E9-7223. Government-Owned Inventions; Availability for Licensing

AGENCY:

National Institutes of Health, Public Health Service, HHS.

ACTION:

Notice.

SUMMARY:

The inventions listed below are owned by an agency of the U.S. Government and are 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. Foreign patent applications are filed on selected inventions to extend market coverage for companies and may also be available for licensing.

ADDRESSES:

Licensing information and copies of any U.S. patent applications listed below may be obtained by writing to the indicated licensing contact at the Office of Technology Transfer, National Institutes of Health, 6011 Executive Boulevard, Suite 325, Rockville, Maryland 20852-3804; telephone: [phone]; fax: [phone]. A signed Confidential Disclosure Agreement will be required to receive copies of the patent applications.

Mouse Monoclonal Antibodies to Human Tristetraprolin (TTP)

Description of Technology: TTP has been implicated in autoimmune and inflammatory diseases through its role as a regulator of the transcripts encoding several pro-inflammatory cytokines, including tumor necrosis factor alpha. However, it has been difficult to study endogenous TTP in man and other animals because it is expressed at very low levels in most cells and tissues, and because of the lack of mouse monoclonal antibodies directed at the human protein.

Scientists at the NIH have developed three mouse monoclonal antibodies (TTP-16, TTP-214 and TTP-409) that react to different regions of the human TTP to allow for the identification and localization of the TTP protein by standard protocols. Although validation has only been conducted at the level of western blotting to date, they do not appear to cross-react with other human members of the TTP protein family.

Potential Applications: Mouse monoclonal antibodies to human TTP will be useful in both clinical and basic research on a variety of inflammatory diseases and studies of mRNA destabilization. They can be used to identify or isolate TTP in cells or tissues by Western blotting, immunoprecipitation, immunohistochemistry, immunofluorescence, flow cytometry, and RNA super-shift assays, and can also be used in cross-linking and immunoprecipitation protocols.

Inventors: Elizabeth A. Kennington and Perry J. Blackshear (NIEHS).

Patent Status: HHS Reference No. E-123-2009/0—Research Tool. Patent protection is not being pursued for this technology.

Licensing Status: Available for licensing.

Licensing Contact: Fatima Sayyid, M.H.P.M.; 301-435-4521; [e-mail].

Use of Anthrax Lethal Factor To Treat Cancer and Screening Methods for MAPK Kinase Protease Activity

Description of Technology: Anthrax toxin, produced by Bacillus anthracis, is composed of three proteins; protective antigen (PA), edema factor (EF), and lethal factor (LF). PA by itself has little or no toxic effect upon cells, but serves to bind cell surface receptors and mediate the entry of EF and LF into the cell. EF has been identified as an adenylate cyclase and together with PA forms a toxin (edema toxin; EdTx) which can induce edema formation when injected subcutaneously. LF and PA together form a toxin (lethal toxin; LeTx) which can cause rapid lysis of certain macrophage-derived cell lines in vitro as well as death when injected intravenously.

Indirect evidence had suggested that LF was a metalloprotease. However, the intracellular target of LF remained unknown until recently when NIH scientists discovered that LF proteolytically inactivates mitogen activated protein kinase kinase 1 and 2 (MAPKK1, 2). Using oocytes of the frog Xenopus laevis as well as tumor derived NIH3T3 (490) cells expressing an effector domain mutant form of the human V12HaRas oncogene these scientists demonstrated that LF induced proteolysis of MAPKK 1 and 2, resulting in their irreversible inactivation. MAPKK 1 and 2 are components of the mitogen activated protein kinase (MAPK) signal transduction pathway, an evolutionarily conserved pathway that controls cell proliferation and differentiation in response to extracellular signals and also plays a crucial role in regulating oocyte meiotic maturation. Further, the MAPK pathway has been shown to be constitutively activated in many primary human as well as in tumor-derived cell lines. Consistent with this, treatment of V12Ha-Ras transformed NIH 3T3 cells with LeTx inhibits cell proliferation and causes their reversion to a non-transformed phenotype.

This invention specifically relates to in vitro and ex vivo methods of screening for modulators, homologues, and mimetics of LF mitogen activated protein kinase kinase (MAPKK) protease activity. Applications for this technology could be:

• A novel tool (LF) for the study of the cellular role of the MAPK pathway in normal or tumor cells.
• Investigation of LF for developing inhibitors for cancer therapy. By analyzing structural-functional relationships, additional compounds with improved specificity, increased potency, and reduced toxicity can be generated. Mimetics which block MAPKK activity or the determination of mechanisms of regulation of proteases that target MAPKK at or near the same site targeted by LF could be developed.
• A protease-based assay for LF by using a peptide to test for LF cleavage. There is no commercial test for anthrax. This assay could be used for testing soldiers for anthrax exposure. Characterization of the interaction between LF and MAPKK at the amino acid level may lead to the generation of inhibitors which may prove useful in treating anthrax.

Inventors: Nicholas S. Duesbery (NCI), Craig Webb (NCI), Stephen H. Leppla (NIDCR), George F. Vande Woude (NCI).

Patent Status:

U.S. Patent 6,485,925 issued 26 Nov. 2002 (HHS Reference No. E-066-1998/0-US-06).

U.S. Patent 6,893,835 issued 17 May 2005 (HHS Reference No. E-066-1998/0-US-07).

U.S. Patent 6,911,203 issued 28 June 2005 (HHS Reference No. E-066-1998/0-US-08).

U.S. Patent 7,056,693 issued 06 June 2006 (HHS Reference No. E-066-1998/0-US-10).

U.S. Patent 7,183,071 issued 27 Feb. 2007 (HHS Reference No. E-066-1998/0-US-11).

International rights available.

Licensing Status: Available for licensing.

Licensing Contact: Surekha Vathyam, PhD; 301-435-4076; [e-mail].

This abstract updates the version published in the Federal Register on Friday, March 13, 2009 (74 FR 10947-10948), to correct the reference numbers from E-068-1998 to E-066-1998.

Dated: March 25, 2009.

Richard U. Rodriguez,

Director, Division of Technology Development and Transfer, Office of Technology Transfer, National Institutes of Health.