Shared antigenic epitopes and pathobiological functions of anti-p185(her2/neu) monoclonal antibodies.

We have studied two anti-p185 antibodies: the monoclonal antibody 7. 16.4 and rhuMAb 4D5, which were raised against the the ectodomain of rat (p185(neu)), and the human (p185(her2/neu)) homolog, respectively. Studies on the structure of these two antibodies indicate that they share structural similarity in the variable region, especially the CDR3 region, which determines the antibody-antigen interaction. Further studies by flow cytometry revealed that 7.16.4 can compete with rhuMAb4D5 for binding to the cell surface p185(her2/neu), suggesting that these two antibodies share an epitope on the p185 receptor. Furthermore, 7.16.4 can also inhibit proliferation and transformation caused by p185(her2/neu). Moreover the rhuMAb 4D5 binds to the rat p185(neu). With the observation that 7.16.4 positively stains human breast cancer tissues that overexpress p185(her2/neu), 7.16.4 may be useful for the pathological diagnosis and therapy of human tumors.

[1]  D. Elder,et al.  Proto-oncogene c-kit expression in malignant melanoma: protein loss with tumor progression. , 1997, Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc.

[2]  D Tripathy,et al.  Phase II study of weekly intravenous recombinant humanized anti-p185HER2 monoclonal antibody in patients with HER2/neu-overexpressing metastatic breast cancer. , 1996, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[3]  M. Pellegrini,et al.  Crystal Structure of a Cross-reaction Complex between Fab F9.13.7 and Guinea Fowl Lysozyme (*) , 1995, The Journal of Biological Chemistry.

[4]  J Navaza,et al.  Three-dimensional structures of the free and the antigen-complexed Fab from monoclonal anti-lysozyme antibody D44.1. , 1994, Journal of molecular biology.

[5]  W G Laver,et al.  The structure of a complex between the NC10 antibody and influenza virus neuraminidase and comparison with the overlapping binding site of the NC41 antibody. , 1994, Structure.

[6]  W. Dougall,et al.  Kinase-deficient neu proteins suppress epidermal growth factor receptor function and abolish cell transformation. , 1994, Oncogene.

[7]  L. Presta,et al.  X-ray structures of the antigen-binding domains from three variants of humanized anti-p185HER2 antibody 4D5 and comparison with molecular modeling. , 1993, Journal of molecular biology.

[8]  A T Brünger,et al.  Three-dimensional structure of an angiotensin II-Fab complex at 3 A: hormone recognition by an anti-idiotypic antibody. , 1992, Science.

[9]  M. Ultsch,et al.  Human growth hormone and extracellular domain of its receptor: crystal structure of the complex. , 1992, Science.

[10]  R. Poljak,et al.  Three-dimensional structure of an idiotope–anti-idiotope complex , 1990, Nature.

[11]  M. Greene,et al.  Intermolecular association of the p185 neu protein and EGF receptor modulates EGF receptor function , 1990, Cell.

[12]  J. Pierce,et al.  Transformation of NIH 3T3 cells by overexpression of the normal coding sequence of the rat neu gene , 1990, Molecular and cellular biology.

[13]  V. Brown,et al.  Synergistic interaction of p185c-neu and the EGF receptor leads to transformation of rodent fibroblasts , 1989, Cell.

[14]  M. Hansen,et al.  Re-examination and further development of a precise and rapid dye method for measuring cell growth/cell kill. , 1989, Journal of immunological methods.

[15]  A. Ullrich,et al.  p185HER2 monoclonal antibody has antiproliferative effects in vitro and sensitizes human breast tumor cells to tumor necrosis factor , 1989, Molecular and cellular biology.

[16]  A. Lesk,et al.  The outline structure of the T‐cell alpha beta receptor. , 1988, The EMBO journal.

[17]  M. Greene,et al.  Monoclonal antibodies specific for the neu oncogene product directly mediate anti-tumor effects in vivo. , 1988, Oncogene.

[18]  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.

[19]  A. Lesk,et al.  Canonical structures for the hypervariable regions of immunoglobulins. , 1987, Journal of molecular biology.

[20]  C R King,et al.  erbB-2 is a potent oncogene when overexpressed in NIH/3T3 cells. , 1987, Science.

[21]  G J Williams,et al.  The Protein Data Bank: a computer-based archival file for macromolecular structures. , 1977, Journal of molecular biology.

[22]  M. Tomayko,et al.  Characterization of human neuroblastoma cell lines that lack N-myc gene amplification. , 1988, Progress in clinical and biological research.