A method for treating ANCA-associated vasculitis using TACI-Fc fusion proteins.

Abstract

This invention relates to a drug for treating ANCA-associated vasculitis (AAV) using an effective dose of the drug, administration regimen, administration interval, and dosage form targeting BlyS and / or APRIL. The provided effective dose of the drug targeting BlyS and / or APRIL has been demonstrated to exhibit good safety and therapeutic efficacy in the treatment or relief of patients with ANCA-associated vasculitis.

Description

Technical Field

[0001] The present invention relates to a TACI-Fc fusion protein agent, dosing regimen, dosing interval, and dosage form for treating ANCA-associated vasculitis.

Background Art

[0002] Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is an autoimmune disease characterized by necrotizing vasculitis of small and medium-sized blood vessels. It includes three disease types, namely granulomatosis with polyangiitis (GPA), eosinophilic granulomatosis with polyangiitis (EGPA, formerly known as Churg-Strauss syndrome), and microscopic polyangiitis (MPA) (Reference 1: Gapud E J, Seo P, Antiochos B. ANCA-associated vasculitis pathogenesis: a commentary[J]. Current rheumatology reports, 2017, 19: 1-7).

[0003] ANCA-associated vasculitis can occur in all age groups, and the prevalence is approximately 46 to 184 cases per million population. The incidence and disease type of AAV vary by region. In recent years, the global incidence of ANCA-associated vasculitis has been gradually increasing. Specifically, the prevalence of granulomatosis with polyangiitis (GPA) is about 1 in 25,000 people, the prevalence of microscopic polyangiitis (MPA) is approximately 1 to 3 per 100,000 population, and the prevalence of eosinophilic granulomatosis with polyangiitis (EGPA) is about 10.7 to 13 per 1,000,000 population. Overall, the increase in the prevalence of ANCA-associated vasculitis may be due to factors such as an increase in the incidence, improvement of disease criteria, increase / expansion of databases, and an increase in survival rate.

[0004] ANCA-associated vasculitis is typically fatal if left untreated, with a 6-month mortality rate of approximately 60% and a 1-year mortality rate of up to 80%. The disease primarily affects small vessels and is pathologically characterized by full-thickness inflammation and necrosis of small vessels, with or without granuloma formation. Common symptoms may include fever, arthralgia, myalgia, malaise, and weight loss. If the lungs, kidneys, gastrointestinal tract, nervous system, or eyes, ears, nose, and throat are affected, corresponding clinical symptoms will appear. Nonspecific but systemic musculoskeletal symptoms are commonly observed. The following clinical symptoms may also occur alone or in combination: chronic recurrent sinusitis with nasal crusting, pulmonary nodules with cavitation, rapidly progressive necrotizing hypocomplexic glomerulonephritis, mononeuritis polyneuritis, pericarditis or myocarditis, and prominent purpura. Acute, severe ANCA-associated vasculitis can present with simultaneous respiratory and renal failure (i.e., "pulmonary-renal syndrome"). Other studies have shown a significantly increased risk of malignancy in patients with ANCA-associated vasculitis compared to the general population, with a standardized morbidity of 1.74.

[0005] Treatment for ANCA-associated vasculitis is primarily divided into two phases: the induction phase and the maintenance phase. The induction phase typically lasts 3 to 6 months. During this phase, patients require immediate treatment to rapidly alleviate inflammation in order to prevent death and limit permanent organ damage. The maintenance phase typically lasts 24 to 48 months. During this phase, patients generally show no signs of disease but require treatment to prevent relapse. Treatment during the induction phase transforms ANCA-associated vasculitis from a life-threatening disease to a chronic one, but relapses are very common, and typically 30% to 50% of patients experience a relapse within 12 to 18 months after discontinuation of immunosuppressive therapy. Overall, the treatments for ANCA-associated vasculitis are currently primarily divided into the following categories. These include glucocorticoids, immunosuppressants (e.g., azathioprine, cyclophosphamide, mycophenolate mofetil), and biological agents (e.g., rituximab, mepolizumab).

[0006] 1. Glucocorticoids (GC): Glucocorticoids play a central role in the treatment of ANCA-associated vasculitis and are an essential component of initial treatment, especially in cases with renal lesions. However, glucocorticoids alone cannot induce sustained remission. In addition, glucocorticoids have a wide range of side effects, including infections, bone disease, glycemic abnormalities, obesity, hypertension, psychiatric disorders, gastrointestinal bleeding, cataracts, adrenal suppression, and a long-term risk of cardiovascular disease. Early studies using glucocorticoids in the treatment of patients with ANCA-associated vasculitis reported common adverse events including weight gain of over 10 kg (29%), newly diagnosed diabetes mellitus (8.2%), peptic ulcer disease (2.6%), fractures (2.5%), and avascular necrosis (0.4%). During long-term follow-up, cataracts (25%), diabetes mellitus (38%), osteoporosis (38%), and hypertension (41%) developed. The severity and frequency of these adverse reactions have also limited the use of glucocorticoids.

[0007] 2. Immunosuppressants: ANCA-associated vasculitis with organ damage and life-threatening signs can be treated with a combination of glucocorticoids and cyclophosphamide (CTX). While this regimen is effective in over 90% of cases, it is limited by its potential toxicity. Studies have shown that CTX is associated with a variety of serious adverse reactions, many of which occur in the early stages (e.g., bone marrow suppression, infections, hemorrhagic cystitis, and infertility), while others may develop 10 years or more after the completion of immunosuppressive therapy (e.g., malignancies).

[0008] 3. Biological Agents: Currently, three biological agents are approved for the treatment of ANCA-associated vasculitis: rituximab, mepolizumab, and avacopan. Rituximab (RTX) is a chimeric anti-CD20 monoclonal antibody. In April 2011, the U.S. FDA approved RTX as an alternative to cyclophosphamide (CTX) used in combination with glucocorticoids for the treatment of severe GPA / MPA. Although the mechanism of action of RTX in patients with ANCA-associated vasculitis is not fully understood, it can treat the disease by reducing ANCA-producing B cells and plasmablasts. In Asian or Chinese patients, infections are associated with a high incidence even when using the recommended dose. In a study of AAV patients, patients were given 375 mg / m². 2 Patients received RTX treatment, either by weekly injections of a certain dose of RTX for four weeks, or by injections of 1 g of RTX twice monthly. During follow-up, 37% of patients developed serious infections. Evidence suggests that administration of corresponding doses of RTX carries a similar risk of adverse reactions. Specifically, 50% of patients developed infections after treatment, which may be due to the use of excessively high doses (Reference 3: Liu L, Lu H, Zou G, et al. Efficacy and safety of low-dose rituximab as induction therapy for antineutrophil cytoplasmic antibody-associated vasculitis with renal involvement: a Chinese case series. BMC Nephrol. 2023 Feb 8;24(1):28).

[0009] The American College of Rheumatology (ACR) first developed management guidelines for ANCA-associated vasculitis in 2021, providing treatment guidelines for granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA) (see Figure 1), as well as guidelines for the treatment of eosinophilic granulomatosis with polyangiitis (EGPA) (see Figure 2) (Reference 2: Chung, SA, Langford, CA, Maz, M., Abril, A., Gorelik, M., Guyatt, G., …Mustafa, RA (2021). 2021 American College of Rheumatology / Vasculitis Foundation Guideline for the Management of Antineutrophil Cytoplasmic Antibody-Associated Vasculitis. Arthritis Care & Research, 73(8), 1088-1105.). [Overview of the project] [Problems that the invention aims to solve]

[0010] However, the level of evidence supporting the recommendations of the above guidelines is generally low. Further research remains essential to provide more targeted drug and disease treatment guidelines for ANCA-associated vasculitis, minimize treatment-related side effects, and prevent organ damage in patients. Therefore, both in China and globally, there remains a real unmet clinical need for the treatment of ANCA-associated vasculitis. In particular, there is a lack of safe and effective clinical treatments for patients who cannot or do not want to undergo long-term hormone therapy due to various diseases.

[0011] Belimumab is a BLyS-specific inhibitor that binds to BLyS and blocks its binding to receptors on B cells, thereby inhibiting the survival of autoreactive B cells and inducing apoptosis in more autoreactive B cells. However, according to the 2020 French Vasculitis Research Group treatment guidelines, the expert group does not recommend the use of belimumab (i.e., belimumab) for induction therapy of GPA or MPA. One study showed that belimumab did not reduce the risk of PSEs (protocol-specified events) or recurrence of vasculitis compared to placebo. The incidence of adverse events in the belimumab group was significantly higher than in the placebo group (92.5% vs. 82.7%). The risk of relapse was not reduced when belimumab was used with azathioprine and glucocorticoids to maintain remission of AAV (Reference 4: David, Jayne, Daniel, et al. Efficacy and Safety of Belimumab and Azathioprine for Maintenance of Remission in Antineutrophil Cytoplasmic Antibody-Associated Vasculitis: A Randomized Controlled Study. Arthritis & Rheumatology (Hoboken, NJ), 2019). This may be related to the expert group's recommendation against using belimumab for remission induction therapy of GPA or MPA.

[0012] Telitacicept is the first recombinant TACI-Fc fusion protein in its lineage to target B cell-associated autoimmune diseases. It can target and neutralize two major cellular signaling molecules in the B cell pathway, BlyS and APRIL. Telitacicept is an antibody-like structure fusion protein for the treatment of human autoimmune diseases, composed of cleaved TACI and immunoglobulin Fc with reduced ADCC and CDC activity after sequence optimization. It possesses excellent biological activity and safety and is currently approved for sale in China for the treatment of systemic lupus erythematosus. [Means for solving the problem]

[0013] However, the inventors were surprised to find that the TACI-Fc fusion protein exhibited excellent biological activity and safety when treating patients with ANCA-associated vasculitis, resulting in significant therapeutic effects.

[0014] In response to this, the present invention provides a method for treating or alleviating ANCA-associated vasculitis, comprising administering a therapeutically effective dose of a drug targeting BlyS and / or APRIL to a patient having ANCA-associated vasculitis.

[0015] The present invention also provides applications for BLyS and / or APRIL-targeted agents in the manufacture of pharmaceuticals for treating or alleviating ANCA-associated vasculitis in patients.

[0016] The present invention also provides the use of TACI-Fc fusion proteins in the manufacture of pharmaceuticals for treating or alleviating ANCA-associated vasculitis in patients.

[0017] The present invention also provides the use of teritacicept in the manufacture of pharmaceuticals for treating or alleviating ANCA-associated vasculitis in patients.

[0018] Furthermore, the agent targeting BLyS and / or APRIL described above is a TACI-Fc fusion protein.

[0019] Furthermore, the TACI-Fc fusion protein described in any one of the above includes (i) the extracellular domain of TACI or a fragment thereof that binds to BLyS and / or APRIL, and (ii) a human immunoglobulin constant region fragment.

[0020] Furthermore, the extracellular domain of TACI or a fragment thereof that binds to BLyS and / or APRIL includes the amino acid sequence shown in SEQ ID NO: 1, SEQ ID NO: 2, or SEQ ID NO: 3.

Number

[0021] Furthermore, the amino acid sequence of the extracellular domain of TACI or a fragment thereof that binds to BLyS and / or APRIL is as shown in SEQ ID NO: 1.

[0022] Furthermore, the human immunoglobulin is IgG1.

[0023] Furthermore, the human immunoglobulin constant region fragment includes the amino acid sequence of SEQ ID NO: 4.

[0024] Furthermore, the human immunoglobulin constant region fragment includes an amino acid sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity to SEQ ID NO: 4.

Number

[0025] Furthermore, the amino acid sequence of the human immunoglobulin constant region fragment is as shown in SEQ ID NO: 4.

[0026] Furthermore, human immunoglobulin constant region fragments contain amino acid modifications at positions 1, 2, 3, 4, 5, 6, 7, 8, or higher, compared to SEQ ID NO: 4.

[0027] Furthermore, modifications include amino acid substitutions, deletions, or insertions.

[0028] Furthermore, the substitutions include one or more of the following: P3T, L8P, L14A, L15E, G17A, A110S, P111S, and A173T.

[0029] Furthermore, the insertion is the insertion of 1, 2, 3, 4, 5, 6, 7, 8, or more amino acids at the N-terminus of a human immunoglobulin constant region fragment.

[0030] Furthermore, the insertion involves the insertion of five amino acids at the N-terminus of a human immunoglobulin constant region fragment.

[0031] Furthermore, the insertion involves the insertion of five amino acids, "EPKSS," at the N-terminus of a human immunoglobulin constant region fragment.

[0032] Furthermore, the human immunoglobulin constant region fragment contains the amino acid sequence of SEQ ID NO: 5.

number

[0033] Furthermore, the human immunoglobulin constant region fragment contains the amino acid sequence of SEQ ID NO: 6.

number

[0034] Furthermore, the TACI-Fc fusion protein has an amino acid sequence that is at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% identical to SEQ ID NO: 7.

number

[0035] Furthermore, the TACI-Fc fusion protein has the amino acid sequence shown in SEQ ID NO: 7.

[0036] Furthermore, the TACI-Fc fusion protein has the amino acid sequence shown in SEQ ID NO: 8.

number

[0037] Furthermore, the TACI-Fc fusion protein has the amino acid sequence shown in SEQ ID NO: 9.

number

[0038] Furthermore, drugs that target BLyS and / or APRIL include teritacicept, atacicept, or popetacicept.

[0039] Furthermore, the TACI-Fc fusion protein is teritacicept.

[0040] Furthermore, ANCA-associated vasculitis includes, but is not limited to, one or more of the following: granulomatosis with polyangiitis (GPA), eosinophilic granulomatosis with polyangiitis (EGPA), and microscopic polyangiitis (MPA).

[0041] In some preferred embodiments, ANCA-associated vasculitis is granulomatosis with polyangiitis; in other preferred embodiments, ANCA-associated vasculitis is eosinophilic granulomatosis with polyangiitis; in other preferred embodiments, ANCA-associated vasculitis is microscopic polyangiitis; in other preferred embodiments, ANCA-associated vasculitis is granulomatosis with polyangiitis complicated by eosinophilic granulomatosis with polyangiitis; in other preferred embodiments, ANCA-associated vasculitis is granulomatosis with polyangiitis complicated by microscopic polyangiitis; in other preferred embodiments, ANCA-associated vasculitis is eosinophilic granulomatosis with polyangiitis complicated by microscopic polyangiitis; and in other preferred embodiments, ANCA-associated vasculitis is granulomatosis with polyangiitis complicated by eosinophilic granulomatosis with microscopic polyangiitis. Clinically, the disease type of ANCA-associated vasculitis may be classified (i.e., further specified as granulomatosis with polyangiitis, eosinophilic granulomatosis with polyangiitis, microscopic polyangiitis, or a combination of two or three) or not classified (i.e., collectively referred to as ANCA-associated vasculitis). Therefore, it is important to understand that disease type should not be considered a limitation of the disease.

[0042] Furthermore, this method includes administering a therapeutically effective dose of a drug targeting BLyS and / or APRIL to patients with ANCA-associated vasculitis during the induction and / or maintenance phases of remission (the drug targeting BLyS and / or APRIL is more preferably a TACI-Fc fusion protein, and even more preferably teritacicept).

[0043] In some preferred embodiments, the method involves administering a therapeutically effective dose of a drug targeting BLyS and / or APRIL to a patient with ANCA-associated vasculitis during the remission induction phase. In other preferred embodiments, the method involves administering a therapeutically effective dose of a drug targeting BLyS and / or APRIL to a patient with ANCA-associated vasculitis during the remission maintenance phase. In other preferred embodiments, the method involves administering a therapeutically effective dose of a drug targeting BLyS and / or APRIL to a patient with ANCA-associated vasculitis during both the remission induction phase and the remission maintenance phase. The drug targeting BLyS and / or APRIL is more preferably a TACI-Fc fusion protein, and even more preferably teritacicept.

[0044] Furthermore, the patient may be an adult or a pediatric patient. In some preferred embodiments, the patient is an adult. In other preferred embodiments, the patient is a pediatric patient.

[0045] Furthermore, patients with ANCA-associated vasculitis are in the treatment phase of a newly diagnosed disease or in the treatment phase of a relapsed disease. In some preferred embodiments, patients with ANCA-associated vasculitis are in the treatment phase of a newly diagnosed disease (i.e., the patient is being diagnosed with ANCA-associated vasculitis for the first time). In other preferred embodiments, patients with ANCA-associated vasculitis are in the treatment phase of a relapsed disease. That is, the BLyS and / or APRIL-targeting agents provided by the present invention (more preferably TACI-Fc fusion protein, even more preferably teritacicept) can be applied in both the treatment phase of a newly diagnosed disease and the treatment phase of a relapsed disease.

[0046] Furthermore, patients with ANCA-associated vasculitis may be inactive, active and severe, or active and non-severe. In some preferred embodiments, patients with ANCA-associated vasculitis are inactive. In other preferred embodiments, patients are active and severe. In other preferred embodiments, patients are active and non-severe.

[0047] Furthermore, patients with ANCA-associated vasculitis often have one or more other autoimmune diseases. Autoimmune diseases (as defined by the American Association for Autoimmune Diseases) include, but are not limited to, psoriasis, Hashimoto's thyroiditis, systemic lupus erythematosus, rheumatoid arthritis, type 1 diabetes, toxic diffuse goiter, inflammatory bowel disease, celiac disease, achalasia, Addison's disease, adult-onset Still's disease, agammaglobulinemia, alopecia areata, amyloidosis, ankylosing spondylitis, anti-glomerular basement membrane nephritis, antiphospholipid syndrome, autoimmune angioedema, autoimmune autonomic ganglionopathy, autoimmune encephalomyelitis, autoimmune hepatitis, autoimmune inner ear disease, autoimmune myocarditis, autoimmune oophoritis, autoimmune orchitis, Autoimmune pancreatitis, autoimmune retinopathy, autoimmune urticaria, acute motor sensory axonal neuropathy, Barlow concentric sclerosis, Behçet's disease, benign mucosal pemphigoid, bullous pemphigoid, Castleman disease, celiac disease, Chagas disease, chronic inflammatory demyelinating polyneuropathy, chronic relapsing polymyelitis, Churg-Strauss syndrome, Cogan syndrome, cold agglutinin disease, congenital heart block, coxsackievirus myocarditis, CRESTO syndrome, Crohn's disease, herpetiform dermatitis, dermatomyositis, Devic's disease, discoid rash, Dressler's syndrome Group, endometriosis, eosinophilic esophagitis, eosinophilic fasciitis, erythema nodosum, essential mixed cryoglobulinemia, Evans syndrome, fibromyalgia, fibrotic alveolitis, giant cell arteritis, giant cell myocarditis, glomerulonephritis, Goodpasture syndrome, granulomatosis with polyangiitis, Graves' disease, Guillain-Barré syndrome, Hashimoto's thyroiditis, hemolytic anemia, Henoch-Schönlein purpura, herpes zoster of pregnancy or bullous pemphigoid of pregnancy, hidradenitis suppurativa, hypogammaglobulinemia, IgA nephropathy, IgG4-related sclerosing disease, immune thrombocytopenic purpura Diseases, inclusion body myositis, interstitial cystitis, juvenile arthritis, juvenile myositis, Kawasaki disease, Lambert-Eaton syndrome, leukocytoclastic vasculitis, lichen planus, sclerosing atrophic lichen, woody conjunctivitis, linear IgA disease, chronic Lyme disease, Meniere's disease, microscopic polyangiitis, mixed connective tissue disease, Mohren's ulcer, Mukka-Habermann disease, multifocal motor neuropathy, multiple sclerosis, myasthenia gravis, myositis, narcolepsy, neonatal lupus, neutropenia, ocular pemphigoid, optic neuritis, relapsing rheumatoid arthritis, PANDAS, paraneoplastic cerebellar degeneration,Paroxysmal nocturnal hemoglobinuria, Parry-Romberg syndrome, ciliary body squamous cellulitis, Personage-Turner syndrome, pemphigus, peripheral neuropathy, perivenous encephalomyelitis, pernicious anemia, POEMS syndrome, polyarteritis nodosa, polymyositis type I, II, III, polymyalgia rheumatica, polymyositis, post-myocardial infarction syndrome, post-pericardiotomy syndrome, primary biliary cholangitis, primary sclerosing cholangitis, progesterone dermatitis, psoriatic arthritis, pure red cell aplasia, pyoderma gangrenosum, Raynaud's phenomenon, reactive arthritis, reflex sympathetic dysentery These include strophy, relapsing polychondritis, restless legs syndrome, retroperitoneal fibrosis, rheumatic fever, sarcoidosis, Schmidt syndrome, scleritis, scleroderma, Sjögren's syndrome, sperm and testicular autoimmunity, stiff-person syndrome, subacute bacterial endocarditis, Suzac syndrome, sympathetic ophthalmitis, Takayasu's arteritis, temporal arteritis, thyroid eye disease, Tolosa-Hunt syndrome, ulcerative colitis, undifferentiated connective tissue disease, uveitis, vasculitis, vitiligo, Vogt-Koyanagi-Harada disease, and antibody-type autoimmune hemolytic anemia.

[0048] Furthermore, patients with ANCA-associated vasculitis have lesions in one or more of the following: the lungs, and / or the kidneys, and / or the gastrointestinal tract, and / or the nervous system, and / or the eyes, ears, nose and throat, and / or the general musculoskeletal system, and / or the serosal membranes, and / or the hematological system, and / or other tissues or organs.

[0049] Furthermore, the patient has not previously received any treatment regimen for ANCA-associated vasculitis.

[0050] Furthermore, the patient has previously received treatment regimens for ANCA-associated vasculitis.

[0051] Furthermore, treatment regimens for ANCA-associated vasculitis include, but are not limited to, one or more of the following: glucocorticoid treatment regimens, immunosuppressant treatment regimens, biological agent treatment regimens, and plasmapheresis.

[0052] In some preferred embodiments, the patient has previously received a treatment regimen for ANCA-associated vasculitis, which is a glucocorticoid treatment regimen, an immunosuppressant treatment regimen, a biological agent treatment regimen, plasma exchange, a regimen of glucocorticoids + immunosuppressants, a regimen of glucocorticoids + biological agents, a regimen of glucocorticoids + plasma exchange, a regimen of immunosuppressants + biological agents, a regimen of immunosuppressants + plasma exchange, a regimen of biological agents + plasma exchange, a regimen of glucocorticoids + immunosuppressants + biological agents, a regimen of glucocorticoids + immunosuppressants + plasma exchange, a regimen of immunosuppressants + biological agents + plasma exchange, or a regimen of glucocorticoids + immunosuppressants + biological agents + plasma exchange.

[0053] Furthermore, this method involves administering a therapeutically effective dose of a drug targeting BlyS and / or APRIL to patients with ANCA-associated vasculitis while one or more of the following are being administered in combination: glucocorticoids, immunosuppressants, biological agents, and plasmapheresis.

[0054] In some preferred embodiments, the method involves administering a therapeutically effective dose of a BLyS and / or APRIL-targeting agent to a patient with ANCA-associated vasculitis. In other preferred embodiments, the method involves administering a combination of a BLyS and / or APRIL-targeting agent, a glucocorticoid, and an immunosuppressant to a patient with ANCA-associated vasculitis, or a combination of a BLyS and / or APRIL-targeting agent, a glucocorticoid, and a biological agent, or a combination of a BLyS and / or APRIL-targeting agent and a glucocorticoid, along with plasmapheresis, or a combination of a BLyS and / or APRIL-targeting agent, an immunosuppressant, and a biological agent, or a combination of a BLyS and / or APRIL-targeting agent and an immunosuppressant This includes administering a combination of the above, along with plasma exchange, or administering a combination of a BLyS and / or APRIL-targeting agent and a biological agent, along with plasma exchange, or administering a combination of a BLyS and / or APRIL-targeting agent, a glucocorticoid, an immunosuppressant, and a biological agent, or administering a combination of a BLyS and / or APRIL-targeting agent, a glucocorticoid, an immunosuppressant, and a biological agent, along with plasma exchange, or administering a combination of a BLyS and / or APRIL-targeting agent, an immunosuppressant, and a biological agent, along with plasma exchange. Preferably, the application of the combination includes simultaneous administration or stepwise administration.

[0055] Preferably, the biological agents described in the present invention include, but are not limited to, rituximab, mepolizumab, avacopan, belimumab, etanercept, benralizumab, depemokimab, abatacept, obinutuzumab, alemtuzumab, tocilizumab, and birobelimab.

[0056] Furthermore, the single-dose dose of drugs targeting BlyS and / or APRIL is approximately 0.1–10 mg / kg, 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 It also contains 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8.0, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9.0, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9, and 10 mg / kg.

[0057] Furthermore, the single dose of a drug targeting BLyS and / or APRIL is 40 to 240 mg, more preferably including 40 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 110 mg, 120 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg, 210 mg, 220 mg, 230 mg, and 240 mg.

[0058] Furthermore, the method for detecting the protein content of the above-mentioned drug is ultraviolet-visible spectrophotometry. This method measures the absorbance value of the teritacicept sample at a wavelength of 280 nm, based on the fact that proteins exhibit maximum ultraviolet absorption at this wavelength. After correcting for the absorbance at 320 nm, the obtained absorbance value at 280 nm is proportional to the protein concentration. The protein concentration is calculated according to the Lambert-Beer law, thereby determining the protein content. The formula for calculating the protein content is as follows:

number

[0059] Furthermore, drugs targeting BLyS and / or APRIL are administered 1 to 8 times between each 1-month interval. That is, the frequency of TACI-Fc fusion protein administration is 1, 2, 3, 4, 5, 6, 7, or 8 times per month.

[0060] Furthermore, drugs targeting BLyS and / or APRIL are administered 1 to 8 times between each 2-month interval. That is, the frequency of TACI-Fc fusion protein administration is 1, 2, 3, 4, 5, 6, 7, or 8 times every 2 months.

[0061] Furthermore, drugs targeting BLyS and / or APRIL are administered 1 to 8 times between each 3-month interval. That is, the frequency of TACI-Fc fusion protein administration is 1, 2, 3, 4, 5, 6, 7, or 8 times every 3 months.

[0062] Furthermore, the administration frequency of drugs targeting BLyS and / or APRIL is once, twice, or three times per week.

[0063] Furthermore, the frequency of administration of drugs targeting BLyS and / or APRIL is once every two weeks, once every three weeks, or once a month.

[0064] Furthermore, the frequency of administration of drugs targeting BLyS and / or APRIL is determined on an as-needed basis.

[0065] Furthermore, the administration of drugs targeting BlyS and / or APRIL includes continuous and / or intermittent administration.

[0066] Furthermore, the administration of drugs targeting BlyS and / or APRIL involves administering them at regular intervals.

[0067] Furthermore, the administration of drugs targeting BlyS and / or APRIL involves administration at irregular intervals.

[0068] Furthermore, the administration methods for drugs targeting BLyS and / or APRIL include subcutaneous, intramuscular, or intravenous administration, with the administration site preferably being the thigh, abdomen, or upper arm. In some specific embodiments, the administration methods for TACI-Fc fusion proteins include subcutaneous, intramuscular, or intravenous injection.

[0069] Furthermore, the injection sites for each injection of a drug targeting BLyS and / or APRIL are either identical or different. In some specific embodiments, the injection sites for each injection of the TACI-Fc fusion protein are identical, while in other specific embodiments, the injection sites for each injection of the TACI-Fc fusion protein are different.

[0070] The present invention also provides a method for treating a patient with ANCA-associated vasculitis who has previously received a treatment regimen for ANCA-associated vasculitis, the method comprising: (1) determining whether the patient has previously received a treatment regimen for ANCA-associated vasculitis; and (2) if the patient has previously received treatment for ANCA-associated vasculitis, administering to the patient an effective amount of a drug that targets BlyS and / or APRIL and is further a TACI-Fc fusion protein.

[0071] The BLyS and / or APRIL-targeting agents provided by the present invention demonstrate unexpected clinical efficacy and favorable safety in the treatment of ANCA-associated vasculitis. Specifically, when the BLyS and / or APRIL-targeting agents provided by the present invention (such as teritacicept) are applied to patients with ANCA-associated vasculitis, they demonstrate better safety and superior therapeutic efficacy compared to existing treatment regimens / methods. Specifically, for patients with ANCA-associated vasculitis, the BLyS and / or APRIL-targeting agents provided by the present invention (such as teritacicept) show favorable therapeutic prospects in both the induction and maintenance phases. Furthermore, even after the patient has achieved remission, continued administration of the BLyS and / or APRIL-targeting agents provided by the present invention (such as teritacicept) can further improve the patient's condition and demonstrate remarkable efficacy. In patients who have not responded to treatment with glucocorticoids, and / or glucocorticoids plus immunosuppressants, and / or glucocorticoids plus immunosuppressants plus biological agents (such as rituximab), or in patients who have experienced repeated relapses after treatment, the BlyS and / or APRIL-targeting agents provided by the present invention (such as teritacicept) also show a favorable therapeutic outlook. In patients with ANCA-associated vasculitis who also have one or more other autoimmune diseases (including, but not limited to, Sjögren's syndrome, systemic lupus erythematosus, nephrotic syndrome, and lupus nephritis), the BlyS and / or APRIL-targeting agents provided by the present invention (such as teritacicept) also show a favorable therapeutic outlook. The BLyS and / or APRIL-targeting agents provided by the present invention (such as teritacicept) exhibit better safety and superior therapeutic efficacy compared to glucocorticoids and / or immunosuppressants, particularly in patients with severe ANCA-associated vasculitis. For patients with a long history of the disease and who experience repeated relapses after treatment, the BLyS and / or APRIL-targeting agents provided by the present invention (such as teritacicept) show promising therapeutic potential.In patients with severe ANCA-associated vasculitis and severe renal impairment, the BLyS and / or APRIL-targeting agents provided by the present invention (such as teritacicept) exhibit good therapeutic efficacy while also demonstrating good safety. [Brief explanation of the drawing]

[0072] [Figure 1] This document presents treatment guidelines for granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA). [Figure 2] This document presents treatment guidelines for eosinophilic granulomatosis with polyangiitis (EGPA). [Figure 3] This shows the changes in the patient's serum creatinine level in Case 1 of Example 1. [Modes for carrying out the invention]

[0073] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those generally understood by those skilled in the art to which this invention pertains. For definitions and terms in the art, experts can specifically refer to Current Protocols in Molecular Biology (Ausubel).

[0074] The three-letter and one-letter abbreviations for amino acids used in this invention are as described in J. Biol. Chem., 243, p. 3558 (1968).

[0075] In this invention, the term "TACI" refers to a transmembrane activator and a CAML interactor, which are members of the tumor necrosis factor receptor superfamily. In this invention, the term "BLyS" refers to a B lymphocyte stimulator, which is a member of the TNF ligand superfamily that exists in two forms: membrane-bound and soluble. It is specifically expressed on the surface of bone marrow cells and selectively stimulates B lymphocyte proliferation and immunoglobulin production. In this invention, the term "APRIL" (proliferation-inducing ligand) refers to a tumor necrosis factor (TNF) analog that can stimulate the proliferation of naive B cells and naive T cells in the body, promote B cell accumulation, and increase spleen content. APRIL can specifically bind to TACI and BCMA, and upon binding, it can prevent APRIL from binding to B cells and inhibit the APRIL-stimulated proliferation response of naive B cells. Furthermore, APRIL can compete with BlyS in binding to its receptors (BCMA, TACI).

[0076] As used in this invention, the term "TACI-Fc fusion protein" refers to a transmembrane activator and calcium regulator and cyclophylline ligand interacting factor (TACI)-immunoglobulin fusion protein (i.e., TACI-Fc fusion protein). The TACI-immunoglobulin fusion protein provided by this invention includes (i) the extracellular domain or fragment of TACI that binds to BLyS and / or APRIL, and (ii) a human immunoglobulin constant region fragment.

[0077] In the present invention, the term "extracellular domain or fragment of TACI that binds to BLyS and / or APRIL" includes 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 Nos. 09 / 569,245 and 09 / 627,206 (the contents of which are incorporated herein by reference), specific fragments of the extracellular domain of TACI that can interact with TACI ligands, and amino acid fragments at positions 13-118 of the extracellular domain of TACI disclosed in Chinese Patent Publication No. CN101323643A.

[0078] Examples of "TACI-Fc fusion proteins" include teritacicept (amino acid sequence: SEQ ID NO: 7), atacicept (amino acid sequence: SEQ ID NO: 8), and pobetacicept (amino acid sequence: SEQ ID NO: 9).

[0079] In the term "human immunoglobulin constant region fragment" as used in the present invention, the immunoglobulin portion is preferably IgG1 and may include a heavy chain constant region such as the human heavy chain constant region. A preferred "human immunoglobulin constant region fragment" of the present invention is an amino acid fragment containing a partial hinge region domain, a CH2 domain, and a CH3 domain. In some more preferred embodiments, the amino acid sequence of the "human immunoglobulin constant region fragment" described in the present invention is as shown in SEQ ID NO: 4, or includes an amino acid sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO: 4. In some more preferred embodiments, the amino acid sequence of the "human immunoglobulin constant region fragment" is as shown in SEQ ID NO: 5.

[0080] As used in this invention, the term "treatment" includes, but is not limited to, inhibiting a disease or condition (e.g., halting the progression of the disease or condition), alleviating a disease or condition (e.g., causing a reduction in the disease or condition), alleviating symptoms caused by a disease or condition (e.g., alleviating, preventing, or treating the symptoms of the disease or condition), or reducing the likelihood of a disease recurrence or preventing a disease recurrence.

[0081] As used in this invention, the term "remission" refers to the absence of clinical symptoms or signs associated with GPA, MPA, or EGPA at the start or end of treatment.

[0082] As used in this invention, the term "amino acid" is understood in its broadest sense and generally refers to a group of organic compounds containing an amino group and a carboxyl group. Preferably, the amino acids involved 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.

[0083] The three-letter and one-letter notations for amino acids used in this invention are as described in J. Biol. Chem., 243, p. 3558 (1968). Various numbering systems exist for amino acid positions, including the Kabat numbering system, the EU numbering system, and sequential numbering. In this invention, the "sequential numbering" system is adopted for amino acid positions. For example, as described in this invention, "positions 3, 8, 14, 15, 17, 110, 111, or 173 of SEQ ID NO: 4" refers to the 3rd, 8th, or 173rd amino acids of SEQ ID NO: 4, and as described in this invention, "P3T" refers to the mutation of the amino acid at position 3 of SEQ ID NO: 4 from the original "P" to "T", and "L8P" refers to the mutation of the amino acid at position 8 of SEQ ID NO: 4 from the original "L" to "P", and so on.

[0084] As an optional embodiment, the constant region of the immunoglobulin provided by 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).

[0085] In this invention, the term "teritacicept" (also referred to as "Tai'ai" as used synonymously in this invention) refers to a TACI-Fc fusion protein whose International Generic Name (INN) is teritacicept, and whose amino acid sequence is as shown in SEQ ID NO: 7, or see https: / / extranet.who.int / soinn / mod / page / view.php?id=137&inn_n=10932.

[0086] The TACI-Fc fusion protein of the present invention can be administered via any of a variety of routes, including, but not limited to, oral, intravenous, intramuscular, intra-arterial, intra-bone marrow, intraperitoneal, intrathecal, intracerebral, transdermal absorption, transdermal mediation, local, subcutaneous, intranasal, enteral, sublingual, vaginal, or rectal routes.

[0087] In the present invention, the term "ANCA-associated vasculitis," i.e., anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV), refers to vasculitis characterized by necrotizing inflammation, and includes microscopic polyangiitis (MPA), granulomatosis with polyangiitis (GPA), and eosinophilic granulomatosis with polyangiitis (EGPA).

[0088] In this invention, the term "microscopic polyangiitis" is also known as microscopic polyarteritis, and is a systemic necrotizing vasculitis without immunoglobulin deposition (hypoimmunodeposition), in which the vasculitis primarily affects small blood vessels, including veins. This disease may present as pulmonary-renal syndrome, which manifests as rapidly progressive glomerulonephritis and alveolar hemorrhage, but the disease type depends on the affected organ.

[0089] In this invention, the term "granulomatosis with polyangiitis" refers to the necrotizing granulomatous vasculitis and autoimmune disease previously known as Wegener's granulomatosis (WG). The lesions of this disease affect the arterioles, veins, and capillaries, and in some cases, the aorta as well. The pathogenesis is characterized by inflammation of the vascular walls, primarily affecting the upper and lower respiratory tracts and the kidneys. It usually begins with localized granulomatous inflammation of the nasal mucosa and lung tissue, and then progresses to diffuse necrotizing granulomatous inflammation of the blood vessels. Clinically, it often presents as rhinitis and sinusitis, pulmonary lesions, and progressive renal failure. It can also affect the joints, eyes, and skin, and further, the eyes, heart, nervous system, and ears, etc.

[0090] In this invention, the term "eosinophilic granulomatosis with polyangiitis" refers to a primary systemic autoimmune vasculitis, also known as Churg-Strauss syndrome (CSS), characterized by a triad of pathological features: tissue eosinophilia, granulomatous inflammation, and vasculitis. This type of vasculitis is often accompanied by asthma and eosinophilia. Patients may have perinuclear anti-neutrophil cytoplasmic antibodies against myeloperoxidase. Such autoantibodies are more common in patients with pronounced vasculitis, such as those with glomerulonephritis.

[0091] In this invention, the term "biological drug therapy regimen" is generally used for the treatment of patients who have not responded to conventional treatment, patients with glucocorticoid resistance or intolerance, patients who have relapsed during glucocorticoid tapering, patients with refractory diseases, or patients with severe diseases. Currently, exemplary promising biological targeted therapies include the following: (1) B-cell depletion therapy: For example, anti-CD20 monoclonal antibodies, anti-CD19 monoclonal antibodies, B lymphocyte activator (BAFF) inhibitors, etc., but not limited to these. (2) Therapies that target T lymphocytes: for example, abatacept, signaling lymphocyte activator family 7 (SLAMF7) monoclonal antibodies, inducible costimulatory ligand (ICOSL) inhibitors, and others. (3) Cytokine-targeted therapies (targeting IL-4, IL-5, and TNF-α) and Janus kinase (JAK) inhibitors that target intracellular signaling pathways, etc.

[0092] As used in this invention, the terms “inactive phase / active phase” refer to the presence of novel, persistent, or worsening clinical symptoms and / or signs associated with GPA, MPA, or EGPA.

[0093] The term "glucocorticoid" as used in this invention refers to regulatory molecules that play a crucial role in bodily development, growth, metabolism, and immune function. They are the most important regulatory hormones for the body's stress response and are also the most widely used and effective anti-inflammatory agents in clinical practice. Preferably, the glucocorticoids involved in this invention include, but are not limited to, prednisone, prednisolone, methylprednisolone, betamethasone, beclomethasone propionate, hydrocortisone, and dexamethasone.

[0094] The term "immunosuppressant" as used in this invention refers to a drug that inhibits the body's immune response. It can inhibit the proliferation and function of cells involved in the immune response (such as macrophages, including T cells and B cells), and is also known as conventional synthetic disease-modifying antirheumatic drugs (cDMARDs). Preferably, immunosuppressants described in this invention include, but are not limited to, mycophenolate mofetil, azathioprine, methotrexate, leflunomide, cyclophosphamide, cyclosporine, tacrolimus, iguratimod, thalidomide, and other drugs that inhibit the body's immune response.

[0095] In this invention, the term "severe illness" refers to the presence of life-threatening symptoms or organ-related symptoms (e.g., alveolar hemorrhage, glomerulonephritis, central nervous system vasculitis, etc.).

[0096] In this invention, the term "approximately" is used to indicate that a value includes error variability inherent in the apparatus or method used to determine the value, or variability present between the tested samples. Unless otherwise stated or clearly indicated in the context, the term "approximately" means within 10 percent above or below the reported value (except where such a number would be greater than 100% of the possible value or less than 0%). When used with a numerical range or sequence, the term "approximately" applies to both ends of the range or to each number listed in the sequence, unless otherwise stated. [Examples]

[0097] Embodiments of the present invention will be described in detail below with reference to examples, but those skilled in the art will understand that the following examples are provided solely to illustrate the present invention and should not be construed as limiting the scope of the invention.

[0098] Example 1: Treatment effect in an actual case [Case 1] One patient experienced sudden abdominal pain, cough with sputum, and intermittent hemoptysis of no apparent cause. Based on multiple indicators, the patient was clinically diagnosed with ANCA-associated vasculitis (complicated by pulmonary and renal impairment). The patient had a history of multiple intramural aortic hematomas and, due to pulmonary lesions, lymphocyte count, and other factors, was unable to tolerate cyclophosphamide pulse therapy.

[0099] Following treatment with a glucocorticoid (methylprednisolone sodium succinate for injection, 250 mg), an immunosuppressant (cyclophosphamide, 0.4 g), and teritacicept (160 mg subcutaneously once weekly), cough and sputum significantly improved, and no hemoptysis was observed. Subsequently, the patient received renal replacement therapy and had a peritoneal dialysis catheter inserted. Subsequently, the patient continued treatment with the glucocorticoid prednisone (25 mg / day), intermittent teritacicept therapy, peritoneal dialysis, and treatment for complications of chronic kidney disease, and most indicators and signs recovered.

[0100] This patient received treatment with low-dose cyclophosphamide in combination with glucocorticoids and teritacicept, and the clinical symptoms of hemoptysis significantly improved. As shown in Figure 3, serum creatinine levels tended to stabilize after treatment, and renal function remained relatively stable. The results were as follows: 1. In patients with severe ANCA-associated vasculitis, teritacicept is safer than cyclophosphamide and can alleviate pulmonary symptoms. In other words, teritacicept shows better safety than cyclophosphamide. 2. For patients who cannot tolerate cyclophosphamide, teritacicept shows better therapeutic efficacy.

[0101] [Case 2] One patient had a 10-year medical history and, based on multiple indicators, was further diagnosed with microscopic polyangiitis (affecting the lungs and kidneys) complicated by Sjögren's syndrome.

[0102] The patient had previously achieved remission with glucocorticoid (methylprednisolone injection, prednisone) treatment, but had relapsed. Subsequently, the patient was treated with glucocorticoid (methylprednisolone) + immunosuppressant (cyclophosphamide), but symptoms did not improve, and fever and cough with sputum persisted. In the latter period, re-examination showed elevated inflammatory markers again, and MPA was not controlled. Subsequently, the treatment regimen was adjusted to "glucocorticoid (methylprednisolone powder for injection) + immunosuppressant (cyclophosphamide) + teritacicept (80 mg, once weekly)." Following treatment, the patient's clinical symptoms of fever, cough with sputum, and malaise were alleviated, pulmonary symptoms were relieved, renal function was relatively stable, myeloperoxidase (MPO) antibody levels decreased, ferritin levels decreased, and erythrocyte sedimentation rate (ESR) decreased.

[0103] Following treatment with low-dose cyclophosphamide in combination with glucocorticoids and teritacicept, the patient's pulmonary symptoms were alleviated, renal function stabilized relatively well, and pANCA antibody levels and abnormal B cells gradually returned to normal. The results were as follows: 1. In patients with microscopic polyangiitis (MPA), teritacicept induction therapy is highly effective. 2. Compared to glucocorticoids and glucocorticoids + immunosuppressants, the glucocorticoid + immunosuppressant + teritacicept treatment regimen exhibits better therapeutic efficacy. 3. In patients with ANCA-associated vasculitis who also have other autoimmune diseases (such as Sjögren's syndrome), teritacicept shows promising therapeutic potential. 4. Teritacicept shows promising therapeutic potential in patients with a long medical history and who have experienced relapse after treatment.

[0104] [Case 3] One patient was first clinically diagnosed with ANCA-associated vasculitis and ANCA-associated glomerulonephritis (with extremely high-risk hypertension, interstitial pneumonia, and pulmonary infection) based on multiple indicators.

[0105] During the induction phase of remission, hormone therapy plus CTX treatment was employed. Specifically, pulse therapy with methylprednisolone 500 mg was administered for 3 days, then gradually reduced to 40 mg qd, and further reduced to 32 mg qd. During the treatment cycle, pulse therapy with cyclophosphamide 0.4 g was administered separately, and the cumulative dose of CTX was 3.2 g. During the maintenance phase of remission, hormone therapy plus teritacicept treatment was employed. Specifically, glucocorticoid (methylprednisolone tablets) + teritacicept (160 mg / dose, once a week, for 4 consecutive weeks).

[0106] Subsequently, the patient discontinued medication for three months due to COVID-19 infection, after which MPO antibodies rebounded. Afterward, treatment was resumed with glucocorticoids (methylprednisolone tablets) + teritacicept (160 mg / dose, once weekly, for two consecutive weeks), and MPO antibodies remained stably controlled.

[0107] The results were as follows: 1. This patient was newly diagnosed with ANCA-associated vasculitis. Following standard induction therapy (hormonetric + cyclophosphamide) and maintenance therapy (hormonetric + teritacicept), MPO levels were further reduced, renal function stabilized, and progression of renal impairment was avoided. This indicates that the use of a hormonetric + teritacicept regimen during the maintenance phase has a significant effect in reducing autoantibody levels and preventing progression of renal function in ANCA patients. 2. The patient discontinued medication for three months during maintenance treatment due to a COVID-19 infection, and their MPO levels increased. The addition of teritacicept reduced the MPO levels. This suggests that in patients with relapsed disease, the use of hormones plus teritacicept contributes to limiting ANCA activity and is expected to achieve the goal of seroconversion to negative autoantibodies.

[0108] [Case 4] One patient was clinically diagnosed with ANCA-associated vasculitis complicated by renal impairment, based on multiple indicators. In the initial stages, standard diagnosis and treatment with glucocorticoids (prednisone) and immunosuppressants (CellCept, i.e., mycophenolate mofetil) was administered for seven years, but the response was unsatisfactory, and ANCA remained persistently positive.

[0109] Subsequently, the patient received treatment with a glucocorticoid (prednisone), an immunosuppressant (CellCept), and rituximab (Mabsela, 100 mg / dose). After one year, B-cell depletion was achieved, but ANCA never became negative, and a decline in renal function began to appear, accompanied by persistent proteinuria.

[0110] Subsequently, the patient was treated with a hormone (methylprednisolone) + immunosuppressant (cyclophosphamide) + teritacicept, with additional anti-infective, hypotensive, renal protection, calcium supplementation, gastric protection, and other symptomatic therapies. The patient did not experience any apparent discomfort after the use of the hormone and cyclophosphamide. Throughout the entire treatment period, teritacicept was administered nine consecutive times at intervals (160 mg / dose), with varying intervals between doses. During this period, CD19+ B cell levels remained low, MPO remained stable, and renal function remained relatively stable. Six months after discontinuation of the medication, CD19+ B cell levels recovered to normal levels, MPO significantly increased, and renal function declined. After a subsequent single dose of teritacicept, CD19+ B cell levels decreased, MPO significantly decreased, and renal function improved. Relevant laboratory data are shown in Table 1. [Table 1]

[0111] The results were as follows: 1. Teritacicept shows promising therapeutic potential in patients with a long medical history and poor response to multiple treatment regimens. 2. For patients who do not respond satisfactorily to hormone therapy plus immunosuppressant therapy (e.g., ANCA never becomes negative), teritacicept shows promising therapeutic potential. 3. For patients whose ANCA test remained positive after rituximab treatment, teritacicept shows promising therapeutic potential. 4. In patients whose renal function deteriorated after rituximab treatment, teritacicept showed better safety. 5. In patients with refractory ANCA-associated vasculitis, continued use of teritacicept results in a significant B-cell depletion effect. 6. Continued use of teritacicept is expected to contribute to limiting ANCA activity and achieve the goal of seroconversion to negative autoantibodies. 7. Continued use of teritacicept is expected to slow the progression of renal function in patients with ANCA-associated glomerulonephritis.

[0112] [Case 5] One patient was hospitalized with fever and proteinuria of no apparent cause. Based on multiple indicators, the patient was clinically diagnosed as ANCA-positive with proliferative systemic lupus erythematosus nephritis. The patient had a history of relapse following treatment with a glucocorticoid (prednisolone acetate) and an immunosuppressant (mycophenolate mofetil dispersible tablets).

[0113] Subsequently, after treatment with hormone therapy + MMF and other symptomatic therapies (anti-inflammatory, hypotensive), renal function was generally stable, with urinary protein of 500-750 mg / day and urinary red blood cell count of 20-25 / hpf. The treatment regimen was then adjusted to hormone therapy + MMF + teritacicept (initial dose: 160 mg qw, adjusted to 80 mg qw after 5 months of treatment). After treatment, urinary red blood cell count remained below 10 / hpf, and renal function remained stable.

[0114] The results were as follows: 1. In patients with ANCA who also have other autoimmune diseases (such as proliferative systemic lupus erythematosus nephritis), concomitant use of teritacicept resulted in urinary red blood cell counts remaining below 10 / hpf and stable renal function. This indicates that teritacicept shows promising therapeutic potential in patients with ANCA who also have other autoimmune diseases. 2. After achieving remission, the application of teritacicept can further improve the patient's condition.

[0115] [Case 6] One patient was clinically diagnosed with ANCA-associated glomerulonephritis (renal injury) complicated by systemic lupus erythematosus, nephrotic syndrome, lupus nephritis, and acute renal failure, based on multiple indicators.

[0116] The first treatment regimen adopted was a glucocorticoid plus immunosuppressant, namely methylprednisolone 500 mg x 3 days, with an initial dose of hydroxychloroquine 200 mg bid + methylprednisolone 40 mg, combined with cyclophosphamide pulse therapy. Subsequently, due to a significant increase in serum creatinine in the patient, accompanied by electrolyte and acid-base imbalances, and significant gastrointestinal symptoms, continuous hemodialysis was administered for 3 days during the treatment period. After that, the administration regimen was adjusted to a glucocorticoid (methylprednisolone tablets, 40 mg qd) + teritacicept (160 mg subcutaneous injection) and other symptomatic regimens (hydroxychloroquine sulfate tablets 200 mg bid), combined with renal replacement therapy (peritoneal dialysis catheter placement) and intermittent cyclophosphamide pulse therapy. Following treatment, re-examination showed no lupus activity in the patient, and creatinine levels were significantly lower than before. Subsequently, the patient continued treatment with glucocorticoids + hydroxychloroquine + intermittent cyclophosphamide + teritacicept.

[0117] Following treatment with cyclophosphamide in combination with glucocorticoids, hydroxychloroquine, and teritacicept, the patient's clinical symptoms significantly improved, renal function stabilized relatively, and dialysis treatment was discontinued. The results were as follows: 1. In patients with severe ANCA-associated vasculitis who have multiple co-occurring autoimmune diseases (such as systemic lupus erythematosus, nephrotic syndrome, and lupus nephritis), teritacicept may still show promising therapeutic potential. 2. In patients with severe ANCA-associated vasculitis and severe renal impairment, teritacicept demonstrates good therapeutic efficacy while also showing good safety.

[0118] [Case 7] One patient was clinically diagnosed with ANCA-associated vasculitis (gastrointestinal vasculitis, vasculitic nephropathy), with complications of hypertension, diabetes, and hyperlipidemia, and had a medical history of 9 years. The patient received successive treatments with glucocorticoids (prednisone), glucocorticoids (prednisone) + immunosuppressant (cyclophosphamide), and glucocorticoids (methylprednisolone) + immunosuppressant (cyclophosphamide) + rituximab, and experienced several relapses.

[0119] Subsequently, the patient received standard hormone therapy (prednisone acetate 7.5 mg once daily) plus intermittent teritacicept (160 mg subcutaneous injection once weekly) and conventional blood pressure and blood glucose management. After three months, both erythrocyte sedimentation rate and C-reactive protein levels returned to normal, and the patient's condition improved.

[0120] The results were as follows: 1. In patients who continued to experience recurrent relapses after treatment with glucocorticoids, glucocorticoids + immunosuppressants, or glucocorticoids + immunosuppressants + rituximab, both erythrocyte sedimentation rate and C-reactive protein levels returned to normal after teritacicept treatment, and the patients' condition was alleviated. 2. In patients with ANCA-associated vasculitis who have a long medical history and still experience recurrent attacks after multiple regimens, teritacicept shows a favorable therapeutic outlook.

[0121] [Case 8] One patient was clinically diagnosed with ANCA-associated vasculitis complicated by systemic lupus erythematosus (affecting the blood system, kidneys, lungs, serosal membranes, eyes, and muscles), based on multiple indicators.

[0122] The patient was treated with hormones, immunosuppressants, and teritacicept. Specifically, methylprednisolone (500 mg on days 1-5, 80 mg on days 6-15, and 40 mg on days 16-29) was used for anti-inflammatory purposes, cyclophosphamide (0.1 g on day 4, 0.2 g on day 7, 0.2 g on day 10, 0.2 g on day 21, and 0.2 g on day 29, totaling 0.9 g) was used for immunomodulation, teritacicept 160 mg was administered subcutaneously once a week for a total of three times (on days 15, 22, and 29), plasmapheresis was performed four times (on days 2, 4, 7, and 10), meropenem was used for anti-infection purposes, and blood transfusions, potassium supplementation, diuretics, and other symptomatic treatments were administered to improve anemia. After discharge, the patient was prescribed prednisone 50 mg / 10 tablets once daily and teritacicept 160 mg subcutaneously once weekly.

[0123] The results showed the following: In ANCA patients with concomitant autoimmune diseases (such as systemic lupus erythematosus nephritis affecting the blood system, kidneys, lungs, serosal membranes, eyes, and muscles), clinical symptoms significantly improved and renal function remained relatively stable after treatment with glucocorticoids + immunosuppressants + teritacicept. This indicates that teritacicept has good therapeutic potential in ANCA patients with concomitant autoimmune diseases.

[0124] [Case 9] One patient was clinically diagnosed with ANCA-associated vasculitis based on multiple indicators. This patient had previously received postoperative treatment with hormones (methylprednisolone), hormones (prednisone) + immunosuppressant (mycophenolate mofetil capsules), and hormones (prednisone) + immunosuppressant (cyclophosphamide and mycophenolate mofetil capsules), and experienced multiple relapses during the hormone tapering process.

[0125] Subsequently, clinical symptoms significantly improved after treatment with hormone therapy (prednisone), immunosuppressant (cyclophosphamide), and teritacicept (160 mg, once weekly).

[0126] The results were as follows: 1. In patients with ANCA-associated vasculitis who still experience recurrent attacks after treatment with glucocorticoids or glucocorticoids plus immunosuppressants, teritacicept can offer a favorable therapeutic outlook. 2. Teritacicept is highly effective in patients with recurrent ANCA-associated vasculitis.

[0127] [Case 10] One patient was clinically diagnosed with ANCA-associated glomerulonephritis based on multiple indicators, and also had nephrotic syndrome, chronic renal failure, and stage 3 chronic kidney disease.

[0128] Following initial treatment with methylprednisolone, prednisone, and plasmapheresis, the patient was unable to tolerate post-hormone therapy nausea, vomiting, and palpitations. The hormones were gradually tapered off and discontinued, leading to a relapse.

[0129] The second course of treatment consisted of cyclophosphamide plus mycophenolate mofetil, and cyclophosphamide was later discontinued due to cellular immunodeficiency.

[0130] The third course of treatment consisted of teritacicept (160 mg, subcutaneous injection, once weekly) plus mycophenolate mofetil. Subsequently, mycophenolate mofetil was discontinued due to cellular immunodeficiency. The patient continued to receive teritacicept, and the frequency of administration was adjusted based on clinical indicators.

[0131] Following treatment, the patient's serum creatinine, a key renal indicator, remained stable and decreased compared to the initial hospitalization. No further progression of renal failure was observed, and nephropathy was effectively alleviated. The patient progressed from massive proteinuria to moderate proteinuria, with a more than 80% reduction in urinary protein and an increase in serum albumin to within the normal range.

[0132] The results were as follows: 1. For patients with ANCA-associated vasculitis who cannot tolerate hormone therapy plus cyclophosphamide, teritacicept can be used as an ideal alternative treatment regimen, offering comparable efficacy, a lower risk of infection, and fewer adverse events compared to hormone therapy plus cyclophosphamide. 2. Teritacicept exhibits superior safety and lower toxicity and side effects compared to hormones and immunosuppressants.

[0133] In summary, compared to existing treatment regimens / methods, teritacicept demonstrates better safety and superior therapeutic efficacy in patients with ANCA-associated vasculitis. Specifically, teritacicept shows a favorable therapeutic outlook in patients with ANCA-associated vasculitis in both the induction and maintenance phases. Furthermore, in patients who have achieved remission, subsequent application of teritacicept can further improve their condition and show significant efficacy. Teritacicept also shows a favorable therapeutic outlook in patients who have failed treatment with glucocorticoids and / or glucocorticoids + immunosuppressants and / or glucocorticoids + immunosuppressants + biological agents (such as rituximab), or who have experienced relapse after treatment. Teritacicept also shows a favorable therapeutic outlook in patients with ANCA-associated vasculitis who have one or more other autoimmune diseases (including, but not limited to, Sjögren's syndrome, systemic lupus erythematosus, nephrotic syndrome, and lupus nephritis). Teritacicept shows better safety and superior therapeutic efficacy compared to glucocorticoids and / or immunosuppressants, particularly in patients with severe ANCA-associated vasculitis. Teritacicept shows good therapeutic potential in patients with a long history of the disease and relapse after treatment. In patients with severe ANCA-associated vasculitis and severe renal impairment, teritacicept shows good therapeutic efficacy while also demonstrating good safety.

[0134] Example 2: Clinical Study Main purpose 1. Regarding the treatment of refractory and relapsed AAV, we will investigate the effectiveness of teritacicept during the remission induction phase,

[0135] 2. To evaluate the efficacy of teritacicept during the remission maintenance phase in the treatment of refractory and relapsed AAV.

[0136] Secondary objective: To evaluate the safety of teritacicept in advance for the treatment of refractory and recurrent ANCA-associated vasculitis.

[0137] The above description relates solely to preferred embodiments and is provided for illustrative purposes only, and does not limit the combination of features necessary to carry out the invention. The titles assigned are not intended to limit the various embodiments of the invention. Terms such as “comprise,” “contain,” and “include” are not intended to limit. Furthermore, unless otherwise explicitly stated, references to singular elements without numerical modifiers are plural, and the terms “or” and “alternatively” mean “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.

[0138] All publications and patents referenced herein are incorporated herein by reference. Various modifications and variations of the methods and compositions of the present invention described herein will be apparent to those skilled in the art without departing from the scope and spirit of the invention. Although the present invention has been described through specific preferred embodiments, it should be understood that the claimed invention should not be unduly limited to these specific embodiments. In fact, various variations of the embodiments described for carrying out the present invention that are apparent to those skilled in the art in the relevant field are intended to be included within the scope of the appended claims.

Claims

1. A method for treating or alleviating ANCA-associated vasculitis, comprising administering a therapeutically effective dose of a drug targeting BlyS and / or APRIL to a patient having said ANCA-associated vasculitis.

2. The method according to claim 1, wherein the drug targeting BlyS and / or APRIL is a TACI-Fc fusion protein.

3. The aforementioned TACI-Fc fusion protein, (i) the extracellular domain or fragment of TACI that binds to BlyS and / or APRIL, (ii) The method according to claim 2, comprising a human immunoglobulin constant region fragment.

4. The method according to claim 3, wherein the extracellular domain of TACI bound to BlyS and / or APRIL, or the fragment thereof, comprises the amino acid sequence shown in SEQ ID NO: 1, SEQ ID NO: 2, or SEQ ID NO:

3.

5. The method according to claim 3, wherein the human immunoglobulin is IgG1, or the human immunoglobulin constant region fragment comprises the amino acid sequence of SEQ ID NO: 4, or comprises an amino acid sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with SEQ ID NO:

4.

6. The method according to claim 5, wherein the human immunoglobulin constant region fragment comprises amino acid modifications at positions 1, 2, 3, 4, 5, 6, 7, 8 or more, compared to SEQ ID NO:

4.

7. The method according to claim 6, wherein the modification is an amino acid substitution, deletion, or insertion.

8. The method according to claim 7, wherein the substitution includes one or more of P3T, L8P, L14A, L15E, G17A, A110S, P111S, and / or A173T.

9. The method according to claim 7, wherein the insertion is the insertion of 1, 2, 3, 4, 5, 6, 7, 8 or more amino acids at the N-terminus of the human immunoglobulin constant region fragment.

10. The method according to claim 6, wherein the human immunoglobulin constant region fragment comprises the amino acid sequence of SEQ ID NO: 5 or SEQ ID NO:

6.

11. The method according to claim 10, wherein the TACI-Fc fusion protein comprises an amino acid sequence having at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% identity with SEQ ID NO:

7.

12. The method according to claim 10 or 11, wherein the TACI-Fc fusion protein has the amino acid sequence shown in SEQ ID NO: 7, SEQ ID NO: 8, or SEQ ID NO:

9.

13. The method according to claim 12, wherein the TACI-Fc fusion protein is teritacicept, atacicept, or pobetacicept.

14. The method according to any one of claims 1 to 13, wherein the ANCA-associated vasculitis includes, but is not limited to, one or more of granulomatosis with polyangiitis (GPA), eosinophilic granulomatosis with polyangiitis (EGPA), and microscopic polyangiitis (MPA).

15. The method according to any one of claims 1 to 14, comprising administering a therapeutically effective dose of a drug targeting BlyS and / or APRIL to a patient having the aforementioned ANCA-associated vasculitis during the induction and / or maintenance phases of remission.

16. The method according to any one of claims 1 to 15, wherein the patient is an adult patient or a pediatric patient.

17. The method according to any one of claims 1 to 16, wherein the patient with ANCA-associated vasculitis is in the treatment phase of a newly diagnosed disease or in the treatment phase of a relapsed disease.

18. The method according to any one of claims 1 to 17, wherein the patient with ANCA-associated vasculitis is a patient in the inactive phase, a patient in the active phase with severe symptoms, or a patient in the active phase with non-severe symptoms.

19. The method according to any one of claims 1 to 18, wherein the patient with ANCA-associated vasculitis also has one or more other autoimmune diseases.

20. The method according to any one of claims 1 to 19, wherein the patient with ANCA-associated vasculitis has lesions of the lungs, and / or kidneys, and / or gastrointestinal tract, and / or nervous system, and / or eyes, ears, nose, and throat, and / or general musculoskeletal system, and / or serosal membranes, and / or hematological system, and / or other tissues or organs.

21. The method according to any one of claims 1 to 20, wherein the patient has previously received a treatment regimen for ANCA-associated vasculitis, or has not previously received a treatment regimen for ANCA-associated vasculitis.

22. The method according to any one of claims 1 to 21, wherein the treatment regimen for ANCA-associated vasculitis comprises, but is not limited to, one or more of a glucocorticoid treatment regimen, an immunosuppressant treatment regimen, a biological agent treatment regimen, and plasmapheresis.

23. The method according to any one of claims 1 to 22, comprising administering a therapeutically effective dose of a drug targeting BlyS and / or APRIL to a patient having the aforementioned ANCA-associated vasculitis while one or more of the following are being administered in combination: a glucocorticoid, an immunosuppressant, a biological agent, and plasma exchange.

24. The method according to any one of claims 1 to 23, wherein the single dose of the agent targeting BlyS and / or APRIL is about 0.1 to 10 mg / kg.

25. The method according to any one of claims 1 to 24, wherein the single dose of the agent targeting BlyS and / or APRIL is 40 to 240 mg, more preferably 40 mg, 60 mg, 80 mg, 100 mg, 120 mg, 140 mg, 160 mg, or 240 mg.

26. The method according to any one of claims 1 to 25, wherein the frequency of administration of the agent targeting BlyS and / or APRIL is administered as needed.

27. The method according to any one of claims 1 to 26, wherein the agent targeting BlyS and / or APRIL is administered 1 to 8 times at intervals of 1 month, 1 to 8 times at intervals of 2 months, and / or 1 to 8 times at intervals of 3 months, or the frequency of administration is once a week, once every 2 weeks, once every 3 weeks, or once a month.

28. The method according to any one of claims 1 to 27, wherein the form of administration of the drug targeting BlyS and / or APRIL is subcutaneous, intramuscular, or intravenous, or the administration site is the thigh, abdomen, or upper arm.

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