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

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.

Systemic administration of anti-CD20 indirectly reduces B cells in the inflamed meninges in a chronic model of central nervous system autoimmunity

“…Importantly, the area of white matter demyelination was significantly reduced in treated mice ( Figure 2D, E ). This did not translate to a significant difference in disease score within this 7d timeframe ( Figure 2F ), consistent with recent observations by others (36) who similarly observed improved tissue pathology after a longer-duration treatment with anti-CD20 that did not translate into a measurable change in disease severity using standard scoring systems. Nevertheless, our observations suggest that meningeal B cells contribute to local tissue pathology.…”

“…Remyelination following more extended anti-CD20 treatment in a different chronic model of EAE was observed by Breakell et.al. (36). The difference in white matter pathology following only 7d of treatment in our studies indicates that the therapeutic benefit of B cell depletion can be rapid, and that it is temporally associated with the reduction of B cells within established clusters in the meninges.…”

Role of autoreactive Tc17 cells in the pathogenesis of experimental autoimmune encephalomyelitis

“…6 This is a major drawback for research on CD8 + T cells, particularly Tc17 cells, in EAE. In addition, studies on different types of EAE models-such as myelin antigen-specific TCRtransgenic mouse EAE models, 6,[61][62][63][64] spontaneous EAE models, 61,65,66 humanized mouse EAE models, 63,[67][68][69] and nonhuman primate EAE models 70-72 -might provide new insights into the pathogenesis of the disease.…”

Key characteristics of anti-CD20 monoclonal antibodies and clinical implications for multiple sclerosis treatment

“…All of the antibodies either approved for or undergoing clinical evaluation for MS in this review are type I antibodies [36,48]. Despite not having undergone extensive clinical evaluation in MS, preclinical data suggest that type II antibodies, such as tositumomab and obinutuzumab, may have future clinical utility for people with MS owing to their ability to deplete B cells in blood and lymphoid tissue more efficiently than type I antibodies [49][50][51]. However, these preclinical results are not disease specific and have yet to be translated into clinical evaluations in people with MS.…”