Comparative toxicity and efficacy of engineered anthrax lethal toxin variants with broad anti-tumor activities

Diane E. Peters, Benjamin Hoover, Loretta Grey Cloud, Shihui Liu, Alfredo A. Molinolo, Stephen H. Leppla, Thomas H. Bugge

Research output: Contribution to journalArticlepeer-review

Abstract

We have previously designed and characterized versions of anthrax lethal toxin that are selectively cytotoxic in the tumor microenvironment and which display broad and potent anti-tumor activities in vivo. Here, we have performed the first direct comparison of the safety and efficacy of three engineered anthrax lethal toxin variants requiring activation by either matrix-metalloproteinases (MMPs), urokinase plasminogen activator (uPA) or co-localized MMP/uPA activities. C57BL/. 6J mice were challenged with six doses of engineered toxins via intraperitoneal (I.P.) or intravenous (I.V.) dose routes to determine the maximum tolerated dose for six administrations (MTD6) and dose-limiting toxicities. Efficacy was evaluated using the B16-BL6 syngraft model of melanoma; mice bearing established tumors were treated with six I.P. doses of toxin and tumor measurements and immunohistochemistry, paired with terminal blood work, were used to elaborate upon the anti-tumor mechanism and relative efficacy of each variant. We found that MMP-, uPA- and dual MMP/uPA-activated anthrax lethal toxins exhibited the same dose-limiting toxicity; dose-dependent GI toxicity. In terms of efficacy, all three toxins significantly reduced primary B16-BL6 tumor burden, ranging from 32% to 87% reduction, and they also delayed disease progression as evidenced by dose-dependent normalization of blood work values. While target organ toxicity and effective doses were similar amongst the variants, the dual MMP/uPA-activated anthrax lethal toxin exhibited the highest I.P. MTD6 and was 1.5-3-fold better tolerated than the single MMP- and uPA-activated toxins. Overall, we demonstrate that this dual MMP/uPA-activated anthrax lethal toxin can be administered safely and is highly effective in a preclinical model of melanoma. This modified bacterial cytotoxin is thus a promising candidate for further clinical development and evaluation for use in treating human cancers.

Original languageEnglish (US)
Pages (from-to)220-229
Number of pages10
JournalToxicology and Applied Pharmacology
Volume279
Issue number2
DOIs
StatePublished - Sep 1 2014
Externally publishedYes

Keywords

  • Bacterial cytotoxin
  • Cancer
  • Melanoma
  • Prodrug
  • Protease

ASJC Scopus subject areas

  • Toxicology
  • Pharmacology

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