Government-Owned Inventions; Availability for Licensing

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: 301/496-7057; fax: 301/402-0220. A signed Confidential Disclosure Agreement will be required to receive copies of the patent applications.

New Inhibitors of Polo-like Kinase 1 (PLK1) as Anti-Cancer Agents

Description of Technology: Tumor formation is the result of uncontrolled cellular growth and invasion. Polo-like kinase 1 (PLK1) is a regulator of cell growth whose overexpression has been associated with several types of cancer (e.g., breast cancer, prostate cancer, ovarian cancer, non-small cell lung carcinoma). It has been shown that inhibition of PLK1 causes cell death (apoptosis) in tumor cells but not normal cells. This suggested that inhibiting PLK1 could be an effective treatment for cancer patients without causing unwanted side-effects.

PLK1 contains a unique protein domain known as the polo box domain (PBD), which is essential for its function. One strategy for inhibiting PLK1 involves preventing the PBD domain from interacting with PLK1 substrates. A synthetic peptide with the ability to selectively bind to the PBD was recently identified. Using this peptide as a platform, NIH inventors have designed peptide mimetics that interact with the PBD with greater affinity than the wild-type peptide. By inhibiting PLK1 and selectively inducing apoptosis in cancer cells, these mimetics could serve as potential anti-cancer therapies.

Applications:

* New anti-cancer therapies that specifically target PLK1

* Platform for the development of further improved PLK1 inhibitors

Advantages:

* The peptide mimetics have an increased affinity for the polo box domain of PLK1 compared to the wild-type peptide, making them superior as inhibitors of PLK1.

* The peptide mimetics provide greater metabolic stability and potential effectiveness over synthetic peptides prepared using coded amino acids.

* Inhibiting PLK1 provides an opportunity for successful treatment of cancer with fewer side effects because only tumor cells are killed.

Development Status: Preclinical stage of development

Inventors: Terrence R. Burke Jr. et al. (NCI)

Patent Status: US Provisional Application No. 61/178,593 (HHS Reference No. E-181-2009/0-US-01)

For more information, see:

1. F Liu et al. SAR by oxime-containing peptide libraries: application to Tsg101 ligand optimization. Chembiochem. 2008 Aug 11;9(12):2000-2004.

2. F Liu et al. Protected aminooxyprolines for expedited library synthesis: Application to Tsg101-directed proline-oxime containing peptides. Bioorg Med Chem Lett. 2008 Feb 1;18(3):1096-1101.

3. PCT Application WO 2004/046317, "Crystal structure of human Polo-like kinase Plk1, Polo Box domain-binding phosphopeptide core sequences, and their therapeutic uses for cancer."

Licensing Status: Available for licensing.

Licensing Contact: David A. Lambertson, PhD; 301-435-4632; lambertsond@mail.nih.gov.

Increasing the Effectiveness of Cancer Treatment: T Cell Receptors Designed To Release Interleukin-12 Specifically at Cancer Sites

Description of Technology: Many conventional chemotherapy drugs currently utilized to treat cancer also yield harsh side effects in patients. In addition, many patients do not respond to generalized chemotherapy and radiation treatments for cancer. There is an urgent need to develop new therapeutic strategies combining fewer side-effects and more specific anti-tumor activity in individual patients. Adoptive immunotherapy is a promising new approach to cancer treatment that engineers an individual's innate and adaptive immune system to fight against specific diseases, including cancer.

T cell receptors (TCRs) are proteins that recognize antigens in the context of infected or transformed cells and activate T cells to mediate an immune response and destroy abnormal cells. TCRs consist of two domains, one variable domain that recognizes the antigen and one constant region that helps the TCR anchor to the membrane and transmit recognition signals by interacting with other proteins. When a TCR is stimulated by an antigen, such as a tumor antigen, some signaling pathways activated in the cell lead to the production of cytokines, which mediate the immune response.

Scientists at the National Institutes of Health (NIH) have developed T cells genetically engineered to express the human interleukin 12 (IL-12) cytokine only in the tumor environment. Specifically, these T cells have been designed to express a human IL-12 gene under the control of the nuclear factor of activated T cells (NFAT) promoter. When the TCR on these T cells recognizes a tumor antigen, IL-12 expression is induced through activation of the NFAT promoter. Thus, IL-12 is only released at the cancer site and only after the activation of the T cell. This technology makes it possible to control the expression of IL-12 to enhance T cell cytolytic activity while also reducing or eliminating the IL-12 toxicity observed with other IL-12 related therapies. Infusing these IL-12 expressing T cells into patients via adoptive immunotherapy could prove to be powerful new tools for attacking tumors.

Applications:

* Immunotherapeutics to treat and/or prevent the recurrence of a variety of human cancers by adoptively transferring the gene-modified T cells into patients.

* A drug component of a combination immunotherapy regimen aimed at targeting the specific tumor-associated antigens expressed by cancer cells within individual patients.

Advantages: The combination of enhanced T cell activity with reduced IL-12 toxicity: IL-12 has shown remarkable properties as an anti-tumor agent, but its clinical development has been hindered by its toxicity. This current technology delivers IL-12 only when and where it is needed--at the tumor site.

Development Status: Clinical trials utilizing this technology are currently in the planning stage.

Market: Cancer continues to be a medical and financial burden on US public health. According to US estimates, cancer is the second leading cause of death with over 565,000 deaths reported in 2008 and almost 1.5 million new cases were reported (excluding some skin cancers) in 2008. In 2007, the NIH estimated that the overall cost of cancer was $219.2 billion dollars and $89 billion went to direct medical costs. Despite our increasing knowledge of oncology and cancer treatment methods, the fight against cancer will continue to benefit from the development of new therapeutics aimed at treating individual patients.

Inventors: Richard A. Morgan et al. (NCI)

Publications:

1. L Zhang et al. Improving adoptive T cell therapy using NFAT driven human single chain IL-12 expression vector. 2009 American Society of Gene Therapy, abstract submitted.

2. B Heemskerk et al. Adoptive cell therapy for patients with melanoma, using tumor-infiltrating lymphocytes genetically engineered to secrete interleukin-2. Hum Gene Ther. 2008 May;19(5):496-510.

3. RA Morgan et al. Cancer regression in patients after transfer of genetically engineered lymphocytes. Science 2006 Oct 6;314(5796):126-129.

Patent Status: U.S. Provisional Application No. 61/174,046 filed 30 Apr 2009 (HHS Reference No. E-170-2009/0-US-01)

Licensing Status: Available for licensing.

Licensing Contact: Samuel E. Bish, Ph.D.; 301-435-5282; bishse@mail. nih.gov.

Collaborative Research Opportunity: The National Cancer Institute, Surgery Branch, is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize adoptive immunotherapies or the development of cancer therapeutics based on the use of T cell receptors. Please contact John D. Hewes, PhD at 301-435-3121 or hewesj@mail.nih.gov for more information.

A Novel System for Producing Infectious Hepatitis C Virus (HCV) Virions and Development of a Novel Reporter System for Studying HCV Entry

Description of Technology: HCV has infected an estimated 3% of the world population in whom viral infection persists for more than two third of the cases, often resulting in life-threatening complications. The standard of care (pegylated interferon alpha-2 plus ribavirin) is efficient in only 50% of treated patients, costly and has numerous side effects. In addition, viral resistance to newly developed drugs--targeting viral protease or RNA polymerase--has been described, but no vaccine is yet available. The difficulty in developing HCV vaccines is largely due to the broad sequence-diversity displayed by HCV, the frequent occurrence of viral mutations within immunogenic epitopes in vivo, and the lack of proper standard/definition for viral neutralization.

One alternative strategy in HCV-vaccine or drug development comprises measuring viral entry, the first step in viral infection. Such measurements are limited by the available screening systems, in that, HCV pseudo-typed retroviral particles have a different envelope conformation and contain foreign components that are likely to interfere with the measured HCV entry. Moreover, HCV lab strain requires intensive replication for its in vitro production, resulting in numerous mutations that impede development of convenient screening tools.

--This is a summary of a Federal Register article originally published on the page number listed below--

Notice.

Citation: "74 FR 31446"

Federal Register Page Number: "31446"

"Notices"

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