Expression of an oncogenic mutant EGF receptor markedly increases the sensitivity of cells to an EGF-receptor-specific antibody-toxin

Int J Cancer. 1998 Mar 16;75(6):878-84. doi: 10.1002/(sici)1097-0215(19980316)75:6<878::aid-ijc10>3.0.co;2-#.

Abstract

EGFRvIII is a ligand-independent, constitutively active variant of the epidermal growth factor receptor (EGFR) that is specifically expressed in gliomas and various other human malignancies and has been proposed as a target for directed tumor therapy. We have recently constructed a highly potent single-chain antibody-toxin, scFv(14E1)-ETA, which consists of the variable domains of the antibody 14E1 specific for human full-length EGFR genetically fused to a truncated form of Pseudomonas exotoxin A. We demonstrate here binding of 14E1 antibody to both full-length and variant EGFR. In contrast to a recombinant toxin containing transforming growth factor-alpha (TGF-alpha) as a cell targeting domain, scFv(14E1)-ETA was highly active on cells expressing EGFRvIII. Surprisingly, scFv(14E1)-ETA displayed cell killing activity on EGFRvIII-expressing cells that was up to 100-fold higher than on control cells expressing full-length EGFR. No differences in the binding affinities of scFv(14E1)-ETA to full-length EGFR or EGFRvIII were observed, suggesting that events downstream of immunotoxin binding are responsible for the increased sensitivity of EGFRvIII-expressing cells. This might have implications for the development of therapeutic reagents simultaneously targeting different forms of the EGFR.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3T3 Cells
  • Animals
  • Antibodies, Monoclonal / chemistry
  • Antibodies, Monoclonal / immunology*
  • Antibody Specificity
  • Cell Survival
  • ErbB Receptors / immunology*
  • Humans
  • Immunotoxins / toxicity*
  • Mice
  • Recombinant Proteins
  • Transfection

Substances

  • Antibodies, Monoclonal
  • Immunotoxins
  • Recombinant Proteins
  • ErbB Receptors