Synergistic down-regulation of receptor tyrosine kinases by combinations of mAbs: Implications for cancer immunotherapy

Lilach M. Friedman, Ariel Rinon, Bilha Schechter, Ljuba Lyass, Sara Lavi, Sarah S. Bacus, Michael Sela, Yosef Yarden

Research output: Contribution to journalArticlepeer-review

207 Scopus citations

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.

Original languageEnglish
Pages (from-to)1915-1920
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume102
Issue number6
DOIs
StatePublished - 8 Feb 2005
Externally publishedYes

Keywords

  • Antibody
  • ErbB
  • Growth factor
  • Oncogene
  • Signal transduction

ASJC Scopus subject areas

  • General

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