2011-25734. 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 the 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.

Platform Technology Using Ubiquitin To Improve the Delivery and Efficacy of Cytosolic Targeted Toxins

Description of Technology: Targeted toxins (TT) are hybrid protein drugs consisting of ligands that bind to the surface of cancer cells and deliver polypeptide toxins that kill malignant cells by inactivating cytosolic protein synthesis and inducing cell death. A major challenge in the construction of targeted toxins is reducing the nonspecific binding of the toxin moiety to normal tissues and increasing the cytotoxicity of the treatment.

To address these issues, the NIH inventors have identified that the protein ubiquitin, a small protein in eukaryotic cells that plays a role in protein recycling, can separate the targeting moiety and the catalytic moiety of a TT in the cytosol of cells. By decoupling the two moieties, the cytotoxicity of the TT treatment can be greatly increased since the catalytic domain remains longer in the cytosol. This technology would be highly useful for all TT and immunotoxins that access the cytosol to either affect cytosolic targets or traffic to further sites of action. To validate this approach, the inventors have tested ubiquitin variants within a TT consisting of anthrax toxin lethal factor N-terminus (LFn) and Pseudomonas exotoxin A catalytic domain (PEIII). Here, they show that the intracellular release of the PEIII (catalytic moiety) is achievable and that ubiquitination of the TT controls the persistence of the TTs in the cytosol and thus controls the observed cytotoxicity.

Potential Commercial Applications:

• Chimeric or fusion molecules for increasing the efficacy and cytotoxicity of targeted toxins and immunotoxins.
• Methods for cytosol delivery of targeted toxins to target cells.

Competitive Advantages:

• Broadly applicable to all cytotoxic immunoconjugates.
• Increased stability and cytotoxicity of the TT without affecting the delivery or specificity of the treatment.
• Therapeutic access to the cytosol and/or trafficking to further sites of action such as the nucleus.
• Rapid cytosolic release of the catalytic moiety and degradation of the targeting moiety.

Development Stage:

• Pre-clinical
• In vitro data available

Inventors: Christopher Bachran (NIAID), Stephen Leppla (NIAID), Shi-hui Liu (NIAID), Thomas Morley

Publications:

1. Tcherniuk S, et al. Construction of tumor-specific toxins using ubiquitin fusion technique. Mol Ther. 2005 Feb;11(2):196-204. [PMID 15668131]

2. Wang F. Selective cytotoxicity to HER2-positive tumor cells by a recombinant e23sFv-TD-tBID protein containing a furin cleavage sequence. Clin Cancer Res. 2010 Apr 15;16(8):2284-2294. [PMID 20371697]

3. Heisler I. A cleavable adapter to reduce nonspecific cytotoxicity of recombinant immunotoxins. Int J Cancer. 2003 Jan 10;103(2):277-282. [PMID 12455044]

Intellectual Property: HHS Reference No. E-150-2011/0—U.S. Provisional Application No. 61/473,450 filed 08 April 2011

Related Technologies:

• HHS Reference No. E-293-1999—Mutated Anthrax Toxin Protective Antigen Proteins That Specifically Target Cells Containing High Amounts of Cell-Surface Metalloproteinases or Plasminogen Activator Receptors (Leppla/NIAID)
• HHS Reference No. E-070-2007—Human Cancer Therapy Using Engineered Metalloproteinase-Activated Anthrax Lethal Toxin That Target Tumor Vasculature (Leppla/NIAID)
• HHS Reference No. E-059-2004—Multimeric Protein Toxins to Target Cells Having Multiple Identifying Characteristics (Leppla/NIAID)

Licensing Contact: Whitney Hastings; 301-451-7337; [e-mail]

NOX5 Immunogenic Peptides and Monoclonal Antibodies for the Detection of Cancer and Inflammatory Responses

Description of Technology: The membrane-associated NADPH oxidase 5 (NOX5) protein is expressed in various fetal tissues, uterus, testis, spleen, lymph nodes and endothelial cells. In addition, the reactive oxygen species (ROS) generated by NOX5 have been shown to participate in signaling cascades regulating proliferation in several cancers and pre-cancerous conditions, such as hairy cell leukemia, melanoma, prostate cancer, and Barret's esophagus. Further, excess ROS produced by NOX5 has been associated with coronary artery disease, inflammation, and atherosclerosis.

The present invention discloses the identification and characterization of a purified monoclonal antibody against NOX5 protein. This NOX5 antibody can detect endogenous levels of NOX5 in human cells and could aid in studies and diagnostic tests of NOX5-based redox signaling involved in cancer, cell growth and differentiation, as well as angiogenic and inflammatory responses. In addition, the NOX5 antibody may have therapeutic applications (e.g. anti-inflammatory, antiangiogenic, or antiproliferative activity) by interfering with NOX5 activation at the cell surface.

Potential Commercial Applications:

• Diagnostic for the detection of NOX5 in human cells and NOX5-based redox signaling
• Antibody can be used in ELISA, Western Blot, Immunofluorescence, Immunoprecipitation and Immunohistochemistry
• Tool to aid in the understanding of NOX5's functional significance in human physiology and pathophysiology
• Possible therapeutic for the treatment of various human diseases associated with NOX5 and/or ROS

Competitive Advantages:

• Antibody is the only mouse monoclonal commercially available to the best of our knowledge
• Antibody is highly specific in recognizing the NOX5 protein with greater efficiency and the accurate detection compared to other Nox5 antibodies

Development Stage: Pre-clinical

Inventors: James H. Doroshow, Krishnendu K. Roy, Smitha Antony (NCI)

Publications:

1. Kamiguti AS, et al. Expression and activity of NOX5 in the circulating malignant B cells of hairy cell leukemia. J Immunol. 2005 Dec 15;175(12):8424-8430. [PMID: 16339585]

2. Brar SS, et al. NOX5 NAD(P)H oxidase regulates growth and apoptosis in DU 145 prostate cancer cells. Am J Physiol Cell Physiol. 2003 Aug;285(2):C353-C369. [PMID: 12686516]

3. Hong J, et al. Bile acid reflux contributes to development of esophageal adenocarcinoma via activation of phosphatidylinositol-specific phospholipase Cgamma2 and NADPH oxidase NOX5-S. Cancer Res. 2010 Feb 1;70(3):1247-1255. [PMID: 20086178]

Intellectual Property: HHS Reference No. E-149-2011/0—U.S. Provisional Application No. 61/471,596 filed 04 April 2011

Licensing Contact: Whitney Hastings; 301-451-7337; [e-mail]

mGluR5 Tumor Mouse Model

Description of Technology: Glutamate receptor mGluR5 has been reported to function in the brain. There were no prior reports of it being involved in melanoma. The NIH investigators have discovered that when over expressed in transgenic animals, mGluR5 induces melanoma. The establishment of an mGluR5 tumor mouse model will provide a unique opportunity to help elucidate the mechanisms underlying tumor formation, and allow the study of aggressive melanoma in animals and a screen of potential therapeutics. Such an mGluR5 tumor mouse model is established at the National Institutes of Health and is available for licensing.

Potential Commercial Applications:

• Drug screening for melanoma therapeutics
• Research Tool

Competitive Advantage: Tumor mouse model only available from the NIH lab.

Development Stage:

• Prototype
• Pre-clinical
• In vivo data available (animal)

Inventors: Katherine W. Roche and Kyu Yeong Choi (NINDS)

Publication: Choi KY, et al. Expression of the metabotropic glutamate receptor 5 (mGluR5) induces melanoma in transgenic mice. Proc Natl Acad Sci USA 2011; published ahead of print September 6, 2011, doi:10.1073/pnas.1107304108.

Intellectual Property: HHS Reference No. E-123-2010/0—Research Tool. Patent protection is not being pursued for this technology.

Licensing Contact: Betty Tong, Ph.D.; 301-594-6565; [e-mail]

Monoclonal Antibodies to FCRL5 (CD307e/IRTA2/FcRH5) as Therapeutics and Diagnostics for B-cell Cancers

Description of Technology: The Fc receptor-like (FCRL) genes (also known as CD307, IRTA, FcRH, IFGP or SPAP) encode cell membrane proteins that are believed to play roles in immunity and B cell differentiation. Some FCRL genes have been implicated in B cell lymphomas and multiple myelomas. Data suggest that the FCRL1-5 proteins are expressed differently on malignant B cells as well as subpopulations of normal B cells. Due to this differential expression, FCRL proteins represent potential targets for the treatment of cancers of a B cell origin.

This technology relates to the development of novel monoclonal antibodies for a specific member of the FCRL protein family: FCRL5. FCRL5 is normally induced on mature B cells upon activation, but its expression is deregulated in multiple myeloma and Burkitt's lymphoma. Due to the correlation of FCRL5 overexpression and B cell malignancies, antibodies to FCRL5 may have value as a therapeutic or diagnostic tool. Specifically, the antibodies can be used as therapeutic agents by themselves or they can be attached to a cytotoxic agent such as Pseudomonas exotoxin A. Alternatively, the antibodies can be used to detect the deregulation of FCRL5 as a means of diagnosing B cell malignancies.

Potential Commercial Applications:

• Detection or diagnosis of B cell cancers using monoclonal antibodies to FCRL5
• Treatment of B cell cancers using monoclonal antibodies to FCRL5 for inducing antibody-dependent cell death
• Treatment of B cell cancers using monoclonal antibodies to FCRL5 for targeting cytotoxic agents specifically to cancer cells (e.g., immunotoxins)

Competitive Advantages:

• No cross-reactivity with other FCRL proteins demonstrates strong selectivity as both a therapeutic and diagnostic agent
• Targeted therapeutics such as monoclonal antibodies and immunotoxins decrease non-specific killing of healthy, essential cells, resulting in fewer side-effects and healthier patients

Development Stage: Pre-clinical

Inventors: Ira H. Pastan et al. (NCI)

Publications:

1. Ise T, et al. Elevation of soluble CD307 (IRTA2/FcRH5) protein in the blood and expression on malignant cells of patients with multiple myeloma, chronic lymphocytic leukemia, and mantle cell lymphoma. Leukemia. 2007 Jan; 21(1):169-174. [PMID 17051241]

2. Ise T, et al. Immunoglobulin superfamily receptor translocation associated 2 protein on lymphoma cell lines and hairy cell leukemia cells detected by novel monoclonal antibodies. Clin Cancer Res. 2005 Jan 1;11(1):87-96. [PMID 15671532]

Intellectual Property: HHS Reference No. E-287-2004/1—U.S. Patent 7,999,077 issued 16 Aug 2011

Licensing Contact: David A. Lambertson, Ph.D.; 301-435-4632; [e-mail]

Potent Inhibitory RNAs for Non-Surgical Treatment of Salivary Gland Cancers

Description of Technology: In the U.S., approximately 40,000 cases of head and neck cancer, including salivary gland tumors, are diagnosed each year. Surgery with post-operative radiotherapy is the most common treatment for salivary gland tumors. However, complete removal is difficult due to the three-dimensional growth pattern of these tumors which impedes a surgeon's ability to determine once the tumor has been fully removed. Both surgeons and patients desire minimal surgical approaches for cosmetic reasons, as well as to preserve nerve function in the facial area. Thus a significant need exists for non-surgical approaches to treating salivary gland tumors.

Researchers at the National Cancer Institute, NIH, have discovered that mucoepidermoid (MEC) salivary gland tumors arise from a chromosomal rearrangement which generates a fusion oncogene, Mect1-Maml2, that functions to alter Notch and CREB signaling pathways. An RNAi vector has been developed that selectively suppresses the oncogene and inhibits growth of certain MEC tumor cell lines containing the oncogene by at least 90%. The RNAi vector has no effect on cells that do not express the oncogene. This ability of the RNAi vectors to block the “gain-of-function” activity of the acquired Mect1-Maml2 oncogene suggests new possibilities for the diagnosis and therapy of these cancers.

Potential Commercial Applications:

• Diagnosis of MEC salivary gland tumors
• Treatment of MEC salivary gland tumors

Competitive Advantages:

• Non-surgical
• Selective
• Potent
• Can be used in combination with other known treatments, such as radiation and chemotherapy

Development Stage:

• Pre-clinical
• In vitro data available

Inventors: Frederic Kaye (formerly NCI), Takefumi Komiya (NCI)

Publications:

1. Tonon G, et al. t(11;19)(q21;p13) translocation in mucoepidermoid carcinoma creates a novel fusion product that disrupts a Notch signaling pathway. Nat Genet. 2003 Feb;33(2):208-213. [PMID 12539049]

2. Martins C, et al. A study of MECT1-MAML2 in mucoepidermoid carcinoma and Warthin's tumor of salivary glands. J Mol Diagn. 2004 Aug;6(3):205-210. [PMID 15269296]

3. Coxon A, et al. Mect1-Maml2 fusion oncogene linked to the aberrant activation of cyclic AMP/CREB regulated genes. Cancer Res. 2005 Aug 15;65(16):7137-7144. [PMID 16103063]

4. Komiya T, et al. Sustained expression of Mect1-Maml2 is essential for tumor cell growth in salivary gland cancers carrying the t(11;19) translocation. Oncogene. 2006 Oct 5;25(45):6128-6132. [PMID 16652146]

5. Kaye FJ. Emerging biology of malignant salivary gland tumors offers new insights into the classification and treatment of mucoepidermoid cancer. Clin Cancer Res. 2006 Jul 1;12(13):3878-3881. [PMID 16818681]

6. Tirado Y, et al. CRTC1/MAML2 fusion transcript in high grade mucoepidermoid carcinomas of salivary and thyroid glands and Warthin's tumors: implications for histogenesis and biologic behavior. Genes Chromosomes Cancer. 2007 Jul;46(7):708-715. [PMID 17437281]

7. Komiya T, et al. Enhanced activity of the CREB co-activator Crtc1 in LKB1 null lung cancer. Oncogene. 2010 Mar 18;29(11):1672-1680. [PMID 20010869]

Intellectual Property: HHS, Reference No. E-086-2003/0 —

• U.S. Patent No. 7,553,822 issued 30 June 2009
• U.S. Patent Application No. 12/493,901 filed 29 June 2009

Licensing Contact: Patrick McCue, Ph.D.; 301-435-5560; [e-mail]

Dated: September 29, 2011.

Richard U. Rodriguez,

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