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Infection and Immunity, May 2002, p. 2344-2350, Vol. 70, No. 5
0019-9567/02/$04.00+0     DOI: 10.1128/IAI.70.5.2344-2350.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Receptor-Based Antidote for Diphtheria

Jeong-Heon Cha, Joanna S. Brooke,^, Mee Young Chang, and Leon Eidels^*

Department of Microbiology, The University of Texas Southwestern Medical Center, Dallas, Texas 75390-9048

Received 10 August 2001/ Returned for modification 23 October 2001/ Accepted 1 February 2002

Although equine diphtheria antitoxin may be an effective therapy for human diphtheria, its use often induces serum sickness. We describe here a strategy for developing an alternative treatment based on the human diphtheria toxin (DT) receptor/heparin-binding epidermal growth factor-like growth factor (HB-EGF) precursor. Recombinant mature human HB-EGF acts as a soluble receptor analog, binding radioiodinated DT and preventing its binding to the cellular DT receptor/HB-EGF precursor. However, the possibility existed that radioiodinated DT-HB-EGF complexes associate with cells due to the binding of the heparin-binding domain of recombinant HB-EGF to cell surface heparan sulfate proteoglycans. This possibility was confirmed by performing DT binding studies in the presence of heparin. A recombinant truncated HB-EGF (residues 106 to 149), which lacks most of the heparin-binding domain, showed an essentially heparin-independent binding of radioiodinated DT to cells. Furthermore, it was a more effective inhibitor of DT binding than was recombinant mature HB-EGF. Since mature HB-EGF is a known ligand for the EGF receptor and is thus highly mitogenic (tumorigenic), we then changed amino acid residues in the EGF-like domain of the recombinant truncated HB-EGF and demonstrated that this DT receptor analog (I117A/L148A) displayed a low mitogenic effect. The truncated (I117A/L148A) HB-EGF protein retained high DT binding affinity, as confirmed by using surface plasmon resonance. Our results suggest that the truncated (I117A/L148A) HB-EGF protein could be an effective, safe antidote for human diphtheria.

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* Corresponding author. Mailing address: Dept. of Microbiology, The University of Texas Southwestern Medical Center, 6000 Harry Hines Blvd., Dallas, TX 75390-9048. Phone: (214) 648-5930. Fax: (214) 648-5907. E-mail: Leon.Eidels{at}UTsouthwestern.edu.

Editor: J. T. Barbieri

Present address: Dept. of Biology, DePaul University, Chicago, IL 60614.

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Infection and Immunity, May 2002, p. 2344-2350, Vol. 70, No. 5
0019-9567/02/$04.00+0     DOI: 10.1128/IAI.70.5.2344-2350.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

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