Synergistic Down-Regulation of Receptor Tyrosine Kinases by Combinations of mAbs: Implications for Cancer Immunotherapy

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 rece...

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Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 2005-02, Vol.102 (6), p.1915-1920
Main Authors: Friedman, Lilach M., Rinon, Ariel, Schechter, Bilha, Lyass, Ljuba, Lavi, Sara, Bacus, Sarah S., Sela, Michael, Yarden, Yosef
Format: Article
Language:English
Subjects:
Animals
Antibodies, Monoclonal - metabolism
Biological Sciences
Cancer
Cellular biology
CHO cells
Down regulation
Dynamins - metabolism
Endocytosis
Endocytosis - physiology
Epitopes
ErbB Receptors - immunology
ErbB Receptors - metabolism
Female
Genes, Reporter
Humans
Immunotherapy
Immunotherapy - methods
Internalization
KB cells
Ligands
Mice
Mice, Nude
Neoplasm Transplantation
Neoplasms - metabolism
Neoplasms - therapy
Proteins
Receptor Protein-Tyrosine Kinases - metabolism
Receptors
Signal transduction
Signal Transduction - physiology
Tumors
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Summary: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.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.0409610102