Ibrutinib antagonizes the antibody-dependent cellular cytotoxicity (ADCC) function of rituximab (RTX) in vitro in ADCC assays and in vivo in the DHL-4 xenograft model through the inhibition of Fc?R signaling in immune effector cells (Kohrt HE, et al. Blood. 2014;123:1957-1960). Obinutuzumab is a glycoengineered anti-CD20 monoclonal antibody that mediates higher direct cell death induction than RTX, and by being glycoengineered mediates the enhanced induction of ADCC. Herter and colleagues aimed to investigate the impact of ibrutinib on the immune effector function of obinutuzumab compared with RTX (Herter S, et al. ASH 2014. Abstract 1765).
In ADCC assays, ibrutinib (dose range, 30, 100, 300 ng/mL) resulted in a reduction of the ADCC potency of obinutuzumab and RTX. However, at saturating antibody concentrations of 10 mg/mL, ADCC mediated by obinutuzumab was retained, whereas ADCC mediated by RTX was strongly reduced. Interestingly, in the whole-blood B-cell depletion assay, there was only a little impact of ibrutinib on obinutuzumab-mediated B-cell depletion in terms of EC50, and maximal killing was observed at clinically meaningful concentrations of ibrutinib (30, 100, 300 ng/mL), whereas the activity of RTX could be completely abolished with 300-ng/mL ibrutinib.
Notably, control experiments demonstrated that the retained B-cell depletion by obinutuzumab in the presence of ibrutinib is not a result of direct cell death induction, but also is a result of immune effector cell–mediated function (ie, ADCC). In the DHL-4 xenograft model, where ibrutinib as a single agent has no antitumor efficacy, the combination resulted in a reduced antitumor efficacy of RTX, whereas the efficacy of obinutuzumab was not affected.
The investigators hypothesize that the differential behaviors of obinutuzumab and RTX may be related to the enhanced Fc?RIII affinity and stronger Fc?RIII signaling activation mediated by obinutuzumab as a consequence of glycoengineering that may subsequently overwrite the inhibitory effects of ibrutinib. Although the clinical relevance of the observed preclinical antagonism for the combination of RTX and ibrutinib still needs further clinical research, these preclinical data strongly support the clinical investigation of ibrutinib in combination with obinutuzumab for the treatment of CLL and other B-cell malignancies.
