Three BTK-Specific Inhibitors, in Contrast to Ibrutinib, Do Not Antagonize Rituximab-Dependent NK-Cell Mediated Cytotoxicity

Introduction: The BTK inhibitor, ibrutinib is FDA-approved in MCL and CLL, with activity in the majority of CD20+ B-cell malignancies. As rituximab-combination chemotherapy is today’s standard of care in CD20+ B-cell malignancies, we previously investigated and determined ibrutinib antagonizes rituximab-dependent NK-cell mediated cytotoxicity (ADCC) due to ibrutinib’s secondary irreversible binding to interleukin-2 inducible tyrosine kinase (ITK) which is required for FcR-stimulated NK cell function including calcium mobilization, granule release, and overall ADCC. We hypothesized that BTK inhibitors, BTK-InhA (ACP-196), BTK-InhB (BGB-3111) and BTK-InhC (undisclosed), each with lower ITK binding, may preserve NK cell function and therefore synergize rather than antagonize rituximab.