Type i CD20 antibodies recruit the B cell receptor for complement-dependent lysis of malignant B cells
| Autor: | Paul W. H. I. Parren, Marleen Voorhorst, Patrick J. Engelberts, Tom Vink, Frank J. Beurskens, Thomas Valerius, Wendy J.M. Mackus, Joost M. Bakker, Stefanie Derer, Tom van Meerten, Esther C.W. Breij, Janine Schuurman, Jan G. J. van de Winkel |
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| Přispěvatelé: | Stem Cell Aging Leukemia and Lymphoma (SALL) |
| Jazyk: | angličtina |
| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
REACTIVE PROTEIN COMPLEXES Lymphoma B-Cell/immunology Immunotherapy Adoptive/methods ACTIVATION Antibodies Monoclonal/genetics 0302 clinical medicine immune system diseases hemic and lymphatic diseases LYMPHOMA Immunology and Allergy CYTOTOXICITY Complement C1/metabolism education.field_of_study biology ANTIGEN RECEPTORS breakpoint cluster region medicine.anatomical_structure 030220 oncology & carcinogenesis Rituximab/genetics Antibody Immunology Population B-cell receptor Antibodies Monoclonal Humanized MEDIATED LYSIS Immunoglobulin M/genetics Immunoglobulin Fab Fragments/metabolism 03 medical and health sciences Classical complement pathway Antigen Cell Line Tumor medicine Humans RITUXIMAB Complement Pathway Classical education B cell Receptors Antigen B-Cell/genetics CHRONIC LYMPHOCYTIC-LEUKEMIA ANTI-CD20 MONOCLONAL-ANTIBODY Antibody-Dependent Cell Cytotoxicity Complement system LIPID RAFTS 030104 developmental biology B-Lymphocytes/drug effects biology.protein Cancer research Immunoglobulin G/genetics Antigens CD20/immunology |
| Zdroj: | Engelberts, P J, Voorhorst, M, Schuurman, J, Van Meerten, T, Bakker, J M, Vink, T, Mackus, W J M, Breij, E C W, Derer, S, Valerius, T, van de Winkel, J G J, Parren, P W H I & Beurskens, F J 2016, ' Type i CD20 antibodies recruit the B cell receptor for complement-dependent lysis of malignant B cells ', Journal of Immunology, vol. 197, no. 12, pp. 4829-4837 . https://doi.org/10.4049/jimmunol.1600811 Journal of Immunology, 197(12), 4829-4837. AMER ASSOC IMMUNOLOGISTS |
| ISSN: | 0022-1767 |
| Popis: | Human IgG1 type I CD20 Abs, such as rituximab and ofatumumab (OFA), efficiently induce complement-dependent cytotoxicity (CDC) of CD20+ B cells by binding of C1 to hexamerized Fc domains. Unexpectedly, we found that type I CD20 Ab F(ab')2 fragments, as well as C1q-binding-deficient IgG mutants, retained an ability to induce CDC, albeit with lower efficiency than for whole or unmodified IgG. Experiments using human serum depleted of specific complement components demonstrated that the observed lytic activity, which we termed "accessory CDC," remained to be dependent on C1 and the classical pathway. We hypothesized that CD20 Ab-induced clustering of the IgM or IgG BCR was involved in accessory CDC. Indeed, accessory CDC was consistently observed in B cell lines expressing an IgM BCR and in some cell lines expressing an IgG BCR, but it was absent in BCR- B cell lines. A direct relationship between BCR expression and accessory CDC was established by transfecting the BCR into CD20+ cells: OFA-F(ab')2 fragments were able to induce CDC in the CD20+BCR+ cell population, but not in the CD20+BCR- population. Importantly, OFA-F(ab')2 fragments were able to induce CDC ex vivo in malignant B cells isolated from patients with mantle cell lymphoma and Waldenström macroglobulinemia. In summary, accessory CDC represents a novel effector mechanism that is dependent on type I CD20 Ab-induced BCR clustering. Accessory CDC may contribute to the excellent capacity of type I CD20 Abs to induce CDC, and thereby to the antitumor activity of such Abs in the clinic. Copyright © 2016 by The American Association of Immunologists, Inc. |
| Databáze: | OpenAIRE |
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