Federal Inventions for December 15, 2000 --- SSTI Weekly Digest

Federal Tech Transfer Opportunities

During the past two weeks, the following agencies have published notice of government-owned inventions available for licensing.

U.S. Department of Agriculture
National Institutes of Health (23 inventions)

U.S. Department of Agriculture

SUMMARY: The invention listed below is owned by the U.S. Government as
represented by the Department of Agriculture and is available for licensing. U.S. Patent Application Serial No. 09/637,031 entitled ``Magnetostrictive Precipitation Gage'' is available for licensing in accordance with 35 U.S.C. 207 and 37 CFR 404 to achieve expeditious commercialization of results of Federally funded research and development. Foreign patents are filed on selected inventions to extend market coverage for U.S. companies and may also be available for licensing.

DATES: Comments must be received on or before January 30, 2001.

FOR FURTHER INFORMATION CONTACT: Technical and licensing information on this invention may be obtained by writing to: Janet I. Stockhausen of the USDA Forest Service, One Gifford Pinchot Drive, Madison, Wisconsin 53705-2398; telephone 608-231-9502; fax: 608-231-9508; or e-mail jistockh@facstaff.wisc.edu. Issued patents may be obtained from the Commissioner of Patents, U.S. Patent and Trademark Office, Washington, DC 20231.

National Institutes of Health

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.

NAG-1: A Non-Steroidal Anti-Inflammatory Drug Related Gene Which Has Anti-Tumorigenic Properties
Thomas E. Eling, Seung Joon Baek (NIEHS)
DHHS Reference No. E-170-00/0 filed 08 Sep 2000
Licensing Contact: Richard Rodriguez; 301/496-7056 ext. 287; e-mail:
rodrigur@od.nih.gov
Non-steroidal anti-inflammatory drugs (NSAIDs) are widely used in the treatment of inflammatory disease, and their anti-inflammatory effects are believed to result from their ability to inhibit the formation of prostaglandins by prostaglandin H synthase (COX). Two forms of prostaglandin H have been identified, COX-1 and COX-2. The former seems to be constitutively expressed in a variety of tissues while the high expression of the latter has been reported in colorectal tumors. NSAIDs have been shown to be effective in reducing human colorectal cancers and possibly breast and lung cancers. While the exact mechanism(s) by which NSAIDs function has not been elucidated, they could potentially play a critical role in detecting, diagnosing and treating inflammatory diseases as well as cancer. The present invention relates to screening methods for the identification of agonistic and/or antagonistic agents for the activation of the promoter region of NAG-1. Additional claims are directed to 1) the DNA sequence of NAG-1, 2) compositions containing the NAG-1 sequence and 3) methods for treating cancer patients using NAG-1.

Novel MHC Class II Restricted T Cell Epitopes from the Cancer Antigen, NY-ESO-1

DHHS Reference No. E-090-00/0 filed 28 Jan 2000 and

MHC Class II Restricted CD4+ T Cell Epitopes From NY-ESO-1 Presented by DP
DHHS Reference No. E-227-00/0 filed 29 Sep 2000
Wang et al. (NCI)
Licensing Contact: Elaine White: 301/496-7056 ext. 282; e-mail:
gesee@od.nih.gov
NY-ESO-1 is a known tumor antigen which is expressed on a broad range of tumor types, including melanoma, breast, bladder, ovarian, prostate, head and neck cancers, neuroblastoma, and small cell lung cancer. The above-referenced inventions embody the identification of a number of novel immunogenic peptide epitopes, and analogs thereof, which are derived from the NY-ESO-1 tumor antigen. DHHS Reference No. E-090-00/0 serves to identify novel MHC Class II restricted epitopes of NY-ESO-1 which are recognized by CD4+ T cells. DHHS Reference No. E-227-00/0 embodies the identification of two additional immunogenic peptide epitopes of NY-ESO-1. The latter two epitopes are presented by HLA-DP4, a prevalent MHC Class II allele present in 43-70% of Caucasians. The inventors also determined that the DP allele is highly associated with the NY-ESO-1 antibody production. In addition, one of these epitopes has dual HLA A2 and DP4 specificity, thereby has the potential to generate both CD4+ and CD8+ tumor specific T cells. These epitopes may be of great value as prophylactic and/or therapeutic cancer vaccines for use against a number of common cancers.

T-Cell Epitope of MAGE-12 and Related Nucleic Acids, Vectors, Cells, Compositions, and Methods of Inducing an Immune Response to Cancer
Monica Panelli, Francesco Marincola, Maria Bettinotti (NCI)
DHHS Reference No. E-056-00/0 filed 03 Mar 2000
Licensing Contact: Elaine White; 301/496-7056 ext. 282; e-mail:
gesee@od.nih.gov
The current invention embodies the identification of a T-cell epitope from the cancer-specific antigen MAGE-12. The MAGE family of genes encodes human tumor specific antigens (TSA), and various genes of this family are expressed by tumors of different histologies (melanoma, lung, colon, breast, laryngeal cancer, sarcomas, certain leukemias) and not by normal cells (except testis and placenta). The MAGE-12 peptide which is the subject of the current invention is a specific epitope within MAGE-12 (residues170-178) which is recognized by tumor infiltrating lymphocytes in the context of HLA-Cw0702 (a common HLA type in the Caucasian population). This T-cell epitope is advantageous in that it represents a novel tumor rejection antigen for use as a peptide vaccine against melanoma or other cancer types expressing MAGE-12 and may therefore be of great value for use in cancer immunotherapy.

Secreted Frizzled Related Protein, sFRP, Fragments and Methods of Use Thereof
JS Rubin, A Uren (both of NCI), and F Reichsman, S Cumberledge
Serial No. 09/546,043 filed 10 April 00
Licensing Contact: Susan S. Rucker; 301/496-7056 ext 245; e-mail: ruckers@od.nih.gov
This application relates to signal transduction pathways and mechanisms. More particularly, the application describes various active fragments of the secreted Wnt binding protein sFRP-1 (secreted Frizzled Related Protein-1). The sFRP-1 fragments described are capable of binding to Wnt and therefore are able to modulate Wnt activity. The fragments may or may not contain the cysteine rich domain (CRD) of sFRP-1 suggesting that the CRD is not essential for Wnt binding. In addition, in contrast to earlier findings employing higher levels of sFRP-1, the ability of sFRP-1 to enhance Wnt signaling at low levels is also described suggesting biphasic regulation of Wnt signaling by sFRP-1. The sFRP-1 fragments described herein may be useful in the further study of Wnt signaling as well as targets for the development of small molecules which can modulate Wnt signaling. PHS also owns additional intellectual property related to sFRP-1 which is described in US Patent Application Serial Number 09/087,031 and which has been published as WO 98/54325 (12/03/1998).

This work has appeared, in part, in Uren, A et al. JBC 275(6): 4374-4382 (Feb 11, 2000).

ADDRESSES: Licensing information and a copy of the U.S. patent application referenced below may be obtained by contacting J. R. Dixon, Ph.D., at the Office of Technology Transfer, National Institutes of Health, 6011 Executive Boulevard, Suite 325, Rockville, Maryland 20852-3804 (telephone 301/496-7056 ext 206; fax 301/402-0220; e-mail: jd212g@nih.gov). A signed Confidential Disclosure Agreement is required to receive a copy of any patent application.

``Discovery of Gene Expressed in Many Cancers and Only Normal Testis''
Inventors: Drs. Ira H. Pastan (NCI), Xiu F. Liu (NCI), Byungkook
Lee (NCI) and Lee J. Helman (NCI).
DHHS Ref. No. E-161-00/0 Filed: September 1, 2000.
Large numbers of expressed sequence tags (EST's) have been cloned from various normal and cancer tissues. Cancer-testis antigens are a distinct class of differentiation antigens that have a restricted pattern of expression in normal tissues. These genes are primarily expressed in the primitive germ cells, spermatogonia, in the normal testis. Malignant transformation is often associated with activation or derepression of silent Cancer-testis genes, and this results in the expression of Cancer-testis antigen in a variable proportion of a wide range of human tumors. Three related genes, termed XAGEs, were recently identified by homology walking using the dbEST database.

The XAGE-1 gene is a human X-linked gene that is strongly expressed in normal testis, Ewing's sarcoma, alveolar rhabdomyosarcoma, as well as breast cancer and other cancers (e.g., lung carcinoma, prostate adenocarcinoma, ovarian carcinoma, pancreatic adenocarcinoma, glioblastoma, etc.). The largest open reading frame of the XAGE-1 transcript encodes a putative protein of 16.3 kD (p16) with a potential transmembrane domain at the amino terminus. In addition, the XAGE-1 transcript contains a second ATG in the reading frame corresponding to residue 66, which would encode a 9 kD protein (p9). In vitro transfection experiments using 293T cells have revealed a 9 kD protein. However, the size of the protein expressed endogenously is not yet known. XAGE-1 shares homology with GAGE/PAGE proteins in the C-terminal end.

The invention relates to the fact that the XAGE-1 gene is expressed in a number of human cancers, specifically: prostate, pancreatic, and ovarian cancers, as well as a large percentage of breast and lung tumors. The protein p9 and p16, immunogenic fragments thereof, analogs of these proteins, and nucleic acids encoding these proteins, fragments, or analogs, can be administered to persons with XAGE-1 expressing cancers to raise or augment an immune response to the cancer. The invention further provides nucleic acid sequences encoding the protein, as well as expression vectors, host cells, and antibodies to the proteins. Further, the invention provides immunoconjugates that comprise an antibody to p16 or to p9, and an effector molecule, such as a label, a radioisotope, or a toxin. The invention also provides methods of inhibiting the growth of XAGE-1 expressing cells by contacting them with immunoconjugates of an anti-p9 or p16 antibody and a toxic moiety. The invention also provides kits for the detection of p9 or p16 proteins in a sample. The XAGE-1 gene and encoded protein could be of value in the development of a cancer diagnostic and cancer immunotherapy.

The above mentioned invention is available for licensing on an exclusive or non-exclusive basis.

The evaluation of new drugs for their potential for inducing mutations is a necessary part of evaluating the safety of pharmaceuticals or environmental chemicals. One advantage of this assay is that it may be automated to be performed in microplate dishes. In addition, this assay has the potential to be utilized in a microarray system because of the limited number of possible mutations. Therefore, it would be more rapid and less expensive than the currently used transgenic systems.

Adult Human Dental Pulp Stem Cells in vitro and in vivo
Dr. Songtao Shi et al. (NIDCR)
DHHS Reference No. E-233-00/0 filed 21 July 2000, Licensing Contact: Marlene Shinn; 301/496-7056 ext. 285; e-mail: shinnm@od.nih.gov
Many individuals with ongoing and severe dental problems are faced with the prospect of permanent tooth loss. Examples include dentinal degradation due to caries or periodontal disease; (accidental) injury to the mouth; and surgical removal of teeth due to tumors associated with the jaw. Clearly, a technology that offers a possible alternative to artificial dentures by designing and transplanting a set of living teeth fashioned from the patient's own pulp cells would greatly improve the individual's quality of life.

The NIH announces a new technology wherein dental pulp stem cells from an individual's own postnatal dental pulp tissue (one or two wisdom teeth) can potentially be used to engineer healthy living teeth. This technology is based upon the discovery of a subpopulation of cells within normal human dental pulp tissue that has the ability to grow and proliferate in vitro. These (dental pulp) stem cells can be induced under defined culture conditions to form calcified nodules in vitro and have been shown to differentiate into a dentin/pulp like structure in vivo.

PTH2 and PTH1 Receptor Ligands
Ted B. Usdin and Samuel R. Hoare (NIMH)
DHHS Reference No. E-123-99/1 filed 15 June 2000, Licensing Contact: Norbert Pontzer; 301/496-7735, ext. 284; e-mail: pontzern@od.nih.gov
Parathyroid hormone receptors found on osteoblasts in bone and renal tubule cells in kidney elevate blood calcium levels when stimulated by parathyroid hormone (PTH) and PTH-related protein (PTHrP). Excessive secretion of PTH from the parathyroid gland results in primary hyperparathyroidism. Production of PTHrP by various tumors results in humoral hypercalcemia of malignancy. In both of these conditions, excessive blood calcium levels lead to clinically significant morbidity. A parathyroid hormone antagonist could therefore have therapeutic value. Until now, no effective antagonists for the classical parathyroid hormone receptor (PTH1 receptor) were known. This invention describes a peptide which binds with high affinity (Kd = 1.3 0.1 nM, dissociation T1/2 = 14 min.) and acts as purely competitive antagonist at the PTH1 receptor. This novel peptide is related to tuberoinfundibular peptides of 39 residues (TIP39), also described in this invention, which binds to a related receptor. Deletion of amino acids from the N-terminus of TIP39 resulted in the high affinity PTH1 receptor antagonist peptide described here. This peptide may be used therapeutically to treat excessive blood calcium caused by PTH or PTHrP, other pathology caused by PTHrP, to demonstrate the utility of parathyroid hormone receptor antagonism in the treatment of hypercalcemia or other conditions, or to help screen for other antagonists at the parathyroid hormone receptor.

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.

A Mouse Model of UV-Inducible Cutaneous Malignant Melanoma
Glenn Merlino et al. (NCI)
DHHS Reference No. E-281-00/0
Licensing Contact: Elaine White; 301/496-7056 ext. 282; e-mail: gesee@od.nih.gov

The current invention embodies a genetically engineered mouse harboring a hepatocyte growth factor/scatter factor transgene (``HGF/SF''). The Met signaling pathway, which has been implicated in the development of human melanoma, is chronically activated in the HGF/SF mice. Upon exposure to a single neonatal dose of erythrogenic UV radiation, the mice develop cutaneous malignant melanoma which is consistent with the epidemiology and pathogenesis of melanomas observed in humans. The mice, therefore, represent a valuable model for studying the development of malignant melanoma in humans, for determining the consequences of ultraviolet radiation, and for assessing the efficacy of therapeutic agents and vaccines against melanoma. While no patent rights are available for this invention, breeding pairs of mice are available for licensing via Biological Materials License Agreements.

Gamma-Glutamyl Transpeptidase Inhibitors: Novel Chemotherapeutic Agents
Robert E. London, Scott A. Gabel (NIEHS)
DHHS Reference No. E-243-00/0 filed 05 Oct 2000
Licensing Contact: Richard Rodriguez; 301/496-7056 ext. 287; e-mail: rodrigur@od.nih.gov
Gamma-glutamyl transpeptidase (GGTP) plays a central role in the metabolism of glutathione. It has been shown to be a marker for neoplasia and cell transformation, and it is induced by the presence of many anti-cancer drugs. Common human epithelial tumors, including, but not necessarily limited to, breast, ovarian and prostate tumors are GGTP-positive. The invention relates to novel inhibitors of GGTP, and their use to treat cancer. In particular, the technology could be used to (1) interfere with glutathione metabolism in GGTP-positive cancers by perhaps altering the cellular orientation of GGTP; (2) potentiate the effects of radiation and chemotherapeutic drugs, in particular, cisplatin, on cancer cells by interfering with cysteine recycling and glutathione regeneration; and (3) reduce renal toxicity for some chemotherapeutic drugs by blocking the metabolism of glutathione-conjugates into toxic agents, e.g., mercapturic acids. The patent application contains composition of matter claims as well as method claims.

Protein Kinase A and the Carney Complex
Constantine A. Stratakis, Lawrence S. Kirschner (NICHD)
DHHS Reference No. 259-00/0 filed 25 Aug 2000
Licensing Contact: Richard Rodriguez; 301/496-7056 ext. 287; e-mail: rodrigur@od.nih.gov
The present invention provides compositions and methods useful in the diagnosis and prognosis of Carney complex (CNC), as well as methods and compositions for the identification of compounds useful in the treatment and/or prevention of CNC. CNC is a multiple endocrine neoplasia syndrome that affects the adrenal cortex, pituitary gland, thyroid gland and gonads. Additionally, compositions and methods are provided for the diagnosis and treatment of conditions associated with skin pigmentation defects, including but not limited to, freckling, as well as endocrine tumors including, but not limited to, adrenal and pituitary tumors. Finally, compositions and methods are provided for the diagnosis and treatment of various types of cancers associated with abnormal protein kinase A activity, and cancers and tumors in which protein kinase A regulatory subunit 1A acts as a tumor-suppressor gene. These actions are possible due to the identification of specific genetic sequences, and the use of this information in assay systems to detect, diagnose and treat the aforementioned conditions.

SH2 Domain Binding Inhibitors
Terrence R. Burke, Yang Gao, Johannes Voight (NCI)
DHHS Reference No. E-262-00/0 filed 22 Aug 2000
Licensing Contact: Richard Rodriguez; 301/496-7056 ext. 287; e-mail: rodrigur@od.nih.gov
Signal transduction, the process of relaying extracellular messages to the intracellular cytoplasm and the nucleus, is critical to normal cellular homeostasis, and protein-tyrosine kinases play a central role in this biological function. Examples of this latter class of enzymes include the PDGF receptor, the FGF receptor, the HGF receptor, members of the EGF receptor family, including the EGF receptor itself and erb-B2, erb-B3 and erb-B4 kinases; the src kinase family, Fak kinase and the Jak kinase family. Protein-tyrosine phosphorylation is known to be involved in modulating the activity of a variety of target enzymes and in the formation of specific complex networks involved in signal transduction via proteins containing specific amino acid sequences, called the Src homology 2, or SH2 domain. A malfunction in this protein-tyrosine phosphorylation through tyrosine kinase overexpression and/or deregulation, can be manifested by various oncogenic and hyperproliferative disorders, such as cancer, inflammation, autoimmune disease, hyperproliferative skin disorders, e.g., psoriasis and allergy/asthma. The disclosed compounds, e.g. peptides, preferably, macrocyclic peptides, are SH2 domain inhibitors with enhanced binding affinity. The claims of the current application are directed to compositions of matter and methods of use which provide for the diagnosis, testing and treatment of the aforementioned disease states.

Use and Targeting of CD98 Light-Chain Proteins in Therapies for Thyroid Hormone Disorders
Yun-Bo Shi (NICHD)
DHHS Reference No. E-054-00/0 filed 30 Jun 2000
Licensing Contact: Marlene Shinn; 301/496-7056 ext. 285; e-mail: shinnm@od.nih.gov
Thyroid hormone disorders are among the most common problems in the Western world. These include hypo-and hyper-thyroidism (including goiter), as well as obesity and developmental abnormalities caused by excess or deficient levels of thyroid hormones during pregnancy. The NIH announces the discovery of a protein, which is a member of the CD98 light-chain permease family, which acts as a thyroid hormone transporter across vertebrate cell membranes. This protein provides a missing link in the chain by which thyroid hormones in the blood reach the cell nucleus. By utilizing the CDNA of this protein, genomic libraries can be screened for sequences capable of being used as primers for use in diagnostics. Also, by targeting this protein through drug discovery, new treatments for thyroid disorders may be found and developed.

Method of Regulating Interleukin-12 (IL-12) Production by Administering CCR5 Agonists and Antagonists
Sher et al. (NIAID)
PCT/US00/01019 filed 14 Jan 2000
Licensing Contact: J.P. Kim; 301/496-7056 ext. 264; e-mail: kimj@od.nih.gov
Interleukin-12 (IL-12) is a cytokine produced by the body which is necessary for the development of effective cellular immunity against many microbial agents. Increasing IL-12 production has been shown to both enhance the immune clearance of microbial agents as well as augment the protection induced by vaccines. At the same time a number of inflammatory diseases are associated with the excess production of this cytokine. Therefore, methods are needed to both boost IL-12 production for the induction of host resistance as well as suppress it to treat these immunopathologic disorders.

The present invention relates to methods for increasing IL-12 production in a cell by administering CCR5 agonists and methods for decreasing IL-12 production in a cell administering CCR5 antagonists. The invention also relates to methods for increasing IL-12 production by administering CCR5 agonists and to methods for decreasing IL-12 production in a subject by administering CCR5 antagonists.

ADDRESSES: Licensing information and copies of the U.S. patent applications listed below may be obtained by contacting Peter A. Soukas, J.D., at the Office of Technology Transfer, National Institutes of Health, 6011 Executive Boulevard, Suite 325, Rockville, Maryland 20852-3804; telephone: 301/496-7056 ext. 268; fax: 301/402-0220; e-mail: soukasp@od.nih.gov. A signed Confidential Disclosure Agreement will be required to receive copies of the patent applications.

Antibodies and Other Ligands Directed Against KIR2DL4 Receptor for Production of Interferon-Gamma
Eric Long, Sumati Rajagopalan (NIAID)
DHHS Reference No. E-255-00/0 filed 23 Oct 2000
Interferon-gamma is a potent antiviral and antimicrobial substance produced by natural killer (NK) white blood cells. NK cells are activated during infections by viruses and by other intracellular pathogens, such as parasites and bacteria. Soluble substances, such as interleukins, produced by infected cells activate NK cells to secrete interferon-gamma. Injection of interleukins into patients to stimulate NK cells to secrete interferon-gamma has not been a successful therapeutic approach because of the toxicity involved. The invention is based on the discovery by the inventors that activation of the KIR2DL4 receptor expressed by all NK cells stimulates them to produce interferon-gamma. The invention claims monoclonal antibodies and derivatives thereof, as well as natural and synthetic ligands of KIR2DL4 that can be utilized to stimulate interferon-gamma production by NK cells without any other stimulus. The possibility of inducing interferon-gamma production by NK cells without the toxic side effects of interleukins could be an effective therapy for various types of infections and of cancers. Also claimed in the invention are methods of treating various cancers and viral infections, methods of treating autoimmune disease, and methods of administration of the antibody or derivatives thereof.

Ixodes scapularis Tissue Factor Pathway Inhibitor
Ivo Francischetti, Jesus Valenzuela, Jose Ribeiro (NIAID)
DHHS Reference No. E-208-00/0 filed 05 Oct 2000
Ixodes scapularis is a blood-sucking tick and the principal vector of Lyme disease, a spirochetal illness caused by Borrelia burgdorferi and now the most common vector-borne infection in the United States; more than 50,000 cases have been reported during the last ten years.

The salivary gland of I. scapularis has a number of pharmacologically active molecules that help the tick to successfully feed on blood, such as inhibitors of complement system, in addition to coagulation and platelet aggregation inhibitors. This invention describes Ixolaris, a protein that inhibits the initiation of blood coagulation by inhibition of components of the extrinsic pathway. Accordingly, Ixolaris blocks Factor X activation by Factor VIIa/TissueFactor, it attenuates Factor Xa production by the prothrombinase, and inhibits fibrin formation in a diluted prothrombin time. Ixolaris is highly specific since it does not inhibit other serine proteases. Because Ixolaris has anticoagulant properties, it could be used to ameliorate a number of clinical conditions such as disseminated intravascular coagulation, and hypercoagulation states. In addition, Ixolaris may be useful as a vaccine candidate for Lyme disease because inactivation of Ixolaris by antibodies may make transmission of Borrelia burgdorferi more difficult. In addition to the composition of Ixolaris, the invention claims vaccines utilizing Ixolaris, methods of stimulating an immune response, and methods of treatment of restenosis, arterial thrombosis, and stroke.

Ixodes Salivary Anticomplement Protein
Jose Ribeiro (NIAID), Jesus Valenzuela (NIAID), Rosane Charlab (NIAID),
Thomas Mather (EM)
DHHS Reference No. E-207-00/0 filed 28 Sep 2000
This invention describes Isac, a novel anticomplement protein that can be isolated and purified from I. scapularis (tick) saliva that may be useful as a peptide vaccine against Lyme disease. Because inactivation of Isac by antibodies will make transmission of Borrelia burgdorferi to humans more difficult, Isac is an ideal candidate for a Lyme disease vaccine. Isac disrupts the alternative complement pathway by inhibiting factors Bb and/or C3b, preventing cell lysis and anaphylatoxin production. The inventors have found no similarity to any protein in GenBank for Isac. Isac may also be used in situations where alternative complement activation is implicated such as in rheumatoid conditions such as lupus erythematosus or juvenile arthritis. The invention is further described in Ribeiro et al., ``Purification, cloning, and expression of a novel salivary anticomplement protein from the tick, Ixodes scapularis,'' J Biol. Chem. 2000 Jun 23; 275(25):18717-23.

LL-37 Is an Immunostimulant
Oleg Chertov (NCI), Joost Oppenheim (NCI), De Yang (NCI), Qian Chen
(NCI), Ji Wang (NCI), Mark Anderson (EM), Joseph Wooters (EM)
DHHS Reference No. E-285-00/0 filed 21 Sep 2000
This invention relates to use of an antimicrobial peptide as a vaccine adjuvant. LL-37 is the cleaved antimicrobial 37-residue C-terminal peptide of hCAP18, the only identified member in humans of a family of proteins called cathelicidins. LL-37/hCAP18 is produced by neutrophils and various epithelial cells. LL-37 is well known as an antimicrobial peptide. However, although antimicrobial peptides have generally been considered to contribute to host innate antimicrobial defense, some of them may also contribute to adaptive immunity against microbial infection. The inventors have shown that LL-37 utilizes formyl peptide receptor-like 1 (FPLR1) as a receptor to activate human neutrophils, monocytes, and T cells. Since leukocytes participate in both innate and adaptive immunity, the fact that LL-37 can chemoattract human leukocytes may provide one additional mechanism by which LL-37 can contribute to host defense against microbial invasion, by participating in the recruitment of leukocytes to sites of infection. The invention claims methods of enhancing immune responses through the administration of LL-37 alone, in conjunction with a vaccine, and methods of treating autoimmune diseases. The invention is further described in Chertov et al., ``LL-37, the neutrophil granule-and epithelial cell-derived cathelicidin, utilizes formyl peptide receptor-like 1 (FPRL1) as a receptor to chemoattract human peripheral blood neutrophils, monocytes, and T cells,'' J Exp. Med. 2000 Oct 2;192(7):1069-74.

A Method for Bioconjugation Using Diels-Alder Cycloaddition
Vince Pozsgay (NICHD)
DHHS Reference No. E-126-00/0 filed 09 Aug 2000
This invention relates to a new method for the synthesis of conjugate vaccines using the Diels-Alder cycloaddition reaction to covalently attach a carbohydrate antigen from a pathogen to a protein carrier. The Diels-Alder reaction has not been extended to conjugation involving biopolymers or other types of polymeric materials. Advantages of this method are that cross-linking during conjugation is entirely avoided in addition to the mild chemical conditions under which this synthesis method proceeds. Diels-Alder reactions commonly take place in high-temperature environments; the method contemplated by this invention takes place at much lower temperatures. In addition to claiming methods of synthesis for conjugate vaccines using the Diels-Alder cycloaddition, the patent application claims vaccines produced utilizing the method, and methods of inducing antibodies which react with the polysaccharides contemplated by the invention.

5-Substituted Derivatives of Conformationally Locked Nucleoside Analogues
Victor Marquez, Pamela Russ (NCI)
DHHS Reference No. E-249-00/0 filed 26 Jul 2000
This invention relates to 5-substituted derivatives of conformationally locked nucleoside analogues and methods of using these derivatives as antiviral and anticancer agents. The compounds contemplated by the invention are nucleoside analogues where the 5-substituent is a halogen, alkyl, alkene, halovinyl or alkyne group, and the nucleotide base is cytosine or uracil. The analogues are particularly effective in treating viral infections, specifically infections of DNA viruses such as Herpes simplex virus (HSV), Varicella zoster virus (VSV), Epstein Barr virus (EBV), and Cytomegalovirus (CMV) as well as members of the Poxviridae family. The inventors have demonstrated in plaque reduction assays that 5-substituted uracils (bromo, iodo, and bromovinyl) attached to a bicyclo[3.1.0]hexane template are thirty times more potent than acyclovir against HSV-1 and HSV-2.

Bacteriophage Having Multiple Host Range
Carl Merril (NIMH), Sankar Adhya (NCI), Dean Scholl (NIMH)
DHHS Reference No. E-257-00/0 filed 25 Jul 2000
Recently, there has been a renewed interest in the use of phages to treat bacterial infections. The inventors have discovered FK1-5, a highly lytic, non-lysogenic, stable bacteriophage with the ability to kill bacteria rapidly, making it a good candidate for phage therapy. The designation FK1-5 denotes the phage's ability to infect E. coli strains that contain the K1 polysaccharide in their outer capsule as well as E. coli strains that contain the K5 polysaccharide in their outer capsule. Sequence analysis of the tail proteins of phage FK1-5 by the inventors has shown that they are arranged in a cassette structure, suggesting that the host range of phages can be broadened to other K antigens, and even possibly other species of bacteria by recombinant techniques. FK1-5 has a particular advantage because it recognizes and attaches to the structures that confer virulence to bacteria. The inventors' demonstration that a phage can contain multiple tail proteins that expand its host range is useful for generating phage with broad-spectrum antibacterial properties for the treatment of infectious diseases. The inventors have completed in vitro studies on this phage.

Furthermore, because of the possibility of engineering the expression of recombinant tail proteins, gene transfer to organisms that are not normally infected by phages is also contemplated by the invention.

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