WO2013158871A1 - Utilisation de l'érythropoïétine et de dérivés pour le traitement de l'hypertension - Google Patents

Utilisation de l'érythropoïétine et de dérivés pour le traitement de l'hypertension Download PDF

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WO2013158871A1
WO2013158871A1 PCT/US2013/037155 US2013037155W WO2013158871A1 WO 2013158871 A1 WO2013158871 A1 WO 2013158871A1 US 2013037155 W US2013037155 W US 2013037155W WO 2013158871 A1 WO2013158871 A1 WO 2013158871A1
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epo
blood pressure
hbsp
rhepo
rats
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PCT/US2013/037155
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English (en)
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Mark I. TALAN
Ismayil AHMET
Edward G. Lakatta
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The United States Of America, As Represented By The Secretary, Department Of Health And Human Services
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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
    • A61K38/18—Growth factors; Growth regulators
    • A61K38/1816—Erythropoietin [EPO]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner

Definitions

  • This disclosure concerns the use of erythropoietin (EPO) and EPO derivatives for reducing blood pressure and/or treating hypertension.
  • EPO erythropoietin
  • Erythropoietin is a natural hormone produced by the kidney and associated with stimulation of red cell production.
  • Recombinant human erythropoietin rhEPO
  • rhEPO Recombinant human erythropoietin
  • Numerous studies in different experimental models reported tissue- protective and specifically cardioprotective properties of rhEPO.
  • Nitric oxide (NO) signaling has previously been associated with EPO, and some studies suggest that rhEPO-induced cardioprotection is the result of NO activation.
  • NO the primarily limiting factor of long-term rhEPO therapy is systemic hypertension resulting from increased blood viscosity and reduction of hypoxic vasodilation in rhEPO-treated anemic patients.
  • NO activation in rhEPO patients is considered to be a factor limiting the hypertensive response through compensatory vasodilation.
  • a method of preventing or treating hypertension in a subject comprising selecting a subject with hypertension or at risk for hypertension and administering to the subject a therapeutically effective amount of EPO or a derivative thereof. Also provided herein is a method of lowering blood pressure in a subject by selecting a subject with elevated blood pressure and administering to the subject a therapeutically effective amount of EPO or a derivative thereof.
  • the EPO is rhEPO. In some embodiments EPO, such as rhEPO, is administered acutely.
  • the EPO derivative does not significantly stimulate erythropoiesis.
  • the EPO derivative comprises carbamylated EPO (CEPO) or a helix B surface peptide (HBSP).
  • the EPO or EPO derivative is administered at a dose of about 100 to about 4000 U/kg, such as about 150 to 3000 U/kg. In other embodiments, the EPO or EPO derivative is administered at a dose of about 10 to about 100 ⁇ g/kg, such as less than about 60 /k ⁇
  • the EPO or EPO derivative is administered intravenously.
  • FIGS. 1A-1C are graphs showing mean arterial blood pressure (FIG. 1A), systolic blood pressure (FIG. IB) and diastolic blood pressure (FIG. 1C) in rats two hours after a single bolus injection of saline or 3000 U/kg rhEPO.
  • FIG. 2 is a bar graph showing arterial blood pressure in rats two hours after a single bolus injection of saline (control), or 150, 750 or 3000 U/kg rhEPO. Shown are systolic blood pressure (BPs), diastolic blood pressure (BPd) and mean blood pressure (BPm).
  • BPs systolic blood pressure
  • BPd diastolic blood pressure
  • BPm mean blood pressure
  • FIG. 3 is a pair of graphs showing the results of open chest pressure-volume loop analysis in rats two hours after a single bolus injection of saline (control) or rhEPO (3000 U/kg).
  • FIG. 4A is a series of images showing MI size in hearts of rats treated with a single bolus injection of rhEPO, L-NAME or rhEPO + L-NAME.
  • FIG. 4B is graph quantitatively showing MI size in rats treated with a single bolus injection of rhEPO, L-NAME or rhEPO + L-NAME. Control rats were administered saline by bolus injection.
  • FIG. 5 is a graph showing systolic blood pressure in a study of Dahl salt- sensitive rats. Rats were placed on a high salt (HS) or low salt (LS) diet and either left untreated (nT), treated with HBSP at the same time as initiating the HS diet (HS+HBSP), or treated with HBSP at week 4 (HS- HBSP delayed) of the HS diet.
  • HS high salt
  • LS low salt
  • FIG. 6 is a series of graphs showing blood pressure of spontaneously hypertensive rats (SHR) treated with HBSP. Shown are systolic (left), diastolic (middle), and mean (right) blood pressure of SHR treated with vehicle (SHR) or SHR treated with HBSP (SHR_HBSP) at 0, 2, 4, 6, and 8 weeks following the initiation of treatment. Wistar- Kyoto rats (WKY) served as controls.
  • FIG. 7A is a graph quantitating collagen in myocardium of spontaneously hypertensive rats (SHR) treated with HBSP to evaluate myocardial fibrosis. Shown is the percentage of collagen in control rats (WKY), SHR treated with vehicle (SHR) and SHR treated with HBSP (SHR_HBSP).
  • FIG. 7B is a graph quantitating kidney lesions in spontaneously hypertensive rats (SHR) treated with HBSP. Shown is the percentage of glomeruli lesions in control rats (WKY), SHR treated with vehicle (SHR) and SHR treated with HBSP (SHR_HBSP).
  • FIG. 8A is a graph showing the concentration of blood nitric oxide metabolites in spontaneously hypertensive rats (SHR) treated with HBSP. Shown is the concentration ( ⁇ ) of nitric oxide metabolites in control rats (WKY), SHR treated with vehicle (SHR) and SHR treated with HBSP (SHR_HBSP).
  • FIG. 8B is a graph showing blood angiotensin II in spontaneously hypertensive rats (SHR) treated with HBSP. Shown is the concentration (ng/ml) of angiotensin II in control rats (WKY), SHR treated with vehicle (SHR) and SHR treated with HBSP (SHR_HBSP).
  • FIG. 9 is a series of graphs showing blood pressure of Dahl's salt-sensitive rats treated with
  • HBSP HBSP. Shown are systolic (left), diastolic (middle), and mean (right) blood pressure of Dahl's rats consuming a high salt diet and treated with either vehicle (HS) or HBSP (HS_HBSP). Dahl's rats consuming a low salt diet and treated with vehicle (LS) served as controls.
  • FIG. 10A is a graph quantitating collagen in myocardium of Dahl's salt- sensitive rats treated with HBSP to evaluate myocardial fibrosis. Shown is the percentage of collagen in Dahl's salt-sensitive rats fed a low-salt diet (LS), Dahl's salt-sensitive rats fed a high-salt diet treated with vehicle (HS) and Dahl's salt- sensitive rats treated with HBSP (HS_HBSP).
  • LS low-salt diet
  • HS high-salt diet treated with vehicle
  • HS_HBSP Dahl's salt- sensitive rats treated with HBSP
  • FIG. 10B is a graph quantitating kidney lesions in Dahl's salt-sensitive rats treated with HBSP. Shown is the percentage of glomeruli lesions in Dahl's salt- sensitive rats fed a low-salt diet (LS), Dahl's salt- sensitive rats fed a high-salt diet treated with vehicle (HS) and Dahl's salt- sensitive rats treated with HBSP (HS_HBSP).
  • LS low-salt diet
  • HS high-salt diet treated with vehicle
  • HS_HBSP Dahl's salt- sensitive rats treated with HBSP
  • FIG. 11A is a graph showing the concentration of blood nitric oxide metabolites in Dahl's salt-sensitive rats treated with HBSP. Shown is the concentration ( ⁇ ) of nitric oxide metabolites in Dahl's salt- sensitive rats fed a low-salt diet (LS), Dahl's salt-sensitive rats fed a high-salt diet treated with vehicle (HS) and Dahl's salt-sensitive rats treated with HBSP (HS + HBSP).
  • FIG. 11B is a graph showing blood angiotensin II in Dahl's salt-sensitive rats treated with HBSP. Shown is the concentration (ng/ml) of angiotensin II in Dahl's salt-sensitive rats fed a low- salt diet (LS), Dahl's salt-sensitive rats fed a high-salt diet treated with vehicle (HS) and Dahl's salt-sensitive rats treated with HBSP (HS + HBSP).
  • LS low- salt diet
  • HS high-salt diet treated with vehicle
  • HBSP Dahl's salt-sensitive rats treated with HBSP
  • FIG. 12 is a series of graphs showing blood pressure of renal mass reduction (RMR) model rats treated with HBSP. Shown are systolic (left), diastolic (middle), and mean (right) blood pressure of RMR rats treated with either vehicle (RMR) or HBSP (RMR_HBSP). Sham-operated mice treated with vehicle (Sham) served as controls.
  • RMR renal mass reduction
  • FIG. 13A is a graph quantitating collagen in myocardium of RMR rats treated with HBSP to evaluate myocardial fibrosis. Shown is the percentage of collagen in control rats (Sham), RMR rats treated with vehicle (RMR) and RMR rats treated with HBSP (RMR HBSP).
  • FIG. 13B is a graph quantitating kidney lesions in nephrectomized rats treated with HBSP. Shown is the percentage of glomeruli lesions in control rats (Sham), nephrectomized rats treated with vehicle (NPHR) and nephrectomized rats treated with HBSP (NPHR+HBSP).
  • FIG. 14A is a graph showing the concentration of blood nitric oxide metabolites in RMR rats treated with HBSP. Shown is the concentration ( ⁇ ) of nitric oxide metabolites in control rats (Sham), RMR rats treated with vehicle (RMR) and RMR rats treated with HBSP (RMR+HBSP).
  • FIG. 14B is a graph showing blood angiotensin II in RMR rats treated with HBSP. Shown is the concentration (ng/ml) of angiotensin II in control rats (Sham), RMR rats treated with vehicle (RMR) and RMR rats treated with HBSP (RMR+HBSP).
  • SEQ ID NO: 1 is the amino acid sequence of HBSP.
  • SEQ ID NO: 2 is the amino acid sequence of mature human EPO (corresponding to residues 28-193 of GenBank ® Accession No. NP_000790). DETAILED DESCRIPTION
  • Administration The introduction of a composition into a subject by a chosen route.
  • the composition is administered by introducing the composition into a vein of the subject.
  • administration is acute administration, such as administration of no more than five doses, such as one, two, three, four or five doses.
  • administration is chronic administration, such as at least 2, at least 5, or at least 10 or more doses, such as daily, weekly or monthly administrations.
  • Blood pressure The pressure exerted by circulating blood upon the walls of blood vessels. Blood pressure generally refers to the arterial pressure of the systemic circulation. During each heartbeat, blood pressure varies between maximum (systolic) and minimum (diastolic) pressure.
  • Blood pressure is typically measured in millimeters of mercury (mmHg).
  • elevated blood pressure generally refers to a systolic blood pressure greater than 120 mmHg and/or a diastolic blood pressure greater than 80 mmHg.
  • Carbamylated erythropoietin EPO that is at least partially to fully
  • the CEPO has less than 90%, less than 80%, less than 70%, less than 60%, less than 50%, less than 40%, less than 30%, less than 20% or less than 10% free primary amines. Methods of making CEPO have been previously described (see, for example, U.S. Patent Application Publication No. 2008/0305990, which is herein incorporated by reference).
  • Erythropoiesis The production of red blood cells.
  • an EPO derivative that does not stimulate "statistically significant erythropoiesis” refers to an EPO derivative that does not stimulate an amount of red blood cell production that is statistically significant compared to a control or standard, such as a known non-erythropoietic peptide.
  • EPO Erythropoietin
  • GenBank ® database For example, human mRNA and amino acid sequences are deposited under GenBank ® Accession No.
  • EPO is the mature human EPO with the amino acid sequence corresponding to residues 28- 193 of GenBank ® Accession No. NP_000790.
  • An "EPO derivative" is any compound that is derived from EPO but includes at least one modification relative to native EPO.
  • EPO derivatives can include chemically modified EPO (e.g. , carbamylated EPO), EPO fragments (e.g. , HBSP), sequence variants or homologs.
  • the EPO derivative retains tissue-protective properties associated with EPO but does not stimulate statistically significant erythropoiesis.
  • Helix B surface peptide An 11 amino acid peptide (QEQLERALNSS; SEQ ID NO: 1) derived from the aqueous face of helix B of EPO.
  • HBSP exhibits tissue-protective activities comparable to EPO, but does not stimulate erythropoiesis (Ueba et al. , Proc Natl Acad Sci USA 107(32): 14357- 14362, 2010).
  • N-terminal glutamine (Q) residues can undergo a spontaneous, irreversible cyclization (particularly at room temperature under acidic conditions) into pyroglutamate (Yu et al., J Pharm Biomed Anal 42:455-463, 2006).
  • HBSP is pyroglutamate helix B surface peptide (i.e. the N-terminal glutamate is cyclized) (see, for example, Ahmet et al., Mol Med 17(3-4): 194-200, 2011; and Brines et al., Proc Natl Acad Sci USA 105(31): 10925- 10930, 2008).
  • Hypertension A condition characterized by elevated arterial blood pressure. Blood pressure measurements are typically reported as a ratio of systolic pressure (arterial pressure during contraction of the heart muscle) to diastolic pressure (residual arterial pressure during relaxation of the heart muscle), reported in units of mmHg.
  • a normal (desirable) diastolic blood pressure in humans is generally between about 60-79 mmHg and a normal (desirable) systolic blood pressure is generally between 90-119 mmHg.
  • a diastolic blood pressure greater than 80 mmHg such as about 81 mmHg, 85 mmHg, 90 mmHg or 100 mmHg or greater
  • a systolic blood pressure greater than 120 mmHg such as about 125 mmHg, 130 mmHg, 140 mmHg or 160 mmHg or greater, is diagnostic of hypertension.
  • hypertension A number of factors have been implicated in the development of hypertension. These include heredity and a number of environmental factors such as salt intake, obesity, occupation, family size, and crowding. Additional factors which may modify the course of hypertension include age, race, sex, stress, diet, smoking, serum cholesterol, and glucose intolerance. The effects of hypertension are numerous, with the most severe being premature death, commonly caused by heart disease related to hypertension. Hypertension imposes an increased work load on the heart; related effects on the heart include angina pectoris, increased myocardial mass or hypertrophy (enlarged heart), and late in the disease, evidence of ischemia or infarction.
  • Intravenous Administration into a vein, such as by injection or infusion.
  • compositions and formulations suitable for pharmaceutical delivery of the compounds herein disclosed are conventional. Remington's Pharmaceutical Sciences, by E. W. Martin, Mack Publishing Co., Easton, PA, 15th Edition (1975), describes compositions and formulations suitable for pharmaceutical delivery of the compounds herein disclosed.
  • parenteral formulations usually comprise injectable fluids that include pharmaceutically and physiologically acceptable fluids such as water, physiological saline, balanced salt solutions, aqueous dextrose, glycerol or the like as a vehicle.
  • pharmaceutically and physiologically acceptable fluids such as water, physiological saline, balanced salt solutions, aqueous dextrose, glycerol or the like as a vehicle.
  • physiologically acceptable fluids such as water, physiological saline, balanced salt solutions, aqueous dextrose, glycerol or the like
  • solid compositions for example, powder, pill, tablet, or capsule forms
  • conventional non-toxic solid carriers can include, for example, pharmaceutical grades of mannitol, lactose, starch, or magnesium stearate.
  • compositions to be administered can contain minor amounts of non-toxic auxiliary substances, such as wetting or emulsifying agents, preservatives, and pH buffering agents and the like, for example sodium acetate or sorbitan monolaurate.
  • non-toxic auxiliary substances such as wetting or emulsifying agents, preservatives, and pH buffering agents and the like, for example sodium acetate or sorbitan monolaurate.
  • Polypeptide A polymer in which the monomers are amino acid residues which are joined together through amide bonds. When the amino acids are alpha-amino acids, either the L-optical isomer or the D-optical isomer can be used.
  • polypeptide or protein as used herein are intended to encompass any amino acid sequence and include modified sequences such as glycoproteins.
  • polypeptide is specifically intended to cover naturally occurring proteins, as well as those which are recombinantly or synthetically produced.
  • amino acid residue includes reference to an amino acid that is incorporated into a protein, polypeptide, or peptide.
  • Conservative amino acid substitutions are those substitutions that, when made, least interfere with the properties of the original protein, that is, the structure and especially the function of the protein is conserved and not significantly changed by such substitutions. Examples of conservative substitutions are shown in the following table.
  • Val He Leu Conservative substitutions generally maintain (a) the structure of the polypeptide backbone in the area of the substitution, for example, as a sheet or helical conformation, (b) the charge or hydrophobicity of the molecule at the target site, or (c) the bulk of the side chain.
  • substitutions which in general are expected to produce the greatest changes in protein properties will be non-conservative, for instance changes in which (a) a hydrophilic residue, for example, seryl or threonyl, is substituted for (or by) a hydrophobic residue, for example, leucyl, isoleucyl, phenylalanyl, valyl or alanyl; (b) a cysteine or proline is substituted for (or by) any other residue; (c) a residue having an electropositive side chain, for example, lysyl, arginyl, or histadyl, is substituted for (or by) an electronegative residue, for example, glutamyl or aspartyl; or (d) a residue having a bulky side chain, for example, phenylalanine, is substituted for (or by) one not having a side chain, for example, glycine.
  • a hydrophilic residue for example, seryl or threonyl
  • Preventing a disease or condition refers to inhibiting the full development of the disease or condition.
  • Treating refers to a therapeutic intervention that ameliorates a sign or symptom of a disease or pathological condition after it has begun to develop.
  • Treating refers to the reduction in the number or severity of signs or symptoms of a disease or condition.
  • a recombinant nucleic acid or polypeptide is one that has a sequence that is not naturally occurring or has a sequence that is made by an artificial combination of two otherwise separated segments of sequence. This artificial combination is often accomplished by chemical synthesis or by the artificial manipulation of isolated segments of nucleic acids, for example, by genetic engineering techniques.
  • Sequence identity The similarity between amino acid or nucleotide sequences is expressed in terms of the similarity between the sequences, otherwise referred to as sequence identity. Sequence identity is frequently measured in terms of percentage identity (or similarity or homology); the higher the percentage, the more similar the two sequences are.
  • BLASTTM The NCBI Basic Local Alignment Search Tool (BLASTTM) (Altschul et al., J. Mol. Biol.
  • Variants and/or fragments of EPO generally comprise at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least 96%, at least 97%, at least 98% or at least about 99% sequence identity with an EPO sequence.
  • fragments When less than the entire sequence is being compared for sequence identity, fragments will typically possess at least 80% sequence identity over the length of the fragment, and can possess sequence identities of at least 85%, 90%, 95% or 99%.
  • sequence identity ranges are provided for guidance only; it is entirely possible that strongly significant homologs could be obtained that fall outside of the ranges provided.
  • Subject Living multi-cellular organisms, including vertebrate organisms, a category that includes both human and non-human mammals.
  • Therapeutically effective amount A quantity of compound, such as EPO or an EPO derivative, sufficient to achieve a desired effect in a subject being treated. For instance, this can be the amount necessary to treat or ameliorate elevated blood pressure, or to measurably decrease blood pressure over a period of time, or to measurably inhibit an increase in blood pressure, in a subject.
  • An effective amount of EPO or an EPO derivative may be administered in a single dose, or in several doses, for example daily, during a course of treatment. However, the effective amount will be dependent on the compound applied, the subject being treated, the severity and type of the affliction, and the manner of administration of the compound.
  • a single bolus administration of rhEPO to rats leads to a significant reduction in both diastolic and systolic blood pressure when administered at doses ranging from 150-3000 U/kg.
  • the reduced blood pressure effect was maintained for more than two hours.
  • the decrease in blood pressure was blocked by an inhibitor of nitric oxide (NO), an important cellular signaling molecule involved in vasodilation.
  • NO nitric oxide
  • administration of HBSP, an EPO derivative, to hypertensive rats prevents elevated blood pressure and can also significantly lower elevated blood pressure.
  • treatment with HBSP reduces myocardial fibrosis and kidney lesions in animal models of hypertension.
  • a method of treating or preventing hypertension in a subject by selecting a subject with hypertension or at risk for hypertension, and administering to the subject a therapeutically effective amount of EPO or an EPO derivative.
  • the subject has a diastolic blood pressure greater than 80 mmHg and/or a systolic blood pressure greater than 120 mmHg. In some examples, the subject has a diastolic blood pressure of at least 90 mmHg, or at least 100 mmHg. In some examples, the subject has a systolic blood pressure of at least 140 mmHg, or at least 160 mmHg.
  • the EPO is recombinant human EPO (rhEPO).
  • rhEPO comprises an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identical to SEQ ID NO: 2.
  • rhEPO comprises or consists of the amino acid sequence of SEQ ID NO: 2.
  • administration is acute administration.
  • acute administration includes no more than five doses, such as one, two, three, four or five doses.
  • the subject is administered an EPO derivative.
  • the EPO derivative can be any modified form of EPO, such as chemically modified EPO, or an EPO fragment, variant of homolog, so long as the derivative retains the ability to lower blood pressure.
  • the EPO derivative does not stimulate statistically significant erythropoiesis.
  • the EPO derivative comprises carbamylated EPO (CEPO) or helix B surface peptide (HBSP), such as pyroglutamate helix B surface peptide.
  • the amino acid sequence of the HBSP is at least 90% identical to the amino acid sequence of SEQ ID NO: 1, or the amino acid sequence of the HBSP comprises or consists of SEQ ID NO: 1.
  • HBSP comprises the amino acid sequence of SEQ ID NO: 1 with 1 or 2 conservative amino acid substitutions, or a deletion of 1 or 2 amino acids, so long as the HBSP retains the capacity to reduce blood pressure.
  • the CEPO can be partially or fully carbamylated. In some examples, the CEPO has less than 90%, less than 80%, less than 70%, less than 60%, less than 50%, less than 40%, less than 30%, less than 20% or less than 10% free primary amines.
  • the CEPO is human recombinant EPO (rhEPO).
  • the rhEPO comprises an amino acid sequence at least 80%, at least 85%, at least 90%. at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identical to SEQ ID NO: 2.
  • the rhEPO comprises or consists of the amino acid sequence of SEQ ID NO: 2.
  • administration of the EPO derivative comprises chronic
  • chronic administration includes as at least 2, at least 5, or at least 10 or more doses, such as daily, weekly or monthly administrations.
  • the subject can be administered any suitable dose of EPO or EPO derivative to achieve the desired therapeutic endpoint, such as a particular diastolic and/or systolic blood pressure.
  • the EPO or EPO derivative is administered at a dose of about 100 to about 4000 U/kg, such as about 100, about 150, about 250, about 500, about 750, about 1000, about 1500, about 2000, about 2500, about 3000, about 3500 or about 4000 U/kg.
  • the EPO or EPO derivative is administered at a dose of about 150 to about 3000 U/kg. In particular non-limiting examples, the EPO or EPO derivative is administered at a dose or 150, 750 or 3000 U/kg.
  • the EPO or EPO derivative is administered at a dose of about 1 to about 200 g/kg, such as about 10 to about 100 g/kg, 20 to about 80 g/kg, 30 to about 60 g/kg, or 40 to 50 ⁇ g/kg.
  • the EPO or EPO derivative is administered at a dose of less than 100, less than 90, less than 80, less than 70, less than 60, less than 50, less than 40 or less than 30 ⁇ g/kg.
  • the EPO or EPO derivative can be administered using any suitable route of administration for lowering blood pressure.
  • the EPO or EPO derivative is administered intravenously.
  • Hypertension remains a major health problem and is a serious risk factor for stroke and chronic heart failure.
  • Antihypertensive drugs developed on the basis of a nature hormone, such as EPO have significant advantages in comparison with existing compounds. For example, while most existing pharmaceutical compounds for treating hypertension are based on the blockade of hypertension-associated hormone production or hormone receptors, antihypertensive properties of EPO or EPO derivatives are based on activation of natural vasodilation mechanisms (i.e. via NO signaling). In addition, antihypertensive effects of EPO derivatives are associated with tissue protective properties. IV. EPO and EPO Derivatives
  • EPO carbamylated EPO
  • HBSP helix B surface peptide
  • the present disclosure contemplates the acute use of rhEPO and acute or chronic use of any derivatives or variants of EPO, including derivatives or variants that are not capable of inducing significant erythropoiesis, to reduce blood pressure.
  • the EPO derivative is CEPO or HBSP.
  • the EPO derivatives retain tissue protective properties but do not stimulate erythropoiesis.
  • 2009/0221482 describes a number of EPO-derived peptide fragments that exhibit tissue protective properties (such as HBSP).
  • the peptides are derived from the three dimensional structure of the EPO protein, such as from regions of EPO that face away from the ligand binding sites and/or the internal portion of the EPO receptor homodimer. Any of the EPO-derived peptide fragments disclosed in U.S. Patent Application Publication No. 2009/0221482 are contemplated for use in the present disclosure.
  • the EPO derivative that retains tissue protective properties but does not significantly induce erythropoiesis is carbamylated EPO (CEPO).
  • CEPO carbamylated EPO
  • 2008/0305990 teaches a method of producing CEPO having less than about 10% (or less than about 7.5%) free primary amines on the lysine residues and the N-terminal amino acid.
  • U.S. Patent Application Publication No. 2006/0135754 also teaches a method of producing CEPO, specifically a method of producing EPO that is nearly fully carbamylated with a low level of polymers or aggregates.
  • CEPO produced according to the methods taught in U.S. Patent Application Publication No. 2008/0305990 or 2006/0135754 are contemplated for use in the methods disclosed herein.
  • U.S. Patent Application Publication No. 2011/0008363 teaches EPO variants expressed in neuronal tissue with cell protective properties, but little to no hematopoietic activity. Any of the EPO variants and homologs disclosed in U.S. Patent Application Publication No. 2011/0008363 can be used with the methods disclosed herein.
  • U.S. Patent Application Publication No. 2003/0104988 teaches EPO molecules with carbohydrate modifications, such as EPO having no sialic acid moieties, EPO having no N-linked or O-linked carbohydrates, and EPO having reduced carbohydrate content due to treatment with a glycosidase. Any of the EPO molecules and derivatives described in U.S. Patent Application Publication No. 2003/0104988 are contemplated for use in the present methods.
  • the following examples are provided to illustrate certain particular features and/or embodiments. These examples should not be construed to limit the disclosure to the particular features or embodiments described.
  • Example 1 Administration of rhEPO reduces blood pressure via NO signaling
  • This example describes the finding that a single bolus injection of rhEPO results in a significant reduction of arterial blood pressure in rats.
  • rrEPO Recombinant rat erythropoietin
  • cardiovascular performances were analyzed via pressure-volume loops analyses (Ahmet et ah, Circulation 110(9): 1083- 1090, 2004). Briefly, after bilateral thoracotomy in the sixth intercostal space, a 2-0 suture was placed around vena cava inferior for volume manipulation and a 1.4F- combined pressure-conductance catheter (Millar Instruments Inc., Houston, TX) was inserted into the left ventricle (LV) through the apex. Prior to collecting cardiac data, the catheter was advanced to the ascending thoracic aorta to record arterial blood pressure for 5 minutes. Then the catheter was repositioned into the LV and measurements of cardiac function were commenced.
  • LV left ventricle
  • rats were anesthetized by isoflurane, chests were opened bilaterally, and 2 ml of 5% Evans blue (Sigma) was injected rapidly into the left ventricle (LV) via the apex, while the aorta was tightly closed by forceps to distinguish the perfused from
  • TTC triphenyltetrazolium chloride
  • rats (Wistar, male, 3-month old) were administered a single bolus injection of rhEPO (3000 U/kg) or saline.
  • Mean blood pressure, systolic blood pressure and diastolic blood pressure were determined under anesthesia two hours after injection of rhEPO or saline.
  • arterial blood pressure began to fall almost immediately after an intravenous bolus injection of 3000 U/kg of rhEPO (FIG. 1A).
  • Both systolic and diastolic pressures continued to fall until leveling off 90 minutes following the EPO injection (FIG. IB and FIG. 1C).
  • the 30-minute averages of both systolic and diastolic blood pressure were consistently and significantly lower in rhEPO treated group compared to control.
  • rhEPO physiological saline
  • saline+L-NAME 15 mg/kg
  • rhEPO+L-NAME physiological saline
  • FIG. 4A shows images of MI size in hearts from one rat from each treatment group. MI size was quantitated and the results are shown in FIG. 4B.
  • AAR myocardium at risk
  • the study disclosed herein also demonstrated a significant reduction of systolic heart function 2 hours after rhEPO administration via comprehensive pressure- volume loop analyses.
  • the reduction of ESP, dP/dt max, and especially PRSW is consistent with a reduced arterial pressure, and indicates lower cardiac work and, therefore, suggests lower oxygen requirement of the working myocardium.
  • the present disclosure describes the discovery of an acute, NO-mediated, hemodynamic effect of a bolus injection of rhEPO, resulting in a reduction in blood pressure and cardiac work.
  • NO signaling nor NO-associated hemodynamic effects mediate the cardioprotective properties of EPO.
  • Example 2 Administration of helix B surface peptide (HBSP) prevents and/or reduces elevated blood pressure
  • HBSP ARA290
  • EPO EPO
  • HBSP is an 1 lmer peptide that is synthesized as the linear sequence of helix B of EPO (QEQLERALNSS; SEQ ID NO: 1).
  • the N-terminal glutamine of HBSP can spontaneously undergo cyclization into pyroglutamate (Bines et al, Proc Natl Acad Sci USA 105(31): 10925- 10930, 2008).
  • the Dahl rat is a model of hypertension that is sensitive to dietary salt. Dahl rats placed on a high salt diet develop hypertension, which can eventually lead to heart failure and death. Dahl rats maintained on a low salt diet have normal blood pressure.
  • HBSP ARA290, Araim Pharmaceuticals
  • HBSP Helix B surface peptide
  • helix B surface peptide (HBSP, ARA290) normalizes elevated blood pressure in three different animal models of hypertension.
  • HBSP treatment was evaluated in spontaneously hypertensive rats (SHR), salt sensitive Dahl's rats consuming a high salt diet, and Wistar rats subjected to a resection of 5/6 ⁇ of the total renal mass (RMR).
  • Osmotic pumps delivering approximately 1 mg/kg to 0.4 mg/kg of HBSP daily (depending on body weight) for 8 weeks were implanted into the abdominal cavity of the test animals.
  • control rats were implanted with vehicle charged osmotic pumps.
  • Wistar- Kyoto (WKY) rats served as control animals for the SHR model.
  • Salt-sensitive Dahl's rats fed a low salt diet were used as controls in the Dahl rat model.
  • RMR model sham-operated animals served as controls.
  • concentration of angiotensin II suggested than blood pressure was controlled through activation of NO signaling.
  • RRR Renal mass reduction
  • HBSP stolic blood pressure

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Abstract

La présente invention concerne la découverte que l'administration aiguë de rhEPO conduit à une réduction significative de la pression sanguine artérielle par l'intermédiaire de la signalisation d'oxyde nitrique. L'invention concerne en outre un dérivé d'EPO, le peptide de surface à hélice B (HBSP), qui réduit significativement la pression sanguine, les lésions rénales et la fibrose myocardique dans des modèles animaux de l'hypertension. La présente invention concerne des méthodes de traitement de l'hypertension ou de diminution de la pression sanguine chez un sujet, par l'administration d'une quantité thérapeutiquement efficace d'EPO ou d'un dérivé d'EPO. Dans certains cas, le dérivé d'EPO ne stimule pas significativement l'érythropoïèse. Les dérivés d'EPO donnés à titre d'exemple qui ne stimulent pas l'érythropoïèse comprennent l'EPO carbamylée (CEPO) et HSBP.
PCT/US2013/037155 2012-04-20 2013-04-18 Utilisation de l'érythropoïétine et de dérivés pour le traitement de l'hypertension WO2013158871A1 (fr)

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