Antitumour activity of the glycoengineered type II anti‐ CD 20 antibody obinutuzumab ( GA 101) in combination with the MDM 2‐selective antagonist idasanutlin ( RG 7388)

Objectives To investigate whether the glycoengineered type II anti‐ CD 20 monoclonal antibody obinutuzumab ( GA 101) combined with the selective MDM 2 antagonist idasanutlin ( RG 7388) offers superior efficacy to monotherapy in treating B‐lymphoid malignancies in preclinical models. Methods The combined effect of obinutuzumab or rituximab plus idasanutlin on direct cell death/apoptosis induction and antibody‐dependent cellular cytotoxicity ( ADCC ) was evaluated using p53 wild‐type Z‐138 and Do HH ‐2 lymphoma cells. Furthermore, whole blood B‐cell depletion was analysed, and tumour growth inhibition was evaluated in subcutaneous xenograft models. Results Idasanutlin induced concentration‐dependent death of Z‐138 and Do HH ‐2 cells. At concentrations >10–100 n m , idasanutlin enhanced obinutuzumab‐induced death of Do HH ‐2 and Z‐138 cells without negatively impacting obinutuzumab‐mediated ADCC , natural killer cell activation or whole blood B‐cell depletion. In the Z‐138 xenograft model, a suboptimal dose of obinutuzumab with idasanutlin yielded substantial tumour growth inhibition and prolonged survival in a time‐to‐event analysis. In the Do HH ‐2 model, idasanutlin plus obinutuzumab showed superior tumour growth inhibition to idasanutlin plus rituximab. Conclusions Obinutuzumab plus idasanutlin enhanced cell death of p53 wild‐type tumour cells vs. rituximab plus idasanutlin without affecting obinutuzumab‐mediated ADCC or B‐cell depletion and showed robust antitumour efficacy in xenograft models, strongly supporting the investigation of this combination in clinical trials.