title: GA201 (RG7160): a novel, humanized, glycoengineered anti-EGFR antibody with enhanced ADCC and superior in vivo efficacy compared with cetuximab.
abstract: OBJECTIVE
  Anti-EGF receptor (EGFR) antibodies and small-molecule tyrosine kinase inhibitors have shown activity in epithelial tumors; however, agents that work by blocking the EGFR growth signal are ineffective when the oncogenic stimulus arises downstream, such as in tumors with KRAS mutations. Antibodies of the IgG1 subclass can also kill tumor cells directly through antibody-dependent cell-mediated cytotoxicity (ADCC), and the efficacy of this is determined by the interaction of the Fc portion of the target cell-bound antibody and Fc receptors present on immune effector cells.
  
  
  METHODS
  We report the development of GA201, a novel anti-EGFR monoclonal antibody with enhanced ADCC properties. GA201 was derived by humanization of the rat ICR62 antibody. The Fc region of GA201 was glycoengineered to contain bisected, afucosylated carbohydrates for enhanced binding to FcγRIIIA.
  
  
  RESULTS
  In vitro binding of GA201 to EGFR inhibited EGF ligand binding, EGFR/HER2 heterodimerization, downstream signaling, and cell proliferation to a similar extent as cetuximab. However, GA201 exhibited superior binding to both the low- and high-affinity variants of FcγRIIIA. This resulted in significantly enhanced induction of ADCC compared with cetuximab against both KRAS-wild-type and -mutant tumor cells lines. This enhanced ADCC translated into superior in vivo efficacy in a series of mouse xenograft models. Efficacy of GA201 was further increased when administered in combination with chemotherapy (irinotecan).
  
  
  CONCLUSIONS
  These data suggest that GA201 may be more effective than cetuximab in patients with EGFR-positive solid tumors and may also represent a first-in-class treatment of patients with KRAS-mutated tumors. Clin Cancer Res; 19(5); 1126-38. ©2012 AACR.
authors.affiliation: The Sol Goldman Pancreatic Cancer Research Center, Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21231, USA.
authors.forename: Christian A
authors.initials: CA
authors.lastname: Gerdes
authors.forename: Valeria Gonzalez
authors.initials: VG
authors.lastname: Nicolini
authors.forename: Sylvia
authors.initials: S
authors.lastname: Herter
authors.forename: Erwin
authors.initials: E
authors.lastname: van Puijenbroek
authors.forename: Sabine
authors.initials: S
authors.lastname: Lang
authors.forename: Michaela
authors.initials: M
authors.lastname: Roemmele
authors.forename: Ekkehard
authors.initials: E
authors.lastname: Moessner
authors.forename: Olivier
authors.initials: O
authors.lastname: Freytag
authors.forename: Thomas
authors.initials: T
authors.lastname: Friess
authors.forename: Carola H
authors.initials: CH
authors.lastname: Ries
authors.forename: Birgit
authors.initials: B
authors.lastname: Bossenmaier
authors.forename: Hans Joachim
authors.initials: HJ
authors.lastname: Mueller
authors.forename: Pablo
authors.initials: P
authors.lastname: Umaña
mesh_terms: D000818:Animals; D061067:Antibodies, Monoclonal, Humanized / Q000494:pharmacology*; D000920:Antibody-Dependent Cell Cytotoxicity / Q000187:drug effects* / Q000276:immunology; D000970:Antineoplastic Agents / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D000068818:Cetuximab; D015195:Drug Design; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D005260:Female; D006023:Glycoproteins / Q000494:pharmacology*; D006031:Glycosylation / Q000187:drug effects; D006801:Humans; D007694:Killer Cells, Natural / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D060847:Metabolic Engineering; D051379:Mice; D016513:Mice, SCID; D008822:Mice, Transgenic; D009369:Neoplasms / Q000188:drug therapy / Q000276:immunology* / Q000378:metabolism; D011134:Polysaccharides / Q000378:metabolism; D051381:Rats; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism; D017452:Receptors, IgG / Q000235:genetics; D013329:Structure-Activity Relationship
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D000068818:Cetuximab; D066246:ErbB Receptors; D006023:Glycoproteins; D011134:Polysaccharides; D018719:Erb-b2 Receptor Tyrosine Kinases; D017452:Receptors, IgG; C496124:FCGR3A protein, human; C569293:imgatuzumab