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WO2013059879A1 - Compositions et procédés destinés au traitement de la fibrose et de maladies fibrogènes - Google Patents

Compositions et procédés destinés au traitement de la fibrose et de maladies fibrogènes Download PDF

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WO2013059879A1
WO2013059879A1 PCT/AU2012/001313 AU2012001313W WO2013059879A1 WO 2013059879 A1 WO2013059879 A1 WO 2013059879A1 AU 2012001313 W AU2012001313 W AU 2012001313W WO 2013059879 A1 WO2013059879 A1 WO 2013059879A1
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Prior art keywords
relaxin
fibrosis
polypeptide
ace inhibitor
composition according
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Inventor
Chrishan SAMUEL
Tim HEWITSON
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Murdoch Childrens Research Institute
Florey Institute of Neuroscience and Mental Health
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Howard Florey Institute of Experimental Physiology and Medicine
Murdoch Childrens Research Institute
Florey Institute of Neuroscience and Mental Health
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Priority claimed from AU2011904449A external-priority patent/AU2011904449A0/en
Application filed by Howard Florey Institute of Experimental Physiology and Medicine, Murdoch Childrens Research Institute, Florey Institute of Neuroscience and Mental Health filed Critical Howard Florey Institute of Experimental Physiology and Medicine
Priority to AU2013202269A priority Critical patent/AU2013202269A1/en
Publication of WO2013059879A1 publication Critical patent/WO2013059879A1/fr
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/401—Proline; Derivatives thereof, e.g. captopril
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • A61K31/405—Indole-alkanecarboxylic acids; Derivatives thereof, e.g. tryptophan, indomethacin
    • 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
    • A61K38/2221—Relaxins
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • 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
    • A61P9/10—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

Definitions

  • compositions and methods for the treatment of fibrosis and fibrotic diseases are provided.
  • the present invention relates generally to the treatment of fibrosis and fibrotic diseases and disorders using combination therapy comprising a relaxin polypeptide together with an angiotensin-converting enzyme (ACE) inhibitor.
  • ACE angiotensin-converting enzyme
  • Fibrosis the abnormal and excessive accumulation of fibrous connective tissue, may result from a number of causes, including physical injury or trauma, inflammation or infection. Fibrosis can effect a range of tissues, most commonly the heart, lungs, kidneys, liver, stomach, skin and joints. If undetected, or untreated or inadequately treated the abnormal accumulation of fibrous tissue can cause organ failure and/or develop into debilitating and life threatening fibrotic diseases. Current therapies for fibrosis and fibrotic diseases are limited and are commonly hampered by a lack of efficacy and significant side effects. There remains a need for the development of improved treatment options.
  • Relaxin is a member of a protein hormone superfamily which also includes insulin, insulin-like grown factors I and II (IGF-I and IGF-II), and the insulin-like hormones INSL3, 4, 5 and 6.
  • the relaxin superfamily members have a wide range of biological activities that are well described in the art.
  • Relaxin is a heterodimeric peptide hormone composed, in its mature form, of an A chain and a B chain linked via disulphide bridges. Human relaxins in their mature form are stabilised by three disulphide bonds, two inter-chain disulphide bonds between the A chain and B chain and one intra-chain disulphide bond between cysteine residues in the A chain.
  • Relaxin has been conserved through vertebrate evolution and has been characterised in a large and diverse range of vertebrate species. In particular the cysteine residues in the B and A chains responsible for the intra- and inter-chain disulphide bonds are highly conserved. Whilst in most species only two forms of relaxin have been identified (relaxin and relaxin-3), in humans three distinct forms of relaxin have been described and the genes and polypeptides characterised. These have been designated HI , H2 and H3. Homologues of HI and H2 relaxin have been identified in other higher primates including chimpanzees, gorillas and orangutans.
  • Differing expression patterns for HI, H2 and H3 relaxin may suggest some differences in biological roles, however all three forms display similar biological activities, as determined for example by their ability to stimulate cAMP activity in cells expressing relaxin receptors, and accordingly share many biological functions in common.
  • relaxins include an ability to inhibit myometrial contractions, to stimulate remodelling of connective tissue and to induce softening of the tissues of the birth canal. Additionally, relaxins increase growth and differentiation of the mammary gland and nipple and induce the breakdown of collagen, one of the main components of connective tissue. Relaxins can cause a widening of blood vessels (vasodilatation) in the kidney, mesocaecum, lung and peripheral vasculature, which leads to increased blood flow or perfusion rates in these tissues. Relaxins can also stimulate an increase in heart rate and coronary blood flow, and increase both glomerular filtration rate and renal plasma flow.
  • Relaxin has been shown to have anti-fibrotic activity.
  • H2 relaxin has been demonstrated to inhibit fibrosis in several experimental models of fibrosis (see, for example, Samuel et al, 201 1, Lab Invest 91:675-690; and Hewitson et al, 2010, Endocrinology 151:4938-4948)
  • H3 relaxin has been shown to inhibit and reverse fibrosis in a model of fibrotic cardiomyopathy (Hossain et al, 2011, Biochemistry 50: 1368-1375).
  • the anti-fibrotic effects of both H2 and H3 relaxin are mediated via their interaction with the RXFPl receptor.
  • further work has been required to better understand the anti-fibrotic activity and mechanism of action of relaxin, and to exploit this to develop more effective treatments for fibrosis and fibrotic diseases.
  • the present invention is predicated on the inventors' finding that a combination of an ACE inhibitor and relaxin provides improved anti-fibrotic efficacy when compared to either ACE inhibitor or relaxin treatment alone in two different mouse models of human fibrotic disease.
  • a first aspect of the invention provides a pharmaceutical composition for use in the treatment of fibrosis or a fibrotic disease, the composition comprising at least one relaxin polypeptide and at least one ACE inhibitor.
  • the fibrosis or fibrotic disorder may affect any tissue or organ including, for example, kidney, heart, lung, liver, skin, bone or bone marrow.
  • the fibrosis may be renal or cardiac fibrosis.
  • the fibrosis may result from tissue or organ damage or injury, such as cardiac injury.
  • the fibrotic disorder may be tubulointerstitial kidney disease, myocardial infarction or other disorders associated with cardiac damage.
  • the relaxin polypeptide comprises an A chain and a B chain.
  • the A chain comprises an amino acid sequence as set forth in SEQ ID NO: l, SEQ ID NO: 3 or SEQ ID NO: 5 or a variant or derivative thereof.
  • the B chain comprises an amino acid sequence as set forth in SEQ ID NO:2, SEQ ID NO:4 or SEQ ID NO:6 or a variant or derivative thereof.
  • the relaxin polypeptide may be a relaxin- 1, relaxin-2 or relaxin-3 polypeptide.
  • the relaxin is a relaxin-2 polypeptide.
  • the relaxin-2 is H2 relaxin.
  • the H2 relaxin may comprise an A chain comprising the sequence set forth in SEQ ID NO: l and a B chain comprising the sequence set forth in SEQ ID NO:2.
  • the relaxin polypeptide may be administered to the subject in the form of a polynucleotide encoding the polypeptide such that the polynucleotide is expressed in vivo producing the polypeptide.
  • the ACE inhibitor may be a synthetic or naturally derived.
  • the synthetic ACE inhibitor may be, for example, a dicarboxylate-containing agent.
  • the ACE inhibitor may be selected from enalapril and perindopril.
  • the invention provides a pharmaceutical composition for use in inhibiting fibrosis, the composition comprising at least one relaxin polypeptide and at least one ACE inhibitor.
  • the invention provides a pharmaceutical composition for use in reducing or preventing progression of existing fibrosis, the composition comprising at least one relaxin polypeptide and at least one ACE inhibitor.
  • the invention provides a method for treating fibrosis or a fibrotic disorder in a subject in need thereof, the method comprising administering to the subject an effective amount of at least one relaxin polypeptide and an effective amount of at least one ACE inhibitor.
  • the relaxin polypeptide and the ACE inhibitor may be formulated together in a single composition or may be administered separately. Where administered separately, administration may be simultaneous or sequential.
  • the invention provides a method for inhibiting fibrosis in a subject in need thereof, the method comprising administering to the subject an effective amount of at least one relaxin polypeptide and an effective amount of at least one ACE inhibitor.
  • the invention provides a method for reducing or preventing progression of existing fibrosis in a subject in need thereof, the method comprising administering to the subject an effective amount of at least one relaxin polypeptide and an effective amount of at least one ACE inhibitor.
  • the invention provides the use of at least one relaxin polypeptide and at least one ACE inhibitor for the manufacture of a medicament for the treatment of fibrosis or a fibrotic disorder.
  • the invention provides the use of at least one relaxin polypeptide and at least one ACE inhibitor for the manufacture of a medicament for the inhibition of fibrosis.
  • the invention provides the use of at least one relaxin polypeptide and at least one ACE inhibitor for the manufacture of a medicament for reducing or preventing progression of existing fibrosis.
  • FIG. 1 Effects of ACE inhibitors and H2 relaxin on renal collagen concentration in UUO model of tubulointerstitial kidney disease (A and B) and ISO model of myocardial infarction and cardiac damage (C). Numbers in parentheses indicate numbers of animals. ***p ⁇ 0.01 vs DO; #p ⁇ 0.05; ##p ⁇ 0.01 vs D5 alone; ⁇ p ⁇ 0.05 vs D5+ 200mg L enalapril alone; +p ⁇ 0.05; ++p ⁇ 0.01 vs DO (control) group.
  • RLX H2 relaxin
  • ATI antagonist Irbesartan
  • FIG. 5 Staining of TGF- ⁇ (A and B) and staining of phosphorylated smad2 (C and D) in left ventricular tissue in mice from the ISO model of myocardial infarction. H2 relaxin used at 0.5mg/kg/d and enalapril used at 200mg/L. Numbers in parentheses indicate numbers of animals. ***p ⁇ 0.001 vs untreated group; #p ⁇ 0.05, ##p ⁇ 0.01, ###p ⁇ 0.001 vs ISO alone group. ⁇ p ⁇ 0.05, ⁇ p ⁇ 0.01 vs ISO + enalapril group. [029] Figure 6.
  • Relative collagen concentration (A), collagen staining (B), TGF- ⁇ staining (C) and phosphorylated smad2 staining (D) in response to enalapril and H2 relaxin administered after the establishment of fibrosis in ISO model of myocardial infarction. Numbers in parentheses indicate numbers of animals. ***p ⁇ 0.001 vs untreated group; #p ⁇ 0.05, ##p ⁇ 0.01, ###p ⁇ 0.001 vs ISO alone group.
  • P refers to fibrosis prevention studies (i.e. H2 relaxin and enalapril administration between days 1 and 17 in the ISO model).
  • R refers to fibrosis reversal studies (i.e. H2 relaxin and enalapril administration between days 10 and 17 in the ISO model).
  • Amino acid sequences of native human relaxin-2 (H2) A and B chains are set forth in SEQ ID NOs: 1 and 2, respectively.
  • Amino acid sequences of native human relaxin- 1 (HI) A and B chains are set forth in SEQ ID NOs: 3 and 4, respectively.
  • Amino acid sequences of native human relaxin-3 (H3) A and B chains are set forth in SEQ ID NOs: 5 and 6, respectively.
  • fibrosis refers to any pathological condition resulting from an accumulation of excess fibrous tissue through either overproduction or insufficient degradation of extracellular matrix.
  • fibrotic disease means any disease, condition or disorder that is associated with fibrosis. The disease, condition or disorder may be characterised by, caused by, or otherwise associated with fibrosis, either directly or indirectly.
  • polypeptide means a polymer made up of amino acids linked together by peptide bonds. The term “peptide” may also be used to refer to such a polymer although in some instances a peptide may be shorter (i.e. composed of fewer amino acid residues) than a polypeptide. Nevertheless, the terms “polypeptide” and “peptide” may be used interchangeably herein.
  • the term "relaxin polypeptide” as used herein means a polypeptide, whether corresponding to a naturally occurring relaxin molecule or a modified form thereof which displays biological activity typically associated with relaxin.
  • the level of such relaxin biological activity displayed by a relaxin polypeptide of the invention may be equivalent to that of a naturally occurring or native relaxin, or may be enhanced or reduced when compared with the activity of a naturally occurring or native relaxin.
  • the "biological activity” typically comprises the ability to bind the relaxin receptor RXFP1.
  • relaxin polypeptide refers to polypeptides that in the mature form either comprise a biologically active B chain capable of binding the RXFP 1 receptor or heterodimeric polypeptides comprising an A chain and a B chain. Also encompassed by the term “relaxin polypeptide” are precursor relaxin polypeptides also comprising a C chain.
  • naturally occurring and nonative refer to relaxin polypeptides as encoded by and produced from the genome of an organism. For example in humans three distinct forms of relaxin have been identified to date, HI , H2 and H3. Each of these forms is considered herein as a different "naturally occurring” or “native” relaxin.
  • the term "derived" in the context of relaxin A and B chains in relaxin polypeptides means that the A and B chain sequences correspond to, originate from, or otherwise share significant sequence homology with naturally occurring A and B chain sequences.
  • the sequence in a relaxin polypeptide need not be physically constructed or generated from the naturally occurring or native sequence, but may be chemically synthesised such that the sequence is "derived” from the naturally occurring or native sequence in that it shares sequence homology and function with the naturally occurring or native sequence.
  • modified as used herein in the context of a relaxin polypeptide means a polypeptide that differs from a naturally occurring or native relaxin polypeptide at one or more amino acid positions in one or more peptide chains of such naturally occurring or native polypeptide.
  • conservative amino acid substitution refers to a substitution or replacement of one amino acid for another amino acid with similar properties within a polypeptide chain (primary sequence of a protein). For example, the substitution of the charged amino acid glutamic acid (Glu) for the similarly charged amino acid aspartic acid (Asp) would be a conservative amino acid substitution. The nature of other conservative amino acid substitutions are well known to those skilled in the art.
  • polynucleotide refers to a single- or double- stranded polymer of deoxyribonucleotide, ribonucleotide bases or known analogues of natural nucleotides, or mixtures thereof. The term includes reference to the specified sequence as well as to the sequence complimentary thereto, unless otherwise indicated.
  • polynucleotide and nucleic acid are used interchangeably herein.
  • treating refers to any and all uses which remedy a disease, disorder or condition or symptoms, prevent the establishment of a condition or disease, or otherwise prevent, hinder, retard, or reverse the progression of a condition or disease or other undesirable symptoms in any way whatsoever.
  • terms “treating” and the like are to be considered in their broadest context. For example, treatment does not necessarily imply that a patient is treated until total recovery.
  • methods of the present invention involve “treating" the disease, disorder or condition in terms of reducing or eliminating the occurrence of a highly undesirable and irreversible outcome of the progression of the condition but may not of itself prevent the initial occurrence of the disease, disorder or condition. Accordingly, treatment includes amelioration of the symptoms of a particular disease, disorder or condition or preventing or otherwise reducing the risk of developing a particular disease, disorder or condition.
  • inhibitors and “inhibiting” and variations thereof as used herein as they relate to fibrosis and fibrotic diseases do not necessarily mean complete inhibition. Rather, inhibition may be to an extent, and/or for a time, sufficient to produce the desired effect. Thus inhibition of fibrosis for example may be partial or complete attenuation of one or more biological causes or effects of fibrosis, and inhibition may be temporally and/or spatially limited. By temporally and/or spatially limited is meant that the inhibition may be limited to particular physiological conditions or circumstances and/or to particular regions of the body.
  • the term "effective amount” includes within its meaning a nontoxic but sufficient amount of an agent or compound to provide the desired effect. The exact amount required will vary from subject to subject depending on factors such as the species being treated, the age and general condition of the subject, the tissue or organ in which the fibrosis occurs, the severity or extent of the fibrosis or fibrotic disease being treated, the particular agent being administered and the mode of administration and so forth. Thus, it is not possible to specify an exact "effective, amount”. However, for any given case, an appropriate "effective amount may be determined by one of ordinary skill in the art using only routine experimentation.
  • subject typically refers to mammals including humans, primates, livestock animals (eg. sheep, pigs, cattle, horses, donkeys), laboratory test animals (eg. mice, rabbits, rats, guinea pigs), companion animals (eg. dogs, cats) and captive wild animals (eg. foxes, kangaroos, deer).
  • livestock animals eg. sheep, pigs, cattle, horses, donkeys
  • laboratory test animals eg. mice, rabbits, rats, guinea pigs
  • companion animals eg. dogs, cats
  • captive wild animals eg. foxes, kangaroos, deer.
  • the mammal is human or a laboratory test animal. Even more preferably, the mammal is a human.
  • compositions and methods for the treatment of fibrosis and fibrotic disorders and for the inhibition of fibrosis involve combination therapy comprising the administration of at least one relaxin polypeptide and at least one ACE inhibitor.
  • the relaxin polypeptide and the ACE inhibitor as described herein are coadministered to facilitate the desired therapeutic outcome.
  • coadministered is meant simultaneous administration in the same formulation or in different formulations via the same or different routes or sequential administration by the same or different routes.
  • sequential administration is meant a time difference of from seconds, minutes, hours, days, weeks, months or years between the administration of the different agents.
  • the agents may be administered in any order.
  • the relaxin polypeptide to be administered may be any suitable relaxin polypeptide, either in mature form or precursor form, which is capable of binding and inducing a biological effect via the RXFP1 relaxin receptor.
  • the relaxin polypeptide comprises an A chain and a B chain.
  • the A chain may comprise an amino acid sequence as set forth in SEQ ID NO:l, SEQ ID NO:3 or SEQ ID NO:5.
  • the B chain may comprise an amino acid sequence as set forth in SEQ ID NO:2, SEQ ID NO:4 or SEQ ID NO:6.
  • the relaxin polypeptide may be a relaxin-l, relaxin-2 or relaxin-3 polypeptide.
  • the relaxin is a relaxin-2 polypeptide. Where the subject is human, typically the relaxin-2 is H2 relaxin.
  • variant refers to substantially similar sequences. Generally, polypeptide sequence variants possess qualitative biological activity in common. Further, these polypeptide sequence variants may share at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity. Also included within the meaning of the term “variant” are homologues of polypeptides of the disclosure. A homologue is typically a polypeptide from a different species but sharing substantially the same biological function or activity as the corresponding polypeptide disclosed herein.
  • variant also includes analogues of the polypeptides of the present disclosure, wherein the term “analogue” means a polypeptide which is a derivative of a polypeptide of the disclosure, which derivative comprises addition, deletion, substitution of one or more amino acids, such that the polypeptide retains substantially the same function.
  • fragment refers to a polypeptide molecule that is a constituent of a polypeptide of the disclosure or variant thereof. Typically the fragment possesses qualitative biological activity in common with the polypeptide of which it is a constituent.
  • the peptide fragment may be between about 5 to about 26 amino acids in length, between about 5 to about 25 amino acids in length, between about 5 to about 20 amino acids in length, or between about 5 to about 15 amino acids in length. Alternatively, the peptide fragment may be between about 5 to about 10 amino acids in length.
  • Relaxin polypeptides of the disclosure can also be modified, for instance, by glycosylation, amidation, carboxylation, or phosphorylation, or by the creation of acid addition salts, amides, esters, in particular C-terminal esters, and N-acyl derivatives of the polypeptides.
  • the polypeptides can also be further modified to create polypeptide derivatives by forming covalent or noncovalent complexes with other moieties.
  • Covalently-bound complexes can be prepared by cross-linking the chemical moieties to functional groups on the side chains of amino acids comprising the peptides, or at the N-or C terminus.
  • a modified polypeptide of the present disclosure may be generated with a polyethylene moiety conjugated at one or more locations (PEGylation) to increase in vivo half life of the polypeptide.
  • PEGylation polyethylene moiety conjugated at one or more locations
  • relaxin polypeptides may be produced using standard techniques of recombinant DNA and molecular biology that are well known to those skilled in the art. Guidance may be obtained, for example, from standard texts such as Sambrook et al, Molecular Cloning: A Laboratory Manual, Cold Spring Harbor, New York, 1989 and Ausubel et al, Current Protocols in Molecular Biology, Greene Publ. Assoc. and Wiley-Intersciences, 1992.
  • Relaxin peptide fragments may be produced by digestion of a polypeptide with one or more proteinases such as endoLys-C, endoArg-C, endoGlu-C and staphylococcus V8- protease.
  • the digested peptide fragments can be purified by, for example, high performance liquid chromatographic (HPLC) techniques.
  • HPLC high performance liquid chromatographic
  • Relaxin polypeptides of the present disclosure may also be synthesised by standard methods of liquid or solid phase chemistry well known to those of ordinary skill in the art.
  • such molecules may be synthesised following the solid phase chemistry procedures of Steward and vYoung (Steward, J. M. & Young, J. D., Solid Phase Peptide Synthesis. (2nd Edn.) Pierce Chemical Co., Illinois, USA (1984).
  • a synthesis method comprises the sequential addition of one or more amino acids or suitably protected amino acids to a growing peptide chain.
  • either the amino or carboxyl group of the first amino acid is protected by a suitable protecting group.
  • the protected amino acid is then either attached to an inert solid support or utilised in solution by adding the next amino acid in the sequence having the complimentary (amino or carboxyl) group suitably protected and under conditions suitable for forming the amide linkage.
  • the protecting group is then removed from this newly added amino acid residue and the next (protected) amino acid is added, and so forth. After all the desired amino acids have been linked, any remaining protecting groups, and if necessary any solid support, is removed sequentially or concurrently to produce the final polypeptide.
  • Embodiments of the invention contemplate the administration of a polynucleotide encoding a relaxin polypeptide as disclosed or contemplated herein.
  • the polynucleotide is typically operably linked to a promoter such that the appropriate polypeptide sequence is produced following administration of the polynucleotide to the subject.
  • the polynucleotide may be cloned into a vector.
  • the vector may be a plasmid vector, a viral vector, or any other suitable vehicle adapted for the insertion of foreign sequences, their introduction into eukaryotic cells and the expression of the introduced sequences.
  • the vector is a eukaryotic expression vector and may include expression control and processing sequences such as a promoter, an enhancer, ribosome binding sites, polyadenylation signals and transcription termination sequences.
  • the polynucleotide to be administered may comprise naked DNA or may be in the form of a composition, together with one or more pharmaceutically acceptable carriers.
  • any ACE inhibitor may be used in combination with a relaxin polypeptide in accordance with embodiments of the invention.
  • the ACE inhibitor may be a dicarboxylate-containing ACE inhibitor, a sulfhydryl-containing ACE inhibitor or a phosphonate-containing ACE inhibitor.
  • ACE inhibitors examples include, but are not limited to, captopril, zofenopril, enalapril, ramipril, quinapril, perindopril, lisinopril, benazepril, imidapril, trandolapril, alacepril, cilazapril, delapril, moexipril, rentiapril, spirapril, temocapril and fosinopril.
  • lactotripeptides Val-Pro-Pro and Ile-Pro-Pro for example as produced by Lactobacillus helveticus, have also been shown to act as ACE inhibitors, and may also be employed in accordance with present embodiments.
  • compositions and methods of the present invention may further comprise the administration of one or more additional therapeutic agents.
  • additional agents are typically anti-fibrotic agents or other agents useful in the treatment of one or more symptoms of a fibrotic disease.
  • additional agents may be formulated into the same composition for administration with a relaxin polypeptide and/or an ACE inhibitor or may be administered separately. Where formulated into a separate composition administration may be simultaneous or sequential and may be by the same or different routes.
  • Fibrosis affects a wide range of organs and tissues including the kidneys, heart, lungs, liver, epidermis, endodermis, muscle, tendon, cartilage, pancreas, uterus, nervous system, testis, ovary, adrenal gland, cardiovascular system such as arteries and veins, the gastrointestinal tract including the stomach, small intestine and colon, and the biliary tract.
  • the fibrosis may be cardiac fibrosis, ,renal fibrosis, hepatic fibrosis, pulmonary fibrosis or myelofibrosis.
  • Treating or inhibiting fibrosis in accordance with embodiments of the present invention may involve decreasing the level of fibrosis relative to an untreated control, as measured by any standard method known to those skilled in the art.
  • a reduction in fibrosis may also be measured by a reduction in any symptom associated with fibrosis or a fibrotic disease.
  • Fibrotic diseases amenable to treatment using the compositions and methods disclosed herein include those caused by or associated with, for example, trauma, acute or chronic tissue or organ damage or injury, surgery, wound healing, inflammation, infection or toxin exposure.
  • cardiac fibrosis and cardiac-related fibrotic diseases examples include, but are not limited to myocardial infarction, ischemia, fibrotic cardiomyopathy, heart failure, artherosclerosis, cardiac hypertension, cardiac reperfusion injury and type 1 diabetes.
  • Examples of renal fibrosis and renal-related fibrotic diseases that may be treated in accordance with the present invention include, but are not limited to renal hypertension, tubulointerstitial kidney disease, chronic papillary necrosis, crescentic glomerulonephritis, and renal insufficiency due to loss of renal mass.
  • Examples of pulmonary fibrosis and pulmonary-related fibrotic diseases that may be treated in accordance with the present invention include, but are not limited to hypoxic pulmonary hypertension, idiopathic pulmonary fibrosis, pulmonary reperfusion injury, interstitial pulmonary fibrosis and allergic airways diseases.
  • Examples of hepatic fibrosis and liver-related fibrotic diseases that may be treated in accordance with the present invention include, but are not limited to cirrhosis.
  • fibrotic diseases that may be treated in accordance with the present invention include, but are not limited to scleroderma, systemic sclerosis, dermal fibrosis, familial cutaneous collagenoma, acute pancreatitis, diabetic retinopathy, and proliferative vitreoretinopathy.
  • compositions in accordance with embodiments of the invention may be administered by standard routes.
  • the compositions may be administered by the parenteral (e.g., intravenous, intraspinal, intracerebroventricular, intranasal, subcutaneous or intramuscular), oral or topical route.
  • Administration may be systemic, regional or local.
  • the particular route of administration to be used in any given circumstance will depend on a number of factors, including the nature of the fibrosis or fibrotic disease to be treated, the severity and extent of the condition, the required amount or dosage of the agents or composition to be delivered and the potential side- effects of the agents or composition.
  • suitable compositions may be prepared according to methods which are known to those of ordinary skill in the art and may include a pharmaceutically acceptable diluent, adjuvant and/or excipient.
  • diluents, adjuvants and excipients must be "acceptable” in terms of being compatible with the other ingredients of the composition, and not deleterious to the recipient thereof.
  • Examples of pharmaceutically acceptable carriers or diluents are demineralised or distilled water; saline solution; vegetable based oils such as peanut oil, safflower oil, olive oil, cottonseed oil, maize oil, sesame oils such as peanut oil, safflower oil, olive oil, cottonseed oil, maize oil, sesame oil, arachis oil or coconut oil; silicone oils, including polysiloxanes, such as methyl polysiloxane, phenyl polysiloxane and methylphenyl polysolpoxane; volatile silicones; mineral oils such as liquid paraffin, soft paraffin or squalane; cellulose derivatives such as methyl cellulose, ethyl cellulose, carboxymethylcellulose, sodium carboxymethylcellulose or hydroxypropylmethyl cellulose; lower alkanols, for example ethanol or iso-propanol; lower aralkanols; lower polyalkylene glycols or lower alkylene glycols, for
  • compositions may be in a form suitable for administration by injection, in the form of a formulation suitable for oral ingestion (such as capsules, tablets, caplets, elixirs, for example), in the form of an ointment, cream or lotion suitable for topical administration, in a form suitable for delivery as an eye drop, in an aerosol form suitable for administration by inhalation, such as by intranasal inhalation or oral inhalation, in a form suitable for parenteral administration, e.g., intravenous, intraspinal, intracerebroventricular, intranasal, subcutaneous or intramuscular.
  • parenteral administration e.g., intravenous, intraspinal, intracerebroventricular, intranasal, subcutaneous or intramuscular.
  • non-toxic parenterally acceptable diluents or carriers can include, Ringer's solution, isotonic saline, phosphate buffered saline, ethanol and 1,2 propylene glycol.
  • cerebrospinal fluid CSF may be used as a carrier.
  • suitable carriers, diluents, excipients and adjuvants for oral use include peanut oil, liquid paraffin, sodium carboxymethylcellulose, methylcellulose, sodium alginate, gum acacia, gum tragacanth, dextrose, sucrose, sorbitol, mannitol, gelatine and lecithin.
  • these oral formulations may contain suitable flavouring and colourings agents.
  • the capsules When used in capsule form the capsules may be coated with compounds such as glyceryl monostearate or glyceryl distearate which delay disintegration.
  • Adjuvants typically include emollients, emulsifiers, thickening agents, preservatives, bactericides and buffering agents.
  • composition may incorporate any suitable surfactant such as an anionic, cationic or non-ionic surfactant such as sorbitan esters or polyoxyethylene derivatives thereof.
  • suitable surfactant such as an anionic, cationic or non-ionic surfactant such as sorbitan esters or polyoxyethylene derivatives thereof.
  • Suspending agents such as natural gums, cellulose derivatives or inorganic materials such as silicaceous silicas, and other ingredients such as lanolin, may also be included.
  • compositions may also be administered in the form of liposomes.
  • Liposomes are generally derived from phospholipids or other lipid substances, and are formed by mono- or multi-lamellar hydrated liquid crystals that are dispersed in an aqueous medium. Any non-toxic, physiologically acceptable and metabolisable lipid capable of forming liposomes can be used.
  • the compositions in liposome form may contain stabilisers, preservatives, excipients and the like.
  • the preferred lipids are the phospholipids and the phosphatidyl cholines (lecithins), both natural and synthetic.
  • agents may be administered to subjects as compositions either therapeutically or preventively.
  • compositions are administered to a patient already suffering from a disease, disorder or condition, in an amount sufficient to cure or at least partially arrest the disease, disorder or condition and its complications.
  • the composition should provide a quantity of the agent sufficient to effectively treat the patient.
  • the therapeutically effective amount for any particular subject will depend upon a variety of factors including: the disorder being treated and the severity of the disorder; activity of the molecule or agent employed; the composition employed; the age, body weight, general health, sex and diet of the subject; the time of administration; the route of administration; the rate of sequestration of the agent; the duration of the treatment; drugs used in combination or coincidental with the treatment, together with other related factors well known in medicine.
  • One skilled in the art would be able, by routine experimentation, to determine an effective, non-toxic amount of agent which would be required to treat applicable diseases.
  • an effective amount is expected to be in the range of about O.OOOlmg to about lOOOmg per kg body weight per 24 hours; typically, about 0.001 mg to about 750mg per kg body weight per 24 hours; about O.Olmg to about 500mg per kg body weight per 24 hours; about 0.1 mg to about 500mg per kg body weight per 24 hours; about 0.1 mg to about 250mg per kg body weight per 24 hours; about l .Omg to about 250mg per kg body weight per 24 hours.
  • an effective dose range is expected to be in the range about l.Omg to about 200mg per kg body weight per 24 hours; about l .Omg to about lOOmg per kg body weight per 24 hours; about l .Omg to about 50mg per kg body weight per 24 hours; about l.Omg to about 25mg per kg body weight per 24 hours; about 5.0mg to about 50mg per kg body weight per 24 hours; about 5.0mg to about 20mg per kg body weight per 24 hours; about 5.0mg to about 15mg per kg body weight per 24 hours.
  • an effective amount may be up to about 500mg/m 2 .
  • an effective dosage is expected to be in the range of about 25 to about 500mg/m 2 , preferably about 25 to about 350mg/m 2 , more preferably about 25 to about 300mg/m 2 , still more preferably about 25 to about 250mg/m 2 , even more preferably about 50 to about 250mg/m 2 , and still even more preferably about 75 to about 150mg/m 2 .
  • the optimal quantity and spacing of individual dosages will be determined by the nature and extent of the disease being treated, the form, route and site of administration, and the nature of the particular individual being treated. Also, such optimum conditions can be determined by conventional techniques. It will also be apparent to one of ordinary skill in the art that the optimal course of treatment, such as, the number of doses of the composition given per day for a defined number of days, can be ascertained by those skilled in the art using conventional course of treatment determination tests.
  • mice were subjected to the unilateral ureteric obstruction (UUO)-induced model of tubulointerstitial kidney disease. This model mimics several features of human disease. Affected mice i) experience fibrosis progression in a relatively short time frame; ii) experience fibrosis progression independently of gender; and iii) experience fibrosis progression independently of blood pressure changes. This latter point is particularly important as it avoids the complications of the blood pressure changes that can be induced by ACE inhibitors.
  • UUO unilateral ureteric obstruction
  • enalapril lOOmg/L or 200mg/L
  • perindopril also known as coversyl; 200mg/L
  • Kidney tissues were cut into four transverse sections (each containing cortex and medulla) for western blotting, hydroxyproline analysis, and fixation in two different fixatives for histochemistry. To ensure standardization, and to enable inter-group comparisons, each assay used the same portion from each animal. Hydroxyproline analysis was used to determine total collagen content and collagen concentration (% collagen content/dry weight tissue) from similar kidney portions from each of the groups studied.
  • mice were administered 200mg/L enalapril in their drinking water, from 2 days prior to surgery until day 5 p st-UUO (over 7 days) or immediately before the first ISO injection until 12-days after the 5 ISO injection (over 17 days).
  • a separate sub-group of mice were subcutaneously implanted with osmotic mini-pumps (with an infusion rate of 0.5 ⁇ 1/ ⁇ ; Alzet, Cupertino, CA) containing recombinant H2 relaxin, from 3 days prior to surgery until day 5 post-UUO (over 8 days) or immediately before the first ISO injection until 12 days after the 5 th ISO injection (over 17 days).
  • H2 relaxin is bioactive in mice, and this rate of infusion produces circulating relaxin levels of ⁇ 20-40ng/ml.
  • H2 relaxin is known to mediate its anti-fibrotic actions via interference of TGF- ⁇ ⁇ signal transduction. Specifically, H2 relaxin activation of its receptor, RXFP1 (in TGF- ⁇ ⁇ -stimulated human renal fibroblasts and renal myofibroblasts isolated from the obstructed kidneys of rats, 3 days post-UUO), inhibits Smad2 phosphosrylation (where Smad2 is a regulatory protein that promotes TGF- ⁇ activity).
  • H2 relaxin As H2 relaxin has also been shown to separately interfere with TGF- ⁇ and angiotensin Il-stimulation of cardiac fibroblast proliferation, differentiation and collagen production, relaxin signal transduction studies were extended to determine if H2 relaxin interferes with angiotensin II stimulation of TGF- ⁇ , as angiotensin II has been shown to promote TGF- ⁇ ⁇ activity and fibrosis progression via the ATI receptor.
  • ⁇ angiotensin II conversion to angiotensin 1-7 can act via the AT2 receptor to block TGF- ⁇ activity and subsequent fibrosis, via a NO-cGMP -dependent mechanism.
  • H2 relaxin (acting through its receptor, RXFP1) may either block the angiotensin Il-induced promotion of TGF- ⁇ activity via the ATI receptor or promote the inhibition of TGF- ⁇ activity via the AT2 receptor and NO signal transduction.
  • H2 relaxin was able to abrogate the actions of angiotensin II on TGF- ⁇ ⁇ activity via the ATI receptor
  • renal myofibroblasts isolated from the obstructed kidneys of rats, 3 days post-UUO were treated with H2 relaxin (lOOng/ml; 16.8nM) in the absence or presence of increasing concentrations (0.1, 1, 10 ⁇ ) of the ATI receptor antagonist, Irbesartan over 72 hours in culture. Untreated cells were used as controls.
  • MMP-2 and MMP-9 activity known to be targets of relaxin activity; by gelatin zymography and densitometry of the resulting MMP bands
  • the cell layer was extracted for protein and assessed by Western blotting for changes in Smad2 phosphorylation (as determined by densitometry of the resulting phosphorylated Smad2 bands).
  • the inventors investigated the effect of an AT2 receptor antagonist (PD12331) on the ability of H2 relaxin to promote latent and active MMP-2 levels. Similar to the results obtained for the ATI receptor antagonist Irbesartan, at PD12331 concentrations of ⁇ . ⁇ ⁇ , ⁇ ⁇ and 10 ⁇ , H2 relaxin-induced upregulation of MMP-2 was completely inhibited (data not shown), but no effect on MMP-2 levels was observed in the absence of H2 relaxin.
  • PD12331 AT2 receptor antagonist
  • the inventors also used immunohistochemical staining and morphometric analysis to investigate TGF- ⁇ expression and Smad2 phosphorylation (the phosphorylation of Smad2 being required to promote TGF- ⁇ signal transduction and pro-fibrotic action) from the ISO model of myocardial injury (described above).
  • Serial sections left ventricular tissue obtained from mice in the ISO model of myocardial infarction were immunohistochemically assessed using a rabbit polyclonal antibody to TGF- ⁇ (1 :200, Santa Cruz Biotechnology, CA, USA) and rabbit monoclonal antibody to phosphorylated-Smad2 (Ser465/467) (pSmad2; 1 :500, Cell Signalling Technology Inc., MA, USA).
  • TGF- ⁇ Citrate antigen retrieval
  • H2 relaxin (0.5mg/kg/d) had a significantly enhanced ability to inhibit TGF- ⁇ staining/expression and Smad2 phosphorylation (pO.01) compared to enalapril (200mg/L) ( Figure 5).
  • the combination of H2 relaxin and enalapril (0.5mg/kg d H2 relaxin + 200mg/L enalapril) also significantly more effective at inhibiting TGF- ⁇ staining (double that of enalapril alone; p ⁇ 0.05) and Smad2 phosphorylation (triple that of enapril alone; p ⁇ 0.01) (Figure 5).
  • combination therapy (0.5mg/kg d H2 relaxin + 200mg/L enalapril) could reduce established fibrosis, representing the clinically relevant situation, when administered over a one week (7 day) period beginning 10 days after the onset of ISO-induced injury (as described above).
  • combination therapy was able to significantly prevent further progression of established fibrosis (total collagen concentration and interstitial collagen staining) by 30-35% of that measured in the ISO alone group; which was also associated with its ability to reduce TGF- ⁇ staining and signal transduction (at the level of Smad2 phosphorylation).

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Abstract

La présente invention concerne des compositions pharmaceutiques comprenant au moins un polypeptide de relaxine et au moins un inhibiteur de l'ACE destinées à être utilisées dans le traitement de la fibrose et des maladies fibrogènes et à réduire ou prévenir la progression d'une fibrose préexistante. L'invention concerne également des procédés de traitement utilisant ces compositions.
PCT/AU2012/001313 2011-10-26 2012-10-26 Compositions et procédés destinés au traitement de la fibrose et de maladies fibrogènes Ceased WO2013059879A1 (fr)

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US10981973B2 (en) 2013-08-22 2021-04-20 Acceleron Pharma Inc. Methods of treating a sclerotic disorder by administering a transforming growth factor beta receptor type II fusion polypeptide
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US10981973B2 (en) 2013-08-22 2021-04-20 Acceleron Pharma Inc. Methods of treating a sclerotic disorder by administering a transforming growth factor beta receptor type II fusion polypeptide
US11008377B2 (en) 2013-08-22 2021-05-18 Acceleron Pharma Inc. Methods of treating a fibrotic disorder by administering transforming growth factor beta receptor II fusion polypeptides
US11951156B2 (en) 2013-11-21 2024-04-09 The Brigham And Women's Hospital, Inc. Methods for treating pulmonary hypertension with a ligand binding domain of a TGF-beta type II receptor
US10682392B2 (en) 2013-11-21 2020-06-16 The Bringham and Women's Hospital, Inc. Methods for treating pulmonary hypertension with a TGF-beta type II receptor-FC fusion protein
WO2015138532A3 (fr) * 2014-03-12 2015-11-26 The Brigham And Women's Hospital, Inc. Méthodes de traitement de la fibrose rénale
US10119168B2 (en) 2014-03-12 2018-11-06 The Brigham And Women's Hospital, Inc. Methods for the treatment of kidney fibrosis
US10557171B2 (en) 2014-03-12 2020-02-11 The Brigham And Women's Hospital, Inc. Methods for the treatment of kidney fibrosis
US11027014B2 (en) 2014-08-01 2021-06-08 The Brigham And Women's Hospital, Inc. Methods using GDF-15 antibodies for treatment of pulmonary arterial hypertension
CN106794233B (zh) * 2014-08-01 2021-11-12 布里格姆及妇女医院股份有限公司 与肺动脉高压的治疗有关的组合物和方法
US12472251B2 (en) 2014-08-01 2025-11-18 The Brigham And Women's Hospital, Inc. Method for treating fibrosis with an anti-GDF-15 antibody
CN106794233A (zh) * 2014-08-01 2017-05-31 布里格姆及妇女医院股份有限公司 与肺动脉高压的治疗有关的组合物和方法
EP3693004A1 (fr) * 2014-08-01 2020-08-12 The Brigham and Women's Hospital, Inc. Un inhibiteur de gdf-15 à utiliser dans le traitement de la fibrose
AU2015296037B2 (en) * 2014-08-01 2021-04-29 The Brigham And Women's Hospital, Inc. Methods and compositions relating to treatment of pulmonary arterial hypertension
EP3174550A4 (fr) * 2014-08-01 2018-06-20 The Brigham and Women's Hospital, Inc. Méthodes et compositions relatives au traitement de l'hypertension artérielle pulmonaire
JP2020125353A (ja) * 2014-08-01 2020-08-20 ザ ブリガム アンド ウィメンズ ホスピタル インコーポレイテッドＴｈｅ Ｂｒｉｇｈａｍ ａｎｄ Ｗｏｍｅｎ’ｓ Ｈｏｓｐｉｔａｌ， Ｉｎｃ． 肺動脈性肺高血圧症の処置に関する方法および組成物
JP2017523200A (ja) * 2014-08-01 2017-08-17 ザ ブリガム アンド ウィメンズ ホスピタル インコーポレイテッドＴｈｅ Ｂｒｉｇｈａｍ ａｎｄ Ｗｏｍｅｎ’ｓ Ｈｏｓｐｉｔａｌ， Ｉｎｃ． 肺動脈性肺高血圧症の処置に関する方法および組成物
US11203624B2 (en) 2015-08-04 2021-12-21 Acceleron Pharma Inc. Method for treating myelofibrosis comprising administering a transforming growth factor beta type II receptor antagonist
EP3777855A1 (fr) * 2016-04-11 2021-02-17 Genfit Procédés de traitement de maladies cholestatiques et fibrotiques
EP3777854A1 (fr) * 2016-04-11 2021-02-17 Genfit Procédés de traitement de maladies cholestatiques et fibrotiques
US11021527B2 (en) 2017-05-04 2021-06-01 Acceleron Pharma Inc. Transforming growth factor beta receptor type II fusion polypeptides
US12195519B2 (en) 2017-05-04 2025-01-14 Acceleron Pharma Inc. Transforming growth factor-beta (TGF-beta) receptor type II fusion polypeptides

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