Treatment of autoimmune encephalitis with satralizumab

Abstract

All currently available treatment options for autoimmune encephalitis, such as anti-NMDAR encephalitis and anti-LGI1 encephalitis, have substantial potential safety risks.In addition, there is no approved treatment for anti-NMDAR encephalitis and anti-LGI1 encephalitis.The present invention provides a means for the treatment of autoimmune encephalitis (AIE), such as NMDAR encephalitis and anti-LGI1 encephalitis, including IL-6 inhibitors, such as anti-IL-6 receptor antibodies or their antigen-binding fragments. TIFF2025502891000011.tif93170

Description

[Technical field]

[0001] The present invention relates to a pharmaceutical product or pharmaceutical composition for treating or reducing the risk of recurrence of autoimmune encephalitis (also called AIE or AE), including but not limited to anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis and anti-leucine-rich glioma inactivated 1 (LGI1) encephalitis, comprising an anti-IL-6 receptor antibody or an antigen-binding fragment thereof. The present invention also relates to a method for treating or reducing the risk of recurrence of said autoimmune encephalitis (AIE), including but not limited to anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis and anti-leucine-rich glioma inactivated 1 (LGI1) encephalitis, by administering an anti-IL-6 receptor antibody or an antigen-binding fragment thereof to a subject in need thereof. [Background technology]

[0002] Acute encephalitis is a rare and debilitating neurological disorder that develops in patients of all ages and manifests as a rapidly progressive brain disorder as a result of brain inflammation [Non-Patent Document 1]. Autoimmune encephalitis (AIE) includes disorders with identifiable pathogenic drivers, usually tumor-associated, and disorders considered idiopathic. Paraneoplastic immune-mediated encephalitis syndromes may be associated with antibodies against intracellular neuronal proteins (onconeuronal proteins such as anti-Hu). These tend to represent syndromes of unknown pathogenic significance and poor response to immunotherapy.

[0003] Identification of antibodies against neuronal cell surface and synaptic proteins that are believed to be directly pathogenic indicates a population that generally responds better to immunotherapy, with or without the identification of associated tumors. Among these AIE subtypes, NMDAR- and LGI1-mediated encephalitis represent two of the most common [Non-Patent Document 2] and best-characterized syndromes.

[0004] NMDAR encephalitis is an immune-mediated disease characterized by a complex neuropsychiatric syndrome including cognitive impairment and seizures, as well as the presence of cerebrospinal fluid (CSF) antibodies against the GluN1 subunit of NMDAR. Using mouse models, these antibodies were shown to crosslink NMDAR, altering its surface dynamics and interactions with other synaptic proteins, and causing its internalization along with severe impairment of synaptic plasticity and NMDAR network function [Non-Patent Documents 3-6]. NMDAR encephalitis has an estimated incidence of 1.5 cases per million population per year, mostly occurring in women (approximately 8:2 female to male ratio), with a median age of onset of 21 years (age range: <1 year old to 85 years old). Patients develop a constellation of symptoms that vary depending on the stage of the disease and are clinically suggestive of the diagnosis [Non-Patent Document 7].

[0005] LGI1 encephalitis is an immune-mediated disease in which most patients present with limbic encephalitis characterized by subacute impairment of memory and behavior, often accompanied by seizures. It is associated with antibodies against the LGI1 protein. LGI1 encephalitis is more common in middle-aged and older men (over 50 years old) [Non-Patent Document 8]. Most LGI1 protein is expressed in the hippocampus and the broader medial temporal lobe, from where it is secreted into the synaptic space. LGI1 is part of an inhibitory pathway that connects presynaptic voltage-gated K+ channels (VGKC) and postsynaptic a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs) [Non-Patent Document 9 and Non-Patent Document 10]. LGI1 encephalitis has an estimated prevalence of 7 per million population [Non-Patent Document 11] and an estimated incidence of 0.83 per million individuals [Non-Patent Document 12].

[0006] There is no approved treatment for NMDAR encephalitis or LGI1 encephalitis. The treatment approach for NMDAR encephalitis and LGI1 encephalitis includes first-line therapy (e.g., steroids, intravenous immunoglobulin [IVIG], or plasma exchange) as detailed in a recent survey conducted by the Autoimmune Encephalitis Alliance Clinicians Network [Non-Patent Document 13]. Although high-dose steroids are most commonly used, the distribution of first-line treatments in the two most common disorders is very similar, as shown below.

[0007] The principles of escalation, the use of second-line therapies, and the specific second-line therapies used are similar between the two disorders, although steroid responsiveness is more commonly seen in LGI1 encephalitis

[14] and long-term use of steroids is more commonly used in this disorder.

[0008] Although the majority of patients with cell surface antibody-positive disease achieve stable status with currently used treatment options, no prospective randomized trials have been reported in this population to date, and all therapeutic agents are used based on anecdotal evidence. Several limitations apply to the current AIE treatment paradigm, which highlights that there remains a significant unmet need for treatments with demonstrated efficacy in terms of rapid and long-term efficacy and safety. For example, not all patients respond to these medications, and deficiencies remain, including cognitive deficits, inadequate seizure recovery, dependence on high-dose corticosteroids, and the need for sustained faster-acting agents. There is an urgent need for prospectively generated evidence in AIE to guide treatment selection to address both the acute and long-term effects of this rare neurological disorder.

[0009] Humanized antibodies such as tocilizumab are first-generation antibody drugs. Second-generation antibody drugs have been developed with improved efficacy, convenience, and cost by improving the first-generation antibody drugs [Patent Document 2 and Patent Document 3]. Among the second-generation antibody drugs, there is satralizumab (SA237), a novel anti-IL-6 receptor antibody that has been improved by techniques such as enhancing antigen binding ability, pharmacokinetics, and stability, and reducing the risk of immunogenicity [Patent Document 3 and Patent Document 4].

[0010] Satralizumab is a humanized anti-IL-6 receptor monoclonal antibody with pH-dependent antigen binding. It specifically targets the human IL-6 receptor (IL-6R) and inhibits IL-6 signaling by inhibiting the binding of IL-6 to membrane-bound IL-6R and soluble IL-6R. Satralizumab was constructed by modifying the amino acid sequence of tocilizumab to extend its plasma half-life. Satralizumab also exhibits a reduced antibody molecule isoelectric point and stronger binding to FcRn compared to tocilizumab. In addition, its Fc region has been modified to minimize antibody-dependent cellular cytotoxicity and complement-dependent cytotoxicity effector activity compared to tocilizumab. The following literature information on prior art related to the invention of this application is provided below.

[0011] Satralizumab has demonstrated efficacy and safety and is indicated in another autoantibody-mediated disease (i.e., NMOSD) as monotherapy or as an add-on to immunosuppressive therapy (IST; i.e., oral corticosteroids [OCS], azathioprine, or mycophenolate mofetil). The double-blind period of the Phase III study in NMOSD included a total of 178 participants. Of the 178 participants, 104 participants were treated with a 120 mg satralizumab dose subcutaneously every 4 weeks (Q4W) and 74 participants were treated with placebo. Overall, satralizumab as monotherapy or in combination with IST was well tolerated by participants with NMOSD.

[0012] All currently available treatment options for AIE (including high-dose corticosteroids and cyclophosphamide) have substantial potential safety risks. There is no evidence from randomized controlled trials to support treatment decisions. In addition, not all patients respond to currently used pharmacotherapy, and deficiencies remain, including cognitive deficits, inadequate seizure recovery, dependence on high-dose corticosteroids, and the need for sustained faster-acting agents. [Prior art documents] [Patent documents]

[0013] [Patent Document 1] US2012 / 0039840 [Patent Document 2] WO2009 / 041621 [Patent Document 3] WO2010 / 035769 [Patent Document 4] WO2016 / 136933 [Non-patent literature]

[0014] [Non-Patent Document 1] Venkatesan A, Tunkel AR, Bloch KC, et al., Clin Infect Dis 2013;57:1114-28 [Non-Patent Document 2] Leypoldt F, Wandinger KP, Bien C, et al., Eur Neurol Rev 2013;8:31-7 [Non-Patent Document 3] Hughes EG, Peng X, Gleichman AJ, et al., J Neurosci 2010;30:5866-75 [Non-Patent Document 4] Mikasova L, De Rossi P, Bouchet D, et al., Brain 2012;135:1606-21

Non-licensed Document 5

Non-licensed Document 6

Non-licensed Document 7

Non-licensed literature 9

Non-licensed literature 10

Non-licensed Document 11

Non-licensed Document 12

Non-licensed Document 13

Non-licensed Document 14

[0015] Current treatments for autoimmune encephalitides (AIE), such as anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis and anti-leucine-rich glioma inactivation 1 (LGI1) encephalitis, exclusively use off-label immunotherapies and are based on expert opinion, retrospective case series, and open-label studies. All currently available treatment options for AIE, including high-dose corticosteroids and cyclophosphamide, have substantial potential safety risks. Furthermore, no approved treatments exist for anti-NMDAR and anti-LGI1 encephalitis. Several unmet needs exist, including the frequent occurrence of long-term cognitive deficits, inadequate seizure control, frequent dependence on high-dose corticosteroids, and faster-acting but durable immunotherapies. Prospectively generated evidence-based treatments are needed to meaningfully reduce the acute and long-term severity of these disorders. [Means for solving the problem]

[0016] To solve the above problems, the inventors designed a Phase III, randomized, double-blind (DB), placebo-controlled, multicenter basket study to evaluate the efficacy, safety, pharmacokinetics, and pharmacodynamics of satralizumab compared with placebo for the treatment of anti-NMDAR encephalitis and anti-LGI1 encephalitis. The study demonstrates that satralizumab addresses the above unmet needs, and also demonstrates the efficacy of satralizumab in patients with NMDAR encephalitis or LGI1 encephalitis for treating AIE, preventing recurrence of AIE, and reducing the risk of recurrence of AIE.

[0017] The present disclosure includes, but is not limited to, the embodiments described below. [A1.1] A pharmaceutical agent comprising an IL-6 inhibitor as an active ingredient for treating autoimmune encephalitis (AIE) or reducing the risk of its recurrence in a subject. [A1.2] The pharmaceutical of A1.1, wherein the IL-6 inhibitor is an anti-IL-6 antibody or an antigen-binding fragment thereof, or an anti-IL-6 receptor antibody or an antigen-binding fragment thereof. [A1.3] The pharmaceutical agent according to A1.1 or A1.2, wherein the IL-6 inhibitor is an anti-IL-6 receptor antibody or an antigen-binding fragment thereof. [A1.4] Any one of the pharmaceutical agents A1.1 to A1.3, wherein the IL-6 inhibitor is a humanized antibody. [A1.5] Any one of the pharmaceuticals A1.1 to A1.4, wherein the IL-6 inhibitor is an anti-IL-6 receptor antibody or an antigen-binding fragment thereof, comprising a heavy chain variable region (VH) CDR1 comprising the amino acid sequence of SEQ ID NO: 5, a VH CDR2 comprising the amino acid sequence of SEQ ID NO: 6, a VH CDR3 comprising the amino acid sequence of SEQ ID NO: 7, a light chain variable region (VL) CDR1 comprising the amino acid sequence of SEQ ID NO: 8, a VL CDR2 comprising the amino acid sequence of SEQ ID NO: 9, and a VL CDR3 comprising the amino acid sequence of SEQ ID NO: 10. [A1.6] The pharmaceutical of A1.5, wherein the anti-IL-6 receptor antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1, and a VL comprising the amino acid sequence of SEQ ID NO: 2. [A1.7] A pharmaceutical agent according to A1.5 or A1.6, wherein the IL-6 inhibitor is an anti-IL-6 receptor antibody comprising a heavy chain comprising the amino acid sequence of SEQ ID NO:3 and a light chain comprising the amino acid sequence of SEQ ID NO:4. [A1.8] Any one of the pharmaceuticals A1.5 to A1.7, wherein the IL-6 inhibitor is satralizumab. [A1.9] Any one of A1.1 to A1.8 for delaying relapses of, reducing the frequency of, reducing the severity of, or reducing the need for salvage therapy for, autoimmune encephalopathy in a subject. [A1.10] Any one of A1.1 to A1.9, wherein the subject is positive for anti-N-methyl-D-aspartate receptor (NMDAR) antibodies or anti-leucine-rich glioma inactivated 1 (LGI1) antibodies. [A1.11] Any one of the pharmaceuticals A1.1 to A1.10, wherein the autoimmune encephalitis is a disease other than Bickerstaff brainstem encephalitis, acute disseminated encephalomyelitis, Hashimoto's encephalopathy, primary central nervous system (CNS) vasculitis, and Rasmussen's encephalitis. [A1.12] Any one of A1.1 to A1.11, wherein the anti-NMDAR antibody is detected in cerebrospinal fluid (CSF) from the subject using a cell-based assay. [A1.13] Any one of the pharmaceuticals A1.1 to A1.12, wherein the autoimmune encephalitis is anti-NMDAR encephalitis. [A1.14] Any one of A1.1 to A1.11, wherein anti-LGI1 antibodies are detected in serum or cerebrospinal fluid (CSF) from the subject using a cell-based assay. [A1.15] A medicinal product according to A1.14, wherein the subject has experienced working memory deficits, seizures, or neurological symptoms suggestive of limbic system involvement. [A1.16] Any one of the pharmaceuticals A1.1 to A1.11 and A1.14 to A1.15, wherein the autoimmune encephalitis is anti-LGI1 encephalitis. [A1.17] Any one of the pharmaceuticals A1.1 to A1.16, wherein the autoimmune encephalitis is anti-NMDAR encephalitis or anti-LGI1 encephalitis. [A1.18] The subject is a patient having an anti-caspr2 antibody, an anti-IgLON5 antibody, an anti-DPPX antibody, an anti-GABA antibody, A Any one of A1.1 to A1.17, negative for antibodies, anti-neurexin-3α antibodies, and anti-myelin oligodendrocyte glycoprotein (MOG) antibodies. [A1.19] Any one of the pharmaceuticals of A1.1 to A1.18, wherein the subject is negative for cell surface neuronal or glial antibodies other than anti-NMDAR antibodies and anti-LGI1 antibodies. [A1.20] Any one of A1.1 to A1.19, wherein the subject is (i) anti-NMDAR antibody positive and 12 years of age or older; or (ii) anti-LGI1 antibody positive and 18 years of age or older. [A1.21] Any one of A1.1 to A1.20, wherein the subject is not receiving any ongoing chronic immunosuppressive therapy. [A1.22] Any one of A1.1 to A1.20, where the subject is receiving ongoing treatment with a stable dose of azathioprine (AZA), mycophenolate mofetil (MMF), intravenous (IV) cyclophosphamide, oral corticosteroids (OCS), or a combination of AZA or MMF or IV cyclophosphamide with OCS. [A1.23] Any one of the pharmaceuticals of A1.5 to A1.22, characterized in that the pharmaceutical is used such that, for each administration, 60 mg or 120 mg, 120 mg or 180 mg, and 180 mg or 240 mg of an anti-IL-6 receptor antibody or antigen-binding fragment thereof are administered to a subject having a body weight of less than 40 kg, 40 to 100 kg, and more than 100 kg, respectively. [A1.24] Any one of the pharmaceuticals A1.5 to A1.22, characterized in that the pharmaceutical is used so that, for each administration, 60 mg of the anti-IL-6 receptor antibody or its antigen-binding fragment is administered to a subject having a body weight of less than 40 kg. [A1.25] Any one of the pharmaceuticals A1.5 to A1.22, characterized in that the pharmaceutical is used so that, for each administration, 120 mg of an anti-IL-6 receptor antibody or an antigen-binding fragment thereof is administered to a subject having a body weight of less than 40 kg. [A1.26] Any one of the pharmaceuticals A1.5 to A1.22, characterized in that the pharmaceutical is used so that, for each administration, 120 mg of the anti-IL-6 receptor antibody or antigen-binding fragment thereof is administered to a subject having a body weight of 40 to 100 kg. [A1.27] Any one of the pharmaceuticals of A1.5 to A1.22, characterized in that the pharmaceutical is used so that, for each administration, 180 mg of the anti-IL-6 receptor antibody or antigen-binding fragment thereof is administered to a subject having a body weight of 40 to 100 kg. [A1.28] Any one of the pharmaceuticals of A1.5 to A1.22, characterized in that the pharmaceutical is used such that, for each administration, 180 mg of an anti-IL-6 receptor antibody or an antigen-binding fragment thereof is administered to a subject having a body weight of more than 100 kg. [A1.29] Any one of the pharmaceuticals of A1.5 to A1.22, characterized in that the pharmaceutical is used such that, for each administration, 240 mg of an anti-IL-6 receptor antibody or an antigen-binding fragment thereof is administered to a subject having a body weight of more than 100 kg. [A1.30] Any one of the pharmaceuticals A1.5 to A1.29, characterized in that the pharmaceutical is used so that the anti-IL-6 receptor antibody or its antigen-binding fragment is administered subcutaneously to a subject. [A1.31] Any one of the pharmaceuticals A1.5 to A1.30, characterized in that the pharmaceutical is used such that the anti-IL-6 receptor antibody or antigen-binding fragment thereof is administered to a subject three times at two-week intervals (Q2W) and then four-weekly (Q4W) at a time. [A1.32] Any one of the pharmaceutical agents A1.1 to A1.31, characterized in that the pharmaceutical agent is used in combination with immunosuppressant therapy (IST). [A1.33] The pharmaceutical product of A1.32, wherein the IST is treatment with: (i) an immunosuppressant selected from the group consisting of azathioprine (AZA), mycophenolate mofetil (MMF), and intravenous (IV) cyclophosphamide; (ii) oral corticosteroids (OCS); or (iii) a combination of (i) and (ii). [A1.34] The pharmaceutical product of A1.33, wherein the immunosuppressant comprises prednisone, prednisolone, or an equivalent thereof. [A1.35] Any one of A1.1 to A1.34 medications that improve the modified Rankin Scale (mRS) score. [A1.36]- Reduce the time to improvement in modified Rankin Scale (mRS) score without the use of rescue therapy; - Delay time to rescue therapy, - delaying the time to seizure freedom or cessation of status epilepticus without the use of rescue therapy; - Improve Clinical Assessment Scale of Encephalitis (CASE) scores; - Improve Montreal Cognitive Assessment (MOCA) total score; - improving Rey Auditory Verbal Learning Test (RAVLT) scores in subjects with anti-LGI1 antibodies, and / or - improve mRS scores in subjects with anti-NMDAR antibodies, A1.35 medicine. [A1.37] Any one of A1.1 to A1.36 that improves a subject's score on one or more of the following scales: modified Rankin Scale (mRS), Clinical Assessment of Encephalitis (CASE), Montreal Cognitive Assessment (MOCA), Rey Auditory Verbal Learning Test (RAVLT), or Columbia-Suicide Severity Rating Scale (C-SSRS). [A1.38] Any one of A1.1 to A1.36 that reduces a subject's modified Rankin Scale (mRS) score or Clinical Assessment of Encephalitis (CASE) score; or increases a subject's Montreal Cognitive Assessment (MOCA) total score or Rey Auditory Verbal Learning Test (RAVLT) score. [A1.39] Any one of A1.1 to A1.38 administered by a subcutaneous administration device. [A1.40] The drug of A1.39, wherein the subcutaneous administration device is a pre-filled syringe (PFS), optionally a pre-filled syringe with needle safety device (PFS-NSD), or an auto-injector (AI).

[0018] [A2.1] A pharmaceutical composition comprising an IL-6 inhibitor as an active ingredient for treating or reducing the risk of recurrence of autoimmune encephalitis (AIE) in a subject. [A2.2] The pharmaceutical composition of A2.1, wherein the IL-6 inhibitor is an anti-IL-6 antibody or an antigen-binding fragment thereof, or an anti-IL-6 receptor antibody or an antigen-binding fragment thereof. [A2.3] The pharmaceutical composition of A2.1 or A2.2, wherein the IL-6 inhibitor is an anti-IL-6 receptor antibody or an antigen-binding fragment thereof. [A2.4] Any one of the pharmaceutical compositions of A2.1 to A2.3, wherein the IL-6 inhibitor is a humanized antibody. [A2.5] Any one of the pharmaceutical compositions of A2.1 to A2.4, wherein the IL-6 inhibitor is an anti-IL-6 receptor antibody or an antigen-binding fragment thereof, comprising a heavy chain variable region (VH) CDR1 comprising the amino acid sequence of SEQ ID NO: 5, a VH CDR2 comprising the amino acid sequence of SEQ ID NO: 6, a VH CDR3 comprising the amino acid sequence of SEQ ID NO: 7, a light chain variable region (VL) CDR1 comprising the amino acid sequence of SEQ ID NO: 8, a VL CDR2 comprising the amino acid sequence of SEQ ID NO: 9, and a VL CDR3 comprising the amino acid sequence of SEQ ID NO: 10. [A2.6] The pharmaceutical composition of A2.5, wherein the anti-IL-6 receptor antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:1, and a VL comprising the amino acid sequence of SEQ ID NO:2. [A2.7] The pharmaceutical composition of A2.5 or A2.6, wherein the IL-6 inhibitor is an anti-IL-6 receptor antibody comprising a heavy chain comprising the amino acid sequence of SEQ ID NO:3 and a light chain comprising the amino acid sequence of SEQ ID NO:4. [A2.8] Any one of the pharmaceutical compositions of A2.5 to A2.7, wherein the IL-6 inhibitor is satralizumab. [A2.9] Any one of the pharmaceutical compositions of A2.1-A2.8 for delaying relapses, reducing the frequency of relapses, reducing the severity of relapses, or reducing the need for rescue therapy for relapses of autoimmune encephalopathy in a subject. [A2.10] Any one of the pharmaceutical compositions of A2.1 to A2.9, wherein the subject is positive for anti-N-methyl-D-aspartate receptor (NMDAR) antibody or anti-leucine-rich glioma inactivated 1 (LGI1) antibody. [A2.11] Any one of the pharmaceutical compositions of A2.1 to A2.10, wherein the autoimmune encephalitis is a disease other than Bickerstaff brainstem encephalitis, acute disseminated encephalomyelitis, Hashimoto's encephalopathy, primary central nervous system (CNS) vasculitis, and Rasmussen's encephalitis. [A2.12] Any one of the pharmaceutical compositions of A2.1-A2.11, wherein the anti-NMDAR antibody is detected in cerebrospinal fluid (CSF) from the subject using a cell-based assay. [A2.13] Any one of the pharmaceutical compositions of A2.1 to A2.12, wherein the autoimmune encephalitis is anti-NMDAR encephalitis. [A2.14] Any one of the pharmaceutical compositions of A2.1 to A2.11, wherein the anti-LGI1 antibody is detected in serum or cerebrospinal fluid (CSF) from the subject using a cell-based assay. [A2.15] The pharmaceutical composition of A2.14, wherein the subject has experienced working memory deficits, seizures, or neurological symptoms suggestive of limbic system involvement. [A2.16] Any one of the pharmaceutical compositions of A2.1 to A2.11 and A2.14 to A2.15, wherein the autoimmune encephalitis is anti-LGI1 encephalitis. [A2.17] Any one of the pharmaceutical compositions of A2.1 to A2.16, wherein the autoimmune encephalitis is anti-NMDAR encephalitis or anti-LGI1 encephalitis. [A2.18] The subject is a patient having anti-caspr2 antibody, anti-IgLON5 antibody, anti-DPPX antibody, anti-GABA antibody, AAny one of A2.1 to A2.17, wherein the pharmaceutical composition is negative for antibodies, anti-neurexin-3α antibodies, and anti-myelin oligodendrocyte glycoprotein (MOG) antibodies. [A2.19] Any one of the pharmaceutical compositions of A2.1 to A2.18, wherein the subject is negative for cell surface neuronal or glial antibodies other than anti-NMDAR antibodies and anti-LGI1 antibodies. [A2.20] Any one of the pharmaceutical compositions of A2.1 to A2.19, wherein the subject is (i) anti-NMDAR antibody positive and 12 years of age or older; or (ii) anti-LGI1 antibody positive and 18 years of age or older. [A2.21] Any one of the pharmaceutical compositions of A2.1 to A2.20, wherein the subject is not receiving any ongoing chronic immunosuppressive therapy. [A2.22] Any one of the pharmaceutical compositions of A2.1 to A2.20, wherein the subject is receiving ongoing treatment with a stable dose of azathioprine (AZA), mycophenolate mofetil (MMF), intravenous (IV) cyclophosphamide, oral corticosteroids (OCS), or a combination of AZA or MMF or IV cyclophosphamide with OCS. [A2.23] Any one of the pharmaceutical compositions of A2.5 to A2.22, wherein the pharmaceutical composition is used such that, for each administration, 60 mg or 120 mg, 120 mg or 180 mg, and 180 mg or 240 mg of an anti-IL-6 receptor antibody or antigen-binding fragment thereof are administered to a subject having a body weight of less than 40 kg, 40 to 100 kg, and more than 100 kg, respectively. [A2.24] Any one of the pharmaceutical compositions of A2.5 to A2.22, characterized in that the pharmaceutical composition is used so that, for each administration, 60 mg of the anti-IL-6 receptor antibody or its antigen-binding fragment is administered to a subject having a body weight of less than 40 kg. [A2.25] Any one of the pharmaceutical compositions of A2.5 to A2.22, wherein the pharmaceutical composition is used so that, for each administration, 120 mg of an anti-IL-6 receptor antibody or an antigen-binding fragment thereof is administered to a subject having a body weight of less than 40 kg. [A2.26] Any one of the pharmaceutical compositions of A2.5 to A2.22, wherein the pharmaceutical composition is used so that, for each administration, 120 mg of the anti-IL-6 receptor antibody or antigen-binding fragment thereof is administered to a subject having a body weight of 40 to 100 kg. [A2.27] Any one of the pharmaceutical compositions of A2.5 to A2.22, wherein the pharmaceutical composition is used so that, for each administration, 180 mg of the anti-IL-6 receptor antibody or antigen-binding fragment thereof is administered to a subject having a body weight of 40 to 100 kg. [A2.28] Any one of the pharmaceutical compositions of A2.5 to A2.22, characterized in that the pharmaceutical composition is used so that, for each administration, 180 mg of an anti-IL-6 receptor antibody or an antigen-binding fragment thereof is administered to a subject having a body weight of more than 100 kg. [A2.29] Any one of the pharmaceutical compositions of A2.5 to A2.22, wherein the pharmaceutical composition is used such that, for each administration, 240 mg of an anti-IL-6 receptor antibody or an antigen-binding fragment thereof is administered to a subject having a body weight of more than 100 kg. [A2.30] Any one of the pharmaceutical compositions A2.5 to A2.29, characterized in that the pharmaceutical composition is used so that the anti-IL-6 receptor antibody or its antigen-binding fragment is administered subcutaneously to a subject. [A2.31] Any one of the pharmaceutical compositions of A2.5 to A2.30, wherein the pharmaceutical composition is used so that the anti-IL-6 receptor antibody or antigen-binding fragment thereof is administered to a subject three times at two-week intervals (Q2W) and then four-weekly (Q4W) intervals. [A2.32] Any one of the pharmaceutical compositions of A2.1 to A2.31, characterized in that the pharmaceutical composition is used in combination with immunosuppressive therapy (IST). [A2.33] The pharmaceutical composition of A2.32, wherein the IST is a treatment with: (i) an immunosuppressant selected from the group consisting of azathioprine (AZA), mycophenolate mofetil (MMF), and intravenous (IV) cyclophosphamide; (ii) an oral corticosteroid (OCS); or (iii) a combination of (i) and (ii). [A2.34] The pharmaceutical composition of A2.33, wherein the immunosuppressant comprises prednisone, prednisolone, or an equivalent thereof. [A2.35] Any one of the pharmaceutical compositions of A2.1 to A2.34, which improves modified Rankin Scale (mRS) score improvement. [A2.36]- Reduce the time to improvement in modified Rankin Scale (mRS) score without the use of rescue therapy; - Delay time to rescue therapy, - delaying the time to seizure freedom or cessation of status epilepticus without the use of rescue therapy; - Improve Clinical Assessment Scale for Encephalitis (CASE) scores; - Improve Montreal Cognitive Assessment (MOCA) total score, - improving Rey Auditory Verbal Learning Test (RAVLT) scores in subjects with anti-LGI1 antibodies, and / or - improve mRS scores in subjects with anti-NMDAR antibodies, A pharmaceutical composition of A2.35. [A2.37] Any one of the pharmaceutical compositions of A2.1 to A2.36, which improves a subject's score on one or more of the modified Rankin Scale (mRS), Clinical Assessment of Encephalitis (CASE), Montreal Cognitive Assessment (MOCA), Rey Auditory Verbal Learning Test (RAVLT), or Columbia-Suicide Severity Rating Scale (C-SSRS). [A2.38] Any one of the pharmaceutical compositions of A2.1 to A2.36 that reduces a subject's modified Rankin Scale (mRS) score or Clinical Assessment of Encephalitis (CASE) score; or increases a subject's Montreal Cognitive Assessment (MOCA) total score or Rey Auditory Verbal Learning Test (RAVLT) score. [A2.39] Any one of the pharmaceutical compositions of A2.1 to A2.38, administered by a subcutaneous administration device. [A2.40] The pharmaceutical composition of A2.39, wherein the subcutaneous administration device is a pre-filled syringe (PFS), optionally a pre-filled syringe with needle safety device (PFS-NSD), or an auto-injector (AI).

[0019] [B1] Use of an IL-6 inhibitor in the preparation of a medicine for treating autoimmune encephalitis (AIE) or reducing the risk of its recurrence in a subject. [B2] Use of B1, wherein the IL-6 inhibitor is an anti-IL-6 antibody or an antigen-binding fragment thereof, or an anti-IL-6 receptor antibody or an antigen-binding fragment thereof. [B3] Use of B1 or B2, wherein the IL-6 inhibitor is an anti-IL-6 receptor antibody or an antigen-binding fragment thereof. [B4] Use of any one of B1 to B3, wherein the IL-6 inhibitor is a humanized antibody. [B5] Use of any one of B1 to B4, wherein the IL-6 inhibitor is an anti-IL-6 receptor antibody or an antigen-binding fragment thereof, comprising a heavy chain variable region (VH) CDR1 comprising the amino acid sequence of SEQ ID NO: 5, a VH CDR2 comprising the amino acid sequence of SEQ ID NO: 6, a VH CDR3 comprising the amino acid sequence of SEQ ID NO: 7, a light chain variable region (VL) CDR1 comprising the amino acid sequence of SEQ ID NO: 8, a VL CDR2 comprising the amino acid sequence of SEQ ID NO: 9, and a VL CDR3 comprising the amino acid sequence of SEQ ID NO: 10. [B6] Use of B5, wherein the anti-IL-6 receptor antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1, and a VL comprising the amino acid sequence of SEQ ID NO: 2. [B7] Use of B5 or B6, wherein the IL-6 inhibitor is an anti-IL-6 receptor antibody comprising a heavy chain comprising the amino acid sequence of SEQ ID NO:3 and a light chain comprising the amino acid sequence of SEQ ID NO:4. [B8] Use of any one of B5 to B7, wherein the IL-6 inhibitor is satralizumab. [B9] The use of any one of B1 to B8, wherein the medicament is for delaying relapses of, reducing the frequency of, reducing the severity of, or reducing the need for rescue therapy for, an autoimmune encephalopathy in a subject. [B10] The use of any one of B1 to B9, wherein the subject is positive for anti-N-methyl-D-aspartate receptor (NMDAR) antibody or anti-leucine-rich glioma inactivated 1 (LGI1) antibody. [B11] Use of any one of B1 to B10, wherein the autoimmune encephalitis is a disease other than Bickerstaff brainstem encephalitis, acute disseminated encephalomyelitis, Hashimoto's encephalopathy, primary central nervous system (CNS) vasculitis, and Rasmussen's encephalitis. [B12] The use of any one of B1 to B11, wherein the anti-NMDAR antibody is detected in cerebrospinal fluid (CSF) from the subject using a cell-based assay. [B13] Use of any one of B1 to B12, wherein the autoimmune encephalitis is anti-NMDAR encephalitis. [B14] Use of any one of B1 to B11, wherein anti-LGI1 antibodies are detected in serum or cerebrospinal fluid (CSF) from the subject using a cell-based assay. [B15] The use of B14, wherein said subject has experienced working memory deficits, seizures, or neurological symptoms suggestive of limbic system involvement. [B16] Use of any one of B1 to B11 and B14 to B15, wherein the autoimmune encephalitis is anti-LGI1 encephalitis. [B17] Use of any one of B1 to B16, wherein the autoimmune encephalitis is anti-NMDAR encephalitis or anti-LGI1 encephalitis. [B18] The subject is an anti-caspr2 antibody, an anti-IgLON5 antibody, an anti-DPPX antibody, an anti-GABA antibody, A Use of any one of B1 to B17 that is negative for antibodies, anti-neurexin-3α antibodies, and anti-myelin oligodendrocyte glycoprotein (MOG) antibodies. [B19] Use of any one of B1 to B18, wherein the subject is negative for cell surface neuronal or glial antibodies other than anti-NMDAR antibodies and anti-LGI1 antibodies. [B20] Use of any one of B1 to B19, wherein the subject is (i) anti-NMDAR antibody positive and aged 12 years or older; or (ii) anti-LGI1 antibody positive and aged 18 years or older. [B21] The use of any one of B1 to B20, wherein the subject is not receiving any ongoing chronic immunosuppressive therapy. [B22] The use of any one of B1-B20, wherein the subject is receiving ongoing treatment with a stable dose of azathioprine (AZA), mycophenolate mofetil (MMF), intravenous (IV) cyclophosphamide, oral corticosteroids (OCS), or a combination of AZA or MMF or IV cyclophosphamide and OCS. [B23] The use of any one of B5 to B22, wherein the pharmaceutical agent is used such that, for each administration, 60 mg or 120 mg, 120 mg or 180 mg, and 180 mg or 240 mg of an anti-IL-6 receptor antibody or an antigen-binding fragment thereof is administered to a subject having a body weight of less than 40 kg, 40 to 100 kg, and more than 100 kg, respectively. [B24] The use of any one of B5 to B22, wherein the pharmaceutical agent is characterized in that for each administration, 60 mg of an anti-IL-6 receptor antibody or an antigen-binding fragment thereof is administered to a subject having a body weight of less than 40 kg. [B25] The use of any one of B5 to B22, wherein the pharmaceutical agent is characterized in that for each administration, 120 mg of an anti-IL-6 receptor antibody or an antigen-binding fragment thereof is administered to a subject having a body weight of less than 40 kg. [B26] The use of any one of B5 to B22, wherein the pharmaceutical agent is characterized in that for each administration, 120 mg of an anti-IL-6 receptor antibody or an antigen-binding fragment thereof is administered to a subject having a body weight of 40 to 100 kg. [B27] The use of any one of B5 to B22, wherein the pharmaceutical agent is characterized in that for each administration, 180 mg of an anti-IL-6 receptor antibody or an antigen-binding fragment thereof is administered to a subject having a body weight of 40 to 100 kg. [B28] The use of any one of B5 to B22, wherein the pharmaceutical agent is characterized in that for each administration, 180 mg of an anti-IL-6 receptor antibody or an antigen-binding fragment thereof is administered to a subject having a body weight of more than 100 kg. [B29] Use of any one of B5 to B22, wherein the pharmaceutical agent is characterized in that for each administration, 240 mg of an anti-IL-6 receptor antibody or an antigen-binding fragment thereof is administered to a subject having a body weight of more than 100 kg. [B30] Use of any one of B5 to B29, wherein the pharmaceutical is characterized in that the anti-IL-6 receptor antibody or its antigen-binding fragment is used for subcutaneous administration to a subject. [B31] The use of any one of B5 to B30, wherein the pharmaceutical agent is characterized in that the anti-IL-6 receptor antibody or its antigen-binding fragment is administered to a subject three times at two-week intervals (Q2W) and then at four-week intervals (Q4W). [B32] The use of any one of B1 to B31, wherein the pharmaceutical agent is used in combination with immunosuppressive therapy (IST). [B33] The use of B32, wherein said IST is treated with: (i) an immunosuppressant selected from the group consisting of azathioprine (AZA), mycophenolate mofetil (MMF), and intravenous (IV) cyclophosphamide; (ii) oral corticosteroids (OCS); or (iii) a combination of (i) and (ii). [B34] The use of B33, wherein said immunosuppressant comprises prednisone, prednisolone, or an equivalent thereof. [B35] Use of any one of B1 to B34, wherein the pharmaceutical agent improves modified Rankin Scale (mRS) score improvement. [B36] The pharmaceutical product is - reducing the time to improvement in modified Rankin Scale (mRS) score without the use of rescue therapy; - Delay time to rescue therapy, - delaying the time to seizure freedom or cessation of status epilepticus without the use of rescue therapy; - Improve Clinical Assessment Scale for Encephalitis (CASE) scores; - Improve Montreal Cognitive Assessment (MOCA) total score, - improving Rey Auditory Verbal Learning Test (RAVLT) scores in subjects with anti-LGI1 antibodies, and / or - improve mRS scores in subjects with anti-NMDAR antibodies, Use of B35. [B37] Use of any one of B1 to B36, wherein the pharmaceutical product improves a subject's score on one or more of the following: modified Rankin Scale (mRS), Clinical Assessment of Encephalitis (CASE), Montreal Cognitive Assessment (MOCA), Rey Auditory Verbal Learning Test (RAVLT), or Columbia Suicide Severity Rating Scale (C-SSRS). [B38] Use of any one of B1 to B36, wherein the pharmaceutical agent reduces the subject's modified Rankin Scale (mRS) score, or Clinical Assessment of Encephalitis (CASE) score; or increases the subject's Montreal Cognitive Assessment (MOCA) total score, or Rey Auditory Verbal Learning Test (RAVLT) score. [B39] The use of any one of B1 to B38, wherein the pharmaceutical agent is administered by a subcutaneous administration device. [B40] The use of B39, wherein the subcutaneous administration device is a pre-filled syringe (PFS), optionally a pre-filled syringe with a needle safety device (PFS-NSD), or an auto-injector (AI).

[0020] [C1] An IL-6 inhibitor for use in treating or reducing the risk of recurrence of autoimmune encephalitis (AIE) in a subject. [C2] An IL-6 inhibitor for use in C1, which is an anti-IL-6 antibody or an antigen-binding fragment thereof, or an anti-IL-6 receptor antibody or an antigen-binding fragment thereof. [C3] An IL-6 inhibitor for use with C1 or C2 that is an anti-IL-6 receptor antibody or an antigen-binding fragment thereof. [C4] An IL-6 inhibitor for use with any one of C1 to C3, which is a humanized antibody. [C5] An IL-6 inhibitor for use of any one of C1 to C4, which is an anti-IL-6 receptor antibody or an antigen-binding fragment thereof, comprising a heavy chain variable region (VH) CDR1 comprising the amino acid sequence of SEQ ID NO: 5, a VH CDR2 comprising the amino acid sequence of SEQ ID NO: 6, a VH CDR3 comprising the amino acid sequence of SEQ ID NO: 7, a light chain variable region (VL) CDR1 comprising the amino acid sequence of SEQ ID NO: 8, a VL CDR2 comprising the amino acid sequence of SEQ ID NO: 9, and a VL CDR3 comprising the amino acid sequence of SEQ ID NO: 10. [C6] An IL-6 inhibitor for use with C5, wherein the anti-IL-6 receptor antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:1, and a VL comprising the amino acid sequence of SEQ ID NO:2. [C7] An IL-6 inhibitor for use with C5 or C6, which is an anti-IL-6 receptor antibody comprising a heavy chain comprising the amino acid sequence of SEQ ID NO:3 and a light chain comprising the amino acid sequence of SEQ ID NO:4. [C8] Satralizumab, an IL-6 inhibitor for use with any one of C5 to C7. [C9] An IL-6 inhibitor for use in any one of C1 to C8 for delaying relapses of, reducing the frequency of, reducing the severity of, or reducing the need for rescue therapy for, autoimmune encephalopathy relapse in a subject. [C10] An IL-6 inhibitor for use according to any one of C1 to C9, wherein the subject is positive for anti-N-methyl-D-aspartate receptor (NMDAR) antibody or anti-leucine-rich glioma inactivated 1 (LGI1) antibody. [C11] An IL-6 inhibitor for use according to any one of C1 to C10, wherein the autoimmune encephalitis is a disease other than Bickerstaff brainstem encephalitis, acute disseminated encephalomyelitis, Hashimoto's encephalopathy, primary central nervous system (CNS) vasculitis, and Rasmussen's encephalitis. [C12] An IL-6 inhibitor for use according to any one of C1 to C11, wherein anti-NMDAR antibodies are detected in cerebrospinal fluid (CSF) from the subject using a cell-based assay. [C13] An IL-6 inhibitor for use according to any one of C1 to C12, wherein the autoimmune encephalitis is anti-NMDAR encephalitis. [C14] An IL-6 inhibitor for use according to any one of C1 to C11, wherein anti-LGI1 antibodies are detected in serum or cerebrospinal fluid (CSF) from a subject using a cell-based assay. [C15] An IL-6 inhibitor for use in C14, wherein the subject has experienced working memory deficits, seizures, or neurological symptoms suggestive of limbic system involvement. [C16] An IL-6 inhibitor for use according to any one of C1 to C11 and C14 to C15, wherein the autoimmune encephalitis is anti-LGI1 encephalitis. [C17] An IL-6 inhibitor for use according to any one of C1 to C16, wherein the autoimmune encephalitis is anti-NMDAR encephalitis or anti-LGI1 encephalitis. [C18] The subject is an anti-caspr2 antibody, an anti-IgLON5 antibody, an anti-DPPX antibody, an anti-GABA antibody, A IL-6 inhibitors for use with any one of C1 to C17 that are negative for antibodies, anti-neurexin-3α antibodies, and anti-myelin oligodendrocyte glycoprotein (MOG) antibodies. [C19] An IL-6 inhibitor for use in any one of C1 to C18, wherein the subject is negative for cell surface neuronal or glial antibodies other than anti-NMDAR antibodies and anti-LGI1 antibodies. [C20] An IL-6 inhibitor for use in any one of C1 to C19, wherein the subject is (i) anti-NMDAR antibody positive and aged 12 years or older; or (ii) anti-LGI1 antibody positive and aged 18 years or older. [C21] An IL-6 inhibitor for use in any one of C1 to C20, wherein the subject is not receiving any ongoing chronic immunosuppressive therapy. [C22] An IL-6 inhibitor for use in any one of C1 to C20, wherein the subject is receiving ongoing treatment with a stable dose of azathioprine (AZA), mycophenolate mofetil (MMF), intravenous (IV) cyclophosphamide, oral corticosteroids (OCS), or a combination of AZA or MMF or IV cyclophosphamide and OCS. [C23] An IL-6 inhibitor for use according to any one of C5 to C22, characterized in that for each administration, 60 mg or 120 mg, 120 mg or 180 mg, and 180 mg or 240 mg of an anti-IL-6 receptor antibody or antigen-binding fragment thereof are administered to a subject weighing less than 40 kg, 40 to 100 kg, and more than 100 kg, respectively. [C24] An IL-6 inhibitor for use according to any one of C5 to C22, characterized in that for each administration, 60 mg of an anti-IL-6 receptor antibody or an antigen-binding fragment thereof is administered to a subject having a body weight of less than 40 kg. [C25] An IL-6 inhibitor for use according to any one of C5 to C22, characterized in that for each administration, 120 mg of an anti-IL-6 receptor antibody or an antigen-binding fragment thereof is administered to a subject having a body weight of less than 40 kg. [C26] An IL-6 inhibitor for use according to any one of C5 to C22, characterized in that for each administration, 120 mg of an anti-IL-6 receptor antibody or an antigen-binding fragment thereof is administered to a subject having a body weight of 40 to 100 kg. [C27] An IL-6 inhibitor for use according to any one of C5 to C22, characterized in that for each administration, 180 mg of an anti-IL-6 receptor antibody or an antigen-binding fragment thereof is administered to a subject having a body weight of 40 to 100 kg. [C28] An IL-6 inhibitor for use in any one of C5 to C22, characterized in that for each administration, 180 mg of an anti-IL-6 receptor antibody or an antigen-binding fragment thereof is administered to a subject having a body weight of more than 100 kg. [C29] An IL-6 inhibitor for use in any one of C5 to C22, characterized in that for each administration, 240 mg of an anti-IL-6 receptor antibody or an antigen-binding fragment thereof is administered to a subject having a body weight of more than 100 kg. [C30] An IL-6 inhibitor for use according to any one of C5 to C29, characterized in that an anti-IL-6 receptor antibody or an antigen-binding fragment thereof is subcutaneously administered to a subject. [C31] An IL-6 inhibitor for use according to any one of C5 to C30, characterized in that an anti-IL-6 receptor antibody or an antigen-binding fragment thereof is administered to a subject three times at two-week intervals (Q2W), and then at four-week intervals (Q4W). [C32] An IL-6 inhibitor for use in combination with immunosuppressive therapy (IST), for the use of any one of C1 to C31. [C33] The IL-6 inhibitor for use in C32, wherein the IST is a treatment with: (i) an immunosuppressant selected from the group consisting of azathioprine (AZA), mycophenolate mofetil (MMF), and intravenous (IV) cyclophosphamide; (ii) oral corticosteroids (OCS); or (iii) a combination of (i) and (ii). [C34] The IL-6 inhibitor for use in C33, wherein the immunosuppressant comprises prednisone, prednisolone, or an equivalent thereof. [C35] An IL-6 inhibitor for use in any one of C1 to C34 that improves modified Rankin Scale (mRS) score improvement. [C36]- Reduce the time to improvement in modified Rankin Scale (mRS) score without the use of rescue therapy; - Delay time to rescue therapy, - delaying the time to seizure freedom or cessation of status epilepticus without the use of rescue therapy; - Improve Clinical Assessment Scale for Encephalitis (CASE) scores; - Improve Montreal Cognitive Assessment (MOCA) total score, - improving Rey Auditory Verbal Learning Test (RAVLT) scores in subjects with anti-LGI1 antibodies, and / or - improve mRS scores in subjects with anti-NMDAR antibodies, C35 for use in IL-6 inhibitors. [C37] An IL-6 inhibitor for use in any one of C1 to C36 to improve a subject's score on one or more of the following: modified Rankin Scale (mRS), Clinical Assessment of Encephalitis (CASE), Montreal Cognitive Assessment (MOCA), Rey Auditory Verbal Learning Test (RAVLT), or Columbia Suicide Severity Rating Scale (C-SSRS). [C38] An IL-6 inhibitor for use in any one of C1 to C36, which reduces a subject's modified Rankin Scale (mRS) score or Clinical Assessment of Encephalitis (CASE) score; or increases a subject's Montreal Cognitive Assessment (MOCA) total score or Rey Auditory Verbal Learning Test (RAVLT) score. [C39] An IL-6 inhibitor for use in any one of C1 to C38, administered by a subcutaneous administration device. [C40] The IL-6 inhibitor for use in C39, wherein the subcutaneous administration device is a pre-filled syringe (PFS), optionally a pre-filled syringe with a needle safety device (PFS-NSD), or an autoinjector (AI).

[0021] [C2.1] Satralizumab for use in treating anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis. [C2.2] Satralizumab for use in treating anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis, where 60 mg of satralizumab per dose is administered subcutaneously every 2 weeks (Q2W) for 3 doses and then every 4 weeks (Q4W) to subjects weighing less than 40 kg. [C2.3] Satralizumab for use in treating anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis, where 120 mg of satralizumab per dose is administered subcutaneously every 2 weeks (Q2W) for 3 doses and then every 4 weeks (Q4W) to subjects weighing less than 40 kg. [C2.4] Satralizumab for use in treating anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis, where 120 mg of satralizumab is administered subcutaneously every 2 weeks (Q2W) for 3 doses and then every 4 weeks (Q4W) to subjects weighing 40 to 100 kg. [C2.5] Satralizumab for use in treating anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis, where 180 mg of satralizumab is administered subcutaneously every 2 weeks (Q2W) for 3 doses and then every 4 weeks (Q4W) to subjects weighing 40 to 100 kg. [C2.6] Satralizumab for use in treating anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis, where 180 mg of satralizumab per dose is administered subcutaneously every 2 weeks (Q2W) for 3 doses and then every 4 weeks (Q4W) to subjects weighing more than 100 kg. [C2.7] Satralizumab for use in treating anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis, where 240 mg of satralizumab per dose is administered subcutaneously every 2 weeks (Q2W) for 3 doses and then every 4 weeks (Q4W) to subjects weighing more than 100 kg. [C2.8] Satralizumab for use in treating anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis, used in combination with azathioprine (AZA) or mycophenolate mofetil (MMF) or intravenous (IV) cyclophosphamide. [C2.9] Satralizumab for use in treating anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis, where 60 mg of satralizumab is administered subcutaneously every 2 weeks (Q2W) for 3 doses and then every 4 weeks (Q4W) to subjects weighing less than 40 kg; and satralizumab is used in combination with azathioprine (AZA) or mycophenolate mofetil (MMF) or intravenous (IV) cyclophosphamide. [C2.10] Satralizumab for use in treating anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis, where 120 mg of satralizumab per dose is administered subcutaneously every 2 weeks (Q2W) for 3 doses and then every 4 weeks (Q4W) to subjects weighing less than 40 kg; and satralizumab is used in combination with azathioprine (AZA) or mycophenolate mofetil (MMF) or intravenous (IV) cyclophosphamide. [C2.11] Satralizumab for use in treating anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis, where 120 mg of satralizumab is administered subcutaneously every 2 weeks (Q2W) for 3 doses and then every 4 weeks (Q4W) to a subject weighing 40 to 100 kg; and satralizumab is used in combination with azathioprine (AZA) or mycophenolate mofetil (MMF) or intravenous (IV) cyclophosphamide. [C2.12] Satralizumab for use in treating anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis, where 180 mg of satralizumab is administered subcutaneously every 2 weeks (Q2W) for 3 doses and then every 4 weeks (Q4W) to subjects weighing 40 to 100 kg; and satralizumab is used in combination with azathioprine (AZA) or mycophenolate mofetil (MMF) or intravenous (IV) cyclophosphamide. [C2.13] Satralizumab for use in treating anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis, where 180 mg of satralizumab per dose is administered subcutaneously every 2 weeks (Q2W) for 3 doses and then every 4 weeks (Q4W) to subjects weighing more than 100 kg; and satralizumab is used in combination with azathioprine (AZA) or mycophenolate mofetil (MMF) or intravenous (IV) cyclophosphamide. [C2.14] Satralizumab for use in treating anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis, where 240 mg of satralizumab per dose is administered subcutaneously every 2 weeks (Q2W) for 3 doses and then every 4 weeks (Q4W) to subjects weighing more than 100 kg; and satralizumab is used in combination with azathioprine (AZA) or mycophenolate mofetil (MMF) or intravenous (IV) cyclophosphamide. [C2.15] Satralizumab for use in treating anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis, used in combination with oral corticosteroids (OCS). [C2.16] Satralizumab for use in treating anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis, where 60 mg of satralizumab per dose is administered subcutaneously every 2 weeks (Q2W) for 3 doses and then every 4 weeks (Q4W) to a subject weighing less than 40 kg; and satralizumab is used in combination with oral corticosteroids (OCS). [C2.17] Satralizumab for use in treating anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis, where 120 mg of satralizumab per dose is administered subcutaneously every 2 weeks (Q2W) for 3 doses and then every 4 weeks (Q4W) to a subject weighing less than 40 kg; and satralizumab is used in combination with an oral corticosteroid (OCS). [C2.18] Satralizumab for use in treating anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis, where 120 mg of satralizumab is administered subcutaneously every 2 weeks (Q2W) for 3 doses and then every 4 weeks (Q4W) to a subject weighing 40 to 100 kg; and satralizumab is used in combination with oral corticosteroids (OCS). [C2.19] Satralizumab for use in treating anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis, where 180 mg of satralizumab is administered subcutaneously every 2 weeks (Q2W) for 3 doses and then every 4 weeks (Q4W) to a subject weighing 40 to 100 kg; and satralizumab is used in combination with oral corticosteroids (OCS). [C2.20] Satralizumab for use in treating anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis, where 180 mg of satralizumab per dose is administered subcutaneously every 2 weeks (Q2W) for 3 doses and then every 4 weeks (Q4W) to a subject weighing more than 100 kg; and satralizumab is used in combination with oral corticosteroids (OCS). [C2.21] Satralizumab for use in treating anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis, where 240 mg of satralizumab per dose is administered subcutaneously every 2 weeks (Q2W) for 3 doses and then every 4 weeks (Q4W) to a subject weighing more than 100 kg; and satralizumab is used in combination with oral corticosteroids (OCS). [C2.22] Satralizumab for use in treating anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis, in combination with (i) azathioprine (AZA), mycophenolate mofetil (MMF), and intravenous (IV) cyclophosphamide, and (ii) oral corticosteroids (OCS). [C2.23] Satralizumab for use in treating anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis, where 60 mg of satralizumab each dose is administered subcutaneously every 2 weeks (Q2W) for 3 doses and then every 4 weeks (Q4W) to subjects weighing less than 40 kg; and satralizumab is used in combination with any one of (i) azathioprine (AZA), mycophenolate mofetil (MMF), and intravenous (IV) cyclophosphamide, and (ii) oral corticosteroids (OCS). [C2.24] Satralizumab for use in treating anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis, where 120 mg of satralizumab each dose is administered subcutaneously every 2 weeks (Q2W) for 3 doses and then every 4 weeks (Q4W) to subjects weighing less than 40 kg; and satralizumab is used in combination with any one of (i) azathioprine (AZA), mycophenolate mofetil (MMF), and intravenous (IV) cyclophosphamide, and (ii) oral corticosteroids (OCS). [C2.25] Satralizumab for use in treating anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis, where 120 mg of satralizumab is administered subcutaneously every 2 weeks (Q2W) for 3 doses and then every 4 weeks (Q4W) to a subject weighing 40 to 100 kg; and satralizumab is used in combination with any one of (i) azathioprine (AZA), mycophenolate mofetil (MMF), and intravenous (IV) cyclophosphamide, and (ii) oral corticosteroids (OCS). [C2.26] Satralizumab for use in treating anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis, where 180 mg of satralizumab is administered subcutaneously every 2 weeks (Q2W) for 3 doses and then every 4 weeks (Q4W) to a subject weighing 40 to 100 kg; and satralizumab is used in combination with any one of (i) azathioprine (AZA), mycophenolate mofetil (MMF), and intravenous (IV) cyclophosphamide, and (ii) oral corticosteroids (OCS). [C2.27] Satralizumab for use in treating anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis, where 180 mg of satralizumab each dose is administered subcutaneously every 2 weeks (Q2W) for 3 doses and then every 4 weeks (Q4W) to subjects weighing more than 100 kg; and satralizumab is used in combination with any one of: (i) azathioprine (AZA), mycophenolate mofetil (MMF), and intravenous (IV) cyclophosphamide, and (ii) oral corticosteroids (OCS). [C2.28] Satralizumab for use in treating anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis, where 240 mg of satralizumab each dose is administered subcutaneously every 2 weeks (Q2W) for 3 doses and then every 4 weeks (Q4W) to subjects weighing more than 100 kg; and satralizumab is used in combination with any one of: (i) azathioprine (AZA), mycophenolate mofetil (MMF), and intravenous (IV) cyclophosphamide, and (ii) oral corticosteroids (OCS). [C2.29] Satralizumab for use in treating anti-leucine-rich glioma inactivated 1 (LGI1) encephalitis. [C2.30] Satralizumab for use in treating anti-leucine-rich glioma inactivation 1 (LGI1) encephalitis, where 60 mg of satralizumab is administered subcutaneously every 2 weeks (Q2W) for 3 doses and then every 4 weeks (Q4W) to subjects weighing less than 40 kg. [C2.31] Satralizumab for use in treating anti-leucine-rich glioma inactivation 1 (LGI1) encephalitis, where 120 mg of satralizumab per dose is administered subcutaneously every 2 weeks (Q2W) for 3 doses and then every 4 weeks (Q4W) to subjects weighing less than 40 kg. [C2.32] Satralizumab for use in treating anti-leucine-rich glioma inactivation 1 (LGI1) encephalitis, where 120 mg of satralizumab is administered subcutaneously every 2 weeks (Q2W) for three doses and then every 4 weeks (Q4W) to subjects weighing 40 to 100 kg. [C2.33] Satralizumab for use in treating anti-leucine-rich glioma inactivation 1 (LGI1) encephalitis, where 180 mg of satralizumab is administered subcutaneously every 2 weeks (Q2W) for three doses and then every 4 weeks (Q4W) to subjects weighing 40 to 100 kg. [C2.34] Satralizumab for use in treating anti-leucine-rich glioma inactivation 1 (LGI1) encephalitis, where 180 mg of satralizumab per dose is administered subcutaneously every 2 weeks (Q2W) for 3 doses and then every 4 weeks (Q4W) to subjects weighing more than 100 kg. [C2.35] Satralizumab for use in treating anti-leucine-rich glioma inactivation 1 (LGI1) encephalitis, where 240 mg of satralizumab per dose is administered subcutaneously every 2 weeks (Q2W) for 3 doses and then every 4 weeks (Q4W) to subjects weighing more than 100 kg. [C2.36] Satralizumab for use in treating anti-leucine-rich glioma inactivation 1 (LGI1) encephalitis, used in combination with azathioprine (AZA) or mycophenolate mofetil (MMF) or intravenous (IV) cyclophosphamide. [C2.37] Satralizumab for use in treating anti-leucine-rich glioma inactivation 1 (LGI1) encephalitis where 60 mg of satralizumab is administered subcutaneously every 2 weeks (Q2W) for 3 doses and then every 4 weeks (Q4W) to subjects weighing less than 40 kg; and satralizumab is used in combination with azathioprine (AZA) or mycophenolate mofetil (MMF) or intravenous (IV) cyclophosphamide. [C2.38] Satralizumab for use in treating anti-leucine-rich glioma inactivation 1 (LGI1) encephalitis where 120 mg of satralizumab per dose is administered subcutaneously every 2 weeks (Q2W) for 3 doses and then every 4 weeks (Q4W) to subjects weighing less than 40 kg; and satralizumab is used in combination with azathioprine (AZA) or mycophenolate mofetil (MMF) or intravenous (IV) cyclophosphamide. [C2.39] Satralizumab for use in treating anti-leucine-rich glioma inactivation 1 (LGI1) encephalitis where 120 mg of satralizumab is administered subcutaneously every 2 weeks (Q2W) for 3 doses and then every 4 weeks (Q4W) to subjects weighing 40 to 100 kg; and satralizumab is used in combination with azathioprine (AZA) or mycophenolate mofetil (MMF) or intravenous (IV) cyclophosphamide. [C2.40] Satralizumab for use in treating anti-leucine-rich glioma inactivation 1 (LGI1) encephalitis where 180 mg of satralizumab is administered subcutaneously every 2 weeks (Q2W) for 3 doses and then every 4 weeks (Q4W) to a subject weighing 40 to 100 kg; and satralizumab is used in combination with azathioprine (AZA) or mycophenolate mofetil (MMF) or intravenous (IV) cyclophosphamide. [C2.41] Satralizumab for use in treating anti-leucine-rich glioma inactivation 1 (LGI1) encephalitis where 180 mg of satralizumab per dose is administered subcutaneously every 2 weeks (Q2W) for 3 doses and then every 4 weeks (Q4W) to subjects weighing more than 100 kg; and satralizumab is used in combination with azathioprine (AZA) or mycophenolate mofetil (MMF) or intravenous (IV) cyclophosphamide. [C2.42] Satralizumab for use in treating anti-leucine-rich glioma inactivation 1 (LGI1) encephalitis where 240 mg of satralizumab per dose is administered subcutaneously every 2 weeks (Q2W) for 3 doses and then every 4 weeks (Q4W) to subjects weighing more than 100 kg; and satralizumab is used in combination with azathioprine (AZA) or mycophenolate mofetil (MMF) or intravenous (IV) cyclophosphamide. [C2.43] Satralizumab for use in treating anti-leucine-rich glioma inactivated 1 (LGI1) encephalitis, used in combination with oral corticosteroids (OCS). [C2.44] Satralizumab for use in treating anti-leucine-rich glioma inactivation 1 (LGI1) encephalitis, where 60 mg of satralizumab is administered subcutaneously every 2 weeks (Q2W) for 3 doses and then every 4 weeks (Q4W) to a subject weighing less than 40 kg; and satralizumab is used in combination with oral corticosteroids (OCS). [C2.45] Satralizumab for use in treating anti-leucine-rich glioma inactivation 1 (LGI1) encephalitis, where 120 mg of satralizumab per dose is administered subcutaneously every 2 weeks (Q2W) for 3 doses and then every 4 weeks (Q4W) to a subject weighing less than 40 kg; and satralizumab is used in combination with oral corticosteroids (OCS). [C2.46] Satralizumab for use in treating anti-leucine-rich glioma inactivation 1 (LGI1) encephalitis, where 120 mg of satralizumab is administered subcutaneously every 2 weeks (Q2W) for 3 doses and then every 4 weeks (Q4W) to a subject weighing 40 to 100 kg; and satralizumab is used in combination with oral corticosteroids (OCS). [C2.47] Satralizumab for use in treating anti-leucine-rich glioma inactivation 1 (LGI1) encephalitis, where 180 mg of satralizumab is administered subcutaneously every 2 weeks (Q2W) for 3 doses and then every 4 weeks (Q4W) to a subject weighing 40 to 100 kg; and satralizumab is used in combination with oral corticosteroids (OCS). [C2.48] Satralizumab for use in treating anti-leucine-rich glioma inactivation 1 (LGI1) encephalitis, where 180 mg of satralizumab per dose is administered subcutaneously every 2 weeks (Q2W) for 3 doses and then every 4 weeks (Q4W) to a subject weighing more than 100 kg; and satralizumab is used in combination with oral corticosteroids (OCS). [C2.49] Satralizumab for use in treating anti-leucine-rich glioma inactivation 1 (LGI1) encephalitis, where 240 mg of satralizumab per dose is administered subcutaneously every 2 weeks (Q2W) for 3 doses and then every 4 weeks (Q4W) to subjects weighing more than 100 kg; and satralizumab is used in combination with oral corticosteroids (OCS). [C2.50] Satralizumab for use in treating anti-leucine-rich glioma inactivation 1 (LGI1) encephalitis in combination with (i) azathioprine (AZA), mycophenolate mofetil (MMF), and intravenous (IV) cyclophosphamide, and (ii) oral corticosteroids (OCS). [C2.51] Satralizumab for use in treating anti-leucine-rich glioma inactivation 1 (LGI1) encephalitis, where 60 mg of satralizumab is administered subcutaneously every 2 weeks (Q2W) for 3 doses and then every 4 weeks (Q4W) to subjects weighing less than 40 kg; and satralizumab is used in combination with any one of (i) azathioprine (AZA), mycophenolate mofetil (MMF), and intravenous (IV) cyclophosphamide, and (ii) oral corticosteroids (OCS). [C2.52] Satralizumab for use in treating anti-leucine-rich glioma inactivation 1 (LGI1) encephalitis, where 120 mg of satralizumab per dose is administered subcutaneously every 2 weeks (Q2W) for 3 doses and then every 4 weeks (Q4W) to subjects weighing less than 40 kg; and satralizumab is used in combination with any one of (i) azathioprine (AZA), mycophenolate mofetil (MMF), and intravenous (IV) cyclophosphamide, and (ii) oral corticosteroids (OCS). [C2.53] Satralizumab for use in treating anti-leucine-rich glioma inactivation 1 (LGI1) encephalitis, where 120 mg of satralizumab is administered subcutaneously every 2 weeks (Q2W) for 3 doses and then every 4 weeks (Q4W) to a subject weighing 40 to 100 kg; and satralizumab is used in combination with any one of (i) azathioprine (AZA), mycophenolate mofetil (MMF), and intravenous (IV) cyclophosphamide, and (ii) oral corticosteroids (OCS). [C2.54] Satralizumab for use in treating anti-leucine-rich glioma inactivation 1 (LGI1) encephalitis, where 180 mg of satralizumab is administered subcutaneously every 2 weeks (Q2W) for 3 doses and then every 4 weeks (Q4W) to a subject weighing 40 to 100 kg; and satralizumab is used in combination with any one of (i) azathioprine (AZA), mycophenolate mofetil (MMF), and intravenous (IV) cyclophosphamide, and (ii) oral corticosteroids (OCS). [C2.55] Satralizumab for use in treating anti-leucine-rich glioma inactivation 1 (LGI1) encephalitis, where 180 mg of satralizumab per dose is administered subcutaneously every 2 weeks (Q2W) for 3 doses and then every 4 weeks (Q4W) to subjects weighing more than 100 kg; and satralizumab is used in combination with any one of (i) azathioprine (AZA), mycophenolate mofetil (MMF), and intravenous (IV) cyclophosphamide, and (ii) oral corticosteroids (OCS). [C2.56] Satralizumab for use in treating anti-leucine-rich glioma inactivation 1 (LGI1) encephalitis, where 240 mg of satralizumab per dose is administered subcutaneously every 2 weeks (Q2W) for 3 doses and then every 4 weeks (Q4W) to subjects weighing more than 100 kg; and satralizumab is used in combination with any one of (i) azathioprine (AZA), mycophenolate mofetil (MMF), and intravenous (IV) cyclophosphamide, and (ii) oral corticosteroids (OCS).

[0022] [D1] A kit for treating autoimmune encephalitis (AIE) in a subject or for reducing the risk of recurrence thereof, comprising: (1) any one of the pharmaceutical compositions of A2.1 to A2.40; and (2) A package insert or labeling that provides instructions for administering the pharmaceutical composition to a subject. The kit comprising: [D2] The subcutaneous administration device is a pre-filled syringe (PFS), optionally a pre-filled syringe with needle safety device (PFS-NSD), or an auto-injector (AI). [D2] A subcutaneous administration device containing a fixed dose of 60 mg of satralizumab in a pharma- ceutically acceptable excipient. [D3] A subcutaneous administration device containing a fixed dose of 240 mg of satralizumab in a pharma- ceutically acceptable excipient. [D4] A subcutaneous administration device of D2 or D3, which is a pre-filled syringe (PFS), optionally a pre-filled syringe with a needle safety device (PFS-NSD). [D5] A subcutaneous administration device of D2 or D3 that is an autoinjector (AI). [D6] A subcutaneous administration device comprising a fixed dose of 60 mg of satralizumab in a pharma- ceutically acceptable excipient, the subcutaneous administration device being a pre-filled syringe with a needle safety device (PFS-NSD). [D7] A subcutaneous administration device comprising a fixed dose of 120 mg of satralizumab in a pharma- ceutically acceptable excipient, the subcutaneous administration device being a pre-filled syringe with a needle safety device (PFS-NSD). [D8] A subcutaneous administration device comprising a fixed dose of 120 mg, 180 mg, or 240 mg of satralizumab in a pharma- ceutically acceptable excipient, wherein the subcutaneous administration device is an autoinjector (AI).

[0023] [E1] A method for treating a subject having autoimmune encephalitis (AIE), comprising administering to the subject an effective amount of an IL-6 inhibitor. [E2] The method of E1, wherein the IL-6 inhibitor is an anti-IL-6 antibody or an antigen-binding fragment thereof, or an anti-IL-6 receptor antibody or an antigen-binding fragment thereof. [E3] The method of E1 or E2, wherein the IL-6 inhibitor is an anti-IL-6 receptor antibody or an antigen-binding fragment thereof. [E4] Any one of the methods E1 to E3, wherein the IL-6 inhibitor is a humanized antibody. [E5] Any one of the methods E1 to E4, wherein the IL-6 inhibitor is an anti-IL-6 receptor antibody or an antigen-binding fragment thereof, comprising a heavy chain variable region (VH) CDR1 comprising the amino acid sequence of SEQ ID NO: 5, a VH CDR2 comprising the amino acid sequence of SEQ ID NO: 6, a VH CDR3 comprising the amino acid sequence of SEQ ID NO: 7, a light chain variable region (VL) CDR1 comprising the amino acid sequence of SEQ ID NO: 8, a VL CDR2 comprising the amino acid sequence of SEQ ID NO: 9, and a VL CDR3 comprising the amino acid sequence of SEQ ID NO: 10. [E6] The method of E5, wherein the anti-IL-6 receptor antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1, and a VL comprising the amino acid sequence of SEQ ID NO: 2. [E7] The method of E5 or E6, wherein the IL-6 inhibitor is an anti-IL-6 receptor antibody comprising a heavy chain comprising the amino acid sequence of SEQ ID NO:3 and a light chain comprising the amino acid sequence of SEQ ID NO:4. [E8] Any one of the methods E5 to E7, wherein the IL-6 inhibitor is satralizumab. [E9] Any one of the methods of E1-E8, wherein the subject is positive for anti-N-methyl-D-aspartate receptor (NMDAR) antibody or anti-leucine-rich glioma inactivated 1 (LGI1) antibody. [E10] Any one of the methods E1-E9, wherein the autoimmune encephalitis is a disease other than Bickerstaff brainstem encephalitis, acute disseminated encephalomyelitis, Hashimoto's encephalopathy, primary central nervous system (CNS) vasculitis, and Rasmussen's encephalitis. [E11] Any one of the methods of E1-E10, wherein anti-NMDAR antibodies are detected in cerebrospinal fluid (CSF) from the subject using a cell-based assay. [E12] Any one of the methods E1 to E11, wherein the autoimmune encephalitis is anti-NMDAR encephalitis. [E13] The method of any one of E1-E10, wherein anti-LGI1 antibodies are detected in serum or cerebrospinal fluid (CSF) from the subject using a cell-based assay. [E14] The method of E13, wherein the subject has experienced working memory deficits, seizures, or neurological symptoms suggestive of limbic system involvement. [E15] Any one of the methods E1 to E10 and E13 to E14, wherein the autoimmune encephalitis is anti-LGI1 encephalitis. [E16] Any one of the methods E1 to E15, wherein the autoimmune encephalitis is anti-NMDAR encephalitis or anti-LGI1 encephalitis. [E17] The subject is an anti-caspr2 antibody, an anti-IgLON5 antibody, an anti-DPPX antibody, an anti-GABA antibody, A any one of methods E1-E16 that are negative for antibodies, anti-neurexin-3α antibodies, and anti-myelin oligodendrocyte glycoprotein (MOG) antibodies. [E18] Any one of the methods of E1-E17, wherein the subject is negative for cell surface neuronal or glial antibodies other than anti-NMDAR and anti-LGI1 antibodies. [E19] Any one of the methods E1-E18, wherein the subject is (i) anti-NMDAR antibody positive and 12 years of age or older; or (ii) anti-LGI1 antibody positive and 18 years of age or older. [E20] Any one of the methods of E1-E19, wherein said subject is not receiving any ongoing chronic immunosuppressive therapy. [E21] Any one of the methods of E1-E19, wherein the subject is receiving ongoing treatment with a stable dose of azathioprine (AZA), mycophenolate mofetil (MMF), intravenous (IV) cyclophosphamide, oral corticosteroids (OCS), or a combination of AZA or MMF or IV cyclophosphamide and OCS. [E22] The subject is determined to have a body weight of less than 40 kg, and the amount of the anti-IL-6 receptor antibody or antigen-binding fragment thereof administered to the subject in each administration is 60 mg or 120 mg; or the subject is determined to have a body weight of 40 to 100 kg, and the amount of the anti-IL-6 receptor antibody or antigen-binding fragment thereof administered to the subject in each administration is 120 mg or 180 mg; or the subject is determined to have a body weight of more than 100 kg, and the amount of anti-IL-6 receptor antibody or antigen-binding fragment thereof administered to the subject in each administration is 180 mg or 240 mg; One of the methods from E5 to E21. [E23] Any one of the methods E5 to E21, wherein the subject is determined to have a body weight of less than 40 kg, and the amount of the anti-IL-6 receptor antibody or antigen-binding fragment thereof administered to the subject in each administration is 60 mg. [E24] Any one of the methods E5 to E21, wherein the subject is determined to have a body weight of less than 40 kg, and the amount of the anti-IL-6 receptor antibody or antigen-binding fragment thereof administered to the subject in each administration is 120 mg. [E25] Any one of the methods E5 to E21, wherein the subject is determined to have a body weight of 40 to 100 kg, and the amount of the anti-IL-6 receptor antibody or antigen-binding fragment thereof administered to the subject in each administration is 120 mg. [E26] Any one of the methods E5 to E21, wherein the subject is determined to have a body weight of 40 to 100 kg, and the amount of the anti-IL-6 receptor antibody or antigen-binding fragment thereof administered to the subject in each administration is 180 mg. [E27] Any one of the methods E5 to E21, wherein the subject is determined to have a body weight of more than 100 kg, and the amount of the anti-IL-6 receptor antibody or antigen-binding fragment thereof administered to the subject in each administration is 180 mg. [E28] Any one of the methods E5 to E21, wherein the subject is determined to have a body weight of more than 100 kg, and the amount of the anti-IL-6 receptor antibody or antigen-binding fragment thereof administered to the subject in each administration is 240 mg. [E29] Any one of the methods E5 to E28, wherein the anti-IL-6 receptor antibody or antigen-binding fragment thereof is administered subcutaneously to a subject. [E30] Any one of the methods E5 to E29, wherein the anti-IL-6 receptor antibody or antigen-binding fragment thereof is administered to the subject three times at two-week intervals (Q2W), and then four-weekly (Q4W) intervals. [E31] Any one of the methods E1-E30, wherein an immunosuppressant therapy (IST) is administered to the subject simultaneously with the IL-6 inhibitor. [E32] The method of E31, wherein the IST comprises: (i) an immunosuppressant selected from the group consisting of azathioprine (AZA), mycophenolate mofetil (MMF), and intravenous (IV) cyclophosphamide; (ii) an oral corticosteroid (OCS); or (iii) a combination of (i) and (ii). [E33] The method of E32, wherein the immunosuppressant comprises prednisone, prednisolone, or an equivalent thereof. [E34] Any one of the methods of E1-E33, wherein administration of an IL-6 inhibitor to the subject improves modified Rankin Scale (mRS) score improvement. [E35] The administration of an IL-6 inhibitor to the subject, - reducing the time to improvement in modified Rankin Scale (mRS) score without the use of rescue therapy; - Delay time to rescue therapy, - delaying the time to seizure freedom or cessation of status epilepticus without the use of rescue therapy; - Improve Clinical Assessment Scale for Encephalitis (CASE) scores; - Improve Montreal Cognitive Assessment (MOCA) total score, - improving Rey Auditory Verbal Learning Test (RAVLT) scores in subjects with anti-LGI1 antibodies, and / or - improve mRS scores in subjects with anti-NMDAR antibodies, E34 method. [E36] Any one of the methods of E1-E35, wherein administration of an IL-6 inhibitor to the subject improves the subject's score on one or more of the modified Rankin Scale (mRS), Clinical Assessment of Encephalitis (CASE), Montreal Cognitive Assessment (MOCA), Rey Auditory Verbal Learning Test (RAVLT), or Columbia-Suicide Severity Rating Scale (C-SSRS). [E37] Any one of the methods of E1-E35, wherein administering an IL-6 inhibitor to the subject reduces the subject's modified Rankin Scale (mRS) score, or Clinical Assessment of Encephalitis (CASE) score; or increases the subject's Montreal Cognitive Assessment (MOCA) total score, or Rey Auditory Verbal Learning Test (RAVLT) score. [E38] Any one of the methods E1-E37, wherein the IL-6 inhibitor is administered by a subcutaneous administration device. [E39] The method of E38, wherein the subcutaneous administration device is a pre-filled syringe (PFS), optionally a pre-filled syringe with needle safety device (PFS-NSD), or an autoinjector (AI).

[0024] [F1] A method for reducing the risk of recurrence of autoimmune encephalitis (AIE) in a subject, the method comprising administering to the subject an effective amount of an IL-6 inhibitor. [F2] The method of F1, wherein the IL-6 inhibitor is an anti-IL-6 antibody or an antigen-binding fragment thereof, or an anti-IL-6 receptor antibody or an antigen-binding fragment thereof. [F3] The method of F1 or F2, wherein the IL-6 inhibitor is an anti-IL-6 receptor antibody or an antigen-binding fragment thereof. [F4] Any one of the methods F1 to F3, wherein the IL-6 inhibitor is a humanized antibody. [F5] Any one of the methods F1 to F4, wherein the IL-6 inhibitor is an anti-IL-6 receptor antibody or an antigen-binding fragment thereof, comprising a heavy chain variable region (VH) CDR1 comprising the amino acid sequence of SEQ ID NO: 5, a VH CDR2 comprising the amino acid sequence of SEQ ID NO: 6, a VH CDR3 comprising the amino acid sequence of SEQ ID NO: 7, a light chain variable region (VL) CDR1 comprising the amino acid sequence of SEQ ID NO: 8, a VL CDR2 comprising the amino acid sequence of SEQ ID NO: 9, and a VL CDR3 comprising the amino acid sequence of SEQ ID NO: 10. [F6] The method of F5, wherein the anti-IL-6 receptor antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1, and a VL comprising the amino acid sequence of SEQ ID NO: 2. [F7] The method of F5 or F6, wherein the IL-6 inhibitor is an anti-IL-6 receptor antibody comprising a heavy chain comprising the amino acid sequence of SEQ ID NO:3 and a light chain comprising the amino acid sequence of SEQ ID NO:4. [F8] Any one of the methods F5 to F7, wherein the IL-6 inhibitor is satralizumab. [F9] Any one of the methods of F1-F8, wherein reducing the risk of recurrence comprises delaying recurrence of, reducing the frequency of, reducing the severity of, or reducing the need for salvage therapy for, the recurrence of the autoimmune encephalopathy in the subject. [F10] Any one of the methods of F1-F9, wherein the subject is positive for anti-N-methyl-D-aspartate receptor (NMDAR) antibody or anti-leucine-rich glioma inactivated 1 (LGI1) antibody. [F11] Any one of the methods F1 to F10, wherein the autoimmune encephalitis is a disease other than Bickerstaff brainstem encephalitis, acute disseminated encephalomyelitis, Hashimoto's encephalopathy, primary central nervous system (CNS) vasculitis, and Rasmussen's encephalitis. [F12] The method of any one of F1-F11, wherein the anti-NMDAR antibody is detected in cerebrospinal fluid (CSF) from the subject using a cell-based assay. [F13] Any one of the methods F1 to F12, wherein the autoimmune encephalitis is anti-NMDAR encephalitis. [F14] The method of any one of F1-F11, wherein the anti-LGI1 antibody is detected in serum or cerebrospinal fluid (CSF) from the subject using a cell-based assay. [F15] The method of F14, wherein the subject has experienced working memory deficits, seizures, or neurological symptoms suggestive of limbic system involvement. [F16] Any one of the methods F1 to F11 and F14 to F15, wherein the autoimmune encephalitis is anti-LGI1 encephalitis. [F17] Any one of the methods F1 to F16, wherein the autoimmune encephalitis is anti-NMDAR encephalitis or anti-LGI1 encephalitis. [F18] The subject is an anti-caspr2 antibody, an anti-IgLON5 antibody, an anti-DPPX antibody, an anti-GABA antibody, AAny one of methods F1-F17 that are negative for antibody, anti-neurexin-3α antibody, and anti-myelin oligodendrocyte glycoprotein (MOG) antibody. [F19] Any one of the methods of F1-F18, wherein the subject is negative for cell surface neuronal or glial antibodies other than anti-NMDAR and anti-LGI1 antibodies. [F20] Any one of the methods F1 to F19, wherein the subject is (i) anti-NMDAR antibody positive and 12 years of age or older; or (ii) anti-LGI1 antibody positive and 18 years of age or older. [F21] Any one of the methods of F1-F20, wherein said subject is not receiving any ongoing chronic immunosuppressive therapy. [F22] Any one of the methods of F1-F21, wherein the subject is receiving ongoing treatment with a stable dose of azathioprine (AZA), mycophenolate mofetil (MMF), intravenous (IV) cyclophosphamide, oral corticosteroids (OCS), or a combination of AZA or MMF or IV cyclophosphamide and OCS. [F23] The subject is determined to have a body weight of less than 40 kg, and the amount of anti-IL-6 receptor antibody or antigen-binding fragment thereof administered to the subject in each administration is 60 mg or 120 mg; or the subject is determined to have a body weight of 40 to 100 kg, and the amount of the anti-IL-6 receptor antibody or antigen-binding fragment thereof administered to the subject in each administration is 120 mg or 180 mg; or the subject is determined to have a body weight of more than 100 kg, and the amount of anti-IL-6 receptor antibody or antigen-binding fragment thereof administered to the subject in each administration is 180 mg or 240 mg; One of the methods from F5 to F22. [F24] Any one of the methods F5 to F22, wherein the subject is determined to have a body weight of less than 40 kg, and the amount of the anti-IL-6 receptor antibody or antigen-binding fragment thereof administered to the subject in each administration is 60 mg. [F25] Any one of the methods F5 to F22, wherein the subject is determined to have a body weight of less than 40 kg, and the amount of the anti-IL-6 receptor antibody or antigen-binding fragment thereof administered to the subject in each administration is 120 mg. [F26] Any one of the methods F5 to F22, wherein the subject is determined to have a body weight of 40 to 100 kg, and the amount of the anti-IL-6 receptor antibody or antigen-binding fragment thereof administered to the subject in each administration is 120 mg. [F27] Any one of the methods F5 to F22, wherein the subject is determined to have a body weight of 40 to 100 kg, and the amount of the anti-IL-6 receptor antibody or antigen-binding fragment thereof administered to the subject in each administration is 180 mg. [F28] Any one of the methods F5 to F22, wherein the subject is determined to have a body weight of more than 100 kg, and the amount of the anti-IL-6 receptor antibody or antigen-binding fragment thereof administered to the subject in each administration is 180 mg. [F29] Any one of the methods F5 to F22, wherein the subject is determined to have a body weight of more than 100 kg, and the amount of the anti-IL-6 receptor antibody or antigen-binding fragment thereof administered to the subject in each administration is 240 mg. [F30] Any one of the methods F5 to F29, wherein the anti-IL-6 receptor antibody or antigen-binding fragment thereof is administered subcutaneously to a subject. [F31] Any one of the methods F5 to F30, wherein the anti-IL-6 receptor antibody or antigen-binding fragment thereof is administered to a subject three times at two-week intervals (Q2W), and then four-weekly (Q4W) intervals. [F32] Any one of the methods F1-F31, wherein an immunosuppressive therapy (IST) is administered to the subject simultaneously with the IL-6 inhibitor. [F33] The method of F32, wherein the IST comprises: (i) an immunosuppressant selected from the group consisting of azathioprine (AZA), mycophenolate mofetil (MMF), and intravenous (IV) cyclophosphamide; (ii) an oral corticosteroid (OCS); or (iii) a combination of (i) and (ii). [F34] The method of F33, wherein the immunosuppressant comprises prednisone, prednisolone, or an equivalent thereof. [F35] Any one of the methods F1 to F34, wherein administration of an IL-6 inhibitor to the subject improves modified Rankin Scale (mRS) score improvement. [F36] The administration of an IL-6 inhibitor to the subject, - reducing the time to improvement in modified Rankin Scale (mRS) score without the use of rescue therapy; - Delay time to rescue therapy, - delaying the time to seizure freedom or cessation of status epilepticus without the use of rescue therapy; - Improve Clinical Assessment Scale for Encephalitis (CASE) scores; - Improve Montreal Cognitive Assessment (MOCA) total score, - improving Rey Auditory Verbal Learning Test (RAVLT) scores in subjects with anti-LGI1 antibodies, and / or - improve mRS scores in subjects with anti-NMDAR antibodies, F35 way. [F37] Any one of the methods of F1 to F36, wherein administration of an IL-6 inhibitor to the subject improves the subject's score on one or more of the modified Rankin Scale (mRS), Clinical Assessment of Encephalitis (CASE), Montreal Cognitive Assessment (MOCA), Rey Auditory Verbal Learning Test (RAVLT), or Columbia-Suicide Severity Rating Scale (C-SSRS). [F38] Any one of the methods of F1 to F36, wherein administration of an IL-6 inhibitor to the subject reduces the subject's modified Rankin Scale (mRS) score or Clinical Assessment of Encephalitis (CASE) score; or increases the subject's Montreal Cognitive Assessment (MOCA) total score or Rey Auditory Verbal Learning Test (RAVLT) score. [F39] Any one of the methods E1-E38, wherein the IL-6 inhibitor is administered by a subcutaneous administration device. [F40] The method of E39, wherein the subcutaneous administration device is a pre-filled syringe (PFS), optionally a pre-filled syringe with needle safety device (PFS-NSD), or an autoinjector (AI). Effect of the Invention

[0025] The present invention can provide a pharmaceutical agent (pharmaceutical composition) comprising satralizumab for treating, preventing, preventing the recurrence of, or reducing the risk of the recurrence of autoimmune encephalitis, such as anti-NMDAR encephalitis and anti-LGI1 encephalitis. [Brief description of the drawings]

[0026] [Figure 1] The study schema of the first-line treatment period of a Phase III, randomized, double-blind, placebo-controlled, multicenter basket study to evaluate the efficacy, safety, pharmacokinetics, and pharmacodynamics of satralizumab in patients with anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis and anti-leucine-rich glioma inactivation 1 (LGI1) encephalitis is shown. AIE = autoimmune encephalitis; LGI1 = leucine-rich glioma inactivation 1; NMDAR = N-methyl-D-aspartate receptor; PK = pharmacokinetics; Q4W = 4-week interval; R = randomized. Note: Week 0 baseline assessment is performed prior to dosing. The specific dose of satralizumab (or corresponding placebo) is based on the individual participant's weight, as follows: <40 kg: 60 mg or 120 mg Q4W; 40-100 kg: 120 mg or 180 mg Q4W; >100 kg: 180 mg or 240 mg Q4W. [Diagram 2]Figure 1 shows the dependence of steady-state exposure parameters and receptor occupancy on body weight after Q4W dosing of 60 mg (<40 kg), 120 mg (40-100 kg), or 180 mg (>100 kg). Note: Predictions of Cmax, Ctrough, and RO are shown from left to right, respectively. Simulations are based on 2000 individuals. Points are simulated data assuming ADA positivity in a similar proportion of participants as observed in the NMOSD study. For body weights <40 kg, ADA is not assumed. Dashed horizontal lines added for reference. ADA = anti-drug antibodies; Cmax = maximum observed concentration; Ctr = steady-state concentration at the end of the dosing interval; NMOSD = neuromyelitis optica spectrum disorder; RO = receptor occupancy; Q4W = 4-week interval. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0027] Description of the Aspects The present invention relates to a pharmaceutical composition comprising an IL-6 inhibitor as an active ingredient for treating autoimmune encephalitis (AIE), including but not limited to anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis and anti-leucine-rich glioma inactivated 1 (LGI1) encephalitis, or for reducing the risk of relapse in autoimmune encephalitis (AIE) in a subject. Relapse is defined as a new clinical episode (e.g., new or worsening acute symptoms and clinical signs of AIE that appear one month after the last attack). In another aspect, the present invention also relates to the use of an IL-6 inhibitor in the preparation of a medicament for treating autoimmune encephalitis (AIE), including but not limited to anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis and anti-leucine-rich glioma inactivated 1 (LGI1) encephalitis, or for reducing the risk of relapse in autoimmune encephalitis (AIE), in a subject. In yet another aspect, the present invention relates to an IL-6 inhibitor for use in treating autoimmune encephalitis (AIE), including but not limited to anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis and anti-leucine-rich glioma inactivated 1 (LGI1) encephalitis, or in reducing the risk of relapse in autoimmune encephalitis (AIE), in a subject. Furthermore, the present invention also relates to a kit for treating autoimmune encephalitis (AIE), including but not limited to anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis and anti-leucine-rich glioma inactivated 1 (LGI1) encephalitis, or for reducing the risk of relapse in autoimmune encephalitis (AIE) in a subject, comprising a pharmaceutical composition comprising an IL-6 inhibitor and a package insert or label instructing administration of the pharmaceutical composition to a subject. Furthermore, the present invention also relates to a method of treating a subject having autoimmune encephalitis (AIE), including but not limited to anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis and anti-leucine-rich glioma inactivated 1 (LGI1) encephalitis, or reducing the risk of relapse in autoimmune encephalitis (AIE), comprising administering to the subject an effective amount of an IL-6 inhibitor. The "IL-6 inhibitor" of the present disclosure is a substance that blocks signal transduction by IL-6 and inhibits the biological activity of IL-6. The IL-6 inhibitor is preferably a substance that inhibits the binding between IL-6 and the IL-6 receptor and / or between the IL-6 / IL-6 receptor complex and gp130. Examples of the IL-6 inhibitor of the present disclosure include, but are not limited to, an anti-IL-6 antibody or an antigen-binding fragment thereof, an anti-IL-6 receptor antibody or an antigen-binding fragment thereof, an anti-gp130 antibody or an antigen-binding fragment thereof, an IL-6 variant, a soluble IL-6 receptor variant, or a partial peptide of IL-6 or IL-6 receptor, and a low molecular weight substance exhibiting similar activity. Examples of the IL-6 inhibitor of the present disclosure may be preferably an anti-IL-6 antibody or an antigen-binding fragment thereof, or an anti-IL-6 receptor antibody or an antigen-binding fragment thereof, more preferably an anti-IL-6 receptor antibody or an antigen-binding fragment thereof, and optionally a humanized antibody.

[0028] In some embodiments of the present disclosure, the IL-6 inhibitor is an anti-IL-6 receptor antibody or an antigen-binding fragment thereof, comprising a heavy chain variable region (VH) CDR1 comprising the amino acid sequence of SEQ ID NO:5, a VH CDR2 comprising the amino acid sequence of SEQ ID NO:6, a VH CDR3 comprising the amino acid sequence of SEQ ID NO:7, a light chain variable region (VL) CDR1 comprising the amino acid sequence of SEQ ID NO:8, a VL CDR2 comprising the amino acid sequence of SEQ ID NO:9, and a VL CDR3 comprising the amino acid sequence of SEQ ID NO:10. In certain embodiments of the present disclosure, the anti-IL-6 receptor antibody or an antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:1, and a VL comprising the amino acid sequence of SEQ ID NO:2. In certain embodiments of the present disclosure, the IL-6 inhibitor is an anti-IL-6 receptor antibody comprising a heavy chain comprising the amino acid sequence of SEQ ID NO:3, and a light chain comprising the amino acid sequence of SEQ ID NO:4. In certain embodiments of the present disclosure, the IL-6 inhibitor is satralizumab. In some embodiments of the present disclosure, the term "satralizumab" refers to an anti-IL-6 receptor antibody comprising a heavy chain CDR1 comprising the amino acid sequence of SEQ ID NO:5, a heavy chain CDR2 comprising the amino acid sequence of SEQ ID NO:6, a heavy chain CDR3 comprising the amino acid sequence of SEQ ID NO:7, a light chain CDR1 comprising the amino acid sequence of SEQ ID NO:8, a light chain CDR2 comprising the amino acid sequence of SEQ ID NO:9, and a light chain CDR3 comprising the amino acid sequence of SEQ ID NO:10; preferably comprising a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:1, and a light chain variable region comprising the amino acid sequence of SEQ ID NO:2; and most preferably comprising a heavy chain comprising the amino acid sequence of SEQ ID NO:3, and a light chain comprising the amino acid sequence of SEQ ID NO:4.

[0029] In certain embodiments of the present disclosure, autoimmune encephalitis (AIE) includes disorders with identifiable pathogenic drivers, usually tumor-associated disorders, and disorders considered idiopathic. In paraneoplastic immune-mediated encephalitis syndromes, they may be associated with antibodies against intracellular neuronal proteins (onco-neuronal proteins such as anti-Hu). In one aspect, AIE is associated with antibodies against Hu (ANNA1), Ma2, GAD, N-terminal enolase (NAE), NMDA receptor, AMPA receptor, GABA receptor, which are thought to be directly pathogenic for AIE. A Receptor, GABA B This is delineated by the identification of antibodies against neuronal cell surface proteins and synaptic proteins such as receptor, mGluR5, dopamine D2 receptor, anti-leucine rich glioma inactivated 1 (LGI1), CASPR2, and DPPX (Graus et al., Lancet Neurol., 15, 391-404, 2016;Lancaster et al., Neurology, 77, 179-189, 2011). The identification of these autoantibodies may help delineate the population that will have a better response to the present invention. In the present disclosure, AIE includes any AIE subtype in which one or more of autoantibodies are considered to be one of the causes of the disease, and anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis and anti-leucine-rich glioma inactivation 1 (LGI1) encephalitis represent two of the most common and best characterized AIE (Leypoldt F, Wandinger KP, Bien C, et al., Eur Neurol Rev 2013;8:31-7). In one aspect, AIE in the present disclosure also includes Bickerstaff brainstem encephalitis, acute disseminated encephalomyelitis, Hashimoto's encephalopathy, primary central nervous system (CNS) vasculitis, and Rasmussen's encephalitis. In the present disclosure, anti-NMDAR encephalitis and anti-LGI1 encephalitis are described as more specific embodiments.

[0030] In the present disclosure, a "subject", which may also be referred to as a "patient", has the above-mentioned autoimmune encephalitis (AIE), such as anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis and anti-leucine-rich glioma inactivated 1 (LGI1) encephalitis. In one aspect, the subject is positive for anti-N-methyl-D-aspartate receptor (NMDAR) antibodies or anti-leucine-rich glioma inactivated 1 (LGI1) antibodies. In one aspect, whether a subject is positive for anti-NMDAR or anti-LGI1 is detected in cerebrospinal fluid (CSF) from the subject using a cell-based assay. In one aspect, a subject with anti-NMDAR encephalitis or anti-LGI1 encephalitis is detected by using an anti-caspr2 antibody, an anti-IgLON5 antibody, an anti-DPPX antibody, an anti-GABA antibody, or an anti-GABA antibody. A The subject with anti-NMDAR encephalitis or anti-LGI1 encephalitis is negative for cell surface neuronal or glial antibodies other than anti-NMDAR and anti-LGI1 antibodies. In one aspect, the subject with anti-NMDAR encephalitis or anti-LGI1 encephalitis has experienced working memory deficits, seizures, or neurological symptoms suggesting limbic system involvement. In another aspect, the subject with anti-NMDAR encephalitis or anti-LGI1 encephalitis has received or has not received, or has received or has not received chronic immunosuppressive therapy (IST). In one aspect, the subject with anti-NMDAR encephalitis or anti-LGI1 encephalitis has, has been, has not been, is or has not been treated with a stable dose of azathioprine (AZA), mycophenolate mofetil (MMF), intravenous (IV) cyclophosphamide, oral corticosteroids (OCS), or a combination of AZA or MMF or IV cyclophosphamide and OCS.In one aspect, the subject with anti-NMDAR encephalitis or anti-LGI1 encephalitis is (i) anti-NMDAR antibody positive and age 12 years or older; or (ii) anti-LGI1 antibody positive and age 18 years or older.

[0031] In certain embodiments, the medicament or pharmaceutical composition of the present invention is used in combination with immunosuppressive therapy (IST).In certain embodiments, the IST is one or more immunosuppressants selected from the group consisting of azathioprine (AZA), mycophenolate mofetil (MMF), and intravenous (IV) cyclophosphamide; (ii) oral corticosteroids (OCS); or (iii) a combination of (i) and (ii).

[0032] In certain embodiments, the medicament or pharmaceutical composition of the present invention can delay the time from administration of an IL-6 inhibitor to the first occurrence of a relapse of autoimmune encephalitis (AIE), including but not limited to anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis and anti-leucine-rich glioma inactivated 1 (LGI1) encephalitis. In certain embodiments, the medicament or pharmaceutical composition of the present invention can further reduce one or more of the following: (a) Rate of relapse of autoimmune encephalitis (AIE); (b) proportion of active lesions on MRI of the neuraxis; (c) the proportion of subjects receiving salvage therapy; or (d) Rate of hospitalization.

[0033] In this disclosure, the term "treatment" is used in the sense that alleviating or improving symptoms to a level where minimal manifestation (MM) can be maintained, or maintaining such a state, is also included in "treatment" of AIE, even if complete remission of AIE is not achieved.

[0034] In the present disclosure, the efficacy, safety, pharmacokinetics, and / or pharmacodynamics of an IL-6 inhibitor such as satralizumab for the treatment of AIE may be evaluated based on one or more aspects and / or scores as described below. i. To improve modified Rankin Scale (mRS) score improvement. ii. Reducing the time to improvement in modified Rankin Scale (mRS) score without the use of rescue therapy. iii. Delaying time to rescue therapy. iv. Delaying the time to seizure freedom or cessation of status epilepticus without the use of rescue therapy. v. Improve Clinical Encephalitis Assessment Scale (CASE) score. vi. Improve Montreal Cognitive Assessment (MOCA) total score. vii. Improving Rey Auditory Verbal Learning Test (RAVLT) scores in subjects with anti-LGI1 antibodies. viii. Improving mRS scores for subjects with anti-NMDAR antibodies. viii. Improve the Modified Fatigue Impact Scale (MFIS). ix. Improving the Montreal Cognitive Assessment (MOCA). x. To improve the Rey Auditory Verbal Learning Test (RAVLT). xi. Improve EQ-5D-5L. xii. To improve the Columbia-Suicide Severity Rating Scale (C-SSRS). xiii. To improve the Beck Depression Inventory (BDI II).

[0035] The given period of time over which the invention is applied (e.g., a medicament or pharmaceutical composition of the invention is administered) to assess efficacy is not particularly limited and includes 1 week, 2 weeks, 4 weeks, 8 weeks, 12 weeks, 24 weeks, 48 ​​weeks, 1 year, 2 years, 3 years, 4 years, and 5 years, and the period of time may be shorter or longer than the exemplified periods.

[0036] In the present invention, a subject (e.g., a patient) with autoimmune encephalitis (AIE) may receive the treatment (e.g., a medicament, pharmaceutical composition, method, etc.) of the present invention, for example, three times at two-week intervals (Q2W) (i.e., at time zero, and further at weeks 2 and 4), and then at four-week intervals (Q4W). In some embodiments, a subject (e.g., a patient) may receive an anti-IL-6 receptor antibody (e.g., satralizumab) or an antigen-binding fragment thereof contained in the medicament or composition of the present invention via a subcutaneous administration route.

[0037] In addition to treating AIE in a subject of the present invention, the present invention is also used to reduce the risk of recurrence in a recurrence of AIE in a subject. In the present invention, reducing the risk of recurrence includes, but is not limited to, delaying the recurrence of AIE, reducing the frequency of the recurrence, or reducing the severity of the recurrence, or reducing the need for rescue therapy for the recurrence.

[0038] The anti-IL-6 receptor antibody or antigen-binding fragment thereof used in the present invention binds to the IL-6 receptor, inhibits the binding of IL-6 to the IL-6 receptor, blocks signal transduction by IL-6, and inhibits the biological activity of IL-6.

[0039] The anti-IL-6 receptor antibody used in the present invention can be obtained using known methods. In particular, the anti-IL-6 receptor antibody used in the present invention is preferably a monoclonal antibody derived from a mammal. Mammalian-derived monoclonal antibodies include those produced by hybridomas and those produced by hosts transformed with an expression vector containing an antibody gene using genetic engineering techniques.

[0040] Preferred examples of the "IL-6 receptor antibody" of the present invention include humanized anti-IL-6 receptor antibodies produced by modifying the variable and constant regions of tocilizumab, specifically antibodies comprising a heavy chain CDR1 comprising the amino acid sequence of SEQ ID NO: 5, a heavy chain CDR2 comprising the amino acid sequence of SEQ ID NO: 6, a heavy chain CDR3 comprising the amino acid sequence of SEQ ID NO: 7, a light chain CDR1 comprising the amino acid sequence of SEQ ID NO: 8, a light chain CDR2 comprising the amino acid sequence of SEQ ID NO: 9, and a light chain CDR3 comprising the amino acid sequence of SEQ ID NO: 10.

[0041] More preferred antibodies of the present invention include antibodies comprising a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 1, and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 2. Even more preferred are antibodies comprising a heavy chain (satralizumab (generic name); SA237 (informal name) heavy chain) comprising the amino acid sequence of SEQ ID NO: 3, and a light chain (satralizumab light chain) comprising the amino acid sequence of SEQ ID NO: 4. Satralizumab (informal name: SA237) is particularly preferred.

[0042] Government marketing approval for satralizumab has been obtained in many countries, including Japan, the United States, and Europe, based on the indication of "prevention of relapses of neuromyelitis optica spectrum disorder (including neuromyelitis optica)." The safety profile identified during international Phase III clinical trials (SA-307JG / BN40898 and SA-309JG / BN40900 studies) targeting patient populations with neuromyelitis optica spectrum disorder (NMOSD) and / or neuromyelitis optica (NMO) was generally adequate. No deaths were reported. The percentage of patients who experienced severe adverse events in the satralizumab group was similar to that in the placebo group. There was no significant difference between the two groups in the frequency of adverse events that led to discontinuation of study drug administration or to drug withdrawal. The safety profile was similar between the SA-309JG study, which was a monotherapy trial, and the SA-307JG study, which was a combination trial with existing therapy (oral steroids and / or immunosuppressants).

[0043] Such antibodies can be obtained according to the methods described in WO2010 / 035769, WO2010 / 107108, WO2010 / 106812, etc. Specifically, the antibodies can be produced based on the above-mentioned IL-6 receptor antibody sequences using gene recombination techniques known to those skilled in the art (see, for example, Borrebaeck CAK and Larrick JW, THERAPEUTIC MONOCLONAL ANTIBODIES, published in the UK by MACMILLAN PUBLISHERS LTD in 1990). Recombinant antibodies can be obtained by cloning DNA encoding the antibody from a hybridoma or an antibody-producing cell, such as an antibody-producing sensitized lymphocyte, inserting the DNA into an appropriate vector, and introducing the vector into a host (host cell) to produce the antibody.

[0044] Such antibodies can be isolated and purified using, but not limited to, isolation and purification methods conventionally used for antibody purification. For example, antibodies can be isolated and purified by appropriately selecting and combining column chromatography, filtration, ultrafiltration, salting out, solvent precipitation, solvent extraction, distillation, immunoprecipitation, SDS-polyacrylamide gel electrophoresis, isoelectric focusing, dialysis, recrystallization, and the like.

[0045] The antibody used in the present invention may be a conjugated antibody, which is bound to various molecules such as polyethylene glycol (PEG), radioactive substances, and toxins. Such conjugated antibodies can be obtained by chemically modifying the obtained antibody. Methods for antibody modification have already been established in this field. Therefore, the term "antibody" in the present invention includes such conjugated antibodies.

[0046] The antibody used in the present invention may be an antibody fragment (also called an antigen-binding fragment of an antibody) or a modified product thereof, so long as it can be suitably used in the present invention. For example, the antibody fragment includes Fab, F(ab')2, Fv, and single chain Fv (scFv) in which the Fv of the H chain and the Fv of the L chain are linked via a suitable linker. Specifically, antibody fragments are produced by treating antibodies with enzymes such as papain or pepsin, or alternatively, by constructing genes encoding these antibody fragments and introducing them into expression vectors and then expressing the vectors in suitable host cells (see, e.g., Co, MS et al., J. Immunol. (1994) 152, 2968-2976; Better, M. & Horwitz, AH, Methods in Enzymology (1989) 178, 476-496; Plueckthun, A. & Skerra, A., Methods in Enzymology (1989) 178, 497-515; Lamoyi, E., Methods in Enzymology (1989) 121, 652-663; Rousseaux, J. et al., Methods in Enzymology (1989) 121, 652-663). 663-666; and Bird, RE et al., TIBTECH (1991) 9, 132-137).

[0047] An scFv can be obtained by linking the H chain V region and the L chain V region of an antibody. In this scFv, the H chain V region and the L chain V region are linked via a linker, preferably via a peptide linker (Huston, JS et al., Proc. Natl. Acad. Sci. USA (1988) 85, 5879-5883). The H chain and L chain V regions in the scFv may be derived from any of the above antibodies. The peptide linker for linking the V regions includes, for example, any single-chain peptide consisting of 12 to 19 amino acid residues.

[0048] DNA encoding an scFv can be obtained by amplifying a DNA portion encoding the desired amino acid sequence in a template sequence by PCR using a primer pair that defines the ends of the portion, in which a DNA encoding the H chain or H chain V region and a DNA encoding the L chain or L chain V region of the above-mentioned antibody are used as templates, and then further amplifying the amplified DNA portion using a DNA encoding a peptide linker portion and a primer pair that defines both ends of the linker so that it can be linked to each of the H chain and the L chain. Once the DNA encoding the scFv has been prepared, an expression vector containing the DNA and a host transformed with the expression vector can be obtained according to a conventional method. In addition, the host can be used to obtain the scFv according to a conventional method. Similarly as above, antibody fragments can be produced by obtaining and expressing the genes themselves and then using a host.

[0049] In the present invention, "as an active ingredient" means that the ingredient is contained in the pharmaceutical composition as a major active ingredient, and the content thereof is not limited unless specifically indicated, so long as the antibody or antigen-binding fragment thereof used in the present invention is included as a medicinal ingredient.

[0050] The dose of the anti-IL-6 receptor antibody or antigen-binding fragment thereof contained in the pharmaceutical or composition of the present invention is not particularly limited, and examples include 50 to 800 mg of antibody per administration, preferably 60 to 240 mg of antibody per administration, and more preferably 60 mg, 120 mg, 180 mg, or 240 mg of antibody. The dose of the anti-IL-6 receptor antibody or antigen-binding fragment thereof contained in the pharmaceutical or composition of the present invention may vary depending on the patient's body weight. In certain embodiments of the present invention, the dose of the anti-IL-6 receptor antibody or antigen-binding fragment suitable for a subject having a body weight of less than 40 kg is 60 mg or 120 mg; the dose suitable for a subject having a body weight of 40 kg to 100 kg is 120 mg or 180 mg; and the dose suitable for a subject having a body weight of more than 100 kg is 180 mg or 240 mg. The pharmaceutical or composition containing the anti-IL-6 receptor antibody or antigen-binding fragment thereof of the present invention is administered to a subject via any route, including but not limited to subcutaneous, intravenous, intramuscular, and injection. The preferred embodiment is subcutaneous administration.

[0051] In a particular embodiment of the present invention, two or more consecutive doses of an anti-IL-6 receptor antibody or antigen-binding fragment thereof contained in the pharmaceutical or composition of the present invention are administered to a subject during an initial period, wherein the doses administered during the initial period are spaced apart by a first administration interval (also referred to as an administration interval shorter than a conventional administration interval), for example, 20 weeks, 8 weeks, 4 weeks, or 2 weeks; and after the administration of the final dose in the initial period, a second administration interval longer than the first administration interval is provided, and then a dose of an anti-IL-6 receptor antibody or antigen-binding fragment thereof contained in the pharmaceutical or composition of the present invention is administered to a human patient, wherein, optionally, multiple consecutive doses are administered after the administration of the final dose in the initial period and are spaced apart by a second administration interval (also referred to as a "conventional administration interval") that is not particularly limited except that it is longer than the first administration interval. Examples of the second administration interval include 1 day to 24 weeks, preferably 2 weeks to 8 weeks, more preferably 3 to 5 weeks, and even more preferably 4 weeks. In a specific embodiment of the present invention, the anti-IL-6 receptor antibody or antigen-binding fragment thereof contained in the pharmaceutical or composition of the present invention is administered to a subject three times at two-week intervals (Q2W) and then four-weekly (Q4W) intervals.

[0052] A preferred administration schedule for the anti-IL-6 receptor antibody or antigen-binding fragment thereof contained in the pharmaceutical or composition of the present invention can be adjusted, for example, by appropriately extending the administration interval by monitoring changes in the disease state and blood test values.

[0053] The present invention also provides a product, such as a kit, device, etc., for use in the method of the present invention, containing the pharmaceutical composition or medicament of the present invention. The pharmaceutical composition or medicament of the present invention comprises an IL-6 inhibitor as described herein. The product may be packaged with additional pharma- ceutically acceptable carriers or vehicles, or instructions for use in the kit, etc.

[0054] In one embodiment, the product comprises a container and a label on the container or a package insert associated with the container. Suitable containers include, for example, bottles, vials, syringes (including prefilled syringes and autoinjectors), IV solution bags, etc. The container can be made of various materials, such as glass or plastic. In one embodiment, the container holds a composition, alone or in combination with another composition that is effective for treating, preventing, and / or diagnosing a condition, and can have a sterile access port (e.g., the container can be a syringe, autoinjector, intravenous solution bag, or a vial with a stopper that can be pierced by a hypodermic needle). At least one active ingredient in the composition is an IL-6 inhibitor as described in the present disclosure, preferably an anti-IL-6 receptor antibody, and more preferably satralizumab.

[0055] In one embodiment, the device as the product of the present invention as described above may be a pre-filled syringe (PFS), which is a pre-filled syringe (PFS-NSD) for injection via any administration route, such as intravenous, subcutaneous, etc., optionally with a needle safety device, comprising a fixed dose of an IL-6 inhibitor as described in the present disclosure, preferably an anti-IL-6 receptor antibody, and more preferably satralizumab, in a pharmaceutically acceptable excipient.In another embodiment, the device may be an auto-injector (AI) for subcutaneous administration, comprising a fixed dose of an IL-6 inhibitor as described in the present disclosure, preferably an anti-IL-6 receptor antibody, and more preferably satralizumab, in a pharmaceutically acceptable excipient.In a particular embodiment, the device is a subcutaneous administration device, such as a pre-filled syringe (PFS) and an auto-injector (AI), which may comprise 60 mg, 120 mg, 180 mg, or 240 mg of satralizumab. In one embodiment, the subcutaneous administration device is a pre-filled syringe (PFS-NSD) with a needle safety device, which contains 60 mg (e.g., 60 mg / mL) satralizumab, for delivering 60 mg or 180 mg dose to a subject.In another embodiment, the subcutaneous administration device is a pre-filled syringe (PFS-NSD) with a needle safety device, which contains 120 mg (e.g., 60 mg / 0.5 mL) satralizumab, for delivering 120 mg, 180 mg or 240 mg dose to a subject.In another embodiment, the subcutaneous administration device is an autoinjector (AI) that contains 120 mg, 180 mg or 240 mg satralizumab.

[0056] In the present invention, the label or package insert indicates that the pharmaceutical composition or medicament is used to treat a selected condition. In addition, the product may include (a) a first container in which a composition comprising an IL-6 inhibitor, preferably an anti-IL-6 receptor antibody, and more preferably satralizumab, as described above is contained; and (b) a second container in which a composition comprising an additional therapeutic agent is contained. The product in this aspect of the present invention may further include a package insert indicating that the composition can be used to treat a particular condition. Alternatively, or in addition, the product may further include a second (or third) container containing a pharma- ceutically acceptable buffer, such as bacteriostatic water for injection (BWFI), phosphate buffered saline, Ringer's solution, and dextrose solution. It may further include other materials desirable from a commercial and user standpoint, including other buffers, diluents, filters, needles, and syringes.

[0057] Attached document The term "package insert" is used to refer to instructions customarily included in commercial packaging of a therapeutic product, which contain information about the indications, usage, dosage, administration, concomitant therapy, contraindications, and / or warnings regarding the use of such therapeutic product.

[0058] The pharmaceutical composition or medicine of the present invention can be formulated to prepare a lyophilized preparation or a solution preparation by mixing with a suitable pharmaceutically acceptable carrier, vehicle, etc., if necessary. Suitable pharmaceutically acceptable carriers and vehicles include, for example, sterilized water, physiological saline, stabilizers, excipients, antioxidants (such as ascorbic acid), buffers (such as phosphates, citrates, histidine, and other organic acids), preservatives, surfactants (such as PEG and Tween), chelating agents (such as EDTA), and binders. Other low molecular weight polypeptides, proteins, such as serum albumin, gelatin, and immunoglobulins, amino acids, such as glycine, glutamine, asparagine, glutamic acid, aspartic acid, methionine, arginine, and lysine, sugars and carbohydrates, such as polysaccharides and monosaccharides, and sugar alcohols, such as mannitol and sorbitol, may also be included in the formulation. When preparing an injectable aqueous solution, isotonic solutions containing physiological saline, glucose and other adjuvants, such as D-sorbitol, D-mannose, D-mannitol, and sodium chloride, may be used; and suitable solubilizers, such as alcohol (e.g., ethanol), polyhydric alcohols (such as propylene glycol and PEG), and non-ionic surfactants (such as polysorbate 80, polysorbate 20, poloxamer 188, and HCO-50), may be used in combination. By mixing hyaluronidase into the formulation, a larger amount of liquid can be administered subcutaneously (Expert Opin. Drug Deliv. 2007 July; 4(4): 427-40). In addition, a syringe may be pre-filled with the pharmaceutical composition of the present invention. The solution formulation may be prepared according to the method described in WO2011 / 090088.

[0059] If necessary, the pharmaceutical compositions or medicaments of the present invention may be encapsulated in microcapsules (e.g., those made of hydroxymethylcellulose, gelatin, and poly(methyl methacrylate)) or incorporated into colloidal drug delivery systems (e.g., liposomes, albumin microspheres, microemulsions, nanoparticles, and nanocapsules) (see, for example, "Remington's Pharmaceutical Science 16th edition", Oslo Ed. (1980)). Methods for formulating drugs as controlled release drugs are also known, and such methods may be applied to the pharmaceutical compositions of the present invention (Langer et al., J. Biomed. Mater. Res. 15: 267-277 (1981); Langer, Chemtech. 12: 98-105 (1982); U.S. Patent No. 3,773,919; European Patent Application Publication No. EP 58,481; Sidman et al., Biopolymers 22: 547-556 (1983); and EP 133,988).

[0060] The anti-IL-6 receptor antibody or antigen-binding fragment thereof contained in the pharmaceutical or composition of the present invention can be administered to a patient via any suitable route. For example, it can be administered to a patient intravenously by bolus injection or continuous infusion, intramuscularly, intraperitoneally, intracerebrospinally, transdermally, subcutaneously, intraarticularly, sublingually, intrasynovially, orally, by inhalation, locally, or externally for a certain period of time. Intravenous or subcutaneous administration is preferred. In a certain embodiment of the present invention, the anti-IL-6 receptor antibody or antigen-binding fragment thereof contained in the pharmaceutical or composition of the present invention is administered subcutaneously to a subject.

[0061] All prior art references cited herein are hereby incorporated by reference. EXAMPLES

[0062] Hereinafter, the present invention will be specifically described with reference to examples, but should not be construed as being limited thereto.

[0063] Example 1: Preparation of Satralizumab (SA237) An antibody having the generic name satralizumab (and the informal name SA237), which is an IL-6 receptor antibody described in patent document WO 2010 / 035769 as comprising a heavy chain having the amino acid sequence of SEQ ID NO:26 (herein SEQ ID NO:3) and a light chain having the amino acid sequence of SEQ ID NO:29 (herein SEQ ID NO:4), was prepared according to the description in the patent document. The amino acid sequence of the heavy chain variable region is shown in SEQ ID NO:1, and the amino acid sequence of the light chain variable region is shown in SEQ ID NO:2. Using the prepared antibody, a subcutaneous administration preparation was prepared by the method described in patent document WO 2011 / 090088.

[0064] Example 2: A Phase III, Randomized, Double-Blind, Placebo-Controlled, Multicenter Basket Study to Evaluate the Efficacy, Safety, Pharmacokinetics, and Pharmacodynamics of Satralizumab in Patients with Anti-N-Methyl-D-Aspartate Receptor (NMDAR) Encephalitis or Anti-Leucine-Rich Glioma Inactivated 1 (LGI1) Encephalitis

[0065] 1. preface 1.1 Study rationale The objective of this study is to evaluate the efficacy, safety, pharmacokinetics, and pharmacodynamics of satralizumab in participants with anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis and anti-leucine-rich glioma inactivated 1 (LGI1) encephalitis. Although NMDAR encephalitis and LGI1 encephalitis are separate, diagnostically distinct disease subtypes, both share core clinical features of seizures and cognitive impairment; therefore, it is appropriate to apply the same study endpoints, study duration, and study design to each subtype, but analyze outcomes in each subtype independently. To balance these considerations, we clearly separate participants with either of these two encephalitides into separate cohorts, each with its own placebo control and analysis. Current treatment of these disorders uses exclusively off-label immunotherapy and is based on expert opinion, retrospective case series, and open-label trials. Several unmet needs exist, including frequent occurrence of long-term cognitive deficits, inadequate seizure control, frequent dependence on high-dose corticosteroids, and faster-acting but durable immunotherapies. Prospectively generated evidence-based treatments are needed to meaningfully reduce the acute and long-term severity of these disorders.

[0066] 1.2 Benefit-Risk Assessment The objective of this study is to evaluate the efficacy and safety of satralizumab, an IL-6R blocker, to address a significant unmet medical need in participants with AIE. Although satralizumab has not been previously tested in patients with either anti-NMDAR- or anti-LGI1-mediated encephalitis, preclinical and clinical data suggest that IL-6 plays a key role in the pathophysiology of these diseases. IL-6 is a proinflammatory cytokine with pleiotropic functions, including induction of differentiation and proliferation of proinflammatory Th17 cells and plasmablasts, as well as plasma cell maturation. IL-6R blockade has the potential to modulate the immunopathogenesis of AIE, independent of the type of autoantibody. Processes regulated by IL-6R signaling, such as B and T cell differentiation, B cell proliferation, and blood-brain barrier regulation, have been suggested to have a role in the pathogenesis of both anti-NMDAR-mediated AIE (Armangue et al. 2018; Martinez-Hernandez et al. 2011; Bien et al. 2012; Leypoldt et al. 2015; Ding et al. 2018) and anti-LGI1-mediated AIE (Helmstaedter et al. 2021).

[0067] Preclinical data generated using IL-6 knockout mice and IL-6 neutralizing antibodies demonstrate a clear role for IL-6 in the pathogenesis of experimental AIE. In rats administered NMDAR antibodies, brain infusion of IL-6 was associated with a worsening of NMDAR-mediated excitatory postsynaptic currents and was accompanied by enhanced impairment of memory and learning abilities (Wang et al. 2019). In addition, increased CSF IL-6 levels have been observed in patients with NMDAR encephalitis and in patients with new-onset refractory status epilepticus, a condition commonly associated with AIE (Jun et al. 2018; Kirmani et al. 2018).

[0068] Furthermore, clinical case series suggest benefits associated with IL-6R antagonism in patients with AIE and related conditions. Retrospective studies have demonstrated significant benefits of anti-IL-6R treatment (tocilizumab) administered to adult patients with various antibody subtypes (including anti-NMDAR and anti-LGI1) who had an incomplete response to prior rituximab (Lee et al. 2016a;Lee et al. 2016b). Similar responses were seen in children (Randell et al. 2018). IL-6R antagonism was also associated with significant clinical improvement when administered to patients with new-onset NMDAR-positive AIE and CASPR2-positive AIE with recent onset of symptoms (Lee et al. 2020;Krogias et al. 2013). Similar beneficial effects were observed in patients with "probable AIE" (i.e., fulfilling AIE clinical criteria but without obvious autoantibody association) (Lee et.al. 2000). Finally, IL-6R inhibition has been associated with the cessation of refractory status epilepticus, a life-threatening condition observed in as many as 30% of patients with AIE in acute care (Cadena et al. 2017; Jun et al. 2018).

[0069] Satralizumab has proven efficacy and safety and is indicated in another autoantibody-mediated disease (i.e., NMOSD) as monotherapy or as an add-on to immunosuppressive therapy (IST; i.e., oral corticosteroids [OCS], azathioprine, or mycophenolate mofetil). The double-blind period of the Phase III study in NMOSD included a total of 178 participants. Of the 178 participants, 104 participants were treated with a 120 mg satralizumab dose subcutaneously every 4 weeks (Q4W) and 74 participants were treated with placebo. Overall, satralizumab as monotherapy or in combination with IST was well tolerated by participants with NMOSD.

[0070] All currently available treatment options for AIE (including high-dose corticosteroids and cyclophosphamide) have substantial potential safety risks. There is no evidence from randomized controlled trials to support treatment decisions. In addition, not all patients respond to currently used pharmacotherapy, and deficiencies remain, including cognitive deficits, inadequate seizure recovery, dependence on high-dose corticosteroids, and the need for sustained faster-acting agents. The proposed satralizumab trial will address these unmet needs and demonstrate efficacy of satralizumab in patients with NMDAR or LGI1 encephalitis. Considering the potential for efficacy in patients for whom no approved drugs exist, the safety profile of satralizumab, and risk mitigation measures for the trial, the benefit-risk ratio is expected to be acceptable for satralizumab in the treatment of both NMDAR and LGI1 encephalitis.

[0071] 2. Objectives and Evaluation Items This study will evaluate the efficacy, safety, pharmacokinetics, and pharmacodynamics of satralizumab compared to placebo in each of the following cohorts: *NMDAR AIE cohort: Adults and adolescents with definite or probable NMDAR encephalitis *LGI1 AIE cohort: Adults with LGI1 encephalitis.

[0072] For efficacy analyses, each cohort will be treated as a separate population with independent type I error control at the 5% significance level. Specific objectives and corresponding endpoints for both cohorts are outlined for Part 1 (first-line treatment period) in Table 1.

[0073] Table 1: Objectives and corresponding evaluation items for Part 1 TIFF2025502891000002.tif128168ADA=Anti-drug antibodies;AIE=Autoimmune encephalitis;BDI-II=Beck Depression Inventory, 2nd edition;CASE=Clinical Rating Scale in Autoimmune Encephalitis;C-SSRS=Columbia Suicide Severity Rating Scale;EEG=Electroencephalogram;LGI1=Leucine-Rich Glioma Inactivation 1;MFIS=Modified Fatigue Impact Scale;MOCA=Montreal Global Cognitive Assessment;mRS=Modified Rankin Scale;NMDAR=N-methyl-D-aspartate receptor;PK=Pharmacokinetics;QOL=Quality of life;RAVLT=Rey Auditory Verbal Learning Test.

[0074] 3. Study design 3.1 Overall design 3.1.1 Study Design Overview This Phase III, randomized, double-blind, placebo-controlled, multicenter study is designed to evaluate the efficacy, safety, pharmacokinetics, and pharmacodynamics of satralizumab compared to placebo for the treatment of NMDAR and LGI1 encephalitis. For efficacy analyses, NMDAR and LGI1 AIE cohorts will be treated as separate populations in a basket study design. The study will include a screening period of up to 28 days, during which patients' eligibility for study participation will be assessed. Screening will be followed by: *Part 1: 52 weeks of first-line treatment *Part 2: An optional extension period lasting approximately 2 years from the time the last participant enters the extension period or until commercially available satralizumab is available for the treatment of AIE. Interim pharmacokinetic (PK) analyses will be performed to confirm that target concentrations are achieved (see Section 7.4.1). Approximately 102 participants in the NMDAR AIE cohort and 50 participants in the LGI1 AIE cohort will be enrolled across all locations in the global enrollment phase. The test schema is provided in FIG.

[0075] 3.1.2 Part 1: Primary treatment period During part 1, participants will be randomly assigned in a 1:1 ratio to receive placebo, or 60 mg (<40 kg), 120 mg (40-100 kg), or 180 mg (>100 kg) of satralizumab in each of the NMDAR AIE and LGI1 AIE cohorts.

[0076] Randomization within each cohort will be stratified by: *Patient population: new onset vs incomplete responders (as described in section 4.1.1) *region.

[0077] Blinded study medication will be administered subcutaneously to participants as monotherapy or in addition to background treatment at weeks 0, 2, 4, and Q4W thereafter until the end of Part 1. During part 1, in addition to satralizumab or placebo, participants in both cohorts may receive background treatment with IST (see Background Treatment in Section 5.1.2) and symptomatic treatment (see Symptomatic Treatment in Section 5.2.2) depending on the stage of disease as outlined in the inclusion criteria.

[0078] Participants receiving oral or IV corticosteroids at baseline and not in a critical care setting (i.e., intensive care unit, high dependency unit) will have their OCS tapered using standard tapering techniques starting 4 weeks after randomization (Week 4).

[0079] For participants in critical care settings (i.e., intensive care unit, skilled nursing unit) and receiving oral or IV corticosteroids at baseline, steroid tapering is optional at the physician's discretion and, if performed, should follow the tapering schedule for non-critical care settings (as shown above). Upon discharge from critical care, the tapering schedule for non-critical care settings will be initiated, provided that 4 weeks have passed since randomization (week 4 or later). The dose of background and symptomatic treatment can be reduced at any time for safety reasons. Pre-specified interim PK analyses and periodic safety reviews will be performed by an independent Data Monitoring Committee (iDMC) during Part 1. The interim PK analyses will be performed with the goal of confirming that achieved satralizumab exposure (and predicted receptor occupancy [RO]) is within the target range. Based on the results from the interim PK analyses and pre-specified criteria, the dose of study drug may be escalated (see Section 3.3 for satralizumab dose rationale). Sponsors, participants, and investigators will remain blinded to the interim PK analyses, periodic safety reviews, and any optional interim efficacy analyses.

[0080] 3.2 Rationale for study design 3.2.1 Rationale for Study Population and Analysis Groups The study will investigate satralizumab as treatment in participants with NMDAR encephalitis and LGI1 encephalitis as separate cohorts within a single study, with each cohort including its own placebo arm and analyzed separately with independent type I error control at the 5% significance level. The study population will include participants who meet the clinical criteria for receiving a diagnosis of NMDAR or LGI1 encephalitis (see section 4.1; adapted from Graus et al. 2016) and whose AIE has resulted in a decline in function and ability to perform previous activities (defined by an mRS score <2).

[0081] The identification of antibodies against neuronal cell surface and synaptic proteins that are thought to be directly pathogenic delineates populations that generally have improved responses to immunotherapy. Among these, anti-NMDAR- and anti-LGI1-mediated encephalitis represent the most common (Leypoldt et al. 2013) and best-characterized syndromes.

[0082] NMDAR encephalitis is associated with CSF IgG antibodies against the GluN1 subunit of NMDAR. These antibodies are highly specific and their pathogenicity has been demonstrated in cultured neurons and in vivo models. In clinical practice, antibody studies should include the analysis of CSF; there is a risk of false-negative or false-positive diagnoses when using serum alone (Graus et al. 2016).

[0083] In clinical practice, access to anti-NMDAR assays, specifically CSF sampling for anti-NMDAR antibodies, may be inconsistent, delayed, or difficult to achieve. Treatment decisions are often based on clinical features. As a result, criteria for highly probable NMDAR encephalitis have been published in consensus documents and have shown high sensitivity and specificity in adults (87.2% and 96.7%, respectively; Kaneko 2018), Australian children (90% and 96%, respectively; Ho et al. 2017), and Japanese children (81.2% and 76.9%, respectively; Nishida et al. 2021).

[0084] All participants in this trial received first-line therapy (e.g., high-dose corticosteroids, IVIG, or plasmapheresis) prior to randomization, and participants in the "incomplete responder" category received immunotherapy treatment >6 weeks after acute first-line therapy. Administration of these therapies may affect the detection of anti-NMDAR antibodies, resulting in both false positives and false negatives (Gruter et al. 2020). Thus, confirming antibody positivity in an already treated population may not be a reliable gold standard for diagnosis, and requiring antibody positivity prior to treatment limits applicability and recruitment.

[0085] Assuming that many patients in clinical practice with highly probable NMDAR encephalitis are treated based on highly suggestive clinical features, and taking into account the proven usefulness of the "high probable" criteria and the expected impact of immunomodulatory therapy on anti-NMDAR antibody detection, the study population will include both definite NMDAR encephalitis (defined by consensus criteria requiring CSF antibody positivity and consistent clinical features) and highly probable NMDAR encephalitis (defined according to consensus criteria requiring strict clinical features together with positive paraclinical investigations [CSF and electroencephalogram; EEG]) in the NMDAR population.

[0086] Despite concerns over assay interference from prior drug use, serum collection is likely to be more widely adopted worldwide given its higher sensitivity than CSF in diagnosing LGI1 encephalitis (van Sonderen et al. 2016). No consensus diagnostic criteria have been published, but diagnostic criteria have been developed and outlined in protocols that require key clinical features described for limbic encephalitis (common clinical presentation) in a consensus document (Graus et al. 2016) and confirmed in the largest published LGI1 AIE series (van Sonderen et al. 2016) in combination with positive serum or CSF samples.

[0087] Due to the unknown significance and pathogenicity of antibodies that associate with intracellular antigens, and their higher association with cancer, patients with a diagnosis or history of these antibodies will be excluded from the study. Specifically, anti-Hu antibodies, anti-Ma2 antibodies, anti-CRMP5 antibodies, anti-Yo antibodies, anti-amphiphysin antibodies, AMPA antibodies, mGluR5 antibodies, and GABA antibodies will be excluded from the study. B Patients with a known diagnosis or history of positive testing for antibodies will be excluded.Similarly, patients with untreated teratoma / thymoma, history of malignancy (unless considered cured with appropriate treatment with no evidence of recurrence for 5 years prior to screening), or a confirmed diagnosis of paraneoplastic encephalitis will be excluded from enrollment.

[0088] 3.2.2 Rationale for a control group The control group in the study will receive a placebo. Participants can continue to receive stable doses of select background therapy during part 1, as outlined in section 5.1.2. The use of a placebo in this setting will help establish the efficacy and safety of satralizumab in a clinical setting that represents a real-world scenario for patients with AIE. Placebo-controlled data in NMDAR and LGI1 encephalitis subtypes will not only provide evidence in these individual syndromes for which there are no approved pharmacological therapies, but may also generate information pertinent to the understanding of the broader spectrum of AIE.

[0089] 3.2.3 Rationale for Pharmacokinetic Sample Collection Schedule To explore the pharmacokinetics of satralizumab in the NMDAR / LGI1 encephalitis population after longer-term treatment, samples to assess serum concentrations of satralizumab will be collected prior to each dose of study drug. These assessments will include analysis of the impact of a range of covariates (e.g., sex, race, age, and weight) on exposure to support recommended doses of satralizumab in the NMDAR / LGI1 encephalitis population, as well as analysis of the relationship between exposure and PD, efficacy, immunogenicity, and safety endpoints. PK assessments will also be used to inform interim PK analyses to confirm appropriate dosing of satralizumab in the AIE population.

[0090] 3.2.4 Rationale for immunogenicity sample collection Serum samples for ADA will be collected in parallel with PK samples to assess the incidence and titer-time profile of ADA in the NMDAR / LGI1 encephalitis population and its impact on satralizumab exposure and on safety and efficacy. ADA data will be included in a blinded review of the PK data at week 8 to aid in the interpretation of satralizumab concentration data, in addition to subsequent analyses based on the full study data set.

[0091] 3.2.5 Rationale for biomarker evaluation The study will evaluate whether biomarkers can help characterize the mechanism of action of satralizumab in NMDAR / LGI1 encephalitis, provide evidence of satralizumab activity in NMDAR / LGI1 encephalitis, or increase knowledge and understanding of NMDAR / LGI1 encephalitis disease biology.

[0092] 3.2.6 Rationale for the Primary Endpoint We propose to use the modified Rankin Scale (mRS) as the primary outcome measure in this Phase III study to evaluate the benefit of satralizumab on multiple symptoms that affect the clinical status and disability of participants with either NMDAR or LGI1 encephalitis. The mRS is a score that measures disability and dependency.

[0093] The choice of the mRS scale is supported by the following: *Its proven validity and reliability: The mRS was developed by Dr. John Rankin to assess stroke severity (seven severity grades: from 0=no symptoms at all to 6=death) and functional limitations in performing activities of daily living (i.e., ability to walk and participate in usual duties and activities) that have been shown to be present and clinically relevant in patients with AIE. The mRS shows good construct validity when correlated with the Clinical Assessment Scale for AIE (CASE), a recently developed scale for AIE that measures symptom severity (r=0.86, p=0.001; Lim et al. 2019). Test-retest reliability was determined in a sample of patients (n=48) referred for two separate evaluations and showed a high degree of reproducibility (r=0.94; Wilson et al. 2005). *Its content validity in NMDAR encephalitis: The complex neuropsychiatric manifestations and global cognitive impairments seen in NMDAR encephalitis lead to disability and dependency in affected individuals, which are well reflected by the mRS score. Moreover, the score is simple and straightforward to administer and understand for clinicians in acute neurological settings. The mRS has also been used in patients with NMDAR encephalitis to study short-term and long-term outcomes of commonly administered medications (Titulaer et al. 2013; Gadoth et al. 2017). Thus, we believe that the mRS scale adequately measures clinically significant neurological improvement in patients with NMDAR encephalitis, while at the same time representing the most clinically meaningful outcome for a group of patients with disabling and often diverse symptoms (Dubey et al. 2015). *Its content validity in LGI1 encephalitis: The impairments in LGI1 encephalitis, dominated by anatomically limited cognitive impairments affecting memory and seizures, but also including behavioral disorders, have a significant impact on abilities and dependencies that are amenable to simple assessment and measurement using the mRS score. Additionally, changes in mRS scores in patients with LGI1 AIE-positive have been shown to generally track changes in key symptoms such as seizure frequency and cognitive deficits (van Sonderen et al. 2016), indicating that the scale is a reasonable measure of how the predominant individual symptoms associated with LGI1 encephalitis affect the patient's daily functioning. For these reasons, the mRS has been used in patients with LGI1 AIE to study short-term and long-term outcomes in the available literature examining the history of treated natural subjects (van Sonderen et al. 2016; Gadoth et al. 2017; Gadoth et al. 2018). *Guidance for assessing grades will be adapted to assess key aspects of AIE including cognitive deficits (memory loss) during patient interview. This guidance will be part of mRS mandatory training across all locations to ensure consistency.

[0094] Finally, the mRS has also been utilized as the primary endpoint in several randomized controlled and open-label trials in AIE, including patients with both NMDAR and LGI encephalitis (NCT04372615, NCT03993262, NCT03542279, and NCT04175522). Available data on the mRS scale in AIE have been used to help inform proposed study designs, particularly with regard to expected changes in the placebo arm (Gadoth et al. 2017; Titulaer et al. 2013).

[0095] The primary endpoint in the NMDAR AIE and LGI1 AIE cohorts will evaluate the difference between satralizumab and placebo in the proportion of responders at week 24 in participants with NMDAR and LGI1 encephalitis, respectively.

[0096] Responders are defined as participants with an mRS score improvement from baseline of 1 point or more at week 24 and no use of rescue therapy. A change of 1 mRS grade is considered clinically significant based on the range of severity covered by the scale grades (Banks and Marotta 2007; Harrison et al. 2013) and is used in clinical practice and observational studies of AIE to represent a meaningful change in a patient's ability to engage in activities of daily living. We propose to include patients who, at baseline, are unable to perform at least all of their previous activities (as measured by an mRS of 2 or more). Thus, a score improvement of 1 (rather than an mRS score of 0 to 2, which generally corresponds to a "good outcome" on the scale) adequately captures meaningful improvement in all participants in the study with different symptom levels and degrees of disability exhibited. Additional data using the mRS scale will be collected as part of secondary and exploratory endpoints (mRS score [measured on a 7-point scale] and percentage of participants with an mRS score of 2 or less).

[0097] 3.3 Rationale for Dosage and Schedule As shown in Table 2, weight-graded dosing via SC injection will be used in this study to investigate the efficacy and safety of satralizumab in NMDAR and LGI1 encephalitis.

[0098] Table 2. Investigational dosing regimens in Phase III trials of satralizumab for the treatment of NMDAR and LGI1 encephalitis TIFF2025502891000003.tif41156PK=pharmacokinetics; Q4W=every 4 weeks. NOTE: Dose may be escalated following interim PK analysis. See details below.

[0099] The dosing regimen will be based on a combination of sources of information, including PK, PD, and safety data for satralizumab for early development in NMOSD.

[0100] The 120 mg fixed dosing regimen (administered at weeks 0, 2, and 4, and Q4W thereafter) investigated in Phase III trials in NMOSD was associated with high predicted trough receptor occupancy (RO) at steady state in most participants (median >95%). tr,ss ) and has been shown to be safe and effective across all weight groups (i.e., ≥40 kg). A 4-week maintenance dosing interval is supported by satralizumab's half-life of approximately 30 days. A predicted RO of <80% tr,ss The few participants with NMOSD who had a baseline weight of >100 kg generally had a baseline weight of >100 kg, and the safety profile was similar across weight groups, although satralizumab exposure in the lightest participants was associated with a near-maximal ROI. tr,ss was in excess of what was needed to maintain it.

[0101] Given the expected similar target expression between participants with NMOSD and those with NMDAR / LGI1 encephalitis, exposures similar to those seen in NMOSD are also expected to be effective in NMDAR and LGI1 encephalitis. Thus, the same near-maximal ROIs for participants with NMDAR and LGI1 encephalitis across the expected weight ranges. tr,ss To estimate the dose required to achieve values, we performed simulations using an existing popPK model (based on data in healthy volunteers and participants with NMOSD) to maximize the potential for efficacy.

[0102] These simulations demonstrate that the proposed weight-graded dosing regimen results in maximum observed steady-state concentrations (C max ) Median (C max,ss ) and steady-state trough concentration (C tr,ss (Figure 2). The predicted exposure range in participants weighing over 100 kg receiving 180 mg satralizumab does not significantly exceed the maximum exposure achieved in Phase III studies in NMOSD and therefore remains within the existing exposure-safety envelope. Conversely, the predicted exposure of the 60 mg regimen in participants weighing less than 40 kg is expected to be sufficient to maintain high target engagement over the dosing interval and avoid unnecessary overexposure.

[0103] The assumption in setting the initial dose of this Phase III study is that the pharmacokinetics of satralizumab in participants with NMDAR and LGI1 encephalitis are similar to those in NMOSD. However, we note that there may be PK differences between the populations, as seen in the higher clearance (CL) values ​​in healthy volunteers compared to the NMOSD population (covariate value: 95.8%; 95% CI: 67.5-124.1). Therefore, the proposed study design provides for an interim PK analysis to confirm the initial dose or, if CL is higher in the NMDAR / LGI1 population (as observed in healthy volunteers), to escalate the dose to a pre-specified level at the recommendation of the iDMC, and the sponsor will remain blinded to help maintain the integrity of this important study. Further details on the proposed interim PK analysis can be found in Section 7.4.1.

[0104] Simulations using existing popPK models are used to define alternative doses if the initially proposed dose does not achieve the target exposure. Assuming that the targets are the same (i.e., for NMOSD and NMDAR / LGI1 encephalitis) and similar target expression is expected for NMDAR and LGI1 encephalitis, the use of existing RO models as the basis for RO prediction in this interim analysis is deemed appropriate. If the CL values ​​in this study reflect those in healthy volunteers (higher than those in the NMOSD population), the dose adaptation option is to escalate the dose to predefined dosing regimens of 120 mg (<40 kg), 180 mg (40-100 kg), and 240 mg (>100 kg) for participants. In either case, the dosing regimen selected is associated with an exposure that does not significantly exceed the existing exposure-safety range.

[0105] PK parameters in minor participants with NMOSD were similar to those in adult participants, and the predicted exposure resulting from this dosing regimen is supported by the existing safety profile established in Phase 3 studies in adult and minor participants with NMOSD.

[0106] 3.4 Definition of End of Study Participants were considered to have completed the study if they had completed all phases of the study, including the last visit / last scheduled procedure. The end of the study will be defined as the date of the last visit of the last participant in the study across both cohorts, or the date the last data point required for statistical analysis or SFU is received from the last participant in either cohort, whichever is later.

[0107] 4. Completion of Part 1 is expected to occur 52 weeks after the last participant is enrolled in the study population. Participants with NMDAR encephalitis and participants with LGI1 encephalitis will be enrolled during the global enrollment phase of the study. Prospective approval of protocol deviations from recruitment and enrollment criteria, also known as protocol waivers or exemptions, will not be permitted.

[0108] 4.1 Inclusion Criteria Participants in the NMDAR AIE cohort must meet the inclusion criteria outlined in Sections 4.1.1 and 4.1.2. Participants in the LGI1 AIE cohort must meet the inclusion criteria outlined in Sections 4.1.1 and 4.1.3.

[0109] 4.1.1 Inclusion criteria for all participants Participants were eligible for inclusion in the study only if the following criteria were met: *Able to give signed informed consent, including compliance with the requirements and limitations listed in the informed consent form and this protocol * Reasonable exclusion of tumor or malignancy prior to the baseline visit (randomization) *Onset of AIE symptoms within 9 months prior to randomization *Meets definition of "new onset" or "incomplete responder" AIE. Participants will be subclassified as either "new onset" or "incomplete responder" based on the interval between their initial first-line treatment and the start of study therapy and any additional treatments they received, as follows: New-onset: defined as a participant with NMDAR AIE or LGI1 AIE meeting the following criteria: - Have a stable (at least 24-hour) mRS score of 2 or more measured at baseline - Have received their first acute first-line therapy within 6 weeks prior to randomization (baseline visit) Acute first-line therapy is defined as a minimum of 3 days of IV methylprednisolone (or equivalent oral glucocorticoid dose) at a dose of ≥500 mg per day and / or at least 3 days of IVIG therapy and / or PLEX, or any combination of these. Both OCS and / or repeat courses (following the first course) of acute first-line therapy are permitted. For participants with LGI AIE receiving OCS, a dose of ≥20 mg prednisolone (or equivalent) daily is required at the time of randomization. After randomization, the tapering schedule in section 3.1.2 should be followed. - No prior treatment with rituximab or any other IST (e.g., cyclophosphamide, mycophenolate mofetil, methotrexate, cyclosporine, tacrolimus, azathioprine) or tocilizumab for AIE. - Incomplete Responder: defined as a participant with an NMDAR AIE or LGI1 AIE who meets the following criteria: - Have a stable (at least 24-hour) mRS score of 2 or more measured at baseline o Have received their first acute first-line therapy >6 weeks prior to randomization (baseline visit), defined as a minimum of 3 days of IV methylprednisolone at a dose of ≥500 mg per day (or equivalent oral glucocorticoid dose) and / or at least 3 days of IVIG therapy and / or PLEX, or any combination of these. Have received immunotherapy beyond their initial acute first-line therapy course. The following criteria must be met: *For participants who have received rituximab, the treatment course must have begun at least 2 months prior to screening, the last dose must have been administered at least 4 weeks prior to randomization, and there must have been no improvement in mRS score within 4 weeks prior to randomization *For participants receiving other IST (i.e., mycophenolate mofetil, cyclophosphamide [IV only], or azathioprine), treatment must have been for at least 2 months prior to screening, at a dose that has been stable for at least 4 weeks prior to screening, and there must be no improvement in mRS score within 4 weeks prior to randomization *For participants receiving OCS, a stable dose of prednisolone ≥ 20 mg daily (or equivalent), no escalation of steroid dose during the 4 weeks prior to screening, and no improvement in mRS score within the 4 weeks prior to randomization *For participants who have received repeated courses (pulses) of acute first-line therapy, treatment must have been completed at least 2 weeks prior to randomization (baseline visit).

[0110] 4.1.2 Additional inclusion criteria for the NMDAR AIE cohort In addition to the criteria outlined in section 4.1.1, participants are eligible for inclusion in the NMDAR AIE cohort if the following criteria apply: *Age 12 or older at the time of signing the informed consent form For minor participants and participants who are otherwise incapable of consent due to the severity of their illness, the participant's consent may be obtained through an informed consent form signed by a legally authorized representative, in accordance with local requirements. * If appropriate (determined by patient age and individual local and national standards), a signed assent form *Probable or confirmed diagnosis of NMDAR encephalitis, including: A diagnosis of NMDAR encephalitis can be made with a high degree of certainty if the following three criteria are met: 1. Rapid onset (<3 months) of at least four of the following six major symptom clusters: - Abnormal (psychiatric) behavior or cognitive impairment -Speech disorders (pressured speech, verbal reduction, selective mutism) - Seizures - Movement disorders, dyskinesia, or rigidity / abnormal posture - Decreased level of consciousness - Autonomic dysfunction or central hypoventilation 2. At least one of the following test results: - Abnormal EEG (focal or diffuse slow or chaotic activity, epileptiform activity, or extreme delta brushing) -CSF with pleocytosis or oligoclonal bands 3. Rational exclusion of alternative causes of encephalitis and other well-defined syndromes (e.g., Bickerstaff brainstem encephalitis, acute disseminated encephalomyelitis, Hashimoto encephalopathy, primary central nervous system [CNS] vasculitis, Rasmussen encephalitis). A diagnosis of NMDAR encephalitis with high probability can also be made in the presence of three of the symptoms in criterion 1 above in the setting of generalized teratoma. A diagnosis of definite NMDAR encephalitis can be made if three of the following criteria are met: 1. Presence of one or more of the six major symptom clusters described in Criterion 1 for probable NMDAR encephalitis 2. Documented history or presence at screening of anti-NMDAR(GluN1) IgG antibodies detected in CSF using a cell-based assay 3. Rational exclusion of alternative causes of encephalitis and other well-defined syndromes (e.g., Bickerstaff brainstem encephalitis, acute disseminated encephalomyelitis, Hashimoto's encephalopathy, primary CNS vasculitis, Rasmussen's encephalitis).

[0111] 4.1.3 Additional inclusion criteria for the LGI1 AIE cohort In addition to the criteria outlined in section 4.1.1, participants are eligible for inclusion in the LGI1 AIE cohort if the following criteria apply: *Age 18 or older at the time of signing the informed consent form For participants who are otherwise incapable of consent due to the severity of their disease, the participant's consent may be obtained through an informed consent form signed by a legally authorized representative, in accordance with local requirements. *Diagnosis of LGI1 encephalitis The diagnosis of LGI1 encephalitis can be made in the presence of the following criteria: 1. Documented history or screening presence of anti-LGI1 IgG antibodies (in serum or CSF) using a cell-based assay 2. Subacute onset (progression of less than 4 months) of working memory deficits, seizures (including facio-brachio dystonic seizures), or neurological symptoms suggestive of limbic system involvement. The diagnosis of LGI1 encephalitis should reasonably exclude alternative causes of encephalitis and other well-defined syndromes (e.g., Bickerstaff brainstem encephalitis, acute disseminated encephalomyelitis, Hashimoto's encephalopathy, primary CNS vasculitis, Rasmussen's encephalitis).

[0112] 4.2 Exclusion criteria Participants will be excluded from the study if any of the following criteria apply to them: *Any untreated teratoma or thymoma at the baseline visit (randomization) Teratomas or thymomas detected before or during the screening period are acceptable if they were considered cured following treatment (usually surgical removal) within 1 week prior to baseline. *History of carcinoma or malignancy (excluding basal and squamous cell carcinoma of the skin or intraepithelial carcinoma of the cervix, which have been completely excised and cured) except those considered cured with appropriate treatment and with no evidence of recurrence for at least 5 years prior to screening *For patients with NMDAR AIE, a history of negative anti-NMDAR antibodies in CSF using a cell-based assay within 9 months of symptom onset *Intracellular antigens highly associated with cancer (e.g., anti-Hu, anti-Ma2, anti-CRMP5, anti-Yo, anti-amphiphysin, AMPA, mGluR5, and GABA B ) or historically known positivity for GAD-65 *Any cell surface neuronal antibody other than NMDAR and LGI1 (e.g., caspr2, IgLON5, DPPX, GABA A , and neurexin-3α) *Confirmed paraneoplastic encephalitis * Confirmed demyelinating disease of the central or peripheral nervous system (e.g., multiple sclerosis, chronic inflammatory demyelinating polyneuropathy) *Another cause of associated symptoms, including CNS infection, septic encephalopathy, metabolic encephalopathy, epileptic disorders, mitochondrial disorders, Klein-Lewin syndrome, Creutzfeldt-Jakob disease, rheumatic disorders, Reye's syndrome, or inborn errors of metabolism *History of herpes simplex virus encephalitis within the prior 24 weeks.

[0113] 5. Study treatment and concomitant therapy Study treatment is defined as any investigational treatment, marketed product, placebo, or medical device intended to be administered to study participants according to the study protocol. The investigational medicinal products (IMPs) for this study are satralizumab and placebo. Background, salvage, and symptomatic treatments are considered non-IMPs.

[0114] 5.1 Study treatment to be administered 5.1.1 Satralizumab and placebo The test product in this study is satralizumab. In this protocol, "study drug" refers to satralizumab (assigned in addition to background therapy) or placebo. In Part 1, study drug is administered at site visits at weeks 0, 2, 4, and Q4W thereafter. Participants receive 60 mg (<40 kg), 120 mg (40-100 kg), or 180 mg (>100 kg) of satralizumab depending on body weight. Study medication will be administered by SC injection in the abdomen or thigh after all other study related procedures have been performed at the site visit.

[0115] 5.1.2 Background treatment Participants classified as incomplete responders (see Section 4.1.1) may have received or continue to receive background therapy in addition to study drug during Part 1.

[0116] Background medications include, for example: *Azathioprine *Mycophenolate mofetil *IV cyclophosphamide.

[0117] For symptomatic medications permitted during the study, see Section 5.2.2. For participants who discontinued background therapy prior to study entry, study eligibility requirements for complete and differential blood counts (see Section 4.2) must be met at the time of randomization.

[0118] 5.2 Concomitant Therapy Concomitant medications consist of any medications (e.g., prescription drugs, over-the-counter medications, vaccines, herbal or homeopathic remedies, and / or dietary supplements) used by the participant in addition to protocol-mandated treatments from 7 days prior to the start of study treatment through the final SFU visit. All such medications must be recorded in the Concomitant Medications eCRF with the following information: *Reasons for use *Dates of administration, including start and end dates *Dosage information, including dose and frequency.

[0119] If you have any questions regarding concurrent or prior therapy, you may consult the medical monitor. Paracetamol / acetaminophen, in doses up to 2 g per day, is permitted at any time during the study and screening period.

[0120] 5.2.1 rescue therapy Rescue therapy is defined as IST medications (see section 5.1.2 for details of acceptable background therapy), rituximab, initiation or dose escalation of OCS, use of repeated first-line immunotherapy (IVIG, IV methylprednisolone, or plasmapheresis), or failure to taper OCS per protocol-directed taper.

[0121] The following rescue techniques may be used: *Plasma exchange (PLEX).

[0122] The following rescue medications may be used: *IVIG *Rituximab *IV cyclophosphamide *Azathioprine *Mycophenolate mofetil *Corticosteroids (OCS or IV methylprednisolone).

[0123] 5.2.2 Symptomatic treatment The use of the following medications commonly used for the symptomatic management of AIE (Abboud et al. 2021) is permitted, as described below: *AEDs (e.g., carbamazepine, lacosamide, levetiracetam) *Pain medications (e.g., topical agents, anticonvulsants [e.g., pregabalin, gabapentin, carbamazepine]) *Antidepressants (e.g., tricyclic antidepressants, serotonin-norepinephrine reuptake inhibitors [e.g., duloxetine]) *Antipsychotics (e.g., quetiapine) * Mood stabilizers (e.g., valproate) *Beta-blockers (e.g., propranolol) *Alpha-2 blockers (e.g., clonidine) *Alpha-adrenergic agonists (e.g., midodrine) *Acetylcholinesterase inhibitors (e.g., pyridostigmine) for increased sympathetic drive *Non-opioid analgesics (e.g. paracetamol or acetaminophen, nonsteroidal anti-inflammatory drugs) *Modafinil or Melatonin for sleep disorders *Antimuscarinics, muscle relaxants, antidopamines, and dopamine agonists for movement disorders.

[0124] 5.2.3 Other acceptable treatments In general, investigators may manage participants' medical care (including pre-existing conditions) through the use of supportive care as clinically indicated and in accordance with local standard practice, excluding prohibited therapies and taking into account treatments of caution. Participants experiencing infusion-related symptoms may be treated symptomatically with paracetamol / acetaminophen, ibuprofen, diphenhydramine, and / or H2 receptor antagonists (e.g., famotidine, cimetidine), or equivalent medications, in accordance with local standard practice. Serious infusion-related events manifested by dyspnea, hypotension, wheezing, bronchospasm, tachycardia, desaturation of oxygen, or respiratory distress should be managed with supportive care as clinically indicated (e.g., supplemental oxygen and beta-2 adrenergic agonists). Premedication with antihistamines, antipyretic medications, and / or analgesics may be administered at the investigator's discretion.

[0125] The use of the following concomitant therapies is permitted as follows: *Oral contraceptives (see section 4.1) *Hormone replacement therapy *Background treatments as listed in section 5.1.2 *Treatment with topical (e.g., eye, nose, ear, skin) corticosteroids for adverse events (i.e., indications other than background AIE therapy), provided that the duration of treatment is kept as short as possible. *Non-pharmacological interventions (e.g., individual psychotherapy, cognitive behavioral therapy, physical therapy, and rehabilitation therapy).

[0126] 6. Test Assessment and Procedures 6.1 Effectiveness evaluation Participants will undergo efficacy assessments at screening and at subsequent time points. Assessments to assess efficacy will include participant-reported outcomes (PROs), performance-based outcomes (PerfOs), and clinician-reported outcomes (ClinROs) (see Section 6.2); as well as any optional assessments that capture disease severity (including lumbar puncture). Additionally, EEG will also be analyzed as an exploratory outcome (see Section 6.3).

[0127] 6.2 Clinical outcome assessment Performance-Based Outcomes (PerfO) and Clinician-Reported Outcomes (ClinRO) documents will be completed to evaluate the treatment benefit of satralizumab. Clinical outcome measures are listed in Table 3.

[0128] (Table 3) Clinical outcome assessment TIFF2025502891000004.tif46128CASE=Clinical Encephalitis Rating Scale;ClinRO=Clinician-Reported Outcome, C-SSRS=Columbia Suicide Severity Rating Scale;MOCA=Montreal Cognitive Assessment;mRS=Modified Rankin Scale;PerfO=Performance-Based Outcomes;RAVLT=Rey Auditory Verbal Learning Test.

[0129] 6.2.1 Data collection methods for clinical outcome assessment At the clinic, documentation will occur before participants receive any information about their disease status, before any non-PRO (participant reported outcome) assessments are performed, and before administration of study treatment, unless otherwise specified.

[0130] PerfO and ClinRO documentation will be completed in the clinic at designated times during the study. PerfO and ClinRO documentation will be completed prior to completion of the physical examination, prior to any safety assessments, and prior to administration of study treatment. Clinicians must complete the official version of each ClinRO documentation as provided by the sponsor. Documentation should not be copied from the protocol.

[0131] 6.2.2 Clinical outcome measures description 6.2.2.1 Modified Rankin Scale (mRS) The mRS is a scale developed to measure global disability after stroke and is widely applied to assess primary outcomes in randomized controlled trials of acute stroke management (Rankin 1957). A 7-point scale measures functional independence, weighting motor function and assessing the ability to walk. The mRS is a clinician-assessed rating and consists of 6 grades from 0 to 5, with 0 corresponding to no symptoms and 5 corresponding to severe disability. Higher scores represent more severe disability. Another (6) category is usually added to classify patients who die before the assessment window. An example of the scale is given in Banks JL et al. (Stroke. 2007;38:1091-1096). The mRS is usually used to measure neurological outcomes in AIE in the absence of validated disease-specific scales. The mRS and its associated structured interview take approximately 15 minutes to complete and are administered at designated time points.

[0132] 6.2.2.2 Clinical Encephalitis Assessment Scale (CASE) CASE is a novel scale for assessing severity in patients with various AIE syndromes, and consists of 9 items (seizures, memory dysfunction, psychiatric symptoms, consciousness, language problems, dyskinesia / dystonia, gait instability and ataxia, brainstem dysfunction, and weakness). Each item is assigned a maximum value of 3 points, with higher scores corresponding to more severe symptoms. Total scores range from 0 to 27. CASE was developed for application in clinical practice and may help in the future to overcome the limitations of current outcome measures for AIE in the context of clinical trials (Lim et al. 2019). An example of this scale is given by Lim JA et al. (Ann Neurol. 2019 Mar;85(3):352-358.). CASE takes approximately 10 minutes to complete and is administered at designated time points.

[0133] 6.2.2.3 Montreal Cognitive Assessment (MOCA) The MOCA is a 30-item measure of global cognitive functioning developed for early detection of suspected cognitive deficits. It covers the following cognitive domains: *Directional orientation: Know the day of the week, date, and your current location *Short-term memory recall: the ability to hear a word and repeat it after a short period of time. * Concentration and spatial awareness: connecting numbered dots in sequence and drawing 3D shapes * Language: Ability to speak and understand complete sentences, and to remember the names of familiar animals or objects. * Concentration: Repeating a simple sequence back and forth *Visuospatial: Perform the clock drawing test (i.e., to assess warning signs of dementia). The MOCA takes only a few minutes to administer and is available in three versions to reduce possible learning effects when administered every 3 months or less. MOCA scores range from 0 to 30. Higher scores represent better cognitive function. A score of 26 or higher is interpreted as normal cognitive function (see https: / / www.mocatest.org / ). The MOCA is administered at designated time points.

[0134] 6.2.2.4 Rey Auditory Verbal Learning Test (RAVLT) The RAVLT is a verbal neuropsychological test that assesses immediate memory span, new learning, susceptibility to interference, and recognition memory. The number of words recalled on each trial is the measure of performance.

[0135] After five repeated free recalls, a second "interference" list (List B) is presented in the same manner and participants are asked to recall as many words as possible from List B. After the interference trials, participants are immediately asked to recall words from List A that they have previously heard five times. After a 30-minute delay, participants are again asked to recall words from List A. After this "delayed recall" task, a list of 50 words is presented that contains all the words from Lists A and B, in addition to 20 phonemically and / or semantically similar words. This test, as opposed to free recall, directly examines recognition memory. The multiple memory processes assessed by the RAVLT provide rich data on memory performance (Peaker and Stewart 1989; Spreen and Strauss 1991). Higher scores represent better memory performance. The RAVLT takes approximately 35 minutes to complete and is administered at designated times.

[0136] 6.2.2.5 Columbia Suicide Severity Rating Scale (C-SSRS) The C-SSRS is a clinician-assessed tool used to assess a patient's lifetime suicidality and to track suicidal events throughout treatment. The scale is administered at designated time points for rapid recollection of suicidal ideation, including the intensity of actual and potentially lethal ideation, behavior, and attempts. The "C-SSRS at Baseline" is collected at baseline, and the "C-SSRS Since Last Visit" is collected at subsequent visits. The C-SSRS takes 5-10 minutes to complete. An example C-SSRS form is available online at https: / / cssrs.columbia.edu / .

[0137] 6.2.2.6 Seizure diary A seizure diary will be provided for completion by the participant or caregiver. Instructions will be provided on how to collect seizure type, frequency, and duration.

[0138] 6.3 Further Exploratory Evaluation 6.3.1 Electroencephalography (EEG) EEG will be performed on participants at designated times. Details of EEG assessment and data handling are described in a separate EEG recording and handling manual.

[0139] 7. Statistical considerations This study will compare satralizumab with a matching placebo administered for 52 weeks in participants with NMDAR and LGI1 encephalitis as defined by the study eligibility criteria. The NMDAR and LGI1 AIE cohorts will be treated as separate populations and analyzed separately. Each cohort will have an independent type I error control at a 5% significance level. Unless specifically stated otherwise, statistical considerations will be the same for the NMDAR and LGI1 AIE cohorts. Participants receiving background therapy will be required to follow the rules defined in the protocol for Part 1, as outlined in Section 5.1.2.

[0140] 7.1 Statistical hypotheses The study aims to demonstrate the superiority of satralizumab over placebo. Primary and secondary efficacy analyses will compare satralizumab to placebo in each of the following cohorts: *NMDAR AIE cohort: Adults and adolescents with definite or probable NMDAR encephalitis *LGI1 AIE cohort: Adults with LGI1 encephalitis.

[0141] The primary efficacy analysis will compare satralizumab to placebo at week 24. The following null and alternative hypotheses will be tested at a 5% two-sided significance level in each of the NMDAR and LGI1 AIE cohorts: TIFF2025502891000005.tif4170 where p サトラリズマブ and p プラセボrefers to the proportion of participants in the satralizumab and placebo groups, respectively, who had at least a 1-point improvement from baseline in the mRS at week 24 and no use of rescue therapy. Similar forms of null and alternative hypotheses will be tested for all secondary efficacy analyses. Note that all hypothesis tests are two-sided unless otherwise stated.

[0142] 7.2 Determining sample size In the NMDAR AIE cohort, approximately 102 participants with NMDAR encephalitis will be randomly assigned to study treatment such that approximately 92 evaluable participants will complete the study in this cohort. In the LGI1 AIE cohort, approximately 50 participants with LGI1 encephalitis will be randomly assigned to study treatment such that approximately 45 evaluable participants will complete the study in this cohort.

[0143] For each cohort, participants will be randomized in a 1:1 ratio to each treatment group (satralizumab or placebo). Randomization will be stratified by the following criteria: *Patient population: new onset vs incomplete responders (as described in section 4.1.1) *region.

[0144] The estimated sample sizes required to demonstrate efficacy with respect to the mRS were calculated separately for the NMDAR AIE and LGI AIE cohorts.

[0145] Based on these assumptions and using a 5% two-sided significance level, the sample sizes to achieve 80% power in each cohort were estimated to be 102 participants (51 per group) in the NMDAR AIE cohort and 50 participants (25 per group) in the LGI1 AIE cohort.

[0146] 7.3 Statistical analysis The Statistical Analysis Plan (SAP) will be finalized prior to study unblinding and database lock and will contain a more technical and detailed description of the statistical analyses described in this section. This section outlines the planned statistical analyses of the most important endpoints, including the primary and key secondary endpoints.

[0147] 7.3.1 Primary endpoint 7.3.1.1 Estimands and estimators of primary efficacy The primary efficacy objective is to evaluate the efficacy of satralizumab versus placebo on the degree of disability and clinical severity in participants with NMDAR and LGI1 encephalitis. The primary comparison of interest is the difference between the placebo and satralizumab groups in the proportion of participants with at least 1-point improvement from baseline in the mRS at week 24 and without the use of rescue therapy. The primary efficacy estimate is evaluated separately in the NMDAR and LGI1 AIE cohorts.

[0148] If a participant drops out of treatment, the reason for dropout will be classified as either related to the study drug or condition (SDCR) or not related to the study drug or condition (NSDCR). More details on this classification will be provided in the SAP. The primary comparison will include participants who dropped out due to both SDCR and NSDCR reasons, assuming that participants who dropped out due to NSDCR reasons continue to receive their randomized treatment.

[0149] The primary comparison will be made whether participants have treatment interruptions (eg, due to infection) or changes in background therapy that are not considered rescue.

[0150] The primary estimand elements, which assess the proportion of participants with a ≥ 1-point improvement from baseline in the mRS at week 24 and no use of rescue therapy, regardless of SDCR dropouts from study treatment, treatment discontinuations, or changes in background therapy not considered rescue, and assume that participants with NSDCR dropouts continue to receive their randomized treatment, are defined in Table 4. The primary analysis approach and sample size determination met the primary estimand.

[0151] (Table 4) Main Estimand Attributes TIFF2025502891000006.tif121167LGI1=leucine-rich glioma inactivated 1; mRS=modified Rankin Scale; NMDAR=N-methyl-D-aspartate receptor; NSDCR=not related to the study drug or condition; SDCR=related to the study drug or condition. a Treatment strategy: The value of the variable is used whether or not an intercurrent event occurs. b Hypothetical: A scenario is envisaged in which the intermediate event does not occur. c Composite: Incorporation of intercurrent events in the definition of the endpoint.

[0152] A supplemental estimand incorporating various approaches to dealing with intercurrent events is detailed in the SAP, including the use of a treatment policy approach for intercurrent events that employs salvage therapy.

[0153] 7.3.1.2 Handling missing data For missing data, longitudinal mRS data are imputed and then the definition of responder (at least 1 point mRS improvement) is applied. For NSDCR dropouts, data are censored at the time of treatment dropout. Any data collected after NSDCR dropout are ignored. Missing data after dropouts determined to be NSDCR (including use of rescue therapy) are imputed using multiple imputation methods with the assumption of "missing at random". Missing data after dropouts determined to be SDCR are imputed using reference based multiple imputation methods with the assumption of "Copy Reference". Use of rescue therapy is imputed based on the placebo arm. This approach is only used if observational data after treatment dropout are not available. If observational data are available, they continue to be included in the analysis. Data after treatment interruptions (e.g. due to infection) and changes in background therapy not considered rescue are included in the analysis. The robustness of the primary estimation method is explored by multiple imputation strategies and a series of sensitivity estimators based on different assumptions underlying the classification of treatment-intercurrent events as SDCR or NSDCR. Further details will be provided by SAP.

[0154] 7.3.2 Secondary endpoints The first endpoint to be tested in both cohorts will be the primary endpoint. Subsequently, analysis of secondary endpoints will follow a cohort-specific hierarchy. The order of secondary endpoints presented below does not necessarily reflect the hierarchy of each cohort.

[0155] The following secondary efficacy endpoints will be analyzed using time-to-event estimators and estimators: * Time to at least 1-point improvement in mRS score from baseline without the use of rescue therapy *Time to salvage therapy *Time to seizure freedom (seizure freedom is defined as the cessation of seizures for at least 6 consecutive weeks) or cessation of status epilepticus without the use of rescue therapy.

[0156] The following secondary efficacy endpoints will be analyzed using estimands and estimators of mean change: *Change in CASE score from baseline at week 24. The following secondary efficacy endpoints will be analyzed using estimators and estimators of mean scores: *MOCA total score at 24 weeks *RAVLT score at 24 weeks (LGI AIE cohort).

[0157] The following secondary efficacy endpoints will be analyzed using categorical score estimators and estimators: *mRS score (measured on a 7-point scale; NMDAR AIE cohort) at week 24. Supplemental estimands for each assessment component are detailed in the SAP.

[0158] 7.3.2.1 Estimands and estimators of time to event The components of the time-to-event estimand are defined in Table 5, using the time-to-salvage therapy endpoint as an example. The comparison of interest is the difference between the placebo and satralizumab groups in the time to rescue therapy, regardless of SDCR dropouts from study treatment, treatment discontinuations, or changes in background therapy that do not qualify as rescue, and assuming that NSDCR dropouts continue to receive their randomized treatment.

[0159] Table 5. Estimand attributes of time to event TIFF2025502891000007.tif176164LGI1=leucine-rich glioma inactivated 1; NMDAR=N-methyl-D-aspartate receptor; NSDCR=not associated with the test drug or condition; SDCR=associated with the test drug or condition. a Treatment strategy: The value of the variable is used whether or not an intercurrent event occurs. bHypothetical: A scenario is envisaged in which the intermediate event does not occur. c Composite: Incorporation of intercurrent events in the definition of the endpoint.

[0160] 7.3.2.2 Estimands and estimators of mean change The estimand components of the mean change are defined in Table 6. The comparison of interest is the difference between the placebo and satralizumab groups in the change in CASE score from baseline at week 24, assuming that no salvage therapy was available and assuming that NSDCR dropouts continue to receive their randomized treatment, regardless of SDCR dropouts from study treatment, treatment discontinuations, or changes in background therapy not considered rescue.

[0161] Table 6. Estimand attributes of mean change TIFF2025502891000008.tif151167CASE=Clinical Encephalitis Rating Scale; LGI1=Leucine-Rich Glioma Inactivation 1; MMRM=Mixed Model Repeated Measures; NMDAR=N-Methyl-D-Aspartate Receptor; NSDCR=Not Related to Study Drug or Condition; SDCR=Related to Study Drug or Condition. a Treatment strategy: The value of the variable is used whether or not an intercurrent event occurs. b Hypothetical: A scenario is envisaged in which the intermediate event does not occur.

[0162] 7.3.2.3 Estimands and estimators of mean scores The components of the mean score estimand are defined in Table 7, using the MOCA total score endpoint as an example. The comparison of interest is the difference between the placebo and satralizumab groups in the MOCA total score at week 24, assuming that no rescue therapy was available and assuming that NSDCR dropouts continue on their randomized treatment, regardless of SDCR dropouts from study treatment, treatment discontinuations, or changes in background therapy not considered rescue.

[0163] (Table 7) Estimand attributes of mean scores TIFF2025502891000009.tif146167LGI1=leucine-rich glioma inactivated 1; MOCA=Montreal Cognitive Assessment; MMRM=mixed model repeated measures; NMDAR=N-methyl-D-aspartate receptor; NSDCR=not related to study drug or condition; SDCR=related to study drug or condition. a Treatment strategy: The value of the variable is used whether or not an intercurrent event occurs. b Hypothetical: A scenario is envisaged in which the intermediate event does not occur.

[0164] 7.3.2.4 Category score estimators and estimators The estimand components of the categorical scores are defined in Table 8. The comparison of interest is the difference between the placebo and satralizumab groups in the mRS score at week 24, assuming that no salvage therapy was available and assuming that participants who dropped out of study NSDCR continued to receive their randomized treatment, regardless of SDCR dropouts from study treatment, treatment discontinuations, or changes in background therapy not considered rescue.

[0165] Table 8. Estimand attributes of category scores TIFF2025502891000010.tif149167LGI1=leucine-rich glioma inactivated 1; mRS=modified Rankin Scale; NMDAR=N-methyl-D-aspartate receptor; NSDCR=not related to study drug or condition; SDCR=related to study drug or condition. a Treatment strategy: The value of the variable is used whether or not an intercurrent event occurs. b Hypothetical: A scenario is envisaged in which the intermediate event does not occur.

[0166] 7.3.2.5 Safety analysis Safety will be assessed through summary of exposure to study treatment, adverse events, changes in clinical laboratory results, and changes in vital signs, weight, height (<18 years only), and ECG. Study treatment exposure (including duration of treatment, total dose received, and dose modifications) will be summarized with descriptive statistics.

[0167] All verbatim adverse event terms will be matched to Medical Dictionary for Regulatory Activities thesaurus terms, and the severity of adverse events will be graded according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v5.0. All adverse events, serious adverse events, adverse events resulting in death, adverse events of special interest, and adverse events resulting in discontinuation of study treatment occurring at or after the first dose of study treatment (i.e., treatment-emergent adverse events) will be summarized by matched term, appropriate thesaurus level, and severity grade. For events of different severity, the highest grade will be used in the summary. Deaths and causes of death will be summarized.

[0168] Relevant laboratory, vital signs (pulse rate, respiratory rate, blood pressure, pulse oximetry, and temperature), and ECG data will be displayed by time and graded where appropriate. Additionally, baseline and maximum post-baseline severity grades will be summarized using shift tables of selected laboratory tests. Changes in vital signs, weight, height (<18 years only), and ECG will be summarized.

[0169] 7.3.3 Exploratory endpoints Subgroup analyses will be performed for the following populations: *Minor participants with NMDAR encephalitis *Participants with probable NMDAR encephalitis. Further details on the definition and analysis of exploratory endpoints will be described in the SAP.

[0170] 7.3.4 Other analyses 7.3.4.1 Pharmacokinetic Analysis The PK analysis population consists of all participants in the safety analysis set with at least one valid post-dose concentration result with dosing records and sampling times. The study will evaluate the PK properties of satralizumab treatment by summary statistics and nonlinear mixed-effects analysis (popPK). Both satralizumab concentration data and the results of the popPK analysis will be reported separately from the CSR.

[0171] 7.3.4.2 Immunogenicity analysis The immunogenicity analysis population will consist of all participants with at least one ADA assessment. Participants will be grouped according to treatment received or, if they had not received any treatment prior to study discontinuation, according to treatment assigned.

[0172] The number and percentage of ADA-positive and ADA-negative participants at baseline (baseline prevalence) and after drug administration (post-baseline incidence) are summarized by treatment group. When determining post-baseline incidence, participants are considered ADA-positive if they show a treatment-induced or treatment-enhanced ADA response. Participants who are ADA-negative or have missing data at baseline, but develop an ADA response after exposure to study drug, have a treatment-induced ADA response. Participants who are ADA-positive at baseline and have one or more post-baseline sample titers at least 4-fold (0.60 titer units) higher than the titer of the baseline sample have a treatment-enhanced ADA response. Participants are considered to be any ADA-negative if they are ADA-negative or have missing data at baseline and all post-baseline samples are negative, or if they are ADA-positive at baseline but do not have any post-baseline samples with titers at least 4-fold (0.60 titer units) higher than the titer of the baseline sample (not affected by treatment).

[0173] The percentage of participants with positive or negative ADA results for satralizumab are summarized in the Table. PK, PD, efficacy parameters, and safety are summarized by anti-satralizumab antibody (i.e., satralizumab ADA) status.

[0174] 7.3.4.3 Pharmacodynamic analysis Serum IL-6 and sIL-6R levels will be summarized graphically and descriptively by treatment group and time point, as appropriate.

[0175] 7.4 Interim Analysis 7.4.1 Planned interim pharmacokinetic analyses An interim PK analysis will be performed at week 8 of treatment with the goal of confirming that the achieved exposure (and predicted RO) is within the expected target range. If the achieved exposure (and predicted RO) is not within the expected target range, the dose may be adapted to 120 mg, 180 mg, and 240 mg for participants <40 kg, 40-100 kg (inclusive), and >100 kg, respectively. The dosing regimen selected will be associated with an exposure that does not significantly exceed the existing exposure-safety range. The iDMC will make a recommendation as to whether (i) the trial can continue at the initial dose or (ii) the dose can be adapted to a pre-specified higher dose.

[0176] 7.4.2 Optional interim analysis To accommodate information that may become evident during the course of the trial, sponsors may choose to perform one interim futility analysis. Below are specifications to ensure that the trial continues to meet the highest standards of integrity if any interim analyses are performed.

[0177] If an interim analysis is performed, the sponsor will remain blinded. The interim analysis will be performed by an external statistical group and reviewed by the iDMC. Dialogue between the iDMC and the sponsor will be conducted as specified in the iDMC Charter.

[0178] The decision to perform any interim analysis will be documented in SAP, along with the rationale, timing, and statistical details of the analysis. The iDMC Charter will be updated to document any potential recommendations the iDMC may make to the sponsor as a result of the analysis (continue the trial without modification, stop the trial due to futility), and the iDMC Charter will also be made available to relevant health authorities.

[0179] If an interim analysis indicates that a trial may be stopped for futility, the threshold for denoting futility may include an assessment of the predicted probability that a specified endpoint will achieve statistical significance. Criteria for recommending that a trial be stopped for futility may be added to the iDMC charter and documented in the SAP. [Industrial Applicability]

[0180] The present invention provides a means for treating autoimmune encephalitis such as NMDAR encephalitis or LGI1 encephalitis, comprising an anti-IL-6 receptor antibody or an antigen-binding fragment thereof, and also for reducing the risk of recurrence of said encephalitis.The present invention also provides a pharmaceutical or pharmaceutical composition for treating said encephalitis or reducing the risk of recurrence, comprising an anti-IL-6 receptor antibody or an antigen-binding fragment thereof.The present invention further provides a method for treating said encephalitis or reducing the risk of recurrence by administering an anti-IL-6 receptor antibody or an antigen-binding fragment thereof to a subject in need thereof.

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Claims

1. A pharmaceutical agent for treating autoimmune encephalitis (AIE) in a subject, comprising satralizumab.

2. 10. The pharmaceutical product of claim 1 for delaying relapse, reducing the frequency of relapse, reducing the severity of relapse, or reducing the risk of relapse of autoimmune encephalitis.

3. 2. The pharmaceutical agent of claim 1, wherein the autoimmune encephalitis is anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis or anti-leucine-rich glioma inactivated 1 (LGI1) encephalitis.

4. A pharmaceutical product described in any one of claims 1 to 3, wherein satralizumab is administered subcutaneously to a subject.

5. A pharmaceutical product described in any one of claims 1 to 3, wherein for each administration, a dosage unit of 60 mg, 120 mg, 180 mg, or 240 mg of satralizumab is administered to a subject.

6. 4. The pharmaceutical product of any one of claims 1 to 3, wherein for each administration, 60 mg of satralizumab is administered to a subject having a body weight of less than 40 kg.

7. 4. The pharmaceutical product of any one of claims 1 to 3, wherein for each administration, 120 mg of satralizumab is administered to a subject having a body weight of less than 40 kg.

8. 4. The pharmaceutical product of any one of claims 1 to 3, wherein for each administration, 120 mg of satralizumab is administered to a subject having a body weight of 40 to 100 kg.

9. 4. The pharmaceutical product of any one of claims 1 to 3, wherein for each administration, 180 mg of satralizumab is administered to a subject having a body weight of 40 to 100 kg.

10. 4. The pharmaceutical product of any one of claims 1 to 3, wherein for each administration, 180 mg of satralizumab is administered to a subject having a body weight of more than 100 kg.

11. 4. The pharmaceutical product of any one of claims 1 to 3, wherein for each administration, 240 mg of satralizumab is administered to a subject having a body weight of more than 100 kg.

12. A pharmaceutical product described in any one of claims 1 to 3, wherein satralizumab is administered to a subject three times at two-week intervals (Q2W) and then four weeks apart (Q4W).

13. The pharmaceutical product according to any one of claims 1 to 3, which is used in combination with immunosuppressive therapy (IST).

14. The IST is (i) an immunosuppressant selected from the group consisting of azathioprine (AZA), mycophenolate mofetil (MMF), and intravenous (IV) cyclophosphamide; (ii) oral corticosteroids (OCS); or (iii) a combination of (i) and (ii); The pharmaceutical product according to claim 13, which is a treatment method using

15. 15. The pharmaceutical product of claim 14, wherein the oral corticosteroid (OCS) is prednisone, prednisolone, or an equivalent thereof.

16. A pharmaceutical product as described in claim 5, wherein satralizumab is administered to a subject by a subcutaneous administration device.

17. 17. The pharmaceutical product of claim 16, wherein the subcutaneous administration device is a pre-filled syringe (PFS), optionally a pre-filled syringe with needle safety device (PFSNSD), or an auto-injector (AI).

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