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

doi:10.1073/pnas.0409610102

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

Departments of ^*Immunology and ^‡Biological Regulation, The Weizmann Institute of Science, Rehovot 76100, Israel; and ^§Targeted Molecular Diagnostics, Westmont, IL 60559

Contributed by Michael Sela, December 23, 2004

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.

Footnotes

↵ ¶ To whom correspondence should be addressed. E-mail: yosef.yarden{at}weizmann.ac.il.
↵ † L.M.F. and A.R. contributed equally to this work.
Author contributions: L.M.F., A.R., B.S., S.S.B., M.S., and Y.Y. designed research; L.M.F., A.R., B.S., L.L., S.L., and S.S.B. performed research; L.M.F., A.R., B.S., L.L., S.S.B., M.S., and Y.Y. analyzed data; and L.M.F., A.R., B.S., L.L., M.S., and Y.Y. wrote the paper.
Abbreviations: EGFR, EGF receptor; GPI, glycosyl-phosphatidylinositol; NDF, Neu differentiation factor; pAb, polyclonal Ab; RTK, receptor tyrosine kinase; ECD-TM, extracellular domain-transmembrane.