title: Epratuzumab modulates B-cell signaling without affecting B-cell numbers or B-cell functions in a mouse model with humanized CD22.
abstract: Treatment of systemic lupus erythematosus patients with epratuzumab (Emab), a humanized monoclonal antibody targeting CD22, leads to moderately reduced B-cell numbers but does not completely deplete B cells. Emab appears to induce immunomodulation of B cells, but the exact mode of action has not been defined. In the present study, we aimed to understand the effects of Emab on B cells using a humanized mouse model (Huki CD22), in which the B cells express human instead of murine CD22. Emab administration to Huki CD22 mice results in rapid and long-lasting CD22 internalization. There was no influence on B-cell turnover, but B-cell apoptosis ex vivo was increased. Emab administration to Huki CD22 mice had no effect on B-cell numbers in several lymphatic organs, nor in blood. In vitro exposure of B cells from Huki CD22 mice to Emab resulted in decreased B-cell receptor (BCR) induced Ca(2+) mobilization, whereas B-cell proliferation after Toll-like receptor (TLR) stimulation was not affected. In addition, IL-10 production was slightly increased after TLR and anti-CD40 stimulation, whereas IL-6 production was unchanged. In conclusion, Emab appears to inhibit BCR signaling in a CD22-dependent fashion without strong influence on B-cell development and B-cell populations.
authors.affiliation: Division of Genetics, Department of Biology, University of Erlangen, Erlangen, Germany.
authors.forename: Lamia
authors.initials: L
authors.lastname: Özgör
authors.affiliation: Division of Genetics, Department of Biology, University of Erlangen, Erlangen, Germany.
authors.forename: Carolin
authors.initials: C
authors.lastname: Brandl
authors.affiliation: UCB Pharma, Slough, UK.
authors.forename: Anthony
authors.initials: A
authors.lastname: Shock
authors.affiliation: Division of Genetics, Department of Biology, University of Erlangen, Erlangen, Germany. lars.nitschke@fau.de.
authors.forename: Lars
authors.initials: L
authors.lastname: Nitschke
mesh_terms: D000818:Animals; D061067:Antibodies, Monoclonal, Humanized / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects / Q000276:immunology; D016175:B-Lymphocyte Subsets / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D001402:B-Lymphocytes / Q000187:drug effects* / Q000502:physiology*; D015415:Biomarkers; D002118:Calcium / Q000378:metabolism; D016207:Cytokines / Q000096:biosynthesis; D004705:Endocytosis; D006801:Humans; D056747:Immunomodulation / Q000187:drug effects; D008213:Lymphocyte Activation / Q000187:drug effects / Q000276:immunology; D018655:Lymphocyte Count; D051379:Mice; D008822:Mice, Transgenic; D010766:Phosphorylation; D011947:Receptors, Antigen, B-Cell / Q000378:metabolism; D051918:Sialic Acid Binding Ig-like Lectin 2 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D015415:Biomarkers; C497867:CD22 protein, human; D016207:Cytokines; D011947:Receptors, Antigen, B-Cell; D051918:Sialic Acid Binding Ig-like Lectin 2; C448700:epratuzumab; D002118:Calcium
keywords: Antibody therapy; B-cell differentiation; B-cell signaling; Systemic lupus erythematosus