WO2018107241A1 - Traitement de troubles en lien avec le fer - Google Patents

Traitement de troubles en lien avec le fer Download PDF

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Publication number
WO2018107241A1
WO2018107241A1 PCT/AU2017/051399 AU2017051399W WO2018107241A1 WO 2018107241 A1 WO2018107241 A1 WO 2018107241A1 AU 2017051399 W AU2017051399 W AU 2017051399W WO 2018107241 A1 WO2018107241 A1 WO 2018107241A1
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WIPO (PCT)
Prior art keywords
peptide
ala
hepcidin
thr
asp
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PCT/AU2017/051399
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English (en)
Inventor
Des Richardson
Michael Huang
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The University Of Sydney
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Priority claimed from AU2016905227A external-priority patent/AU2016905227A0/en
Application filed by The University Of Sydney filed Critical The University Of Sydney
Publication of WO2018107241A1 publication Critical patent/WO2018107241A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/06—Antianaemics
    • 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
    • A61K38/22—Hormones
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/81—Protease inhibitors
    • C07K14/8107—Endopeptidase (E.C. 3.4.21-99) inhibitors

Definitions

  • the invention relates to diseases of iron metabolism including anemia, especially to anemia of chronic disease, to hepcidin, and to the synthesis and design of peptides contemplated for therapeutic use as competitive inhibitors.
  • Iron is an essential transition metal for life [1 ,2]. In most organisms, a highly coordinated system controls the regulation and cellular and systemic metabolism of iron [1 .2]. Hepcidin, the 'hormone of iron metabolism' appears to be a major regulator of systemic iron homeostasis [3].
  • hepcidin The dysregulation of hepcidin is etiologically involved in many diseases of iron metabolism. Pathologically low hepcidin induces iron overload (e.g., in hereditary hemochromatosis types 1 -3), while pathologically high hepcidin typically induces iron- limited anemia [1 ], with the anemia of chronic disease being of particular concern [4].
  • Hepcidin is believed to exert its effects, principally through binding to the iron release transporter, ferroportin [3].
  • Ferroportin acts to release cellular iron into the circulation and results in the absorption of iron from the gut.
  • hepcidin down-regulates ferroportin levels by causing its cellular internalisation and degradation [7].
  • This decrease in ferroportin prevents (1 ) iron being released from cellular stores ⁇ e.g., the liver) into the blood; and (2) iron uptake from the gut into the blood [7].
  • pathologically high hepcidin levels as occurs in the anemia of chronic disease, leads to a debilitating anemia (as ferroportin expression is reduced) [3].
  • ferroportin has been suggested as a target for the development of inhibitors for treatment of diseases of iron metabolism, whereby it has been hypothesised that inhibition of ferroportin I - hepcidin binding might enable treatment of these diseases [5].
  • the hepcidin pharmacophore at the ferroportin binding site was established [5].
  • the hepcidin analogs utilized in that study to define the pharmacophore were observed not to inhibit hepcidin binding to ferroportin in a ferroportin-GFP assay when hepcidin and each analog were co-incubated [5].
  • Hepcidin has also been shown to bind to other molecules including oc-2 macroglobulin [6], and the latter has been proposed as a target for screening for inhibitors for treatment of diseases of iron metabolism by increasing urinary excretion of hepcidin arising from competitive inhibition of hepcidin binding with -2 macroglobulin [8].
  • WO201 0/065815, WO2013/086143, WO2014/071015 and WO2016/1 09363 (all by The Regents of University of California) and WO2014/145561 and WO201 5/200916 (by Protagonist Therapeutics Inc) each propose peptides having hepcidin activity, especially activity for binding to ferroportin to cause degradation or internalisation of same, for treatment of iron related disorders.
  • the invention seeks to address one or more of the above mentioned needs or limitations and in one embodiment provides peptides and methods of use of same for antagonising the binding of hepcidin to oc2 macroglobulin, or for increasing excretion of hepcidin from the body, or for increasing ferroportin -mediated export of Fe ions from a cell, or for improving red blood cell production, or for treating a disease of iron metabolism, especially a disease associated with excessive hepcidin production, expression or activity, and in particular, for treating anemia of chronic disease.
  • the peptides utilised in the methods of the invention for treatment of diseases associated with excessive hepcidin production or activity inhibit the binding of hepcidin to cc2 macroglobulin, and otherwise do not have hepcidin activity in the presence of natural or endogenous hepcidin. That is, they do not bind to ferroportin to cause internalisation or degradation of ferroportin that would otherwise prevent ferroportin - mediated export of Fe ions from inside a cell in the presence of natural or endogenous hepcidin because they do not inhibit hepcidin from binding to ferroportin the presence of natural or endogenous hepcidin.
  • a method of treating a disease associated with excessive hepcidin production or activity including providing an individual in need of said treatment with a peptide that: (i) inhibits the binding of hepcidin to a2 macroglobulin; and (ii) that does not have hepcidin activity, for example, does not prevent ferroportin from export of Fe ions from a cell, in the presence of natural or endogenous hepcidin.
  • a method of treating anemia of chronic disease including providing an individual in need of said treatment with a peptide that: (i) inhibits the binding of hepcidin to oc2 macroglobulin; and (ii) that does not inhibit the binding of hepcidin to ferroportin.
  • the peptide has an amino acid sequence with at least 90% or greater amino acid homology to the sequence shown in SEQ ID No:1 , provided that at position 4, the residue is not Phe, and at position 6, the residue is not lie:
  • a method of treating a disease associated with excessive hepcidin production or activity preferably for treating anemia of chronic disease, including providing in an individual in need of said treatment a peptide that inhibits the binding of hepcidin to oc2 macroglobulin, wherein the peptide does not have hepcidin activity, or does not inhibit the binding of hepcidin to ferroportin, and wherein the peptide includes or consists of an amino acid sequence according to Formula 1 A:
  • X3 is His, Asp or Glu
  • X 4 is Phe, Leu, Nle, Lys, lie or Val
  • X 5 is Pro, Ala or Gly
  • ⁇ is lie, Lys, Arg, or His
  • the peptide may consist of about 25 amino acids.
  • the peptide may have the sequence:
  • Xi to X 6 are as described above;
  • B is a positively charged residue, for example His, Asn, Arg or Lys
  • X is any amino acid residue.
  • the peptide may have the sequence:
  • the peptide may be linear or cyclic.
  • the peptides of the invention bind to oc2 macroglobulin with a binding affinity sufficient to inhibit the binding of hepcidin to oc2 macroglobulin.
  • the peptides of the invention are designed not to provide hepcidin hormonal activity in the presence of natural or endogenous hepcidin. As such, they do not generally prevent ferroportin from exporting Fe ions from a cell, for example by causing the degradation or internalisation of ferroportin that is otherwise seen when hepcidin binds to ferroportin.
  • the peptides of the invention may be referred to as "null hepcidin analogues".
  • a null hepcidin analog may mimic a hepcidin function or activity (such as oc2 macroglobulin-binding) although as mentioned above, a null hepcidin analog does not prevent ferroportin from export Fe ions from a cell in the presence of natural or endogenous hepcidin.
  • a method of treating anemia of chronic disease comprising providing a peptide which does not bind to ferroportin in the presence of natural or endogenous hepcidin, wherein the peptide is selected from the group consisting of D1 A (SEQ ID No: 6), T2A (SEQ ID No: 7), H3D (SEQ ID No: 8), F4Nle (SEQ ID No: 9), F4K (SEQ ID No: 10), P5A (SEQ ID No: 1 1 ), I6K (SEQ ID No: 12), D1 A/H3D (SEQ ID No: 13), D1 A/F4K (SEQ ID No: 14), I6D (SEQ ID No: 15), C7G (SEQ ID No: 1 6) or cyclic Hep9 or CHH1 as described herein.
  • a natural or endogenous hepcidin has the amino acid sequence shown in SEQ ID No: 17.
  • compositions and medicaments which comprise at least one peptide, which may be isolated, synthesized and/or purified, comprising, consisting essentially, or consisting of Formula 1 A or 1 B as set forth herein.
  • the present invention provides method of manufacturing medicaments for the treatment of diseases of iron metabolism, particularly disease that arise from or are associated with excessive hepcidin production, expression or activity, which comprise at least one peptide, which may be isolated and/or purified, comprising, consisting essentially or consisting of Formula 1 A or 1 B as set forth herein.
  • a disease of iron metabolism in a subject such as a mammalian subject, preferably a human subject, which comprises administering at least one peptide, which may be isolated and/or purified, comprising, consisting essentially or consisting of Formula 1 A or 1 B, as set forth herein, or a composition comprising said at least one peptide to the subject.
  • the peptide is administered in a therapeutically effective amount.
  • the therapeutically effective amount is an effective daily dose administered as a single daily dose or as divided daily doses.
  • the peptides of the present invention can also be administered at a variety of doses.
  • the dose is given as a weekly dose, e.g. from 1 -10,000 g/kg/dose.
  • the daily dose is about 1 -1 ,000, preferably about 10-500 g/kg/day. Dosages can vary according to the type of formulation of peptidyl drug administered as well as the route of administration.
  • composition to be administered is formulated for oral, pulmonary or mucosal administration.
  • Some embodiments include any dosage with any route of administration which results in an effective pharmacokinetic and pharmacodynamic profile that decreases serum hepcidin levels and increases serum iron levels. Some preferred doses include those that result in a desired reduction in serum hepcidin.
  • Administration of the peptidyl or protein formulations of the present invention includes both direct administration, including self-administration, and indirect administration, including the act of prescribing a drug. For example, a physician who instructs a patient to self-administer a drug and/or provides a patient with a prescription for a drug is considered to be administering the drug to the patient.
  • the present invention provides methods of binding an a2 macroglobulin, which comprises contacting the a2 macroglobulin with at least one peptide or composition as disclosed herein.
  • the present invention provides kits comprising at least one peptide or composition as disclosed herein packaged together with a reagent, a device, instructional material, or a combination thereof.
  • the present invention provides complexes which comprise at least one peptide as disclosed herein bound to an cx2 microglobulin, preferably a human a2 macroglobulin, or an antibody, such as an antibody which specifically binds a peptide as disclosed herein, or a combination thereof.
  • the present invention provides the use of at least one peptide, which may be isolated and/or purified, comprising, consisting essentially or consisting of Formula 1 A or 1 B as set forth herein or a composition comprising, consisting essentially of, or consisting of said at least one peptide for the manufacture of a medicament for treating a disease of iron metabolism and/or increasing the amount of extracellular iron in a subject in need thereof, wherein the medicament is prepared to be administered at an effective daily dose, as a single daily dose, or as divided daily doses.
  • the dose is about 1 -1 ,000, preferably about 1 0-500 pg/kg/day.
  • the medicament is formulated for subcutaneous injection or oral, pulmonary or mucosal administration.
  • FIG. 1 Sequestration and transport of hepcidin in the circulation by native and activated a2-macroglobulin (a2M).
  • a2M a2-macroglobulin
  • 1 Hepcidin binds to native and activated a2M.
  • Hepcidin binding to native and activated a2M is labile and in the presence of its target, ferroportin (Fpn1 ), hepcidin can dissociate from ⁇ 2 ⁇ . Release of hepcidin and binding to Fpn1 prevents cellular iron release leading to increased iron storage.
  • a particularly important finding of the invention is that certain peptides that had previously been considered not useful for treatment of diseases of iron metabolism, because they do not competitively inhibit binding of hepcidin with ferroportin and therefore, do not have hepcidin activity for degradation of ferroportin in the presence of natural or endogenous hepcidin, have been found to inhibit the binding of oc-2 macroglobulin to hepcidin.
  • This inhibition is important because the binding of oc 2 macroglobulin to hepcidin enables hepcidin to function as a hormone and increases the half-life of hepcidin in the body. That is, in the absence of hepcidin binding to high molecular weight oc-2 macroglobulin protein (725 kDa), the low molecular weight hepcidin hormone (2kDa) is excreted by the kidney into the urine.
  • these peptides could be used to ostensibly elute hepcidin from oc2 macroglobulin, thereby enabling excretion of hepcidin via the kidney.
  • the result is to reduce the amount of hepcidin in individuals having pathologically excessive hepcidin production, expression or activity.
  • the present invention provides peptides which are useful in the study and treatment of diseases of iron metabolism, and in particular, diseases associated with, or arising from, excessive hepcidin activity or production.
  • a disease may be one where aberrant iron metabolism directly causes the disease, or where iron blood levels are dysregulated causing disease, or where iron dysregulation is a consequence of another disease, or where diseases can be treated by modulating iron levels, and the like.
  • the disease is an anemia including anemia of chronic disease, anemia of inflammation, anemia of infection, hypochromic microcytic anemia, iron- deficiency anemia, iron-refractory iron deficiency anemia, anemia of chronic kidney disease, iron deficiency of obesity, congenital dyserythropoietic anemia, or other anemias.
  • the disease may be a condition, for example a benign or malignant tumor that overproduces hepcidin, or induces its over-production, conditions with hepcidin excess, Friedreich ataxia, gracile syndrome, Hallervorden-Spatz disease, Wilson's disease, pulmonary hemosiderosis, hepatocellular carcinoma, cancer, hepatitis, cirrhosis of liver, pica, chronic renal failure, insulin resistance, diabetes, atherosclerosis, neurodegenerative disorders, multiple sclerosis, Parkinson's disease, Huntington's disease, and Alzheimer's disease.
  • a benign or malignant tumor that overproduces hepcidin, or induces its over-production, conditions with hepcidin excess, Friedreich ataxia, gracile syndrome, Hallervorden-Spatz disease, Wilson's disease, pulmonary hemosiderosis, hepatocellular carcinoma, cancer, hepatitis, cirrhosis of liver, pica, chronic renal failure, insulin resistance, diabetes, athe
  • the disease of iron metabolism is anemia of chronic disease.
  • Anemia of chronic disease is a condition well known in the art, affecting more than 80% of hospitalised patients suffering from infections, malignancy and inflammation (NEJM 2005;352;1 01 1 ). This disorder is associated with excessive levels of hepcidin, as a response to chronic diseases. Excessive hepcidin promotes liver iron storage, leading to inadequate iron release for red blood cell production, causing a severe anemia.
  • the peptides of the present invention may be made using methods known in the art including chemical synthesis (solid-phase, solution phase, or a combination of both), biosynthesis, or in vitro synthesis using recombinant DNA methods,. See e.g. Kelly & Winkler (1990) Genetic Engineering Principles and Methods, vol. 12, J. K. Setlow ed., Plenum Press, NY, pp. 1 -1 9; Merrifield (1964) J Amer Chem Soc 85:2149; Houghten (1985) PNAS USA 82:51 31 -5135; and Stewart & Young (1 984) Solid Phase Peptide Synthesis, 2ed. Pierce, Rockford, IL, which are herein incorporated by reference.
  • the peptides of the present invention may be purified using protein purification techniques known in the art such as reverse phase high- performance liquid chromatography (HPLC), ion-exchange or immunoaffinity chromatography, precipitation, filtration, size exclusion, or electrophoresis. See Olsnes, S. and A. Pihl (1973) Biochem. 12(16):31 21 - 31 26; and Scopes (1 982) Protein Purification, Springer- Verlag, NY, which are herein incorporated by reference.
  • HPLC reverse phase high- performance liquid chromatography
  • ion-exchange or immunoaffinity chromatography precipitation, filtration, size exclusion, or electrophoresis.
  • the peptides of the present invention may be made by recombinant DNA techniques known in the art.
  • polynucleotides that encode the polypeptides of the present invention are contemplated herein.
  • the polynucleotides are isolated.
  • isolated polynucleotides refers to polynucleotides that are in an environment different from that in which the polynucleotide naturally occurs.
  • the peptides of the present invention are substantially purified.
  • a “substantially purified” compound refers to a compound that is at least about 60% free, preferably about 75% free, and most preferably about 90% free from other macromolecular components with which the compound may otherwise be associated, or a compound that is at least about 60%> free, preferably about 75% free, and most preferably about 90% free from other peptide components as measured by HPLC with detection at 214 nm.
  • the peptides of the present invention bind a2 macroglobulin, preferably human oc2 macroglobulin. Preferred peptides of the present invention specifically bind human oc2 macroglobulin.
  • "specifically binds" refers to a specific binding agent's preferential interaction with a given ligand over other agents in a sample.
  • a specific binding agent that specifically binds a given ligand binds the given ligand, under suitable conditions, in an amount or a degree that is observable over that of any nonspecific interaction with other components in the sample. Suitable conditions are those that allow interaction between a given specific binding agent and a given ligand.
  • a disease of iron metabolism especially anemia of chronic disease
  • a method for treating a disease of iron metabolism, especially anemia of chronic disease including the step of administering a peptide effective for inhibiting the binding of hepcidin to a2- macroglobulin, to an individual requiring said treatment, wherein the peptide has an amino acid sequence according to Formula 1 :
  • Xi is Asp, Ala, Gly, Ser or Thr
  • X 2 is Thr, Ala or Gly
  • X 3 is His, Asp or Glu
  • X 4 is Phe, Leu, Nle, Lys, lie or Val
  • X 5 is Pro, Ala or Gly X& is lie, Lys, Arg, or His wherein the peptide does not have hepcidin activity in the presence of
  • the peptide has a binding affinity similar to that of hepdicin for a-2 macroglobulin in a competitive binding assay described herein.
  • Xi is Ala, Gly, Ser or Thr, and X 2 is Thr, X 3 is His, X 4 is Phe, X 5 is Pro, and X 6 is lie.
  • Xi is Ala.
  • Xi is Asp
  • X2 is Ala or Gly
  • X3 is His
  • X 4 is Phe
  • X5 is Pro
  • e lie.
  • X2 is Ala.
  • Xi is Asp
  • X2 is Thr
  • X3 is Asp or Glu
  • X 4 is Phe
  • X5 is
  • X3 is Asp.
  • Xi is Asp
  • X2 is Thr
  • X3 is His
  • X 4 is Leu
  • X 5 is Pro
  • X 6 is lie.
  • X 4 is Nle or Leu.
  • Xi is Asp
  • X2 is Thr
  • X 3 is His
  • X 4 is Phe
  • X5 is Ala or Gly
  • X 6 is lie.
  • X 5 is Ala.
  • Xi is Asp
  • X2 is Thr
  • X 3 is His
  • X 4 is Phe
  • X5 is Pro
  • X 6 is Lys, Arg or His.
  • X 6 is Lys.
  • X ⁇ is Ala, Gly, Ser or Thr, and X 2 is Thr
  • X 3 is Asp or Glu
  • X 4 is Phe
  • X5 is Pro
  • Xe is lie.
  • Xi is Ala and X3 is Asp.
  • Xi is Ala, Gly, Ser or Thr, and X 2 is Thr
  • X 3 is His
  • X is Lys
  • X5 is Pro
  • X& is lie.
  • Xi is Ala and X 4 is Lys.
  • the peptide may be linear or cyclic, preferably linear.
  • the peptide may contain an alkyl group at the C-terminal residue.
  • a peptide as described above may be provided for use in the method of the invention in the form of a pharmaceutical composition including the peptide and an excipient, diluent or carrier.
  • peptides and uses of same for treatment of iron disorders, particularly disorders such as anemia of chronic disease are provided. These peptides do not have hepcidin activity in the presence of natural or endogenous hepcidin. These peptides inhibit the binding of hepcidin to 2- macroglobulin.
  • a peptide for inhibiting the binding of hepcidin to a2- macroglobulin wherein the peptide has an amino acid sequence according to Formula 1 :
  • Xi is Ala, Gly, Ser or Thr, and X 2 is Thr, X 3 is Asp or Glu, X 4 is Phe, X 5 is Pro, and X 6 is lie.
  • Xi is Ala and X 3 is Asp.
  • the peptide has an amino acid sequence according to
  • Xi is Ala, Gly, Ser or Thr, and X 2 is Thr, X 3 is Asp or Glu, X is Phe, X 5 is Pro, and is lie.
  • Xi is Ala and X 3 is Asp.
  • B is a positively charged residue, for example His, Asn, Arg or Lys
  • X is any amino acid residue.
  • peptide of Formula 1 C may have the sequence:
  • a peptide for inhibiting the binding of hepcidin to oc2- macroglobulin wherein the peptide has an amino acid sequence according to Formula 1 :
  • Xi is Ala, Gly, Ser or Thr, and X 2 is Thr, X 3 is His, X 4 is Lys, Arg or His, X5 is Pro, and X 6 is lie.
  • Xi is Ala and X 4 is Lys.
  • the peptide has an amino acid sequence according to Formula 1 C: XiX 2 X 3 X 4 X5X6CysllePheCysCysGlyCysCysBBXXCysGlyXCysCysBThr wherein
  • Xi is Ala, Gly, Ser or Thr, and X 2 is Thr, X 3 is His, X 4 is Lys, Arg or His, X5 is Pro, and X 6 is lie.
  • Xi is Ala and X 4 is Lys.
  • B is a positively charged residue, for example His, Asn, Arg or Lys
  • X is any amino acid residue.
  • peptide of Formula 1 C may have the sequence:
  • Xi is Asp, Ala, Gly, Ser or Thr
  • X 2 is Thr, Ala or Gly
  • X 3 is His, Asp or Glu
  • X is any amino acid residue. wherein the peptide does not have hepcidin activity in the presence of natural or endogenous hepcidin.
  • X 5 is Pro
  • X 6 is lie.
  • X 2 is Ala.
  • Xi is Asp
  • X 2 is Thr
  • X 3 is Asp or Glu
  • X 4 is Phe
  • X5 is Pro
  • X& is lie.
  • X3 is Asp.
  • Xi is Asp
  • X2 is Thr
  • X3 is His
  • X 4 is Phe
  • X 5 is Ala or Gly
  • X 6 is lie.
  • X 5 is Ala.
  • Xi is Ala, Gly, Ser or Thr, and X 2 is Thr, X 3 is His, X 4 is Lys, Arg or His, X5 is Pro, and X& is lie.
  • Xi is Ala and X 4 is Lys.
  • Suitable pH-buffering agents may, e.g., be phosphate, citrate, acetate, tris(hydroxymethyl)aminomethane (TRIS), N-tris(hydroxymethyl)methyl-3- aminopropanesulfonic acid (TAPS), ammonium bicarbonate, diethanolamine, histidine, arginine, lysine or acetate (e.g. as sodium acetate), or mixtures thereof.
  • TIS tris(hydroxymethyl)aminomethane
  • TAPS N-tris(hydroxymethyl)methyl-3- aminopropanesulfonic acid
  • ammonium bicarbonate diethanolamine
  • histidine histidine
  • arginine arginine
  • lysine or acetate e.g. as sodium acetate
  • the term further encompasses any carrier agents listed in the US Pharmacopeia for use in animals, including humans.
  • null hepcidin analogue of the invention i.e., one or more null hepcidin analogue peptide monomers of the invention or one or more null hepcidin analogue peptide dimers of the present invention
  • a pharmaceutical composition also encompasses inclusion of a pharmaceutically acceptable salt or solvate of a null hepcidin analogue of the invention.
  • the pharmaceutical compositions further comprise one or more pharmaceutically acceptable carrier, excipient, or vehicle.
  • null hepcidin analogues of the present invention may be formulated as pharmaceutical compositions which are suited for administration with or without storage, and which typically comprise a therapeutically effective amount of at least one null hepcidin analogue of the invention, together with a pharmaceutically acceptable carrier, excipient or vehicle.
  • the null hepcidin analogue pharmaceutical compositions of the invention are in unit dosage form. In such forms, the composition is divided into unit doses containing appropriate quantities of the active component or components.
  • the unit dosage form may be presented as a packaged preparation, the package containing discrete quantities of the preparation, for example, packaged tablets, capsules or powders in vials or ampoules.
  • a biodegradable matrix is a matrix of one of either polylactide, polyglycolide, or polylactide co-glycolide (co-polymers of lactic acid and glycolic acid).
  • the compositions are administered enterally or parenterally.
  • the compositions are administered orally, intracisternally, intravaginally, intraperitoneally, intrarectally, topically (as by powders, ointments, drops, suppository, or transdermal patch, including delivery intravitreally, intranasally, and via inhalation) or buccally.
  • parenteral refers to modes of administration which include intravenous, intramuscular, intraperitoneal, intrasternal, subcutaneous, intradermal and intraarticular injection and infusion. Accordingly, in certain embodiments, the compositions are formulated for delivery by any of these routes of administration.
  • Proper fluidity may be maintained, for example, by the use of coating materials such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.
  • These compositions may also contain adjuvants such as preservative, wetting agents, emulsifying agents, and dispersing agents.
  • Prolonged absorption of an injectable pharmaceutical form may be brought about by the inclusion of agents which delay absorption, such as aluminum monostearate and gelatin.
  • Injectable depot forms include those made by forming microencapsule matrices of the null hepcidin analogue in one or more biodegradable polymers such as polylactide-polyglycolide, poly(orthoesters), poly(anhydrides), and (poly)glycols, such as PEG. Depending upon the ratio of peptide to polymer and the nature of the particular polymer employed, the rate of release of the null hepcidin analogue can be controlled. Depot injectable formulations are also prepared by entrapping the null hepcidin analogue in liposomes or microemulsions compatible with body tissues.
  • the injectable formulations may be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium just prior to use.
  • Topical administration includes administration to the skin or mucosa, including surfaces of the lung and eye.
  • Compositions for topical lung administration may involve solutions and suspensions in aqueous and nonaqueous formulations and can be prepared as a dry powder which may be pressurized or non-pressurized.
  • the active ingredient may be finely divided form may be used in admixture with a larger-sized pharmaceutically acceptable inert carrier comprising particles having a size, for example, of up to 100 micrometers in diameter.
  • Suitable inert carriers include sugars such as lactose.
  • the composition may be pressurized and contain a compressed gas, such as nitrogen or a liquefied gas propellant.
  • a compressed gas such as nitrogen or a liquefied gas propellant.
  • the liquefied propellant medium and indeed the total composition may be such that the active ingredient does not dissolve therein to any substantial extent.
  • the pressurized composition may also contain a surface active agent, such as a liquid or solid non-ionic surface active agent or may be a solid anionic surface active agent. It is preferred to use the solid anionic surface active agent in the form of a sodium salt.
  • a null hepcidin analogue of the invention may be delivered in a pharmaceutically acceptable ophthalmic vehicle, such that the null hepcidin analogue is maintained in contact with the ocular surface for a sufficient time period to allow the null hepcidin analogue to penetrate the corneal and internal regions of the eye, as for example the anterior chamber, posterior chamber, vitreous body, aqueous humor, vitreous humor, cornea, iris/ciliary, lens, choroid/retina and sclera.
  • the pharmaceutically acceptable ophthalmic vehicle may, for example, be an ointment, vegetable oil or an encapsulating material.
  • the null hepcidin analogues of the invention may be injected directly into the vitreous and aqueous humour.
  • compositions for rectal or vaginal administration include suppositories which may be prepared by mixing the null hepcidin analogues of this invention with suitable non- irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax, which are solid at room temperature but liquid at body temperature and, therefore, melt in the rectum or vaginal cavity and release the active compound.
  • suitable non- irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax, which are solid at room temperature but liquid at body temperature and, therefore, melt in the rectum or vaginal cavity and release the active compound.
  • Null hepcidin analogues of the present invention may also be administered in liposomes or other lipid-based carriers.
  • liposomes are generally derived from phospholipids or other lipid substances. Liposomes are formed by mono- or multi-lamellar hydrated liquid crystals that are dispersed in an aqueous medium. Any non-toxic, physiologically acceptable and metabolizable lipid capable of forming liposomes can be used.
  • the present compositions in liposome form can contain, in addition to a null hepcidin analogue of the present invention, stabilizers, preservatives, excipients, and the like.
  • the lipids comprise phospholipids, including the phosphatidyl cholines (lecithins) and serines, both natural and synthetic. Methods to form liposomes are known in the art.
  • compositions to be used in the invention suitable for parenteral administration may comprise sterile aqueous solutions and/or suspensions of the peptide inhibitors made isotonic with the blood of the recipient, generally using sodium chloride, glycerin, glucose, mannitol, sorbitol, and the like.
  • the invention provides a pharmaceutical composition for oral delivery.
  • Compositions and null hepcidin analogues of the instant invention may be prepared for oral administration according to any of the methods, techniques, and/or delivery vehicles described herein. Further, one having skill in the art will appreciate that the null hepcidin analogues of the instant invention may be modified or integrated into a system or delivery vehicle that is not disclosed herein, yet is well known in the art and compatible for use in oral delivery of peptides.
  • formulations for oral administration may comprise adjuvants (e.g. resorcinols and/or nonionic surfactants such as polyoxyethylene oleyl ether and n-hexadecylpolyethylene ether) to artificially increase the permeability of the intestinal walls, and/or enzymatic inhibitors (e.g. pancreatic trypsin inhibitors, diisopropylfluorophosphate (DFF) or trasylol) to inhibit enzymatic degradation.
  • adjuvants e.g. resorcinols and/or nonionic surfactants such as polyoxyethylene oleyl ether and n-hexadecylpolyethylene ether
  • enzymatic inhibitors e.g. pancreatic trypsin inhibitors, diisopropylfluorophosphate (DFF) or trasylol
  • the null hepcidin analogue of a solid-type dosage form for oral administration can be mixed with at least one additive, such as sucrose, lactose, cellulose, mannitol, trehalose, raffmose, maltitol, dextran, starches, agar, alginates, chitins, chitosans, pectins, gum tragacanth, gum arabic, gelatin, collagen, casein, albumin, synthetic or semisynthetic polymer, or glyceride.
  • at least one additive such as sucrose, lactose, cellulose, mannitol, trehalose, raffmose, maltitol, dextran, starches, agar, alginates, chitins, chitosans, pectins, gum tragacanth, gum arabic, gelatin, collagen, casein, albumin, synthetic or semisynthetic polymer, or glyceride.
  • These dosage forms can also contain other type(s) of additives, e.g., inactive diluting agent, lubricant such as magnesium stearate, paraben, preserving agent such as sorbic acid, ascorbic acid, alpha-tocopherol, antioxidants such as cysteine, disintegrators, binders, thickeners, buffering agents, pH adjusting agents, sweetening agents, flavoring agents or perfuming agents.
  • additives e.g., inactive diluting agent, lubricant such as magnesium stearate, paraben, preserving agent such as sorbic acid, ascorbic acid, alpha-tocopherol, antioxidants such as cysteine, disintegrators, binders, thickeners, buffering agents, pH adjusting agents, sweetening agents, flavoring agents or perfuming agents.
  • oral dosage forms or unit doses compatible for use with the null hepcidin analogues of the present invention may include a mixture of null hepcidin analogue and nondrug components or excipients, as well as other non- reusable materials that may be considered either as an ingredient or packaging.
  • Oral compositions may include at least one of a liquid, a solid, and a semi-solid dosage forms.
  • an oral dosage form is provided comprising an effective amount of null hepcidin analogue, wherein the dosage form comprises at least one of a pill, a tablet, a capsule, a gel, a paste, a drink, a syrup, ointment, and suppository.
  • an oral dosage form is provided that isdesigned and configured to achieve delayed release of the null hepcidin analogue in the subject's small intestine and/or colon.
  • an oral pharmaceutical composition comprising a null hepcidin analogue of the present invention comprises an enteric coating that is designed to delay release of the null hepcidin analogue in the small intestine.
  • a pharmaceutical composition is provided which comprises a null hepcidin analogue of the present invention and a protease inhibitor, such as aprotinin, in a delayed release pharmaceutical formulation.
  • compositions of the instant invention comprise an enteric coat that is soluble in gastric juice at a pH of about 5.0 or higher.
  • a pharmaceutical composition comprising an enteric coating comprising a polymer having dissociable carboxylic groups, such as derivatives of cellulose, including hydroxypropylmethyl cellulose phthalate, cellulose acetate phthalate and cellulose acetate trimellitate and similar derivatives of cellulose and other carbohydrate polymers.
  • a pharmaceutical composition comprising a null hepcidin analogue of the present invention is provided in an enteric coating, the enteric coating being designed to protect and release the pharmaceutical composition in a controlled manner within the subject's lower gastrointestinal system, and to avoid systemic side effects.
  • null hepcidin analogues of the instant invention may be encapsulated, coated, engaged or otherwise associated within any compatible oral drug delivery system or component.
  • a null hepcidin analogue of the present invention is provided in a lipid carrier system comprising at least one of polymeric hydrogels, nanoparticles, microspheres, micelles, and other lipid systems.
  • some embodiments of the present invention comprise a hydrogel polymer carrier system in which a null hepcidin analogue of the present invention is contained, whereby the hydrogel polymer protects the null hepcidin analogue from proteolysis in the small intestine and/or colon.
  • the null hepcidin analogues of the present invention may further be formulated for compatible use with a carrier system that is designed to increase the dissolution kinetics and enhance intestinal absorption of the peptide. These methods include the use of liposomes, micelles and nanoparticles to increase Gl tract permeation of peptides.
  • a null hepcidin analogue of the instant invention is used in combination with a bioresponsive system, such as hydrogels and mucoadhesive polymers with hydrogen bonding groups (e.g., PEG, poly(methacrylic) acid [PMAA], cellulose, Eudragit®, chitosan and alginate) to provide a therapeutic agent for oral administration.
  • a bioresponsive system such as hydrogels and mucoadhesive polymers with hydrogen bonding groups (e.g., PEG, poly(methacrylic) acid [PMAA], cellulose, Eudragit®, chitosan and alginate) to provide a therapeutic agent for oral administration.
  • null hepcidin analogue disclosed herein, wherein the surface of the null hepcidin analogue surface is modified to comprise mucoadhesive properties through hydrogen bonds, polymers with linked mucins or/and hydrophobic interactions.
  • modified peptide molecules may demonstrate increase drug residence time within the subject, in accordance with a desired feature of the invention.
  • targeted mucoadhesive systems may specifically bind to receptors at the enterocytes and M-cell surfaces, thereby further increasing the uptake of particles containing the null hepcidin analogue.
  • null hepcidin analogue of the present invention comprises a method for oral delivery of a null hepcidin analogue of the present invention, wherein the null hepcidin analogue is provided to a subject in combination with permeation enhancers that promote the transport of the peptides across the intestinal mucosa by increasing paracellular or transcellular permeation.
  • a permeation enhancer is combined with a null hepcidin analogue, wherein the permeation enhancer comprises at least one of a long-chain fatty acid, a bile salt, an amphiphilic surfactant, and a chelating agent.
  • a permeation enhancer comprising sodium N-[hydroxybenzoyl)amino] caprylate is used to form a weak noncovalent association with the null hepcidin analogue of the instant invention, wherein the permeation enhancer favors membrane transport and further dissociation once reaching the blood circulation.
  • a null hepcidin analogue of the present invention is conjugated to oligoarginine, thereby increasing cellular penetration of the peptide into various cell types.
  • a noncovalent bond is provided between a peptide inhibitor of the present invention and a permeation enhancer selected from the group consisting of a cyclodextrin (CD) and a dendrimers, wherein the permeation enhancer reduces peptide aggregation and increasing stability and solubility for the null hepcidin analogue molecule.
  • a permeation enhancer selected from the group consisting of a cyclodextrin (CD) and a dendrimers, wherein the permeation enhancer reduces peptide aggregation and increasing stability and solubility for the null hepcidin analogue molecule.
  • Other embodiments of the invention provide a method for treating a subject with a null hepcidin analogue of the present invention having an increased half-life.
  • the total daily dose of the null hepcidin analogues of the invention to be administered to a human or other mammal host in single or divided doses may be in amounts, for example, from 0.0001 to 300 mg/kg body weight daily or 1 to 300 mg/kg body weight daily.
  • a dosage of a null hepcidin analogue of the present invention is in the range from about 0.0001 to about 1 00 mg/kg body weight per day, such as from about 0.0005 to about 50 mg/kg body weight per day, such as from about 0.001 to about 10 mg/kg body weight per day, e.g. from about 0.01 to about 1 mg/kg body weight per day, administered in one or more doses, such as from one to three doses.
  • the drug holiday may be a reduction in the dosage of the drug (e.g. to below the therapeutically effective amount for a certain interval of time).
  • administration of the drug is stopped for a certain interval of time before administration is started again using the same or a different dosing regimen (e.g. at a lower or higher dose and/or frequency of administration).
  • a drug holiday of the invention may thus be selected from a wide range of time-periods and dosage regimens.
  • An exemplary drug holiday is two or more days, one or more weeks, or one or more months, up to about 24 months of drug holiday.
  • the null hepcidin analogues may be delivered via an administration regime which comprises two or more administration phases separated by respective drug holiday phases. During each administration phase, the null hepcidin analogue is administered to the recipient subject in a therapeutically effective amount according to a pre-determined administration pattern.
  • the administration pattern may comprise continuous administration of the drug to the recipient subject over the duration of the administration phase.
  • the administration pattern may comprise administration of a plurality of doses of the null hepcidin analogue to the recipient subject, wherein said doses are spaced by dosing intervals.
  • a dosing pattern may comprise at least two doses per administration phase, at least five doses per administration phase, at least 1 0 doses per administration phase, at least 20 doses per administration phase, at least 30 doses per administration phase, or more.
  • Said dosing intervals may be regular dosing intervals, which may be as set out above, including once daily, twice daily, once every two, three, four, five or six days, once or twice weekly, once or twice monthly, or a regular and even less frequent dosing interval, depending on the particular dosage formulation, bioavailability, and pharmacokinetic profile of the null hepcidin analogue of the present invention.
  • An administration phase may have a duration of at least two days, at least a week, at least 2 weeks, at least 4 weeks, at least a month, at least 2 months, at least 3 months, at least 6 months, or more.
  • the duration of the following drug holiday phase is longer than the dosing interval used in that administration pattern.
  • the duration of the drug holiday phase may be greater than the mean interval between doses over the course of the administration phase.
  • the duration of the drug holiday may be longer than the longest interval between consecutive doses during the administration phase.
  • the duration of the drug holiday phase may be at least twice that of the relevant dosing interval (or mean thereof), at least 3 times, at least 4 times, at least 5 times, at least 10 times, or at least 20 times that of the relevant dosing interval or mean thereof.
  • a drug holiday phase may have a duration of at least two days, at least a week, at least 2 weeks, at least 4 weeks, at least a month, at least 2 months, at least 3 months, at least 6 months, or more, depending on the administration pattern during the previous administration phase.
  • An administration regime comprises at least 2 administration phases. Consecutive administration phases are separated by respective drug holiday phases. Thus the administration regime may comprise at least 3, at least 4, at least 5, at least 10, at least 1 5, at least 20, at least 25, or at least 30 administration phases, or more, each separated by respective drug holiday phases.
  • Consecutive administration phases may utilise the same administration pattern, although this may not always be desirable or necessary. However, if other drugs or active agents are administered in combination with a null hepcidin analogue of the invention, then typically the same combination of drugs or active agents is given in consecutive administration phases.
  • the recipient subject is human.
  • Example 1 Screening assays for determining appropriate a2- macroqlobulin binders.
  • BioHepcidin biotinylated hepcidin
  • BioHepcidin was incubated at a 4: 1 molar ratio of BioHepcidin:a2M/a2M-MA in the presence of unlabeled hepcidin or its analogues.
  • 27.6 pmol of a2M or a2M-MA were incubated with 1 1 0.4 pmol BioHepcidin in the presence of hepcidin or its analogue at 25, 50, 1 00 or 200 molar excess of BioHepcidin, for 1 h at 37 °C.
  • Assay to determine the activity of hepcidin analogues were performed in two stages. First, cells were pre-treated with culture media alone (DMEM + 10% fetal calf serum; control), or this medium containing DFO or FAC for 24 h/37°C (primary incubation). This medium was then removed and the cells rinsed with serum-free media. In the second stage, cells were incubated with serum-free DMEM or this medium containing DFO (100 ⁇ ) or FAC (250 pg/mL) in the presence or absence of either: hepcidin and hepcidin analogues (0.7 ⁇ ), for 6 h/37°C (secondary incubation). At the end of the secondary incubation, cells were lysed for assessment of Fpn1 expression by Western analysis. The activity of hepcidin analogues are measured in terms of Fpn1 expression relative to cell treated with hepcidin.
  • Example 3 Screening assays for determining peptides that do not degrade/cause internalisation of Ferroportin.
  • 100 ⁇ _ 0.9% saline (Control) or this vehicle containing: Hepcidin (0.9 nmole), or hepcidin analogues at 0.9 nmole (1 x), 9 nmole (10x) or 90 nmole (100x) in the presence or absence of Hepcidin (0.9 nmole) were injected into the tail vein of mice.
  • blood 600 ⁇ _
  • Serum iron was measured using a Konelab Clinical Chemistry Analyzer (Thermo Scientific, Waltham, MA).

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Abstract

Le traitement d'une maladie du métabolisme du fer comprend l'étape d'administration d'un peptide efficace pour inhiber la liaison de l'hepcidine à l'alpha 2-macroglobuline, à un individu nécessitant ledit traitement.
PCT/AU2017/051399 2016-12-16 2017-12-15 Traitement de troubles en lien avec le fer WO2018107241A1 (fr)

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KR102580377B1 (ko) * 2021-01-22 2023-09-19 주식회사 오디세우스바이오 사이토카인 방출 증후군의 치료 및 예방을 위한 헵시딘 유래 변이 펩타이드 및 이를 포함하는 조성물

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