Recombinant heregulin-Pseudomonas exotoxin fusion proteins: interactions with the heregulin receptors and antitumor activity in vivo

• Published in: Clinical cancer research Vol. 4; no. 4; pp. 993 - 1004
• Main Authors: DAJUN YANG, KUAN, C.-T, PAYNE, J, KIHARA, A, MURRAY, A, WANG, L.-M, ALIMANDI, M, PIERCE, J. H, PASTAN, I, LIPPMAN, M. E
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 01.04.1998
• Subjects: Animals; Antineoplastic agents; Antineoplastic Agents - pharmacokinetics; Antineoplastic Agents - pharmacology; Antineoplastic Agents - therapeutic use; Biological and medical sciences; Carcinoma - drug therapy; Chemotherapy; Colony-Forming Units Assay; Exotoxins - pharmacokinetics; Exotoxins - pharmacology; Exotoxins - therapeutic use; Female; Genes, erbB - drug effects; Glycoproteins - pharmacokinetics; Glycoproteins - pharmacology; Glycoproteins - therapeutic use; Humans; Immunotoxins - pharmacokinetics; Immunotoxins - pharmacology; Immunotoxins - therapeutic use; Medical sciences; Mice; Mice, Nude; Pharmacology. Drug treatments; Phosphorylation; Proto-Oncogene Proteins - drug effects; Receptor, Epidermal Growth Factor - drug effects; Receptor, ErbB-3; Recombinant Fusion Proteins - pharmacokinetics; Recombinant Fusion Proteins - pharmacology; Recombinant Fusion Proteins - therapeutic use; Stomach Neoplasms - drug therapy; Tumor Cells, Cultured - drug effects; Tyrosine - metabolism; Pseudomonadales; Antineoplastic agent; Cytotoxicity; Heregulin; Pseudomonas; Epidermal growth factor; Bacteria; Pseudomonadaceae; Isoform; Exotoxin; Mammary gland; Fusion protein; Protein-tyrosine kinase; Biological receptor; Enzyme; Transferases; Cytokine; Rodentia; Intratumoral administration; Malignant tumor; Experimental study; In vitro; Biological activity; Mammary gland diseases; In vivo; Vertebrata; Mammalia; Mouse; Polypeptide; Analog; Animal; Pharmacokinetics; Growth factor
• ISSN: 1078-0432; 1557-3265

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 ErbB-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 HRG13 and HRGbeta2 fused to PE38KDEL showed the highest cytotoxic activity, with a IC50 of < or = 0.001 ng/ml. The alpha isoforms that were fused to PE38KDEL were 100-fold less active than the beta isoforms. The HRG-Pseudomonas exotoxin (PE) toxins show extremely high activity against cells expressing ErbB-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 ErbB-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 microg of fusion proteins per day for 5 days. Continuous i.p. administration of EGF-like domain of HRGbeta1-PE38KDEL for 7 days via a miniosmotic pump at a dose of 40 microg/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.