⁇ j and/or VCAM-1 and/or fibronectin or a derivative, homologue, analogue, chemical equivalent or mimetic thereof for a time and under conditions sufficient to induce, up-regulate or otherwise elicit and immune response directed to said Integrin ⁇ 4 ⁇ j and/or said VCAM-1 and/or fibronectin.
  • Still yet another further aspect of the present invention provids a method for the treatment or prophylaxis of a disease condition involving unwanted endogenously produced molecule functional activity in a subject said method comprising administering to said subject an effective amount of an agent, the agent comprising said molecule and/or molecule ligand or a derivative, homologue, analogue, chemical equivalent or mimetic thereof for a time and under conditions sufficient to induce, up-regulate or otherwise elicit an immune response directed to said molecule and/or molecule ligand wherein the functional level of said molecule is down-regulated.
  • an agent comprising said molecule and/or molecule ligand or a derivative, homologue, analogue, chemical equivalent or mimetic thereof for a time and under conditions sufficient to induce, up-regulate or otherwise elicit an immune response directed to said molecule and/or molecule ligand wherein the functional level of said molecule is down-regulated.
  • the present invention provides an immunogenic agent for use in inducing, up-regulating or otherwise eliciting an immune response to an endogenously- produced molecule or ligand thereof, said composition comprising at least one B cell epitope linked, bound or otherwise associated with at least one T cell epitope.
  • the present invention also provides an immunogenic agent for use in inducing, up- regulating or otherwise eliciting an immune response to an endogenously-produced molecule or ligand thereof said composition comprising at least two B cell epitopes which epitopes are each linked, bound or otherwise associated with at least three T cell epitopes.
  • Yet another aspect of the present invention provides a pharmaceutical composition for use in down-regulating the functional activity of an endogenously-produced molecule comprising an agent as hereinbefore defined together with any one or more pharmaceutically acceptable carriers and/or diluents. These components are referred to as the active ingredients.
  • Yet another aspect of the present invention is directed to an immunogenic agent as hereinbefore defined when used in accordance with the method of the present invention.
  • Still another aspect of the present invention provides an agent useful for down-regulating the functional level of an endogenously-produced molecule in a subject as hereinbefore defined.
  • Still yet another aspect of the present invention provides an immunogenic agent in the manufacture of a medicament for the treatment of a disease condition characterised by unwanted endogenously-produced molecule levels.
  • the present invention is predicated, in part, on the development of a method for reducing the functional levels of one or more endogenously produced molecules in an individual by eliciting, in said individual, autoantibodies to the molecule or its ligand. This has facilitated the development of controlled methods for therapeutically and/or prophylactically treating disease conditions by selectively reducing functional levels of one or more specific molecules such as complement components, cytokines or adhesion molecules.
  • one aspect of the present invention provides a method of down regulating or otherwise reducing the functional level of an endogenously-produced molecule in a subject said method comprising administering to said subject an effective amount of an agent, the agent comprising said molecule or the ligand of said molecule or a derivative, homologue, analogue, chemical equivalent or mimetic thereof for a time and under conditions sufficient to induce, upregulate or otherwise elicit an immune response directed to said molecule and/or said ligand.
  • Reference to an "endogenously-produced molecule” should be understood as a reference to any molecule which is produced, in vivo, by a subject.
  • the molecule may be constitutively produced or may be produced as a result of a specific stimulus. It should be understood that the molecule may be soluble (such as, but not limited to, complement components or cytokines) or the molecule may be bound to a structure such as a cell membrane or extracellular matrix (for example, adhesion molecules).
  • Reference to the "ligand" of an endogenously produced molecule should be understood as a reference to any other molecule to which the endogenously produced molecule binds or otherwise associates.
  • the endogenously produced molecule is a cytokine
  • the cytokine receptor is a ligand.
  • the antigen/antibody complex to which it binds is a ligand, or where the endogenously produced molecule is C2
  • the ligand may be C4b.
  • the endogenously produced molecule is a complement component, cytokine or adhesion molecule.
  • the present invention provides a method of down-regulating or otherwise reducing the functional level of a complement component in a subject said method comprising administering to said subject an effective amount of an agent, the agent comprising said complement component or the ligand of said complement component or a derivative, homologue, analogue, chemical equivalent or mimetic thereof for a time and under conditions sufficient to induce, upregulate or otherwise elicit an immune response directed to said complement component and/or said ligand.
  • complement component should be understood as a reference to any component of the alternative or classical complement pathway or the cleavage product of said component or the complement complexes which are formed at the various stages of the complement cascade.
  • complement components include, but is not limited to, Clq, Clr, Cls, C3, C4, Factor D, plasma protease, Factor B, the cleavage products C2b, C2a, C3b, or the complexes C3bBb, C4b2b or the membrane attack complex.
  • the present invention provides a method of down-regulating or otherwise reducing the functional level of a cytokine in a subject said method comprising administering to said subject an effective amount of an agent, the agent comprising said cytokine and/or said cytokine receptor or a derivative, homologue, analogue, chemical equivalent or mimetic thereof for a time and under conditions sufficient to induce, upregulate or otherwise elicit an immune response directed to said cytokine or said cytokine receptor.
  • agent should be understood as a reference to the composition which is administered to the subject in accordance with the method of the present invention.
  • the agent may comprise the immunogenic molecule alone or it may also comprise other proteinaceious or non-proteinaceous molecules such as, but not limited to, a T cell epitope, carrier molecule or adjuvant.
  • the agent may therefore take the form of, for example, a purified cytokine or a derivative, homologue, analogue, chemical equivalent or mimetic thereof or a pharmaceutical formulation, such as a vaccine formulation, which comprises for example, said purified cytokine or derivative, homologue, analogue, chemical equivalent or ⁇ iimetic thereof alone or together with another protemaceous or non-proteinaceous molecule such as a T cell epitope, carrier molecule or adjuvant.
  • a vaccine formulation which comprises for example, said purified cytokine or derivative, homologue, analogue, chemical equivalent or ⁇ iimetic thereof alone or together with another protemaceous or non-proteinaceous molecule such as a T cell epitope, carrier molecule or adjuvant.
  • subject should be understood as a reference to any animal or bird such as but not limited to a human, primate, livestock animal (e.g. sheep, cow, horse, donkey, pig), companion animal (e.g. dog, cat), laboratory test animal (e.g. mouse, rabbit, rat, guinea pig, hamster), captive wild animal (e.g. fox, deer), caged bird (e.g. parrot) and poultry bird (e.g. chicken, duck, pheasant, turkey.
  • livestock animal e.g. sheep, cow, horse, donkey, pig
  • companion animal e.g. dog, cat
  • laboratory test animal e.g. mouse, rabbit, rat, guinea pig, hamster
  • captive wild animal e.g. fox, deer
  • caged bird e.g. parrot
  • poultry bird e.g. chicken, duck, pheasant, turkey.
  • the subject is a human or primate.
  • the subject is
  • references to the "functional level" of an endogenously produced molecule should be understood as a reference to the level of molecule, in a subject, which is able to fulfil its biological role of binding to a ligand thereby contributing to a biological effect.
  • the "functional level” of a molecule may be down-regulated by any one of a number of mechanisms including, but not limited to:
  • cytokine should be understood as a reference to a protein hormone.
  • the cytokine may be in a soluble form or may be anchored to a surface such as, but not limited to, a cell membrane or an extracellular matrix surface. Even where a cytokine is anchored, for example to an extracellular matrix, the cytokine may still exhibit functional activity by binding to localised cells expressing the receptor for that cytokine. In this regard, it may therefore also be desirable to reduce the capacity of these cytokines to bind to a target.
  • Particularly preferred cytokines are those which are unwanted such as those which are associated with any one or more symptoms of a disease condition. Reduction of the functional levels of those cytokines thereby reduces or ameliorates any one or more symptoms associated with such a disease condition.
  • GM-CSF, M-CSF, TNF ⁇ , IL-1 and/or IL-6 are present in elevated levels in rheumatoid arthritis, Crohn's disease, Type I diabetes, multiple sclerosis, psoriasis and chronic inflammatory lung disease (for example, asthma, chronic bronchitis, emphysema, chronic obstructive airway disease).
  • IL-4 and IL-5 are active in allergic lung diseases such as asthma, bronchopulmonary aspergillosus, allergic granulomatous disease, anaphylactic reactions and parasitaemia.
  • Interferon- ⁇ , IL-12 and TNF ⁇ are functionally active in infectious and non-infectious lung disease such as chronic bronchitis and cystic fibrosis while TGF ⁇ is produced during formation of lung fibrosis.
  • the onset of inflammatory bowel disease involves the production of GM-CSF, M-CSF, TNF ⁇ and IL-1 while interferon- ⁇ and interferon- ⁇ are produced in an individual suffering from Type I diabetes or multiple sclerosis.
  • GM-CSF and M-CSF are also involved in atherosclerosis, osteoporosis, myeloid leukaemia and solid tumours.
  • Angiogenesis is known to involve the production of NEGF, FGF and Fips/CTGF.
  • said cytokines are GM-CSF, M-CSF and T ⁇ F- ⁇ .
  • the present invention provides a method of down- regulating or otherwise reducing the functional level of GM-CSF in a subject said method comprising administered to said subject an effective amount of an agent, the agent comprising GM-CSF and/or GM-CSF receptor or a derivative, homologue, analogue, chemical equivalent or mimetic thereof for a time and under conditions sufficient to induce, up-regulate or otherwise elicit an immune response directed to GM-CSF and/or GM-CSF receptor.
  • the present invention provides a method of down- regulating or otherwise reducing the functional level of M-CSF in a subject said method comprising administering to said subject an effective amount of an agent, the agent comprising M-CSF and/or M-CSF receptor or a derivative, homologue, analogue, chemical equivalent or mimetic thereof for a time and under conditions sufficient to induce, up-regulate or otherwise elicit an immune response directed to said M-CSF and/or M-CSF receptor.
  • the present invention provides a method of down-regulating or otherwise reducing the functional level of TNF- ⁇ in a subject said method comprising administering to said subject an effective amount of an agent, the agent comprising TNF- ⁇ and/or TNF- ⁇ receptor or a derivative, homologue, analogue, chemical equivalent or mimetic thereof for a time and under conditions sufficient to induce, upregulate or otherwise elicit an immune response directed to said TNF- ⁇ and/or TNF- ⁇ receptor.
  • Adhesion molecules are involved in, inter alia, leukocyte migration across tissues (such across the vascular endothelium), homing and cell-cell interactions. By reducing the availability of either the adhesion molecule or its ligand, the modulation of leukocyte homing, interactions and migration can be achieved.
  • functional levels has the same meaning with respect to adhesion molecule ligands and adhesion molecules as it does with respect to cytokines and cytokine receptors, respectively.
  • another embodiment of the present invention provides a method of down- regulating or otherwise reducing the functional level of an adhesion molecule in a subject said method comprising administering to said subject an effective amount of an agent, the agent comprising said adhesion molecule and/or adhesion molecule ligand or a derivative, homologue, analogue, chemical equivalent or mimetic thereof for a time and under conditions sufficient to induce, up-regulate or otherwise elicit an immune response directed to said adhesion molecule and/or adhesion molecule ligand.
  • Adhesion molecule should be understood as a reference to any molecule, the functional activity of which includes, facilitating leukocyte migration, homing or interaction. These molecules are generally anchored to a cell membrane or extracellular matrix.
  • Adhesion molecules can be broadly grouped as selectins, mucin-like vascular addressins, integrins and the adhesion molecules of the immunoglobulin super family. Particularly preferred adhesion molecules are the integrins such as, but not limited to, Integrin ⁇ 4 ⁇ j which is bound by VCAM-1 and fibronectin (CS-1) integrin ⁇ 4 ⁇ j is also known as VLA-4, LPAM-1, CD49d/CD29. Without limiting the invention in any way, the integrins comprise an ⁇ and ⁇ chain.
  • the present invention provides a method of down- regulating or otherwise reducing the functional level of Integrin ⁇ 4 ⁇ , in a subject said method comprising administering to said subject an effective amount of an agent comprising said Integrin ⁇ 4 ⁇ j and/or VCAM-1 and/or fibronectin or a derivative, homologue, analogue, chemical equivalent or mimetic thereof for a time and under conditions sufficient to induce, up-regulate or otherwise elicit and immune response directed to said Integrin ⁇ 4 ⁇ ! and/or said VCAM-1 and/or fibronectin.
  • Derivatives should be understood to include fragments, parts, portions, mutants, cyclised peptides, and mimetics from natural, synthetic or recombinant sources including fusion proteins. Fragments and parts may be epitope regions, for example. Derivatives may be derived from insertion, deletion or substitution of amino acids. Amino acid insertional derivatives include amino and/or carboxylic terminal fusions as well as intrasequence insertions of single or multiple amino acids. Insertional amino acid sequence variants are those in which one or more amino acid residues are introduced into a predetermined site in the protein although random insertion is also possible with suitable screening of the resulting product. Deletional variants are characterized by the removal of one or more amino acids from the sequence.
  • substitutional amino acid variants are those in which at least one residue in the sequence has been removed and a different residue inserted in its place.
  • An example of substitutional amino acid variants are conservative amino acid substitutions.
  • Conservative amino acid substitutions typically include substitutions within the following groups: glycine and alanine; valine, isoleucine and leucine; aspartic acid and glutamic acid; asparagine and glutamine; serine and threonine; lysine and arginine; and phenylalanine and tyrosine. Additions to amino acid sequences including fusions with other peptides, polypeptides or proteins.
  • Homologues of the protein contemplated herein include, but are not limited to, proteins derived from different species.
  • Chemical and functional equivalents should be understood as molecules exhibiting any one or more of the functional activities and may be derived from any source such as being chemically synthesized or identified via screening processes such as natural product screening.
  • the derivatives include fragments having particular epitopes of parts of the entire protein fused to peptides, polypeptides or other proteinaceous or non-proteinaceous molecules.
  • Analogues contemplated herein include, but are not limited to, modification to side chains, incorporating of unnatural amino acids and/or their derivatives during peptide, polypeptide or protein synthesis and the use of crosslinkers and other methods which impose conformational constraints on the proteinaceous molecules or their analogs.
  • Derivatives of nucleic acid sequences may similarly be derived from single or multiple nucleotide substitutions, deletions and/or additions including fusion with other nucleic acid molecules.
  • the derivatives of the nucleic acid molecules of the present invention include oligonucleotides, PCR primers, antisense molecules, molecules suitable for use in cosuppression and fusion of nucleic acid molecules.
  • Derivatives of nucleic acid sequences also include degenerate variants.
  • side chain modifications contemplated by the present invention include modifications of amino groups such as by reductive alkylation by reaction with an aldehyde followed by reduction with NaBH ⁇ amidination with methylacetimidate; acylation with acetic anhydride; carbamoylation of amino groups with cyanate; trinitrobenzylation of amino groups with 2, 4, 6-trinitrobenzene sulphonic acid (TNBS); acylation of amino groups with succinic anhydride and tetrahydrophthalic anhydride; and pyridoxylation of lysine with pyridoxal-5-phosphate followed by reduction with NaBH
  • modifications of amino groups such as by reductive alkylation by reaction with an aldehyde followed by reduction with NaBH ⁇ amidination with methylacetimidate; acylation with acetic anhydride; carbamoylation of amino groups with cyanate; trinitrobenzylation of amino groups with 2, 4, 6-trinitrobenzene sulphonic acid (TNBS); acylation of amino groups with
  • the guanidine group of arginine residues may be modified by the formation of heterocyclic condensation products with reagents such as 2,3-butanedione, phenylglyoxal and glyoxal.
  • the carboxyl group may be modified by carbodiimide activation via O-acylisourea formation followed by subsequent derivitisation, for example, to a corresponding amide.
  • Sulphydryl groups may be modified by methods such as carboxymethylation with iodoacetic acid or iodoacetamide; performic acid oxidation to cysteic acid; formation of a mixed disulphides with other thiol compounds; reaction with maleimide, maleic anhydride or other substituted maleimide; formation of mercurial derivatives using 4- chloromercuribenzoate, 4-chloromercuriphenylsulphonic acid, phenylmercury chloride, 2- chloromercuri-4-nitrophenol and other mercurials; carbamoylation with cyanate at alkaline pH.
  • Tryptophan residues may be modified by, for example, oxidation with N- bromosuccinimide or alkylation of the indole ring with 2-hydroxy-5-nitrobenzyl bromide or sulphenyl halides.
  • Tyrosine residues on the other hand, may be altered by nitration with tetranitromethane to form a 3-nitrotyrosine derivative.
  • Modification of the imidazole ring of a histidine residue may be accomplished by alkylation with iodoacetic acid derivatives or N-carboethoxylation with diethy lpy rocarbonate .
  • Examples of incorporating unnatural amino acids and derivatives during protein synthesis include, but are not limited to, use of norleucine, 4-amino butyric acid, 4-amino-3- hydroxy-5-phenylpentanoic acid, 6-aminohexanoic acid, t-butylglycine, norvaline, phenylglycine, ornithine, sarcosine, 4-amino-3-hydroxy-6-methylheptanoic acid, 2-thienyl alanine and/or D-isomers of amino acids.
  • a list of unnatural amino acid contemplated herein is shown in Table 1.
  • Non-conventional Code Non-conventional Code amino acid amino acid
  • references to "down-regulating or otherwise reducing" the functional level of an endogenously-produced molecule should be understood as a reference to either partially or completely reducing the functional level of said molecule. For example, it may be necessary to render non-functional all available cytokine, adhesion molecule or complement component or only a portion thereof, depending on the required outcome. For example, it may be necessary to eliminate or merely reduce the severity of one or more symptoms which result from the availability of the functionally active cytokine, adhesion molecules or complement component.
  • cytokine or adhesion molecule or complement component may be desirable to systemically reduce functional levels of, for example, a cytokine or adhesion molecule or complement component or to functionally reduce a cytokine, adhesion molecule or complement component level in a localised region only, such as a region of inflammation (for example, an arthritic joint).
  • Cytokines form part of a complex network wherein the functional activity induced by any one cytokine may include the up or down-regulation of the synthesis of another cytokine.
  • IL-1 and TNF ⁇ are known to stimulate the production of GM-CSF.
  • a related aspect of the present invention should be understood to extend to indirectly reducing the functional level of a cytokine by administering an effective amount of another cytokine or cytokine receptor, the functional down-regulation of which leads to down-regulation of the production of the former cytokine.
  • the production of GM-CSF will also be decreased.
  • Reference to "inducing, up-regulating or otherwise eliciting an immune response directed to" an endogenously-produced molecule should be understood as a reference to eliciting a humoral and/or T helper cell response to said molecule.
  • the immune response comprises the stimulation of a Th2 humoral response to provide help to a B cell response which produces antibodies specifically directed to the molecule or ligand of interest.
  • the agent is administered in an amount effective to induce an immune response to the molecule or ligand which it comprises. (These molecules are herein collectively referred to as the "antigens").
  • an "effective amount” should be understood as a reference to an amount of agent necessary to at least partly achieve the desired outcome.
  • the desired outcome is effectively an autoimmune response since the immune response of the subject will comprise the production of antibodies specifically directed to one or more molecules or ligands produced by that individual.
  • the method of the present invention provides the opportunity of blocking the ligand at specific sites. This facilitates the minimisation of systemic adverse effects or toxicological events.
  • the method of the present invention is particularly useful since it permits the production of a short lived immune response as a result of a transient expansion and/or activation of B cells thereby providing the option of a short term autoimmune response directed to one or more of these molecules.
  • the condition being treated is transient (such as a transient inflammatory response due to an allergic reaction) and thereby the alleviation of symptoms associated with that condition is necessary only for a finite length of time.
  • the method of the present invention should also be understood to extend to the induction of long lived immune responses where it is desirable to reduce functional levels of a given cytokine or adhesion molecule on an ongoing basis.
  • the method of the present invention can be utilised to provide a sustained action over a period of inter alia up to months after initial dosing, thereby reducing the problem of compliance to daily dosing.
  • a chronic condition such as rheumatoid arthritis, Crohn's disease, Type I diabetes, multiple sclerosis, psoriasis or chronic inflammatory lung disease
  • a chronic condition such as rheumatoid arthritis, Crohn's disease, Type I diabetes, multiple sclerosis, psoriasis or chronic inflammatory lung disease
  • GM-CSF or other cytokine for indefinite time periods for the purpose of providing some relief from the symptoms of inflammation associated with this disease.
  • the method of the present invention may be directed to inducing an immune response to one particular antigen.
  • the method also extends to simultaneously eliciting an immune response to a combination of antigens such as, but not limited to, two or more different cytokines, two or more complement components, one or more cytokines and one or more cytokine receptors, one or more adhesion molecules and one or more adhesion molecule ligands.
  • the method of the present invention is useful in relation to disease conditions, one or more symptoms or causes of which are directly or indirectly due to the production of a particular molecule or a disease condition which otherwise involves unwanted production of molecules such as cytokines, adhesion molecules or complement components.
  • a disease condition which otherwise involves unwanted production of molecules such as cytokines, adhesion molecules or complement components.
  • TNF ⁇ and IL-1 in patients suffering from inflammatory conditions such as rheumatoid arthritis, Crohn's disease, Type I diabetes, multiple sclerosis, psoriasis and chronic inflammatory lung disease results in the induction of localised sites of inflammation. Chronic inflammation is also facilitated by the presence of GM-CSF and M-CSF.
  • elevated levels of TNF- ⁇ are involved in congestive cardiac failure and in Type 2 diabetes, where it is linked to the development of insulin resistance.
  • Osteoporosis and atherosclerosis are associated with increased M- CSF levels.
  • the unwanted cytokine production, adhesion molecule expression or complement activation may be due to the subject's immune response which is naturally induced as a result of the disease condition or the treatment schedule itself. Any unwanted effects, whether occurring naturally due to the immune response or due to therapeutic treatment, are referred to herein as "unwanted endogenously-produced molecule functional activity".
  • a method for the treatment or prophylaxis of a disease condition involving unwanted endogenously produced molecule functional activity in a subject comprising administering to said subject an effective amount of an agent, the agent comprising said molecule and/or molecule ligand or a derivative, homologue, analogue, chemical equivalent or mimetic thereof for a time and under conditions sufficient to induce, up-regulate or otherwise elicit an immune response directed to said molecule and/or molecule ligand wherein the functional level of said molecule is down-regulated.
  • said molecule is a cytokine, adhesion molecule or complement component.
  • said disease condition is a chronic inflammatory disease condition and even more particularly rheumatoid arthritis, Type I diabetes, multiple sclerosis, psoriasis or chronic inflammatory lung disease such as asthma, chronic bronchitis, emphysema or chronic obstructive airway disease.
  • said disease condition is a non-inflammatory disease condition and even more particularly congestive heart failure, osteoporosis, atherosclerosis or Type 2 diabetes. It should be understood that it may be desirable to apply the method of the present invention to prevent the onset of symptoms due to unwanted endogenous molecule production or activity. For example, where it is predicted that unwanted cytokine production or adhesion molecule expression is likely to occur, the method of the present invention may be utilised prophylactically to prevent the initiation of any symptoms.
  • the agent which is administered in accordance with the method of the present invention preferably comprises specific immunogenic peptide regions of the subject antigen to which it is desired to elicit a specific immune response.
  • the peptide region may be the region which interacts with the cytokine receptor.
  • the peptide region may be the region which interacts with the cytokine.
  • Any given agent may comprise two or more peptide regions from the same cytokine, cytokine receptor, adhesion molecule or adhesion molecule ligand. This would facilitate, for example, the induction of an immune response to more than one site on the subject antigen.
  • the agent may also comprise two or more peptide regions from different cytokines, cytokine receptors, adhesion molecules or adhesion molecule ligands.
  • the latter agents would facilitate the elicitation of immune responses directed to two or more cytokines, cytokine receptors, adhesion molecule or adhesion molecule ligands.
  • particularly preferred agents for use in the method of the present invention comprise at least one B cell epitope and at least one T cell epitope.
  • the T cell epitope is designed to stimulate a Th2 humoral response which provides "help" in relation to the antibody response which is generated to the one or more B cell epitopes which comprise the agent.
  • B cell epitope should be understood as a reference to any molecule to which an antibody may bind. It should be understood that although reference to “B cell epitope” is a reference to a molecule to which an antibody can bind, it is not intended to be limited to only that part of the molecule to which the antibody actually binds. Accordingly, the B cell epitope may be a larger molecule which comprises a discrete antibody binding region. In accordance with the present invention, the B cell epitope may also be a small peptide the entirety of which comprises the antibody binding site. Where the B cell epitope is a larger molecule, it may comprise, for example, all or part of one chain of a cytokine.
  • the epitopes which comprise the agents used in the present invention may be separate molecules or they may comprise discrete regions of a single larger molecule.
  • the epitope may be immunogenic in its own right or it may require coupling to a carrier molecule and/or administration together with an adjuvant and/or a co-adjuvant to stimulate a humoral immune response.
  • T cell epitope should be understood as a reference to a molecule which, following antigen presenting cell processing and MHC Class II expression will induce a T-helper cell response.
  • the T-helper cell response is a Th2 humoral response which supports the induction of a humoral immune response.
  • the B cell epitope must be selected from the antigen to which the humoral immune response is to be directed, this is not necessarily the case with the T cell epitope.
  • the T cell epitope may be any molecule which will stimulate a Th2 humoral immune response such as, but not limited to, viral proteins, Ovalbumin 323-339 [Kjerrulf M., 1997], F protein of measles 288-302 [Partidos C, 1992], T cell epitope (P30) tetanus toxoid [Astori M., 1996], Haemagglutinin (H) of measles virus peptide 39 [Obeid O., 1993], E-7 protein of human papiUpmavirus (AHYNIVTFCCK) [ ⁇ 400> 1] [Vandebriel R., 1995], immunodominant T cell epitope on cholera toxin [Cong Y., 1996] and peptides from influenza haemagglutinin.
  • viral proteins Ovalbumin 323-339
  • F protein of measles 288-302 [Partidos C, 1992]
  • the T cell epitope may comprise part of the subject antigen. It should be understood that the T cell epitope may be larger than the peptide which is ultimately processed and expression in the MHC Class II cleft. In fact, a single molecule may, upon processing, give rise to two or more different peptides which are expressed by the antigen presenting cells.
  • the B cell epitopes and T cell epitopes are selected such as to minimise the poly valency of the antigen. Without limiting the present invention to any one theory or mode of action, this will reduce the number of antibodies that bind to the antigen thereby maintaining the solubility of the antigen-antibody complex. This minimises the risk of developing an inflammatory immune response to insoluble complexes (i.e. the Arthus reaction). This is of use, ter alia, where the method of the present invention is utilised in the treatment of chronic diseases where prolonged treatment requiring repeated dosing of the antigen may be required.
  • the B cell epitope and the T cell epitope may be linked, bound or otherwise associated. This association may be direct whereby the B cell epitope is linked to the T cell epitope via any suitable mechanism such as covalent bonds, ionic interaction, electrostatic interaction or Van der Waals Forces. Alternatively, the B cell epitope and T cell epitope may be indirectly linked via an unrelated proteinaceous or non-proteinaceous molecule.
  • the B and T cell epitopes may be administered in isolation or together with an adjuvant or other immunomodulatory molecule.
  • Adjuvants suitable for use in the present invention are well known to the person skilled in the art. However, examples of suitable adjuvants include, but are not limited to, MS59 (Chiron), Montanide ISA 720 (SEPPIC, France), Quilimmune (Aquila Biopharmaceutical), aluminium salts, colloidal iron hyroxide, incomplete Freunds, Co- adjuvants are agents included to enhance the immune response and examples include GM-CSF, Quil A, LPS, muramyl dipeptide.
  • the present invention provides an immunogenic agent for use in inducing, up-regulating or otherwise eliciting an immune response to an endogenously-produced molecule or ligand thereof, said composition comprising at least one B cell epitope linked, bound or otherwise associated with at least one T cell epitope.
  • the present invention provides an immunogenic agent for use in inducing, up-regulating or otherwise eliciting an immune response to an endogenously- produced molecule or ligand thereof said composition comprising at least two B cell epitopes which epitopes are each linked, bound or otherwise associated with at least three T cell epitopes.
  • said molecule is a complement component, cytokine or adhesion molecule.
  • said cytokine is M-CSF, GM-CSF and/or TNF ⁇ and said adhesion molecule is Integrin ⁇ 4 ⁇ ,.
  • immunogenic agents according to these aspects of the present invention comprise the structure:
  • T cell epitope 1 T cell epitope 2 T cell epitope 3 (5-200ug) (5-200ug) (5-200ug)
  • T cell epitope 1 T cell epitope 2 T cell epitope 3 (5-200ug) (5-200ug) (5-200ug)
  • compositions for use in down-regulating the functional activity of an endogenously-produced molecule comprising an agent as hereinbefore defined together with any one or more pharmaceutically acceptable carriers and/or diluents. These components are referred to as the active ingredients.
  • the immunogenic agent in the form of a pharmaceutical composition, may be performed by any convenient means.
  • the immunogenic agent is contemplated to exhibit therapeutic activity when administered in an amount which depends on the particular case. The variation depends, for example, on the human or animal and the agent chosen.
  • a broad range of doses may be applicable. Considering a patient, for example, from about l.O ⁇ g to about lmg of agent may be administered per dosing, and more preferably l.O ⁇ g to about 50 ⁇ g per dosing. Dosage regimes may be adjusted to provide the optimum therapeutic response. For example, doses may be administered weekly, monthly or other suitable time intervals or the dose may be proportionally reduced as indicated by the exigencies of the situation.
  • the agent may be administered in a convenient manner such as by the oral, intravenous (where water soluble), intranasal, intraperitoneal, intramuscular, subcutaneous, intradermal or suppository routes or implanting (e.g. using slow release molecules).
  • these agents may be administered in the form of pharmaceutically acceptable nontoxic salts, such as acid addition salts or metal complexes, e.g. with zinc, iron or the like (which are considered as salts for purposes of this application).
  • acid addition salts are hydrochloride, hydrobromide, sulphate, phosphate, maleate, acetate, citrate, benzoate, succinate, malate, ascorbate, tartrate and the like.
  • the tablet may contain a binder such as tragacanth, corn starch or gelatin; a disintegrating agent, such as alginic acid; and a lubricant, such as magnesium stearate.
  • a binder such as tragacanth, corn starch or gelatin
  • a disintegrating agent such as alginic acid
  • a lubricant such as magnesium stearate.
  • Routes of administration include but are not limited to intravenously, intraperitioneal, subcutaneously, intracranial, intradermal, intramuscular, intraocular, intrathecal, intracerebrally, intranasally, infusion, orally, rectally, via iv drip, patch and implant. Intravenous routes are particularly preferred.
  • compositions suitable for injectable use include sterile aqueous solutions (where water soluble) and/or emulsions or liposome preparations or sterile powders for the extemporaneous preparation of sterile injectable solutions. They must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms such as bacteria and fungi.
  • the carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol and liquid polyethylene glycol, and the like), suitable mixtures thereof and vegetable oils.
  • the preventions of the action of microorganisms can be brought about by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thirmerosal and the like. In many cases, it will be preferable to include isotonic agents, for example, sugars or sodium chloride. Prolonged absorption of the injectable compositions can be brought about by the use in the compositions of agents delaying absorption, for example, aluminum monostearate and gelatin or encapsulation in a biocompatible polymer such as PLA polylactic and/or PLG poly gy colic acid.
  • Sterile injectable solutions are prepared by incorporating the active compounds in the required amount in the appropriate solvent with various of the other ingredients enumerated above, as required, followed by, for example, filter sterilization or sterilization by other appropriate means.
  • Dispersions are also contemplated and these may be prepared by incorporating the various sterilized active ingredients into a sterile vehicle which contains the basic dispersion medium and the required other ingredients from those enumerated above.
  • a preferred method of preparation includes vacuum drying and the freeze-drying technique which yield a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution.
  • the active ingredients When the active ingredients are suitably protected, they may be orally administered, for example, with an inert diluent or with an assimilable edible carrier, or it may be enclosed in hard or soft shell gelatin capsule, or it may be compressed into tablets.
  • the active compound may be incorporated with excipients and used in the form of ingestible tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, wafers, and the like.
  • the percentage of the compositions and preparations may, of course, be varied and may conveniently be between about 5 to about 80% of the weight of the unit.
  • the amount of active compound in such therapeutically useful compositions such that a suitable dosage will be obtained.
  • Preferred compositions or preparations according to the present invention are prepared so that an oral dosage unit form contains between about OJng and 2000 mg of active compound.
  • the tablets, troches, pills, capsules and the like may also contain the components as listed hereafter: A binder such as gum, acacia, corn starch or gelatin; excipients such as dicalcium phosphate; a disintegrating agent such as corn starch, potato starch, alginic acid and the like; a lubricant such as magnesium stearate; and a sweetening agent such a sucrose, lactose or saccharin may be added or a flavouring agent such as peppermint, oil of winter green, or cherry flavouring.
  • a binder such as gum, acacia, corn starch or gelatin
  • excipients such as dicalcium phosphate
  • a disintegrating agent such as corn starch, potato starch, alginic acid and the like
  • a lubricant such as magnesium stearate
  • a sweetening agent such as sucrose, lactose or saccharin
  • a flavouring agent such as peppermint, oil of winter green, or cherry
  • tablets, pills, or capsules may be coated with shellac, sugar or both.
  • a syrup or elixir may contain the active compound, sucrose as a sweetening agent, methyl and propylparabens as preservatives, a dye and flavouring such as cherry or orange flavour. Any material used in preparing any dosage unit form should be pharmaceutically pure and substantially non-toxic in the amounts employed.
  • the active compound(s) may be incorporated into sustained-release preparations and formulations.
  • the present invention also extends to forms suitable for topical application such as creams, lotions and gels.
  • Pharmaceutically acceptable carriers and/or diluents include any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents and the like.
  • the use of such media and agents for pharmaceutically active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active ingredient, use thereof in the therapeutic compositions is contemplated. Supplementary active ingredients can also be incorporated into the compositions.
  • Dosage unit form refers to physically discrete units suited as unitary dosages for the mammalian subjects to be treated; each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier.
  • the specification for the novel dosage unit forms of the invention are dictated by and directly dependent on (a) the unique characteristics of the active material and the particular therapeutic effect to be achieved and (b) the limitations inherent in the art of compounding such an active material.
  • Effective amounts of the composition contemplated by the present invention will vary depending on the severity of the pain and the health and age of the recipient. In general terms, effective amounts may vary from 0.01 ng/kg body weight to about 1 mg/kg body weight and preferably 0.01 ng/kg body weight to about l ⁇ g/kg body weight. Alternative amounts include for about 0J ng/kg body weight about 10 ⁇ g/kg body weight or from 1.0 ng/kg body weight to about 80 ⁇ g/kg body weight.
  • the pharmaceutical composition may also comprise genetic molecules such as a vector capable of transfecting target cells where the vector carries a nucleic acid molecule or derivative or analogue thereof capable of expressing an endogenously produced molecule or derivative, homologue, analogue or mimetic thereof.
  • the vector may, for example, be a viral vector.
  • the agent may also be linked to a targeting means such as monoclonal antibody, which provides specific delivery of the agent to a target region.
  • a targeting means such as monoclonal antibody, which provides specific delivery of the agent to a target region.
  • the immunogenic agent may be coadmimstered with one or more other compounds or molecules.
  • the agent may be coadmimstered with an unrelated cytokine, such as cytokine which up-regulates a humoral and/or Th2 humoral immune response.
  • the agent may be coadministered with another molecule designed to reduce or alleviate any one or more symptoms of the inflammatory response.
  • coadministered is meant simultaneous administration in the same formulation or in two different formulations via the same or different routes or sequential administration by the same or different routes.
  • sequential administration is meant a time difference of from seconds, minutes, hours or days between the administration of the two types of molecules. These molecules may be administered in any order.
  • Yet another aspect of the present invention is directed to an immunogenic agent as hereinbefore defined when used in accordance with the method of the present invention.
  • Still another aspect of the present invention provides an agent useful for down-regulating the functional level of an endogenously-produced molecule in a subject as hereinbefore defined.
  • Still yet another aspect of the present invention provides an immunogenic agent in the manufacture of a medicament for the treatment of a disease condition characterised by unwanted endogenously produced molecule levels.
  • said disease condition is chronic inflammatory disease and even more particularly rheumatoid arthritis, Crohn's disease, Type I diabetes, multiple sclerosis, psoriasis or chronic inflammatory lung disease (asthma, chronic bronchitis, emphysema or chronic obstructive airway disease).
  • the present invention should also be understood to extend to down-regulating or otherwise reducing the functional level of an endogenously-produced molecule in a subject via ex vivo immunisation.
  • Ex vivo immunisation is achieved by the in vitro exposure of autologous dendritic cells and autologous B cells to the B cell epitope and the T cell epitope. Said dendritic cells and B cells undergo in vitro colony expansion utilising colony expansion factors and cytokines.
  • the primed colony expanded dendritic cells and B cells are introduced into the subject for a time and under conditions sufficient to induce, up-regulate or otherwise elicit an immune response to said molecule or ligand thereof.
  • Antigen, X cytokine and/or same cytokine receptor and/or peptide fragment of cytokine and/or same cytokine receptor
  • Antigen will be at least two or more peptide sequences one or more from the cytokine and one or more from the cytokine receptor.
  • T cell epitopes will be at least three per peptide with 3-6 per B cell peptide Adjuvant Water in oil emulsion Montanide ISA 720 (SEPPIC, France) (3 parts saline plus 7 parts adjuvwnt)
  • T cell epitope 1 T cell epitope 2 T cell epitope 3 (5-200ug) (5-200ug) (5-200ug)
  • EXAMPLE 2 VACCINE FORMULATION
  • Antigen is two or more peptide sequences, one or more from the cytokine and one or more from the receptor.
  • T cell epitopes will be at least three per peptide.
  • Components in each formulation are covalently linked.
  • T cell epitope 1 T cell epitope 2 T cell epitope 3 (5-200ug) (5-200ug) (5-200ug) fatty acid C n> 9 fatty acid C n> 9 fatty acid C n> 9 fatty acid C n> 9
  • B cell epitope X cytokine and/or receptor and/or peptide fragment of cytokine and/or receptor
  • the antigen is a peptide from the N terminus alpha-helix region of GM-CSF. This region includes residues 14-25 but extends to encompass those residues that can contribute to an antigen that can produce an antibody that blocks the biological activity of GM-CSF.
  • the peptide sequence will be at least six residues and may be linear or cyclised to produce a spatial conformation such as an alpha helix.
  • the second element is a peptide from the GM-CSF receptor including residues around residue 367 of the alpha unit.
  • the antigen is a peptide that includes the residues 106-127 within the fourth helix near the carboxy terminal tail. This region includes residues 106-127 but extends to encompass those residues that can contribute to an antigen that can produce an antibody that blocks the biological activity of GM-CSF.
  • the peptide sequence is at least six residues and may be linear or cyclised to produce a spatial conformation such as an alpha helix.
  • the second element is a peptide from the GM-CSF receptor including residues around residue 280 of the alpha unit.
  • This antigen is a peptide that includes residues 78-94 in the middle of the third alpha helix.
  • the antigen is a peptide from the N terminus alpha-helix region of M-CSF. This region includes residues 9, 15 and 19 but extends to encompass those residues that can contribute to an antigen that can produce an antibody that blocks the biological activity of M-CSF.
  • the peptide sequence is at least six residues and may be linear or cyclised to produce a spatial conformation such as an alpha helix.
  • the second element is a peptide from the M-CSF receptor including residues within the three N-terminal immunoglobulin-like domains.
  • the antigen is a peptide from the N terminus alpha-helix region of TNF. This region includes residues 32-42, 81-88 and 133-137 but extends to encompass those residues that can contribute to an antigen that can produce an antibody that blocks the biological activity of TNF.
  • the peptide sequence is at least six residues and may be linear or cyclised to produce a spatial conformation such as an alpha helix.
  • the second element is a peptide from the TNF receptor including residues 116-
  • the antigen is a peptide from the beta-mrn structure of the third N-terminal repeat in alpha-4 of integrin alpha4-betal.
  • This region includes residues 181-190 (GAPGSSYWTG [ ⁇ 400> 2]) but extends to encompass those residues that can contribute to an antigen that can produce an antibody that blocks the biological activity of integrin alpha4-betal .
  • the peptide sequence is at least six residues and may be linear or cyclised to produce a spatial conformation such as an alpha helix.
  • the second element is a peptide from the VCAM receptor including residues 36- 43 but extending to encompass those residues that can contribute to an antigen that can produce an antibody that blocks the biological activity of integrin alpha4- betal.

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Abstract

Cette invention se rapporte, d'une façon générale, à un procédé pour réguler à des niveaux inférieurs ou pour réduire de quelque autre façon les niveaux fonctionnels d'une molécule produite à l'état endogène, chez un sujet, et à des agents utilisables dans ce procédé. Cette invention se rapporte plus particulièrement à un procédé pour réduire les niveaux fonctionnels d'un ou de plusieurs composants compléments, d'une cytokine ou d'une molécule d'adhésion chez un sujet, et à des agents utilisables dans ce procédé. Cette invention se rapporte encore plus particulièrement à un procédé pour réguler à des niveaux inférieurs ou pour réduire de quelque autre façon les niveaux fonctionnels d'une cytokine, en administrant à ce sujet une composition immunogène de cytokine et/ou de récepteur de cytokine, ou d'un dérivé, homologue, analogue, équivalent chimique de celui-ci. Ce procédé est notamment utile dans une large gamme d'applications thérapeutiques et prophylactiques.
PCT/AU2000/000424 1999-05-07 2000-05-08 Procede de prophylaxie et de traitement et agents utilisables dans ce procede WO2000067777A1 (fr)

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WO2005046657A2 (fr) * 2003-11-05 2005-05-26 Celltech R & D Limited Methode de traitement de la maladie intestinale inflammatoire
WO2005046657A3 (fr) * 2003-11-05 2005-11-03 Celltech R&D Ltd Methode de traitement de la maladie intestinale inflammatoire
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