Association between B-cell depletion and attack risk in neuromyelitis optica spectrum disorder: An exploratory analysis from N-MOmentum, a double-blind, randomised, placebo-controlled, multicentre phase 2/3 trial

BACKGROUND: Inebilizumab is an anti-CD19 antibody approved for the treatment of neuromyelitis optica spectrum disorder (NMOSD) in adults with aquaporin-4 autoantibodies. The relationship between B-cell, plasma-cell (PC), and immunoglobulin depletion with longitudinal reductions in NMOSD activity after inebilizumab treatment was characterised post hoc in an exploratory analysis from the N-MOmentum study (NCT02200770). METHODS: Peripheral blood CD20+ B cells, PC gene signature, and immunoglobulin levels were assessed throughout N-MOmentum (follow-up =2.5 years); correlations with clinical metrics and magnetic resonance imaging (MRI) lesion activity were assessed. FINDINGS: Inebilizumab induced durable B-cell and PC depletion within 1 week versus placebo. Although no association was observed between B-cell counts at time of attack and NMOSD activity, depth of B-cell depletion after the first dosing period correlated with clinical outcomes. All participants receiving inebilizumab demonstrated a robust long-term therapeutic response, and participants with =4 cells/µL after the first 6-month dosing interval had persistently deeper B-cell depletion, lower annualised attack rates (estimated rate [95% CI]: 0.034 [0.024–0.04] vs 0.086 [0.056–0.12]; p = 0.045), fewer new/enlarging T2 MRI lesions (0.49 [0.43–0.56] vs 1.36 [1.12–1.61]; p < 0.0001), and a trend towards decreased Expanded Disability Status Scale worsening (0.076 [0.06–0.10] vs 0.14 [0.10–0.18]; p = 0.093). Antibodies to inebilizumab, although present in a proportion of treated participants, did not alter outcomes. INTERPRETATION: This analysis suggests that compared with placebo, inebilizumab can provide specific, rapid, and durable depletion of B cells in participants with NMOSD. Although deep and persistent CD20+ B-cell depletion correlates with long-term clinical stability, early, deep B-cell depletion correlates with improved disease activity metrics in the first 2 years

PhD

dissertationDuring the process of animal development, initially uniform fields of cells acquire distinct identities. One manifestation of this process is the generation of unique morphology within a metameric series, such as the segments of the Drosophila larva or the vertebrae of the mammalian skeleton. The Drosophila homeotic genes, and the homologous murine Hox genes, control morphologic diversification of the segmental pattern. These genes encode transcription factors that direct groups of cells down specific developmental pathways, by controlling the expression of so-called 'downstream' genes. To understand homeotic/Hox gene function, we must therefore identify these downstream genes and analyze their roles in mediating homeotic control of development. Unfortunately, few targets of the Drosophila homeotic genes, and even fewer of the murine Hox genes, have been identified. The work described here begins with a screen for novel targets of homeotic gene regulation. As a result of this screen, the Drosophila segmentation gene odd-paired was cloned and identified as a target of homeotic gene regulation. Genetic analysis demonstrates that odd-paired, like the homeotic genes that regulate its expression, is required for morphogenesis of specific constrictions in the embryonic midgut late in development. Temporal analysis of odd-paired function supports the hypothesis that odd-paired functions downstream of homeotic genes in the genetic hierarchy controlling midgut constriction formation. Phenotypic analysis also demonstrates that odd-paired is required in the early embryo, prior to homeotic gene expression, for segmental subdivision of the ectoderm and for formation of the mesodermal component of the midgut. Thus, odd-paired functions upstream of the homeotics to control ectodermal and mesodermal development, in addition to its proposed function downstream of the homeotics in controlling midgut constriction formation. Spatial analysis of odd-paired function in the early embryo suggests that inductive interactions between the ectoderm and mesoderm play a role in mesodermal development

B cell-based therapies in CNS autoimmunity: differentiating CD19 and CD20 as therapeutic targets

Increasing recognition of the role of B cells in the adaptive immune response makes B cells an important therapeutic target in autoimmunity. Numerous current and developmental immunotherapies target B cells for elimination through recognition of cell-surface proteins expressed specifically on B cells, in particular CD19 and CD20. Similarities and differences in the function and expression of these two molecules predict some shared, and some distinct, pharmacological effects of agents targeting CD19 versus CD20, potentially leading to differences in the clinical safety and efficacy of such agents. Here, we review current knowledge of CD19 and CD20 function and biology, survey current and developmental therapies that target these molecules, and discuss potential differences in elimination of B cells by drugs that target CD19 versus CD20, with particular focus on the central nervous system autoimmune diseases multiple sclerosis and neuromyelitis optica. The principles and mechanisms herein discussed might also be relevant to a variety of other nervous system autoimmune disorders, including NMDA (N-methyl-D-aspartate) receptor encephalitis, transverse myelitis and myasthenia gravis