05-5082. Government-Owned Inventions; Availability for Licensing

AGENCY:

National Institutes of Health, Public Health Service, DHHS.

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.

CpG Oligonucleotide Prodrugs

Daniela Verthelyi, Serge Beaucage, Andrzej Grajkowski (FDA).

U.S. Provisional Patent Application filed 13 Dec 2004 (DHHS Reference No. E-215-2004/0-US-01).

Licensing Contact: Michael Shmilovich; [phone]; [e-mail].

Available for licensing and commercial development into prodrugs and methods of synthesizing the same are CpG oligonucleotides that include thermolabile substituent on at least one nucleotide. The invention also provides compositions that include carriers and therapeutically effective amounts of at least one CpG oligonucleotide prodrug. Therapeutic methods of using such thermolabile CpG oligonucleotide prodrugs are also provided (e.g., a prodrug that elicits an immune response). The thermolabile substituent is typically bonded to the non-bridging oxygen atom of at least one phosphate or phosphorothioate in the oligonucleotide.

The thermolabile CpG oligonucleotide prodrugs of the present invention can be administered to a patient as a prodrug of the parent CpG oligonucleotides in vivo. The thermolabile CpG oligonucleotide prodrugs of the present invention are rapidly internalized by immune cells (B cells, macrophages, dendritic cells, and monocytes) and localized in endocytic vesicles where they can interact with Toll-like receptor 9. This interaction triggers an immunostimulatory cascade characterized by B-cell proliferation, dendritic cell maturation, natural killer cell activation and the secretion of a variety of cytokines, chemokines and polyreactive immunoglobulins. Administration of the thermolabile CpG oligonucleotide prodrugs of the present invention to a host, for example, can improve the resistance of the host against infectious pathogenic microorganisms, e.g., parasites, bacteria, and viruses.

Identification of Proteins in a Genome

James L. Hartley, Dominic Esposito, and Kelly Jeanne Stanard (SAIC/NCI).

U.S. Provisional Application No. 60/628,948 filed 19 Nov 2004 (DHHS Reference No. E-161-2004/0-US-01).

Licensing Contact: Cristina Thalhammer-Reyero; [phone]; [e-mail].

Available for licensing and commercial development are methods for identifying soluble proteins in a sample. Identification and characterization of bioactive compounds is a critical step in drug discovery, and there is a need for improved methods for identifying soluble proteins. One method provided, which produces soluble deletion derivatives of a protein, includes the steps of incubating a vector with a nucleic acid sequence encoding the protein, flanked by a first and second site-specific recombination sites, in the presence of one or more transposons with a third and fourth site-specific recombination sites and a transposase protein, to insert the one or more transposons into the vector, followed by transfer to further vectors with additional site-specific recombination sites, which are propagated, isolated, combined and recombined in the presence of a recombinase. A second method is for identifying two or more soluble proteins and includes the steps of expressing two or more vectors with the nucleic acid sequence encoding a soluble protein operatively linked to a promoter in one or more cells, and identifying and quantifying the isolated two or more soluble proteins by mass spectroscopy. The above methods can be used alone or in combination. These methods will enable researchers to identify both individual protein targets of drugs, as well as protein families or protein signaling pathways, thereby enhancing drug development.

In addition to licensing, the technology is available for further development through collaborative research opportunities with the inventors.

An Epitope-Enhancement of Human CD4 HIV Epitope

Jay A. Berzofsky (NCI), Takahiro Okazaki (NCI).

U.S. Provisional Application No. 60/567,073 filed 30 Apr 2004 (DHHS Reference No. E-076-2004/0-US-01).

Licensing Contact: Robert M. Joynes; [phone]; [e-mail].

This invention relates to an epitope of the HIV-1 envelope protein recognized by a CD4⁺ T cell line that was developed from immunization with canarypox vectors expressing gp120 of HIV-1. Virus-specific CD4⁺ T cell help and CD8⁺ cytotoxic T cell responses are critical for the maintenance of effective immunity in chronic viral infections. The importance of the CD4⁺ T cell has been documented in HIV infection. A T1-specific CD4⁺ T cell line from a healthy volunteer immunized with a canarypox vector expressing gpl20 has been developed. This T1-specific CD4⁺ T cell line was restricted to DR13, which is common in the U.S. in both Caucasians and African-Americans and is one of the major haplotypes in Africans. The present invention provides isolated polypeptides comprising an enhanced T1 epitope. Amino acid substitutions in the T1 epitope were made to induce a stronger epitope-specific CD4⁺ T cell response than the original epitope resulting in an improved CD4 epitope (also designated an epitope enhancement). A polypeptide comprising the enhanced CD4 epitope can be used as a component in composition either alone or in combination with other adjuvants and other immunogenic compositions to provide a more effective immune response to HIV infection.

In addition to licensing, the technology is available for further development through collaborative research opportunities with the inventors.

CC Chemokine Receptor 5 DNA, New Animal Models and Therapeutic Agents for HIV Infection

C. Combadiere, Y. Feng, E.A. Berger, G. Alkahatib, P.M. Murphy, C.C. Broder, P.E. Kennedy (NIAID);

U.S. Provisional Application No. 60/018,508 filed 28 May 1996 (DHHS Reference No. E-090-1996/0-US-01);

U.S. Patent Application No. 08/864,458 filed 28 May 1997 (DHHS Reference No. E-090-1996/0-US-04);

U.S. Patent Application No. 10/439,845 filed 15 May 2003 (DHHS Reference No. E-090-1996/0-US-05);

U.S. Patent Application No. 10/700,313 filed 31 Oct 2003 (DHHS Reference No. E-090-1996/0-US-06);

U.S. Patent Application No. 10/846,185 filed 14 May 2004 (DHHS Reference No. E-090-1996/0-US-07);

PCT Application No. PCT/US97/09586 filed 28 May 1997 (DHHS Reference No. E-090-1996/0-PCT-02);

European Patent Application No. 97929777.7 filed 28 May 1997 (DHHS Reference No. E-090-1996/0-EP-03).

Licensing Contact: Peter Soukas; [phone]; [e-mail].

Chemokine receptors are expressed by many cells, including lymphoid cells, and function to mediate cell trafficking and localization. CC chemokine receptor 5 (CCR5) is a seven-transmembrane, G protein-coupled receptor (GPCR) which regulates trafficking and effector functions of memory/effector T-lymphocytes, macrophages, and immature dendritic cells. Chemokine binding to CCR5 leads to cellular activation through pertussis toxin-sensitive heterotrimeric G proteins as well as G protein-independent signalling pathways. Like many other GPCR, CCR5 is regulated by agonist-dependent processes which involve G protein coupled receptor kinase (GRK)-dependent phosphorylation, beta-arrestin-mediated desensitization and internalization.

Human CCR5 also functions as the main coreceptor for the fusion and entry of many strains of human immunodeficiency virus (HIV-1, HIV-2). HIV-1 transmission almost invariably involves such CCR5-specific variants (designated R5); individuals lacking functional CCR5 (by virtue of homozygosity for a defective CCR5 allele) are almost completely resistant to HIV-1 infection. Specific blocking of CCR5 (e.g. with chemokine ligands, anti-CCR5 antibodies, CCR5-blocking low MW inhibitors, etc.) inhibits entry/infection of target cells by R5 HIV strains. Cells expressing CCR5 and CD4 are useful for screening for agents that inhibit HIV by binding to CCR5. Such agents represent potential new approaches to block HIV transmission and to treat infected people. A small animal expressing both human CCR5 along with human CD4 supports entry of HIV into target cells, a necessary hurdle that must be overcome for development of a small animal model (e.g. transgenic mouse, rat, rabbit, mink) to study HIV infection and its inhibition.

The invention embodies the CCR5 genetic sequence, cell lines and transgenic mice, the cells of which coexpress human CD4 and CCR5, and which may represent valuable tools for the study of HIV infection and for screening anti-HIV agents. The invention also embodies anti-CCR5 agents that block HIV env-mediated membrane fusion associated with HIV entry into human CD4-positive target cells or between HIV-infected cells and uninfected human CD4-positive target cells.

This technology was reported in Alkhatib et al., “CC CKR5: a RANTES, MIP-1alpha, MIP-1beta receptor as a fusion cofactor for macrophage-tropic HIV-1,” Science 272:1955-1958 (1996). The technology is available for exclusive or nonexclusive licensing.

Dated: March 7, 2005.

Steven M. Ferguson,

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