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Protein Engineering vol. 4 no. 8 pp. 989-994, 1991
© 1991 Oxford University Press

RESEARCH-ARTICLE

Diphtheria toxin receptor-binding domain substitution with interleukin 6: genetic construction and interleukin 6 receptor-specific action of a diphtheria toxin-related interleukin 6 fusion protein

Lee-Fong L. Jean1,2 and John R. Murphy1,3

1Evans Department of Clinical Research and the Department of Medicine, The University Hospital 88 East Newton Street, Boston, MA 02118, USA 2Department of Microbiology, Boston University School of Medicine Boston, MA 02118, USA

3To whom correspondence should be addressed

We have genetically replaced that portion of the diphtheria toxin structural gene which encodes the native receptor-binding domain with a synthetic gene encoding the cytokine interleukin 6 (IL-6/IFN-ß2/BSF-2). The resulting gene fusion encodes the chimeric toxin DAB389-IL-6. Following expression and purification, we demonstrate that DAB389-IL-6 is selectively cytotoxic for eukaryotic cells bearing the interleukin 6 receptor. In addition, the cytotoxic action of DAB389-IL-6 is shown to require binding to the IL-6 receptor, internalization by receptor-mediated endocytosis and passage through an acidic compartment. Following the delivery of the catalytically active fragment A to the cytosol of target cells, cellular protein synthesis is inhibited by the ADP-ribosylation of elongation factor 2. While eukaryotic cells which are devoid of the IL-6 receptor are uniformly resistant to the action of this fusion toxin, the data presented suggest that a minimal number of IL-6 receptors may be necessary to mediate the internalization of sufficient levels of DAB389-IL-6 to result in the intoxication of target cells.

Keywords: diphtheria toxin/eukaryotic cells/interleukin 6

Received July 1, 1991; accepted September 9, 1991.


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