Inebilizumab and methods of using it for sustained B cell depletion

Abstract

Compositions and methods for using ine bilizumab to treat autoimmune diseases are disclosed herein. In particular, the use of ine bilizumab and exemplary treatment regimens for treating neuromyelitis optica spectrum disorder are provided. This specification provides a method of treating or preventing neuromyelitis optica spectrum disorder (NMOSD), the method comprising administering ine bilizumab to a subject in need thereof having a B cell level of less than about 4 cells / μL of blood, thereby treating NMOSD.

Description

Technical Field

[0001] Cross - Reference to Related Applications This application claims priority to U.S. Provisional Patent Application No. 63 / 369,590, filed Jul. 27, 2022, which is hereby incorporated by reference in its entirety for all purposes.

[0002] Reference to a Sequence Listing The electronic sequence listing (HOPA_045_01WO_SeqList_ST26.xml; size: 10,611 bytes; and created on Sep. 19, 2022) is hereby incorporated by reference in its entirety.

[0003] The present disclosure relates to compositions comprising inebilizumab and methods of using it for sustained B - cell depletion.

Background Art

[0004] Inebilizumab is an anti - CD19 monoclonal antibody approved in Japan and the United States for the treatment of neuromyelitis optica spectrum disorder (NMOSD). However, the relationship between B - cell, plasma - cell, and immunoglobulin depletion after inebilizumab treatment and the reduction of NMOSD disease activity after inebilizumab treatment remains unclear, and further elucidation of this relationship requires analysis to clarify optimized treatment methods for subjects with NMOSD.

Summary of the Invention

Means for Solving the Problems

[0005] This specification provides a method for treating or preventing neuromyelitis optica spectrum disorder (NMOSD), the method comprising administering Inebilizumab to a subject in need thereof having a B cell level of less than about 4 cells / μL of blood, thereby treating NMOSD. In an aspect, the Fc gamma receptor IIIa (FCGR3A) gene of the subject in need thereof comprises the rs396991 polymorphism. In some aspects, the subject in need thereof comprises the V allele as determined by the V / F or V / V genotype.

[0006] A method of treatment comprising assaying a blood sample from a subject in need thereof for the presence of the rs396991 polymorphism of the FCGR3A gene and, if the determination is positive for the rs396991 polymorphism, administering Inebilizumab to the subject in need thereof is provided. In an aspect, the subject in need thereof has an autoimmune disease. In an aspect, the autoimmune disease is selected from the group consisting of neuromyelitis optica spectrum disorder (NMOSD), myasthenia gravis (MG), and IgG4-related disease (IgG4RD). In an aspect, the autoimmune disease is NMOSD. In an aspect, the autoimmune disease is MG. In an aspect, the autoimmune disease is IgG4RD. In an aspect, the subject in need thereof has at least two autoimmune diseases. In an aspect, the at least two autoimmune diseases are selected from the group consisting of neuromyelitis optica spectrum disorder (NMOSD), myasthenia gravis (MG), and IgG4RD.

[0007] A method of treating neuromyelitis optica spectrum disorder (NMOSD) comprising administering Inebilizumab to a subject in need thereof comprising the rs396991 polymorphism of the FCGR3A gene, wherein the administering is more effective in reducing the B cell or plasma cell level of the subject in need thereof comprising the rs396991 polymorphism of the FCGR3A gene as compared to an equivalent subject except for lacking the rs396991 polymorphism is provided.

[0008] In an aspect, the level of B cells or plasma cells is determined at least 1, 2, 4, 8, 12, 16, 22, 28, and / or 32 weeks after administration. In an aspect, administration is effective to reduce a criterion selected from the group consisting of annualized attack rate (AAR), incidence of disability as evaluated by the Expanded Disability Status Scale (EDSS) score, incidence of hospitalization, magnetic resonance imaging (MRI) lesions, and combinations thereof. In an aspect, administration is effective to reduce the AAR, and the reduction is at least about 20%, 30%, 40%, 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, 97%, or up to about 100%. In an aspect, administration is effective to reduce MRI lesions, and the reduction is at least about 20%, 30%, 40%, 50%, 60%, 70%, 73%, 75%, 80%, 85%, 90%, 95%, 97%, or up to about 100%. In an aspect, administration is repeated. In an aspect, administration is repeated daily, monthly, or annually. In an aspect, administration is repeated monthly. In an aspect, administration is repeated every 6 months. In an aspect, administration is continued for at least about 1 year, 2 years, 3 years, 4 years, 5 years, or up to the approximate lifespan of the subject in need thereof. In an aspect, the subject in need thereof has been previously administered ineclizumab. In an aspect, administration is intravenous. In an aspect, administration is by intravenous infusion. In an aspect, ineclizumab is administered at a dose of about 300 mg.

[0009] A method of treating or preventing an autoimmune disease, the method comprising administering 300 mg of ineclizumab to a subject in need thereof having a B cell level of less than about 4 cells / μL of blood, wherein administration is repeated every 6 months, the method is provided. In an aspect, the autoimmune disease is selected from the group consisting of neuromyelitis optica spectrum disorder (NMOSD), myasthenia gravis (MG), and IgG4-related disease (IgG4RD). In an aspect, the autoimmune disease is NMOSD. In an aspect, the autoimmune disease is MG. In an aspect, the autoimmune disease is IgG4RD.

[0010] A method of treating or preventing neuromyelitis optica spectrum disorder (NMOSD), the method comprising administering 300 mg of ine bilizumab to a subject in need thereof having a B cell level of less than about 4 cells / μL of blood, wherein the administering is repeated every 6 months, the method is provided.

[0011] A method of treating or preventing an autoimmune disease, the method comprising administering 300 mg of ine bilizumab to a subject in need thereof having a B cell level of less than about 4 cells / μL of blood, wherein the administering is repeated every 6 months, and wherein the autoimmune disease is selected from the group consisting of neuromyelitis optica spectrum disorder (NMOSD), myasthenia gravis (MG), and IgG4-related disease (IgG4RD), the method is provided. In an aspect, the administering is continued for at least about 2.5 years.

[0012] A method of treating neuromyelitis optica spectrum disorder, the method comprising administering ine bilizumab to a subject in need thereof, wherein the subject does not have anti-aquaporin 4 immunoglobulin G antibody (AQP4-IgG-) and has immunoglobulin G antibody against myelin oligodendrocyte glycoprotein (MOG-IgG+), the method is provided. In an aspect, about 300 mg of ine bilizumab is administered. In an aspect, the administration is continued for at least 6 months, 1 year, 2 years, or 3 years. In an aspect, the administration is continued indefinitely. In an aspect, the administration is continued for at least 2 years. In an aspect, the subject in need thereof has increased serum autoreactivity to autoantibodies not related to NMOSD as compared to a healthy control subject.

Brief Description of the Drawings

[0013]

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Mode for Carrying Out the Invention

[0014] Eculizumab and methods of using it to reduce B cell-mediated immune responses in a subject having a disease or disorder are described herein. Also provided are methods including subject / subject stratification to optimize the treatment of NMOSD with eculizumab based on the presence of biomarkers such as polymorphisms of the FCGR3A gene. Also provided is a treatment regimen comprising eculizumab for the treatment of NMOSD.

[0015] Definitions The following terms are considered to be well understood by those skilled in the art, but the following definitions are set forth to facilitate the description of the subject matter disclosed herein. All technical and scientific terms used herein are intended to have the same meaning as commonly understood by one of ordinary skill in the art, unless specifically defined otherwise below. References to techniques used herein are intended to refer to techniques as commonly understood in the art, including variations and / or equivalent substitutions of those techniques that would be apparent to one of ordinary skill in the art.

[0016] Any range recited herein is intended to include its endpoints. For example, the range of 2-4 includes 2 and 4, as well as the values therebetween.

[0017] As used herein, the singular forms “a,” “an,” and “the” include plural references unless the context clearly dictates otherwise.

[0018] The term "about" or "approximately", when preceding a numerical value, means within a range of plus or minus 10% of that value. For example, "about 50" can mean 45 - 55, unless the context of the present disclosure specifically dictates otherwise or such an interpretation is inconsistent, and "about 25,000" can mean 22,500 - 27,500. In the context of a list of numerical values such as "about 49, about 50, about 55,...", "about 50" means a range extending up to less than half the interval between the preceding and following values, for example, greater than 49.5 and less than 52.5. Further, phrases such as "about - less than" values or "about - greater than" values should be understood in view of the definition of the term "about" provided herein.

[0019] When referring to nucleic acid sequences or protein sequences, the term "identity" is used to indicate the similarity between two sequences. Unless otherwise indicated, the percent identity described herein is determined using the BLAST algorithm available at the World Wide Web address: blast.ncbi.nlm.nih.gov / Blast.cgi using default parameters.

[0020] As used herein, the term "subject" refers to any individual for whom diagnosis, prognosis, or therapy is desired, e.g., a human or non - human mammal. The term "subject" can mean a human or non - human mammal that has, may have, or is suspected of having a disease, e.g., an autoimmune disease or condition. The terms "subject" and "patient" are used interchangeably herein. The compositions provided herein are primarily directed to compositions suitable for administration to humans, but one of ordinary skill in the art will understand that such compositions are generally suitable for administration to any type of subject. In aspects, the subject is a mammal. Mammals include primates such as humans, monkeys, chimpanzees, and apes, as well as laboratory animals (rabbits and rodents such as guinea pigs, rats, or mice), and domestic pets and livestock (e.g., cats, dogs, pigs, cows, sheep, goats, horses, rabbits), including non - primates such as non - domestic livestock and wildlife, birds, reptiles, fish, etc.

[0021] As used herein, "treating" or "treatment" describes the management and care of a subject for the purpose of combating a disease, condition, or disorder, and includes the administration of a composition used in the methods described herein to alleviate the symptoms or complications of a disease, condition, or disorder, or to eliminate the disease, condition, or disorder. Thus, the term "treating" or "treatment" refers to both therapeutic and prophylactic or preventative means, with the goal of preventing, slowing down (mitigating), or improving the progression of a disease (e.g., an autoimmune disease). Beneficial or desired clinical results include, but are not limited to, alleviation of symptoms, diminishment of the extent of a disease, stabilization (i.e., not worsening) of a disease state, delay or slowing of disease progression, improvement or alleviation of a disease state, and regression (whether partial or total) of a disease. The term "treating" can also include the treatment of cells in vitro or in an animal model.

[0022] Inebilizumab Inebilizumab (also known as MEDI-551) is a humanized, affinity-optimized, defucosylated IgG1 kappa monoclonal antibody (mAb) known as 16C-aFuc that binds to the B cell-specific surface antigen CD19 and results in the reduction or elimination of CD19+ B cells. Inebilizumab is glycoengineered by the expression of mAb 16C4 in a fucosyltransferase-deficient Chinese hamster ovary cell line (BioWa Potelligent® Technology) that produces uniformly fucosylated antibodies with enhanced antibody-dependent cellular cytotoxicity. In contrast to the anti-CD20 mAb rituximab, inebilizumab does not mediate complement-dependent cytotoxicity but eliminates B cells via antibody-dependent cellular cytotoxicity and antibody-mediated cell phagocytosis mechanisms.

[0023] In an embodiment, Inebilizumab contains the CDR sequences in Table 1. In an embodiment, Inebilizumab contains variable heavy chain CDR1 - CDR3 corresponding to SEQ ID NOs: 2 - 4. In an embodiment, Inebilizumab contains variable light chain CDR1 - CDR3 corresponding to SEQ ID NOs: 6 - 8. In an embodiment, Inebilizumab contains the VH amino acid sequence and VL amino acid sequence in Table 1 corresponding to SEQ ID NOs: 1 and 5 respectively. In an embodiment, Inebilizumab contains the heavy chain amino acid sequence and light chain amino acid sequence in Table 1 corresponding to SEQ ID NOs: 9 and 10 respectively.

[0024] In an embodiment, Inebilizumab or a derivative of Inebilizumab has at least about or at most about 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or up to about 100% identity with any one of SEQ ID NOs: 1 - 10 shown in Table 1. In an embodiment, any one of the sequences in Table 1 can be modified. In an embodiment, the modification includes one or more truncations, deletions, insertions, and combinations thereof. In an embodiment, the modification does not change the function of Inebilizumab. The modification can occur at any of the residues provided in Table 1 and any number of residues from Table 1. In an embodiment, the modification can include 1 - 3, 1 - 5, 1 - 10, 5 - 20, 1 - 3, 1 - 5, 1 - 10, 1 - 20, 3 - 8, 3 - 10, 3 - 15, 5 - 8, 5 - 10, or 5 - 20 residues. In an embodiment, the modification can occur at 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 20, 30, 40, 50, 60, 70, 80, 90, 100, 200, 300, 400, or 450 residues. In an embodiment, all of the residues in Table 1 include the modification.

[0025]

Table 1

[0026] Inbevizumab and methods of making it are described in the specification of International PCT Patent Application PCT / US2007 / 077916, published as International Publication No. 2008 / 031056, which is incorporated herein by reference (the specification of PCT / US2007 / 077916 refers to VIB551 as "16C4"). In some embodiments, VIB551 (also referred to as HZN551, MEDI551, UPLIZNA™, or inbevizumab; disclosed in U.S. Patent Application Publication No. 11 / 852,106 and International Application No. PCT / US2020 / 029613, which are incorporated herein by reference in their entireties) is administered by any of the methods disclosed herein.

[0027] In some embodiments, inbevizumab is a clear to slightly milky white, colorless to slightly yellow solution that contains no or substantially no visible particles. Inbevizumab is a sterile liquid formulation (nominal 100 mg of inbevizumab per vial) intended for IV infusion after dilution with saline. In some embodiments, inbevizumab for IV administration can be supplied as a sterile liquid in a 10 mL nominal fill volume 10R glass vial with a 20 mm stopper and a flip-off cap over seal. In some embodiments, the formulation may not contain a preservative. In some embodiments, inbevizumab for IV administration is supplied as a sterile liquid filled to a nominal volume of 10 mL in a 10R vial. In some embodiments, the vial contains inbevizumab formulated at 10 mg / mL in 20 mM histidine / histidine hydrochloride, 70 mM NaCl, 106 mM (4% [w / v]) trehalose dihydrate, and 0.01% (w / v) polysorbate 80, pH 6.0. Alternative formulations are also contemplated and are further described below.

[0028] Method In an aspect, Inebilizumab is used to treat an autoimmune disease or disorder. In an aspect, the present disclosure provides a method of treating neuromyelitis optica spectrum disorder (NMOSD), the method comprising administering Inebilizumab to a subject in need of treatment for NMOSD. In an aspect, Inebilizumab may be administered as a first-line therapy.

[0029] In an aspect, the autoimmune disease is selected from the group consisting of neuromyelitis optica spectrum disorder (NMOSD), myasthenia gravis (MG), and IgG4-related disease (IgG4RD). In an aspect, the autoimmune disease or disorder includes neuromyelitis optica spectrum disorder (NMOSD). In an aspect, the autoimmune disease or disorder includes MG. In an aspect, the autoimmune disease or disorder includes IgG4RD.

[0030] Treatment of the autoimmune disease or disorder can be in a form that suppresses a B cell- or T cell-mediated immune response that can be a reduction in class-switch antibodies, a reduction in circulating B cell subsets, a reduction in plasma activity, or a reduction in plasma cells and plasma cell gene signatures. Treatment of the autoimmune disease or disorder can be a reduction in markers of inflammation. Markers of inflammation can be one or more of autoantibody levels, plasma cells (PCs), or PC gene signatures (signatures characterized by the expression of the genes IGHA1, IGJ, IGKC, IGKV4-1, and TNFRSF17), circulating B cell subsets, and class-switch antibodies. Treatment of the autoimmune disease or disorder can be a reduction in clinical signs and symptoms such as those measured by a comprehensive assessment by the subject or physician. In an aspect, administration is effective to reduce one or more of the annualized attack rate (AAR), the incidence of disability as evaluated by the Expanded Disability Status Scale (EDSS) score, the incidence of hospitalizations, magnetic resonance imaging (MRI) lesions, and combinations thereof.

[0031] Treatment of an autoimmune disease or disorder can be characterized by at least a 20% reduction in the clinical symptoms of the disease or disorder, or by a reduction in inflammation, or by a reduction in biomarkers of the disease or disorder, compared to their levels prior to treatment with inebilizumab. The reduction in any of these symptoms, or inflammation, or biomarkers can be at least a 50% reduction compared to their levels prior to initiation of treatment with inebilizumab. The reduction can be such that the autoimmune disease or disorder is characterized as being in a remission state.

[0032] In one aspect, the autoimmune disease or disorder is NMOSD. NMOSD is a rare autoimmune disease of the central nervous system (CNS), and approximately 75-90% of subjects have pathogenic immunoglobulin (Ig)G autoantibodies against aquaporin 4 water channels (AQP4-IgG). Recurrent severe episodes of optic neuritis and myelitis are typical signs of the disease, but brain and brainstem lesions also occur. B cells play a role in the etiology of NMOSD and act through several mechanisms. Exemplary mechanisms include B cell secretion of pro-inflammatory cytokines, such as interleukin (IL)-6 and IL-17, which can stimulate a pathogenic pro-inflammatory immune response. Second, B cells can act as antigen-presenting cells and promote the generation and activation of autoreactive T cells. Third, the maturation of B cells results in the generation of AQP4-IgG-producing plasmablasts and plasma cells.

[0033] When ineabilizumab is used to treat NMOSD, it may treat NMOSD by reducing the worsening of the subject's Kurtzke Expanded Disability Status Scale (EDSS), or by reducing the number of the subject's active magnetic resonance imaging (MRI) lesions, or by reducing the worsening of the subject's modified Rankin Score, or by reducing the frequency of the subject's inpatient hospitalizations related to NMOSD, or by reducing the risk of the subject's NMOSD-related seizures, or by reducing optic neuritis, or by reducing the severity of the subject's NMOSD-related seizures, or by reducing the subject's pain, or by reducing the subject's NMOSD-related damage, or by reducing the subject's NMOSD-related attacks.

[0034] Inebilizumab treats the subject's NMOSD by reducing the worsening of the subject's EDSS score, and if the subject has a baseline EDSS score of 0, the subject's EDSS score may worsen by less than 2 points, or less than 1 point, or less than 0.5 points. This reduction in the worsening of the EDSS score of subjects with a baseline score of 0 can be over a period of at least 6 months, 9 months, 1 year, 2 years, 3 years, 4 years, 5 years, 7.5 years, or 10 years. Inebilizumab treats the subject's NMOSD by reducing the worsening of the subject's EDSS score, and if the subject has a baseline score of 1 - 5, the subject's EDSS score may worsen by less than 1 point, or less than 0.5 points. This reduction in worsening for subjects with a baseline EDSS score of 1 - 5 can be a reduction in worsening over a period exceeding 6 months, 9 months, 1 year, 2 years, 3 years, 4 years, 5 years, 7.5 years, or 10 years. Inebilizumab treats the subject's NMOSD by reducing the worsening of the subject's EDSS score, and if the subject has a baseline EDSS score of 5.5 or higher, the subject's EDSS score may worsen by less than 0.5 points, or less than 0.25 points. This reduction in worsening for subjects with a baseline score of 5.5 or higher can be a reduction in the worsening of the EDSS score over a period exceeding 6 months, 9 months, 1 year, 2 years, 3 years, 4 years, 5 years, 7.5 years, or 10 years.

[0035] When inebilizumab treats the subject's NMOSD by reducing the number of active MRI lesions, the treatment can be a reduction in the number of enlarged T2 MRI lesions, gadolinium-enhanced (GD+) lesions, or a reduction in the number of new MRI lesions, or a reduction in the number of enlarged T2 MRI lesions, gadolinium-enhanced (GD+) lesions, and new MRI lesions. The reduction in lesions can be a reduction in brain lesions, brainstem lesions, spinal cord lesions, optic nerve lesions, or a reduction in lesions in any combination of two or more of the brain, brainstem, spinal cord, and optic nerve. The new MRI lesions may not be clinically symptomatic.

[0036] When treating a subject's NMOSD by reducing the risk of NMOSD-related seizures with ine bilizumab, the subject's seizure risk can be reduced by 60% to 85%, or can be reduced by 65% to 75%, or can be reduced by 70% to 80%. The subject's seizure risk can be reduced by at least 70%, at least 75%, at least 76%, at least 77%, at least 78%, at least 79%, or at least 80%. The subject's seizure risk can be reduced by 70%, 75%, 76%, 77%, 78%, 79%, or 80%.

[0037] When treating a subject's NMOSD by reducing the risk of NMOSD-related seizures with ine bilizumab, as a result of the reduction in the risk of NMOSD-related seizures, the probability that there are no NMOSD-related seizures in the subject to be treated can be more than 70% for at least 6 months after treatment, or more than 70% for at least 12 months after treatment, or more than 70% for at least 18 months after treatment. As a result of the reduction in the risk of NMOSD-related seizures, the probability that there are no NMOSD-related seizures in the subject to be treated can be more than 75% for at least 6 months after treatment, or more than 75% for at least 12 months after treatment, or more than 75% for at least 18 months after treatment. In addition, as a result of the reduction in the risk of NMOSD-related seizures, the probability that there are no NMOSD-related seizures in the subject to be treated can be more than 80% for at least 6 months after treatment, or more than 80% for at least 12 months after treatment, or more than 80% for at least 18 months after treatment. Also, as a result of the reduction in the risk of NMOSD-related seizures, the probability that there are no NMOSD-related seizures in the subject to be treated can be more than 85% for at least 6 months after treatment, or more than 85% for at least 12 months after treatment, or more than 85% for at least 18 months after treatment.

[0038] Furthermore, when treating the subject's NMOSD by reducing the risk of NMOSD-related seizures with ine bilizumab, as a result of the risk reduction, the annualized risk of NMOSD-related seizures to be treated can be reduced to 0.18 - 0.08, or can be reduced to 0.15 - 0.08, or can be reduced to 0.14, or 0.13, or 0.12, or 0.11, or 0.10, or 0.09, or 0.08, or 0.07. When the subject during the treatment of NMOSD is AQP4-IgG serum positive, the annualized risk of NMOSD-related seizures of the subject can be reduced to 0.15 - 0.11, or can be reduced to 0.14 - 0.12, or can be reduced to 0.14, 0.13, 0.12, or 0.11. When the subject during the treatment of NMOSD is AQP4-IgG serum reaction negative, the annualized risk of NMOSD-related seizures of the subject can be reduced to 0.09 - 0.07, or can be reduced to 0.09, 0.08, or 0.07. NMOSD-related seizures can have their risk reduced like the treatment of NMOSD subjects, but can be seizures characterized by the appearance of new NMOSD symptoms or the worsening of existing NMOSD symptoms. The new or existing symptoms can be eye symptoms. When the new or existing symptoms are eye symptoms, there can be eye pain, new optic neuropathy, enlarged optic neuropathy, haze, vision loss, or in a low-contrast Landolt C break-ring chart, there can be a missing of more than 5 characters. The new or existing symptoms can be spinal cord symptoms. When the new or existing symptoms are spinal cord symptoms, it can be severe or fundamental pain, limb paresthesia, weakness, sphincter dysfunction, Lhermitte's sign, new spinal cord lesions or enlarged spinal cord lesions. The new or existing symptoms can be brain or brainstem symptoms. When the new or existing symptoms are brain or brainstem symptoms, it can be nausea, diplopia, oculomotor palsy, dizziness, intractable vomiting, intractable hiccups, dysarthria, dysphagia, weakness, encephalopathy, hypothalamic dysfunction, new brain or brainstem lesions, or enlarged brain or brainstem lesions. The new or worsening symptoms can be any combination of two or more of eye, spinal cord, or brain / brainstem symptoms. It can be any combination of two, three, or four of these symptoms.

[0039] In an embodiment, inebilizumab treats the subject's NMOSD by reducing optic neuritis, and then the subject may experience a reduction in eye pain, reduction in vision loss, reduction in visual field loss, reduction in color vision loss, or reduction in the flickering or twinkling of light associated with eye movement. Reduction of optic neuritis can result in improvement of vision and / or relief of eye pain.

[0040] In an embodiment, inebilizumab treats the subject's NMOSD by reducing the severity of the subject's NMOSD-related attacks, and then the severity of any NMOSD-related attack the subject is suffering from may be classified as mild or moderate rather than severe. A mild attack can be a transient attack, an attack that requires only minimal treatment or therapeutic intervention, and / or an attack that does not prevent normal activities of daily life. A moderate attack can be an attack that can be alleviated by specific additional therapeutic interventions. Any moderate attack can be an attack that interferes with normal activities of daily life and / or causes discomfort but does not pose a significant or permanent risk to the subject. Reduction of the severity of the subject's NMOSD-related attacks can primarily be a reduction of the attacks the subject is suffering from that are classified. Such major attacks can be attacks that require intensive therapeutic intervention, attacks that interrupt normal activities of daily life, or attacks that significantly affect the subject's clinical condition. Such major attacks may require inpatient hospitalization.

[0041] In an embodiment, the method includes stratifying the subject. Stratification of the subject can be based on a B cell level of less than about 4 cells / μL of blood in the subject after the first or pre-dose of inebilizumab. In an embodiment, the method includes repeating the administration of inebilizumab in subjects with a B cell count of less than 4 cells / μL after the initial dosing period. In an embodiment, the method includes maintaining B cell suppression or reduction in subjects who require it.

[0042] Inebilizumab can also be used in a method of reducing AQP4-IgG titer in AQP4-IgG+ subjects in need of treatment for NMOSD. A method is provided that includes administering inebilizumab to a subject having a high AQP4-IgG titer. In an embodiment, the titer is greater than about 1:20, 480. In an embodiment, the present disclosure is a method of reducing AQP4-IgG titer in AQP4-IgG+ subjects in need of treatment for NMOSD, the method including administering the anti-CD19 antibody inebilizumab to a subject in need of treatment for NMOSD, the subject having been previously treated with an anti-CD20 antibody and having had an NMOSD attack while being treated with the anti-CD20 antibody; and inebilizumab being administered intravenously at a dose of 300 mg every 6 months. In an embodiment, the present disclosure is a method of reducing AQP4-IgG titer in AQP4-IgG+ subjects in need of treatment for NMOSD, the method including administering the anti-CD19 antibody inebilizumab to a subject in need of treatment for NMOSD, the subject having been previously treated with an anti-CD20 antibody and having had an NMOSD attack within 6 months of the last dose of the anti-CD20 antibody; and inebilizumab being administered intravenously at a dose of 300 mg every 6 months. In an embodiment, the administration can be continued indefinitely. When inebilizumab is used in a method of reducing AQP4-IgG titer in AQP4-IgG+ subjects in need of treatment for NMOSD, inebilizumab can reduce the AQP4-IgG titer by 75% to 100%, or 75% to 90%, or 75% to 85%, or 80% to 100%, or 85% to 100%, or 90% to 95%, or 75%, 80%, 85%, 90%, 95 or 100%. Inebilizumab can reduce the AQP4-IgG titer over a duration of at least 2 months, at least 3 months, at least 4 months, at least 5 months, at least 6 months, at least 7 months, at least 8 months, at least 9 months, at least 10 months, at least 11 months, or at least 12 months after administration of the inebilizumab dose. In an embodiment, a method of treating neuromyelitis optica spectrum disorder is provided.In an aspect, the method includes administering ine bilizumab to a subject who does not have anti-aquaporin 4 immunoglobulin G antibody (AQP4-IgG-) and has immunoglobulin G antibody against myelin oligodendrocyte glycoprotein (MOG-IgG+). In an aspect, about 300 mg of ine bilizumab is administered. In an aspect, the administration is continued for at least about 6 months, 1 year, 2 years, 3 years, or indefinitely. In an aspect, the administration is continued for at least 2 years. In an aspect, the subject in need has increased serum autoreactivity against autoantibodies not related to NMOSD as compared to healthy control subjects. In an aspect, administering is effective in reducing AAR. An attack includes the presence of one or more new symptoms that meet at least one of the neurological examination criteria defined in 18 protocols for attacks including myelitis, optic neuritis, and brain / brainstem domain symptoms or the worsening of one or more existing symptoms related to NMOSD. In an aspect, the reduction of AAR is at least about 20%, 30%, 40%, 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, 97%, or up to about 100%.

[0043] In an aspect, administering is effective in reducing MRI lesions. In an aspect, the reduction of MRI lesions is at least about 20%, 30%, 40%, 50%, 60%, 70%, 73%, 75%, 80%, 85%, 90%, 95%, 97%, or up to about 100%.

[0044] In an aspect, the administration of ine bilizumab is effective in preventing disease progression. For example, a single or repeated dosing scheme of ine bilizumab can be effective in delaying NMOSD progression by at least about 1 month, 2 months, 3 months, 5 months, 6 months, 8 months, 10 months, 12 months, 1.5 years, 2 years, 3 years, 5 years, or 5 years or more. In an aspect, the subjects administered ine bilizumab have a reduced NMOSD progression determined by the reduction of AAR, the annual conversion rate of new / enlarged T2 lesion detection or gadolinium enhancement (Gd+) lesion detection, the hospitalization rate, and / or the annual conversion rate of EDSS worsening.

[0045] In an embodiment, the method includes determining the level of B cell levels in peripheral blood. In an embodiment, the method includes B cell monitoring. The monitoring can be performed on any subject sample including, but not limited to, whole foods, PBMCs, bone marrow, tissues, tumors, and combinations thereof. In an embodiment, B cell monitoring is performed on whole blood. The monitoring can be performed once or repeatedly. In an embodiment, B cell monitoring is performed daily, weekly, monthly, bi-weekly, or annually. In an embodiment, the level of B cells or plasma cells is determined at least 1, 2, 4, 8, 12, 16, 22, 28, and / or 32 weeks after administration of inebilizumab.

[0046] To determine B cell levels, flow cytometry and / or FACS analysis can be utilized. In an embodiment, CD20 is used as a FACS marker to count B cells (bound inebilizumab interferes with CD19-based FACS). In an embodiment, the B cell subset is also measured by CD20+ B cells defined as CD45hi[CD3-, CD56-, CD14-], CD33-, CD20. In addition, analysis of plasmablast / plasma cell numbers (CD45hi[CD3-, CD14-, CD56-], CD27+, HLA-DR hi / low , CD38+) can also be performed. In an embodiment, the levels of CD20+ B cells and CD27+ memory B cells are determined. In an embodiment, the level of the B cell subset is determined in peripheral blood.

[0047] In an embodiment, the subject being treated includes a reduction in the level of CD20+ B cells, CD27+ memory B cells, or both, compared to a subject equivalent except for lack of treatment with inebilizumab. In an embodiment, the subject being treated includes a reduction in CD27+ and CD20+ B cell levels of at least about 1-fold, 3-fold, 5-fold, 10-fold, 20-fold, 40-fold, 60-fold, 80-fold, 100-fold, 130-fold, 150-fold, 175-fold, 200-fold, 300-fold, 400-fold, or up to about 500-fold.

[0048] In an aspect, the method includes maintaining a reduction in B cell levels in a subject in need thereof. In an aspect, the reduction in B cell levels is maintained for at least about 1 month, 3 months, 5 months, 6 months, 8 months, 10 months, 1 year, 1.5 years, 2 years, or up to about 3 years after treatment with inebilizumab.

[0049] In an aspect, the method includes determining plasma cell-specific gene expression. Gene expression can be determined using quantitative reverse transcription PCR of blood RNA. A plasma cell gene signature can be obtained based on expression analysis of genes (IGHA1, IGJ, IGKV4-1, and TNFRSF17) mainly expressed by plasma cells in the blood. The signature can be calculated as the mean expression of the four plasma cell-specific genes minus the mean expression of five control genes (B2M, GAPDH, TFRC, GUSB, and UBC) at the time point of interest. The fold change in the plasma cell gene expression signature at each time point can be calculated relative to a pool of healthy donor samples and interpreted as the plasma cell abundance relative to the expected morbidity under a non-activated immune state.

[0050] In an aspect, single nucleotide polymorphism analysis is performed on a subject sample. TaqMan single nucleotide polymorphism profiling can be used to examine a possible association between the rs396991 polymorphism in the FCGR3A gene and impaired B cell depletion. In an aspect, the analysis includes determining the presence of a G to T single nucleotide substitution (SNP) at cDNA nucleotide position 559 of the FCGR3A gene. This SNP encodes two different FcγRIIIa allotypes: one has valine (V) at amino acid position 158 and the other has phenylalanine (F), known as the FcγRIIIA-V158F polymorphism (rs396991). The rs396991 polymorphism encodes a valine / phenylalanine substitution at position 158 of FCGR3A associated with a reduced binding affinity for Ig Fc, and thus potentially impairs the ADCC mechanism in which the Fc region of inebilizumab is optimized. In an aspect, the method includes polymorphism analysis to confirm that a subject is eligible for dosing with inebilizumab.

[0051] In an aspect, the method includes determining the presence of a V allele in a subject. The V allele can be determined by a V / F or V / V genotype. The presence of the V allele can inform the administration of inebilizumab. In an aspect, the method includes stratifying a population of subjects based on the presence of the V allele for dosing inebilizumab. In an aspect, the method includes administering inebilizumab to a subject in need thereof, including the rs396991 polymorphism of the FCGR3A gene. In an aspect, treatment with inebilizumab may be effective in reducing B cell or plasma cell levels in a subject in need thereof, including the rs396991 polymorphism of the FCGR3A gene, compared to comparable subjects except for lacking the rs396991 polymorphism.

[0052] A method is also provided that includes determining autoreactivity against a nuclear antigen. An antinuclear antibody (ANA) test can determine the presence of an autoimmune disease or can be used to monitor the status of an autoimmune disease in a subject. Antibodies against extractable nuclear antigens (ENAs) are ribonucleoproteins extractable from the cell nucleus (e.g., protein antigens that do not contain DNA). Exemplary ENAs include Ro (SS-A), La (SS-B), Sm, and RNP. In an aspect, the method includes determining the level of autoreactivity in a subject before treatment and monitoring the level during treatment. In an aspect, autoreactivity is determined weekly, monthly, twice a year, or annually.

[0053] Methods are also provided that include determining the level or presence of a self - antigen in a subject. In an aspect, the response to a self - antigen by one or more of IgG, IgM, IgA, and IgE (e.g., ANA and / or RNP) is evaluated. In an aspect, the self - antigen is associated with the presence of an autoimmune disease. Exemplary self - antigens include Mi - 2 (CHD4), signal recognition particle (SRP), transcriptional intermediate factor 1 - gamma (TIF1 - γ; TRIM 33), nuclear matrix protein - 2 (NXP2; MORC3), 3 - hydroxy - 3 - methylglutaryl - coA reductase (HMGCR), melanoma - associated differentiation gene - 5 (MDA5), small ubiquitin - like modifier activating enzymes SAE - 1 and SAE - 2, topoisomerase - 1, centromere proteins A, B & C (「CENP」), fibrillarin, components of the small nucleolar U3 (snoRNP) complex, nucleophosmin (NPM; B23), RNA polymerase I, II & III, multi - component PMSCL; consisting of 10 proteins, and the most commonly targeted RNA exosome complex is EXOSC9 & EXOSC10, the Ku 70 / 80 component of DNA - dependent protein kinase, Ro52 (TRIM 21), Ro60, La (SS - B), gamma interferon - inducible protein - 16 (IFI16), proteinase - 3 (PR3), myeloperoxidase (MPO), ACPA (anti - citrullinated protein antibody), peptidylarginine deiminase - 4 (PAD4), ds DNA, components of the Sm splicing ribonucleoprotein (the most commonly targeted subunits A - G are B, B’ & D), U1 - RNP, ribosomal protein P, cardiolipin, anionic phospholipid / protein complex, N - methyl - D - aspartic acid (NMDA) receptor, CENP - A, CENP - B, core histones, DNA polymerase beta (POLB), dsDNA, EBNA1, genomic DNA, histone H1, histone H2A, histone H2B, histone H3, histone H4, Jo - 1, KU (P70 / P80), La / SSB, Mi - 2, PCNA, PL - 7, PL - 12, PM / Scl - 75, PM / Scl 100, ribophorin P0, ribophorin P1, ribophorin P2, Ro / SSA(52Kda), Ro / SSA (60 Kda), S100, Scl-70 / topoisomerase I, Sm, Sm / RNP, SmD, SmD1, SmD2, SRP54, ssDNA, ssRNA, U1-snRNP 68 / 70, U1-snRNP A, U1-snRNP B / B, U1-snRNP C, total histone, total histone citrullination human genomic DNA, KU (P70 / P80), Nup 62, Ro / SSA (52+60), U1-snRNP, etc. In an embodiment, the autoantigen is CENP-A, CENP-B, core histone, DNA polymerase beta (POLB), dsDNA, EBNA1, genomic DNA, histone H1, histone H2A, histone H2B, histone H3, histone H4, Jo-1, KU (P70 / P80), La / SSB, Mi-2, PCNA, PL-7, PL-12, PM / Scl-75, PM / Scl 100, ribophorin P0, ribophorin P1, ribophorin P2, Ro / SSA (52 Kda), Ro / SSA (60 Kda), S100, Scl-70 / topoisomerase I, Sm, Sm / RNP, SmD, SmD1, SmD2, SRP54, ssDNA, ssRNA, U1-snRNP 68 / 70, U1-snRNP A, U1-snRNP B / B, U1-snRNP C, total histone, total histone citrullination human genomic DNA, KU (P70 / P80), Nup 62, Ro / SSA (52+60), and U1-snRNP, and is selected from the group consisting of. In an embodiment, the administration of inebilizumab is effective to reduce the level of autoantigen in the subject to be treated as compared to the baseline level in the same subject or the level of an equivalent untreated control subject. The level can be reduced by at least about 5%, 10%, 20%, 30%, 40%, 50%, 75%, 100%, 150%, 200%, 300%, 350%, or up to about 400%.

[0054] Methods are also provided that include determining the level of interferon-induced gene expression. In embodiments, gene expression profiling can be performed using, for example, a microarray to determine the levels of mRNA transcripts in a biological sample of a subject. In embodiments, the gene expression profiling evaluates type I interferon-α / β (IFNα / β)-induced genes. Upregulation of these genes can correlate with disease activity, and downregulation can occur when the disease is controlled, for example, by treatment with inebilizumab. In embodiments, the upregulation or downregulation is about 5%, 10%, 20%, 30%, 40%, 50%, 75%, 100%, 150%, 200%, 300%, 350%, or up to about 400%. In embodiments, administration of inebilizumab is effective to reduce the level of interferon-induced gene expression in a treated subject as compared to the baseline level in the same subject or the level of an equivalent untreated control subject.

[0055] Pharmaceutical composition Pharmaceutical compositions are provided. Also provided are pharmaceutical compositions comprising inebilizumab. In embodiments, a treatment regimen includes a pharmaceutical composition, such as one comprising inebilizumab. The treatment regimen can also include additional pharmaceutical compositions that are not inebilizumab.

[0056] Inebilizumab can be administered at any dosage. In some embodiments, inebilizumab is administered at a dosage of about 0.5 mg to 1000 mg. In some embodiments, inebilizumab is administered at a dosage of about 10 mg to 30 mg, 20 mg to 100 mg, 50 mg to 200 mg, 100 mg to 300 mg, 150 mg to 350 mg, 200 mg to 400 mg, 250 mg to 450 mg, 300 mg to 500 mg, 300 mg to 700 mg, or 400 mg to 1000 mg.In an embodiment, Inebilizumab is administered at a dose of about 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 105 mg, 110 mg, 115 mg, 120 mg, 125 mg, 130 mg, 135 mg, 140 mg, 145 mg, 150 mg, 155 mg, 160 mg, 165 mg, 170 mg, 175 mg, 180 mg, 185 mg, 190 mg, 195 mg, 200 mg, 205 mg, 210 mg, 215 mg, 220 mg, 225 mg, 230 mg, 235 mg, 240 mg, 245 mg, 250 mg, 255 mg, 260 mg, 265 mg, 270 mg, 275 mg, 280 mg, 285 mg, 290 mg, 295 mg, 300 mg, 305 mg, 310 mg, 315 mg, 320 mg, 325 mg, 330 mg, 335 mg, 340 mg, 345 mg, 350 mg, 355 mg, 360 mg, 365 mg, 370 mg, 375 mg, 380 mg, 385 mg, 390 mg, 395 mg, 400 mg, 405 mg, 410 mg, 415 mg, 420 mg, 425 mg, 430 mg, 435 mg, 440 mg, 445 mg, 450 mg, 455 mg, 460 mg, 465 mg, 470 mg, 475 mg, 480 mg, 485 mg, 490 mg, 495 mg, 500 mg, 505 mg, 510 mg, 515 mg, 520 mg, 525 mg, 530 mg, 535 mg, 540 mg, 545 mg, 550 mg, 555 mg, 560 mg, 565 mg, 570 mg, 575 mg, 580 mg, 585 mg, 590 mg, 595 mg, 600 mg, 605 mg, 610 mg, 615 mg, 620 mg, 625 mg, 630 mg, 635 mg, 640 mg, 645 mg, 650 mg, 655 mg, 660 mg, 665 mg, 670 mg, 675 mg, 680 mg, 685 mg, 690 mg, 695 mg, 700 mg, 705 mg, 710 mg, 715 mg, 720 mg, 725 mg, 730 mg, 735 mg, 740 mg, 745 mg, 750 mg, 755 mg, 760 mg, 765 mg, 770 mg, 775 mg, 780 mg, 785 mg, 790 mg, 795 mg, 800 mg, or up to about 1000 mg. In an embodiment, a subject in need thereof is administered 300 mg.

[0057] In an embodiment, Inebilizumab is administered repeatedly. The administration can be daily, monthly, or yearly. The dosage of Inebilizumab may be administered approximately bi-weekly, or twice a month. The dosage of Inebilizumab may also be administered approximately weekly or approximately once a month. The dosage of Inebilizumab may be administered every 7 days, every 10 days, every 14 days, every 15 days, every 16 days, every 14 - 10 days, every 14 - 16 days, or every 30 days. In an embodiment, Inebilizumab is administered every 6 months. Inebilizumab can be administered for at least about 1 year, 2 years, 2.5 years, 3 years, 4 years, 5 years, or up to approximately the lifespan of the subject in need thereof. In an embodiment, the administration is continued for at least about 2.5 years.

[0058] If the dosage of Inebilizumab administered is one of 1000 mg, 1500 mg, or between approximately 1000 mg and approximately 1500 mg, the dosage may be administered bi-weekly, or twice a month. If the dosage of Inebilizumab is 3000 mg, the dosage of Inebilizumab may be administered once a month. If the dosage of Inebilizumab is 500 mg or 750 mg, the dosage of Inebilizumab may be administered once every two weeks, or twice a month. In an embodiment, the subject receives 0 - 2, 0 - 3, 0 - 5, 0 - 10, 1 - 3, 1 - 5, or 1 - 10 administrations.

[0059] In an embodiment, Inebilizumab may be administered at a dose of about 300 mg. In an embodiment, Inebilizumab may be administered at a dose of about 250 mg to about 350 mg, about 275 mg to about 325 mg, about 290 mg to about 310 mg, about 205 mg to about 305 mg, or may be at a dose of 300 mg. In an embodiment, the subject may receive one or more initial doses of Inebilizumab. In an embodiment, the subject may receive one, two, three or more initial doses. In an embodiment, the initial dose may be about 300 mg. In an embodiment, Inebilizumab may be administered at an initial dose of about 250 mg to about 350 mg, about 275 mg to about 325 mg, about 290 mg to about 310 mg, about 205 mg to about 305 mg, or an initial dose of 300 mg. In an embodiment, Inebilizumab may be administered intravenously at an initial dose of about 300 mg for the first initial dose, about 300 mg for the second initial dose two weeks after the first initial dose, and subsequent doses of about 300 mg every six months after the first initial dose.

[0060] The inevitable dosage that can be used in a method of treating a subject in need thereof can be a dosage administered intravenously approximately once every six months, or once every seven months, or once every eight months, or once every nine months, or once every ten months, or once every eleven months, once a year, and / or at intervals indefinitely. In an embodiment, the inebilizumab administered in the methods disclosed herein can be at intervals of approximately every six months. By approximately every six months is meant administration every six months, every 180 days, every 170 - 190 days, every 175 - 185 days, every 175 - 190 days, or every 170 - 185 days. By approximately every six months is meant administration every 26 weeks, every 25 weeks, every 27 weeks, every 25 - 27 weeks, every 25 - 26 weeks, or every 26 - 27 weeks. In an embodiment, the administration is continued indefinitely. Before administering inebilizumab approximately every six months in the methods disclosed herein, a first inebilizumab dosage may be administered to the subject in need thereof. The first inebilizumab dosage may be administered approximately two weeks prior to the inebilizumab dosing every six months. Administering the first inebilizumab dosage approximately two weeks prior to the inebilizumab dosing every six months may be administering the first inebilizumab dosage 12, 13, 14, 15, or 16 days prior to the inebilizumab dosing every six months.

[0061] The dosage and dosing regimen of Inebilizumab may be such that any therapeutic effect achieved from the administration of Inebilizumab for treating any autoimmune / inflammatory disease or disorder can be "long-lasting". The "sustained" effect of Inebilizumab in the treatment of an autoimmune / inflammatory disease or disorder is that the therapeutic effect achieved by Inebilizumab is maintained for at least 4 weeks, at least 6 weeks, at least 8 weeks, at least 10 weeks, at least 12 weeks, at least 16 weeks, at least 20 weeks, or at least 24 weeks after the administration of the last dose in the course of Inebilizumab. A series of Inebilizumab may be administered at a dosing interval of once every 7 to 31 days (e.g., every 7 days, every 10 days, every 14 days, every 15 days, every 16 days, every 14 to 10 days, every 14 to 16 days, or every 30 days) over a period of approximately 8 to 24 weeks (e.g., 8 weeks, or 10 weeks, or 12 weeks, or 14 weeks, or 16 weeks, or 18 weeks, or 20 weeks, or 22 weeks, or 24 weeks, or 2 months, or 4 months, or 6 months) at a dose of 500 mg to 3000 mg (e.g., 500 mg, 750 mg, 1000 mg, 1250 mg, 1500 mg, 1750 mg, 2000 mg, 2250 mg, 2500 mg, 2750 mg, or 3000 mg).

[0062] In an embodiment, the administration is intravenous. In an embodiment, the administration is by infusion.

[0063] The pharmaceutical composition may comprise an immunosuppressant. Immunosuppressive therapy may include administration of one or more immunosuppressants such as cytokine transcription inhibitors (e.g., cyclosporine A, tacrolimus), nucleotide synthesis (e.g., azathioprine, mycophenolate mofetil), growth factor signaling (e.g., sirolimus, rapamycin), and inhibitors of the T cell interleukin-2 receptor (e.g., daclizumab, basiliximab). In certain embodiments, the immunosuppressants used in combination with the compositions and methods of the invention are: doxorubicin, azathioprine, busulfan, cyclophosphamide, cyclosporine A (“CyA”), cytotoxic, fludarabine, 5-fluorouracil, methotrexate, mycophenolate mofetil (MOFETIL), non-steroidal anti-inflammatory drugs (NSAIDs), rapamycin, and one or more of tacrolimus (FK506). The immunosuppressant may also include an inhibitor of complement, such as soluble complement receptor-1, anti-C5 antibody, or a small molecule inhibitor of CI as described, for example, in Buerke et al. (J. Immunol., 167:5375-80 (2001)).

[0064] In an aspect, the pharmaceutical composition comprises an amount of an immunosuppressant effective to immunosuppress a subject to be treated. In an aspect, the subject has been pre-treated or has previously received an immunosuppressive drug prior to treatment with inebilizumab. Any immunosuppressive drug may be administered. In an aspect, the subject has been previously treated with one or both of azathioprine (AZA) and / or mycophenolate mofetil (MMF).

[0065] One of ordinary skill in the art can recognize or confirm many equivalents to the specific embodiments described herein using only routine experimentation. Such equivalents are intended to be encompassed by the following claims.

[0066] Incorporation by reference This patent application is incorporated by reference in its entirety for all purposes into the following patent publications: International Publication No. WO 2008 / 031056 Pamphlet and International Publication No. WO 2020 / 219743 Pamphlet.

[0067] All publications, patents, and patent applications mentioned in this specification are incorporated herein by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated herein by reference.

[0068] Numbered embodiments Embodiment 1. A method of treating or preventing neuromyelitis optica spectrum disorder (NMOSD), the method comprising administering ine bilizumab to a subject in need thereof having a B cell level of less than about 4 cells / μL of blood, thereby treating NMOSD.

[0069] Embodiment 2. The method of embodiment 1, wherein the Fc gamma receptor IIIa (FCGR3A) gene of the subject in need thereof comprises the rs396991 polymorphism.

[0070] Embodiment 3. The method of embodiment 2, wherein the subject in need thereof comprises a V allele determined by the V / F or V / V genotype.

[0071] Embodiment 4. A method of treatment, the method comprising assaying a blood sample from a subject in need thereof for the presence of the rs396991 polymorphism of the FCGR3A gene, and if the determination is positive for the rs396991 polymorphism, administering ine bilizumab to the subject in need thereof.

[0072] Embodiment 5. The method of embodiment 4, wherein the subject in need thereof has an autoimmune disease.

[0073] Embodiment 6. The method of embodiment 5, wherein the autoimmune disease is selected from the group consisting of neuromyelitis optica spectrum disorder (NMOSD), myasthenia gravis (MG), and IgG4RD.

[0074] Embodiment 7. The method of embodiment 6, wherein the autoimmune disease is NMOSD.

[0075] Embodiment 8. The method according to Embodiment 6, wherein the autoimmune disease is MG.

[0076] Embodiment 9. The method according to Embodiment 6, wherein the autoimmune disease is IgG4RD.

[0077] Embodiment 10. The method according to Embodiment 4, wherein the subject in need has at least two autoimmune diseases.

[0078] Embodiment 11. The method according to Embodiment 10, wherein the at least two autoimmune diseases are selected from the group consisting of neuromyelitis optica spectrum disorder (NMOSD), myasthenia gravis (MG), and IgG4RD.

[0079] Embodiment 12. A method of treating neuromyelitis optica spectrum disorder (NMOSD), the method comprising administering ineclizumab to a subject in need, the subject comprising the rs396991 polymorphism of the FCGR3A gene, and the administering being more effective in reducing the level of B cells or plasma cells of the subject in need comprising the rs396991 polymorphism of the FCGR3A gene as compared to an equivalent subject except for lacking the rs396991 polymorphism.

[0080] Embodiment 13. The method according to Embodiment 12, wherein the level of B cells or plasma cells is determined at least 1, 2, 4, 8, 12, 16, 22, 28, and / or 32 weeks after the administering.

[0081] Embodiment 14. The method according to any one of Embodiments 1 to 13, wherein the administering is effective in reducing a criterion selected from the group consisting of annualized attack rate (AAR), incidence of disorders evaluated by the Expanded Disability Status Scale (EDSS) score, incidence of hospitalization, magnetic resonance imaging (MRI) lesions, and combinations thereof.

[0082] Embodiment 15. The method according to Embodiment 14, wherein administration is effective for reducing AAR, and the reduction is at least about 20%, 30%, 40%, 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, 97%, or up to about 100%.

[0083] Embodiment 16. The method according to Embodiment 14, wherein administration is effective for reducing MRI lesions, and the reduction is at least about 20%, 30%, 40%, 50%, 60%, 70%, 73%, 75%, 80%, 85%, 90%, 95%, 97%, or up to about 100%.

[0084] Embodiment 17. The method according to Embodiment 14, wherein administration is effective for reducing EDSS.

[0085] Embodiment 18. The method according to Embodiment 14, wherein administration is effective for reducing the incidence of hospitalization.

[0086] Embodiment 19. The method according to any one of Embodiments 1 to 18, wherein administration is repeated.

[0087] Embodiment 20. The method according to Embodiment 19, wherein administration is repeated daily, monthly, or annually.

[0088] Embodiment 21. The method according to Embodiment 20, wherein administration is repeated monthly.

[0089] Embodiment 22. The method according to Embodiment 21, wherein administration is repeated every six months.

[0090] Embodiment 23. The method according to any one of Embodiments 19 to 22, wherein administration is continued for at least about 1 year, 2 years, 3 years, 4 years, 5 years, or up to approximately the lifespan of the subject in need thereof.

[0091] Embodiment 24. The method according to any one of Embodiments 1 to 23, wherein inebilizumab has been previously administered to the subject in need thereof.

[0092] Embodiment 25. The method according to any one of Embodiments 1 to 24, wherein the administration is intravenous.

[0093] Embodiment 26. The method according to Embodiment 25, wherein the administration is by intravenous injection.

[0094] Embodiment 27. The method according to any one of Embodiments 1 to 26, wherein Inebilizumab is administered at a dose of about 300 mg.

[0095] Embodiment 28. A method of treating or preventing an autoimmune disease, the method comprising administering 300 mg of Inebilizumab to a subject in need thereof having a B cell level of less than about 4 cells / μL of blood, wherein the administration is repeated every 6 months.

[0096] Embodiment 29. The method according to Embodiment 28, wherein the administration is repeated every 6 months for at least about 1 year.

[0097] Embodiment 30. The method according to Embodiment 28 or 29, wherein the autoimmune disease is selected from the group consisting of neuromyelitis optica spectrum disorder (NMOSD), myasthenia gravis (MG), and IgG4-related disease (IgG4RD).

[0098] Embodiment 31. The method according to Embodiment 30, wherein the autoimmune disease is NMOSD.

[0099] Embodiment 32. The method according to Embodiment 30, wherein the autoimmune disease is MG.

[0100] Embodiment 33. The method according to Embodiment 30, wherein the autoimmune disease is IgG4RD.

[0101] Embodiment 34. A method of treating or preventing neuromyelitis optica spectrum disorder (NMOSD), the method comprising administering 300 mg of ine bilizumab to a subject in need having a B cell level of less than about 4 cells / μL of blood, wherein the administering is repeated every 6 months.

[0102] Embodiment 35. A method of treating or preventing an autoimmune disease, the method comprising administering 300 mg of ine bilizumab to a subject in need having a B cell level of less than about 4 cells / μL of blood, wherein the administering is repeated every 6 months, and wherein the autoimmune disease is selected from the group consisting of neuromyelitis optica spectrum disorder (NMOSD), myasthenia gravis (MG), and IgG4RD.

[0103] Embodiment 36. The method according to embodiment 34 or 35, wherein the administering is continued for at least about 2.5 years.

[0104] Embodiment 37. A method of treating neuromyelitis optica spectrum disorder, the method comprising administering ine bilizumab to a subject in need, wherein the subject does not have anti-aquaporin 4 immunoglobulin G antibody (AQP4-IgG-), and has immunoglobulin G antibody against myelin oligodendrocyte glycoprotein (MOG-IgG+).

[0105] Embodiment 38. The method according to embodiment 37, wherein about 300 mg of ine bilizumab is administered.

[0106] Embodiment 39. The method according to embodiment 37 or 38, wherein the administering is continued for at least 6 months, 1 year, 2 years, or 3 years.

[0107] Embodiment 40. The method according to embodiment 39, wherein the administering is continued for at least 2 years.

[0108] Embodiment 41. The method according to any one of embodiments 1 to 40, wherein the subject in need has an increased serum autoreactivity against autoantibodies not related to NMOSD as compared to a healthy control subject.

Example

[0109] Example 1 - Safety and Efficacy of Inebilizumab as a Treatment for Neuromyelitis Optica Spectrum Disorder Presented Newly A study was completed to evaluate the safety and efficacy of inebilizumab in newly diagnosed subjects compared with subjects who had had ≥2 previous NMOSD attacks.

[0110] Method A double - masked, placebo - controlled, randomized phase 2 / 3 trial (Figure 1A) was conducted to evaluate the efficacy and safety of inebilizumab in adults with NMOSD, with a period: a maximum 28 - week randomized control period (RCP; 3:1 for inebilizumab [intravenous, 300 mg] or placebo) or adjudication of attack; and an optional open - label period (OLP; inebilizumab every 28 weeks) of ≥2 years. Immunosuppressive drugs were not used except for oral corticosteroids during the first 2 weeks with a 1 - week taper. This study included adults with NMOSD who had received treatment for ≥1 attack in the past 1 year or ≥2 attacks in the past 2 years and had an EDSS score of ≤8.0. The primary endpoint was the time to the first adjudicated attack during the RCP. Secondary endpoints included the annualized attack rate (AAR) and the progression of disability as evaluated via the Expanded Disability Status Scale (EDSS). Safety evaluations included treatment - emergent adverse events (TEAEs) and AEs that emerged under treatment of particular interest. Subjects who received inebilizumab at any point during the study were pooled into the "any inebilizumab" group for data analysis. In this study, a post - hoc analysis was performed on subjects with AQP4+NMOSD enrolled after the first attack.

[0111] Baseline Characteristics and Demographics A total of 37 subjects with newly diagnosed AQP4+NMOSD and 176 subjects with ≥2 pre - study attacks were included in this analysis (Table 2).

[0112]

Table 2

[0113] Among these, 37 newly diagnosed subjects and 173 subjects with ≥2 pre-study seizures were included in each of the "any inebilizumab" groups. The characteristics of the subjects were similar between the newly diagnosed subjects and those with ≥2 pre-study seizures.

[0114] Results The attack risk of NMOSD is reduced by inebilizumab treatment The attack risk was reduced in all subjects treated with inebilizumab. Newly diagnosed subjects treated with inebilizumab had a lower incidence of adjudicated attacks, a lower AAR, and a higher probability of remaining seizure-free at the end of RCP than the placebo group, regardless of the number of pre-study seizures (Figure 1B and Figure 1C, Table 3). Similar results were observed in patients with ≥2 pre-study seizures. In OLP, the AAR continued to decrease over time with inebilizumab, and the AAR was low in both newly diagnosed "any inebilizumab" subjects and those with ≥2 pre-study seizures.

[0115] [Table 3]

[0116] EDSS worsening is stabilized with inebilizumab treatment During RCP, fewer subjects had EDSS worsening with inebilizumab treatment compared to placebo in both newly diagnosed subjects and those with ≥2 pre-study seizures (Table 4).

[0117] [Table 4]

[0118] EDSS stabilization was seen in both groups throughout OLP.

[0119] Safety and tolerability of inebilizumab treatment During the RCP, the rates of AEs and AESIs that occurred under treatment, when divided by treatment group, were not higher in newly diagnosed subjects with ≥2 pre-study seizures than in those with <2 pre-study seizures (Table 5).

[0120] [Table 5-1]

[0121] [Table 5-2]

[0122] In summary, ine bilizumab was effective and generally well tolerated in newly diagnosed AQP4+ adults, similar to what has been seen in those previously treated with other immunotherapies. In both subgroups, subjects who received ine bilizumab had fewer seizures, were more likely to remain seizure-free, and had less worsening of EDSS than those who received placebo.

[0123] Example 2 - Degree of B cell depletion is associated with reduced disease activity in neuromyelitis optica spectrum disorder The study characterized the relationship between B cell depletion and outcomes in subjects who received long-term ine bilizumab in a double-blind placebo-controlled phase 2 / 3 trial.

[0124] Methods The study included a maximum 28-week randomized placebo-controlled period (RCP) followed by an optional open-label period (OLP) of at least 2 years. High-resolution flow cytometry (lower limit of quantification, 0.2 cells / μL) was used to determine B cell counts. Disease activity was measured using the annualized attack rate (AAR) and the number of new / enlarged T2 lesions.

[0125] Results Inebilizumab induced rapid and sustained B cell depletion over multiple dosing compared to placebo (normal range, 74.4 - 441.1 cells / μL; mean ± standard deviation [SD], week [W] 4 of RCP: inebilizumab, 6.1 ± 9.6 cells / μL; placebo, 147.7 ± 89.4 cells / μL; OLP W156: inebilizumab, 10.4 ± 37 cells / μL). B cell levels at the end of the first inebilizumab dosing period (W28) predicted stable and deep depletion with long-term exposure. Clinical and imaging metrics of disease activity were lower in subjects with B-L at W28 (n = 139 / 200) compared to those with >4 cells / μL (n = 61 / 200); odds ratio (95% confidence interval [CI]) was 0.4 (0.16 - 0.98), p = 0.049 for AAR, and 0.36 (0.23 - 0.56) for new / enlarged T2 lesions, p < 0.0001. The AAR (mean [standard error]) in both groups was lower than that in the RCP placebo group; L: AAR, 0.03 (0.02 - 0.04); new / enlarged T2 lesions, 0.49 (0.43 - 0.56); >4 cells / μL: AAR, 0.09 (0.06 - 0.12); new / enlarged T2 lesions, 1.36 (1.12 - 1.61); placebo: AAR, 1.01 (0.79 - 1.23); new / enlarged T2 lesions, 2.72 (1.99 - 3.46). After 2.5 years, long-term inebilizumab treatment sustained B cell depletion, reduced metrics of NMOSD disease activity, and resulted in a significant reduction in AAR (97%) and new / enlarged T2 lesions (73%) compared to the RCP placebo group (both p < 0.05).

[0126] Inebilizumab provides rapid and long-lasting B cell depletion in subjects with NMOSD. These findings suggest that profound and persistent B cell depletion is beneficial in NMOSD and that monitoring of B cell numbers may be beneficial for inebilizumab treatment.

[0127] Subjects with neuromyelitis optica spectrum disorder exhibit features of systemic autoimmunity: broad serum autoreactivity against nuclear antigens and increased interferon-inducible gene expression Serum autoreactivity and blood type I interferon-induced gene signatures (IFNGS) were profiled, and the study was completed to characterize their relationships with disease activity in individuals with NMOSD in the study.

[0128] Methods The study was a multicenter, double-blind, randomized, placebo-controlled phase 2 / 3 trial that tested the efficacy and safety of ine bilizumab, a humanized affinity-optimized anti-CD19 monoclonal antibody, for the treatment of NMOSD. The study included a randomized control period (RCP) of up to 28 weeks, followed by an optional open-label period of at least 2 years. Serum samples were obtained from 220 / 230 subjects with NMOSD randomized in the study and 25 healthy controls (HC) collected from an independent commercial source. Baseline samples were hybridized to a self-antigen microarray to profile serum immunoglobulin (Ig) G, IgM, IgA, and IgE autoreactivity against 122 self-antigens (excluding AQP4) involved in human autoimmune diseases: CENP-A, CENP-B, core histones, DNA polymerase beta (POLB), dsDNA, EBNA1, genomic DNA, histone H1, histone H2A, histone H2B, histone H3, histone H4, Jo-1, KU (P70 / P80), La / SSB, Mi-2, PCNA, PL-7, PL-12, PM / Scl-75, PM / Scl 100, ribophorin P0, ribophorin P1, ribophorin P2, Ro / SSA (52 Kda), Ro / SSA (60 Kda), S100, Scl-70 / topoisomerase I, Sm, Sm / RNP, SmD, SmD1, SmD2, SRP54, ssDNA, ssRNA, U1-snRNP 68 / 70, U1-snRNP A, U1-snRNP B / B, U1-snRNP C, total histones, total citrullinated histones, genomic DNA, KU (P70 / P80), Nup 62, Ro / SSA (52+60), and U1-snRNP. Autoreactivity was confirmed by signals exceeding the HC mean by more than 5 standard deviations. The autoantibody score was calculated by summing the number of spots with signals exceeding the HC mean by more than 5 standard deviations. Baseline IFNGS was analyzed simultaneously in blood RNA samples from 219 subjects with NMOSD and 10 HC. IFNGS positivity was confirmed by a 4-fold change in signals exceeding the HC mean. The possible associations between baseline autoreactivity and IFNGS positivity and pre-study NMOSD disease activity were estimated using negative binomial regression.Disease activity was measured by annualized attack rate (AAR) or mean annual disability worsening on the Expanded Disability Status Scale (EDSS) between diagnosis and research baseline in subjects with a disease duration of more than 4 years.

[0129] Results Baseline autoreactivity in subjects with NMOSD At baseline, 197 / 220 subjects (90%) with NMOSD had serum autoreactivity to at least one self - antigen, mainly ribonucleoprotein (RNP), consistent with previous findings (Figure 2A). In contrast, HC showed no autoreactivity to any of the antigens studied. Serum autoreactivity was mainly observed in the IgG subclass (83%, [n = 183]).

[0130] Baseline IFNGS in subjects with NMOSD Overall, 27% (59 / 219) of subjects with NMOSD were IFNGS - positive at baseline (>4 - fold change from HC mean) (Figure 2B). A higher proportion of IFNGS - positive subjects than IFNGS - negative subjects were reactive to one or more RNPs (68% vs 46%) (Figure 2C). A statistically significant difference in ANA score was observed between IFNGS - positive and IFNGS - negative subjects (Figure 2D). IgG RNP - immunoreactive subjects had increased IFNGS at baseline.

[0131] Previous diagnosis of NMOSD and inflammatory diseases Most subjects with NMOSD having high self - antigen immunoreactivity and IFNGS - positivity had no prior diagnosis of other co - existing inflammatory diseases, as reported by the study physicians (Figure 2E). In total, 23 subjects (10%) received a diagnosis of systemic inflammatory disease in addition to NMOSD. Eight subjects (4%) had a prior diagnosis of two or more systemic inflammatory diseases in addition to NMOSD (Table 6).

[0132]

Table 6

[0133] Neither baseline autoantibodies and IFNGS positivity nor NMOSD disease-activity IgG autoantibodies and IFNGS positivity at baseline were associated with increased NMOSD disease activity prior to the study (Tables 7 and 8).

[0134]

Table 7

[0135]

Table 8

[0136] Similar results were observed for IgM, IgA, and IgE autoantibodies. In summary, subjects with NMOSD showed higher serum autoreactivity against autoantibodies known to be associated with other systemic autoimmune diseases than HC. Furthermore, subjects with NMOSD and elevated serum immunoreactivity against at least one RNP tended to show increased blood IFNGS at baseline. Most subjects with NMOSD with high serum immunoreactivity against autoantigens and high blood IFNGS did not show co-existing autoimmune diseases. Serum autoreactivity and IFGNS positivity at baseline do not seem to be associated with increased NMOSD disease activity.

[0137] Example 4 - The degree of B-cell depletion is associated with reduced disease activity in neuromyelitis optica spectrum disorder A study was completed to characterize the relationship between B-cell depletion and outcomes in subjects who received long-term ine bilizumab in the study.

[0138] In this study, the relationship between B-cell, plasma cell, and immunoglobulin depletion after ine bilizumab treatment and the long-term reduction of NMOSD disease activity after ine bilizumab treatment was characterized.

[0139] Methods Peripheral blood (PB) B cells, plasma cell signatures, and immunoglobulin levels were regularly evaluated throughout the study and analyzed for correlation with clinical metrics and magnetic resonance imaging (MRI) lesion activity.

[0140] The trial included a randomized control period (RCP) of up to 28 weeks and an optional open-label period (OLP) during which subjects were assigned to intravenous ine bilizumab 300 mg or placebo (3:1), during which all subjects received intravenous ine bilizumab 300 mg every 6 months for at least 2 years (Figure 1).

[0141] Evaluation of B cell pharmacodynamics During the RCP, blood samples were collected at baseline and at study visits at weeks 1, 2, 4, 8, 12, 16, 22, and 28 to evaluate B cell counts, at baseline and at study visits at weeks 2, 4, 8, 12, 16, and 28 to evaluate plasma cell-specific gene expression, and at study visits at weeks 12 and 28 to evaluate Ig levels. During the OLP, blood samples were collected every 13 weeks for evaluation of B cell counts, plasma cell-specific gene expression, and Ig levels. Blood samples for evaluation of B cell counts and plasma cell gene expression were also collected at any evaluation visit for new or worsening NMOSD symptoms during the RCP and OLP. Samples for attack evaluation were taken prior to initiation of treatment for NMOSD attacks.

[0142] The B-cell levels in peripheral blood were assayed by flow cytometry using fluorescence-activated cell sorting (FACS) performed in a central laboratory within 72 hours of sample collection. Whole blood samples were collected into Streck Cytochex cell preservation tubes and transported to the central laboratory on the day of collection. A minimum of 100,000 lymph events were acquired. B lineage cells were counted using CD20 as the FACS marker (bound inebilizumab interferes with CD19-based FACS). The measured B-cell subset included CD20+ B cells defined as CD45hi[CD3-, CD56-, CD14-], CD33-, CD20. In addition, analysis of plasmablast / plasma cell numbers (CD45hi[CD3-, CD14-, CD56-], CD27+, HLA-DRhi / low, CD38+) was performed on the subset of subjects using FACS. The lower limit of quantification (LLOQ) for all cell populations was set at 0.2 cells / μL. Samples with cell counts below the LLOQ for any given cell population were input at 0.05 cells / μL.

[0143] Plasma cell-specific gene expression was evaluated by quantitative reverse transcription polymerase chain reaction of blood RNA samples. The plasma cell gene signature was based on the expression analysis of four genes (IGHA1, IGJ, IGKV4-1, and TNFRSF17) mainly expressed by plasma cells in the blood. The signature was calculated as the mean expression of the four plasma cell-specific genes minus the mean expression of five control genes (B2M, GAPDH, TFRC, GUSB, and UBC) at each time point. The fold change in the plasma cell gene expression signature at each time point was calculated relative to a pool of 10 healthy donor samples and interpreted as the abundance of plasma cells relative to the expected morbidity under a non-activated immune state.

[0144] Using TaqMan single nucleotide polymorphism profiling, a potential association between the rs396991 polymorphism in the FCGR3A gene and B cell depletion disorder was investigated in a subgroup of subjects who consented to genomic analysis. The rs396991 polymorphism is widespread and encodes a valine / phenylalanine substitution at position 158 of FCGR3A, which is associated with a decreased binding affinity for Ig Fc, thus impairing the ADCC mechanism in which the Fc region of inebilizumab is optimized.

[0145] Results Compared with placebo, inebilizumab resulted in rapid B cell and plasmacyte depletion (within the normal concentration reference range, 74 - 441 cells / μL) and persisted with multiple dosing (Figure 3A). All subjects had a reduction in B cells within 1 week of the first treatment. At the 4th week of RCP, the median (interquartile range [IQR]) B cell count was 2.5 (1.0 - 7.6) cells / μL in the inebilizumab group and 112.3 (96.3 - 176.9) cells / μL in the placebo group. At the 156th week of OLP, the median (IQR) B cell count was 0.33 (<LLoQ - 1.0) cells / μL with inebilizumab.

[0146] Effect of inebilizumab on long - term B cell depletion B cell levels at the end of the first inebilizumab dosing period (28 weeks) predicted stable deep depletion with long - term exposure (Figure 3B). Of the 200 subjects, 70% (n = 139) had B cell depletion to ≤4 cells / μL and persistent B cell depletion with multiple doses of inebilizumab. Subjects with B cell counts ≤4 cells / μL had persistently deeper B cell depletion compared to subjects with B cell counts ≥4 cells / μL (Figure 3B). Persistent B cell depletion was also observed in the >4 cells / μL subgroup with continuous inebilizumab treatment.

[0147] Inebilizumab treatment significantly reduced the circulating levels of B cells and plasma cells relative to placebo during RCP (Figure 3A, Figures 6A-6F). Total Ig levels also decreased, with the greatest reduction seen in the IgE, IgA, and IgM classes. Overall NMOSD disease activity, as measured by annualized attack rate [AAR], EDSS worsening, NMOSD-related hospitalizations, and new or enlarging T2 MRI lesions, decreased significantly with inebilizumab treatment during RCP18 and continued to decrease with additional doses of inebilizumab (Figures 7A-7D). After 2.5 years of inebilizumab treatment, there were progressive reductions in AAR, annualized rate of new / enlarging T2 lesions, EDSS worsening, and NMOSD-related inpatient hospitalizations.

[0148] Association between B cell kinetics and long-term NMOSD outcomes Because long-term inebilizumab treatment resulted in a progressive reduction in NMOSD disease activity, it was hypothesized that the depth of B cell depletion correlated with the treatment effect. CD20+ peripheral blood B cell counts were examined in subjects with and without attacks, via RCP and OLP, during attack-independent, pre-attack, attack, and post-attack epochs (Figures 8A-8C). No significant increase in peripheral blood CD20+ B cell levels was observed at the time of attack in samples from all subjects or from a subset of subjects who received three or more doses of inebilizumab (Figures 8A-8C and 12A-12B). No significant increase in B cell counts was observed during attack assessments, regardless of whether an attack occurred during or after the initial dosing period.

[0149] At 6 months, clinical and imaging metrics of NMOSD disease activity were generally lower in subjects with B cell counts ≤4 cells / μL (n / N = 139 / 200) than in those with >4 cells / μL (n / N = 61 / 200) (Figures 3C-3F). Subsequent doses of inebilizumab further decreased the metrics of NMOSD activity over time in both subsets, but subjects in the ≤4 cells / μL subset achieved a more rapid decrease in the metrics of NMOSD activity. All subjects showed a similar level of reduction in NMOSD activity metrics after 2.5 years of inebilizumab exposure, regardless of B cell counts after the initial dosing interval.

[0150] Therefore, it was investigated whether the degree of B cell depletion within the first dosing interval could predict the subsequent depth of B cell depletion and the reduction of NMOSD disease activity. Negative binomial regression revealed a linear relationship between the B cell count at the end of the first 6-month dosing interval and the disease activity that occurred after the first dosing period with ine bilizumab (Table 9). Multiple additional time points beyond 6 months were also correlated with future disease activity in the regression analysis by the inventors. Indeed, the B cell count from samples taken 3 months after the start of ine bilizumab treatment was correlated with future NMOSD disease activity after the first dosing interval. However, the B cell counts from these early time points were not correlated with NMOSD disease activity within the first dosing period of treatment.

[0151]

Table 9

[0152] A cut-off point of 4 cells / μL separated subjects in whom the risk of NMOSD activity decreased during subsequent ine bilizumab dosing. Sensitivity analysis showed that a cut-off of 4 cells / μL was the highest threshold that maintained favorable odds ratios across multiple NMOSD activity metrics (Figures 13A-13D). In total, 139 / 200 subjects (70%) had a B cell count of ≤4 cells / μL at the end of the first dosing interval and maintained long-lasting B cell depletion with continued treatment (Figures 9A-9B). When compared to subjects with a B cell count >4 cells / μL, subjects with ≤4 cells / μL had persistently low B cell counts (Figure 9B), a low AAR (0.034 vs. 0.086; p = 0.0494), fewer new / enlarged T2 lesions (0.49 vs. 1.36; p < 0.0001), fewer EDSS deteriorations (0.076 vs. 0.14; p = 0.09), and a tendency for fewer hospitalizations (0.08 vs. 0.18; p = 0.11; Table 10). Similar disease activity outcomes were observed when the AQP4 serum-positive subject population was analyzed separately (Table 10, Figures 14A-14D).

[0153]

Table 10

[0154] Even with continued inebilizumab administration, durable B cell depletion was still observed in the >4 cells / μL subset (Figure 9B), and by week 117, the median CD20+ B cell count was similar between subjects in both the >4 cells / μL and ≤4 cells / μL groups.

[0155] In particular, no increase in overall B cell count was observed at the time of onset of the attacks that occurred during this time frame (Figures 8A–8C and 12A–12B).

[0156] Effect of long-term inebilizumab on NMOSD disease activity Since NMOSD disease activity was reduced long-term by long-term inebilizumab treatment, the short-term and long-term relationships between clinical and imaging metrics and the 6-month B cell count in the subset of >4 cells / μL or ≤4 cells / μL were evaluated. During the RCP, NMOSD disease activity (measured by AAR, new / enlarged T2 hyperintense MRI lesions, worsening of the EDSS score, and inpatient hospitalizations) decreased in both subsets after the first dosing period of inebilizumab treatment compared to placebo. Subsequent doses of inebilizumab further decreased disease activity over time in both subsets. NMOSD activity decreased more rapidly between subjects with ≤4 cells / μL than in the >4 cells / μL subset, particularly in new T2 hyperintense lesions. However, after 2.5 years of inebilizumab exposure, all subjects showed similar levels of NMOSD activity (Figures 3C–3E and 10).

[0157] After 2.5 years, treatment with inebilizumab was associated with a decrease in NMOSD disease activity compared to placebo during the RCP (Figure 3G). The AAR was reduced by 97%. The annualized rate of new or enlarged T2 lesions was reduced by 73%.

[0158] In summary, treatment with ine bilizumab resulted in rapid and long-lasting depletion of B cells in subjects with NMOSD compared to placebo. The greater the B cell depletion, the more it was associated with improved outcomes with long-term treatment with ine bilizumab. These findings suggest that at least profound and persistent B cell depletion is beneficial in preventing relapses in subjects with NMOSD and / or that regular monitoring of B cell counts may provide a valuable approach to ensuring the most effective use of ine bilizumab in the management of NMOSD.

[0159] Evaluation of Subject Subgroups Three separate, but not mutually exclusive, mechanisms may affect B cell counts at the end of the first ine bilizumab dosing interval.

[0160] Pharmacokinetic loss of ine bilizumab may result in B cell replication First, pharmacokinetic (PK) loss of ine bilizumab after administration of two loading doses may have resulted in B cell replication in some subjects by the end of the first dosing interval. The PK profile of ine bilizumab was compared in subgroups with B cell counts >4 cells / μL and ≤4 cells / μL at the end of the first dosing interval. Subjects with less B cell depletion had lower ine bilizumab concentrations compared to subjects with stable B cell depletion: ine bilizumab was undetectable at week 22 in the serum of most subjects with B cell counts >4 cells / μL (LLOQ: 100.5 pg / mL, Figure 15). Further analysis of baseline covariates revealed that age, sex, race, weight, and BMI were not significantly associated with higher B cell counts (defined as >4 cells / μL at W28). Previous use of rituximab was also not associated with higher B cell counts. These subjects showed a significantly increased CD19+ B cell count, plasma cell signature, and Ig concentration on day 1 of RCP (false discovery rate <0.10), (Figures 16A–16C).

[0161] Shallow depletion may be associated with the rs396991 polymorphism of FCGR3A Second, the increase in B cell count at the end of the first dosing interval can be caused, in part, by shallow cell depletion due to the rs396991 polymorphism in FCGR3A. Rs396991 F / F homozygosity was profiled within a subgroup of subjects who consented to genomic analysis. F / F homozygosity was observed in 100.0% (10 / 10) of subjects who did not achieve CD20+ ≤ 4 cells / μL during the first dosing interval, 43% (12 / 28) of subjects whose B cell levels depleted to ≤ 4 cells / μL but repopulated to > 4 cells / μL by the end of the first 6-month treatment period, and 45.2% (38 / 84) in whom persistent B cell depletion was ≤ 4 cells / μL (Figures 17A–17B).

[0162] Anti-drug antibodies can alter B cell depletion Third, anti-drug antibodies (ADA) that bind or neutralize inebilizumab can potentially affect changes in B cell numbers. In total, 33 / 225 subjects (14.7%) treated with inebilizumab were intermittently tested positive for ADA in the study (minimum titer 1:50 dilution; median of maximum titers = 100), and these titers decreased overall with long-term inebilizumab treatment (Figure 18A). Generally, B cell numbers increased slightly with ADA positivity, but no significant overlap was found between ADA-positive subjects and subjects with B cell levels > 4 cells / μL before completion of the first dosing interval (Figure 18B). The median B cell count in samples taken 90 days from the period of ADA positivity was higher than that from samples from subjects who were persistently ADA negative (1.5 cells / μL vs. 0.4 cells / μL; Figure 18C).

[0163] Example 5 - Persistent B cell depletion with inebilizumab is associated with reduced disease activity in aquaporin-4 serum-positive neuromyelitis spectrum disorder As previously described in Example 3 and Figure 1, a study was completed to characterize the relationship between B cell depletion and outcome in subjects who received long-term inebilizumab in the N-MOmentum trial.

[0164] Effect of inebilizumab on B cell depletion Compared with placebo, ine bilizumab provided rapid B cell depletion. All subjects had reduced B cells 1 week after the first treatment; the reduction was maintained over time with multiple doses. After the first dosing interval (6 months), 126 / 186 (68%) of the subjects had B cell counts ≤4 cells / μL. The remaining subjects (n / N = 60 / 186 [32%]) had >4 cells / μL but were well below the normal lower limit. Long-term (>2.5 years) ine bilizumab treatment provided sustained B cell depletion in all subjects regardless of the depth of short-term B cell depletion.

[0165] Short-term effects of B cell depletion on metrics of disease activity Immediate clinical utility compared to placebo was seen in both groups, but subjects with ≤4 cells / μL had greater improvement in metrics of disease activity than subjects with >4 cells / μL during the first dosing interval. After the first dosing interval, 111 / 124 (90%) of the subjects with ≤4 cells / μL and 50 / 59 (85%) of the subjects with >4 cells / μL were seizure-free. Subsequent doses of ine bilizumab further decreased the metrics of NMOSD activity over time in both subgroups, but subjects with ≤4 cells / μL achieved a more rapid decrease in the metrics of NMOSD activity.

[0166]

Table 11

[0167] Effect of long-term (>2.5 years) ine bilizumab-related B cell depletion on metrics of disease activity When compared to placebo during RCP, long-term treatment with ine bilizumab was associated with a decrease in AAR in both subgroups (Figure 4A), a decrease in EDSS worsening in both subgroups (Figure 4B), and the depth of B cell depletion after the first dosing interval was not correlated with the risk of infection (Figure 4C).

[0168] In summary, ine bilizumab provided rapid and durable B cell depletion in subjects with NMOSD. After the initial dosing interval, there were differences in B cell depletion and subsequent reduction in disease activity among subjects. Monitoring of B cell counts may be useful for optimizing ine bilizumab treatment. Long-term ine bilizumab treatment provided profound B cell depletion and reduced disease activity in all subjects, regardless of the depth of B cell depletion during their initial dosing period. The depth of B cell depletion after long-term ine bilizumab treatment or after the initial dosing interval did not correlate with the risk of infection.

[0169] Example 6 - Subjects with neuromyelitis optica spectrum disorder exhibit features of systemic autoimmunity: broad serum autoreactivity against nuclear antigens and increased interferon-inducible gene expression A study was completed to profile autoreactivity and type 1 interferon-inducible gene signatures (IFNGS) in blood and characterize their relationship to disease activity in NMOSD.

[0170] Methods Serum samples were obtained from 220 / 230 subjects with NMOSD randomized in NMOmentum and 25 healthy controls (HC). Baseline samples were profiled for serum immunoglobulin (Ig) G, IgM, IgA, and IgE autoreactivity by hybridizing the samples to a microarray of 122 autoantigens (excluding AQP4) involved in human autoimmune diseases (e.g., systemic lupus erythematosus, rheumatoid arthritis, Sjögren's syndrome). Autoreactivity was confirmed by signals >5 standard deviations above the HC mean. Baseline IFNGS was analyzed in blood RNA samples from 219 subjects and 10 HC. Subjects with >4-fold change in signals above the HC mean were IFNGS positive. The possible associations of baseline autoreactivity and IFNGS positivity with pre-study NMOSD disease activity (annualized attack rate or mean annual disability worsening on the expanded disability status scale between diagnosis and baseline in subjects with >4 years of disease history) were studied by negative binomial regression.

[0171] Results At baseline, HC did not show autoreactivity against any of the antigens studied, but 90% (n = 197) of the subjects with NMOSD had autoreactivity against self-antigens, mainly in the IgG subclass (83% [n = 183]), but also in the IgA (41% [n = 90]), IgM (25% [n = 56]), and IgE (6% [n = 14]) subclasses. In total, 27% (n = 59) of the subjects were IFNGS positive at baseline, and 4% (n = 8) had a previous diagnosis of systemic autoimmune disease. Serum autoreactivity against nuclear antigen (NA) was higher than that against other antigens. A proportionally higher number of IFNGS-positive subjects were reactive against NA compared to IFNGS-negative subjects (68% [40 / 59] vs. 46% [71 / 153]; area under the ROC curve, 0.63; p = 0.002). Neither serum autoreactivity nor IFNGS positivity at baseline was associated with an increased risk of pre-study NMOSD disease activity.

[0172] Subjects with NMOSD show higher serum autoreactivity against autoantibodies known to be associated with other systemic autoimmune diseases than healthy controls. However, this autoreactivity does not appear to be associated with an increase in NMOSD disease activity.

[0173] Example 7 - Influence of Low-Affinity Immunoglobulin Gamma Fc Region Receptor III-A Gene Polymorphism in Neuromyelitis Optica Spectrum Disorder and Its Significance for Treatment Outcome A study was conducted to characterize the relationship between the rs396991 polymorphism, NMOSD disease activity, and treatment response.

[0174] Methods The study had a randomized control period (RCP) of up to 28 weeks (inebilizumab 300 mg or placebo on days 1 and 15), followed by an open-label period (OLP). One hundred and forty-two subjects (104 randomized to inebilizumab and 38 randomized to placebo) consented to genotyping of the polymorphic genotype by TaqMan qPCR assay.

[0175] Results The change in the annualized attack rate (AAR) and Expanded Disability Status Scale (EDSS) score from NMOSD onset to enrollment in the past were nominally higher in the rs396991 V allele group (V; V / V or V / F genotype; n = 74) than in the F / F allele group (F / F; n = 68): mean (±SEM) AAR: V, 1.0 (0.8 1.3); F / F, 0.7 (0.5 0.9); change in EDSS score: V, 0.6 (0.5 0.7); F / F, 0.4 (0.3 0.5). In the placebo group, the attack rate, new / enlarged T2 MRI lesions, and NMOSD-related hospitalization rate were higher in the V allele group (n = 22) than in the F / F allele group (n = 16), but not statistically significant: mean (±SEM) AAR: V, 1.3 (0.9 1.7); F / F, 0.8 (0.5 1.2); new T2 lesions: V, 4.5 (2.6 6.3); F / F, 2.1 (1.0 3.1); hospitalization: V, 0.5 (0.2 0.8); F / F, 0.2 (0.0 0.4). At the end of RCP, V allele carriers randomized to ine bilizumab (n = 52) had higher median (IQR) B cells, plasma cells, and Ig depletion than F / F homozygotes (n = 52): B cells; V, 0.6 (0.1 3.2) vs F / F, 1.3 (0.5 4.2) cells / μl; plasma cells: V, 0.04 (0.02 0.2) vs F / F, 0.05 (0.03 0.2) fold change from control mean; Ig: V, 1050 (867 1284) vs F / F, 1238 (1076 1455) Ig / μL. V allele carriers also had a lower attack rate and new / enlarged T2 lesions than F / F homozygotes, but the differences were not statistically significant: mean (±SEM): AAR: V, 0.1 (0.1 0.2); F / F, 0.3 (0.2 0.4); new T2 lesions: V, 1.4 (0.9 1.8); F / F, 1.7 (1.2 2.2). There were few differences between subgroups in clinical metrics or B cell depletion by dose 4 during OLP.

[0176] In summary, V allele carriers may have increased NMOSD disease activity but may have a higher initial pharmacodynamic response to ine bilizumab compared to those with the wild F / F genotype.

[0177] Example 8 - Influence of Low - Affinity IgG Fc Region Receptor III - A Gene Polymorphism on the Treatment Outcome of Neuromyelitis Optica Spectrum Disorder A study was conducted to characterize the relationship between the rs396991 polymorphism, NMOSD disease activity, and treatment response.

[0178] Methods The study was a double - blind, randomized, placebo - controlled phase 2 / 3 trial of the efficacy and safety of inebilizumab in 230 adults with NMOSD. The study included a randomized control period (RCP) of up to 28 weeks in which subjects were assigned (3:1) to intravenous (i.v.) inebilizumab 300 mg or placebo, followed by an optional open - label period (OLP) of at least 2 years (all subjects received i.v. inebilizumab 300 mg every 26 weeks). The primary endpoint was the risk of NMOSD attacks, which was evaluated as the time to the onset of NMOSD attacks. Overall, 142 subjects (inebilizumab, n = 104; placebo, n = 38) consented to genotype determination of the polymorphic gene by TaqMan quantitative polymerase chain reaction assay.

[0179] In a post - hoc analysis, data from subjects with different FCGR3A genotypes were compared for disease severity and response to inebilizumab. The outcomes analyzed included attacks, disability (evaluated by the Expanded Disability Status Scale [EDSS] score), NMOSD - related hospitalizations, and magnetic resonance imaging (MRI) lesions.

[0180] Results Disease Severity Before the Study in Subjects with the V Allele The historical annualized attack rate (AAR) from NMOSD onset to enrollment was nominally higher in V allele carriers (Figure 5B) (V / F or V / V genotype; n = 25) than in F / F genotype carriers (F / F; n = 25). Median (interquartile range [IQR]): V allele, 0.9 (0.5–1.4); F / F genotype, 0.4 (0.3–0.8). The change in EDSS score was nominally higher between V allele carriers than in F / F genotype carriers (Figure 5B). Median (IQR): V allele, 0.5 (0.4–0.9); F / F genotype, 0.4 (0.3–0.7). The EDSS score was assumed to be zero at NMOSD disease onset for all subjects for this analysis. No significant differences were observed across the entire cohort. Disease activity among V allele carriers in the study. In the RCP, subjects with V alleles who received placebo had higher AAR and rates of new / enlarged T2 MRI lesions and NMOSD-related hospitalizations than subjects who were homozygous for F alleles (however, these differences did not achieve statistical significance). The mean (±standard error of the mean [SEM]) values of these parameters in V allele versus F / F genotype carriers were as follows: attacks, 1.3 (0.9–1.7) vs. 0.8 (0.5–1.2) (Figure 5C); new / enlarged T2 lesions, 4.5 (2.6–6.3) vs. 2.1 (1.0–3.1) (Figure 5C); NMOSD-related hospitalizations, 0.5 (0.2–0.8) vs. 0.2 (0.0–0.4) (Figure 5C).

[0181] Effect of Inebilizumab in V Allele Carriers The annualized rates of AAR and new / enlarged T2 lesions were lower in the inebilizumab-treated V allele group than in the F allele group. The mean (±SEM) values of these parameters in the V allele vs. F / F genotype groups were as follows: AAR, 0.1 (0.1 - 0.2) vs. 0.3 (0.2 - 0.4) (Figure 5D); annualized rate of new / enlarged T2 lesions, 1.4 (0.9 - 1.8) vs. 1.7 (1.2 - 2.2) (Figure 5D). However, these differences did not reach statistical significance. Depletion of B cells, plasma cells, and IgG was greater in the inebilizumab-treated V allele group than in the F / F allele group. At the end of RCP, the median (IQR) values of these parameters in the V allele group (n = 52) vs. the F / F genotype group (n = 52) were as follows: B cell depletion, 0.6 (0.1 - 3.2) vs. 1.3 (0.5 - 4.2) cells / μL (Figure 5E); plasma cell depletion, fold change from control mean of 0.04 (0.02 - 0.2) vs. 0.05 (0.03 - 0.2) (Figure 5E); IgG level, 1050 (867 - 1284) vs. 1238 (1076 - 1455) mg / dL (Figure 5E).

[0182] Long-term inebilizumab treatment In repeated inebilizumab dosing during OLP (1.5 - 2.5 years), there were few differences in clinical metrics of NMOSD activity or B cell depletion between the V allele and F / F genotype subgroups (Figure 5F).

[0183] In summary, the FCGR3A F176V polymorphism (V / F or V / V genotype) was not associated with a significant difference in NMOSD disease activity compared to the F / F genotype. Subjects with the V allele may have a greater pharmacodynamic response to ineclizumab than subjects with the F / F genotype. In subjects treated with ineclizumab, V-allele subjects tended to have greater B cell and plasma cell depletion, as well as a lower attack rate and fewer new / enlarged T2 lesions. Furthermore, V-allele carriers may have increased NMOSD disease activity compared to F / F allele homozygotes. In this study of ineclizumab-treated subjects, no significant differences in outcomes were seen between subjects with F and V allele genotypes.

[0184] Ineclizumab reduces the risk of relapse independent of the low-affinity IgG Fc region receptor III-A gene polymorphism in neuromyelitis optica spectrum disorder V-allele carriers (V-allele genotype [V / V or V / F], n = 74) and F / F allele homozygotes (n = 68) did not show significant differences in baseline demographics or disease duration. Depletion of CD20+ B cells was similar in V-allele vs F / F subjects (0.6 (0.1–3.2) vs 1.3 (0.5–4.2) cells / μl at the end of RCP) and persisted in both groups throughout the study period. No differences in the risk of relapse (OR 0.94 (0.39, 2.24)) or worsening of the expanded disability status scale (OR: 1.55 (0.54, 4.70)) were seen in V vs F / F subjects. The annualized attack rate (SEM) in ineclizumab-treated patients was 0.00 (0.00) for V / V, 0.10 (0.04) for V / F, and 0.06 (0.03) for F / F. Ineclizumab-treated subjects in the N-MOmentum trial did not demonstrate a difference in clinical outcomes between subjects with F and V allele genotypes.

[0185] Example 9 - Outcome in a study of myelin oligodendrocyte glycoprotein immunoglobulin g in aquaporin 4-seronegative patients with neuromyelitis optica spectrum disorder A study was conducted to report the outcomes among subjects with serotype AQP4-IgG- / MOG-IgG+ who received long-term inebilizumab in a double-blind placebo-controlled phase 2 / 3 study.

[0186] Methods The study included a randomized control period (RCP) of up to 28 weeks in which subjects were assigned (3:1) to intravenous inebilizumab (300 mg) or placebo, followed by an optional open-label period (OLP) of at least 2 years in which all subjects received inebilizumab (Figure 19A). Data on any exposure to inebilizumab included time during the RCP and OLP.

[0187] The expert eligibility committee reviewed all screened AQP4-IgG- subjects; subjects meeting the 2006 NMOSD diagnostic criteria (Wingerchuk DM et al. Neurology 2006;66:1485-9) were randomized.

[0188] Endpoints included (1) time to NMOSD onset as determined by the adjudication committee (AC; annualized attack rate [AAR] was also determined); (2) worsening of the Expanded Disability Status Scale (EDSS) score; (3) cumulative total number of active lesions or new / enlarged T2 lesions detected by magnetic resonance imaging; (4) number of NMOSD-related hospitalizations; (5) number of B cells in peripheral blood; (6) serum immunoglobulin levels; (7) adverse events (AE), and (8) adverse events of special interest (AESI).

[0189] Results Efficacy in AQP4-IgG- / MOG-IgG+ Subjects Overall, 17 / 231 subjects (7.4%) with NMOSD were AQP4-IgG-; 7 of these (3.0%) were MOG-IgG+ (inebilizumab, n = 6; placebo, n = 1). Among subjects randomized to inebilizumab, there was (occurring in separate subjects) (Table 12, Figure 19B): one AC-determined attack 78 days after the first dose; one case of disability worsening; and one hospitalization.

[0190]

Table 12

[0191] In the 2 years before registration, the mean (95% confidence interval) AAR for AQP4-IgG− / MOG-IgG+ subjects was 3.12 (1.52–4.72); during the study, it was 0.05 (0.01–0.35). The exposure to ineclizumab in RCP and OLP was 20.05 person-years (n = 7).

[0192] CD19 B cells and immunoglobulin levels in AQP4-IgG− / MOG-IgG+ subjects In most AQP4-IgG− / MOG-IgG+ subjects, B cell depletion by ineclizumab was rapid and sustained. See Figure 19C. The levels of IgG and IgM fell below the lower limit of normal from 1 year after the first dose of ineclizumab in at least half of the subjects with serotype AQP4-IgG− / MOG-IgG+. See Table 13.

[0193]

Table 13

[0194] Considering subjects with any exposure to ineclizumab, the safety profile was similar to that seen in RCP; 1 subject had some mild (grade 1) infusion-related reactions (Table 14). No neutrophil- or lymphocyte-related AEs were reported, and no new safety signals were observed.

[0195]

Table 14

[0196] Conclusion These post hoc analyses from the study suggest that inebilizumab is generally well tolerated and reduces NMOSD attacks in subjects with NMOSD and serotype AQP4-IgG− / MOG-IgG+.

[0197] Example 10 - Association between B cell subsets and aquaporin-4 antibody titers and disease activity in subjects receiving inebilizumab A study was conducted to evaluate B cell subsets and AQP4 IgG titers in the peripheral blood of subjects receiving treatment with inebilizumab.

[0198] Methods Subjects received 300 mg of inebilizumab or placebo (PBO) on days 1 and 15 during a randomized control period (RCP) and every 6 months during an optional open-label period (OLP). The absolute numbers of CD20+ B cells and CD27+ memory B cells were evaluated by flow cytometry (RCP + OLP). Plasma cell (PC) gene expression was evaluated by qRT-PCR (RCP only). AQP4 IgG titers were determined by a cell-based assay (RCP only). All measurements were performed on peripheral blood.

[0199] Results In the placebo group, a significant increase in CD20+ B cells and CD27+ memory B cells was observed at the time of seizure compared to the previous visit (p<0.05). The increase in the PC subset had already been observed at the previous visit compared to the baseline (p<0.01). During the seizure, an increase of >2-fold from the baseline was seen in 4 / 20 (20%) of CD20+ B cells, 3 / 19 (16%) of memory B cells, and 11 / 20 (55%) of PCs. Inebilizumab significantly decreased all B cell subsets. No significant increase in any B cell subset at the time of seizure was observed in the inebilizumab group compared to the previous visit. There was no significant difference in the change in AQP4 IgG titer from the baseline until the seizure between the treatment groups (p=0.15). At the end of RCP, 9 / 50 (18%) of the PBO subjects vs 59 / 159 (37%) of the inebilizumab subjects (p=0.014) had a ≥2-fold decrease in AQP4-IgG (0% vs 11% ≥8-fold decrease, p=0.008).

[0200] An increase in the level of B cell subsets at the time of seizure was observed in the placebo group but not in the inebilizumab group, especially in the plasma cell subset. Inebilizumab treatment was associated with a reduction in AQP4-IgG in the subsets of interest.

[0201] Example 11 - Safety and Efficacy of Inebilizumab in Subjects with AQP4+ NMOSD with a History of Immunosuppressive Treatment A study was completed to evaluate the long-term outcomes of inebilizumab treatment in subjects with AQP4+ NMOSD with a history of immunosuppressive therapy compared to subjects without a history of immunosuppressive therapy.

[0202] Methods The subject had previously completed a 28-week randomized Phase 2 / 3 trial of ine bilizumab versus placebo with optional open-label extension (OLE) (>2 years). Immunosuppressive therapy for the prevention or treatment of NMOSD recurrence was permitted prior to dosing on Day 1. In this post hoc analysis, AQP4+ subjects who received ine bilizumab (via OLE) were grouped by acute NMOSD attack (naïve), or no history of immunosuppressive therapy beyond previous azathioprine (AZA) and / or mycophenolate mofetil (MMF) therapy. Outcomes compared between these two groups included annualized relapse rate and hospitalization rate, and safety assessment.

[0203] Results Among the subjects who received ine bilizumab during the study, 94 had previously received AZA / MMF and 103 were immunosuppressive-naïve. The total patient-years of ine bilizumab treatment in the previous AZA / MMF group was 300.35, and 335.7 in immunosuppressive-naïve subjects. The annualized relapse rate (95%, confidence interval [CI]) in subjects with previous AZA / MMF was 0.11 (0.07, 0.17), compared with 0.08 (0.05, 0.14) in naïve subjects. The annualized NMOSD-related inpatient hospitalization rate (annualized rate [95% CI]) for previous AZA / MMF was 0.15 (0.08, 0.27), and 0.12 (0.06, 0.22) for naïve subjects. The percentage of subjects with treatment-emergent adverse events (TEAEs) occurring under treatment with ≥1 study drug was 30.9% (29 / 94) in pre-AZA / MMF and 47.6% (49 / 103) in naïve subjects; 4.3% (4) in pre-AZA / MMF and 5.8% (6) in immunosuppressive-naïve subjects in whom ≥1 study drug-related serious adverse events were reported. Most adverse events were infection-related for both groups (72.3% (68 / 94) for previous AZA / MMF and 77.7% (80 / 94) for naïve subjects).

[0204] In conclusion, a post hoc analysis evaluating the long-term outcomes of ine bilizumab in AQP4+ NMOSD subjects previously treated with AZA / MMF therapy demonstrated an efficacy and safety profile similar to that of subjects who had not received prior immunosuppressive therapy.

Claims

1. 1. A composition for use in a method for treating or preventing neuromyelitis optica spectrum disorder (NMOSD), comprising an anti-CD19 antibody, said method comprising administering said anti-CD19 antibody to a subject in need thereof, wherein said subject has a B-cell level of less than about 4 cells / μL of blood, and said anti-CD19 antibody comprises a variable heavy chain comprising SEQ ID NO: 1 and a variable light chain comprising SEQ ID NO:

5.

2. 2. The composition for use of claim 1, wherein the subject in need thereof has an Fc gamma receptor IIIa (FCGR3A) gene comprising the rs396991 polymorphism.

3. 3. The composition for use of claim 2, wherein the subject in need thereof comprises a V allele at amino acid position 158 of the FCGR3A gene as determined by a V / F or V / V genotype.

4. A composition for use according to any one of claims 1 to 3, wherein the antibody is inebilizumab.

5. A composition for use in a method for treating an autoimmune disease, comprising an anti-CD19 antibody, said method comprising determining the presence of an rs396991 polymorphism in the FCGR3A gene of a subject in need thereof, and if said determination is positive for said rs396991 polymorphism, administering said anti-CD19 antibody to said subject in need thereof, wherein said anti-CD19 antibody comprises a variable heavy chain comprising SEQ ID NO: 1 and a variable light chain comprising SEQ ID NO:

5.

6. 6. The composition for use according to claim 5, wherein the autoimmune disease is NMOSD.

7. The composition for use according to claim 5, wherein the autoimmune disease is MG.

8. The composition for use according to claim 5, wherein the autoimmune disease is IgG4RD.

9. 6. The composition for use according to claim 5, wherein the subject in need thereof has at least two autoimmune diseases.

10. A composition for use according to claim 1 or claim 5, wherein the antibody is inebilizumab.

11. 6. The composition for use of claim 1 or claim 5, wherein said administering is effective to reduce a criterion selected from the group consisting of annualized attack rate (AAR), incidence of disability as assessed by Expanded Disability Status Scale (EDSS) score, incidence of hospitalization, number of lesions detected by magnetic resonance imaging, and combinations thereof.

12. 6. The composition for use according to claim 1 or claim 5, wherein the anti-CD19 antibody is administered at a dose of about 300 mg every six months.

13. 1. A composition for use in a method for treating or preventing an autoimmune disease, comprising an anti-CD19 antibody, said method comprising administering 300 mg of said anti-CD19 antibody to a subject in need thereof, said subject having a B-cell level of less than about 4 cells / μL of blood, said administering being repeated every 6 months, and said anti-CD19 antibody comprising a variable heavy chain comprising SEQ ID NO: 1 and a variable light chain comprising SEQ ID NO:

5.

14. 14. The composition for use according to claim 13, wherein the autoimmune disease is NMOSD.

15. The composition for use according to claim 13, wherein the autoimmune disease is MG.

16. The composition for use according to claim 13, wherein the autoimmune disease is IgG4RD.

17. A composition for use according to any one of claims 13 to 16, wherein the antibody is inebilizumab.

18. 1. A composition for use in a method for treating or preventing neuromyelitis optica spectrum disorder (NMOSD), comprising an anti-CD19 antibody, said method comprising administering 300 mg of said anti-CD19 antibody to a subject in need thereof, said subject having a B-cell level of less than about 4 cells / μL of blood, wherein said administering is repeated every 6 months, and wherein said anti-CD19 antibody comprises a variable heavy chain comprising SEQ ID NO: 1 and a variable light chain comprising SEQ ID NO:

5.

19. 1. A composition for use in a method for treating or preventing an autoimmune disease, comprising an anti-CD19 antibody, said method comprising administering 300 mg of said anti-CD19 antibody to a subject in need thereof having a B-cell level of less than about 4 cells / μL of blood, said administering being repeated every 6 months, said autoimmune disease being selected from the group consisting of neuromyelitis optica spectrum disorder (NMOSD), myasthenia gravis (MG), and IgG4RD, and said anti-CD19 antibody comprising a variable heavy chain comprising SEQ ID NO: 1 and a variable light chain comprising SEQ ID NO:

5.

20. 1. A composition for use in a method for treating neuromyelitis optica spectrum disorder, comprising an anti-CD19 antibody, said method comprising administering said anti-CD19 antibody to a subject in need thereof, wherein said subject does not have anti-aquaporin 4 immunoglobulin G antibodies (AQP4-IgG-) but has immunoglobulin G antibodies against myelin oligodendrocyte glycoprotein (MOG-IgG+), and said anti-CD19 antibody comprises a variable heavy chain comprising SEQ ID NO: 1 and a variable light chain comprising SEQ ID NO:

5.

21. 21. The composition for use according to claim 20, wherein about 300 mg of the anti-CD19 antibody is administered.

22. 21. The composition for use according to any one of claims 1, 5, 13, 18, 19 and 20, wherein the subject in need thereof has increased serum autoreactivity to autoantibodies not associated with NMOSD compared to healthy control subjects.

23. The composition for use according to any one of claims 1, 5, 13, 18, 19 and 20, wherein the antibody is inebilizumab.

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