New anti-
cancer agents are being developed which incorporate
cancer-cell-specific recognition functions and are thus able to distinguish between normal and
tumor cells. Recognition is dependent on the enhanced expression of
antigenic determinants on the surface of
tumor cells. The
ErbB-2 receptor (ErbB-2R) is overproduced in a high percentage of
adenocarcinomas arising in the breast, ovary, lung and stomach, when compared to normal cells. The
tumor-enriched expression and extracellular accessibility make this receptor a suitable target for directed
tumor therapy. A gene expressing the single-chain antibody molecule (scFv), specific for the extracellular domain of the ErbB-2R, was constructed by joining cDNAs encoding the light- and heavy-chain variable domains of the
monoclonal antibody (mAb) FRP5. This scFv-encoding gene has been used as a targeting domain for two effectors: (i) A recombinant
immunotoxin-encoding gene was constructed by adding sequences encoding a modified Pseudomonas aeroginosa
exotoxin A (ETA) to the scFv-encoding
DNA. (ii) Cytotoxic T-lymphocytes (CTL) with specificity for ErbB-2R-producing
tumor cells were generated by retroviral transfer of a chimeric gene which encodes the scFv(FRP5), a hinge region and the zeta-chain of the
T-cell receptor (TCR) complex. The bacterially produced recombinant
immunotoxin scFv(FRP5)-ETA binds specifically to the ErbB-2R and displays both in vitro and in vivo cytotoxic effects selective for
tumor cells producing high levels of the ErbB-2R. Target cells expressing the ErbB-2R gene were lysed in vitro with high specificity by the scFv::hinge::zeta-expressing T-cells.(ABSTRACT TRUNCATED AT 250 WORDS)