Method for treating autoimmune encephalitis with taci-fc fusion protein

Abstract

A method for treating or alleviating autoimmune encephalitis with an effective amount of a medicament targeting Blys and / or APRIL. Results show that the effective amount of the medicament targeting Blys and / or APRIL exhibits a good safety profile and a relatively good therapeutic effect in the process of treating or alleviating autoimmune encephalitis.

Description

Method for treating autoimmune encephalitis using TACI-Fc fusion protein Technical Field

[0001] The present invention relates to a TACI-Fc fusion protein drug for treating or alleviating autoimmune encephalitis, a dosage regimen, a dosing interval and an administration method. Background Art

[0002] Autoimmune encephalitis (AE) refers to a brain infection caused by the immune system recognizing self-antigens expressed in the central nervous system (CNS) as foreign antigens, resulting in an erroneous immune response. Its main symptoms include mental and behavioral abnormalities, cognitive impairment, recent memory loss, epileptic seizures, speech disorders, movement disorders, involuntary movements, decreased consciousness and coma, and autonomic dysfunction. Based on the different anti-neuronal antibodies and corresponding clinical syndromes, autoimmune encephalitis is generally divided into the following three main types clinically: ① Anti-NMDAR encephalitis, with the characteristic clinical manifestation of diffuse encephalitis, which is different from classic limbic encephalitis; ② Limbic encephalitis, with mental and behavioral abnormalities, epileptic seizures and recent memory impairment as the main symptoms, and electroencephalogram and imaging consistent with limbic system involvement. Encephalitis associated with anti-glutamic acid decarboxylase (GAD) antibodies, anti-LGI1 antibodies, anti-GABABR antibodies and anti-AMPAR antibodies is consistent with the characteristics of limbic encephalitis; ③ Other AE syndromes, including Morvan syndrome (also known as Morvan syndrome), anti-GABAAR antibody-related encephalitis, progressive encephalomyelitis with tonic and myoclonus (PERM), anti-DPPX antibody-related encephalitis, anti-IgLON5 antibody-related encephalopathy, etc. These AE syndromes either involve both the central and peripheral nervous systems or manifest as characteristic clinical syndromes.

[0003] Since the first discovery of anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis in 2007, a variety of new pathogenic antibodies have been discovered (Reference 1: Dalmau J, Graus F. Antibody-Mediated Encephalitis. N Engl J Med 2018; 378(9): 840-51). Among them, anti-NMDAR encephalitis has the highest proportion, accounting for approximately 54% to 80% of AE cases, followed by anti-leucine-rich glioma-inactivated protein 1 (LGI1), antibody-related encephalitis and anti-γ-amino butyric acid type B receptor (GABABR) antibody-related encephalitis (see Table 1).

[0004] Table 1. Anti-neuronal antibodies associated with autoimmune encephalitis

[0005] Autoimmune encephalitis can occur in both adolescents, children, and adults. Research data show that the incidence of autoimmune encephalitis is 0.8 / 100,000 people / year and the prevalence is 13.7 / 100,000 people (Reference 2: Abboud H, Probasco JC, Irani S, et al. Autoimmune encephalitis: proposed best practice recommendations for diagnosis and acute management [J]. J Neurol Neurosurg Psychiatry, 2021.). Because some cases of autoimmune encephalitis are associated with specific autoantibodies against cell surface molecules and intracellular targets, and antibodies are not always tested during testing, the sensitivity and specificity of tests vary, and the test results also depend on the type of test performed. Because antibody testing is often negative, clinicians often need to combine clinical manifestations, neuroimaging, electroencephalogram (EEG), and cerebrospinal fluid (CSF) results to make a diagnosis. Furthermore, in some patients' CSF studies, antibody-mediated syndromes may not be associated with any evidence of inflammation, and EEG results are often nonspecific (Reference 3: Escudero D, Guasp M, Arino H, et al. Antibody-associated CNS syndromes without signs of inflammation in the elderly. Neurology 2017;89:1471–1475.). Therefore, high-quality diagnostic and treatment research is still lacking.

[0006] According to the Chinese Expert Consensus on the Diagnosis and Treatment of Autoimmune Encephalitis (2022 Edition), the treatment of autoimmune encephalitis includes immunotherapy, symptomatic treatment of epileptic seizures and psychiatric symptoms, supportive care, rehabilitation therapy, and anti-tumor treatment such as tumor resection for patients with concurrent tumors. Immunotherapy can be further subdivided into first-line immunotherapy, second-line immunotherapy, long-term (maintenance) immunotherapy, escalated immunotherapy, and add-on immunotherapy. Table 2 summarizes the relevant treatment options for immunotherapy, symptomatic treatment of epileptic seizures and psychiatric symptoms, and paraneoplastic AEs.

[0007] Table 2. Treatment options for autoimmune encephalitis

[0008] As can be seen in Table 2, common first-line immunotherapy includes glucocorticoids, intravenous immunoglobulin, and plasma exchange.

[0009] ① Glucocorticoids (GC): Glucocorticoids are typically the preferred treatment for autoimmune encephalitis. Their principle is that glucocorticoids bind to specific receptors, thereby inducing T lymphocyte apoptosis and inhibiting Th1 cell differentiation. When combined with first-line drugs, the most common combinations are glucocorticoids combined with intravenous immunoglobulin (IVIg) or glucocorticoids combined with plasma exchange. Although glucocorticoids have a therapeutic effect on AEs, evidence suggests that distinguishing AEs from infectious encephalitis during the acute phase can be difficult, often delaying the use of glucocorticoids. Furthermore, glucocorticoids have a much smaller effect on reducing circulating B cell counts than on reducing T cell counts, and their effect on serum antibody titers is also relatively limited. Furthermore, long-term or high-dose glucocorticoids may induce or aggravate psychiatric symptoms associated with adverse events, such as neurodegenerative diseases, depression, insomnia, agitation, and psychosis. The safety of immunotherapy drugs warrants further investigation.

[0010] ② Immunosuppressants: For patients who are insensitive to first-line treatment, immunosuppressants are usually used for treatment. For example, cyclophosphamide, an immunosuppressant that can inhibit the proliferation of T cells and B cells, is generally injected intravenously at a dose of 750 mg / m2 of body surface area and dissolved in 100 mL of physiological sodium chloride solution.

[0011] ③ Biological agents: Although a variety of biological agents have been used in clinical studies of autoimmune encephalitis (see Table 3), there is no drug approved for marketing for this indication. In China, the use of biological agents such as rituximab and tocilizumab for autoimmune encephalitis is considered off-label use. When using the drugs, special attention should be paid to possible infections, and the patient's right to make independent decisions should be respected, and full informed consent and corresponding procedures should be implemented. Among them, rituximab is a chimeric monoclonal antibody against the CD20 antigen on the surface of B cells. It can kill B lymphocytes with CD20 by binding to CD20, producing complement-dependent and antibody-dependent cytotoxicity, and it also affects the number and function of T cells. The recommended dose is 375 mg / m 2Rituximab is administered via intravenous drip once weekly for a course of 3-4 weeks. However, particular attention should be paid to the potential complications and adverse reactions associated with rituximab. Other promising targeted biological therapies include satelizumab, rozanolixizumab, and daratumumab. Satelizumab is the most advanced, currently in Phase III clinical trials (https: / / clinicaltrials.gov / study / NCT05503264?term=NCT05503264&rank=1), followed closely by rozanolixizumab, which is in Phase II clinical trials (https: / / www.clinicaltrials.gov / study / NCT02220153?term=NCT02220153&rank=1).

[0012] Table 3. Biologics used to treat autoimmune encephalitis

[0013] Since there are currently no approved drugs for the treatment of autoimmune encephalitis, the clinical diagnostic standards and guidelines for this disease are based on expert consensus. There is also a lack of randomized controlled trials for the treatment of autoimmune encephalitis, and the level of supporting evidence for immunotherapy drugs is limited, so safety issues warrant further study. In addition, biologics such as rituximab may cause serious side effects such as infection. Therefore, there is still an unmet clinical need for the treatment of autoimmune encephalitis, especially for patients who have poor responses to immunosuppressive drugs, are intolerant to other biologics, or experience serious adverse reactions. There is an urgent need for a safe and effective drug.

[0014] Povetacicept (ALPN-303) is an Fc fusion protein with an engineered TACI domain. As a BAFF / APRIL dual antagonist, it is being explored for the treatment of lupus nephritis (Phase I / II), membranous nephropathy (Phase I / II), IgA nephropathy (Phase I / II), immune thrombocytopenia (Phase I / II), cold agglutinin disease (Phase I / II), warm antibody-type autoimmune hemolytic anemia (Phase I / II), systemic lupus erythematosus (Phase I), autoimmune cytopenia (Phase I), myasthenia gravis (preclinical) and other indications, and is currently in different stages of research.

[0015] Alpine Immune Sciences has announced information on three povetacicept clinical trials. RUBY 1 (NCT05034484) is a Phase I safety study in healthy volunteers, which showed that povetacicept has acceptable safety and tolerability and exhibits the expected PD effect on circulating Ig. RUBY 3 (NCT05732402) is an open-label Phase 1b / 2a study of povetacicept for the treatment of autoimmune kidney diseases. Preliminary results showed that povetacicept 80mg SC Q4W was well tolerated after multiple doses in patients with IgA nephropathy and is expected to reduce urine protein-creatinine ratio (UPCR) and Gd-IgA1. RUBY 4 (NCT05757570) is an open-label Phase 1b study of povetacicept for the treatment of autoimmune cytopenias, which is currently ongoing. In addition, povetacicept is intended for the treatment of inflammatory diseases involving BAFF and / or APRIL, such as systemic lupus erythematosus, and clinical trials are underway in China (registration number CTR20234038).

[0016] Atacicept is a recombinant fusion protein consisting of the extracellular ligand-binding portion of the TACI receptor and the Fc portion of human IgG, capable of binding to BLyS and APRIL. The drug is currently in various clinical stages of development for the treatment of IgA nephropathy (Stage III), lupus nephritis (Stage III), systemic lupus erythematosus (Stage II / III), and autoimmune diseases.

[0017] The Phase 2b ORIGIN trial (NCT04716231) of atacicept for the treatment of IgA nephropathy achieved positive results, with atacicept treatment achieving the primary endpoint and key secondary endpoints. In addition, the safety of the atacicept and placebo treatment groups was comparable. A Phase III clinical trial (NCT04716231) of atacicept for the treatment of IgA nephropathy is currently recruiting, with the dose of atacicept in the trial group being 150 mg subcutaneously, administered once a week. In addition, a Phase IIb / III clinical trial (registration number: CTR20242150) evaluating the efficacy and safety of atacicept in subjects with IgA nephropathy (IgAN) is currently underway in China. Results from a Phase III clinical trial (NCT00624338) evaluating the efficacy and safety of atacicept in preventing moderate to severe systemic lupus erythematosus (SLE) showed that only the 150mg atacicept group showed efficacy compared with the placebo group (43% vs. 60%; OR 0.49 (0.26, 0.92), p=0.027). However, the trial was stopped early in the 150mg atacicept group due to the death of two subjects from pneumonia complicated by pulmonary hemorrhage. Three completed Phase II clinical trials of atacicept for the treatment of rheumatoid arthritis, NCT00595413, NCT00430495, and NCT00664521, have been terminated because they did not reach their primary endpoints.

[0018] Tatasip (RC18) is a first-in-class recombinant TACI-Fc fusion protein for B cell-related autoimmune diseases. It targets and neutralizes BLyS and APRIL, two key cell signaling molecules in the B cell pathway. It is an antibody-like fusion protein for the treatment of human autoimmune diseases, consisting of a truncated TACI and an immunoglobulin Fc sequence optimized to reduce ADCC and CDC effects. It exhibits excellent biological activity and safety and has been approved for marketing in China for the treatment of systemic lupus erythematosus. It has also been approved for combination with methotrexate for the treatment of adult patients with moderately to severely active rheumatoid arthritis (RA) who have responded inadequately to methotrexate.

[0019] Summary of the Invention

[0020] The present invention surprisingly discovered during the treatment of real-world cases that the TACI-Fc fusion protein produced significant therapeutic effects in treating or alleviating patients with autoimmune encephalitis.

[0021] To this end, the present invention provides a method for treating or alleviating autoimmune encephalitis, comprising administering a therapeutically effective amount of a drug targeting Blys and / or APRIL to a patient suffering from the autoimmune encephalitis.

[0022] The present invention also provides use of a drug targeting Blys and / or APRIL in preparing a drug for treating or alleviating autoimmune encephalitis.

[0023] The present invention also provides a use of the TACI-Fc fusion protein in preparing a drug for treating or alleviating autoimmune encephalitis.

[0024] The present invention also provides the use of tetarcept in preparing a medicine for treating or alleviating autoimmune encephalitis patients.

[0025] Furthermore, the drug targeting Blys and / or APRIL is a TACI-Fc fusion protein.

[0026] Furthermore, the TACI-Fc fusion protein described in any one of the above items comprises:

[0027] (i) the extracellular domain of TACI or a fragment thereof that binds to Blys and / or APRIL; and

[0028] (ii) Human immunoglobulin constant region fragments.

[0029] Furthermore, the extracellular region of TACI or the fragment thereof that binds to Blys and / or APRIL comprises the amino acid sequence shown in SEQ ID NO: 1 or SEQ ID NO: 2 or SEQ ID NO: 3.

[0030] Furthermore, the amino acid sequence of the TACI extracellular region or the fragment thereof that binds to Blys and / or APRIL is shown in SEQ ID NO: 1.

[0031] Furthermore, the human immunoglobulin is IgG1.

[0032] Furthermore, the human immunoglobulin constant region fragment comprises the amino acid sequence of SEQ ID NO:4.

[0033] Furthermore, the human immunoglobulin constant region fragment comprises an amino acid sequence that is 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% identical to SEQ ID NO:4.

[0034] Furthermore, the amino acid sequence of the human immunoglobulin constant region fragment is shown in SEQ ID NO: 4.

[0035] Furthermore, the human immunoglobulin constant region fragment comprises amino acid modifications at one or more positions corresponding to positions 3, 8, 14, 15, 17, 110, 111 or 173 of SEQ ID NO:4.

[0036] Furthermore, the human immunoglobulin constant region fragment contains 1, 2, 3, 4, 5, 6, 7, 8 or more amino acid modifications compared to SEQ ID NO:4.

[0037] Furthermore, the modification is amino acid substitution, deletion or insertion.

[0038] Furthermore, the substitution comprises one or more of P3T, L8P, L14A, L15E, G17A, A110S, P111S and A173T.

[0039] Furthermore, the insertion is to insert 1, 2, 3, 4, 5, 6, 7, 8 or more amino acids into the N-terminus of the human immunoglobulin constant region fragment.

[0040] Furthermore, the insertion is to insert 5 amino acids into the N-terminus of the human immunoglobulin constant region fragment.

[0041] Furthermore, the insertion is to insert the five amino acids EPKSS into the N-terminus of the human immunoglobulin constant region fragment.

[0042] Furthermore, the human immunoglobulin constant region fragment comprises the amino acid sequence of SEQ ID NO: 5.

[0043] Furthermore, the TACI-Fc fusion protein comprises the amino acid sequence shown in SEQ ID NO:6.

[0044] 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.

[0045] Furthermore, the amino acid sequence of the TACI-Fc fusion protein is shown in SEQ ID NO:7.

[0046] Furthermore, the TACI-Fc fusion protein has the amino acid sequence shown in SEQ ID NO:8.

[0047] Furthermore, the TACI-Fc fusion protein has the amino acid sequence shown in SEQ ID NO:9.

[0048] Furthermore, the drug targeting Blys and / or APRIL is telitacicept, atacicept, or povetacicept.

[0049] Furthermore, the TACI-Fc fusion protein is telitacicept.

[0050] Furthermore, the autoimmune encephalitis includes but is not limited to: anti-NMDAR encephalitis, Morvan syndrome, progressive encephalomyelitis with rigidity and myoclonus, anti-dipeptidyl peptidase-like protein-6 (DPPX) antibody encephalitis, anti-dopamine type 2 receptor antibody-related basal ganglia encephalitis, anti-LGI1 antibody-related encephalitis, anti-GABABR antibody-related encephalitis, anti-CASPR2 antibody-related encephalitis, anti-IgLON5 antibody-related encephalopathy, anti-AMPAR antibody-related encephalitis, anti-GABAAR antibody-related encephalitis, anti-mGluR5 antibody-related encephalitis, anti-synapsin-3α antibody-related encephalitis, anti-GAD65 encephalitis, anti-AK5 antibody-related encephalitis, anti-Hu antibody-related encephalitis, anti-CV2 antibody-related encephalitis, anti-Ma2 antibody-related encephalitis, anti-Kelch-like protein 11 antibody-related encephalitis, anti-Ri antibody-related encephalitis, anti-Yo antibody-related encephalitis, anti-VGKC encephalitis, anti-VGCC encephalitis and immune checkpoint inhibitor-related encephalitis. One or more.

[0051] In some preferred embodiments, the autoimmune encephalitis is anti-NMDAR encephalitis; in other preferred embodiments, the autoimmune encephalitis is Morvan syndrome; in other preferred embodiments, the autoimmune encephalitis is progressive encephalomyelitis with rigidity and myoclonus; in other preferred embodiments, the autoimmune encephalitis is anti-dipeptidyl peptidase-like protein-6 (DPPX) antibody encephalitis; in other preferred embodiments, the autoimmune encephalitis is anti-dopamine type 2 receptor antibody-related basal ganglia encephalitis; in other preferred embodiments, the autoimmune encephalitis is anti-LGI1 antibody-related encephalitis. Inflammation; in other preferred embodiments, the autoimmune encephalitis is anti-GABABR antibody-related encephalitis; in other preferred embodiments, the autoimmune encephalitis is anti-CASPR2 antibody-related encephalitis; in other preferred embodiments, the autoimmune encephalitis is anti-IgLON5 antibody-related encephalopathy; in other preferred embodiments, the autoimmune encephalitis is anti-AMPAR antibody-related encephalitis; in other preferred embodiments, the autoimmune encephalitis is anti-GABAAR antibody-related encephalitis; in other preferred embodiments, the autoimmune encephalitis is anti-mGluR5 antibody-related encephalitis. In other preferred embodiments, the autoimmune encephalitis is anti-synapsin-3α antibody-related encephalitis; in other preferred embodiments, the autoimmune encephalitis is anti-GAD65 encephalitis; in other preferred embodiments, the autoimmune encephalitis is anti-AK5 antibody-related encephalitis; in other preferred embodiments, the autoimmune encephalitis is anti-CV2 antibody-related encephalitis; in other preferred embodiments, the autoimmune encephalitis is anti-Ma antibody-related encephalitis; in other preferred embodiments, the autoimmune encephalitis is anti-Kelch-like protein 11 antibody-related encephalitis; in another preferred embodiment, the autoimmune encephalitis is anti-Kelch-like protein 11 antibody-related encephalitis. In some preferred embodiments, the autoimmune encephalitis is anti-Ri antibody-related encephalitis; in other preferred embodiments, the autoimmune encephalitis is anti-Yo antibody-related encephalitis; in other preferred embodiments, the autoimmune encephalitis is anti-VGKC antibody-related encephalitis; in other preferred embodiments, the autoimmune encephalitis is anti-VGCC encephalitis; in other preferred embodiments, the autoimmune encephalitis is anti-immune checkpoint inhibitor-related encephalitis; in other preferred embodiments, the autoimmune encephalitis is one of the above-mentioned autoimmune encephalitis combined with one or more other autoimmune encephalitis. It is understandable that in clinical practice, there is a classification of the disease type of autoimmune encephalitis (i.e., further determined to be one or two or more of the above-mentioned autoimmune encephalitis combined), and there is also a situation where the type of autoimmune encephalitis is not classified (i.e., collectively referred to as autoimmune encephalitis). Therefore, the type of disease should not be regarded as a limitation of the disease.

[0052] Furthermore, the patient is an adult patient or a pediatric patient. In some preferred embodiments, the patient is an adult patient. In other preferred embodiments, the patient is a pediatric patient.

[0053] Furthermore, the patient is an antibody-positive autoimmune encephalitis patient or an antibody-negative autoimmune encephalitis patient. In some preferred embodiments, the patient is an antibody-positive autoimmune encephalitis patient. In other preferred embodiments, the patient is an antibody-negative autoimmune encephalitis patient.

[0054] Furthermore, the antibody-positive autoimmune encephalitis patient is a patient with one or more antibody-positive autoimmune encephalitis.

[0055] Furthermore, the autoimmune encephalitis patient is in the new disease treatment stage or the recurrent disease treatment stage. In some preferred embodiments, the autoimmune encephalitis patient is in the new disease treatment stage (i.e., the patient is diagnosed with autoimmune encephalitis for the first time). In other preferred embodiments, the autoimmune encephalitis patient is in the recurrent disease treatment stage. That is to say, the drug targeting Blys and / or APRIL provided by the present invention (further preferably TACI-Fc fusion protein, more preferably tetasip) can be applied to the patient's new disease treatment stage, and can also be applied to the patient's recurrent disease treatment stage.

[0056] Furthermore, the patient with autoimmune encephalitis suffers from one or more other autoimmune diseases. Wherein, the autoimmune diseases (with reference to the disease list listed by the American Association of 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, gluten-induced bowel disease, achalasia, Addison's disease, adult Still's disease, agammaglobulinemia, alopecia areata, amyloidosis, ankylosing spondylitis, anti-glomerular basement membrane antibody nephritis, antiphospholipid syndrome, autoimmune angioedema, autoimmune autonomic dysfunction, 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 disease, Behçet disease, benign mucous membrane pemphigoid, bullous pemphigoid, giant lymphadenopathy, celiac disease, Chagas disease, chronic inflammatory demyelinating polyneuropathy, chronic relapsing multifocal osteomyelitis, Churg-Strauss syndrome, Cogan syndrome, cold agglutinin disease, congenital heart block, coxsackievirus myocarditis, CREST syndrome, Crohn's disease, dermatitis herpetiformis, dermatomyositis, Devic's disease, discoid lupus, Dressler syndrome, endometriosis, eosinophilic esophagitis, eosinophilic fasciitis, erythema nodosum, essential mixed cryoglobulinemia, Evans syndrome, fibromyalgia, fibrosing alveolitis, giant cell arteritis, giant cell myocarditis, glomerulonephritis, Goodpasture syndromegranulomatosis with polyangiitis, Graves' disease, Guillain-Barré syndrome, Hashimoto's thyroiditis, hemolytic anemia, Henoch-Schonlein purpura, herpes gestationis or pemphigoid gestationis, hidradenitis suppurativa, hypogammaglobulinemia, IgA nephropathy, IgG4-related sclerosing disease, immune thrombocytopenic purpura, inclusion body myositis, interstitial cystitis, juvenile arthritis, juvenile myositis, Kawasaki disease, Lambert-Eaton syndrome, leukocytic vasculitis, lichen planus, atrophic scleroderma Lichen planus, woody conjunctivitis, linear IgA disease, chronic Lyme disease, Meniere's disease, microscopic polyangiitis, mixed connective tissue disease, Mooren's ulcer, Mucha-Habermann disease, multifocal motor neuropathy, multiple sclerosis, myasthenia gravis, myositis, narcolepsy, neonatal lupus, neutropenia, ocular cicatricial pemphigoid, optic neuritis, relapsing rheumatic disease, Panda disease, paraneoplastic cerebellar degeneration, paroxysmal nocturnal hemoglobinuria, Parry-Romberg syndrome, ciliary Pars planitis, Parsonage-Turner syndrome, pemphigus, peripheral neuropathy, perivenous encephalomyelitis, pernicious anemia, POEMS syndrome, polyarteritis nodosa, polyglandular syndrome type I, II, and III, polymyalgia rheumatica, polymyositis, post-myocardial infarction syndrome, postpericardiotomy syndrome, primary biliary cirrhosis, primary sclerosing cholangitis, progestogen-induced dermatitis, psoriatic arthritis, pure red cell aplasia, pyoderma gangrenosum, Raynaud's phenomenon, reactive arthritis, reflex sympathetic dystrophy benign prostatic hyperplasia (BPH), relapsing polychondritis, restless legs syndrome, retroperitoneal fibrosis, rheumatic fever, sarcoidosis, Schmidt syndrome, scleritis, scleroderma, Sjögren's syndrome, sperm and testicular autoimmunity, stiff-man syndrome, subacute bacterial endocarditis, Susac's syndrome, sympathetic ophthalmia, Takayasu's arteritis, temporal arteritis, thyroid eye disease, Tolosa-Hunt syndrome, ulcerative colitis, undifferentiated connective tissue disease, uveitis, vasculitis, vitiligo, Koyanagi-Harada disease, and antibody-type autoimmune hemolytic anemia.

[0057] Furthermore, the patient with autoimmune encephalitis suffers from one or more other tumor diseases. The tumor diseases are solid tumors or non-solid tumors, including but not limited to breast cancer, ovarian cancer, cervical cancer, uterine cancer, prostate cancer, kidney cancer, urethral cancer, bladder cancer, liver cancer, gastric cancer, endometrial cancer, salivary gland cancer, esophageal cancer, lung cancer, colon cancer, rectal cancer, colorectal cancer, bone cancer, skin cancer, thyroid cancer, pancreatic cancer, melanoma, glioma, neuroblastoma, glioblastoma multiforme, sarcoma, lymphoma, teratoma, testicular germ cell tumor, mediastinal hamartoma, small cell lung cancer, leukemia and other solid tumors or blood tumors.

[0058] Furthermore, the patient has not received any previous treatment for autoimmune encephalitis.

[0059] Furthermore, the patient has previously received treatment for autoimmune encephalitis.

[0060] Furthermore, the treatment regimen for autoimmune encephalitis includes, but is not limited to, one or more of a glucocorticoid treatment regimen, an immunosuppressant treatment regimen, a biological agent treatment regimen, and plasma exchange.

[0061] In some preferred embodiments, the patient has previously received an autoimmune encephalitis treatment regimen, and the autoimmune encephalitis treatment regimen is a glucocorticoid treatment regimen, an immunosuppressant treatment regimen, a biologic treatment regimen, plasma exchange, a glucocorticoid + immunosuppressant combination regimen, a glucocorticoid + biologic combination regimen, a glucocorticoid + plasma exchange combination regimen, an immunosuppressant + biologic combination regimen, an immunosuppressant + plasma exchange combination regimen, a biologic + plasma exchange combination regimen, a glucocorticoid + immunosuppressant + biologic combination regimen, a glucocorticoid + immunosuppressant + plasma exchange combination regimen, an immunosuppressant + biologic + plasma exchange combination regimen, or a glucocorticoid + immunosuppressant + biologic + plasma exchange combination regimen.

[0062] Furthermore, the method comprises administering a therapeutically effective amount of a drug targeting Blys and / or APRIL to a patient with the autoimmune encephalitis, and simultaneously administering one or more of glucocorticoids, immunosuppressants, biological agents, and plasma exchange.

[0063] In some preferred embodiments, the method comprises administering a therapeutically effective amount of a drug targeting Blys and / or APRIL to the patient having the autoimmune encephalitis. In other preferred embodiments, the method comprises administering to the patient with the autoimmune encephalitis a drug targeting Blys and / or APRIL, a glucocorticoid, and an immunosuppressant; or a drug targeting Blys and / or APRIL, a glucocorticoid, and a biologic; or a drug targeting Blys and / or APRIL, a glucocorticoid, and plasma exchange; or a drug targeting Blys and / or APRIL, an immunosuppressant, and a biologic; or a drug targeting Blys and / or APRIL, an immunosuppressant, and plasma exchange; or a drug targeting Blys and / or APRIL, a biologic, and plasma exchange; or a drug targeting Blys and / or APRIL, a glucocorticoid, an immunosuppressant, and a biologic; or a drug targeting Blys and / or APRIL, a glucocorticoid, an immunosuppressant, and a biologic; or a drug targeting Blys and / or APRIL, a glucocorticoid, an immunosuppressant, and plasma exchange; or a drug targeting Blys and / or APRIL, an immunosuppressant, a biologic, and plasma exchange. Preferably, the combined administration is simultaneous or staged.

[0064] Glucocorticoids are regulatory molecules that play an important role in the body's 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 the present invention include, but are not limited to, prednisone, prednisone, methylprednisolone, betamethasone, beclomethasone dipropionate, prednisolone, hydrocortisone, dexamethasone, and the like.

[0065] The "immunosuppressants" mentioned herein are drugs that have an inhibitory effect on the body's immune response, inhibiting the proliferation and function of cells related to the immune response (macrophages such as T cells and B cells). They are also called conventional synthetic disease-modifying anti-rheumatic drugs (cDMARDs). Preferably, the immunosuppressants described in the present invention include, but are not limited to, mycophenolate mofetil, azathioprine, methotrexate, leflunomide, cyclophosphamide, cyclosporine, tacrolimus, iguratimod, thalidomide, and other drugs that have an inhibitory effect on the body's immune response.

[0066] Preferably, the biological agents of the present invention include but are not limited to: one or more of rituximab, satralizumab, rozanolixizumab, tocilizumab, daratumumab, human immunoglobulin and immunoglobulin G.

[0067] Furthermore, the single dose of the drug targeting Blys and / or APRIL is about 0.1 to 10 mg / kg, further including 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6. 2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8.0, 8.1, 8 .2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9.0, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9, 10mg / kg.

[0068] Furthermore, the single dose of the drug targeting Blys and / or APRIL is 40-240 mg, and more preferably 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.

[0069] Furthermore, the protein content of the above-mentioned drug is detected by UV-visible spectrophotometry. Based on the maximum UV absorption of protein at 280 nm, the absorbance value of the tetasip sample at this wavelength is measured. After correcting the absorbance at 320 nm, the absorbance value at 280 nm is proportional to the protein concentration. The protein concentration is calculated according to the Lambert-Beer law to determine the protein content. The protein content calculation formula is as follows:

[0070] Where: ε is the extinction coefficient of tetasip, unit is (mg / ml) -1 cm -1 ;

[0071] A 280 is the average absorbance of the sample solution at 280 nm;

[0072] A 280 (Correction) is the average value of the corrected absorbance of the sample solution at 280 nm.

[0073] Furthermore, the drug targeting Blys and / or APRIL is used 1-5 times during each monthly interval, that is, the administration frequency of the TACI-Fc fusion protein is 1, 2, 3, 4 or 5 times per month.

[0074] Furthermore, the drug targeting Blys and / or APRIL is used 1-10 times every two months, that is, the administration frequency of the TACI-Fc fusion protein is 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 times every two months.

[0075] Furthermore, the drug targeting Blys and / or APRIL is used 1-10 times during every three months, that is, the administration frequency of the TACI-Fc fusion protein is 1 time, 2 times, 3 times, 4 times, 5 times, 6 times, 7 times, 8 times, 9 times, 10 times, 11 times, 12 times, 13 times, 14 times or 15 times every three months.

[0076] Furthermore, the drug targeting Blys and / or APRIL is administered once a week.

[0077] Furthermore, the drug targeting Blys and / or APRIL is administered on demand.

[0078] Furthermore, the drug targeting Blys and / or APRIL is administered continuously and / or intermittently.

[0079] Furthermore, the drug targeting Blys and / or APRIL is administered at regular intervals.

[0080] Furthermore, the drug targeting Blys and / or APRIL is administered at irregular intervals.

[0081] Furthermore, the drug targeting Blys and / or APRIL is administered subcutaneously, intramuscularly, or intravenously, preferably into the thigh, abdomen, or upper arm. In some specific embodiments, the TACI-Fc fusion protein is administered subcutaneously, intramuscularly, or intravenously.

[0082] Furthermore, the drug targeting Blys and / or APRIL is injected into the same or different sites each time. In some specific embodiments, the TACI-Fc fusion protein is injected into the same site each time; in other specific embodiments, the TACI-Fc fusion protein is injected into different sites each time.

[0083] The present invention also provides a method for treating an autoimmune encephalitis patient who has previously received a treatment regimen for autoimmune encephalitis, the method comprising (1) determining whether the patient has previously received a treatment regimen for autoimmune encephalitis, and (2) if the patient has previously received treatment for autoimmune encephalitis, administering to the patient having the autoimmune encephalitis an effective amount of a drug targeting Blys and / or APRIL, further comprising a TACI-Fc fusion protein. DETAILED DESCRIPTION

[0084] Unless otherwise defined, all terms used herein have the same meanings as understood by those of ordinary skill in the art. For definitions and terms in this field, professionals can refer to Current Protocols in Molecular Biology (Ausubel).

[0085] The three-letter and one-letter codes for amino acids used in the present invention are as described in J. biol. chem, 243, p3558 (1968).

[0086] The term "TACI" as used herein stands for transmembrane activator and CAML interactor, a member of the tumor necrosis factor receptor superfamily. The term "BLys" as used herein refers to B lymphocyte stimulator, a member of the TNF ligand superfamily that exists in both membrane-bound and soluble forms. It is specifically expressed on the surface of bone marrow cells and selectively stimulates B lymphocyte proliferation and immunoglobulin production. The term "APRIL" (a proliferation-inducing ligand) as used herein refers to a tumor necrosis factor (TNF) analog that stimulates the proliferation of naive B and T cells in the body, promoting B cell accumulation and increasing splenic levels. APRIL specifically binds to TACI and BCMA, preventing APRIL from binding to B cells and inhibiting APRIL-stimulated naive B cell proliferation. Furthermore, APRIL competes with BLys for binding to receptors (BCMA and TACI).

[0087] The term "TACI-Fc fusion protein" as used herein refers to a transmembrane activator, calcium regulator, and cyclophilin ligand interactor (TACI)-immunoglobulin fusion protein (i.e., TACI-Fc fusion protein). The TACI-immunoglobulin fusion protein provided herein comprises: (i) a TACI extracellular domain or a fragment thereof that binds to Blys and / or APRIL; and (ii) a human immunoglobulin constant region fragment. Examples of TACI-Fc fusion proteins include, but are not limited to, telitacicept (amino acid sequence: SEQ ID NO: 7), atacicept (amino acid sequence: SEQ ID NO: 8), and povetacicept (amino acid sequence: SEQ ID NO: 9).

[0088] The term "TACI extracellular region or a fragment thereof that binds to Blys and / or APRIL" in the present invention includes the extracellular domain of TACI in U.S. Patent Nos. 5,969,102, 6,316,222 and 6,500,428 and U.S. patent applications 09 / 569,245 and 09 / 627,206 (the contents of which are incorporated herein by reference), as well as specific fragments of the TACI extracellular domain that can interact with the TACI ligand, and the amino acid fragment of position 13-118 of the TACI extracellular domain disclosed in Chinese Patent Publication No. CN101323643A.

[0089] In the term "human immunoglobulin constant region fragment", the immunoglobulin portion is preferably IgG1, which may include a heavy chain constant region, such as a human heavy chain constant region. The preferred "human immunoglobulin constant region fragment" of the present invention is an amino acid fragment containing part of the hinge region domain, the CH2 domain, and the CH3 domain. In some more preferred embodiments, the amino acid sequence of the "human immunoglobulin constant region fragment" of the present invention is as shown in SEQ ID NO: 4, or comprises an amino acid sequence that is 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% identical to 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.

[0090] The term "treatment" as used herein is related to a given disease or condition, including but not limited to: inhibiting the disease or condition, such as preventing the development of the disease or condition; alleviating the disease or condition, such as causing the disease or condition to relapse; or alleviating the symptoms caused by the disease or condition, such as alleviating, preventing or treating the symptoms of the disease or condition; or reducing the chance of recurrence of the disease or preventing recurrence of the disease.

[0091] The term "remission" used in the present invention refers to the absence of clinical symptoms or signs related to autoimmune encephalitis at the beginning or end of treatment.

[0092] The term "amino acid" used in the present invention is understood in the broadest sense and is a general term for a class of organic compounds containing amino and carboxyl groups. Preferably, the amino acids used in the present invention are the main units that make up proteins in living organisms, including but not limited to glycine, alanine, valine, leucine, isoleucine, methionine (methionine), proline, tryptophan, serine, tyrosine, cysteine, phenylalanine, asparagine, glutamine, threonine, aspartic acid, glutamic acid, lysine, arginine and histidine.

[0093] The amino acid three-letter codes and single-letter codes used in the present invention are as described in J. biol. chem, 243, p3558 (1968). There are various ways to number amino acid sites, such as the Kabat numbering system, the EU numbering system, and sequential numbering. In the present invention, the numbering of amino acid sites is carried out in a "sequential numbering" manner. For example, "position 3, 8, 14, 15, 17, 110, 111, or 173 of SEQ ID NO: 4" as described in the present invention refers to the 3rd amino acid, the 8th amino acid of SEQ ID NO: 4, and so on; for example, "P3T" as described in the present invention refers to the mutation of the 3rd amino acid sequence of SEQ ID NO: 4 from the previous "P" to "T", and for example, "L8P" refers to the mutation of the 8th amino acid sequence of SEQ ID NO: 4 from the previous "L" to "P", and so on.

[0094] As an alternative embodiment, the constant region of the immunoglobulin provided by the present invention can introduce one or more amino acid changes, such as substitution (ie, mutation), addition (ie, insertion) or deletion (ie, deletion).

[0095] The term "telitacicept" (or "Telitacicept" or RC18, which can be used interchangeably in the present invention) in the present invention is a TACI-Fc fusion protein, whose INN name is telitacicept, and whose amino acid sequence is shown in SEQ ID NO: 7, or as shown in https: / / extranet.who.int / soinn / mod / page / view.php?id=137&inn_n=10932.

[0096] The term "atacicept" in the present invention refers to a TACI-Fc fusion protein, whose INN name is atacicept, and whose amino acid sequence is shown in SEQ ID NO: 8, or as shown in https: / / extranet.who.int / soinn / mod / page / view.php?id=137&inn_n=8669.

[0097] The term "povetacicept" in the present invention, i.e., ALPN-303, is a TACI-Fc fusion protein, whose INN name is povetacicept, and whose amino acid sequence is shown in SEQ ID NO: 9, or as shown in https: / / extranet.who.int / soinn / mod / page / view.php?id=137&inn_n=12264.

[0098] The TACI-Fc fusion protein of the present invention can be administered by any of a variety of routes, including but not limited to oral, intravenous, intramuscular, intraarterial, intramedullary, intraperitoneal, intrathecal, intracardiac, transdermal, transdermal, topical, subcutaneous, intranasal, enteral, sublingual, vaginal or rectal routes.

[0099] The term "autoimmune encephalitis" in the present invention refers to a disease caused by the immune system's response to central nervous system antigens, with acute or subacute onset of epilepsy, cognitive impairment and mental disorders as the main clinical features.

[0100] The term "anti-NMDAR encephalitis" as used herein refers to anti-N-methyl-D-aspartate receptor encephalitis, which is characterized by the presence of IgG anti-NMDAR autoantibodies in the cerebrospinal fluid. Most patients with anti-NMDAR encephalitis develop a multi-stage disease progression, ranging from psychosis, seizures, language impairment, to an unresponsive state.

[0101] The term "Morvan syndrome" (also known as Morvan syndrome) in this invention refers to an autoimmune disease characterized by overexcitability of the central nervous system, peripheral nervous system, and autonomic nervous system. Anti-CASPR2 antibodies play an important pathogenic role in Morvan syndrome. CASPR2 is a protein expressed in the central nervous system and the nodular region around myelinated nerves. Detection of anti-CASPR2 antibodies in serum and / or cerebrospinal fluid is of great significance for the diagnosis of this disease.

[0102] The term "progressive encephalomyelitis with rigidity and myoclonus" in the present invention refers to a serious life-threatening autoimmune disease characterized by rigidity, muscle pain and spasm, deep and superficial sensory disturbances, brainstem and spinal cord symptoms, autonomic function, dyspnea, sudden spontaneous and stimulus-induced myoclonus.

[0103] The term "anti-dipeptidyl peptidase-like protein-6 antibody encephalitis" in the present invention is also called anti-DPPX (dipeptidyl-peptidase-like protein-6) antibody encephalitis. It is a chronic or subacute progressive autoimmune encephalitis mediated by DPPX antibodies in serum and (or) cerebrospinal fluid. The clinical manifestations are complex and diverse. Gastrointestinal dysfunction, cognitive-mental disorders and central nervous system hyperexcitability are typical manifestations. It may be accompanied by lymphoma. Immunotherapy is effective but prone to relapse.

[0104] The term "anti-dopamine type 2 receptor (D2R) antibody-associated basal ganglia encephalitis" as used herein refers to a type of autoimmune encephalitis associated with anti-neuronal surface antibodies, primarily affecting the basal ganglia. The main manifestations are movement disorders and mental disorders characterized by Parkinson's disease, dystonia, and chorea.

[0105] The term "anti-LGI1 antibody-associated encephalitis" as used herein refers to encephalitis associated with antibodies to leucine-rich glioma-inactivated protein 1 (LGI1), a type of limbic encephalitis. LGI1 antibodies are autoantibodies mediated against cell membrane antigens. Specific symptoms include faciobrachial dystonia, characterized by brief and frequent involuntary movements on one side of the face, arms, and legs.

[0106] The term "anti-GABABR antibody-associated encephalitis" in the present invention refers to anti-γ-aminobutyric acid type B receptor (GABABR) antibody-associated encephalitis. GABABR antibodies are cell surface antibodies and are often accompanied by obvious epileptic seizures or status epilepticus. Some patients have tumors, mainly small cell lung cancer.

[0107] The term "anti-CASPR2 antibody-associated encephalitis" used herein is associated with peripheral nerve hyperexcitability (e.g., myokymia, fasciculations, and spasms) and encephalitis. Other symptoms in patients with this disease include autonomic dysfunction and excitatory insomnia. Nearly one-third of patients present with Morvan syndrome, characterized by upper limb distal movement disorders, peripheral nerve hyperexcitability, autonomic dysfunction, pain, and encephalitis.

[0108] Patients who are IgLON5 antibody-positive in the term "anti-IgLON5 antibody-associated encephalopathy" in the present invention exhibit unique abnormalities in non-rapid eye movement (NREM) and rapid eye movement (REM) sleep, accompanied by obstructive sleep apnea, stridor, paroxysmal central hypoventilation, dementia, gait instability, chorea, dysarthria, dysphagia, autonomic nervous system disorders and supranuclear gaze palsy.

[0109] The term "anti-AMPAR antibody-associated encephalitis" in the present invention refers to anti-α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor antibody-associated encephalitis, where AMPAR is a tetramer composed of four subunits of GluR1-4 (GluRA-D). The main clinical manifestations are acute / subacute global encephalitis, but the impact on cognitive ability, attention or speech function is relatively small.

[0110] The term "anti-GABAAR antibody-associated encephalitis" in the present invention refers to recurrent, uncontrollable epilepsy, which often progresses to refractory status epilepticus, often accompanied by cognitive impairment, behavioral changes, decreased consciousness, and movement disorders.

[0111] The term "anti-mGluR5 antibody-associated encephalitis" as used herein refers to encephalitis associated with antibodies against metabotropic glutamate receptor 5. Metabotropic glutamate receptor 5 belongs to the Group I subclass of the metabotropic glutamate receptor family and is widely expressed on postsynaptic membranes in brain regions responsible for memory and learning (such as the cerebral cortex, hippocampus, and basal ganglia), playing a key role in regulating synaptic transmission and plasticity. Anti-mGluR5-associated encephalitis is extremely rare and is mostly associated with Hodgkin's lymphoma. Neurological symptoms typically appear before tumor diagnosis, but may also be associated with other tumors such as small cell lung cancer or be non-paraneoplastic.

[0112] The synapsin in the term "anti-synapsin-3α antibody-associated encephalitis" in the present invention is a family of synaptic cell adhesion molecules that plays a key role in synaptic development and function. It is encoded by three genes, NRXN1, NRXN2, and NRXN3. Each gene can encode two fragment products of different lengths, of which the longer fragment is α. Synapsin-3α can specifically bind to leucine-rich repeat transmembrane neuronal protein 2, mediating the release of neurotransmitters induced by calcium ions. Synapsin-3α antibodies can lead to a decrease in synapsin-3α on the surface of nerves, but do not lead to a decrease in the number of synapses, thereby causing synaptic excitatory and inhibitory dysfunction. Patients suffer from cognitive impairment, mental and behavioral abnormalities, intractable epilepsy, autonomic dysfunction (tachycardia, rapid respiratory rate), and symptoms such as involuntary movements around the mouth and lateral limbs.

[0113] The term "anti-GAD65 encephalitis" as used herein refers to encephalitis that is resistant to glutamic acid decarboxylase (GAD65). GAD65 catalyzes the conversion of glutamate into the neurotransmitter GABA. Anti-GAD65 antibodies are associated with other extraneural autoimmune diseases, such as type 1 diabetes. Major neurological diseases associated with anti-GAD65 antibodies include stiff-person syndrome, cerebellar ataxia, epilepsy, and limbic encephalitis.

[0114] The term "anti-AK5 antibody-associated encephalitis" in the present invention refers to limbic encephalitis caused by anti-adenylate kinase 5 antibodies, which mainly affects middle-aged and elderly patients, mostly males, and is mainly manifested by rapidly progressive situational amnesia, depression, anxiety, abnormal behavior and mental symptoms.

[0115] The term "anti-Hu antibody-associated encephalitis" as used herein is also referred to as anti-neuronal nuclear antibody type I-associated encephalitis. Anti-Hu antibodies are intracellular antibodies primarily found in small cell lung cancer, with approximately three-quarters of patients positive for these antibodies also developing small cell lung cancer. Lesions caused by anti-Hu antibodies primarily affect the limbic system, but can also affect the brainstem, cerebellum, spinal cord, and other areas. Clinical manifestations include recent memory loss, behavioral disturbances, and epileptic seizures. The cerebellum is also frequently affected, manifesting as subacute cerebellar degeneration. Peripheral nerve involvement can also manifest as subacute sensory neuronopathy or sensory / motor neuronopathy.

[0116] The term "anti-CV2 antibody-associated encephalitis" in the present invention is characterized by clinical manifestations including memory loss, mental and behavioral abnormalities, epileptic seizures, choreiform movement abnormalities, and Parkinson's-like symptoms in a few cases.

[0117] The term "anti-Ma antibody-associated encephalitis" in the present invention is an autoimmune encephalitis associated with anti-intracellular antigen antibodies. Anti-Ma (Ma1 / Ma2 / Ma3) is a type of paraneoplastic-related neuro-tumor antigen. In addition to clinical manifestations such as cognitive decline, mental symptoms and epilepsy, there may also be symptoms of upper brainstem and diencephalon dysfunction, and it is often closely related to tumor occurrence.

[0118] The term "anti-Kelch-like protein 11 (KLHL11) antibody-associated encephalitis" as used herein refers to a paraneoplastic rhombencephalitis associated with testicular seminoma, which may also present with limbic encephalitis. Vertigo, hearing loss, and tinnitus are common and unique clinical symptoms in patients with this disease.

[0119] The term "anti-Ri antibody-associated encephalitis" in the present invention is also called "anti-neuronal nuclear antibody type 2-associated encephalitis". Ri antigen is confined to neurons in the central nervous system, and anti-Ri antibodies are mainly found in the brain, brainstem, and spinal cord. It is one of the specific markers of breast cancer or small cell lung cancer.

[0120] The term "anti-Yo antibody-associated encephalitis" as used herein is also referred to as "Purkinje cell antigen type I antibody-associated encephalitis." Anti-Yo antibodies are polyclonal, complement-fixing IgG antibodies that primarily target the Yo antigen, a cytoplasmic protein, within cerebellar Purkinje cells. Typical symptoms of anti-Yo antibody-associated encephalitis include subacute cerebellar ataxia, manifested by ataxia affecting the trunk and limbs, vertigo, nystagmus, and dysarthria. It can also present as severe encephalomyelitis, brainstem encephalitis, quadriplegia, and impaired consciousness.

[0121] The term "anti-VGKC encephalitis" in the present invention refers to anti-VGKC (voltage-gated potassium channel) encephalitis, which is the most common type of neuronal surface AE, mainly manifested as typical limbic encephalitis, especially progressive refractory epilepsy.

[0122] The term "anti-VGCC encephalitis" in the present invention refers to anti-VGCC (voltage-gated calcium channel receptor) encephalitis, which is less common in women and children and is characterized by involvement of structures outside the limbic system, showing gyral enhancement and cortical laminar necrosis.

[0123] The term "immune checkpoint inhibitor-associated encephalitis" as used in this application refers to autoimmune encephalitis caused by the use of immune checkpoint inhibitors (ICIs). Clinical manifestations include headache, fever, weakness, fatigue, confusion, disorientation and concentration problems, memory impairment, drowsiness, hallucinations, seizures, and neck stiffness.

[0124] The term "biologic drug treatment regimen" in the present invention is often used to treat patients whose disease has failed traditional treatment, who have hormone resistance or intolerance, who have relapsed during hormone reduction, or who are refractory or severely ill. Exemplary biological targeted therapies with current application prospects include:

[0125] (1) B cell depletion therapy: non-limiting examples include anti-CD20 monoclonal antibody, anti-CD19 monoclonal antibody, B lymphocyte activating factor (BAFF) inhibitors, etc.

[0126] (2) Targeting T lymphocytes: non-limiting examples include abatacept, signaling lymphocyte activation molecule family member 7 (SLAMF 7) monoclonal antibody, and inducible co-stimulatory molecule ligand (ICOSL) inhibitor;

[0127] (3) Targeted cytokines (IL-4, IL-5\TNF-α) and intracellular signaling pathway JAK inhibitors, etc.

[0128] The term "about" is used herein to indicate that a numerical value includes the inherent error variation of the device or method used to determine the numerical value, or the variation between the samples tested. Unless otherwise stated or obvious from the context, the term "about" means within 10% of the reported numerical value (unless the number will exceed 100% or be less than 0% of the possible value). When used in conjunction with a numerical range or series, the term "about" applies to the endpoints of the range or each value listed in the series unless otherwise stated.

[0129] The embodiments of the present invention will be described in detail below with reference to examples. However, those skilled in the art will understand that the following examples are only used to illustrate the present invention and should not be regarded as limiting the scope of the present invention.

[0130] Example 1 Affinity Study

[0131] Compare the affinities of RC18, ALPN-303, APRIL and BAFF.

[0132] The affinity of RC18 and ALPN-303 for APRIL homotrimers and Blys homotrimers was tested using an enzyme-linked immunosorbent assay (ELISA), using null-IgG1 as a blank control. The experimental results are detailed in Table 4.

[0133] Table 4. April or Blys homotrimer ELISA binding assay

[0134] Note: “NB” means not bound.

[0135] in conclusion

[0136] In the April or Blys homotrimer ELISA binding test, RC18 and ALPN-303 can achieve good binding with both April and Blys.

[0137] Example 2: Treatment effects in real-world cases

[0138] Case 1

[0139] The patient experienced symptoms such as dizziness, unsteady walking, blurred vision, restricted eye movement, and involuntary head movement. Clinically, combined with multi-indicator diagnosis, it was considered to be autoimmune encephalitis (GAD65 type).

[0140] The patient received neurotrophic, circulatory, and steroid pulse therapy, along with rituximab. Following treatment, he developed generalized tremors and pallor, and the infusion was immediately discontinued. He was subsequently treated with immunosuppressants (mycophenolate mofetil 0.75 g bid) and glucocorticoids (prednisone 60 mg daily), but dizziness and unsteadiness persisted. He was then given immunosuppressants (cyclophosphamide 0.8 g daily, mycophenolate mofetil 0.75 g bid) and glucocorticoids (prednisone 45 mg daily), but his symptoms did not improve. The prednisone dose was subsequently increased to 30 mg daily, but the patient's condition remained unchanged, and he was unable to walk. The treatment regimen was subsequently adjusted to immunosuppressants (mycophenolate mofetil 0.75 g bid) and glucocorticoids (prednisone 15 mg daily) plus tetasipram (160 mg weekly). This treatment was effective, and blood tests revealed a CD19 lymphocyte count of 0.26% and normal immunoglobulins.

[0141] The results show:

[0142] ① For patients with AE who have difficulty tolerating hormones + rituximab, tetanusip can be used as an ideal alternative treatment drug, which is more effective than hormones + rituximab and has fewer adverse reactions.

[0143] ② For patients whose condition did not improve after repeated treatment with glucocorticoids + rituximab and glucocorticoids + immunosuppressants, their blood immunoglobulins returned to normal and their condition was relieved after treatment with tetasipir.

[0144] In summary, compared with existing treatment options and methods, tetasip shows better safety and efficacy in the treatment of patients with autoimmune encephalitis.

[0145] Case 2

[0146] The patient developed unexplained headaches, a low-grade fever, limb weakness, and a gradual inability to walk. He also developed slurred speech, loud yelling, and an inability to communicate. He also experienced dysphagia and incontinence. Cell localization revealed positive antibodies for astrocytes and neurons, with a positive intensity of +++. Combined with other clinical findings, the diagnosis was autoimmune encephalitis.

[0147] The patient had been treated with anti-anxiety and depression, brain protection, and nerve nutrition treatments, but with no significant improvement.

[0148] The patient was then given glucocorticoids (methylprednisolone 120 mg, IVD, qd) + intravenous human immunoglobulin (15 g, IVD, qd), and symptomatic treatment including anti-epileptic, anti-infective, improvement of mental symptoms, correction of electrolyte imbalance, etc. The patient developed sudden status epilepticus, decreased blood pressure, rapid heart rate, shortness of breath, unresponsiveness and coma.

[0149] On this basis, the patient underwent endotracheal intubation and double plasma exchange three times, but still had seizures. Subsequently, the steroid dosage was reduced, and an immunosuppressant (mycophenolate mofetil 0.5g bid) was added, with signs of improvement. Due to a relapse, the patient was re-evaluated and treated with immunoadsorption therapy twice, with continued steroid dosage reduction, mycophenolate mofetil 0.5g bid, and continued symptomatic treatment, including anti-epileptic and psychiatric management.

[0150] The patient came back for follow-up due to relapse of the disease and was given tetanusip (160 mg, qw), continued reduction of hormones (methylprednisolone 8 mg, qd), and symptomatic treatment.

[0151] The patient's symptoms improved after treatment with glucocorticoids combined with tadalafil, his mental symptoms were controlled, he was able to communicate with others, he had no infection, his muscle strength improved, and his liver and kidney functions were roughly normal.

[0152] The results show:

[0153] ① For the treatment regimens of glucocorticoids and glucocorticoids + immunosuppressants, the glucocorticoids + tetasip treatment regimen has better therapeutic effects.

[0154] ② For patients with a long medical history and repeated relapses after treatment, Tetasip shows good therapeutic potential.

[0155] Case 3

[0156] The patient had been experiencing poor spirits, moodiness, severe insomnia accompanied by sleep talking, excessive sweating, frequent urination, weakness in both lower limbs with a burning sensation in both feet, pain in both lower limbs, muscle tremors, and unsteady gait for two months, as well as a 15kg weight loss. An autoimmune encephalitis antibody panel revealed positive serum IgG for anti-contactin-associated protein 2 (CASPR2) antibodies, with no other abnormalities. Combined with other clinical findings, the patient was diagnosed with autoimmune encephalitis subtype: Morvan syndrome.

[0157] The patient received methylprednisolone pulse therapy with a gradual taper (200mg-160mg-80mg-40mg), and concurrently initiated tetasip 160mg subcutaneous injection every week for three months. During this time, symptomatic treatment with gabapentin and antianxiety and depression medications was administered. Bilateral lower limb weakness, pain, and muscle tremors improved; memory, mood, and sleep improved (MMSE 30, Moca 28, HAMA 8, HAMD 12); hyperhidrosis resolved, and urinary frequency improved. Steroids were successfully tapered to 15mg / day of prednisone, and the heart rate decreased to 94 bpm. Tacrolimus maintenance therapy was subsequently initiated.

[0158] The results show:

[0159] The patient was treated with hormones combined with tetanus for 3 months, and his symptoms improved significantly. At the same time, the hormone dosage was reduced smoothly, indicating that the tetanus treatment was effective.

[0160] Case 4

[0161] The patient had a subacute onset, with the main manifestations being paroxysmal limb convulsions, loss of consciousness, and difficulty speaking. Physical examination revealed difficulty finding words. Laboratory examinations showed increased meningeal enhancement in the cerebral hemispheres on MRI, positive NMDAR and MOG antibodies for autoimmune encephalitis, and abnormal electroencephalogram. Combined with other clinical findings, the patient was diagnosed with autoimmune encephalitis (MOG and NMDAR double antibody positive).

[0162] The patient was given immunoglobulin (0.4 g / kg, sufficient for a full course of 5 days) and glucocorticoid treatment (500 mg for 3 days, reduced to 240 mg*3 days, reduced to 120 mg*3 days, reduced to methylprednisolone 60 mg / d orally, and reduced by 1 tablet (i.e. 5 mg) every 5 days. Because the glucocorticoid chemical drug test indicated a high risk of inducing femoral head necrosis, the patient had a strong desire to reduce or stop hormones). At the same time, he was given sequential subcutaneous injections of 160 mg of tetasip every qw, and was given potassium supplementation, stomach protection, nutrition, and symptomatic treatment. Anti-epileptic treatment included sodium valproate and levetiracetam.

[0163] At the first follow-up, there were no further paroxysmal limb convulsions, loss of consciousness, or difficulty speaking, and clinical symptoms were relieved. The dose of glucocorticoid treatment was successfully reduced to 12 mg / d of methylprednisolone and continued to be reduced. Tetasip 160 mg was administered subcutaneously once a week for 12 weeks, and the dose was reduced to 160 mg every 10 days. Blood tests for NMDAR and MOG antibodies were negative, and the electroencephalogram was normal. The blood routine test, liver and kidney function tests were within normal range, and the blood concentration of sodium valproate was within normal range.

[0164] At the second follow-up, there were no further episodes of paroxysmal limb convulsions, loss of consciousness, or dysphasia, and clinical symptoms had completely resolved. Glucocorticoid therapy with methylprednisolone was discontinued, and the dose of tetasipram 160 mg was administered subcutaneously once weekly. After 12 weeks of regular use, the dose was reduced to 160 mg every 10 days. Blood routine, liver, and kidney function tests were within normal limits, as was the blood concentration of sodium valproate.

[0165] The results show:

[0166] The patient was treated with immunoglobulin, hormones and tetanercept for 3 months, and his symptoms were significantly improved. At the same time, immunoglobulin and hormones were successfully discontinued, and he was given tetanercept for maintenance treatment. After the follow-up visit, the symptoms completely disappeared, the antibodies turned negative, and the EEG returned to normal, indicating that the tetanercept treatment was effective.

[0167] Example 3 Clinical Study

[0168] Main Purpose

[0169] To explore the effectiveness of tetacept in treating or alleviating autoimmune encephalitis;

[0170] Secondary purpose

[0171] To preliminarily evaluate the safety of tetanuscept in treating or alleviating autoimmune encephalitis.

[0172] The above description is merely a preferred embodiment, which is intended to be illustrative and non-limiting of the combinations of features necessary to implement the present invention. The titles provided are not intended to limit the various embodiments of the present invention. Terms such as "comprising," "including," and "including" are not intended to be limiting. In addition, unless otherwise indicated, the absence of a numeral modifier includes the plural form, and "or" and "or" 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.

[0173] All disclosures and patents mentioned in this application are incorporated herein by reference. Without departing from the scope and spirit of the present invention, multiple modifications and variants of the described method and composition of the present invention will be apparent to those skilled in the art. Although the present invention has been described by specific preferred embodiments, it should be understood that the claimed invention should not be unduly limited to these specific embodiments. In fact, those multiple variants of the described pattern that are apparent to those skilled in the relevant art are intended to be included in the scope of the appended claims.

Claims

1. A method for treating or alleviating autoimmune encephalitis, the method comprising administering a therapeutically effective amount of a drug targeting Blys and / or APRIL to a patient with the autoimmune encephalitis. 2 . The method according to claim 1 , wherein the drug targeting Blys and / or APRIL is TACI-Fc fusion protein.

3. The method according to claim 2, characterized in that The TACI-Fc fusion protein comprises: (i) the extracellular domain of TACI or a fragment thereof that binds to Blys and / or APRIL; and (ii) Human immunoglobulin constant region fragments.

4. The method according to claim 3, characterized in that The TACI extracellular region or the fragment binding to Blys and / or APRIL comprises the amino acid sequence shown in SEQ ID NO:1 or SEQ ID NO:2 or SEQ ID NO:

3.

5. The method according to claim 3, characterized in that: 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 that is 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% identical to SEQ ID NO:

4.

6. The method according to claim 5, characterized in that The human immunoglobulin constant region fragment comprises amino acid modifications at one or more positions corresponding to positions 3, 8, 14, 15, 17, 110, 111 or 173 of SEQ ID NO:4; preferably, the human immunoglobulin constant region fragment comprises amino acid modifications at 1, 2, 3, 4, 5, 6, 7, 8 or more positions compared with SEQ ID NO:

4.

7. The method according to claim 6, characterized in that The modification is an amino acid substitution, deletion or insertion; preferably, the substitution comprises one or more of P3T, L8P, L14A, L15E, G17A, A110S, P111S and A173T; preferably, the insertion is the insertion of 1, 2, 3, 4, 5, 6, 7, 8 or more amino acids into the N-terminus of the human immunoglobulin constant region fragment.

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

6.

9. The method according to claim 8, characterized in that 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.

10. The method according to claim 8 or 9, characterized in that: The TACI-Fc fusion protein has an amino acid sequence shown in SEQ ID NO:7 or SEQ ID NO:8 or SEQ ID NO:

9.

11. The method according to claim 10, characterized in that The TACI-Fc fusion protein is telitacicept, atacicept or povetacicept.

12. The method according to any one of claims 1 to 11, characterized in that: The autoimmune encephalitis includes, but is not limited to, anti-cell surface antigen antibody encephalitis, anti-intracellular synaptic antigen antibody encephalitis, and anti-intracellular antigen antibody encephalitis.

13. The method according to any one of claims 1 to 12, characterized in that: The autoimmune encephalitis includes, but is not limited to, anti-NMDAR encephalitis, Morvan syndrome, progressive encephalomyelitis with tonicity and myoclonus, anti-dipeptidyl peptidase-like protein-6 (DPPX) antibody encephalitis, anti-dopamine type 2 receptor antibody-related basal ganglia encephalitis, anti-LGI1 antibody-related encephalitis, anti-GABABR antibody-related encephalitis, anti-CASPR2 antibody-related encephalitis, anti-IgLON5 antibody-related encephalopathy, anti-AMPAR antibody-related encephalitis, anti-GABAAR antibody-related encephalitis, anti-mGluR5 antibody-related encephalitis, anti-synaptic protein-3α antibody-related encephalitis, anti-glutamic acid decarboxylase (GAD) antibody One or more of the following: autoimmune encephalitis, anti-AK5 antibody-related encephalitis, anti-Hu antibody-related encephalitis, anti-CV2 antibody-related encephalitis, anti-Ma antibody-related encephalitis, anti-Kelch-like protein 11 antibody-related encephalitis, anti-Ri antibody-related encephalitis, anti-Yo antibody-related encephalitis, anti-VGKC encephalitis, anti-VGCC encephalitis and immune checkpoint inhibitor-related encephalitis; preferably, the anti-glutamic acid decarboxylase (GAD) antibody encephalitis is selected from anti-glutamic acid decarboxylase (GAD) 65 antibody encephalitis; preferably, the autoimmune encephalitis includes: anti-NMDAR encephalitis, Morvan syndrome, and anti-glutamic acid decarboxylase (GAD) 65 antibody encephalitis.

14. The method according to any one of claims 1 to 13, characterized in that: The autoimmune encephalitis patient is in the new disease treatment stage or the recurrent disease treatment stage; preferably, the patient is an adult patient or a pediatric patient; further preferably, the patient is an antibody-positive autoimmune encephalitis patient or an antibody-negative autoimmune encephalitis patient; further preferably, the antibody-positive autoimmune encephalitis patient is an autoimmune encephalitis patient with one or more antibodies.

15. The method according to any one of claims 1 to 14, characterized in that: The autoimmune encephalitis patient suffers from one or more other autoimmune diseases; preferably, the autoimmune encephalitis patient suffers from one or more other tumor diseases.

16. The method according to any one of claims 1 to 15, characterized in that: The patients may have previously received treatment for autoimmune encephalitis or may not have previously received treatment for autoimmune encephalitis.

17. The method according to any one of claims 1 to 16, characterized in that: The treatment regimen for autoimmune encephalitis includes, but is not limited to, one or more of a glucocorticoid treatment regimen, an immunosuppressant treatment regimen, a biological agent treatment regimen, and plasma exchange; preferably, the glucocorticoid is selected from prednisone and / or methylprednisone; preferably, the immunosuppressant is selected from cyclophosphamide and / or mycophenolate mofetil; preferably, the biological agent is selected from one or more of rituximab, human immunoglobulin, and immunoglobulin G.

18. The method according to any one of claims 1 to 17, characterized in that: The method comprises administering a therapeutically effective amount of a drug targeting Blys and / or APRIL to a patient with the autoimmune encephalitis, and at the same time, applying one or more of glucocorticoids, immunosuppressants, biological agents, and plasma exchange in combination; preferably, the immunosuppressant is mycophenolate mofetil; preferably, the glucocorticoid is prednisone or methylprednisone; preferably, the biological agent is selected from one or more of rituximab, human immunoglobulin and immunoglobulin G; further preferably, administering a therapeutically effective amount of a drug targeting Blys and / or APRIL and at the same time, applying a glucocorticoid in combination, the drug targeting Blys and / or APRIL is administered once a week and the glucocorticoid is administered once a day; further preferably, administering a therapeutically effective amount of a drug targeting Blys and / or APRIL and at the same time, applying a glucocorticoid and an immunosuppressant in combination, the drug targeting Blys and / or APRIL is administered once a week, the glucocorticoid is administered once a day, and the immunosuppressant is administered twice a day.

19. The method according to any one of claims 1 to 18, characterized in that: The single dosage of the drug targeting Blys and / or APRIL is about 0.1 to 10 mg / kg; preferably, the single dosage of the drug targeting Blys and / or APRIL is 40-240 mg, further preferably 40 mg, 60 mg, 80 mg, 100 mg, 120 mg, 140 mg, 160 mg, 240 mg.

20. The method according to any one of claims 1 to 19, characterized in that: The drug targeting Blys and / or APRIL is administered on demand; preferably, the drug targeting Blys and / or APRIL is used 1-5 times during each monthly interval, and / or 1-10 times during each two-month interval, and / or 1-15 times during each three-month interval; further preferably, the drug targeting Blys and / or APRIL is administered once a week or once every 10 days; further preferably, the drug targeting Blys and / or APRIL is administered subcutaneously, intramuscularly or intravenously, or the administration site is the thigh, abdomen or upper arm.

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