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 Citations (Scopus)

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

Fingerprint

Neuregulin-1
Exotoxins
Pseudomonas
ErbB-3 Receptor
Proteins
Epidermal Growth Factor Receptor
Epidermal Growth Factor
Protein Isoforms
Nude Mice
Immunotoxins
Neoplasms
Growth Factor Receptors
Receptor Protein-Tyrosine Kinases
Inhibitory Concentration 50
Breast
Therapeutics
Phosphorylation
Cell Line
Injections

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Yang, D., Kuan, C. T., Payne, J., Kihara, A., Murray, A., Wang, L. M., ... 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.

Recombinant heregulin-pseudornonas exotoxin fusion proteins : Interactions with the heregulin receptors and antitumor activity in vivo. / Yang, Dajun; Kuan, Chien Tsun; Payne, Jeniffer; Kihara, Ako; Murray, Ann; Wang, Ling Mei; Alimandi, Maurizio; Pierce, Jacalyn H.; Pastan, Ira; Lippman, Marc E.

In: Clinical Cancer Research, Vol. 4, No. 4, 01.04.1998, p. 993-1004.

Research output: Contribution to journalArticle

Yang, D, Kuan, CT, Payne, J, Kihara, A, Murray, A, Wang, LM, Alimandi, M, Pierce, JH, Pastan, I & Lippman, ME 1998, 'Recombinant heregulin-pseudornonas exotoxin fusion proteins: Interactions with the heregulin receptors and antitumor activity in vivo', Clinical Cancer Research, vol. 4, no. 4, pp. 993-1004.
Yang, Dajun ; Kuan, Chien Tsun ; Payne, Jeniffer ; Kihara, Ako ; Murray, Ann ; Wang, Ling Mei ; Alimandi, Maurizio ; Pierce, Jacalyn H. ; Pastan, Ira ; Lippman, Marc E. / Recombinant heregulin-pseudornonas exotoxin fusion proteins : Interactions with the heregulin receptors and antitumor activity in vivo. In: Clinical Cancer Research. 1998 ; Vol. 4, No. 4. pp. 993-1004.
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