[Federal Register: March 15, 1999 (Volume 64, Number 49)] [Notices] [Page 12815-12816] From the Federal Register Online via GPO Access [wais.access.gpo.gov] [DOCID:fr15mr99-50] ----------------------------------------------------------------------- DEPARTMENT OF HEALTH AND HUMAN SERVICES National Institutes of Health Government-Owned Inventions; Availability for Licensing AGENCY: National Institutes of Health, Public Health Service, DHHS. ACTION: Notice. ----------------------------------------------------------------------- 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 contacting 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). A signed Confidential Disclosure Agreement is required to receive a copy of any patent application. Title: ``Anthrax Lethal Factor is a MAPK Kinase Protease'' Inventors: Drs. Nicholas S. Duesbery (NCI-FCRDC), Craig Webb (NCI- FCRDC), Stephen H. Leppla (NIDCR), and Dr. George Vande Woude (NCI- FCRDC) DHHS Ref. No. E-066-98/0--Filed April 1, 1998 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 [[Page 12816]] 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) cell 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 signal 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: 1. A novel tool (LF) for the study of the cellular role of the MAPK pathway in normal or tumor cells. 2. 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. 3. 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 LT and MAPKK at the amino acid level may lead to the generation of inhibitors which may prove useful in treating anthrax. The above mentioned invention is available for licensing on an exclusive or non-exclusive basis. Dated: March 5, 1999. Jack Spiegel, Director, Division of Technology Development and Transfer, Office of Technology Transfer. [FR Doc. 99-6205 Filed 3-12-99; 8:45 am] BILLING CODE 4140-01-M