A bivalent single-chain antibody-toxin specific for ErbB-2 and the EGF receptor.
ErbB-2 and EGF receptors are often co-expressed in human tumors and have been shown to synergize in the transformation of cells in experimental model systems. Transactivation of ErbB-2 can occur via ligand-induced heterodimerization with EGF receptor or other members of the ErbB family of receptor tyrosine kinases. We have previously described the potent anti-tumoral activity of the monospecific single-chain antibody-toxins scFv(FRP5)-ETA and scFv(225)-ETA binding to, respectively, ErbB-2 and the EGF receptor. Here we report the construction and functional characterization of a novel bivalent, bispecific single-chain antibody-toxin, scFv2(FRP5/225)-ETA. The fusion protein consists of 2 scFv domains specific for ErbB-2 and the EGF receptor linked to a modified Pseudomonas exotoxin A. ScFv2(FRP5/225)-ETA displayed in vitro cell killing activity on tumor cells overexpressing either ErbB-2 or the EGF receptor similar to that of the monospecific toxins. It was more potent in vitro and in vivo in inhibiting the growth of tumor cells expressing both receptors. Treatment of A431 cells with scFv2(FRP5/225)-ETA led to an increase in EGF receptor and ErbB-2 phosphotyrosine content, most likely via the induction of receptor heterodimers. This may explain the enhanced toxicity of the bispecific antibody-toxin.
Schmidt
M
M
Institute for Experimental Cancer Research, Tumor Biology Center, Freiburg, Germany.
Hynes
N E
NE
Groner
B
B
Wels
W
W
D036002:ADP Ribose Transferases; D000818:Animals; D018033:Antibodies, Bispecific / Q000627:therapeutic use*; D001427:Bacterial Toxins; D001483:Base Sequence; D066246:ErbB Receptors / Q000276:immunology*; D005098:Exotoxins / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D000922:Immunotoxins / Q000494:pharmacology / Q000627:therapeutic use*; D051379:Mice; D008819:Mice, Nude; D008969:Molecular Sequence Data; D009374:Neoplasms, Experimental / Q000628:therapy; D014407:Tumor Cells, Cultured; D037521:Virulence Factors; D000097668:Pseudomonas aeruginosa Exotoxin A
D036002:ADP Ribose Transferases; D018033:Antibodies, Bispecific; D001427:Bacterial Toxins; D066246:ErbB Receptors; D005098:Exotoxins; D000922:Immunotoxins; D037521:Virulence Factors; D000097668:Pseudomonas aeruginosa Exotoxin A