Use of anti-CD19 antibodies to treat autoimmune diseases

Abstract

Disclosed herein are methods for treating autoimmune diseases using anti-CD19 antibodies. In particular, the use of VIB551, a humanized, affinity-optimized, non-fucosylated IgG1 kappa monoclonal antibody, for treating neuromyelitis optica spectrum disorder is disclosed.

Description

[Technical Field]

[0001] cross reference This application claims the interests of U.S. Provisional Patent Application No. 63 / 107,182, filed on 29 October 2020, No. 63 / 143,541, filed on 29 January 2021, and No. 63 / 178,286, filed on 22 April 2021, the contents of which are incorporated herein by reference.

[0002] Sequence listing reference This application incorporates, by reference, the sequence listing submitted along with this application via EFS-Web as a text file named "HOPA_030_03WO_SeqList_ST25" with a size of 9.50 kilobytes, created on October 27, 2021. [Background technology]

[0003] background Neuromyelitis optica spectrum disorder (NMOSD) is a severe autoimmune inflammatory central nervous system disorder with a prevalence of 0.5–4.4 / 100,000. (Cree BA, Bennett JL, Sheehan M, et al. Placebo-controlled study in neuromyelitis optica-ethical and design considerations. Mult Scler 2016;22:862-72 (Non-patent Literature 1)). NMOSD presents with optic neuritis, transverse myelitis, and, less commonly, seizures of the diencephalon, brainstem, and cerebral hemispheres. (Cree BA, Bennett JL, Sheehan M, et al. Placebo-controlled study in neuromyelitis optica-ethical and design considerations. Mult Scler 2016;22:862-72 (Non-patent Literature 1)). Patients typically do not fully recover from seizures and are at risk of death from respiratory failure. (Wingerchuk DM, Lennon VA, Lucchinetti CF, Pittock SJ, Weinshenker BG. The spectrum of neuromyelitis optica. Lancet Neurol 2007;6:805-15 (Non-patent document 2).)

[0004] Although once considered a variant of multiple sclerosis, NMOSD is now recognized as a distinct disease characterized by astrocytopathic injury, demyelination, and significant neuronal loss, with most injuries occurring during acute attacks (Wingerchuk DM, Lennon VA, Lucchinetti CF, Pittock SJ, Weinshenker BG. The spectrum of neuromyelitis optica. Lancet Neurol 2007;6:805-15 (Non-patent Literature 2); Fujihara K, Misu T, Nakashima I, et al. Neuromyelitis optica should be classified as an astrocytopathic disease rather than a demyelinating disease. Clin Exp Neuroimmunol 2012;3:58-73 (Non-patent Literature 3)).Highly specific serum autoantibodies against astrocyte water channel aquaporin-4 (AQP4)-immunoglobulin G (IgG) have been detected in 60-80% of patients, suggesting a high probability of etiology (Weinshenker BG, Wingerchuk DM, Vukusic S, et al. Neuromyelitis optica IgG predicts relapse after longitudinally extensive transverse myelitis. Ann Neurol 2006;59:566-9 (Non-patent Literature 4); Bennett JL, Lam C, Kalluri SR, et al. Intrathecal pathogenic anti-aquaporin-4 antibodies in early neuromyelitis optica. Ann Neurol 2009;66:617-29 (Non-patent Literature 5); Jarius S, Frederikson J, Waters P, et al. Frequency and prognostic impact of antibodies to aquaporin-4 in patients with optic neuritis. J Neurol Sci 2010;298:158-62 (Non-patent Literature 6); Saadoun S, Waters P, Bell BA, Vincent A, Verkman AS, Papadopoulos MC. Intra-cerebral injection of neuromyelitis optica immunoglobulin G and human complement produces neuromyelitis optica lesions in mice. Brain 2010;133:349-61 (Non-patent Literature 7). In the presence of complement or inflammatory T cell responses, AQP4-IgG induces disease-specific central nervous system injury.(Bennett JL, Lam C, Kalluri SR, et al. Intrathecal pathogenic anti-aquaporin-4 antibodies in early neuromyelitis optica. Ann Neurol 2009;66:617-29 (Non-patent Literature 5).) Multiple pieces of evidence suggest that NMOSD is primarily a B-cell disorder resulting from the production of pathological autoantibodies, secretion of inflammatory cytokines, and B-cell antigen presentation. (Bennett JL, O'Connor KC, Bar-Or A, et al. B lymphocytes in neuromyelitis optica. Neurol Neuroimmunol Neuroinflamm 2015;2:e104 (Non-patent Literature 8).)

[0005] VIB551 is a humanized, affinity-optimized non-fucosylated IgG1 kappa monoclonal antibody that binds to the B cell surface antigen CD19. In contrast to anti-CD20 monoclonal antibodies that recognize and deplete a subset of CD20-expressing T lymphocytes (in addition to B lymphocytes) (Palanichamy A, Jahn S, Nickles D, et al. Rituximab efficiently depletes increased CD20-expressing T cells in multiple sclerosis patients. J Immunol 2014;193:580-6 (Non-patent Literature 9)), anti-CD19 antibodies recognize and deplete lymphocytes only from the B cell lineage. [Prior art documents] [Non-patent literature]

[0006] [Non-Patent Document 1] Cree BA, Bennett JL, Sheehan M, et al.Placebo-controlled study in neuromyelitis optica-ethical and design considerations.Mult Scler 2016;22:862-72 [Non-licensed document 2] Wingerchuk DM, Lennon VA, Lucchinetti CF, Pittock SJ, Weinshenker BG. The spectrum of neuromyelitis optica. Lancet Neurol 2007;6:805-15 [Non-licensed document 3] Fujihara K, Misu T, Nakashima I, et al. Neuromyelitis optica should be classified as an astrocytopathic disease rather than a demyelinating disease. Clin Exp Neuroimmunol 2012;3:58-73

Non-licensed Document 4

Non-licensed Document 5

Non-licensed Document 6

Non-licensed Document 7

[0007] overview This specification provides a method for treating neuromyelitis optica spectrum disorder (NMOSD), comprising the step of administering the anti-CD19 antibody VIB551 to a patient requiring treatment for NMOSD, wherein the patient has been previously treated with an anti-CD20 antibody and has experienced an NMOSD attack while being treated with the anti-CD20 antibody. This specification provides a method for treating NMOSD, comprising the step of administering the anti-CD19 antibody VIB551 to a patient requiring treatment for NMOSD, wherein the patient has been previously treated with an anti-CD20 antibody and has experienced an NMOSD attack within six months of the last dose of the anti-CD20 antibody. In some embodiments, VIB551 is administered intravenously at a dose of 300 mg every six months.

[0008] This specification provides a method for treating neuromyelitis optica spectrum disorder (NMOSD), comprising the step of administering an anti-CD19 antibody VIB551 to a patient in need of treatment for NMOSD, wherein the patient has been previously treated with an anti-CD20 antibody, has not been treated with anti-CD20 for 6 or 12 months prior to administration of the anti-CD19 antibody VIB551, and optionally, the patient has experienced an NMOSD attack while being treated with an anti-CD20 antibody. This specification provides a method for treating NMOSD, comprising the step of administering an anti-CD19 antibody VIB551 to a patient in need of treatment for NMOSD, wherein the patient has been previously treated with an anti-CD20 antibody, and the patient has experienced an NMOSD attack within 6 months of the last administration of the anti-CD20 antibody. In some embodiments, VIB551 is administered intravenously at a dose of 300 mg every 6 months.

[0009] This specification provides a method for treating NMOSD, comprising the step of administering the anti-CD19 antibody VIB551 to a patient in need of treatment for NMOSD, wherein the patient is an astrocyte water channel aquaporin-4 (AQP4)-IgG+ patient, VIB551 is administered intravenously at a dose of 300 mg every six months, the patient has been previously treated with an anti-CD20 antibody, and the patient has experienced an NMOSD attack while being treated with the anti-CD20 antibody. This specification provides a method for treating NMOSD, comprising the step of administering the anti-CD19 antibody VIB551 to a patient in need of treatment for NMOSD, wherein the patient is an AQP4-IgG+ patient, VIB551 is administered intravenously at a dose of 300 mg every six months, the patient has been previously treated with an anti-CD20 antibody, and the patient has experienced an NMOSD attack within six months of the last dose of the anti-CD20 antibody.

[0010] In some embodiments, the patient is administered at least one initial dose of VIB551. In some embodiments, VIB551 is administered intravenously at a first initial dose of 300 mg, at a second initial dose of 300 mg two weeks after the first initial dose, and at subsequent doses of 300 mg every six months after the first initial dose. In some embodiments, an oral corticosteroid is co-administered to the patient with the initial dose of VIB551. In certain embodiments, the oral corticosteroid is administered daily for at least two weeks. In one embodiment, the anti-CD20 antibody is rituximab.

[0011] In some embodiments, the treatment is a reduction in the worsening of the Kurtzke Expanded Disability Status Scale (EDSS) in the patient. In some embodiments, the reduction in the worsening of the EDSS in the patient is a worsening of less than 2 points in the EDSS score if the patient has a baseline score of 0, a worsening of less than 1 point if the patient has a baseline score of 1 - 5, or a worsening of less than 0.5 points if the patient has a baseline score of 5.5 or greater.

[0012] In some embodiments, the treatment is a decrease in the number of active magnetic resonance imaging (MRI) lesions. In some embodiments, the active MRI lesions are enlarging T2 MRI lesions. In certain embodiments, the treatment is a decrease in the number of new MRI lesions.

[0013] In some embodiments, treatment is reducing the worsening of the patient's modified Rankin score. In certain embodiments, treatment is reducing the frequency of hospitalizations in patients associated with NMOSD. In some embodiments, treatment is reducing the patient's risk of NMOSD-related seizures. In one embodiment, an NMOSD-related seizure is characterized by the appearance of new symptoms associated with NMOSD or the worsening of existing symptoms. In certain embodiments, the symptoms are ocular symptoms. In some embodiments, ocular symptoms are eye pain, blurred vision, visual impairment, or the appearance of optic nerve lesions detected by MRI. In some embodiments, the symptoms are spinal cord symptoms. In one embodiment, spinal cord symptoms are deep pain or radicular pain, limb paresthesia, weakness, sphincter dysfunction, Lhermitt's sign, or spinal cord lesions detectable by MRI. In some embodiments, the symptoms are brain or brainstem symptoms. In some embodiments, brain or brainstem symptoms include nausea, diplopia, oculomotor nerve palsy, dizziness, refractory vomiting, refractory hiccups, dysarthria, dysphagia, weakness, encephalopathy, hypothalamic dysfunction, or brain or brainstem lesions detectable by MRI. In some embodiments, the reduction in the risk of NMOSD-related seizures is 60–85%. In one embodiment, treatment is a reduction in optic neuritis. In certain embodiments, treatment is a reduction in the severity of NMOSD-related seizures. In some embodiments, a reduction in the severity of NMOSD-related seizures is a reduction in NMOSD-related seizures graded as grand mal seizures. In some embodiments, a reduction in the severity of NMOSD-related seizures is a reduction in NMOSD seizures requiring hospitalization. In certain embodiments, treatment is a reduction in NMOSD-related pain in the patient. In some embodiments, a reduction in NMOSD-related pain is determined by measuring the patient's leg pain.

[0014] In some embodiments, an initial dose of 300 mg of VIB551 is administered to the subject two weeks prior to the first dose of 300 mg of VIB551 every six months. In certain embodiments, an oral corticosteroid is administered to the patient concurrently with the initial dose of 300 mg of VIB551. In some embodiments, the patient is AQP4-IgG seropositive.

[0015] This specification provides a method for reducing active MRI lesions in a patient diagnosed with NMOSD, comprising the step of administering the anti-CD19 antibody VIB551 to a patient requiring treatment for NMOSD, wherein the patient has been previously treated with an anti-CD20 antibody and has experienced an NMOSD attack while being treated with the anti-CD20 antibody. This specification provides a method for reducing active MRI lesions in a patient diagnosed with NMOSD, comprising the step of administering the anti-CD19 antibody VIB551 to a patient requiring treatment for NMOSD, wherein the patient has been previously treated with an anti-CD20 antibody and has experienced an NMOSD attack within six months of the last dose of the anti-CD20 antibody. In some embodiments, VIB551 is administered intravenously at a dose of 300 mg every six months.

[0016] This specification provides a method for reducing active MRI lesions in a patient diagnosed with NMOSD, comprising the step of administering the anti-CD19 antibody VIB551 to a patient requiring treatment for NMOSD, wherein the patient has been previously treated with an anti-CD20 antibody, the patient has experienced an NMOSD attack while being treated with the anti-CD20 antibody, and VIB551 is administered intravenously at a dose of 300 mg every six months. This specification provides a method for reducing active MRI lesions in a patient diagnosed with NMOSD, comprising the step of administering the anti-CD19 antibody VIB551 to a patient requiring treatment for NMOSD, wherein the patient has been previously treated with an anti-CD20 antibody, the patient has experienced an NMOSD attack within six months of the last dose of the anti-CD20 antibody, and VIB551 is administered intravenously at a dose of 300 mg every six months.

[0017] This specification provides a method for reducing the AQP4-IgG titer of an AQP4-IgG+ patient requiring treatment for NMOSD, comprising the step of administering the anti-CD19 antibody VIB551 to the patient requiring treatment for NMOSD, wherein the patient has been previously treated with an anti-CD20 antibody and has experienced an NMOSD seizure while being treated with the anti-CD20 antibody. This specification provides a method for reducing the AQP4-IgG titer of an AQP4-IgG+ patient requiring treatment for NMOSD, comprising the step of administering the anti-CD19 antibody VIB551 to the patient requiring treatment for NMOSD, wherein the patient has been previously treated with an anti-CD20 antibody and has experienced an NMOSD seizure within 6 months of the last administration of the anti-CD20 antibody. In some embodiments, VIB551 is administered intravenously at a dose of 300 mg every 6 months.

[0018] This specification provides a method for reducing the AQP4-IgG titer of an AQP4-IgG+ patient requiring treatment for NMOSD, comprising the step of administering the anti-CD19 antibody VIB551 to the patient requiring treatment for NMOSD, wherein the patient has been previously treated with an anti-CD20 antibody, the patient has experienced an NMOSD attack while being treated with the anti-CD20 antibody, and VIB551 is administered intravenously at a dose of 300 mg every six months. This specification provides a method for reducing the AQP4-IgG titer of an AQP4-IgG+ patient requiring treatment for NMOSD, comprising the step of administering the anti-CD19 antibody VIB551 to the patient requiring treatment for NMOSD, wherein the patient has been previously treated with an anti-CD20 antibody, the patient has experienced an NMOSD attack within six months of the last dose of the anti-CD20 antibody, and VIB551 is administered intravenously at a dose of 300 mg every six months.

[0019] In some embodiments, administration depletes at least 90% of circulating CD20+ B cells for at least 6 months. In some embodiments, administration does not increase the risk of infection in the patient. In certain embodiments, VIB551 reduces peripheral blood CD20 plasmablasts and plasma cells within 8 days after administration.

[0020] This specification provides a method for reducing NMOSD-related disorders in a patient diagnosed with NMOSD, comprising the step of administering an anti-CD19 antibody VIB551 to a patient requiring treatment for NMOSD, wherein the patient has been previously treated with an anti-CD20 antibody and has experienced an NMOSD attack while being treated with the anti-CD20 antibody. This specification provides a method for reducing NMOSD-related disorders in a patient diagnosed with NMOSD, comprising the step of administering an anti-CD19 antibody VIB551 to a patient requiring treatment for NMOSD, wherein the patient has been previously treated with an anti-CD20 antibody and has experienced an NMOSD attack within six months of the last dose of the anti-CD20 antibody. In some embodiments, VIB551 is administered intravenously at a dose of 300 mg every six months.

[0021] This specification provides a method for reducing NMOSD-related disorders in patients diagnosed with NMOSD, comprising the step of administering the anti-CD19 antibody VIB551 to a patient requiring treatment for NMOSD, wherein the patient has been previously treated with an anti-CD20 antibody, the patient has experienced an NMOSD attack while being treated with the anti-CD20 antibody, and VIB551 is administered intravenously at a dose of 300 mg every six months. This specification provides a method for reducing NMOSD-related disorders in patients diagnosed with NMOSD, comprising the step of administering the anti-CD19 antibody VIB551 to a patient requiring treatment for NMOSD, wherein the patient has been previously treated with an anti-CD20 antibody, the patient has experienced an NMOSD attack within six months of the last dose of the anti-CD20 antibody, and VIB551 is administered intravenously at a dose of 300 mg every six months.

[0022] In some embodiments, reduction of NMOSD-related disorders in a patient is a reduction in the rate of exacerbation of NMOSD-related disorders in the patient. In some embodiments, reduction of NMOSD-related disorders in a patient is a mitigation of NMOSD-related disorders in the patient. In one embodiment, NMOSD-related disorders are neurological disorders. In some embodiments, reduction of NMOSD-related disorders is determined using the EDSS.

[0023] This specification provides a method for reducing NMOSD-related seizures in a patient requiring treatment for NMOSD, comprising the step of administering the anti-CD19 antibody VIB551 to the patient requiring treatment for NMOSD, wherein the patient has been previously treated with an anti-CD20 antibody and has experienced NMOSD seizures while being treated with the anti-CD20 antibody. This specification provides a method for reducing NMOSD-related seizures in a patient requiring treatment for NMOSD, comprising the step of administering the anti-CD19 antibody VIB551 to the patient requiring treatment for NMOSD, wherein the patient has been previously treated with an anti-CD20 antibody and has experienced NMOSD seizures within six months of the last dose of the anti-CD20 antibody. In some embodiments, VIB551 is administered intravenously at a dose of 300 mg every six months.

[0024] This specification provides a method for reducing NMOSD-related seizures in a patient requiring treatment for NMOSD, comprising the step of administering the anti-CD19 antibody VIB551 to the patient requiring treatment for NMOSD, wherein the patient has been previously treated with an anti-CD20 antibody, the patient has experienced an NMOSD seizure while being treated with the anti-CD20 antibody, and VIB551 is administered intravenously at a dose of 300 mg every six months. This specification provides a method for reducing NMOSD-related seizures in a patient requiring treatment for NMOSD, comprising the step of administering the anti-CD19 antibody VIB551 to the patient requiring treatment for NMOSD, wherein the patient has been previously treated with an anti-CD20 antibody, the patient has experienced an NMOSD seizure within six months of the last dose of the anti-CD20 antibody, and VIB551 is administered intravenously at a dose of 300 mg every six months.

[0025] In some embodiments, the NMOSD-related seizures experienced by the patient include one or more of the following: optic neuritis, myelitis, or brainstem seizures. In one embodiment, the NMOSD-related seizures experienced by the patient are clinically asymptomatic.

[0026] In some embodiments, the patient is administered at least one initial dose of VIB551. In some embodiments, VIB551 is administered intravenously in a first initial dose of 300 mg, a second initial dose of 300 mg two weeks after the first initial dose, and a subsequent dose of 300 mg every six months after the first initial dose. In some embodiments, an oral corticosteroid is administered to the patient co-administered with the initial dose of 300 mg of VIB551. In some embodiments, the oral corticosteroid is administered daily for at least two weeks. In some embodiments, the anti-CD20 antibody is rituximab.

[0027] In some embodiments, VIB551 comprises a heavy chain variable region (VH) containing the amino acid of SEQ ID NO: 1 and a light chain variable region (VL) containing the amino acid of SEQ ID NO: 2.

[0028] This specification provides a method for treating NMOSD, comprising the step of administering an anti-CD19 antibody to a patient requiring treatment for NMOSD, wherein the patient has been previously treated with an anti-CD20 antibody, and the patient has experienced an NMOSD seizure while being treated with the anti-CD20 antibody. This specification also provides a method for treating NMOSD, comprising the step of administering an anti-CD19 antibody to a patient requiring treatment for NMOSD, wherein the patient has been previously treated with an anti-CD20 antibody, and the patient has experienced an NMOSD seizure within six months of the last administration of the anti-CD20 antibody.

[0029] This specification provides a method for treating NMOSD, comprising the step of administering the anti-CD19 antibody VIB551 to a patient in need of treatment for NMOSD, the patient being an AQP4-IgG+ patient, and VIB551 being administered intravenously in a first initial dose of 300 mg, a second initial dose of 300 mg two weeks after the first initial dose, and a subsequent dose of 300 mg every six months after the first initial dose, the patient having been previously treated with an anti-CD20 antibody, and the patient having experienced an NMOSD attack while being treated with the anti-CD20 antibody. This specification provides a method for treating NMOSD, comprising the step of administering the anti-CD19 antibody VIB551 to a patient in need of treatment for NMOSD, wherein the patient is an AQP4-IgG+ patient, and VIB551 is administered intravenously in a first initial dose of 300 mg, a second initial dose of 300 mg two weeks after the first initial dose, and a subsequent dose of 300 mg every six months after the first initial dose, wherein the patient has been previously treated with an anti-CD20 antibody, and the patient has experienced an NMOSD attack within six months of the last administration of the anti-CD20 antibody. [Invention 1001] A method for treating neuromyelitis optica spectrum disorder (NMOSD), The process includes administering the anti-CD19 antibody VIB551 to patients requiring treatment for NMOSD. The aforementioned patient has been previously treated with an anti-CD20 antibody. The aforementioned method. [Invention 1002] A method for treating NMOSD, The process includes administering the anti-CD19 antibody VIB551 to patients requiring treatment for NMOSD. The patient has been previously treated with an anti-CD20 antibody, and the patient has experienced an NMOSD seizure while being treated with the anti-CD20 antibody, or within six months of the last dose of the anti-CD20 antibody. The aforementioned method. [Invention 1003] The method according to invention 1001 or 1002, wherein VIB551 is administered intravenously at a dose of 300 mg every six months. [Invention 1004] A method for treating NMOSD, The process includes administering the anti-CD19 antibody VIB551 to patients requiring treatment for NMOSD. The aforementioned patient had astrocyte water channel aquaporin-4 (AQP4)-immunoglobulin (Ig) G + The patient, The aforementioned VIB551 is administered intravenously at a dose of 300 mg every 6 months. The patient has been previously treated with an anti-CD20 antibody, and the patient has experienced an NMOSD seizure while being treated with the anti-CD20 antibody. The aforementioned method. [Invention 1005] A method for treating NMOSD, The process includes administering the anti-CD19 antibody VIB551 to patients requiring treatment for NMOSD. The aforementioned patient had AQP4-IgG + The patient, The aforementioned VIB551 is administered intravenously at a dose of 300 mg every 6 months. The patient has been previously treated with an anti-CD20 antibody, and the patient has experienced an NMOSD seizure within 6 months of the last dose of the anti-CD20 antibody. The aforementioned method. [Invention 1006] The method according to any one of items 1003 to 1005 of the present invention, wherein the patient is administered at least one initial dose of VIB551. [Invention 1007] The method according to any one of the present invention 1003 to 1006, wherein VIB551 is administered intravenously in a first initial dose of 300 mg, a second initial dose of 300 mg two weeks after the first initial dose, and a subsequent dose of 300 mg every six months after the first initial dose. [Invention 1008] The method according to the present invention 1006 or 1007, wherein an oral corticosteroid is administered to the patient simultaneously with the initial dose of VIB551. [Invention 1009] The method of the present invention 1008, wherein the oral corticosteroid is administered daily for at least two weeks. [Invention 1010] The method according to any one of the present invention 1001 to 1009, wherein the anti-CD20 antibody is rituximab. [Invention 1011] The treatment is to reduce the deterioration of the Kurtzke Comprehensive Disability Rating Scale (EDSS) in the patient. Any method according to invention 1001 to 1010. [Invention 1012] The reduction in the worsening of the EDSS in the aforementioned patient is If the patient has a baseline score of 0, then a deterioration of less than 2 points in the EDSS score; If the patient has a baseline score of 1 to 5, worsening by less than 1 point; or If the patient has a baseline score of 5.5 or higher, a deterioration of less than 0.5 points is considered acceptable. The method of the present invention 1011. [Invention 1013] The method according to any one of the present invention 1001 to 1010, wherein the treatment is a reduction in the number of active magnetic resonance imaging (MRI) lesions. [Invention 1014] The method of the present invention 1013, wherein the active MRI lesion is an expanding T2 MRI lesion. [Invention 1015] The method according to any one of the present invention 1001 to 1010, wherein the treatment is a reduction in the number of new MRI lesions. [Invention 1016] The method according to any one of the present invention 1001 to 1010, wherein the treatment is a reduction in the deterioration of the patient's modified Rankin score. [Invention 1017] A method according to any one of the present invention 1001 to 1010, wherein the treatment is a reduction in the frequency of hospitalizations of the patient associated with NMOSD. [Invention 1018] A method according to any one of the present invention 1001 to 1010, wherein the treatment is a reduction in the patient's risk of NMOSD-related seizures. [Invention 1019] The method of the present invention 1018, wherein the NMOSD-related seizure is characterized by the appearance of new symptoms related to NMOSD or the worsening of existing symptoms. [Invention 1020] The method of the present invention 1019, wherein the aforementioned symptoms are ocular symptoms. [Invention 1021] The method of the present invention 1020, wherein the aforementioned ocular symptoms are eye pain, blurred vision, loss of visual acuity, or the appearance of optic nerve lesions detected by MRI. [Invention 1022] The method of the present invention 1019, wherein the aforementioned symptoms are spinal cord symptoms. [Invention 1023] The method of the present invention 1022, wherein the spinal cord symptoms are deep or radicular pain, limb paresthesia, weakness, sphincter dysfunction, Lhermitt's sign, or a spinal cord lesion detectable by MRI. [Invention 1024] The method of the present invention 1019, wherein the aforementioned symptoms are symptoms of the brain or brainstem. [Invention 1025] The method of the present invention 1024, wherein the symptoms of the brain or brainstem are nausea, diplopia, oculomotor nerve palsy, dizziness, intractable vomiting, intractable hiccups, dysarthria, dysphagia, weakness, encephalopathy, hypothalamic dysfunction, or a brain or brainstem lesion detectable by MRI. [Invention 1026] The method of the present invention 1018, wherein the risk of NMOSD-related seizures is reduced by 60-85%. [Invention 1027] The method according to any of the present invention 1001 to 1010, wherein the treatment is a reduction in optic neuritis. [Invention 1028] The method according to any one of the present invention 1001 to 1010, wherein the treatment is a reduction in the severity of NMOSD-related seizures. [Invention 1029] The method of the present invention 1028, wherein the reduction in the severity of the NMOSD-related seizures is a reduction in NMOSD-related seizures that have been classified as major seizures. [Invention 1030] The method of the present invention 1028, wherein the reduction in the severity of the NMOSD-related seizures is a reduction in the number of NMOSD seizures requiring hospitalization. [Invention 1031] A method according to any one of the present invention 1001 to 1010, wherein the treatment is a reduction in NMOSD-related pain in the patient. [Invention 1032] The method of the present invention 1031, wherein the reduction in NMOSD-related pain is determined by measuring the leg pain of the patient. [Invention 1033] A method according to any one of items 1001 to 1005 of the present invention, wherein an initial dose of 300 mg of VIB551 is administered to the subject two weeks before the first dose of 300 mg of VIB551 administered every six months. [Invention 1034] The method of the present invention 1033, wherein an oral corticosteroid is administered to the patient simultaneously with the initial dose of 300 mg of VIB551. [Invention 1035] The method according to the present invention 1001 or 1002, wherein the patient is AQP4-IgG seropositive. [Invention 1036] A method for reducing active MRI lesions in patients diagnosed with NMOSD, The process includes administering the anti-CD19 antibody VIB551 to patients requiring treatment for NMOSD. The patient has been previously treated with an anti-CD20 antibody, and the patient has experienced an NMOSD seizure while being treated with the anti-CD20 antibody. The aforementioned method. [Invention 1037] A method for reducing active MRI lesions in patients diagnosed with NMOSD, The process includes administering the anti-CD19 antibody VIB551 to patients requiring treatment for NMOSD. The patient has been previously treated with an anti-CD20 antibody, and the patient has experienced an NMOSD seizure within 6 months of the last dose of the anti-CD20 antibody. The aforementioned method. [Invention 1038] The method according to invention 1036 or 1037, wherein VIB551 is administered intravenously at a dose of 300 mg every six months. [Invention 1039] A method for reducing active MRI lesions in patients diagnosed with NMOSD, The process includes administering the anti-CD19 antibody VIB551 to patients requiring treatment for NMOSD. The patient has been previously treated with an anti-CD20 antibody, and the patient has experienced an NMOSD seizure while being treated with the anti-CD20 antibody. The aforementioned VIB551 is administered intravenously at a dose of 300 mg every six months. The aforementioned method. [Invention 1040] A method for reducing active MRI lesions in patients diagnosed with NMOSD, The process includes administering the anti-CD19 antibody VIB551 to patients requiring treatment for NMOSD. The patient has been previously treated with an anti-CD20 antibody, and the patient has experienced an NMOSD seizure within 6 months of the last administration of the anti-CD20 antibody. The aforementioned VIB551 is administered intravenously at a dose of 300 mg every six months. The aforementioned method. [Invention 1041] AQP4-IgG requiring treatment for NMOSD + A method for reducing the AQP4-IgG titer of a patient, The process includes administering the anti-CD19 antibody VIB551 to patients requiring treatment for NMOSD. The patient has been previously treated with an anti-CD20 antibody, and the patient has experienced an NMOSD seizure while being treated with the anti-CD20 antibody. The aforementioned method. [Invention 1042] AQP4-IgG requiring treatment for NMOSD + A method for reducing the AQP4-IgG titer of a patient, The process includes administering the anti-CD19 antibody VIB551 to patients requiring treatment for NMOSD. The patient has been previously treated with an anti-CD20 antibody, and the patient has experienced an NMOSD seizure within 6 months of the last dose of the anti-CD20 antibody. The aforementioned method. [Invention 1043] The method according to invention 1041 or 1042, wherein VIB551 is administered intravenously at a dose of 300 mg every six months. [Invention 1044] AQP4-IgG requiring treatment for NMOSD + A method for reducing the AQP4-IgG titer of a patient, The process includes administering the anti-CD19 antibody VIB551 to patients requiring treatment for NMOSD. The patient has been previously treated with an anti-CD20 antibody, and the patient has experienced an NMOSD seizure while being treated with the anti-CD20 antibody. The aforementioned VIB551 is administered intravenously at a dose of 300 mg every six months. The aforementioned method. [Invention 1045] AQP4-IgG requiring treatment for NMOSD + A method for reducing the AQP4-IgG titer of a patient, The process includes administering the anti-CD19 antibody VIB551 to patients requiring treatment for NMOSD. The patient has been previously treated with an anti-CD20 antibody, and the patient has experienced an NMOSD seizure within 6 months of the last administration of the anti-CD20 antibody. The aforementioned VIB551 is administered intravenously at a dose of 300 mg every six months. The aforementioned method. [Invention 1046] The method according to any of items 1001 to 1045 of the present invention, wherein the administration depletes at least 90% of circulating CD20+ B cells for at least 6 months. [Invention 1047] A method according to any one of the present invention 1001 to 1046, wherein the administration does not increase the risk of infection in the patient. [Invention 1048] The aforementioned VIB551 is detected in peripheral blood CD20 within 8 days after administration. - A method of depriving plasmablasts and plasma cells, as described in any of the present invention 1001 to 1047. [Invention 1049] A method for reducing NMOSD-related disorders in patients diagnosed with NMOSD, The process includes administering the anti-CD19 antibody VIB551 to patients requiring treatment for NMOSD. The patient has been previously treated with an anti-CD20 antibody, and the patient has experienced an NMOSD seizure while being treated with the anti-CD20 antibody. The aforementioned method. [Invention 1050] A method for reducing NMOSD-related disorders in patients diagnosed with NMOSD, The process includes administering the anti-CD19 antibody VIB551 to patients requiring treatment for NMOSD. The patient has been previously treated with an anti-CD20 antibody, and the patient has experienced an NMOSD seizure within 6 months of the last dose of the anti-CD20 antibody. The aforementioned method. [Invention 1051] The method according to invention 1049 or 1050, wherein VIB551 is administered intravenously at a dose of 300 mg every six months. [Invention 1052] A method for reducing NMOSD-related disorders in patients diagnosed with NMOSD, The process includes administering the anti-CD19 antibody VIB551 to patients requiring treatment for NMOSD. The patient has been previously treated with an anti-CD20 antibody, and the patient has experienced an NMOSD seizure while being treated with the anti-CD20 antibody. The aforementioned VIB551 is administered intravenously at a dose of 300 mg every six months. The aforementioned method. [Invention 1053] A method for reducing NMOSD-related disorders in patients diagnosed with NMOSD, The process includes administering the anti-CD19 antibody VIB551 to patients requiring treatment for NMOSD. The patient has been previously treated with an anti-CD20 antibody, and the patient has experienced an NMOSD seizure within 6 months of the last administration of the anti-CD20 antibody. The aforementioned VIB551 is administered intravenously at a dose of 300 mg every six months. The aforementioned method. [Invention 1054] A method according to any one of the present invention 1049 to 1053, wherein the reduction of the NMOSD-related disorder in the patient is a reduction in the rate of progression of the NMOSD-related disorder in the patient. [Invention 1055] A method according to any of the present invention 1049 to 1054, wherein the reduction of the NMOSD-related disorder in the patient is the alleviation of the NMOSD-related disorder in the patient. [Invention 1056] The method according to any of the present invention 1049 to 1055, wherein the NMOSD-related disorder is a neurological disorder. [Invention 1057] Any method 1049 to 1056 of the present invention, wherein the reduction of the NMOSD-related disorder is determined using EDSS. [Invention 1058] A method for reducing NMOSD-related seizures in patients requiring treatment for NMOSD, The process includes administering the anti-CD19 antibody VIB551 to patients requiring treatment for NMOSD. The patient has been previously treated with an anti-CD20 antibody, and the patient has experienced an NMOSD seizure while being treated with the anti-CD20 antibody. The aforementioned method. [Invention 1059] A method for reducing NMOSD-related seizures in patients requiring treatment for NMOSD, The process includes administering the anti-CD19 antibody VIB551 to patients requiring treatment for NMOSD. The patient has been previously treated with an anti-CD20 antibody, and the patient has experienced an NMOSD seizure within 6 months of the last dose of the anti-CD20 antibody. The aforementioned method. [Invention 1060] The method according to invention 1058 or 1059, wherein VIB551 is administered intravenously at a dose of 300 mg every six months. [Invention 1061] A method for reducing NMOSD-related seizures in patients requiring treatment for NMOSD, The process includes administering the anti-CD19 antibody VIB551 to patients requiring treatment for NMOSD. The patient has been previously treated with an anti-CD20 antibody, and the patient has experienced an NMOSD seizure while being treated with the anti-CD20 antibody. The aforementioned VIB551 is administered intravenously at a dose of 300 mg every six months. The aforementioned method. [Invention 1062] A method for reducing NMOSD-related seizures in patients requiring treatment for NMOSD, The process includes administering the anti-CD19 antibody VIB551 to patients requiring treatment for NMOSD. The patient has been previously treated with an anti-CD20 antibody, and the patient has experienced an NMOSD seizure within 6 months of the last administration of the anti-CD20 antibody. The aforementioned VIB551 is administered intravenously at a dose of 300 mg every six months. The aforementioned method. [Invention 1063] The method of the present invention 1061 or 1062, wherein the NMOSD-related seizures experienced by the patient include one or more of optic neuritis, myelitis, or brainstem seizures. [Invention 1064] The method of the present invention 1063, wherein the NMOSD-related seizures experienced by the patient are clinically asymptomatic. [Invention 1065] The method according to any one of items 1036 to 1064 of the present invention, wherein the patient is administered at least one initial dose of VIB551. [Invention 1066] The method of the present invention 1065, wherein VIB551 is administered intravenously in a first initial dose of 300 mg, a second initial dose of 300 mg two weeks after the first initial dose, and a subsequent dose of 300 mg every six months after the first initial dose. [Invention 1067] The method of the present invention 1066, wherein an oral corticosteroid is administered to the patient simultaneously with the initial dose of 300 mg of VIB551. [Invention 1068] The method of the present invention 1067, wherein the oral corticosteroid is administered daily for at least two weeks. [Invention 1069] The method according to any of the present invention 1036 to 1068, wherein the anti-CD20 antibody is rituximab. [Invention 1070] The method according to any one of the present invention 1001 to 1069, wherein the VIB551 comprises a heavy chain variable region (VH) containing the amino acid of SEQ ID NO: 1 and a light chain variable region (VL) containing the amino acid of SEQ ID NO: 2. [Invention 1071] A method for treating NMOSD, The process includes administering an anti-CD19 antibody to a patient requiring treatment for NMOSD. The patient has been previously treated with an anti-CD20 antibody, and the patient has experienced an NMOSD seizure while being treated with the anti-CD20 antibody. The aforementioned method. [Invention 1072] A method for treating NMOSD, The process includes administering an anti-CD19 antibody to a patient requiring treatment for NMOSD. The patient has been previously treated with an anti-CD20 antibody, and the patient has experienced an NMOSD seizure within 6 months of the last dose of the anti-CD20 antibody. The aforementioned method. [Invention 1073] A method for treating NMOSD, The process includes administering the anti-CD19 antibody VIB551 to patients requiring treatment for NMOSD. The aforementioned patient had AQP4-IgG + The patient, The VIB551 is administered intravenously in a first initial dose of 300 mg, a second initial dose of 300 mg two weeks after the first initial dose, and a subsequent dose of 300 mg every six months after the first initial dose. The patient has been previously treated with an anti-CD20 antibody, and the patient has experienced an NMOSD seizure while being treated with the anti-CD20 antibody. The aforementioned method. [Invention 1074] A method for treating NMOSD, The process includes administering the anti-CD19 antibody VIB551 to patients requiring treatment for NMOSD. The aforementioned patient had AQP4-IgG + The patient, The VIB551 is administered intravenously in a first initial dose of 300 mg, a second initial dose of 300 mg two weeks after the first initial dose, and a subsequent dose of 300 mg every six months after the first initial dose. The patient has been previously treated with an anti-CD20 antibody, and the patient has experienced an NMOSD seizure within 6 months of the last dose of the anti-CD20 antibody. The aforementioned method. [Invention 1075] Before the aforementioned administration, A step of confirming that the patient has been previously treated with the anti-CD20 antibody; The aforementioned patient (i) Having experienced at least one NMOSD seizure while being treated with the anti-CD20 antibody; or (ii) Have you experienced at least one NMOSD seizure within six months of the last administration of the anti-CD20 antibody? The process of determining; and (i) or (ii) the step of selecting the patient to administer the anti-CD19 antibody as a result of the decision in (ii). Any method of the present invention 1001 to 1074, further comprising the above. [Brief explanation of the drawing]

[0030] [Figure 1] Flowchart of the multiplicity adjustment strategy in the N-MOmentum clinical trial. [Figure 2] Clinical trial design flowchart for N-MOmentum. (AC: Adjudication Committee; FU: Follow-up; iv: Intravenous; max: Maximum; min: Minimum; NMO / NMOSD: Neuromyelitis Optica / Neuromyelitis Optica Spectrum Disorder; OLP: Open-label period; RCP: Randomized Controlled Period; Q26: Every 26 (weeks); SFP: Safety Follow-up Period) [Figure 3] N-MOmentum Clinical Trial CONSORT Flowchart. (*Efficacy endpoints were evaluated in the intent-to-treat population (defined as participants who were randomized and administered the investigational drug and were analyzed according to the randomized treatment group, regardless of whether they received interventions other than the planned one). †Safety endpoints were evaluated in the as-treated population (defined as participants who received the investigational drug). However, participants randomized to VIB551 who received all placebo doses were included in the placebo group. Conversely, participants randomized to placebo who received at least one dose of VIB551 were included in the active treatment group). ‡Other cases include the need for treatment with prohibited drugs, inaccurate randomization of ineligible participants, and cases of pre-treatment discontinuation due to seizures on the day of randomization (VIB551 group), and patient decision (placebo group). CONSORT, Integrated Criteria for Clinical Trial Reporting; iv, Intravenous; RCP, Randomization-to-Control Period. [Figure 4] The amino acid sequences of VH (SEQ ID NO: 1) and VL (SEQ ID NO: 2) of the VIB551 antibody. [Figure 5] Seizure history of N-MOmentum participants with a history of rituximab use. [Figure 6] The probability of seizure-free survival, stratified by history of rituximab use. [Figure 7] Individual absolute CD20+ B cell counts for participants with a history of rituximab use during the randomized controlled period (weeks 0–28) and the open-label extension period (>week 28). All participants received inebilizumab during the open-label extension period. [Figure 8] IgG concentrations at baseline and at inebilizumab administration in participants with and without prior rituximab use. IgG, immunoglobulin G. [Figure 9] The amino acid sequences of the heavy chain (SEQ ID NO: 3) and light chain (SEQ ID NO: 4) of the VIB551 antibody. [Modes for carrying out the invention]

[0031] Detailed explanation This specification describes a method for treating patients diagnosed with NMOSD using VIB551 (also known as MEDI551, Uplizna®, or inebilizumab), wherein the patient has previously received treatment with an anti-CD20 antibody. This specification also describes a method for reducing active MRI lesions in patients diagnosed with NMOSD using VIB551, wherein the patient has previously received treatment with an anti-CD20 antibody. Furthermore, this specification describes AQP4-IgG, which requires treatment for NMOSD using VIB551. + A method for reducing the AQP4-IgG titer of a patient, wherein the patient has previously received treatment with an anti-CD20 antibody, is described herein. Furthermore, a method for reducing NMOSD-related disorders in a patient diagnosed with NMOSD using VIB551, wherein the patient has previously received treatment with an anti-CD20 antibody, is described herein. Also described herein is a method for reducing NMOSD-related seizures in a patient requiring treatment for NMOSD using VIB551, wherein the patient has previously received treatment with an anti-CD20 antibody, is described herein.

[0032] In some embodiments of the methods described herein, VIB551 may be used to treat patients diagnosed with NMOSD who have experienced one or more NMOSD seizures while being treated with an anti-CD20 antibody. In some embodiments, VIB551 may be used to treat patients diagnosed with NMOSD who have experienced one or more NMOSD seizures within six months of the last dose of an anti-CD20 antibody. In certain embodiments, the patient may be an astrocyte water channel aquaporin-4 (AQP4)-IgG+ patient. In some embodiments, the anti-CD20 antibody that the patient may have been previously treated with is rituximab (antibody C2B8 in International Publication No. 94 / 11026, which is incorporated herein by reference in its entirety).In some embodiments, the anti-CD20 antibodies that the patient may have been previously treated with include: ABP-300 (Abpro), B-001 (Shanghai Pharmaceuticals Holding), BAT-4306F (Bio-Thera Solutions), BAT-4406F (Bio-Thera Solutions), BCD-132 (Biocad Biotechnology), BVX-20 (Vaccinex), CYT-202 (Cytovia Therapeutics), epcolitamab (Genmab), GB-261 (Genor Biopharma), GD-CO1620 (ManysmarT); grofitamab (Roche), HS-006 (Zhejiang Hisun Pharmaceutical), IGM-2323 (IGM Biosciences), IMM-0306 (ImmuneOnco Biopharma); MIL-62 (Beijing Mabworks) These include Biotech, mosnetuzumab (Roche), MRG-001 (Shanghai Miracogen), obinutuzumab (Roche), ocrelizumab (Roche, Niogen), odronextumab (Regeneron); ofatumumab (Genmab, Novartis), pramotamab (Xencor), SM-09 (SinoMab BioScience), TRS-005 (Zhejiang Teruisi Biopharma), ubrituximab (rEVO Biologics), or YBL-031 (Y-Biologics).

[0033] In some embodiments, the Disclosure provides a method for treating neuromyelitis optica spectrum disorder (NMOSD), comprising the step of administering an anti-CD19 antibody VIB551 to a patient in need of treatment for NMOSD, wherein the patient has been previously treated with an anti-CD20 antibody, and the patient has experienced an NMOSD seizure while being treated with the anti-CD20 antibody. In some embodiments, the Disclosure provides a method for treating NMOSD, comprising the step of administering an anti-CD19 antibody VIB551 to a patient in need of treatment for NMOSD, wherein the patient has been previously treated with an anti-CD20 antibody, and the patient has experienced an NMOSD seizure within six months of the last dose of the anti-CD20 antibody.

[0034] When VIB551 is used to treat NMOSD, VIB551 may treat NMOSD by reducing the progression of the patient's Kurtzke Comprehensive Disability Rating Scale (EDSS), or by reducing the number of active magnetic resonance imaging (MRI) lesions in the patient, or by reducing the progression of the patient's modified Rankin score, or by reducing the frequency of hospitalizations in patients associated with NMOSD, or by reducing the patient's risk of NMOSD-related seizures, or by reducing optic neuritis, or by reducing the severity of NMOSD-related seizures in the patient, or by reducing the patient's pain, or by reducing NMOSD-related injury, or by reducing NMOSD-related seizures in the patient.

[0035] When VIB551 treats a patient's NMOSD by reducing the worsening of the patient's EDSS score, if the patient has a baseline EDSS score of 0, the worsening of the patient's EDSS score may be less than 2 points, less than 1 point, or less than 0.5 points. This reduction in the worsening of the EDSS score in a patient with a baseline score of 0 may occur 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. When VIB551 treats a patient's NMOSD by reducing the worsening of the patient's EDSS score, if the patient has a baseline score of 1 to 5, the worsening of the patient's EDSS score may be less than 1 point, or less than 0.5 points. This reduction in worsening in a patient with a baseline EDSS score of 1 to 5 may occur over a period of more than 6 months, 9 months, 1 year, 2 years, 3 years, 4 years, 5 years, 7.5 years, or 10 years. When VIB551 treats a patient's NMOSD by reducing the worsening of their EDSS score, if the patient has a baseline EDSS score of 5.5 or higher, the worsening of the patient's EDSS score may be less than 0.5 points or less than 0.25 points. This reduction in worsening in patients with a baseline score of 5.5 or higher may be a reduction in EDSS score worsening over periods exceeding 6 months, 9 months, 1 year, 2 years, 3 years, 4 years, 5 years, 7.5 years, or 10 years.

[0036] When VIB551 treats a patient's NMOSD by reducing the number of active MRI lesions, the treatment may be a reduction in the number of expanding T2 MRI lesions, a reduction in the number of new MRI lesions, or a reduction in both expanding T2 MRI lesions and new MRI lesions. The reduction in lesions may be a reduction in brain lesions, brainstem lesions, spinal cord lesions, optic nerve lesions, or lesions in any two or more combinations of the brain, brainstem, spinal cord, and optic nerve. New MRI lesions may be clinically asymptomatic.

[0037] When VIB551 treats a patient's NMOSD by reducing the worsening of the patient's modified Rankin score, the reduction in worsening may be such that the patient's modified Rankin score worsens by less than 2 points or less than 1 point over a period of at least 6 months, or at least 9 months, or at least 1 year, or at least 2 years, or at least 3 years, or at least 4 years, or at least 5 years, or at least 7.5 years, or at least 10 years.

[0038] When VIB551 treats a patient's NMOSD by reducing the risk of NMOSD-related seizures, the patient's seizure risk may be reduced by 60% to 85%, or by 65% ​​to 75%, or by 70% to 80%. The patient's seizure risk may 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 patient's seizure risk may be reduced by 70%, 75%, 76%, 77%, 78%, 79%, or 80%.

[0039] When VIB551 treats a patient's NMOSD by reducing the risk of NMOSD-related seizures, as a result of this reduction in risk, the probability that a treated patient will not experience an NMOSD-related seizure may be greater than 70% for at least 6 months after VIB551 treatment, or greater than 70% for at least 12 months after VIB551 treatment, or greater than 70% for at least 18 months after VIB551 treatment. As a result of this reduction in risk, the probability that a treated patient will not experience an NMOSD-related seizure may be greater than 75% for at least 6 months after VIB551 treatment, or greater than 75% for at least 12 months after VIB551 treatment, or greater than 75% for at least 18 months after VIB551 treatment. Furthermore, as a result of the reduced risk of NMOSD-related seizures, the probability that treated patients will not experience NMOSD-related seizures may be greater than 80% for at least 6 months after VIB551 treatment, or greater than 80% for at least 12 months after VIB551 treatment, or greater than 80% for at least 18 months after VIB551 treatment.

[0040] Furthermore, when VIB551 treats a patient's NMOSD by reducing the risk of NMOSD-related seizures, as a result of this risk reduction, the annual risk of NMOSD-related seizures in the treated patient may be reduced to 0.18–0.08, or to 0.15–0.08, or to 0.14, 0.13, 0.12, 0.11, 0.10, 0.09, 0.08, or 0.07. If a patient undergoing treatment for NMOSD is AQP4-IgG seropositive, the annual risk of NMOSD-related seizures in the patient may be reduced to 0.15–0.11, or to 0.14–0.12, or to 0.14, 0.13, 0.12, or 0.11. If a patient undergoing treatment for NMOSD is AQP4-IgG seronegative, the patient's annual risk of NMOSD-related seizures may be reduced to 0.09–0.07, or to 0.09, 0.08, or 0.07.

[0041] NMOSD-related seizures may be characterized by the appearance of new NMOSD symptoms or an exacerbation of existing NMOSD symptoms, although the risk of such seizures may be reduced, as in the treatment of NMOSD patients. New or existing symptoms may be ocular symptoms. If new or existing symptoms are ocular symptoms, they may be eye pain, new optic nerve lesions, expansion of optic nerve lesions, blurred vision, visual acuity loss, or a decrease of 5 or more letters on a low-contrast Landolt ring visual acuity chart. New or existing symptoms may be spinal symptoms. If new or existing symptoms are spinal symptoms, they may be deep pain or radicular pain, limb paresthesia, weakness, sphincter dysfunction, Lhermitt's sign, new spinal lesions, or expansion of spinal lesions. New or existing symptoms may be brain or brainstem symptoms. If the new or existing symptoms are brain or brainstem symptoms, they may be nausea, diplopia, oculomotor palsy, dizziness, refractory vomiting, refractory hiccups, dysarthria, dysphagia, weakness, encephalopathy, hypothalamic dysfunction, a new brain or brainstem lesion, or an expansion of a brain or brainstem lesion. The new or worsening symptoms may be any combination of two or more of the ocular, spinal cord, or brain / brainstem symptoms. It may be any combination of two, three, or four of these symptoms.

[0042] When VIB551 treats a patient's NMOSD by reducing optic neuritis, the patient may experience reduced eye pain, reduced visual acuity loss, reduced visual field loss, reduced color vision loss, or reduced flashing or flickering of lights associated with eye movement. The reduction of optic neuritis may result in improved visual acuity and / or reduced eye pain.

[0043] When VIB551 treats a patient's NMOSD by reducing the severity of their NMOSD-related seizures, the severity of the seizures may be graded as mild or moderate, rather than severe. Mild seizures may be transient, require minimal treatment or therapeutic intervention, and / or do not interfere with normal daily activities. Moderate seizures may be seizures that can be mitigated by certain additional therapeutic interventions. Any moderate seizure may interfere with normal daily activities and / or cause discomfort, but do not pose a risk of significant or permanent harm to the patient. Reduction in the severity of a patient's NMOSD-related seizures may include reduction in seizures that the patient has experienced and which are graded as major seizures. Such major seizures may require intensive therapeutic intervention and may interfere with normal daily activities or significantly affect the patient's clinical condition. Such major seizures may require hospitalization of the patient.

[0044] When VIB551 treats a patient's NMOSD by reducing the patient's pain, the reduction may be determined by a reduction in pain in the patient's eyes, legs, arms, upper back, and / or lower back. The pain reduction may occur in any one, two, three, four, or all five of these areas. The pain reduction can be measured by a numerical pain rating scale (PRS). The pain reduction may be monitored against a baseline PRS level across a scale of 1 to 10. The pain reduction may be a reduction of at least 1 on the scale, at least 2 on the scale, at least 3 on the scale, at least 4 on the scale, or at least 5 on the scale. The pain reduction may be a reduction between 1 and 5 on the scale, or between 1 and 3 on the scale, or between 1 and 2 on the scale.

[0045] When VIB551 treats a patient's NMOSD by reducing NMOSD-related injury, NMOSD-related injury may be the development of new, clinically asymptomatic MRI lesions in the patient. If NMOSD-related injury is the development of new, clinically asymptomatic MRI lesions, it may occur in patients who have not experienced symptoms of NMOSD-related seizures, or in patients who have experienced symptoms of NMOSD-related seizures.

[0046] When new clinically asymptomatic MRI lesions occur in patients who have not experienced symptoms of NMOSD-related seizures, VIB551 may reduce the occurrence or likelihood of new clinically asymptomatic MRI lesions in any one or more areas of the patient, such as the brain / brainstem, optic nerve, or spinal cord. The occurrence or reduction of the occurrence of new clinically asymptomatic MRI lesions may be a prevention of the occurrence of new clinically asymptomatic MRI lesions. Patients who have not experienced symptoms of NMOSD-related seizures and whose NMOSD-related injury is reduced by VIB551 may be patients who have not experienced symptoms of NMOSD-related seizures for at least 3 months, at least 6 months, at least 9 months, at least 12 months, at least 15 months, at least 18 months, at least 21 months, or at least 24 months. By administering VIB551 to patients who have not experienced symptoms of NMOSD-related seizures, the occurrence or likelihood of new clinically asymptomatic MRI lesions may be reduced during the patient's treatment period with VIB551. In patients who have not experienced symptoms of NMOSD-related seizures, administration of VIB551 may initiate the development or reduction of the likelihood of new MRI lesions within one month, two months, or three months following the administration of the first dose of VIB551, and may continue for at least six months, at least twelve months, at least eighteen months, at least 24 months, at least 30 months, at least 36 months, at least 42 months, at least 48 months, at least 54 months, or at least 60 months following the administration of the first dose of VIB551.

[0047] If a new clinically asymptomatic MRI lesion occurs in a patient who has experienced symptoms of an NMOSD-related seizure, VIB551 may reduce the occurrence or likelihood of such a lesion occurring in areas other than those in which the patient experienced symptoms of an NMOSD-related seizure. For example, if a patient experiences symptoms of an NMOSD-related seizure in the spinal cord, VIB551 may reduce the occurrence or likelihood of such a lesion occurring in the optic nerve, brain / brainstem, or both. If VIB551 reduces the occurrence or likelihood of a new clinically asymptomatic MRI lesion associated with an NMOSD-related seizure, VIB551 may completely reduce, i.e., prevent, the occurrence of a new clinically asymptomatic MRI lesion in the patient. Furthermore, VIB551 may not only reduce or reduce the likelihood of a new clinically asymptomatic MRI lesion in a patient who has experienced symptoms of an NMOSD-related seizure, but may also reduce or reduce the likelihood of a new MRI lesion occurring in areas in which the patient experienced symptoms of an NMOSD-related seizure.

[0048] VIB551 may also be used in methods to reduce active MRI lesions in patients diagnosed with NMOSD. In some embodiments, the disclosure provides a method to reduce active MRI lesions in patients diagnosed with NMOSD, comprising the step of administering an anti-CD19 antibody VIB551 to a patient requiring treatment for NMOSD, wherein the patient has been previously treated with an anti-CD20 antibody and has experienced an NMOSD attack while being treated with the anti-CD20 antibody. In some embodiments, the disclosure provides a method to reduce active MRI lesions in patients diagnosed with NMOSD, comprising the step of administering an anti-CD19 antibody VIB551 to a patient requiring treatment for NMOSD, wherein the patient has been previously treated with an anti-CD20 antibody and has experienced an NMOSD attack within six months of the last dose of the anti-CD20 antibody. When VIB551 is used in a method to reduce active MRI lesions in a patient, VIB551 may reduce the cumulative total of new expanding lesions in the patient. When VIB551 is used in a method to reduce active MRI lesions in patients diagnosed with NMOSD, VIB551 may reduce the cumulative total of new gadolinium [Gd]-enhancing lesions, new T2 lesions, and expanding T2 lesions in patients. When VIB551 is used in a method to reduce active MRI lesions in patients diagnosed with NMOSD, VIB551 may reduce the number of new T2 lesions and the number of expanding T2 lesions in patients. When VIB551 is used in a method to reduce active MRI lesions in patients diagnosed with NMOSD, VIB551 may reduce the number of new T2 lesions or the number of expanding T2 lesions in patients. The reduced active MRI lesions in patients may be the cumulative total of lesions in the brain / brainstem, spinal cord, and optic nerve, or one or two lesions in the brain / brainstem, spinal cord, or optic nerve. The reduced active MRI lesions in patients may be clinically symptomatic MRI lesions or clinically asymptomatic MRI lesions. When MRI lesions are clinically asymptomatic, they may be new MRI lesions occurring in patients who have not experienced symptoms of NMOSD-related seizures.When MRI lesions are clinically asymptomatic, they may be new MRI lesions that occur in the patient in relation to NMOSD-related seizures, but not in the same areas where the patient experiences symptoms of NMOSD-related seizures.

[0049] VIB551 also requires treatment for AQP4-IgG, which is associated with NMOSD. + It may be used in a method to reduce the AQP4-IgG titer of a patient. In some embodiments, the disclosure provides a method for reducing the AQP4-IgG titer of an AQP4-IgG+ patient requiring treatment for NMOSD, comprising the step of administering an anti-CD19 antibody VIB551 to the patient requiring treatment for NMOSD, wherein the patient has been previously treated with an anti-CD20 antibody, the patient has had an NMOSD attack while being treated with the anti-CD20 antibody, and VIB551 is administered intravenously at a dose of 300 mg every six months. In some embodiments, the disclosure provides a method for reducing the AQP4-IgG titer of an AQP4-IgG+ patient requiring treatment for NMOSD, comprising the step of administering an anti-CD19 antibody VIB551 to the patient requiring treatment for NMOSD, wherein the patient has been previously treated with an anti-CD20 antibody, the patient has had an NMOSD attack within six months of the last dose of the anti-CD20 antibody, and VIB551 is administered intravenously at a dose of 300 mg every six months. AQP4-IgG requiring treatment for NMOSD + When VIB551 is used in a method to reduce AQP4-IgG titer in patients, VIB551 can reduce 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 by 75%, 80%, 85%, 90%, 95%, or 100%. VIB551 can reduce AQP4-IgG titer for 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 a VIB551 dose.

[0050] VIB551 may also be used in methods to reduce NMOSD-related disorders in patients diagnosed with NMOSD. In some embodiments, the disclosure provides a method to reduce NMOSD-related disorders in patients diagnosed with NMOSD, comprising the step of administering an anti-CD19 antibody VIB551 to a patient requiring treatment for NMOSD, wherein the patient has been previously treated with an anti-CD20 antibody, and the patient has experienced an NMOSD attack while being treated with the anti-CD20 antibody. In some embodiments, the disclosure provides a method to reduce NMOSD-related disorders in patients diagnosed with NMOSD, comprising the step of administering an anti-CD19 antibody VIB551 to a patient requiring treatment for NMOSD, wherein the patient has been previously treated with an anti-CD20 antibody, and the patient has experienced an NMOSD attack within six months of the last dose of the anti-CD20 antibody. Reduction of NMOSD-related disorders in a patient may be a reduction in the exacerbation of NMOSD-related disorders in the patient, or an alleviation of NMOSD-related disorders in the patient. NMOSD-related disorders may be the manifestation of neurological disorders or neurological impairments. NMOSD-related disorders may be characterized by one or more of the following: eye pain, color vision loss, general vision loss, blurred vision, diplopia, general weakness or paralysis, weakness or paralysis of the arms or legs, radiculopathy, uncontrolled hiccups, uncontrolled nausea or vomiting, loss of control of the bladder or bowels, paralysis, and / or fatigue.

[0051] The reduction in NMOSD-related disorders may be determined using the EDSS, the modified Rankin scale (mRS), or both the EDSS and mRS. The reduction in NMOSD-related disorders may be detectable within 6–12 months, 6–8 months, or 6–7 months following administration of the dose of VIB551 or the first dose of VIB551.

[0052] When the reduction of NMOSD-related disorders is determined using the EDSS, this reduction may be a reduction in the deterioration of the patient's EDSS score or a decrease in the patient's EDSS score.

[0053] If the reduction of NMOSD-related disability is defined as a reduction in the deterioration of the patient's EDSS score, and the patient's baseline EDSS score is 0, then the deterioration reduction may be a deterioration of the patient's EDSS score to 0.5, or 1 or less, or 1.5 or less, or 2 or less over a certain period of time. The period over which a patient's score deteriorates from a baseline score of 0 to 0.5 or less, 1 or less, 1.5 or less, or 2 or less may be at least 6 months, 9 months, 1 year, 1.5 years, 2 years, 3 years, 4 years, 5 years, 7.5 years, or 10 years. If the reduction of NMOSD-related disability is defined as a reduction in the deterioration of the patient's EDSS score, and the patient's baseline EDSS score is between 1 and 5, then the deterioration reduction may be a deterioration of 0.5 points, or 1 point or less, in the patient's EDSS score over a certain period of time. For patients with a baseline score of 1–5, the period during which the score worsens by 0.5 points or less than 1 point may be at least 6 months, 9 months, 1 year, 1.5 years, 2 years, 3 years, 4 years, 5 years, 7.5 years, or 10 years. If the reduction in NMOSD-related disorder is a reduction in the worsening of the patient's EDSS score, and the patient's baseline EDSS score is 5.5 or higher, the reduction in worsening may be a worsening of 0.5 points or less in the patient's EDSS score. For patients with a baseline score of 5.5, the period during which the score worsens by 0.5 points or less may be at least 6 months, 9 months, 1 year, 1.5 years, 2 years, 3 years, 4 years, 5 years, 7.5 years, or 10 years. The patient's baseline EDSS score may be determined within approximately 1 month, 2 weeks, 1 week, 3 days, 2 days, or 1 day after administration of the first VIB551 dose. The patient's baseline EDSS score may be determined at the same time as the administration of the first VIB551 dose, or within 1 day, 2 days, 3 days, 1 week, 2 weeks, or 1 month after the administration of the first VIB551 dose.

[0054] If the reduction in NMOSD-related disorders is due to a decrease in the patient's EDSS score, the patient's EDSS score may decrease by at least 0.5 points, or at least 1 point, or at least 1.5 points, or at least 2 points. A decrease or reduction of at least 0.5 points, at least 1 point, at least 1.5 points, or at least 2 points in the patient's EDSS score may occur over a period of approximately 2 weeks, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 9 months, 12 months, or 18 months. The period during which the patient's EDSS score decreases or declines may begin within 1 month, 2 weeks, 1 week, 3 days, 2 days, or 1 day after administration of the first VIB551 dose, or concurrently with administration of the first VIB551 dose, or may begin within 1 day, 2 days, 3 days, 1 week, 2 weeks, or 1 month after administration of the first VIB551 dose. The period during which a patient's EDSS score decreases or declines may begin at the time of an NMOSD seizure, or within 1, 2, 3, 4, 5, 6, or 7 days after the NMOSD seizure.

[0055] When the reduction of NMOSD-related disorders is determined using the mRS, the reduction of NMOSD-related disorders may be a reduction in the patient's mRS progression or a decrease in the patient's mRS score.

[0056] If the reduction of NMOSD-related disorder is defined as a reduction in the deterioration of the patient's mRS score, then the reduction in mRS score deterioration may be a deterioration of 0.5 points or less, 1 point or less, 1.5 points or less, or 2 points or less from the patient's baseline mRS score over a period of time. The period over which the patient's baseline mRS score deteriorates by 0.5 points or less, 1 point or less, 1.5 points or less, or 2 points or less may be at least 6 months, 9 months, 1 year, 1.5 years, 2 years, 3 years, 4 years, 5 years, 7.5 years, or 10 years. The baseline mRS score of a patient for whom a reduction in deterioration is determined may be the patient's mRS score approximately 1 month, 2 weeks, 1 week, 3 days, 2 days, or 1 day prior to the administration of the first dose of VIB551. The patient's baseline mRS score may be the patient's mRS score at the time of administration of the first VIB551 dose, or the patient's mRS score within 1 day, 2 days, 3 days, 1 week, 2 weeks, or 1 month after administration of the first VIB551 dose.

[0057] If the reduction in NMOSD-related impairment is due to a decrease in the patient's mRS score, the patient's mRS score may decrease or decline by at least 0.5 points, at least 1 point, at least 1.5 points, or at least 2 points. A decrease or decline of at least 0.5 points, at least 1 point, at least 1.5 points, or at least 2 points in the patient's mRS score may occur over a period of approximately 2 weeks, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 9 months, 12 months, or 18 months. The period over which the patient's mRS score decreases may begin within 1 month, 2 weeks, 1 week, 3 days, 2 days, or 1 day after administration of the first VIB551 dose, or may occur concurrently with administration of the first VIB551 dose, or may occur within 1 day, 2 days, 3 days, 1 week, 2 weeks, or 1 month after administration of the first VIB551 dose. The period during which a patient's mRS score declines may begin at the time of an NMOSD seizure, or within 1, 2, 3, 4, 5, 6, or 7 days after the onset of an NMOSD seizure.

[0058] VIB551 may also be used in a method for reducing NMOSD-related seizures in a patient requiring treatment for NMOSD, wherein the patient has previously been treated with an anti-CD20 antibody. In some embodiments, the disclosure provides a method for reducing NMOSD-related seizures in a patient requiring treatment for NMOSD, comprising the step of administering an anti-CD19 antibody VIB551 to the patient requiring treatment for NMOSD, wherein the patient has previously been treated with an anti-CD20 antibody and has experienced NMOSD seizures while being treated with the anti-CD20 antibody. In some embodiments, the disclosure provides a method for reducing NMOSD-related seizures in a patient requiring treatment for NMOSD, comprising the step of administering an anti-CD19 antibody VIB551 in a dose of approximately 300 mg to the patient requiring treatment for NMOSD, wherein the patient has previously been treated with an anti-CD20 antibody and has not experienced NMOSD seizures while being treated with the anti-CD20 antibody. For example, prior to administration of VIB551, the patient may have received anti-CD20 antibody therapy for up to 1 month, 2 months, 4 months, 6 months, 12 months, 2 years, 3 years, 4 years, 5 years, 6 years, or longer. Typically, prior anti-CD20 antibody therapy is administered for at least approximately 12 months before administering VIB551. VIB551 may be administered in doses of approximately 300 mg, and optionally, one or more subsequent 300 mg VIB551 bolus doses may be administered every 6 months thereafter.

[0059] VIB551 may also be used in methods for treating NMOSD in patients. In some embodiments, the method involves administering the anti-CD19 antibody VIB551 as monotherapy, on an optional basis, to patients requiring treatment for NMOSD, the patients having previously been treated with an anti-CD20 antibody for at least 12 months and up to 5 years, and receiving one or more doses of approximately 300 mg of the anti-CD19 antibody VIB551 (each dose of VIB551 is administered at intervals of approximately 6 months) after discontinuation of anti-CD20 treatment.

[0060] In some embodiments, a method of treating NMOSD in a patient comprises administering the anti-CD19 antibody VIB551 as monotherapy, on an optional basis, to a patient requiring treatment for NMOSD, wherein the patient has been previously treated with an anti-CD20 antibody, and anti-CD20 treatment is discontinued after one, two, or three NMOSD-related seizures, and after discontinuation of anti-CD20 treatment, one or more doses of the anti-CD19 antibody VIB551 of approximately 300 mg are administered, with each dose of VIB551 administered at intervals of approximately 6 months.

[0061] In some embodiments, the disclosure provides a method for reducing NMOSD-related seizures in a patient requiring treatment for NMOSD, comprising the step of administering an anti-CD19 antibody VIB551 to a patient requiring treatment for NMOSD, wherein the patient has been previously treated with an anti-CD20 antibody and has experienced an NMOSD seizure within six months of the last dose of the anti-CD20 antibody. The reduction in NMOSD-related seizures in the patient may be a reduction in the number of NMOSD-related seizures the patient experienced in a first period compared to a second period. The first period may occur after administration of a first dose of VIB551 and the second period may occur before administration of the first dose of VIB551. The first period may occur immediately after administration of the first dose of VIB551 and the second period may end immediately before administration of the first dose of VIB551. The first and second periods may be of equal length. For example, both the first and second periods could be at least 6 months, or 6 months, or at least 12 months, or 12 months, or at least 18 months, or 18 months, or at least 24 months, or 24 months, or at least 30 months, or 30 months, or at least 36 months, or 36 months, or at least 42 months, or 42 months, or at least 48 months, or 48 months, or at least 54 months, or 54 months, or at least 60 months, or 60 months.

[0062] The reduction in the number of NMOSD-related seizures experienced by the patient in the first period compared to the second period may be such that the patient experiences at least one fewer seizure, or at least two fewer seizures, or at least three fewer seizures, or at least four fewer seizures, or at least five fewer seizures, or at least five fewer seizures, compared to the second period. NMOSD-related seizures experienced by the patient in the first and / or second periods may be optic neuritis seizures, myelitis seizures, or brainstem seizures. If the patient experiences NMOSD-related seizures in the first period, these seizures may not be in the same area as the NMOSD-related seizures experienced by the patient in the second period, e.g., the optic nerve, spinal cord, or brain / brainstem.

[0063] In patients requiring treatment for NMOSD, the number of NMOSD-related seizures that may be reduced may be NMOSD-related seizures characterized by the appearance of new NMOSD symptoms, exacerbation of existing NMOSD symptoms, or the appearance of new MRI lesions, whether or not they are symptomatic.

[0064] If an NMOSD-related seizure is characterized by a new symptom or an exacerbation of an existing symptom, the new or exacerbating symptom may be an ocular symptom. If the new or exacerbating symptom is an ocular symptom, it may be eye pain, a new optic nerve lesion, an enlargement of an optic nerve lesion, blurred vision, visual acuity loss, or a decrease of 5 or more letters on a low-contrast Landolt ring visual acuity chart.An NMOSD-related seizure characterized by new ocular symptoms or exacerbation of existing ocular symptoms may additionally / alternatively meet one or more of the following criteria: a decrease of more than 15 letters on a high-contrast Landolt visual acuity chart since the most recent visit, measured in the previously affected eye, and no other ophthalmic explanation; a decrease of two or more steps from CF (counting fingers) to NLP (no light perception) since the most recent visit, measured in the previously affected eye, and no other ophthalmic explanation; a decrease of seven or more letters on a low-contrast Landolt visual acuity chart since the most recent visit, measured in only one eye (monocular), and a new RAPD (relative afferent pupillary response deficit) in the affected eye; a decrease of seven or more letters on a low-contrast Landolt visual acuity chart since the most recent visit, measured in only one eye (monocular), and a previously recorded RAPD deficit in the other eye. A decrease of 5 or more letters on a high-contrast Landolt ring visual acuity chart since the most recent visit, measured in one eye, and a new RAPD in the affected eye; a decrease of 5 or more letters on a high-contrast Landolt ring visual acuity chart since the most recent visit, measured in one eye only (monocular), and a previously recorded RAPD deficit in the other eye; a decrease of 1 step § or more from CF to NLP (no light perception) since the most recent visit, measured in the previously affected eye, and a new RAPD in the affected eye; a decrease of 1 step § or more from CF to NLP (no light perception) since the most recent visit, measured in the previously affected eye, and a previously recorded RAPD deficit in the other eye; a decrease of 7 or more letters on a low-contrast Landolt ring visual acuity chart since the most recent visit, measured in one eye only (monocular), and a new Gd-enhancing or new / expanding T2 in the corresponding optic nerve. MRI lesions, a decrease of 5 letters or more on the high-contrast Landolt ring visual acuity chart measured in only one eye (monocular) since the most recent visit, and a new Gd-enhancing or new / expanding T2 MRI lesion in the corresponding optic nerve, or a decrease of 1 step § or more from CF to NLP (no light perception) measured in the previously affected eye since the most recent visit, and a new Gd-enhancing or new / expanding T2 MRI lesion in the corresponding optic nerve.

[0065] If an NMOSD-related seizure is characterized by a new symptom or an exacerbation of an existing symptom, the new or exacerbated symptom may be a spinal cord symptom. If the new or exacerbated symptom is a spinal cord symptom, it may be deep pain or radicular pain, limb paresthesia, weakness, sphincter dysfunction, Lhermitt's sign, a new spinal cord lesion, or an expansion of a spinal cord lesion. An NMOSD-associated seizure characterized by new spinal cord symptoms or worsening of existing spinal cord symptoms may additionally / alternatively meet one or more of the following criteria: worsening of at least one of the relevant (pyramidal, bladder / enterol, sensory) FSS scores by 2 points or more compared to the most recent visit; worsening of at least one EDSS score compared to the most recent visit if the previous EDSS score was 5.5 or higher; worsening of at least two of the relevant (pyramidal, bladder / enterol, sensory) FSS scores by 1 point or more compared to the most recent visit if the most recent visit score was 1 or higher, and a new Gd-enhancing or new / expanding T2 MRI lesion in the spinal cord; worsening of at least 0.5 points in the EDSS score compared to the most recent visit if the previous EDSS score was 5.5 or higher, and a new Gd-enhancing or new / expanding T2 MRI lesion in the spinal cord.

[0066] If an NMOSD-related seizure is characterized by a new symptom or an exacerbation of an existing symptom, the new or exacerbated symptom may be a brain or brainstem symptom. If the new or existing symptom is a brain or brainstem symptom, it may be nausea, diplopia, oculomotor palsy, dizziness, refractory vomiting, refractory hiccups, dysarthria, dysphagia, weakness, encephalopathy, hypothalamic dysfunction, a new brain or brainstem lesion, or an expansion of a brain or brainstem lesion. An NMOSD-associated seizure characterized by new brain / brainstem symptoms or exacerbation of existing brain / brainstem symptoms may additionally / alternatively meet one or more of the following criteria: isolated (not present at the most recent visit) refractory nausea, vomiting, and / or hiccups lasting more than 48 hours, and a new Gd-enhancing or new / expanding T2 MRI lesion in the brainstem, a worsening of 2 or more points on at least one of the relevant (brainstem, cerebellar) FSS compared to the most recent visit, and a new Gd-enhancing or new / expanding T2 MRI lesion in the brainstem, or a worsening of 2 or more points on at least one of the relevant (cerebral, sensory, pyramidal) FSS compared to the most recent visit (score of 3 or higher at the original visit), and a new Gd-enhancing or new / expanding T2 MRI lesion in the brain consistent with the clinical presentation.

[0067] NMOSD-related seizures may be characterized by any combination of one, two, or more new and / or worsening symptoms in the eyes, spinal cord, or brain / brainstem. NMOSD-related seizures may be characterized by any combination of two, three, or four confirmed symptoms or other criteria in one or more of the eyes, spinal cord, or brain / brainstem.

[0068] Furthermore, NMOSD-related seizures may be characterized by the appearance of new MRI lesions in the patient. These new MRI lesions may, but not necessarily, be symptomatic.

[0069] NMOSD patients to whom VIB551 is administered in the methods disclosed herein may or may not be AQP4-IgG seropositive. NMOSD patients may be screened for AQP4-IgG before administration of VIB551. In some embodiments, VIB551 may be administered in any of the methods disclosed herein to patients with elevated serum Nfl levels above baseline levels (as described in U.S. Provisional Patent Applications No. 63 / 052,093 and No. 63 / 071,092 (these documents are incorporated herein by reference in their entirety)). In some embodiments, VIB551 is administered to patients whose sGFAP concentration is approximately 160 pg / mL, approximately 165 pg / mL, approximately 166 pg / mL, approximately 167 pg / mL, approximately 168 pg / mL, approximately 169 pg / mL, approximately 170 pg / mL, approximately 171 pg / mL, approximately 172 pg / mL, or approximately 173 pg / mL or greater (as described in U.S. Provisional Patent Application No. 63 / 046,133, which is incorporated herein by reference in its entirety). When VIB551 is administered to a patient whose sGFAP concentration is approximately 160 pg / mL, 165 pg / mL, 166 pg / mL, 167 pg / mL, 168 pg / mL, 169 pg / mL, 170 pg / mL, 171 pg / mL, 172 pg / mL, or 173 pg / mL or higher, it can be determined that the patient's sGFAP concentration before administration is approximately 160 pg / mL, 165 pg / mL, 166 pg / mL, 167 pg / mL, 168 pg / mL, 169 pg / mL, 170 pg / mL, 171 pg / mL, 172 pg / mL, or 173 pg / mL or higher.

[0070] In some embodiments, anti-CD19 antibodies other than VIB551, such as MOR00208 (also known as Xmab 5574 or tafacitamab; disclosed in U.S. Patent Application Publication No. 2017 / 0137516), may be used in the therapeutic methods disclosed herein. In certain embodiments of these embodiments, the Disclosure provides a method for treating NMOSD comprising the step of administering an anti-CD19 antibody to a patient in need of treatment for NMOSD, wherein the patient has been previously treated with an anti-CD20 antibody, and the patient has experienced an NMOSD attack while being treated with the anti-CD20 antibody. In some embodiments, the Disclosure provides a method for treating NMOSD comprising the step of administering an anti-CD19 antibody to a patient in need of treatment for NMOSD, wherein the patient has been previously treated with an anti-CD20 antibody, and the patient has experienced an NMOSD attack within six months of the last administration of the anti-CD20 antibody. In some embodiments, the anti-CD20 antibody may be rituximab (antibody C2B8 in international publication brochure 94 / 11026).In some embodiments, the anti-CD20 antibodies that the patient may have been previously treated with include: ABP-300 (Abpro), B-001 (Shanghai Pharmaceuticals Holding), BAT-4306F (Bio-Thera Solutions), BAT-4406F (Bio-Thera Solutions), BCD-132 (Biocad Biotechnology), BVX-20 (Vaccinex), CYT-202 (Cytovia Therapeutics), epcolitamab (Genmab), GB-261 (Genor Biopharma), GD-CO1620 (ManysmarT); grofitamab (Roche), HS-006 (Zhejiang Hisun Pharmaceutical), IGM-2323 (IGM Biosciences), IMM-0306 (ImmuneOnco Biopharma); MIL-62 (Beijing Mabworks) These include Biotech, mosnetuzumab (Roche), MRG-001 (Shanghai Miracogen), obinutuzumab (Roche), ocrelizumab (Roche, Niogen), odronextumab (Regeneron); ofatumumab (Genmab, Novartis), pramotamab (Xencor), SM-09 (SinoMab BioScience), TRS-005 (Zhejiang Teruisi Biopharma), ubrituximab (rEVO Biologics), or YBL-031 (Y-Biologics).

[0071] In some embodiments, other than VIB551 (also known as MEDI551, Uplizna® or inebilizumab; disclosed in U.S. Patent Application No. 11 / 852,106 and International Patent Application No. PCT / US20 / 29613, these documents are incorporated herein by reference in their entirety), for example, MOR00208 (also known as Xmab 5574 or tafacitamab; disclosed in U.S. Patent Application Publication No. 2017 / 0137516, this document is incorporated herein by reference in its entirety); blinatumomab (Amgen; Astellas; MicroMet); ronkastuximab tesirin (ADC Therapeutics); GTB-1550 / OXS-1550 (Oxis Biotech Inc); obexerimab / XmAb5871 (Xencor The anti-CD19 antibody administered to the patient is either Inc); AFM11 (Affimed); or cortuximab / labtansine (ImmunoGen Inc).

[0072] In some embodiments, when the anti-CD19 antibody VIB551 is administered in any of the methods disclosed herein, VIB551 may have the VH amino acid sequence and VL amino acid sequence shown in Figure 4. In some embodiments, VIB551 may include a heavy chain variable region (VH) containing the amino acid of SEQ ID NO: 1 and a light chain variable region (VL) containing the amino acid of SEQ ID NO: 2. VIB551 administered in this method may have the VH amino acid sequence and VL amino acid sequence shown in Figure 4, apart from changes in one or more amino acid residues that do not alter the function of the VIB551 amino acid sequence. The number of amino acid changes may be one amino acid residue change, two amino acid residue changes, three amino acid residue changes, four amino acid residue changes, or five amino acid residue changes. In certain embodiments, VIB551 used in the methods disclosed herein is at least about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, or identical to the VH and VL sequences disclosed in Figure 4. The VIB551 administered in the methods may include the complementarity-determining region (CDR) amino acid sequences of the VH and VL sequences shown in Figure 4 and Sequence Listing 1, but may have one or more modifications in the framework region (i.e., residues other than CDR residues) of the VH and VL domain sequences shown in Figure 4 and Table 1. Alternatively, the VIB551 administered in any of the methods disclosed herein may have the heavy-chain amino acid sequence and light-chain amino acid sequence shown in Figure 9. In some embodiments, VIB551 may include a heavy chain containing the amino acids of SEQ ID NO: 3 and a light chain containing the amino acids of SEQ ID NO: 4. The VIB551 administered in this method may have the heavy-chain and light-chain amino acid sequences shown in Figure 9, apart from changes in one or more amino acid residues that do not alter the function of the VIB551 amino acid sequence. The number of amino acid changes may be one, two, three, four, or five amino acid residues.In some embodiments, VIB551 used in the manner disclosed herein is at least about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, or identical to the heavy and light chain sequences disclosed in Figure 9.

[0073] (Table 1) VIB551 TIFF0007900888000001.tif41166

[0074] In any method disclosed herein, if VIB551 is an anti-CD19 antibody administered to a patient in need, VIB551 may be administered in a dose of approximately 300 mg. In some embodiments, VIB551 may be administered in doses of approximately 250 mg to approximately 350 mg, approximately 275 mg to approximately 325 mg, approximately 290 mg to approximately 310 mg, approximately 205 mg to approximately 305 mg, or 300 mg. In some embodiments, a patient may be administered one or more initial doses of VIB551. In one embodiment, a patient may be administered one, two, three, or more initial doses. In certain embodiments, the initial dose may be approximately 300 mg. In some embodiments, VIB551 may be administered in initial doses of approximately 250 mg to approximately 350 mg, approximately 275 mg to approximately 325 mg, approximately 290 mg to approximately 310 mg, approximately 205 mg to approximately 305 mg, or 300 mg. In certain embodiments, VIB551 is administered intravenously in a first initial dose of approximately 300 mg, a second initial dose of approximately 300 mg two weeks after the first initial dose, and a subsequent dose of approximately 300 mg every six months after the first initial dose.

[0075] When VIB551 is administered in the manner disclosed herein, it may be administered at intervals of approximately 6 months. In some embodiments, VIB551 may be administered intravenously. The approximately 6-month interval may be every 6 months, every 180 days, every 170-190 days, every 175-185 days, every 175-190 days, or every 170-185 days. The approximately 6-month interval may be every 26 weeks, every 25 weeks, every 27 weeks, every 25-27 weeks, every 25-26 weeks, or every 26-27 weeks. In this method, an initial dose of VIB551 may be administered to the NMOSD patient before the approximately 6-month interval VIB551 administration. The initial dose of VIB551 may be administered approximately 2 weeks before the approximately 6-month interval VIB551 administration. The initial dose of VIB551 administered approximately two weeks before the approximately six-month VIB551 administration may be administered 12, 13, 14, 15, or 16 days before the approximately six-month VIB551 administration. The initial dose of VIB551 may or may not be administered concurrently with oral corticosteroids.

[0076] In some embodiments, the present disclosure provides a method for treating NMOSD, comprising the step of administering an anti-CD19 antibody VIB551 to a patient in need of treatment for NMOSD, the patient being an AQP4-IgG+ patient, the VIB551 being administered intravenously in a first initial dose of 300 mg, a second initial dose of 300 mg two weeks after the first initial dose, and a subsequent dose of 300 mg every six months after the first initial dose, the patient having been previously treated with an anti-CD20 antibody, and the patient having experienced an NMOSD seizure while being treated with the anti-CD20 antibody. In one embodiment, the present disclosure provides a method for treating NMOSD, comprising the step of administering an anti-CD19 antibody VIB551 to a patient in need of treatment for NMOSD, the patient being an AQP4-IgG+ patient, and VIB551 being administered intravenously in a first initial dose of 300 mg, a second initial dose of 300 mg two weeks after the first initial dose, and a subsequent dose of 300 mg every six months after the first initial dose, the patient having been previously treated with an anti-CD20 antibody, and the patient having experienced an NMOSD attack within six months of the last administration of the anti-CD20 antibody. In some embodiments, the anti-CD20 antibody is rituximab (antibody C2B8 in International Publication No. 94 / 11026).

[0077] A method for treating pediatric patients with AQP4-IgG seropositive NMOSD using the anti-CD19 antibody VIB551 is also provided herein. NMOSD in pediatric patients can be determined according to the criteria of Wingerchuk et al. “International consensus diagnostic criteria for neuromyelitis optica spectrum disorders. Neurology.” 2015;85(2):177-89. Subjects are typically seropositive for AQP4-IgG, but subjects with NMOSD, but seronegative for AQP4-IgG are also intended. In some embodiments, patients have experienced one or more acute relapses of NMOSD in the last year prior to treatment, or two or more acute relapses of NMOSD in the last two years. Pediatric subjects may be male or female and may be between 2 and under 18 years of age, e.g., 2 to under 6 years, 6 to under 12 years, 12 to under 18 years, or 2 to under 12 years.

[0078] The dose administered to pediatric patients is determined by body weight. If the patient's weight is 37.5 kg or less, 8 mg / kg is administered intravenously. If the patient's weight exceeds 37.5 kg, 300 mg is administered intravenously. Patients whose weight increases from 37.5 kg or less to over 37.5 kg during treatment with the anti-CD19 antibody VIB551 can have their regimen switched from 8 mg / kg to 300 mg. The anti-CD19 antibody VIB551 is typically administered as monotherapy. One or more subsequent doses may be administered after the initial dose. Subsequent doses may be administered at intervals of approximately 24-28 weeks, 12 months, 30 months, 36 months, or 48 months, and treatment is maintained as long as necessary. While the anti-CD19 antibody VIB551 is typically administered as monotherapy, corticosteroids may be administered concurrently in the early stages of treatment for pediatric patients. However, corticosteroid therapy is typically tapered off immediately after the initiation of antibody therapy, for example, one, two, three, or four weeks after the first dose is administered. In some embodiments, VIB551 is administered intravenously in a first initial dose of 300 mg, a second initial dose of 300 mg two weeks after the first initial dose, and a subsequent dose of 300 mg every six months after the first initial dose.

[0079] The monoclonal antibody VIB551 may be administered to hepatitis B virus carriers. In hepatitis B virus carriers who have previously received anti-CD20 monoclonal antibody therapy to reduce B cell counts, death due to fulminant hepatitis, exacerbation of hepatitis, or liver failure during or after treatment have been reported. Hepatitis B virus reactivation has also been reported in these patients. However, these reactions have not been reported with the anti-CD19 monoclonal antibody VIB551. Nevertheless, to provide improved patient confidence and health management, patients may have their HBV status assessed before initiating VIB551 therapy and / or be monitored for signs and symptoms of hepatitis B virus reactivation through regular liver function tests and monitoring of hepatitis virus markers.

[0080] In patients already receiving treatment for HBV infection, liver status can be monitored using parameters such as an elevated or fluctuating ALT (alanine aminotransferase) / AST (aspartate aminotransferase) ratio and an increase in serum viral load. (Villadolid et al., “Hepatitis B reactivation and rituximab in the oncology practice.” Oncologist. 2010;15(10):1113-21).

[0081] Before administering the anti-CD19 antibody VIB551, the patient's HBV status can be tested. For example, the following blood tests can be used: First, a blood sample is prepared from the patient, serum is obtained, and HB antigen (hereinafter, HBsAg) is measured. If the HBsAg test is positive, the patient is considered to have an active HBV infection, and the anti-CD19 antibody VIB551 is contraindicated. If the HBsAg test is negative, HBc antibody (hereinafter, HBcAb) and / or HBs antibody (hereinafter, HBsAb) are measured, and if either is positive, VIB551 may be administered. Patients who are negative for HBsAg, HBcAb, and HBsAb do not require regular liver function tests and monitoring of hepatitis virus markers.

[0082] HBsAg, HBcAb, or HBsAb can be measured by ELISA or CLIA (including equivalent FEIA / ECLIA / CLEIA / BLEIA) using their respective antibody or antigen detection / measurement reagents. For example, HBsAg can be measured by STACIA CLEIA HB antigen (LSI Medience Corp. Japan) (www.info.pmda.go.jp / downfiles / ivd / pdf / 750524_21800 AMX10883000_A_01_09.pdf), and samples with a cutoff index of 1 or higher are considered positive. HBcAb can be measured by CLIA using ARCHITECT G06277R09 (Abbott Japan LLC; www.info.pmda.go.jp / downfiles / ivd / PDF / 100159_22100AMX02283000_A_02_01.pdf), and samples with a cutoff index of 1 or more are considered positive. For example, HBsAb can be measured by CLIA using ARCHITECT G06255R03 (Abbott Japan LLC.) (www.info.pmda.go.jp / downfiles / ivd / PDF / 100159_21000 AMY00120000_A_01_10.pdf).

[0083] In any method disclosed herein, VIB551 may be packaged in a 10 mL vial filled with a nominal 10 mL solution of VIB551. In some embodiments, VIB551 may be formulated at a concentration of 10 mg / mL. In some embodiments, the VIB551 formulation may comprise 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.

[0084] In some embodiments, the dose of VIB551 administered to a patient is determined by body weight. If the subject's body weight is 37.5 kg or less, 8 mg / kg is administered intravenously. If the patient's body weight is greater than 37.5 kg, 300 mg is administered intravenously. Subjects whose body weight increases from 37.5 kg or less to greater than 37.5 kg during treatment with the anti-CD19 antibody VIB551 can have their regimen switched from 8 mg / kg to 300 mg. The anti-CD19 antibody VIB551 is typically administered as monotherapy.

[0085] The dose of VIB551 that may be used in a method of treating patients requiring treatment for NMOSD may be a dose of VIB551 that depletes at least 90% of circulating CD20+ B cells for at least 6 months without increasing the risk of infection in the patient. The VIB551 dose may be approximately 250 mg to approximately 350 mg, approximately 275 mg to approximately 325 mg, approximately 290 mg to approximately 310 mg, approximately 205 mg to approximately 305 mg, or 300 mg. In some embodiments, the patient may be administered one or more initial doses of VIB551. In one embodiment, the patient may be administered one, two, three, or more initial doses. In certain embodiments, the initial dose may be approximately 300 mg. In some embodiments, VIB551 may be administered in initial doses of approximately 250 mg to approximately 350 mg, approximately 275 mg to approximately 325 mg, approximately 290 mg to approximately 310 mg, approximately 205 mg to approximately 305 mg, or 300 mg. In certain embodiments, VIB551 is administered intravenously in a first initial dose of approximately 300 mg, a second initial dose of approximately 300 mg two weeks after the first initial dose, and a subsequent dose of approximately 300 mg every six months after the first initial dose.

[0086] A dose of VIB551 that can be used in a method of treating patients requiring treatment for NMOSD, which deprives at least 90% of circulating CD20+ B cells for at least 6 months without increasing the risk of infection in the patient, may be a dose administered intravenously at intervals of approximately every 6 months, every 7 months, every 8 months, every 9 months, every 10 months, every 11 months, or every year.

[0087] VIB551 is also used in a method of treating patients requiring treatment for NMOSD, where VIB551 is administered in a dose that (i) depletes at least 90% of circulating CD20+ B cells for at least 6 months and (ii) does not increase the risk of infection in the patient. The dose that depletes at least 90% of circulating CD20+ B cells for at least 6 months is also the dose that does not increase the risk of infection in peripheral blood CD20 - It can cause a deficiency of plasmablasts and plasma cells. A dose that deprives at least 90% of circulating CD20+ B cells for at least 6 months can also reduce or eliminate the plasma cell genetic signature in patients requiring treatment for NMOSD. A dose that deprives at least 90% of circulating CD20+ B cells can cause a deficiency of circulating CD20+ B cells for longer than 6 months. It can cause a deficiency of at least 90% of circulating CD20+ B cells for at least 9 months or at least 1 year.

[0088] A dose of VIB551 that deprives at least 90% of circulating CD20+ B cells for at least 6 months in a treatment regimen also does not increase the risk of infection in NMOSD patients. In NMOSD patients, the risk of infection may not be increased compared to the risk of infection before VIB551 administration. In NMOSD patients, the risk of infection may not be increased compared to NMOSD patients who are not treated with VIB551. The risk of infection is the risk of infection with or may be the risk of infection resulting from typical pneumonia, beta-hemolytic streptococcal infection, bronchitis, conjunctivitis, viral conjunctivitis, fungal skin infection, gastroenteritis, viral gastroenteritis, gastrointestinal infection, gingivitis, cystitis, herpes zoster, influenza, laryngitis, viral meningitis, muscle abscess, oral herpes, otitis externa, periodontitis, pneumonia, rhinitis, retinitis, pyelonephritis, retinitis, sinusitis, urinary tract infection, tinea urinari, septic shock, or upper respiratory tract infection.

[0089] Any method provided herein may further include, before administering an anti-CD19 antibody, for example VIB551, (i) confirming that the patient has been previously treated with an anti-CD20 antibody; (ii) determining whether the patient has had at least one NMOSD seizure while being treated with an anti-CD20 antibody or at least one NMOSD seizure within six months of the last administration of an anti-CD20 antibody; and (iii) selecting the patient to administer the anti-CD19 antibody as a result of that determination.

[0090] Those skilled in the art can recognize or confirm many equivalents to the particular embodiments described herein simply through routine experimentation. Such equivalents are intended to be covered by the appended claims.

[0091] All publications, patents, and patent applications referenced herein are incorporated by reference to the same extent that each individual publication, patent, or patent application is specifically and individually indicated as being incorporated by reference herein.

[0092] Numbered Embodiments of the Invention Notwithstanding the attached claims, this disclosure describes the following numbered embodiments: Embodiment 1. A method for treating neuromyelitis optica spectrum disorder (NMOSD), The process includes administering the anti-CD19 antibody VIB551 to patients requiring treatment for NMOSD. The patient has been previously treated with an anti-CD20 antibody, and the patient has experienced an NMOSD seizure while being treated with the anti-CD20 antibody. method. Embodiment 2. A method for treating NMOSD, The process includes administering the anti-CD19 antibody VIB551 to patients requiring treatment for NMOSD. The patient has been previously treated with anti-CD20 antibodies, and the patient has experienced an NMOSD seizure within 6 months of the last dose of anti-CD20 antibodies. method. Embodiment 3. The method according to Embodiment 1 or Embodiment 2, wherein VIB551 is administered intravenously at a dose of 300 mg every 6 months. Embodiment 4. A method for treating NMOSD, The process includes administering the anti-CD19 antibody VIB551 to patients requiring treatment for NMOSD. The patient has astrocyte water channel aquaporin-4 (AQP4)-immunoglobulin (Ig) G + The patient, VIB551 is administered intravenously at a dose of 300 mg every 6 months. The patient has been previously treated with anti-CD20 antibodies, and the patient experienced NMOSD seizures while being treated with anti-CD20 antibodies. method. Embodiment 5. A method for treating NMOSD, The process includes administering the anti-CD19 antibody VIB551 to patients requiring treatment for NMOSD. Patients with AQP4-IgG + The patient, VIB551 is administered intravenously at a dose of 300 mg every 6 months. The patient has been previously treated with an anti-CD20 antibody and has had an NMOSD attack within 6 months of the last administration of the anti-CD20 antibody. Method. Embodiment 6. The method according to any one of embodiments 3 to 5, wherein the patient is administered at least one initial dose of VIB551. Embodiment 7. The method according to any one of embodiments 3 to 6, wherein VIB551 is administered intravenously at an initial dose of 300 mg, at a second initial dose of 300 mg 2 weeks after the first initial dose, and at subsequent doses of 300 mg every 6 months after the first initial dose. Embodiment 8. The method according to embodiment 6 or embodiment 7, wherein an oral corticosteroid is co-administered to the patient with the initial dose of VIB551. Embodiment 9. The method according to embodiment 8, wherein the oral corticosteroid is administered daily for at least 2 weeks. Embodiment 10. The method according to any one of embodiments 1 to 9, wherein the anti-CD20 antibody is rituximab. Embodiment 11. The treatment is a reduction in the worsening of the Kurtzke Expanded Disability Status Scale (EDSS) in the patient. The method according to any one of embodiments 1 to 10. Embodiment 12. The reduction in the worsening of the EDSS in the patient is When the patient has a baseline score of 0, a worsening of less than 2 points in the EDSS score; When the patient has a baseline score of 1 to 5, a worsening of less than 1 point; or When the patient has a baseline score of 5.5 or higher, a worsening of less than 0.5 points The method according to embodiment 11. Embodiment 13. The treatment is a reduction in the number of active magnetic resonance imaging (MRI) lesions. The method according to any one of embodiments 1 to 10. Embodiment 14. The method according to embodiment 13, wherein the active MRI lesions are enlarged T2 MRI lesions. Embodiment 15. The treatment is a reduction in the number of new MRI lesions. The method according to any one of embodiments 1 to 10. Embodiment 16. The method according to any one of Embodiments 1 to 10, wherein the treatment is reduction of deterioration of the patient's modified Rankin score. Embodiment 17. The method according to any one of Embodiments 1 to 10, wherein the treatment is reduction of the frequency of hospitalization of a patient associated with NMOSD. Embodiment 18. The method according to any one of Embodiments 1 to 10, wherein the treatment is reduction of the risk of NMOSD-related seizures in a patient. Embodiment 19. The method according to Embodiment 18, wherein the NMOSD-related seizure is characterized by the appearance of new symptoms associated with NMOSD or the exacerbation of existing symptoms. Embodiment 20. The method according to Embodiment 19, wherein the symptom is an ocular symptom. Embodiment 21. The method according to Embodiment 20, wherein the ocular symptom is eye pain, blurred vision, vision loss, or the appearance of optic neuropathy detected by MRI. Embodiment 22. The method according to Embodiment 19, wherein the symptom is a spinal cord symptom. Embodiment 23. The method according to Embodiment 22, wherein the spinal cord symptom is deep or radicular pain, limb paresthesia, weakness, sphincter dysfunction, Lhermitte's sign, or a spinal cord lesion detectable by MRI. Embodiment 24. The method according to Embodiment 19, wherein the symptom is a symptom of the brain or brainstem. Embodiment 25. The method according to Embodiment 24, wherein the symptom of the brain or brainstem is nausea, diplopia, oculomotor nerve palsy, dizziness, intractable vomiting, intractable hiccups, dysarthria, dysphagia, weakness, encephalopathy, hypothalamic dysfunction, or a lesion of the brain or brainstem detectable by MRI. Embodiment 26. The method according to Embodiment 1, wherein the reduction of the risk of NMOSD-related seizures is 60-85%. Embodiment 27. The method according to any one of Embodiments 1 to 10, wherein the treatment is reduction of optic neuritis. Embodiment 28. The method according to any one of Embodiments 1 to 10, wherein the treatment is reduction of the severity of NMOSD-related seizures. Embodiment 29. The method according to Embodiment 28, wherein the reduction of the severity of NMOSD-related seizures is the reduction of NMOSD-related seizures graded as grand mal seizures. Embodiment 30. The method according to Embodiment 28, wherein the reduction in the severity of NMOSD-related seizures is defined as a reduction in NMOSD seizures requiring hospitalization. Embodiment 31. The method according to any one of Embodiments 1 to 10, wherein the treatment is a reduction in NMOSD-related pain in the patient. Embodiment 32. The method according to Embodiment 31, wherein the reduction in NMOSD-related pain is determined by measuring the patient's leg pain. Embodiment 33. The method according to any one of Embodiments 1 to 5, wherein the initial dose of 300 mg of VIB551 is administered to the subject two weeks before the first dose of 300 mg of VIB551 administered every 6 months. Embodiment 34. The method according to Embodiment 33, wherein an oral corticosteroid is administered to the patient simultaneously with an initial dose of 300 mg of VIB551. Embodiment 35. The method according to Embodiment 1 or Embodiment 2, wherein the patient is AQP4-IgG seropositive. Embodiment 36. A method for reducing active MRI lesions in patients diagnosed with NMOSD, The process includes administering the anti-CD19 antibody VIB551 to patients requiring treatment for NMOSD. The patient has been previously treated with anti-CD20 antibodies, and the patient experienced NMOSD seizures while being treated with anti-CD20 antibodies. method. Embodiment 37. A method for reducing active MRI lesions in patients diagnosed with NMOSD, The process includes administering the anti-CD19 antibody VIB551 to patients requiring treatment for NMOSD. The patient has been previously treated with anti-CD20 antibodies, and the patient has experienced an NMOSD seizure within 6 months of the last dose of anti-CD20 antibodies. method. Embodiment 38. The method according to Embodiment 36 or 37, wherein VIB551 is administered intravenously at a dose of 300 mg every six months. Embodiment 39. A method for reducing active MRI lesions in patients diagnosed with NMOSD, The process includes administering the anti-CD19 antibody VIB551 to patients requiring treatment for NMOSD. The patient has been previously treated with anti-CD20 antibodies, and the patient experienced NMOSD seizures while being treated with anti-CD20 antibodies. VIB551 is administered intravenously at a dose of 300 mg every six months. method. Embodiment 40. A method for reducing active MRI lesions in patients diagnosed with NMOSD, The process includes administering the anti-CD19 antibody VIB551 to patients requiring treatment for NMOSD. The patient has been previously treated with anti-CD20 antibodies, and the patient has experienced an NMOSD seizure within 6 months of the last dose of anti-CD20 antibodies. VIB551 is administered intravenously at a dose of 300 mg every six months. method. Embodiment 41. AQP4-IgG requiring treatment for NMOSD + A method for reducing the AQP4-IgG titer of a patient, The process includes administering the anti-CD19 antibody VIB551 to patients requiring treatment for NMOSD. The patient has been previously treated with anti-CD20 antibodies, and the patient experienced NMOSD seizures while being treated with anti-CD20 antibodies. method. Embodiment 42. AQP4-IgG requiring treatment for NMOSD + A method for reducing the AQP4-IgG titer of a patient, The process includes administering the anti-CD19 antibody VIB551 to patients requiring treatment for NMOSD. The patient has been previously treated with anti-CD20 antibodies, and the patient has experienced an NMOSD seizure within 6 months of the last dose of anti-CD20 antibodies. method. Embodiment 43. The method according to Embodiment 41 or 42, wherein VIB551 is administered intravenously at a dose of 300 mg every six months. Embodiment 44. AQP4-IgG requiring treatment for NMOSD + A method for reducing the AQP4-IgG titer of a patient, The process includes administering the anti-CD19 antibody VIB551 to patients requiring treatment for NMOSD. The patient has been previously treated with anti-CD20 antibodies, and the patient experienced NMOSD seizures while being treated with anti-CD20 antibodies. VIB551 is administered intravenously at a dose of 300 mg every six months. method. Embodiment 45. AQP4-IgG requiring treatment for NMOSD + A method for reducing the AQP4-IgG titer of a patient, The process includes administering the anti-CD19 antibody VIB551 to patients requiring treatment for NMOSD. The patient has been previously treated with anti-CD20 antibodies, and the patient has experienced an NMOSD seizure within 6 months of the last dose of anti-CD20 antibodies. VIB551 is administered intravenously at a dose of 300 mg every six months. method. Embodiment 46. The method according to any one of Embodiments 1 to 45, wherein the administration depletes at least 90% of circulating CD20+ B cells for at least 6 months. Embodiment 47. The method according to any one of Embodiments 1 to 46, wherein the administration does not increase the risk of infection in the patient. Embodiment 48.VIB551 is administered to peripheral blood CD20 within 8 days after administration. - A method according to any one of Embodiments 1 to 47, which depletes plasmablasts and plasma cells. Embodiment 49. A method for reducing NMOSD-related disorders in patients diagnosed with NMOSD, The process includes administering the anti-CD19 antibody VIB551 to patients requiring treatment for NMOSD. The patient has been previously treated with anti-CD20 antibodies, and the patient experienced NMOSD seizures while being treated with anti-CD20 antibodies. method. Embodiment 50. A method for reducing NMOSD-related disorders in patients diagnosed with NMOSD, The process includes administering the anti-CD19 antibody VIB551 to patients requiring treatment for NMOSD. The patient has been previously treated with an anti-CD20 antibody and has had an NMOSD attack within 6 months from the last administration of the anti-CD20 antibody. Method. The method according to embodiment 49 or 50, wherein VIB551 is administered intravenously at a dose of 300 mg every 6 months. A method for reducing NMOSD-related disorders in a patient diagnosed with NMOSD, comprising the step of administering an anti-CD19 antibody VIB551 to a patient who requires treatment for NMOSD, The patient has been previously treated with an anti-CD20 antibody and has had an NMOSD attack during treatment with the anti-CD20 antibody. VIB551 is administered intravenously at a dose of 300 mg every 6 months. Method. A method for reducing NMOSD-related disorders in a patient diagnosed with NMOSD, comprising the step of administering an anti-CD19 antibody VIB551 to a patient who requires treatment for NMOSD, The patient has been previously treated with an anti-CD20 antibody and has had an NMOSD attack within 6 months from the last administration of the anti-CD20 antibody. VIB551 is administered intravenously at a dose of 300 mg every 6 months. Method. The method according to any one of embodiments 49 to 53, wherein the reduction of the patient's NMOSD-related disorder is a reduction in the rate of deterioration of the patient's NMOSD-related disorder. The method according to any one of embodiments 49 to 54, wherein the reduction of the patient's NMOSD-related disorder is a remission of the patient's NMOSD-related disorder. The method according to any one of embodiments 49 to 55, wherein the NMOSD-related disorder is neuropathy. The method according to any one of embodiments 49 to 56, wherein the reduction of the NMOSD-related disorder is determined using the EDSS. A method for reducing NMOSD-related attacks in a patient who requires treatment for NMOSD, The process includes administering the anti-CD19 antibody VIB551 to patients requiring treatment for NMOSD. The patient has been previously treated with anti-CD20 antibodies, and the patient experienced NMOSD seizures while being treated with anti-CD20 antibodies. method. Embodiment 59. A method for reducing NMOSD-related seizures in patients requiring treatment for NMOSD, The process includes administering the anti-CD19 antibody VIB551 to patients requiring treatment for NMOSD. The patient has been previously treated with anti-CD20 antibodies, and the patient has experienced an NMOSD seizure within 6 months of the last dose of anti-CD20 antibodies. method. Embodiment 60. The method according to Embodiment 58 or 59, wherein VIB551 is administered intravenously at a dose of 300 mg every six months. Embodiment 61. A method for reducing NMOSD-related seizures in patients requiring treatment for NMOSD, The process includes administering the anti-CD19 antibody VIB551 to patients requiring treatment for NMOSD. The patient has been previously treated with anti-CD20 antibodies, and the patient experienced NMOSD seizures while being treated with anti-CD20 antibodies. VIB551 is administered intravenously at a dose of 300 mg every six months. method. Embodiment 62. A method for reducing NMOSD-related seizures in patients requiring treatment for NMOSD, The process includes administering the anti-CD19 antibody VIB551 to patients requiring treatment for NMOSD. The patient has been previously treated with anti-CD20 antibodies, and the patient has experienced an NMOSD seizure within 6 months of the last dose of anti-CD20 antibodies. VIB551 is administered intravenously at a dose of 300 mg every six months. method. Embodiment 63. The method according to Embodiment 61 or Embodiment 62, wherein the NMOSD-related seizures experienced by the patient include one or more of the following: optic neuritis, myelitis, or brainstem seizures. Embodiment 64. The method according to Embodiment 63, wherein the NMOSD-related seizures experienced by the patient are clinically asymptomatic. Embodiment 65. The method according to any one of Embodiments 36 to 64, wherein the patient is administered at least one initial dose of VIB551. Embodiment 66. The method according to Embodiment 65, wherein VIB551 is administered intravenously in a first initial dose of 300 mg, a second initial dose of 300 mg two weeks after the first initial dose, and a subsequent dose of 300 mg every six months after the first initial dose. Embodiment 67. The method according to Embodiment 66, wherein an oral corticosteroid is administered to the patient simultaneously with an initial dose of 300 mg of VIB551. Embodiment 68. The method according to Embodiment 67, wherein an oral corticosteroid is administered daily for at least two weeks. Embodiment 69. The method according to any one of Embodiments 36 to 68, wherein the anti-CD20 antibody is rituximab. Embodiment 70. The method according to any one of Embodiments 1 to 69, wherein VIB551 comprises a heavy chain variable region (VH) containing the amino acid of SEQ ID NO: 1 and a light chain variable region (VL) containing the amino acid of SEQ ID NO: 2. Embodiment 71. A method for treating NMOSD, The process includes administering an anti-CD19 antibody to a patient requiring treatment for NMOSD. The patient has been previously treated with anti-CD20 antibodies, and the patient experienced NMOSD seizures while being treated with anti-CD20 antibodies. method. Embodiment 72. A method for treating NMOSD, The process includes administering an anti-CD19 antibody to a patient requiring treatment for NMOSD. The patient has been previously treated with anti-CD20 antibodies, and the patient has experienced an NMOSD seizure within 6 months of the last dose of anti-CD20 antibodies. method. Embodiment 73. A method for treating NMOSD, The process includes administering the anti-CD19 antibody VIB551 to patients requiring treatment for NMOSD. Patients with AQP4-IgG + The patient, VIB551 is administered intravenously as a first initial dose of 300 mg, a second initial dose of 300 mg two weeks after the first initial dose, and a subsequent dose of 300 mg every six months after the first initial dose. The patient has been previously treated with anti-CD20 antibodies, and the patient experienced NMOSD seizures while being treated with anti-CD20 antibodies. method. Embodiment 74. A method for treating NMOSD, The process includes administering the anti-CD19 antibody VIB551 to patients requiring treatment for NMOSD. Patients with AQP4-IgG + The patient, VIB551 is administered intravenously as a first initial dose of 300 mg, a second initial dose of 300 mg two weeks after the first initial dose, and a subsequent dose of 300 mg every six months after the first initial dose. The patient has been previously treated with anti-CD20 antibodies, and the patient has experienced an NMOSD seizure within 6 months of the last dose of anti-CD20 antibodies. method. Embodiment 75. Before administration, A step to confirm that the patient has been previously treated with an anti-CD20 antibody; Patient (i) At least one NMOSD seizure occurred while being treated with an anti-CD20 antibody; or (ii) Have you experienced at least one NMOSD seizure within 6 months of your last dose of anti-CD20 antibody? The process of determining; and (i) or (ii) the step of selecting a patient to administer an anti-CD19 antibody as a result of the decision. The method according to any one of embodiments 1 to 74, further comprising: Embodiment 76. A method for treating neuromyelitis optica spectrum disorder (NMOSD), The process includes administering the anti-CD19 antibody VIB551 to patients requiring treatment for NMOSD. The patient has been previously treated with anti-CD20 antibodies, and the patient experienced NMOSD seizures while being treated with anti-CD20 antibodies. The procedure includes the steps of collecting a blood sample from a patient before administering the anti-CD19 antibody VIB551, testing the sample for the presence of HBs antigen, HBc antibody, and HBs antibody, and administering the anti-CD19 antibody VIB551 to a patient who is negative for the HBs antigen test and positive for HBc antibody or HBs antibody or both. The procedure includes, optionally, monitoring of regular liver function tests during and after treatment with the anti-CD19 antibody VIB551, and monitoring of hepatitis virus markers. method. Embodiment 77. A method for treating neuromyelitis optica spectrum disorder (NMOSD), The process includes administering the anti-CD19 antibody VIB551 to patients requiring treatment for NMOSD. The patient is HBs antigen negative and HBs antibody positive, HBc antibody positive, or both. method. Embodiment 78. The method according to Embodiment 77, wherein the patient has been previously treated with an anti-CD20 antibody. Embodiment 79. The method according to Embodiment 78, wherein the patient is experiencing an NMOSD seizure while being treated with an anti-CD20 antibody. [Examples]

[0093] Example 1 - Rationale for elements of the clinical trial design Summary. The N-MOmentum NMOSD clinical trial was designed as a randomized, placebo-controlled, double-blind, 197-day Phase 2 / 3 trial with an open-label extension period to evaluate the efficacy and safety of VIB551 (also known as VIB551 or MedI551), a B-cell depleting anti-CD19 antibody, in NMOSD patients recruited from 99 sites in 24 countries. Participants were randomized (3:1) to receive intravenous VIB551 300 mg or placebo on days 1 and 15, respectively, using an interactive voice response system / interactive web response system. Efficacy endpoints were evaluated in the intent-to-treat population, and safety endpoints were evaluated in the as-treated population. The primary endpoint was the time of the first seizure, and secondary endpoints included disability progression, magnetic resonance imaging (MRI) lesion activity, and hospitalization. A more detailed description of the N-Momentum clinical trial is provided in Cree et al., Lancet 394:1352-1363 (2019) and in International Patent Application No. PCT / US20 / 29613, which is incorporated herein by reference in its entirety.

[0094] Selection of treatment group. The placebo-controlled treatment group was selected because there are currently no approved medications for the treatment of neuromyelitis optica spectrum disorder. The use of the placebo group allows for a clear and robust evaluation of VIB551, avoids confounding effects of other treatments, provides the best sensitivity and robustness to detect efficacy, and helps to yield clinically meaningful outcomes for this study.

[0095] Randomization. The 3:1 randomization ratio used in this study was an effective and efficient approach to building an enhanced safety database for VIB551 while maintaining the minimum acceptable number of events or patients required in the placebo group. This randomization ratio also addressed, to some extent, the ethical concerns of the investigators and patients regarding the enrollment of patients in the placebo group. In addition to limiting the number of patients who received placebo, the study was designed to limit the actual duration of placebo exposure to a maximum of 197 days or the time until the onset of a seizure, whichever came first, after which all patients entered an open-label period with the option to receive VIB551.

[0096] Prior to randomization, patients were stratified based on AQP4-IgG serum status (measured at screening) and region (Japan vs. non-Japan). Within each stratification, patients were randomized in a 3:1 ratio using an interactive voice response system / interactive web response system (IVRS / IWRS) with a replacement-block randomization scheme to the treatment group and the assignment of blinded investigational drug kit numbers. Patients were considered randomized to the study when the principal investigator notified IVRS / IWRS that the patient met the eligibility criteria and IVRS / IWRS assigned the patient a masked investigational drug kit number.

[0097] Blinded. This was a double-blind study. VIB551 and placebo were similarly labeled and indistinguishable in appearance. Both were supplied as clear to milky white, colorless to yellow liquids and contained no or substantially no particles. The doses of VIB551 and placebo could not be distinguished during dose preparation, handling, and injection.

[0098] Neither the patient / legal representative involved in the patient's treatment or clinical evaluation, nor the principal investigator or staff of the clinical trial sponsor, were aware of the treatment received. If the patient's medication allocation became known, the clinical trial sponsor was immediately notified.

[0099] The administration of a blinded dose of VIB551 or placebo on day 15 of the open-label period was necessary to ensure that patients previously randomized to placebo received the exact intravenous loading dose of VIB551 600 mg, or to ensure that patients previously randomized to VIB551 did not receive any additional doses. This blinding mechanism was performed via IVRS to ensure that details of the randomized dosing were not revealed to the investigational sites.

[0100] VIB551 is known to deplete CD19+ B cells. Therefore, flow cytometry results for counting B cells could have been deblinded. These data were not available at the randomized clinical trial sites for the remainder of the trial.

[0101] Early-stage development data in a non-tumor patient population treated with VIB551 suggested that administration may be associated with a potential, unspecified, mild decrease in total immunoglobulins in individual patients. These data were not available to the trial sites after randomization for the remainder of the trial because this decrease could lead to deblinding.

[0102] Example 2 - Requirements and Criteria for Enrolling Clinical Trial Subjects Summary. The primary inclusion criteria were a diagnosis of NMOSD (Wingerchuk DM, Lennon VA, Lucchinetti CF, Pittock SJ, Weinshenker BG. The spectrum of neuromyelitis optica. Lancet Neurol 2007;6:805-15; Wingerchuk DM, Lennon VA, Pittock SJ, Lucchinetti CF, Weinshenker BG. Revised diagnostic criteria for neuromyelitis optica. Neurology 2006;66:1485-9), an EDSS score ≤8.0, and a history of at least one seizure requiring rescue therapy (intravenous corticosteroids, intravenous immunoglobulin, and / or plasma exchange) within one year prior to screening, or at least two seizures requiring rescue therapy within two years prior to screening. Patients with AQP4-IgG seropositive and seronegative status were eligible, and seronegative participants had to meet the Wingerchuk 2006 criteria. (Wingerchuk DM, Lennon VA, Lucchinetti CF, Pittock SJ, Weinshenker BG. Revised diagnostic criteria for neuromyelitis optica. Neurology 2006;66:1485-9). There were no pre-planned recruitment targets regarding AQP4-IgG serostatism. Recruitment was considered to reflect the known demographics of a patient population of approximately 80% seropositive and 20% seronegative. (Wingerchuk DM, Lennon VA, Lucchinetti CF, Pittock SJ, Weinshenker BG. Revised diagnostic criteria for neuromyelitis optica. Neurology 2006;66:1485-9). All participants provided written informed consent.

[0103] Sample size. Initial sample size calculations concluded that 212 patients needed to be recruited to observe the required 67 seizures. This number of cases was calculated assuming annual seizure hazard rates of 1.5 and 1.0 in the placebo group for the seropositive and seronegative groups, respectively. These hazard rates were based on seizure rates observed in four open-label cohort studies (Bedi, et al. Impact of rituximab on relapse rate and disability in neuromyelitis optica. Mult Scler 2011;17:1225-30.; Costanzi, et al. Azathioprine: tolerance, efficiency, and predictors of benefit in neuromyelitis optica. Neurology 2011;77:659-66; Jacob, et al. Treatment of neuromyelitis optica with rituximab: retrospective analysis of 25 patients. Muscle Nerve 2008;39:87-90; Kim, et al. Repeated treatment with rituximab based on the assessment of peripheral circulating memory B cells in patients with relapsing neuromyelitis optica over 2 years. Arch Neurol). 2011;68:1412-20;Pittock, et al.Eculizumab in AQP4-IgG -positive relapsing neuromyelitis optica spectrum disorders: an open-label pilot study.Lancet Neurol 2013;12:554-62).

[0104] The primary endpoint and four secondary endpoints were considered to establish control over Type I errors.

[0105] Primary endpoint: Time (in days) from day 1 to day 197 or earlier, to the onset of a neuromyelitis optica spectrum disorder seizure as determined by the review committee. A seizure is defined as the presence of a new neuromyelitis optica-related symptom or an exacerbation of an existing symptom that meets at least one of the protocol definition criteria for a neuromyelitis optica spectrum disorder seizure.

[0106] Four primary secondary endpoints: 1. Worsening of EDSS score from baseline at the last visit during the randomized controlled trial period. EDSS assessments in the trial were performed by independent, blinded assessors at each site using an electronic data capture system developed by the University of Basel and Neurostatus GmBH. This system included an internal algorithm to provide assessor feedback regarding discrepancies in EDSS assessments; 2. Change from baseline in binocular low-contrast visual acuity scores as measured by a low-contrast Landolt ring visual acuity chart at the last visit during the randomized controlled trial period; 3. Cumulative total number of active MRI lesions (new gadolinium enhancement or new / expanding T2 lesions) during the randomized controlled trial period; 4. Number of hospitalizations related to neuromyelitis optica (hospitalizations were defined as stays longer than one night).

[0107] Example 3 - Clinical Trial Protocol Screening period: Participants diagnosed with NMO / NMOSD were screened over 28 days to determine eligibility for the study based on inclusion and exclusion criteria. All eligible participants were randomly assigned to the study.

[0108] Randomization. Participants were randomly assigned in a 3:1 ratio to receive either VIB551 (300 mg) or placebo intravenously, as shown in Table 2. Randomization was performed on day 1 and stratified by AQP4-IgG serological status (approximately 80:20 serologically positive to serologically negative ratios) and region (Japan vs. non-Japan).

[0109] (Table 2) Dosage regimens during the randomized controlled period TIFF0007900888000002.tif23140

[0110] Randomization period (Day 1 to Day 197). After randomization on Day 1, subjects received either VIB551 or placebo on Day 1 and Day 15. An oral corticosteroid course (prednisone 20 mg / day or an equivalent oral glucocorticoid) was initiated on Day 1 and continued until Day 14. Tapering of oral corticosteroids was performed from Day 15 to Day 21 (for prednisone: 15 mg on Day 15, 10 mg on Day 16, 7.5 mg on Day 17, 5 mg on Days 18 and 19, and 2.5 mg on Days 20 and 21). Tapering was completed by Day 21. The rationale for using oral corticosteroids (prednisone 20 mg / day, or an equivalent oral glucocorticoid) for the first 14 days (with a 1-week tapering period) was to provide prophylaxis against neuromyelitis optica spectrum disorder attacks during the period when the pharmacodynamic effects of VIB551 were not expected. Approximately 2–4 weeks are required for maximum B-cell deficiency to occur.

[0111] During the randomized controlled period, participants were followed up at scheduled trial visits and via telephone interviews. Each participant's randomized controlled period was planned to be 197 days. All participants who completed the randomized controlled period without experiencing an NMO / NMOSD seizure were given the option to proceed to the open-label period.

[0112] Open-label period. Subjects were given the option to enter the open-label period if (1) they completed the 197-day randomized controlled period; (2) they experienced an NMO / NMOSD seizure as determined by the Adjudication Committee during the randomized controlled period; (3) they were in the randomized controlled period when 67 NMO / NMOSD seizures as determined by the Adjudication Committee occurred; or (4) they were in the randomized controlled period when enrollment was discontinued based on the DMC's recommendation based on evidence of efficacy and safety.

[0113] Patients who discontinued the randomized controlled period for reasons other than the occurrence of a determined seizure or 67 determined seizures were not eligible for the open-label period. The reasons for patients not entering the open-label period were identified. These patients were then followed up for safety during the safety follow-up period.

[0114] Entering the open-label period for one of the four reasons outlined above, patients received 300 mg of VIB551 every 26 weeks. However, patients randomized to placebo during the randomized controlled period received an additional 300 mg dose on day 15 of the open-label period to maintain a total initial dose of 600 mg. Table 3 provides the dosing regimen for the open-label period.

[0115] (Table 3) Dosage regimens during the open-label period TIFF0007900888000003.tif35160IV=intravenous; OLP=non-inflammation period; Q26W=every 26 weeks; RCP=randomized control period; SFP=safety follow-up period. The OLP will continue for a minimum of one year from the enrollment of the last subject, a maximum of three years from the enrollment of the last subject, or until regulatory approval of MEDI-551 in the participating country, or until the sponsor discontinues development of MEDI-551 for this indication, whichever comes first. Subjects may choose to terminate the OLP at any time for any reason, including seeking alternative treatment options, and will enter the SFP at that point (unless consent is withdrawn).

[0116] During the open-label period, patients were followed up at scheduled trial visits and continued to receive VIB551 therapy for up to three years (after the last patient enrolled), until regulatory approval of VIB551 in each participating country or until the sponsor discontinued development of VIB551 for this indication, whichever came first. Patients were followed up for seizures in the same manner as in the randomized controlled period, and events were centrally determined.

[0117] Patients could choose to terminate the open-label period at any time for any reason, including seeking alternative treatment options, at which point they entered the safety follow-up period (unless consent was withdrawn).

[0118] Safety follow-up period. The safety follow-up period began when a patient withdrew early from the randomized controlled period or the open-label period. The length of the safety follow-up period was determined by the time elapsed from the last dose to the early withdrawal, and a total of 52 weeks were completed. During the safety follow-up period, patients were monitored for adverse / serious adverse events, B-cell levels, anti-drug antibodies, and immunoglobulin levels. Patients were allowed, at the discretion of the principal investigator, to receive standard treatment for their condition.

[0119] Figure 2 shows a flowchart of the overall test design.

[0120] Example 4 - Summary of Test Results Primary endpoint: Time (in days) from day 1 to day 197 or earlier, to the onset of a neuromyelitis optica spectrum disorder seizure as determined by the review committee. A seizure is defined as the presence of a new symptom or exacerbation of an existing symptom related to neuromyelitis optica that meets at least one of the protocol definition criteria for a neuromyelitis optica spectrum disorder seizure.

[0121] Secondary endpoints. Four primary secondary endpoints were considered for Type I error control per trial: (1) deterioration from baseline in EDSS score at the last visit during the randomized controlled period. EDSS assessments in the trials were performed by independent, blinded assessors at each site using an electronic data capture system developed by the University of Basel and Neurostatus GmBH, which included an internal algorithm to provide assessor feedback on inconsistencies in EDSS assessments; (2) change from baseline in binocular low-contrast visual acuity scores measured using a low-contrast Landolt ring visual acuity chart at the last visit during the randomized controlled period; (3) cumulative total number of active MRI lesions (new gadolinium enhancement or new / expanding T2 lesions) during the randomized controlled period; (4) number of hospitalizations related to neuromyelitis optica (hospitalizations were defined as stays longer than one night).

[0122] The remaining secondary endpoints were: (1) the annual seizure rate during the period of exposure to VIB551 (total number of determined seizures, normalized by person-years); (2) adverse events occurring during administration (including serious adverse events occurring during administration); (3) laboratory values ​​and their changes or shifts from baseline over time; (4) the pharmacokinetic profile of VIB551; and (5) the incidence of anti-drug antibodies against VIB551 during the study period (both pre- and post-administration for each patient).

[0123] Exploratory endpoints: (1) Changes from baseline in the 4-week recall 36-item Short-Form Health Survey, version 2, physical component score and mental component score at the last visit during the randomized controlled trial period; (2) Changes from baseline in five pain quantification scales at the last visit during the randomized controlled trial period; (3) B cell count (total and subset); (4) Changes from baseline in plasma cell gene signature; (5) Serum AQP4-IgG titer.

[0124] Example 5 - Characteristics of the test participants From January 2015 to October 2018, 467 participants were screened at 99 participating sites in 24 countries. Of these, 231 were enrolled, and 175 were randomized to VIB551 (AQP4-IgG seropositive, n=161) and 56 to placebo (AQP4-IgG seropositive, n=52; Figure 1). On September 7, 2018, the data monitoring committee recommended halting participation before the target of 252 participants / 67 diagnosed seizures was met, in order to clearly demonstrate efficacy and conditional power exceeding 99%. On September 21, 2018, the sponsor discontinued enrollment, with treatment allocation blinded, before database locking.

[0125] Of the subjects assigned to VIB551, 174 (99.4%) were included in the analysis population (1 participant [0.6%] did not receive the investigational drug), 169 participants (97.1%) completed the randomized controlled period, and 6 discontinued due to adverse events (n=2), withdrawal of consent (n=1), or "other" (n=3). All 56 participants assigned to the placebo group received the intervention and were included in the analysis, with 54 (96.4%) completing the randomized controlled group and 2 discontinued (n=1 withdrawal of consent and n=1 "other"; Figure 3). Most participants were female (n=209, 90.9%; Table 4) and Caucasian (n=120, 52.2%, Table 4). Participant demographics were broadly similar across treatment groups, both overall and within the AQP4-IgG seropositive population (Table 4). The open-label period is ongoing, and 213 participants have received VIB551 (initial randomization: VIB551, n=162; placebo, n=51).

[0126] (Table 4) Patient demographic and baseline characteristics TIFF0007900888000004.tif252170

[0127] (Table 5) AC decision based on recovery grade, NMOSD seizures, randomized controlled period (intent-to-treat group) TIFF0007900888000005.tif74169AC=Judgment Committee; AQP4-IgG=Autoantibody against aquaporin-4; ITT=intent-to-treat; NMOSD=Neuromyelitis Optica Spectrum Disorder; ON=Optic Neuritis; RCP=Randomized Controlled Period; sero+=Sero Positive; sero-=Sero Negative. a. In the placebo group, recovery data was collected from 17 subjects. Using this as the denominator, the percentages are as follows: large, 11.8%; small, 35.5%; no recovery, 52.9%. b. In the inebilizumab group, recovery data was collected from 13 subjects. Using this as the denominator, the percentages are as follows: large, 15.4%; small, 38.5%; no recovery, 46.2%.

[0128] Furthermore, the annual seizure rate during exposure to VIB551 (total number of AC-determined NMOSD seizures normalized by person-years) was also determined. Notably, since subjects were excluded from the placebo-controlled portion of the trial after an AC-determined seizure, the annual seizure rate during the placebo period could not be calculated either. Therefore, such calculations during the placebo period would be biased and potentially overestimate the seizure rate. However, since subjects in the VIB551 group remained in the trial where VIB551 was administered after a seizure, an estimate of the annual seizure rate during the period when subjects received VIB551 could be calculated.

[0129] The annual AC-determined NMOSD seizure rate in any subject treated with VIB551 was low at 0.126. See Table 6. When calculated separately for AQP4-IgG seropositive and AQP4-IgG seronegative subjects, the annual seizure rates were 0.13 and 0.088, respectively.

[0130] (Table 6) Annual seizure rate for NMOSD determined by the judging committee (arbitrary VIB551 population) TIFF0007900888000006.tif22160AC=Judgment Committee; AQP4-IgG=Autoantibody against aquaporin-4; SFP=Safety follow-up period; sero-=Sero-negative; sero+=Sero-positive. a. Total person-years are calculated as the sum of the person-years of individual subjects. The person-years of individual subjects are defined as (date of the last day before SFP - date of first inebilizumab administration + 1) / 365.25. b. The annual seizure rate is defined as the total number of AC-determined seizures divided by the total person-years.

[0131] Because the effectiveness was clearly demonstrated, the trial was terminated early on the recommendation of the independent data monitoring committee.

[0132] (Table 7) Major secondary outcomes TIFF0007900888000007.tif81170 * The p-values ​​shown were adjusted for multiple comparison tests, and a difference of p<0.05 was considered statistically significant. † The proportion of participants whose EDSS score worsened from baseline, and the OR, were calculated using a logistic regression model with treatment, serological status, and baseline score as explanatory variables, and with non-responders being compensated for (missing values ​​were considered to indicate worsening). ‡ The LSM difference in LCVAB score changes was evaluated using a covariance analysis model with treatment, serum status, and baseline Landolt ring visual acuity chart binocular score as explanatory variables, and the last non-missing low-contrast visual acuity score. § The cumulative number of active MRI lesions from baseline (including gadolinium-enhanced or new / expanding T2 lesions), and the response rate (RR), were assessed using negative binomial regression with treatment and serum status as explanatory variables. ¶ RR analysis is based on the entire population, not just the individuals who caused the event. The cumulative number of patient hospitalizations associated with ophthalmic neuromyelitis from baseline, and the risk factor (RR), were assessed using negative binomial regression with treatment and serological status as explanatory variables. (TIFF0007900888000008.tif4128) AQP4-IgG, 161 aquaporin-4-immunoglobulin G; CI, confidence interval; EDSS, diastolic impairment scale; ITT, intent-to-treat; LCVAB, low-contrast binocular visual acuity; LSM, least squares mean; MRI, magnetic resonance imaging; OR, odds ratio; RR, rate ratio; SD, standard deviation; SE, standard error.

[0133] Example 6: Safety and efficacy of VIB551 in patients with a history of rituximab exposure. Seventeen subjects (7.4%) enrolled in the N-MOmentum had a history of rituximab treatment. Table 8 shows the demographic and baseline characteristics of N-MOmentum participants with a history of rituximab use, with a median time from the last use of rituximab to randomization of 1.5 years. The baseline characteristics of participants with a history of rituximab use were similar to those of participants without a history of rituximab use (n=208).

[0134] (Table 8) Characteristics of N-MOmentum participants with a history of rituximab use TIFF0007900888000009.tif95160AQP4, aquaporin-4; AAR, annual seizure rate; IgG, immunoglobulin G; IQR, interquartile range

[0135] Figure 5 shows a summary of the seizure history for each of the 17 N-MOmentum participants with a history of rituximab use. Three of the 17 participants experienced seizures after exposure to inebilizumab. Of the three seizures, one occurred during the RCP in participants randomly assigned to the inebilizumab group, and two occurred during the OLP in participants randomly assigned to the placebo group. The annual seizure rates (AAR) before and after inebilizumab administration were 0.78 (median: 1.08) and 0.11 (95% CI 0.02-0.33), respectively, and the AARs with and without a history of rituximab exposure were 0.083 and 0.102, respectively. Three rituximab-experienced participants who experienced seizures while receiving inebilizumab each experienced one seizure during the study period (1.54 years for participants randomly assigned to inebilizumab; 0.51 years and 2.74 years for participants randomly assigned to placebo). All three seizures were myelitis, one of which was mildly graded on the Optic and Spinal Cord Dysfunction Scale.

[0136] Of the 17 patients, 7 participated in the trial as rituximab "failures," defined as those who experienced an NMOSD seizure during the period between (or within 6 months of) the last dose of rituximab. None of the 7 failures were diagnosed with seizures determined after inevilizumab administration (mean follow-up period 2.6 years).

[0137] Figure 6 shows the probability of seizure-free life stratified by prior rituximab use. After the initial administration of inebilizumab, the AAR (academic attendance rate) in participants with prior rituximab experience was similar to that of participants without prior rituximab use (0.083 and 0.102 seizures / person-year, respectively). Secondary endpoints such as the change from baseline in EDSS score, the number of active lesions on MRI, and the number of NMOSD-related hospitalizations were also evaluated. See Table 9. Of the 13 participants with prior rituximab use who received inebilizumab during the randomized controlled period, 2 (15%) experienced a worsening of EDSS score, 6 (46%) had active lesions on MRI, and 1 (8%) had an NMOSD-related hospitalization. One of the two cases of EDSS score worsening and hospitalization was associated with a seizure occurring during the randomized controlled period. Secondary outcomes in the inebilizumab group were generally similar regardless of prior rituximab use.

[0138] (Table 9) Secondary endpoints during the randomized controlled period based on prior rituximab use. TIFF0007900888000010.tif45160EDSS, Overall Disability Scale; MRI, Magnetic Resonance Imaging; NMOSD, Neuromyelitis Optica Spectrum Disorder; SD, Standard Deviation. a This includes all participants who were randomly assigned to the placebo group regardless of their prior rituximab use. b Gadolinium enhancement or new or expanding T2 lesions measured across the optic nerve, brain, brainstem, and spinal cord. 11 c Among participants with lesions detected by MRI. d A hospital stay longer than one night. 11 e Among the participants who were hospitalized.

[0139] Furthermore, B-cell deficiency dynamics in participants previously treated with rituximab were investigated and were similar to those of the general inebilizumab-treated study population. See Figure 7. After inebilizumab administration, participants, regardless of prior rituximab use, experienced an annual decrease in IgG levels from baseline of 42.3 mg / dL / year and 49.5 mg / dL / year, respectively (P=0.6687). Six participants (35%) who received inebilizumab but had a history of rituximab use and 30 participants (15%) who had no prior rituximab use had IgG concentrations below 500 mg / dL (Figure 8). Previous analyses of the N-MOmentum trial did not observe a correlation between IgG levels and infection. In the inevilizumab-treated group, similar lymphocyte and neutrophil counts were generally observed for each toxicity grade, regardless of prior experience with rituximab, with the majority of both groups reporting grade 0 / 1.

[0140] Adverse events observed in this group included infusion reactions (2), infections (16), and cytopenia (1). Table 10 provides a summary of adverse events that occurred during administration, comparing subjects with prior rituximab use to those without.

[0141] Ninebilizumab-related TEAEs (Teased Endocrine Emissions) were experienced in 9 out of 17 participants (53%) with a history of rituximab use and in 79 out of 208 participants (38%) without a history of rituximab use (Table 10). The incidence of serious TEAEs related to inebilizumab was low in both groups. Serious TEAEs related to inebilizumab were reported in 2 participants (12%) with a history of rituximab use, and included urinary tract infections and cellulitis. The proportion of participants experiencing infusion-related reactions during inebilizumab administration was similar regardless of their history of rituximab use. Most participants, regardless of their prior experience with rituximab (94% and 70%, respectively), experienced one or more infections during inebilizumab administration. Severe infections of grade 3 or higher occurred in 3 participants (18%) with prior experience of rituximab and in 20 participants (10%) without prior experience of rituximab. Among participants with a history of rituximab use, serious and / or grade 3 or higher infections included nasopharyngitis (grade 3), urinary tract infection (severe and grade 3), cellulitis (severe and grade 3), and perforated appendicitis (severe and grade 4), each occurring in one participant. No deaths, opportunistic infections, or cases of progressive multifocal leukoencephalopathy as a complication of B-cell deficiency therapy were reported among the 17 participants with prior experience of rituximab. The most common adverse events (AEs) among participants with a history of rituximab use were urinary tract infections and influenza.

[0142] (Table 10) TEAEs after inebilizumab administration, serious TEAEs, and TEAEs of particular interest TIFF0007900888000011.tif136160PML, Progressive Multifocal Leukoencephalopathy; TEAE, Adverse Events Occurring Under Treatment

Claims

1. For use in methods of treating neuromyelitis optica spectrum disorder (NMOSD), Heavy chain variable region (VH) complementarity-determining region (CDR) 1 containing the amino acid sequence of SEQ ID NO: 5; VH CDR2 containing the amino acid sequence of SEQ ID NO: 6; VH CDR3 containing the amino acid sequence of SEQ ID NO: 7; Light chain variable region (VL) complementarity-determining region (CDR) 1 containing the amino acid sequence of SEQ ID NO: 8; VL CDR2 containing the amino acid sequence of SEQ ID NO: 9; and VL CDR3 containing the amino acid sequence of SEQ ID NO: 10 A pharmaceutical product containing an anti-CD19 antibody, The method includes administering the anti-CD19 antibody to a subject who has previously been treated with an anti-CD20 antibody, The subject experienced an NMOSD seizure while being treated with the anti-CD20 antibody, or within six months of the last administration of the anti-CD20 antibody. The aforementioned anti-CD20 antibody is rituximab. The aforementioned pharmaceutical.

2. The pharmaceutical product according to claim 1, wherein the anti-CD19 antibody comprises a heavy chain variable region (VH) containing the amino acid sequence of SEQ ID NO: 1 and a light chain variable region (VL) containing the amino acid sequence of SEQ ID NO:

2.

3. The pharmaceutical product according to claim 1 or 2, wherein the anti-CD19 antibody is inebilizumab.

4. The pharmaceutical product according to any one of claims 1 to 3, wherein the NMOSD seizure includes one or more of optic neuritis, myelitis, or brainstem seizures.

5. The pharmaceutical product according to any one of claims 1 to 4, wherein the method comprises intravenously administering the anti-CD19 antibody to a subject at a dose of 300 mg every six months.

6. The pharmaceutical product according to any one of claims 1 to 4, wherein the method comprises intravenously administering the anti-CD19 antibody to a subject in a first initial dose of 300 mg, a second initial dose of 300 mg two weeks after the first initial dose, and a subsequent dose of 300 mg every six months after the first initial dose.

7. The pharmaceutical product according to claim 6, wherein the method comprises simultaneously administering a corticosteroid to the subject together with the first initial dose.

8. The pharmaceutical product according to any one of claims 1 to 7, wherein the subject is seropositive for astrocyte water channel aquaporin-4 (AQP4)-immunoglobulin (Ig) G.

9. The above method, before the administration, A step to confirm that the subject has previously been treated with the anti-CD20 antibody; The aforementioned subject is, (i) Having experienced at least one NMOSD seizure while being treated with the anti-CD20 antibody; or (ii) Have you experienced at least one NMOSD seizure within six months of the last administration of the anti-CD20 antibody? The process of determining; and The step of selecting the subject to administer the anti-CD19 antibody as a result of the decision in (i) or (ii). A pharmaceutical product according to any one of claims 1 to 8, further comprising:

10. For use in methods of treating neuromyelitis optica spectrum disorder (NMOSD), Heavy chain variable region (VH) complementarity-determining region (CDR) 1 containing the amino acid sequence of SEQ ID NO: 5; VH CDR2 containing the amino acid sequence of SEQ ID NO: 6; VH CDR3 containing the amino acid sequence of SEQ ID NO: 7; Light chain variable region (VL) complementarity-determining region (CDR) 1 containing the amino acid sequence of SEQ ID NO: 8; VL CDR2 containing the amino acid sequence of SEQ ID NO: 9; and VL CDR3 containing the amino acid sequence of SEQ ID NO: 10 A pharmaceutical product containing an anti-CD19 antibody, The method comprises administering the anti-CD19 antibody to a subject who has been previously treated with an anti-CD20 antibody and is seropositive for astrocyte water channel aquaporin-4 (AQP4)-immunoglobulin (Ig) G. The subject experienced an NMOSD seizure while being treated with the anti-CD20 antibody, or within six months of the last administration of the anti-CD20 antibody. The aforementioned anti-CD20 antibody is rituximab. The aforementioned pharmaceutical.

11. The pharmaceutical product according to claim 10, wherein the anti-CD19 antibody comprises a heavy chain variable region (VH) containing the amino acid sequence of SEQ ID NO: 1 and a light chain variable region (VL) containing the amino acid sequence of SEQ ID NO:

2.

12. The pharmaceutical product according to claim 10 or 11, wherein the anti-CD19 antibody is inebilizumab.

13. The pharmaceutical product according to any one of claims 10 to 12, wherein the method comprises intravenously administering the anti-CD19 antibody to a subject at a dose of 300 mg every six months.

14. The pharmaceutical product according to any one of claims 10 to 12, wherein the method comprises intravenously administering the anti-CD19 antibody to a subject in a first initial dose of 300 mg, a second initial dose of 300 mg two weeks after the first initial dose, and a subsequent dose of 300 mg every six months after the first initial dose.

15. The pharmaceutical product according to claim 14, wherein the method comprises simultaneously administering a corticosteroid to the subject together with the first initial dose.

16. The aforementioned anti-CD19 antibody, within 8 days after administration, is detected in peripheral blood CD20 － A pharmaceutical product according to any one of claims 10 to 15, which causes a deficiency of plasmablasts and plasma cells.

17. The above method, before the administration, A step to confirm that the subject has previously been treated with the anti-CD20 antibody; The aforementioned subject is, (i) Having experienced at least one NMOSD seizure while being treated with the anti-CD20 antibody; or (ii) Have you experienced at least one NMOSD seizure within six months of the last administration of the anti-CD20 antibody? The process of determining; and The step of selecting the subject to administer the anti-CD19 antibody as a result of the decision in (i) or (ii). A pharmaceutical product according to any one of claims 10 to 16, further comprising:

18. The aforementioned treatment, Reduction of deterioration in the Kurtzke Global Disability Scale (EDSS) in the aforementioned subjects; Reduction in the number of active magnetic resonance imaging (MRI) lesions; Reduction of the deterioration of the modified ranking score of the aforementioned target; A decrease in the frequency of hospitalizations in the aforementioned subjects related to NMOSD; Reduction of NMOSD-related pain in the aforementioned subjects; and / or Reduction of the risk of NMOSD-related seizures in the aforementioned target group. A pharmaceutical product according to any one of claims 10 to 17, which brings about the following:

19. For use in methods to reduce active MRI lesions in subjects diagnosed with NMOSD, Heavy chain variable region (VH) complementarity-determining region (CDR) 1 containing the amino acid sequence of SEQ ID NO: 5; VH CDR2 containing the amino acid sequence of SEQ ID NO: 6; VH CDR3 containing the amino acid sequence of SEQ ID NO: 7; Light chain variable region (VL) complementarity-determining region (CDR) 1 containing the amino acid sequence of SEQ ID NO: 8; VL CDR2 containing the amino acid sequence of SEQ ID NO: 9; and VL CDR3 containing the amino acid sequence of SEQ ID NO: 10 A pharmaceutical product containing an anti-CD19 antibody, The method includes administering the anti-CD19 antibody to a subject who has previously been treated with an anti-CD20 antibody, The subject experienced an NMOSD seizure while being treated with the anti-CD20 antibody, or within six months of the last administration of the anti-CD20 antibody. The aforementioned anti-CD20 antibody is rituximab. The aforementioned pharmaceutical.

20. For use in methods to reduce NMOSD-related disorders in subjects diagnosed with NMOSD, Heavy chain variable region (VH) complementarity-determining region (CDR) 1 containing the amino acid sequence of SEQ ID NO: 5; VH CDR2 containing the amino acid sequence of SEQ ID NO: 6; VH CDR3 containing the amino acid sequence of SEQ ID NO: 7; Light chain variable region (VL) complementarity-determining region (CDR) 1 containing the amino acid sequence of SEQ ID NO: 8; VL CDR2 containing the amino acid sequence of SEQ ID NO: 9; and VL CDR3 containing the amino acid sequence of SEQ ID NO: 10 A pharmaceutical product containing an anti-CD19 antibody, The method includes administering the anti-CD19 antibody to a subject who has previously been treated with an anti-CD20 antibody, The subject experienced an NMOSD seizure while being treated with the anti-CD20 antibody, or within six months of the last administration of the anti-CD20 antibody. The aforementioned anti-CD20 antibody is rituximab. The aforementioned pharmaceutical.

21. For use in methods to reduce NMOSD-related seizures in the subject, Heavy chain variable region (VH) complementarity-determining region (CDR) 1 containing the amino acid sequence of SEQ ID NO: 5; VH CDR2 containing the amino acid sequence of SEQ ID NO: 6; VH CDR3 containing the amino acid sequence of SEQ ID NO: 7; Light chain variable region (VL) complementarity-determining region (CDR) 1 containing the amino acid sequence of SEQ ID NO: 8; VL CDR2 containing the amino acid sequence of SEQ ID NO: 9; and VL CDR3 containing the amino acid sequence of SEQ ID NO: 10 A pharmaceutical product containing an anti-CD19 antibody, The method includes administering the anti-CD19 antibody to a subject who has previously been treated with an anti-CD20 antibody, The subject experienced an NMOSD seizure while being treated with the anti-CD20 antibody, or within six months of the last administration of the anti-CD20 antibody. The aforementioned anti-CD20 antibody is rituximab. The aforementioned pharmaceutical.

22. For use in a method for treating neuromyelitis optica spectrum disorder (NMOSD), Heavy chain variable region (VH) complementarity-determining region (CDR) 1 containing the amino acid sequence of SEQ ID NO: 5; VH CDR2 containing the amino acid sequence of SEQ ID NO: 6; VH CDR3 containing the amino acid sequence of SEQ ID NO: 7; Light chain variable region (VL) complementarity-determining region (CDR) 1 containing the amino acid sequence of SEQ ID NO: 8; VL CDR2 containing the amino acid sequence of SEQ ID NO: 9; and VL CDR3 containing the amino acid sequence of SEQ ID NO: 10 A pharmaceutical product containing an anti-CD19 antibody, The method comprises intravenously administering the anti-CD19 antibody to a subject previously treated with an anti-CD20 antibody in a first initial dose of 300 mg, a second initial dose of 300 mg two weeks after the first initial dose, and a subsequent dose of 300 mg every six months after the first initial dose. The subject experienced an NMOSD seizure while being treated with the anti-CD20 antibody, or within six months of the last administration of the anti-CD20 antibody. The aforementioned anti-CD20 antibody is rituximab. The aforementioned pharmaceutical.

23. A pharmaceutical product comprising an anti-CD19 antibody for use in a method of treating neuromyelitis optica spectrum disorder (NMOSD), comprising a heavy chain variable region (VH) containing the amino acid sequence of SEQ ID NO: 1 and a light chain variable region (VL) containing the amino acid sequence of SEQ ID NO: 2, The method includes administering the anti-CD19 antibody to a subject who has previously been treated with an anti-CD20 antibody, The subject experienced an NMOSD seizure while being treated with the anti-CD20 antibody, or within six months of the last administration of the anti-CD20 antibody. The aforementioned anti-CD20 antibody is rituximab. The aforementioned pharmaceutical.

24. A pharmaceutical product comprising an anti-CD19 antibody for use in a method of treating neuromyelitis optica spectrum disorder (NMOSD), The aforementioned anti-CD19 antibody is inebilizumab, and The method includes administering the anti-CD19 antibody to a subject who has previously been treated with an anti-CD20 antibody, The subject experienced an NMOSD seizure while being treated with the anti-CD20 antibody, or within six months of the last administration of the anti-CD20 antibody. The aforementioned anti-CD20 antibody is rituximab. The aforementioned pharmaceutical.

25. A pharmaceutical product comprising an anti-CD19 antibody for use in a method of treating neuromyelitis optica spectrum disorder (NMOSD), comprising a heavy chain variable region (VH) containing the amino acid sequence of SEQ ID NO: 1 and a light chain variable region (VL) containing the amino acid sequence of SEQ ID NO: 2, The method comprises administering the anti-CD19 antibody to a subject who has been previously treated with an anti-CD20 antibody and is seropositive for astrocyte water channel aquaporin-4 (AQP4)-immunoglobulin (Ig) G. The subject experienced an NMOSD seizure while being treated with the anti-CD20 antibody, or within six months of the last administration of the anti-CD20 antibody. The aforementioned anti-CD20 antibody is rituximab. The aforementioned pharmaceutical.

26. A pharmaceutical product comprising an anti-CD19 antibody for use in a method of treating neuromyelitis optica spectrum disorder (NMOSD), The aforementioned anti-CD19 antibody is inebilizumab, and The method comprises administering the anti-CD19 antibody to a subject who has been previously treated with an anti-CD20 antibody and is seropositive for astrocyte water channel aquaporin-4 (AQP4)-immunoglobulin (Ig) G. The subject experienced an NMOSD seizure while being treated with the anti-CD20 antibody, or within six months of the last administration of the anti-CD20 antibody. The aforementioned anti-CD20 antibody is rituximab. The aforementioned pharmaceutical.

Images