B cell-extrinsic and intrinsic factors linked to early immune repletion after anti-CD20 therapy in patients with multiple sclerosis of African ancestry

TL;DR

This study explores why some patients of African ancestry with MS recover B cells faster after anti-CD20 therapy, linking it to drug antibodies and genetic factors.

Contribution

The study identifies both extrinsic and intrinsic factors linked to early B cell repletion in African ancestry MS patients after anti-CD20 therapy.

Findings

Early B cell repletion in some AA MS patients is associated with anti-drug antibodies and undetectable drug levels.

Another subset of AA patients with early B cell repletion has genetic polymorphisms linked to B cell survival and immune pathways.

These findings suggest variability in treatment response that may affect therapeutic outcomes in AA MS patients.

Abstract

Recent investigations have identified patients of African ancestry (AA) with Multiple Sclerosis (MS), who display more rapid B-cell repopulation after standard semi-annual infusions with an anti-CD20 monoclonal antibody for B cell depletion. In this study, we explored the immunologic and genetic factors, with serum drug monitoring, that may contribute to a faster rate of B-cell repletion that follows during recovery from treatment with anti-CD20 antibody.

In AA MS patients treated with an anti-CD20 antibody that had early repopulation of peripheral blood B cells, we assessed for extrinsic factors, including the presence of anti-drug antibodies against ocrelizumab, which may contribute to early repletion. We also documented the associated serum drug levels. In addition, we examined for inheritance of intrinsic gene polymorphisms associated with B cell survival and immune function.

Our findings identified a subset of AA patients with early B cell repletion after anti-CD20 treatment associated with anti-drug antibodies and an absence of detectable drug. Furthermore, a separate set of AA patients with the early B cell repletion phenotype without anti-drug antibodies had significant over-representation of genetic polymorphisms that map to genes for the B cell survival factor, BAFF, to antibody-dependent cytotoxicity, and to pathways involved in inflammation, leukocyte activation and B cell differentiation.

In AA patients with MS, after anti-CD20 antibody treatment we found an unexpected high occurrence of early B cell replenishment. This was associated with the presence of anti-drug antibodies and/or specific genetic polymorphisms. Larger studies are now needed to determine whether these factors may lead to impaired therapeutic benefits of B cell targeted therapy and clinical progression, and these findings may be useful to guide future optimized personalized therapeutic strategies.

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