Summary Epidermal growth factor (EGF) receptor-overexpression is characteristic of many human tumours of epithelial origin and has been correlated with unfavourable patient prognosis. Its involvement in the malignant process, its elevated expression in tumours and its accessibility on the tumour cell surface make the EGF receptor a potential target for directed tumour therapy. We have previously characterized a recombinant antibody -Pseudomonas exotoxin A fusion protein, scFv(225)-ETA, which displayes antitumoral activity towards EGF receptor-overexpressing tumour cells but is less potent in tumour cell killing than TGF-a-ETA, a recombinant toxin using the natural EGF receptor ligand transforming growth factor a (TGF-a) as a targeting domain. Here, we describe the construction and functional characterization in vitro of a novel single-chain antibody-toxin, scFv(14E1)-ETA, based on the independently isolated EGF receptor-specific monoclonal antibody 1 4E1. ScFv(14E1 )-ETA binds to an EGF receptor epitope that is very similar or identical to that of scFv(225)-ETA with nine times higher affinity than the latter and displays more than tenfold higher cytotoxic activity on EGF receptor-overexpressing tumour cells. ScFv(14E1)-ETA cell killing activity was very similar to that of TGF-a-ETA on receptor-overexpressing cells but, in contrast to the latter, scFv(1 4E1 )-ETA was much more selective and did not display significant cytotoxic activity on cells expressing moderate EGF receptor levels.Keywords: single chain Fv; epidermal growth factor receptor; exotoxin A; directed tumour therapy The erbB/EGF receptor-related gene family encodes growth factor receptors with intrinsic tyrosine kinase activity. Four members of this family have been identified: ErbBlEGF receptor, ErbB-2, ErbB-3 and ErbB-4 (Peles and Yarden, 1993). Members of this family have been implicated in the development of a variety of human malignancies. EGF receptor gene amplification and overexpression have been observed in a high percentage of primary human carcinomas of epithelial origin, including glioblastoma and cancer of the lung, breast, head and neck and bladder, and correlates with an unfavourable prognosis for the patients (Gullick, 1991). Increased receptor expression in tumour cells is often accompanied by increased production of TGF-a (Derynck et al, 1987; Van de Vijver et al, 1991), which leads to receptor activation by an autocrine pathway and contributes to malignant transformation. Because of its accessibility on the cell surface, its overexpression in several types of cancer and its involvement as a marker for an unfavourable prognosis, the EGF receptor is under intensive scrutiny as a therapeutic target for novel anti-tumour reagents.Various strategies have been used to target the EGF receptor for tumour therapy. Monoclonal antibodies directed towards the extracellular domain of the EGF receptor have proven effective in the inhibition of tumour cell growth. The EGF receptor-specific monoclonal antibody (MAb) 225 competes with EGF for bind...
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