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J. Biol. Chem., Vol. 283, Issue 1, 529-540, January 4, 2008

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Matrix Metalloproteinase-activated Anthrax Lethal Toxin Demonstrates High Potency in Targeting Tumor Vasculature^*

Shihui Liu, Hailun Wang, Brooke M. Currie, Alfredo Molinolo, Howard J. Leung, Mahtab Moayeri, John R. Basile, Randall W. Alfano^¶, J. Silvio Gutkind, Arthur E. Frankel^¶, Thomas H. Bugge¹, and Stephen H. Leppla²

From the Laboratory of Bacterial Diseases, NIAID, National Institutes of Health, Bethesda, Maryland 20892, Oral and Pharyngeal Cancer Branch, NIDCR, National Institutes of Health, Bethesda, Maryland 20892, and ^¶Cancer Research Institute of Scott & White Memorial Hospital, Temple, Texas 76502

Anthrax lethal toxin (LT), a virulence factor secreted by Bacillus anthracis, is selectively toxic to human melanomas with the BRAF V600E activating mutation because of its proteolytic activities toward the mitogen-activated protein kinase kinases (MEKs). To develop LT variants with lower in vivo toxicity and high tumor specificity, and therefore greater potential for clinical use, we generated a mutated LT that requires activation by matrix metalloproteinases (MMPs). This engineered toxin was less toxic than wild-type LT to mice because of the limited expression of MMPs by normal cells. Moreover, the systemically administered toxin produced greater anti-tumor effects than wild-type LT toward human xenografted tumors. This was shown to result from its greater bioavailability, a consequence of the limited uptake and clearance of the modified toxin by normal cells. Furthermore, the MMP-activated LT had very potent anti-tumor activity not only to human melanomas containing the BRAF mutation but also to other tumor types, including lung and colon carcinomas regardless of their BRAF status. Tumor histology and in vivo angiogenesis assays showed that this anti-tumor activity is due largely to the indirect targeting of tumor vasculature and angiogenic processes. Thus, even tumors genetically deficient in anthrax toxin receptors were still susceptible to the toxin therapy in vivo. Moreover, the modified toxin also displayed lower immunogenicity compared with the wild-type toxin. All these properties suggest that this MMP-activated anti-tumor toxin has potential for use in cancer therapy.

Received for publication, September 4, 2007 , and in revised form, October 25, 2007.

^* This work was supported by the intramural research programs of the NIAID and the NIDCR, National Institutes of Health. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Fig. S1.

¹ To whom correspondence may be addressed. Tel.: 301-435-1840; Fax: 301-402-0823; E-mail: thomas.bugge{at}nih.gov.

² To whom correspondence may be addressed. Tel.: 301-594-2865; Fax: 301-480-0326; E-mail: sleppla{at}niaid.nih.gov.

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