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WO2025024729A1 - Nouveaux conjugués chitosane-il-36ra pour libération prolongée, ajustable et distribution tissulaire - Google Patents

Nouveaux conjugués chitosane-il-36ra pour libération prolongée, ajustable et distribution tissulaire Download PDF

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WO2025024729A1
WO2025024729A1 PCT/US2024/039664 US2024039664W WO2025024729A1 WO 2025024729 A1 WO2025024729 A1 WO 2025024729A1 US 2024039664 W US2024039664 W US 2024039664W WO 2025024729 A1 WO2025024729 A1 WO 2025024729A1
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compound
seq
amino acid
sequence
polypeptide
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WO2025024729A9 (fr
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Anna SPAGNOLI
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Rush University Medical Center
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Rush University Medical Center
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    • 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
    • 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
    • A61K38/177—Receptors; Cell surface antigens; Cell surface determinants
    • A61K38/1793—Receptors; Cell surface antigens; Cell surface determinants for cytokines; for lymphokines; for interferons
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/56—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule
    • A61K47/61—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule the organic macromolecular compound being a polysaccharide or a derivative thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/69—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
    • A61K47/6921—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a particulate, a powder, an adsorbate, a bead or a sphere
    • A61K47/6927—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a particulate, a powder, an adsorbate, a bead or a sphere the form being a solid microparticle having no hollow or gas-filled cores
    • A61K47/6929—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a particulate, a powder, an adsorbate, a bead or a sphere the form being a solid microparticle having no hollow or gas-filled cores the form being a nanoparticle, e.g. an immuno-nanoparticle
    • A61K47/6931—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a particulate, a powder, an adsorbate, a bead or a sphere the form being a solid microparticle having no hollow or gas-filled cores the form being a nanoparticle, e.g. an immuno-nanoparticle the material constituting the nanoparticle being a polymer
    • A61K47/6939—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a particulate, a powder, an adsorbate, a bead or a sphere the form being a solid microparticle having no hollow or gas-filled cores the form being a nanoparticle, e.g. an immuno-nanoparticle the material constituting the nanoparticle being a polymer the polymer being a polysaccharide, e.g. starch, chitosan, chitin, cellulose or pectin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis

Definitions

  • novel compounds disclosed include modified IL-36 receptor antagonist peptides for prolonged time release and consistent tissue distribution. Also disclosed herein are methods for treating diseases characterized by an IL-36 receptor antagonist (IL-36Ra) deficiency such as osteoarthritis or a failure or a defect in regeneration of a damage organ or tissue.
  • IL-36Ra IL-36 receptor antagonist
  • Osteoarthritis is a debilitating disease causing cartilage damage.
  • Other conditions such as osteophytosis (bone spurs), subchondral bone sclerosis (thickening of the bones under cartilage in joints), and synovitis (inflammation of the connective tissue around joints) may also occur with OA.
  • Patients experience a range of painful symptoms including joint tenderness, joint stiffness, and pain.
  • Current management of OA is limited by the lack of therapeutic interventions that alter the rate of progression of the disease.
  • TGF-cytokine superfamily has garnered attention with respect to joint development and OA. Mice with prenatally inactivated TGF-p type 2 receptor ( Tgfbr2) in osteochondral progenitors do not undergo joint formation. See A. Spagnoli, (2007), incorporated by reference with regard to such background teaching. TGF-p signaling is also required to maintain adulthood cartilage homeostasis as disrupted TGF-p signaling is evident during OA progression. See K. W. Finnson, et.
  • 3 is capable of attenuating surgically induced OA progression. See L. Xie, et. al., (2016), incorporated by reference with regard to such background teaching.
  • TGF-p signaling has multifaceted nichedependent roles within joints, meaning systemic actions outside the joint with other transcriptional regulation targets have a high risk for causing multi-organ side effects. Therefore, effective TGF-p modulation for OA prevention must be accomplished using relevant local and downstream signaling mechanisms.
  • IL-36a is one of several IL-1 cytokine subfamilies and includes three activating ligands (IL-36a, IL-36
  • avascular nature of joint cartilage makes systemic delivery of drugs inefficient. Utilizing intra-articular (i.a.) injection may be effective due to local bioavailability and less systemic exposure.
  • the efficacy of an i.a. drug depends on the “dwell time,’’ that is the time that the molecule is cleared from the joint space by the lymphatic system. Because the lymphatic system is highly efficient, the dwell time of proteins is short, with a t 1 /2 in the order of 0.1 -2 hours, making promising short-term effects of i.a. drugs not sustainable over time.
  • the present disclose addresses the need for a deliverable therapy which sustainably and predictably releases IL-36 receptor antagonist peptides for the inactivation of TGF-p signaling and attenuation of pathological changes in OA.
  • the disclosed compounds and methods include compositions of modified IL-36a peptides that have been altered to prolong time release and allow consistent tissue distribution for the treatment of diseases characterized by an IL-36 receptor antagonist deficiency such as OA, or a failure, or a defect, in regeneration of a damage organ or tissue.
  • the present disclosure includes compounds for the treatment of diseases characterized by an IL-36 receptor antagonist deficiency comprising a polypeptide comprising the amino acid sequence of SEQ ID No: 1 or a sequence which is at least 70% homologous thereto; and a chitosan nanoparticle.
  • the compounds described herein comprises a chitosan nanoparticle covalently linked by an amine group to a carboxyl group of a polypeptide.
  • the compounds described herein comprise a polypeptide comprising an amino acid sequence selected from the group consisting of SEQ ID NO: 1 , SEQ ID NO: 2, SEQ ID NO: 3, SEQ ID NO: 4, SEQ ID NO: 5, SEQ ID NO: 6, and SEQ ID NO: 7.
  • the compounds described herein comprise a polypeptide comprising the amino acid sequence of SEQ ID NO: 1 or a sequence which is at least 80% homologous thereto, or an analogue, derivative, fragment, variant, or peptidomimetic thereof.
  • the compounds described herein comprise a polypeptide comprising the amino acid sequence of SEQ ID NO: 2 or a sequence which is at least 80% homologous thereto, or an analogue, derivative, fragment, variant, or peptidomimetic thereof.
  • the compounds described herein comprise a polypeptide comprising the amino acid sequence of SEQ ID NO: 3 or a sequence which is at least 80% homologous thereto, or an analogue, derivative, fragment, variant, or peptidomimetic thereof.
  • the compounds described herein comprise a polypeptide comprising the amino acid sequence of SEQ ID NO: 4 or a sequence which is at least 80% homologous thereto, or an analogue, derivative, fragment, variant, or peptidomimetic thereof.
  • the compounds described herein comprise a polypeptide comprising the amino acid sequence of SEQ ID NO: 5 or a sequence which is at least 80% homologous thereto, or an analogue, derivative, fragment, variant, or peptidomimetic thereof.
  • the compounds described herein comprise a polypeptide comprising the amino acid sequence of SEQ ID NO: 6 or a sequence which is at least 80% homologous thereto, or an analogue, derivative, fragment, variant, or peptidomimetic thereof.
  • the compounds described herein comprise a polypeptide comprising the amino acid sequence of SEQ ID NO: 7 or a sequence which is at least 80% homologous thereto, or an analogue, derivative, fragment, variant, or peptidomimetic thereof.
  • the compounds described herein comprise a nanoparticle comprising beta-cholanic acid-chitosan.
  • the compounds described herein comprise a nanoparticle further comprising a cholanic acid core.
  • the compounds described herein comprise a polypeptide covalently coupled to the surface of the nanoparticle.
  • the compounds described herein comprise a nanoparticle that has amino or amine functionality for attachment of a polypeptide to the surface of the nanoparticle.
  • a pharmaceutical composition comprising the compound of the disclosure and a pharmaceutically acceptable carrier.
  • compositions comprising a therapeutically effective amount of the compound of the disclosure and one or more pharmaceutically acceptable carriers or vehicles.
  • Another embodiment described herein is a method of treating or lessening the severity in a subject of a disease characterized by an IL-36 receptor antagonist deficiency comprises administering a therapeutically effective amount of any of the compounds described herein or a pharmaceutical composition comprising any of the compounds described herein.
  • the method includes the diseases osteo-arthritis, myocardial infarction, fibrotic diseases and disorders, injury-induced organ damage, or injury-induced tissue damage.
  • the method of administration comprises administration to a tissue.
  • the tissue is cartilage.
  • the method includes administration to a knee joint, shoulder joint, or hip joint.
  • the subject that is a mammal.
  • any of the compounds described herein or a pharmaceutical composition comprising any of the compounds described herein for use in treating or lessening the severity of a disease or condition in a subject characterized by a deficiency in IL-36 receptor antagonist.
  • any of the compounds described herein or a pharmaceutical composition comprising any of the compounds described herein for use as a medicament.
  • any of the compounds described herein or a pharmaceutical composition comprising any of the compounds described herein for use in the manufacture of a medicament for the treatment of disease associated with an IL-36 receptor antagonist deficiency.
  • FIG. 1. illustrates the components of the protein-conjugated nanoparticles.
  • FIG. 2 illustrates the modifications to the human IL-36RN sequence by mutating to insert aspartic acid residues (Mutant 1) and the heparin binding consensus sequence motif, namely XBBBXXBX, where B is a basic amino acid exposed on one side and X is a neutral or hydrophobic amino acid, to either the C-terminus of the protein without (Mutant 2) or in tandem with aspartic acids residues (Mutant 3).
  • FIG. 3 illustrates the modifications to the mouse IL-36Ra sequence by mutating to insert aspartic acid residues (Mutant 4) and the heparin binding consensus sequence motif, namely XBBBXXBX, where B is a basic amino acid exposed on one side and X is a neutral or hydrophobic amino acid, to either the C-terminus of the protein without (Mutant 5) or in tandem with aspartic acids residues (Mutant 6).
  • FIG. 4 illustrates the strategy used to obtain purified HGC-IL-36 receptor antagonist conjugates with the fractions collected throughout the preparation. Starting solution (F1 ), after loading-evaporation (F2), unloaded “free” fraction (F3) and loaded fraction (F4).
  • FIG. 6 illustrates the tissue distribution of HGC-BSA nanoparticles i.a. injected into joints.
  • Limbs from E15.5 old mice were i.a. (interphalangeal joint) injected with HGC-BSA (A) or HGC (B) or left non-injected (C).
  • CBR-3BA staining (A-C) was performed on frozen sections, IHC for BSA was performed on adjacent frozen sections (DF). 100X magnifications are depicted.
  • FIG. 7 illustrates that hlL-36RN is decreased in human cartilage affected by degenerative OA.
  • C RT-PCR results for hlL-36RN are shown using human tissues with and without impact 2 and 14 days after impact occurred.
  • FIG. 8 illustrates that mlL-36Ra (wt) attenuates injury-induced OA in mice.
  • Mice DMM and sham
  • had daily i.a. injections of mlL-36Ra (wt) (250ng/dose) or PBS started after DMM/Sham for 5 days. Euthanasia after 20 weeks. n 5.
  • the present disclosure relates to nanoparticle conjugates and methods of using the targeted nanoparticle conjugates to deliver a therapeutic amount of modified IL-36 receptor antagonist to a targeted cell or tissue of a subject or mammal.
  • the modified IL-36 receptor antagonist nanoparticle conjugates may distribute across tissues with an abundance of extracellular matrix including those high in glycosaminoglymans.
  • the particle-based drug delivery also allows the sustained and adjustable release of therapeutic agent to the targeted tissue.
  • the articles “a,” “an,” and “the” are used herein to refer to one or to more than one (i.e., to at least one) of the grammatical object of the article.
  • an element may mean one element or more than one element.
  • the term “about” or “approximately” refers to a quantity, level, value, number, frequency, percentage, dimension, size, amount, weight or length that varies by as much as 10, 9, 8, 7, 6, 5, 4, 3, 2 or 1 % to a reference quantity, level, value, number, frequency, percentage, dimension, size, amount, weight or length.
  • the terms “about” or “approximately” when preceding a numerical value indicates the value plus or minus a range of 10%, 5%, or 1%.
  • an effective amount refers to an amount that causes relief of symptoms of a disorder or disease as noted through clinical testing and evaluation, patient observation, and/or the like.
  • An “effective amount” may further designate a dose that causes a detectable change in biological or chemical activity. The detectable changes may be detected and/or further quantified by one skilled in the art for the relevant mechanism or process.
  • an “effective amount” may designate an amount that maintains a desired physiological state, i.e., reduces or prevents significant decline and/or promotes improvement in the condition of interest.
  • An “effective amount” may further refer to a “therapeutically effective amount”.
  • Such synthetic amino acids include, for example, aminocyclohexane carboxylic acid, norleucine, a-amino n-demayoic acid, homoserine, S-acetylaminomethyl-cysteine, trans-3- and trans-4-hydroxyproline, 4- aminophenylalanine, 4-nitrophenylalanine, 4-chlorophenylalanine, 4-carboxyphenylalanine, [3- phenylserine [3-hydroxyphenylalanine, phenylglycine, a-naphthylalanine, cyclohexylalanine, cyclohexylglycine, indoline-2-carboxylic acid, 1 ,2,3,4-tetrahydroisoquinoline-3-carboxylic acid, aminomalonic acid, aminomalonic acid monoamide, N’-benzyl-N’-methyl-lysine, N’,N’-dibenzyl- ly
  • amino acids are referred to herein by either their commonly known three-letter symbols or by the one-letter symbols recommended by IUPACIUB Biochemical Nomenclature Commission. Nucleotides, likewise, may be referred to by their commonly accepted single letter codes.
  • the term “expression,” “recombinantly expressed,” and “over expression” includes any step involved in the production of the polypeptide including, but not limited to, transcription, post-transcriptional modification, translation, and post-translational modification. In some embodiments, the term also encompasses secretion of the polypeptide from a cell.
  • variants in relation to a nucleotide sequence include any substitution of, variation of, modification of, replacement of, deletion of or addition of one (or more) nucleic acid from or to the sequence.
  • variants in relation to a polypeptide sequence include any substitution of, variation of, modification of, replacement of, deletion of or addition of one (or more) amino acid from or to the sequence, and “a functional variant” means a variant of an polypeptide sequence which has one or more of the aforementioned changes to the reference sequence but still retains full or part of the functions of the reference sequence.
  • percent similarity when referring to a particular sequence are used as set forth in the University of Wisconsin GCG software program BestFit.
  • Other algorithms may be used, e.g. BLAST, psiBLAST or TBLASTN (which use the method of Altschul et al. (1990) J. Mol. Biol. 215: 405-410), FASTA (which uses the method ofPearson and Lipman (1988) PNAS USA 85: 2444-2448).
  • nanoparticle refers to a structure comprising one or more polymers that have been collapsed into a stable sub-micron sized particle.
  • treatment refers to reversing, alleviating, mitigating, or slowing the progression of, or inhibiting the progress of, a disorder or disease or symptoms associated with such disorder or disease, and as described in more detail herein.
  • the term "individual”, “subject”, or “patient” are often used interchangeably and refer to any human or domestic animal that may be treated with the methods disclosed herein. Suitable subjects (e.g., patients) include humans and domestic animals or pets (such as a cat or dog). Non-human primates and human patients are included. In one embodiment, subjects may include human patients that have been diagnosed with osteoarthritis. As used herein, the term “patient” refers to a subject that may receive a treatment of a disease or condition.
  • each intervening number there between with the same degree of precision is explicitly contemplated.
  • the numbers 7 and 8 are contemplated in addition to 6 and 9, and for the range 6.0-7.0, the number 6.0, 6.1 , 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, and 7.0 are explicitly contemplated.
  • the present disclosure describes novel compounds comprising a hydrophobic chitosan nanoparticle conjugated to modified IL-36 receptor antagonist (IL-36Ra) peptides with improved conjugation. Also described herein are pharmaceutical compositions and methods of using the compounds described herein. The compounds prolong time release and biological actions. Interleukin 36 receptor antagonist is also known as IL-36Ra in mice and IL-36RN in humans. GenBank ID: 26525 (human) and 54450 (mouse).
  • compounds of the present disclosure may be used for the treatment of diseases characterized by an IL-36 receptor antagonist deficiency including a polypeptide comprising the amino acid sequence of SEQ ID NO: 1 , a wild-type IL-36Ra peptide.
  • the polypeptide described herein comprises an amino acid sequence having at least 70% identity to to SEQ ID NO: 1 , conjugated to a chitosan nanoparticle.
  • modified sequences comprise a poly-aspartic acid tail of 1 -10 residues.
  • modified sequences comprise Heparin binding consensus sequence motifs, where B represents a basic amino acid exposed on one side, and X is a neutral or hydrophobic amino acid.
  • the compounds of the present disclosure includes a polypeptide comprising an amino acid sequence selected from the group consisting of SEQ ID NO: 1 , SEQ ID NO: 2, SEQ ID NO: 3, SEQ ID NO: 4, SEQ ID NO: 5, SEQ ID NO: 6, and SEQ ID NO: 7, or polypeptide sequences comprising the amino acid sequence of SEQ ID Nos: 1 - 7 that are at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 99%, or at least about 100% homologous to the sequence, as described in Table 1 .
  • the compounds of the disclosure includes a polypeptide comprising the amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 99%, or at least about 100% homologous to the sequence set forth in SEQ ID NO: 1 .
  • the polypeptide may comprise an analogue, derivative, fragment, variant or peptidomimetic of the amino acid sequence set forth in SEQ ID NO: 1 .
  • the compounds of the disclosure includes a polypeptide comprising the amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 99%, or at least about 100% homologous to the sequence set forth in SEQ ID NO: 2.
  • the polypeptide may comprise an analogue, derivative, fragment, variant or peptidomimetic of the amino acid sequence set forth in SEQ ID NO: 2.
  • the compounds of the disclosure includes a polypeptide comprising the amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 99%, or at least about 100% homologous to the sequence set forth in SEQ ID NO: 3.
  • the polypeptide may comprise an analogue, derivative, fragment, variant or peptidomimetic of the amino acid sequence set forth in SEQ ID NO: 3.
  • the compounds of the disclosure includes a polypeptide comprising the amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 99%, or at least about 100% homologous to the sequence set forth in SEQ ID NO: 4.
  • the polypeptide may comprise an analogue, derivative, fragment, variant or peptidomimetic of the amino acid sequence set forth in SEQ ID NO: 4.
  • the compounds of the disclosure includes a polypeptide comprising the amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 99%, or at least about 100% homologous to the sequence set forth in SEQ ID NO: 5.
  • the polypeptide may comprise an analogue, derivative, fragment, variant or peptidomimetic of the amino acid sequence set forth in SEQ ID NO: 5.
  • the compounds of the disclosure includes a polypeptide comprising the amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 99%, or at least about 100% homologous to the sequence set forth in SEQ ID NO: 6.
  • the polypeptide may comprise an analogue, derivative, fragment, variant or peptidomimetic of the amino acid sequence set forth in SEQ ID NO: 6.
  • the compounds of the disclosure includes a polypeptide comprising the amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 99%, or at least about 100% homologous to the sequence set forth in SEQ ID NO: 7.
  • the polypeptide may comprise an analogue, derivative, fragment, variant or peptidomimetic of the amino acid sequence set forth in SEQ ID NO: 7.
  • chitosan nanoparticles The use of chitosan nanoparticles is supported by in vivo studies reporting safety profiles for chitosans with high biodegradability, no immunogenicity, and absence of local or systemic side effects. See Li, T. et. al. J. Control. Release, 2010, 144(1), 101. Notably, the FDA considers chitosan as GRAS (Generally Recognized As Safe) and has approved its use in foods and drugs. However, its clinical use is limited by its insolubility at the physiological pH of 7.4. Hydrophobically modified glycol chitosan nanoparticles made of hydrophilic glycol chitosan conjugated with hydrophobic beta-cholanic acid resolves this issue. See Park, KM. Tissue Eng. Regen.
  • the fabricated beta cholanic acid chitosan nanoparticles self-aggregate in aqueous solution, are soluble at a neutral pH, and are capable of encapsulating peptides for continuous release.
  • Chitosan may be obtained by alkaline deacetylation of chitin, which is a rich polysaccharide next to cellulose. Chitosan is positively charged by amine groups, making it suitable for binding to negatively charged molecules and to react with the carboxyl group of amino acids to therefore conjugate chitosan to the protein.
  • the compounds of the disclosure include a nanoparticle conjugated to the polypeptides described herein.
  • the nanoparticle comprises chitosan.
  • the compounds of the disclosure include a nanoparticle comprising beta-cholanic acid-chitosan.
  • the compounds of the disclosure include a nanoparticle comprising a cholanic acid core.
  • the compounds of the disclosure include a polypeptide covalently coupled to the surface of the nanoparticle.
  • the compounds of the disclosure include a nanoparticle with amino or amine functionality for conjugation of the polypeptide to the nanoparticle to form the chitosan-IL-36Ra conjugates described in Figure 1 .
  • the chitosan nanoparticle is covalently linked by an amine group to a carboxyl group of the polypeptide.
  • the disclosure provides compounds that are antagonists of IL- 36 receptor protein, and thus the present compounds, are useful for the treatment of diseases, disorders, and conditions including, but not limited to a disease characterized by an IL-36 receptor antagonist deficiency, such as osteo-arthritis, myocardial infarction, fibrotic diseases and disorders, injury-induced organ damage, injury-induced tissue damage, or tissue regeneration failure or defect.
  • a disease characterized by an IL-36 receptor antagonist deficiency such as osteo-arthritis, myocardial infarction, fibrotic diseases and disorders, injury-induced organ damage, injury-induced tissue damage, or tissue regeneration failure or defect.
  • the pharmaceutically acceptable compositions of the disclosure additionally comprise a pharmaceutically acceptable carrier, adjuvant, or vehicle, which, as used herein, includes any and all solvents, diluents, or other liquid vehicle, dispersion or suspension aids, surface active agents, isotonic agents, thickening or emulsifying agents, preservatives, solid binders, lubricants and the like, as suited to the particular dosage form desired.
  • a pharmaceutically acceptable carrier, adjuvant, or vehicle which, as used herein, includes any and all solvents, diluents, or other liquid vehicle, dispersion or suspension aids, surface active agents, isotonic agents, thickening or emulsifying agents, preservatives, solid binders, lubricants and the like, as suited to the particular dosage form desired.
  • Remington s Pharmaceutical Sciences, Sixteenth Edition, E. W. Martin (Mack Publishing Co., Easton, Pa., 1980) discloses various carriers used in formulating pharmaceutically acceptable compositions and known
  • any conventional carrier medium is incompatible with the compounds of the disclosure, such as by producing any undesirable biological effect or otherwise interacting in a deleterious manner with any other component(s) of the pharmaceutically acceptable composition, its use is contemplated to be within the scope of this invention.
  • materials which may serve as pharmaceutically acceptable carriers include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, or potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, wool fat, sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragamayth; malt; gelatin; talc
  • composition comprising any of the chitosan-IL-36Ra conjugate compounds described herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
  • composition comprising a therapeutically effective amount of any of the chitosan-IL-36Ra conjugate compounds described herein, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers or vehicles.
  • the compounds described herein may thus be useful for the treatment of disorders characterized by depletion of IL-36Ra.
  • disorders may thus be diverse in nature, and include, for example, arthritic disorders, inflammatory disorders and cardiovascular disorders, and may further include diverse tissue types.
  • the disclosure includes a method of treating or lessening the severity in a subject of a disease characterized by an IL-36 receptor antagonist deficiency comprising administering a therapeutically effective amount of any of the chitosan-IL-36Ra conjugate compounds of the disclosure or a pharmaceutical composition.
  • the disease comprises one or more of osteo-arthritis, myocardial infarction, fibrotic diseases and disorders, injury-induced organ damage, or injury-induced tissue damage. In other aspect, the disease comprises osteo-arthritis.
  • the solubility characteristics of the compounds described herein make them well suited for tissues with rich extracellular matrices, including, for example, cartilage.
  • the administration of the compounds described herein is to cartilage tissues.
  • the administration of the compounds described herein is to a joint.
  • Exemplary joints include any joint that may be compromised by inflammation or IL-36Ra depletion.
  • administration is to a knee joint, shoulder joint, or hip joint.
  • the disclosure includes the method of treating or lessening the severity in a subject of regeneration failure or defect due to IL-36 receptor antagonist deficiency comprising administering a therapeutically effective amount of any of the chitosan-IL-36Ra compounds described herein or a pharmaceutical composition.
  • a chitosan-IL-36Ra compound as described herein or a pharmaceutical composition for use in antagonizing the IL-36R receptor in a subject is a chitosan-IL-36Ra compound as described herein or a pharmaceutical composition for use in treating or lessening the severity of a disease or condition in a subject characterized by a deficiency in IL-36 receptor antagonist.
  • a chitosan-IL-36Ra compound as described herein or a features a compound of the disclosure or a pharmaceutical composition for use in treating or lessening the severity of fibrotic diseases and disorders in a subject.
  • a chitosan-IL-36Ra compound as described herein or a pharmaceutical composition for use as a medicament is a chitosan-IL-36Ra compound as described herein or a pharmaceutical composition for use as a medicament.
  • a chitosan-IL-36Ra compound as described herein or a pharmaceutical composition for use in the manufacture of a medicament is a chitosan-IL-36Ra compound as described herein or a pharmaceutical composition for use in the manufacture of a medicament.
  • a chitosan-IL-36Ra compound as described herein or a pharmaceutical composition for use in the manufacture of a medicament for the treatment of disease associated with an IL-36 receptor antagonist deficiency is a chitosan-IL-36Ra compound as described herein or a pharmaceutical composition for use in the manufacture of a medicament for the treatment of disease associated with an IL-36 receptor antagonist deficiency.
  • compositions may be administered using any amount and any route of administration effective for treating or lessening the severity of one or more of the disease associated with an IL-36 receptor antagonist deficiency recited herein.
  • the exact amount required will vary from subject to subject, depending on the species, age, and general condition of the subject, the severity of the condition, the particular agent, its mode of administration, and the like.
  • the compounds, salts, and compositions of the invention are preferably formulated in dosage unit form for ease of administration and uniformity of dosage.
  • dosage unit form refers to a physically discrete unit of agent appropriate for the subject to be treated.
  • the total daily usage of the compounds, salts, and compositions of the invention will be decided by the attending physician within the scope of sound medical judgment.
  • the specific effective dose level for any particular subject or organism will depend upon a variety of factors including the disorder being treated and the severity of the disorder; the activity of the specific compound or salt employed; the specific composition employed; the age, body weight, general health, sex and diet of the subject; the time of administration, route of administration, and rate of excretion of the specific compound or salt employed; the duration of the treatment; drugs used in combination or coincidental with the specific compound or salt employed, and like factors well known in the medical arts.
  • compositions of this invention may be administered to humans and other animals via intra articular injection or the like, depending on the severity of the condition being treated.
  • the compound, salts, and compositions of the invention may be administered at dosage levels of about 0.001 mg/kg to about 1000 mg/kg, one or more times a day, effective to obtain the desired therapeutic effect.
  • Liquid dosage forms for oral administration include are contemplated herein, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs.
  • the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1 ,3-butylene glycol, dimethylformamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.
  • inert diluents commonly used in the art such as, for
  • Injectable preparations for example, sterile injectable aqueous or oleaginous suspensions may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents.
  • the sterile injectable preparation may also be a sterile injectable solution, suspension or emulsion in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1 ,3-butanediol.
  • the acceptable vehicles and solvents that may be employed are water, Ringer’s solution, U.S.P. and isotonic sodium chloride solution.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium.
  • any bland fixed oil may be employed including synthetic mono- or diglycerides.
  • fatty acids such as oleic acid are used in the preparation of injectables.
  • 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 that may be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.
  • the rate of compound release may be controlled.
  • biodegradable polymers include poly(orthoesters) and poly(anhydrides).
  • Depot injectable formulations are also prepared by entrapping the compound in liposomes or microemulsions that are compatible with body tissues.
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules.
  • the active compound or salt is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and/or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example, cety
  • Solid compositions of a similar type may also be employed as fillers in soft and hard- filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.
  • the solid dosage forms of tablets, dragees, capsules, pills, and granules may be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They may optionally contain opacifying agents and may also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions that may be used include polymeric substances and waxes. Solid compositions of a similar type may also be employed as fillers in soft and hard- filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.
  • the active compound or salt may also be in microencapsulated form with one or more excipients as noted above.
  • the solid dosage forms of tablets, dragees, capsules, pills, and granules may be prepared with coatings and shells such as enteric coatings, releasecontrolling coatings and other coatings well known in the pharmaceutical formulating art.
  • the active compound or salt may be admixed with at least one inert diluent such as sucrose, lactose or starch.
  • Such dosage forms may also comprise, as is normal practice, additional substances other than inert diluents, e.g., tableting lubricants and other tableting aids such a magnesium stearate and microcrystalline cellulose.
  • the dosage forms may also comprise buffering agents. They may optionally contain opacifying agents and may also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner.
  • buffering agents include polymeric substances and waxes.
  • Dosage forms for topical or transdermal administration of a compound or salt of this invention include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches.
  • the active component is admixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives or buffers as may be required.
  • Ophthalmic formulation, eardrops, and eye drops are also contemplated as being within the scope of this invention.
  • the invention contemplates the use of transdermal patches, which have the added advantage of providing controlled delivery of a compound to the body.
  • Such dosage forms are prepared by dissolving or dispensing the compound in the proper medium.
  • Absorption enhancers may also be used to increase the flux of the compound across the skin. The rate may be controlled by either providing a rate controlling membrane or by dispersing the compound in a polymer matrix or gel.
  • the compounds of the invention are useful as inhibitors of IL-36 receptor signaling.
  • the compounds are inhibitors of the IL-36 receptor and thus, without wishing to be bound by any particular theory, the compounds and compositions are particularly useful for treating or lessening the severity of a disease, condition, or disorder where activation or hyperactivity of the IL-36 receptor is implicated in the disease, condition, or disorder.
  • the disease, condition, or disorder may also be referred to as a “IL-36 receptor- mediated disease, condition or disorder.” Accordingly, in another aspect, the invention provides a method for treating or lessening the severity of a disease, condition, or disorder where activation or hyperactivity of the IL-36 receptor is implicated in the disease state.
  • the beta-cholanic, betalain, and lectin provide the chemical charges of chitosan that improve solubility and in part the release time, but a further improvement in release time and binding ability are provided by mutations of IL-36 receptor antagonists.
  • the amine groups of chitosan react with the carboxyl group of amino acid side chains to form a bond that links the chitosan to the protein.
  • standard methods were used to mutate the IL-36 receptor antagonist protein to have up to 10 aspartic acid residues in tandem that are inserted to either the N- or C-terminal of the protein (Mutants 1 and 4) (FIG. 2 and FIG. 3).
  • GAGs are important components of the ECM of articular cartilage. GAGs are essential molecules that regulate diverse biological processes including cell adhesion, differentiation, signaling and growth, by interaction with a wide variety of proteins. With the exception of hyaluronan, GAGs are synthesized covalently bound to core proteins to form proteoglymays such as aggremay that is abundant in articular cartilage. GAGs endow the articular cartilage with resistance to compressive loading and are involved in many biological interactions. Using the heparin binding consensus sequence motifs to bind with GAG prolongs time release and distributes modified proteins across GAG rich tissue, such as cartilage to reach the biological target (i.e. chondrocytes).
  • IL-36RN was mutated by inserting the heparin binding consensus sequence motif, namely XBBBXXBX, where B is a basic amino acid exposed on one side and X is a neutral or hydrophobic amino acid, to either the N- or C-terminal of the protein without (Mutant 2) or in tandem with aspartic acids residues (Mutant 3) (FIG. 2).
  • Mutant 4 contains up to 10 (1 to 10) aspartic acid residues in tandem that are inserted to either the N- or C-terminal of the protein (FIG. 3).
  • Mutant 5 contains a heparin binding consensus sequence motif without aspartic acid residues while Mutant 6 contains a heparin binding consensus sequence motif in tandem with aspartic acids residues (FIG 3).
  • Hydrophobic chitosan nanoparticles will be resuspended in a solution containing distilled water/ethanol (1 :1 , v/v) and then mixed with dH 2 O containing the mutated protein (any of Mutants 1 , 2, 3, 4, 5, or 6). Additional ethanol will be added to final ratio of distilled water/ethanol (1 :2, v/v) to obtain the respective ChitoKine(s).
  • the solvents will be evaporated using a rotary evaporator to prepare a thin polymer/peptide film. After addition of distilled water, the solution will be gently stirred and then filtered. The resulting filtrates will be collected and lyophilized.
  • Fractions will also be collected at each of the preparation steps to determine protein concentration using either western blot analysis or ELISA for either hlL-36RN and modified hlL- 36RN or mlL-36Ra and modified mlL-36Ra.
  • the schematic in FIG. 4 outlines the conjugate preparation.
  • the morphology and size distribution of nanoparticles loaded or unloaded with proteins will be characterized using dynamic light scattering and transmission electron microscopy.
  • Biological assays will be performed to evaluate biological activity in vivo and in vitro as well as binding receptor affinity. Biodistribution will be performed using Cibacron Brilliant Red-3BA staining for chitosan nanoparticles.
  • HGC protein loading efficiency was evaluated via Western blot using the fractions collected (fractions designated as F1 to F4) at each of the preparation and purification steps.
  • the loading efficiency of BSA to HGC expressed as the percentage of the starting concentration (F1 ) to the concentration detected in the final fraction (F4), was determined to be 84 ⁇ 3% and the loading ability of mlL-36Ra (wt) was determined to be been 82 ⁇ 4%.
  • Increasing the loading efficiency of IL-36 receptor antagonists motivated the mutational studies (Mutants 1 - 6).
  • FIG. 5 shows the size and morphology of HGC after protein loading by DSL and TEM analyses.
  • the mean diameter of HGC nanoparticles is 196 nm (FIG. 5A).
  • HGC-BSA (FIG. 5B) and HGC-mlL-36Ra (wt) (FIG. 5C) had a larger diameter respectively of 361 nm (FIG. 5B) and 350nm (Figure 5C).
  • TEM analyses indicate that HGC-BSA and HGC-mlL-36Ra (wt) loaded nanoparticles display a spherical shape similar to unloaded HGC but larger.
  • DSL analyses were performed daily for 5 days in HGC and HGC-BSA preparations maintained at 4 °C. No signifimayt changes in the average size were observed in the protein loaded and unloaded preparations.
  • the BSA release profile showed that 84 ⁇ 3% of the protein was released, from the HGC nanoparticles within 48 hours following linear kinetics; a minimal additional release was observed after that time. These results demonstrated the sustained release properties of HGC nanoparticles at a physiological pH.
  • RNA samples from E14.5 interzone cells and adjacent growth plate chondrocytes were obtained using laser capturing microdissection (LCM). After verifying RNA quality, specimens were subjected to microarray analysis. Normalized data were expressed as fold changes of a maydidate gene in the interzone sample compared to the expression found in the sample from adjacent growth plate chondrocyte. hlL-36RN was increased by 4.34 folds in the interzone compared to adjacent growth plate chondrocytes, indicating that hlL-3RN is a joint morphogenic articular cartilage chondroinductive factor.
  • h II-36RN was evaluated for its chondroprotective role in maintaining the homeostasis of the articular cartilage and its role related to OA degeneration.
  • a deficiency in IL-36 receptor antagonist correlates with the severity of cartilage degeneration.
  • FIG 7, consistently indicate a decrease in hlL-36RN in human cartilage and in several models for OA in experimental animals.
  • FIG. 7B In human knee cartilage with a range of histologically graded OA severity (from intact, grade 0 to end stage), (FIG. 7) the decrease in expressions of hlL-36RN correlated with OA severity.
  • FIG. 7B an ex-vivo model for injury-induced OA (FIG. 7B), in which Grade 0 human articular cartilage was mechanically injured (impacted), hlL-36RRN’s expression decreased after impact and remained decreased with the progression of degeneration (2 days and 14 days after impact).

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Abstract

La présente divulgation concerne de nouveaux composés décrits comprenant des peptides antagonistes du récepteur IL-36 modifiés pour une libération prolongée dans le temps et une distribution tissulaire cohérente. L'invention concerne également des méthodes de traitement de maladies caractérisées par une déficience en antagoniste du récepteur IL-36 telle que l'arthrose ou une défaillance ou un défaut dans la régénération d'un organe ou tissu endommagé.
PCT/US2024/039664 2023-07-27 2024-07-25 Nouveaux conjugués chitosane-il-36ra pour libération prolongée, ajustable et distribution tissulaire Pending WO2025024729A1 (fr)

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