Treatment method for membranous nephropathy using TACI-Fc fusion protein

Abstract

The present invention relates to a therapeutic drug for membranous nephropathy using TACI-Fc fusion protein, its dosage scheme, administration interval and administration method.The results show that the TACI-Fc fusion protein of the present invention has better clinical efficacy and good safety in treating patients with membranous nephropathy.

Description

[Technical Field]

[0001] The present invention relates to TACI-Fc fusion protein drugs, dosage schemes, administration intervals and methods of administration for treating membranous nephropathy. [Background technology]

[0002] Membranous nephropathy (MN) is an antibody-mediated glomerular disease characterized by the formation of immunoprecipitates containing antigens, IgG, and complement components beneath the epithelial cells of the glomerular capillary loops, resulting in sublethal damage to the epithelial cells, cellular simplification, and destruction of the glomerular filtration barrier, resulting in proteinuria and other symptoms of nephrotic syndrome.

[0003] Clinically, membranous nephropathy can be divided into primary and secondary membranous nephropathy based on the underlying cause. Most cases of membranous nephropathy are primary membranous nephropathy (also known as idiopathic membranous nephropathy), an organ-specific autoimmune disease that occurs without any clear cause or initiating event. Approximately 20-30% of cases of membranous nephropathy are secondary membranous nephropathy, and common causes include autoimmune diseases (e.g., lupus), viruses (hepatitis B, hepatitis C, syphilis), tumors, certain medications (e.g., painkillers), and exposure to heavy metals (e.g., lead and mercury). Membranous nephropathy is the most common cause of nephrotic syndrome in non-diabetic adults, accounting for up to one-third of nephrotic syndrome biopsy results. Its main clinical symptoms include edema, proteinuria, hypoalbuminemia, and hyperlipidemia. It primarily has a negative impact on the function of the glomerular basement membrane, potentially increasing the risk of developing thrombosis, infections, cardiovascular diseases, and other conditions.

[0004] Currently, the global incidence of membranous nephropathy is approximately 1 case per 100,000 people per year. While it is unclear whether the incidence rate of membranous nephropathy varies by region or race, it has been confirmed that it can affect patients of all ages and races. In the United States, the incidence rate of membranous nephropathy is approximately 12 cases per million people per year, with the average age of onset being in the 50s and 60s. In China, the incidence rate of membranous nephropathy has been steadily increasing over the past 20 years, and studies have shown that the high incidence of membranous nephropathy may be linked to worsening air pollution. Statistics show that among these patients with membranous nephropathy, approximately 60% will develop renal dysfunction if left untreated for a long period of time, and 30–40% will progress to end-stage renal failure within 10 years. Even with immunosuppressive therapy, 20–40% of patients will experience persistent massive proteinuria during the course of the disease and will progress to end-stage renal failure within 10 years, requiring renal replacement therapy or kidney transplantation.

[0005] Treatment for membranous nephropathy depends on the type and underlying disease. Currently, the main treatments for membranous nephropathy are as follows: (1) Conventional Treatment: If the urinary protein excretion level measured in a 24-hour urine collection test is 3.5g or less or between 3.5g and 8g, but the renal function is normal and there are no high-risk events, prill drugs and sartan drugs are usually used to reduce urinary protein excretion, and supportive therapy such as diuretics, antihypertensives, and anticoagulants is administered. (2) Combination of hormones and immunosuppressants: If the urinary protein excretion level measured in a 24-hour urine collection test is greater than 3.5g and accompanied by renal dysfunction, or if the urinary protein excretion level is greater than 8g, a combination of hormones and immunosuppressants is used. (3) Monoclonal antibody treatment: Rituximab and other monoclonal antibody drugs are used.

[0006] [Table 1]

[0007] The KDIGO 2021 guidelines recommend five treatments for membranous nephropathy: regular or continuous administration of cyclophosphamide, rituximab, tacrolimus, and cyclosporine (see Table 1). (1) Regular or continuous administration of cyclophosphamide requires the concomitant use of hormones (e.g., prednisone). However, hormones have significant side effects, and cyclophosphamide itself has side effects such as reproductive toxicity, bone marrow suppression, infection, and hemorrhagic cystitis. Furthermore, even after treatment with hormone and cyclophosphamide, approximately half of patients still experience no relief of symptoms, and discontinuing the medication after symptom improvement can lead to relapse. (2) Tacrolimus and cyclosporine are calcineurin inhibitors (CNIs), a type of immunosuppressant. Patients who do not wish to receive glucocorticoids and cyclophosphamide or who have contraindications for this treatment can be treated with CNIs. However, while cyclosporine therapy has the advantages of rapid onset of action, greater efficacy than cyclophosphamide, and fewer and milder side effects than cyclophosphamide, it also has the disadvantages of a lower overall remission rate than cyclophosphamide therapy and a significantly higher short-term relapse rate than cyclophosphamide. Tacrolimus, while 10- to 100-fold more immunosuppressive than cyclosporine, suffers from the same high relapse rate as cyclosporine and severe side effects such as impaired glucose tolerance and new-onset diabetes. (3) Currently, rituximab alone or in combination with a calcineurin inhibitor is recommended for the initial treatment of intermediate-risk, high-risk, and very-high-risk primary membranous nephropathy, achieving a remission rate of 67%. Rituximab is also suitable for both anti-PLA2R antibody-positive and anti-PLA2R antibody-negative patients. However, rituximab is expensive, difficult to obtain for most patients, and has severe fluid sensitivity.Various studies have reported that the incidence of rituximab-related infusion reactions ranges from 26% to 85%. Rituximab has also been reported to cause rare adverse events, such as hepatitis B virus reactivation and severe skin reactions (e.g., toxic epidermal necrolysis and Stevens-Johnson syndrome) in patients with hematological malignancies (Reference 1: Alsharhan L, Beck LH Jr. Membranous Nephropathy: Core Curriculum 2021. Am J Kidney Dis. 2021 Mar;77(3):440-453.). In summary, membranous nephropathy typically has a slowly progressive clinical course and is toxic to existing treatments. Existing treatment regimens have certain limitations and risks, and their therapeutic efficacy is insufficient. However, from a clinical perspective, when combined treatment with hormones and immunosuppressants is ineffective, monoclonal antibodies (e.g., rituximab) are commonly used for treatment. Therefore, in the current treatment of membranous nephropathy, the development of new biologics (such as monoclonal antibody drugs) is urgently needed.

[0008] [Table 2]

[0009] As of September 22, 2022, only two biologics for membranous nephropathy—rituximab and obinutuzumab—had been approved for sale worldwide, with two other drugs undergoing Phase III clinical trials (see Table 2). Of these drugs, rituximab was selected as the recommended treatment for membranous nephropathy in the 2021 KDIGO guidelines, but it had issues such as a low remission rate, high infusion reaction rates, serious side effects, and high cost. Obinutuzumab, which also targets CD20, has shown some therapeutic efficacy in patients with membranous nephropathy who have failed clinical treatment. However, because antibodies and immune complexes are not completely removed and damage to the renal basement membrane still exists, resulting in leakage of some urinary protein, the associated therapeutic effect remains partial, not complete. Furthermore, because obinutuzumab has stronger cytotoxicity and B cell depletion capabilities than rituximab, it may face greater challenges in terms of side effects (Reference 2: Hudson, R., Rawlings, C., Mon, SY et al. Treatment resistant M-type phosphorylipase A2 receptor related membranous nephropathy responds to obinutuzumab: a report of two cases. BMC Nephrol 23, 134 (2022).). Therefore, there are still many unmet clinical needs in the treatment of membranous nephropathy both in China and around the world. Summary of the Invention

[0010] The present inventors have surprisingly discovered that significant therapeutic effects occur when treating patients with membranous nephropathy with TACI-Fc fusion proteins.

[0011] Specifically, the present invention provides a method for treating membranous nephropathy, which comprises administering a therapeutically effective amount of a TACI-Fc fusion protein to a patient with membranous nephropathy.

[0012] Specifically, the present invention further provides a method for treating a patient with membranous nephropathy who has previously undergone a therapeutic regimen for membranous nephropathy, the method comprising: (1) determining whether the patient has previously undergone a therapeutic regimen for membranous nephropathy; and (2) if the patient has previously undergone a therapeutic regimen for membranous nephropathy, administering a therapeutically effective amount of a TACI-Fc fusion protein to the patient with membranous nephropathy.

[0013] Specifically, the present invention further provides the use of a TACI-Fc fusion protein in the manufacture of a medicament for treating a patient with membranous nephropathy.

[0014] Furthermore, the TACI-Fc fusion protein according to any one of the above aspects comprises (i) the TACI extracellular domain or a fragment thereof that binds to Blys and / or APRIL, and (ii) a fragment of a human immunoglobulin constant region.

[0015] Preferably, the TACI extracellular domain or fragment thereof comprises the amino acid sequence shown in SEQ ID NO:1.

[0016] [Table 3]

[0017] Preferably, the human immunoglobulin is IgG1.

[0018] Furthermore, the fragment of the constant region of the human immunoglobulin comprises the amino acid sequence of SEQ ID NO:2 or 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.

[0019] [Table 4]

[0020] Additionally, the fragment of the human immunoglobulin constant region comprises an amino acid modification corresponding to one or more of positions 3, 8, 14, 15, 17, 110, 111, or 173 of SEQ ID NO:2.

[0021] Furthermore, the modification may be an amino acid substitution, deletion or insertion.

[0022] Further, the substitutions are selected from the group consisting of P3T, L8P, L14A, L15E, G17A, A110S, P111S and A173T.

[0023] Preferably, the fragment of the constant region of a human immunoglobulin comprises the amino acid sequence shown in SEQ ID NO:3.

[0024] [Table 5]

[0025] Preferably, the TACI-Fc fusion protein has the amino acid sequence shown in SEQ ID NO:4.

[0026] [Table 6]

[0027] Preferably, the TACI-Fc fusion protein is telitacicept.

[0028] Furthermore, the single dose of the TACI-Fc fusion protein is about 0.1 to 10 mg / kg, and further includes 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, 5.10, 5.11, 5.12, 5.13, 5.14, 5.15, 5.16, 5.17, 5.18, 5.19, 5.20, 5.21, 5.22, 5.23, 5.24, 5.25, 5.26, 5.27, 5.28, 5.29, 5.30, 5.31, 5.32, 5.33, 5.34, 5.35, 5.36, 5.37, 5.38, 5.39, 5.40, 5.41, 5.42, 5.43, 5.44, 5.45, 5.46, 5.47, 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, 10 mg / kg.

[0029] Furthermore, the single dose of the TACI-Fc fusion protein is 160 to 240 mg, and preferably 160 mg, 170 mg, 180 mg, 190 mg, 200 mg, 210 mg, 220 mg, 230 mg, or 240 mg.

[0030] Furthermore, the content of the fusion protein was detected by UV-visible spectroscopy, which measures the absorbance of telitacicept at 280 nm, since the protein has a maximum UV absorption at this wavelength. After correcting for the absorbance at 320 nm, a direct proportional relationship between the absorbance at 280 nm and the protein concentration was obtained, and the protein concentration was calculated according to the Beer-Lambert law to determine the protein content. The protein content was calculated according to the following formula:

[0031]

number

[0032] where ε is the extinction coefficient of telitacicept, in mg / ml -1 ·cm -1 A 280 is the average absorbance of the sample solution at 280 nm. 280 (corrected) is the corrected average absorbance at 280 nm of the sample solution.

[0033] Furthermore, the TACI-Fc fusion protein is administered two to four times at intervals of one month, i.e., the TACI-Fc fusion protein is administered twice a month, three times a month, or four times a month.

[0034] Additionally, the TACI-Fc fusion protein is administered once a week.

[0035] More preferably, the treatment is continued for about 2 to 50 weeks, and even more preferably, the treatment is continued for 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50 weeks.

[0036] More preferably, the TACI-Fc fusion protein is administered subcutaneously, intramuscularly, or intravenously at an administration site in the thigh, abdomen, or upper arm. In some specific examples, the TACI-Fc fusion protein is administered subcutaneously, intramuscularly, or intravenously.

[0037] More preferably, the injection site of the TACI-Fc fusion protein can be the same or different each time. In some specific embodiments, the injection site of the TACI-Fc fusion protein is the same each time. In other specific embodiments, the injection site of the TACI-Fc fusion protein is different each time.

[0038] Furthermore, the membranous nephropathy is primary membranous nephropathy or secondary membranous nephropathy.

[0039] Furthermore, the membranous nephropathy may manifest as PLA2R positive or PLA2R negative.

[0040] Furthermore, the patient may be an adult or a pediatric patient.

[0041] Additionally, the patient has previously undergone a treatment regimen for membranous nephropathy.

[0042] Furthermore, treatment regimens for membranous nephropathy include conventional treatments for membranous nephropathy, treatments using hormones and immunosuppressants in combination, and treatments using monoclonal antibody-based pharmaceuticals.

[0043] Furthermore, the treatment regimen for membranous nephropathy may include periodically administering to the patient a combination of clophosfamide and a hormone-based drug, continuously administering to the patient a combination of clophosfamide and a hormone-based drug, administering to the patient tacrolimus, administering to the patient cyclosporine, administering to the patient rituximab, administering to the patient obinutuzumab, administering to the patient MIL62, or administering to the patient obinutuzumab.

[0044] The TACI-Fc fusion protein according to the present invention showed unexpected clinical efficacy and favorable safety in treating patients with membranous nephropathy. [Brief explanation of the drawings]

[0045] [Figure 1] 1 shows the change in albumin levels during treatment of the subjects in Example 1. [Figure 2] 1 shows a time course analysis of the percentage change in immunoglobulin IgG levels compared to baseline during treatment for subjects in Example 1. [Figure 3] 1 shows a time course analysis of the percentage change in immunoglobulin IgM levels compared to baseline during treatment of subjects in Example 1. [Figure 4] 1 shows a time course analysis of the percentage change in immunoglobulin IgA levels compared to baseline during treatment for subjects in Example 1. DETAILED DESCRIPTION OF THE INVENTION

[0046] Unless otherwise defined, technical and scientific terms used herein have the same meaning as understood by one of ordinary skill in the art. For definitions and terms of the art, those skilled in the art can refer specifically to Current Protocols in Molecular Biology (Ausubel).

[0047] The three-letter and one-letter codes for amino acids used in the present invention are as described in J. Biol. Chem, 243, p. 3558 (1968).

[0048] The term "TACI," i.e., transmembrane activator and calmodulin ligand interactor, as used herein refers to a member of the tumor necrosis factor receptor superfamily. The term "BLys," as used herein refers to B lymphocyte stimulator, a member of the TNF ligand superfamily that exists in two forms, membrane-bound and soluble. It is specifically expressed on the surface of myeloid cells and selectively stimulates B lymphocyte proliferation and immunoglobulin production. The term "APRIL" (a proliferation-inducing ligand) as used herein refers to a tumor necrosis factor (TNF) analog that stimulates the proliferation of primitive B cells and T cells in the body, promoting the accumulation of B cells and increasing their content in the spleen. APRIL can specifically bind to TACI and BCMA, and upon binding, inhibits APRIL from binding to B cells and suppresses the proliferative response of primitive B cells stimulated by APRIL. Furthermore, APRIL can compete with BLys to bind to receptors (BCMA, TACI).

[0049] As used herein, the term "TACI-Fc fusion protein" refers to a transmembrane activator, calcium regulator, and cyclophilin ligand interactor (TACI)-immunoglobulin fusion protein (i.e., a TACI-Fc fusion protein). The TACI-immunoglobulin fusion protein provided herein comprises (i) the TACI extracellular domain or a fragment thereof that binds to Blys and / or APRIL, and (ii) a fragment of a human immunoglobulin constant region.

[0050] The term "TACI extracellular domain or a fragment thereof that binds to Blys and / or APRIL" specifically refers to the extracellular domain of TACI and specific fragments of the TACI extracellular domain that can interact with TACI ligands 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), or the amino acid fragment from amino acids 13 to 118 of the TACI extracellular domain disclosed in Chinese Patent Publication No. CN101323643A.

[0051] In the term "fragment of a human immunoglobulin constant region," the immunoglobulin portion is preferably IgG1 and can include a heavy chain constant region, such as a human heavy chain constant region. A preferred "fragment of a human immunoglobulin constant region" of the present invention is an amino acid fragment containing a portion of the hinge region domain, CH2 domain, and CH3 domain. In some more preferred embodiments, the amino acid sequence of the "fragment of a human immunoglobulin constant region" described in the present invention is set forth 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. In some even more preferred embodiments, the amino acid sequence of the "fragment of a human immunoglobulin constant region" is as set forth in SEQ ID NO:3.

[0052] The term "treatment" as used herein relates to a given disease or condition, and includes, but is not limited to, suppressing the disease or condition, such as arresting the progression of the disease or condition, alleviating the disease or condition, such as causing regression of the disease or condition, or alleviating the symptoms caused by the disease or condition, such as alleviating, preventing, or treating the symptoms of the disease or condition.

[0053] The term "amino acid" in the present invention is understood in the broadest sense and is a general term for a type of organic compound containing an amino group and a carboxyl group. Preferably, the amino acid in the present invention is a main unit constituting proteins in living organisms, such as, but not limited to, glycine, alanine, valine, leucine, isoleucine, methionine, proline, tryptophan, serine, tyrosine, cysteine, phenylalanine, asparagine, glutamine, threonine, aspartic acid, glutamic acid, lysine, arginine, and histidine.

[0054] The three-letter and one-letter amino acid codes used in the present invention are described in J. Biol. Chem., 243, p. 3558 (1968). There are various methods for numbering amino acid positions, such as Kabat numbering, EU numbering, and ordinal numbering. In the present invention, the "ordinal numbering" method is used as the method for numbering amino acid positions. For example, "positions 3, 8, 14, 15, 17, 110, 111, or 173 of SEQ ID NO: 2" in the present invention refers to the third amino acid, the eighth amino acid, etc. of SEQ ID NO: 2, as deduced in this example. In the present invention, "P3T" means that the third amino acid in SEQ ID NO: 2 is mutated from the original "P" to "T," and "L8P" means that the eighth amino acid in SEQ ID NO: 2 is mutated from the original "L" to "P," as deduced in this example.

[0055] In one alternative embodiment, the constant regions of the immunoglobulins provided herein can have one or more amino acid changes introduced, such as substitutions (i.e., mutations), additions (i.e., insertions) or deletions (i.e., deletions).

[0056] The term "telitacicept" (called "Tai Ai" in Chinese, which can be used interchangeably in the present invention) in the present invention is a TACI-Fc fusion protein, whose INN name is Telitaccept, and whose amino acid sequence is shown in SEQ ID NO: 4, or see https: / / extranet.who.int / soinn / mod / page / view.php?id=137&inn_n=10932.

[0057] The TACI-Fc fusion proteins of the present invention can be administered via any route, including, but not limited to, oral administration, intravenous injection, intramuscular injection, intraarterial injection, intramedullary injection, intraperitoneal injection, intrathecal injection, intracardiac, transdermal, intradermal, topical, subcutaneous, intranasal, enteral, sublingual, intravaginal, and rectal routes.

[0058] In the present invention, the term "membranous nephropathy" refers to a group of diseases that share a common histopathological pattern of the presence of immunoglobulin- and complement-containing immunoprecipitates in subepithelial sites.

[0059] The term "idiopathic membranous nephropathy" as used herein refers to an organ-specific autoimmune disease that occurs without any definite cause or initiating event, including, but not limited to, PLA2R-associated idiopathic membranous nephropathy, THS7A-associated idiopathic membranous nephropathy, NELL-1-associated idiopathic membranous nephropathy, Sema3B-associated idiopathic membranous nephropathy, and other related idiopathic membranous nephropathy.

[0060] The term "secondary membranous nephropathy" as used herein refers to a definite systemic disease that leads to kidney disease or a glomerular disease that has pathologically evolved into membranous nephropathy. The etiologies that cause secondary membranous nephropathy include immune diseases (e.g., systemic lupus erythematosus, type 1 diabetes, rheumatoid arthropathy, Hashimoto's thyroiditis, Graves' disease, mixed connective tissue disease, anaphylactoid purpura, primary biliary cirrhosis, small bowel enteropathy syndrome, anti-glomerular basement membrane nephritis, ANCN-associated crescentic nephritis, graft-versus-host disease, bone marrow / stem cell transplantation, etc.), infectious and parasitic diseases (e.g., HBV, HCV, syphilis, filariasis, cysticercosis, schistosomiasis, malaria parasites, leprosy, etc.), drugs and toxins (e.g., gold compounds, D-penicillamine, nonsteroidal anti-inflammatory drugs, mercury, captopril, formaldehyde, hydrocarbons, etc.), and others (e.g., tumors, kidney transplantation, etc.).

[0061] In the present invention, the term "PLA2R positive" refers to the detection of PLA2R in the patient's blood, that is, the positive result for PLA2R in a serological test.

[0062] In the present invention, the term "PLA2R negative" refers to the fact that PLA2R was not detected in the patient's blood.

[0063] The term "conventional treatment for membranous nephropathy" as used herein refers to, for example, when the amount of urinary protein measured in a 24-hour urine collection test for membranous nephropathy is less than 3.5 g or within the range of 3.5 g to 8 g, and renal function is normal and there are no high-risk phenomena, a method of reducing urinary protein using prills, sartans, etc., while providing supportive therapy using diuretics, antihypertensives, anticoagulants, etc.

[0064] The term "therapeutic regimen using a combination of hormone and immunosuppressant" as used herein refers to treatment using a combination of hormone and immunosuppressant when, for example, the amount of urinary protein measured in a 24-hour urine collection test exceeds 3.5 g and is accompanied by renal dysfunction, or when the amount of urinary protein excreted exceeds 8 g. Examples of immunosuppressants include, but are not limited to, tacrolimus and cyclosporine.

[0065] The term "therapeutic regimen with monoclonal antibody-based pharmaceuticals" as used herein refers to, but is not limited to, rituximab treatment, such as intravenous administration of 1000 mg of rituximab twice within two weeks, or administration of 375 mg of rituximab per square meter of body surface area once a week for a total of one to four doses, as recommended in the KDIGO 2021 guidelines.

[0066] The term "cyclical administration of a combination of cyclophosphamide and hormones" in this invention refers to the administration of 1 g of methylprednisolone intravenously for three consecutive days during the first few days of the first, third, and fifth months, and oral prednisone at 0.5 mg / kg per day, followed by oral cyclophosphamide at 2.5 mg / kg per day during the second, fourth, and sixth months, as recommended in the KDIGO 2021 guidelines.

[0067] The term "continuous administration of cyclophosphamide and hormone combination drugs" in the present invention refers to the recommended regimen in the KDIGO 2021 guidelines, which involves intravenous administration of 1 g of methylprednisolone for three consecutive days during the first few days of the first, third, and fifth months, administration of prednisone at 0.5 mg / kg every other day for one to six months, followed by gradually reducing the dose, and oral administration of cyclophosphamide at 1.5 mg / kg per day for 16 months. [Example]

[0068] Hereinafter, the embodiments of the present invention will be described in detail with reference to the embodiments of the present invention, but it will be understood by those skilled in the art that the following examples are used to illustrate the present invention and should not be considered as limiting the scope of the present invention.

[0069] Example 1 Clinical Trial to Treat Membranous Nephropathy with Telitaciccept 1. Research method This study is a prospective, single-center, open-label, single-arm clinical trial with the primary objective of evaluating the efficacy and safety of telitacicept in the treatment of membranous nephropathy, and also to investigate the adverse effects of telitacicept in the treatment of refractory membranous nephropathy. Thirty patients with membranous nephropathy (12 patients currently recruited, interim analysis) were selected as subjects and planned to receive telitacicept at a dose of 160 mg subcutaneously once weekly for a total of 48 weeks.

[0070] 2. Selected patients Subjects were selected based on the following criteria: ●Primary membranous nephropathy diagnosed by renal pathological puncture and PLA2R antibody positive Being; ●Age between 18 and 70 years; Prior to enrollment, patients must have received adequate ACEI / ARB therapy for at least 3 months. After receiving the treatment, the 24-hour urinary protein excretion (UTP) was ≥ 3.5 g; ● Blood pressure is stable and below 140 / 90mmHg; Estimated glomerular filtration rate (eGFR) ≥ 45 mL / min / 1.73 m 2 Being; • Agree to maintain a stable diet and sodium intake for the duration of the study. ●Agree and sign the informed consent form.

[0071] Subjects who met the following criteria were excluded. The amount of urinary protein excreted has been unstable for the past two months, and the measured 24-hour urinary protein amount has not changed. If activity reaches 2 g / day or more; - If you have chronic liver disease or liver enzymes exceed the upper limit of normal by more than three times; Cardiovascular disease and cerebrovascular disease (acute coronary syndrome, heart failure, cerebral infarction, stroke) within the past three months If you develop: ● If you are diagnosed with severe uncontrolled hypertension; • If there was a malignant tumor; ● For patients with severe infections; - Patients who have previously received teritacicept, or who have an allergy or other symptoms to teritacicept In patients with contraindications; ●If you are pregnant or breastfeeding; - predicted life expectancy of less than six months; ● If you are currently participating in another clinical trial; ●If you are otherwise deemed inappropriate to participate in this study.

[0072] 3.Endpoint Indicator

[0073] [Table 7]

[0074] [Table 8]

[0075] 5. Key results of interim analysis 5.1 Primary Treatment Efficacy Endpoint The primary endpoint of this study was the 24-hour urinary protein excretion level at week 48. A 24-hour urinary protein excretion level of less than 0.3 g / 24 h was considered a complete remission. A 24-hour urinary protein excretion level between 0.3 and 3.5 g / 24 h or a 50% reduction in urinary protein excretion compared to baseline was considered a partial remission. At week 48 or the end of treatment, 10 subjects (83.3% of the total enrolled population) had a decrease in urinary protein compared to baseline. Of these, five subjects had a 24-hour urinary protein content between 0.3 and 3.5 g / 24 h, and three had a reduction of 50% or more compared to baseline (reduction rates from baseline were 70.86%, 77.42%, and 94.17%, respectively). Thus, five subjects achieved partial remission in this study, accounting for 42% of the total enrolled population. At week 48 or end of treatment, subjects' 24-hour urinary protein index and percent reduction from baseline are detailed in the table below.

[0076] [Table 9]

[0077] 5.2 Secondary Treatment Efficacy Endpoints 5.2.1. Analysis of changes in urinary protein / creatinine ratio and urinary albumin / creatinine ratio In this study, subjects' urinary protein-to-creatinine ratio (UPCR) and urinary albumin-to-creatinine ratio decreased compared to baseline, and the decrease compared to baseline was statistically significant.

[0078] 5.2.2. Analysis of changes in estimated glomerular filtration rate (eGFR) In this study, the estimated glomerular filtration rate (eGFR) increased in four subjects after treatment was discontinued. The subject with the largest increase in eGFR was 47.9 mL / min / 1.73 m. 2 to 62.46 mL / min / 1.73 m 2 The increase was 30.4%.

[0079] 5.2.3. Serum Albumin Analysis over Time In this study, mean albumin levels decreased over the course of treatment. After treatment ended, the mean serum albumin level of enrolled subjects decreased by 0.59 g / L compared to baseline. The change in albumin over time is shown in Figure 1.

[0080] 5.2.4. Immunological indicators (IgG, IgM, IgA) 5.2.4.1. Time course analysis of immunoglobulin (IgG) Compared to baseline, after 48 weeks of treatment, the rate of change in the mean IgG levels of enrolled subjects tended to decrease overall, with the mean IgG levels decreasing by approximately 2.60 g / L (a 38.8% decrease). The rate of change in the mean IgG levels of enrolled subjects over time is shown in Figure 2.

[0081] 5.2.4.2. Time course analysis of immunoglobulin (IgM) Compared to baseline, the rate of change in the mean IgM levels of enrolled subjects also tended to decrease overall, with the mean IgM levels decreasing by approximately 0.708 g / L after 48 weeks of administration (a 70.1% decrease). The rate of change in the mean IgM levels of enrolled subjects over time is shown in Figure 3.

[0082] 5.2.4.3. Time course analysis of immunoglobulin (IgA) Compared to baseline, the rate of change in the mean IgA levels of the enrolled subjects also tended to decrease overall, with the mean IgA levels decreasing by approximately 0.717 g / L after 48 weeks of administration (a 39.7% decrease). The rate of change in the mean IgA levels of the enrolled subjects over time is shown in Figure 4.

[0083] 5.3 Efficacy Results In this study, prior data demonstrated that telitacicept demonstrated sustained clinical improvement in the treatment of patients with primary membranous nephropathy, with subjects' urinary protein-to-creatinine ratio (UPCR) and urinary albumin-to-creatinine ratio (UCAR) decreasing compared to baseline. The decreases compared to baseline were statistically significant. Compared to baseline, subjects' mean IgG, IgA, and IgM levels significantly decreased after telitacicept administration.

[0084] 5.4 Safety results The current results of this study demonstrate a favorable safety profile for telitacicept 160 mg administered once weekly in the treatment of patients with primary membranous nephropathy. The severity of adverse events / reactions was mild (CTCAE Grade 1), with no CTCAE Grade 2, 3, 4, or 5 adverse events / reactions. No adverse events / reactions leading to subject discontinuation or death were observed, and no serious adverse events / reactions were observed. Two subjects experienced adverse events during the study. One subject experienced abdominal pain and vomiting, but this adverse event / reaction was not considered to be related to telitacicept. Another subject experienced itchy skin, which improved 2-3 days after discontinuing the drug.

[0085] 5.5 Conclusion Based on the above results and analysis, this study revealed that the current experimental data showed that the use of telitacicept in the treatment of patients with membranous nephropathy showed good clinical efficacy and safety.

[0086] The above description is merely a preferred embodiment and is used for illustration only, but does not limit the combination of features necessary to implement the present invention. The titles provided herein are not intended to limit the various embodiments of the present invention. Terms such as "comprises," "includes," and "included" are not intended to be limiting. Furthermore, unless otherwise specified, when not modified by a number, plural forms are included, and "or" means "and / or." Unless otherwise defined herein, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art.

[0087] All publications and patents mentioned herein are incorporated herein by reference. It will be apparent to those skilled in the art that various modifications and variations can be made to the methods and combinations described herein without departing from the scope and spirit of the invention. Although the invention has been described in terms of specific preferred embodiments, it should be understood that the invention for which protection is sought should not be unduly limited to these specific embodiments. Indeed, various variations of modes for carrying out the invention which are obvious to those skilled in the art are intended to be within the scope of the following claims.

Claims

1. In patients with membranous nephropathy, (i) the TACI extracellular domain or a fragment thereof that binds to Blys and / or APRIL; (ii) a fragment of a constant region of a human immunoglobulin; A method for treating membranous nephropathy, comprising administering a therapeutically effective amount of a TACI-Fc fusion protein comprising:

2. 2. The method of claim 1, wherein the TACI extracellular domain or a fragment thereof that binds to Blys and / or APRIL comprises the amino acid sequence set forth in SEQ ID NO:

1.

3. the human immunoglobulin is IgG1, or 3. The method of claim 2, wherein the fragment of the constant region of a human immunoglobulin comprises the amino acid sequence of SEQ ID NO:2 or 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.

4. 4. The method of claim 3, wherein the fragment of the constant region of a human immunoglobulin comprises an amino acid modification corresponding to one or more of positions 3, 8, 14, 15, 17, 110, 111, or 173 of SEQ ID NO:

2.

5. 5. The method of claim 4, wherein the modification is an amino acid substitution, deletion, or insertion.

6. 6. The method of claim 5, wherein the substitutions are selected from the group consisting of P3T, L8P, L14A, L15E, G17A, A110S, P111S and A173T.

7. The method of claim 7, wherein the fragment of the constant region of the human immunoglobulin comprises the amino acid sequence shown in SEQ ID NO:

3.

8. The method of claim 1, wherein the TACI-Fc fusion protein has the amino acid sequence shown in SEQ ID NO:

4.

9. The method of claim 8, wherein the TACI-Fc fusion protein is telitacicept.

10. The method according to claim 8 or 9, wherein the membranous nephropathy is primary membranous nephropathy or secondary membranous nephropathy.

11. The method according to claim 10, characterized in that the membranous nephropathy manifests as PLA2R positive or PLA2R negative.

12. 12. The method of claim 11, wherein the patient is an adult or pediatric patient.

13. 13. The method of claim 12, wherein the patient has previously undergone a treatment regimen for membranous nephropathy.

14. The method according to claim 12 or 13, characterized in that the TACI-Fc fusion protein is administered in a single dose of about 0.1 to 10 mg / kg.

15. The method according to claim 12 or 13, characterized in that the TACI-Fc fusion protein is administered in a single dose of 160 to 240 mg, preferably 160 mg or 240 mg.

16. The method according to claim 12 or 13, characterized in that the TACI-Fc fusion protein is administered subcutaneously, intramuscularly or intravenously at an administration site in the thigh, abdomen or upper arm.

17. The method according to claim 12 or 13, characterized in that the TACI-Fc fusion protein is used 2-4 times with an interval period of one month and / or the treatment lasts for about 2-50 weeks.

18. 18. The method of claim 17, wherein the TACI-Fc fusion protein is administered once a week.

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