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J Neuroimmune Pharmacol. 2019 Dec;14(4):709-719. doi: 10.1007/s11481-019-09872-z. Epub 2019 Aug 21.

Low-Dose Subcutaneous Anti-CD20 Treatment Depletes Disease Relevant B Cell Subsets and Attenuates Neuroinflammation.

Author information

1
Autoimmunity, Transplantation and Inflammation, Novartis Institutes for Biomedical Research, Basel, Switzerland. catherine.huck@novartis.com.
2
Neuroscience Development Unit, Novartis Pharma AG, Basel, Switzerland.
3
Autoimmunity, Transplantation and Inflammation, Novartis Institutes for Biomedical Research, Basel, Switzerland.
4
Genomics Institute of the Novartis Research Foundation, San Diego, CA, USA.

Abstract

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. 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. 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 B cells of lymph nodes and MZ B-cells of the spleen. 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. Graphical Abstract *p < 0.05; **p < 0.01. CD, cluster of differentiation; DNP-KLH, dinitrophenyl-keyhole limpet hemocyanin; EC50, concentration of a drug that gives half-maximal response; Ig, immunoglobulin; MZ, marginal zone; s.c., subcutaneous; SEM, standard error of mean; TNP-LPS, trinitrophenylatedlipopolysaccharide.

KEYWORDS:

Anti-CD20 monoclonal antibody; Lymph node; Marginal zone B cells; Ofatumumab; Spleen; Subcutaneous

PMID:
31435856
DOI:
10.1007/s11481-019-09872-z

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