title: Effect of kinase inhibitors on the therapeutic properties of monoclonal antibodies.
abstract: Targeted therapies of malignancies currently consist of therapeutic monoclonal antibodies and small molecule kinase inhibitors. The combination of these novel agents raises the issue of potential antagonisms. We evaluated the potential effect of 4 kinase inhibitors, including the Bruton tyrosine kinase inhibitor ibrutinib, and 3 PI3K inhibitors idelalisib, NVP-BEZ235 and LY294002, on the effects of the 3 monoclonal antibodies, rituximab and obinutuzumab (directed against CD20) and trastuzumab (directed against HER2). We found that ibrutinib potently inhibits antibody-dependent cell-mediated cytotoxicity exerted by all antibodies, with a 50% inhibitory concentration of 0.2 microM for trastuzumab, 0.5 microM for rituximab and 2 microM for obinutuzumab, suggesting a lesser effect in combination with obinutuzumab than with rituximab. The 4 kinase inhibitors were found to inhibit phagocytosis by fresh human neutrophils, as well as antibody-dependent cellular phagocytosis induced by the 3 antibodies. Conversely co-administration of ibrutinib with rituximab, obinutuzumab or trastuzumab did not demonstrate any inhibitory effect of ibrutinib in vivo in murine xenograft models. In conclusion, some kinase inhibitors, in particular, ibrutinib, are likely to exert inhibitory effects on innate immune cells. However, these effects do not compromise the antitumor activity of monoclonal antibodies in vivo in the models that were evaluated.
authors.affiliation: a Centre de Recherche en Cancérologie de Lyon (CRCL); INSERM UMR 1052/CNRS 5286 ; Lyon , France.
authors.forename: Minh Ngoc
authors.initials: MN
authors.lastname: Duong
authors.forename: Eva-Laure
authors.initials: EL
authors.lastname: Matera
authors.forename: Doriane
authors.initials: D
authors.lastname: Mathé
authors.forename: Anne
authors.initials: A
authors.lastname: Evesque
authors.forename: Sandrine
authors.initials: S
authors.lastname: Valsesia-Wittmann
authors.forename: Béatrice
authors.initials: B
authors.lastname: Clémenceau
authors.forename: Charles
authors.initials: C
authors.lastname: Dumontet
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D000912:Antibodies, Neoplasm / Q000494:pharmacology*; D000920:Antibody-Dependent Cell Cytotoxicity / Q000187:drug effects* / Q000276:immunology; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006801:Humans; D051379:Mice; D016513:Mice, SCID; D009504:Neutrophils / Q000276:immunology*; D010587:Phagocytosis / Q000187:drug effects* / Q000276:immunology
chemical_list: D000911:Antibodies, Monoclonal; D000912:Antibodies, Neoplasm; D004791:Enzyme Inhibitors
keywords: ADCC; ADCC, antibody-dependent cell-mediated cytotoxicity; ADCP; ADCP, antibody-dependent cellular phagocytosis; NHL, non-Hodgkin's lymphoma; NK, natural killer; ibrutinib; idelalisib; kinase inhibitors; monoclonal antibodies; obinutuzumab; rituximab; trastuzumab