title: Premedication and Chemotherapy Agents do not Impair Imgatuzumab (GA201)-Mediated Antibody-Dependent Cellular Cytotoxicity and Combination Therapies Enhance Efficacy.
abstract: Imgatuzumab (GA201) is a novel anti-EGFR mAb that is glycoengineered for enhanced antibody-dependent cellular cytotoxicity (ADCC). Future treatment schedules for imgatuzumab will likely involve the use of potentially immunosuppressive drugs, such as premedication therapies, to mitigate infusion reactions characteristic of mAb therapy and chemotherapy combination partners. Because of the strong immunologic component of mode of action of imgatuzumab, it is important to understand whether these drugs influence imgatuzumab-mediated ADCC and impact efficacy.
  
  
  
  We performed a series of ADCC assays using human peripheral blood mononuclear cells that were first preincubated in physiologically relevant concentrations of commonly used premedication drugs and cancer chemotherapies. The ability of common chemotherapy agents to enhance the efficacy of imgatuzumab in vivo was then examined using orthotopic xenograft models of human cancer.
  
  
  
  A majority of premedication and chemotherapy drugs investigated had no significant effect on the ADCC activity of imgatuzumab in vitro Furthermore, enhanced in vivo efficacy was seen with imgatuzumab combination regimens compared with single-agent imgatuzumab, single-agent chemotherapy, or cetuximab combinations.
  
  
  
  These data indicate that medications currently coadministered with anti-EGFR therapies are unlikely to diminish the ADCC capabilities of imgatuzumab. Further studies using syngeneic models with functional adaptive T-cell responses are now required to fully understand how chemotherapy agents will influence a long-term response to imgatuzumab therapy. Thus, this study and future ones can provide a framework for designing imgatuzumab combination regimens with enhanced efficacy for investigation in phase II trials. Clin Cancer Res; 22(10); 2453-61. ©2015 AACR.
authors.affiliation: Pharma Research and Early Development, Roche Innovation Center Zurich, Schlieren, Switzerland.
authors.forename: Valeria
authors.initials: V
authors.lastname: Gonzalez-Nicolini
authors.affiliation: Pharma Research and Early Development, Roche Innovation Center Zurich, Schlieren, Switzerland.
authors.forename: Sylvia
authors.initials: S
authors.lastname: Herter
authors.affiliation: Pharma Research and Early Development, Roche Innovation Center Zurich, Schlieren, Switzerland.
authors.forename: Sabine
authors.initials: S
authors.lastname: Lang
authors.affiliation: Pharma Research and Early Development, Roche Innovation Center Zurich, Schlieren, Switzerland.
authors.forename: Inja
authors.initials: I
authors.lastname: Waldhauer
authors.affiliation: Pharma Research and Early Development, Roche Innovation Center Zurich, Schlieren, Switzerland.
authors.forename: Marina
authors.initials: M
authors.lastname: Bacac
authors.affiliation: Pharma Research and Early Development, Roche Innovation Center Zurich, Schlieren, Switzerland.
authors.forename: Michaela
authors.initials: M
authors.lastname: Roemmele
authors.affiliation: Pharma Research and Early Development, Roche Innovation Center Zurich, Schlieren, Switzerland.
authors.forename: Esther
authors.initials: E
authors.lastname: Bommer
authors.affiliation: Pharma Research and Early Development, Roche Innovation Center Zurich, Schlieren, Switzerland.
authors.forename: Olivier
authors.initials: O
authors.lastname: Freytag
authors.affiliation: Pharma Research and Early Development, Roche Innovation Center Zurich, Schlieren, Switzerland.
authors.forename: Erwin
authors.initials: E
authors.lastname: van Puijenbroek
authors.affiliation: Pharma Research and Early Development, Roche Innovation Center Zurich, Schlieren, Switzerland.
authors.forename: Pablo
authors.initials: P
authors.lastname: Umaña
authors.affiliation: Pharma Research and Early Development, Roche Innovation Center Zurich, Schlieren, Switzerland. christian.gerdes@roche.com.
authors.forename: Christian A
authors.initials: CA
authors.lastname: Gerdes
mesh_terms: D000072283:A549 Cells; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D000920:Antibody-Dependent Cell Cytotoxicity / Q000187:drug effects*; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D000068818:Cetuximab / Q000627:therapeutic use; D003131:Combined Modality Therapy / Q000379:methods; D066246:ErbB Receptors / Q000037:antagonists & inhibitors; D019073:HT29 Cells; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000378:metabolism
chemical_list: D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D066246:ErbB Receptors; D000068818:Cetuximab