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Low-dose subcutaneous anti-CD20 treatment depletes disease relevant B-cell subsets and attenuates neuroinflammation

Huck, Catherine and Leppert, David and Wegert, Vanessa and Schmid, Cindy and Dunn, Bob and Weckbecker, Gisbert and Smith, Paul (2019) Low-dose subcutaneous anti-CD20 treatment depletes disease relevant B-cell subsets and attenuates neuroinflammation. Journal of neuroimmune pharmacology., 14 (1557-1). pp. 1-11. ISSN 1557-1904; 1557-1890

Abstract

Objective: To explore the B-cell depleting capacity of a low-dose (20 µg) subcutaneous mouse anti-CD20 antibody treatment on disease-relevant B-cell populations within lymph nodes and the spleen.
Methods: B-cell depleting capacity was explored in healthy female C57BL/6 and BALB/c mice; following immune activation in two different mouse models: trinitrophenylated lipopolysaccharide model (thymus-independent response) and dinitrophenyl-keyhole limpet hemocyanin model (thymus-dependent response); and in a chronic neuroinflammation experimental autoimmune encephalomyelitis model. CD20 protein expression on B-cell subpopulations was also studied.
Results: The subcutaneous anti-CD20 regimen resulted in rapid depletion of B cells in blood, lymph nodes and spleen. Low-dose subcutaneous treatment did not reduce antigen-specific immunoglobulin M and immunoglobulin G titers in all subgroups, and relatively spared splenic marginal zone (MZ) B cells in both T-cell dependent and T-cell independent B-cell immunization models. Analysis of immune compartments during anti-CD20-modulated autoimmune neuroinflammation showed that the maximal B-cell depletion was achieved within 2 days of treatment and was highest in the lymph node. Regardless of the tissues analyzed, low-dose subcutaneous treatment was characterized by rapid B-cell repletion following treatment cessation. CD20 protein expression was consistent on all B-cell subsets in blood, and was more pronounced in germinal center (GC) B cells of lymph nodes and MZ B-cells of the spleen.
Interpretation: Low-dose subcutaneous anti-CD20 therapy effectively depleted B cells within lymphatic tissues and reduced the severity of neuroinflammation. These data suggest that subcutaneous anti-CD20 therapies can effectively target disease-relevant B-cell populations, have shorter repletion kinetics and maintain vaccination responses, thereby achieving autoimmune amelioration without severely impacting immune surveillance functions.

Item Type: Article
Keywords: subcutaneous, anti-CD20 monoclonal antibody, ofatumumab, marginal zone B cells, lymph node, spleen
Date Deposited: 09 Sep 2019 00:45
Last Modified: 09 Sep 2019 00:45
URI: https://oak.novartis.com/id/eprint/39514

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