Durable B‐Cell Impairment While Sparing IgA B Cells After Ocrelizumab Therapy in Multiple Sclerosis

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OBJECTIVES: Ocrelizumab (OCR), a humanized anti-CD20 monoclonal antibody, is highly efficient in relapsing-remitting multiple sclerosis (RR-MS). We assessed early cellular B-cell profiles in patients prior to OCR treatment, on OCR treatment, and after 15 months of therapy discontinuation. This study aims to provide new clues about the mechanisms of action of OCR and about disease pathophysiology. METHODS: Patients with early, treatment-naive, RR-MS were included from 11 centers participating in an ancillary study of the ENSEMBLE trial (NCT03085810) to evaluate the effectiveness and safety of OCR. The phenotypic B-cell immune profile was comprehensively assessed in 18 patients by spectral flow cytometry at baseline, after 1 year of OCR treatment, and compared with 10 healthy volunteers (HVs) (matched for age and sex) on cryopreserved peripheral blood mononuclear cells (PBMC). We also analyzed B-cell reconstitution after a median time of 15 months after trial withdrawal in three patients by flow cytometry and single-cell RNA sequencing. RESULTS: Using spectral flow cytometry we defined the proportions and absolute numbers of naive, transitional, Ig-G, Ig-A, Ig-M memory B cells, Ig-G, Ig-A, Ig-M plasmablasts, and plasma cells. At baseline we found an increased frequency of IgG-secreting B cells in MS patients compared to HV. During OCR treatment, the proportion of the different subsets of B cells was strongly modified. In the mature clusters, we observed that the treatment partially spared memory IgA B cells. In parallel, we observed that differentiated IgA plasmablasts and plasma cells were more increased than the other differentiated clusters. Interestingly, in the three patients who stopped the treatment single-cell RNA sequencing showed that the B cells that reappeared were mainly naive with an inflammatory and migratory phenotype concomitantly to a rise of regulatory B cells. DISCUSSION: Our findings support an increased regulatory phenotype of remaining B cells under treatment with OCR and replenishment of undifferentiated B cells accumulating features of inflammatory and migratory patterns after OCR discontinuation, counterbalanced by an increased proportion of regulatory B cells.

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