WO2022148403A1 - 靶向il-17c的抑制剂在治疗炎症相关慢性肾脏疾病中的用途 - Google Patents

靶向il-17c的抑制剂在治疗炎症相关慢性肾脏疾病中的用途 Download PDF

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WO2022148403A1
WO2022148403A1 PCT/CN2022/070550 CN2022070550W WO2022148403A1 WO 2022148403 A1 WO2022148403 A1 WO 2022148403A1 CN 2022070550 W CN2022070550 W CN 2022070550W WO 2022148403 A1 WO2022148403 A1 WO 2022148403A1
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inflammation
nephropathy
chronic kidney
antibody
kidney disease
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French (fr)
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孙洪臣
边超
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孙洪臣
边超
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    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
    • C12Q1/68—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving nucleic acids
    • C12Q1/6876—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes
    • C12Q1/6883—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for diseases caused by alterations of genetic material
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/68—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids
    • G01N33/6863—Cytokines, i.e. immune system proteins modifying a biological response such as cell growth proliferation or differentiation, e.g. TNF, CNF, GM-CSF, lymphotoxin, MIF or their receptors
    • G01N33/6869—Interleukin
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/68—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids
    • G01N33/6893—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids related to diseases not provided for elsewhere
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q2600/00—Oligonucleotides characterized by their use
    • C12Q2600/158—Expression markers
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2333/00—Assays involving biological materials from specific organisms or of a specific nature
    • G01N2333/435—Assays involving biological materials from specific organisms or of a specific nature from animals; from humans
    • G01N2333/52—Assays involving cytokines
    • G01N2333/54—Interleukins [IL]
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2800/00—Detection or diagnosis of diseases
    • G01N2800/04—Endocrine or metabolic disorders
    • G01N2800/042—Disorders of carbohydrate metabolism, e.g. diabetes, glucose metabolism
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2800/00—Detection or diagnosis of diseases
    • G01N2800/34—Genitourinary disorders
    • G01N2800/347—Renal failures; Glomerular diseases; Tubulointerstitial diseases, e.g. nephritic syndrome, glomerulonephritis; Renovascular diseases, e.g. renal artery occlusion, nephropathy

Definitions

  • the invention relates to the field of biomedicine, in particular to the use of an inhibitor targeting IL-17C in the treatment of inflammation-related chronic kidney diseases such as diabetic nephropathy.
  • Diabetic nephropathy is one of the most important comorbidities in diabetic patients. In the diabetic population, the incidence rate is 20%-40%, and in patients with end-stage renal disease, the 5-year survival rate is less than 20%.
  • the incidence of diabetic nephropathy in my country is on the rise as the incidence of diabetes rises, and it has become the second cause of end-stage renal disease, second only to various glomerulonephritis. Due to its complex metabolic disorders, once it develops into end-stage renal disease, it is often more difficult to treat than other renal diseases. Therefore, timely prevention and treatment is of great significance for delaying diabetic nephropathy.
  • Diabetic nephropathy is one of the complications of systemic microangiopathy of diabetes, so diabetic nephropathy is often accompanied by microangiopathy of other organs or systems, such as diabetic retinopathy and peripheral neuropathy. Diabetic nephropathy in patients with type 1 diabetes mostly occurs in about 10-15 years of onset, while the time for diabetic nephropathy in patients with type 2 diabetes is shorter, which is related to factors such as age and other underlying diseases.
  • the purpose of the present invention is to provide a medicine for treating inflammation-related chronic kidney diseases such as diabetic nephropathy.
  • the first aspect of the present invention provides the use of an IL-17C gene or IL-17C protein or a detection reagent thereof for preparing a reagent or kit for detecting inflammation-related chronic kidney disease.
  • the inflammation-related chronic kidney disease is selected from the group consisting of diabetic nephropathy, obstructive nephropathy, primary glomerulonephritis, secondary glomerulonephritis, hypertensive renal arterioles, chronic Pyelonephritis, hereditary nephritis, chronic uric acid nephropathy, drug-induced nephropathy, ischemic nephropathy, or a combination thereof.
  • the kit includes: reagents for quantitatively detecting the protein or mRNA of IL-17C-related molecules and corresponding labels or instructions.
  • the reagents include specific primers, specific antibodies, probes and/or chips for IL-17C-related molecules.
  • the IL-17C-related molecules include: IL-17C gene (including cDNA sequence, and/or mRNA), IL-17C receptor gene (including cDNA sequence, and/or mRNA), IL-17C protein, IL-17C receptor protein, or a combination thereof.
  • the receptor of IL-17C includes IL-17RE.
  • the above-mentioned reagents include: detection chips, such as nucleic acid chips and protein chips.
  • the nucleic acid chip includes a substrate and specific oligonucleotide probes for inflammation-related mRNA spotted on the substrate, and the specific oligonucleotide probes for inflammation-related genes Included are probes that specifically bind to IL-17C-related mRNA.
  • the protein chip includes a substrate and specific antibodies for inflammation-related proteins spotted on the substrate, and the specific antibodies for inflammation-related proteins include anti-IL-17C-related protein specific antibodies Antibody.
  • the IL-17C-related proteins include fusion proteins and non-fusion proteins.
  • the reagent or kit includes: IL-17C nucleic acid molecule (eg mRNA) or IL-17C protein as a standard.
  • the reagent or kit further includes: a detection reagent for detecting IL-17C nucleic acid molecule or IL-17C protein.
  • kits for detecting inflammation-related chronic kidney disease contains a container, and the container contains a detection reagent for detecting IL-17C-related protein or mRNA; and Labels or instructions, the labels or instructions state that the kit is used to detect inflammation-related chronic kidney disease.
  • the inflammation-related chronic kidney disease is a type of kidney disease in which the expression of IL-17C-related molecules is abnormally up-regulated at the same time.
  • the content indicated in the label or the description is selected from the following group:
  • the detection reagents include: specific primers, specific antibodies, probes and/or chips.
  • the kit is used to detect isolated kidney tissue samples (including patient samples and normal samples).
  • the third aspect of the present invention provides the use of an IL-17C inhibitor for preparing a pharmaceutical composition for preventing and/or treating inflammation-related chronic kidney disease.
  • the inflammation-related chronic kidney disease is a kidney disease with high expression of IL-17C, IL-17A, IL-17RE, IL-6 and/or IL-1 ⁇ .
  • the inflammation-related chronic kidney disease is selected from the group consisting of diabetic nephropathy, obstructive nephropathy, primary glomerulonephritis, secondary glomerulonephritis, hypertensive renal arterioles, chronic Pyelonephritis, hereditary nephritis, chronic uric acid nephropathy, drug-induced nephropathy, ischemic nephropathy, or a combination thereof.
  • the diabetes in the diabetic nephropathy, is type I diabetes or type II diabetes.
  • the inhibitor is selected from the group consisting of: an antibody or small molecule inhibitor targeting IL-17C and/or its receptor protein; a target targeting IL-17C and/or its receptor gene To a nucleic acid molecule or a gene editor; or a combination thereof.
  • the small molecule inhibitor includes small molecule inhibitor compounds and pharmaceutically acceptable salts thereof.
  • the receptor of IL-17C is IL-17RE.
  • the antibody is selected from the group consisting of polyclonal antibodies, monoclonal antibodies, chimeric antibodies, bispecific antibodies, antibody conjugates, small molecule antibodies, antibody fusion proteins, and combinations thereof.
  • the small molecule antibody is selected from the group consisting of single-chain antibody ScFv, Fab antibody, Fv fragment, and combinations thereof.
  • the ScFv antibody includes a secretory single-chain antibody expressed (including overexpressed) in the treatment cells.
  • the inhibitor is selected from the group consisting of: plant extract inhibitor, small molecule compound inhibitor, nucleic acid inhibitor, peptide inhibitor, polysaccharide inhibitor, viral vector inhibitor, lipid inhibitor Plastid carrier inhibitor, or nanoparticle carrier inhibitor.
  • the vector includes: bacterial plasmid, bacteriophage, yeast plasmid, plant cell virus, mammalian cell virus such as adenovirus, retrovirus, or other vectors.
  • the pharmaceutical composition further includes a second therapeutic agent, wherein the second therapeutic agent is selected from the group consisting of "renin-angiotensin blockers” (RAS blockers) Drugs, e.g., valsartan, losartan, candesartan, telmisartan, benazepril, perindopril, etc.; "sodium-glucose cotransporter 2 inhibitor" (ie SGLT2i) class of drugs , for example, dapagliflozin, canagliflozin, empagliflozin, soxagliflozin; or a combination thereof.
  • RAS blockers Drugs, e.g., valsartan, losartan, candesartan, telmisartan, benazepril, perindopril, etc.
  • sodium-glucose cotransporter 2 inhibitor ie SGLT2i
  • dapagliflozin canagliflozin, empagli
  • the pharmaceutical composition further includes a pharmaceutically acceptable carrier.
  • a fourth aspect of the present invention provides a method for treating inflammation-related chronic kidney disease, comprising the steps of: administering a therapeutically effective amount of an IL-17C inhibitor to a subject in need, thereby treating the disease.
  • the subject is a mammal.
  • the subject is selected from the group consisting of human, rat or mouse.
  • the inflammation-related chronic kidney disease is selected from the group consisting of diabetic nephropathy, obstructive nephropathy, primary glomerulonephritis, secondary glomerulonephritis, hypertensive renal arterioles, chronic Pyelonephritis, hereditary nephritis, chronic uric acid nephropathy, drug-induced nephropathy, ischemic nephropathy, or a combination thereof.
  • Figure 1 is the expression level of IL-17C in the renal tissue of patients with diabetic nephropathy; IL-17C (A), its receptor IL-17RE (B) and IL-17C in the renal tissue of patients with diabetic nephropathy and normal human renal tissue are shown respectively Expression levels of other important inflammatory cytokines (IL-6(C) and IL-1 ⁇ (D)), calculated as mRNA abundance; "Control”: normal kidney tissue, "DN”: kidney tissue from diabetic nephropathy patients.
  • Figure 2 is the expression level of IL-17C in the kidney tissue of db/db mice; IL-17C (E), its receptor IL-17RE ( F) and other important inflammatory cytokines (IL-6(G) and IL-1 ⁇ (H)) expression levels, calculated as mRNA abundance; where "db/db”: homozygous spontaneous type II diabetic mice ; “db/m”: heterozygous experimental control mice.
  • Figure 3 shows the therapeutic effect of targeting IL-17C and blocking the IL-17C signaling pathway on diabetic nephropathy in db/db mice; wherein, "db/db”: homozygous spontaneous type II diabetic mice, “db /m”: heterozygous experimental control mice; “IgG control”: IgG-type mouse monoclonal antibody irrelevant control; “IL-17C antibody”: mouse IL-17C neutralizing monoclonal antibody.
  • Detection indicators A: blood glucose, B: serum creatinine, C: kidney weight index, D: proteinuria, E: glomerular mesangial matrix index.
  • Figure 4 shows the therapeutic effect of targeting IL-17C and blocking IL-17C signaling pathway on renal tissue inflammation in db/db mice; wherein, "db/db”: homozygous spontaneous type II diabetic mice,” db/m”: heterozygous experimental control mice.
  • "IgG control” IgG-type mouse monoclonal antibody irrelevant control;
  • IL-17C antibody mouse IL-17C neutralizing monoclonal antibody.
  • Detection indicators A: Renal monocyte chemotactic protein, B: Renal IL-6 inflammatory cytokine, C: Renal IL-1 ⁇ inflammatory cytokine, D: Renal IL-17A inflammatory cytokine.
  • the present inventors provided the use of an inhibitor of IL-17C in the treatment of inflammation-related chronic kidney disease through a large number of screening and testing.
  • the inventors unexpectedly discovered for the first time that the present invention discovered for the first time the high expression of IL-17C in kidney disease, and the therapeutic effect of IL-17C inhibitor on kidney disease.
  • the expression level of IL-17C was significantly increased in the renal tissue of patients with diabetic nephropathy and in the renal tissue of spontaneous type II diabetic mice (db/db mice); IL-17C was blocked by antibodies targeting IL-17C
  • the method of signaling pathway can significantly reduce urinary albumin in db/db mice, significantly reduce the level of renal tissue fibrosis in db/db mice, especially significantly reduce the level of inflammation in their renal tissue, thereby treating inflammation-related diseases such as diabetic nephropathy. Chronic kidney disease.
  • the present invention has been completed on this basis.
  • the term “about” means that the value may vary by no more than 1% from the recited value.
  • the expression “about 100” includes all values between 99 and 101 and (eg, 99.1, 99.2, 99.3, 99.4, etc.).
  • the terms "containing” or “including (including)” can be open, semi-closed and closed. In other words, the term also includes “consisting essentially of,” or “consisting of.”
  • room temperature or "normal temperature” refers to a temperature of 4-40°C, preferably, 25 ⁇ 5°C.
  • the term "high expression” or “abnormally up-regulated expression” refers to the ratio of the expression level C1 (C1/C0) of a certain indicator (eg, mRNA, protein) in a subject compared to a normal control C0 (C1/C0) ⁇ 1.2, compared with a normal control C0.
  • a certain indicator eg, mRNA, protein
  • treating refers to a drug that, when administered to a subject alone or in combination with another therapeutic agent, results in regression of disease, which is manifested as a reduction in the severity of symptoms of the disease, a period without symptoms of the disease Increase in frequency and duration, or prevent impairment or disability due to disease.
  • prevention refers to inhibiting the occurrence or recurrence of a disease when a drug is administered alone or in combination with another therapeutic agent to a subject at risk of developing the disease or suffering from recurrence of the disease.
  • the interleukin 17 (interleukin 17, IL-17) family includes six members, namely IL-17A, IL-17B, IL-17C, IL-17D, IL-17E and IL-17F.
  • IL-17A and IL-17F are structurally similar, while IL-17B, C, D, and E have very low homology to IL-17A.
  • IL-17 receptors are also a family, IL-17RA to IL-17RE, respectively.
  • the receptor for IL-17C is mainly IL-17RE.
  • the IL-17C inhibitor can be selected from the following group: antibodies or small molecule inhibitors targeting IL-17C and/or its receptor protein; targeting IL-17C and/or its receptor gene A nucleic acid molecule or a gene editor; or a combination thereof.
  • the IL-17C inhibitor is an IL-17C monoclonal antibody.
  • the present invention discovers the high expression of IL-17C in kidney disease for the first time, and the therapeutic effect of IL-17C inhibitor on kidney disease.
  • IL-17C inhibitors can significantly reduce the damage to the kidneys caused by inflammation-related chronic kidney disease. Protein levels and lowering of glomerular mesangial matrix index have various effects on the treatment of inflammation-related chronic kidney disease.
  • One aspect of the present invention provides the use of an IL-17C gene or IL-17C protein or a detection reagent thereof, for preparing a reagent or kit for detecting inflammation-related chronic kidney disease.
  • kits for detecting inflammation-related chronic kidney disease comprising a container containing a detection reagent for detecting IL-17C-related protein or mRNA; and a label or instructions, the label or instructions state that the kit is used to detect inflammation-related chronic kidney disease.
  • Another aspect of the present invention provides the use of an IL-17C inhibitor for preparing a pharmaceutical composition for preventing and/or treating inflammation-related chronic kidney disease.
  • a method for treating inflammation-related chronic kidney disease comprising the steps of: administering a therapeutically effective amount of an IL-17C inhibitor to a subject in need, thereby treating the disease.
  • compositions and methods of administration are provided.
  • the pharmaceutical composition of the present invention contains the above-mentioned IL-17C inhibitor as an active ingredient.
  • the IL-17C inhibitor has a significant effect on the treatment of inflammation-related chronic kidney diseases such as diabetic nephropathy, and can be used to prepare medicines for the treatment of inflammation-related chronic kidney diseases such as diabetic nephropathy.
  • the pharmaceutical composition of the present invention comprises the inhibitor of the present invention or a pharmacologically acceptable salt thereof and a pharmacologically acceptable excipient or carrier within a safe and effective amount.
  • terapéuticaally effective dose refers to any amount of a drug, as described below, that, when used alone or in combination with another therapeutic agent, promotes disease regression, which manifests as disease symptoms decrease the severity of disease, increase the frequency and duration of disease-free periods, or prevent impairment or disability resulting from the disease.
  • a “therapeutically effective dose” of a drug of the present invention also includes a “prophylactically effective dose", which is any amount of the drug as described below, when the amount of the drug is administered alone or in combination with another therapeutic agent In a subject at risk of developing the disease or suffering from relapse of the disease, the occurrence or relapse of the disease can be inhibited.
  • the pharmaceutical composition contains 1-2000 mg of the active ingredient/dose of the present invention, more preferably, 10-500 mg of the active ingredient/dose of the present invention.
  • the "one dose” is a capsule or tablet.
  • “Pharmaceutically acceptable carrier” means: one or more compatible solid or liquid filler or gel substances which are suitable for human use and which must be of sufficient purity and sufficiently low toxicity. "Compatibility” as used herein means that the components of the composition can be blended with the active ingredients of the present invention and with each other without significantly reducing the efficacy of the active ingredients.
  • Examples of pharmaceutically acceptable carrier moieties include cellulose and its derivatives (such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid) , magnesium stearate), calcium sulfate, vegetable oils (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerol, mannitol, sorbitol, etc.), emulsifiers (such as Tween) ), wetting agents (such as sodium lauryl sulfate), colorants, flavors, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.
  • cellulose and its derivatives such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.
  • gelatin such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate
  • the mode of administration of the active ingredient or pharmaceutical composition of the present invention is not particularly limited, and representative modes of administration include (but are not limited to): oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous), and topical administration medicine.
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules.
  • the active ingredient is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with (a) fillers or extenders, such as , starch, lactose, sucrose, glucose, mannitol and silicic acid; (b) binders such as hydroxymethyl cellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and acacia; (c) humectants , for example, glycerol; (d) disintegrants, such as agar, calcium carbonate, potato starch or tapioca, alginic acid, certain complex silicates, and sodium carbonate; (e) slow solvents, such as paraffin; (f) ) absorption accelerators, such as quaternary amine compounds; (g) wetting agents, such as cetyl alcohol and glyceryl mono
  • Solid dosage forms such as tablets, dragees, capsules, pills and granules can be prepared using coatings and shell materials, such as enteric coatings and other materials well known in the art. They may contain opacifying agents and the release of the active ingredient in such compositions may be in a certain part of the digestive tract in a delayed manner. Examples of embedding components that can be employed are polymeric substances and waxes. If desired, the active active ingredient may also be in microencapsulated form with one or more of the above-mentioned excipients.
  • Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures.
  • liquid dosage forms may contain inert diluents conventionally employed in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-Butanediol, dimethylformamide and oils, especially cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil, or mixtures of these substances, and the like.
  • inert diluents conventionally employed in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-Butanediol, dimethylformamide
  • compositions can also contain adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring and perfuming agents.
  • adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring and perfuming agents.
  • Suspensions in addition to the active ingredient, may contain suspending agents such as ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances, and the like .
  • suspending agents such as ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances, and the like .
  • compositions for parenteral injection may comprise physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions.
  • Suitable aqueous and non-aqueous carriers, diluents, solvents or excipients include water, ethanol, polyols and suitable mixtures thereof.
  • Dosage forms for topical administration of the active ingredients of the present invention include ointments, powders, patches, sprays and inhalants.
  • the active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants that may be required if necessary.
  • the active ingredients of the present invention may be administered alone or in combination with other pharmaceutically acceptable therapeutic agents.
  • the pharmaceutical composition further comprises one or more "renin-angiotensin blocker” (RAS blocker) drugs and/or “sodium-glucose cotransporter 2 inhibitor” "Agent” (ie SGLT2i) class of drugs, preferably, the therapeutic agent is selected from the group consisting of: valsartan, losartan, candesartan, telmisartan, benazepril, perindopril; Gugliflozin, canagliflozin, empagliflozin, soxagliflozin, etc.
  • RAS blocker renin-angiotensin blocker
  • Agent ie SGLT2i
  • the active ingredients of the present invention are administered concomitantly with, or sequentially with, other agents as part of a combination therapy regimen, in the same or separate formulations.
  • Typical ranges for therapeutically effective doses of compositions of active ingredients of the present invention will be: about 1-2000 mg/day, about 10 to about 1000 mg/day, about 10 to about 500 mg/day, about 10 to about 250 mg/day, about 10 to about 100 mg/day, or about 10 to about 50 mg/day.
  • a therapeutically effective dose will be administered in one or more doses. It is to be understood, however, that the particular dosage of a compound of the present invention for any particular patient will depend on a variety of factors, eg, the age, sex, weight, general health, diet, individual response, time of administration, and treatment of the patient to be treated. disease severity, activity of the particular compound administered, dosage form, mode of application, and concomitant medications.
  • a therapeutically effective amount for a given situation can be determined using routine experimentation and is within the ability and judgment of the clinician or physician.
  • the compound or composition will be administered in multiple doses based on the individual condition of the patient and in a manner that allows delivery of a therapeutically effective amount.
  • the present invention finds for the first time that IL-17C is highly expressed in inflammation-related chronic kidney diseases, and is a targeted therapeutic target for inflammation-related chronic kidney diseases such as diabetic nephropathy, thereby providing the inhibition of targeting IL-17C.
  • RNA from kidney tissue was extracted using TRIzoL reagent (Invitrogen).
  • cDNA reverse transcription reagents and real-time PCR reagents were from TaKaRa.
  • the real-time PCR instrument was from Thermo.
  • kidney tissue RNA extraction The steps of kidney tissue RNA extraction are as follows:
  • Example 1 The expression level of IL-17C was significantly increased in the renal tissue of patients with diabetic nephropathy
  • Non-diabetic nephropathy should be excluded for the diagnosis of diabetic nephropathy patients, and renal biopsy should be used for identification when the identification is difficult.
  • the diagnostic criteria for diabetic nephropathy follow the KDIGO guidelines, and one of the following needs to be met:
  • Microalbuminuria occurs in type I diabetes with a duration of diabetes of more than 10 years.
  • the patients with diabetic nephropathy in this study were all diagnosed by renal biopsy.
  • control group diabetic nephropathy patients number 7 7 age 42.1 ⁇ 5.4 57.5 ⁇ 4.6 gender 4 male, 3 female 2 male, 5 female Race Asia Asia Pathological manifestations Minor changes or no apparent kidney damage diabetic nephropathy Fasting blood glucose, mmol/L 4.4 ⁇ 1.2 7.9 ⁇ 0.2* Urea nitrogen, mmol/L 6.1 ⁇ 0.3 9.5 ⁇ 1.8 Creatinine, ⁇ mol/L 83 ⁇ 6.7 124.9 ⁇ 7.8 Urine protein, g/24hr 0.11 ⁇ 0.3 4.6 ⁇ 1.2*
  • IL-17C The mRNA levels of IL-17C, IL-17RE, IL-6 and IL-1 ⁇ in the kidney tissue of the experimental subjects were detected.
  • Example 2 The expression level of IL-17C was significantly increased in the kidney tissue of db/db mice
  • db/db mice were provided by Nanjing Institute of Biomedical Sciences, Nanjing University.
  • the db/db mouse (diabetes mouse) is derived from the C57BL/KsJ inbred strain autosomal recessive and belongs to the type II diabetes model. Animals started gluttony and obesity at 1 month, followed by hyperglycemia, hyperinsulinemia, and increased glucagon. db/db mice generally died within 10 months. Diabetic db/db mice (C57BL/6Jdb/db) spontaneously developed severe diabetes symptoms, weight loss and premature death. Significant nephropathy can occur in db/db mice. db/db mice were bred by heterozygous mating, where heterozygous db/m mice were used for further breeding or experimental controls.
  • mice selected in this experiment were included in the group if they were over 8 weeks old, their blood glucose level was greater than 15 mmol/L, and they had developed severe hyperglycemia.
  • IL-17C The mRNA levels of IL-17C, IL-17RE, IL-6 and IL-1 ⁇ in the kidney tissue of experimental mice were detected.
  • Example 3 Targeting IL-17C and blocking the IL-17C signaling pathway effectively reduced kidney damage in db/db mice
  • the IL-17C neutralizing antibody was from R&D, and the control antibody was mouse IgG.
  • the subtype, prepared from the laboratory, was administered to each mouse at a dose of 10 mg/kg, twice a week for 8 consecutive weeks. After the drug treatment is completed, biological samples such as serum or kidney tissue are taken for testing.
  • db/m mice served as control mice without drug administration.
  • the index detection method is as follows:
  • Kidney weight index the ratio of kidney weight to body weight is the kidney weight index.
  • 24-h urinary albumin amount 24-hour urine was collected from mice using a metabolic cage, and then measured with an enzyme-linked immunosorbent assay (ELISA) kit (Abeam, Cambridge, USA) to evaluate the 24-h urinary albumin amount. See the manufacturer's instructions for the use of the enzyme-linked immunosorbent assay (ELISA) kit.
  • ELISA enzyme-linked immunosorbent assay
  • mice were sacrificed, the kidneys were taken out, the kidney tissue was fixed in formalin, dehydrated in ethanol solution, embedded in paraffin, sectioned (thickness 3 ⁇ m), stained with PAS, and the mouse kidney tissue was observed under a microscope Structural changes. The mesangial matrix area was assessed semiquantitatively.
  • Example 4 Targeting IL-17C and blocking the IL-17C signaling pathway significantly reduced renal tissue inflammation in db/db mice
  • the IL-17C neutralizing antibody was from R&D, and the control antibody was mouse IgG subtype, which was prepared by the laboratory. Mice were administered at a dose of 10 mg/kg twice a week for 8 consecutive weeks. db/m mice served as control mice without drug administration.
  • IL-17C As an important member of the IL-17 family, IL-17C is secreted in large quantities by intestinal epithelial cells and skin stratum corneum cells when the human body encounters intestinal or skin inflammation. IL-17C in turn acts on its secretory cells to make a rapid early response to external stimuli. In this way, the early inflammatory response mediated by IL-17C and the subsequent lymphocyte infiltration mediated by IL-17A together constitute the host's mucosal immune defense line, providing an important barrier for the body to eliminate pathogenic microorganisms to maintain its own homeostasis. Similarly, the persistence of IL-17C can also lead to the occurrence of various autoimmune diseases.
  • IL-17C IL-17C signaling pathway plays an important biological role in a mouse model of acute kidney injury induced by ischemia-reperfusion.
  • acute kidney injury and diabetic nephropathy a chronic kidney disease highly associated with inflammation
  • the above studies cannot explain the physiological or pathological role of IL-17C in chronic kidney diseases that are highly related to inflammation, such as diabetic nephropathy, other than acute kidney injury.
  • the present application found that the expression of IL-17C in the renal tissue of patients with diabetic nephropathy was significantly higher than that in the renal tissue of normal people (Fig. 1, A), while the receptor of IL-17C, IL-17RE, was significantly higher in the renal tissue of patients with diabetic nephropathy.
  • the expression in tissue was not significantly increased compared with normal human kidney tissue (Fig. 1, B). This phenomenon is more obvious in the kidney tissue of spontaneous type II diabetic mice (db/db mice).
  • db/db mice the expression of IL-17C in the kidney tissue of db/db mice is significantly increased ( Fig. 2, E), while the expression of IL-17RE in the kidney tissue of db/db mice was not different from that of control mice (Fig. 2, F). This shows that targeting IL-17C may have different therapeutic effects in clinical treatment compared to targeting IL-17RE.
  • the present invention provides a new treatment method for treating inflammatory-related renal diseases by targeting and inhibiting IL-17C, and IL-17C as a target for inflammatory-related renal diseases is compared with drug development or Marketed inflammatory factor targets, such as: IL-17A, IL-6, IL-23, etc., have clear indications for nephropathy and a definite therapeutic effect, and are likely to form a therapeutic effect with the above targets.
  • drug development or Marketed inflammatory factor targets such as: IL-17A, IL-6, IL-23, etc.

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Abstract

本发明提供了一种靶向IL-17C的抑制剂在治疗炎症相关慢性肾脏疾病中的用途。本发明首次发现白细胞介素17C(interleukin17C，IL-17C)是糖尿病肾病等炎症相关慢性肾脏疾病的一个治疗靶点，从而提供了IL-17C抑制剂这类可预防和/或治疗糖尿病肾病等炎症相关慢性肾脏疾病的药物。

Description

靶向IL-17C的抑制剂在治疗炎症相关慢性肾脏疾病中的用途 技术领域
本发明涉及生物医药领域，具体涉及一种靶向IL-17C的抑制剂在治疗糖尿病肾病等炎症相关慢性肾脏疾病中的用途。
背景技术
糖尿病肾病是糖尿病病人最重要的合并症之一。在糖尿病人群中，发病率在20％-40％，伴有终末期肾病的患者，5年生存率＜20％。我国糖尿病肾病的发病率随糖尿病发病率上升而呈上升趋势，目前已成为终末期肾脏病的第二位原因，仅次于各种肾小球肾炎。由于其存在复杂的代谢紊乱，一旦发展到终末期肾脏病，往往比其他肾脏疾病的治疗更加棘手，因此及时防治对于延缓糖尿病肾病的意义重大。糖尿病肾病是糖尿病全身微血管病性合并症之一，因此发生糖尿病肾病时也往往同时合并其他器官或系统的微血管病如糖尿病视网膜病变和外周神经病变。1型糖尿病病人发生糖尿病肾病多在起病10-15年左右，而2型糖尿病病人发生糖尿病肾病的时间则更短，与年龄、合并其他基础疾病等因素有关。
因此，本领域急需提供新的治疗糖尿病肾病等炎症相关慢性肾脏疾病的药物。
发明内容
本发明的目的是提供一种治疗糖尿病肾病等炎症相关慢性肾脏疾病的药物。
本发明的第一方面，提供了一种IL-17C基因或IL-17C蛋白或其检测试剂的用途，用于制备检测炎症相关慢性肾脏疾病的试剂或试剂盒。
在另一优选例中，所述炎症相关慢性肾脏疾病选自下组：糖尿病肾病、梗阻性肾病、原发性肾小球肾炎、继发性肾小球肾炎、高血压肾小动脉硬化、慢性肾盂肾炎、遗传性肾炎、慢性尿酸性肾病、药物性肾病、缺血性肾病,或其组合。
在另一优选例中，所述的试剂盒包括：对IL-17C相关分子的蛋白或mRNA进行定量检测的试剂以及相应的标签或说明书。
在另一优选例中，所述的试剂包括IL-17C相关分子的特异性引物、特异性抗体、探针和/或芯片。
在另一优选例中，所述的IL-17C相关分子包括：IL-17C基因(包括cDNA序列、和/或mRNA)、IL-17C受体的基因(包括cDNA序列、和/或mRNA)、IL-17C蛋白、IL-17C受体蛋白、或其组合。
在另一优选例中，所述的IL-17C的受体包括IL-17RE。
在另一优选例中，上述的试剂包括：检测用芯片，例如核酸芯片和蛋白质芯片。
在另一优选例中，所述的核酸芯片包括基片和点样在基片上的炎症相关mRNA的特异性寡核苷酸探针，所述的炎症相关基因的特异性寡核苷酸探针包括与IL-17C相关mRNA特异性结合的探针。
在另一优选例中，所述的蛋白质芯片包括基片和点样在基片上的炎症相关蛋白的特异性抗体，所述的炎症相关蛋白的特异性抗体包括抗IL-17C相关蛋白的特异性抗体。
在另一优选例中，所述的IL-17C相关蛋白包括融合蛋白和非融合蛋白。
在另一优选例中，在所述试剂或试剂盒中，包括：作为标准品的IL-17C核酸分子(如mRNA)或IL-17C蛋白。
在另一优选例中，在所述试剂或试剂盒中，还包括：用于检测IL-17C核酸分子或IL-17C蛋白的检测试剂。
本发明的第二方面，提供了一种用于检测炎症相关慢性肾脏疾病的试剂盒，所述的试剂盒含有一容器，所述容器中含有检测IL-17C相关蛋白或mRNA的检测试剂；以及标签或说明书，所述标签或说明书注明所述试剂盒用于检测炎症相关慢性肾脏疾病。
在另一优选例中，所述的炎症相关慢性肾脏疾病是IL-17C相关分子表达同时异常上调型的肾脏疾病。
在另一优选例中，所述的标签或说明书中注明内容，选自下组：
a)当检测对象的IL-17C的mRNA表达水平A1与正常对照的IL-17C的mRNA表达水平A0之比(A1/A0)≥2，则提示该检测对象患炎症相关慢性肾脏疾病的几率高于普通人群；和
b)当检测对象的IL-17C的mRNA表达水平与正常对照的IL-17C的mRNA表达水平之比A1/A0≥2，如果该A1/A0比值越高，则提示所述检测对象患炎症 相关慢性肾脏疾病的严重程度更高。
在另一优选例中，所述的检测试剂包括：特异性引物、特异性抗体、探针和/或芯片。
在另一优选例中，所述的试剂盒用于检测离体的肾脏组织样品(包括患者样本和正常样本)。
本发明第三方面，提供了一种IL-17C抑制剂的用途，用于制备一药物组合物，所述药物组合物用于预防和/或治疗炎症相关慢性肾脏疾病。
在另一优选例中，所述炎症相关慢性肾脏疾病为IL-17C、IL-17A、IL-17RE、IL-6和/或IL-1β高表达的肾脏疾病。
在另一优选例中，所述炎症相关慢性肾脏疾病选自下组：糖尿病肾病、梗阻性肾病、原发性肾小球肾炎、继发性肾小球肾炎、高血压肾小动脉硬化、慢性肾盂肾炎、遗传性肾炎、慢性尿酸性肾病、药物性肾病、缺血性肾病，或其组合。
在另一优选例中，所述糖尿病肾病中，所述糖尿病为I型糖尿病或II型糖尿病。
在另一优选例中，所述抑制剂选自下组：靶向IL-17C和/或其受体蛋白的抗体或小分子抑制剂；靶向IL-17C和/或其受体基因的靶向核酸分子或基因编辑器；或其组合。
在另一优选例中，所述小分子抑制剂包括小分子抑制剂化合物及其药学上可接受的盐。
在另一优选例中，所述IL-17C的受体为IL-17RE。
在另一优选例中，所述抗体选自下组：多克隆抗体、单克隆抗体、嵌合抗体、双特异性抗体、抗体偶联物、小分子抗体、抗体融合蛋白，及其组合。
在另一优选例中，所述小分子抗体选自下组：单链抗体ScFv，Fab抗体，Fv片段，及其组合。
在另一优选例中，所述ScFv抗体包括在治疗细胞中表达(包括过表达)的分泌型单链抗体。
在另一优选例中，所述抑制剂选自下组：植物提取物抑制剂、小分子化合物 抑制剂、核酸类抑制剂、肽类抑制剂、多糖类抑制剂、病毒载体抑制剂、脂质体载体抑制剂、或纳米颗粒载体抑制剂。
在另一优选例中，所述载体包括：细菌质粒、噬菌体、酵母质粒、植物细胞病毒、哺乳动物细胞病毒如腺病毒、逆转录病毒、或其他载体。
在另一优选例中，所述药物组合物还包括第二治疗剂，其中，所述第二治疗剂选自下组：“肾素-血管紧张素阻滞剂”(RAS阻滞剂)类药物，例如，缬沙坦、氯沙坦、坎地沙坦、替米沙坦、贝那普利、培哚普利等；“钠-葡萄糖协同转运蛋白2抑制剂”(即SGLT2i)类药物，例如，达格列净、卡格列净、恩格列净、索格列净；或其组合。
在另一优选例中，所述药物组合物还包括药学上可接受的载体。
本发明第四方面，提供了一种治疗炎症相关慢性肾脏疾病的方法，包括步骤：给予有需要的对象治疗有效量的IL-17C抑制剂，从而治疗所述疾病。
在另一优选例中，所述对象为哺乳动物。
在另一优选例中，所述对象选自下组：人、大鼠或小鼠。
在另一优选例中，所述炎症相关慢性肾脏疾病选自下组：糖尿病肾病、梗阻性肾病、原发性肾小球肾炎、继发性肾小球肾炎、高血压肾小动脉硬化、慢性肾盂肾炎、遗传性肾炎、慢性尿酸性肾病、药物性肾病、缺血性肾病，或其组合。
应理解，在本发明范围内中，本发明的上述各技术特征和在下文(如实施例)中具体描述的各技术特征之间都可以互相组合，从而构成新的或优选的技术方案。限于篇幅，在此不再一一累述。
附图说明
图1为IL-17C在糖尿病肾病患者的肾组织中的表达水平；分别示出了糖尿病肾病患者肾组织和正常人肾组织中IL-17C(A)、其受体IL-17RE(B)和其他重要炎性细胞因子(IL-6(C)和IL-1β(D))的表达水平，以mRNA丰度计算；”Control”：正常肾脏组织，“DN”：糖尿病肾病患者肾组织。
图2为IL-17C在db/db小鼠的肾组织中的表达水平；分别示出了db/db小鼠及对照小鼠肾组织中IL-17C(E)、其受体IL-17RE(F)和其他重要炎性细胞因子 (IL-6(G)和IL-1β(H))的表达水平，以mRNA丰度计算；其中”db/db”：纯合子自发型II型糖尿病小鼠；”db/m”：杂合子实验对照小鼠。
图3示出了靶向IL-17C，阻断IL-17C信号通路对db/db小鼠糖尿病肾病的治疗作用；其中，“db/db”：纯合子自发型II型糖尿病小鼠，”db/m”：杂合子实验对照小鼠；“IgG control”：IgG型小鼠单克隆抗体无关对照；”IL-17C antibody”：鼠IL-17C中和性单克隆抗体。检测指标，A：血葡萄糖，B：血清肌酐，C：肾脏重量指数，D：蛋白尿，E：肾小球系膜基质指数。
图4示出了靶向IL-17C，阻断IL-17C信号通路对db/db小鼠肾组织炎症的治疗作用；其中，“db/db”：纯合子自发型II型糖尿病小鼠，”db/m”：杂合子实验对照小鼠。“IgG control”：IgG型小鼠单克隆抗体无关对照；”IL-17C antibody”：鼠IL-17C中和性单克隆抗体。检测指标，A：肾单核细胞趋化蛋白，B：肾IL-6炎性细胞因子，C：肾IL-1β炎性细胞因子，D：肾IL-17A炎性细胞因子。
具体实施方式
本发明人经过广泛而深入的研究，通过大量筛选和测试，提供了IL-17C的抑制剂在治疗炎症相关慢性肾脏疾病中的用途。发明人意外地首次发现，本发明首次发现了IL-17C在肾脏疾病中的高表达，以及IL-17C抑制剂对肾脏疾病的治疗作用。
IL-17C表达水平在糖尿病肾病患者的肾组织与自发型II型糖尿病小鼠(db/db小鼠)的肾组织中均明显升高；通过靶向IL-17C的抗体，阻断IL-17C信号通路的方法，可以显著减少db/db小鼠的尿白蛋白，显著降低db/db小鼠肾组织纤维化水平，尤其是显著减轻了其肾组织的炎症水平，从而治疗糖尿病肾病等炎症相关慢性肾脏疾病。在此基础上完成了本发明。
术语
除非另有定义，否则本文中所用的全部技术术语和科学术语均具有如本发明所属领域普通技术人员通常理解的相同含义。
如本文所用，在提到具体列举的数值中使用时，术语“约”意指该值可以从列举的值变动不多于1％。例如，如本文所用，表述“约100”包括99和101和之间的全部值(例如，99.1、99.2、99.3、99.4等)。
如本文所用，术语“含有”或“包括(包含)”可以是开放式、半封闭式和封闭 式的。换言之，所述术语也包括“基本上由…构成”、或“由…构成”。
如本文所用，术语“室温”或“常温”是指温度为4-40℃，较佳地，25±5℃。
如本文所用，术语“高表达”或“表达异常上调”指与正常对照C0相比，对象中的某一指标(如mRNA、蛋白质)的表达水平C1之比(C1/C0)≥1.2，较佳地，≥1.5，更佳地，≥2.0、≥2.5或≥3，如约4、5、10、20、30或40倍。
如本文所用，术语“治疗”是指将药物单独施用或者与另一种治疗剂组合施用于受试者时，可使疾病消退，疾病消退表现为疾病症状的严重度降低、无疾病症状期的频率和持续时间增加、或者防止由患病导致的障碍或失能。术语“预防”指当将药物单独施用或者与另一种治疗剂组合施用于具有发生疾病的风险或者遭受疾病复发的受试者时，可抑制疾病的发生或复发。
白细胞介素17抑制剂
白细胞介素17(interleukin 17,IL-17)家族包括6个成员，分别是IL-17A、IL-17B、IL-17C、IL-17D、IL-17E和IL-17F。IL-17A和IL-17F在结构上很相似，而IL-17B、C、D、E与IL-17A同源性很低。
IL-17受体也是一个家族，分别为IL-17RA到IL-17RE。IL-17C的受体主要是IL-17RE。
本发明中，IL-17C抑制剂可选自下组：靶向IL-17C和/或其受体蛋白的抗体或小分子抑制剂；靶向IL-17C和/或其受体基因的靶向核酸分子或基因编辑器；或其组合。优选地，所述IL-17C抑制剂为IL-17C单克隆抗体。
用途
本发明首次发现了IL-17C在肾脏疾病中的高表达，以及IL-17C抑制剂对肾脏疾病的治疗作用。
实验证明，IL-17C抑制剂可显著减轻炎症相关慢性肾脏疾病对肾脏的损伤，更具体地，与未给予IL-17C抑制剂相比，IL-17C抑制剂可降低肾脏重量指数、降低尿白蛋白水平、降低肾小球系膜基质指数，具有多方面的治疗炎症相关慢性肾脏疾病的作用。
本发明一方面，提供了一种IL-17C基因或IL-17C蛋白或其检测试剂的用途，用于制备检测炎症相关慢性肾脏疾病的试剂或试剂盒。
本发明另一方面，提供了一种用于检测炎症相关慢性肾脏疾病的试剂盒，所述的试剂盒含有一容器，所述容器中含有检测IL-17C相关蛋白或mRNA的 检测试剂；以及标签或说明书，所述标签或说明书注明所述试剂盒用于检测炎症相关慢性肾脏疾病。
本发明另一方面，提供了一种IL-17C抑制剂的用途，用于制备一药物组合物，所述药物组合物用于预防和/或治疗炎症相关慢性肾脏疾病。
本发明又一方面，提供了一种治疗炎症相关慢性肾脏疾病的方法，包括步骤：给予有需要的对象治疗有效量的IL-17C抑制剂，从而治疗所述疾病。
药物组合物和施用方法
本发明的药物组合物包含上述IL-17C抑制剂作为活性成分。
实验证明，IL-17C抑制剂具有显著的治疗糖尿病肾病等炎症相关慢性肾脏疾病的效果，可用于制备治疗糖尿病肾病等炎症相关慢性肾脏疾病的药物。
本发明的药物组合物包含安全有效量范围内的本发明抑制剂或其药理上可接受的盐及药理上可以接受的赋形剂或载体。
如本文所用，术语“治疗有效剂量”是指药物的任何如下所述的量，当单独使用或与另一种治疗剂组合使用该量的药物时，可促进疾病消退，疾病消退表现为疾病症状的严重度降低、无疾病症状期的频率和持续时间增加、或者防止由患病导致的障碍或失能。
本发明药物的“治疗有效剂量”也包括“预防有效剂量”，“预防有效剂量”是药物的任何如下所述的量，当将该量的药物单独施用或者与另一种治疗剂组合施用于具有发生疾病的风险或者遭受疾病复发的受试者时，可抑制疾病的发生或复发。
通常，药物组合物含有1-2000mg本发明活性成分/剂，更佳地，含有10-500mg本发明活性成分/剂。较佳地，所述的“一剂”为一个胶囊或药片。
“药学上可接受的载体”指的是：一种或多种相容性固体或液体填料或凝胶物质，它们适合于人使用，而且必须有足够的纯度和足够低的毒性。“相容性”在此指的是组合物中各组份能和本发明的活性成分以及它们之间相互掺和，而不明显降低活性成分的药效。药学上可以接受的载体部分例子有纤维素及其衍生物(如羧甲基纤维素钠、乙基纤维素钠、纤维素乙酸酯等)、明胶、滑石、固体润滑剂(如硬脂酸、硬脂酸镁)、硫酸钙、植物油(如豆油、芝麻油、花生油、橄榄油等)、多元醇(如丙二醇、甘油、甘露醇、山梨醇等)、乳化剂(如吐温
Figure PCTCN2022070550-appb-000001
)、 润湿剂(如十二烷基硫酸钠)、着色剂、调味剂、稳定剂、抗氧化剂、防腐剂、无热原水等。
本发明活性成分或药物组合物的施用方式没有特别限制，代表性的施用方式包括(但并不限于)：口服、瘤内、直肠、肠胃外(静脉内、肌肉内或皮下)、和局部给药。
用于口服给药的固体剂型包括胶囊剂、片剂、丸剂、散剂和颗粒剂。在这些固体剂型中，活性活性成分与至少一种常规惰性赋形剂(或载体)混合，如柠檬酸钠或磷酸二钙，或与下述成分混合：(a)填料或增容剂，例如，淀粉、乳糖、蔗糖、葡萄糖、甘露醇和硅酸；(b)粘合剂，例如，羟甲基纤维素、藻酸盐、明胶、聚乙烯基吡咯烷酮、蔗糖和阿拉伯胶；(c)保湿剂，例如，甘油；(d)崩解剂，例如，琼脂、碳酸钙、马铃薯淀粉或木薯淀粉、藻酸、某些复合硅酸盐、和碳酸钠；(e)缓溶剂，例如石蜡；(f)吸收加速剂，例如，季胺化合物；(g)润湿剂，例如鲸蜡醇和单硬脂酸甘油酯；(h)吸附剂，例如，高岭土；和(i)润滑剂，例如，滑石、硬脂酸钙、硬脂酸镁、固体聚乙二醇、十二烷基硫酸钠，或其混合物。胶囊剂、片剂和丸剂中，剂型也可包含缓冲剂。
固体剂型如片剂、糖丸、胶囊剂、丸剂和颗粒剂可采用包衣和壳材制备，如肠衣和其它本领域公知的材料。它们可包含不透明剂，并且，这种组合物中活性活性成分的释放可以延迟的方式在消化道内的某一部分中释放。可采用的包埋组分的实例是聚合物质和蜡类物质。必要时，活性活性成分也可与上述赋形剂中的一种或多种形成微胶囊形式。
用于口服给药的液体剂型包括药学上可接受的乳液、溶液、悬浮液、糖浆或酊剂。除了活性活性成分外，液体剂型可包含本领域中常规采用的惰性稀释剂，如水或其它溶剂，增溶剂和乳化剂，例知，乙醇、异丙醇、碳酸乙酯、乙酸乙酯、丙二醇、1,3-丁二醇、二甲基甲酰胺以及油，特别是棉籽油、花生油、玉米胚油、橄榄油、蓖麻油和芝麻油或这些物质的混合物等。
除了这些惰性稀释剂外，组合物也可包含助剂，如润湿剂、乳化剂和悬浮剂、甜味剂、矫味剂和香料。
除了活性活性成分外，悬浮液可包含悬浮剂，例如，乙氧基化异十八烷醇、聚氧乙烯山梨醇和脱水山梨醇酯、微晶纤维素、甲醇铝和琼脂或这些物质的混合物等。
用于肠胃外注射的组合物可包含生理上可接受的无菌含水或无水溶液、分 散液、悬浮液或乳液，和用于重新溶解成无菌的可注射溶液或分散液的无菌粉末。适宜的含水和非水载体、稀释剂、溶剂或赋形剂包括水、乙醇、多元醇及其适宜的混合物。
用于局部给药的本发明活性成分的剂型包括软膏剂、散剂、贴剂、喷射剂和吸入剂。活性成分在无菌条件下与生理上可接受的载体及任何防腐剂、缓冲剂，或必要时可能需要的推进剂一起混合。
本发明活性成分可以单独给药，或者与其他药学上可接受的治疗剂联合给药。在另一优选例中，所述药物组合物还包含一种或多种“肾素-血管紧张素阻滞剂”(RAS阻滞剂)类药物和/或“钠-葡萄糖协同转运蛋白2抑制剂”(即SGLT2i)类药物，优选地，所述治疗剂选自下组：缬沙坦、氯沙坦、坎地沙坦、替米沙坦、贝那普利、培哚普利；达格列净、卡格列净、恩格列净、索格列净等。
在某些实施方式中，本发明的活性成分在相同或分开的制剂中与作为联合治疗方案的部分的其它试剂同时使用，或与所述其它试剂依次使用。
本发明的活性成分的组合物的治疗有效剂量的一般范围将是：约1-2000mg/天、约10-约1000mg/天、约10-约500mg/天、约10-约250mg/天、约10-约100mg/天，或约10-约50mg/天。治疗有效剂量将以一个或多个剂量给予。然而，应理解，对于任何特定患者的本发明化合物的特定剂量将取决于多种因素，例如，待治疗的患者的年龄、性别、体重、一般健康状况、饮食、个体响应，给予时间、待治疗的疾病的严重性、施用的具体化合物的活性、剂型、应用模式和伴用药物。给定情况的治疗有效量能用常规实验测定，并在临床医生或医师能力和判断范围内。在任何情况中，所述化合物或组合物将基于患者的个体情况以多个剂量给予并以允许递送治疗有效量的方式给予。
本发明的主要优点包括：
1.本发明首次发现了IL-17C在炎症相关慢性肾脏疾病中存在高表达，是糖尿病肾病等炎症相关慢性肾脏疾病的一个具有针对性的治疗靶点，从而提供了靶向IL-17C的抑制剂在治疗糖尿病肾病等炎症相关的慢性肾脏疾病中的用途。
2.实验证明，通过抑制IL-17C可有效减少糖尿病肾病等疾病造成的炎症和肾脏损伤，因而提供了一种靶向治疗炎症相关慢性肾脏疾病的药物和治疗方 法。
下面结合具体实施，进一步阐述本发明。应理解，这些实施例仅用于说明本发明而不用于限制本发明的范围。下列实施例中未注明具体条件的实验方法，通常按照常规条件，例如Sambrook等人，分子克隆：实验室手册(New York:Cold Spring Harbor Laboratory Press,1989)中所述的条件，或按照制造厂商所建议的条件。除非另外说明，否则百分比和份数按重量计算。
通用方法
mRNA检测方法
肾组织全RNA提取采用TRIzoL试剂(Invitrogen)。cDNA反转录试剂和荧光定量PCR试剂来自TaKaRa。荧光定量PCR仪来自Thermo。
肾组织RNA提取步骤如下：
(1)获得肾组织后，立即以加入液氮，以研磨的方式打破细胞。
(2)每50-100mg组织用1ml Trizol试剂对组织进行裂解。
(3)将上述组织的Trizol裂解液转入EP管中，在15～30℃下放置5分钟。
(4)在上述EP管中，按照每1ml Trizol加0.2ml氯仿的量加入氯仿，盖上EP管盖子，在手中用力震荡15秒，在室温下(15-30℃)放置2-3分钟后，12000g(2-8℃)离心15分钟。
(5)去上层水相置于新EP管中，按照每1ml Trizol加0.5ml异丙醇的量加入异丙醇，在室温下(15-30℃)放置10分钟后，12000g(2-8℃)离心10分钟。
(6)弃上清，按照每1ml Trizol加1ml 75％乙醇进行洗涤，涡旋混合，7500g(2-8℃)离心5分钟，弃上清。
(7)让沉淀的RNA在室温在自然干燥。
(8)用RNase-free water溶解RNA沉淀。
去除基因组DNA反应实验步骤如下：
(1)于冰上配置反应混合液。
Figure PCTCN2022070550-appb-000002
(2)在PCR仪上进行反应：
42℃2min
4℃
cDNA反转录实验步骤如下：
(1)配置反应体系，在冰上进行操作。
Figure PCTCN2022070550-appb-000003
(2)在PCR仪上进行反转录反应。
37℃15min
85℃5sec
4℃
荧光定量PCR实验步骤如下：
(1)在冰上配置PCR反应体系。
Figure PCTCN2022070550-appb-000004
(2)进行PCR反应。
Figure PCTCN2022070550-appb-000005
(3)实验结果分析
反应结束后确认RT-PCR的扩增曲线和融解曲线，制作PCR定量标准曲线等。分析方法参见仪器的操作手册。所检测细胞因子引物序列参见表2所示。
表1实时荧光定量PCR引物信息
Figure PCTCN2022070550-appb-000006
Figure PCTCN2022070550-appb-000007
实施例1.IL-17C表达水平在糖尿病肾病患者的肾组织中明显升高
糖尿病肾病患者诊断入组需排除非糖尿病肾病，鉴别困难时需肾脏穿刺病理检查来鉴别。糖尿病肾病的诊断标准遵循KDIGO指南，需满足以下任一条：
(1)糖尿病患者出现大量蛋白尿。
(2)糖尿病视网膜病变伴微量蛋白尿。
(3)在10年以上糖尿病病程的I型糖尿病中出现微量白蛋白尿。
本研究糖尿病肾病患者均已通过肾脏穿刺病理证实诊断。
相关实验组和对照组临床信息参见表1。
表2糖尿病肾病患者及对照组临床诊断信息
  对照组 糖尿病肾病患者
数目 7 7
年龄 42.1±5.4 57.5±4.6
性别 4男,3女 2男,5女
种族 亚洲 亚洲
病理表现 微小变化或无明显肾损伤 糖尿病肾病
空腹血糖,mmol/L 4.4±1.2 7.9±0.2*
尿素氮,mmol/L 6.1±0.3 9.5±1.8
肌酐,μmol/L 83±6.7 124.9±7.8
尿蛋白,g/24hr 0.11±0.3 4.6±1.2*
*p<0.05,vs对照组
对实验对象的肾脏组织中IL-17C、IL-17RE、IL-6与IL-1β的mRNA水平进行检测。
结果如图1所示，糖尿病肾病患者肾活检组织的IL-17C、IL-17RE、IL-6 与IL-1βmRNA(A、B、C、D)水平相比正常人肾组织显著升高(患者组和对照组，n＝7/组)。
实施例2.IL-17C表达水平在db/db小鼠的肾组织中明显升高
db/db小鼠由南京大学南京生物医学研究所提供。db/db小鼠(diabetes mouse)由C57BL/KsJ近亲交配株常染色体隐性遗传衍化而来，属Ⅱ型糖尿病模型。动物在1个月时开始贪食及发胖，继而产生高血糖、高血胰岛素、胰高血糖素也升高。db/db小鼠一般在10个月内死亡。糖尿病db/db小鼠(C57BL/6Jdb/db)自发严重的糖尿病症状，体重下降和早死。db/db小鼠可发生明显的肾病。db/db小鼠通过杂合子交配进行繁殖，其中杂合子db/m小鼠，用于进一步繁殖或实验对照。
本实验选取的db/db小鼠，入组标准为8周龄以上，血糖水平大于15mmol/L，已发生严重高血糖症。
对实验小鼠的肾组织中的IL-17C、IL-17RE、IL-6与IL-1β进行mRNA水平检测。
结果由图2所示，可以看出，db/db小鼠肾组织IL-17C、IL-6与IL-1βmRNA水平和对照小鼠相比显著升高，而IL-17RE mRNA水平与db/m对照小鼠相比无显著差异(n＝8/组，*p<0.05vs.db/m)。
实施例3.靶向IL-17C，阻断IL-17C信号通路有效减轻了db/db小鼠的肾脏损伤
db/db糖尿病小鼠分两组(n＝8/组，12周龄，糖尿病肾病早期阶段)，分别采用尾静脉注射施用药物治疗，IL-17C中和抗体来自R&D，对照抗体为小鼠IgG亚型，来自实验室自备，每只小鼠施用剂量为10mg/kg，每周施用2次，连续施用8周。完成药物治疗后，取血清或肾组织等生物标本进行检测。db/m小鼠作为对照小鼠未施加药物。
指标检测方法如下：
(1)血糖，使用血糖仪(罗氏，巴塞尔，瑞士)测定血糖水平。
(2)肌酐，使用自动生化分析仪(7600；日本东京，日立)测量血清肌酐。
(3)肾脏重量指数，肾脏重量与体重之比为肾脏重量指数。
(4)24h尿白蛋白量，使用代谢笼从小鼠收集24小时尿液，然后用酶联免疫吸附测定(ELISA)试剂盒(Abcam，Cambridge，USA)进行测量，以评估24h 尿白蛋白量。酶联免疫吸附(ELISA)试剂盒使用方法见厂家使用说明书。
(5)系膜基质指数，将小鼠处死，取出双肾，福尔马林固定肾组织，乙醇溶液脱水，石蜡包埋后切片(厚度3μm)，PAS染色，于显微镜下观察小鼠肾组织结构改变情况。通过半定量评估肾小球系膜基质面积。
结果如图3所示，IL-17C中和抗体基本不影响db/db小鼠血糖和血清肌酐水平(A-B)；但可有效减轻db/db小鼠的肾脏损伤(C-E)(n＝8/组，*p<0.05vs.db/m，#p<0.05vs.db/db+IgGcontrol)，从而确证了IL-17C抑制剂对糖尿病肾病等炎症相关慢性肾脏疾病的治疗作用。
实施例4.靶向IL-17C，阻断IL-17C信号通路显著减轻了db/db小鼠的肾组织炎症
db/db糖尿病小鼠分两组n＝8/组，分别采用尾静脉注射施用药物治疗，IL-17C中和抗体来自R&D，对照抗体为小鼠IgG亚型，来自实验室自备，每只小鼠施用剂量为10mg/kg，每周施用2次，连续施用8周。db/m小鼠作为对照小鼠未施加药物。
结果如图4所示，可以看出IL-17C中和抗体显著减轻了db/db小鼠肾组织MCP-1、IL-6、IL-1β及IL-17A(A-D)的表达(n＝8/组，*p<0.05vs.db/m，#p<0.05vs.db/db+IgGcontrol)，可对炎症相关慢性肾脏疾病产生明显的治疗作用。
讨论
IL-17C作为IL-17家族的重要成员，在人体遭遇肠道或皮肤炎症时，被肠道上皮细胞和皮肤角质层细胞大量分泌。IL-17C又会作用于它的分泌细胞使之快速的对外来刺激做出早期反应。这样，这种由IL-17C介导的早期炎症反应加之随后IL-17A介导的淋巴细胞侵润，共同构成了宿主的粘膜免疫防线，为机体清除病原微生物维持自身稳态提供了重要屏障。同样，IL-17C的持续存在也会导致多种自身免疫病的发生。
目前少有对IL-17C在肾脏疾病中发挥作用的研究。有研究发现IL-17C信号通路在缺血再灌注所引起的急性肾脏损伤的小鼠模型中发挥了重要的生物学作用。但是，急性肾脏损伤和糖尿病肾病(一种和炎症高度相关的慢性肾脏疾病)在发病机制、临床表现、治疗手段上存在显著不同，在动物模型构建上也存在巨大差异。上述研究不能说明IL-17C在急性肾损伤之外的，糖尿病肾病等炎症高度相关的慢性肾脏疾病中发挥的生理学或病理学作用。
而本申请发现，IL-17C在糖尿病肾病患者肾组织内的表达显著高于正常人肾组织内的表达(附图1，A)，而IL-17C的受体IL-17RE在糖尿病肾病患者肾组织内的表达与正常人肾组织相比增加的并不明显(附图1，B)。这一现象在自发型II型糖尿病小鼠(db/db小鼠)肾组织内表现的更加明显，与对照小鼠相比，IL-17C在db/db小鼠肾组织内表达显著升高(附图2，E)，而IL-17RE在db/db小鼠肾组织内的表达与对照小鼠相比没有区别(附图2，F)。这说明，靶向IL-17C相较于靶向IL-17RE在临床治疗中可能会出现不同的治疗效果。
值得注意的是，本研究还发现，靶向IL-17C可在db/db小鼠肾组织内显著降低IL-17A的表达水平(附图4，D)，这提示IL-17C可以作为IL-17A、IL-6和/或IL-1β上游药物靶标，调节其在肾组织内的表达水平。
综上所述，本发明提供了一种新的通过靶向抑制IL-17C来治疗炎性相关肾脏疾病的治疗方法，且IL-17C作为炎性相关肾脏疾病的靶点相较有药物开发或上市的炎性因子靶点，如：IL-17A、IL-6、IL-23等，具有明确的肾病适应症针对性和确定的治疗效果，并有很大的可能和上述靶点形成治疗上的协同效应，临床应用效果更佳。
在本发明提及的所有文献都在本申请中引用作为参考，就如同每一篇文献被单独引用作为参考那样。此外应理解，在阅读了本发明的上述讲授内容之后，本领域技术人员可以对本发明作各种改动或修改，这些等价形式同样落于本申请所附权利要求书所限定的范围。

Claims (15)

  1. 一种IL-17C基因或IL-17C蛋白或其检测试剂的用途，其特征在于，用于制备检测炎症相关慢性肾脏疾病的试剂或试剂盒。
  2. 如权利要求1所述的用途，其特征在于，所述炎症相关慢性肾脏疾病选自下组：糖尿病肾病、梗阻性肾病、原发性肾小球肾炎、继发性肾小球肾炎、高血压肾小动脉硬化、慢性肾盂肾炎、遗传性肾炎、慢性尿酸性肾病、药物性肾病、缺血性肾病,或其组合。
  3. 如权利要求1所述的用途，其特征在于，所述的试剂包括IL-17C相关分子的特异性引物、特异性抗体、探针和/或芯片。
  4. 如权利要求1所述的用途，其特征在于，所述的IL-17C相关分子包括：IL-17C基因(包括cDNA序列、和/或mRNA)、IL-17C受体的基因(包括cDNA序列、和/或mRNA)、IL-17C蛋白、IL-17C受体蛋白、或其组合。
  5. 如权利要求1所述的用途，其特征在于，所述试剂为核酸芯片或蛋白质芯片。
  6. 如权利要求5所述的用途，其特征在于，所述的核酸芯片包括基片和点样在基片上的炎症相关mRNA的特异性寡核苷酸探针，所述的炎症相关基因的特异性寡核苷酸探针包括与IL-17C相关mRNA特异性结合的探针。
  7. 如权利要求5所述的用途，其特征在于，所述的蛋白质芯片包括基片和点样在基片上的炎症相关蛋白的特异性抗体，所述的炎症相关蛋白的特异性抗体包括抗IL-17C相关蛋白的特异性抗体。
  8. 一种用于检测炎症相关慢性肾脏疾病的试剂盒，所述的试剂盒含有一容器，所述容器中含有检测IL-17C相关蛋白或mRNA的检测试剂；以及标签或说明书，所述标签或说明书注明所述试剂盒用于检测炎症相关慢性肾脏疾病。
  9. 一种IL-17C抑制剂的用途，用于制备一药物组合物，所述药物组合物用于预防和/或治疗炎症相关慢性肾脏疾病。
  10. 如权利要求9所述的用途，其特征在于，所述炎症相关慢性肾脏疾病选自下组：糖尿病肾病、梗阻性肾病、原发性肾小球肾炎、继发性肾小球肾炎、高血压肾小动脉硬化、慢性肾盂肾炎、遗传性肾炎、慢性尿酸性肾病、药物性肾病、缺血性肾病，或其组合。
  11. 如权利要求10所述的用途，其特征在于，所述炎症相关慢性肾脏疾病为IL-17C、IL-17A、IL-17RE、IL-6和/或IL-1β高表达的肾脏疾病。
  12. 如权利要求9所述的用途，其特征在于，所述抑制剂选自下组：靶向IL-17C和/或其受体蛋白的抗体或小分子抑制剂；靶向IL-17C和/或其受体基因的靶向核酸分子或基因编辑器；或其组合。
  13. 如权利要求9所述的用途，其特征在于，所述抗体选自下组：多克隆抗体、单克隆抗体、嵌合抗体、双特异性抗体、抗体偶联物、小分子抗体、抗体融合蛋白，及其组合。
  14. 如权利要求9所述的用途，其特征在于，所述药物组合物还包括第二治疗剂，其中，所述第二治疗剂选自下组：“肾素-血管紧张素阻滞剂”(RAS阻滞剂)类药物，例如，缬沙坦、氯沙坦、坎地沙坦、替米沙坦、贝那普利、培哚普利等；“钠-葡萄糖协同转运蛋白2抑制剂”(即SGLT2i)类药物，例如，达格列净、卡格列净、恩格列净、索格列净；或其组合。
  15. 如权利要求9所述的用途，其特征在于，所述药物组合物还包括药学上可接受的载体。
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