CN116583538A

CN116583538A - Treatment of autoimmune diseases using anti-CD 19 antibodies

Info

Publication number: CN116583538A
Application number: CN202180073551.9A
Authority: CN
Inventors: 佘德伟; J·拉奇福德; E·卡茨; W·里斯
Original assignee: MedImmune Ltd
Current assignee: MedImmune Ltd
Priority date: 2020-10-29
Filing date: 2021-10-29
Publication date: 2023-08-11

Abstract

Disclosed herein are methods for treating autoimmune diseases using anti-CD 19 antibodies. In particular, VIB551, a humanized, affinity optimized, afucosylated IgG1 kappa monoclonal antibody, is used to treat neuromyelitis optica lineage disorders.

Description

Treatment of autoimmune diseases using anti-CD 19 antibodies

Cross reference

The application claims the benefit of U.S. provisional application No. 63/107,182, U.S. provisional application No. 63/143,541, filed on 29 of 10 months 2020, and U.S. provisional application No. 63/178,286, filed on 22 of 4 months 2021, each of which is incorporated herein by reference.

Reference to sequence Listing

The present application incorporates by reference a sequence listing submitted with the present application via EFS-Web in the form of a text file with the name "hopa_030_03wo_seqlist_st25", created 10 month 27 in 2021 and 9.50 kilobytes in size.

Background

Neuromyelitis spectrum disorder (NMOSD) is a severe autoimmune inflammatory central nervous system disorder with an prevalence of 0.5-4.4/100 000 (Cree BA, bennett JL, shehan M et al, placebo-controlled study in neuromyelitis optica-ethical and design considerations [ Placebo control study of neuromyelitis-ethical and design considerations ]. Mult Scler [ multiple sclerosis ]2016; 22:862-72.). NMOSD accompanies optic neuritis, transverse myelitis, and less commonly, inter-brain, brain stem and hemispheric attacks. (Cree BA, bennett JL, sheahan M et al, placebo-controlled study in neuromyelitis optica-ethical and design considerations [ Placebo control study of neuromyelitis-ethical and design considerations ]. Mult Scler [ multiple sclerosis ]2016; 22:862-72.). Incomplete recovery from the seizure is typical and patients are at risk of death from respiratory failure (Winger chuk DM, lennon VA, lucchinetti CF, pittock SJ, weinhenker BG.the spectrum of neuromyelitis optica [ neuromyelitis pedigree ]. Lancet Neurol [ Lancet neurology ]2007; 6:805-15.).

NMOSD was once thought to be a variant of multiple sclerosis and is now thought to be a different disease characterized by astrocyte damage, demyelination and significant neuronal loss; most lesions occur during acute episodes (Winger Chuk DM, lennon VA, lucchinetti CF, pittock SJ, weinhenker BG.the spectrum of neuromyelitis optica [ neuromyelitis pedigree ]. Lancet Neurol [ Lancet neurology ]2007;6:805-15;Fujihara K,Misu T,Nakashima I et al, neuromyelitis optica should be classified as an astrocytopathic disease rather than a demyelinating disease [ neuromyelitis optica ] should be classified as a astrocytopathic disease rather than a demyelinating disease ]. Clin Exp Neuroimmunol [ clinical and experimental neuroimmunology ]2012, 3:58-73.). Highly specific serum autoantibodies against astrocyte water channel aquaporin 4 (AQP 4) -immunoglobulin G (IgG) were detected in 60% -80% of patients, and these autoantibodies may be pathogenic (weinhenker BG, wingerchuk DM, vukusic S et al, neuromyelitis optica IgG predicts relapse after longitudinally extensive transverse myelitis [ neuromyelitis IgG predicts recurrence after long-segment transverse myelitis ]. Ann neurool [ neurological yearbook ]2006;59:566-9;Bennett JL,Lam C,Kalluri SR et al, intrathecal pathogenic anti-aquaporin-4antibodies in early neuromyelitis optica [ intrathecal pathogenic aquaporin early neuromyelitis ] 2009:617-29;Jarius S,Frederikson J,Waters P et al, frequency and prognostic impact of antibodies to aquaporin-4in patients with optic neuritis [ frequency and prognostic impact of aquaporin 4antibodies in neuromyelitis patients ]. J Neurol Sci [ journal of neuroscience ] 298:158-62;Saadoun S,Waters P,Bell BA,Vincent A,Verkman AS,Papadopoulos MC.Intra-cerebral injection of neuromyelitis optica immunoglobulin Gand human complement produces neuromyelitis optica lesions in mice [ Brain endoneuromyelitis and human neuromyelitis optical complement 2010:133 ] mouse. AQP4-IgG causes disease-specific central nervous system injury in the presence of complement or inflammatory T-cell responses (Bennett JL, lam C, kallleri SR et al Intrathecal pathogenic anti-aquaporin-4antibodies in early neuromyelitis optica [ intrathecal pathogenic aquaporin 4 antibody in early neuromyelitis ]. Ann Neurol [ neurological annual. 2009; 66:617-29.). Several lines of evidence suggest that NMOSD is a B cell mediated disorder mainly caused by pathological autoantibody production, pro-inflammatory cytokine secretion and B cell antigen presentation (Bennett JL, O' Connor KC, bar-Or A et al, B lymphocytes in neuromyelitis optica [ B lymphocytes in neuromyelitis ]. Neurol Neuroimmunol Neuroinflamm [ neurological: neuroimmunology and neuroinflammatory ]2015;2: e 104.).

VIB551 is a humanized, affinity optimized, afucosylated IgG1 kappa monoclonal antibody that binds to the B cell surface antigen CD 19. In contrast to anti-CD 20 monoclonal antibodies which recognize and deplete a portion of CD20 expressing T lymphocytes (other than B lymphocytes) (Palanichmy A, jahn S, nickes D et al, rituximab efficiently depletes increased CD-expressing T cells in multiple sclerosis patients [ rituximab effectively depletes CD20 expressing T cells increased in multiple sclerosis patients ]. J Immunol [ journal of immunology ]2014; 193:580-6), anti-CD 19 antibodies exclusively recognize and deplete lymphocytes from the B cell lineage.

Disclosure of Invention

The present specification provides a method of treating neuromyelitis optica spectrum disorder (NMOSD), the method comprising: an anti-CD 19 antibody VIB551 is administered to a patient in need of NMOSD treatment, wherein the patient has been previously treated with an anti-CD 20 antibody, and wherein the patient has an NMOSD episode during treatment with the anti-CD 20 antibody. The present specification provides a method of treating NMOSD, the method comprising: an anti-CD 19 antibody VIB551 is administered to a patient in need of NMOSD treatment, wherein the patient has been previously treated with an anti-CD 20 antibody, wherein the patient has an NMOSD episode within 6 months of the last dose of anti-CD 20 antibody. In various aspects, VIB551 is administered intravenously every 6 months at a dose of 300 mg.

The present specification provides a method of treating neuromyelitis optica spectrum disorder (NMOSD), the method comprising: administering an anti-CD 19 antibody VIB551 to a patient in need of NMOSD treatment, wherein the patient has been previously treated with an anti-CD 20 antibody, and wherein the patient has not been treated with anti-CD 20 for up to 6 months or up to 12 months prior to administration of the anti-CD 19 antibody VIB551, optionally wherein the patient has an NMOSD episode during treatment with the anti-CD 20 antibody. The present specification provides a method of treating NMOSD, the method comprising: an anti-CD 19 antibody VIB551 is administered to a patient in need of NMOSD treatment, wherein the patient has been previously treated with an anti-CD 20 antibody, wherein the patient has an NMOSD episode within 6 months of the last dose of anti-CD 20 antibody. In various aspects, VIB551 is administered intravenously every 6 months at a dose of 300 mg.

The present specification provides a method of treating NMOSD, the method comprising: administering an anti-CD 19 antibody VIB551 to a patient in need of NMOSD treatment, wherein the patient is an astrocyte aquaporin 4 (AQP 4) -igg+ patient, wherein the VIB551 is administered intravenously every 6 months at a dose of 300mg, wherein the patient has been previously treated with an anti-CD 20 antibody, and wherein the patient has an NMOSD episode during treatment with the anti-CD 20 antibody. The present specification provides a method of treating NMOSD, the method comprising: administering an anti-CD 19 antibody VIB551 to a patient in need of NMOSD treatment, wherein the patient is an AQP4-igg+ patient, wherein the VIB551 is administered intravenously every 6 months at a dose of 300mg, wherein the patient has been previously treated with an anti-CD 20 antibody; and wherein the patient has an onset of NMOSD within 6 months of the last dose of anti-CD 20 antibody.

In various aspects, the patient receives at least one initial dose of VIB551. In various aspects, VIB551 is administered intravenously at a first initial dose of 300mg, two weeks after the first initial dose, at a second initial dose of 300mg, and then, after the first initial dose, at a dose of 300mg every 6 months. In various aspects, an oral corticosteroid is co-administered to the patient with the initial VIB551 dose. In a particular aspect, the oral corticosteroid is administered daily for at least 2 weeks. In one aspect, the anti-CD 20 antibody is rituximab.

In aspects, the treatment is a reduction in the deterioration of the patient's Kurtzke Extended Disability Severity Scale (EDSS). In various aspects, the reduction in EDSS deterioration in the patient is: if the patient has a baseline score of 0, the deterioration in the EDSS score is less than 2 points; if the patient has a baseline score of 1 to 5, the exacerbation is less than 1 score; or less than 0.5 score if the patient has a baseline score of 5.5 or more.

In various aspects, the treatment is a reduction in the number of active Magnetic Resonance Imaging (MRI) lesions. In various aspects, the active MRI lesion is an expanding T2 MRI lesion. In a particular aspect, the treatment is a reduction in the number of new MRI lesions.

In aspects, the treatment is a reduction in worsening of the patient's modified rankine (Rankin) score. In a particular aspect, the treatment is a reduction in the frequency of NMOSD-related hospitalizations of the patient. In aspects, the treatment is a reduction in risk of an NMOSD-related episode of the patient. In one aspect, the NMOSD associated episode is characterized by the appearance of new symptoms or worsening of existing NMOSD associated symptoms. In a particular aspect, the symptom is an ocular symptom. In various aspects, the ocular symptom is ocular pain, blurred vision, vision loss, or appearance of an optic nerve lesion detected by MRI. In various aspects, the symptom is a spinal cord symptom. In one aspect, the spinal symptom is deep pain or nerve root pain, limb paresthesia, inoxidism, sphincter dysfunction, lehr Mi Teshi sign (lhemitte's sign), or spinal lesions detectable by MRI. In various aspects, the symptom is a brain or brain stem symptom. In various aspects, the brain or brain stem symptom is nausea, double vision, paralysis of the eye movements, dizziness, intractable vomiting, intractable hiccup, dysarthria, dysphagia, weakness, encephalopathy, hypothalamic dysfunction, or brain stem lesions detectable by MRI. In aspects, the risk of an NMOSD-related episode is reduced by between 60% and 85%. In one aspect, the treatment is a reduction in optic neuritis. In a particular aspect, the treatment is a reduction in severity of an NMOSD associated episode. In aspects, the reduction in severity of an NMOSD-related episode is a reduction in NMOSD-related episodes that are graded as severe. In various aspects, the reduction in severity of an NMOSD associated episode is a reduction in the occurrence of an NMOSD requiring hospitalization. In a particular aspect, the treatment is a reduction in NMOSD associated pain in the patient. In aspects, the reduction in the NMOSD associated pain is determined by measuring the patient's leg pain.

In aspects, the subject is administered an initial 300mg vib551 dose two weeks before the first administration of the 300mg vib551 every 6 months. In a particular aspect, an oral corticosteroid is co-administered to the patient with the initial 300mg vib551 dose. In various aspects, the patient is AQP4-IgG seropositive.

The present specification provides a method of reducing active MRI lesions in a patient diagnosed with NMOSD, the method comprising: an anti-CD 19 antibody VIB551 is administered to a patient in need of NMOSD treatment, wherein the patient has been previously treated with an anti-CD 20 antibody, wherein the patient has an NMOSD episode during treatment with the anti-CD 20 antibody. The present specification provides a method of reducing active MRI lesions in a patient diagnosed with NMOSD, the method comprising: an anti-CD 19 antibody VIB551 is administered to a patient in need of NMOSD treatment, wherein the patient has been previously treated with an anti-CD 20 antibody, wherein the patient has an NMOSD episode within 6 months of the last dose of anti-CD 20 antibody. In various aspects, the VIB551 is administered intravenously every 6 months at a dose of 300 mg.

The present specification provides a method of reducing active MRI lesions in a patient diagnosed with NMOSD, the method comprising: administering an anti-CD 19 antibody VIB551 to a patient in need of NMOSD treatment, wherein the patient has been previously treated with an anti-CD 20 antibody, wherein the patient has an NMOSD episode during treatment with the anti-CD 20 antibody; and wherein the VIB551 is administered intravenously every 6 months at a dose of 300 mg. The present specification provides a method of reducing active MRI lesions in a patient diagnosed with NMOSD, the method comprising: administering an anti-CD 19 antibody VIB551 to a patient in need of NMOSD treatment, wherein the patient has been previously treated with an anti-CD 20 antibody, wherein the patient has an NMOSD episode within 6 months of the last dose of anti-CD 20 antibody; and wherein the VIB551 is administered intravenously every 6 months at a dose of 300 mg.

The present specification provides a method for reducing AQP4-IgG titers in AQP4-igg+ patients in need of NMOSD treatment comprising: an anti-CD 19 antibody VIB551 is administered to a patient in need of NMOSD treatment, wherein the patient has been previously treated with an anti-CD 20 antibody, wherein the patient has an NMOSD episode during treatment with the anti-CD 20 antibody. The present specification provides a method for reducing AQP4-IgG titers in AQP4-igg+ patients in need of NMOSD treatment comprising: an anti-CD 19 antibody VIB551 is administered to a patient in need of NMOSD treatment, wherein the patient has been previously treated with an anti-CD 20 antibody, wherein the patient has an NMOSD episode within 6 months of the last dose of anti-CD 20 antibody. In various aspects, the VIB551 is administered intravenously every 6 months at a dose of 300 mg.

The present specification provides a method for reducing AQP4-IgG titers in AQP4-igg+ patients in need of NMOSD treatment comprising: administering an anti-CD 19 antibody VIB551 to a patient in need of NMOSD treatment, wherein the patient has been previously treated with an anti-CD 20 antibody, wherein the patient has an NMOSD episode during treatment with the anti-CD 20 antibody; and wherein the VIB551 is administered intravenously every 6 months at a dose of 300 mg. The present specification provides a method for reducing AQP4-IgG titers in AQP4-igg+ patients in need of NMOSD treatment comprising: administering an anti-CD 19 antibody VIB551 to a patient in need of NMOSD treatment, wherein the patient has been previously treated with an anti-CD 20 antibody, wherein the patient has an NMOSD episode within 6 months of the last dose of anti-CD 20 antibody; and wherein the VIB551 is administered intravenously every 6 months at a dose of 300 mg.

In various aspects, the administration depletes at least 90% of circulating cd20+ B cells for at least six months. In aspects, the administration does not increase the risk of infection for the patient. In a particular aspect, the VIB551 depletes peripheral blood CD 20-plasmablasts and plasma cells within 8 days after the administration.

The present specification provides a method of reducing NMOSD associated disability in a patient diagnosed with NMOSD, the method comprising: an anti-CD 19 antibody VIB551 is administered to a patient in need of NMOSD treatment, wherein the patient has been previously treated with an anti-CD 20 antibody, wherein the patient has an NMOSD episode during treatment with the anti-CD 20 antibody. The present specification provides a method of reducing NMOSD associated disability in a patient diagnosed with NMOSD, the method comprising: an anti-CD 19 antibody VIB551 is administered to a patient in need of NMOSD treatment, wherein the patient has been previously treated with an anti-CD 20 antibody, wherein the patient has an NMOSD episode within 6 months of the last dose of anti-CD 20 antibody. In various aspects, the VIB551 is administered intravenously every 6 months at a dose of 300 mg.

The present specification provides a method of reducing NMOSD associated disability in a patient diagnosed with NMOSD, the method comprising: administering an anti-CD 19 antibody VIB551 to a patient in need of NMOSD treatment, wherein the patient has been previously treated with an anti-CD 20 antibody, wherein the patient has an NMOSD episode during treatment with the anti-CD 20 antibody; and wherein the VIB551 is administered intravenously every 6 months at a dose of 300 mg. The present specification provides a method of reducing NMOSD associated disability in a patient diagnosed with NMOSD, the method comprising: administering an anti-CD 19 antibody VIB551 to a patient in need of NMOSD treatment, wherein the patient has been previously treated with an anti-CD 20 antibody, wherein the patient has an NMOSD episode within 6 months of the last dose of anti-CD 20 antibody; and wherein the VIB551 is administered intravenously every 6 months at a dose of 300 mg.

In various aspects, reducing the patient's NMOSD associated disability is reducing the patient's rate of exacerbation of NMOSD associated disability. In various aspects, reducing the patient's NMOSD associated disability is reducing the patient's NMOSD associated disability. In one aspect, the NMOSD associated disability is neurological disability. In various aspects, reducing the NMOSD-related disability is determined using EDSS.

The present specification provides a method of reducing NMOSD related episodes in a patient in need of NMOSD treatment, the method comprising: an anti-CD 19 antibody VIB551 is administered to a patient in need of NMOSD treatment, wherein the patient has been previously treated with an anti-CD 20 antibody, wherein the patient has an NMOSD episode during treatment with the anti-CD 20 antibody. The present specification provides a method of reducing NMOSD related episodes in a patient in need of NMOSD treatment, the method comprising: an anti-CD 19 antibody VIB551 is administered to a patient in need of NMOSD treatment, wherein the patient has been previously treated with an anti-CD 20 antibody, wherein the patient has an NMOSD episode within 6 months of the last dose of anti-CD 20 antibody. In various aspects, the VIB551 is administered intravenously every 6 months at a dose of 300 mg.

The present specification provides a method of reducing NMOSD related episodes in a patient in need of NMOSD treatment, the method comprising: administering an anti-CD 19 antibody VIB551 to a patient in need of NMOSD treatment, wherein the patient has been previously treated with an anti-CD 20 antibody, wherein the patient has an NMOSD episode during treatment with the anti-CD 20 antibody; and wherein the VIB551 is administered intravenously every 6 months at a dose of 300 mg. The present specification provides a method of reducing NMOSD related episodes in a patient in need of NMOSD treatment, the method comprising: administering an anti-CD 19 antibody VIB551 to a patient in need of NMOSD treatment, wherein the patient has been previously treated with an anti-CD 20 antibody, wherein the patient has an NMOSD episode within 6 months of the last dose of anti-CD 20 antibody; and wherein the VIB551 is administered intravenously every 6 months at a dose of 300 mg.

In aspects, the NMOSD related episodes suffered by the patient include any one or more of optic neuritis, myelitis, or brainstem episodes. In one aspect, the patient is suffering from the NMOSD associated episodes that are clinically asymptomatic.

In various aspects, the patient receives at least one initial dose of VIB551. In various aspects, the VIB551 is administered intravenously at a first initial dose of 300mg, two weeks after the first initial dose, at a second initial dose of 300mg, and then, after the first initial dose, at a dose of 300mg every 6 months. In various aspects, an oral corticosteroid is co-administered to the patient with the initial 300mg vib551 dose. In various aspects, the oral corticosteroid is administered daily for at least 2 weeks. In various aspects, the anti-CD 20 antibody is rituximab.

In various aspects, the VIB551 comprises a heavy chain variable region (VH) comprising the amino acid of SEQ ID NO. 1 and a light chain variable region (VL) comprising the amino acid of SEQ ID NO. 2.

The present specification provides a method of treating NMOSD, the method comprising: administering an anti-CD 19 antibody to a patient in need of NMOSD treatment, wherein the patient has been previously treated with an anti-CD 20 antibody, wherein the patient has an NMOSD episode during treatment with the anti-CD 20 antibody. The present specification provides a method of treating NMOSD, the method comprising: administering an anti-CD 19 antibody to a patient in need of NMOSD treatment, wherein the patient has been previously treated with an anti-CD 20 antibody, wherein the patient has an NMOSD episode within 6 months of the last dose of anti-CD 20 antibody.

The present specification provides a method of treating NMOSD, the method comprising: administering an anti-CD 19 antibody VIB551 to a patient in need of NMOSD treatment, wherein the patient is an AQP4-igg+ patient, wherein the VIB551 is administered intravenously at a first initial dose of 300mg, administered intravenously two weeks after the first initial dose at a second initial dose of 300mg, and subsequently administered intravenously at a dose of 300mg every 6 months after the first initial dose, wherein the patient has been previously treated with an anti-CD 20 antibody, and wherein the patient has an NMOSD episode during treatment with the anti-CD 20 antibody. The present specification provides a method of treating NMOSD, the method comprising: administering an anti-CD 19 antibody VIB551 to a patient in need of NMOSD treatment, wherein the patient is an AQP4-igg+ patient, wherein the VIB551 is administered intravenously at a first initial dose of 300mg, two weeks after the first initial dose, at a second initial dose of 300mg, and subsequently administered intravenously at a dose of 300mg every 6 months after the first initial dose, wherein the patient has been previously treated with an anti-CD 20 antibody; and wherein the patient has an onset of NMOSD within 6 months of the last dose of anti-CD 20 antibody.

Drawings

FIG. 1 is a flow chart of a multiplex adjustment strategy for an N-MOmentum clinical trial.

FIG. 2. Study design flow chart of N-MOmentum clinical trial. (AC, committee of arbitration; FU follow-up; i.v., intravenous; max, maximum, min, minimum, NMO/NMOSD, neuromyelitis/neuromyelitis pedigree disorder; OLP, open label period; RCP, random control period; Q26, every 26 weeks; SFP, safety follow-up period).

FIG. 3-N-MOmentum clinical trial CONSORT flowchart. Efficacy endpoints were evaluated in the intended treatment population, defined as participants randomized and receiving any study product and analyzed according to their randomized treatment group, whether or not the participants received an unscheduled intervention.SecureSex-endpoints are assessed in a population receiving treatment, defined as participants receiving any study product; however, participants randomized into VIB551 who received all placebo doses were included in the placebo group. In contrast, participants who received at least one dose of VIB551 randomized to placebo were included in the active treatment group. />Other cases included erroneous randomized groupings of non-eligible participants, each requiring treatment with illicit drugs, and withdrawal prior to dosing due to seizure and patient decision (placebo) occurring on the day of randomized grouping (group VIB 551). CONSORT, reporting comprehensive standards of the test; v. intravenous; RCP, random control period).

FIG. 4 amino acid sequences of VH (SEQ ID NO: 1) and VL (SEQ ID NO: 2) of the VIB551 antibody.

FIG. 5. History of onset of N-MOmentum participants who had previously used pertuzumab.

Fig. 6 shows the probability of seizure free stratification according to prior rituximab use.

Figure 7 absolute cd20+ B cell counts of individual participants who had previously used rituximab during the randomized control period (0-28 weeks) and the open label extended period (> 28 weeks). During the extended period of open label, all participants received the panitumumab.

Figure 8 IgG concentrations at baseline and in the treatment with inibizumab for participants who had previously used and who had not previously used rituximab. IgG, immunoglobulin G.

FIG. 9 shows the amino acid sequences of the heavy chain (SEQ ID NO: 3) and the light chain (SEQ ID NO: 4) of the VIB551 antibody.

Detailed Description

Described herein are methods for using VIB551 (also known as MEDI551,Or irinotecan) treat a patient diagnosed with NMOSD, wherein the patient has previously been treated with an anti-CD 20 antibody. Also described herein is for use inA method of VIB551 reducing active MRI lesions in a patient diagnosed with NMOSD, wherein the patient has been previously treated with an anti-CD 20 antibody. In addition, the use of VIB551 to reduce AQP4-IgG in need of NMOSD treatment is described herein ⁺ A method of AQP4-IgG titers in a patient, wherein the patient has been previously treated with an anti-CD 20 antibody. Further described herein are methods of reducing NMOSD-related disability in a patient diagnosed with NMOSD using VIB551, wherein the patient has been previously treated with an anti-CD 20 antibody. Also described herein are methods of reducing NMOSD related episodes in a patient in need of NMOSD treatment using VIB551, wherein the patient has previously been treated with an anti-CD 20 antibody.

In various aspects, in the methods described herein, VIB551 may be used to treat patients diagnosed with NMOSD who have one or more NMOSD episodes during treatment with an anti-CD 20 antibody. In various aspects, VIB551 may be used to treat patients diagnosed with NMOSD who have one or more NMOSD episodes within 6 months of the last dose of anti-CD 20 antibody. In a particular aspect, the patient may be an astrocyte aquaporin 4 (AQP 4) -igg+ patient. In various aspects, the anti-CD 20 antibody that may have been previously used to treat a patient is rituximab (antibody C2B8 in WO 94/11026, which is incorporated herein by reference in its entirety). In various aspects, the anti-CD 20 antibody that was previously potentially useful for treating a patient is ABP-300 (Abpro corporation); b-001 (Shanghai pharmaceutical group Co., ltd. (Shanghai Pharmaceuticals Holding)); BAT-4306F (BioTheta Biotechnology Co., ltd.); BAT-4406F (Baiottai Bio-pharmaceutical Co., ltd.); BCD-132 (Bokang Biotechnology Co., ltd. (Biocad Biotechnology)); BVX-20 (Vaccinex corporation (Vaccinex)); CYT-202 (Shimadzui Biomedicine Co., ltd. (Cytovia Therapeutics)); elcatuzumab (epcoritamab) (Genmab corporation (Genmab)); GB-261 (Jia and Biopharma Co., ltd.); GD-CO1620 (bayweisheng technologies inc (manymar)); glifeitumumab (Roche); HS-006 (Zhejiang Zhengpharmaceutical Co., ltd. (Zhejiang Hisun Pharmaceutical)); IGM-2323 (IGM Biosciences); IMM-0306 (Yimingke biomedical technologies Co., ltd. (ImmuneOnco Biopharma)); MIL-62 (Beijing Tianguangzhi Biotechnology Co., ltd. (Beijing Mabworks Biotech)); mosuteuzumab (rochanter company); MRG-001 (Shanghai Meiya Ke Biotechnology Co., ltd. (Shanghai Miracogen)); olanbituzumab (robutuzumab) (roche company); orivizumab (Rocrelizumab) (Roche, inc.; new York (Niogen)); ornitumumab (Regeneron); ofatumumab (Genmab; novartis); palatinosa (plamotamab) (Xencor corporation (Xencor)); SM-09 (China antibody pharmaceutical Co., ltd. (SinoMab BioScience)); TRS-005 (Zhejiang Terisi pharmaceutical Co., ltd. (Zhejiang Teruisi Biopharma)); wu Tuo Acximab (ublituximab) (rEVO Biologics)); or YBL-031 (Y-Biologics).

In aspects, the present disclosure provides a method of treating neuromyelitis optica spectrum disorder (NMOSD), the method comprising: an anti-CD 19 antibody VIB551 is administered to a patient in need of NMOSD treatment, wherein the patient has been previously treated with an anti-CD 20 antibody, and wherein the patient has an NMOSD episode during treatment with the anti-CD 20 antibody. In aspects, the present disclosure provides a method of treating NMOSD, the method comprising: an anti-CD 19 antibody VIB551 is administered to a patient in need of NMOSD treatment, wherein the patient has been previously treated with an anti-CD 20 antibody, wherein the patient has an NMOSD episode within 6 months of the last dose of anti-CD 20 antibody.

If VIB551 is used to treat an NMOSD, it can treat the NMOSD by reducing the worsening of the patient's kurtz Extended Disability Severity Scale (EDSS), or by reducing the number of active Magnetic Resonance Imaging (MRI) lesions of the patient, or by reducing the worsening of the patient's modified rankine score, or by reducing the frequency of patient's NMOSD-related hospitalization, or by reducing the risk of patient's NMOSD-related episodes, or by reducing optic neuritis, or by reducing the severity of patient's NMOSD-related episodes, or by reducing patient's pain, or by reducing patient's NMOSD-related lesions, or by reducing patient's NMOSD-related episodes.

If VIB551 treats the patient's NMOSD by reducing the deterioration of the patient's EDSS score, and the patient's baseline EDSS score is 0, the patient's EDSS score may deteriorate less than 2 points, or less than 1 point, or less than.5 points. For a patient with a baseline score of 0, this reduction in the deterioration in EDSS score may be over a period of at least 6 months, 9 months, 1 year, 2 years, 3 years, 4 years, 5 years, 7.5 years, or 10 years. If the VIB551 treats the patient's NMOSD by reducing the patient's deterioration in EDSS score, and the patient's baseline score is 1 to 5, the patient's EDSS score may deteriorate less than 1 score, or less than.5 score. For patients with baseline EDSS scores of 1 to 5, the reduction in this exacerbation may be a reduction in exacerbation over a period of 6 months, 9 months, 1 year, 2 years, 3 years, 4 years, 5 years, 7.5 years, or 10 years. If the VIB551 treats the patient's NMOSD by reducing the deterioration of the patient's EDSS score, and the patient's baseline EDSS score is 5.5 or more, the patient's EDSS score may deteriorate less than 0.5 points, or less than.25 points. For patients with baseline scores of 5.5 or more, the reduction in this exacerbation may be a reduction in the worsening EDSS score 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.

If VIB551 treats the patient's NMOSD by reducing the number of active MRI lesions, the treatment may be to reduce the number of T2 MRI lesions that are expanding, or may be to reduce the number of new MRI lesions, or may be to reduce both the number of T2 MRI lesions that are expanding and the number of new MRI lesions. The reduction in lesions may be a reduction in brain foci, a reduction in brain stem lesions, a reduction in spinal cord lesions, a reduction in optic nerve lesions, or a reduction in lesions of any two or more of the brain, brain stem, spinal cord and optic nerve. New MRI lesions may be clinically asymptomatic.

If the VIB551 treats the NMOSD of the patient by reducing the deterioration of the patient's modified rankine score, the reduction in deterioration may be such that the deterioration of the patient's modified rankine score is less than 2 points or less than 1 point for 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.

If the VIB551 treats the patient's NMOSD by reducing the risk of an NMOSD related episode, the patient's risk of an episode may be reduced between 60% and 85%, or may be reduced between 65% and 75%, or may be reduced between 70% and 80%. The risk of onset of the patient 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 risk of onset in a patient may be reduced by 70%, 75%, 76%, 77%, 78%, 79% or 80%.

If VIB551 treats the patient's NMOSD by reducing the risk of an NMOSD related episode, the probability that the treated patient has no NMOSD related episode may be greater than 70% for at least 6 months after treatment of VIB551, or greater than 70% for at least 12 months after treatment of VIB551, or greater than 70% for at least 18 months after treatment of VIB551, due to the reduced risk of an NMOSD related episode. The probability of no NMOSD related episodes in the treated patient 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, due to the reduced risk of NMOSD related episodes. Furthermore, due to the reduced risk of NMOSD related episodes, the probability of no NMOSD related episodes in the treated patient 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. In addition, due to the reduced risk of NMOSD related episodes, the probability of no NMOSD related episodes in the treated patient may be greater than 85% for at least 6 months after VIB551 treatment, or greater than 85% for at least 12 months after VIB551 treatment, or greater than 85% for at least 18 months after VIB551 treatment.

Furthermore, if VIB551 treats the patient's NMOSD by reducing the risk of an NMOSD related episode, the annual risk of the treated patient's NMOSD related episode may be reduced to between 0.18 and 0.08, or may be reduced to between 0.15 and 0.08, or may be reduced to 0.14, or 0.13, or 0.12, or 0.11, or 0.10, or 0.09, or 0.08, or 0.07 due to the reduced risk. If the patient receiving NMOSD treatment is AQP4-IgG seropositive, the patient's risk of aging of NMOSD-related attacks may be reduced to between 0.15 and 0.11, or to between 0.14 and 0.12, or to 0.14, 0.13, 0.12 or 0.11. If the patient receiving NMOSD treatment is AQP4-IgG seronegative, the patient's risk of aging of NMOSD-related attacks may be reduced to between 0.09 and 0.07, or may be reduced to 0.09, 0.08 or 0.07.

An NMOSD related episode, which may reduce the risk of an NMOSD patient when it is treated, may be an episode characterized by the appearance of new symptoms of NMOSD or worsening of existing symptoms of NMOSD. The new or existing symptom may be an ocular symptom. If the new or existing symptom is an ocular symptom, it may be eye pain, a new optic nerve focus, an enlarged optic nerve focus, blurred vision, vision loss, or a drop in the low contrast Landolt C Broken ring eye chart (Landolt C Broken Rings Chart) by 5 or more characters. The new or existing symptom may be a spinal symptom. If the new or existing symptom is spinal symptoms, it may be deep pain or nerve root pain, limb paresthesia, inoxism, sphincter dysfunction, lehr Mi Teshi sign, new spinal lesions, or enlarged spinal lesions. The new or existing symptom may be a brain or brainstem symptom. If the new or existing symptom is a brain or brain stem symptom, it may be nausea, double vision, eye movement paralysis, dizziness, intractable vomiting, intractable hiccup, dysarthria, dysphagia, weakness, encephalopathy, hypothalamic dysfunction, a new brain or brain stem lesion, or an expanding brain or brain stem lesion. The new or worsening symptoms may be ocular, spinal, or a combination of any two or more of brain/brainstem symptoms. It may be a combination of any two, three or four of these symptoms.

If VIB551 treats the patient's NMOSD by reducing optic neuritis, the patient may experience reduced eye pain, reduced vision loss, reduced visual field loss, reduced color vision loss, or reduced glints or flickering sensations of light with eye movement. A decrease in optic neuritis may result in improved vision and/or relief of eye pain.

If the VIB551 treats the patient's NMOSD by reducing the severity of the patient's NMOSD related episode, the severity of any NMOSD related episode suffered by the patient may be graded as mild or moderate, rather than graded as severe. A mild episode may be a transient episode, may be an episode that requires only minimal therapeutic or therapeutic intervention, and/or may not interfere with the usual activities of daily living. Moderate seizures may be seizures that are alleviated by specific additional therapeutic intervention. Any moderate episode may interfere with the usual activities of daily living and/or cause discomfort without causing significant or permanent risk of injury to the patient. The reduction in severity of the patient's NMOSD-related episode may be a reduction in episodes that the patient suffers graded as severe. Such severe episodes may be episodes requiring intensive therapeutic intervention, interrupting the usual activities of daily living, or significantly affecting the clinical state of the patient. Such severe episodes may require hospitalization.

If VIB551 treats the patient's NMOSD by reducing the patient's pain, this reduction may be determined by a reduction in the patient's eye, leg, arm, upper back, and/or lower back pain. The reduction in pain may occur in any one, any two, any three, any four or all five of these areas. The reduction in pain can be measured by the pain digital rating scale (PRS). The reduction in pain can be monitored in the range of 1 to 10 relative to the baseline PRS level. The reduction in pain may be a reduction in pain of at least 1 on a scale, at least 2 on a scale, at least 3 on a scale, at least 4 on a scale, or at least 5 on a scale. The reduction in pain may be a reduction in pain on a scale between 1 and 5, or a reduction in pain on a scale between 1 and 3, or a reduction in pain on a scale between 1 and 2.

If the VIB551 treats the patient's NMOSD by reducing the NMOSD related damage, the NMOSD related damage may be a new MRI lesion for the patient that is clinically asymptomatic. If the NMOSD-related lesion is a new MRI lesion that is clinically asymptomatic, it may occur in patients who have not experienced symptoms of the NMOSD-related episode or in patients who have experienced symptoms of the NMOSD-related episode.

If a new clinically asymptomatic MRI lesion occurs in a patient who does not experience symptoms of an NMOSD-related episode, VIB551 may reduce the likelihood of the new clinically asymptomatic MRI lesion occurring in or within any one or more domains of the patient (e.g., brain/brain stem, optic nerve, or spinal cord). Reducing the occurrence or likelihood of occurrence of a new clinically asymptomatic MRI lesion may be preventing occurrence of a new clinically asymptomatic MRI lesion. The patient who does not experience symptoms of an NMOSD related episode and whose NMOSD related damage is reduced by VIB551 may be a patient who does not experience symptoms of an NMOSD related episode 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. During treatment of a patient with VIB551, administration of VIB551 to a patient who does not experience symptoms of an nmosfet-related episode may reduce the occurrence or likelihood of occurrence of a new MRI lesion that is clinically asymptomatic. Administration of VIB551 to a patient who does not experience symptoms of an NMOSD-related episode may result in a reduction in the occurrence or likelihood of occurrence of a new MRI lesion starting within 1 month, within 2 months, or within 3 months after administration of the first dose of VIB551, and may last at least 6 months, at least 12 months, at least 18 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 after administration of the first dose of VIB 551.

If a clinically asymptomatic new MRI lesion occurs in a patient experiencing symptoms of an NMOSD-related episode, VIB551 may reduce the occurrence or likelihood of occurrence of a clinically asymptomatic new MRI lesion in a domain outside of the domain where the patient experienced symptoms of an NMOSD-related episode. For example, if a patient experiences symptoms of an NMOSD-related episode in the spinal cord, the VIB551 may reduce the occurrence or likelihood of occurrence of a new MRI lesion in the optic nerve or brain/brain stem, or both. If VIB551 reduces the occurrence or reduces the likelihood of occurrence of a new clinically asymptomatic MRI lesion associated with an NMOSD-related episode, it may be completely reduced, i.e., prevented from occurring in the patient's new clinically asymptomatic MRI lesion. In addition, VIB551 may reduce the occurrence or likelihood of a new MRI lesion in the domain of a patient experiencing symptoms of an NMOSD-related episode as well as reduce the clinical asymptomatic new MRI lesion or likelihood of occurrence of a new MRI lesion in a patient experiencing symptoms of an NMOSD-related episode.

VIB551 may also be used in a method of reducing active MRI lesions in patients diagnosed with NMOSD. In various aspects, the present disclosure provides a method of reducing active MRI lesions in a patient diagnosed with NMOSD, the method comprising: an anti-CD 19 antibody VIB551 is administered to a patient in need of NMOSD treatment, wherein the patient has been previously treated with an anti-CD 20 antibody, wherein the patient has an NMOSD episode during treatment with the anti-CD 20 antibody. In various aspects, the present disclosure provides a method of reducing active MRI lesions in a patient diagnosed with NMOSD, the method comprising: an anti-CD 19 antibody VIB551 is administered to a patient in need of NMOSD treatment, wherein the patient has been previously treated with an anti-CD 20 antibody, wherein the patient has an NMOSD episode within 6 months of the last dose of anti-CD 20 antibody. If VIB551 is used in a method of reducing active MRI lesions in a patient, VIB551 may reduce the cumulative total of new lesions and expanding lesions in the patient. If VIB551 is used in a method of reducing active MRI lesions in a patient diagnosed with NMOSD, VIB551 may reduce the cumulative total of new gadolinium [ Gd ] enhanced lesions, new T2 lesions, and expanding T2 lesions in the patient. If VIB551 is used in a method of reducing active MRI lesions in a patient diagnosed with NMOSD, VIB551 may reduce the number of new T2 lesions in the patient and the number of expanding T2 lesions in the patient. If VIB551 is used in a method of reducing active MRI lesions in a patient diagnosed with NMOSD, VIB551 may reduce the number of new T2 lesions in the patient or the number of enlarged T2 lesions in the patient. The reduced patient activity MRI lesion may be a cumulative lesion of the brain/brain stem, spinal cord and optic nerve, or may be a lesion in one or both of the brain/brain stem, spinal cord or optic nerve. The reduced patient activity MRI lesions may be clinically symptomatic or clinically asymptomatic MRI lesions. If these MRI lesions are clinically asymptomatic, they may be new MRI lesions that occur in patients who have not experienced symptoms of NMOSD-related attacks. If these MRI lesions are clinically asymptomatic, they may be new MRI lesions that occur in the patient that are associated with NMOSD-related attacks, but not in the same domain as the patient experienced symptoms of NMOSD-related attacks.

VIB551 can also be used to reduce AQP4-IgG in need of NMOSD treatment ⁺ In a method of patient AQP4-IgG titre. In various aspects, the present disclosure provides a method of reducing AQP4-IgG titers in AQP4-igg+ patients in need of NMOSD treatment comprising: administering an anti-CD 19 antibody VIB551 to a patient in need of NMOSD treatment, wherein the patient has been previously treated with an anti-CD 20 antibody, wherein the patient has an NMOSD episode during treatment with the anti-CD 20 antibody; and wherein the VIB551 is administered intravenously every 6 months at a dose of 300 mg. In various aspects, the present disclosure provides a method of reducing AQP4-IgG titers in AQP4-igg+ patients in need of NMOSD treatment comprising: administering an anti-CD 19 antibody VIB551 to a patient in need of NMOSD treatment, wherein the patient has been previously treated with an anti-CD 20 antibody, wherein the patient has an NMOSD episode within 6 months of the last dose of anti-CD 20 antibody; and wherein the VIB551 is administered intravenously every 6 months at a dose of 300 mg. If VIB551 is used to reduce AQP4-IgG in need of NMOSD treatment ⁺ In the method of reducing the AQP4-IgG titer in a patient, VIB551 can reduce the AQP4-IgG titer by 75% to 100%, or 75% to 90%, or 75% to 85%, or 80% to 100%, or 85% to 100%, or 90% to 95%, or 75%, 80%, 85%, 90%, 95% or 100%. VIB551 may reduce the 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 the dose of VIB 551.

The VIB551 may also be used in a method for reducing NMOSD related disability in patients diagnosed with NMOSD. In various aspects, the present disclosure provides a method of reducing NMOSD-related disability in a patient diagnosed with NMOSD, the method comprising: an anti-CD 19 antibody VIB551 is administered to a patient in need of NMOSD treatment, wherein the patient has been previously treated with an anti-CD 20 antibody, wherein the patient has an NMOSD episode during treatment with the anti-CD 20 antibody. In various aspects, the present disclosure provides a method of reducing NMOSD-related disability in a patient diagnosed with NMOSD, the method comprising: an anti-CD 19 antibody VIB551 is administered to a patient in need of NMOSD treatment, wherein the patient has been previously treated with an anti-CD 20 antibody, wherein the patient has an NMOSD episode within 6 months of the last dose of anti-CD 20 antibody. Reducing the patient's NMOSD related disability may be reducing the patient's deterioration of the NMOSD related disability or may be reducing the patient's NMOSD related disability. NMOSD-related disability may be neurological disability or manifestations of neurological disability. The NMOSD-related disability may be characterized by one or more of eye pain, loss of color vision, loss of vision integrity, blurred vision, multiple vision, general weakness or paralysis, arm or leg weakness or paralysis, nerve root pain, uncontrolled hiccup, uncontrolled nausea or vomiting, bladder or bowel loss, paralysis and/or fatigue.

The reduction in NMOSD-related disability may be determined using EDSS, or may be determined using a modified rankine scale (mRS), or may be determined using EDSS and mRS. A reduction in NMOSD-related disability can be detected within 6 to 12 months, 6 to 8 months, or 6 to 7 months of administration of one dose of VIB551 or administration of the first dose of VIB 551.

If the reduction in NMOSD-related disability is determined using EDSS, the reduction in NMOSD-related disability may be a reduction in patient EDSS score deterioration or a reduction in patient EDSS score.

If the reduction in NMOSD-related disability is a reduction in patient EDSS score deterioration and the patient's baseline EDSS score is 0, the reduction in deterioration may be such that if the patient's EDSS score deterioration, it deteriorates to a score of.5, or a score of no more than 1, or a score of no more than 1.5, or a score of no more than 2, over a period of time. A period of time for which a patient with a baseline score of 0 worsens to a score of.5, no more than 1, no more than 1.5, or no more than 2 may be a period of time of 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 disability is a reduction in patient EDSS score deterioration and the patient's baseline EDSS score is 1 to 5, the reduction in deterioration may be a patient EDSS score deterioration of.5 points or no more than 1 point over a period of time. A patient with a baseline score of 1 to 5 worsens for a period of.5 minutes or no more than 1 minute may be a period of 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 disability is a reduction in patient EDSS score deterioration and the patient's baseline EDSS score is 5.5 or more, the reduction in deterioration may be a patient EDSS score deterioration of no more than.5 points. The period of time that the patient with a baseline score of 5.5 does not deteriorate more than.5 minutes may be a period of time of 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 EDSS score for the patient may be determined within about 1 month, 2 weeks, 1 week, 3 days, 2 days, or 1 day of administration of the first dose of VIB 551. The baseline EDSS score for a patient may be determined simultaneously with administration of the first dose of VIB551, or may be determined within 1 day, 2 days, 3 days, 1 week, 2 weeks, or 1 month of administration of the first dose of VIB 551.

If reducing NMOSD-related disability is to decrease the patient's EDSS score, the patient's EDSS score may decrease by at least.5 points, or at least 1 point, or at least 1.5 points, or at least 2 points. A decrease or decrease in EDSS score in a patient of at least.5, at least 1, at least 1.5, or at least 2 points may occur over a period of about 2 weeks, about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 9 months, about 12 months, or about 18 months. The period of reduced patient EDSS score or reduced patient EDSS score may begin within 1 month, 2 weeks, 1 week, 3 days, 2 days, or 1 day of administration of the first dose of VIB 551; or it may be synchronized with the administration of the first dose VIB 551; or it may begin within 1 day, 2 days, 3 days, 1 week, 2 weeks, or 1 month of administration of the first dose of VIB 551. The period of time during which the patient's EDSS score decreases or decreases may begin at the onset of the NMOSD or may begin within 1, 2, 3, 4, 5, 6 or 7 days of the time of the NMOSD onset.

If the reduction in NMOSD-related disability is determined using mRS, the reduction in NMOSD-related disability may be a reduction in patient mRS score deterioration or a reduction in patient mRS score.

If the reduction in NMOSD-related disability is a reduction in patient mRS score deterioration, the reduction in mRS score deterioration may be a patient's baseline mRS score deterioration of no more than.5 points, or no more than 1 point, or no more than 1.5 points, or no more than 2 points over a period of time. The period of time that the patient baseline mRS score deteriorates by no more than.5 minutes, no more than 1 minute, no more than 1.5 minutes, or no more than 2 minutes may be a period of time of 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 baseline mRS score from determining the reduction in deterioration may be the patient mRS score at about 1 month, about 2 weeks, about 1 week, about 3 days, about 2 days, or about 1 day prior to administration of the first dose of VIB 551. The patient baseline mRS score may be the patient mRS score at the time of administration of the first dose of VIB551, or may be the patient mRS score within 1 day, within 2 days, within 3 days, within 1 week, within 2 weeks, or within 1 month after administration of the first dose of VIB 551.

If reducing NMOSD-related disability is to decrease the mRS score of the patient, the mRS score of the patient may decrease or decrease by at least.5 points, or at least 1 point, or at least 1.5 points, or at least 2 points. The decrease or decrease in patient mRS score of at least.5, at least 1, at least 1.5, or at least 2 points may be a decrease or decrease that occurs over a period of about 2 weeks, about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 9 months, about 12 months, or about 18 months. The period of reduced mRS score in the patient may begin within 1 month, 2 weeks, 1 week, 3 days, 2 days, or 1 day of administration of the first dose of VIB 551; or it may be synchronized with the administration of the first dose VIB 551; or it may occur within 1 day, 2 days, 3 days, 1 week, 2 weeks, or 1 month of administration of the first dose of VIB 551. The period of time during which the patient's mRS score decreases may begin at the onset of the NMOSD or may begin within 1, 2, 3, 4, 5, 6 or 7 days of the time of the NMOSD onset.

VIB551 may also be used in a method of reducing NMOSD related episodes in a patient in need of NMOSD treatment, wherein the patient has previously received an anti-CD 20 antibody. In various aspects, the present disclosure provides a method of reducing NMOSD related episodes in a patient in need of NMOSD treatment, the method comprising: an anti-CD 19 antibody VIB551 is administered to a patient in need of NMOSD treatment, wherein the patient has been previously treated with an anti-CD 20 antibody, wherein the patient has an NMOSD episode during treatment with the anti-CD 20 antibody. In various aspects, the present disclosure provides a method of reducing NMOSD related episodes in a patient in need of NMOSD treatment, the method comprising: a dose of about 300mg of anti-CD 19 antibody VIB551 is administered to a patient in need of NMOSD treatment, wherein the patient has been previously treated with an anti-CD 20 antibody, wherein the patient has not had an NMOSD episode during treatment with the anti-CD 20 antibody. For example, prior to administration of VIB551, the patient may have received anti-CD 20 antibody therapy for up to 1 month, up to 2 months, up to 4 months, up to 6 months, up to 12 months, up to 2 years, up to 3 years, up to 4 years, up to 5 years, up to 6 years, or more. Typically, at least 12 months of anti-CD-20 antibody was previously received prior to administration of VIB551. The VIB551 may be administered in a dose of about 300mg VIB551, optionally followed by one or more additional 300mg of VIB551 administered every 6 months thereafter.

VIB551 may also be used in a method of treating NMOSD in a patient. In various aspects, the method comprises administering to a patient in need of NMOSD treatment an anti-CD 19 antibody VIB551, optionally as monotherapy, wherein the patient has been previously treated with the anti-CD 20 antibody for at least 12 months and up to 5 years, and wherein one or more doses of about 300mg of the anti-CD 19 antibody VIB551 are administered after cessation of the anti-CD 20 therapy, each dose of VIB551 being administered about 6 months apart.

In various aspects, a method of treating NMOSD in a patient comprises administering to a patient in need of NMOSD treatment an anti-CD 19 antibody VIB551, optionally as monotherapy, wherein the patient has been previously treated with an anti-CD 20 antibody, wherein the anti-CD 20 therapy is discontinued after 1, 2, or 3 NMOSD related episodes and wherein one or more doses of about 300mg of the anti-CD 19 antibody VIB551 are administered after the discontinuation of the anti-CD 20 therapy, each dose of VIB551 being administered about 6 months apart.

In various aspects, the present disclosure provides a method of reducing NMOSD related episodes in a patient in need of NMOSD treatment, the method comprising: an anti-CD 19 antibody VIB551 is administered to a patient in need of NMOSD treatment, wherein the patient has been previously treated with an anti-CD 20 antibody, wherein the patient has an NMOSD episode within 6 months of the last dose of anti-CD 20 antibody. The reduction in the number of NMOSD related episodes of the patient may be a reduction in the number of NMOSD related episodes the patient suffers during the first period of time relative to the second period of time. The first period of time may occur after administration of the first dose of VIB551, and the second period of time may occur before administration of the first dose of VIB 551. The first period of time may begin immediately after the administration of the first dose of VIB551, and the second period of time may end immediately prior to the administration of the first dose of VIB 551. The time lengths of the first and second time periods may be equal. For example, the number of the cells to be processed, the first and second time periods may each be at least 6 months, or at least 12 months, or at least 18 months, or at least 24 months, or at least 30 months or 30 months, or at least 36 months, or at least 42 months, or at least 48 months, or at least 54 months, or at least 60 months, or 60 months.

The reduction in the number of NMOSD related episodes a patient suffers during a first time period relative to a second time period may cause the patient to suffer during the first time period at least 1 episode less, or at least 2 episodes less, or at least 3 episodes less, or at least 4 episodes less, or at least 5 episodes less, or 5 episodes less relative to the second time period. The NMOSD related episode suffered by the patient during the first and/or second time period may be an NMOSD related episode as an optic neuritis episode, a myelitis episode or a brainstem episode. If the patient suffers an NMOSD related episode during a first period of time, the NMOSD related episode may or may not be in the same domain as the one or more NMOSD related episodes the patient suffers during a second period of time, such as the optic nerve, spinal cord or brain/brain stem.

The NMOSD related episode suffered by the patient (whose number may be reduced in a patient in need of NMOSD treatment) may be an NMOSD related episode characterized by the appearance of new or worsening symptoms of NMOSD or the appearance of new MRI lesions that may or may not be symptomatic.

If the NMOSD-related episode is an episode characterized by new symptoms or worsening of existing symptoms, the new symptoms or worsening symptoms may be ocular symptoms. If the new or worsening condition is an ocular condition, it may be eye pain, a new optic nerve focus, an expanding optic nerve focus, blurred vision, vision loss, or a drop in the low contrast Landolt C Broken ring visual chart by 5 or more characters. An NMOSD related episode characterized by new or worsening ocular symptoms may further/alternatively meet any one or more of the following criteria: the high contrast Landolt C Broken ring eye chart dropped by >15 characters (as measured in the previously affected eye) since the last clinical visit and no other ophthalmic interpretation; CF (digital finger) to NLP (no light sensation) decrease by ≡2 steps (as measured in the previously affected eye) since the last clinical visit and without other ophthalmic interpretation; the low contrast Landolt Broken ring eye chart reduced by ≡7 characters (as measured in either eye alone (monocular)) since the last clinical visit and new RAPD (comparative pupil entry defect) occurred in the affected eye; the low contrast Landolt Broken ring eye chart reduced by ≡7 characters (as measured in either eye alone (monocular)) since the last clinical visit and the previously recorded RAPD loss occurred in the contralateral eye; the high contrast Landolt C Broken ring eye chart reduced by ≡5 characters (as measured in either eye alone (monocular)) since the last clinical visit and new RAPD appeared in the affected eye; the high contrast Landolt C Broken ring eye chart reduced by ≡5 characters (as measured in either eye alone (monocular)) since the last clinical visit and the previously recorded RAPD loss occurred in the contralateral eye; CF to NLP decrease by ≡1 step ≡3 (as measured in the previously affected eye) since the last clinical visit and new RAPD appears in the affected eye; CF to NLP decrease by ≡1 step ≡3 (as measured in the previously affected eye) since the last clinical visit and previously recorded RAPD loss occurred in the contralateral eye; the low contrast Landolt C Broken ring eye chart decreased by ≡7 characters (as measured in either eye alone (monocular)) since the last clinical visit and a new Gd-enhanced or new/expanding T2 MRI lesion appeared in the corresponding optic nerve; the high contrast Landolt cbrooken ring eye chart reduced by ≡5 characters (as measured in either eye alone (monocular)) since the last clinical visit and a new Gd-enhanced or new/expanding T2 MRI lesion appeared in the corresponding optic nerve; CF to NLP decrease by ≡1 step ≡3 (as measured in the previously affected eye) since the last clinical visit and new Gd-enhanced or new/expanding T2 MRI lesions appear in the corresponding optic nerve.

If the NMOSD-related episode is an episode characterized by new symptoms or worsening of existing symptoms, the new symptoms or worsening symptoms may be spinal cord symptoms. If the new or worsening condition is a spinal cord condition, it may be deep pain or nerve root pain, limb paresthesia, inoperability, sphincter dysfunction, lehr Mi Teshi sign, new spinal cord foci or expanding spinal cord foci. NMOSD related episodes characterized by new spinal symptoms or worsening of existing spinal symptoms may further/alternatively meet any one or more of the following criteria: at least one associated (pyramidal, bladder/bowel, sensory) FSS worsened by ≡2 score compared to the recent clinical visit; the EDSS score worsens by > 1 score (if the previous EDSS score is > 5.5) compared to the recent clinical visit; at least two associated (cone, bladder/intestine, sensation) FSS worsens by > 1 score compared to the recent clinical visit (when the recent clinical visit score > 1), and new Gd-enhanced or new/expanding T2 MRI lesions appear in the spinal cord; the EDSS score worsened by > 0.5 points compared to the most recent visit (if the previous EDSS score was > 5.5), and new GD-enhanced or new/expanding T2 MRI lesions appeared in the spinal cord.

If the NMOSD-related episode is an episode characterized by new symptoms or worsening of existing symptoms, the new symptoms or worsening symptoms may be brain or brainstem symptoms. If the new or existing symptom is a brain or brain stem symptom, it may be nausea, double vision, eye movement paralysis, dizziness, intractable vomiting, intractable hiccup, dysarthria, dysphagia, weakness, encephalopathy, hypothalamic dysfunction, a new brain or brain stem lesion, or an expanding brain or brain stem lesion. An NMOSD-related episode characterized by new brain/brain stem symptoms or worsening of existing brain/brain stem symptoms may further/alternatively meet any one or more of the following criteria: isolated (absent on recent clinical visits) refractory nausea, vomiting and/or hiccup persist for >48 hours, and new Gd-enhanced or new/expanding T2 MRI lesions appear in the brainstem; at least one associated (brainstem, cerebellum) FSS worsened by ≡2 score compared to the recent clinical visit, and new Gd-enhanced or new/expanding T2 MRI lesions appear in brainstem; at least one associated (brain, sensation, cone) FSS worsened by > 2 score (score at recent visit > 3) compared to recent clinical visits, and consistent with clinical manifestations, new Gd-enhanced or new/expanding T2 MRI lesions appear in the brain.

An NMOSD related episode may be an episode characterized by any combination of new symptoms and/or worsening symptoms in any one, two or more of the eye, spinal cord or brain/brainstem. An NMOSD-related episode may be an episode characterized by any combination of two, three, or four symptoms or other criteria identified for any one or more of the eye, spinal cord, or brain/brain stem.

Furthermore, an NMOSD related episode may be an episode characterized by a patient presenting with a new MRI lesion. New MRI lesions may, but need not, be symptomatic.

In the methods disclosed herein, the NMOSD patient administered VIB551 may or may not be AQP4-IgG seropositive. Prior to administration of VIB551, the NMOSD patients can be subjected to AQP4-IgG screening. In various aspects, in any of the methods disclosed herein, VIB551 may be administered to a patient with an increased level of serum Nfl relative to baseline (as described in U.S. provisional application nos. 63/052,093 and 63/071,092, which are incorporated herein by reference in their entireties). In various aspects, VIB551 is administered to a patient having a sGFAP concentration of about 160pg/mL, about 165pg/mL, about 166pg/mL, about 167pg/mL, about 168pg/mL, about 169pg/mL, about 170pg/mL, about 171pg/mL, about 172pg/mL, or about 173pg/mL or greater (as described in U.S. provisional application No. 63/046,133, which is incorporated herein by reference in its entirety). If VIB551 is administered to a patient having a sGFAP concentration of about 160pg/mL, about 165pg/mL, about 166pg/mL, about 167pg/mL, about 168pg/mL, about 169pg/mL, about 170pg/mL, about 171pg/mL, about 172pg/mL, or about 173pg/mL or more, then the patient's sGFAP concentration may be determined to be about 160pg/mL, about 165pg/mL, about 166pg/mL, about 167pg/mL, about 168pg/mL, about 169pg/mL, about 170pg/mL, about 171pg/mL, about 172pg/mL, or about 173pg/mL or more prior to administration.

In various aspects, anti-CD 19 antibodies other than VIB551, such as MOR00208 (also known as Xmab 5574 or tafasitamab; disclosed in U.S. patent application No. 20170137516), may be used in the methods of treatment disclosed herein. In certain of these aspects, the present disclosure provides a method of treating NMOSD, the method comprising: administering an anti-CD 19 antibody to a patient in need of NMOSD treatment, wherein the patient has been previously treated with an anti-CD 20 antibody, wherein the patient has an NMOSD episode during treatment with the anti-CD 20 antibody. In aspects, the present disclosure provides a method of treating NMOSD, the method comprising: administering an anti-CD 19 antibody to a patient in need of NMOSD treatment, wherein the patient has been previously treated with an anti-CD 20 antibody, wherein the patient has an NMOSD episode within 6 months of the last dose of anti-CD 20 antibody. In various aspects, the anti-CD 20 antibody may be rituximab (antibody C2B8 in WO 94/11026). In various aspects, the anti-CD 20 antibody that was previously potentially useful for treating a patient is ABP-300 (Abpro corporation); b-001 (Shanghai pharmaceutical group Co., ltd.); BAT-4306F (Baiottai Bio Inc.); BAT-4406F (Baiottai Bio-pharmaceutical Co., ltd.); BCD-132 (Bokang Biotechnology Co.); BVX-20 (Vaccinex corporation); CYT-202 (re-slush biomedical limited); elcatuzumab (Genmab); GB-261 (Jia and Bio-pharmaceutical Co., ltd.); GD-CO1620 (propovigor technologies limited); gefituzumab (roche); HS-006 (Zhejiang Zhengzheng pharmaceutical Co., ltd.); IGM-2323 (IGM biotechnology company); IMM-0306 (Yimingke biomedical technologies Co., ltd.); MIL-62 (Beijing Tianguangzhi Biotechnology Co., ltd.); mosuteuzumab (rochanter); MRG-001 (Shanghai Meiya Ke Biotechnology Co., ltd.); olanbituzumab (roche company); origizumab (Roche, inc.; new York); ornitumumab (regenerator pharmaceutical); ofatuzumab (Genmab; nohua); palamotuzumab (Xencor corporation); SM-09 (chinese antibody pharmaceutical limited); TRS-005 (Zhejiang Terisi pharmaceutical Co., ltd.); wu Tuo Acximab (rEVO Biologics Co.); or YBL-031 (Y-Biologics).

In various aspects, the anti-CD 19 antibody administered to the patient, if other than VIB551 (also known as MEDI551, uplizna ^TM Or anibizumab; disclosed in U.S. application Ser. No. 11/852,106 and International application Ser. No. 20/29613, which are incorporated herein by reference in their entirety), may be, for example, any of the following: MOR00208 (also known as Xmab 5574 or tafasitamab; disclosed in U.S. patent application No. 20170137516, incorporated herein by reference in its entirety); bonauzumab (blinatumomab) (Amgen, amuna; an Si Talars; astella; microMet, microMet); loncastuximab tesirine (ADC Therapeutics); GTB-1550/OXS-1550 (Oxis Biotech Inc.); oreg Bei Lishan anti (obexelimab)/XmAb 5871 (Xencor Co.); AFM11 (Affimed Co.); or Lei Xing-cetuximab/ravtannine (ImmunoGen Inc.).

In various aspects, if the anti-CD 19 antibody VIB551 is administered in any of the methods disclosed herein, the VIB551 can have a VH amino acid sequence and a VL amino acid sequence as shown in fig. 4. In various aspects, VIB551 may comprise a heavy chain variable region (VH) comprising the amino acid of SEQ ID NO. 1 and a light chain variable region (VL) comprising the amino acid of SEQ ID NO. 2. The VIBs 551 administered in these methods may have the VH amino acid sequence and VL amino acid sequence shown in fig. 4, except for one or more amino acid residue changes that do not alter the function of the VIB551 amino acid sequence. The number of amino acid changes may be 1 amino acid residue change, 2 amino acid residue change, 3 amino acid residue change, 4 amino acid residue change, or 5 amino acid residue change. In particular aspects, the VIB551 used in the methods disclosed herein has at least about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, or about 100% identity to the VH and VL sequences disclosed in fig. 4. The VIBs 551 administered in these methods may contain Complementarity Determining Region (CDR) amino acid sequences of VH and VL sequences as shown in fig. 4 and sequence listing 1, but may have one or more changes in the framework regions (i.e., residues other than CDR residues) of the VH and VL domain sequences shown in fig. 4 and table 1. Alternatively, VIB551 administered in any of the methods disclosed herein can have a heavy chain amino acid sequence and a light chain amino acid sequence as shown in fig. 9. In various aspects, VIB551 may comprise a heavy chain comprising the amino acid of SEQ ID NO. 3 and a light chain comprising the amino acid of SEQ ID NO. 4. The VIBs 551 administered in these methods may have the heavy and light chain amino acid sequences as shown in fig. 9, except for one or more amino acid residue changes that do not alter the function of the VIB551 amino acid sequence. The number of amino acid changes may be 1 amino acid residue change, 2 amino acid residue change, 3 amino acid residue change, 4 amino acid residue change, or 5 amino acid residue change. In various aspects, VIB551 for use in the methods disclosed herein has at least about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, or about 100% identity to the heavy and light chain sequences disclosed in fig. 9.

TABLE 1 VIB551

In any of the methods disclosed herein, if VIB551 is an anti-CD 19 antibody administered to a patient in need thereof, the VIB551 may be administered at a dose of about 300mg. In various aspects, the VIB551 may be administered at a dose of about 250mg to about 350mg, about 275mg to about 325mg, about 290mg to about 310mg, about 205mg to about 305mg, or may be a dose of 300mg. In various aspects, the patient may receive one or more initial doses of VIB551. In one aspect, the patient may receive an initial dose of one, two, three or more times. In a particular aspect, the initial dose may be about 300mg. In various aspects, the VIB551 may be administered in an initial dose of about 250mg to about 350mg, about 275mg to about 325mg, about 290mg to about 310mg, about 205mg to about 305mg, or an initial dose of 300mg. In a particular aspect, VIB551 may be administered intravenously at a first initial dose of about 300mg, two weeks after the first initial dose at a second initial dose of about 300mg, and then at a dose of about 300mg every 6 months after the first initial dose.

If VIB551 is administered in the methods disclosed herein, it may be administered at intervals of about once every 6 months. In various aspects, VIB551 may be administered intravenously. The administration may be every 6 months, every 180 days, every 170 to 190 days, every 175 to 185 days, every 175 to 190 days, or every 170 to 185 days, about every 6 months. About every 6 months may be administered every 26 weeks, every 25 weeks, every 27 weeks, every 25 to 26 weeks, or every 26 to 27 weeks. In this method, an initial VIB551 dose may be administered to an nmosc patient prior to administration of VIB551 every about 6 months. The initial VIB551 dose may be administered about 2 weeks prior to about every 6 months of VIB551 dosing. The initial VIB551 dose administered about 2 weeks prior to every about 6 months of VIB551 administration may be 12 days, 13 days, 14 days, 15 days, or 16 days prior to about 6 months of VIB551 administration. The initial VIB551 dose may or may not be co-administered with an oral corticosteroid.

In aspects, the present disclosure provides a method of treating NMOSD, the method comprising: administering an anti-CD 19 antibody VIB551 to a patient in need of NMOSD treatment, wherein the patient is an AQP4-igg+ patient, wherein the VIB551 is administered intravenously at a first initial dose of 300mg, administered intravenously at a second initial dose of 300mg two weeks after the first initial dose, and subsequently administered intravenously at a dose of 300mg every 6 months after the first initial dose, wherein the patient has been previously treated with an anti-CD 20 antibody, and wherein the patient has an NMOSD episode during treatment with an anti-CD 20 antibody. In one aspect, the present disclosure provides a method of treating NMOSD, the method comprising: administering an anti-CD 19 antibody VIB551 to a patient in need of NMOSD treatment, wherein the patient is an AQP4-igg+ patient, wherein the VIB551 is administered intravenously at a first initial dose of 300mg, two weeks after the first initial dose, at a second initial dose of 300mg, and subsequently administered intravenously at a dose of 300mg every 6 months after the first initial dose, wherein the patient has been previously treated with an anti-CD 20 antibody; and wherein the patient has an onset of NMOSD within 6 months of the last dose of anti-CD 20 antibody. In various aspects, the anti-CD 20 antibody is rituximab (antibody C2B8 in WO 94/11026).

Also provided are methods for treating pediatric patients with AQP4-IgG seropositive NMOSD using anti-CD 19 antibody VIB 551. The NMOSD of a pediatric patient may be determined according to the following criteria: wingerchuk et al, "International consensus diagnostic criteria for neuromyelitis optica spectrum disorders [ international consensus diagnostic criteria for neuromyelitis spectrum disorders ]. Neurology [ neurological ]," 2015;85 (2):177-89. Although subjects are typically AQP4-IgG seropositive, subjects with NMOSD but AQP4-IgG seronegative are also contemplated. In various aspects, the patient may have one or more acute recrudescence of NMOSD within the previous year of treatment, or 2 or more acute recrudescence of NMOSD within the last 2 years. Pediatric subjects may be male or female, and may range in age from 2 years to <18 years; for example, 2 to <6 years, 6 to <12 years, 12 to <18 or 2 to <12 years.

The dose administered to a pediatric patient is determined by body weight. If the subject's body weight is less than or equal to 37.5kg, 8mg/kg IV is administered. If the patient's body weight is >37.5kg, the subject receives 300mg IV. Subjects who had a body weight of 37.5kg or less to >37.5kg and who received concurrent anti-CD 19 antibody VIB551 therapy could switch the regimen from 8mg/kg to 300mg. anti-CD 19 antibody VIB551 is typically administered as monotherapy. After the first dose, one or more doses may be administered subsequently. Subsequent doses may be about 24 to 28 weeks apart, about 12 months apart, about 30 months apart, about 36 months apart, or about 48 months apart, as long as needed to maintain therapy. The anti-CD 19 antibody VIB551 is typically administered as monotherapy, but may be co-administered with a corticosteroid during the early stages of treatment of a pediatric patient. However, corticosteroid therapy is typically gradually reduced shortly after initiation of antibody therapy, e.g., 1 week, 2 weeks, 3 weeks, or 4 weeks after administration of the first dose. In aspects, wherein the VIB551 is administered intravenously at a first initial dose of 300mg, two weeks after the first initial dose, at a second initial dose of 300mg, and then, after the first initial dose, at a dose of 300mg every 6 months.

Monoclonal antibody VIB551 may be administered to a hepatitis b virus carrier. Hepatitis B virus carriers previously receiving anti-CD 20 monoclonal antibody therapy have been reported to have reduced B cell numbers, reduced death due to fulminant hepatitis, exacerbating hepatitis or liver failure during or after treatment. The presence of hepatitis B virus reactivation in these patients is also reported. However, no report of these reactions was seen with the use of anti-CD 19 monoclonal antibody VIB551. However, to promote patient confidence and health management, the patient's HBV status may be assessed prior to initiation of VIB551 therapy and/or the patient's signs and symptoms of hepatitis b virus reactivation may be monitored by periodic liver function testing and hepatitis virus marker monitoring.

For patients who are already receiving HBV infection therapy, their liver status may be monitored using parameters such as ALT (alanine aminotransferase)/AST (aspartate aminotransferase) ratio elevation or fluctuations and serum viral load increase (vildaolid et al, "Hepatitis B reactivation and rituximab in the oncology practice [ rituximab in hepatitis b revival and oncology practice ]".

Prior to administration of anti-CD 19 antibody VIB551, the HBV status of the patient can be tested. For example, the following blood test is used. First, a blood sample of a patient is prepared, serum is obtained, and HBs antigen (hereinafter abbreviated as HBsAg) is measured. If the HBsAg test is positive, the patient is considered to have active HBV infection and the anti-CD 19 antibody VIB551 is disabled. If the HBsAg test is negative, the measurement is performed on HBc antibody (hereinafter HBcAb) and/or HBs antibody (hereinafter HBsAb), and if one of them is positive, VIB551 may be administered. Patients negative for HBsAg, HBcAb and HBsAb do not require periodic liver function tests and hepatitis virus marker monitoring.

HBsAg, HBcAb or HBsAb can be measured by ELISA or CLIA (including equivalent FEIA/ECLIA/CLEIA/BLEIA) using respective antibodies or antigen detection/measurement reagents. For example, HBsAg can be measured by CLEIA, and a sample using STACIA CLEIA HBs antigen (LSI science corp. Japan) (www.info.pmda.go.jp/downfiles/ivd/PDF/750524_21800amx10883000_a_01_09. PDF) and a cut-off index of 1 or more will be regarded as 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 a cut-off index greater than or equal to 1 will be considered positive. For example, HBsAb can be measured by CLIA using ARCHITECT G06255R03 (yaban japan contract) (www.info.pmda.go.jp/downfiles/ivd/PDF/100159_21000 amuy 001200020000_a_01_10. PDF).

In any of the methods disclosed herein, the VIB551 may be packaged in a 10-mL vial filled with a nominal 10-mL of VIB551 solution. In various aspects, VIB551 may be formulated at a concentration of 10 mg/mL. In various aspects, a VIB551 formulation may comprise 20mM histidine/histidine hydrochloride, 70mM NaCl, 106mM (4% [ w/v ]) anhydrotrehalose, and 0.01% (w/v) polysorbate 80 (pH 6.0).

In some embodiments, the dose of VIB551 administered to the patient is determined by body weight. If the subject's body weight is less than or equal to 37.5kg, 8mg/kg IV is administered. If the patient's body weight is >37.5kg, the subject receives 300mg IV. Subjects who had a body weight of 37.5kg or less to >37.5kg and who received concurrent anti-CD 19 antibody VIB551 therapy could switch the regimen from 8mg/kg to 300mg. anti-CD 19 antibody VIB551 is typically administered as monotherapy.

The dose of VIB551 that can be used in a method of treating a patient in need of NMOSD treatment can be a VIB551 dose that depletes at least 90% of circulating cd20+ B cells for at least six months and does not increase the risk of infection in the patient. The VIB551 dose may be a dose of about 250mg to about 350mg, about 275mg to about 325mg, about 290mg to about 310mg, about 205mg to about 305mg, or may be a dose of 300mg. In various aspects, the patient may receive one or more initial doses of VIB551. In one aspect, the patient may receive one, two, three or more initial doses. In a particular aspect, the initial dose may be about 300mg. In various aspects, the VIB551 may be administered in an initial dose of about 250mg to about 350mg, about 275mg to about 325mg, about 290mg to about 310mg, about 205mg to about 305mg, or an initial dose of 300mg. In a particular aspect, VIB551 may be administered intravenously at a first initial dose of about 300mg, two weeks after the first initial dose at a second initial dose of about 300mg, and then at a dose of about 300mg every 6 months after the first initial dose.

The dose of VIB551 (wherein the VIB551 dose is depleted of at least 90% of circulating cd20+ B cells for at least six months and does not increase the risk of infection in the patient) that can be used in a method of treating a patient in need of NMOSD therapy can be a dose administered intravenously at intervals of about once every 6 months, about once every 7 months, about once every 8 months, about once every 9 months, about once every 10 months, about once every 11 months, or about once a year.

VIB551 may also be used in a method of treating a patient in need of NMOSD treatment, wherein the VIB551 is administered at the following doses: (i) Circulating cd20+ B cells depleted by at least 90% over at least six months; and (ii) does not increase the risk of infection in the patient. The dose of circulating CD20+ B cells depleted by at least 90% over at least six months also depletes peripheral blood CD20 ^- Plasmablasts and plasmablasts. A dose of circulating cd20+ B cells that is depleted by at least 90% over at least six months may also reduce or eliminate the plasma cell gene signature of a patient in need of NMOSD treatment. A dose that depletes at least 90% of circulating cd20+ B cells may deplete circulating cd20+ B cells for more than six months. It can deplete at least 90% of circulating cd20+ B cells for at least 9 months or at least 1 year.

The VIB551 dose of circulating cd20+ B cells, which was depleted by at least 90% over at least six months in the treatment method, also did not increase the risk of infection in NMOSD patients. The risk of infection for the NMOSD patient may not be increased relative to the risk of infection prior to administration of VIB 551. The risk of infection in NMOSD patients may not be increased compared to NMOSD patients not treated with VIB 551. The risk of infection may be or lead to the following: typical pneumonia, beta hemolytic streptococcus infection, bronchitis, conjunctivitis, viral conjunctivitis, fungal skin infection, viral gastroenteritis, gastrointestinal infection, gingivitis, cystitis, shingles, influenza, laryngitis, viral meningitis, muscle abscess, oral herpes, otitis externa, periodontitis, pneumonia, rhinitis, retinitis, renal pelvis cystitis, sinusitis, urinary tract infection, tinea cruris, septic shock or upper respiratory tract infection.

Any of the methods provided herein may further comprise the following steps prior to administration of the anti-CD 19 antibody (e.g., VIB 551): (i) identifying a patient who has been previously treated with an anti-CD 20 antibody; (ii) Determining that the patient has suffered at least one nmosfet during treatment with the anti-CD 20 antibody or at least one nmosfet within 6 months of the last dose of the anti-CD 20 antibody, and (iii) selecting the patient for administration of the anti-CD 19 antibody based on the result of the determination.

Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific aspects described herein. Such equivalents are intended to be encompassed by the following claims.

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

Numbered embodiments of the invention

The present disclosure sets forth the following numbered embodiments, although the appended claims:

embodiment 1. A method of treating neuromyelitis optica spectrum disorder (NMOSD), the method comprising:

administering an anti-CD 19 antibody VIB551 to a patient in need of NMOSD treatment,

wherein the patient has been previously treated with an anti-CD 20 antibody, and wherein the patient has an nmosfer episode during treatment with the anti-CD 20 antibody.

Embodiment 2. A method of treating NMOSD comprising:

wherein the patient has been previously treated with an anti-CD 20 antibody, wherein the patient has an nmosfet episode within 6 months of the last dose of the anti-CD 20 antibody.

Example 3. The method as described in example 1 or example 2, wherein VIB551 is administered intravenously every 6 months at a dose of 300 mg.

Embodiment 4. A method of treating NMOSD comprising:

wherein the patient is astrocyte water channel aquaporin 4 (AQP 4) -immunoglobulin (Ig) G ⁺ The patient's position of his head is,

wherein the VIB551 is administered intravenously every 6 months at a dose of 300mg,

Embodiment 5. A method of treating NMOSD comprising:

wherein the patient is AQP4-IgG ⁺ The patient's position of his head is,

wherein the patient has been previously treated with an anti-CD 20 antibody; and wherein the patient has an onset of NMOSD within 6 months of the last dose of anti-CD 20 antibody.

Embodiment 6. The method of any of embodiments 3-5, wherein the patient receives at least one initial dose of VIB551.

Embodiment 7 the method of any of embodiments 3-6 wherein the VIB551 is administered intravenously at a first initial dose of 300mg, a second initial dose of 300mg two weeks after the first initial dose, and then administered intravenously at a dose of 300mg every 6 months after the first initial dose.

Example 8 the method of example 6 or example 7, wherein an oral corticosteroid is co-administered to the patient with the initial VIB551 dose.

Example 9. The method of example 8, wherein the oral corticosteroid is administered daily for at least 2 weeks.

Embodiment 10. The method of any one of embodiments 1-9, wherein the anti-CD 20 antibody is rituximab.

Example 11. The method of any of examples 1-10, wherein the treatment is a reduction in the deterioration of the patient's kurtz Extended Disability Severity Scale (EDSS).

Example 12. The method of example 11, wherein the reduction in EDSS deterioration in the patient is:

if the patient has a baseline score of 0, the deterioration in the EDSS score is less than 2 points;

if the patient has a baseline score of 1 to 5, the exacerbation is less than 1 score; or (b)

If the patient has a baseline score of 5.5 or more, the exacerbation is less than 0.5 score.

Embodiment 13. The method of any of embodiments 1-10, wherein the treatment is a reduction in the number of active Magnetic Resonance Imaging (MRI) lesions.

Example 14. The method of example 13, wherein the active MRI lesions are expanding T2 MRI lesions.

Embodiment 15. The method of any one of embodiments 1-10, wherein the treatment is a reduction in the number of new MRI lesions.

Embodiment 16. The method of any one of embodiments 1-10, wherein the treatment is a reduction in worsening of the patient's improved rankine score.

Embodiment 17. The method of any one of embodiments 1-10, wherein the treatment is a reduction in the frequency of NMOSD-related hospitalization of the patient.

Embodiment 18. The method of any one of embodiments 1-10, wherein the treatment is a reduction in risk of an nmosfet-related episode of the patient.

Embodiment 19. The method of embodiment 18, wherein the onset of NMOSD associated is characterized by new symptoms occurring or existing NMOSD associated symptoms worsening.

Embodiment 20. The method of embodiment 19, wherein the symptom is an ocular symptom.

Embodiment 21. The method of embodiment 20, wherein the ocular symptom is ocular pain, blurred vision, vision loss, or appearance of an optic nerve lesion detected by MRI.

Embodiment 22. The method of embodiment 19, wherein the symptom is spinal cord symptom.

Embodiment 23. The method of embodiment 22, wherein the spinal symptom is deep pain or radicular pain, limb paresthesia, inoxism, sphincter dysfunction, lehr Mi Teshi sign, or spinal lesions detectable by MRI.

Embodiment 24. The method of embodiment 19, wherein the symptom is brain or brainstem symptom.

Embodiment 25 the method of embodiment 24, wherein the brain or brain stem symptom is nausea, double vision, paralysis of eye movements, dizziness, refractory vomiting, refractory hiccup, dysarthria, dysphagia, weakness, encephalopathy, hypothalamic dysfunction, or brain stem lesions detectable by MRI.

Embodiment 26. The method of embodiment 18, wherein the risk of an nmosfet-related episode is reduced by between 60% and 85%.

Embodiment 27. The method of any of embodiments 1-10, wherein the treatment is a reduction in optic neuritis.

Embodiment 28. The method of any one of embodiments 1-10, wherein the treatment is a reduction in severity of an NMOSD associated episode.

Embodiment 29. The method of embodiment 28, wherein the reduction in severity of an NMOSD associated episode is a reduction in NMOSD associated episodes graded as severe.

Embodiment 30. The method of embodiment 28, wherein the reduction in severity of an nmosfet-related episode is a reduction in an nmosfet episode requiring hospitalization.

Embodiment 31. The method of any one of embodiments 1-10, wherein the treatment is a reduction in NMOSD associated pain in the patient.

Embodiment 32. The method of embodiment 31, wherein the reduction in the NMOSD associated pain is determined by measuring the patient's leg pain.

Embodiment 33 the method of any one of embodiments 1-5, wherein the subject is administered an initial 300mg vib551 dose two weeks before the 300mg vib551 administered first every 6 months.

Example 34 the method of example 33, wherein an oral corticosteroid is co-administered to the patient with the initial 300mg vib551 dose.

Example 35 the method of example 1 or example 2 wherein the patient is AQP4-IgG seropositive.

Embodiment 36. A method of reducing active MRI lesions in a patient diagnosed with NMOSD, the method comprising:

wherein the patient has been previously treated with an anti-CD 20 antibody, wherein the patient has an nmosfet episode during treatment with the anti-CD 20 antibody.

Embodiment 37. A method of reducing active MRI lesions in a patient diagnosed with NMOSD, the method comprising:

Example 38 the method of example 36 or 37, wherein the VIB551 is administered intravenously every 6 months at a dose of 300 mg.

Embodiment 39. A method of reducing active MRI lesions in a patient diagnosed with NMOSD, the method comprising:

wherein the patient has been previously treated with an anti-CD 20 antibody, wherein the patient has an nmosfer episode during treatment with the anti-CD 20 antibody; and, in addition, the processing unit,

wherein the VIB551 is administered intravenously every 6 months at a dose of 300 mg.

Embodiment 40. A method of reducing active MRI lesions in a patient diagnosed with NMOSD, the method comprising:

wherein the patient has been previously treated with an anti-CD 20 antibody, wherein the patient has an nmosfet episode within 6 months of the last dose of anti-CD 20 antibody; and, in addition, the processing unit,

Example 41A reduction of AQP4-IgG in need of NMOSD treatment ⁺ A method of AQP4-IgG titres in a patient, the method comprising:

Example 42A reduction of AQP4-IgG in need of NMOSD treatment ⁺ A method of AQP4-IgG titres in a patient, the method comprising:

Example 43 the method of example 41 or 42, wherein the VIB551 is administered intravenously every 6 months at a dose of 300 mg.

EXAMPLE 44A reduction of AQP4-IgG in need of NMOSD treatment ⁺ A method of AQP4-IgG titres in a patient, the method comprising:

Example 45A reduction of AQP4-IgG in need of NMOSD treatment ⁺ A method of AQP4-IgG titres in a patient, the method comprising:

Embodiment 46 the method of any one of embodiments 1-45, wherein the administration depletes at least 90% of circulating cd20+ B cells for at least six months.

Embodiment 47. The method of any one of embodiments 1-46, wherein the administering does not increase the risk of infection for the patient.

Embodiment 48 the method of any one of embodiments 1-47, wherein the VIB551 depletes peripheral blood CD20 within 8 days after the administration ^- Plasmablasts and plasmablasts.

Embodiment 49. A method of reducing NMOSD associated disability in a patient diagnosed with NMOSD, the method comprising:

Embodiment 50. A method of reducing NMOSD-related disability in a patient diagnosed with NMOSD, the method comprising:

Example 51 the method of example 49 or 50, wherein the VIB551 is administered intravenously every 6 months at a dose of 300 mg.

Embodiment 52. A method of reducing NMOSD associated disability in a patient diagnosed with NMOSD, the method comprising:

Embodiment 53. A method of reducing NMOSD associated disability in a patient diagnosed with NMOSD, the method comprising:

Embodiment 54. The method of any of embodiments 49-53, wherein reducing the patient's NMOSD associated disability is reducing the patient's rate of exacerbation of NMOSD associated disability.

Embodiment 55. The method of any of embodiments 49-54, wherein reducing the patient's NMOSD associated disability is reducing the patient's NMOSD associated disability.

Embodiment 56. The method of any one of embodiments 49-55, wherein the NMOSD associated disability is neurological disability.

Embodiment 57. The method of any of embodiments 49-56, wherein reducing the NMOSD associated disability is determined using EDSS.

Embodiment 58. A method of reducing NMOSD related episodes in a patient in need of NMOSD treatment, the method comprising:

Embodiment 59. A method of reducing NMOSD related episodes in a patient in need of NMOSD treatment, the method comprising:

Example 60 the method of example 58 or 59, wherein the VIB551 is administered intravenously every 6 months at a dose of 300 mg.

Embodiment 61. A method of reducing NMOSD related episodes in a patient in need of NMOSD treatment, the method comprising:

Embodiment 62. A method of reducing NMOSD related episodes in a patient in need of NMOSD treatment, the method comprising:

Embodiment 63 the method of embodiment 61 or embodiment 62, wherein the NMOSD associated episodes suffered by the patient comprise any one or more of optic neuritis, myelitis or brainstem episodes.

Example 64 the method of example 63, wherein the NMOSD associated episodes suffered by the patient are clinically asymptomatic.

Embodiment 65 the method of any of embodiments 36-64, wherein the patient receives at least one initial dose of VIB551.

The method of example 66, wherein the VIB551 is administered intravenously at a first initial dose of 300mg, a second initial dose of 300mg two weeks after the first initial dose, and then administered intravenously at a dose of 300mg every 6 months after the first initial dose.

Example 67 the method of example 66, wherein an oral corticosteroid is co-administered to the patient with the initial 300mg vib551 dose.

Example 68 the method of example 67, wherein the oral corticosteroid is administered daily for at least 2 weeks.

Embodiment 69 the method of any one of embodiments 36-68, wherein the anti-CD 20 antibody is rituximab.

Embodiment 70 the method of any one of embodiments 1-69, wherein the VIB551 comprises a heavy chain variable region (VH) comprising the amino acid of SEQ ID No. 1 and a light chain variable region (VL) comprising the amino acid of SEQ ID No. 2.

Embodiment 71. A method of treating NMOSD, the method comprising:

administering an anti-CD 19 antibody to a patient in need of NMOSD treatment,

Embodiment 72. A method of treating NMOSD, the method comprising:

administering an anti-CD 19 antibody to a patient in need of NMOSD treatment,

Embodiment 73. A method of treating NMOSD, the method comprising:

wherein the patient is AQP4-IgG ⁺ The patient's position of his head is,

wherein the VIB551 is administered intravenously at a first initial dose of 300mg, at a second initial dose of 300mg two weeks after the first initial dose, and subsequently, at a dose of 300mg every 6 months after the first initial dose,

Embodiment 74. A method of treating NMOSD, the method comprising:

wherein the patient is AQP4-IgG ⁺ The patient's position of his head is,

Embodiment 75 the method of any one of embodiments 1-74, further comprising, prior to administration:

Identifying a patient who has been previously treated with the anti-CD 20 antibody;

determining the patient:

(i) At least one nmodson episode during treatment with the anti-CD 20 antibody; or (b)

(ii) At least one nmod episode was suffered within 6 months of the last dose of anti-CD 20 antibody; and

based on the results of determining (i) or (ii), selecting a patient for administration of the anti-CD 19 antibody.

Embodiment 76 a method of treating neuromyelitis optica spectrum disorder (NMOSD), the method comprising:

wherein the patient has been previously treated with an anti-CD 20 antibody, and wherein the patient has an nmosfer episode during treatment with the anti-CD 20 antibody; the method comprises obtaining a blood sample of the patient prior to administration of the anti-CD 19 antibody VIB551, testing the sample for the presence of HBs antigen, HBc antibody and HBs antibody, and administering the anti-CD 19 antibody VIB551 to a patient that is negative for HBs antigen testing and positive for either HBc antibody or HBs antibody or both; and optionally monitoring periodic liver function tests and monitoring hepatitis virus markers during or after treatment with the anti-CD 19 antibody VIB 551.

Example 77 a method of treating neuromyelitis optica spectrum disorder (NMOSD), the method comprising:

wherein the patient is HBs antigen negative and is HBs antibody positive, HBc antibody positive, or both.

Embodiment 78 the method of embodiment 77, wherein the patient has been previously treated with an anti-CD 20 antibody.

Embodiment 79. The method of embodiment 78, wherein the patient has an onset of NMOSD during treatment with the anti-CD 20 antibody.

Examples

EXAMPLE 1 basic principles of clinical trial design elements

Summary. NMOSD clinical trial N-MOmentum was designed as a randomized, placebo-controlled, double-blind, 197-day, 2/3-phase study (with open-label extension) to evaluate efficacy and safety of VIB551 (also known as VIB551 or MedI551, an anti-CD 19B cell depleting antibody) in NMOSD patients enrolled from 99 sites in 24 countries. Participants were randomly grouped using an interactive voice response system/interactive network response system as either intravenous administration of VIB551 300mg or placebo (3:1) on day 1 and day 15, respectively. Efficacy endpoints were assessed in the intended treatment population and safety endpoints were assessed in the treatment-receiving population. The primary endpoint is the time of first adjudication of the episode; secondary endpoints include exacerbations of disability, magnetic Resonance Imaging (MRI) lesion activity, and hospitalization. A more detailed description of the N-Momentum clinical trial can be found in Cree et al, lancet [ Lancet ]394:1352-1363 (2019) and International application number PCT/US 20/29613, which are incorporated herein by reference in their entireties.

Group selection. Placebo comparator treated groups were selected because there are no currently approved drugs for the treatment of neuromyelitis optica spectrum disorders. The use of placebo group allows a clear and robust assessment of VIB551, avoids confounding effects of other treatments, provides the highest sensitivity and robustness to detect efficacy, and helps provide clinically significant results of the study.

And (5) random grouping. The 3:1 random grouping ratio used in this study is an effective and efficient method to build a rich safety database for VIB551 while keeping the number of required events or patients in the placebo group at a minimum acceptable level. This random grouping ratio also solves to some extent the problems of investigators and patient ethics with respect to recruiting patients into the placebo group. In addition to limiting the number of patients receiving placebo, the study also aimed at limiting the actual duration of placebo exposure to at most 197 days or the time of onset (based on earlier occurrences), after which all patients had the option of entering the open label phase and receiving the VIB551.

Patients were stratified based on AQP4-IgG serum status (determined at screening) and region (japan versus non-japan) prior to random grouping. Within each layer, patients were randomized using an interactive voice response system/interactive web response system (IVRS/IWRS) at a 3:1 ratio, using a treatment group permutation block randomization scheme and blind study product kit number assignment. When the researcher notifies the IVRS/IWRS that the patient meets the qualification criteria and the IVRS/IWRS assigns the patient a masked study product kit number, the patient is considered to be randomly grouped into the study.

Blind method. This is a double blind study. VIB551 and placebo are marked identically in appearance and indistinguishable; both are supplied as transparent to milky white, colorless to yellow liquids and contain no or little particles. VIB551 and placebo doses were indistinguishable during dose preparation, treatment and infusion.

Neither the patient/legal representative nor any investigator or sponsor staff involved in the treatment or clinical assessment of the patient is aware of the treatment received. In the event that the patient's treatment allocation is known, the sponsor is immediately notified.

The administration of a blinding dose of VIB551 or placebo on day 15 of the open label period is necessary to administer a loading dose of VIB551 600mg injection either correctly intravenously to the patients previously randomized to placebo or to ensure that the patients previously randomized to VIB551 do not receive additional therapeutic doses. This blind mechanism is implemented by the IVRS to ensure that the details of the randomized treatment are not revealed to the site.

VIB551 is known to deplete cd19+ B cells; thus, the results of flow cytometry on B-cell counts may be blinded. Throughout the rest of the study, the study site did not acquire these data after random grouping.

Early development data from a non-tumor patient population receiving VIB551 indicated that administration may be associated with a potential, unspecified, mild reduction in total immunoglobulins for individual patients. Throughout the rest of the study, the study site did not acquire this data after random grouping, as the reduction may have been potentially blinded.

Example 2-clinical trial subject recruitment requirements and criteria

Summary. The key inclusion criteria are: an adult diagnosed with NMOSD (Winger Chuk DM, lennon VA, lucchinetti CF, pittock SJ, weinhenker BG, the spectrum of neuromyelitis optica [ neuromyelitis optica lineage ]. Lancet Neurol [ Lancet Neurology ]2007;6:805-15;Wingerchuk DM,Lennon VA,Pittock SJ,Lucchinetti CF,Weinshenker BG,Revised diagnostic criteria for neuromyelitis optica [ revised neuromyelitis diagnostic criteria ]. Neurology [ Neurology ]2006; 66:1485-9) and EDSS score less than 8.0 and with a medical history of at least one episode of rescue therapy (intravenous corticosteroids, intravenous immunoglobulins and/or plasmapheresis) in the previous year of screening or at least two episodes of rescue therapy in the previous 2 years of screening. AQP4-IgG seropositive and seronegative patients are eligible; seronegative participants must meet the Winger chuk 2006 standard. Winger chuk DM, lennon VA, pittock SJ, lucchinetti CF, weinhenker BG, revised diagnostic criteria for neuromyelitis optica [ revised neuromyelitis diagnostic criteria ]. Neurology [ Neurology ]2006;66:1485-9. There was no pre-planned recruitment objective for AQP4-IgG serum status. It is assumed that the recruitment will reflect known demographics of an approximately 80% seropositive, 20% seronegative patient population. Winger chuk DM, lennon VA, pittock SJ, lucchinetti CF, weinhenker BG, revised diagnostic criteria for neuromyelitis optica [ revised neuromyelitis diagnostic criteria ]. Neurology [ Neurology ]2006;66:1485-9. All participants provided written informed consent.

Sample size. The initial sample size calculation concludes that 212 patients will need to be enrolled to observe the 67 episodes required. The number of patients was calculated by assuming a risk ratio of episodes in the seropositive and seronegative groups of 1.5 per year and 1.0 per year in the placebo group, respectively. These risk ratios are based on observed episodes observed in four open label cohort studies (Bedi et al Impact of rituximab on relapse rate and disability in neuromyelitis optica [ influence of rituximab on neuromyelitis recurrence rate and disability ]. Mult Scler [ multiple sclerosis ]2011; 17:1225-30; costanzi et al Azathioprines: tolearity, efficace, and predictors of benefit in neuromyelitis optica [ Azathioprine: tolerance, efficacy and benefit predictor of neuromyelitis ]. Neurology [ neurological ]2011;77:659-66; jacob et al Treatment of neuromyelitis optica with rituximab: retrospective analysis of of parameters [ rituximab for treatment of neuromyelitis: retrospective analysis of 25patients ]. Musce Nerve [ Muscle Nerve ] 2008:39-90; kim et al Repeated treatment with rituximab based on the assessment of peripheral circulating memory B cells in patients with relapsing neuromyelitis optica over [ based on evaluation of peripheral circulating memory B cells of recurrent neuromyelitis patients; rituximab ]. 2:IgG: 35:35:35:35:4 in open-35 AQ-35B-35, et al, visual pool-35:4.

The primary endpoint and four secondary endpoints are considered to establish class 1 error control.

The main end point is: time (in days) from day 1 to onset of neuromyelitis optica spectrum disorder as determined by the committee of the adjunctions at or before day 197. Attacks are defined as the presence of one or more new symptoms associated with neuromyelitis optica or the worsening of one or more existing symptoms, which meet at least one of the criteria for the onset of a defined neuromyelitis optica spectrum disorder.

Four key secondary endpoints: 1. EDSS scores worsened relative to baseline at the last visit during the randomized control period. The EDSS assessment under study was performed by an independent blind evaluator at each site using an electronic data capture system developed by the university of bassell (University of Basel) and the nervous system status company (Neurostatus GmBH) that contains an internal algorithm that provides feedback to the evaluator regarding the EDSS assessment inconsistency; 2. changes in low contrast vision binocular score from baseline measured by the low contrast Landolt C Broken ring chart at the last visit during the randomized control period; 3. cumulative total of active MRI lesions (new gadolinium enhanced or new/expanding T2 lesions) during randomized control; 4. the number of neuromyelitis associated hospitalizations, defined as stay for more than one night.

EXAMPLE 3 clinical trial protocol

And (3) screening period. Subjects diagnosed with NMO/nmosfs were screened for 28 days based on inclusion and exclusion criteria to determine their eligibility to participate in the study. All subjects meeting the eligibility criteria were randomized into the study.

And (5) random grouping. Subjects were randomized into the study at a 3:1 ratio (receiving intravenous VIB551 (30 mg) or placebo) as described in table 2. Random grouping occurred on day 1 and was stratified by AQP4-IgG serum status (about 80:20 ratio for seropositive and seronegative subjects, respectively) and regional (japan versus non-japan).

Table 2: random control phase treatment regimen

Treatment group	Treatment regimen
		1	300mg of MEDI-551 intravenously on day 1 and day 15
2	Intravenous placebo on day 1 and day 15

Random control period (day 1 to 197). Following the randomized cohort on day 1, subjects were treated with VIB551 or placebo on days 1 and 15. A course of oral corticosteroid (prednisone 20 mg/day or equivalent oral glucocorticoid) was started on day 1 and continued until day 14. Oral corticosteroids gradually decrease from day 15 to day 21 (for prednisone: 15mg prednisone on day 15, 10mg prednisone on day 16, 7.5mg prednisone on day 17, 5mg prednisone on days 18 and 19, and 2.5mg prednisone on days 20 and 21). By day 21, the taper is completed. The rationale for using oral corticosteroids (prednisone 20 mg/day or equivalent oral glucocorticoids) for the first 14 days (progressive 1 week reduction) is to provide prophylaxis against the onset of neuromyelitis optica spectrum disorders for a period of time that would require a period of about 2-4 weeks to maximize B cell depletion in the event that the pharmacodynamic effects of VIB551 are not expected.

Subjects were tracked during the randomized controls, with scheduled study visits and telephone interviews. The duration of the randomized control period for each subject was planned to be 197 days. All subjects who completed the randomized control period without experiencing NMO/nmosfd episodes can opt to enter the open label period.

Open label period. The subject may choose to enter the open label period if they: (1) a 197-day random control period is completed; (2) NMO/NMOSD attacks determined by the adjudication Committee were experienced during the randomized control period; (3) At random control period when 67 NMO/NMOSD attacks determined by the adjudication Committee occur; or (4) in a random control period when the DMC ceases recruitment as suggested by evidence of efficacy and safety.

Patients who discontinued the randomized control period for reasons other than or 67 episodes of adjunctive therapy did not meet the open label period. The reason why the patient did not enter the open label period is captured. These patients were then subjected to a safety follow-up during a safety follow-up period.

After entering the open label period for one of the four reasons described above, the patient received 551 300mg of VIB every 26 weeks; however, patients randomized to placebo during the randomized control received an additional 300mg dose on day 15 of the open label period to maintain a total initial dose of 600 mg. Table 3 provides open label phase treatment regimens.

Table 3: open label phase treatment regimen

IV = intravenous; OLP = open label period; q26w=every 26 weeks; RCP = random control period; SFP = security follow-up period.

^a OLP will last for a minimum of 1 year and a maximum of 3 years after the last subject entered (after the last subject entered), or until the participating country has approved the supervision of MEDI-551, or until the sponsor ceases to develop MED1-551 in this indication (based on the first producer). Subjects may opt out of OLP at any time for any reason, including seeking alternative treatment regimens, where they will enter SFP (unless consent is withdrawn).

During the open label period, patients follow up with scheduled study visits and continue to receive VIB551 therapy for up to 3 years (after the last patient entry) until each participating country has had regulatory approval for VIB551, or until the sponsor ceases developing VIB551 in this indication (subject to the preexisting). The patient's episodes were followed in the same manner as the randomized control period and events were centrally adjudicated.

Patients may opt out of the open label period at any time for any reason, including seeking alternative treatment regimens, when they enter a safety follow-up period (unless consent is withdrawn).

Security follow-up period. The safety follow-up period begins when the patient ceases the randomized controlled or open label period in advance. The length of the safety follow-up period is determined by the elapsed time from the last administration to the early discontinuation for a total of 52 weeks. During safety follow-up, patients were monitored for adverse/serious adverse events, B cell levels, anti-drug antibodies and immunoglobulin levels. At the discretion of the investigator, the patient may receive standard treatment for his condition.

FIG. 2 provides a general study design flow chart.

Example 4 summary of study results

The primary endpoint. Time (in days) from day 1 to onset of neuromyelitis optica spectrum disorder as determined by the committee of the adjunctions at or before day 197. Attacks are defined as the presence of one or more new symptoms associated with neuromyelitis optica or the worsening of one or more existing symptoms, which meet at least one of the criteria for the onset of a defined neuromyelitis optica spectrum disorder.

Secondary endpoint. Class 1 error control of the split study considered four key secondary endpoints: (1) EDSS scores worsened relative to baseline at the last visit during the randomized control period. The EDSS assessment under study was performed by independent blind evaluators at each site using an electronic data capture system developed by the university of bassell and nervous system status company, which contains internal algorithms that provide feedback to the evaluators regarding the EDSS assessment inconsistency; (2) Changes in low contrast vision binocular score from baseline measured by the low contrast Landolt C Broken ring chart at the last visit during the randomized control period; (3) Cumulative total of active MRI lesions (new gadolinium enhanced or new/expanding T2 lesions) during randomized control; (4) The number of neuromyelitis associated hospitalizations, defined as stay for more than one night.

Remaining secondary endpoint. (1) The annual seizure rate (total number of adjudicated seizures, normalized by person year) during any VIB551 exposure; (2) Adverse events occurring during the treatment period, including serious adverse events occurring during the treatment period; (3) Laboratory measurements, and their changes or shifts over time relative to baseline; (4) pharmacokinetic profile of VIB 551; (5) Incidence of anti-drug antibodies against VIB551 before and after dosing for each patient during the duration of the study.

Exploratory endpoint. (1) Recall the change from baseline in version 2 of 36 concise health surveys at week 4, the physical and psychological component scores at the last visit during the randomized control period; (2) Changes from baseline in the pain digital rating scale for the five sites at the last visit during the randomized control period; (3) B cell count (total and subset); (4) a change in a gene signature of the plasma cell relative to baseline; (5) serum AQP4-IgG titer.

Example 5-test participant characterization

From month 1 2015 to month 10 2018, 467 participants were screened in 99 participating sites in 24 countries. Of these, 231, 175 were randomized to VIB551 (AQP 4-IgG seropositive, n=161), and 56 were randomized to placebo (AQP 4-IgG seropositive, n=52; fig. 1). On day 7, 9 in 2018, the data monitoring committee recommended discontinuation of recruitment, as efficacy and over 99% of conditional screening was clearly demonstrated before the goal of 252 participants/67 adjudications episodes was met. Sponsors withheld the recruitment in the 21 th of 2018, 9, before the database was locked, while remaining blinded to treatment assignments.

Of the patients assigned to VIB551, 174 (99.4%) were included in the analysis population (one participant [ 0.6% ] received no study drug); 169 (97.1%) participants completed the randomized control period, six were discontinued due to adverse events (n=2), withdrawal consent (n=1) or 'others' (n=3). All 56 participants assigned to placebo received intervention and were included in the analysis, with 54 (96.4%) completing the random control period; two participants were discontinued (n=1 withdraw agreement, n=1 "other"; fig. 3). Most participants were females (n=209, 90.9%; table 4) and whites (n=120, 52.2%; table 4). The demographics of the participants between the treatment groups were substantially similar in the overall and AQP4-IgG seropositive populations (table 4). An open label period is in progress, with 213 participants receiving VIB551 (initial random grouping: VIB551, n=162; placebo, n=51).

Table 4: patient demographics and baseline characteristics

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TABLE 5 NMOSD attacks in the random control period (intended treatment population) as determined by recovery-grade AC

AC = committee; AQP4-IgG = autoantibody against aquaporin 4; ITT = intent-to-treat; NMOSD = neuromyelitis optica spectrum disorder; ON = optic neuritis; RCP = random control period; sero+=seropositive; sero- = seronegative.

a in the placebo group, the number of subjects who collected recovery data was 17. Calculating the percentages using this as a denominator yields the following results: severe, 11.8%; mild, 35.5%; without recovery, 52.9%.

b in the panizumab group, the number of subjects who collected recovery data was 13. Calculating the percentages using this as a denominator yields the following results: heavy, 15.4%; mild, 38.5%; without recovery, 46.2%.

The annual episode rate (total number of NMOSD episodes determined per person's annual normalized AC) during any VIB551 exposure was also determined. Notably, the annual episode rate for the placebo treatment period could not be calculated as subjects were removed from the placebo-controlled portion of the study after AC-arbitrated episodes. Thus, any such calculation of placebo period will deviate and will likely overestimate the seizure rate. However, subjects in the VIB551 treated group remained in the study receiving VIB551 after the seizure, so an estimate of the annual seizure rate during treatment of subjects with VIB551 can be calculated.

The annual rate of onset of AC-determined NMOSD was low, 0.126 in any subjects treated with VIB 551. See table 6. The annual incidence rate was 0.13 and 0.088, respectively, when calculated for AQP4-IgG seropositive and AQP4-IgG seronegative subjects, respectively.

Table 6: NMOSD attack rate (any group VIB 551) determined by the annual adjudication committee

AC = committee; AQP4-IgG = autoantibody against aquaporin 4; SFP = security follow-up period; sero- = seronegative; sero+=seropositive.

The total annual a will be calculated as the sum of the years of the individual subjects. The human year of an individual subject is defined as (date of last day before SFP-date of 1 st time of administration of inibizumab +1)/365.25.

The b-year seizure rate is defined as the total number of seizures determined by AC divided by the total years of man.

Due to the clear demonstration of efficacy, the study was stopped early according to the recommendations of the independent data monitoring committee.

Table 7: critical secondary results

* Adjusting the presented p-value to perform a multiple comparison test; if p < 0.05, the difference is considered significant.

The proportion of participants who had worsened EDSS scores relative to baseline was calculated using a logistic regression model (treatment, serum status and baseline scores as explanatory variables) and non-responder interpolation (missing values were considered worsening).

LSM differences in LCVAB score changes were assessed using covariance model analysis (treatment, serum status and baseline Landolt C Broken ring eye chart binocular score as explanatory variables) and the last non-missing low contrast vision score.

Cumulative number of active MRI lesions (including gadolinium enhanced or new/positively enlarged T2 lesions) from baseline, RR was assessed using negative binomial regression (treatment and serum status as explanatory variables).

RR analysis is based on the entire population, not just those in which an event has occurred.

Cumulative number of neuromyelitis optica-related hospitalizations from baseline, RR was assessed using negative binomial regression (treatment and serum status as explanatory variables).

AQP4-IgG,161 aquaporin 4-immunoglobulin G; CI, confidence interval; EDSS, expand the disabled state scale; ITT, intent therapy; LCVAB, low contrast vision binocular; LSM, least squares mean; MRI, magnetic resonance imaging; OR, odds ratio; RR, rate ratio; SD, standard deviation; SE, standard error.

Example 6: safety and efficacy of VIB551 on patients with prior rituximab exposure

17 subjects recruited to N-MOmentum (7.4%) were preceded by rituximab treatment. The demographics and baseline characteristics of the participants in N-MOmentum who had previously used rituximab are shown in Table 8, including a median time of 1.5 years from last rituximab use to random grouping. The baseline characteristics of the participants who had previously used rituximab were similar to those of the participants who had not previously undergone rituximab (n=208).

Table 8: participant characterization in N-MOmentum past use of perrituximab

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AQP4, aquaporin 4; AAR, annual incidence; igG, immunoglobulin G; iQR, tetrad bit difference

The previous history of onset for each of the 17N-MOmentum participants who used perrituximab is summarized in FIG. 5. Three of the 17 participants developed seizures after exposure to the inib. Of these three episodes, one occurred during RCP of participants randomized to the panobilizumab group, and the remaining two occurred during OLP of participants randomized to the placebo group. The annual incidence rate (AAR) before and after administration of the irinotecan was 0.78 (median: 1.08), and 0.11 (95% CI 0.02-0.33), respectively; and AAR of participants with and without prior rituximab exposure are.083 and.102, respectively. Three participants experiencing rituximab who had developed episodes when administered with itubizumab each developed 1 episode during the time of the study (1.54 years for participants randomized to itubizumab; 0.51 and 2.74 years for participants randomized to placebo). The 3 episodes were all myelitis, with one graded as mild according to the optic nerve injury scale.

Seven of the 17 patients entered the study in a rituximab "failed" state, defined as an NMOSD episode occurring at the time of the last dose of rituximab (or within 6 months). None of the 7 failed patients had an adjunctive episode (2.6 years average follow-up) after receiving the irinotecan.

Figure 6 provides a stratification of probability of no onset according to prior rituximab use. After the first administration of the itumumab, the AAR of the participants who had undergone rituximab was similar to the AAR of the participants who had not previously used rituximab (0.083 and 0.102 episodes/year, respectively). Secondary endpoints (e.g., change in EDSS score from baseline, number of active MRI lesions, and number of NMOSD-related hospitalizations) were also assessed. See table 9. Of the 13 participants who received the prior use of rituximab with the irinotecan during the randomized control, 2 (15%) underwent deterioration of the EDSS score, 6 (46%) had active MRI lesions, and 1 (8%) had NMOSD-related hospitalization. One of the 2 cases of deterioration in EDSS scores and hospitalization were associated with episodes that occurred during the randomized control period. The secondary results for the group of itumomab were substantially similar regardless of whether or not previous rituximab was used.

Table 9: secondary endpoint during randomized control based on previous rituximab use

EDSS, expand the disabled state scale; MRI, magnetic resonance imaging; NMOSD, neuromyelitis optica spectrum disorders; SD, standard deviation. ^a All participants included random groupings to placebo, whether or not previously used pertuzumab. ^b Gadolinium enhanced or new or expanding T2 lesions measured in optic nerve, brain stem and spinal cord. ^11c Among participants who were judged to have lesions based on MRI. ^d Longer than one night in hospital. ^11e Among the participants in the hospital.

The kinetics of B cell depletion of the participants who were previously treated with rituximab were also examined and were similar to the kinetics of the study population of general treatment with itumomab. See fig. 7. Following treatment with irinotecan, participants who had and had not previously used rituximab experienced a 42.3 mg/dL/year and 49.5 mg/dL/year reduction in IgG levels (p= 0.6687) from baseline, respectively. When receiving irinotecan, 6 (35%) of the participants who had previously used rituximab and 30 (15%) of the participants who had not had previously used rituximab experienced IgG levels <500mg/dL (fig. 8). In the previous N-MOmentum study analysis, igG levels and infection were not relevant. In the treatment group with panitumumab, substantially similar lymphocyte and neutrophil counts graded according to toxicity were observed, whether or not rituximab was previously experienced, with the majority of the two groups reported as grade 0/1.

Adverse events of interest in this group included infusion reactions (2), infections (16), and cytopenias (1). Table 10 provides a summary of adverse events that occurred during the treatment period of subjects who had been previously used and who had not been previously used rituximab.

Nine of 17 participants who had previously used rituximab (53%) and 79 of 208 participants who had not had previously used rituximab (38%) experienced TEAE associated with the irinotecan (table 10). In both groups, the incidence of severe TEAE associated with anibizumab was low. Previous 2 (12%) participants with perrituximab reported severe TEAE associated with the panitumumab, including urinary tract infection and cellulitis. Regardless of whether rituximab was used previously, the proportion of participants who underwent infusion-related reactions during the period of time when the irinotecan was received was similar. Most participants (either previously experienced or not previously experienced rituximab (94% and 70%, respectively)) had ≡1 infection when receiving irinotecan. 3 (18%) participants who had previously undergone rituximab and 20 (10%) participants who had not had previously undergone rituximab developed severe and > 3-grade infections. In past patients with rituximab, severe and/or grade > 3 infections include nasopharyngitis (grade 3), urinary tract infections (severe and grade 3), cellulitis (severe and grade 3), and perforating appendicitis (severe and grade 4), all each occurring in 1 participant. Among 17 participants who underwent rituximab, no mortality, opportunistic infections, or complications of progressive multifocal leukoencephalopathy cases and accepted B cell depletion therapies were reported. The most common AEs among the past participants who used perrituximab were urinary tract infection and influenza.

Table 10: TEAE, severe TEAE, and TEAE of particular interest following receipt of Inbizumab

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PML, progressive multifocal leukoencephalopathy; TEAE, adverse events occurring during the treatment period.

Sequence listing

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Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile

325 330 335

Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val

340 345 350

Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser

355 360 365

Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu

370 375 380

Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro

385 390 395 400

Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val

405 410 415

Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met

420 425 430

His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser

435 440 445

Pro Gly Lys

450

<210> 4

<211> 218

<212> PRT

<213> artificial sequence

<220>

<223> recombinant peptide

<400> 4

Glu Ile Val Leu Thr Gln Ser Pro Asp Phe Gln Ser Val Thr Pro Lys

1 5 10 15

Glu Lys Val Thr Ile Thr Cys Arg Ala Ser Glu Ser Val Asp Thr Phe

20 25 30

Gly Ile Ser Phe Met Asn Trp Phe Gln Gln Lys Pro Asp Gln Ser Pro

35 40 45

Lys Leu Leu Ile His Glu Ala Ser Asn Gln Gly Ser Gly Val Pro Ser

50 55 60

Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Asn

65 70 75 80

Ser Leu Glu Ala Glu Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Ser Lys

85 90 95

Glu Val Pro Phe Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg

100 105 110

Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln

115 120 125

Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr

130 135 140

Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser

145 150 155 160

Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr

165 170 175

Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys

180 185 190

His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro

195 200 205

Val Thr Lys Ser Phe Asn Arg Gly Glu Cys

210 215

<210> 5

<211> 5

<212> PRT

<213> artificial sequence

<220>

<223> recombinant peptide

<400> 5

Ser Ser Trp Met Asn

1 5

<210> 6

<211> 17

<212> PRT

<213> artificial sequence

<220>

<223> recombinant peptide

<400> 6

Arg Ile Tyr Pro Gly Asp Gly Asp Thr Asn Tyr Asn Val Lys Phe Lys

1 5 10 15

Gly

<210> 7

<211> 12

<212> PRT

<213> artificial sequence

<220>

<223> recombinant peptide

<400> 7

Ser Gly Phe Ile Thr Thr Val Arg Asp Phe Asp Tyr

1 5 10

<210> 8

<211> 15

<212> PRT

<213> artificial sequence

<220>

<223> recombinant peptide

<400> 8

Arg Ala Ser Glu Ser Val Asp Thr Phe Gly Ile Ser Phe Met Asn

1 5 10 15

<210> 9

<211> 7

<212> PRT

<213> artificial sequence

<220>

<223> recombinant peptide

<400> 9

Glu Ala Ser Asn Gln Gly Ser

1 5

<210> 10

<211> 9

<212> PRT

<213> artificial sequence

<220>

<223> recombinant peptide

<400> 10

Gln Gln Ser Lys Glu Val Pro Phe Thr

1 5

Claims

1. A method of treating neuromyelitis optica spectrum disorder (NMOSD), the method comprising:

wherein the patient has been previously treated with an anti-CD 20 antibody.

2. A method of treating NMOSD, the method comprising:

wherein the patient has been previously treated with an anti-CD 20 antibody, wherein the patient has an onset of NMOSD during treatment with the anti-CD 20 antibody or within 6 months of the last dose of the anti-CD 20 antibody.

3. The method of claim 1 or claim 2, wherein VIB551 is administered intravenously every 6 months at a dose of 300 mg.

4. A method of treating NMOSD, the method comprising:

5. A method of treating NMOSD, the method comprising:

wherein the patient is AQP4-IgG ⁺ The patient's position of his head is,

6. The method of any one of claims 3-5, wherein the patient receives at least one initial dose of VIB551.

7. The method of any one of claims 3-6, wherein the VIB551 is administered intravenously at a first initial dose of 300mg, at a second initial dose of 300mg two weeks after the first initial dose, and then at a dose of 300mg every 6 months after the first initial dose.

8. The method of claim 6 or claim 7, wherein an oral corticosteroid is co-administered to the patient with the initial VIB551 dose.

9. The method of claim 8, wherein the oral corticosteroid is administered daily for at least 2 weeks.

10. The method of any one of claims 1-9, wherein the anti-CD 20 antibody is rituximab.

11. The method of any one of claims 1-10, wherein the treatment is a reduction in the deterioration of the patient's kurtz Extended Disability Severity Scale (EDSS).

12. The method of claim 11, wherein the reduction in EDSS deterioration in the patient is:

13. The method of any one of claims 1-10, wherein the treatment is a reduction in the number of active Magnetic Resonance Imaging (MRI) lesions.

14. The method of claim 13, wherein the active MRI lesion is an expanding T2 MRI lesion.

15. The method of any one of claims 1-10, wherein the treatment is a decrease in the number of new MRI lesions.

16. The method of any one of claims 1-10, wherein the treatment is a reduction in worsening of the patient's modified rankine score.

17. The method of any one of claims 1-10, wherein the treatment is a reduction in the frequency of NMOSD-related hospitalizations of the patient.

18. The method of any one of claims 1-10, wherein the treatment is a reduction in the risk of an NMOSD-related episode of the patient.

19. The method of claim 18, wherein the onset of NMOSD associated is characterized by new symptoms occurring or worsening of existing NMOSD associated symptoms.

20. The method of claim 19, wherein the symptom is an ocular symptom.

21. The method of claim 20, wherein the ocular symptom is ocular pain, blurred vision, vision loss, or appearance of an optic nerve lesion detected by MRI.

22. The method of claim 19, wherein the symptom is spinal cord symptom.

23. The method of claim 22, wherein the spinal symptom is deep pain or radicular pain, limb paresthesia, inotropic, sphincter dysfunction, lehr Mi Teshi sign, or spinal foci detectable by MRI.

24. The method of claim 19, wherein the symptom is brain or brainstem symptom.

25. The method of claim 24, wherein the brain or brain stem symptom is nausea, double vision, eye movement paralysis, dizziness, refractory vomiting, refractory hiccup, dysarthria, dysphagia, weakness, encephalopathy, hypothalamic dysfunction, or brain stem lesions detectable by MRI.

26. The method of claim 18, wherein the risk of an NMOSD associated episode is reduced by between 60% and 85%.

27. The method of any one of claims 1-10, wherein the treatment is a reduction in optic neuritis.

28. The method of any one of claims 1-10, wherein the treatment is a reduction in severity of an nmosfd-related episode.

29. The method of claim 28, wherein the lessening of the severity of the NMOSD associated episode is a reduction of the NMOSD associated episode graded as severe.

30. The method of claim 28, wherein the reduction in severity of the NMOSD associated episode is a reduction in NMOSD episode requiring hospitalization.

31. The method of any one of claims 1-10, wherein the treatment is a reduction in NMOSD associated pain of the patient.

32. The method of claim 31, wherein the reduction in the NMOSD associated pain is determined by measuring the patient's leg pain.

33. The method of any one of claims 1-5, wherein an initial 300mg vib551 dose is administered to the subject two weeks before the first administration of the 300mg vib551 every 6 months.

34. The method of claim 33, wherein oral corticosteroid is co-administered to the patient with the initial 300mg vib551 dose.

35. The method of claim 1 or claim 2, wherein the patient is AQP4-IgG seropositive.

36. A method of reducing active MRI lesions in a patient diagnosed with NMOSD, the method comprising:

37. A method of reducing active MRI lesions in a patient diagnosed with NMOSD, the method comprising:

38. The method of claim 36 or 37, wherein the VIB551 is administered intravenously every 6 months at a dose of 300 mg.

39. A method of reducing active MRI lesions in a patient diagnosed with NMOSD, the method comprising:

40. A method of reducing active MRI lesions in a patient diagnosed with NMOSD, the method comprising:

41. AQP4-IgG for reducing NMOSD treatment ⁺ A method of AQP4-IgG titres in a patient, the method comprising:

42. AQP4-IgG for reducing NMOSD treatment ⁺ A method of AQP4-IgG titres in a patient, the method comprising:

43. The method of claim 41 or 42, wherein the VIB551 is administered intravenously every 6 months at a dose of 300 mg.

44. AQP4-IgG for reducing NMOSD treatment ⁺ A method of AQP4-IgG titres in a patient, the method comprising:

45. AQP4-IgG for reducing NMOSD treatment ⁺ A method of AQP4-IgG titres in a patient, the method comprising:

46. The method of any one of claims 1-45, wherein the administration depletes at least 90% of circulating cd20+ B cells for at least six months.

47. The method of any one of claims 1-46, wherein the administration does not increase the risk of infection of the patient.

48. The method of any one of claims 1-47, wherein the VIB551 depletes peripheral blood CD20 within 8 days after the administration ^- Plasmablasts and plasmablasts.

49. A method of reducing NMOSD-related disability in a patient diagnosed with NMOSD, the method comprising:

50. A method of reducing NMOSD-related disability in a patient diagnosed with NMOSD, the method comprising:

51. The method of claim 49 or 50, wherein the VIB551 is administered intravenously every 6 months at a dose of 300 mg.

52. A method of reducing NMOSD-related disability in a patient diagnosed with NMOSD, the method comprising:

53. A method of reducing NMOSD-related disability in a patient diagnosed with NMOSD, the method comprising:

54. The method of any one of claims 49-53, wherein reducing the patient's NMOSD-related disability is reducing the patient's exacerbation rate of NMOSD-related disability.

55. The method of any one of claims 49-54, wherein reducing the patient's NMOSD associated disability is reducing the patient's NMOSD associated disability.

56. The method of any one of claims 49-55, wherein the NMOSD associated disability is neurological disability.

57. The method of any one of claims 49-56, wherein reducing the NMOSD associated disability is determined using EDSS.

58. A method of reducing NMOSD related episodes in a patient in need of NMOSD treatment, the method comprising:

59. A method of reducing NMOSD related episodes in a patient in need of NMOSD treatment, the method comprising:

60. The method of claim 58 or 59, wherein the VIB551 is administered intravenously every 6 months at a dose of 300 mg.

61. A method of reducing NMOSD related episodes in a patient in need of NMOSD treatment, the method comprising:

62. A method of reducing NMOSD related episodes in a patient in need of NMOSD treatment, the method comprising:

63. The method of claim 61 or claim 62, wherein the NMOSD associated episodes suffered by the patient include any one or more of optic neuritis, myelitis or brainstem episodes.

64. The method of claim 63, wherein the NMOSD associated episodes suffered by the patient are clinically asymptomatic.

65. The method of any one of claims 36-64, wherein the patient receives at least one initial dose of VIB551.

66. The method of claim 65, wherein the VIB551 is administered intravenously at a first initial dose of 300mg, at a second initial dose of 300mg two weeks after the first initial dose, and then at a dose of 300mg every 6 months after the first initial dose.

67. The method of claim 66, wherein oral corticosteroid is co-administered to the patient with the initial 300mg vib551 dose.

68. The method of claim 67, wherein the oral corticosteroid is administered daily for at least 2 weeks.

69. The method of any one of claims 36-68, wherein the anti-CD 20 antibody is rituximab.

70. The method of any one of claims 1-69, wherein the VIB551 comprises a heavy chain variable region (VH) comprising the amino acid of SEQ ID No. 1 and a light chain variable region (VL) comprising the amino acid of SEQ ID No. 2.

71. A method of treating NMOSD, the method comprising:

administering an anti-CD 19 antibody to a patient in need of NMOSD treatment,

72. A method of treating NMOSD, the method comprising:

administering an anti-CD 19 antibody to a patient in need of NMOSD treatment,

73. A method of treating NMOSD, the method comprising:

wherein the patient is AQP4-IgG ⁺ The patient's position of his head is,

74. A method of treating NMOSD, the method comprising:

wherein the patient is AQP4-IgG ⁺ The patient's position of his head is,

75. The method of any one of claims 1-74, further comprising, prior to administration:

determining the patient: