WO2024114777A1 - 用TACI-Fc融合蛋白治疗微小病变型肾病的方法 - Google Patents

用TACI-Fc融合蛋白治疗微小病变型肾病的方法 Download PDF

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WO2024114777A1
WO2024114777A1 PCT/CN2023/135762 CN2023135762W WO2024114777A1 WO 2024114777 A1 WO2024114777 A1 WO 2024114777A1 CN 2023135762 W CN2023135762 W CN 2023135762W WO 2024114777 A1 WO2024114777 A1 WO 2024114777A1
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taci
weeks
fusion protein
minimal change
change nephropathy
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PCT/CN2023/135762
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English (en)
French (fr)
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王文祥
房健民
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荣昌生物制药(烟台)股份有限公司
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Publication of WO2024114777A1 publication Critical patent/WO2024114777A1/zh

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K19/00—Hybrid peptides, i.e. peptides covalently bound to nucleic acids, or non-covalently bound protein-protein complexes

Definitions

  • the present invention relates to a TACI-Fc fusion protein drug for treating minimal change nephropathy, a dosage regimen, a dosing interval and an administration method.
  • nephropathy is the most common cause of primary nephrotic syndrome, accounting for 70%-90% of patients (Reference 3: Eddy AA, Symons JM:Nephrotic syndrome in childhood. Lancet 362:629–639,200.).
  • minimal change nephropathy can be divided into primary minimal change nephropathy and secondary minimal change nephropathy according to the cause.
  • the cause of primary minimal change nephropathy is still unclear, and the common causes of secondary minimal change nephropathy include drug-related, infection-related, tumor-related, allergy-related and genetic factors.
  • the clinical manifestations of minimal change nephropathy are normal glomeruli under light microscopy, without obvious pathological changes, nonspecific sclerosis, no specific immune deposition under immunofluorescence microscopy, nonspecific IgM deposition may exist, and extensive fusion of cell foot processes under electron microscopy. Its main clinical symptoms are sudden onset of edema, massive proteinuria, hypoproteinemia and hyperlipidemia. In adult patients, symptoms such as hypertension, hematuria and acute kidney injury are more common.
  • minimal change nephropathy is related to age. It is more common in children and adolescents, often occurring in children aged 1 to 6 years old. The incidence of minimal change nephropathy in children is 15 to 50 cases per 100,000 people per year. In addition, minimal change nephropathy can affect patients of all races, and the disease is more common in Asian populations (Reference 4: Vivarelli M, Massella L, Ruggiero B, et al. Minimal Change Disease. American Society of Nephrology, 2017 (2).).
  • KDIGO Global Organization Developing And Implementing Evidence-Based Clinical Practice Guidelines In Kidney Disease
  • KDIGO recommends that the initial treatment for minimal change disease is high-dose oral glucocorticoids.
  • other drugs such as cyclophosphamide, calcineurin inhibitors or mycophenolate mofetil, including rituximab, can be considered.
  • Cihan et al. (Reference 5: Heybeli C, Erickson S B, Fervenza F C, et al. Comparison of treatment options in adults with frequently relapsing or steroid-dependent minimal change disease [J].
  • Nephrol Dial Transplant, 2021, 36(10): 1821-1827.) retrospectively analyzed the clinical data of 76 patients with frequently relapsing/steroid-dependent MCD who received corticosteroids as first-line treatment, and compared the relapse time, treatment changes and progression of different treatment regimens.
  • Ravani et al. (Reference 8: Boyer O, Niaudet P. Nephrotic syndrome: Rituximab in childhood steroid-dependent nephrotic syndrome [J]. Nat Rev Nephrol, 2013, 9 (10): 562-563.) proposed that rituximab can only temporarily prevent recurrence of the disease, and patients may be dependent on steroids or calcium. Patients have switched from phosphatase inhibitors to rituximab. Studies have found that rituximab has serious infusion reactions. Various studies have reported that the incidence of rituximab-related infusion reactions is 26% to 85%.
  • rituximab has also been reported to cause rare adverse events such as hepatitis B virus reactivation and severe skin reactions (such as toxic epidermal necrolysis and Stevens-Johnson syndrome) (Reference 9: Alsharhan L, Beck LH Jr. Membranous Nephropathy: Core Curriculum 2021. Am J Kidney Dis. 2021 Mar; 77(3):440-453.).
  • rituximab also has serious side effects, including fulminant myocarditis (Reference 10: Sellier-Leclerc A L, Belli E, Guerin V, et al. Fulminant viral myocarditis after rituximab therapy in pediatric nephrotic syndrome[J].
  • the present invention surprisingly found that TACI-Fc fusion protein produced significant therapeutic effects in treating patients with minimal change nephropathy.
  • the present invention provides a method for treating minimal change nephropathy, comprising administering a therapeutically effective amount of TACI-Fc fusion protein to a patient with minimal change nephropathy.
  • the present invention also provides a method for treating a patient with minimal change disease who has received a minimal change disease treatment regimen, the method comprising (1) determining whether the patient has received a minimal change disease treatment regimen, and (2) if the patient has previously received minimal change disease treatment, administering an effective amount of TACI-Fc fusion protein to the patient with the minimal change disease.
  • the present invention also provides a use of a TACI-Fc fusion protein in preparing a drug for treating patients with minimal change nephropathy.
  • the present invention also provides a method for treating minimal change nephropathy, the method comprising administering a therapeutically effective amount of TACI-Fc fusion protein and other therapeutic drugs to a patient with minimal change nephropathy, wherein the TACI-Fc fusion protein comprises:
  • the TACI-Fc fusion protein described in any of the above items comprises: (i) the TACI extracellular region or a fragment thereof that binds to Blys and/or APRIL; and (ii) a human immunoglobulin-constant region fragment.
  • the TACI extracellular region or its fragment contains the amino acid sequence shown in SEQ ID NO:1.
  • the human immunoglobulin is IgG1.
  • the human immunoglobulin constant region fragment comprises the amino acid sequence of SEQ ID NO:2 or comprises an amino acid sequence that is at least 90%, at least 91%, at least 92%, at least 93%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO:2.
  • human immunoglobulin constant region fragment contains modifications of amino acids at one or more positions corresponding to positions 3, 8, 14, 15, 17, 110, 111 or 173 of SEQ ID NO:2.
  • the modification is amino acid substitution, deletion or insertion.
  • substitution is selected from the following group: P3T, L8P, L14A, L15E, G17A, A110S, P111S and A173T.
  • the human immunoglobulin constant region fragment contains the amino acid sequence of SEQ ID NO:3.
  • the TACI-Fc fusion protein has the amino acid sequence shown in SEQ ID NO:4.
  • the TACI-Fc fusion protein is Telitacicept.
  • the single dose of the TACI-Fc fusion protein is about 0.1 to 10 mg/kg, further including 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4.0, 4.1, 4.2, 4.3, 4.4, 4.5 , 4.6,4.7,4.8,4.9,5.0,5.1,5.2,5.3,5.4,5.5,5.6,5.7,5.8,5.9,6.0,6.1,6.2,6.3,6.4,6.5,6.6,6.7,6.8,6.9,7.0,7.1,7.2,7.3,7.4,7.5,7.6,7.7,7.8,7.9,8.0,8.1,8.2,8.3,8.4,8.5
  • the single dose of the TACI-Fc fusion protein is 80-240 mg, and more preferably 80 mg, 90 mg, 100 mg, 110 mg, 120 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg, 210 mg, 220 mg, 230 mg, or 240 mg.
  • the detection method of the protein content of the above-mentioned drug is: UV-visible spectrophotometry, based on the maximum UV absorption of protein at 280nm, the absorbance value of the tetasip sample at this wavelength is measured. After correcting the absorbance at 320nm, the absorbance value at 280nm is proportional to the protein concentration.
  • the protein concentration is calculated according to the Lambert-Beer law to determine the protein content.
  • the protein content calculation formula is as follows:
  • ⁇ is the extinction coefficient of tadalafil, unit is (mg/ml) -1 ⁇ cm -1 ;
  • A280 is the average absorbance of the sample solution at 280 nm
  • A280 (corrected) is the average corrected absorbance of the sample solution at 280 nm.
  • the TACI-Fc fusion protein is used 1-4 times at intervals of one month; or the intervals of one month are once a month, twice a month, three times a month, or four times a month.
  • the administration frequency of the TACI-Fc fusion protein is once a week.
  • the TACI-Fc fusion protein is administered once every two weeks.
  • the TACI-Fc fusion protein is administered once every three weeks.
  • the TACI-Fc fusion protein is administered once every four weeks.
  • the treatment lasts for about 2-50 weeks. Further preferably, the treatment lasts for 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, 25 weeks, 26 weeks, 27 weeks, 28 weeks, 29 weeks, 30 weeks, 31 weeks, 32 weeks, 33 weeks, 34 weeks, 35 weeks, 36 weeks, 37 weeks, 38 weeks, 39 weeks, 40 weeks, 41 weeks, 42 weeks, 43 weeks, 44 weeks, 45 weeks, 46 weeks, 47 weeks, 48 weeks, 49 weeks, 50 weeks.
  • the TACI-Fc fusion protein is administered subcutaneously, intramuscularly or intravenously, and the administration site is preferably the thigh, abdomen or upper arm. In some specific embodiments, the TACI-Fc fusion protein is administered subcutaneously, intramuscularly or intravenously.
  • the injection sites of the TACI-Fc fusion protein are the same or different each time. In some specific embodiments, the injection sites of the TACI-Fc fusion protein are the same each time; in other specific embodiments, the injection sites of the TACI-Fc fusion protein are different each time.
  • the minimal change nephropathy is primary minimal change nephropathy or secondary minimal change nephropathy.
  • the patient is an adult patient or a pediatric patient.
  • the patient had previously received treatment for minimal change nephropathy.
  • the treatment regimen for minimal change nephropathy includes: general treatment for minimal change nephropathy, hormone combined with immunosuppressant treatment regimen, and monoclonal antibody drug treatment regimen.
  • the treatment regimen for minimal change nephropathy includes: administering glucocorticoids to patients, or administering glucocorticoids combined with immunosuppressants to patients, or administering cyclophosphamide to patients, or administering calcineurin inhibitors to patients, or administering mycophenolate mofetil, mycophenolate sodium to patients, or administering rituximab to patients, or administering obinutuzumab to patients, or other regimens.
  • the other therapeutic drugs preferably include glucocorticoids, immunosuppressants, rituximab, and obinutuzumab.
  • glucocorticoids include but are not limited to cortisone, hydrocortisone, prednisone, prednisolone, methylprednisolone, triamcinolone acetonide, dexamethasone, and betamethasone.
  • the immunosuppressants include but are not limited to cyclophosphamide (CTX), calcineurin inhibitors, mycophenolate mofetil (MMF), mycophenolate sodium, tacrolimus, chlorambucil, cyclosporine, levamisole, angiotensin converting enzyme inhibitors (ACEI), thioguanine, azathioprine, and leflunomide.
  • CX cyclophosphamide
  • MMF mycophenolate mofetil
  • ACEI angiotensin converting enzyme inhibitors
  • thioguanine thioguanine
  • azathioprine azathioprine
  • leflunomide leflunomide
  • the other therapeutic drugs are one or more of cortisone, hydrocortisone, prednisone, prednisolone, methylprednisolone, triamcinolone acetonide, dexamethasone, betamethasone, cyclophosphamide (CTX), calcineurin inhibitors, mycophenolate mofetil (MMF), mycophenolate sodium, tacrolimus, chlorambucil, cyclosporine, levamisole, angiotensin-converting enzyme inhibitors (ACEI), thioguanine, azathioprine, leflunomide, rituximab, and obinutuzumab.
  • the other therapeutic drugs are one or more of cortisone, hydrocortisone, prednisone, prednisolone, methylprednisolone, triamcinolone acetonide, dexamethasone, betamethasone, cyclophosphamide (CTX),
  • the combined drug is tetascept + cortisone, or tetascept + hydrocortisone, or tetascept + prednisone, or tetascept + prednisolone, or tetascept + methylprednisolone, or tetascept + triamcinolone acetonide, or tetascept + dexamethasone, or tetascept + betamethasone, or tetascept + cyclophosphamide (CTX), or tetascept + calcineurin inhibitor, or tetascept + It is selected from the group consisting of tacicept + mycophenolate mofetil (MMF), tacicept + mycophenolate sodium,
  • the other therapeutic drugs can be adjusted during the treatment process according to the specific conditions of the patient.
  • the single dose of the TACI-Fc fusion protein is about 0.1 to 10 mg/kg, further including 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5,
  • the single administration dose of the TACI-Fc fusion protein can be adjusted during the treatment according to the specific conditions of the patient.
  • the single dose of the TACI-Fc fusion protein is 80-240 mg, and more preferably 80 mg, 90 mg, 100 mg, 110 mg, 120 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg, 210 mg, 220 mg, 230 mg, or 240 mg.
  • the single administration dose of the TACI-Fc fusion protein can be adjusted during the treatment according to the specific conditions of the patient.
  • the TACI-Fc fusion protein is used 1-4 times at intervals of one month, or the intervals of one month are once a month, twice a month, three times a month, or four times a month.
  • the administration frequency of the TACI-Fc fusion protein is once a week.
  • the administration frequency of the TACI-Fc fusion protein is once every two weeks.
  • the administration frequency of the TACI-Fc fusion protein is once every three weeks.
  • the administration frequency of the TACI-Fc fusion protein is once every four weeks.
  • the administration frequency and interval of the TACI-Fc fusion protein can be adjusted during the treatment according to the specific conditions of the patient.
  • the TACI-Fc fusion protein is administered for about 2-50 weeks.
  • the TACI-Fc fusion protein is administered continuously for 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, 25 weeks, 26 weeks, 27 weeks, 28 weeks, 29 weeks, 30 weeks, 31 weeks, 32 weeks, 33 weeks, 34 weeks, 35 weeks, 36 weeks, 37 weeks, 38 weeks, 39 weeks, 40 weeks, 41 weeks, 42 weeks, 43 weeks, 44 weeks, 45 weeks, 46 weeks, 47 weeks, 48 weeks, 49 weeks, and 50 weeks.
  • the treatment cycle of the TACI-Fc fusion protein can be adjusted during the treatment process according to the specific conditions of the patient.
  • the single dose of the other therapeutic drugs is about 0.001 to 10 mg/kg, further including 0.001, 0.002, 0.003, 0.004, 0.005, 0.006, 0.007, 0.008, 0.009, 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4.0, 4.1, 4.2, 4.3, 4.4, 4.5,
  • the single dose of the other therapeutic drugs can be adjusted during the treatment process according to the specific conditions of the patient.
  • the single dose of the other therapeutic drugs is about 1-50 mg, and more preferably 1 mg, 1.5 mg, 2 mg, 2.5 mg, 3 mg, 3.5 mg, 4 mg, 4.5 mg, 5 mg, 5.5 mg, 6 mg, 6.5 mg, 7 mg, 7.5 mg, 8 mg, 8.5 mg, 9 mg, 9.5 mg, 10 mg, 10.5 mg, 11 mg, 11.5 mg, 12 mg, 12.5 mg, 13 mg, 13.5 mg, 14 mg, 14.5 mg, 15 mg, 15.5 mg, 16 mg, 16.5 mg, 17 mg, 17.5 mg, 18 mg, 18.5 mg, 19 mg, 19.5 mg, 20 mg, 20.5 mg, 21 mg, 21.5 mg, 22 mg, 22.5 mg, 23mg, 23.5mg, 24mg, 24.5mg, 25mg, 25.5mg, 26mg, 26.5mg, 27mg, 2
  • the single dose of the other therapeutic drugs can be adjusted during the treatment process according to the specific conditions of the patient.
  • the other therapeutic drugs are used 1-90 times at intervals of one month.
  • the administration frequency of the other therapeutic drugs is once a day, twice a day, three times a day, four times a day, five times a day, six times a day, once a week, twice a week, three times a week, four times a week, five times a week, six times a week, seven times a week, eight times a week, nine times a week, ten times a week, eleven times a week, twelve times a week, thirteen times a week, fourteen times a week, fifteen times a week, sixteen times a week, seventeen times a week, or eighteen times a week.
  • the administration frequency and interval of the other therapeutic drugs can be adjusted during the treatment process according to the specific conditions of the patient.
  • the other therapeutic drugs are continued for about 2-50 weeks.
  • the other therapeutic drug is administered continuously for 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, 25 weeks, 26 weeks, 27 weeks, 28 weeks, 29 weeks, 30 weeks, 31 weeks, 32 weeks, 33 weeks, 34 weeks, 35 weeks, 36 weeks, 37 weeks, 38 weeks, 39 weeks, 40 weeks, 41 weeks, 42 weeks, 43 weeks, 44 weeks, 45 weeks, 46 weeks, 47 weeks, 48 weeks, 49 weeks, and 50 weeks.
  • the treatment cycle of the other therapeutic drugs can be adjusted during the treatment process according to the specific conditions of the patient.
  • the other therapeutic drugs are administered orally, subcutaneously, intramuscularly or intravenously, wherein the subcutaneous, intramuscular or intravenous administration site is preferably the thigh, abdomen or upper arm.
  • the TACI-Fc fusion protein provided by the present invention shows unexpected clinical efficacy and good safety in the process of treating patients with minimal change nephropathy.
  • Figure 1 shows the patient's renal biopsy results
  • FIG 2 shows the changes in the examination indicators of albumin (ALB) and urine albumin-to-creatinine ratio (UACR) within 4 weeks of the patient's third treatment (prednisone + tacrolimus) and current treatment (tacrolimus + prednisone);
  • FIG3 is a graph showing the reduction of prednisone during current treatment (tetrasep+prednisone);
  • FIG 4 shows the changes in albumin test indicators of patients during the current treatment (tetrasep + prednisone);
  • Figure 5 shows the changes in urine albumin-creatinine ratio test indicators of patients during the current treatment (tetrasep + prednisone).
  • TACI transmembrane activator and CAML interactor, which is a member of the tumor necrosis factor receptor superfamily.
  • B lymphocyte stimulator which is a member of the TNF ligand superfamily that exists in two forms: membrane-bound and soluble. It is specifically expressed on the surface of bone marrow cells and selectively stimulates B lymphocyte proliferation and immunoglobulin production;
  • APRIL a proliferation-inducing ligand
  • TNF tumor necrosis factor
  • APRIL can specifically bind to TACI and BCMA, and after binding, it can prevent APRIL from binding to B cells and inhibit the proliferation response of primitive B cells stimulated by APRIL. Moreover, APRIL can competitively bind to receptors (BCMA, TACI) with BLys.
  • TACI-Fc fusion protein involved in the present invention refers to a transmembrane activator, calcium regulator and cyclophilin ligand interactor (TACI)-immunoglobulin fusion protein (i.e., TACI-Fc fusion protein).
  • the TACI-immunoglobulin fusion protein provided by the present invention includes: (i) a TACI extracellular region or a fragment thereof that binds to Blys and/or APRIL; and (ii) a human immunoglobulin constant region fragment.
  • TACI extracellular region or a fragment thereof that binds to Blys and/or APRIL can be specifically referred to the extracellular domain of TACI disclosed in U.S. Patent Nos. 5,969,102, 6,316,222 and 6,500,428 and U.S. patent applications 09/569,245 and 09/627,206 (the contents of which are incorporated herein by reference), as well as specific fragments of the extracellular domain of TACI that can interact with the TACI ligand, or the amino acid fragment of position 13-118 of the TACI extracellular domain disclosed in Chinese Patent Publication No. CN101323643A.
  • the immunoglobulin part is preferably IgG1, which may include a heavy chain constant region, such as a human heavy chain constant region.
  • the preferred "human immunoglobulin constant region fragment” of the present invention is an amino acid fragment containing part of the hinge region domain, the CH2 domain and the CH3 domain.
  • the amino acid sequence of the "human immunoglobulin constant region fragment” of the present invention is as shown in SEQ ID NO:2, or comprises an amino acid sequence that is at least 90%, at least 91%, at least 92%, at least 93%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO:2.
  • the amino acid sequence of the "human immunoglobulin constant region fragment" is as shown in SEQ ID NO:3.
  • treatment is related to a given disease or condition, including but not limited to: inhibiting the disease or condition, such as preventing the development of the disease or condition; alleviating the disease or condition, such as causing the disease or condition to regress; or alleviating the symptoms caused by the disease or condition, such as alleviating, preventing or treating the symptoms of the disease or condition.
  • amino acid involved in the present invention is understood in the broadest sense, and is a general term for a class of organic compounds containing amino and carboxyl groups.
  • the amino acids involved in the present invention are the main units that constitute proteins in living organisms, including but not limited to: glycine, alanine, valine, leucine, isoleucine, methionine (methionine), proline, tryptophan, serine, tyrosine, cysteine, phenylalanine, asparagine, glutamine, threonine, aspartic acid, glutamic acid, lysine, arginine and histidine.
  • the three-letter code and the single-letter code of amino acids used in the present invention are as described in J. biol. chem, 243, p3558 (1968).
  • There are many ways to number amino acid sites such as the Kabat numbering system, the EU numbering system, the sequential numbering system, etc.
  • the numbering method of amino acid sites is carried out in the form of "sequential numbering".
  • position 3, 8, 14, 15, 17, 110, 111 or 173 of SEQ ID NO: 2 refers to the 3rd amino acid, the 8th amino acid of SEQ ID NO: 2, and so on;
  • P3T as described in the present invention refers to the mutation of the 3rd amino acid sequence of SEQ ID NO: 2 from the previous "P” to "T”
  • L8P refers to the mutation of the 8th amino acid sequence of SEQ ID NO: 2 from the previous "L” to "P", and so on.
  • the constant region of the immunoglobulin provided by the present invention may introduce one or more amino acid changes, such as substitution (ie, mutation), addition (ie, insertion) or deletion (ie, deletion).
  • the TACI-Fc fusion protein of the present invention can be administered by any of a variety of routes, including but not limited to: oral, intravenous, intramuscular, intraarterial, intramedullary, intraperitoneal, intrathecal, intracardiac, transdermal, percutaneous, topical, subcutaneous, intranasal, enteral, sublingual, vaginal or rectal routes.
  • minimal change nephropathy in the present invention is also known as lipoid nephropathy in the past, which refers to one of the various types of nephrotic syndrome with mild mesangial proliferation, fatty degeneration of proximal tubular epithelial cells, and massive proteinuria, hypoproteinemia, edema, and hyperproteinemia as basic characteristics.
  • lipoid nephropathy in the past, which refers to one of the various types of nephrotic syndrome with mild mesangial proliferation, fatty degeneration of proximal tubular epithelial cells, and massive proteinuria, hypoproteinemia, edema, and hyperproteinemia as basic characteristics.
  • primary minimal change nephropathy in the present invention refers to a type of disease in which the cause of kidney disease is unknown. The most likely cause is that the abnormal immune system causes lymphokines secreted by T lymphocytes to trigger certain damage to glomerular podocytes. This damage may be the extensive disappearance of foot processes of glomerular podocytes and changes in the charge barrier of the glomerular basement membrane.
  • secondary minimal change nephropathy in the present invention refers to a type of glomerular disease caused by other factors.
  • Common causes of secondary minimal change nephropathy include drug-related (non-steroidal anti-inflammatory drugs, antibiotics, interferon, etc.), infection-related (HIV, Guillain-Barré syndrome, syphilis, parasites, etc.), tumor-related (Hodgkin's disease, non-Hodgkin's disease, solid tumors, eosinophilic lymphoma), allergy-related (food, pollen, dust, insect bites) and genetic factors.
  • glucocorticoids include but are not limited to cortisone, hydrocortisone, prednisone, prednisolone, methylprednisolone, triamcinolone acetonide, dexamethasone, and betamethasone.
  • hormone combined with immunosuppressant treatment regimen refers illustratively to the 2021 KDIGO guidelines, which recommends the use of a combined hormone + immunosuppressant method as the initial treatment for patients with contraindications to glucocorticoids, wherein immunosuppressants include but are not limited to cyclophosphamide, calcineurin inhibitors, mycophenolate mofetil, and mycophenolate sodium.
  • the term "monoclonal antibody drug treatment regimen" in the present invention refers to, by way of example, the recommendation in the 2021 KDIGO guidelines for the use of, but not limited to, rituximab treatment to prolong remission and reduce relapse rates for frequently relapsing/hormone-dependent minimally changing diseases.
  • the patient a female, had typical nephrotic syndrome as the main manifestation, with edema of both eyelids, mild pitting edema of both lower limbs, urine protein (3+), urine occult blood (1+), 24h urine protein of 5055mg, blood albumin of 25.5g/L, total cholesterol of 8.71mmol/L, triglycerides of 0.99mmol/L, and creatinine of 50 ⁇ mol/L.
  • Figure 1 shows the results of the patient's renal biopsy. Under light microscopy, a total of 19 glomeruli were found, with no proliferation in the glomerular mesangial area, 1-3 mesangial cells/mesangial area, no enlargement of the mesangial matrix, no thickening of the glomerular capillary wall, and swollen podocytes and endothelial cells.
  • MASSON staining no obvious erythropoietin deposition, small focal atrophy of renal tubules, swelling of some epithelial cells, scattered protein casts, small focal fibrosis of renal interstitium, infiltration of a small number of lymphocytes and monocytes, no thickening of the wall of small arteries in the interstitium.
  • Immunofluorescence showed 3 glomeruli in total, no obvious immunofluorescence distribution, IgA (-), IgG (-), C3 (-), F (-), IgM (-), C1q (-), ⁇ (-), ⁇ (-).
  • tacrolimus was discontinued and tetasipir 160 mg ih qw was added.
  • Figure 2 shows the changes in the patient's albumin (ALB) and urine albumin-creatinine ratio (UACR) during the third treatment and 4 weeks of the current treatment.
  • the patient was reexamined 25 days after the current treatment.
  • the patient's albumin level was 41.6 g/L and the urine albumin-creatinine ratio was 0.03 g/g.
  • Clinical remission was achieved after 4 weeks of medication.
  • the patient was maintained on treatment for 6 months, with the dose of temetasipr reduced to 80 mg subcutaneously every 14 days, and the dose of prednisone rapidly reduced from 30 mg/day to 5 mg/day.
  • the patient's albumin and urine albumin-creatinine ratio were continuously monitored during the reduction period.
  • Table 2 shows the dosage of temetasipr and prednisone during the current treatment (temetasipr + prednisone) and the changes in urine albumin-creatinine ratio, plasma albumin and total cholesterol.
  • Figure 3 shows the reduction of prednisone during the current treatment (temetasipr + prednisone).
  • Figure 4 shows the changes in the patient's albumin test indicators during the current treatment (temetasipr + prednisone).
  • Figure 5 shows the changes in the patient's urine albumin-creatinine ratio test indicators during the current treatment (temetasipr + prednisone). The results showed that the patient did not have a relapse of the disease during the medication reduction treatment.
  • the patient in this case had typical nephrotic syndrome as the main manifestation, and renal biopsy confirmed minimal change nephropathy.
  • the patient's hormone and immunosuppressant treatment was effective, but relapsed during the drug reduction process.
  • the patient himself was resistant to high-dose hormone treatment and refused to be hospitalized for medication treatment. Therefore, he was treated with tadalafil.
  • the random urine protein level dropped to the normal range and remained stable. All clinical indicators were significantly improved.
  • the hormone dosage was quickly reduced from 30 mg/day to 5 mg/day. After the disease was completely relieved, it was observed for 6 months and remained stable without recurrence.
  • tadalafil is a new treatment option for patients with minimal change nephropathy.
  • the present invention discloses for the first time a case of tadalafil treatment of minimal change nephropathy, and there is no related research at present.
  • the patient's condition was relieved after treatment with hormones and tacrolimus and other drugs, but relapsed during the drug reduction process.
  • tadalafil treatment complete remission was achieved, administration was convenient, no adverse drug events occurred, and rapid reduction of hormones was achieved, and long-term stability without recurrence was achieved.

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Abstract

本发明涉及利用TACI-Fc融合蛋白治疗微小病变型肾病的药物、剂量方案、给药间隔及施用方式。结果显示，本发明提供的TACI-Fc融合蛋白在治疗微小病变型肾病患者过程中表现出良好的临床疗效和安全性。

Description

用TACI-Fc融合蛋白治疗微小病变型肾病的方法 技术领域
本发明涉及一种治疗微小病变型肾病的TACI-Fc融合蛋白药物、剂量方案、给药间隔及施用方式。
背景技术
微小病变型肾病(Minimal change disease，MCD)是肾病综合征的一种常见病理类型，其特征是严重蛋白尿、水肿和血管内有效血容量减少。在成人中，微小病变型肾病(MCD)约占肾病综合征患者的20％-35％(文献1：Nachman PH,Jennette JC,Falk RJ:Primary glomerular disease.In:The Kidney,8th Ed.,edited by Brenner BM,Philadelphia,Saunders Elsevier,2008,pp 987–1066；文献2：Cameron JS:The nephrotic syndrome and its complications.Am J Kidney Dis 10:157–171,1987.)，在较年轻的年龄段中，微小病变型肾病可达到更高的比例，在>1岁的儿童中，微小病变型肾病是原发性肾病综合征最常见的病因，占患者的70％-90％(文献3：Eddy AA,Symons JM:Nephrotic syndrome in childhood.Lancet 362:629–639,200.)。
在临床上，微小病变型肾病根据病因可分为原发性微小病变型肾病和继发性微小病变型肾病，其中原发性微小病变型肾病的病因尚不明确，继发性微小病变型肾病的常见病因包括药物相关性、感染相关性、肿瘤相关性、过敏相关性以及遗传等因素。微小病变型肾病的临床表现是在光镜下为正常肾小球，无明显病理改变，可见非特异性的硬化，在免疫荧光镜下无特异性免疫沉积，可存在非特异的IgM沉积，在电镜下则表现为细胞足突的广泛融合。它的主要临床症状是突然发作的水肿、大量蛋白尿、低蛋白血症和高脂血症，在成人患者群体中，高血压、血尿和急性肾损伤等症状更为常见。
目前，微小病变型肾病的发病率与年龄有关，以儿童和青少年多见，常发生于1～6岁儿童，儿童微小病变型肾病的发病率为每年每10万人15～50例。另外，微小病变型肾病可影响所有种族的患者，该病在亚洲人群中更为常见(文献4：Vivarelli M,Massella L,Ruggiero B,et al.Minimal Change Disease.American Society ofNephrology,2017(2).)。
2021年，KDIGO(即Global Organization Developing And Implementing Evidence-Based Clinical Practice Guidelines In Kidney Disease)明确了成人微小病变型肾病的治疗方案(参见表1)，KDIGO推荐的微小病变型肾病初始治疗为口服大剂量糖皮质激素，对于有激素禁忌症的患者，可考虑环磷酰胺、钙调神经磷酸酶抑制剂或霉酚酸酯等其他药物，包括利妥昔单抗。对于频繁复发型/类固醇依赖型MCD，推荐使用环磷酰胺、利妥昔单抗、钙调神经磷酸酶抑制剂或霉酚酸类似物进行治疗(https://kdigo.org/wp-content/uploads/2017/02/KDIGO-GD-Guideline-Key-Takeaways-for-Clinicians-Minimal-Change-Disease.pdf)。
表1 2021-KDIGO成人微小病变型肾病临床实践指南
然而，上述疗法目前仍存在严重且难以克服的治疗弊端，Cihan等(文献5：Heybeli C,Erickson S B,Fervenza F C,et al.Comparison of treatment options in adults with frequently relapsing or steroid-dependent minimal change disease[J].Nephrol Dial Transplant,2021,36(10):1821-1827.)回顾性地分析了76例接受皮质类固醇作为一线治疗的频繁复发型/类固醇依赖型MCD患者的临床资料，比较不同治疗方案的复发时间、治疗变化和进展，发现所有治疗方案尽管均改善了类固醇依赖性，但需要使用类固醇保留剂进行长期治疗，并且截至目前，最佳糖皮质激素方案尚未在临床实践中获得完全统一，每种治疗方法均有其独特的风险，例如：环磷酰胺的生殖系统毒性，钙调磷酸酶抑制剂长期应用的肾毒性等。另外，由于该病具有较高的复发率，有数据表明，成人患者的复发率约为65％-80％，且大多数复发发生在在缓解后的3-6个月内，并且在年龄<45岁成年人中，更容易复发，复发率可高达88％(文献6：Nolasco F,Cameron JS,Heywood EF,Hicks J,Ogg C,Williams DG:Adult-onset minimal change nephrotic syndrome:A long-term follow-up.Kidney Int 29:1215–1223,1986.)，然而在这些频繁复发或类固醇依赖的成年人中重复使用类固醇会增加严重不良事件的风险(文献7：Korbet,S.M.,&Whittier,W.L.(2019).Management ofAdult Minimal Change Disease.Clinical Journal oftheAmerican Society ofNephrology,CJN.01920219.)对于利妥昔单抗，Ravani等(文献8：Boyer O,Niaudet P.Nephrotic syndrome:Rituximab in childhood steroid-dependent nephrotic syndrome[J].Nat Rev Nephrol,2013,9(10):562-563.)提出，利妥昔单抗只能暂时预防病情复发，患者可能由依赖类固醇或钙调神经磷酸酶抑制剂转为依赖利妥昔单抗，有研究发现，利妥昔单抗具有严重的输液反应，各项研究报道利妥昔单抗相关的输液相关反应发生率为26％～85％，在血液肿瘤患者中还报道了利妥昔单抗可导致乙型肝炎病毒再激活、严重皮肤反应(如中毒性表皮坏死松解症和史蒂文斯-约翰逊综合征)等罕见不良事件(文献9：Alsharhan L,Beck LH Jr.Membranous Nephropathy:Core Curriculum 2021.Am J Kidney Dis.2021 Mar；77(3):440-453.)，另外，利妥昔单抗还存在着严重的副作用，包括暴发性心肌炎(文献10：Sellier-Leclerc A L,Belli E,Guerin V,et al.Fulminant viral myocarditis after rituximab therapy in pediatric nephrotic syndrome[J].PediatrNephrol,2013,28(9):1875-1879.)、致命性肺纤维化(文献11：Chaumais M C,Garnier A,Chalard F,et al.Fatal pulmonary fibrosis after rituximab administration[J].Pediatr Nephrol,2009,24(9):1753-1755.)等，且利妥昔单抗价格昂贵，患者可及性不高。
因此无论是在中国还是全球，微小病变型肾病的治疗仍存在一定的挑战，相关治疗领域仍存在着巨大的未满足的临床需求。
发明内容
本发明惊奇地发现了TACI-Fc融合蛋白在治疗微小病变型肾病患者时，产生了显著的治疗效果。
具体的，本发明提供了一种治疗微小病变型肾病的方法，所述方法包括对具有所述微小病变型肾病患者施用治疗有效量的TACI-Fc融合蛋白。
具体的，本发明还提供了一种治疗已经接受过微小病变型肾病治疗方案的微小病变型肾病患者的方法，该方法包括(1)确定患者是否已经接受过微小病变型肾病治疗方案，并(2)如果该患者既往接受过微小病变型肾病治疗，对具有所述微小病变型肾病的患者施用有效量的TACI-Fc融合蛋白。
具体的，本发明还提供了一种TACI-Fc融合蛋白在制备治疗微小病变型肾病患者药物中的用途。
具体的，本发明还提供了一种治疗微小病变型肾病的方法，所述方法包括对具有所述微小病变型肾病患者联合施用治疗有效量的TACI-Fc融合蛋白和其他治疗药物，其中，所述的TACI-Fc融合蛋白包含：
(i)TACI胞外区或其结合Blys和/或APRIL的片段；和
(ii)人免疫球蛋白-恒定区片段。
进一步的，上述任一项所述的TACI-Fc融合蛋白包含：(i)TACI胞外区或其结合Blys和/或APRIL的片段；和(ii)人免疫球蛋白-恒定区片段。
优选的，所述的TACI胞外区或其片段包含SEQ ID NO:1所示的氨基酸序列。
SEQ ID NO:1
优选的，所述的人免疫球蛋白为IgG1。
进一步的，所述的人免疫球蛋白恒定区片段包含SEQ ID NO:2的氨基酸序列或者包含与SEQ ID NO:2至少90％、至少91％、至少92％、至少93％、至少95％、至少96％、至少97％、至少98％、或至少99％一致性的氨基酸序列。
SEQ ID NO:2
进一步的，所述的人免疫球蛋白恒定区片段包含对应于SEQ ID NO:2的位点3、8、14、15、17、110、111或173的一个或多个位点上的氨基酸的修饰。
进一步的，所述的修饰是氨基酸的取代、删除或插入。
进一步的，所述的取代选自以下组：P3T、L8P、L14A、L15E、G17A、A110S、P111S和A173T。
优选的，所述的人免疫球蛋白恒定区片段包含SEQ ID NO:3的氨基酸序列。
SEQ ID NO:3
优选的，所述的TACI-Fc融合蛋白具有SEQ ID NO:4所示的氨基酸序列。
SEQ ID NO:4
优选的，所述的TACI-Fc融合蛋白为泰它西普(Telitacicept)。
进一步的，所述的TACI-Fc融合蛋白的单次给药剂量为约0.1至10mg/kg,进一步包括0.1，0.2，0.3，0.4，0.5，0.6，0.7，0.8，0.9，1.0，1.1，1.2，1.3，1.4，1.5，1.6，1.7，1.8，1.9，2.0，2.1，2.2，2.3，2.4，2.5，2.6，2.7，2.8，2.9，3.0，3.1，3.2，3.3，3.4，3.5，3.6，3.7，3.8，3.9，4.0，4.1，4.2，4.3，4.4，4.5，4.6，4.7，4.8，4.9，5.0，5.1，5.2，5.3，5.4，5.5，5.6，5.7，5.8，5.9，6.0，6.1，6.2，6.3，6.4，6.5，6.6，6.7，6.8，6.9，7.0，7.1，7.2，7.3，7.4，7.5，7.6，7.7，7.8，7.9，8.0，8.1，8.2，8.3，8.4，8.5，8.6，8.7，8.8，8.9，9.0，9.1，9.2，9.3，9.4，9.5，9.6，9.7，9.8，9.9，10mg/kg。
进一步的，所述TACI-Fc融合蛋白的单次给药剂量为80-240mg，进一步优选为80mg，90mg，100mg，110mg，120mg，130mg，140mg，150mg，160mg，170mg，180mg，190mg，200mg，210mg，220mg，230mg，或240mg。
进一步的，上述药物蛋白含量的检测方法为：紫外-可见分光光度法，根据蛋白质在280nm下有最大紫外吸收，测定该波长下泰它西普样品的吸光度值。对320nm处的吸光度进行校正后，得到280nm处的吸光度值与蛋白质浓度呈正比，根据朗伯-比尔定律计算蛋白浓度，确定蛋白质含量。蛋白质含量计算公式如下：
式中：ε为泰它西普消光系数值，单位为(mg/ml)-1·cm-1；
A280为样品溶液在280nm下吸光度的平均值；
A280(校正)为样品溶液在280nm下经过校正后吸光度的平均值。
进一步的，所述的TACI-Fc融合蛋白在一个月的间隔期间使用1-4次；或一个月的间隔期间是每月1次或每月2次或每月3次或每月4次。
进一步优选的，所述的TACI-Fc融合蛋白的给药频次为每周1次。
进一步优选的，所述的TACI-Fc融合蛋白的给药频次为每两周1次。
进一步优选的，所述的TACI-Fc融合蛋白的给药频次为每三周1次。
进一步优选的，所述的TACI-Fc融合蛋白的给药频次为每四周1次。
进一步优选的，所述的治疗持续约2-50周。进一步优选的，所述的治疗持续2周、3周、4周、5周、6周、7周、8周、9周、10周、11周、12周、13周、14周、15周、16周、17周、18周、19周、20周、21周、22周、23周、24周、25周、26周、27周、28周、29周、30周、31周、32周、33周、34周、35周、36周、37周、38周、39周、40周、41周、42周、43周、44周、45周、46周、47周、48周、49周、50周。
进一步优选的，所述的TACI-Fc融合蛋白的施用方式为皮下、肌肉或静脉施用，施用位置优选为大腿、腹部或者上臂。在一些具体的实施例中，所述的TACI-Fc融合蛋白的施用方式为皮下注射、肌肉注射或静脉注射。
进一步优选的，所述的TACI-Fc融合蛋白每次注射的位点相同或者不同。在一些具体的实施例中，所述的TACI-Fc融合蛋白每次注射的位点相同；在另一些具体的实施例中，所述的TACI-Fc融合蛋白每次注射的位点不同。
进一步的，所述的微小病变型肾病为原发性微小病变型肾病或继发性微小病变型肾病。
进一步的，所述的患者为成人患者或儿童患者。
进一步的，所述的患者既往接受过微小病变型肾病的治疗方案。
进一步的，所述的微小病变型肾病的治疗方案包含：微小病变型肾病一般性治疗、激素联合免疫抑制剂治疗方案、单抗类药物治疗方案。
进一步的，所述的微小病变型肾病的治疗方案包含：向患者施用糖皮质激素类药物、或向患者施用糖皮质激素联合免疫抑制剂类药物、或向患者施用环磷酰胺、或向患者施用钙调神经磷酸酶抑制剂、或向患者施用霉酚酸酯、霉酚酸钠、或向患者施用利妥昔单抗、或向患者施用奥妥珠单抗、或其他方案。
本发明提供的联合施用治疗有效量的TACI-Fc融合蛋白和其他治疗药物治疗微小病变型肾病的方法中，所述的其他治疗药物优选的包括糖皮质激素、免疫抑制剂、利妥昔单抗、奥妥珠单抗。
进一步的，所述的糖皮质激素包括但不限于可的松、氢化可的松、泼尼松、泼尼松龙、甲泼尼龙、曲安奈德、地塞米松、倍他米松。
进一步的，所述的免疫抑制剂包括但不限于环磷酰胺(CTX)、钙调磷酸酶抑制剂、霉酚酸酯(mycophenolate mofetil，MMF)、霉酚酸钠、他克莫司、苯丁酸氮芥、环孢素、左旋咪唑、血管紧张素转化酶抑制剂(ACEI)，硫鸟嘌呤，硫唑嘌呤、来氟米特。
进一步的，本发明提供的联合施用治疗有效量的TACI-Fc融合蛋白和其他治疗药物治疗微小病变型肾病的方法中，所述的其他治疗药物为可的松、氢化可的松、泼尼松、泼尼松龙、甲泼尼龙、曲安奈德、地塞米松、倍他米松、环磷酰胺(CTX)、钙调磷酸酶抑制剂、霉酚酸酯(mycophenolate mofetil，MMF)、霉酚酸钠、他克莫司、苯丁酸氮芥、环孢素、左旋咪唑、血管紧张素转化酶抑制剂(ACEI)，硫鸟嘌呤，硫唑嘌呤、来氟米特、利妥昔单抗、奥妥珠单抗中的一种或几种。
优选的，所述的联合施用治疗有效量的TACI-Fc融合蛋白和其他治疗药物治疗微小病变型肾病的方法中，联合药物为泰它西普+可的松、或者为泰它西普+氢化可的松、或者为泰它西普+泼尼松、或者为泰它西普+泼尼松龙、或者为泰它西普+甲泼尼龙、或者为泰它西普+曲安奈德、或者为泰它西普+地塞米松、或者为泰它西普+倍他米松、或者为泰它西普+环磷酰胺(CTX)、或者为泰它西普+钙调磷酸酶抑制剂、或者为泰它西普+霉酚酸酯(mycophenolate mofetil，MMF)、或者为泰它西普+霉酚酸钠、或者为泰它西普+他克莫司、或者为泰它西普+苯丁酸氮芥、或者为泰它西普+环孢素、或者为泰它西普+左旋咪唑、或者为泰它西普+血管紧张素转化酶抑制剂(ACEI)，或者为泰它西普+硫鸟嘌呤，或者为泰它西普+硫唑嘌呤、或者为泰它西普+来氟米特、或者为泰它西普+利妥昔单抗、或者为泰它西普+奥妥珠单抗。
进一步优选的，上述所述的联合施用治疗有效量的TACI-Fc融合蛋白和其他治疗药物治疗微小病变型肾病的方法中，所述的其他治疗药物可根据患者的具体情况在治疗过程中进行调整。
进一步的，上述所述的联合施用治疗有效量的TACI-Fc融合蛋白和其他治疗药物治疗微小病变型肾病的方法中，所述的TACI-Fc融合蛋白的单次给药剂量为约0.1至10mg/kg，进一步包括0.1，0.2，0.3，0.4，0.5，0.6，0.7，0.8，0.9，1.0，1.1，1.2，1.3，1.4，1.5，1.6，1.7，1.8，1.9，2.0，2.1，2.2，2.3，2.4，2.5，2.6，2.7，2.8，2.9，3.0，3.1，3.2，3.3，3.4，3.5，3.6，3.7，3.8，3.9，4.0，4.1，4.2，4.3，4.4，4.5，4.6，4.7，4.8，4.9，5.0，5.1，5.2，5.3，5.4，5.5，5.6，5.7，5.8，5.9，6.0，6.1，6.2，6.3，6.4，6.5，6.6，6.7，6.8，6.9，7.0，7.1，7.2，7.3，7.4，7.5，7.6，7.7，7.8，7.9，8.0，8.1，8.2，8.3，8.4，8.5，8.6，8.7，8.8，8.9，9.0，9.1，9.2，9.3，9.4，9.5，9.6，9.7，9.8，9.9，10mg/kg。
进一步优选的，上述所述的联合施用治疗有效量的TACI-Fc融合蛋白和其他治疗药物治疗微小病变型肾病的方法中，所述的TACI-Fc融合蛋白的单次给药剂量可根据患者的具体情况在治疗过程中进行调整。
进一步的，上述所述的联合施用治疗有效量的TACI-Fc融合蛋白和其他治疗药物治疗微小病变型肾病的方法中，所述TACI-Fc融合蛋白的单次给药剂量为80-240mg，进一步优选为80mg，90mg，100mg，110mg，120mg，130mg，140mg，150mg，160mg，170mg，180mg，190mg，200mg，210mg，220mg，230mg，或240mg。
进一步优选的，上述所述的联合施用治疗有效量的TACI-Fc融合蛋白和其他治疗药物治疗微小病变型肾病的方法中，所述的TACI-Fc融合蛋白的单次给药剂量可根据患者的具体情况在治疗过程中进行调整。
进一步的，上述所述的联合施用治疗有效量的TACI-Fc融合蛋白和其他治疗药物治疗微小病变型肾病的方法中，所述的TACI-Fc融合蛋白在一个月的间隔期间使用1-4次，或一个月的间隔期间是每月1次或每月2次或每月3次或每月4次。
进一步优选的，上述所述的联合施用治疗有效量的TACI-Fc融合蛋白和其他治疗药物治疗微小病变型肾病的方法中，所述的TACI-Fc融合蛋白的给药频次为每周1次。
进一步优选的，上述所述的联合施用治疗有效量的TACI-Fc融合蛋白和其他治疗药物治疗微小病变型肾病的方法中，所述的TACI-Fc融合蛋白的给药频次为每两周1次。
进一步优选的，上述所述的联合施用治疗有效量的TACI-Fc融合蛋白和其他治疗药物治疗微小病变型肾病的方法中，所述的TACI-Fc融合蛋白的给药频次为每三周1次。
进一步优选的，上述所述的联合施用治疗有效量的TACI-Fc融合蛋白和其他治疗药物治疗微小病变型肾病的方法中，所述的TACI-Fc融合蛋白的给药频次为每四周1次。
进一步优选的，上述所述的联合施用治疗有效量的TACI-Fc融合蛋白和其他治疗药物治疗微小病变型肾病的方法中，所述的TACI-Fc融合蛋白的给药频次和给药间隔可根据患者的具体情况在治疗过程中进行调整。
进一步优选的，上述所述的联合施用治疗有效量的TACI-Fc融合蛋白和其他治疗药物治疗微小病变型肾病的方法中，所述的联合施用治疗方案中，所述的TACI-Fc融合蛋白持续约2-50周。进一步优选的，所述的联合施用治疗方案中，所述的TACI-Fc融合蛋白持续给药2周、3周、4周、5周、6周、7周、8周、9周、10周、11周、12周、13周、14周、15周、16周、17周、18周、19周、20周、21周、22周、23周、24周、25周、26周、27周、28周、29周、30周、31周、32周、33周、34周、35周、36周、37周、38周、39周、40周、41周、42周、43周、44周、45周、46周、47周、48周、49周、50周。
进一步优选的，上述所述的联合施用治疗有效量的TACI-Fc融合蛋白和其他治疗药物治疗微小病变型肾病的方法中，所述的TACI-Fc融合蛋白的治疗周期可根据患者的具体情况在治疗过程中进行调整。
进一步的，上述所述的联合施用治疗有效量的TACI-Fc融合蛋白和其他治疗药物治疗微小病变型肾病的方法中，所述的其他治疗药物的单次给药剂量为约0.001至10mg/kg，进一步包括0.001，0.002，0.003，0.004，0.005，0.006，0.007，0.008，0.009，0.01，0.02，0.03，0.04，0.05，0.06，0.07，0.08，0.09，0.1，0.2，0.3，0.4，0.5，0.6，0.7，0.8，0.9，1.0，1.1，1.2，1.3，1.4，1.5，1.6，1.7，1.8，1.9，2.0，2.1，2.2，2.3，2.4，2.5，2.6，2.7，2.8，2.9，3.0，3.1，3.2，3.3，3.4，3.5，3.6，3.7，3.8，3.9，4.0，4.1，4.2，4.3，4.4，4.5，4.6，4.7，4.8，4.9，5.0，5.1，5.2，5.3，5.4，5.5，5.6，5.7，5.8，5.9，6.0，6.1，6.2，6.3，6.4，6.5，6.6，6.7，6.8，6.9，7.0，7.1，7.2，7.3，7.4，7.5，7.6，7.7，7.8，7.9，8.0，8.1，8.2，8.3，8.4，8.5，8.6，8.7，8.8，8.9，9.0，9.1，9.2，9.3，9.4，9.5，9.6，9.7，9.8，9.9，10mg/kg。
进一步优选的，上述所述的联合施用治疗有效量的TACI-Fc融合蛋白和其他治疗药物治疗微小病变型肾病的方法中，所述的其他治疗药物的单次给药剂量可根据患者的具体情况在治疗过程中进行调整。
进一步的，上述所述的联合施用治疗有效量的TACI-Fc融合蛋白和其他治疗药物治疗微小病变型肾病的方法中，所述的其他治疗药物的单次给药剂量约为1-50mg，进一步优选为1mg、1.5mg、2mg、2.5mg、3mg、3.5mg、4mg、4.5mg、5mg、5.5mg、6mg、6.5mg、7mg、7.5mg、8mg、8.5mg、9mg、9.5mg、10mg、10.5mg、11mg、11.5mg、12mg、12.5mg、13mg、13.5mg、14mg、14.5mg、15mg、15.5mg、16mg、16.5mg、17mg、17.5mg、18mg、18.5mg、19mg、19.5mg、20mg、20.5mg、21mg、21.5mg、22mg、22.5mg、23mg、23.5mg、24mg、24.5mg、25mg、25.5mg、26mg、26.5mg、27mg、27.5mg、28mg、28.5mg、29mg、29.5mg、30mg、30.5mg、31mg、31.5mg、32mg、32.5mg、33mg、33.5mg、34mg、34.5mg、35mg、35.5mg、36mg、36.5mg、37mg、37.5mg、38mg、38.5mg、39mg、39.5mg、40mg、40.5mg、41mg、41.5mg、42mg、42.5mg、43mg、43.5mg、44mg、44.5mg、45mg、45.5mg、46mg、46.5mg、47mg、47.5mg、48mg、48.5mg、49mg、49.5mg、或50mg。
进一步优选的，上述所述的联合施用治疗有效量的TACI-Fc融合蛋白和其他治疗药物治疗微小病变型肾病的方法中，所述的其他治疗药物的单次给药剂量可根据患者的具体情况在治疗过程中进行调整。
进一步的，上述所述的联合施用治疗有效量的TACI-Fc融合蛋白和其他治疗药物治疗微小病变型肾病的方法中，所述的其他治疗药物在一个月的间隔期间使用1-90次，优选的，所述的其他治疗药物的给药频次为每日1次、每日2次、每日3次、每日4次、每日5次、每日6次、每周1次、每周2次、每周3次、每周4次、每周5次、每周6次、每周7次、每周8次、每周9次、每周10次、每周11次、每周12次、每周13次、每周14次、每周15次、每周16次、每周17次、每周18次、每周19次、每周20次、每周21次、每周22次、每周23次、每周24次、每周25次、每周26次、每周27次、每月1次、每月2次、每月3次、每月4次、每月5次、每月6次、每月7次、每月8次、每月9次、每月10次、每月11次、每月12次、每月13次、每月14次、每月15次、每月16次、每月17次、每月18次、每月19次、每月20次、每月21次、每月22次、每月23次、每月24次、每月25次、每月26次、每月27次、每月28次、每月29次、每月30次。
进一步优选的，上述所述的联合施用治疗有效量的TACI-Fc融合蛋白和其他治疗药物治疗微小病变型肾病的方法中，所述的其他治疗药物的给药频次和给药间隔可根据患者的具体情况在治疗过程中进行调整。
进一步优选的，上述所述的联合施用治疗有效量的TACI-Fc融合蛋白和其他治疗药物治疗微小病变型肾病的方法中，所述的联合施用治疗方案中，其他治疗药物持续约2-50周。进一步优选的，所述的联合施用治疗中，其他治疗药物持续给药2周、3周、4周、5周、6周、7周、8周、9周、10周、11周、12周、13周、14周、15周、16周、17周、18周、19周、20周、21周、22周、23周、24周、25周、26周、27周、28周、29周、30周、31周、32周、33周、34周、35周、36周、37周、38周、39周、40周、41周、42周、43周、44周、45周、46周、47周、48周、49周、50周。
进一步优选的，上述所述的联合施用治疗有效量的TACI-Fc融合蛋白和其他治疗药物治疗微小病变型肾病的方法中，所述的其他治疗药物的治疗周期可根据患者的具体情况在治疗过程中进行调整。
进一步优选的，上述所述的联合施用治疗有效量的TACI-Fc融合蛋白和其他治疗药物治疗微小病变型肾病的方法中，所述的其他治疗药物的施用方式为口服、皮下、肌肉或静脉施用，其中，皮下、肌肉或静脉的施用位置优选为大腿、腹部或者上臂。
本发明提供的TACI-Fc融合蛋白在治疗微小病变型肾病患者过程中表现出意料不到的临床疗效和良好的安全性。
附图说明
图1为患者肾活检结果；
图2为患者第三次治疗(泼尼松+他克莫司)和现行治疗(泰它西普+泼尼松)4周内白蛋白(ALB)和尿白蛋白肌酐比值(UACR)的检查指标变化情况；
图3为现行治疗(泰它西普+泼尼松)期间波尼松的减量曲线图；
图4为现行治疗(泰它西普+泼尼松)期间患者的白蛋白检查指标变化情况；
图5为现行治疗(泰它西普+泼尼松)期间患者的尿白蛋白肌酐比值检查指标变化情况。
具体实施方式
除非另有定义，本文使用的所有科技术语具有本领域普通技术人员所理解的相同含义。关于本领域的定义及术语，专业人员具体可参考Current Protocols in Molecular Biology(Ausubel)。
本发明所用氨基酸三字母代码和单字母代码如J.biol.chem，243，p3558(1968)中所述。
本发明中的术语“TACI”即transmembrane activator and CAML interactor，是一种肿瘤坏死因子受体超家族中的成员之一。本发明中的术语“BLys”是指B淋巴细胞刺激物(B lymphocyte stimulator)，它是一种以膜结合型和可溶型2种形式存在的TNF配体超家族成员之一,它特异性表达于骨髓细胞表面，并选择性刺激B淋巴细胞增殖和免疫球蛋白的产生；本发明中的术语“APRIL”(a proliferation-inducing ligand)是一种肿瘤坏死因子(TNF)类似物，它能激发体内的原始B细胞和T细胞增殖，促进B细胞累积。APRIL能和TACI、BCMA特异性结合，结合后能阻止APRIL与B细胞结合，并抑制APRIL激发的原始B细胞增殖反应。而且APRIL能和BLys竞争性结合受体(BCMA、TACI)。
本发明涉及的术语“TACI-Fc融合蛋白”是指跨膜激活剂、钙调节剂和亲环蛋白配体相互作用剂(TACI)-免疫球蛋白融合蛋白(即TACI-Fc融合蛋白)，本发明提供的TACI-免疫球蛋白融合蛋白包括：(i)TACI胞外区或其结合Blys和/或APRIL的片段；和(ii)人免疫球蛋白恒定区片段。
术语“TACI胞外区或其结合Blys和/或APRIL的片段”具体可参见美国专利NO.5,969,102、6,316,222和6,500,428和美国专利申请09/569,245和09/627,206(其内容纳入本文作参考)公开的TACI的胞外结构域以及能与TACI配体相互作用的TACI胞外结构域特定片段，或者公开号为CN101323643A的中国专利公开的TACI胞外结构域第13-118位氨基酸片段。
术语“人免疫球蛋白恒定区片段”中，免疫球蛋白部分优选为IgG1，其可以包含重链恒定区，如人的重链恒定区。本发明优选的“人免疫球蛋白恒定区片段”是含有部分铰链区结构域、CH2结构域和CH3结构域的氨基酸片段。在一些更优选的实施例中，本发明所述的“人免疫球蛋白恒定区片段”的氨基酸序列如SEQ ID NO:2所示，或者包含与SEQ ID NO:2至少90％、至少91％、至少92％、至少93％、至少95％、至少96％、至少97％、至少98％、或至少99％一致性的氨基酸序列。在一些更优选的实施例中，所述的“人免疫球蛋白恒定区片段”的氨基酸序列如SEQ ID NO:3所示。
本发明涉及的术语“治疗”与某给定的疾病或病症相关，包括但不限于：抑制该疾病或病症，例如阻止疾病或病症的发展；减轻该疾病或病症，例如导致该疾病或病症消退；或减轻该疾病或病症引起的症状，例如减轻、预防或治疗该疾病或病症的症状。
本发明涉及的术语“氨基酸”以最广义定义理解，是一类含有氨基和羧基的有机化合物的通称，优选的，本发明中涉及的氨基酸是组成生命体中的蛋白质的主要单元，其包括但不限于：甘氨酸、丙氨酸、缬氨酸、亮氨酸、异亮氨酸、甲硫氨酸(蛋氨酸)、脯氨酸、色氨酸、丝氨酸、酪氨酸、半胱氨酸、苯丙氨酸、天冬酰胺、谷氨酰胺、苏氨酸、天冬氨酸、谷氨酸、赖氨酸、精氨酸和组氨酸。
本发明所用氨基酸三字母代码和单字母代码如J.biol.chem，243，p3558(1968)中所述。氨基酸位点的编号方式有多种，如Kabat编号系统、EU编号系统、顺序编号等，在本发明中，氨基酸位点的编号方式采用“顺序编号”的方式进行，如本发明所述的“SEQ ID NO:2的位点3、8、14、15、17、110、111或173”是指SEQ ID NO:2的第3位氨基酸、第8位氨基酸，并依此类推；如本发明所述的“P3T”是指将SEQ ID NO:2的第3位氨基酸序列由之前的“P”突变为“T”，再如“L8P”是指将SEQ ID NO:2的第8位氨基酸序列由之前的“L”突变为“P”，并以此例类推。
作为一种可选择的实施方案，本发明提供的免疫球蛋白的恒定区可以引入一个或多个氨基酸的改变，如取代(即突变)、增加(即插入)或缺失(即删除)。
本发明中的术语“泰它西普”(或称“泰爱”，其在本发明中可以互换使用)是一种TACI-Fc融合蛋白，其INN名为Telitacicept，其氨基酸序列如SEQ ID NO:4所示，或参见https://extranet.who.int/soinn/mod/page/view.php？id＝137&inn_n＝10932所示。
本发明的TACI-Fc融合蛋白可以通过任意多种途径给药，其包括但不局限于：口服、静脉注射、肌肉内注射、动脉内注射、髓内注射、腹腔内注射、鞘内注射、心脑内、透皮、经皮肤、外用、皮下、鼻内、肠内、舌下、阴道内或直肠途经等多种途径。
本发明中的术语“微小病变型肾病”既往也称为类脂性肾病，是指其有轻度系膜增生，近端肾小管上皮细胞可见脂肪变性等特点，以大量蛋白尿、低蛋白血症、水肿、高质血症为基本特征的肾病综合征的多种类型之一。其在光镜下肾小球无明显病变，免疫荧光阴性，只有通过电镜下特征性改变，即广泛的肾小球脏层上皮细胞足突融合来进行确诊。
本发明中的术语“原发性微小病变型肾病”是指肾病病因不明，较有可能的原因是由免疫系统异常导致T淋巴细胞分泌的淋巴因子引发肾小球足细胞的某种损伤而导致的一类疾病，这一损伤可能为肾小球足细胞的广泛足突消失及肾小球基底膜的电荷屏障改变。
本发明中的术语“继发性微小病变型肾病”是指由其他因素所引起的一类肾小球疾病，引起继发性微小病变型肾病的常见病因包括药物相关性(非甾体类消炎药、抗生素、干扰素等)、感染相关性(HIV、格林-巴利综合征、梅毒、寄生虫等)、肿瘤相关性(霍奇金病、非霍金奇病、实体瘤、嗜酸细胞性淋巴瘤)、过敏相关性(食物、花粉、尘土、昆虫叮咬)以及遗传等因素。
本发明中的术语“一般性治疗”示例性的指2021年KDIGO指南中推荐的，对于微小病变型肾病患者的初始治疗方案中采用大剂量的糖皮质激素的方法进行治疗，其中糖皮质激素包括但不限于可的松、氢化可的松、泼尼松、泼尼松龙、甲泼尼龙、曲安奈德、地塞米松、倍他米松。
本发明中的术语“激素联合免疫抑制剂治疗方案”示例性的指2021年KDIGO指南中推荐的，对糖皮质激素禁忌症患者的初始治疗方案中采用联合激素+免疫抑制剂的方法进行治疗，其中免疫抑制剂包括但不限于环磷酰胺、钙调神经磷酸酶抑制剂、霉酚酸酯、霉酚酸钠。
本发明中的术语“单抗类药物治疗方案”示例性的是指2021年KDIGO指南中推荐的，对于频繁复发/激素依赖性微小变化疾病，利用但不限于利妥昔单抗治疗来延长缓解期并降低复发率。
下面将结合实施例对本发明的实施方案进行详细描述，但是本领域技术人员将会理解，下面实施例仅用于说明本发明，而不应视为限定本发明的范围。
实施例1
患者，女，以典型肾病综合征为主要表现，双眼睑浮肿，双下肢轻度凹陷性水肿，查尿蛋白(3+)，尿潜血(1+)，24h尿蛋白量5055mg，血白蛋白25.5g/L，总胆固醇8.71mmol/L，甘油三酯0.99mmol/L，肌酐50μmol/L。
临床排除继发性肾病综合征，肾活检，图1给出了患者肾活检结果，光镜下共查见19个肾小球，肾小球系膜区无增殖，系膜细胞1-3个/系膜区，系膜基质无扩大，肾小球毛细血管壁无增厚，足细胞肿胀，内皮细胞肿胀。
MASSON染色：未见明显嗜复红蛋白沉积，肾小管小灶性萎缩，部分上皮细胞肿胀，可见散在蛋白管型，肾间质小灶性纤维化，少量淋巴细胞、单核细胞浸润，间质内细小动脉管壁无增厚。免疫荧光共查见3个肾小球，未见明显免疫荧光分布，IgA(-)，IgG(-)，C3(-)，F(-)，IgM(-)，C1q(-)，κ(-)，λ(-)。电镜下肾小球系膜细胞及系膜基质无增生扩大，肾小球毛细血管壁基底膜无增厚，未见电子致密物沉积，足突细胞弥漫性足突融合，肾小管上皮细胞肿胀，细胞器肿胀，间质灶性水肿，患者符合微小病变性肾小球肾炎。
【第一次治疗】给予雷公藤多苷片、厄贝沙坦片及利尿消肿等治疗2个月后未完全缓解。
【第二次治疗】给予泼尼松30mg/天+他克莫司1mg/天治疗，病情完全缓解，药物逐渐减量，当泼尼松减量至10mg/天后病情复发，查UACR0.29g/g。患者对大剂量激素治疗抵触，泼尼松加量至15mg/天治疗，一个月后复查UACR 1.38g/g，病情加重。
【第三次治疗】给予泼尼松30mg/天+他克莫司1.5mg/天治疗1个月后病情未完全缓解。
在第三次治疗病情未完全缓解后，停用他克莫司，加用泰它西普160mg ih qw治疗。
图2给出了患者第三次治疗和现行治疗4周内白蛋白(ALB)和尿白蛋白肌酐比值(UACR)的检查指标变化情况，在现行治疗25天后复查，患者白蛋白41.6g/L，尿白蛋白肌酐比值0.03g/g，用药4周即达临床缓解。
继续对患者维持治疗6个月，泰它西普减量至每14天皮下注射80mg，泼尼松由30mg/天快速减量至5mg/天，减药期间对患者的白蛋白和尿白蛋白肌酐比值指标持续进行监测，表2给出了现行治疗(泰它西普+泼尼松)期间泰它西普和波尼松的给药剂量情况和尿白蛋白肌酐比值、血浆白蛋白以及总胆固醇变化情况，图3给出了现行治疗(泰它西普+泼尼松)期间波尼松的减量情况，图4给出了现行治疗(泰它西普+泼尼松)期间患者的白蛋白检查指标变化情况，图5给出了现行治疗(泰它西普+泼尼松)期间患者的尿白蛋白肌酐比值检查指标变化情况，结果表明，患者在减药治疗期间，未有病情复发。
表2现行治疗(泰它西普+泼尼松)期间药物调整及检查指标汇总
讨论
本例患者以典型肾病综合征为主要表现，肾活检证实微小病变肾病。患者激素及免疫抑制剂治疗有效，但药物减量过程中复发，患者本人对大剂量激素治疗较抵触，拒绝住院用药治疗，遂加用泰它西普治疗，用药4周后随机尿蛋白水平降至正常区间并维持稳定，各项临床指标均明显改善，激素用量由30mg/天快速降至5mg/天，病情完全缓解后观察6个月仍稳定无复发，且由于泰它西普给药方便，患者无需住院治疗，短期副作用少，提示泰它西普对于微小病变肾病患者不失为一种治疗新选择。本发明首次公开了泰它西普治疗微小病变肾病1例，目前尚无相关研究。患者经激素和他克莫司等药物治疗后病情缓解，但在药物减量过程中复发，给予泰它西普治疗后获得完全缓解，给药方便，未发生药物不良事件，并且实现激素快速减量，长期稳定无复发。
实施例2进一步的临床研究验证
主要目的
探索泰它西普治疗或缓解微小病变肾病的有效性；
次要目的
初步评价泰它西普治疗或缓解微小病变肾病的安全性。
以上描述地仅是优选实施方案，其只作为示例而不限制实施本发明所必需特征的组合。所提供的标题并不意指限制本发明的多种实施方案。术语例如“包含”、“含”和“包括”不意在限制。此外，除非另有说明，没有数词修饰时包括复数形式，以及“或”、“或者”意指“和/或”。除非本文另有定义，本文使用的所有技术和科学术语的意思与本领域技术人员通常理解的相同。
本申请中提及的所有公开物和专利通过引用方式并入本文。不脱离本发明的范围和精神，本发明的所描述的方法和组合物的多种修饰和变体对于本领域技术人员是显而易见的。虽然通过具体的优选实施方式描述了本发明，但是应该理解所要求保护的本发明不应该被不适当地局限于这些具体实施方式。事实上，那些对于相关领域技术人员而言显而易见的用于实施本发明的所描述的模式的多种变体意在包括在随附的权利要求的范围内。

Claims (21)

  1. 一种治疗微小病变型肾病的方法，所述方法包括对具有所述微小病变型肾病患者施用治疗有效量的TACI-Fc融合蛋白，其中，所述的TACI-Fc融合蛋白包含：
    (i)TACI胞外区或其结合Blys和/或APRIL的片段；和
    (ii)人免疫球蛋白恒定区片段。
  2. 根据权利要求1所述的方法，其特征在于，所述的TACI胞外区或其结合Blys和/或APRIL的片段包含SEQ ID NO:1所示的氨基酸序列。
  3. 根据权利要求2所述的方法，其特征在于，所述的人免疫球蛋白为IgG1或所述的人免疫球蛋白恒定区片段包含SEQ ID NO:2的氨基酸序列或者包含与SEQ ID NO:2至少90％、至少91％、至少92％、至少93％、至少95％、至少96％、至少97％、至少98％、或至少99％一致性的氨基酸序列。
  4. 根据权利要求3所述的方法，其特征在于，所述的人免疫球蛋白恒定区包含对应于SEQ ID NO:2的位点3、8、14、15、17、110、111或173的一个或多个位点上的氨基酸的修饰。
  5. 根据权利要求4所述的方法，其特征在于，所述的修饰是氨基酸的取代、删除或插入。
  6. 根据权利要求5所述的方法，其特征在于，所述的取代选自以下组：P3T、L8P、L14A、L15E、G17A、A110S、P111S和A173T。
  7. 根据权利要求6所述的方法，其特征在于，所述的人免疫球蛋白恒定区包含SEQ ID NO:3的氨基酸序列。
  8. 根据权利要求1所述的方法，其特征在于，所述的TACI-Fc融合蛋白具有SEQ ID NO:4所示的氨基酸序列。
  9. 根据权利要求8所述的方法，其特征在于，所述的TACI-Fc融合蛋白为泰它西普(Telitacicept)。
  10. 根据权利要求8或9所述的方法，其特征在于，所述的微小病变型肾病包括原发性微小病变型肾病和继发性微小病变型肾病。
  11. 根据权利要求10所述的方法，其特征在于，所述的患者为成人患者或儿童患者。
  12. 根据权利要求11所述的方法，其特征在于，所述的患者既往接受过微小病变型肾病治疗方案。
  13. 根据权利要求11或12所述的方法，其特征在于，所述的TACI-Fc融合蛋白的单次给药剂量为约0.1至10mg/kg。
  14. 根据权利要求11或12所述的方法，其特征在于，其中，所述TACI-Fc融合蛋白的单次给药剂量为80-240mg，进一步优选为80mg或160mg或240mg。
  15. 根据权利要求11或12所述的方法，其特征在于，所述的TACI-Fc融合蛋白的施用方式为皮下、肌肉或静脉施用或者施用部位为大腿、腹部或者上臂。
  16. 根据权利要求11或12所述的方法，其特征在于，所述的TACI-Fc融合蛋白在一个月的间隔期间使用1-4次和/或治疗持续约2-50周。
  17. 根据权利要求16所述的方法，其特征在于，所述的TACI-Fc融合蛋白的给药频次为每周一次或者每两周1次或者每3周1次或者每4周1次。
  18. 一种治疗微小病变型肾病的方法，所述方法包括对具有所述微小病变型肾病患者联合施用治疗有效量的TACI-Fc融合蛋白和其他治疗药物，其中，所述的TACI-Fc融合蛋白包含：
    (i)TACI胞外区或其结合Blys和/或APRIL的片段；和
    (ii)人免疫球蛋白-恒定区片段。
  19. 根据权利要求18所述的方法，其特征在于，所述的其他治疗药物包括糖皮质激素、免疫抑制剂、利妥昔单抗、奥妥珠单抗。
  20. 根据权利要求19所述的方法，其特征在于，所述的糖皮质激素包括但不限于可的松、氢化可的松、泼尼松、泼尼松龙、甲泼尼龙、曲安奈德、地塞米松、倍他米松。
  21. 根据权利要求19所述的方法，其特征在于，所述的免疫抑制剂包括但不限于环磷酰胺(CTX)、钙调磷酸酶抑制剂、霉酚酸酯(mycophenolate mofetil，MMF)、霉酚酸钠、他克莫司、苯丁酸氮芥、环孢素、左旋咪唑、血管紧张素转化酶抑制剂(ACEI)，硫鸟嘌呤，硫唑嘌呤、来氟米特。
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