Air Force Inventions Available for Licensing

Pursuant to the provisions of Part 404 of Title 37, Code of Federal Regulations, which implements Pub. L. 96-517, the Department of the Air Force announces the availability of certain Air Force-owned inventions. The following patent applications:

are available for Nonexclusive or Exclusive Licensing from the Air Force Research Laboratory (AFRL/IF) at Rome, New York. Additional information concerning the inventions is available upon request.

All communications concerning this Notice should be sent to Dr. Harold L. Burstyn, Patent Attorney, 26 Electronic Parkway, Rome, NY 13441-4514, (315) 330-2087, e-mail: Harold.Burstyn@rl.af.mil, or fax to (315) 330-7583.

NIH Inventions Available for Licensing

The four inventions described below are assigned to the National Institutes of Health, have been filed in the United States Patent and Trademark Office, and are available for licensing in the United States.

Number 1: "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''

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: jd212g@NIH.GOV). 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: 60/155,961 [=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 <INF>167</INF> 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.

Number 2: "Compositions and Methods for Specifically Targeting Tumors--Using a Blocker Reagent''

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; E-Mail: jd212g@NIH.GOV). A signed Confidential Disclosure Agreement is required to receive a copy of any patent application.

SUPPLEMENTARY INFORMATION: Invention Title: "Compositions and Methods for Specifically Targeting Tumors''
Inventors: Drs. Waldemar Debinski (EM) and Raj K. Puri  (U.S.F.D.A.). USPA SN: 08/706,207 [=DHHS Ref. No. E-042-00/0]--Filed with the U.S.P.T.O. on August 30, 1996.

Abstract
In a chimeric molecule, two or more molecules that exist separately in their native state are joined together to form a single entity (i.e., molecule) having the desired functionality of all of its constituent molecules. Frequently, one of the constituent molecules of a chimeric molecule is a "targeting molecule''. The targeting molecule is a molecule such as a ligand or an antibody that specifically binds to its corresponding target, for example a receptor on a cell surface. Thus, for example, where the targeting molecule is an antibody, the chimeric molecule will specifically bind (target) cells and tissues bearing the epitope to which the antibody is directed. Another constituent of the chimeric molecule may be an "effector molecule''. The effector molecule refers to a molecule that is to be specifically transported to the target to which the chimeric molecule is specifically directed. The effector molecule typically has a characteristic activity that is desired to be delivered to the target cell. Effector molecules include cytotoxins, labels, radionuclides, other ligands, drugs, prodrugs, liposome, etc. In particular, where the effector component is a cytotoxin, the chimeric molecule may act as a potent cell-killing agent specifically targeting the cytotoxin to cells bearing a particular target molecule. For example, chimeric fusion protein which include interleukin-4 ("IL-4'') or transforming growth factor (RGF<greek-a>'') fused to Pseudomonas exotoxin ("PE'') or interleukin-2 ("IL-2'') fused to Diphtheria toxin ("DT'') have been shown to specifically target and kill cancer cells. Generally, it is desirable to increase specificity and affinity and decrease cross-reactivity of chimeric cytotoxins with targets to be spared in order to increase their efficacy. To the extent a chimeric modecule preferentially selects and binds to its target (e.g., a tumor cell) and not to a non-target (e.g., a healthy cell), side effects of the chimeric molecule will be minimized. Unfortunately, many targets to which chimeric cytotoxins have been directed (e.g., the IL-2 receptor), while showing elevated expression on tumor cells, are also expressed to some extent, and often at significant levels, on healthy cells. Thus, chimeric cytotoxins directed to these targets frequently show adverse side-effects as they bind non-target (e.g., healthy) cells that also express the targeted receptor.

Technology
The technology disclosed in the 08/706,207 patent application is directed to a method and compositions to deliver an effector molecule to tumor cell. Specifically the technology relates to a chimeric molecule that specifically binds to IL-13 receptors which when combined with a blocker reagent (e.g., interleukin-4, an interleukin-4 antagonist, an interleukin-4 receptor binding antibody etc.) specifically delivers receptor directed cytotoxins to tumors over expressing IL-13 receptors without causing undesired cytotoxicity to normal cells. This is because a variety of human cancer cells including brain tumors, kidney tumors, and AIDS-associated Kaposi's tumors etc. over express private IL-13 receptors and normal cells express low levels of shared IL-13 receptors with IL-4 receptors. IL-13 cytotoxin remains very cytotoxic to cancel cells in the presence of IL-4 receptor blocker agents while cytotoxicity and undesired side effects of cytotoxin administration are prevented in normal cells. This approach provides unique specificity of delivering IL-13 receptor directed cytotoxic agents to cancer cells.

Number 3: Artificial Salivary Gland

Licensing information and a copy of the U.S. patent application referenced below may be obtained by contacting J.E. Fahner-Vihtelic at the Office of Technology Transfer, National Institutes of Health, 6011 Executive Boulevard, Suite 325, Rockville, Maryland 20852-3804; Telephone: 301/496-7735 ext. 270; Fax: 301/402-0220; E-mail; jf36z@nih.gov. A signed Confidential Disclosure Agreement is required to receive a copy of any patent application.

Bruce J. Baum et al. (NIDCR)
Serial No. 60/121,335
Filed 24 Feb 1999

Abstract
The present application describes an artificial fluid secreting prosthetic device for non-invasive insertion and methods of using this device. Specifically, compositions and methods based on the discovery of an artificial fluid secreting prosthesis are disclosed in this application. Currently, there is no conventional effective treatment for salivary gland hypofunction. And although the transplantation of mammalian salivary glands has also been tried, this option has not proven desirable due to lack of sufficient donor supplies. To date, the inventors have performed experiments that have demonstrated: (1) Subjects having irradiated salivary gland cells can be induced to secrete fluid subsequent to transfer of a gene; (2) heterologous genes can be transferred to salivary gland cells; and (3) an artificial gland has been designed having a support, an attachment surface joined to the support, and a monolayer of allogenic cells, engineered to secrete ions and water unidirectionally, joined to the attachment surface.

Number 4: Variants of Humanized Anti-Carcinoma Monoclonal Antibody CC49

Syed V. Kashmiri (NCI), Eduardo A. Padlan (NIDDK), Jeffrey Schlom (NCI) U.S. Provisional Patent Applications 60/106,534 filed 31 Oct 1998 and 60/106,757 filed 02 Nov 1998

ADDRESSES: Licensing information and a copy of the U.S. patent application referenced below may be obtained by contacting Elaine Gese at the Office of Technology Transfer, National Institutes of Health, 6011 Executive Boulevard, Suite 325, Rockville, Maryland 20852-3804; Telephone: 301/496-7056 ext. 282; Fax: 301/402-0220; E-mail: eg46t@nih.gov. A signed Confidential Disclosure Agreement is required to receive a copy of any patent application.

Abstract
The invention embodied in these two patent applications describes the humanization of a murine anti-carcinoma antibody which has been shown to react with Tumor Associated Glycoprotein 72 (TAG-72), an antigen which is expressed on human breast, colorectal, and other carcinomas. The humanization process, which renders the antibody minimally immunogenic to humans, has been accomplished by a method different from the current procedure for the humanization of a rodent antibody which is based on grafting all the Complementarity Determining Residues (CDRs) of a rodent antibody onto a human antibody framework.

This new humanization protocol involves identifying the Specificity Determining Residues (SDRs), the amino acid residues in the hypervariable regions of an antibody that are most critical for antigen binding activity. The CDRs, which are found not to contain SDRs and hence are dispensable for antigen binding activity, are not grafted onto the human antibody frameworks. Rather, only the SDRs of the essential CDRs are transferred to the human antibody molecule. The resulting molecule is believed to elicit an immune response in humans which is significantly less than that elicited through administration of other humanized antibodies.

Embodied in the current invention are methods of identifying the SDRs, and of rendering any antibody minimally immunogenic in humans by transferring the SDRs of the antibody to a human antibody framework.

The resulting humanized antibodies, including CDR variants therof (including a CH2 deleted version), are also embodied in the invention, as are methods of using the antibodies for therapeutic and diagnostic purposes.

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