A monoclonal antibody recognizing human cancers with amplification/overexpression of the human epidermal growth factor receptor.
Epidermal growth factor receptor (EGFR) has attracted considerable attention as a target for cancer therapy. Wild-type (wt)EGFR is amplified/overexpressed in a number of tumor types, and several mutant forms of the coding gene have been found, with DeltaEGFR, a deletion mutation lacking exons 2-7 of the external domain, being the most common and particularly associated with glioblastoma. We generated monoclonal antibodies (mAbs) against NR6(DeltaEGFR) (mouse fibroblast line NR6 transfected with DeltaEGFR). mAb 806 with selective reactivity for NR6(DeltaEGFR) in mixed hemadsorption assays, fluorescence-activated cell sorting, Western blot, and immunohistochemistry was analyzed in detail and compared with mAbs 528 (anti-wtEGFR) and DH8.3 (anti-DeltaEGFR). In xenograft tumors and molecularly pretyped glioblastomas, the reactivity pattern was as follows: 528 reactive with amplified and nonamplified wtEGFR; DH8.3 reactive with DeltaEGFR; and 806 reactive with amplified/overexpressed wtEGFR (with or without DeltaEGFR). In normal tissues, 528 but not DH8.3 or 806 was widely reactive with many organs, e.g., liver expressing high EGFR levels. In glioblastoma and non-CNS tumor panels, 806 was reactive with a high proportion of glioblastomas and a substantial number of epithelial cancers of lung and of head and neck. DH8.3 reactivity was restricted to DeltaEGFR-positive glioblastoma. Thus, 806 represents a category of mAbs that recognizes tumors with EGFR amplification/overexpression but not normal tissues or tumors with normal EGFR levels. Our study also indicates that DeltaEGFR is restricted to glioblastoma, in contrast to other reports that this mutation is found in tumors outside the brain.
Jungbluth
Achim A
AA
Ludwig Institute for Cancer Research, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10021, USA. jungblua@mskcc.org
Stockert
Elisabeth
E
Huang
H J Su
HJ
Collins
Vincent P
VP
Coplan
Keren
K
Iversen
Kristin
K
Kolb
Denise
D
Johns
Terrance J
TJ
Scott
Andrew M
AM
Gullick
William J
WJ
Ritter
Gerd
G
Cohen
Leonard
L
Scanlan
Matthew J
MJ
Cavenee
Webster K
WK
Old
Lloyd J
LJ
Cavanee
Webster K
WK
D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D066246:ErbB Receptors / Q000032:analysis / Q000235:genetics* / Q000276:immunology*; D005909:Glioblastoma / Q000737:chemistry / Q000628:therapy; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000737:chemistry / Q000628:therapy*; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured
D000911:Antibodies, Monoclonal; D066246:ErbB Receptors