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

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‐α (TGF‐α) 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. Int. J. Cancer 75:878–884, 1998. © 1998 Wiley‐Liss, Inc.