EP1765377A2 - Medicament - Google Patents

Medicament

Info

Publication number
EP1765377A2
EP1765377A2 EP05758978A EP05758978A EP1765377A2 EP 1765377 A2 EP1765377 A2 EP 1765377A2 EP 05758978 A EP05758978 A EP 05758978A EP 05758978 A EP05758978 A EP 05758978A EP 1765377 A2 EP1765377 A2 EP 1765377A2
Authority
EP
European Patent Office
Prior art keywords
disease
crf
pomc
serum
neuropathy
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP05758978A
Other languages
German (de)
English (en)
Inventor
Deirdre Aimsco Limited MCINTOSH
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Aimsco Ltd
Original Assignee
Aimsco Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from GBGB0415359.9A external-priority patent/GB0415359D0/en
Application filed by Aimsco Ltd filed Critical Aimsco Ltd
Publication of EP1765377A2 publication Critical patent/EP1765377A2/fr
Withdrawn legal-status Critical Current

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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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    • 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
    • A61K38/33—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans derived from pro-opiomelanocortin, pro-enkephalin or pro-dynorphin
    • A61K38/34—Melanocyte stimulating hormone [MSH], e.g. alpha- or beta-melanotropin
    • A—HUMAN NECESSITIES
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    • 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
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    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/08—Peptides having 5 to 11 amino acids
    • A61K38/095—Oxytocins; Vasopressins; Related peptides
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    • A61K38/33—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans derived from pro-opiomelanocortin, pro-enkephalin or pro-dynorphin
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    • A—HUMAN NECESSITIES
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    • 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
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    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
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    • A—HUMAN NECESSITIES
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    • A—HUMAN NECESSITIES
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    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/575—Hormones
    • C07K14/57509—Corticotropin releasing factor [CRF] (Urotensin)
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/665—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans derived from pro-opiomelanocortin, pro-enkephalin or pro-dynorphin
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • the present invention relates to a medicament, and in particular to a pharmaceutical composition.
  • the medicament is considered particularly suited to treatment of neural disorders, although a number of other disorders may be treatable with the invention.
  • aspects of the invention also relate to methods of preparation of such a medicament, and to methods of treatment of disorders using said medicament.
  • Approximately 400 cc of blood is taken from a goat under sterile technique.
  • the animal may typically be re-bled in 10 to 14 days, once the volume of blood is replenished.
  • a pre-bleeding regime may be useful to stimulate production of the active components of the serum.
  • the blood is then centrifuged to separate the serum, and the serum filtered to remove large clots and particulate matter.
  • the serum is then treated with supersaturated ammonium sulphate (47% solution at 4 0 C) to precipitate antibodies and other material.
  • the resulting solution is centrifuged in a Beckman J6M/E centrifuge at 3500 rpm for 45 minutes, after which the supernatant fluid is removed.
  • the precipitated immunoglobulin and other solid material are resuspended in PBS buffer (phosphate buffered saline) sufficient to redissolve the precipitate.
  • the solution is then subjected to diafiltration against a PBS buffer with a molecular weight cut-off of 10,000 Daltons. at 4°C After diafiltration the product is filtered through a 0.2 micron filter into a sterile container and adjusted to a protein concentration of 4rng/ml. The solution is put into vials to give single doses of ImI, and stored at -22°C prior to use.
  • This product is referred to herein as the serum composition, the composition, or the product, while treatment of a patient involves administering the composition to the patient by an appropriate route (usually subcutaneously).
  • HIV-3B viral Iysate as an immunogen is not believed to be essential for the production of active serum; it is believed that a medium which has been used for growth of a viral culture, or which is suitable for such growth, may also produce a suitable response when used as an immunogen.
  • the supernate of a cell culture growth medium such as PBMC or the cancer immortal cell line as used to grow HIV-3B are given as an example.
  • the HIV or other virus does not need to be present to produce an effective immunogen to create the composition.
  • Other suitable immunogens are recited on pages 12 and 13 of WO03/064472.
  • a pyrogenic material for example, RIBI or Freund's adjuvant
  • RIBI RIBI
  • Freund's adjuvant Another possible factor may be exposure of the animal to daylight, with greater daylight hours (or exposure to daylight equivalent) may increase active component serum levels.
  • the composition is believed to be effective against a number of disorders, in particular multiple sclerosis. Reference is also made in the previously-identified publications to the composition as being useful in the treatment of inflammatory diseases such as rheumatoid arthritis; optic neuritis; motor neurone disease; autoimmune diseases; axonal or nerve damage; and cancers.
  • the composition is also believed to cause a reduction in vira! load in HIV patients, and an increase in CD4+ cells.
  • a non-exhaustive list of disorders against which the serum composition is believed to be effective includes cancers, in particular myelomas, melanomas, and lymphomas; cardiovascular diseases; and neural disorders, both demyelinating and non-demyelinating.
  • non-demyelinating disorders which may be treated, and which are considered to have a degenerative component include multiple system atrophy; epilepsy; muscular dystrophy; schizophrenia; bipolar disorder; and depression.
  • Other non-demyelinating disorders which may be treated include channelopathies; myaesthenia gravis; pain due to malignant neoplasia; chronic fatigue syndrome; fibromyositis; irritable bowel syndrome; work related upper limb disorder; cluster headache; migraine; and chronic daily headache.
  • Demyelinating disorders which may be treatable include infections of the nervous system; nerve entrapment and focal injury; traumatic spinal cord injury; brachial plexopathy (idiopathic and traumatic, brachial neuritis, parsonage turner syndrome, neuralgic amyotrophy); radiculopathy; channelopathies; and tic douloureux,
  • composition may be useful in the treatment of autoimmune diseases including lupus, psoriasis, eczema, thyroiditis, and polymyositis.
  • composition is also believed to be effective against inflammatory conditions.
  • the composition is useful in the treatment of all kinds of peripheral neuropathy of axonal and demyelinating type, including hereditary motor and sensor neuropathy of all types; Charcot-Marie-Tooth disease (CMT) types CMTlA, CMTlB, CMT2, CMT3 (Dejerine Sottas disease), CMT4 (Types A, B C and D), X- linked Charcot-Marie-Tooth disease (CMTX); Hereditary Neuropathy with liability to pressure palsies (HNPP) - also called Tomaculous neuropathy; Hereditary Motor and Sensory Neuropathy with Deafness - Lorn (HMSNL); Proximal Hereditary Motor and Sensory Neuropathy / Neuronopathy (HMSNP); Hereditary Neuralgic Amyotrophy; Hereditary Sensory and Autonomic Neuropathies (HSANl, HSAN2, HSAN3 (also called Riley-Day syndrome or familial dysautonomia), HSAN4, HSAN5); Familial Amyloid polyneuropathies (Type I, Type
  • cerebellar ataxia all types - SCAl, SCA2, SCA3, SCA4, SCA5, SCA6, SCA7, SCA8, SCAlO, SCAIl, SCA12, SCA13, SCA14, SCA16; Spinocerebellar Ataxia; Cockayne's syndrome; and Giant axonal neuropathy.
  • composition may also be useful in the treatment of chronic inflammatory demyelinating polyneuropathy (CIDP), and Guillain-Barre syndrome,
  • CIDP chronic inflammatory demyelinating polyneuropathy
  • Guillain-Barre syndrome CIDP
  • composition may also have anti-angiogenic properties, caused by the molecules thrombospondin-1 (TSP-I) and platelet factor-4 (PF-4).
  • TSP-I thrombospondin-1
  • PF-4 platelet factor-4
  • composition may also be effective for treatment of animals, in particular, but not exclusively, the treatment of canine atopic dermatitis, canine oral melanoma, and equine pulmonary disorders.
  • the serum composition has exhibited many surprising effects, and has been studied extensively, until now the active component or components of the serum have not yet been identified. This has been disadvantageous, both in terms of isolating the active component for further study, and in terms of exploring possible alternative sources of the active component or components. Further, it has been necessary to administer the treatment to patients as serum, which necessitates injections, and imposes certain restrictions on the handling and processing of the composition. It is believed that the serum has bioactive components sensitive to protease degradation.
  • the invention resides in a bioactive composition which triggers a molecular cascade in treated patients.
  • a pharmaceutical composition comprising a corticotropin releasing factor (CRF) peptide.
  • CRF corticotropin releasing factor
  • CRF is also known as corticotropin releasing hormone (CRH).
  • CRF is a peptide produced in the hypothalamus, and is believed to be involved in stress response.
  • Human CRF is described in detail in entry 122560 of OMIM (online mendelian inheritance in man, accessible through http://www.ncbi.nlm.nih.goV/i
  • the nucleotide and amino acid sequence of human CRF is also known, and has GENBANK accession number BC011031. Knowledge of the sequence and size data for human CRF will allow the skilled person to determine the equivalent information for non-human CRF, including goat CRF.
  • a CRF peptide is meant any peptide having a corresponding sequence, structure, or function. It will be apparent to the skilled person that the canonical nucleotide and/or amino acid sequences given for human CRF in the GENBANK entry referenced above may be varied to a certain degree without affecting the structure or function of the peptide. In particular, allelic variants and functional mutants are included within this definition. Mutants may include conservative amino acid substitutions; and fragments and derivatives of CRF.
  • CRF proopiomelanocortin
  • POMC is a peptide (prohormone) produced in the pituitary gland (as well as a number of other organs, certain tumours such as melanomas, and normal skin cells) which is the precursor of a set of corticotrophic hormones which exert a number of effects on the host.
  • POMC is the precursor to alpha, beta, and gamma melanocyte stimulating hormone (MSH); adrenocorticotrophin (ACTH); beta and gamma lipotropin (LPH); and beta endorphin. All of these hormones are cleaved from a single large precursor, POMC, and are termed herein "POMC products".
  • the pharmaceutical composition comprises non-human CRF; conveniently ungulate CRF; and most preferably goat CRF.
  • goat serum contains CRF, particularly when the goat is stimulated by physiological stress, such as bleeding or immunization.
  • CRF may have a self-sustaining effect in the patient, in that administration of an initial amount of CRF leads to endogenous production of CRF in the patient; thus, an initial administration of a low level of CRF may have a significant effect on the patient, including an increase in the levels of POMC peptides.
  • Administration of pharmaceutical compositions of the invention may be accomplished orally or parenterally.
  • compositions include topical, intra-arterial, intramuscular, subcutaneous, intramedullary, intrathecal, intraventricular, intravenous, intraperitoneal, or intranasal administration.
  • compositions may comprise suitable pharmaceutically acceptable carriers comprising excipients and other components which facilitate processing of the active compounds into preparations suitable for pharmaceutical administration.
  • compositions for oral administration can be formulated using pharmaceutically acceptable carriers known in the art in dosages suitable for oral administration.
  • Such carriers enable the compositions to be formulated as tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, suspensions, and the like suitable for ingestion by the subject,
  • compositions for oral use can be obtained through combination of active compounds with a solid excipient, optionally grinding a resulting mixture, and processing the mixture of granules, after adding suitable additional compounds if desired to obtain tablets or dragee cores.
  • Suitable excipients include carbohydrate or protein fillers such as sugars, including lactose, sucrose, mannitol, sorbitol; starch from corn, wheat, rice, potato, or other plants; cellulose such as methylceilulose, hydroxypropylmethylcellulose, or sodium carboxymethylcellulose; and gums including arable and tragacanth; as well as proteins such as gelatin and collagen.
  • disintegrating or solubilising agents may be added, such as cross linked polyvinyl pyrrolidone, agar, alginic acid, or a salt thereof.
  • Dragee cores can be provided with suitable coatings such as concentrated sugar solutions, which may also contain gum arable, talc, polyvinyl pyrrolidone, carbopol gel, polyethylene glycol, titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures. Dyestuffs or pigments may be added to the tablets or dragee coatings for product identification or to characterise the quantity of active compound.
  • suitable coatings such as concentrated sugar solutions, which may also contain gum arable, talc, polyvinyl pyrrolidone, carbopol gel, polyethylene glycol, titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures.
  • Dyestuffs or pigments may be added to the tablets or dragee coatings for product identification or to characterise the quantity of active compound.
  • compositions which can be used orally include push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a coating such as glycerol or sorbitol.
  • Push-fit capsules can contain active ingredients mixed with a filler or binders such as lactose or starches, lubricants such as talc or magnesium stearate, and, optionally stabilisers.
  • the active compounds can be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycol with or without stabilisers.
  • compositions for parenteral administration include aqueous solutions of active compounds.
  • the pharmaceutical compositions of the invention may be formulated in aqueous solutions, preferably in physiologically compatible buffers such as Hanks's solution, Ringer's solution, or physiologically buffered saline.
  • Aqueous suspension injections can contain substances which increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran.
  • suspensions of the active compounds can be prepared as appropriate oily injection suspensions.
  • Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes.
  • the suspension can also contain suitable stabilisers or agents which increase the solubility of the compounds to allow for the preparation of highly concentrated solutions.
  • penetrants appropriate to the particular barrier to be permeated may be used in the formulation.
  • compositions of the present invention can be manufactured substantially in accordance with standard manufacturing procedures known in the art.
  • the composition may also comprise one or more peptide regulatory or releasing factors, which may induce a cascade of release of further peptides by a variety of cells in the patient.
  • additional factors are preferably derived from the same source as the CRF, in particular goat serum. Suitable factors include ⁇ - HLA, TGF- ⁇ , and IL-IO, among others.
  • the composition may comprise one or more of vasopressin, beta endorphin, and an enkephalin.
  • the composition may comprise CRF binding protein, CRF-BP. This binds CRF and may act as a reservoir for subsequent release of CRF to the patient.
  • composition may further comprise a POMC peptide or a POMC product; certain POMC products may be useful to administer to a patient to stimulate further production, or to obtain a desired response before endogenous POMC can be produced.
  • Human POMC is described in detail in entry 176830 of OMIM (online mendelian inheritance in man, accessible through http://www.ncbi. nlm.nih.qovA).
  • the nucleotide and amino acid sequence of human POMC is also known, and has GENBANK accession number BC065832.
  • Human POMC gives rise to a glycosylated protein precursor having a molecular weight of 31 kDa.
  • a POMC peptide is meant any peptide having a corresponding sequence, structure, or function. It will be apparent to the skilled person that the canonical nucleotide and/or amino acid sequences given for human POMC in the GENBANK entry referenced above may be varied to a certain degree without affecting the structure or function of the peptide. In particular, allelic variants and functional mutants are included within this definition. Mutants may include conservative amino acid substitutions.
  • a POMC peptide refers to any peptide acting as a precursor to at least one form of MSH, ACTH, at least one form of LPH, p endorphin, met-enkephalin and leu-enkephalin; and preferably ail of ⁇ , ⁇ , and ⁇ MSH; ACTH; ⁇ and ⁇ LPH; and ⁇ endorphin, met- enkephalin and leu-enkephalin
  • the pharmaceutical composition comprises non-human POMC; conveniently ungulate POMC; and most preferably goat POMC.
  • POMC is produced in the pituitary gland, and so would not be expected to be present in serum, at least at significant levels, it has been surprisingly identified that goat serum contains POMC, POMC-related peptides, and molecules associated with the POMC cascade, particularly when the goat is stimulated by physiological stress, such as bleeding or immunization. This provides a convenient source for POMC for pharmaceutical compositions of the present invention.
  • POMC may have a self-sustaining effect in the patient, in that administration of an initial amount of POMC leads to endogenous production of POMC in the patient; thus, an initial administration of a low level of POMC may have a significant effect on the patient.
  • the peptide is proteolysed to provide one or more of the products of
  • POMC in a readily available form to the subject; there is also the induction of a molecular cascade which stimulates the hypothalamo-pituitary-adrenal axis
  • HPA hypertension activator protein
  • alpha MSH is known to have an effect on IL-IO and TGF- ⁇ production, which results in an antiinflammatory effect, consistent with that which has been observed with goat serum.
  • Alpha MSH is also known to inhibit the release of pro-inflammatory cytokines.
  • the composition may also have anti-inflammatory properties. We believe there is a passive transfer of anti-inflammatory response from the goat or other anima! used to produce the serum to the patient. This is a consequence of the purification process used to prepare the composition, in which a variety of active factors are retained in the serum.
  • the composition may also comprise additional active components which provide an anti-inflammatory effect.
  • a further aspect of the present invention therefore provides a method of stimulating POMC production in a patient, comprising administering exogenous POMC to the patient.
  • the exogenous POMC is preferably non-human, and more preferably goat POMC.
  • administration is subcutaneous; this gives a subcutaneous depot of active composition for subsequent slow release into the patient's system.
  • a further aspect of the present invention provides a pharmaceutical composition comprising a POMC peptide.
  • a pharmaceutical composition comprising two or more of alpha, beta, and gamma melanocyte stimulating hormone (MSH); adrenocorticotrophin (ACTH); beta and gamma lipotropin (LPH); and beta endorphin.
  • MSH melanocyte stimulating hormone
  • ACTH adrenocorticotrophin
  • LPH beta and gamma lipotropin
  • beta endorphin beta endorphin.
  • the pharmaceutical composition may provide the recited hormones as individual peptides, or as one or more precursor molecules (for example, partial breakdown products of POMC).
  • Preferably three, four, five, six, or seven of the hormones are included in the pharmaceutical composition which (optionally together with CRF) induce a cascade for continued production of such molecules.
  • the various components may be provided in combination with one or more carrier molecules which bind one or more of the components, and so act as a depot or reservoir for release of the component
  • a carrier molecule may also be used in combination with POMC and its related peptide
  • a method of treatment for a disease selected from multiple sclerosis; rheumatoid arthritis; optic neuritis; motor neurone disease; autoimmune diseases including lupus, psoriasis, eczema, thyroiditis, and polymyositis; axonal or nerve damage; cancers, in particular myelomas, melanomas, and lymphomas; neural disorders, both demyelinating and non-demyelinating; inflammatory conditions; obesity; nerve conduction disorders; and sexual dysfunction, in particular erectile dysfunction; the method comprising administering CRF to a patient in need thereof.
  • the method may comprise administering POMC.
  • the optimal dosage of the treatment has not yet been determined; however it may be appropriate to administer the treatment in a dosage of between 0.01 and 10 mg/kg to the subject; more preferably between 0.01 and 5 mg/kg, between 0.025 and 2 mg/kg, and most preferably between 0.05 and 1 mg/kg.
  • a serum product has been administered to patients with a total protein concentration of 4 mg/ml.
  • the precise dosage to be administered may be varied depending on such factors as the age, sex and weight of the patient, the method and formulation of administration, as well as the nature and severity of the disorder to be treated. Other factors such as diet, time of administration, condition of the patient, drug combinations, and reaction sensitivity may be taken into account.
  • An effective treatment regimen may be determined by the clinician responsible for the treatment.
  • One or more administrations may be given, and typically the benefits are observed after a series of at least three, five, or more administrations. Repeated administration may be desirable to maintain the beneficial effects of the composition.
  • the treatment may be administered by any effective route, preferably by subcutaneous injection, although alternative routes which may be used include intramuscular or intralesiona! injection, oral, aerosol, parenteral, or topical.
  • the treatment is preferably administered as a liquid formulation, although other formulations may be used.
  • the treatment may be mixed with suitable pharmaceutically acceptable carriers, and may be formulated as solids (tablets, pills, capsules, granules, etc) in a suitable composition for oral, topical or parenteral administration.
  • the invention also provides the use of CRF in the preparation of a medicament for the treatment of one or more of the diseases recited above.
  • CRF or the POMC may be isolated, purified CRF or POMC, although it is preferred that they are administered in combination with the various other components as discussed above.
  • bioactive carrier proteins and vasopressin may be used.
  • a method of producing CRF comprising the steps of obtaining a blood sample from a goat; separating the serum from the remaining blood components; and purifying the serum by precipitation of solids.
  • the precipitate may further be resuspended in a physiologically acceptable buffer; for example, PBS buffer.
  • a physiologically acceptable buffer for example, PBS buffer.
  • the resuspended precipitate may further be purified by dialysis or diafiltration; for example, with a molecular weight cut-off of 50,000 Da, preferably 40,000 Da, and more preferably 31,000 Da.
  • the precipitate may undergo further purification to isolate CRF; for example, antibody or other affinity purification.
  • CRF may be bound by antibodies raised against CRF, or by use of CRF-BP.
  • Separation of the serum may be achieved by centrifugation.
  • the serum may further be purified by viral filtration; it is preferred that any purification method used does not inactivate or remove any of the bioactive components of the serum, which may include components other than CRF / POMC.
  • Precipitation may be carried out by ammonium sulphate precipitation, or by caprylic acid purification. Other suitable precipitating agents may be used.
  • the goat is an immunized goat. It is believed that immunization of the goat stimulates the production of CRF and vasopressin, such that it is present in the serum in higher levels.
  • the method may also comprise the step of immunizing a goat.
  • the goat may be subject to physiological stress, for example, bleeding.
  • an immunogen may not be necessary, and that useful product may be obtained from a non- immunised animal (that is, one which has not been pre-immunised with a specific immunogen). It is accepted that a normal goat may well have been previously exposed to environmental immunogens, and such goats may be used in preparation of the compositions of the present invention.
  • the present invention is therefore intended also to encompass pharmaceutical compositions comprising serum obtained from a non-immunised goat.
  • the invention also extends to uses of such compositions or such serum in the treatment of, or in the preparation of medicaments for the treatment of, the various diseases or disorders recited above in the section headed "uses of the serum composition".
  • the invention still further extends to the preparation of POMC and/or CRF from serum obtained from a non-immunised goat
  • Figures 1 to 4 show mass spectrometry analyses of tryptic digests of serum components
  • Figures 5 to 7 show mass spectrometry analyses of patient sera before and after treatment with the composition
  • Figures 8 and 9 show analyses of induction of POMC peptides by treatment with the composition
  • Figures 10 to 14 show evidence for a switch in inflammatory profile of patients following treatment with the composition
  • Figure 15 shows levels of vasopressin in human serum and the composition
  • Figure 16 shows levels of CRF in human serum and the composition
  • Figure 17 shows a summary diagram of the proposed elements of the composition and their method of action.
  • Approximately 400 cc of blood is taken from a goat under sterile technique.
  • the animal may typically be re-bled in 10 to 14 days, once the volume of blood is replenished.
  • a pre-bleeding regime may be useful to stimulate production of the active components of the serum.
  • the blood is then centrifuged to separate the serum, and the serum filtered to remove large clots and particulate matter.
  • the serum is then treated with supersaturated ammonium sulphate (47% solution at 4°C) to precipitate antibodies and other material.
  • the resulting solution is centrifuged in a Beckman J6M/E centrifuge at 3500 rpm for 45 minutes, after which the supernatant fluid is removed.
  • the precipitated immunoglobulin and other solid material are resuspended in PBS buffer (phosphate buffered saline) sufficient to redissolve the precipitate.
  • the solution is then subjected to diafiltration against a PBS buffer with a molecular weight cut-off of 10,000 Daltons. at 4°C. After diafiltration the product is filtered through a 0.2 micron filter into a sterile container and adjusted to a protein concentration of 4mg/ml. The solution is put into vials to give single doses of ImI, and stored at -22°C prior to use.
  • a sample of the composition was size fractionated on a gel, and a Western blot performed using antibodies to ⁇ endorphin. A strong signal was detected, indicating the presence of ⁇ endorphin, although the apparent molecular weight was approximately 31 kDa, far larger than the expected size of ⁇ endorphin. This suggested that ⁇ endorphin was present in the sample as part of a larger peptide; the size being consistent with that of POMC.
  • POMC peptides and CRF-BP have been identified in the product by Thermofinnegan LCQ mass spectrometry.
  • CRF mainiy regulates the synthesis and secretion of ACTH in the anterior pituitary.
  • the administration of POMC and/or its component peptides in addition to CRF and CRF-BP is thought to initiate a cascade effect thus enhancing the production of systemic and sustained elevated concentrations of POMC peptides.
  • CRF-BP has the ability to act as a reservoir for CRF.
  • Figures 1 to 4 show the hits obtained from mass spectrometry analysis of tryptic digests from the product separated from contaminating proteins by SDS- PAGE. As mentioned above, some of these molecules are inducers and regulators of the POMC cascade. Further investigation using more focused analysis (e.g. peptide fractionation, immunopre ⁇ pitation and concentration) will reveal more of the peptides present.
  • Figure 1 indicates the presence of a POMC-derived corticotropin
  • Figure 2 that of CRF-BP
  • Figure 3 that of proenkephalin A
  • Figure 4 that of proenkephalin B
  • the presence of CRF-BP suggests that the product contains some CRF, while POMC and related peptides are also clearly present.
  • Figure 5 shows mass spectrometry of patients' sera before and after treatment. The spectra from 2 to 10 kD are compared. This molecular weight range is associated with the bioactive peptides of interest. Clear differences in the peptide expression in the 2 to 6 kD region can be seen by comparing the profiles in the pre and post treatment sera. For ease of comparison an overlapping view of the profiles is also provided.
  • Figure 6 shows comparative peptide / protein expression in six treated patients. Each patient shows increased levels of induced peptide / protein expression particularly in the 4 kD region.
  • Figure 7a shows the mass spectrometry profiles of unprocessed goat serum before vaccination (pre-immune profile, top panel), unprocessed serum 53 days post-immunisation, and the processed product. It can be seen that in the lower two panels the profile of the serum is significantly different to that of the pre- immune profile, indicative of the induction of protein expression.
  • the profiles present here represent the active product, and a specific immunisation / bleed protocol has been shown to be useful in the induction of this serum profile. An overlapping view of the profiles is shown ( Figure 7b).
  • Figure 9 compares levels of p endorphin in the serum of treated patients with that in the sera of the same patients before treatment. This is compared with levels in the sera of healthy volunteers and in the product. Sera were diluted 1:100 and quantified by an ELISA of sera compared with the product. Data are the mean of three determinations +/- standard errors. The data show that treatment increases p endorphin levels. Evidence for a switch from a proinflammatory TH-I profile to an anti ⁇ inflammatory TH-2 cytokine profile in treated patients Figure 10 shows the levels of TGF-p in the serum of two groups of patients before and after treatment.
  • the data show that treatment induces increased concentration of the anti-inflammatory cytokine TGF- ⁇ .
  • Figure 13 shows the levels of IFN- ⁇ in the serum of one group of patients before and after treatment. It can be seen that after treatment (post 2 nd and post 5 th ) the levels of IFN- ⁇ are reduced in the patients' sera.
  • FIG 14 shows that treatment of human peripheral blood cells (PBMCs) induces the production of the anti-inflammatory cytokine IL-IO in the monocyte sub population. T and B lymphocytes and monocytes were separated from PBMCs.
  • PBMCs obtained from human volunteers. All cell types were treated with equivalent doses of product for 16h, and their supematants assayed for IL-IO content using ELISA. It can be seen that IL-IO levels produced by the T cell population were unaffected by treatment and that only a small increase in IL-IO was induced in the B cells, However, a significant elevation of IL-IO concentration was induced in the monocytes population by the treatment. All determinations were made in triplicate +/- standard deviations. These data are representative of at least three separate experiments.
  • composition effects are consistent with the active component being CRF which leads to POMC production.
  • effects on leukocyte adherence may be attributable to beta endorphin.
  • the serum product increases IL-IO production by human PBMC; alpha MSH affects IL-IO production.
  • Effects on nerve conduction and neuroprotective effects may be ascribed to ACTH and vasopressin; effects on appetite may be due to alpha MSH.
  • the product itself also contains significant levels of IL-IO and TGF- ⁇ (data not shown).
  • Alpha MSH has potent anti-inflammatory effects in all major forms of inflammation and it antagonises the effects of pro-inflammatory cytokines such as TNF ⁇ and ILl- ⁇ .
  • the serum product has previously been shown to be very sensitive to proteolytic degradation; this is consistent with the theory that the POMC is proteolysed to give individual hormones on administration, but that further degradation destroys activity.
  • alpha MSH is believed to have significantly reduced activity if a terminal tripeptide sequence is removed; again, this is consistent with the active component including POMC.
  • the product itself is unstable by nature as its active components are short-lived, but exhibit powerful effects.
  • the product may also induce tyrosine phosphorylation in human brain microglial cells, and has been shown by Western blotting to modulate the NFKB pathway (data not shown).
  • NFKB IS known to regulate the transcription of genes involved in the regulation of pro-inflammatory cytokines, hence the inhibition of NFKB would act to reduce the pro-inflammatory cytokine response in autoimmune disease and reduce inflammatory responses. Further experiments to investigate this are underway.
  • Receptors for some POMC peptides are found in the retinal ganglion cells that form the optic nerve and may be stimulated by POMC peptides produced after treatment. This may account for some of the rapid improvements in vision experienced by MS patients with optic neuritis which have previously been described. It is known that ACTH triggers the corticosteroid pathway which can exert effects in as little as 20 to 30 minutes. Preliminary data suggests that the concentrations of the peptides in the product may be insufficient to elicit therapeutic responses in patients after dilution in the blood volume of the patient.
  • the product could act locally (as it is injected in a subcutaneous bolus) to induce a biochemical cascade which triggers the synthesis and release of the bioactive peptides in the treated patients. It is now known that any medical treatments that interfere with the product, for example by competing for receptors or blocking molecules in the HPA should be avoided.
  • the product is anti-inflammatory in nature it does not completely inhibit the inflammatory response.
  • Our data suggest that the product induces a shift from the unfavourable TH-I cytokine profile seen in auto-immune diseases to a more favourable balanced cytokine level. This may appear initially after treatment as a rapid anti-inflammatory TH-2 shift as the
  • TH-I network is turned off. Later on after treatment the TH-I network operates albeit at a lower level.
  • the reported effects of the serum product on tumours leads us to consider the possibility of anti-angiogenic effects of the serum.
  • the proteins thrombospondin-1 (TSP-I) and platelet factor 4 (PF-4) have been identified in the product by mass spectrometry of tryptic digests from SDS PAGE gels. Computer database searches using Biowork Browser for peptide identification yielded strong matches across several species including Homo sapiens. Although precise quantification of the TSP-I and PF-4 protein content of the product has not yet been established, the visible nature of the protein bands on SDS PAGE gels indicates that the proteins are present in biologically significant (upper nanogram) quantities.
  • FIG. 17 A summary of the hypothesised components of the product, and the method of action, is shown in Figure 17.
  • the product is thought to contain CRF, with some levels of CRF-BP, beta endorphin, vasopressin, and enkephalins.
  • CRF induces production of further CRF in the patient, as do beta endorphin and the enkephalins.
  • Endogenous CRF causes production of POMC, which gives rise to among others ACTH, alpha MSH, and beta endorphin.
  • This iast product acts in a feedback loop, with low levels stimulating further CRF release, while high levels inhibit CRF release.
  • This whole CRF / POMC cascade is thought to induce an immunological switch in the patient, which could explain the surprising beneficial effects seen in a variety of conditions.

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Abstract

L'analyse d'un produit du sérum de chèvre possédant de nombreux effets thérapeutique est décrite. Ce produit est identifié comme contenant de la pro-opiomélanocortine (POMC) ainsi que des peptides de corticolibérine , ainsi que des produits de dégradation de ces peptides. Des méthodes de traitement de maladies, dont le cancer, la sclérose en plaques et des troubles neurologiques, à l'aide de ces peptides et de leurs produits, que des médicaments comprenant lesdits peptides ainsi que des méthodes de production de ces peptides sont décrits.
EP05758978A 2004-07-08 2005-07-08 Medicament Withdrawn EP1765377A2 (fr)

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AU2005276242A1 (en) 2006-03-02
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