Interleukin-13 binding cyclic oligopeptides and methods of using the same

Abstract

The present disclosure relates to cyclic oligopeptides that bind to interleukin-13 (IL-13), which are therapeutically useful in methods of treating or preventing IL-13-related skin disorders or conditions. The present disclosure also provides methods of treating or preventing an IL-13-related skin disorder or condition with an IL-13-binding cyclic oligopeptide. The present disclosure further provides methods of generating an IL-13-binding cyclic oligopeptide. The present disclosure provides cyclic oligopeptides that bind to IL-13, and methods of using such cyclic oligopeptides to treat IL-13-related skin disorders or conditions.

Description

Technical Field

[0001] Cross - reference to Related Applications This application is a PCT international application claiming the benefit of priority of U.S. Provisional Patent Application No. 63 / 351,712, filed on June 13, 2022, and U.S. Provisional Patent Application No. 63 / 418,715, filed on October 24, 2022. The content and disclosure of each of the foregoing applications are hereby incorporated by reference in their entirety into this specification. Sequence Listing This disclosure includes a sequence listing, which is submitted electronically in XML format and is hereby incorporated by reference in its entirety into this specification. The XML copy was created on June 13, 2023, named "000388 - 0004 - WO1.xml", and is 25,927 bytes in size.

Background Art

[0002] Background of the Disclosure Interleukin - 13 (IL - 13) is one of the important cytokines involved in type 2 (T2) immune responses. Recent studies have shown that IL - 13 plays an important role in driving inflammation in the periphery. IL - 13 is secreted from T lymphocytes and mast cells and has been identified as a major cytokine involved in atopic dermatitis (AD) inflammation, as demonstrated by local overexpression of IL - 13. IL - 13 affects skin biology through recruitment of inflammatory cells, changes in the skin microbiota, and reduction of epidermal barrier function. Alopecia areata (AA) is an autoimmune disorder that shares phenotypic similarities with AD, such as pruritus, elevated IgE levels, and filaggrin mutations. Genome studies in patients with AA have identified susceptibility of the IL - 13 gene. Furthermore, lesional scalp in AA patients has shown increased IL - 13 mRNA compared to non - lesional scalp. Additionally, AA patients have been shown to have significantly elevated serum IL - 13 levels compared to healthy control groups. IL-13 significantly affects the immune response and barrier function of the skin, in part due to its ability to activate STAT6, resulting in decreased expression of major structural proteins such as filaggrin, filaggrin 2, loricrin, involucrin, keratin 1, keratin 10, hornelin, desmoglein, and desmocollin 1, and a decrease in the lipid composition of the skin. These changes contribute to the increased trans-epidermal water loss (TEWL) that is characteristic of AD. IL-13 also reduces the production of AMP by keratinocytes and is thereby reported to be involved in the skin dysbiosis characterized by the strong colonization of Staphylococcus aureus that precedes the appearance of AD lesions.

[0003] In view of the role of IL-13 in the development and maintenance of the inflammatory response and its significant impact on the epidermal barrier function, pharmacological approaches targeting the pathways induced by IL-13 have been developed. Such approaches include small molecules that interfere with the interaction between IL-13 and its receptor; small molecules that interfere with intracellular signaling pathways, such as kinase inhibitors; and biological agents such as monoclonal antibodies that block IL-13 from binding to its receptor site. For example, tralokinumab is a fully human IgG4 antibody that binds to IL-13 at an epitope that overlaps with the binding site of the IL-13Rα receptor and prevents IL-13 from binding to both IL-13Rα1 and IL-13Rα2.

[0004] However, all of these approaches have significant limitations in their application to the treatment of dermatitis conditions and diseases such as AD and AA. For example, current treatments using topical corticosteroids for atopic dermatitis can cause undesirable side effects such as skin atrophy or thinning, striae or stretch marks, easy bruising, and telangiectasia. Continuous treatment with topical steroids can also result in withdrawal or rebound effects after treatment discontinuation, the symptoms of which include, for example, skin flushing, itching, and peeling. Furthermore, treatment with existing antibodies against AD such as tralokinumab is administered by injection. Accordingly, there remains a need for therapeutic agents that target IL-13 for treating skin diseases and conditions, particularly those suitable for topical application. SUMMARY OF THE INVENTION MEANS FOR SOLVING THE PROBLEM

[0005] SUMMARY OF THE DISCLOSURE The present disclosure provides cyclic oligopeptides that bind to IL-13 and methods of using such cyclic oligopeptides for treating IL-13-related skin disorders or conditions.

[0006] A first aspect of the present disclosure provides a cyclic oligopeptide that binds to IL-13. In some embodiments, the cyclic oligopeptide comprises between 2 and 22 amino acid residues. In some embodiments, the cyclic oligopeptide comprises between 6 and 8 amino acid residues. In some embodiments, the cyclic oligopeptide comprises an L-proline residue or a D-proline residue.

[0007] In some embodiments, the cyclic oligopeptide comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 1-11. In some embodiments, the cyclic oligopeptide comprises the amino acid sequence of D-ARG D-PHE D-VAL TYR GLU PRO (SEQ ID NO: 1). Optionally, the cyclic oligopeptide comprises the amino acid sequence of ARG THR D-VAL GLU D-PHE D-PRO (SEQ ID NO: 2), the cyclic oligopeptide of Embodiment 5. The cyclic oligopeptide may comprise the amino acid sequence of GLU D-THR D-VAL TRP D-PRO D-PRO (SEQ ID NO: 3). In some embodiments, the cyclic oligopeptide comprises the amino acid sequence of ARG GLU D-VAL TRP D-PRO D-PRO (SEQ ID NO: 4). Optionally, the cyclic oligopeptide comprises the amino acid sequence of TRP VAL ARG GLU D-PRO D-PRO (SEQ ID NO: 5). The cyclic oligopeptide may comprise the amino acid sequence of TYR ARG GLU D-THR D-VAL D-PRO (SEQ ID NO: 6). In some embodiments, the cyclic oligopeptide comprises the amino acid sequence of THR ARG D-PHE PRO D-LEU D-PRO (SEQ ID NO: 7). Optionally, the cyclic oligopeptide comprises the amino acid sequence of D-LEU ARG GLU PRO TRP MET PRO (SEQ ID NO: 8). The cyclic oligopeptide may comprise the amino acid sequence of D-ARG LEU D-TRP TRP D-THR GLU PRO (SEQ ID NO: 9). In some embodiments, the cyclic oligopeptide comprises the amino acid sequence of ARG ASP TYR CYS D-PRO D-TRP D-PRO (SEQ ID NO: 10). Optionally, the cyclic oligopeptide comprises the amino acid sequence of VAL PRO D-LEU D-TRP D-VAL LEU ARG PRO (SEQ ID NO: 11).

[0008] In some embodiments, the cyclic oligopeptide has the structure of any one of Compounds 1-11 as defined herein. In some embodiments, the cyclic oligopeptide has the structure of Compound 1 as defined herein. Optionally, the cyclic oligopeptide has the structure of Compound 2 as defined herein. The cyclic oligopeptide may have the structure of Compound 3 as defined herein. In some embodiments, the cyclic oligopeptide has the structure of Compound 4 as defined herein. Optionally, the cyclic oligopeptide has the structure of Compound 5 as defined herein. The cyclic oligopeptide may have the structure of Compound 6 as defined herein. In some embodiments, the cyclic oligopeptide has the structure of Compound 7 as defined herein. Optionally, the cyclic oligopeptide has the structure of Compound 8 as defined herein. The cyclic oligopeptide may have the structure of Compound 9 as defined herein. In some embodiments, the cyclic oligopeptide has the structure of Compound 10 as defined herein. Optionally, the cyclic oligopeptide has the structure of Compound 11 as defined herein.

[0009] In some embodiments, the cyclic oligopeptide is lipidated. In some embodiments, the cyclic oligopeptide is PEGylated.

[0010] A second aspect of the present disclosure provides a pharmaceutical formulation comprising a cyclic oligopeptide disclosed herein and a pharmaceutically acceptable carrier.

[0011] A third aspect of the present disclosure provides a method of treating or preventing an IL-13 related skin disorder or condition in a subject in need thereof. In some embodiments, the method comprises administering to the subject a therapeutically effective amount of a cyclic oligopeptide disclosed herein, or a combination thereof. In some embodiments, the subject is human.

[0012] In some embodiments, the IL-13 related skin disorder or condition is an inflammatory, allergic or autoimmune disorder or condition. In some embodiments, the IL-13 related skin disorder or condition is selected from the group consisting of atopic dermatitis, allergic contact dermatitis, urticaria, eczema, chronic hand eczema, vesicular disease (bullous pemphigoid), alopecia areata, prurigo and molluscum contagiosum. Optionally, the IL-13 related skin disorder or condition is atopic dermatitis. The IL-13 related skin disorder or condition can be allergic contact dermatitis. In some embodiments, the IL-13 related skin disorder or condition is urticaria. Optionally, the IL-13 related skin disorder or condition is eczema. The IL-13 related skin disorder or condition can be chronic hand eczema. In some embodiments, the IL-13 related skin disorder or condition is a vesicular disease (bullous pemphigoid). Optionally, the IL-13 related skin disorder or condition is alopecia areata. The IL-13 related skin disorder or condition can be prurigo. In some embodiments, the IL-13 related skin disorder or condition is molluscum contagiosum.

[0013] In some embodiments, the cyclic oligopeptide or combination thereof binds to IL-13 and reduces the biological activity of IL-13 and / or the IL-13 receptor (IL-13R). In some embodiments, the cyclic oligopeptide or combination thereof binds to IL-13. In some embodiments, the cyclic oligopeptide or combination thereof reduces the biological activity of IL-13 and / or the IL-13 receptor (IL-13R). In some embodiments, the cyclic oligopeptide or combination thereof reduces the biological activity of IL-13. In some embodiments, the cyclic oligopeptide or combination thereof reduces the biological activity of the IL-13 receptor (IL-13R). In some embodiments, the cyclic oligopeptide or combination thereof reduces the biological activity of IL-13 and the IL-13 receptor (IL-13R).

[0014] In some embodiments, the cyclic oligopeptide or a combination thereof is administered locally. Optionally, the cyclic oligopeptide or a combination thereof is administered transdermally. In some embodiments, the cyclic oligopeptide or a combination thereof is administered subcutaneously. Optionally, the cyclic oligopeptide or a combination thereof is administered intravenously. In some embodiments, the cyclic oligopeptide or a combination thereof is administered orally.

[0015] A third aspect of the present disclosure provides a method for generating a cyclic oligopeptide that binds to IL-13. In some embodiments, the method comprises: (1) contacting FMOC (9-fluorenylmethyloxycarbonyl)-D-Pro-2cl-resin or FMOC-Pro-2cl-resin with a first amino acid residue, under conditions suitable for forming a peptide bond between the first amino acid residue and D-Pro or Pro attached to the resin to form an oligopeptide attached to the resin; (2) washing the oligopeptide attached to the resin to remove unbound amino acid residues; (3) contacting the oligopeptide attached to the resin with a further amino acid residue, under conditions suitable for forming a peptide bond between the further amino acid residue and the oligopeptide attached to the resin; (4) washing the oligopeptide attached to the resin to remove any unbound amino acid residues; (5) removing the resin from the oligopeptide; and (6) cyclizing the oligopeptide.

[0016] In some embodiments, the conditions suitable for forming a peptide bond in steps (1) and (3) include the addition of O-(benzotriazol-1-yl)-N,N,N’,N’-tetramethyluronium tetrafluoroborate (TBTU). Optionally, the conditions suitable for forming a peptide bond in steps (1) and (3) further include the addition of N,N-dimethylformamide (DMF) and N,N-diisopropylethylamine (DIEA).

[0017] In some embodiments, steps (3) and (4) are repeated from 1 to 20 times before the resin is removed from the oligopeptide.

[0018] In some embodiments, the cyclization step involves forming a covalent bond with one or more amino groups of a linear oligopeptide and includes a carboxyl group of a D-Pro or Pro residue. In some embodiments, the cyclization step involves adding DMF, PyBOP (benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate), HOBT (1-hydroxybenzotriazole), and DIEA to the linear oligopeptide, and incubating the mixture at room temperature.

[0019] In some embodiments, the cyclic oligopeptide that binds to IL-13 is the cyclic oligopeptide disclosed herein.

[0020] Certain embodiments of the present disclosure are described in the following numbered paragraphs: 1. A cyclic oligopeptide that binds to IL-13. 2. The cyclic oligopeptide of embodiment 1, wherein the cyclic oligopeptide comprises amino acid residues between 2 and 22. 3. The cyclic oligopeptide of embodiment 2, wherein the cyclic oligopeptide comprises amino acid residues between 6 and 8. 4. The cyclic oligopeptide of any one of embodiments 1 to 3, wherein the cyclic oligopeptide comprises an L-proline residue or a D-proline residue. 5. The cyclic oligopeptide of any one of embodiments 1 to 4, wherein the cyclic oligopeptide comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 1 to 11. 6. The cyclic oligopeptide of embodiment 5, wherein the cyclic oligopeptide comprises the amino acid sequence D-ARG D-PHE D-VAL TYR GLU PRO (SEQ ID NO: 1). 7. The cyclic oligopeptide, wherein the cyclic oligopeptide comprises the amino acid The cyclic oligopeptide of Embodiment 5, comprising an array (array number 2). 8. The cyclic oligopeptide of Embodiment 5, wherein the cyclic oligopeptide comprises the amino acid sequence (SEQ ID NO: 3) of GLU D-THR D-VAL TRP D-PRO D-PRO. 9. The cyclic oligopeptide of Embodiment 5, wherein the cyclic oligopeptide comprises the amino acid sequence (SEQ ID NO: 4) of ARG GLU D-VAL TRP D-PRO D-PRO. 10. The cyclic oligopeptide of Embodiment 5, wherein the cyclic oligopeptide comprises the amino acid sequence (SEQ ID NO: 5) of TRP VAL ARG GLU D-PRO D-PRO. 11. The cyclic oligopeptide of Embodiment 5, wherein the cyclic oligopeptide comprises the amino acid sequence (SEQ ID NO: 6) of TYR ARG GLU D-THR D-VAL D-PRO. 12. The cyclic oligopeptide of Embodiment 5, wherein the cyclic oligopeptide comprises the amino acid sequence (SEQ ID NO: 7) of THR ARG D-PHE PRO D-LEU D-PRO. 13. The cyclic oligopeptide of Embodiment 5, wherein the cyclic oligopeptide comprises the amino acid sequence (SEQ ID NO: 8) of D-LEU ARG GLU PRO TRP MET PRO. 14. The cyclic oligopeptide of Embodiment 5, wherein the cyclic oligopeptide comprises the amino acid sequence (SEQ ID NO: 9) of D-ARG LEU D-TRP TRP D-THR GLU PRO. 15. The cyclic oligopeptide of Embodiment 5, wherein the cyclic oligopeptide comprises the amino acid sequence (SEQ ID NO: 10) of ARG ASP TYR CYS D-PRO D-TRP D-PRO. 16. The cyclic oligopeptide of Embodiment 5, wherein the cyclic oligopeptide comprises the amino acid sequence (SEQ ID NO: 11) of VAL PRO D-LEU D-TRP D-VAL LEU ARG PRO. 17. The cyclic oligopeptide of Embodiment 1, wherein the cyclic oligopeptide has the structure of any one of Compounds 1 to 11 as defined herein. 18. The cyclic oligopeptide of embodiment 17, wherein the cyclic oligopeptide has the structure of compound 1 as defined herein. 19. The cyclic oligopeptide of embodiment 17, wherein the cyclic oligopeptide has the structure of compound 2 as defined herein. 20. The cyclic oligopeptide of embodiment 17, wherein the cyclic oligopeptide has the structure of compound 3 as defined herein. 21. The cyclic oligopeptide of embodiment 17, wherein the cyclic oligopeptide has the structure of compound 4 as defined herein. 22. The cyclic oligopeptide of embodiment 17, wherein the cyclic oligopeptide has the structure of compound 5 as defined herein. 23. The cyclic oligopeptide of embodiment 17, wherein the cyclic oligopeptide has the structure of compound 6 as defined herein. 24. The cyclic oligopeptide of embodiment 17, wherein the cyclic oligopeptide has the structure of compound 7 as defined herein. 25. The cyclic oligopeptide of embodiment 17, wherein the cyclic oligopeptide has the structure of compound 8 as defined herein. 26. The cyclic oligopeptide of embodiment 17, wherein the cyclic oligopeptide has the structure of compound 9 as defined herein. 27. The cyclic oligopeptide of embodiment 17, wherein the cyclic oligopeptide has the structure of compound 10 as defined herein. 28. The cyclic oligopeptide of embodiment 17, wherein the cyclic oligopeptide has the structure of compound 11 as defined herein. 29. The cyclic oligopeptide of any one of embodiments 1 to 28, wherein the cyclic oligopeptide is lipidated. 30. The cyclic oligopeptide of any one of embodiments 1 to 28, wherein the cyclic oligopeptide is PEGylated. 31. A pharmaceutical formulation comprising the cyclic oligopeptide of any one of embodiments 1 to 30 and a pharmaceutically acceptable carrier. 32. A method of treating or preventing an IL-13-related skin disorder or condition in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of any one of the cyclic oligopeptides of Embodiments 1 to 30, or a combination thereof. 33. The method of Embodiment 32, wherein the subject is human. 34. The method of Embodiment 32 or 33, wherein the cyclic oligopeptide comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 1 to 11. 35. The method of Embodiments 32 to 34, wherein the cyclic oligopeptide has the structure of any one of Compounds 1 to 11. 36. The method of any one of Embodiments 32 to 35, wherein the IL-13-related skin disorder or condition is an inflammatory, allergic or autoimmune disorder or condition. 37. The method of any one of Embodiments 32 to 35, wherein the IL-13-related skin disorder or condition is selected from the group consisting of atopic dermatitis, allergic contact dermatitis, urticaria, eczema, chronic hand eczema, blistering diseases (bullous pemphigoid), alopecia areata, prurigo and molluscum contagiosum. 38. The method of any one of Embodiments 32 to 35, wherein the IL-13-related skin disorder or condition is atopic dermatitis. 39. The method of any one of Embodiments 32 to 35, wherein the IL-13-related skin disorder or condition is allergic contact dermatitis. 40. The method of any one of Embodiments 32 to 35, wherein the IL-13-related skin disorder or condition is urticaria. 41. The method of any one of Embodiments 32 to 35, wherein the IL-13-related skin disorder or condition is eczema. 42. The method of any one of Embodiments 32 to 35, wherein the IL-13-related skin disorder or condition is chronic hand eczema. 43. The method of any one of Embodiments 32 to 35, wherein the IL-13-related skin disorder or condition is a blistering disease (bullous pemphigoid). 44. The method of any one of Embodiments 32 to 35, wherein the IL-13-related skin disorder or condition is alopecia areata. 45. The method according to any one of embodiments 32 to 35, wherein the IL-13-related skin disorder or condition is prurigo. 46. The method according to any one of embodiments 32 to 35, wherein the IL-13-related skin disorder or condition is molluscum contagiosum. 47. The method according to any one of embodiments 32 to 46, wherein the cyclic oligopeptide or combination thereof binds to IL-13 and reduces the biological activity of IL-13 and / or the IL-13 receptor (IL-13R). 48. The method according to any one of embodiments 32 to 47, wherein the cyclic oligopeptide or combination thereof is administered topically. 49. The method according to any one of embodiments 32 to 47, wherein the cyclic oligopeptide or combination thereof is administered transdermally. 50. The method according to any one of embodiments 32 to 47, wherein the cyclic oligopeptide or combination thereof is administered subcutaneously. 51. The method according to any one of embodiments 32 to 47, wherein the cyclic oligopeptide or combination thereof is administered intravenously. 52. A method for generating a cyclic oligopeptide that binds to IL-13, comprising: (1) contacting FMOC (9-fluorenylmethyloxycarbonyl)-D-Pro-2cl-resin or FMOC-Pro-2cl-resin with a first amino acid residue, the step being carried out under conditions suitable for forming a peptide bond between the first amino acid residue and D-Pro or Pro bound to the resin to form an oligopeptide bound to the resin; (2) washing the oligopeptide bound to the resin to remove unbound amino acid residues; (3) contacting the oligopeptide bound to the resin with a further amino acid residue, the step being carried out under conditions suitable for forming a peptide bond between the further amino acid residue and the oligopeptide bound to the resin; (4) washing the oligopeptide bound to the resin to remove any unbound amino acid residues; (5) removing the resin from the oligopeptide; and (6) Step of cyclizing the oligopeptide A method comprising: 53. a) The method according to embodiment 52, wherein the conditions suitable for forming peptide bonds in steps (1) and (3) include the addition of O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate (TBTU). 54. The method according to embodiment 53, wherein the conditions suitable for forming peptide bonds in steps (1) and (3) further include the addition of N,N-dimethylformamide (DMF) and N,N-diisopropylethylamine (DIEA). 55. The method according to any one of embodiments 52 to 54, wherein steps (3) and (4) are repeated 1 to 20 times before the resin is removed from the oligopeptide. 56. The method according to any one of embodiments 52 to 55, wherein the step of cyclizing comprises a carboxyl group of a D-Pro or Pro residue that forms a covalent bond with one or more amino groups of the linear oligopeptide. 57. The method according to embodiment 52, wherein the step of cyclizing comprises the addition of DMF, PyBOP (benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate), HOBT (1-hydroxybenzotriazole), and DIEA to the linear oligopeptide, and incubation of these mixtures at room temperature. 58. The method according to any one of embodiments 52 to 57, wherein the cyclic oligopeptide that binds to IL-13 is any one of the cyclic oligopeptides of embodiments 1 to 30. 59. The cyclic oligopeptide according to any one of embodiments 1 to 30, having a skin permeability of at least 25% after 24 hours. 60. The cyclic oligopeptide according to any one of embodiments 1 to 30, having a skin permeability of at least 30% after 24 hours. 61. The cyclic oligopeptide according to any one of embodiments 1 to 30, having a skin permeability of at least 35% after 24 hours. 62. The cyclic oligopeptide according to any one of Embodiments 1 to 30, having a skin permeability of at least 40% after 24 hours. 63. The cyclic oligopeptide according to any one of Embodiments 1 to 30, having a skin permeability of at least 45% after 24 hours. 64. The cyclic oligopeptide according to any one of Embodiments 1 to 30, having a skin permeability of at least 50% after 24 hours. 65. The cyclic oligopeptide according to any one of Embodiments 1 to 30, having a skin permeability of at least 55% after 24 hours. 66. The cyclic oligopeptide according to any one of Embodiments 1 to 30, having a skin permeability of at least 60% after 24 hours. 67. The cyclic oligopeptide according to any one of Embodiments 1 to 30, having a skin permeability of at least 10% after 1 hour. 68. The cyclic oligopeptide according to any one of Embodiments 1 to 30, having a skin permeability of at least 15% after 1 hour. 69. The cyclic oligopeptide according to any one of Embodiments 1 to 30, having a skin permeability of at least 20% after 1 hour. 70. The cyclic oligopeptide according to any one of Embodiments 1 to 30, having a skin permeability of at least 25% after 1 hour. 71. The cyclic oligopeptide according to any one of Embodiments 1 to 30, having an average skin permeability coefficient of at least 1.0×10 -5 cm / hr after 24 hours. 72. The cyclic oligopeptide according to any one of Embodiments 1 to 30, having an average skin permeability coefficient of at least 2.0×10 -5 cm / hr after 24 hours. 73. The cyclic oligopeptide according to any one of Embodiments 1 to 30, having an average skin permeability coefficient of at least 5.0×10 -5Any one of the cyclic oligopeptides of Embodiments 1 to 30 having an average skin permeability coefficient of cm / hr. 74. Any one of the cyclic oligopeptides of Embodiments 1 to 30, wherein the cyclic oligopeptide has an average skin permeability coefficient of at least 1.0×10 -4 cm / hr after 24 hours. 75. Any one of the cyclic oligopeptides of Embodiments 1 to 30, wherein the cyclic oligopeptide has an average skin permeability coefficient of at least 1.0×10 -2 cm / hr after 1 hour. 76. Any one of the cyclic oligopeptides of Embodiments 1 to 30, wherein the cyclic oligopeptide has an average skin permeability coefficient of at least 2.0×10 -2 cm / hr after 1 hour. 77. Any one of the cyclic oligopeptides of Embodiments 1 to 30, wherein the cyclic oligopeptide has an average skin permeability coefficient of at least 3.0×10 -2 cm / hr after 1 hour. 78. Any one of the cyclic oligopeptides of Embodiments 1 to 30, wherein the cyclic oligopeptide has an average skin permeability coefficient of at least 4.0×10 -2 cm / hr after 1 hour. 79. Any one of the cyclic oligopeptides of Embodiments 1 to 30 and 59 to 78, wherein the cyclic oligopeptide is fast-acting after topical application. 80. Any one of the cyclic oligopeptides of Embodiments 1 to 30 and 59 to 78, wherein the cyclic oligopeptide is suitable for long-term delivery after topical application.

Brief Description of the Drawings

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Mode for Carrying Out the Invention

[0033] Detailed Description of the Disclosure Unless otherwise specifically defined herein, scientific and technical terms used in this application shall have the meanings generally understood by those skilled in the art. In case of conflict, this specification (including definitions) shall prevail.

[0034] Any embodiment described in this specification (including embodiments described only in the examples), including those described under different aspects of the present disclosure and different parts of this specification, can be combined with one or more other embodiments of the present disclosure, unless explicitly disclaimed or inappropriate. Combinations of embodiments are not limited to the specific combinations claimed via multiple dependent claims.

[0035] All publications, patents, and published patent applications referred to in this application are hereby incorporated by reference in their entirety. In case of conflict, the present specification (including its specific definitions) will control.

[0036] When aspects or embodiments are described in terms of Markush groups or other alternative groupings, this application is intended to cover not only the entire recited group as a whole, but also each individual member of the group, and all possible subgroups of the main group, and even the main group with one or more members of the group absent.

[0037] Throughout this specification, variations such as the words "comprise", "comprises", or "comprising" are to be understood to mean including the recited integer (or component) or group of integers (or components), but not to mean excluding other integers (or components) or group of integers (or components).

[0038] Throughout this specification, when a composition is described as having, including, or comprising (or a variation thereof) a particular component, it is intended that the composition may also consist essentially of or consist of the recited components. Similarly, when a method or process is described as having, including, or comprising a particular process step, the process may also consist essentially of or consist of the recited process steps. Further, it is to be understood that the order of steps or the order in which a particular operation is performed is not critical as long as the compositions and methods described herein remain practicable. Further, two or more steps or operations may be performed simultaneously.

[0039] As used herein, the term "including" means "including, but not limited to". The terms "including" and "including, but not limited to" are used interchangeably. Accordingly, these terms are understood to mean including the recited integer (or component) or group of integers (or components), but not to mean excluding other integers (or components) or group of integers (or components).

[0040] Any examples following the terms "e.g." or "for example" are not meant to be exhaustive or limiting.

[0041] Unless the context otherwise requires, singular terms shall include the plural and plural terms shall include the singular.

[0042] As used herein, the articles "a", "an", and "the" are used to refer to one or more (i.e., at least one) of the grammatical objects of the articles.

[0043] Although the numerical ranges and parameters disclosed are approximations, the numerical values set forth in the specific examples are reported as precisely as possible. Nevertheless, each numerical value inherently contains a certain error resulting from the standard deviation found in the individual test measurements. Accordingly, as used herein, the term "about" encompasses a variation of ±10%. As used herein, the term "about" refers to and (and describes) embodiments directed to the value or parameter itself. Further, all ranges disclosed herein are to be understood to encompass any and all subranges subsumed therein. For example, a range described as "1 to 10" includes any and all subranges between the minimum value of 1 and the maximum value of 10 (and including these values) and individual numerical values; that is, any minimum value of 1 or greater, for example, starting at 1 and ending at 6.1, any maximum value of 10 or less, for example, starting at 5.5 and ending at 10, or individual numerical values within the recited range or subranges, for example, 2, 5, 8, or 10.

[0044] As used herein, an amino acid having an L-configuration is represented using the standard three-letter code, e.g., Ala for alanine, Gly for glycine, Val for valine, Leu for leucine, Ile for isoleucine, Pro for proline, Ser for serine, Thr for threonine, Asn for asparagine, Gln for glutamine, Cys for cysteine, Met for methionine, Phe for phenylalanine, Tyr for tyrosine, Trp for tryptophan, Asp for aspartic acid, Glu for glutamic acid, His for histidine, Lys for lysine, and Arg for arginine. As used herein, an amino acid having a D-configuration is represented by adding "D-" before the standard three-letter code, e.g., D-Ala for D-alanine, D-Gly for D-glycine, D-Val for D-valine, D-Leu for D-leucine, D-Ile for D-isoleucine, D-Pro for D-proline, D-Ser for D-serine, D-Thr for D-threonine, D-Asn for D-asparagine, D-Gln for D-glutamine, D-Cys for D-cysteine, D-Met for D-methionine, D-Phe for D-phenylalanine, D-Tyr for D-tyrosine, D-Trp for D-tryptophan, D-Asp for D-aspartic acid, D-Glu for D-glutamic acid, D-His for D-histidine, D-Lys for D-lysine, and D-Arg for D-arginine.

[0045] Definitions To facilitate a better understanding of the present disclosure, certain terms are first defined. These definitions should be read in view of the remainder of the disclosure, as would be understood by one of ordinary skill in the art. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art.

[0046] As used herein, the terms "administer" and "administration" include any route suitable for providing the cyclic oligopeptides or pharmaceutical compositions of the present disclosure to a subject for the treatment of a skin disorder or condition, such as an IL-13 related skin disorder or condition. For example, the cyclic oligopeptides or pharmaceutical compositions can be administered topically, transdermally, subcutaneously, intravenously, or orally. Dosage forms useful in the methods of the present disclosure can include films, dispersions, suspensions, solutions, ointments, lotions, creams, powders, drops (e.g., eye drops or ear drops), sprays, and patches, among others. Administration can also be carried out, for example, once, a plurality of times, and / or over one or more extended periods. In some embodiments, administration includes both direct administration, including self-administration, and indirect administration, including the act of prescribing a drug. For example, as used herein, a physician who instructs a patient to self-administer a drug or to administer a drug to the patient by another person, and / or a physician who provides a prescription for a drug to the patient, will be administering the drug to the patient. Where the method is part of a treatment regimen that includes two or more pharmaceutical compositions or modes of treatment, the present disclosure contemplates that the pharmaceutical compositions can be administered at the same or different times via the same or different routes of administration.

[0047] As used herein, the terms "bind" and "binding" refer to the molecular binding of two or more molecules, such as the molecular binding of IL-13 and a cyclic oligopeptide, which is an attractive interaction between two or more molecules that results in a stable association of the molecules in proximity to each other. The strength of the molecular binding or affinity between the binding molecules in the present disclosure can be quantified, for example, by surface plasmon resonance (SPR) assay.

[0048] As used herein, the term "cyclic oligopeptide" refers to an oligopeptide chain containing a cyclic array of linkages. Cyclic oligopeptides are typically prepared first as linear oligopeptides and then cyclized, for example, by chemical or enzymatic means. The cyclic array of linkages can be formed, for example, by a linkage between the amino terminus and the carboxyl terminus of a linear oligopeptide, a linkage between the amino terminus of a linear oligopeptide and the side chain of one of the amino acid residues in the oligopeptide, a linkage between the carboxyl terminus of a linear oligopeptide and the side chain of one of the amino acid residues in the oligopeptide, and / or by the side chains of two different amino acid residues in the oligopeptide. The length of the cyclic oligopeptides of the present disclosure ranges from 2 amino acid residues to 20 amino acid residues. In some embodiments, the length of the cyclic oligopeptides of the present disclosure ranges from 4 amino acid residues to 10 amino acid residues. In some embodiments, the length of the cyclic oligopeptides of the present disclosure ranges from 6 amino acid residues to 10 amino acid residues.

[0049] As used herein, the term "dosage unit form" refers to physically discrete units suitable as unit dosages for the mammalian subject to be treated; each unit contains a predetermined quantity of the active compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier.

[0050] As used herein, the terms "interleukin-13" and "IL-13" refer to the protein encoded by the IL13 gene in humans, or the protein encoded by a homologous gene of the human IL13 gene in non-human species.

[0051] As used herein, the term "IL-13 related skin disorder or condition" refers to a skin disease, skin disorder or skin condition associated with a malfunction of IL-13 involved in immune regulation. The IL-13 related skin disorder or condition may be an inflammatory, allergic or autoimmune disorder or condition. Non-limiting examples of IL-13 related skin disorders or conditions include atopic dermatitis, allergic contact dermatitis, urticaria, eczema, chronic hand eczema, blistering diseases (bullous pemphigoid), alopecia areata, prurigo and molluscum contagiosum.

[0052] The term "oligopeptide" refers to a polymer of amino acid residues. This term also applies to amino acid polymers in which one or more amino acids are chemical analogs or modified derivatives of the corresponding naturally occurring amino acids.

[0053] As used herein, "pharmaceutically acceptable carrier" and "pharmaceutically acceptable excipient" are used interchangeably and refer to any physiologically compatible solvent, dispersion medium, coating, antibacterial and antifungal agents, as well as isotonic and absorption delaying agents, etc. Pharmaceutically acceptable carriers are well known in the art. See, for example, Remington’s Pharmaceutical Sciences and U.S. Pharmacopeia: National Formulary, Mack Publishing Company, Easton, PA (1984), which are incorporated herein by reference. Some examples of pharmaceutically acceptable carriers are water, saline, phosphate buffered saline, dextrose, glycerol, and ethanol, etc., as well as combinations thereof. In many cases, it may be preferable to include in the above compositions an isotonic agent, for example, a polyhydric alcohol such as sugars, mannitol, sorbitol or sodium chloride. Additional examples of pharmaceutically acceptable substances are wetting agents, or minor amounts of auxiliary substances, such as wetting or emulsifying agents, preservatives, or buffering agents, which enhance the shelf life or effectiveness of the antibody.The pharmaceutical composition can be prepared by mixing the antibodies disclosed herein with an acceptable carrier, excipient, or stabilizer in the form of, for example, a lyophilized powder, slurry, aqueous solution, or suspension (see, e.g., Brunton et al. (eds.), Goodman and Gilman’s The Pharmacological Basis of Therapeutics, Thirteenth Edition, (2018) McGraw-Hill, New York, NY; Adejare, A. (ed.), Remington: The Science and Practice of Pharmacy, Twenty-Third Edition, (2020) Academic Press, New York, NY; Nema, et al. (eds.), Pharmaceutical Dosage Forms: Parenteral Medications, Third Edition, (2010) Informa Healthcare, NY, Augsburger et al. (eds.), Pharmaceutical Dosage Forms: Tablets, Third Edition (2008) CRC Press, NY; Lieberman, et al. (eds.) Pharmaceutical Dosage Forms: Disperse Systems, Second Edition, (2010) Informa Helathcare, NY; Weiner and Kotkoskie, Excipient Toxicity and Safety, (2007) Informa Healthcare, New York, NY, each of which is incorporated herein by reference).

[0054] As used herein, the term "pharmaceutically acceptable salt" refers to salts suitable for pharmaceutical use, such as use without undue irritation and allergic reactions in humans and lower animals. Pharmaceutically acceptable salts of amines, carboxylic acids, and other types of compounds are well known in the art. For example, S.M. Berge et al. describe pharmaceutically acceptable salts in detail in J Pharmaceutical Sciences, 66: 1-19 (1977), which is incorporated herein by reference. The salts can be prepared in situ during the final isolation and purification of the cyclic oligopeptides disclosed herein, or can be prepared separately by reacting the free base functional group or the free acid functional group with a suitable reagent as generally described below. For example, the free base functional group can be reacted with a suitable acid. Suitable pharmaceutically acceptable salts include metal salts such as alkali metal salts, e.g., sodium salts, potassium salts, and lithium salts; and alkaline earth metal salts, e.g., calcium salts or magnesium salts. Examples of pharmaceutically acceptable non-toxic acid addition salts are salts of amino groups formed using inorganic acids, e.g., hydrochloric acid, hydrobromic acid, hydroiodic acid, phosphoric acid, sulfuric acid, and perchloric acid, salts of amino groups formed using organic acids, e.g., acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid, or salts of amino groups formed using other methods used in the art, e.g., ion exchange.Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemi sulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, and valerate, etc.

[0055] The term "residue", as used herein, refers to the position in an oligopeptide and the identity of the corresponding amino acid.

[0056] The terms "subject", "patient" and "individual" are used interchangeably and include, but are not limited to, human patients and non-human primates, as well as mammalian animals such as experimental animals, e.g., rabbits, dogs, cats, rats, mice and other animals. Thus, the term "subject" or "patient", as used herein, means a patient or subject of any mammalian animal to which the cyclic oligopeptides or related compositions of the present disclosure can be administered. In some embodiments, the subject is a human patient. Subjects of the present invention include those having an IL-13 related disorder or condition.

[0057] The term "therapeutically effective amount" or "therapeutically effective dose", as described herein, refers to the amount of the cyclic oligopeptides of the present disclosure that reduces to some extent one or more of the symptoms of an IL-13 related skin disease or condition in a patient, and this amount results in a beneficial and / or desired change, for example, in the overall health of a patient suffering from an IL-13 related skin disorder or condition. A complete therapeutic effect does not necessarily occur upon administration of a single dose and may occur only after administration of a series of doses. Thus, a therapeutically effective amount may be administered in one or multiple administrations. The exact effective amount required for a subject will depend, for example, on the size, health and age of the subject, the nature and extent of the disease, the therapeutic agent or combination of therapeutic agents selected for administration, and the mode of administration. A person of ordinary skill in the art can readily determine the effective amount for a given situation by routine experimentation. The methods of treatment or therapy described herein are not to be construed as "curing" the disease or limited to "curing" the disease.

[0058] As used herein, the term "treating" and its cognates refer to reversing, reducing, or preventing the symptoms, clinical signs, and underlying pathology of an IL-13 related skin disease or condition so as to improve or stabilize the condition of a subject. As used herein, and as is well understood in the art, "treatment" is an approach for obtaining a beneficial or desirable result, including clinical results. Beneficial or desirable results include, but are not limited to, alleviating or ameliorating one or more symptoms or conditions, reducing the degree of a disease, stabilizing the state of a disease (i.e., not worsening), preventing the spread of a disease, delaying or slowing the progression of a disease, relieving or temporarily reducing the disease state, reducing the recurrence of a disease, and remitting (partially or fully). In some embodiments, the term "treating atopic dermatitis" refers to an approach for obtaining one or more beneficial or desirable results including, but not limited to, alleviating or ameliorating: dry skin, pruritus, red to brownish-gray macules, small raised bumps, thickened, cracked, scaly skin, and sensitive, swollen skin that is raw from scratching. In some embodiments, the term "treating atopic dermatitis" refers to an approach for reducing the degree of one or more symptoms of atopic dermatitis, including, but not limited to, dry skin, pruritus, red to brownish-gray macules, small raised bumps, thickened, cracked, scaly skin, and sensitive, swollen skin that is raw from scratching. In some embodiments, the term "treating atopic dermatitis" refers to an approach for stabilizing (i.e., preventing worsening) the state of one or more symptoms of atopic dermatitis, including, but not limited to, dry skin, pruritus, red to brownish-gray macules, small raised bumps, thickened, cracked, scaly skin, and sensitive, swollen skin that is raw from scratching.In some embodiments, the term "treating atopic dermatitis" refers to an approach for preventing the spread of one or more symptoms of atopic dermatitis, where the one or more symptoms include, but are not limited to, dry skin, itching, red to brownish-gray patches, small raised bumps, thickened, cracked, scaly skin, and sensitive, swollen skin that is exposed due to scratching. In some embodiments, the term "treating atopic dermatitis" refers to an approach for delaying or slowing the progression of one or more symptoms of atopic dermatitis, where the one or more symptoms include, but are not limited to, dry skin, itching, red to brownish-gray patches, small raised bumps, thickened, cracked, scaly skin, and sensitive, swollen skin that is exposed due to scratching. In some embodiments, the term "treating atopic dermatitis" refers to an approach for reducing or alleviating the recurrence of one or more symptoms of atopic dermatitis, either partially or completely, where the one or more symptoms include, but are not limited to, dry skin, itching, red to brownish-gray patches, small raised bumps, thickened, cracked, scaly skin, and sensitive, swollen skin that is exposed due to scratching.

[0059] As used herein, the term "skin permeability" of a cyclic oligopeptide refers to the percentage of the cyclic oligopeptide that penetrates into artificial skin (Start M, Merck) measured using artificial skin and after a specific time. For example, if 60% of the total amount of the cyclic oligopeptide of the present disclosure penetrates into the artificial skin after 24 hours, the skin permeability of the cyclic oligopeptide is 60% after 24 hours.

[0060] As used herein, the term "skin permeability coefficient (Kp)" refers to the rate at which a cyclic oligopeptide measured using artificial skin (Start M, Merck) penetrates into this skin. In some embodiments, the permeability coefficient (Kp) (cm / hr) is calculated by the following formula:

Equation

[0061] As used herein, the term "rapid efficacy" or "immediate efficacy" refers to the ability of a drug to penetrate the skin at a relatively fast rate after application to the skin. In some embodiments, a drug with rapid efficacy or immediate efficacy has a skin permeation rate of at least 10% after 1 hour. In some embodiments, a drug with rapid efficacy or immediate efficacy has an average permeation coefficient of at least 1.0×10 -2 cm / hr. In some embodiments, a drug with rapid efficacy or immediate efficacy has an average permeation coefficient of at least 2.0×10 -2 cm / hr.

[0062] As used herein, the term "sustained delivery" refers to the ability of a drug to penetrate the skin over a relatively long period after application to the skin. In some embodiments, a sustained delivery agent has a skin permeation rate of at least 25% after 24 hours. In some embodiments, a sustained delivery agent has an average permeation coefficient of at least 1.0×10 -5 cm / hr. In some embodiments, a sustained delivery agent has an average permeation coefficient of at least 2.0×10 -5 cm / hr. The cyclic oligopeptides of the present disclosure

[0063] In a first aspect, the present disclosure provides cyclic oligopeptides that bind to IL-13. Without being bound by theory, the cyclic oligopeptides disclosed herein are advantageous for use as active ingredients in the treatment of diseases and in other contexts because they have both the high specificity of biological molecules and the bioavailability of small molecules. Furthermore, these cyclic oligopeptides can be topically applied with excellent skin permeability in a concentrated manner to skin regions affected by IL-13-related disorders or conditions. Although linear oligopeptides have been demonstrated to be effective when used against target extracellular receptors, their application is limited by instability due to degradation by proteases. The conformationally rigid cyclic oligopeptides disclosed herein are advantageous compared to their linear counterparts, in part because target affinity and specificity are improved and stability is improved due to resistance to proteolysis.

[0064] In some embodiments, the cyclic oligopeptide that binds to IL-13 comprises amino acid residues between 2 and 22. In some embodiments, the cyclic oligopeptide that binds to IL-13 comprises amino acid residues between 4 and 10. In some embodiments, the cyclic oligopeptide that binds to IL-13 comprises amino acid residues between 6 and 8. In some embodiments, the cyclic oligopeptide that binds to IL-13 comprises 6 amino acid residues. In some embodiments, the cyclic oligopeptide that binds to IL-13 comprises 7 amino acid residues. In some embodiments, the cyclic oligopeptide that binds to IL-13 comprises 8 amino acid residues.

[0065] In some embodiments, the cyclic oligopeptide that binds to IL-13 comprises an L-proline residue or a D-proline residue. In some embodiments, the cyclic oligopeptide that binds to IL-13 comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 1-11. In some embodiments, the cyclic oligopeptide that binds to IL-13 comprises the amino acid sequence of SEQ ID NO: 1. In some embodiments, the cyclic oligopeptide that binds to IL-13 comprises the amino acid sequence of SEQ ID NO: 2. In some embodiments, the cyclic oligopeptide that binds to IL-13 comprises the amino acid sequence of SEQ ID NO: 3. In some embodiments, the cyclic oligopeptide that binds to IL-13 comprises the amino acid sequence of SEQ ID NO: 4. In some embodiments, the cyclic oligopeptide that binds to IL-13 comprises the amino acid sequence of SEQ ID NO: 5. In some embodiments, the cyclic oligopeptide that binds to IL-13 comprises the amino acid sequence of SEQ ID NO: 6. In some embodiments, the cyclic oligopeptide that binds to IL-13 comprises the amino acid sequence of SEQ ID NO: 7. In some embodiments, the cyclic oligopeptide that binds to IL-13 comprises the amino acid sequence of SEQ ID NO: 8. In some embodiments, the cyclic oligopeptide that binds to IL-13 comprises the amino acid sequence of SEQ ID NO: 9. In some embodiments, the cyclic oligopeptide that binds to IL-13 comprises the amino acid sequence of SEQ ID NO: 10. In some embodiments, the cyclic oligopeptide that binds to IL-13 comprises the amino acid sequence of SEQ ID NO: 11.

[0066] In some embodiments, the cyclic oligopeptide that binds to IL-13 has the structure of any one of Compounds 1 to 11 as defined herein (see, for example, Table 1). In some embodiments, the cyclic oligopeptide that binds to IL-13 has the structure of Compound 1 as defined herein. In some embodiments, the cyclic oligopeptide that binds to IL-13 has the structure of Compound 2 as defined herein. In some embodiments, the cyclic oligopeptide that binds to IL-13 has the structure of Compound 3 as defined herein. In some embodiments, the cyclic oligopeptide that binds to IL-13 has the structure of Compound 4 as defined herein. In some embodiments, the cyclic oligopeptide that binds to IL-13 has the structure of Compound 5 as defined herein. In some embodiments, the cyclic oligopeptide that binds to IL-13 has the structure of Compound 6 as defined herein. In some embodiments, the cyclic oligopeptide that binds to IL-13 has the structure of Compound 7 as defined herein. In some embodiments, the cyclic oligopeptide that binds to IL-13 has the structure of Compound 8 as defined herein. In some embodiments, the cyclic oligopeptide that binds to IL-13 has the structure of Compound 9 as defined herein. In some embodiments, the cyclic oligopeptide that binds to IL-13 has the structure of Compound 10 as defined herein. In some embodiments, the cyclic oligopeptide that binds to IL-13 has the structure of Compound 11 as defined herein.

[0067] In some embodiments, the cyclic oligopeptide that binds to IL-13 has the structure of any one of Compounds 1 to 11 as defined herein (see, for example, Table 1), or a pharmaceutically acceptable salt thereof. In some embodiments, the cyclic oligopeptide that binds to IL-13 has the structure of Compound 1 as defined herein or a pharmaceutically acceptable salt thereof. In some embodiments, the cyclic oligopeptide that binds to IL-13 has the structure of Compound 2 as defined herein or a pharmaceutically acceptable salt thereof. In some embodiments, the cyclic oligopeptide that binds to IL-13 has the structure of Compound 3 as defined herein or a pharmaceutically acceptable salt thereof. In some embodiments, the cyclic oligopeptide that binds to IL-13 has the structure of Compound 4 as defined herein or a pharmaceutically acceptable salt thereof. In some embodiments, the cyclic oligopeptide that binds to IL-13 has the structure of Compound 5 as defined herein or a pharmaceutically acceptable salt thereof. In some embodiments, the cyclic oligopeptide that binds to IL-13 has the structure of Compound 6 as defined herein or a pharmaceutically acceptable salt thereof. In some embodiments, the cyclic oligopeptide that binds to IL-13 has the structure of Compound 7 as defined herein or a pharmaceutically acceptable salt thereof. In some embodiments, the cyclic oligopeptide that binds to IL-13 has the structure of Compound 8 as defined herein or a pharmaceutically acceptable salt thereof. In some embodiments, the cyclic oligopeptide that binds to IL-13 has the structure of Compound 9 as defined herein or a pharmaceutically acceptable salt thereof. In some embodiments, the cyclic oligopeptide that binds to IL-13 has the structure of Compound 10 as defined herein or a pharmaceutically acceptable salt thereof. In some embodiments, the cyclic oligopeptide that binds to IL-13 has the structure of Compound 11 as defined herein or a pharmaceutically acceptable salt thereof.

[0068] In some embodiments, the cyclic oligopeptide that binds to IL-13 is lipidated. In some embodiments, the cyclic oligopeptide that binds to IL-13 is PEGylated.

[0069] In some embodiments, the cyclic oligopeptide that binds to IL-13 has a skin permeability of at least 25% after 24 hours. In some embodiments, the cyclic oligopeptide that binds to IL-13 has a skin permeability of at least 30% after 24 hours. In some embodiments, the cyclic oligopeptide that binds to IL-13 has a skin permeability of at least 35% after 24 hours. In some embodiments, the cyclic oligopeptide that binds to IL-13 has a skin permeability of at least 40% after 24 hours. In some embodiments, the cyclic oligopeptide that binds to IL-13 has a skin permeability of at least 45% after 24 hours. In some embodiments, the cyclic oligopeptide that binds to IL-13 has a skin permeability of at least 50% after 24 hours. In some embodiments, the cyclic oligopeptide that binds to IL-13 has a skin permeability of at least 55% after 24 hours. In some embodiments, the cyclic oligopeptide that binds to IL-13 has a skin permeability of at least 60% after 24 hours. In some embodiments, the cyclic oligopeptide that binds to IL-13 has a skin permeability of 65% or less after 24 hours. In some embodiments, the cyclic oligopeptide that binds to IL-13 has a skin permeability of about 25% after 24 hours. In some embodiments, the cyclic oligopeptide that binds to IL-13 has a skin permeability of about 30% after 24 hours. In some embodiments, the cyclic oligopeptide that binds to IL-13 has a skin permeability of about 35% after 24 hours. In some embodiments, the cyclic oligopeptide that binds to IL-13 has a skin permeability of about 40% after 24 hours. In some embodiments, the cyclic oligopeptide that binds to IL-13 has a skin permeability of about 45% after 24 hours. In some embodiments, the cyclic oligopeptide that binds to IL-13 has a skin permeability of about 50% after 24 hours. In some embodiments, the cyclic oligopeptide that binds to IL-13 has a skin permeability of about 55% after 24 hours. In some embodiments, the cyclic oligopeptide that binds to IL-13 has a skin permeability of about 60% after 24 hours.

[0070] In some embodiments, the cyclic oligopeptide that binds to IL-13 has a skin permeability between 25% and 60% after 24 hours. In some embodiments, the cyclic oligopeptide that binds to IL-13 has a skin permeability between 25% and 55% after 24 hours. In some embodiments, the cyclic oligopeptide that binds to IL-13 has a skin permeability between 25% and 50% after 24 hours. In some embodiments, the cyclic oligopeptide that binds to IL-13 has a skin permeability between 25% and 45% after 24 hours. In some embodiments, the cyclic oligopeptide that binds to IL-13 has a skin permeability between 25% and 40% after 24 hours. In some embodiments, the cyclic oligopeptide that binds to IL-13 has a skin permeability between 25% and 35% after 24 hours. In some embodiments, the cyclic oligopeptide that binds to IL-13 has a skin permeability between 25% and 30% after 24 hours. In some embodiments, the cyclic oligopeptide that binds to IL-13 has a skin permeability between 30% and 60% after 24 hours. In some embodiments, the cyclic oligopeptide that binds to IL-13 has a skin permeability between 35% and 60% after 24 hours. In some embodiments, the cyclic oligopeptide that binds to IL-13 has a skin permeability between 40% and 60% after 24 hours. In some embodiments, the cyclic oligopeptide that binds to IL-13 has a skin permeability between 45% and 60% after 24 hours. In some embodiments, the cyclic oligopeptide that binds to IL-13 has a skin permeability between 50% and 60% after 24 hours. In some embodiments, the cyclic oligopeptide that binds to IL-13 has a skin permeability between 55% and 60% after 24 hours. In some embodiments, the cyclic oligopeptide that binds to IL-13 has a skin permeability between 30% and 50% after 24 hours. In some embodiments, the cyclic oligopeptide that binds to IL-13 has a skin permeability between 35% and 45% after 24 hours. In some embodiments, the cyclic oligopeptide that binds to IL-13 has a skin permeability between 30% and 40% after 24 hours.In some embodiments, the cyclic oligopeptide that binds to IL-13 has a skin permeability between 35% and 40% after 24 hours. In some embodiments, the cyclic oligopeptide that binds to IL-13 has a skin permeability between 40% and 45% after 24 hours.

[0071] In some embodiments, the cyclic oligopeptide that binds to IL-13 has a skin permeability of at least 10% after 1 hour. In some embodiments, the cyclic oligopeptide that binds to IL-13 has a skin permeability of at least 15% after 1 hour. In some embodiments, the cyclic oligopeptide that binds to IL-13 has a skin permeability of at least 20% after 1 hour. In some embodiments, the cyclic oligopeptide that binds to IL-13 has a skin permeability of at least 25% after 1 hour. In some embodiments, the cyclic oligopeptide that binds to IL-13 has a skin permeability of 30% or less after 1 hour. In some embodiments, the cyclic oligopeptide that binds to IL-13 has a skin permeability of about 10% after 1 hour. In some embodiments, the cyclic oligopeptide that binds to IL-13 has a skin permeability of about 15% after 1 hour. In some embodiments, the cyclic oligopeptide that binds to IL-13 has a skin permeability of about 20% after 1 hour. In some embodiments, the cyclic oligopeptide that binds to IL-13 has a skin permeability of about 25% after 1 hour.

[0072] In some embodiments, the cyclic oligopeptide that binds to IL-13 has a skin permeability between 10% and 25% after 1 hour. In some embodiments, the cyclic oligopeptide that binds to IL-13 has a skin permeability between 10% and 20% after 1 hour. In some embodiments, the cyclic oligopeptide that binds to IL-13 has a skin permeability between 10% and 15% after 1 hour. In some embodiments, the cyclic oligopeptide that binds to IL-13 has a skin permeability between 15% and 25% after 1 hour. In some embodiments, the cyclic oligopeptide that binds to IL-13 has a skin permeability between 20% and 25% after 1 hour. In some embodiments, the cyclic oligopeptide that binds to IL-13 has a skin permeability between 15% and 20% after 1 hour.

[0073] In some embodiments, the cyclic oligopeptide that binds to IL-13 has at least 1.0x10 -5 cm / hr average skin permeability coefficient after 24 hours. In some embodiments, the cyclic oligopeptide that binds to IL-13 has at least 2.0x10 -5 cm / hr average skin permeability coefficient after 24 hours. In some embodiments, the cyclic oligopeptide that binds to IL-13 has at least 5.0x10 -5 cm / hr average skin permeability coefficient after 24 hours. In some embodiments, the cyclic oligopeptide that binds to IL-13 has at least 1.0x10 -4 cm / hr average skin permeability coefficient after 24 hours. In some embodiments, the cyclic oligopeptide that binds to IL-13 has at least 2.0x10 -4 cm / hr average skin permeability coefficient after 24 hours. In some embodiments, the cyclic oligopeptide that binds to IL-13 has at least 3.0x10 -4 cm / hr average skin permeability coefficient after 24 hours. In some embodiments, the cyclic oligopeptide that binds to IL-13 has at least 4.0x10 -4It has an average skin permeability coefficient of cm / hr. In some embodiments, the cyclic oligopeptide that binds to IL-13 has an average skin permeability coefficient of 5.0x10 -4 cm / hr or less after 24 hours. In some embodiments, the cyclic oligopeptide that binds to IL-13 has an average skin permeability coefficient of about 1.0x10 -5 cm / hr after 24 hours. In some embodiments, the cyclic oligopeptide that binds to IL-13 has an average skin permeability coefficient of about 2.0x10 -5 cm / hr after 24 hours. In some embodiments, the cyclic oligopeptide that binds to IL-13 has an average skin permeability coefficient of about 5.0x10 -5 cm / hr after 24 hours. In some embodiments, the cyclic oligopeptide that binds to IL-13 has an average skin permeability coefficient of about 1.0x10 -4 cm / hr after 24 hours. In some embodiments, the cyclic oligopeptide that binds to IL-13 has an average skin permeability coefficient of about 2.0x10 -4 cm / hr after 24 hours. In some embodiments, the cyclic oligopeptide that binds to IL-13 has an average skin permeability coefficient of about 3.0x10 -4 cm / hr after 24 hours. In some embodiments, the cyclic oligopeptide that binds to IL-13 has an average skin permeability coefficient of about 4.0x10 -4 cm / hr after 24 hours. In some embodiments, the cyclic oligopeptide that binds to IL-13 has an average skin permeability coefficient of about 4.5x10 -4 cm / hr after 24 hours.

[0074] In some embodiments, the cyclic oligopeptide that binds to IL-13 has an average skin permeability coefficient of 1.0x10 -5 cm / hr to 5.0x10 -4 cm / hr after 24 hours. In some embodiments, the cyclic oligopeptide that binds to IL-13 has an average skin permeability coefficient of 5.0x10 -5 cm / hr to 5.0x10 -4has an average skin permeability coefficient between 1.0x10 -4 cm / hr and 5.0x10 -4 cm / hr. In some embodiments, the cyclic oligopeptide that binds to IL-13 has an average skin permeability coefficient between 1.0x10 -5 cm / hr and 1.0x10 -4 cm / hr after 24 hours. In some embodiments, the cyclic oligopeptide that binds to IL-13 has an average skin permeability coefficient between 1.0x10 -5 cm / hr and 5.0x10 -5 cm / hr. In some embodiments, the cyclic oligopeptide that binds to IL-13 has an average skin permeability coefficient between 5.0x10 -5 cm / hr and 1.0x10 -4 cm / hr.

[0075] In some embodiments, the cyclic oligopeptide that binds to IL-13 has an average skin permeability coefficient of at least 1.0x10 -2 cm / hr after 1 hour. In some embodiments, the cyclic oligopeptide that binds to IL-13 has an average skin permeability coefficient of at least 2.0x10 -2 cm / hr after 1 hour. In some embodiments, the cyclic oligopeptide that binds to IL-13 has an average skin permeability coefficient of at least 3.0x10 -2 cm / hr after 1 hour. In some embodiments, the cyclic oligopeptide that binds to IL-13 has an average skin permeability coefficient of at least 4.0x10 -2 cm / hr after 1 hour. In some embodiments, the cyclic oligopeptide that binds to IL-13 has an average skin permeability coefficient of at least 5.0x10 -2 cm / hr after 1 hour. In some embodiments, the cyclic oligopeptide that binds to IL-13 has an average skin permeability coefficient of 6.0x10 -2It has an average skin permeability coefficient of less than or equal to -2 cm / hr. In some embodiments, the cyclic oligopeptide that binds to IL-13 has an average skin permeability coefficient of about 1.0x10 -2 cm / hr. In some embodiments, the cyclic oligopeptide that binds to IL-13 has an average skin permeability coefficient of about 2.0x10 -2 cm / hr. In some embodiments, the cyclic oligopeptide that binds to IL-13 has an average skin permeability coefficient of about 3.0x10 -2 cm / hr. In some embodiments, the cyclic oligopeptide that binds to IL-13 has an average skin permeability coefficient of about 4.0x10 -2 cm / hr. In some embodiments, the cyclic oligopeptide that binds to IL-13 has an average skin permeability coefficient of about 5.0x10 -2 cm / hr.

[0076] In some embodiments, the cyclic oligopeptide that binds to IL-13 has an average skin permeability coefficient between 1.0x10 -2 cm / hr and 5.0x10 -2 cm / hr. In some embodiments, the cyclic oligopeptide that binds to IL-13 has an average skin permeability coefficient between 2.0x10 -2 cm / hr and 5.0x10 -2 cm / hr. In some embodiments, the cyclic oligopeptide that binds to IL-13 has an average skin permeability coefficient between 3.0x10 -2 cm / hr and 5.0x10 -2 cm / hr. In some embodiments, the cyclic oligopeptide that binds to IL-13 has an average skin permeability coefficient between 4.0x10 -2 cm / hr and 5.0x10 -2 cm / hr. In some embodiments, the cyclic oligopeptide that binds to IL-13 has an average skin permeability coefficient of 1.0x10 -2cm / hr to 4.0x10 -2 has an average skin permeability coefficient between cm / hr. In some embodiments, the cyclic oligopeptide that binds to IL-13 is 1.0x10 after 1 hour -2 cm / hr to 3.0x10 -2 cm / hr. In some embodiments, the cyclic oligopeptide that binds to IL-13 is 1.0x10 after 1 hour -2 cm / hr to 2.0x10 -2 cm / hr. In some embodiments, the cyclic oligopeptide that binds to IL-13 is 2.0x10 after 1 hour -2 cm / hr to 4.0x10 -2 cm / hr. In some embodiments, the cyclic oligopeptide that binds to IL-13 is 3.0x10 after 1 hour -2 cm / hr to 4.0x10 -2 cm / hr. In some embodiments, the cyclic oligopeptide that binds to IL-13 is 2.0x10 after 1 hour -2 cm / hr to 3.0x10 -2 cm / hr. Pharmaceutical Compositions and Administration

[0077] In a second aspect, the disclosure provides a pharmaceutical formulation comprising a cyclic oligopeptide disclosed herein and a pharmaceutically acceptable carrier. In some embodiments, the pharmaceutical composition comprises a therapeutically effective amount of the cyclic oligopeptide described herein.

[0078] The pharmaceutical composition can be in various forms, such as liquid, semi-solid and solid dosage forms, such as liquid solutions (e.g., injectable and infusible solutions), dispersions or suspensions, powders, capsules, pills, tablets as well as liposomes. The preferred form depends on the intended mode of administration and therapeutic application. In some embodiments, the pharmaceutical composition is in the form of an injectable or infusible solution. Optionally, the mode of administration is topical. The pharmaceutical composition can be administered by intravenous infusion or injection. In some embodiments, the pharmaceutical composition is formulated for subcutaneous injection. Optionally, the pharmaceutical composition is formulated for transdermal administration. In some embodiments, the cyclic oligopeptide is formulated into a tape or patch. Injectable formulations can be presented in unit dosage form in, for example, ampoules, pre-filled syringes, or multi-dose containers, with or without the addition of preservatives. The pharmaceutical composition can take the form of, for example, suspensions, solutions, or emulsions in oily or aqueous vehicles and can contain formulating agents, such as suspending, stabilizing and / or dispersing agents. Alternatively, the active ingredient can be prepared in powder form for reconstitution before use with a suitable vehicle, such as sterile pyrogen-free water.

[0079] Therapeutic compositions generally must be sterile and stable under the conditions of manufacture and storage. The compositions can be formulated as solutions, microemulsions, dispersions, liposomes, or other ordered structures suitable for high drug concentrations. Sterile injectable solutions can be prepared by incorporating the cyclic oligopeptide in the required amount into a suitable solvent having one or a combination of the ingredients enumerated above, followed by filter sterilization if necessary. Dispersions can be prepared by incorporating the cyclic oligopeptide into a sterile vehicle containing a basic dispersion medium and the other necessary ingredients (from those enumerated above). In the case of sterile powders for preparing sterile injectable solutions or topical solutions, preferred methods of preparation include vacuum drying and freeze drying to obtain the powder from a previously sterile filtered solution of the cyclic oligopeptide and any additional desirable ingredients. The proper fluidity of the solution can be maintained, for example, by the use of coatings such as lecithin, in the case of dispersions, by maintaining the required particle size, and / or by the use of surfactants. Prolongation of the absorption of injectable compositions can be brought about by including in the composition agents that delay absorption, such as monostearates and gelatin.

[0080] Pharmaceutical compositions can be administered by a variety of methods known in the art. In some embodiments, the route of administration / dosage form is topical, transdermal, subcutaneous injection, intravenous infusion, or oral. In some embodiments, the route of administration / dosage form is topical, transdermal, or subcutaneous injection. In some embodiments, the route of administration / dosage form is topical. In some embodiments, the route of administration / dosage form is transdermal. In some embodiments, the route of administration / dosage form is subcutaneous injection. In some embodiments, the route of administration / dosage form is intravenous infusion. In some embodiments, the route of administration / dosage form is oral. As will be understood by those skilled in the art, the route of administration and / or dosage form will vary depending on the desired results.

[0081] The dosing regimen can be adjusted so as to obtain an optimal desirable response (e.g., a therapeutic or prophylactic response). For example, a single bolus administration can be performed, doses can be administered over time in several portions, or the dose can be proportionally increased or decreased depending on the urgency of the treatment situation. For ease of administration and uniformity of dosage, it can be advantageous to formulate the pharmaceutical composition in dosage unit form. The specifications of the dosage unit form can be influenced by, and can directly depend on, (a) the characteristics specific to the cyclic oligopeptide and the particular therapeutic or prophylactic effect to be achieved, and (b) the limitations inherent in the technique of formulating such cyclic oligopeptide for the treatment of an individual's hypersensitivity. The value of the dosage can vary depending on the type and severity of the condition to be alleviated. For any particular subject, a specific dosing regimen can be adjusted over time according to the individual needs and the professional judgment of the person administering the composition or the person prescribing its administration, and the dosage ranges described herein are merely exemplary and are not intended to limit the scope or practice of the composition briefly described above. Methods of treating IL-13 related skin diseases and conditions

[0082] In a third aspect, the present disclosure provides a method of treating or preventing an IL-13 related skin disorder or condition in a subject in need thereof. In some embodiments, the method comprises administering to the subject a therapeutically effective amount of any one of the cyclic oligopeptides disclosed herein, or a combination thereof. In some embodiments, the subject is human. The cyclic oligopeptide can be administered as the pharmaceutical composition disclosed herein. The cyclic oligopeptide can be administered according to any of the administration routes disclosed herein.

[0083] In some embodiments, the cyclic oligopeptide used for treatment comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 1-11. In some embodiments, the cyclic oligopeptide used for treatment comprises the amino acid sequence of D-ARG D-PHE D-VAL TYR GLU PRO (SEQ ID NO: 1). Optionally, the cyclic oligopeptide used for treatment comprises the amino acid sequence of ARG THR D-VAL GLU D-PHE D-PRO (SEQ ID NO: 2), the cyclic oligopeptide of Embodiment 5. The cyclic oligopeptide used for treatment may comprise the amino acid sequence of GLU D-THR D-VAL TRP D-PRO D-PRO (SEQ ID NO: 3). In some embodiments, the cyclic oligopeptide used for treatment comprises the amino acid sequence of ARG GLU D-VAL TRP D-PRO D-PRO (SEQ ID NO: 4). Optionally, the cyclic oligopeptide used for treatment comprises the amino acid sequence of TRP VAL ARG GLU D-PRO D-PRO (SEQ ID NO: 5). The cyclic oligopeptide used for treatment may comprise the amino acid sequence of TYR ARG GLU D-THR D-VAL D-PRO (SEQ ID NO: 6). In some embodiments, the cyclic oligopeptide used for treatment comprises the amino acid sequence of THR ARG D-PHE PRO D-LEU D-PRO (SEQ ID NO: 7). Optionally, the cyclic oligopeptide used for treatment comprises the amino acid sequence of D-LEU ARG GLU PRO TRP MET PRO (SEQ ID NO: 8). The cyclic oligopeptide used for treatment may comprise the amino acid sequence of D-ARG LEU D-TRP TRP D-THR GLU PRO (SEQ ID NO: 9). In some embodiments, the cyclic oligopeptide used for treatment comprises the amino acid sequence of ARG ASP TYR CYS D-PRO D-TRP D-PRO (SEQ ID NO: 10). Optionally, the cyclic oligopeptide used for treatment comprises the amino acid sequence of VAL PRO D-LEU D-TRP D-VAL LEU ARG PRO (SEQ ID NO: 11).

[0084] In some embodiments, the cyclic oligopeptide used for treatment has the structure of any one of Compounds 1 to 11 as defined herein (see, for example, Table 1). In some embodiments, the cyclic oligopeptide used for treatment has the structure of Compound 1 as defined herein. Optionally, the cyclic oligopeptide used for treatment has the structure of Compound 2 as defined herein. The cyclic oligopeptide used for treatment may have the structure of Compound 3 as defined herein. In some embodiments, the cyclic oligopeptide used for treatment has the structure of Compound 4 as defined herein. Optionally, the cyclic oligopeptide used for treatment has the structure of Compound 5 as defined herein. The cyclic oligopeptide used for treatment may have the structure of Compound 6 as defined herein. In some embodiments, the cyclic oligopeptide used for treatment has the structure of Compound 7 as defined herein. Optionally, the cyclic oligopeptide used for treatment has the structure of Compound 8 as defined herein. The cyclic oligopeptide used for treatment may have the structure of Compound 9 as defined herein. In some embodiments, the cyclic oligopeptide used for treatment has the structure of Compound 10 as defined herein. Optionally, the cyclic oligopeptide used for treatment has the structure of Compound 11 as defined herein.

[0085] In some embodiments, the cyclic oligopeptide used for treatment has the structure of any one of Compounds 1 to 11 as defined herein (see, for example, Table 1), or a pharmaceutically acceptable salt thereof. In some embodiments, the cyclic oligopeptide used for treatment has the structure of Compound 1 as defined herein, or a pharmaceutically acceptable salt thereof. Optionally, the cyclic oligopeptide used for treatment has the structure of Compound 2 as defined herein, or a pharmaceutically acceptable salt thereof. The cyclic oligopeptide used for treatment may have the structure of Compound 3 as defined herein, or a pharmaceutically acceptable salt thereof. In some embodiments, the cyclic oligopeptide used for treatment has the structure of Compound 4 as defined herein, or a pharmaceutically acceptable salt thereof. Optionally, the cyclic oligopeptide used for treatment has the structure of Compound 5 as defined herein, or a pharmaceutically acceptable salt thereof. The cyclic oligopeptide used for treatment may have the structure of Compound 6 as defined herein, or a pharmaceutically acceptable salt thereof. In some embodiments, the cyclic oligopeptide used for treatment has the structure of Compound 7 as defined herein, or a pharmaceutically acceptable salt thereof. Optionally, the cyclic oligopeptide used for treatment has the structure of Compound 8 as defined herein, or a pharmaceutically acceptable salt thereof. The cyclic oligopeptide used for treatment may have the structure of Compound 9 as defined herein, or a pharmaceutically acceptable salt thereof. In some embodiments, the cyclic oligopeptide used for treatment has the structure of Compound 10 as defined herein, or a pharmaceutically acceptable salt thereof. Optionally, the cyclic oligopeptide used for treatment has the structure of Compound 11 as defined herein, or a pharmaceutically acceptable salt thereof.

[0086] In some embodiments, the IL-13 related skin disorder or condition is an inflammatory, allergic or autoimmune disorder or condition. In some embodiments, the IL-13 related skin disorder or condition is an inflammatory disorder or condition. In some embodiments, the IL-13 related skin disorder or condition is an allergic disorder or condition. In some embodiments, the IL-13 related skin disorder or condition is an autoimmune disorder or condition. In some embodiments, the IL-13 related skin disorder or condition is selected from the group consisting of atopic dermatitis, allergic contact dermatitis, urticaria, eczema, chronic hand eczema, vesicular disease (bullous pemphigoid), alopecia areata, and prurigo and molluscum contagiosum. In some embodiments, the IL-13 related skin disorder or condition is atopic dermatitis. In some embodiments, the IL-13 related skin disorder or condition is allergic contact dermatitis. In some embodiments, the IL-13 related skin disorder or condition is urticaria. In some embodiments, the IL-13 related skin disorder or condition is eczema. In some embodiments, the IL-13 related skin disorder or condition is chronic hand eczema. In some embodiments, the IL-13 related skin disorder or condition is vesicular disease (bullous pemphigoid). In some embodiments, the IL-13 related skin disorder or condition is alopecia areata. In some embodiments, the IL-13 related skin disorder or condition is prurigo. In some embodiments, the IL-13 related skin disorder or condition is molluscum contagiosum.

[0087] In some embodiments, one or more cyclic oligopeptides bind to IL-13 and reduce the biological activity of IL-13 and / or the IL-13 receptor (IL-13R). In some embodiments, one or more cyclic oligopeptides bind to IL-13 and reduce the biological activity of IL-13. In some embodiments, one or more cyclic oligopeptides bind to IL-13 and reduce the biological activity of the IL-13 receptor (IL-13R). In some embodiments, one or more cyclic oligopeptides bind to IL-13 and reduce the biological activity of IL-13 or the IL-13 receptor (IL-13R). In some embodiments, one or more cyclic oligopeptides bind to IL-13 and reduce the biological activity of IL-13 and the IL-13 receptor (IL-13R).

[0088] In some embodiments, the present disclosure provides a method of treating or preventing an IL-13-related skin disorder or condition in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of any one of the cyclic oligopeptides of the present disclosure, or a combination thereof. In some embodiments, the cyclic oligopeptide or combination thereof is administered topically. In some embodiments, the cyclic oligopeptide or combination thereof is administered transdermally. In some embodiments, the cyclic oligopeptide or combination thereof is administered subcutaneously. In some embodiments, the cyclic oligopeptide or combination thereof is administered intravenously. In some embodiments, the cyclic oligopeptide or combination thereof is administered orally. Methods for orally administering biologically active proteins and peptides are known in the art. Many strategies have been proposed to prevent the degradation of orally administered peptides. Examples of methods for orally administering cyclic oligopeptides include, but are not limited to, the following uses: core-shell particles (US7,090,868) and nanotubes (US7,195,780); liposomes and aqueous emulsions and suspensions (US7,316,818; WO06 / 062544; US6,071,535; and US5,874,105); gas-filled liposomes (US6,551,576; US6,808,720; and US7,083,572); nano-droplets dispersed in an aqueous medium (US2007 / 0184076); matrix carriers containing peptide-effectors that penetrate through biological barriers to the administration of hydrophobic proteins (WO06 / 097793, WO05 / 094785, and WO03 / 066859); the use of non-covalent protein-polysaccharide conjugates (EP0491114B1); the use of the pharmaceutical compositions described in US8,936,786; the use of the Peptelligence® system (US8,377,863; WO2014 / 138241; and WO2016 / 115082) (all of these publications and patents are expressly incorporated herein by reference).

[0089] Method for producing cyclic oligopeptide In a fourth aspect, the present disclosure provides a method for generating a cyclic oligopeptide that binds to IL-13. In some embodiments, the method comprises: (1) contacting an FMOC (9-fluorenylmethyloxycarbonyl)-D-Pro-2cl-resin or an FMOC-Pro-2cl-resin with a first amino acid residue, under conditions suitable for forming a peptide bond between the first amino acid residue and D-Pro or Pro attached to the resin to form an oligopeptide attached to the resin; (2) washing the oligopeptide attached to the resin to remove unbound amino acid residues; (3) contacting the oligopeptide attached to the resin with a further amino acid residue, under conditions suitable for forming a peptide bond between the further amino acid residue and the oligopeptide attached to the resin; (4) washing the oligopeptide attached to the resin to remove any unbound amino acid residues; (5) removing the resin from the oligopeptide; and (6) cyclizing the oligopeptide.

[0090] In some embodiments, the conditions suitable for forming a peptide bond in steps (1) and (3) include the addition of O-(benzotriazol-1-yl)-N,N,N’,N’-tetramethyluronium tetrafluoroborate (TBTU). In some embodiments, the conditions suitable for forming a peptide bond in steps (1) and (3) further include the addition of N,N-dimethylformamide (DMF) and N,N-diisopropylethylamine (DIEA). In some embodiments, steps (3) and (4) are repeated from 1 to 20 times before the resin is removed from the oligopeptide.

[0091] In some embodiments, the cyclization step involves the carboxyl group of a D-Pro or Pro residue that forms a covalent bond with one or more amino groups of the linear oligopeptide. In some embodiments, the cyclization step involves the addition of DMF, PyBOP (benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate), HOBT (1-hydroxybenzotriazole), and DIEA to the linear oligopeptide, and incubation of these mixtures at room temperature.

[0092] In some embodiments, the cyclic oligopeptide that binds to IL-13 is the cyclic oligopeptide disclosed herein. In some embodiments, the methods disclosed herein are used to generate the cyclic oligopeptides of the present disclosure.

Examples

[0093] Exemplary methods and materials are described herein, but methods and materials similar or equivalent to those described herein can also be used in the practice or testing of various aspects and embodiments of the present disclosure. The materials, methods, and examples are illustrative only and are not intended to be limiting. (Example 1) Generation of a cyclic oligopeptide that binds to IL-13

[0094] The cyclic oligopeptides of the present disclosure were generated using the following steps: 1) FMOC (9-fluorenylmethyloxycarbonyl)-D-Pro-2cl-resin or FMOC-Pro-2cl-resin (selected according to the sequence and structure of the oligopeptide to be generated) was weighed, placed in a glass reaction column, dichloromethane (methylene chloride or DCM) was added, and incubated for 30 minutes to swell the resin. 2) The DCM was removed in vacuo. 3) The resin 3 was washed several times with N,N-dimethylformamide (DMF). 4) 20% piperidine / DMF solution was added and incubated for 20 minutes to remove the FMOC protecting group. 5) The liquid solution was removed by vacuum and the resin was washed 6 times with DMF. 6) The second amino acid to be added to the N-terminus of D-Pro or Pro and TBTU (O-(benzotriazol-1-yl)-N,N,N’,N’-tetramethyluronium tetrafluoroborate) were weighed and added to the resin. 7) DIEA (N,N-diisopropylethylamine) was dissolved in DMF, added to the resin, and reacted for 30 minutes. The progress of the reaction was monitored using a color detection reaction. The reaction was determined to be complete when the solution turned bright yellow and the resin turned yellow. 8) The solvent was removed by vacuum. 9) Steps 6) to 8) were repeated to add each additional amino acid residue to the N-terminus of the growing oligopeptide until the last amino acid residue was added to the oligopeptide. The last amino acid residue is the C-terminus of the first D-Pro or Pro residue and the subsequently cyclized residue as shown in the structure of Table 1 below. 10) The resin was washed 3 times with DMF, DCM, and methanol and dried by vacuum. 11) A fully protected dissolution solution was added and the resin was removed by filtering the solution using a sand core. 12) 0.5 ml of DIEA (N,N-diisopropylethylamine) was added to the filtrate. 13) DCM was removed from the filtrate by spin drying using a vacuum rotary evaporator until the solution became viscous. Analytically pure DMF, PyBOP (benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate), HOBT (1-hydroxybenzotriazole), and DIEA were added and incubated at room temperature for 4 hours. 14) After the reaction was completed, an acidic solution was added to separate the solid and dried under vacuum. 15) A dissolution solution was added to remove the protecting group from the amino acid side chain. 16) Ether was added to the solution, and the solid product was separated, centrifuged, washed three times, and then dried under vacuum.

[0095] The synthesized cyclic oligopeptides were analyzed for purity and structural characteristics by MS (mass spectrometry) (see Figures 2A, 3A, 4A, 5A, 6A, 7A, 8A, 9A, 10A, 11A, and 12A) and HPLC (see Figures 2B, 3B, 4B, 5B, 6B, 7B, 8B, 9B, 10B, 11B, and 12B). Exemplary structures and amino acid sequences of cyclic oligopeptides that bind to IL-13 are shown in Table 1.

Table 1-1

Table 1-2

Table 1-3

Table 1-4

Table 1-5

Table 1-6

Table 1-7

Table 1-8

[0096] The cyclic oligopeptide created in Example 1 was subjected to an SPR assay using a BIAcore 8K plus device (GE Healthcare) to determine its binding affinity for IL-13. Human IL-13 with an Fc tag was immobilized on the surface of a Series S Sensor CM5 (GE Healthcare) chip within the range of 5000 resonance units (RU). The binding kinetics were performed at a flow rate of 30 μL / min at 25°C. The cyclic oligopeptide was analyzed in a running buffer containing 20 mM PBS, 2.7 mM KCl, 37 mM NaCl, 0.05% Surfactant P20, pH 7.4, and 1% DMSO, starting from 100 μM and using a 10-fold serial dilution gradient in solvent correction mode. The K D The affinity between IL-13 and the cyclic oligopeptide, as indicated by the K value, was determined using the BIAcore 8K plus evaluation software.

[0097] The efficiency and effectiveness of the SPR assay were confirmed using tralokinumab, a monoclonal antibody against IL-13, as a positive control. Figures 2C, 3C, 4C, 5C, 6C, 7C, 8C, 9C, 10C, 11C, and 12C provide the SPR response curves of the cyclic oligopeptides created in Example 1, where the x-axis represents the reaction time and the y-axis represents the height of the response (response units). As summarized in Table 2 below, the exemplary cyclic oligopeptides of the present disclosure were shown to bind to IL-13 with K values in the range of 16 to 622 μM based on the SPR results. D values.

Table 2

[0098] The skin permeability of the cyclic oligopeptide prepared in Example 1 was measured using a Transdermal Diffusion Tester (TK-12D, Shanghai Kai Kai Industrial Co Ltd) and artificial skin (Start M, Merck). For each sample, three parallel experimental groups were set up. The skin permeability of the cyclic oligopeptide was evaluated by the following steps: 1) 2.0 mg of the cyclic oligopeptide was weighed and dissolved in 100 μL of DMSO. For each cyclic oligopeptide, three parallel experimental groups were set up. The cyclic oligopeptide-containing solution was then slowly added dropwise to 1900 μL of 1×PBS solution and mixed uniformly to prepare a PBS solution containing 1.0 mg / mL of the cyclic polypeptide at a final concentration. 2) The magnetron was inserted into the Franz cell diffusion cell, and the artificial skin was sandwiched in the center of the diffusion cell with the smooth surface of the artificial skin facing up. Then, after the diffusion cell was assembled, it was fixed with a clamp. 3) Then, 7.75 ml of 1×PBS solution was added to the diffusion cell while preventing bubbles from forming inside the diffusion cell. Then, the sampling port of the diffusion cell was sealed with parafilm to suppress evaporation. 4) Then, the temperature of the Transdermal Diffusion Tester was set to 32°C, and the magnetron speed was set to 180 r / min. 5) Then, the assembled diffusion cell was placed in the Transdermal Diffusion Tester and preheated for 5 - 10 min. 6) Then, 400 μL of the 1.0 mg / mL cyclic oligopeptide solution prepared in step 1) was added to the upper chamber of the diffusion cell and uniformly dispersed on the surface of the artificial skin without bubbles. Then, the top port of the diffusion cell was covered with parafilm to suppress evaporation. 7) Starting from the time when the cyclic oligopeptide solution was added, at six time points of 1 h, 2 h, 4 h, 8 h, 12 h, and 24 h, a plastic pipette was used to take out a sample from the sampling port of the diffusion cell, and a sample of about 0.5 mL of the receiving solution was collected. The receiving solution was prepared by adding 0.5 mL of 1×PBS solution to the diffusion cell to restore the initial volume. During sampling, the diffusion cell was tilted appropriately to avoid the generation of bubbles. Then, the samples were numbered and stored at -20°C. 8) The BCA assay (Micro BCA Protein Assay Kit, Thermo Scientific) was performed to measure the concentration of the cyclic oligopeptide in the samples obtained in step 7) (the actual concentration of the cyclic oligopeptide at a specific time point). Three parallel groups were used. The weight of the cyclic oligopeptide in each sample obtained in step 7) is equal to the actual concentration × 0.5 mL. 9) The permeability of each cyclic oligopeptide at each time point was calculated according to the following formula:

Equation

[0099] All cyclic oligopeptides had an average permeability of more than 25% after 24 hours. As shown in Table 3, Compound 9 and Compound 10 had a permeability of more than 60% after 24 hours. Compound 1 and Compound 5 had a permeability between 40% and 50% after 24 hours. Compound 2, Compound 3, Compound 4, Compound 6, Compound 7, and Compound 8 had a permeability between 30% and 40% after 24 hours. Compound 11 had a permeability of approximately 26% after 24 hours. As shown in FIGS. 2D, 3D, 4D, 5D, 6D, 7D, 8D, 9D, 10D, 11D, and 12D, the permeability of the oligopeptides steadily increased from 1 hour to 24 hours. These data indicated that the skin permeation efficiency of the cyclic oligopeptides of the present disclosure was relatively high over a relatively long period.

[0100] Furthermore, as shown in Table 3 and FIGS. 2D, 3D, 4D, 5D, 6D, 7D, 8D, 9D, 10D, 11D, and 12D, all cyclic oligopeptides had an average permeability of more than 10% after 1 hour. Compound 5, Compound 7, and Compound 9 had a permeability of more than 20% after 1 hour. Compound 1, Compound 3, Compound 4, Compound 6, and Compound 10 had a permeability between 15% and 20% after 1 hour. Compound 2, Compound 8, and Compound 11 had a permeability between 10% and 15% after 24 hours. These data demonstrated the rapid efficacy of the oligopeptides of the present disclosure when topically applied, based on the relatively high percentage of skin permeability within the first hour. [Table 3]

[0101] The value of the skin permeation coefficient (Kp) (cm / hr) of the cyclic oligopeptides was also calculated by the following formula: [Equation] (where Q (mg) refers to the total amount of cyclic oligopeptide passing through the artificial skin within a specific time; A (cm 2represents the internal cross-sectional area of the artificial skin in the diffusion cell; T (hr) represents the total time of cyclic oligopeptide permeation; ΔC (mg / mL) represents the concentration difference of the cyclic oligopeptide between both sides of the artificial skin).

[0102] As shown in Table 4 and as shown in FIGS. 2E, 3E, 4E, 5E, 6E, 7E, 8E, 9E, 10E, 11E and 12E, all cyclic oligopeptides had an average Kp value of more than 2×10 -5 after 24 hours. Compounds 1, 4, 8, 9 and 10 had an average Kp value higher than 1×10 -4 cm / hr after 24 hours. Compounds 2, 3, 5, 6, 7 and 11 had an average Kp value between 1×10 -5 cm / hr and 1×10 -4 cm / hr after 24 hours. These data also showed that the cyclic oligopeptides of the present disclosure can penetrate the skin over a relatively long period of time.

[0103] Furthermore, as also shown in Table 4 and as also shown in FIGS. 2E, 3E, 4E, 5E, 6E, 7E, 8E, 9E, 10E, 11E and 12E, all cyclic oligopeptides had an average Kp value of more than 2×10 -2 cm / hr within the first hour, indicating that the cyclic oligopeptides of the present disclosure were fast-acting after topical application to the skin.

Table 4

Claims

1. A cyclic oligopeptide that binds to IL-13.

2. The cyclic oligopeptide according to claim 1, wherein the cyclic oligopeptide comprises amino acid residues between 2 and 22.

3. The cyclic oligopeptide according to claim 1 or 2, wherein the cyclic oligopeptide comprises an L-proline residue or a D-proline residue.

4. The aforementioned cyclic oligopeptide (a) D-ARG D-PHE D-VAL TYR GLU PRO (Sequence ID 1); (b) ARG THR D-VAL GLU D-PHE D-PRO (Sequence ID 2); (c) GLU D-THR D-VAL TRP D-PRO D-PRO (Sequence ID 3); (d) ARG GLU D-VAL TRP D-PRO D-PRO (Sequence ID 4); (e) TRP VAL ARG GLU D-PRO D-PRO (Sequence ID 5); (f) TYR ARG GLU D-THR D-VAL D-PRO (Sequence ID 6); (g) THR ARG D-PHE PRO D-LEU D-PRO (Sequence ID 7); (h) D-LEU ARG GLU PRO TRP MET PRO (Sequence ID 8); (i) D-ARG LEU D-TRP TRP D-THR GLU PRO (Sequence ID 9); (j) ARG ASP TYR CYS D-PRO D-TRP D-PRO (Sequence ID 10); and (k) VAL PRO D-LEU D-TRP D-VAL LEU ARG PRO (SEQ ID NO: 11) A cyclic oligopeptide according to claim 1 or 2, comprising an amino acid sequence selected from the group consisting of the following.

5. The cyclic oligopeptide has the structure of any one of compounds 1 to 11 or a pharmaceutically acceptable salt thereof. Compound 1, 【Chemistry 1】 or having a pharmaceutically acceptable salt structure thereof; Compound 2, 【Chemistry 2】 or having a pharmaceutically acceptable salt structure thereof; Compound 3, 【Transformation 3】 or having a pharmaceutically acceptable salt structure thereof; Compound 4, 【Chemistry 4】 or having a pharmaceutically acceptable salt structure thereof; Compound 5, 【Transformation 5】 or having a pharmaceutically acceptable salt structure thereof; Compound 6, 【Transformation 6】 or having a pharmaceutically acceptable salt structure thereof; Compound 7, 【Transformation 7】 or having a pharmaceutically acceptable salt structure thereof; Compound 8, 【Transformation 8】 or having a pharmaceutically acceptable salt structure thereof; Compound 9, 【Chemistry 9】 or having a pharmaceutically acceptable salt structure thereof; Compound 10, 【Chemistry 10】 or having a pharmaceutically acceptable salt structure thereof; Compound 11, 【Chemistry 11】 A cyclic oligopeptide according to claim 1 or 2, having the structure of a pharmaceutically acceptable salt thereof.

6. The cyclic oligopeptide has the structure of any one of compounds 1 to 11, Compound 1, 【Chemistry 12】 It has the structure of; Compound 2, 【Chemistry 13】 It has the structure of; Compound 3, 【Chemistry 14】 It has the structure of; Compound 4, 【Chemistry 15】 It has the structure of; Compound 5, 【Chemistry 16】 It has the structure of; Compound 6, 【Chemistry 17】 It has the structure of; Compound 7, [Chemistry 18] It has the structure of; Compound 8, 【Chemistry 19】 It has the structure of; Compound 9, 【Chemistry 20】 It has the structure of; Compound 10, 【Chemistry 21】 It has the structure of; Compound 11, 【Chemistry 22】 A cyclic oligopeptide according to claim 1 or 2, having the structure described above.

7. A pharmaceutical or cosmetic formulation comprising a cyclic oligopeptide according to claim 1 or 2 and a pharmaceutically or cosmetically acceptable carrier.

8. A composition comprising the cyclic oligopeptide according to claim 1 or 2 for treating or preventing IL-13-related skin disorders or conditions in subjects requiring such treatment or prevention, or a pharmaceutical or cosmetic formulation comprising the cyclic oligopeptide according to claim 1 or 2 and a pharmaceutically or cosmetically acceptable carrier.

9. The aforementioned cyclic oligopeptide (a) Whether it contains an amino acid sequence selected from the group consisting of SEQ ID NOs: 1 to 11; (b) Having the structure of any one of compounds 1 to 11 or a pharmaceutically acceptable salt thereof; or (c) The composition, pharmaceutical formulation or cosmetic formulation according to claim 8, having the structure of any one of compounds 1 to 11.

10. The composition, pharmaceutical formulation or cosmetic formulation according to claim 8, wherein the IL-13-related skin disorder or condition is inflammation, allergy, or autoimmune disorder or condition, and optionally, the IL-13-related skin disorder or condition is selected from the group consisting of atopic dermatitis, allergic contact dermatitis, urticaria, eczema, chronic hand eczema, bullous disease (bullous pemphigoid), alopecia areata, prurigo, and molluscum contagiosum.

11. The composition, pharmaceutical formulation, or cosmetic formulation according to claim 8, wherein the cyclic oligopeptide or a combination thereof is administered topically, transdermally, subcutaneously, or intravenously.

12. A method for producing a cyclic oligopeptide that binds to IL-13, (1) A step of contacting an FMOC(9-fluorenylmethyloxycarbonyl)-D-Pro-2cl-resin or an FMOC-Pro-2cl-resin with a first amino acid residue, wherein the step is carried out under conditions suitable for forming a peptide bond between the first amino acid residue and the D-Pro or Pro bonded to the resin, thereby forming an oligopeptide bonded to the resin; (2) A step of washing the oligopeptides bound to the resin to remove any unbound amino acid residues; (3) A step of bringing the oligopeptide bound to the resin into contact with further amino acid residues, wherein the step is carried out under conditions suitable for forming peptide bonds between the further amino acid residues and the oligopeptide bound to the resin; (4) Washing the oligopeptides bound to the resin to remove any unbound amino acid residues; (5) The step of removing the resin from the oligopeptide; and (6) Step of cyclizing the oligopeptide. Methods that include...

13. a) The conditions suitable for forming peptide bonds in steps (1) and (3) include the addition of O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate (TBTU); b) The conditions suitable for forming peptide bonds in steps (1) and (3) further include the addition of N,N-dimethylformamide (DMF) and N,N-diisopropylethylamine (DIEA); c) Steps (3) and (4) are repeated 1 to 20 times before the resin is removed from the oligopeptide; d) The cyclization step includes the carboxyl group of the D-Pro or Pro residue that forms a covalent bond with one or more amino groups of the linear oligopeptide; e) The cyclization step comprises adding DMF, PyBOP (benzotriazole-1-yloxytripyrrolidinophosphonium hexafluorophosphate), HOBT (1-hydroxybenzotriazole), and DIEA to the linear oligopeptide, and incubation of the mixture thereof at room temperature; and / or f) The method according to claim 12, wherein the cyclic oligopeptide bound to IL-13 is the cyclic oligopeptide according to claim 1 or 2.

14. The cyclic oligopeptide according to claim 1 or 2, wherein the cyclic oligopeptide has a skin permeability of at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, or at least 60% after 24 hours, and / or the cyclic oligopeptide has a skin permeability of at least 10%, at least 15%, at least 20%, or at least 25% after 1 hour.

15. The cyclic oligopeptide contains at least 1.0 × 10⁶ units after 24 hours. －５ cm / hr, at least 2.0 × 10⁻⁶ －５ cm / hr, at least 5.0 × 10 －５ cm / hr, or at least 1.0 × 10⁻⁶ －４ Having an average skin permeability coefficient of cm / hr, and / or, the cyclic oligopeptide has at least 1.0 × 10⁻¹⁶ of permeability after 1 hour. －２ cm / hr, at least 2.0 × 10⁻⁶ －２ cm / hr, at least 3.0 × 10⁻⁶ －２ cm / hr, or at least 4.0 × 10⁻⁶ －２ A cyclic oligopeptide according to claim 1 or 2, having an average skin permeability coefficient of cm / hr.

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