title: A nonfucosylated anti-HER2 antibody augments antibody-dependent cellular cytotoxicity in breast cancer patients.
abstract: OBJECTIVE
  Removal of fucose residues from the oligosaccharides of human antibody is a powerful approach to enhance antibody-dependent cellular cytotoxicity (ADCC), a potential important antitumor mechanism of therapeutic antibodies. To provide clinically relevant evidence of this mechanism, we investigated ADCC of a fucose-negative version of trastuzumab [anti-human epidermal growth factor receptor 2 (HER2) humanized antibody] using peripheral blood mononuclear cells (PBMC) from breast cancer patients as effector cells.
  
  
  METHODS
  Thirty volunteers, including 20 breast cancer patients and 10 normal healthy control donors, were recruited randomly, and aliquots of peripheral blood were collected. ADCC of commercial trastuzumab (fucosylated) and its fucose-negative version were measured using PBMCs drawn from the volunteers as effector cells and two breast cancer cell lines with different HER2 expression levels as target cells. Relationships between cytotoxicity and characteristics of the patients, such as content of natural killer cells in PBMCs, type of therapy, FCGR3A genotypes, etc. were also analyzed.
  
  
  RESULTS
  ADCC was significantly enhanced with the fucose-negative antibody compared with the fucose-positive antibody using PBMCs from either normal donors or breast cancer patients. Enhancement of ADCC was observed irrespective of the various clinical backgrounds of the patients, even in the chemotherapy cohort that presented with a reduced number of natural killer cells and weaker ADCC.
  
  
  CONCLUSIONS
  This preliminary study suggests that the use of fucose-negative antibodies may improve the therapeutic effects of anti-HER2 therapy for patients independent of clinical backgrounds.
authors.affiliation: Breast Group, Komagome Hospital, Tokyo Metropolitan Cancer and Infectious Diseases Center, Tokyo, Japan.
authors.forename: Eiji
authors.initials: E
authors.lastname: Suzuki
authors.forename: Rinpei
authors.initials: R
authors.lastname: Niwa
authors.forename: Shigehira
authors.initials: S
authors.lastname: Saji
authors.forename: Mariko
authors.initials: M
authors.lastname: Muta
authors.forename: Makiko
authors.initials: M
authors.lastname: Hirose
authors.forename: Shigeru
authors.initials: S
authors.lastname: Iida
authors.forename: Yukimasa
authors.initials: Y
authors.lastname: Shiotsu
authors.forename: Mitsuo
authors.initials: M
authors.lastname: Satoh
authors.forename: Kenya
authors.initials: K
authors.lastname: Shitara
authors.forename: Masahide
authors.initials: M
authors.lastname: Kondo
authors.forename: Masakazu
authors.initials: M
authors.lastname: Toi
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D000911:Antibodies, Monoclonal / Q000737:chemistry* / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized; D000920:Antibody-Dependent Cell Cytotoxicity / Q000187:drug effects*; D001943:Breast Neoplasms / Q000235:genetics / Q000276:immunology* / Q000473:pathology / Q000628:therapy; D016466:CHO Cells; D045744:Cell Line, Tumor; D006224:Cricetinae; D003412:Cricetulus; D005260:Female; D005643:Fucose / Q000737:chemistry*; D006801:Humans; D007167:Immunotherapy; D007962:Leukocytes / Q000187:drug effects; D008875:Middle Aged; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000276:immunology*; D017452:Receptors, IgG / Q000235:genetics; D000068878:Trastuzumab
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D005643:Fucose; D018719:Erb-b2 Receptor Tyrosine Kinases; D017452:Receptors, IgG; D000068878:Trastuzumab; C496124:FCGR3A protein, human