Targeted inhibition of tumour cell growth by a bispecific single-chain toxin containing an antibody domain and TGF alpha

Br J Cancer. 1996 Sep;74(6):853-62. doi: 10.1038/bjc.1996.448.

Abstract

Overexpression of the epidermal growth factor receptor (EGFR) and ErbB-2 has been observed in a variety of human tumours, making these receptors promising targets for directed tumour therapy. Since many tumour cells express both ErbB-2 and EGFR and these receptors synergise in cellular transformation, therapeutic reagents simultaneously binding to ErbB-2 and EGFR might offer advantages for tumour therapy. We have previously described the potent anti-tumoral activity of a bispecific antibody toxin that contains ErbB-2- and EGFR-specific single-chain Fv (scFv) domains. Here we report the construction and functional characterisation of a novel bispecific recombinant toxin, scFv(FRP5)-TGF alpha-ETA. The fusion protein consists of the antigen-binding domain of the ErbB-2-specific MAb, FRP5, and the natural EGFR ligand, TGF alpha, inserted at different positions in truncated Pseudomonas exotoxin A. ScFv(FRP5)-TGF alpha-ETA protein displayed binding to EGFR and ErbB-2, thereby inducing activation of the receptors, which was dependent on the cellular context and the level of EGFR and ErbB-2 expression. The bispecific molecule was cytotoxic in vitro for tumour cells expressing various levels of the target receptors. In vivo scFv(FRP5)-TGF alpha-ETA potently inhibited the growth of established A431 tumour xenografts in nude mice.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ADP Ribose Transferases*
  • Animals
  • Antibodies, Bispecific / therapeutic use*
  • Bacterial Toxins*
  • ErbB Receptors / metabolism
  • Exotoxins / therapeutic use*
  • Humans
  • Immunotoxins / therapeutic use*
  • Mice
  • Neoplasms, Experimental / therapy
  • Receptor, ErbB-2 / immunology*
  • Recombinant Fusion Proteins / therapeutic use*
  • Transforming Growth Factor alpha / immunology*
  • Tumor Cells, Cultured
  • Virulence Factors*

Substances

  • Antibodies, Bispecific
  • Bacterial Toxins
  • Exotoxins
  • Immunotoxins
  • Recombinant Fusion Proteins
  • Transforming Growth Factor alpha
  • Virulence Factors
  • ADP Ribose Transferases
  • toxA protein, Pseudomonas aeruginosa
  • ErbB Receptors
  • Receptor, ErbB-2