title: Antitumour activity of the glycoengineered type II anti-CD20 antibody obinutuzumab (GA101) in combination with the MDM2-selective antagonist idasanutlin (RG7388).
abstract: OBJECTIVE
  To investigate whether the glycoengineered type II anti-CD20 monoclonal antibody obinutuzumab (GA101) combined with the selective MDM2 antagonist idasanutlin (RG7388) 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 DoHH-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 DoHH-2 cells. At concentrations >10-100 nm, idasanutlin enhanced obinutuzumab-induced death of DoHH-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 DoHH-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.
authors.affiliation: Roche Pharmaceutical Research and Early Development, Roche Innovation Center Munich, Munich, Germany.
authors.forename: Frank
authors.initials: F
authors.lastname: Herting
authors.affiliation: Roche Pharmaceutical Research and Early Development, Roche Innovation Center Zurich, Schlieren, Switzerland.
authors.forename: Sylvia
authors.initials: S
authors.lastname: Herter
authors.affiliation: Roche Pharmaceutical Research and Early Development, Roche Innovation Center Munich, Munich, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Friess
authors.affiliation: Roche Pharmaceutical Research and Early Development, Roche Innovation Center Munich, Munich, Germany.
authors.forename: Gunther
authors.initials: G
authors.lastname: Muth
authors.affiliation: Roche Pharmaceutical Research and Early Development, Roche Innovation Center Zurich, Schlieren, Switzerland.
authors.forename: Marina
authors.initials: M
authors.lastname: Bacac
authors.affiliation: Roche Pharmaceutical Research and Early Development, Roche Innovation Center Zurich, Schlieren, Switzerland.
authors.forename: Jitka
authors.initials: J
authors.lastname: Sulcova
authors.affiliation: Roche Pharmaceutical Research and Early Development, Roche Innovation Center Zurich, Schlieren, Switzerland.
authors.forename: Pablo
authors.initials: P
authors.lastname: Umana
authors.affiliation: Roche Pharmaceutical Research and Early Development, Roche Innovation Center Munich, Munich, Germany.
authors.forename: Markus
authors.initials: M
authors.lastname: Dangl
authors.affiliation: Roche Pharmaceutical Research and Early Development, Roche Innovation Center Zurich, Schlieren, Switzerland. christian.klein.ck1@roche.com.
authors.forename: Christian
authors.initials: C
authors.lastname: Klein
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D061067:Antibodies, Monoclonal, Humanized / Q000494:pharmacology*; D000920:Antibody-Dependent Cell Cytotoxicity; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007694:Killer Cells, Natural / Q000276:immunology / Q000378:metabolism; D008212:Lymphocyte Depletion; D016393:Lymphoma, B-Cell / Q000188:drug therapy / Q000276:immunology / Q000473:pathology; D051379:Mice; D051736:Proto-Oncogene Proteins c-mdm2 / Q000037:antagonists & inhibitors*; D011759:Pyrrolidines / Q000494:pharmacology*; D047368:Tumor Burden; D023041:Xenograft Model Antitumor Assays; D062366:para-Aminobenzoates / Q000494:pharmacology*
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D011759:Pyrrolidines; C586849:RG7388; D062366:para-Aminobenzoates; D051736:Proto-Oncogene Proteins c-mdm2; C543332:obinutuzumab
keywords: CD20; MDM2; antibody; combination; p53