IL1RA-derived peptide for the treatment of diabetic nephropathy

Abstract

The present disclosure relates to peptides derived from the IL-1R antagonist protein (IL1RA) for the treatment of, and for use in, the treatment of diabetic nephropathy.

Description

Technical Field

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[0001] The present disclosure relates to peptides derived from interleukin-1 receptor antagonist protein (IL1RA) for the treatment of diabetic nephropathy.

Background Art

[0002] Interleukin 1 (IL-1) is a common name for two different pro-inflammatory cytokine proteins, IL-1α and IL-1β. IL-1 exerts its effects by binding to specific transmembrane receptors (IL-1R) on multiple cell types. The effects of IL-! are counteracted by natural inhibitors such as soluble IL-1 receptor and interleukin-1 receptor antagonist protein (IL1RA). IL1RA inhibits the effects of IL-1 by blocking its interaction with cell surface receptors.

[0003] Therapeutic approaches for targeting IL-1 for anti-inflammatory purposes have been addressed in the art. These include administration of recombinant IL-1 receptor antagonist protein, IL-1 trap fusion protein, anti-IL-1 antibody, anti-IL-1RI, and soluble IL-1RI and II in experimental models of arthritis (reviewed in Non-Patent Document 1).

[0004] Anakinra (Patent Document 1) is a recombinant production protein containing a methionylated non-glycosylated version of human IL-1RA that blocks the action of IL-1 without detectable agonist activity. Anakinra has been tested for the treatment of rheumatoid arthritis, adult-onset Still's disease, systemic-onset juvenile idiopathic arthritis, osteoarthritis, and type 2 diabetes mellitus. Anakinra is approved for the treatment of rheumatoid arthritis; it is delivered as a 100 mg injection concentrate at each dose; it is prepared from genetically modified Escherichia coli using recombinant DNA technology; and it has a high molecular weight.

[0005] Patent documents 2 and 3 disclose a 10-amino acid peptide derived from IL1RA: SGRKSSKMQA (SEQ ID NO: 1) and its use in the treatment of various disorders. SEQ ID NO: 1 has been previously shown to inhibit interleukin-1β-induced NF-κB signaling and macrophage secretion of TNFα, and is therefore a potent inhibitor of inflammatory responses (Non-patent document 2).

[0006] Diabetic nephropathy (DKD), also known as diabetic nephropathy, has historically not been considered an immune-mediated disease, as metabolic and hemodynamic factors have been thought to be the primary causes of kidney damage. However, recent research supports the role of the innate immune system in both the onset and progression of DKD. Associations between both systemic and focal nephritis and increased levels of pro-inflammatory and anti-inflammatory cytokines, including IL-1 and IL-4, have been found in the kidneys of patients with diabetic nephropathy, and in some cases in the peripheral blood, compared to healthy controls (Non-patent Literature 3-5).

[0007] Progressive non-infectious inflammation involves glomeruli and tubular cells, leading to a gradual loss of renal function. Blood glucose and blood pressure must be kept as normal as possible to slow the loss of renal function. However, no specific treatment for this congenital inflammation has been developed, and the decline in glomerular filtration and tubular function does not stop, leading to continued loss of renal function. In end-stage renal failure, treatment involves chronic dialysis, and in some cases, kidney transplantation. Therefore, interventions that prevent or stop the planned pro-inflammatory decline in all nephron functions must focus on suppressing renal inflammation.

[0008] Patients are diagnosed with diabetic nephropathy by measuring albumin in their urine. Urinary albumin is often measured in a spot urine sample and corrected for creatinine in the same urine sample (ACR mg / g). ACR is divided into three groups: normal albuminuria ACR < 30 mg / g, microalbuminuria ACR > 30 mg / g < 300 mg / g, and macroalbuminuria ACR > 300 mg / g. There is clinical evidence that higher ACR indicates more advanced kidney damage.

[0009] Urinary albumin and kidney injury molecule-1 (KIM-1) are both biomarkers for congenital renal inflammation found in various autoimmune diseases involving the kidney, as well as other non-autoimmune diseases (Non-Patent Literature 6-8). Human renal biopsies have confirmed the presence of inflammatory cells in both the glomeruli, tubules, and interstitium at all stages of diabetic nephropathy (Non-Patent Literature 9 and 10). [Prior art documents] [Patent Documents]

[0010] [Patent Document 1] U.S. Patent No. 5075222 [Patent Document 2] International Publication No. 2012 / 122985 [Patent Document 3] International Publication No. 2017 / 063657 [Non-patent literature]

[0011] [Non-Patent Document 1] Gabay C et al. 2010 [Non-Patent Document 2] Klementiev 2014 [Non-Patent Document 3] Hickey 2018 [Non-Patent Document 4] Araujo 2020 [Non-Patent Document 5] Murakoshi 2020 [Non-Patent Document 6] Coca 2017 [Non-Patent Document 7] Cai 2019 [Non-Patent Document 8] Levey 2019 [Non-Patent Document 9] Kahn 2019 [Non-Patent Document 10] Calle 2021

Summary of the Invention

Problems to be Solved by the Invention

[0012]

Means for Solving the Problems

[0013] The IL1RA-derived peptides according to the present disclosure are shown herein to significantly reduce albuminuria corrected for creatinine (ACR) and kidney injury molecule-1 corrected for creatinine (KIM-1 / CR). Both albuminuria and KIM-1 are biomarkers of renal innate inflammation seen in various kidney-related diseases, including diabetic nephropathy.

[0014] Since diabetic nephropathy has not historically been regarded as an immune-mediated disease, there is a need for compounds and medicaments that address the immune-mediated and renal inflammatory aspects of diabetic nephropathy.

[0015] Based on the experimental data provided herein, the IL4RA-derived peptides and compounds according to the present disclosure are likely to be able to prevent or halt the expected reduction in inflammation induction in various functions of the renal nephrons.

[0016] Based on the experimental data provided herein, the IL4RA-derived peptides and compounds according to the present disclosure are likely to be able to inhibit the renal inflammation observed in diabetic nephropathy.

[0017] In one aspect, the present disclosure relates to a method for treating diabetic nephropathy, comprising administering an effective amount of a compound to an individual who needs it, wherein the compound is a peptide derived from an IL-1R antagonist protein (IL1RA), or a variant thereof that is at least 70% identical to the peptide derived from IL1RA.

[0018] According to one aspect, the present disclosure relates to a compound for use in the treatment of diabetic nephropathy, which is a peptide derived from the IL-1R antagonist protein (IL1RA), or a variant thereof that is at least 70% identical to the peptide derived from IL1RA.

[0019] According to one aspect, the present disclosure relates to the use of a compound for manufacturing a medicament for treating diabetic nephropathy, wherein the compound is a peptide derived from the IL-1R antagonist protein (IL1RA), or a variant thereof that is at least 70% identical to the peptide derived from IL1RA.

[0020] According to one aspect, the present disclosure relates to a method for treating diabetic nephropathy, which comprises administering an effective amount of a compound to an individual who needs it, wherein the compound comprises one or more peptides, and each peptide consists of the amino acid sequence SGRKSSKMQA (SEQ ID NO: 1), or a variant of SEQ ID NO: 1 comprising 1, 2 or 3 amino acid substitutions.

[0021] According to one aspect, the present disclosure relates to a compound for use in the treatment of diabetic nephropathy, wherein the compound comprises one or more peptides, and each peptide consists of the amino acid sequence SGRKSSKMQA (SEQ ID NO: 1), or a variant of SEQ ID NO: 1 comprising 1, 2 or 3 amino acid substitutions.

[0022] According to one aspect, the present disclosure relates to the use of a compound for manufacturing a medicament for treating diabetic nephropathy, wherein the compound comprises one or more peptides, and each peptide consists of the amino acid sequence SGRKSSKMQA (SEQ ID NO: 1), or a variant of SEQ ID NO: 1 comprising 1, 2 or 3 amino acid substitutions.

[0023] In one embodiment, the present disclosure relates to a method for treating diabetic nephropathy, comprising administering an effective amount of a polymer compound to an individual in need thereof, wherein the polymer compound comprises at least two peptides, each peptide consisting of the amino acid sequence SGRKSSKMQA (SEQ ID NO: 1), or a variant of SEQ ID NO: 1 comprising one, two, or three amino acid substitutions.

[0024] In one embodiment, the present disclosure relates to a polymer compound for use in the treatment of diabetic nephropathy, wherein the polymer compound comprises at least two peptides, each peptide consisting of the amino acid sequence SGRKSSKMQA (SEQ ID NO: 1), or a variant of SEQ ID NO: 1 comprising one, two, or three amino acid substitutions.

[0025] In one embodiment, the disclosure relates to the use of a polymer compound for manufacturing a pharmaceutical for treating diabetic nephropathy, wherein the polymer compound comprises at least two peptides, each peptide consisting of the amino acid sequence SGRKSSKMQA (SEQ ID NO: 1), or a variant of SEQ ID NO: 1 comprising one, two, or three amino acid substitutions.

[0026] In one embodiment, the present disclosure relates to a method for treating diabetic nephropathy, comprising administering an effective amount of a compound to an individual in need thereof, wherein the compound is a peptide comprising the amino acid sequence of SEQ ID NO: 1 (SGRKSSKMQA) or a variant of SEQ ID NO: 1 comprising one or two conservative amino acid substitutions.

[0027] In one embodiment, the present disclosure relates to a compound for use in the treatment of diabetic nephropathy, wherein the compound is a peptide comprising the amino acid sequence of SEQ ID NO: 1 (SGRKSSKMQA) or a variant of SEQ ID NO: 1 comprising one or two conservative amino acid substitutions.

[0028] In one embodiment, the disclosure relates to the use of a compound for manufacturing a pharmaceutical for treating diabetic nephropathy, wherein the compound is a peptide comprising the amino acid sequence of SEQ ID NO: 1 (SGRKSSKMQA) or a variant of SEQ ID NO: 1 comprising one or two conservative amino acid substitutions.

[0029] According to one embodiment, the present disclosure relates to a method for treating diabetic nephropathy, comprising administering an effective amount of a polymer compound to an individual in need thereof, wherein the polymer compound is i) Two or more peptides consisting of 10 to 14 consecutive amino acid residues derived from IL1RA, wherein each peptide is: a. Consisting of the amino acid sequence of Sequence ID No. 1 and, optionally, an additional amino acid sequence of up to 11-14 amino acid residues; or b. A peptide consisting of a variant of SEQ ID NO: 1 comprising one conservative amino acid substitution and optionally an additional amino acid residue of up to 11-14 amino acid residues, and ii) Depending on the case, it may consist of one or more linker groups.

[0030] According to one aspect, the present disclosure relates to a polymer compound for use in the treatment of diabetic nephropathy, wherein the polymer compound is i) Two or more peptides consisting of 10 to 14 consecutive amino acid residues derived from IL1RA, wherein each peptide is: a. Consisting of the amino acid sequence of Sequence ID No. 1 and, optionally, an additional amino acid sequence of up to 11-14 amino acid residues; or b. A peptide consisting of a variant of SEQ ID NO: 1 comprising one conservative amino acid substitution and optionally an additional amino acid residue of up to 11-14 amino acid residues, and ii) Depending on the case, it may consist of one or more linker groups.

[0031] In one aspect, the disclosure relates to the use of a polymer compound for the manufacture of a pharmaceutical product for treating diabetic nephropathy, wherein the polymer compound is i) Two or more peptides consisting of 10 to 14 consecutive amino acid residues derived from IL1RA, wherein each peptide is: a. Consisting of the amino acid sequence of Sequence ID No. 1 and, optionally, an additional amino acid sequence of up to 11-14 amino acid residues; or b. A peptide consisting of a variant of SEQ ID NO: 1 comprising one conservative amino acid substitution and optionally an additional amino acid residue of up to 11-14 amino acid residues, and ii) Depending on the case, it may consist of one or more linker groups. [Brief explanation of the drawing]

[0032] [Figure 1] Figure 1 shows creatinine-corrected urinary albumin (ACR) in urine samples from renin-AAV unilateral nephrectomized db / db (renin-AAV UNx) mice after treatment with vehicle, 3 mg / kg SER140, 10 mg / kg SER140, and 20 mg / kg SER140 over a 77-day period. Figure 1 shows the median values ​​for different groups. See Example 1. [Figure 2] Figure 2 shows the corrected urinary KIM-1 (KIM-1 / CR) for creatinine in urine samples after treatment with 3 mg / kg SER140, 10 mg / kg SER140, and 20 mg / kg SER140 over 77 days in renin-AAV unilateral nephrectomy (renin-AAV UNx) mice. Figure 2 shows the mean values ​​for different groups. See Example 1. [Modes for carrying out the invention]

[0033] Definitions and abbreviations ACR: Albumin Corrected for Creatinine DKD: Diabetic kidney disease. IL1RA or IL1Ra: The IL-1 receptor antagonist protein may also be referred to as the IL-1 receptor antagonist in this specification. IL-1: Interleukin-1. IL1R1 or IL1R1: IL1 receptor type 1. KIM-1: Kidney Injury Molecule-1 KIM-1 / CR: KIM-1 corrected for creatinine Renin-AAV UNx mice: Renin-AAV unilateral nephrectomy db / db mice

[0034] The terms "diabetic nephropathy" and "diabetic kidney disease (DKD)" are used interchangeably to refer to the same condition. Diabetic nephropathy is a type of progressive kidney disease that can occur in individuals with diabetes mellitus. It affects individuals with type 1 and type 2 diabetes, and the risk increases with the duration of the disease as well as other risk factors such as hypertension and a family history of kidney disease.

[0035] The term “individual” refers to vertebrates, specific members of mammalian species, preferably primates including humans. Where used herein, “subject” and “individual” may be used interchangeably.

[0036] "An individual that needs it" refers to an individual that can benefit from this disclosure. In one embodiment, the individual that needs it is a diseased individual. In one embodiment, the individual that needs it is a diseased individual, in particular an individual having diabetes mellitus type 1 or type 2.

[0037] "Simultaneous administration" or "co-administration" of the compounds and other pharmaceuticals of this disclosure, as used herein, means administering one or more compounds and another pharmaceutical within a certain period of time. This period may be less than 72 hours, e.g., 48 hours, e.g., less than 24 hours, e.g., less than 12 hours, e.g., less than 6 hours, e.g., less than 3 hours. However, these terms also mean that the compounds and therapeutic compositions may be administered together. Co-administration may be simultaneous, separate, or sequential.

[0038] An "effective dose" of a compound can be administered in a single dose or through multiple doses totaling the effective dose, for example, within 24 hours. It can be determined using standard clinical procedures for determining the appropriate dose and timing of administration. It is understood that the "effective dose" may be the result of empirical and / or individualized (case-by-case) decisions on the part of the treating healthcare professional and / or individual.

[0039] As used herein, “sequence identity” refers to the number of amino acid residues that exactly match between two different sequences being compared. If a variant is 90% identical to a sequence having 10 amino acid residues, the variant may differ from the sequence by a single amino acid substitution.

[0040] As used herein, the terms “to treat,” “treatment,” and “therapy” are equivalent to curative therapy, prophylactic or preventive therapy, and modal or palliative therapy. This term includes approaches to obtain clinically established beneficial or desired physiological outcomes. For the purposes of this disclosure, beneficial or desired clinical outcomes include, but are not limited to, symptom relief, reduction in the severity of the disease, stabilized (i.e., non-exacerbating) symptoms, delay or stagnation of the progression or worsening of symptoms / symptoms, improvement or remission of symptoms or symptoms, and remission (whether partial or total), whether detectable or undetectable. As used herein, the term “remission” and its variations mean that the severity and / or undesirable signs of a physiological symptom or symptom are reduced and / or the time course of progression is slowed or prolonged compared to no administration of the composition of this disclosure.

[0041] A “treatment effect” or “therapeutic effect” is observed when there is a change in the treated symptom, measured by the criteria that constitute the definitions of the terms “treatment” and “treatment.” There is a “change” in the treated symptom if there is an improvement of at least 5%, or 10%, or at least 25%, or at least 50%, for example, at least 75%, or at least 100%. The change may be based on an improvement in the severity of the treated symptom in the individual, or on a difference in the frequency of the improved symptom between a population of individuals treated with the compound or the compound in combination with the pharmaceutical composition of this disclosure and a population of individuals that are not treated.

[0042] The actions described herein may be preventive, corrective, or curative.

[0043] The term "variant" means that the peptide sequence can be modified, for example, by the substitution of one or more amino acid residues. Both L-amino acids and D-amino acids may be used. Other modifications may include derivatives such as esters and sugars, e.g., methyl and acetyl esters, as well as polyethylene glycol modifications.

[0044] Furthermore, the amine group of the peptide may be converted to an amide, and the acidic portion of the amide is a fatty acid.

[0045] The group of conserved amino acids is as follows: A, G (neutral, weakly hydrophobic), Q, N, S, T (hydrophilic, uncharged) E, D (hydrophilic, acidic) H, K, R (hydrophilic, basic) L, P, I, V, M, F, Y, W (hydrophobic, aromatic) C (crosslink formation)

[0046] Conservative substitutions may be introduced at any position of a given peptide preferred for use in accordance with this disclosure. However, it may also be desirable to introduce non-conservative substitutions, not limited to any one or more positions.

[0047] The peptide sequences of this disclosure may be prepared by any conventional synthesis method, recombinant DNA technology, enzymatic cleavage of a full-length protein from which the peptide sequence is derived, or a combination thereof.

[0048] Formulations of the compounds of this disclosure can be prepared by techniques known to those skilled in the art. The formulations may contain pharmaceutically acceptable carriers and excipients, including microspheres, liposomes, microcapsules, and nanoparticles. The active compounds may be formulated in neutral or salt form.

[0049] Detailed description of the invention According to one embodiment, the present disclosure relates to a method for treating diabetic nephropathy, comprising administering an effective amount of a compound to an individual in need thereof, wherein the compound is a peptide derived from the IL-1R antagonist (IL1RA) protein, or a variant thereof that is at least 70% identical to the peptide derived from IL1RA.

[0050] According to one embodiment, the present disclosure relates to a compound for use in the treatment of diabetic nephropathy, which is a peptide derived from the IL-1R antagonist (IL1RA) protein, or a variant thereof that is at least 70% identical to a peptide derived from IL1RA.

[0051] According to one embodiment, the present disclosure relates to the use of a compound for manufacturing a pharmaceutical for treating diabetic nephropathy, wherein the compound is a peptide derived from IL-1R antagonist protein (IL1RA), or a variant thereof that is at least 70% identical to a peptide derived from IL1RA.

[0052] In one embodiment of this disclosure, the IL1RA protein has a sequence selected from SEQ ID NOs: 2-5. In one embodiment of this disclosure, the IL1RA protein has a sequence selected from SEQ ID NOs: 2-4.

[0053] In one embodiment of this disclosure, the IL1RA protein is Sequence ID No. 1.

[0054] In one embodiment of this disclosure, the IL1RA protein is Sequence ID No. 2.

[0055] In one embodiment of this disclosure, the IL1RA protein is SEQ ID NO: 3.

[0056] In one embodiment of this disclosure, the IL1RA protein is SEQ ID NO: 4.

[0057] In another embodiment of the present disclosure, the compound to be used is a peptide consisting of 5 to 35 adjacent amino acid residues derived from an IL1RA protein sequence selected from SEQ ID NOs: 2 to 5, or a variant thereof that is at least 70% identical to a peptide derived from an IL1RA protein sequence selected from SEQ ID NOs: 2 to 5.

[0058] In another embodiment of the present disclosure, the peptide consists of up to 30 adjacent amino acid residues, or up to 25 adjacent amino acid residues, or up to 20 adjacent amino acid residues, or up to 15 adjacent amino acid residues, or up to 10 adjacent amino acid residues, derived from an IL1RA protein sequence selected from SEQ ID NOs: 2-5.

[0059] In another embodiment of the present disclosure, the peptide consists of 5 to 35 adjacent amino acid residues from an IL1RA protein sequence selected from SEQ ID NOs: 2 to 5, or 5 to 30, 5 to 25, 5 to 20, 5 to 15, 10 to 20, or 8 to 18 adjacent amino acid residues from an IL1RA protein sequence selected from SEQ ID NOs: 2 to 5.

[0060] In another embodiment of the present disclosure, the peptide consists of 5 to 35 adjacent amino acid residues from an IL1RA protein sequence selected from SEQ ID NOs: 2 to 5, for example 5 to 6, for example 6 to 7, for example 7 to 8, for example 8 to 9, for example 9 to 10, for example 10 to 11, for example 11 to 12, for example 12 to 13, for example 13 to 14, for example 14 to 15, for example 15 to 20, for example 20 to 25, for example 25 to 30, for example 30 to 35 consecutive amino acid residues from an IL1RA protein sequence selected from SEQ ID NOs: 2 to 5.

[0061] In another embodiment of the present disclosure, the variant is at least 75%, or 80%, or 85%, or 90%, or 95% identical to a peptide derived from an IL1RA protein sequence selected from SEQ ID NOs. 2-5.

[0062] In another embodiment of the present disclosure, the variant is at least 71-80% identical, or 81-85% identical, or 86-90% identical, or 91-95% identical, for example, 96-99% identical, to a peptide derived from an IL1RA protein sequence selected from SEQ ID NOs. 2-5.

[0063] In some embodiments of the present disclosure, the compound for use is a peptide consisting of 5 to 35 adjacent amino acid residues derived from an IL1RA protein sequence selected from SEQ ID NOs: 2 to 5, or a variant thereof that is at least 70% identical to a peptide derived from an IL1RA protein sequence selected from SEQ ID NOs: 2 to 5, wherein the peptide includes at least the amino acid sequence SGRKSSKMQA (SEQ ID NO: 1), or a variant of SEQ ID NO: 1 comprising 1, 2, or 3 amino acid substitutions.

[0064] In some embodiments of the present disclosure, the compound for use is a peptide consisting of 5 to 20 adjacent amino acid residues derived from an IL1RA protein sequence selected from SEQ ID NOs: 2 to 5, or a variant thereof that is at least 70% identical to a peptide derived from an IL1RA protein sequence selected from SEQ ID NOs: 2 to 5, wherein the peptide consists of the amino acid sequence SGRKSSKMQA (SEQ ID NO: 1), or a variant of SEQ ID NO: 1 comprising 1, 2, or 3 amino acid substitutions and optionally 11 to 20 additional amino acid residues up to the full length of, for example, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 amino acid residues.

[0065] In some embodiments of this disclosure, the peptide binds to interleukin-1 receptor type 1 (IL1R1) and / or interferes with the binding of IL-1 to IL1R1.

[0066] According to one embodiment, the present disclosure relates to a method for treating diabetic nephropathy, comprising administering an effective amount of a compound to an individual in need thereof, wherein the compound comprises one or more peptides, each peptide comprising the amino acid sequence SGRKSSKMQA (SEQ ID NO: 1), or a variant of SEQ ID NO: 1 comprising one, two or three amino acid substitutions and optionally 11 to 20 additional amino acid residues up to the full length of, for example, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 amino acid residues.

[0067] According to one embodiment, the present disclosure relates to a compound for use in the treatment of diabetic nephropathy, the compound comprising one or more peptides, each peptide comprising the amino acid sequence SGRKSSKMQA (SEQ ID NO: 1), or a variant of SEQ ID NO: 1 comprising one, two or three amino acid substitutions and optionally 11 to 20 additional amino acid residues up to the full length of, for example, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 amino acid residues.

[0068] According to one embodiment, the present disclosure relates to a method for treating diabetic nephropathy, comprising administering an effective amount of a compound to an individual in need thereof, wherein the compound comprises one or more peptides, each peptide consisting of the amino acid sequence SGRKSSKMQA (SEQ ID NO: 1), or a variant of SEQ ID NO: 1 comprising one, two, or three amino acid substitutions.

[0069] According to one embodiment, the present disclosure relates to a compound for use in the treatment of diabetic nephropathy, the compound comprising one or more peptides, each peptide comprising the amino acid sequence SGRKSSKMQA (SEQ ID NO: 1), or a variant of SEQ ID NO: 1 comprising one, two, or three amino acid substitutions.

[0070] According to one embodiment, the disclosure relates to the use of a compound for manufacturing a pharmaceutical for treating diabetic nephropathy, wherein the compound comprises one or more peptides, each peptide comprising the amino acid sequence SGRKSSKMQA (SEQ ID NO: 1), or a variant of SEQ ID NO: 1 comprising one, two, or three amino acid substitutions.

[0071] In some embodiments of this disclosure, the peptide binds to IL-1 receptor type 1 (ILR1) and / or interferes with the binding of IL-1β to IL1R1.

[0072] In some embodiments of this disclosure, the variant of SEQ ID NO: 1 includes one or two amino acid substitutions. In some embodiments of this disclosure, the variant of SEQ ID NO: 1 includes one amino acid substitution.

[0073] In another embodiment of this disclosure, the amino acid substitution(s) are conservative amino acid substitutions.

[0074] In some embodiments of the present disclosure, the variant of SEQ ID NO: 1 comprises one, two, or three conservative amino acid substitutions.

[0075] In another embodiment of this disclosure, one or more peptides are each i) The amino acid sequence of Sequence ID No. 1, and / or ii) A fragment consisting of five or more consecutive amino acids of SEQ ID NO: 1, and / or iii) A variant of SEQ ID NO: 1 having at least 90% identity with SEQ ID NO: 1, and / or iv) Consists of a variant of SEQ ID NO: 1 containing one amino acid substitution.

[0076] In some embodiments of the present disclosure, the one or more peptides consist of a fragment comprising five or more consecutive amino acids as shown in SEQ ID NO: 1.

[0077] In some embodiments of the present disclosure, the one or more peptides consist of a fragment comprising the 5, 6, 7, 8, or 9 consecutive amino acids of SEQ ID NO: 1.

[0078] In some embodiments of the present disclosure, the one or more peptides consist of the amino acid sequence SGRKSSKMQA (SEQ ID NO: 1) and optionally 11 to 20 additional amino acid residues up to the full length of, for example, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 amino acid residues.

[0079] In some embodiments of the present disclosure, the one or more peptides consist of the amino acid sequence of SEQ ID NO: 1, or a variant having one amino acid substitution.

[0080] In some embodiments of the present disclosure, the one or more peptides consist of a variant of SEQ ID NO: 1 having one amino acid substitution.

[0081] In some embodiments of this disclosure, the one or more peptides consist of the amino acid sequence of SEQ ID NO: 1.

[0082] According to one embodiment, the present disclosure relates to a method for treating diabetic nephropathy, comprising administering an effective amount of a compound to an individual in need thereof, wherein the compound is a peptide comprising the amino acid sequence of SEQ ID NO: 1 (SGRKSSKMQA) or a variant of SEQ ID NO: 1 comprising one or two conservative amino acid substitutions.

[0083] According to one embodiment, the disclosure relates to a compound for use in the treatment of diabetic nephropathy, wherein the compound is a peptide comprising the amino acid sequence of SEQ ID NO: 1 (SGRKSSKMQA) or a variant of SEQ ID NO: 1 comprising one or two conservative amino acid substitutions.

[0084] According to one embodiment, the disclosure relates to the use of a compound for manufacturing a pharmaceutical for treating diabetic nephropathy, wherein the compound is a peptide comprising the amino acid sequence of SEQ ID NO: 1 (SGRKSSKMQA) or a variant of SEQ ID NO: 1 comprising one or two conservative amino acid substitutions.

[0085] In another embodiment of this disclosure, the C-terminal amino acid exists as a free carboxylic acid ("-OH"). In another embodiment, the C-terminal amino acid is an amidated derivative ("-NH-2"). In another embodiment, the N-terminal amino acid contains a free amino group ("H-"). In another embodiment, the N-terminal amino acid is an acetylated derivative ("-acetyl" or "COCH3").

[0086] In some embodiments of this disclosure, the compound for use is a monomer. In some embodiments of this disclosure, the compound is a monomer comprising one peptide according to this disclosure.

[0087] In some embodiments of the present disclosure, the compound for use is a multimer. In some embodiments of the present disclosure, the compound for use is a multimer comprising at least two peptides according to the present disclosure, for example, two or more peptides.

[0088] In some embodiments of this disclosure, the compound to be used is a multimer.

[0089] In some embodiments of the present disclosure, the compound for use is a multimer comprising two or more peptides, each peptide comprising SEQ ID NO: 1, or a variant of SEQ ID NO: 1 comprising one, two, or three amino acid substitutions.

[0090] In some embodiments of this disclosure, the compound is a dimer, trimer, or tetramer.

[0091] In some embodiments of the present disclosure, the compound for use is a dimer comprising two peptides, each peptide comprising SEQ ID NO: 1, or a variant of SEQ ID NO: 1 comprising one, two, or three amino acid substitutions.

[0092] In some embodiments of the present disclosure, the compound for use is a tetramer comprising four peptides, each peptide comprising SEQ ID NO: 1, or a variant of SEQ ID NO: 1 comprising one, two, or three amino acid substitutions.

[0093] In some embodiments, the compound is a dendrimer. In some embodiments, the dendrimer is a dimeric dendrimer. In some embodiments, the dendrimer is a tetrameric dendrimer.

[0094] Dendrimers are higher-order branched polymer molecules. Typically, dendrimers are symmetrical with respect to their core and often take on a spherical three-dimensional form.

[0095] In some embodiments of the present disclosure, the compound for use is a dimeric dendrimer comprising two peptides, each peptide comprising SEQ ID NO: 1, or a variant of SEQ ID NO: 1 comprising one, two, or three amino acid substitutions.

[0096] In some embodiments of the present disclosure, the compound for use is a tetrameric dendrimer comprising four peptides, each peptide comprising SEQ ID NO: 1, or a variant of SEQ ID NO: 1 comprising one, two, or three amino acid substitutions.

[0097] In some embodiments of this disclosure, two or more peptides are linked via peptide bonds.

[0098] In some embodiments of this disclosure, two or more peptides are linked via a linker group.

[0099] In some embodiments of the present disclosure, the linker group is a lysine skeleton, for example, one or more lysine residues, or a lysine skeleton comprising multiple lysine residues.

[0100] In some embodiments of this disclosure, the linker group comprises one or more lysine residues.

[0101] In some embodiments of the present disclosure, the compound for use is a dimeric dendrimer comprising two peptides, each peptide comprising SEQ ID NO: 1, or a variant of SEQ ID NO: 1 comprising one, two, or three amino acid substitutions and a lysine backbone.

[0102] In some embodiments of the present disclosure, the compound for use is a tetrameric dendrimer comprising four peptides, each peptide comprising SEQ ID NO: 1, or a variant of SEQ ID NO: 1 comprising one, two, or three amino acid substitutions and a lysine skeleton.

[0103] In some embodiments of the present disclosure, the peptide is a tetrameric dendrimer consisting of four peptides, each peptide comprising SEQ ID NO: 1 and a lysine backbone.

[0104] In another embodiment of the present disclosure, the linker group is a polymer carrier, such as a protein carrier.

[0105] According to one embodiment, the present disclosure relates to a method for treating diabetic nephropathy, comprising administering an effective amount of a polymer compound to an individual in need thereof, wherein the polymer compound comprises at least two peptides, each peptide consisting of the amino acid sequence SGRKSSKMQA (SEQ ID NO: 1), or a variant of SEQ ID NO: 1 comprising one, two, or three amino acid substitutions.

[0106] According to one embodiment, the disclosure relates to a polymer compound for use in the treatment of diabetic nephropathy, wherein the polymer compound comprises at least two peptides, each peptide consisting of the amino acid sequence SGRKSSKMQA (SEQ ID NO: 1), or a variant of SEQ ID NO: 1 comprising one, two, or three amino acid substitutions.

[0107] According to one embodiment, the disclosure relates to the use of a polymer compound for manufacturing a pharmaceutical for treating diabetic nephropathy, wherein the polymer compound comprises at least two peptides, each peptide consisting of the amino acid sequence SGRKSSKMQA (SEQ ID NO: 1), or a variant of SEQ ID NO: 1 comprising one, two, or three amino acid substitutions.

[0108] In some embodiments of this disclosure, the polymer compound is a dendrimer.

[0109] In some embodiments of this disclosure, the polymer compound is a dimer, trimer, or tetramer.

[0110] In some embodiments of this disclosure, the polymer compound is a dimer.

[0111] In some embodiments of this disclosure, the polymer compound is a tetramer.

[0112] In another embodiment of this disclosure, at least two peptides are identical.

[0113] According to one embodiment, the present disclosure relates to a method for treating diabetic nephropathy, comprising administering an effective amount of a polymer compound to an individual in need thereof, wherein the polymer compound comprises four peptides, each peptide consisting of the amino acid sequence SGRKSSKMQA (SEQ ID NO: 1), or a variant of SEQ ID NO: 1 comprising one, two, or three amino acid substitutions.

[0114] According to one embodiment, the present disclosure relates to a polymer compound for use in the treatment of diabetic nephropathy, the polymer compound comprising four peptides, each peptide consisting of the amino acid sequence SGRKSSKMQA (SEQ ID NO: 1), or a variant of SEQ ID NO: 1 comprising one, two, or three amino acid substitutions.

[0115] In some embodiments of this disclosure, the four peptides are linked via peptide bonds.

[0116] In some embodiments of this disclosure, the four peptides are linked via a linker group.

[0117] In some embodiments of the present disclosure, the linker group is a lysine skeleton comprising one or more lysine residues, for example, a plurality of lysine residues.

[0118] In some embodiments of this disclosure, the four peptides are identical.

[0119] In some embodiments, each of the four peptides is defined in accordance with this disclosure.

[0120] According to one embodiment, the present disclosure relates to a polymer compound for use in the treatment of diabetic nephropathy, wherein the polymer compound is i) Two or more peptides consisting of 10 to 14 consecutive amino acid residues derived from IL1RA, wherein each peptide is: a. Consisting of the amino acid sequence of Sequence ID No. 1 and, optionally, an additional amino acid sequence of up to 11-14 amino acid residues; or b. A peptide consisting of a variant of SEQ ID NO: 1 comprising one conservative amino acid substitution and optionally an additional amino acid residue of up to 11-14 amino acid residues, and ii) Depending on the case, it may consist of one or more linker groups.

[0121] In another embodiment of this disclosure, the compound is formulated as a pharmaceutical composition.

[0122] In another embodiment of the present disclosure, the peptide or compound reduces the urinary albumin-to-creatinine ratio (ACR). In another embodiment, the peptide or compound reduces the urinary albumin-to-creatinine ratio (ACR) in a dose-dependent manner.

[0123] In another embodiment of this disclosure, the peptide or compound reduces the urinary level of the biomarker kidney injury molecule-1 (KIM-1). In another embodiment, the peptide or compound reduces the urinary KIM-1 to creatinine ratio (KIM-1 / CR). In yet another embodiment, the urinary level of KIM-1 or the urinary KIM-1 to creatinine ratio (KIM-1 / CR) decreases in a dose-dependent manner.

[0124] A compound for use or by any of the methods described in the preceding items, wherein the level of KIM-1 is measured in a urine sample, such as a urine sample from an individual.

[0125] In another embodiment of the present disclosure, the individual has diabetes mellitus, an ACR level greater than 30, and / or elevated blood pressure. In another embodiment, the individual has normal blood pressure. In another embodiment, the individual has type 1 diabetes mellitus or type 2 diabetes mellitus.

[0126] In another embodiment of this disclosure, the individual is treated with an antidiabetic drug. In another embodiment, the individual is treated with an antihypertensive drug.

[0127] In another embodiment of the present disclosure, the compound is administered in combination with an effective amount of an antidiabetic compound and / or an antihypertensive compound. In another embodiment, the antihypertensive compound is an ACE inhibitor or an angiotensin receptor antagonist.

[0128] In another embodiment of the present disclosure, the method further comprises the step of administering an effective amount of an antidiabetic compound and / or antihypertensive compound to an individual.

[0129] In another embodiment of the present disclosure, the antidiabetic compound and / or antihypertensive compound is administered simultaneously with, before, or after the administration of the compound according to the present disclosure.

[0130] item 1. A method for treating diabetic nephropathy, comprising administering an effective amount of a compound to an individual in need thereof, wherein the compound is a peptide derived from interleukin-1 (IL-1) receptor antagonist (IL1RA) protein, or a variant thereof that is at least 70% identical to the peptide derived from IL1RA protein.

[0131] 2. A compound for use in the treatment of diabetic nephropathy, which is a peptide derived from the IL-1 receptor antagonist (IL1RA) protein, or a variant thereof that is at least 70% identical to said peptide derived from the IL1RA protein.

[0132] 3. A compound for use or the method described in any of the preceding items, wherein the IL1RA protein has a sequence selected from SEQ ID NOs. 2 to 5.

[0133] 4. The method or compound for use described in any of the preceding items, wherein the compound is a peptide consisting of 5 to 35 adjacent amino acid residues derived from the IL1RA protein selected from SEQ ID NOs: 2 to 5, or a variant thereof that is at least 70% identical to the peptide derived from the IL1RA protein selected from SEQ ID NOs: 2 to 5.

[0134] 5. A compound for use according to any of the preceding items, wherein the peptide consists of up to 30 adjacent amino acid residues, or up to 25 adjacent amino acid residues, or up to 20 adjacent amino acid residues, or up to 15 adjacent amino acid residues, or 10 adjacent amino acid residues, derived from an IL1RA protein sequence selected from SEQ ID NOs. 2 to 5.

[0135] 6. A compound for use according to any of the preceding items, wherein the peptide consists of 5 to 35 adjacent amino acid residues from an IL1RA protein sequence selected from SEQ ID NOs. 2 to 5, or 5 to 30, 5 to 25, 5 to 20, 5 to 15, 10 to 20, or 8 to 18 adjacent amino acid residues from an IL1RA protein sequence selected from SEQ ID NOs. 2 to 5.

[0136] 7. The method or compound for use described in any of the preceding items, wherein the peptide consists of 5 to 35 adjacent amino acid residues from an IL1RA protein sequence selected from SEQ ID NOs: 2 to 5, for example 5 to 6, for example 6 to 7, for example 7 to 8, for example 8 to 9, for example 9 to 10, for example 10 to 11, for example 11 to 12, for example 12 to 13, for example 13 to 14, for example 14 to 15, for example 15 to 20, for example 20 to 25, for example 25 to 30, for example 30 to 35 consecutive amino acid residues from an IL1RA protein sequence selected from SEQ ID NOs: 2 to 5.

[0137] 8. The method or compound for use described in any of the preceding items, wherein the variant is at least 75%, 80%, 85%, 90%, or 95% identical to the peptide derived from an IL1RA protein sequence selected from SEQ ID NOs. 2-5.

[0138] 9. The method or compound for use described in any of the preceding items, wherein the variant is at least 71-80% identical, or 81-85% identical, or 86-90% identical, or 91-95% identical, for example, 96-99% identical to the peptide derived from the IL1RA protein sequence selected from SEQ ID NOs. 2-5.

[0139] 10. The method or compound for use described in any of the preceding items, wherein the IL1RA protein has a sequence selected from SEQ ID NOs: 2-4.

[0140] 11. A compound for use according to any of the preceding items, wherein the peptide comprises at least the amino acid sequence SGRKSSKMQA (SEQ ID NO: 1), or a variant of SEQ ID NO: 1 comprising one, two, or three amino acid substitutions.

[0141] 12. A compound for use according to any of the preceding items, wherein the peptide comprises the amino acid sequence SGRKSSKMQA (Sequence ID 1), or a variant of Sequence ID 1 comprising one, two, or three amino acid substitutions and optionally 11 to 20 additional amino acid residues up to the full length of, for example, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 amino acid residues.

[0142] 13. A method for treating diabetic nephropathy, comprising administering an effective amount of a compound to an individual in need thereof, wherein the compound comprises one or more peptides, each peptide comprising the amino acid sequence SGRKSSKMQA (Sequence ID 1), or a variant of Sequence ID 1 comprising one, two or three amino acid substitutions and optionally 11 to 20 additional amino acid residues up to the full length of, for example, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 amino acid residues.

[0143] 14. Compounds for use in the treatment of diabetic nephropathy, comprising one or more peptides, each peptide consisting of a variant of SEQ ID NO: 1, comprising the amino acid sequence SGRKSSKMQA (SEQ ID NO: 1), or one, two or three amino acid substitutions and optionally 11 to 20 additional amino acid residues up to the full length of, for example, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 amino acid residues.

[0144] 15. A method for treating diabetic nephropathy, comprising administering an effective amount of a compound to an individual in need thereof, wherein the compound comprises one or more peptides, each peptide consisting of the amino acid sequence SGRKSSKMQA (SEQ ID NO: 1), or a variant of SEQ ID NO: 1 comprising one, two, or three amino acid substitutions.

[0145] 16. A compound for use in the treatment of diabetic nephropathy, comprising one or more peptides, each peptide consisting of the amino acid sequence SGRKSSKMQA (SEQ ID NO: 1), or a variant of SEQ ID NO: 1 comprising one, two, or three amino acid substitutions.

[0146] 17. A compound for use by any of the preceding items, wherein the peptide binds to IL-1 receptor type 1 (ILR1) and / or interferes with the binding of IL-1β to IL1R1.

[0147] 18. A compound for use by any of the preceding items, wherein the variant comprises one or two amino acid substitutions.

[0148] 19. A compound for use by any of the preceding items, wherein the variant comprises one amino acid substitution.

[0149] 20. A compound for use by any of the preceding items, wherein the one or more amino acid substitutions are conservative amino acid substitutions.

[0150] 21. A compound for use according to any of the preceding items, wherein one or more peptides consist of a fragment of five or more consecutive amino acids as of SEQ ID NO: 1.

[0151] 22. A compound for use according to any of the preceding items, wherein the one or more peptides consist of a fragment of sequence 5, 6, 7, 8, or 9 amino acids of SEQ ID NO: 1.

[0152] 23. A compound for use according to any of the preceding items, wherein one or more peptides consist of the amino acid sequence SGRKSSKMQA (Sequence ID 1) and optionally 11 to 20 additional amino acid residues up to the full length of, for example, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 amino acid residues.

[0153] 24. A compound for use according to any of the preceding items, wherein one or more peptides consist of the amino acid sequence of SEQ ID NO: 1 or a variant having one amino acid substitution.

[0154] 25. A compound for use according to any of the preceding items, wherein one or more peptides consist of a variant of SEQ ID NO: 1 having one amino acid substitution.

[0155] 26. A compound for use or according to any of the preceding items, wherein one or more peptides consist of the amino acid sequence of SEQ ID NO: 1.

[0156] 27. A method for treating diabetic nephropathy, comprising administering an effective amount of a compound to an individual in need thereof, wherein the compound is a peptide comprising the amino acid sequence of SEQ ID NO: 1 (SGRKSSKMQA) or a variant of SEQ ID NO: 1 comprising one, two, or three conservative amino acid substitutions.

[0157] 28. A compound for use in the treatment of diabetic nephropathy, which is a peptide comprising the amino acid sequence of SEQ ID NO: 1 (SGRKSSKMQA) or a variant of SEQ ID NO: 1 containing one, two, or three conservative amino acid substitutions.

[0158] 29. A compound for use in any of the preceding items, wherein the peptide binds to IL-1 receptor type 1 (ILR1) and / or interferes with the binding of IL-1β to IL1R1.

[0159] 30. A compound for use by or according to any of the preceding items, wherein the variant comprises one or two amino acid substitutions.

[0160] 31. A compound for use by any of the preceding items, wherein the variant comprises one amino acid substitution.

[0161] 32. A compound for use in any of the preceding items, wherein the one or more amino acid substitutions are conservative amino acid substitutions.

[0162] 33. A compound for use in any of the preceding items, wherein the C-terminal amino acid of the peptide is present as a free carboxylic acid ("-OH").

[0163] 34. A compound for use in any of the preceding items, wherein the C-terminal amino acid of the peptide is an amidated derivative ("-NH-2").

[0164] 35. A compound for use in any of the preceding items, wherein the N-terminal amino acid of the peptide contains a free amino group ("H-").

[0165] 36. A compound for use in or according to any of the preceding items, wherein the N-terminal amino acid of the peptide is an acetylated derivative ("-acetyl" or "COCH3").

[0166] 37. A compound according to or for use of any of the preceding items, wherein the compound is a monomer, for example, a monomer comprising one peptide.

[0167] 38. A compound according to or for use of any of the preceding items, wherein the compound is a multimer, for example, a multimer comprising two or more peptides.

[0168] 39. A compound for use or according to any of the preceding items, wherein the compound is a dimer, trimer, or tetramer.

[0169] 40. A compound according to or for use according to any of the preceding items, wherein the compound is a dimer comprising two peptides, each peptide comprising either SEQ ID NO: 1 or a variant thereof comprising one, two, or three amino acid substitutions.

[0170] 41. A compound according to or for use according to any of the preceding items, wherein the compound is a tetramer comprising four peptides, each peptide comprising SEQ ID NO: 1 or a variant thereof comprising one, two, or three amino acid substitutions.

[0171] 42. A compound for use by any of the preceding items, wherein the compound is a dendrimer.

[0172] 43. A method or compound for use according to any of the preceding items, wherein the dendrimer is a dimeric dendrimer or a tetrameric dendrimer.

[0173] 44. A compound according to or for use according to any of the preceding items, wherein the compound is a dimeric dendrimer comprising two peptides, each peptide comprising SEQ ID NO: 1 or a variant thereof comprising one, two, or three amino acid substitutions.

[0174] 45. A compound according to or for use of any of the preceding items, wherein the compound is a tetrameric dendrimer comprising four peptides, each peptide comprising SEQ ID NO: 1 or a variant thereof comprising one, two, or three amino acid substitutions.

[0175] 46. ​​A compound for use in any of the preceding items, wherein two or more peptides are linked via peptide bonds.

[0176] 47. A compound for use according to any of the preceding items, wherein two or more peptides are linked via one or more linker groups, such as linker groups.

[0177] 48. A compound according to any of the preceding items or for use thereof, wherein the linker group is a lysine skeleton comprising one or more lysine residues, for example, multiple lysine residues.

[0178] 49. The peptide is a tetrameric dendrimer consisting of four peptides, each peptide comprising SEQ ID NO: 1 and a lysine skeleton, as described in or for use in any of the preceding items.

[0179] 50. A compound for use according to any of the preceding items, wherein the linker group is a polymer carrier such as a protein carrier.

[0180] 51. A method for treating diabetic nephropathy, comprising administering an effective amount of a polymer compound to an individual in need thereof, wherein the polymer compound comprises at least two peptides, each peptide consisting of the amino acid sequence SGRKSSKMQA (SEQ ID NO: 1), or a variant of SEQ ID NO: 1 comprising one, two, or three amino acid substitutions.

[0181] 52. A polymer compound for use in the treatment of diabetic nephropathy, comprising at least two peptides, each peptide consisting of the amino acid sequence SGRKSSKMQA (SEQ ID NO: 1), or a variant of SEQ ID NO: 1 comprising one, two, or three amino acid substitutions.

[0182] 53. A method or a polymer compound for use according to any of the preceding items, wherein the polymer compound is a dimer, trimer, or tetramer.

[0183] 54. A method or a polymer compound for use according to any of the preceding items, wherein the polymer compound is a tetramer.

[0184] 55. A method or a polymer compound for use according to any of the preceding items, wherein at least two of the peptides are identical.

[0185] 56. A method for treating diabetic nephropathy, comprising administering an effective amount of a polymer compound to an individual in need thereof, wherein the polymer compound comprises four peptides, each peptide consisting of the amino acid sequence SGRKSSKMQA (SEQ ID NO: 1), or a variant of SEQ ID NO: 1 comprising one, two, or three amino acid substitutions.

[0186] 57. A polymer compound for use in the treatment of diabetic nephropathy, comprising four peptides, each peptide consisting of the amino acid sequence SGRKSSKMQA (SEQ ID NO: 1), or a variant of SEQ ID NO: 1 containing one, two, or three amino acid substitutions.

[0187] 58. A compound for use as described in any of the preceding items, wherein the four peptides are linked by peptide bonds.

[0188] 59. A compound for use or according to any of the preceding items, wherein the four peptides are linked via a linker group.

[0189] 60. The method or compound for use according to any of the preceding items, wherein the linker group is a lysine skeleton comprising one or more lysine residues, for example, multiple lysine residues.

[0190] 61. A polymer compound comprising at least two peptides or four peptides, as defined in any one of the preceding items, by or for use in any of the preceding items.

[0191] 62. A compound for use or a method described in any of the preceding items, wherein the compound is formulated as a pharmaceutical composition.

[0192] 63. The peptide or compound that reduces the urinary albumin-to-creatinine ratio (ACR) according to any of the preceding items, or a compound for use thereof.

[0193] 64. The method or compound for use of any of the preceding items, wherein the peptide or compound dose-dependently reduces the urinary albumin-to-creatinine ratio (ACR).

[0194] 65. The peptide or compound that reduces the urinary level of the biomarker kidney injury molecule-1 (KIM-1) as described in any of the preceding items, or a compound for use in such a manner.

[0195] 66. The peptide or compound that reduces the urinary KIM-1 to creatinine ratio (KIM-1 / CR) as described in any of the preceding items, or a compound for use as described in the preceding items.

[0196] 67. A method or compound for use described in any of the preceding items that dose-dependently reduces urinary KIM-1 levels or the urinary KIM-1 to creatinine ratio (KIM-1 / CR).

[0197] 68. A compound for use or by any of the methods described in any of the preceding items, wherein the level of KIM-1 is measured in a urine sample, such as a urine sample from the individual concerned.

[0198] 69. The method or compound for use described in any of the preceding items, wherein the individual has diabetes mellitus, has an ACR level greater than 30, and / or elevated blood pressure.

[0199] 70. A compound for use by any of the preceding items, wherein the individual has normal blood pressure.

[0200] 71. A compound for use by any of the preceding items, relating to an individual having type 1 diabetes mellitus or type 2 diabetes mellitus.

[0201] 72. The individual is treated with an antidiabetic drug, the method described in any of the preceding items, or a compound for use.

[0202] 73. The individual is treated with an antihypertensive drug, the method described in any of the preceding items, or a compound for use in such a manner.

[0203] 74. A compound used in or according to any of the preceding items, wherein the compound is administered in combination with an effective amount of an antidiabetic compound and / or an antihypertensive compound.

[0204] 75. A compound for use in the manner described in any of the preceding items, wherein the antihypertensive compound is an ACE inhibitor or an angiotensin receptor antagonist.

[0205] 76. The method of any of the preceding items, further comprising the step of administering an effective amount of an antidiabetic compound and / or an antihypertensive compound to the individual.

[0206] 77. The antidiabetic compound and / or the antihypertensive compound, administered simultaneously with, before, or after administering, the compound described in any of the preceding items, the method or use described in any of the preceding items. [Examples]

[0207] Example 1: Efficacy of IL1RA-derived peptide om marker in diabetic nephropathy

[0208] material and method animal 56 female mice (BKS.Cg-Dock7m+ / +Lepradb / db BLKS, 5 weeks old) were transferred to the animal unit at Gubra Research. The animals were housed in groups until unilateral nephrectomy, and then individually thereafter. Throughout the acclimatization and study periods, the animals were kept in rooms with controlled light, temperature, and humidity, and had free access to food and water. All animal experiments were conducted in accordance with Gubra's bioethical guidelines, which fully adhere to internationally accepted principles for the management and use of laboratory animals.

[0209] The animals were slaughtered on day 77. Blood samples were taken, weights were recorded, and spot urine samples were collected for subsequent analysis.

[0210] compound SER140 was provided by Phlogo ApS in Copenhagen, Denmark (10 mg / ml of miliQ water diluted to different dose formulations). SER140 is a dendrimer composed of four monomeric peptides, each having the sequence SGRKSSKMQA (SEQ ID NO: 1), bound to a lysine backbone. The vehicle was miliQ:PBS 1:5.

[0211] In vivo procedure After a one-week acclimatization period, mice were intravenously injected with renin-adenosine-associated virus (AAV). One week later, all mice underwent unilateral nephrectomy. Two weeks after intravenous injection of renin-AAV, the mice were randomly divided into four groups according to their blood glucose levels: a vehicle group (n=14), a 3 mg / kg SER140 group, a 10 mg / kg SER140 group, and a 20 mg / kg SER140 group. The compound and vehicle were administered subcutaneously once daily.

[0212] biochemical analysis All blood samples were collected from the tail of mice in heparinized tubes, plasma was separated, and stored at -80°C until analysis. Non-fasting blood glucose (BG) was measured using a BIOSEN c-line glucose meter (EKF-diagnostics, Germany), and blood for HbA1c analysis was immediately suspended in hemolysis reagent and stored until analysis using a Cobas C-111 automated analyzer with a commercially available kit (Roche Diagnostics, Germany) and plasma urea with a commercially available kit (Roche Diagnostics).

[0213] Urine samples were stored at -80°C until analysis. Urine samples for albumin and creatinine measurement were centrifuged at 2000g for 2 minutes and then analyzed. Urine albumin was measured using a commercially available ELISA kit (Bethyl Laboratories, Inc.) according to the manufacturer's instructions, and urine creatinine was measured using a commercially available kit (Roche Diagnostics) on a Cobas c 501 automated analyzer according to the manufacturer's instructions. Urine KIM-1 was measured using a commercially available ELISA kit (R&D Systems) according to the manufacturer's instructions.

[0214] result The test compound SER140 significantly reduced ACR mg / g (Figure 1) and KIM-1 / CR pg / g (Figure 2) in a dose-dependent manner.

[0215] Since there was no change in HbA1c% between the vehicle and SER140 treatment, it was shown that the effects of SER140 on ACR and KIM-1 are not mediated through effects on HbA1c.

[0216] Consideration The renin-AAV UNx db / db mouse has been described as one of the best pharmacological models for explaining the development of diabetic nephropathy (DKD) and elucidating the effects of compounds on disease progression (Nguyen 2019, Sembach 2020). Recent studies have shown that activation of the immune system and imbalances in immune homeostasis play important roles in the development and progression of diabetic nephropathy.

[0217] It is well known that IL-1 cytokines consist of three different forms: Il-1α, Il-1β (both IL-1 receptor agonists), and IL-1Ra, a native IL-1 receptor antagonist. All are ligands for the same IL-1R1 receptor. While both Il-1α and Il-1β are pro-inflammatory cytokines and are activated downstream, IL-1Ra binds to the IL-1R1 receptor without activation and therefore acts as a receptor antagonist, modulating various IL-1-related immune and inflammatory responses (Arend 2000, Dinarello 2012, Park 2015).

[0218] Both urinary albumin and KIM-1 are biomarkers for congenital renal inflammation found in various autoimmune diseases involving the kidney. Human renal biopsies have confirmed the presence of inflammatory cells in both the glomeruli, tubules, and interstitium at all stages of diabetic nephropathy (Kahn 2019, Calle 2021).

[0219] SER140 is a peptide derived from the human IL-1RA N-terminal domain, which is involved in interaction with IL-1R1. SER140 has been shown to inhibit receptor binding of IL-1β and, consequently, reduce the downstream activation of TNFα, particularly macrophage release (Klementiev 2014).

[0220] This document demonstrates that SER140 significantly reduced both urinary albumin, a biomarker primarily for glomerular endothelial and podocyte cell damage, and KIM-1, a biomarker for proximal tubular apical membrane damage. These biomarkers are undetectable in the urine of patients with normal kidney function, but are detectable in response to ischemic or toxic injuries, including diabetes (Alderson 2016, Treacy 2019).

[0221] Array Overview [ka]

[0222] reference ●Andrew S Levey 1: Change in Albuminuria and GFR as End Points for Clinical Trials in Early Stages of CKD: A Scientific Workshop Sponsored by the National Kidney Foundation in Collaboration With the US Food and Drug Administration and European Medicines Agency. Am J Kidney Dis. 2020 Jan;75(1). ●Araujo SL et al: Renal expression of cytokines and chemokines in diabetic nephropathy. BMC Nephrology volume 21, Article number: 308 (2020). ●Boris Klementiev et al: Anti-inflammatory properties of a novel peptide interleukin 1 receptor antagonist. Journal of Neuroinflammation volume 11, Article number: 27 (2014). ●Cem Gabay, Celine Lamacchia, Gaby Palmer: IL-1 pathways in inflammation and human diseases. Review Nat Rev Rheumatol. 2010 Apr;6(4):232-41. ●Fatima Abid Khan, Syeda Sadia Fatima, Ghulam Mustafa Khan, Sana Shahid: Evaluation of kidney injury molecule-1 as a disease progression biomarker in diabetic nephropathy. Pak J Med Sci. Jul-Aug 2019;35(4):992-996. doi: 10.12669 / pjms.35.4.154. ●Fionnuala B Hickey, Finian Martin: Role of the Immune System in Diabetic Kidney Disease. Review Curr Diab Rep. 2018 Mar 12;18(4):20. ●Frederikke E Sembach, Mette V Ostergaard, Niels Vrang, Bo Feldt-Rasmussen, Keld Fosgerau, Jacob Jelsing, Lisbeth N Fink: Rodent models of diabetic kidney disease: human translatability and preclinical validity. Review Drug Discov Today. 2021 Jan;26(1):200-217. ●Giulio Cavalli et al: Interleukin 1α: a comprehensive review on the role of IL-1α in the pathogenesis and treatment of autoimmune and inflammatory diseases. Review Autoimmun Rev. 2021 Mar;20(3). ●Helen V. Alderson et al: The Associations of Blood Kidney Injury Molecule-1 and Neutrophil Gelatinase-Associated Lipocalin with Progression from CKD to ESRD. Clin J Am Soc Nephrol. 2016 Dec 7; 11(12): 2141-2149. ●Isabel Nguyen, Arianne van Koppen, and Jaap A. Joles: Animal Models of Diabetic Kidney Disease. ●Jieru Cai: Kidney injury molecule-1 expression predicts structural damage and outcome in histological acute tubular injury. Ren Fail. 2019 Nov;41(1):80-87. ●Maki Murakoshi 1, Tomohito Gohda 1, Yusuke Suzuki 1: Circulating Tumor Necrosis Factor Receptors: A Potential Biomarker for the Progression of Diabetic Kidney Disease. Review Int J Mol Sci. 2020 Mar 13;21(6):1957. ●Oliver Treacy, Nigel N. Brown, and Goce Dimeski: Biochemical evaluation of kidney disease. Transl Androl Urol. 2019 May; 8(Suppl 2): S214-S223. ●Priscila Calle and Georgina Hotter: Macrophage Phenotype and Fibrosis in Diabetic Nephropathy. Int J Mol Sci. 2020 Apr; 21(8): 2806. ●Steven G. Coca, Girish N. Nadkarni, Yuan Huang, Dennis G. Moledina, Veena Rao, Jane Zhang, Bart Ferket, Susan T. Crowley, Linda F. Fried and Chirag R. Parikh: Plasma Biomarkers and Kidney Function Decline in Early and Established Diabetic Kidney Disease. JASN September 2017, 28 (9) 2786-2793. ●W. Arend and C. Guthridge: Biological role of interleukin 1 receptor antagonist isoforms. Ann Rheum Dis. 2000 Nov; 59(Suppl 1).

Claims

[Claim 1] A pharmaceutical composition comprising a compound for use in the treatment of diabetic nephropathy, wherein the compound is a tetrameric dendrimer comprising four peptides, each of which has the amino acid sequence SGRKSSKMQA (SEQ ID NO: 1), and further comprises a lysine skeleton.

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