Circulating regulatory B cell subsets in patients with neuromyelitis optica spectrum disorders

AIM: Neuromyelitis optica spectrum disorders (NMOSD) is an autoantibody-mediated, B cell-driven disease. Inebilizumab is a humanized, affinity-optimized, afucosylated IgG1 kappa monoclonal antibody that binds to the B cell specific surface antigen CD19, resulting in rapid, profound, and sustained depletion of circulating peripheral B cells in NMOSD subjects (pivotal study). The objective of this study was to conduct population modeling of B cell response following inebilizumab treatment in adult subjects with NMOSD, and to assess the impact of drug exposure to outcome. METHODS: A hematopoietic transit model was developed to describe the joint effects of reducing influx from pro-B cells and accelerating CD20+ B cell depletion in the blood by inebilizumab. Furthermore, the relationships between inebilizumab pharmacokinetic (PK) exposure and the primary efficacy endpoint and key secondary efficacy endpoints were evaluated. KEY RESULTS: At the 300 mg dose, there was no apparent relationship between efficacy (reduction in disease attack risk, risk of worsening from baseline in Expanded Disability Status Scale, cumulative total active MRI lesions, and the number of NMOSD-related in-patient hospitalizations) and PK exposure. Subjects with low, medium, and high PK exposure had a similar hazard ratio of NMOSD attack vs placebo group. CONCLUSIONS: The pharmacodynamic modeling confirmed effective depletion of B cells is achieved with a 300 mg intravenous dose of inebilizumab administered on Day 1 and Day 15 and every 6 months thereafter. The PK variability between patients had no apparent effect on clinical efficacy.

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Peripheral CD19+ B-cell counts and infusion intervals as a surrogate for long-term B-cell depleting therapy in multiple sclerosis and neuromyelitis optica/neuromyelitis optica spectrum disorders

Journal of Neurology ◽

10.1007/s00415-018-9092-4 ◽

2018 ◽

Vol 266 (1) ◽

pp. 57-67 ◽

Cited By ~ 20

Author(s):

Gisa Ellrichmann ◽

Jan Bolz ◽

Maren Peschke ◽

Alexander Duscha ◽

Kerstin Hellwig ◽

...

Keyword(s):

Multiple Sclerosis ◽

B Cell ◽

Neuromyelitis Optica ◽

Neuromyelitis Optica Spectrum Disorders ◽

Cell Counts ◽

Spectrum Disorders

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Treatment of neuromyelitis optica and neuromyelitis optica spectrum disorders with rituximab using a maintenance treatment regimen and close CD19 B cell monitoring. A six-year follow-up

Journal of the Neurological Sciences ◽

10.1016/j.jns.2016.11.016 ◽

2017 ◽

Vol 372 ◽

pp. 92-96 ◽

Cited By ~ 10

Author(s):

M.E. Evangelopoulos ◽

E. Andreadou ◽

G. Koutsis ◽

V. Koutoulidis ◽

M. Anagnostouli ◽

...

Keyword(s):

B Cell ◽

Treatment Regimen ◽

Neuromyelitis Optica ◽

Maintenance Treatment ◽

Neuromyelitis Optica Spectrum Disorders ◽

Cell Monitoring ◽

Spectrum Disorders

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Naive B cells in neuromyelitis optica spectrum disorders: impact of steroid use and relapses

Brain Communications ◽

10.1093/braincomms/fcaa197 ◽

2020 ◽

Vol 2 (2) ◽

Author(s):

Malou Janssen ◽

Arlette L Bruijstens ◽

Jamie van Langelaar ◽

YuYi Wong ◽

Annet F Wierenga-Wolf ◽

...

Keyword(s):

B Cells ◽

B Cell ◽

Neuromyelitis Optica ◽

Immunoglobulin G ◽

Myelin Oligodendrocyte Glycoprotein ◽

Healthy Controls ◽

Neuromyelitis Optica Spectrum Disorders ◽

Toll Like Receptor ◽

Spectrum Disorders

Abstract Neuromyelitis optica spectrum disorders are a group of rare, but severe autoimmune diseases characterized by inflammation of the optic nerve(s) and/or spinal cord. Although naive B cells are considered key players by escaping central tolerance checkpoints, it remains unclear how their composition and outgrowth differ in patients with neuromyelitis optica spectrum disorders. Under complete treatment-naive circumstances, we found that naive mature/transitional B-cell ratios were reduced in the blood of 10 patients with aquaporin-4 immunoglobulin G-positive disease (neuromyelitis optica spectrum disorders) as compared to 11 both age- and gender-matched healthy controls, eight patients with myelin oligodendrocyte glycoprotein-immunoglobulin G-associated disorders and 10 patients with multiple sclerosis. This was the result of increased proportions of transitional B cells, which were the highest in patients with neuromyelitis optica spectrum disorders with relapses and strongly diminished in a separate group of nine patients with neuromyelitis optica spectrum disorders and myelin oligodendrocyte glycoprotein-immunoglobulin G-associated disorders who received corticosteroid treatment. These findings need to be confirmed in longitudinal studies. For purified naive mature B cells of seven patients with neuromyelitis optica spectrum disorders and myelin oligodendrocyte glycoprotein-immunoglobulin G-associated disorders with relapses, Toll-like receptor 9 ligand synergized with interferon-γ to enhance plasmablast formation during germinal centre-like cultures. This was not seen for 11 patients without relapses and nine healthy controls. In the neuromyelitis optica spectrum disorders group, in vitro plasmablast formation corresponded to total and anti-aquaporin-4 immunoglobulin G secretion, of which the latter was found only for relapsing cases. These data indicate that naive B-cell homoeostasis is different and selectively targeted by corticosteroids in patients with neuromyelitis optica spectrum disorders. This also supports further exploration of naive B cells for their use in Toll-like receptor 9-dependent in vitro platforms in order to predict the activity of neuromyelitis optica spectrum disorders.

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