02-15148. Prospective Grant of Exclusive License: Cytotoxic Treatment of Cancer Cells That Overexpress Matrix Metalloproteinases, Plasminogen Activators and/or Plasminogen Activator Receptors

AGENCY:

National Institutes of Health, Public Health Service, HHS.

ACTION:

Notice.

SUMMARY:

This notice, in accordance with 35 U.S.C. 209(c)(1) and 37 CFR Part 404.7(a)(1)(i), that the National Institutes of Health, Department of Health and Human Services is contemplating the grant of an exclusive patent license to practice the inventions embodied in U.S. Patent Application, 60/155,961 (refiled): “Mutated anthrax toxin protective antigen proteins that specifically target cells containing high amounts of cell-surface metalloproteinase or plasminogen activator receptors' (DHHS Ref. E-293-99/0); PCT Patent Application, PCT/US00/26192 [WO01/21656] (refiled): “Mutated anthrax toxin protective antigen proteins that specifically target cells containing high amounts of cell-surface metalloproteinase or plasminogen activator receptors' (DHHS Ref. E-293-99/1); U.S. Patent Application, S/N 10/088,952: “Mutated anthrax toxin protective antigen proteins that specifically target cells containing high amounts of cell-surface metalloproteinase or plasminogen activator receptors' (DHHS Ref. E-293-99/2); U.S. Patent 5,591,631, S/N 08/021,601, which issued on January 7, 1997 (DHHS Ref. E-064-93/0), entitled, “Anthrax toxin fusion proteins, nucleic acid encoding same”; U.S. Patent 5,677,274, S/N 08/082,849, which issued on October 14, 1997 (DHHS Ref. E-064-93/1), entitled, “Anthrax toxin fusion proteins and related methods”; and any related foreign filed national stage applications claiming priority to such cases to OncoTac Pharmaceuticals which is located in Medicon Valley, Denmark. The patent rights in these inventions have been assigned to the United States of America.

The prospective exclusive license territory will be worldwide and the field of use may be limited to human therapeutics for the treatment of cancer by a mechanism involving cancer-associated enzymes and/or receptors.

DATES:

Only written comments and/or license applications that are received by the National Institutes of Health on or before August 16, 2002, will be considered.

ADDRESSES:

Requests for copies of the patent, inquiries, comments and other materials relating to the contemplated exclusive license should be directed to: Richard U. Rodriguez, M.B.A., Technology Licensing Specialist, Office of Technology Transfer, National Institutes of Health, 6011 Executive Boulevard, Suite 325, Rockville, MD. 20852-3804. Telephone: [phone], X287; Facsimile: [phone]; and E-mail: [e-mail].

SUPPLEMENTARY INFORMATION:

The primary technology relates to an immunotoxin treatment system that is targeted to cancer cells via an anthrax-based pathway. Native anthrax toxin is a three-component toxin consisting of protective antigen (PrAg), lethal factor (LF), and edema factor (EF). PrAg binds to the recently identified cell surface anthrax receptor and the subsequent steps in toxin action is dependent on cleavage of PrAg at the sequence,¹⁶⁴ RKKR1⁶⁷, by a cell-surface, furin-like protease. The carboxyl-terminal 63-kDa fragment (PrAg63) remains bound to receptor, forms a heptamer, and binds and internalizes LF and EF. LF kills animals and lyses mouse macrophages due to proteolytic cleavage of MAP kinase kinases. EF damages cells due to its intracellular adenylate cyclase activity. A potent PrAg dependent cytotoxin, FP59, created by fusing LF amino acids 1-254 to the ADP-ribosylation domain of Pseudomonas exotoxin A can kill any cell having receptors for PrAg and the ability to activate PrAg by cleavage at amino acids 164-167.

Activation of the native PrAg is dependent on a cell surface located furin-like proteolytic activity. In the current technology, the furin-site has been manipulated to generate mutant PrAg proteins that are specific for matrix metalloproteinases (MMPs) or the urokinase plasminogen activator (uPA). A combination of the mutated toxins PrAg and FP59 has been shown to be an effective cytotoxic agent that is strictly dependent on cell surface localized MMP and/or uPA-activity.

The prospective exclusive license will be royalty bearing and will comply with the terms and conditions of 35 U.S.C. 209 and 37 CFR part 404.7. The prospective exclusive license may be granted unless within sixty (60) days from the date of this published notice, the NIH receives written evidence and argument that establish that the grant of the license would not be consistent with the requirements of 35 U.S.C. 209 and 37 CFR part 404.7.

Applications for a license in the field of use filed in response to this notice will be treated as objections to the grant of the contemplated exclusive license. Comments and objections submitted to this notice will not be made available for public inspection and, to the extent permitted by law, will not be released under the Freedom of Information Act, 5 U.S.C. 552.

Dated: June 7, 2002.

Jack Spiegel,

Director, Division of Technology Development and Transfer, Office of Technology Transfer.