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 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.

[1]  Daniel Jones.  Anticancer drugs: To the rescue? , 2004, Nature Reviews Drug Discovery.

[2]  Y. Yarden,et al.  Role of protein ubiquitylation in regulating endocytosis of receptor tyrosine kinases , 2004, Oncogene.

[3]  C. Arteaga,et al.  Herceptin-induced inhibition of phosphatidylinositol-3 kinase and Akt Is required for antibody-mediated effects on p27, cyclin D1, and antitumor action. , 2002, Cancer research.

[4]  Richard G. W. Anderson,et al.  Second Cysteine-rich Region of Epidermal Growth Factor Receptor Contains Targeting Information for Caveolae/Rafts* , 2002, The Journal of Biological Chemistry.

[5]  J. Uhr,et al.  Targeting multiple Her-2 epitopes with monoclonal antibodies results in improved antigrowth activity of a human breast cancer cell line in vitro and in vivo. , 2002, Clinical cancer research : an official journal of the American Association for Cancer Research.

[6]  Y. Yarden,et al.  A mutant EGF‐receptor defective in ubiquitylation and endocytosis unveils a role for Grb2 in negative signaling , 2002, The EMBO journal.

[7]  Y. Yarden,et al.  Untangling the ErbB signalling network , 2001, Nature Reviews Molecular Cell Biology.

[8]  Y. Yarden,et al.  Tumor-inhibitory antibodies to HER-2/ErbB-2 may act by recruiting c-Cbl and enhancing ubiquitination of HER-2. , 2000, Cancer research.

[9]  L. Presta,et al.  Inhibitory Fc receptors modulate in vivo cytoxicity against tumor targets , 2000, Nature Medicine.

[10]  R. Finn,et al.  Remission of human breast cancer xenografts on therapy with humanized monoclonal antibody to HER-2 receptor and DNA-reactive drugs , 1998, Oncogene.

[11]  Yosef Yarden,et al.  A subclass of tumor-inhibitory monoclonal antibodies to ErbB-2/HER2 blocks crosstalk with growth factor receptors , 1997, Oncogene.

[12]  Y. Yarden,et al.  Suppression and promotion of tumor growth by monoclonal antibodies to ErbB-2 differentially correlate with cellular uptake. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[13]  J. Mendelsohn,et al.  Antibody-induced epidermal growth factor receptor dimerization mediates inhibition of autocrine proliferation of A431 squamous carcinoma cells. , 1994, The Journal of biological chemistry.

[14]  S. Schmid,et al.  Induction of mutant dynamin specifically blocks endocytic coated vesicle formation , 1994, The Journal of cell biology.

[15]  R. Prywes,et al.  Two pathways for serum regulation of the c-fos serum response element require specific sequence elements and a minimal domain of serum response factor , 1994, Molecular and cellular biology.

[16]  N. Hynes,et al.  Monoclonal antibodies directed to the erbB-2 receptor inhibit in vivo tumour cell growth. , 1993, British Journal of Cancer.

[17]  R. Lupu,et al.  Neu differentiation factor (heregulin) induces expression of intercellular adhesion molecule 1: implications for mammary tumors. , 1993, Cancer research.

[18]  Yinhua Yu,et al.  Antibody‐induced growth inhibition is mediated through immunochemically and functionally distinct epitopes on the extracellular domain of the c‐erbb‐2 (her‐2/neu) gene product p185 , 1993, International journal of cancer.

[19]  P. P. Di Fiore,et al.  Therapy of an animal model of human gastric cancer using a combination of anti-erbB-2 monoclonal antibodies. , 1992, Cancer research.

[20]  L. Presta,et al.  Humanization of an anti-p185HER2 antibody for human cancer therapy. , 1992, Proceedings of the National Academy of Sciences of the United States of America.

[21]  R. Bast,et al.  Requirements for the internalization of a murine monoclonal antibody directed against the HER-2/neu gene product c-erbB-2. , 1991, Cancer research.

[22]  A. Ullrich,et al.  Mechanistic aspects of the opposing effects of monoclonal antibodies to the ERBB2 receptor on tumor growth. , 1991, Proceedings of the National Academy of Sciences of the United States of America.

[23]  W Godolphin,et al.  Studies of the HER-2/neu proto-oncogene in human breast and ovarian cancer. , 1989, Science.

[24]  M. Sela,et al.  Efficacy of antibodies to epidermal growth factor receptor against KB carcinoma in vitro and in nude mice. , 1988, Journal of the National Cancer Institute.

[25]  M. Greene,et al.  Monoclonal antibodies reactive with distinct domains of the neu oncogene-encoded p185 molecule exert synergistic anti-tumor effects in vivo. , 1988, Oncogene.

[26]  J. Mendelsohn,et al.  Growth inhibition of human tumor cells in athymic mice by anti-epidermal growth factor receptor monoclonal antibodies. , 1984, Cancer research.