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Human Cancer Therapy Using Engineered Anthrax Lethal Toxin

Posted Jun 15 2010 5:00pm

Description of Invention:
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.

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


Development Status:
The technology is at the preclinical stage.

Inventors:
Stephen H Leppla (NIAID)
Shi-hui Liu (NIAID)
Thomas H Bugge (NIDCR)
John R Basile (NIDCR)
Brooke Currie (NIDCR)


Patent Status:
HHS, Reference No. E-070-2007/2
PCT, Application No. PCT/US2007/087664 filed 14 Dec 2007 , which published as WO 2008/076939 on 26 Jun 2008, claiming priority to 14 Dec 2006
US, Application No. 12/519,362 filed 15 Jun 2009


Relevant Publication:
  1. S Liu et al. Intermolecular complementation achieves high-specificity tumor targeting by anthrax toxin. Nat Biotechnol. 2005 Jun;23(6):725-730. [ PubMed abs ]
  2. 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 ]


Licensing Status:
Available for licensing.

Collaborative Research 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.


Portfolios:
Cancer
Cancer - Therapeutics
In-vivo Data



For Additional Information Please Contact:
Whitney Hastings
NIH Office of Technology Transfer
6011 Executive Blvd. Suite 325,
Rockville, MD 20852
United States
Email: hastingw@mail.nih.gov
Phone: 301-451-7337
Fax: 301-402-0220


Ref No: 1494

Updated: 06/2010

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