title: Synergistic down-regulation of receptor tyrosine kinases by combinations of mAbs: implications for cancer immunotherapy.
abstract: mAbs to receptor tyrosine kinases such as EGF receptor/ErbB-1 and HER2/ErbB-2 inhibit the tumorigenic growth of certain cancer cells, but although recombinant versions of such Abs are already used in oncology wards, the mechanism underlying immunotherapy remains unknown. We report that anti-EGF receptor Abs promote a slow endocytic process distinct from the rapid EGF-induced receptor internalization. Combining mAbs that engage distinct epitopes significantly accelerates receptor degradation. In addition, mAb combinations are more effective than single Abs in inhibiting HER2 signaling in vitro and tumorigenesis in animals. We present a model attributing efficacy of immunotherapy to the size of Ab-receptor lattices formed at the cell surface, which dictates the rate of endocytic clearance and extent of signaling blockade.
authors.affiliation: Department of Immunology, The Weizmann Institute of Science, Rehovot 76100, Israel.
authors.forename: Lilach M
authors.initials: LM
authors.lastname: Friedman
authors.forename: Ariel
authors.initials: A
authors.lastname: Rinon
authors.forename: Bilha
authors.initials: B
authors.lastname: Schechter
authors.forename: Ljuba
authors.initials: L
authors.lastname: Lyass
authors.forename: Sara
authors.initials: S
authors.lastname: Lavi
authors.forename: Sarah S
authors.initials: SS
authors.lastname: Bacus
authors.forename: Michael
authors.initials: M
authors.lastname: Sela
authors.forename: Yosef
authors.initials: Y
authors.lastname: Yarden
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000378:metabolism*; D015536:Down-Regulation; D034281:Dynamins / Q000378:metabolism; D004705:Endocytosis / Q000502:physiology; D000939:Epitopes; D066246:ErbB Receptors / Q000276:immunology / Q000378:metabolism*; D005260:Female; D017930:Genes, Reporter; D006801:Humans; D007167:Immunotherapy / Q000379:methods*; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000378:metabolism* / Q000628:therapy*; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology
chemical_list: D000911:Antibodies, Monoclonal; D000939:Epitopes; D066246:ErbB Receptors; D020794:Receptor Protein-Tyrosine Kinases; D034281:Dynamins