Effect of kinase inhibitors on the therapeutic properties of monoclonal antibodies.

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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 antibodydependent 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 coadministration 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.

Introduction

Targeted therapies of malignancies aim to exploit molecu- lar specificities of tumor cells and spare normal tissues. Tar- gets typically include cell surface antigens for immunotherapeutic approaches and intracellular proteins for small molecule inhibitors. The number of approved targeted therapies is increasing rapidly, and novel candidates in clini- cal trials are one of the fastest growing segments in pharma- cology.¹ In spite of this progress targeted therapy is generally used in combination with other agents, including conven- tional chemotherapeutics. Improving therapeutic efficacy while improving tolerance represents a strong incentive to combine targeted agents, with reduced use of cytotoxic agents.^2,3 These novel approaches raise the issue of the addi- tivity, synergism or antagonism of combined targeted thera- pies. An example of antagonism between 2 biotherapeutic proteins, erythropoietin and trastuzumab, that was caused by conflicting effects on signalization pathways was reported by Liang et al.⁴ Lymphoid malignancies represent a field of choice to explore this hypothesis given the availability of targeted therapies with different mechanisms of action in these diseases. Recent literature data has raised the issue that small molecule targeted therapies such as Bruton tyrosine kinase inhibitors may be antagonistic with therapeutic monoclonal antibodies. Kohrt et al. studied the effect of ibrutinib on natural killer (NK) cell cytokine secretion, degranulation and cytotoxicity in antibody-dependent cell-medi- ated cytotoxicity (ADCC) assays in CD20 and HER2 positive models.⁵ Ibrutinib was found to be inhibitory in vitro at low con- centrations (0.1 and 1 microM), and to inhibit the antitumor activity of rituximab and trastuzumab on xenografts in vivo when administered concurrently with the antibodies. In order to investigate the potential synergism or antagonism of targeted therapies, we evaluated the potential effects of 4 kinase inhibitors, ibrutinib (PCI-32765; Bruton tyrosine kinase inhibitor),⁶ and the PI3-kinase inhibitors: idelalisib (CAL-101; PI3Kdelta selective inhibitor),^7,8 NVP-BEZ235 (dual pan PI3K/ mTOR competitive inhibitor)⁹ and LY294002 (pan PI3K inhibi- tor), on the biological properties of 3 monoclonal antibodies, trastuzumab, which targets HER2, and rituximab and obinutu- zumab, which target CD20.¹⁰   Duong M mAbs 2015