title: Endogenous anti-HER2 antibodies block HER2 phosphorylation and signaling through extracellular signal-regulated kinase.
abstract: Immunologic targeting of the oncoprotein HER2/neu with monoclonal antibodies is an important component of current therapeutic strategies for patients with locally and systemically advanced breast cancer. Engineered antibodies targeting HER2 may have agonist or antagonist effects on HER2, but little is known about whether endogenous antibodies modulate HER2 activity. Vaccination of patients with HER2 peptides successfully induced antibodies in a minority of patients with HER2-expressing malignancy. A subset of antibodies specifically suppressed phosphorylation of HER2 on tyrosine Y1248, a residue critical for HER2 signaling through extracellular signal-regulated kinase. These antibodies also suppressed extracellular signal-regulated kinase phosphorylation and inhibited colony formation in soft agar. The majority of the antibodies that suppressed HER2 phosphorylation displayed specificity for amino acids 328 to 345 and 369 to 384. The isotype of anti-HER2 antibodies was predominantly IgG3 of low avidity, suggesting a Th1 response to peptide vaccine. Endogenous anti-HER2 antibodies can effectively suppress HER2 kinase activity and downstream signaling to inhibit the transformed phenotype of HER2-expressing tumor cells.
authors.affiliation: Division of Oncology, Department of Medicine, VA Puget Sound HCS/University of Washington, Seattle, WA 98108, USA. rbmontgo@u.washington.edu
authors.forename: R Bruce
authors.initials: RB
authors.lastname: Montgomery
authors.forename: Ekram
authors.initials: E
authors.lastname: Makary
authors.forename: Kathy
authors.initials: K
authors.lastname: Schiffman
authors.forename: Vivian
authors.initials: V
authors.lastname: Goodell
authors.forename: Mary L
authors.initials: ML
authors.lastname: Disis
mesh_terms: D000912:Antibodies, Neoplasm / Q000096:biosynthesis / Q000276:immunology*; D000915:Antibody Affinity; D000918:Antibody Specificity; D001943:Breast Neoplasms / Q000276:immunology / Q000628:therapy; D019496:Cancer Vaccines / Q000276:immunology* / Q000494:pharmacology; D005260:Female; D006801:Humans; D020935:MAP Kinase Signaling System / Q000276:immunology*; D010051:Ovarian Neoplasms / Q000276:immunology / Q000628:therapy; D010446:Peptide Fragments / Q000276:immunology; D010766:Phosphorylation; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000276:immunology* / Q000378:metabolism*
chemical_list: D000912:Antibodies, Neoplasm; D019496:Cancer Vaccines; D010446:Peptide Fragments; D018719:Erb-b2 Receptor Tyrosine Kinases