title: Ibrutinib interferes with the cell-mediated anti-tumor activities of therapeutic CD20 antibodies: implications for combination therapy.
abstract: 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.
authors.affiliation: Center of Cellular Therapy "G. Lanzani", Division of Hematology, Azienda Ospedaliera Papa Giovanni XXIII, Bergamo, Italy.
authors.forename: Fabio
authors.initials: F
authors.lastname: Da Roit
authors.affiliation: Genmab, Utrecht, the Netherlands.
authors.forename: Patrick J
authors.initials: PJ
authors.lastname: Engelberts
authors.affiliation: Department of Biochemistry and Molecular Genetics, University of Virginia School of Medicine, Charlottesville, VA, USA.
authors.forename: Ronald P
authors.initials: RP
authors.lastname: Taylor
authors.affiliation: Genmab, Utrecht, the Netherlands.
authors.forename: Esther C W
authors.initials: EC
authors.lastname: Breij
authors.affiliation: Center of Cellular Therapy "G. Lanzani", Division of Hematology, Azienda Ospedaliera Papa Giovanni XXIII, Bergamo, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Gritti
authors.affiliation: Center of Cellular Therapy "G. Lanzani", Division of Hematology, Azienda Ospedaliera Papa Giovanni XXIII, Bergamo, Italy.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Rambaldi
authors.affiliation: Center of Cellular Therapy "G. Lanzani", Division of Hematology, Azienda Ospedaliera Papa Giovanni XXIII, Bergamo, Italy.
authors.forename: Martino
authors.initials: M
authors.lastname: Introna
authors.affiliation: Genmab, Utrecht, the Netherlands Department of Cancer and Inflammation Research, Institute of Molecular Medicine, University of Southern Denmark, Odense, Denmark.
authors.forename: Paul W H I
authors.initials: PW
authors.lastname: Parren
authors.affiliation: Genmab, Utrecht, the Netherlands.
authors.forename: Frank J
authors.initials: FJ
authors.lastname: Beurskens
authors.affiliation: Center of Cellular Therapy "G. Lanzani", Division of Hematology, Azienda Ospedaliera Papa Giovanni XXIII, Bergamo, Italy jgolay@hpg23.it.
authors.forename: Josée
authors.initials: J
authors.lastname: Golay
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D000920:Antibody-Dependent Cell Cytotoxicity; D018951:Antigens, CD20 / Q000276:immunology*; D000971:Antineoplastic Combined Chemotherapy Protocols; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D016022:Case-Control Studies; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D003167:Complement Activation / Q000187:drug effects; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D006801:Humans; D007694:Killer Cells, Natural / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D016393:Lymphoma, B-Cell / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D008264:Macrophages / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D009504:Neutrophils / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D010587:Phagocytosis / Q000187:drug effects / Q000276:immunology; D010880:Piperidines; D011687:Purines / Q000494:pharmacology*; D011720:Pyrazoles / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D052999:Quinazolinones / Q000494:pharmacology*
chemical_list: D000911:Antibodies, Monoclonal; D018951:Antigens, CD20; D010880:Piperidines; D011687:Purines; D011720:Pyrazoles; D011743:Pyrimidines; D052999:Quinazolinones; C551803:ibrutinib; D000225:Adenine; C552946:idelalisib