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WO2024067756A1 - 用TACI-Fc融合蛋白治疗膜性肾病的方法 - Google Patents

用TACI-Fc融合蛋白治疗膜性肾病的方法 Download PDF

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Publication number
WO2024067756A1
WO2024067756A1 PCT/CN2023/122388 CN2023122388W WO2024067756A1 WO 2024067756 A1 WO2024067756 A1 WO 2024067756A1 CN 2023122388 W CN2023122388 W CN 2023122388W WO 2024067756 A1 WO2024067756 A1 WO 2024067756A1
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taci
membranous nephropathy
fusion protein
amino acid
weeks
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French (fr)
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杨向东
郭玲
李登任
房健民
王文祥
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Remegen Co Ltd
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Remegen Co Ltd
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Priority to EP23870981.0A priority Critical patent/EP4595980A4/en
Priority to JP2025518025A priority patent/JP2025532251A/ja
Priority to CN202380059055.7A priority patent/CN119698304A/zh
Publication of WO2024067756A1 publication Critical patent/WO2024067756A1/zh
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/177—Receptors; Cell surface antigens; Cell surface determinants
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/46—Hybrid immunoglobulins

Definitions

  • the present invention relates to a TACI-Fc fusion protein drug for treating membranous nephropathy, a dosage scheme, a dosing interval and an administration method.
  • Membranous nephropathy is an antibody-mediated glomerular disease characterized by the formation of immune precipitates containing antigens, IgG, and complement components beneath the epithelial cells in the glomerular loops. Sublethal damage to the epithelial cells leads to cellular simplification and destruction of the glomerular filtration barrier, resulting in proteinuria and other manifestations of nephrotic syndrome.
  • membranous nephropathy can be divided into primary membranous nephropathy and secondary membranous nephropathy according to the cause.
  • Most membranous nephropathy is primary membranous nephropathy, also called idiopathic membranous nephropathy, which is an organ-specific autoimmune disease that occurs without any definite cause or initiating event.
  • membranous nephropathy is secondary membranous nephropathy, and common causes are autoimmune diseases (such as lupus), viruses (hepatitis B, hepatitis C, syphilis), tumors, certain drugs (such as painkillers), poisons (such as exposure to heavy metals such as lead and mercury), etc.
  • Membranous nephropathy is one of the most common causes of nephrotic syndrome in non-diabetic adults, accounting for up to 1/3 of the nephrotic syndrome biopsy results. Its main clinical symptoms are edema, proteinuria, hypoalbuminemia and hyperlipidemia, etc., which mainly affect the function of the glomerular basement membrane and increase the risk of thrombosis, infection, cardiovascular disease, etc.
  • membranous nephropathy At present, the global incidence of membranous nephropathy is about 1 case per 100,000 people per year. It is not clear whether the incidence of membranous nephropathy varies by region or race, but it can be confirmed that membranous nephropathy can affect patients of all ages and races. In the United States, the incidence of membranous nephropathy is about 12 cases per million people per year, and the average age of onset is between 50 and 60 years old. In China, the incidence of membranous nephropathy in China has been rising steadily in the past 20 years. Other studies have shown that the high incidence of membranous nephropathy may be related to the increasingly serious air pollution.
  • the treatment of membranous nephropathy depends on its type and cause.
  • the treatment of membranous nephropathy mainly includes the following treatment methods: 1 Conventional treatment: If the 24-hour urine protein quantity of membranous nephropathy is 1 Below 3.5g; or between 3.5g-8g, with normal renal function and no high-risk phenomenon, usually pril drugs and sartans are used to reduce urine protein, and supportive treatment such as diuretics, antihypertensives, and anticoagulation are given; 2 Hormone combined with immunosuppressants: If the 24-hour urine protein quantity of membranous nephropathy exceeds 3.5g and is accompanied by renal impairment, or the urine protein exceeds 8g, the combined hormone + immunosuppressant method is used for treatment; 3 Monoclonal antibody drugs: such as rituximab.
  • the 2021 KDIGO guidelines recommend five treatment options for membranous nephropathy (see Table 1), which are cyclical or continuous use of cyclophosphamide, rituximab, tacrolimus, and cyclosporine. Among them: 1
  • the cyclical or continuous use of cyclophosphamide must be combined with hormone drugs (such as prednisone), and hormones have great side effects.
  • hormone drugs such as prednisone
  • Cyclophosphamide also has adverse reactions such as reproductive toxicity, bone marrow suppression, infection, and hemorrhagic cystitis.
  • CNIs calcineurin inhibitors
  • the advantages of cyclosporine treatment are rapid onset of action, better efficacy than cyclophosphamide, fewer and milder adverse reactions than cyclophosphamide, and disadvantages are that the overall remission rate is not higher than that of the cyclophosphamide regimen and the short-term recurrence rate is significantly higher than that of cyclophosphamide; the immunosuppressive efficacy of tacrolimus is 10 to 100 times higher than that of cyclosporine, but its disadvantages are similar to those of cyclosporine. Tacrolimus also has the problem of high recurrence rate. In addition, the more prominent adverse reaction of tacrolimus is impaired glucose tolerance and new-onset diabetes.
  • rituximab alone or in combination with calcium Phosphatase inhibitors are recommended for the initial treatment of primary MN with intermediate, high, and very high risk.
  • the remission rate for MN is 67%, and rituximab is applicable to patients with MN who are positive or negative for anti-PLA2R antibodies.
  • rituximab is expensive, has low patient accessibility, and has severe infusion reactions.
  • Various studies have reported that the incidence of rituximab-related infusion-related 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 1: Alsharhan L, Beck LH Jr. Membranous Nephropathy: Core Curriculum 2021. Am J Kidney Dis. 2021 Mar; 77(3): 440-453.).
  • the clinical course of membranous nephropathy is often indolent and existing treatments are toxic. Existing treatment options have certain limitations and risks, and the treatment effects are not satisfactory.
  • obinutuzumab which also targets CD20, can achieve certain therapeutic effects for patients with membranous nephropathy who have failed treatment clinically, the relevant treatment effect is only partial relief, not complete relief, because it cannot completely eliminate antibodies and immune complexes, the basement membrane of the kidney is still damaged, and some urine protein will still leak out.
  • obinutuzumab has stronger cytotoxicity and stronger B cell consumption ability than rituximab, its adverse reactions may face greater challenges (Reference 2: Hudson, R., Rawlings, C., Mon, SY et al. Treatment resistant M-type phospholipase A2 receptor associated Membranous nephropathy responds to obinutuzumab: a report of two cases. BMC Nephrol 23, 134 (2022).), Therefore, there is a huge unmet clinical need in the treatment of membranous nephropathy both in China and globally.
  • the present invention surprisingly found that TACI-Fc fusion protein produced significant therapeutic effects when treating patients with membranous nephropathy.
  • the present invention provides a method for treating membranous nephropathy, comprising administering a therapeutically effective amount of TACI-Fc fusion protein to a patient with the membranous nephropathy.
  • the present invention also provides a method for treating a patient with membranous nephropathy who has received a treatment regimen for membranous nephropathy, the method comprising (1) determining whether the patient has received a treatment regimen for membranous nephropathy, and (2) if the patient has previously received treatment for membranous nephropathy, administering an effective amount of TACI-Fc fusion protein to the patient with the membranous nephropathy.
  • the present invention also provides a use of a TACI-Fc fusion protein in preparing a drug for treating patients with membranous nephropathy.
  • 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 a fragment thereof comprises 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 comprises 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 dosage 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, 6.6, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.7, 7.6, 7.7, 7.8,
  • the single dosage of the TACI-Fc fusion protein is 160-240 mg, and more preferably 160 mg, 170 mg, 180 mg, 190 mg, 200 mg, 210 mg, 220 mg, 230 mg, or 240 mg.
  • the detection method of the above fusion protein content 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, the 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 2-4 times at intervals of one month, that is, the administration frequency of the TACI-Fc fusion protein is 2 times per month, 3 times per month, or 4 times per month.
  • the TACI-Fc fusion protein is administered once a week.
  • 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 locations are different.
  • the membranous nephropathy is idiopathic membranous nephropathy or secondary membranous nephropathy.
  • membranous nephropathy is manifested as PLA2R positivity or PLA2R negativity.
  • the patient is an adult patient or a pediatric patient.
  • the patient has previously received a treatment regimen for membranous nephropathy.
  • the membranous nephropathy treatment regimen includes: conventional treatment for membranous nephropathy, hormone combined with immunosuppressant treatment regimen, and monoclonal antibody drug treatment regimen.
  • the treatment regimen for membranous nephropathy comprises: periodically administering cyclophosphamide combined with hormone drugs to the patient, or continuously administering cyclophosphamide combined with hormone drugs to the patient, or administering tacrolimus to the patient, or administering cyclosporine to the patient, or administering rituximab to the patient, or administering obinutuzumab to the patient, or administering MIL62 to the patient, or administering fezinomab to the patient.
  • the TACI-Fc fusion protein provided by the present invention shows unexpected clinical efficacy and good safety in the process of treating patients with membranous nephropathy.
  • FIG1 is a graph showing the change in albumin during treatment of a subject in Example 1;
  • FIG2 is a diachronic analysis of the rate of change of immunoglobulin IgG levels compared to the baseline during the treatment of the subjects in Example 1;
  • FIG3 is a diachronic analysis of the rate of change of immunoglobulin IgM levels compared to the baseline during treatment of the subjects in Example 1;
  • FIG. 4 is a diachronic analysis of the rate of change of immunoglobulin IgA levels compared with the baseline during the treatment of the subjects in Example 1.
  • TACI transmembrane activator and CAML interactor, which is a member of the tumor necrosis factor receptor superfamily.
  • B lymphocyte stimulator which is a APRIL 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 used 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 used in the present invention are the main units that constitute proteins in living organisms, including but not limited to: glycine, alanine, valine, leucine, amino acids, including amino acids, lysine, arginine, 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.
  • membrane nephropathy in the present invention represents a spectrum of diseases with a common histopathological pattern, namely the presence of immunoglobulins and complement-containing immune precipitates in a subepithelial location.
  • idiopathic membranous nephropathy in the present invention refers to an organ-specific autoimmune disease that occurs without any definite cause or initiating event, including but not limited to PLA2R -related idiopathic membranous nephropathy, THS7A-related idiopathic membranous nephropathy, NELL-1-related idiopathic membranous nephropathy, Sema3B-related idiopathic membranous nephropathy and other related idiopathic membranous nephropathy.
  • second membranous nephropathy in the present invention refers to a disease with a clear systemic disease involving Kidney disease, glomerular disease with pathological changes into membranous nephropathy, the causes of secondary membranous nephropathy include immune diseases (such as systemic lupus erythematosus, type 1 diabetes, rheumatoid arthritis, Hashimoto's thyroiditis, Graves' disease, mixed connective tissue disease, Henoch-Schonlein purpura, primary biliary cirrhosis, enteropathic syndrome, anti-glomerular basement membrane nephritis, ANCA-associated crescentic nephritis, graft-versus-host disease, bone marrow and stem cell transplantation, etc.), infections and parasitic diseases (such as HBV, HCV, syphilis, filariasis, cysticercosis, schistosomiasis, malarial parasites, leprosy,
  • immune diseases
  • PLA2R positive in the present invention means that PLA2R is detected in the blood of a patient, that is, PLA2R is serologically positive.
  • PLA2R negative in the present invention means that PLA2R cannot be detected in the blood of a patient.
  • the term "conventional treatment of membranous nephropathy” in the present invention exemplarily refers to if the 24-hour urine protein quantity of membranous nephropathy is below 3.5g; or between 3.5g-8g, and the renal function is normal and there is no high-risk phenomenon, usually pril drugs and sartans are used to reduce urine protein, and supportive treatments such as diuretics, antihypertensives, and anticoagulation are given.
  • hormone combined with immunosuppressant treatment regimen exemplarily refers to the use of a combination of hormones + immunosuppressants for treatment if the 24-hour urine protein quantity of membranous nephropathy exceeds 3.5g and is accompanied by renal impairment, or the urine protein exceeds 8g, wherein the immunosuppressants include but are not limited to tacrolimus and cyclosporine.
  • the term "monoclonal antibody drug treatment regimen" in the present invention refers to the treatment recommended in the 2021 KDIGO guidelines, using but not limited to rituximab, 1000 mg of rituximab intravenously twice within two weeks; rituximab 375 mg per square meter of body surface area, once a week for a total of 1 to 4 times.
  • cyclical administration of cyclophosphamide combined with hormone drugs refers to the recommendation in the 2021 KDIGO guidelines: intravenous injection of 1 gram of methylprednisolone for three consecutive days in the first few days of the 1st, 3rd, and 5th months; oral administration of prednisone 0.5 mg/kg per day; in the 2nd, 4th, and 6th months, change to oral cyclophosphamide, 2.5 mg per kilogram of body weight per day.
  • continuous administration of cyclophosphamide combined with hormone drugs refers to the recommendation in the 2021 KDIGO guidelines: intravenous injection of 1 gram of methylprednisolone for three consecutive days on the first day of the 1st, 3rd, and 5th months; oral administration of prednisone 0.5 mg/kg every other day for 1-6 months and then gradually reducing the dose; oral administration of cyclophosphamide, 1.5 mg/kg of body weight per day, for 16 months.
  • This study is a prospective, single-center, unblinded, single-arm clinical trial.
  • the main purpose is to evaluate the efficacy and safety of tetasip in the treatment of membranous nephropathy, and to explore the side effects of tetasip in the treatment of refractory membranous nephropathy. It is planned to enroll 30 patients with membranous nephropathy (12 patients have been enrolled, interim analysis) as subjects, who will receive subcutaneous injection of tetasip once a week, 160 mg each time, for 48 weeks.
  • Urine protein quantity is unstable in the past 2 months, and the fluctuation of 24-hour urine protein quantity is >2g/d;
  • the primary endpoint of this study is the excretion level of 24-hour urine protein at week 48.
  • the 24-hour urine protein content is less than 0.3g/24h, it is considered to be completely relieved.
  • the 24-hour urine protein content is 0.3-3.5g/24h or the urine protein is reduced by 50% compared with the baseline, it is considered to be partially relieved.
  • At week 48 or the end of treatment there were 10 subjects (accounting for 83.3% of the current enrollment) with a decrease in urine protein compared with the baseline, of which 5 had a 24-hour urine protein content between 0.3-3.5g/24h, and 3 subjects had a decrease of more than 50% compared with the baseline (the decrease ratios from the baseline were 70.86%, 77.42% and 94.17%, respectively). Therefore, there were 5 subjects who achieved partial remission in this trial, accounting for 42% of the total enrollment. Details of the subjects' 24-hour urine protein indicators and the decrease ratios from the baseline at baseline and week 48 or the end of treatment. See Table 2.
  • the estimated glomerular filtration rate (eGFR) of 4 subjects increased, among which the subject with the highest increase had eGFR increase from 47.9 mL/min/1.73 m 2 to 62.46 mL/min/1.73 m 2 , with an increase rate of 30.4%.
  • the average IgG level of the subjects showed an overall downward trend, with the average IgG level decreasing by approximately 2.60 g/L (a decrease of 38.8%).
  • the temporal change rate of the average IgG level of the subjects is shown in Figure 2.
  • the average IgM change rate of the enrolled subjects also showed an overall downward trend. After 48 weeks of administration, the average IgM value decreased by approximately 0.708 g/L (a decrease of 70.1%).
  • the temporal change rate of the average IgM level of the enrolled subjects is shown in Figure 3.
  • the change rate of the average IgA level of the enrolled subjects also showed an overall downward trend. After 48 weeks of administration, the average IgA level decreased by approximately 0.717 g/L (a decrease of 39.7%).
  • the temporal change rate of the average IgA level of the enrolled subjects is shown in Figure 4.

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Abstract

本发明涉及利用TACI-Fc融合蛋白治疗膜性肾病的药物、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融合蛋白在治疗膜性肾病患者过程中表现出较好的临床疗效和良好的安全性。

Description

用TACI-Fc融合蛋白治疗膜性肾病的方法 技术领域
本发明涉及一种治疗膜性肾病的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
膜性肾病(Membranous nephropathy，MN)是一种抗体介导的肾小球疾病，其特征是肾小球血管袢(Capillary Loops)中的上皮细胞下方形成含有抗原、IgG和补体成分的免疫沉淀，上皮细胞的亚致死性损伤导致细胞的简化和肾小球滤过屏障的破坏，出现蛋白尿和肾病综合征的其他表现。
临床上，膜性肾病根据病因可分为原发性膜性肾病和继发性膜性肾病，大多数膜性肾病为原发性膜性肾病，又叫特发性膜性肾病，是在没有任何确定原因或起始事件的情况下发生的器官特异性自身免疫性疾病。约20-30％膜性肾病为继发性膜性肾病，常见病因是自身免疫病(如狼疮)、病毒(乙肝、丙肝、梅毒)、肿瘤、某种药物(如止痛药)、毒物(如接触铅汞等重金属)等。膜性肾病是非糖尿病成人发生肾病综合征最常见的原因之一，在肾病综合征活检结果中的占比高达1/3，它的主要临床症状是水肿、蛋白尿、低白蛋白血症和高脂血症等，主要影响肾小球基底膜功能，同时增加血栓、感染、心血管疾病等风险。
目前，膜性肾病的全球发病率约为每年每10万人1例，膜性肾病的发病率是否因地区或种族而异尚不清楚，但是可以确认的是，膜性肾病可影响所有年龄和种族的患者。在美国，膜性肾病的发病率约为每年12例/百万人口，平均发病年龄在50至60岁之间。在中国，近20年来中国的膜性肾病的发病率正在节节攀升，另有研究表明，膜性肾病的高发可能和日益严重的空气污染有关。据统计，这些膜性肾病患者中，长期未经治疗的患者有将近60％发生肾功能减退，且30-40％将在10年内最终进展为终末期肾病。即使接受免疫抑制剂治疗，仍有20％-40％患者在病程中表现为持续大量蛋白尿，并在10年内进展至终末期肾脏病，需要肾脏替代或移植治疗。
膜性肾病的治疗取决于其类型和病因，目前对膜性肾病的治疗，主要包括以下治疗方法：①常规治疗：如果膜性肾病的24小时尿蛋白定量在 3.5g以下；或是在3.5g-8g之间，且肾功能正常、无高危现象，通常采用普利类药物和沙坦类药物等降低尿蛋白，并给予利尿、降压、抗凝等支持治疗；②激素联合免疫抑制剂：如果膜性肾病的24小时尿蛋白定量超过3.5g且伴有肾功能减退，或是尿蛋白超过了8g，则采用联合激素+免疫抑制剂的方法进行治疗；③单抗类药物：如利妥昔单抗等。
表1 2021年KDIGO指南中膜性肾病治疗方案的推荐
2021年KDIGO指南中推荐了5种膜性肾病的治疗方案(参见表1)，其分别为周期性使用或者连续使用环磷酰胺、利妥昔单抗、他克莫司、环孢素，其中：①周期性使用或者连续使用环磷酰胺方法必须联合使用激素药物(如泼尼松)，而激素副作用大，并且环磷酰胺也有生殖毒性、骨髓抑制、感染及出血性膀胱炎等不良反应，并且从应用情况来看，采用激素+环磷酰胺方案治疗后，仍有近一半的患者得不到缓解，并且得到缓解的患者一旦停药，很可能会引起疾病的复发。②他克莫司和环孢素是钙调磷酸酶抑制剂(CNIs)，属于一大类免疫抑制药物，对于不愿接受糖皮质激素+环磷酰胺或存在治疗禁忌的患者，可使用CNIs治疗。其中，环孢素治疗的优点是起效快，疗效优于环磷酰胺，不良反应比环磷酰胺少且轻，缺点是总体缓解率并不高于环磷酰胺方案且短期复发率明显高于环磷酰胺；他克莫司的免疫抑制效力比环孢素高10～100倍，但其缺点与环孢素类似，他克莫司同样存在复发率高的问题，另外他克莫司更突出的不良反应是导致糖耐量异常和新发糖尿病。③目前，利妥昔单抗单药或者联合钙 调磷酸酶抑制剂被推荐用于中危、高危、极高危风险的原发性膜性肾病初始治疗，其对膜性肾病的缓解率为67％，并且利妥昔单抗对抗PLA2R抗体阳性或阴性的膜性肾病患者均适用。但是，利妥昔单抗价格昂贵，患者可及性不高，且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1：Alsharhan L,Beck LH Jr.Membranous Nephropathy:Core Curriculum 2021.Am J Kidney Dis.2021 Mar；77(3):440-453.)。总体来说，膜性肾病的临床病程常为惰性且现有治疗具有毒性，现有的治疗方案存在一定的局限性和风险性、治疗效果也不尽如人意，但从临床应用上看，如果激素联合免疫抑制剂治疗无效，则通常会使用单抗类药物(比如利妥昔单抗)等进行治疗，因此开发新的生物类药物(如单抗类药物)成为了当前膜性肾病治疗的迫切需求。
表2已获批/临床III期研究的治疗膜性肾病的生物类药物
截止到2022年09月22日，全球仅两款针对膜性肾病的生物类药物获批上市，它们分别是利妥昔单抗和奥妥珠单抗，另有两款药物处于临床III期研究阶段(参见表2)，在这些药物中，利妥昔单抗尽管在2021年被纳入KDIGO指南的膜性肾病推荐治疗方案中，但是其仍面临着较低的缓解率、较高的输液反应、较严重的不良反应以及较高的价格等问题。而同为CD20靶点的奥妥珠单抗，尽管临床上针对治疗失败的膜性肾病患者能够取得一定的治疗效果，但相关治疗效果仅为部分缓解，而不是完全缓解，因为它不能完全消除抗体和免疫复合物，肾脏的基底膜仍然存在损伤，仍会使一部分尿蛋白漏出。另外，由于奥妥珠单抗的细胞毒性相较于利妥昔单抗更强，对B细胞的消耗能力也更强，因此其不良反应方面可能会面对更大的挑战(文献2：Hudson,R.,Rawlings,C.,Mon,S.Y.et al.Treatment resistant M-type phospholipase A2receptor associated  membranous nephropathy responds to obinutuzumab:a report of two cases.BMC Nephrol 23,134(2022).)，因此，无论是在中国还是全球，膜性肾病治疗领域都存在巨大的未满足的临床需求。
发明内容
本发明惊奇的发现了TACI-Fc融合蛋白在治疗膜性肾病的患者时，产生了显著的治疗效果。
具体的，本发明提供了一种治疗膜性肾病的方法，所述方法包括对具有所述膜性肾病的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膜性肾病治疗方案的膜性肾病患者的方法，该方法包括(1)确定患者是否已经接受过膜性肾病治疗方案，并(2)如果该患者既往接受过膜性肾病治疗，对具有所述膜性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膜性肾病患者药物中的用途。
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。
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。

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。
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。
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0.1，0.2，0.3，0.4，0.5，0.6，0.7，0.8，0.9，1.0，1.1，1.2，1.3，1.4，1.5，1.6，1.7，1.8，1.9，2.0，2.1，2.2，2.3，2.4，2.5，2.6，2.7，2.8，2.9，3.0，3.1，3.2，3.3，3.4，3.5，3.6，3.7，3.8，3.9，4.0，4.1，4.2，4.3，4.4，4.5，4.6，4.7，4.8，4.9，5.0，5.1，5.2，5.3，5.4，5.5，5.6，5.7，5.8，5.9，6.0，6.1，6.2，6.3，6.4，6.6，6.6， 6.7，6.8，6.9，7.0，7.1，7.2，7.3，7.4，7.7，7.6，7.7，7.8，7.9，8.0，8.1，8.2，8.3，8.4，8.8，8.6，8.7，8.8，8.9，9.0，9.1，9.2，9.3，9.4，9.9，9.6，9.7，9.8，9.9，10mg/kg。
进一步的，所述TACI-Fc融合蛋白的单次给药剂量为160-240mg，进一步优选为160mg，170mg，180mg，190mg，200mg，210mg，220mg，230mg，或240mg。
进一步的，上述融合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。在对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成正比，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2-4次，即所述的TACI-Fc融合蛋白的给药频次为每月2次或每月3次或每月4次。
进一步的，所述的TACI-Fc融合蛋白的给药频次为每周一次。
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，所述的膜性肾病为特发性膜性肾病或者继发性膜性肾病。
进一步的，所述的膜性肾病表现为PLA2R阳性或者PLA2R阴性。
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膜性肾病治疗方案。
进一步的，所述的膜性肾病治疗方案包含：膜性肾病常规治疗、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，所述的膜性肾病治疗方案包含：向患者周期性施用环磷酰胺联合激素类药物、或向患者连续施用环磷酰胺联合激素类药物、或向患者施用他克莫司、或向患者施用环孢素、或向患者施用利妥昔单抗、或向患者施用奥妥珠单抗、或向患者施用MIL62、或向患者施用菲泽妥单抗。
本发明提供的TACI-Fc融合蛋白在治疗膜性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为实施例1中受试者治疗过程中白蛋白变化值；
图2为实施例1中受试者治疗过程中免疫球蛋白IgG水平较基线变化率历时性分析；
图3为实施例1中受试者治疗过程中免疫球蛋白IgM水平较基线变化率历时性分析；
图4为实施例1中受试者治疗过程中免疫球蛋白IgA水平较基线变化率历时性分析。
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细胞累积并增加脾含量。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“膜性肾病”代表具有共同组织病理学模式的一系列疾病，即在上皮下位置存在免疫球蛋白和含有补体的免疫沉淀物。
本发明中的术语“特发性膜性肾病”是指在没有任何确定原因或起始事件的情况下发生的器官特异性自身免疫性疾病，包括但不限于PLA2R相关特发性膜性肾病、THS7A相关特发性膜性肾病、NELL-1相关特发性膜性肾病、Sema3B相关特发性膜性肾病及其他相关特发性膜性肾病。
本发明中的术语“继发性膜性肾病”是指有明确的系统性疾病中累及 肾病、病理改变为膜性肾病的肾小球疾病，引起继发性膜性肾病的病因有免疫性疾病(如系统性红斑狼疮、1型糖尿病、类风湿性关节炎、桥本甲状腺炎、Graves病、混合性结缔组织病、过敏性紫癜、原发性胆汁性肝硬化、小肠肠病综合征、抗肾小球基膜性肾炎、ANCA相关性新月体肾炎、移植物抗宿主病、骨髓和干细胞移植等)、感染和寄生虫病(如HBV、HCV、梅毒、丝虫病、包囊虫病、血吸虫、疟原虫、麻风等)、药物和毒素(如：金制剂、青霉胺、非固醇类消炎药、汞、卡托普利、甲醛、碳氢化合物)及其他(如肿瘤、肾移植)。
本发明中的术语“PLA2R阳性”是指在患者血液中检测到PLA2R，即PLA2R呈血清学阳性。
本发明中的术语“PLA2R阴性”是指在患者血液中检测不到PLA2R。
本发明中的术语“膜性肾病常规治疗”示例性的是指如果膜性肾病的24小时尿蛋白定量在3.5g以下；或是在3.5g-8g之间，且肾功能正常、无高危现象，通常采用普利类药物和沙坦类药物等降低尿蛋白，并给予利尿、降压、抗凝等支持治疗。
本发明中的术语“激素联合免疫抑制剂治疗方案”示例性的指如果膜性肾病的24小时尿蛋白定量超过3.5g且伴有肾功能减退，或是尿蛋白超过了8g，则采用联合激素+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他克莫司和环孢素。
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，利用但不限于利妥昔单抗治疗，利妥昔单抗1000个毫克静脉使用两周内两次；利妥昔单抗375个毫克每平方米体表面积，每周一次共使用1～4次。
本发明中的术语“周期性施用环磷酰胺联合激素类药物”是指2021年KDIGO指南中推荐的，第1、第3、第5个月的开始几天，静脉注射甲基泼尼松龙1克连续三天；泼尼松0.5个毫克每公斤每天口服；第2、第4、第6个月改成环磷酰胺口服，每公斤体重2.5毫克每天。
本发明中的术语“连续施用环磷酰胺联合激素类药物”是指2021年KDIGO指南中推荐的，第1、第3、第5个月的开始儿天，静脉注射甲基泼尼松龙1克连续三天；泼尼松0.5个毫克每公斤隔天口服1-6个月后逐渐减量；环磷酸胺口服，每公斤体重1.5毫克每天，16个月。
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泰它西普治疗膜性肾病的临床试验
1.研究方法
本研究是一项前瞻性、单中心、不设盲的单臂临床试验，主要目的是评估泰它西普治疗膜性肾病的有效性和安全性，另探索性地研究泰它西普在治疗难治性膜性肾病出现的副作用。计划纳入30例(现完成入组12例，中期分析)膜性肾病患者作为受试者，接受皮下注射泰它西普，每周1次，每次160mg，疗程48周。
2.入选患者
受试者纳入标准：
●经肾脏病理穿刺诊断为原发性膜性肾病的患者，同时PLA2R抗体阳性；
●年龄18-70岁；
●入组前需在足量ACEI/ARB类药物的治疗至少3个月的基础上保持24小时尿蛋白(UTP)≥3.5g；
●血压稳定，≤140/90mmHg；
●估计肾小球滤过率(eGFR)≥45mL/min/1.73m2；
●同意研究期间保持饮食及钠摄入稳定；
●同意并签署知情同意书。
受试者同时排除以下标准：
●最近2月内尿蛋白定量不稳定，24小时尿蛋白定量波动>2g/d；
●合并慢性肝病，或肝酶超过正常上限3倍以上；
●3月内有新发心脑血管疾病(急性冠脉综合征、心衰、脑梗死、脑卒中)；
●未控制的重度高血压；
●恶性肿瘤；
●严重感染患者；
●既往应用泰它西普的患者，或对泰它西普过敏或其他禁忌证；
●孕期或哺乳期；
●预期寿命不足6个月；
●目前正在参加其他临床研究；
●研究者认为不适于参加本研究的其他情况。
3.终点指标
(1)主要终点指标
(2)次要终点指标
5.中期分析主要结果
5.1主要疗效终点
本研究的主要终点是第48周时，24h尿蛋白的排泄水平。其中当24h尿蛋白含量低于0.3g/24h时，视为完全缓解。当24h尿蛋白含量为0.3-3.5g/24h或尿蛋白较基线减少50％时，视为部分缓解。第48周或治疗结束时，尿蛋白较基线下降的受试者有10人(占目前入组人数的83.3％)，其中24h尿蛋白含量在0.3-3.5g/24h间的共有5例，而较基线下降大于50％以上的受试者有3人(较基线下降比例分别为70.86％，77.42％及94.17％)，因此，该试验中达到部分缓解的受试者为5人，占全部入组人数的42％。基线和第48周或治疗结束时受试者24h尿蛋白指标及较基线下降比例详 见表2。
表2. 24h尿蛋白含量及较基线下降比例
5.2次要疗效终点
5.2.1.尿蛋白/肌酐比值和尿白蛋白/肌酐比值变化分析
本研究中，受试者的尿蛋白/肌酐比(UPCR)和尿白蛋白肌酐比(UCAR)平均水平较基线下降。较基线相比，下降具有统计学意义。
5.2.2.估计肾小球滤过率(eGFR)的变化分析
在本研究中，用药结束后，有4位受试者的估计肾小球滤过率(eGFR)指标上升，其中上升最高的受试者的eGFR从47.9mL/min/1.73m2上升至62.46mL/min/1.73m2，上升比例为30.4％。
5.2.3.血清白蛋白的历时性分析
在本研究中，治疗过程中的白蛋白平均水平出现下降，用药结束后与基线相比，入组受试者的血清白蛋白平均值水平下降了0.59g/L，白蛋白的历时性变化值如图1所示。
5.2.4.免疫学指标(IgG、IgM、IgA)
5.2.4.1.免疫球蛋白(IgG)的历时性分析
与基线相比，给药48周后，入组受试者IgG平均值变化率水平呈整体下降的趋势，IgG平均值约下降了2.60g/L(下降比例为38.8％)，入组受试者IgG平均水平的历时性变化率如图2所示。
5.2.4.2.免疫球蛋白(IgM)的历时性分析
与基线相比，入组受试者IgM平均值变化率水平也呈整体下降的趋势，给药48周后，IgM平均值约下降了0.708g/L(下降比例为70.1％)， 入组受试者IgM平均水平的历时性变化率如图3所示。
5.2.4.3.免疫球蛋白(IgA)的历时性分析
与基线相比，入组受试者IgA平均值变化率水平同样呈整体下降的趋势，给药48周后，IgA平均值约下降了0.717g/L(下降比例为39.7％)，入组受试者IgA平均水平的历时性变化率如图4所示。
5.3有效性结果
在本研究中，现有数据表明，泰它西普治疗原发性膜性肾病患者表现出持续改善的临床疗效，受试者的尿蛋白/肌酐比(UPCR)和尿白蛋白肌酐比(UCAR)平均水平较基线下降。较基线相比，下降具有统计学意义。与基线相比，泰它西普用药后明显降低受试者IgG、IgA和IgM的平均值水平。
5.4安全性结果
在本研究中，目前结果表明每周给药一次泰它西普160mg治疗原发性膜性肾病患者具有良好的安全性。不良事件/不良反应严重程度为轻度(CTCAE 1级)，无CTCAE 2级、3级、4级和5级不良事件/不良反应发生。未发生导致受试者退出研究或死亡的不良事件/不良反应，无严重不良反应发生。研究期间有2例受试者发生不良事件，其中一例出现腹痛及呕吐，但不考虑该不良事件/不良反应的发生与泰它西普相关，另外一例出现皮肤瘙痒的症状，未用药物2-3天后出现好转。
5.5结论
基于以上结果和分析，在本研究中，目前试验数据显示，将泰它西普用于治疗膜性肾病患者表现出良好的临床疗效和安全性。
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 (18)

  1. 一种治疗膜性肾病的方法，所述方法包括对具有所述膜性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。
  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7所述的方法，其特征在于，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。
  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，所述的膜性肾病包括原发性膜性肾病或者继发性膜性肾病。
  11. 根据权利要求10所述的方法，其特征在于，所述的膜性肾病表现为PLA2R阳性或者PLA2R阴性。
  12. 根据权利要求11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。
  13. 根据权利要求12所述的方法，其特征在于，所述的患者既往接受过膜性肾病治疗方案。
  14. 根据权利要求12或13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。
  15. 根据权利要求12或13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160-240mg，进一步优选为160mg或240mg。
  16. 根据权利要求12或13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。
  17. 根据权利要求12或13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2-4次和/或治疗持续约2-50周。
  18. 根据权利要求17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。
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