Abstract
Epratuzumab, a humanized anti-CD22 antibody, is currently in clinical trials of B-cell lymphomas and autoimmune diseases, demonstrating therapeutic activity in non-Hodgkin lymphoma (NHL) and systemic lupus erythematosus (SLE). Thus, epratuzumab offers a promising option for CD22-targeted immunotherapy, yet its mechanism of action remains poorly understood. Here we report for the first time that epratuzumab promptly induces a marked decrease of CD22 (>80%), CD19 (>50%), CD21 (>50%), and CD79b (>30%) on the surface of B cells in peripheral blood mononuclear cells (PBMCs) obtained from normal donors or SLE patients, and of NHL cells (Daudi and Raji) spiked into normal PBMCs. Although some Fc-independent loss of CD22 is expected from internalization by epratuzumab, the concurrent and prominent reduction of CD19, CD21, and CD79b is Fc dependent and results from their transfer from epratuzumab-opsonized B cells to FcγR-expressing monocytes, natural killer cells, and granulocytes via trogocytosis. The findings of reduced levels of CD19 are implicative for the efficacy of epratuzumab in autoimmune diseases because elevated CD19 has been correlated with susceptibility to SLE in animal models as well as in patients. This was confirmed herein by the finding that SLE patients receiving epratuzumab immunotherapy had significantly reduced CD19 compared with treatment-naïve patients.
MeSH terms
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Antibodies, Monoclonal, Humanized / pharmacology*
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Antigens, CD19 / genetics
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Antigens, CD19 / immunology
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Antineoplastic Agents / pharmacology*
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B-Lymphocytes / drug effects*
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B-Lymphocytes / immunology
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B-Lymphocytes / pathology
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CD79 Antigens / antagonists & inhibitors
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CD79 Antigens / genetics
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CD79 Antigens / immunology
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Clinical Trials as Topic
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Coculture Techniques
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Gene Expression / drug effects
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Granulocytes / cytology
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Granulocytes / drug effects
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Granulocytes / immunology
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Humans
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Immunotherapy
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Killer Cells, Natural / cytology
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Killer Cells, Natural / drug effects
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Killer Cells, Natural / immunology
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Lupus Erythematosus, Systemic / drug therapy*
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Lupus Erythematosus, Systemic / genetics
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Lupus Erythematosus, Systemic / immunology
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Lupus Erythematosus, Systemic / pathology
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Lymphoma, Non-Hodgkin / drug therapy*
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Lymphoma, Non-Hodgkin / genetics
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Lymphoma, Non-Hodgkin / immunology
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Lymphoma, Non-Hodgkin / pathology
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Monocytes / cytology
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Monocytes / drug effects
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Monocytes / immunology
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Phagocytosis / drug effects*
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Phagocytosis / immunology
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Primary Cell Culture
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Receptors, Complement 3d / antagonists & inhibitors
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Receptors, Complement 3d / genetics
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Receptors, Complement 3d / immunology
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Sialic Acid Binding Ig-like Lectin 2 / antagonists & inhibitors
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Sialic Acid Binding Ig-like Lectin 2 / genetics
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Sialic Acid Binding Ig-like Lectin 2 / immunology*
Substances
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Antibodies, Monoclonal, Humanized
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Antigens, CD19
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Antineoplastic Agents
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CD22 protein, human
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CD79 Antigens
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CD79B protein, human
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Receptors, Complement 3d
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Sialic Acid Binding Ig-like Lectin 2
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epratuzumab