Human Cancer Therapy Using Engineered Anthrax Lethal Toxin


Anthrax lethal toxin (LeTx) consists of two components: the protective antigen (PrAg) and the lethal factor (LF). PrAg binds to the cell surface where it is activated by furin protease, followed by the formation of a PrAg heptamer. LF is then translocated into the cytosol of a cell via this heptamer, where it acts as a metalloprotease on all but one mitogen-activated protein kinase kinase (MAPKK). Approximately 70% of human melanomas contain a mutation (B-RAF V600E) that constitutively activates a MAPKK pathway, and LeTx has been shown to have significant toxicity towards cells which have this mutation. This suggested a potential use for LeTx in cancer therapy. Unfortunately, native LeTx is toxic to normal cells, detracting from its in vivo applicability.

PrAg has been engineered to be activated by a matrix metalloprotease (MMP), instead of by furin protease. Because MMPs are highly expressed in tumor cells, this modification increases selectivity towards cancer cells. Surprisingly, mouse data shows that the modified LeTx (denoted PrAg-L1/LF) is less cytotoxic to "normal" cells in vivo, when compared to wild-type LeTx. Significantly, PrAg-L1/LF maintained its high toxicity toward human tumors in mouse xenograft models of human tumors, including melanomas. However, this toxicity applied not only to tumors having mutations that constitutively activate MAPKKs, but also to other tumor types such as lung and colon carcinomas. The absence of toxicity to "normal" cells coupled to its effectiveness on a wide range of cancer cell types suggests that PrAg-L1/LF may represent a novel cancer therapeutic.

Potential Commercial Applications: Competitive Advantages:
  • PrAg-L1/LF has applications as a human cancer therapeutic
  • Applicability extends beyond melanomas, including lung and colon carcinomas
 


Development Stage:
The technology is at the preclinical stage.

Inventors:

Stephen Leppla (NIAID)  ➽ more inventions...

Shihui Liu (NIAID)  ➽ more inventions...

Thomas Bugge (NIDCR)  ➽ more inventions...

John Basile (NIDCR)  ➽ more inventions...

Brooke Currie (NIDCR)  ➽ more inventions...


Intellectual Property:
PCT Application No. PCT/US2007/087664
US Application No. 12/519,362

Publications:
S Liu et al. Intermolecular complementation achieves high-specificity tumor targeting by anthrax toxin. Nat Biotechnol. 2005 Jun;23(6):725-730. PubMed abs
RJ Abi-Habib et al. A urokinase-activated recombinant anthrax toxin is selectively cytotoxic to many human tumor cell types. Mol Cancer Ther. 2006 Oct;5(10):2556-2562. PubMed abs

Collaboration Opportunity:

The NIAID Laboratory of Bacterial Diseases is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize PrAg-L1/LF as a novel cancer therapeutic. Please contact Stephen H. Leppla, Ph.D. at 301/594-2865 and/or sleppla@niaid.nih.gov for more information.


Licensing Contact:
Admin. Licensing Specialist (ALS),
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OTT Reference No: E-070-2007-2
Updated: Jun 16, 2010