Recombinant heregulin-pseudornonas exotoxin fusion proteins: Interactions with the heregulin receptors and antitumor activity in vivo

Dajun Yang, Chien Tsun Kuan, Jeniffer Payne, Ako Kihara, Ann Murray, Ling Mei Wang, Maurizio Alimandi, Jacalyn H. Pierce, Ira Pastan, Marc E. Lippman

Research output: Contribution to journalArticle

26 Scopus citations

Abstract

Growth factor receptors provide unique opportunities for development of targeted anticancer therapy. Members of the type I receptor tyrosine kinase family, including epidermal growth factor (EGF) receptor (EGFR) and ErhB- 2/neu, are often overexpressed in various human cancer cells, including breast. Recently, it has been shown that both ErbB-3 and ErbB-4 are receptors for heregulin (HRG)/Neu differentiation factor. Eight chimeric toxins composed of the extracellular and EGF-like domains of four different HRG isoforms and truncated Pseudomonas exotoxin (PE38KDEL) were constructed. The fusion proteins exhibited activity similar to the native HRG in inducing ErbB receptors phosphorylation. The EGF-like domain of HRGβI and HRGβ2 fused to PE38KDEL showed the highest cytotoxic activity, with a IC50 of ≤0.001 ng/ml. The α isoforms that were fused to PE38KDEL were 100-fold less active than the β isoforms. The HRG -Pseudomonas exotoxin (PE) toxins show extremely high activity against cells expressing ErhB-4 receptor, alone or together with other members of the ErbB receptor family. Cells that do not express ErbB-4 but express ErbB-3 receptor, together with the ErhB-2 or EGFR, exhibited moderate sensitivity to HRG-PE toxins. HRG-PE toxins have little or no activity against cells expressing EGFR, ErbB-2, or ErbB-3 alone. More than an 80% tumor regression was achieved by intratumor injection of 1 μg of fusion proteins per day for 5 days. Continuous i.p. administration of EGF- like domain of HRGβ1-PE38KDEL for 7 days via a miniosmotic pump at a dose of 40 μg/kg/day inhibited the growth of ErbB-4 receptor positive but not ErbB- 4 receptor negative cell lines in athymic nude mice. We conclude that there is therapeutic potential of HRG-PE toxins in the therapy of cancers overexpressing the ErbB-4 or ErbB-2 plus ErbB-3 receptors.

Original languageEnglish (US)
Pages (from-to)993-1004
Number of pages12
JournalClinical Cancer Research
Volume4
Issue number4
StatePublished - Apr 1 1998

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Yang, D., Kuan, C. T., Payne, J., Kihara, A., Murray, A., Wang, L. M., Alimandi, M., Pierce, J. H., Pastan, I., & Lippman, M. E. (1998). Recombinant heregulin-pseudornonas exotoxin fusion proteins: Interactions with the heregulin receptors and antitumor activity in vivo. Clinical Cancer Research, 4(4), 993-1004.