03-6443. 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 agencies 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.

IL-21 Critically Regulates Immunoglobulin Production

Warren J. Leonard, Katsutoshi Ozaki, and Rosanne Spolski (NHLBI)

U.S. Provisional Patent Application 60/393,215 filed 01 Jul 2002

Licensing Contact: Brenda Hefti; 301/435-4632; [e-mail].

The invention includes a mouse in which the IL-21 receptor gene is disrupted by homologous recombination, the disruption being sufficient to prevent expression of the IL-21 receptor and thus to inhibit the action of IL-21. The invention also includes a mouse in which both the IL-21 receptor gene and the IL-4 gene are simultaneously disrupted in fashions being sufficient to inhibit the action of IL-21 and the production of IL-4. In a homozygous state, these mutations produce a mouse that has diminished B cell function.

This invention also relates to the use of agents that inhibit the interaction of IL-21 with the IL-21 receptor to modulate an immune response. This invention may be used to alter B cell activity, to treat a subject with Job's disorder, to treat an allergic reaction in a subject, or prevent an allergic reaction in a subject.

Grafting of a Murine Antibody Onto a Human Framework

S. Rybak, J. Krauss, M. Arndt, and A. Martin (NCI)

U.S. Provisional Patent Application 60/390,033 filed 17 June 2002

Licensing Contact: Brenda Hefti; 301/435-4632; [e-mail].

This invention relates to humanization of antibodies specifically providing novel biophysically stable human framework sequences that can be used to humanize antibody single chain Fv (scFv) fragments. An exemplary RFB4 humanized scFv antibody was constructed using the new sequences. The novel sequences were obtained after stringent panning of a human phage display library on (irrelevant) antigen. These antibody variable domain frameworks were subsequently used as human acceptor scaffolds for grafting the murine antibody specificity. The general approach described here differs from other humanization procedures wherein appropriate human acceptor scaffolds are selected from either antibodies with solved crystal structures or (germline) sequence databases. In the current invention, human acceptor frameworks were first pre-selected for stability. Appropriate framework sequences with high sequence identities to the murine antibody to be humanized were then chosen from the pre-selected pool of stable scaffolds. As a result, humanized scFv fragments with low immunogenic potential and high biophysical stability were generated.

In contrast to other methodologies, unusual human framework residues were identified by aligning the human variable domain sequences to several sequence reference templates from antibody repertoires. The structural role of each identified unusual residue was further examined on the basis of information of antibodies with known crystal structures. Several residues were considered critical for interfering with the structural integrity of the antigen binding site and were successively back-mutated to the murine donor sequence. As a result, a panel of three humanized scFv antibodies with nanomolar affinity constants were generated. Importantly, the introduced back-mutations did not alter the biophysical properties of the constructs.

Tumor Suppressor Gene Polypeptides and Related Nucleic Acids, Host Cells, Compositions, and Methods of Use in Inhibition of Cell Growth, Modulation of Gene Expression, and Enhancement of Immune-Response Inducing Effect of a Vaccine

Denise Simmons (NCI)

DHHS Reference No. E-052-02/0 filed 03 May 2002

Licensing Contact: Matthew Kiser; 301/435-5236; [e-mail].

Many cell lines have specific suppressor proteins that can inhibit the proliferation of cancer cells. These regulatory proteins are crucial in maintaining the fine line between appropriate proliferation and over proliferation. It is when these regulatory suppressor proteins become inactivated or over/under expressed that uncontrolled cell growth leading to neoplasia can result.

It has been established that certain suppressor proteins can inhibit cell proliferation: tazarotene-induced gene 3 (H-TIG-3), and Hras Revertant gene 107 (H-rev107). Modification or over/under expression of these proteins can cause excessive cellular proliferation. It is now known that these proteins, as well as a candidate tumor suppressor protein, lecithin:retinol acyl transferase (LRAT) share a homologous region. The subject invention pertains to a group of short polypeptide sequences that are based on this homologous region. These short polypeptides are effective tumor suppressors.

The scope of this invention includes amino acid sequences and the corresponding nucleic acid sequences that encode the polypeptides. Modifications of the polypeptide sequences include both substitution and additions. The subject invention also applies to the method of inhibiting cell growth, a method of modulating gene expression, and a method of enhancing the immune response-inducing effect of a vaccine.

Material and Methods for Inhibiting Wip1

Dimtry V. Bulavin (NCI), Ettore Appella (NCI), Albert Fornace (NCI), Anne Kallioniemi (NCI)

DHHS Reference No. E-002-02/0 filed 22 Mar 2002

Licensing Contact: Matthew Kiser; 301/435-5236; [e-mail].

p53 protein is an attractive cancer-therapeutics target since it is expressed in all normal cells and is important for cancer cell apoptosis (death). The p53 protein provides a cellular self-destruct signal when DNA damage has occurred. Under expression of this protein can cause damaged cells to proliferate causing cancer. A potential proto-oncogene, wild-type p53-induced phosphatase 1 (Wip1), has been implicated in the down regulation of p53. Therapeutic strategies that can block Wip1 will increase the activity of p53 thus preventing cancer cell proliferation in p53 wt tumors that over-express Wip1. The subject invention pertains to isolated and purified oligonucleotides or isolated and purified morpholino oligonucleotides with the ability to inhibit Wip1 expression. These oligomers can be used for the treatment of cancer. In addition to practical uses of the oligomers, a methodology for screening standard and morpholino oligonucleotides for Wip1 inhibition is included. Finally, a methodology to test the efficacy of standard and morpholino test oligonucleotides completes this invention.

Attenuated and Dominant Negative Variant cDNAs of STAT6: STAT6b and STAT6c

William LaRochelle, Bharvin K.R. Patel, Jacalyn H. Pierce (all of NCI)

Serial No. 09/511,625 filed 23 Feb. 2000, now U.S. Patent 6,368,828 issued 09 Apr. 2002.

Licensing Contact: Susan S. Rucker; 301/435-4478; [e-mail].

This patent relates to signal transduction pathways. In particular, the patent relates to transcription factors. The transcription factors described in the patent are members of the family of transcription factors known as Signal Transducers and Activators of Transcription (STATs). More particularly, the patent discloses the identification, isolation, sequencing and cloning of cDNAs that encode naturally occurring variants, Stat6b and Stat6c, of the protein STAT6.

The Stat6b variant contains an NH₂ terminal deletion of naturally occurring Stat6. The Stat6c variant contains an internal deletion, within the SH2 domain, of naturally occurring Stat6. The naturally occurring variants exhibit different properties. Stat6b acts as an attenuated variant, with respect to IL-4 induced MHC class II and Fc receptor cell surface expression, promoter binding and transcriptional activation when compared to Stat6. Stat6c acts as a dominant negative variant with respect to IL-4 mediated up-regulation of the cell surface antigens CD16/CD32 and CD23. The role of both variants in mediating IL-4 activity suggests that either could be useful in developing drugs for targeting diseases involving inflammatory and cell-mediated immune responses such as asthma.

The patent includes claims to the Stat6 variant polypeptides, the nucleic acids, vectors for expression of the variants, cells into which the variants have been introduced and methods of producing the Stat6 variant polypeptides.

This work has been published in part at B.K.R. Patel et al., PNAS USA 95: 175-77 (Jan. 1998).

Dated: March 12, 2003.

Steven M. Ferguson,

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