Obinutuzumab-Induced B Cell Depletion Reduces Spinal Cord Pathology in a CD20 Double Transgenic Mouse Model of Multiple Sclerosis.

Thomas Breakell,Verena Schropp,Sabine Tacke,Eduard Urich,Henrik Zetterberg,Kaj Blennow,Stefanie Kuerten

doi:10.3390/ijms21186864

Abstract

B cell-depleting therapies have recently proven to be clinically highly successful in the treatment of multiple sclerosis (MS). This study aimed to determine the effects of the novel type II anti-human CD20 (huCD20) monoclonal antibody (mAb) obinutuzumab (OBZ) on spinal cord degeneration in a B cell-dependent mouse model of MS. Double transgenic huCD20xHIGR3 (CD20dbtg) mice, which express human CD20, were immunised with the myelin fusion protein MP4 to induce experimental autoimmune encephalomyelitis (EAE). Both light and electron microscopy were used to assess myelination and axonal pathology in mice treated with OBZ during chronic EAE. Furthermore, the effects of the already established murine anti-CD20 antibody 18B12 were assessed in C57BL/6 wild-type (wt) mice. In both models (18B12/wt and OBZ/CD20dbtg) anti-CD20 treatment significantly diminished the extent of spinal cord pathology. While 18B12 treatment mainly reduced the extent of axonal pathology, a significant decrease in demyelination and increase in remyelination were additionally observed in OBZ-treated mice. Hence, the data suggest that OBZ could have neuroprotective effects on the CNS, setting the drug apart from the currently available type I anti-CD20 antibodies.

Highlights

Multiple sclerosis (MS), a chronic inflammatory disease of the central nervous system (CNS) [1], manifests in dysfunction and apoptosis of oligodendrocytes and results in neurodegeneration [2]
Summarising our key findings, this study demonstrates a significant amelioration of spinal cord pathology using anti-CD20 treatment in both the wt and CD20dbtg model with slightly differential effects regarding axonal damage as well as de- and remyelination
In the CD20dbtg cohort 1, n = 12 CD20dbtg mice were immunised with MP4, of which n = 6 were treated with OBZ and n = 6 with huIgG1 starting on day 30 after the peak of EAE

Summary

Introduction

Multiple sclerosis (MS), a chronic inflammatory disease of the central nervous system (CNS) [1], manifests in dysfunction and apoptosis of oligodendrocytes and results in neurodegeneration [2]. It has a multifactorial etiology, with theories including genetics, viral causes, diet and vitamin D deficiency [3,4,5]. Available and clinically developing antibodies, e.g., rituximab, ocrelizumab, ofatumumab and ublituximab are type I monoclonal antibodies (mAbs) While they are efficient at peripheral B cell depletion, primarily through induction of complement-dependent cytotoxicity (CDC) [10,11], they do not significantly deplete B cells within the CNS even when applied intrathecally. This is attributed to the rapid efflux of the drug from the CNS into peripheral blood [12]

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