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 a TACI-Fc fusion protein drug, a dosage regimen, an administration interval, and an administration method for treating membranous nephropathy. BACKGROUND ART

[0002] Membranous nephropathy (MN) is an antibody-mediated glomerular disease characterized by the formation of immune deposits containing antigens, IgG and complement components under the epithelial cells of glomerular capillary loops, sublethal damage to epithelial cells leading to cell simplification and destruction of the glomerular filtration barrier, and the appearance of symptoms such as proteinuria and other nephrotic syndromes.

[0003] Clinically, membranous nephropathy is divided into primary membranous nephropathy and secondary membranous nephropathy according to its etiology. Most cases of membranous nephropathy are primary membranous nephropathy (also called idiopathic membranous nephropathy), which is an organ-specific autoimmune disease that occurs in the absence of any definite cause or initiating event. About 20-30% of membranous nephropathy is secondary membranous nephropathy, and common etiological diseases include autoimmune diseases (such as lupus), viruses (hepatitis B, hepatitis C, syphilis), tumors, specific drugs (such as analgesics), poisons (such as exposure to heavy metals like lead and mercury), etc. Membranous nephropathy accounts for up to one-third of biopsy results of nephrotic syndrome, and is one of the most common causes of nephrotic syndrome in non-diabetic adults. Its main clinical symptoms include edema, proteinuria, hypoalbuminemia, hyperlipidemia, etc. It mainly adversely affects the function of the glomerular basement membrane, and may increase the risk of developing diseases such as thrombosis, infection and cardiovascular diseases.

[0004] Currently, the global incidence of membranous nephropathy (MEP) is approximately 1 case per 100,000 people per year. While it was unclear whether the incidence of MEP varied by region or race, it has been confirmed that it can affect patients of all ages and races. In the United States, the incidence of MEP is approximately 12 cases per million people per year, with the average age of onset being in the 50s or 60s. In China, the incidence of MEP has been steadily increasing over the past 20 years, and research suggests that this high incidence may be linked to worsening air pollution. Statistics indicate that among these MEP patients, approximately 60% of those without long-term treatment will develop renal dysfunction, and 30-40% will progress to end-stage renal failure within 10 years. Even with immunosuppressive therapy, 20-40% of patients will experience persistent high levels of proteinuria throughout the course of the disease and progress to end-stage renal failure within 10 years, requiring renal replacement therapy or a kidney transplant.

[0005] Treatment for membranous nephropathy is determined by its type and the underlying disease. Currently, the following are the main treatment methods for membranous nephropathy: (1) Conventional treatment: If the amount of protein excreted in urine measured by a 24-hour urine collection test for membranous nephropathy is 3.5g or less, or within the range of 3.5g to 8g, but renal function is normal and there are no high-risk phenomena, then usually prill drugs and sartan drugs are used to reduce protein excretion in urine, and supportive therapy such as diuretics, antihypertensives, and anticoagulants is administered. (2) Combination therapy with hormones and immunosuppressants: If the amount of protein excreted in urine measured by a 24-hour urine collection test for membranous nephropathy exceeds 3.5g and is accompanied by renal dysfunction, or if the amount of protein excreted in urine exceeds 8g, then combination therapy with hormones and immunosuppressants is performed. (3) Monoclonal antibody treatment: Rituximab and other similar drugs are used.

[0006] [Table 1]

[0007] The KDIGO 2021 guidelines recommend five treatment methods 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 (such as prednisone), but hormones have significant side effects, and cyclophosphamide also has side effects such as reproductive toxicity, bone marrow suppression, infection, and hemorrhagic cystitis. Furthermore, from the perspective of application, even after treatment with hormone + cyclophosphamide therapy, about half of patients still do not experience symptom relief, and there is a risk of relapse if the medication is stopped after symptoms have improved. (2) Tacrolimus and cyclosporine are calcineurin inhibitors (CNIs), which belong to the same class of immunosuppressants, and can be used to treat patients who do not wish to receive glucocorticoid + cyclophosphamide, or who have contraindications to such treatment. However, while cyclosporine therapy has advantages such as a rapid onset of action, higher efficacy than cyclophosphamide, and fewer and milder side effects, it also has disadvantages such as a lower overall remission rate than cyclophosphamide therapy and a significantly higher short-term relapse rate. Tacrolimus, on the other hand, has an immunosuppressive effect 10 to 100 times higher than cyclosporine, but it also has the same problem as cyclosporine: a high relapse rate and serious side effects such as impaired glucose tolerance and new-onset diabetes. (3) Currently, rituximab alone or in combination with calcineurin inhibitors is recommended for the initial treatment of moderate-risk, high-risk, and very high-risk primary membranous nephropathy, with 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 and difficult for most patients to obtain, and it also has serious fluid reactivity issues.Various studies have reported a rituximab-related fluid reactivity rate of 26% to 85%, and rituximab has also been reported to cause rare adverse events in patients with hematological malignancies, such as hepatitis B virus reactivation and severe skin reactions (toxic epidermal necrolysis and Stevens-Johnson syndrome, etc.) (Reference 1: Alsharhan L, Beck LH Jr. Membranous Nephropathy: Core Curriculum 2021. Am J Kidney Dis. 2021 Mar;77(3):440-453.). In short, membranous nephropathy is characterized by a typically slow-progressing clinical course, toxicity to existing treatments, limitations and risks to existing treatment regimens, and insufficient therapeutic efficacy. However, from a clinical application perspective, when combination therapy with hormones and immunosuppressants is ineffective, monoclonal antibody drugs (such as rituximab) are commonly used for treatment. Therefore, the development of new biologics (such as monoclonal antibody drugs) is urgently needed for the current treatment of membranous nephropathy.

[0008] [Table 2]

[0009] As of September 22, 2022, only two biologics for membranous nephropathy, rituximab and obinutuzumab, had been approved for sale worldwide, while two other drugs were in Phase III clinical trials (see Table 2). Of these drugs, rituximab was selected in 2021 as a recommended treatment for membranous nephropathy according to the KDIGO guidelines, but it had problems such as a low remission rate, high fluid response, serious side effects, and high cost. Similarly, obinutuzumab, which also targets CD20, showed some therapeutic effect in membranous nephropathy patients who had failed clinical treatment, but because antibodies and immune complexes were not completely removed and damage to the renal basement membrane remained, causing some urinary protein to still leak out, the related therapeutic effect was limited to partial remission and did not lead to complete remission. Furthermore, because obinutuzumab has stronger cytotoxicity and B-cell scavenging ability than rituximab, it may face greater challenges in terms of side effects (Reference 2: Hudson, R., Rawlings, C., Mon, S. et al. Treatment resistant M-type phosphollipase 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 worldwide. [Overview of the Initiative]

[0010] The inventors of this invention have surprisingly discovered that a remarkable therapeutic effect was observed when using TACI-Fc fusion protein to treat patients with membranous nephropathy.

[0011] Specifically, the present invention provides a method for treating membranous nephropathy, comprising administering a therapeutically effective dose of TACI-Fc fusion protein to a patient having the aforementioned membranous nephropathy.

[0012] Specifically, the present invention further provides a method for treating patients with membranous nephropathy who have previously received a treatment regimen for membranous nephropathy. This method comprises (1) determining whether the patient has received a treatment regimen for membranous nephropathy, and (2) if the patient has previously received a treatment regimen for membranous nephropathy, administering a therapeutically effective dose of 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 pharmaceutical product for treating patients with membranous nephropathy.

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

[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 constant region fragment of the human immunoglobulin contains the amino acid sequence of SEQ ID NO: 2, or contains 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] Further, the fragment of the constant region of said human immunoglobulin comprises amino acid modifications corresponding to one or more of positions 3, 8, 14, 15, 17, 110, 111 or 173 of SEQ ID NO: 2.

[0021] Further, said modification is amino acid substitution, deletion or insertion.

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

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

[0024] [Table 5]

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

[0026] [Table 6]

[0027] Preferably, said TACI-Fc fusion protein is Telitacicept.

[0028] Furthermore, the single dose of the TACI-Fc fusion protein is approximately 0.1 to 10 mg / kg, and also 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, or 10 mg / kg.

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

[0030] Furthermore, the method for detecting the content of the fusion protein is ultraviolet-visible spectroscopy, which measures the absorbance value of teritacicept at around 280 nm, since the protein has maximum ultraviolet absorption at this wavelength. After correcting for the absorbance at 320 nm, a positive proportional relationship is obtained between the absorbance value at 280 nm and the protein concentration, and the protein concentration is calculated according to the Lambert-Beer law to determine the protein content. The protein content is calculated according to the following formula.

[0031]

number

[0032] Here, ε is the extinction coefficient of teritasicept, and its unit is (mg / ml). -1 ·cm -1 A 280 This represents the average absorbance of the sample solution at 280 nm. 280 (Corrected) represents the corrected average absorbance of the sample solution at 280 nm.

[0033] Furthermore, the TACI-Fc fusion protein is administered 2 to 4 times at intervals of one month, that is, the TACI-Fc fusion protein is administered at a frequency of 2 times, 3 times, or 4 times per month.

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

[0035] More preferably, the treatment is sustained for approximately 2 to 50 weeks. Even more preferably, the treatment is sustained 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, and 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 embodiments, the TACI-Fc fusion protein is administered subcutaneously, intramuscularly, or intravenously.

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

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

[0039] Furthermore, the aforementioned membranous nephropathy can manifest as either PLA2R-positive or PLA2R-negative.

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

[0041] Furthermore, the patient in question has previously received treatment for membranous nephropathy.

[0042] Furthermore, treatment regimens for membranous nephropathy include conventional treatments, combination therapy with hormones and immunosuppressants, and treatment with monoclonal antibody drugs.

[0043] Furthermore, treatment regimens for membranous nephropathy may include administering clophosphamide and an hormonal agent to the patient regularly, administering clophosphamide and an hormonal agent to the patient continuously, administering tacrolimus to the patient, administering cyclosporine to the patient, administering rituximab to the patient, administering obinutuzumab to the patient, administering MIL62 to the patient, or administering obinutuzumab to the patient.

[0044] The TACI-Fc fusion protein according to the present invention demonstrated unexpected clinical efficacy and good safety in the treatment of patients with membranous nephropathy. [Brief explanation of the drawing]

[0045] [Figure 1] The changes in albumin levels during treatment for the subjects in Example 1 are shown. [Figure 2] This shows a time-course analysis of the percentage change in immunoglobulin IgG levels in the subjects of Example 1 compared to baseline during treatment. [Figure 3] This shows a time-course analysis of the percentage change in immunoglobulin IgM levels in the subjects of Example 1 compared to baseline during treatment. [Figure 4] This shows a time-course analysis of the percentage change in immunoglobulin IgA levels in the subjects of Example 1 compared to baseline during treatment. [Modes for carrying out the invention]

[0046] Unless otherwise defined, technical and scientific terms used herein have the same meaning as they would be understood by those skilled in the art. Those skilled in the art should specifically refer to *Current Protocols in Molecular Biology* (Ausubel) for definitions and terms in this art.

[0047] The three-letter and one-letter codes for the amino acids used in this invention are as described in J.biol.chem, 243, p3558 (1968).

[0048] In this invention, the term "TACI," i.e., transmembrane activator and calmodulin ligand interactor, is a member of the tumor necrosis factor receptor superfamily. In this invention, the term "BLys" refers to B lymphocyte stimulators, which are members of the TNF ligand superfamily that exist in two forms: membrane-bound and soluble. They are specifically expressed on the surface of bone marrow cells and selectively stimulate B lymphocyte proliferation and immunoglobulin production. In this invention, the term "APRIL" (a proliferation-inducing ligand) is a tumor necrosis factor (TNF) analog that stimulates the proliferation of primitive B cells and T cells in the body, promoting B cell accumulation and increasing spleen content. APRIL can specifically bind to TACI and BCMA, and upon binding, it inhibits APRIL from binding to B cells and suppresses the proliferation response of primitive B cells stimulated by APRIL. Furthermore, APRIL can compete with Blys to bind to its receptors (BCMA, TACI).

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

[0050] The term “TACI extracellular domain or its fragments that bind to Blys and / or APRIL” should specifically refer 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 to the amino acid fragments between the 13th and 118th amino acids of the TACI extracellular domain disclosed in Chinese Patent Publication No. CN101323643A.

[0051] In the term “fragment of the constant region of human immunoglobulin,” the immunoglobulin portion is preferably IgG1 and may include a heavy chain constant region such as the human heavy chain constant region. A preferred “fragment of the constant region of human immunoglobulin” of the present invention is an amino acid fragment containing a hinge region domain, a CH2 domain, and a portion of the CH3 domain. In some more preferred embodiments, the amino acid sequence of the “fragment of the constant region of human immunoglobulin” described in the present invention is shown in SEQ ID NO: 2, or includes 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 the constant region of human immunoglobulin” is as shown in SEQ ID NO: 3.

[0052] In this invention, the term "treatment" relates to a given disease or illness. "Treatment" includes, but is not limited to, suppression of the disease or illness, such as preventing the progression of the disease or illness; reduction of the disease or illness, such as causing the disease or illness to regress; or reduction of symptoms caused by the disease or illness, such as reducing, preventing, or treating the symptoms of the disease or illness.

[0053] In this invention, the term "amino acid" is understood in its broadest sense as a general term for one type of organic compound containing an amino group and a carboxyl group. Preferably, the amino acids in this invention are the main units that make up proteins in living organisms, and include, but are 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 this invention are described in J.biol.chem, 243, p3558 (1968). There are various methods for numbering amino acid sites, such as Kabat numbering, EU numbering, and sequential numbering, but in this invention, the "sequential numbering" method is adopted as the method for numbering amino acid sites. For example, "sites 3, 8, 14, 15, 17, 110, 111, or 173 of SEQ ID NO: 2" in this invention refers to the third amino acid, the eighth amino acid, etc., of SEQ ID NO: 2, and is inferred as in this example. In this invention, "P3T" means that the third amino acid sequence of SEQ ID NO: 2 is changed from the original "P" to "T", and furthermore, "L8P" means that the eighth amino acid sequence of SEQ ID NO: 2 is changed from the original "L" to "P", and is inferred as in this example.

[0055] As one possible embodiment, the constant region of the immunoglobulin provided in the present invention may be subjected to one or more amino acid changes, such as substitution (i.e., mutation), addition (i.e., insertion), or deletion (i.e., deletion).

[0056] In this invention, the term "Telitacicept" (pronounced "Tai'ai" in Chinese, and interchangeably used in this invention) refers to a TACI-Fc fusion protein whose INN name is Telitacicept, 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 protein of the present invention can be administered via any route. These routes include, but are not limited to, oral administration, intravenous injection, intramuscular injection, intra-arterial injection, intrathecal injection, intraperitoneal injection, intrathecal injection, intracardiac injection, transdermal injection, intradermal injection, topical injection, subcutaneous injection, intranasal injection, intestinal injection, sublingual injection, vaginal injection, and rectal injection.

[0058] In this invention, the term "membranous nephropathy" refers to a group of diseases that exhibit a common histopathological pattern of having immunoglobulin and complement-containing immunoprecipitates in the subepithelial region.

[0059] In this invention, the term "idiopathic membranous nephropathy" refers to an organ-specific autoimmune disease that occurs without any definite cause or trigger, and includes, but is 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.

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

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

[0062] In this invention, the term "PLA2R negative" refers to the absence of PLA2R in the patient's blood.

[0063] In this invention, the term "conventional treatment for membranous nephropathy" refers, for example, to cases where the amount of urinary protein measured by a 24-hour urine collection test for membranous nephropathy is less than 3.5g, or within the range of 3.5g to 8g, and renal function is normal with no high-risk phenomena, and the urinary protein is usually reduced using prill-type drugs and sartan-type drugs, while supportive therapy such as diuretics, antihypertensive drugs, and anticoagulants is administered.

[0064] In this invention, the term "treatment regimen using a combination of hormones and immunosuppressants" refers to treatment using a combination of hormones and immunosuppressants when, for example, the amount of urinary protein measured in a 24-hour urine collection test for membranous nephropathy exceeds 3.5 g and is accompanied by renal dysfunction, or when the amount of urinary protein excretion exceeds 8 g. Examples of immunosuppressants here include, but are not limited to, tacrolimus and cyclosporine.

[0065] In this invention, the term "treatment regimen with monoclonal antibody drugs" refers to, for example, rituximab treatment as recommended in the KDIGO 2021 guidelines, which involves intravenous administration of rituximab at a dose of 1000 mg twice within two weeks, or administration of rituximab at a dose of 375 mg per square meter of body surface area once a week for a total of 1 to 4 doses, but is not limited to these.

[0066] In this invention, the term "periodic administration of cyclophosphamide and hormone combination therapy" refers to the KDIGO 2021 guidelines, which recommend intravenous administration of 1 g of methylprednisolone for three consecutive days during the first few days of months 1, 3, and 5, oral intake of prednisone at 0.5 mg / kg per day, and then switching to oral intake of cyclophosphamide at 2.5 mg / kg per day during months 2, 4, and 6.

[0067] In this invention, the term "continuous administration of cyclophosphamide and hormone combination therapy" refers to the KDIGO 2021 guidelines, which recommend intravenous administration of 1 g of methylprednisolone for three consecutive days during the first few days of months 1, 3, and 5, followed by administration of prednisone at 0.5 mg / kg every other day for 1 to 6 months, after which the dosage is gradually reduced, and oral administration of cyclophosphamide at 1.5 mg / kg per day for 16 months. [Examples]

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

[0069] Example 1: Clinical trial to treat membranous nephropathy with teritacicept 1. Research method This study is a promising, single-center, open-label, single-arm clinical trial primarily aimed at evaluating the efficacy and safety of teritacicept in the treatment of membranous nephropathy, and also at investigating the side effects of teritacicept in the treatment of refractory membranous nephropathy. Thirty patients with membranous nephropathy (12 recruited so far, interim analysis underway) were selected as subjects, and a treatment plan was developed in which teritacicept would be administered subcutaneously at a dose of 160 mg once a week for a total of 48 weeks.

[0070] 2. Selected patients The subjects were selected based on the following criteria. ●Primary membranous nephropathy diagnosed by renal pathological puncture, and positive for PLA2R antibody. A certain thing; ● Must be between 18 and 70 years old; ● Before registering, you must have received adequate treatment with ACEI / ARB drugs for at least 3 months. After receiving the test, the 24-hour urinary protein excretion (UTP) was ≥ 3.5g; ● Blood pressure must be stable and below 140 / 90 mmHg; ● Estimated glomerular filtration rate (eGFR) ≥ 45 mL / min / 1.73 m 2 Being; ● You agree to maintain a stable diet and sodium intake throughout the study period. ● Agree to and sign the informed consent form.

[0071] Individuals who met the following criteria were excluded from being subjects. ●Urinary protein excretion has been unstable over the past two months, and the measured 24-hour urinary protein level has changed. If the intake exceeds 2g / day; ● If it is complicated by chronic liver disease, or if liver enzyme levels exceed three times the upper limit of normal; ● Cardiovascular and cerebrovascular diseases (acute coronary syndrome, heart failure, cerebral infarction, stroke) within the last 3 months If the disease develops; ● If diagnosed with uncontrolled severe hypertension; ● If a malignant tumor is present; ● In the case of a patient with a severe infection; ● Patients who have previously received teritacicept, or who have an allergy to teritacicept or other In the case of a patient with a contraindication; ● If you are pregnant or breastfeeding; ●When life expectancy is predicted to be less than 6 months; ● If you are currently participating in another clinical trial; ●Other cases where participation in this study is deemed inappropriate.

[0072] 3. Endpoint Indicator

[0073] [Table 7]

[0074] [Table 8]

[0075] 5. Main results of the interim analysis 5.1 Endpoints of primary treatment efficacy The primary endpoint of this study was the 24-hour urinary protein excretion level at week 48. Complete remission was considered achieved if the 24-hour urinary protein excretion was less than 0.3 g / 24h. Partial remission was considered achieved if the 24-hour urinary protein excretion was within the range of 0.3–3.5 g / 24h, or if the urinary protein excretion decreased by 50% compared to baseline. At week 48 or the end of treatment, 10 patients (83.3% of the total enrolled population) had reduced urinary protein compared to baseline, of which 5 had 24-hour urinary protein content within the range of 0.3–3.5 g / 24h, and 3 showed a reduction of 50% or more compared to baseline (reductions from baseline were 70.86%, 77.42%, and 94.17%, respectively). Thus, 5 subjects achieved partial remission in this trial, representing 42% of the total enrolled population. At week 48 or at the end of treatment, the subjects' 24-hour urinary protein index and the percentage reduction from baseline are shown in detail in the table below.

[0076] [Table 9]

[0077] 5.2 Endpoints of secondary therapeutic effects 5.2.1. Analysis of changes in urinary protein / creatinine ratio and urinary albumin / creatinine ratio In this study, the subjects' urinary protein / creatinine ratio (UPCR) and urinary albumin / creatinine ratio decreased compared to baseline. The rate of 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 discontinuing medication. The subject with the largest increase had an eGFR of 47.9 mL / min / 1.73 m². 2 From 62.46 mL / min / 1.73 m 2 It increased to 30.4%.

[0079] 5.2.3. Time-course analysis of serum albumin In this study, mean albumin levels decreased during the treatment course. After the completion of medication, the mean serum albumin level of enrolled subjects decreased by 0.59 g / L compared to baseline. The changes in albumin over time are shown in Figure 1.

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

[0081] 5.2.4.2. Time-course analysis of immunoglobulins (IgM) Compared to baseline, the average percentage change in IgM levels among enrolled subjects generally showed a decrease, with the average IgM level decreasing by approximately 0.708 g / L after 48 weeks of administration (a decrease of 70.1%). The percentage change in average IgM levels over time among enrolled subjects is shown in Figure 3.

[0082] 5.2.4.3. Time-course analysis of immunoglobulin (IgA) Compared to baseline, the average percentage change in IgA levels among enrolled subjects generally showed a decrease, with the average IgA level decreasing by approximately 0.717 g / L after 48 weeks of administration (a decrease of 39.7%). The percentage change in average IgA levels over time among enrolled subjects is shown in Figure 4.

[0083] 5.3 Efficacy Results This study revealed, based on previous data, that teritacicept demonstrated a sustained improvement in the treatment of patients with primary membranous nephropathy, with subjects showing a decrease in urinary protein / creatinine ratio (UPCR) and urinary albumin / creatinine ratio (UCAR) compared to baseline. The decrease compared to baseline was statistically significant. Compared to baseline, the mean IgG, IgA, and IgM levels of subjects decreased significantly after teritacicept administration.

[0084] 5.4 Safety results This study, based on current results, demonstrates good safety with once-weekly administration of teritacicept 160 mg in the treatment of patients with primary membranous nephropathy. The severity of adverse events / reactions was mild (CTCAE Grade 1), and no adverse events / reactions of CTCAE Grade 2, 3, 4, or 5 occurred. No adverse events / reactions occurred that led to discontinuation of the trial or death among subjects, and no serious adverse reactions were observed. Two subjects experienced adverse events during the study period. One of them experienced abdominal pain and vomiting, but this adverse event / side effect was not considered to be related to teritacicept. Another subject experienced symptoms of itchy skin, but the symptoms improved 2-3 days after discontinuing the medication.

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

[0086] The above description is merely a preferred embodiment and is for illustrative purposes only, and is not intended to limit the combination of features necessary to carry out the invention. The title provided herein is not intended to limit the various embodiments of the invention. Terms such as “include,” “contain,” and “include” are not intended to limit. Furthermore, unless otherwise specified, plurals include “include” and “or” mean “and / or.” Unless otherwise specified 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 referenced herein are incorporated herein by reference. It will be apparent to those skilled in the art that various modifications and changes 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 through specific preferred embodiments, it should be understood that the invention for which protection is sought should not be unjustly limited to these specific embodiments. In practice, various variations of modes for carrying out the invention, which will be obvious to those skilled in the art, are included in the appended claims.

Claims

1. A pharmaceutical composition for the treatment of patients with membranous nephropathy comprising (i) a fragment thereof that binds to the extracellular domain of TACI or Blys and / or APRIL, and (ii) a fragment of the constant region of human immunoglobulin, a TACI-Fc fusion protein.

2. The pharmaceutical composition for treating patients with membranous nephropathy according to claim 1, characterized in that the fragment that binds to the TACI extracellular domain or Blys and / or APRIL contains the amino acid sequence shown in SEQ ID NO:

1.

3. The aforementioned human immunoglobulin is IgG1, or The pharmaceutical composition for treating patients with membranous nephropathy according to claim 2, characterized in that the fragment of the constant region of the human immunoglobulin contains the amino acid sequence of SEQ ID NO: 2, or contains 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. The pharmaceutical composition for treating patients with membranous nephropathy according to claim 3, characterized in that the fragment of the constant region of the human immunoglobulin comprises amino acid modifications corresponding to one or more sites among sites 3, 8, 14, 15, 17, 110, 111, or 173 of SEQ ID NO:

2.

5. The pharmaceutical composition for the treatment of membranous nephropathy patients according to claim 4, characterized in that the modification is an amino acid substitution, deletion, or insertion.

6. The pharmaceutical composition for treating patients with membranous nephropathy according to claim 5, characterized in that the substitution is selected from the group consisting of P3T, L8P, L14A, L15E, G17A, A110S, P111S, and A173T.

7. The pharmaceutical composition for treating patients with membranous nephropathy according to claim 1, characterized in that a fragment of the constant region of the human immunoglobulin contains the amino acid sequence shown in SEQ ID NO:

3.

8. The pharmaceutical composition for treating patients with membranous nephropathy according to claim 1, characterized in that the TACI-Fc fusion protein has the amino acid sequence shown in SEQ ID NO:

4.

9. The pharmaceutical composition for the treatment of membranous nephropathy patients according to claim 8, characterized in that the TACI-Fc fusion protein is teritacicept.

10. A pharmaceutical composition for the treatment of a patient with membranous nephropathy according to any one of claims 1 to 9, characterized in that the membranous nephropathy is primary membranous nephropathy or secondary membranous nephropathy.

11. The pharmaceutical composition for treating patients with membranous nephropathy according to claim 10, characterized in that the membranous nephropathy appears as PLA2R-positive or PLA2R-negative.

12. The pharmaceutical composition for treating membranous nephropathy patients according to claim 11, characterized in that the patient is an adult patient or a pediatric patient.

13. The pharmaceutical composition for treating a patient with membranous nephropathy according to claim 12, characterized in that the patient has previously received a treatment regimen for membranous nephropathy.

14. A pharmaceutical composition for the treatment of membranous nephropathy patients according to any one of claims 1 to 9, characterized in that the TACI-Fc fusion protein is administered at a dose of about 0.1 to 10 mg / kg.

15. A pharmaceutical composition for the treatment of membranous nephropathy patients according to any one of claims 1 to 9, characterized in that the TACI-Fc fusion protein is administered in a dose of 160 to 240 mg, preferably 160 mg or 240 mg.

16. A pharmaceutical composition for the treatment of membranous nephropathy patients according to any one of claims 1 to 9, characterized in that the TACI-Fc fusion protein is administered subcutaneously, intramuscularly, or intravenously at an administration site of the thigh, abdomen, or upper arm.

17. A pharmaceutical composition for the treatment of a patient with membranous nephropathy according to any one of claims 1 to 9, characterized in that the TACI-Fc fusion protein is administered two to four times a month and / or the treatment is sustained for about 2 to 50 weeks.

18. The pharmaceutical composition for treating membranous nephropathy patients according to claim 17, characterized in that the TACI-Fc fusion protein is administered once a week.

19. The pharmaceutical composition for the treatment of membranous nephropathy patients according to claim 17, characterized in that the TACI-Fc fusion protein is administered once a week in a dose of 160 to 240 mg, preferably 160 mg or 240 mg.

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