E6-1653. 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.

Oligodeoxyribonucleotides Comprising O⁶ 6-Benzylguanine and Their Use

Robert C. Moschel et al. (NCI)

U.S. Patent No. 6,060,458 issued 09 May 2000 (HHS Reference No. E-104-1998/0-US-01).

Licensing Contact: George G. Pipia, PhD.; 301/435-5560; [e-mail].

Chemotherapy is a common treatment for a variety of cancers. Chemotherapeutic alkylating agents represent a key category of commonly used antineoplastic drugs. These drugs are active against chronic leukemias, non-Hodgkin lymphoma, Hodgkin disease, multiple myeloma, lung, breast, ovarian cancer, and certain other cancers. The DNA repair protein, O⁶-alkylguanine-DNA alkyltransferase (AGT), is a primary source of tumor cell resistance to the alkylating drugs that alkylate the O⁶ position of guanine in DNA. AGT therefore becomes the prime target for modulation. Currently, AGT inactivators are used as adjuvants to enhance chemotherapy by the alkylating drugs.

O⁶-Benzylguanine is the prototype AGT inactivator in phase I, II and III clinical trials as an adjuvant to improve chemotherapy. Although O⁶-benzylguanine is a promising AGT inactivator, it is not an ideal drug. O⁶-Benzylguanine is only sparingly soluble in water, and it is not effective in inactivating some mutant alkyltransferase proteins that could possibly be produced after repeated chemotherapy cycles. The present invention describes oligodeoxyribonucleotides containing O⁶-benzylguanine residues as another class of AGT inactivators, and discusses the advantages of their use in comparison to O⁶-benzylguanine as the free base. Oligodeoxyribonucleotides containing O⁶-benzylguanine residues are extremely water soluble and can efficiently inactivate AGT at much lower concentrations than O⁶-benzylguanine. In addition, they are effective in inactivating several mutant alkyltransferase proteins that are highly resistant to inactivation by O⁶-benzylguanine. Furthermore, positioning O⁶-benzylguanine near the 3′-or 5′-terminus of these oligodeoxyribonucleotides improves their resistance to degradation by cellular nuclease proteins. Therefore, oligodeoxyribonucleotides containing multiple O⁶-benzylguanine residues may be more effective chemotherapy adjuvants than O⁶-benzylguanine.

The CCHC Zinc Fingers of the Retroviral Nucleocapsid Protein Comprises a New Target Useful in Identification and Evaluation of Anti-HIV Therapeutics

Louis E. Henderson et al. (NCI)

U.S. Patent No. 6,001,555 issued 14 Dec 1999 (HHS Reference No. E-174-1993/1-US-01).

Licensing Contact: Sally H. Hu, PhD., M.B.A.; 301/435-5606; [e-mail].

According to a recently released report from the WHO, an estimated 40.3 million people worldwide are currently living with HIV infection, and more than three million people died of AIDS-related illnesses in 2005. In response to increased prevalence of HIV/AIDS, the search for effective antiretroviral therapy is intensive. The present invention describes compounds that may be useful for developing new types of antiretroviral therapeutics for HIV infection.

HIV-1 contains domains known as “CCHC zinc fingers” in the retroviral nucleocapsid (NC) protein. Nucleocapsid CCHC zinc fingers are highly conserved throughout nearly all retroviruses. They are sequences of 14 amino acids with four invariant residues, Cys(X)₂ Cys(X)₄ His(X)₄ Cys, which chelate zinc and perform essential functions in viral infectivity. HIV-1 NC has two CCHC zinc fingers, both of which are necessary for infectivity. Many compounds that disrupt the CCHC zinc fingers also inactivate HIV-1 by preventing the initiation of reverse transcription and by blocking production of infectious virus from previously infected cells. Compounds with this activity may be useful for developing new types of antiretroviral drugs. In addition, compounds with this activity can be useful for production of chemically inactivated retroviral particles that lack infectivity but retain structurally and functionally intact envelope glycoproteins. Such inactivated particles may be useful both as in vitro reagents in a variety of applications and as immunogens for whole inactivated virus vaccines.

The present invention concerns antiretroviral compounds that disrupt the CCHC zinc fingers and assays for identifying such compounds. The invariant nature of retroviral zinc fingers also extends the usefulness of these compounds to other retroviruses. Thus these assays are also useful for screening compounds effective against adult T cell leukemia, tropical spastic paraparesis caused by HTLV-I and HTLV-II, feline leukemia virus, feline immunodeficiency virus, equine infectious virus, and lentivirus infections in other animals, and potentially useful for the production of whole inactivated particle vaccines against the pathogens.

Use of Inhibitors of 3-Hydroxy-3-Methylglutaryl Coenzyme A Reductase as a Modality in Cancer Therapy

Charles Myers et al. (NCI)

U.S. Patent No. 6,040,334 issued 21 Mar 2000 (HHS Reference No. E-146-1992/0-US-23).

Licensing Contact: George G. Pipia, PhD.; 301/435-5560; [e-mail].

HMG Co-A reductase inhibitors, also known as statins, are a type of drugs taken by millions of Americans to lower blood cholesterol levels. In the United States, statins available by prescription include atorvastatin (Lipitor^TM), lovastatin (Mevacor^TM), and simvastatin (Zocor^TM). Recently, there has been a surge in interest in the potential use of statins in the treatment or prevention of cancer. By exploring the effects of statins on the process of cancer at the molecular level, scientists have found that they work against critical cellular functions that may help control tumor initiation, tumor growth, and metastasis. With years of strong evidence that these agents are relatively safe, statins present themselves as good candidates for cancer therapeutics with added advantages.

This invention describes a method for treating mammalian adenocarcinomas and sarcomas with an effective amount of an inhibitor of HMG Co-A reductase or homologues of the inhibitor. Adenocarcinoma is known to afflict the prostate, stomach, lung, breast and colon, as well as other sites. Lovastatin and simvastatin, as well as their homologues, are examples of compounds useful in the present invention. Also included are compounds classified as HMG Co-A reductase inhibitors, as well as their homologues or analogues. Though the inhibitors of HMG Co-A reductase are generally known to reduce serum cholesterol in humans, the present invention focuses rather on the compounds' ability to treat selected cancers, such as adenocarcinomas of the prostate, stomach, lung, breast and colon and certain sarcomas such as Ewing's sarcoma.

Also provided by the invention is a method of reducing prostate specific antigen (PSA) levels in a patient having prostatic adenocarcinoma by administration of an effective amount of a compound which is an inhibitor of HMG Co-A reductase or a homologue of such inhibitor, as well as a method of reducing PSA in conjunction with another treatment modality.

Potent Peptide for Stimulation of Cytotoxic T Lymphocyte Specific for the HIV-1 Envelope

Jay A. Berzofsky et al. (NCI)

U.S. Patent No. 5,976,541 issued 02 Nov 1999 (HHS Reference No. E-072-1992/0-US-01).

Licensing Contact: Robert M. Joynes, J.D.; 301/594-6565; [e-mail].

According to a new annual report from the WHO, an estimated 40.3 million people worldwide are currently living with HIV infection, and more than three million people died of AIDS-related illnesses in 2005. Despite intensive efforts to improve antiretroviral treatment, a safe and effective HIV preventive vaccine is the best long-term hope to bring the HIV/AIDS epidemic under control. Though there are many clinical trial studies being conducted for HIV/AIDS vaccine, there is no such vaccine approved for use yet.

This invention described peptide constructs that may be of clinical importance in HIV/AIDS vaccine development. A vaccine for the prevention and/or treatment of HIV infection would ideally elicit a response in a broad range of the population. It would also have the capability of inducing high titered neutralizing antibodies, cytotoxic T lymphocytes, and helper T cells specific for HIV-1 gp160 envelope protein. A vaccine based on the synthetic or recombinant peptides has been developed which elicits these responses while avoiding the potential safety risks of live or killed viruses. Unlike previously developed vaccines, this invention avoids those regions of gp 160 which may contribute to acceleration of infection or the development of immune deficiency. Peptides having high activity in the eliciting of a cytotoxic T lymphocyte response to the HIV-1 envelope glycoprotein gp160 are described. The activation of 12-15 residue peptides by proteolytic degradation to shorter peptides is shown as are general techniques for characterizing such activation processes. The peptide described is recognized by both human and murine cytotoxic T lymphocytes, and is immunodominant in H-2d mice such as BALB/c, B10.D2, DBA/2, etc. This makes it ideal for determining responses in animal models preclinically before use in human trials. It is also ideal for detecting cytotoxic T lymphocyte responses to HIV envelope in these strains of mice.

Multideterminant Peptides That Elicit Helper T-Lymphocyte Cytotoxic T-Lymphocyte and Neutralizing Antibody Responses Against HIV-1

Jay A. Berzofsky et al. (NCI)

U.S. Patent No. 6,294,322 issued 25 Sep 2001 (HHS Reference No. E-152-1991/1-US-01).

Licensing Contact: Robert M. Joynes, J.D.; 301/594-6565; [e-mail].

According to a new annual report from the WHO, an estimated 40.3 million people worldwide are currently living with HIV infection, and more than three million people died of AIDS-related illnesses in 2005. Despite intensive efforts to improve antiretroviral treatment, a safe and effective HIV preventive vaccine is the best long-term hope to bring the HIV/AIDS epidemic under control. Though there are many clinical trial studies being conducted for HIV/AIDS vaccine, there is no such vaccine approved for use yet.

This invention described peptide constructs that may be of clinical importance in HIV/AIDS vaccine development. A vaccine for the prevention and/or treatment of HIV infection would ideally elicit a response in a broad range of the population. It would also have the capability of inducing high titered neutralizing antibodies, cytotoxic T lymphocytes, and helper T cells specific for HIV-1 gp 160 envelope protein. A vaccine based on synthetic or recombinant peptides has been developed which elicits these responses while avoiding the potential safety risks of live or killed viruses. Unlike previously developed vaccines this invention avoids those regions of gp 160 which may contribute to acceleration of infection or the development of immune deficiency. This invention provides peptides up to 44 amino acid residues long that stimulate helper T-cell response to HIV in a range of human subjects. Six multideterminant regions have been identified in which overlapping peptides are recognized by mice of either three or all four MHC types. Four of the six regions have sequences relatively conserved among HIV-I isolates. These multideterminant cluster peptides are recognized by T cells from humans of multiple HLA types, and have been found in a phase I clinical trial to elicit neutralizing antibodies, cytotoxic T cells, and helper T cells in at least some of the human subjects. These peptides are currently being tested in primates. Once delivery systems and a stronger mucosal response are induced, NCI plans to use these peptides in human clinical trials.

Dated: January 30, 2006.

Steven M. Ferguson,

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