[Federal Register Volume 65, Number 14 (Friday, January 21, 2000)]
[Notices]
[Page 3466]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 00-1423]


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DEPARTMENT OF HEALTH AND HUMAN SERVICE

National Institutes of Health


Government-Owned Invention; Availability for Licensing: 
``Therapeutic Methods to Treat Tumor Cells--Mutated Anthrax Toxin 
Protective Antigen Proteins That Specifically Target Cells Containing 
High Amounts of Cell-Surface Metalloproteinases or Plasminogen 
Activators''

AGENCY: National Institutes of Health, Public Health Service, DHHS.

ACTION: Notice.

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SUMMARY:  The invention listed below is owned by an agency of the U.S. 
Government and is available for licensing in the U.S. in accordance 
with 35 U.S.C. 207 to achieve expeditious commercialization of results 
of federally funded research and development.

ADDRESSES:  Licensing information and a copy of the U.S. patent 
application referenced below may be obtained by contacing J.R. Dixon, 
Ph.D., at the Office of Technology Transfer, National Institutes of 
Health, 6011 Executive Boulevard, Suite 325, Rockville, Maryland 20852-
3804 (telephone 301/496-7056 ext 206; fax 301/402-0220; E-Mail: 
[email protected]). A signed Confidential Disclosure Agreement is required 
to receive a copy of any patent application.

SUPPLEMENTARY INFORMATION:
     Invention Title: ``Mutated Anthrax Toxin Protective Antigen 
Proteins that Specifically Target Cells Containing High Amounts of 
Cell-Surface Metalloproteinases or Plasminogen Activators.''
    Inventors: Drs. Stephen H. Leppla (NIDCR), Shi-Hui Liu (NIDCR), 
Sarah Netzel-Arnett (NIDCR), Henning Birkedal-Hansen (NIDCR), and 
Thomas H. Bugge (NIDCR).
    USPA SN: 60/155,061 [=DHHS Ref. No. E-293-99/0]--Filed with the 
U.S.P.T.O. on Friday, September 24, 1999.

Abstract

    Anthrax toxin is a three-part toxin secreted by Bacillus anthracis 
consisting of Protective Antigen (``PA'', 83kDa), Lethal Factor 
(``LF'', 90 kDa) and Edema Factor (``EF'', 89kDa), which are 
individually non-toxic. PA, recognized as central, receptor-binding 
component, binds to an unidentified receptor and is cleaved at the 
sequence RKKR 167 by cell-surface furin or furin-like 
proteases into two fragments: PA63, a 63 kDa C-terminal fragment, which 
remains receptor-bound and PA20, a 20 kDa N-terminal fragment, which is 
released into the medium. The resulting hetero-oligomeric complex is 
internalized by endocytosis and acidification of the vesicle causes 
insertion of the PA63 heptamer into the endosomal membrane to produce a 
channel through which LF or EF translocate to the cytosol, where LF or 
EF induce cytotoxic events. Thus, the combination of PA+LF, named 
anthrax lethal toxin, kills animals and certain cultured cells, due to 
intracellular delivery and action of LF, recently proven to be a zinc-
dependent metalloprotease that is known to cleave at least two targets, 
mitogen-activated protein kinase kinase 1 and 2. The combination of 
PA+EF, named edema toxin, disables phagocyte and probably other cells, 
due to the intracellular adenylate cyclase activity of EF.

Technology

    The technology disclosed in the 60/155,961 patent application 
relates to anthrax toxin protective antigen (PA) mutants in which the 
furin site is replaced by sequences specifically cleaved by matrix 
metalloproteinases (MMPs) or plasminogen activators. These MMP or 
plasminogen activator targeted PA mutants are only activated by 
plasminogen activator or MMP-expressing tumor cells so as to 
specifically deliver a toxin or a therapeutic agent. This is important 
because a wide variety of tumor cell lines and tissues overexpress MMPs 
or plasminogen activators, and this overexpression is highly correlated 
to tumor invasion and metastasis. Activation of these mutants occurs 
mainly on the cell surface and the targeted agent is then translocated 
to the interior of the cell. Current treatment models include the use 
of MMP inhibitors. The disclosed technology provides a viable 
alternative to this model and has the advantage of being highly 
targetable and specific to tumor cells expressing MMPs or plasminogen 
activators.
    The above mentioned Invention is available, including any available 
foreign intellectual property rights, for licensing.

    Dated: January 12, 2000.
Jack Spiegel,
Division of Technology Development & Transfer, Office of Technology 
Transfer.
[FR Doc. 00-1423 Filed 1-20-00; 8:45 am]
BILLING CODE 4140-01-M