Ibrutinib interferes with the cell-mediated anti-tumor activities of therapeutic CD20 antibodies: implications for combination therapy
| Autor: | Martino Introna, Paul W. H. I. Parren, Fabio Da Roit, Alessandro Rambaldi, Ronald P. Taylor, Giuseppe Gritti, Josée Golay, Frank J. Beurskens, Esther C.W. Breij, Patrick J. Engelberts |
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| Rok vydání: | 2014 |
| Předmět: |
Pyrazoles/pharmacology
Neutrophils Chronic lymphocytic leukemia Fluorescent Antibody Technique Lymphoma B-Cell/drug therapy Apoptosis Pharmacology Complement Activation/drug effects Cell Proliferation/drug effects chemistry.chemical_compound Piperidines Obinutuzumab hemic and lymphatic diseases Antineoplastic Combined Chemotherapy Protocols Pyrimidines/pharmacology Complement Activation Cells Cultured Killer Cells Natural/drug effects CD20 biology Neutrophils/cytology Antibodies Monoclonal Articles Hematology Flow Cytometry Quinazolinones/pharmacology Killer Cells Natural Leukemia Ibrutinib Idelalisib Purines/pharmacology Lymphoma B-Cell Phagocytosis/drug effects Blotting Western Ofatumumab Phagocytosis medicine Humans Bruton's tyrosine kinase Cell Proliferation Quinazolinones Adenine Macrophages Apoptosis/drug effects Antibody-Dependent Cell Cytotoxicity Macrophages/cytology Leukemia Lymphocytic Chronic B-Cell/drug therapy Antigens CD20 medicine.disease Leukemia Lymphocytic Chronic B-Cell Antibodies Monoclonal/pharmacology Pyrimidines chemistry Purines Case-Control Studies biology.protein Pyrazoles Antigens CD20/immunology |
| Zdroj: | Da Roit, F, Engelberts, P J, Taylor, R P, Breij, E C, Gritti, G, Rambaldi, A, Introna, M, Parren, P W, Beurskens, F J & Golay, J 2015, ' Ibrutinib interferes with the cell-mediated anti-tumor activities of therapeutic CD20 antibodies: implications for combination therapy ', Haematologica, vol. 100, no. 1, pp. 77-86 . https://doi.org/10.3324/haematol.2014.107011 |
| ISSN: | 1592-8721 0390-6078 |
| DOI: | 10.3324/haematol.2014.107011 |
| Popis: | The novel Bruton tyrosine kinase inhibitor ibrutinib and phosphatidyl-4-5-biphosphate 3-kinase-δ inhibitor idelalisib are promising drugs for the treatment of chronic lymphocytic leukemia and B-cell non-Hodgkin lymphoma, either alone or in combination with anti-CD20 antibodies. We investigated the possible positive or negative impact of these drugs on all known mechanisms of action of both type I and type II anti-CD20 antibodies. Pretreatment with ibrutinib for 1 hour did not increase direct cell death of cell lines or chronic lymphocytic leukemia samples mediated by anti-CD20 antibodies. Pre-treatment with ibrutinib did not inhibit complement activation or complement-mediated lysis. In contrast, ibrutinib strongly inhibited all cell-mediated mechanisms induced by anti- CD20 antibodies rituximab, ofatumumab or obinutuzumab, either in purified systems or whole blood assays. Activation of natural killer cells, and antibody-dependent cellular cytotoxicity by these cells, as well as phagocytosis by macrophages or neutrophils were inhibited by ibrutinib with a half maximal effective concentration of 0.3-3 μM. Analysis of anti-CD20 mediated activation of natural killer cells isolated from patients on continued oral ibrutinib treatment suggested that repeated drug dosing inhibits these cells in vivo. Finally we show that the phosphatidyl- 4-5-biphosphate 3-kinase-δ inhibitor idelalisib similarly inhibited the immune cell-mediated mechanisms induced by anti-CD20 antibodies, although the effects of this drug at 10 μM were weaker than those observed with ibrutinib at the same concentration. We conclude that the design of combined treatment schedules of anti- CD20 antibodies with these kinase inhibitors should consider the multiple negative interactions between these two classes of drugs. |
| Databáze: | OpenAIRE |
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