Subcutaneous anti-CD20 antibody treatment delays gray matter atrophy in human myelin oligodendrocyte glycoprotein-induced EAE mice

Exp Neurol. 2021 Jan;335:113488. doi: 10.1016/j.expneurol.2020.113488. Epub 2020 Sep 28.

Abstract

Background: The human myelin oligodendrocyte glycoprotein-induced experimental autoimmune encephalomyelitis (huMOG-EAE) model, generates B-cell driven demyelination in mice, making it a suitable multiple sclerosis model to study B cell depletion.

Objectives: We investigated the effect of subcutaneous anti-CD20 antibody treatment on huMOG-EAE gray matter (GM) pathology.

Methods: C57Bl/6, 8-week old mice were immunized with 200 huMOG1-125 and treated with 50 μg/mouse of anti-CD20 antibody (n = 16) or isotype control (n = 16). Serial brain volumetric 9.4 T MRI scans was performed at baseline, 1 and 5 wkPI. Disease severity was measured by clinical disability score (CDS) and performance on rotarod test.

Results: Anti-CD20 antibody significantly reduced brain volume loss compared with the isotype control across all timepoints longitudinally in the basal ganglia (p = 0.01), isocortex (p = 0.025) and thalamus (p = 0.023). The CDS was reduced significantly with anti-CD20 antibody vs. the isotype control at 3 (p = 0.003) and 4 (p = 0.03) wkPI, while a trend was observed at 5 (p = 0.057) and 6 (p = 0.086) wkPI. Performance on rotarod was also improved significantly at 3 (p = 0.007) and 5 (p = 0.01) wkPI compared with the isotype control. At cellular level, anti-CD20 therapy suppressed the percentage of proliferative nuclear antigen positive microglia in huMOG-EAE isocortex (p = 0.016). Flow cytometry confirmed that anti-CD20 antibody strongly depleted the CD19-expressing B cell fraction in peripheral blood mononuclear cells, reducing it from 39.7% measured in isotype control to 1.59% in anti-CD20 treated mice (p < 0.001).

Conclusions: Anti-CD20 antibody treatment delayed brain tissue neurodegeneration in GM, and showed clinical benefit on measures of disease severity in huMOG-EAE mice.

Keywords: Anti-CD20 antibody; Brain atrophy; Gray matter atrophy; Histology; MRI; Multiple sclerosis; huMOG-EAE.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibodies / therapeutic use*
  • Antigens, CD20 / immunology*
  • Atrophy
  • B-Lymphocytes / immunology
  • Brain / diagnostic imaging
  • Brain / pathology
  • Demyelinating Diseases / chemically induced
  • Demyelinating Diseases / pathology
  • Encephalomyelitis, Autoimmune, Experimental / chemically induced*
  • Encephalomyelitis, Autoimmune, Experimental / diagnostic imaging
  • Encephalomyelitis, Autoimmune, Experimental / drug therapy*
  • Female
  • Gray Matter / diagnostic imaging
  • Gray Matter / pathology*
  • Humans
  • Macrophages / immunology
  • Magnetic Resonance Imaging
  • Mice
  • Mice, Inbred C57BL
  • Myelin-Oligodendrocyte Glycoprotein* / immunology
  • Postural Balance / drug effects
  • Psychomotor Performance / drug effects

Substances

  • Antibodies
  • Antigens, CD20
  • MOG protein, human
  • Myelin-Oligodendrocyte Glycoprotein