Selected NIH Technologies Available for Licensing

Uncle Sam wants you… to license some of its world-class discovery-stage pharmaceutical technology. Over the years, the National Institutes of Health (part of the Dept. of Health and Human Services) has performed and funded world-class pharmaceutical research. Some NIH inventions, in fact, have made it to the marketplace (click here for related story).

The following inventions—mostly small-molecule drugs—are available for negotiable licensing plus royalty arrangements as of June 2, 1999. Listed for each invention are the title, inventor(s), agency affiliation, reference number, and licensing contact.

• Modulation Of N-Acetyl-Transferase To Improve Therapy And Prevent Cancer
• N-Acylphosphoramidites And Their Use In Oligonucleotide Synthesis
• Methods For Inhibiting Chaperone Proteins
• Identification And Use Of High Efficacy Vaccine Antigens
• Polymorphic Human GABAA Receptor Alpha-6 Subunit
• Identification Of The Geldanamycins As Inhibitors Of The HGF/SF-Met-uPA Proteolytic Network
• A Method of Immunizing Humans Against Salmonella typhi Using A Vi-rEPA Conjugate Vaccine
• Antagonists Of The aEb7 Integrin As Therapeutic Agents For Inflammatory Diseases
• Modified HCV Peptide Vaccine
• Conformationally Locked Nucleoside Analogues

Modulation Of N-Acetyl-Transferase To Improve Therapy And Prevent Cancer (Back to Top)

• Jerry M. Collins, Raymond W. Klecker, Aspandiar G. Katki (FDA)
• DHHS Reference No. E-268-98/0 filed 16 Apr 99
• Licensing Contact: Girish C. Barua; 301-496-7056 ext. 263; email: gb18t@nih.gov.

This technology describes a method in which an inhibitor of an arylamine N-acetyl transferase (NAT), a member of a common enzyme family, is administered to a human to inhibit acetylation reactions resulting in production of cytotoxic or carcinogenic compounds in the treated individual. Nearly all drugs are metabolized in the human body by enzymes. Although metabolism generally lowers the toxicity of drugs, the opposite effect is often encountered with NAT. With NAT, the resulting metabolite is more toxic than the parent drug.

Administering an inhibitor of NAT with such drugs is believed to result in decreased toxicity to the patient because of reduced exposure to the metabolite. Reduced exposure to the metabolite is believed to be beneficial to patients because the reduction in toxicity results in the maximization of the benefits of the parent drug. Accordingly, this method could be utilized in many therapeutic areas, since drugs that are metabolized by NAT are used in most medical disciplines, including heart disease, infectious diseases, and oncology.

The technology also describes the acetylation capacity of NAT's link to human tumors. The acetylation capacity can be reduced by an enzyme inhibitor, which may lead to a decrease in human cancer. This concept identifies NAT as a novel target, to expand and improve a general strategy that is currently-emerging, known as "chemoprevention." Finally, the technology describes specific inhibitors of NAT in human hepatocoytes, e.g., para-amino salicylate (PAS) for NAT1 and dichlorphenamide for NAT2, which can be used either in chemoprevention of cancer or in conjunction with a chemotherapeutic which metabolizes NAT, potentially resulting in reduced toxicity to the patient. Since these inhibitors are currently marketed drugs, clinical development can be accelerated, and pilot studies are already underway.

N-Acylphosphoramidites And Their Use In Oligonucleotide Synthesis (Back to Top)

• Serge Beaucage et al. (FDA)
• DHHS Reference No. E-031-98/0 filed 24 Mar 99
• Licensing Contact: Charles Maynard; 301-496-7735 ext. 243; email: cm251n@nih.gov.

This technology relates to the synthesis of oligonucleotides, and intermediates useful in its synthesis. The therapeutic application of oligonucleotides is based on the selective formation of hybrids between antisense oligonucleotides and complimentary nucleic acids, such as messenger RNAs. Such hybrids inhibit gene expression by blocking protein translation. Successful inhibition of gene expression requires the antisense oligonucleotide to be nuclease resistant, so that it can be successfully transported through biological membranes and can hybridize selectively to a target complementary nucleic acid, thereby actively blocking protein translation. This present invention of synthesizing polymers has tremendous synthetic advantages that are unprecedented with respect to the synthesis of oligonucleotides, in that it enables the facile production of P-chiral oligomeric or polymeric products, with complete control of stereochemistry with respect to the phosphorous atom.

Methods For Inhibiting Chaperone Proteins (Back to Top)

• Monica G. Marcu, Leonard M. Neckers, Theodor W. Schulte (NCI)
• Serial No. 60/124,135 filed 12 Mar 99
• Licensing Contact: Girish C. Barua; 301-496-7056 ext. 263; email: gb18t@nih.gov.

This technology describes the use of an antibiotic, Novobiocin, that has been used clinically in people for many years. This compound and structural analogues such as chlorobiocin and coumermycin A1, which are coumarins, have been discovered to bind to Heat Shock Protein 90 (Hsp90), resulting in the destabilization and proteolytic degradation of a number of proteins whose function and stability depend on their association with Hsp90. These proteins include oncogenic kinases such as Raf, Her2/neu(erbB2), and Src, and transcription factors such as mutant p53. Novobiocin has demonstrated an ability to deplete Raf from the spleens of mice, suggesting that it may have anti-Hsp90 biologic properties in humans. Novobiocin and its analogues are an improvement over currently known chemotherapeutics such as geldanamycin, because these compounds lack both a quinone and a macrocycle in their chemical structure and are thus better tolerated and less toxic to humans at high dosages.

Identification And Use Of High Efficacy Vaccine Antigens (Back to Top)

• Ronald N. Germain (NIAID), Irena Stefanova (NIAID), Roland Martin (NINDS), Marco Vergelli (NINDS), Bernhard Hemmer (NINDS)
• Serial No. 60/124,064 filed 12 Mar 99
• Licensing Contact: Richard U. Rodriguez; 301-496-7056 ext. 287; email: rr154z@nih.gov.

The invention relates to the identification and use of high efficacy antigens or immunogens. Antigen-specific or adaptive immunity in higher vertebrates is mediated by lymphoid effector cells, T- and B-lymphocytes. T-lymphocytes have ab-receptors (TCR) that recognize ligands comprised of cell-surface molecules encoded in the major histocompatibility complex (MHC) bound to short peptide fragments of protein antigens. These antigen-specific effector T-lymphocytes are involved in resistance to infections, in anti-tumor immunity and in autoimmune-diseases. Studies have shown that activation of the TCR by a peptide-MHC complex triggers an intracellular biochemical signaling cascade. These studies have also shown that different peptide-MHC complexes can yield different levels of responses, thus affecting the effectiveness of an immune response to various disease states.

The inventors provide methods to efficiently identify optimized or heteroclitic-ligands (superagonists) which would have utility in the formation of anti-cancer and anti-pathogen vaccines with enhanced potency compared to the natural self or foreign peptide ligand. This is achieved by a "biochemical fingerprinting" process that involves the analysis of various phosphorylation patterns elicited in specific T-cells by TCR activation using peptide-MHC complexes. These patterns enable direct identification of how optimal a given ligand is for the test T-cells. When the initial ligand proves suboptimal by this technique, improved ligands can be identified by making variants of the original peptide, and then analyzing the phosphorylation patterns elicited by these variants until an optimal pattern is achieved. In this manner, specific peptides can be tested until a "superagonist" is isolated and development of this "superagonist" as a potential vaccine can proceed.

These methods provide a direct evaluation of the immunologic "quality" of an initial vaccine candidate. Their use should greatly reduce the number of potential antigen candidates that need to be researched and focus important resources on antigen candidates with superior potential to succeed.

Polymorphic Human GABAA Receptor Alpha-6 Subunit (Back to Top)

• Nakao Iwata, David Goldman, and Mark Shuckit (NIAAA)
• Reference Number E-061-98/0 filed 19 Feb 99
• Licensing Contact: Marlene Shinn; 301-496-7056 ext. 285; email: ms482m@nih.gov.

Human heritability studies using twins and adoptees have indicated that alcoholism is a complex disorder having a genetic component. Studies of children of alcoholics (COA) have determined that there is a differential decrease in sensitivity to benzodiazepine drugs (BZD) and ethanol within this specific population. g-Aminobutryric Acid (GABA) receptors are implicated in various neurological and psychiatric disorders. There are two major types of GABA receptors: A, which is associated with a Cl- channel; and B, which is associated with K+ and Ca2+ channels.

Differential expression of individual subunits of the multimeric protein appears to provide a mechanism for the body to convey different physiological functions. The a subunit displays benzodiazepine activity, and the a6 subunit has been associated with alcohol related activity. A proline-to-serine substitution at amino acid position 385 in the a6 subunit of the GABAA receptor within the COA population has displayed a statistical correlation to the average smooth pursuit eye movement after diazepam administration. The point mutation can be used as a genetic marker to investigate susceptibility to alcoholism as well as the biochemical and physiological responses to both pre- and post-treatment with benzodiazepines. It is also useful in the investigation of psychiatric disorders such as schizophrenia, affective disorder, or anxiety disorders in which abnormal function of the GABAergic neuronal system is implicated.

Identification Of The Geldanamycins As Inhibitors Of The HGF/SF-Met-uPA Proteolytic Network (Back to Top)

• Craig Webb, Curtis Hose, Anne P. Monks, George F. Vande Woude, Edward A. Sausville (NCI)
• Serial No. 60/119,114 filed 08 Feb 99
• Licensing Contact: Girish C. Barua; 301-496-7056 ext. 263; email: gb18t@nih.gov.

This technology describes a class of compounds (Geldanamycins) as important inhibitors to the HGF-SF-Met-uPA-plasmin signaling pathway. Considerable evidence demonstrates that the HGF-SF-Met pathway plays a significant role in the etiology of human cancers and the formation of secondary metastases. These compounds have the ability to revert certain transformed phenotypes through down regulation of the expression of the Met receptor at sub-nanomolar concentrations. Thus, these compounds could have utility in the treatment and therapy of invasive human cancers where the HGF-SF-Met pathway is implicated.

A Method of Immunizing Humans Against Salmonella typhi Using A Vi-rEPA Conjugate Vaccine (Back to Top)

• Zuzana Kossaczka, Shousun C. Szu and John B. Robbins (NICHD)
• Reference No. E-020-99/0 filed 04 Dec 98 (PCT/US98/25746)
• Licensing Contact: Robert Benson; 301-496-7056 ext. 267; email: rb20m@nih.gov

This invention is a method of immunizing against typhoid fever using a conjugate vaccine comprising the capsular polysaccharide of Salmonella typhi, Vi, conjugated through an adipic dihydrazide linker to nontoxic recombinant exoprotein A (rEPA) from Pseudomonas aeruginosa. The three licensed vaccines against typhoid fever, attenuated S. typhi Ty21a, killed whole cell vaccines and Vi polysaccharide, have limited efficacy, in particular for children under 5 years of age, which make an improved vaccine desirable. It is generally recognized that an effective vaccine against Salmonella typhi is one that increases serum anti-Vi IgG eight-fold six weeks after immunization. The conjugate vaccine of the invention increases anti-Vi IgG, 48-fold, 252-fold, and 400-fold in adults, 5–14 year-old children, and 2–4 year-old children, respectively. Thus, this is a highly effective vaccine suitable for children and should find utility in endemic regions and as a traveler's vaccine. The route of administration can also be combined with routine immunization. The synthesis of the conjugates, not including the superior clinical results, is described in Infection & Immunity 65(7), pp. 2088–2093, June 1997.

Antagonists Of The aEb7 Integrin As Therapeutic Agents For Inflammatory Diseases (Back to Top)

• Bjorn R. Ludviksson, Warren Strober, Rolf Ehrhardt (NIAID)
• Serial No. 60/109,957 filed 25 Nov 98
• Licensing Contact: Richard U. Rodriguez; 301-496-7056 ext. 287; email: rr154z@nih.gov.

The disclosed invention relates to a method of treating and/or preventing the inflammatory response of an autoimmune disease, an allergic disease, a graft-versus-host disease, and a transplantation rejection. In particular, this treatment or prevention is accomplished by administering antagonists of the aEb7 integrin. aEb7 is expressed on intra-epithelial lymphocytes (IELs) and on lamina propria (LP) lymphocytes. aEb7 can be upregulated by TGF-b, and it is speculated to have regulatory functions such as homing or retention. The pathogenesis of chronic intestinal inflammation may depend on the traffic of lymphocytes from sites of induction to sites of inflammation. The inventors have shown that chronic intestinal inflammation can be prevented and reversed in an IL-2 -/- murine model. Administration of anti-aEb7 prevents colonic inflammation and reverses pre-existing inflammation. Therefore, this technology can be used to treat, prevent, or reverse inflammatory conditions as well as providing a method of screening for substances effective in reducing the inflammatory effects of aEb7.

Modified HCV Peptide Vaccine (Back to Top)

• Jay A. Berzofsky (NCI), Pablo Sarobe (NCI), CD Pendleton (NCI), Stephen M. Feinstone (FDA)
• Serial No. 60/097,446 filed 21 Aug 98
• Licensing Contact: Carol Salata; 301-496-7735 ext. 232; email: cs253n@nih.gov.

Hepatitis C virus (HCV) is a single stranded RNA virus responsible for the majority of non-A, non-B hepatitis. Hepatitis C virus (HCV) has a worldwide distribution and is a major cause of liver cirrhosis and hepatocellular carcinoma in the US, Europe, and Japan. For this reason, development of a vaccine against hepatitis C is of great importance. The present invention provides immunogenic peptides of HCV core protein which elicit an enhanced immune response, methods for making these peptides, and methods for using these peptides for a variety of therapeutic, diagnostic, and prognostic applications, including a vaccine. More specifically, the present invention provides an isolated peptide, an isolated HCV core polypeptide, a fragment of an HCV core polypeptide, and nucleic acids that encode the peptides and polypeptides of this invention. The invention provides a modified HCV core peptide that is more immunogenic than the corresponding natural core peptide for eliciting human cytotoxic T lymphocytes.

Conformationally Locked Nucleoside Analogues (Back to Top)

• Victor E. Marquez, Juan B. Rodriguez, Marc C. Nicklaus, Joseph J. Barchi, Jr., Maqbool A. Siddiqui (NCI)
• U.S. Patent Numbers: 5,840,728 (filed August 7, 1997, with priority back to August 7, 1996); 5,869,666 (filed March 14, 1997); 5,629,454 (filed September 23, 1994, with priority back to September 24, 1993)
• Foreign Filing: PCT/US94/10794 (issued as European Patent Number 0720604 and Australian Patent Number 677441)
• Licensing Contact: Peter Soukas; 301/496-7056 ext. 268; e-mail: ps193c@nih.gov.

The compounds of the present invention represent the first examples of carbocyclic dedeoxynucleosides that in solution exist locked in a defined N-geometry (C3'-endo) conformation typical of conventional nucleosides. These analogues exhibit increased stability due to the substitution of carbon for oxygen in the ribose ring. The invention includes 4'-6'-cyclopropane fused carbocyclic dideoxynucleosides, 2'-deoxynucleosides and ribonucleosides as well as oligonucleotides derived from these analogues; the preferred embodiment of the invention is carbocyclic-4'-6'-cyclopropane-fused analogues of dideoxypurines, dideoxypyrimidines, deoxypurines, deoxypyrimidines, purine ribonucleosides, and pyrimidine ribonucleosides.

In addition, oligonucleotides derived from one or more of the nucleosides in combination with the naturally occurring nucleosides are within the scope of the present invention. The second invention discloses a method for the treatment of herpes virus infections by the administration of cyclopropanated carbocyclic 2'-deoxynucleosides to an affected individual. This invention is a method of administration of the compounds described above. The compounds of this invention are particularly efficacious against herpes simplex viruses 1 and 2 (HSV-1 and HSV 2), Epstein-Barr Virus (EBV) and human cytomegalovirus (CMV), although the nucleoside analogues of the invention may be used to treat any condition caused by a herpes virus. Specifically, the N-methanocarba-T (Thymidine) analogue has been shown to exhibit strong activity against HSV-1 and HSV-2, and moderate to strong activity against EBV. Significantly, the anti-HSV activity of the Thymidine analogue is stronger than that of Acyclovir (shown in a plaque reduction assay), a widely used anti-HSV therapeutic. Furthermore, the Thymidine analogue is also non-toxic against stationary cells and is potent against rapidly dividing cells. Dosage amounts for the compounds are similar to those of Acyclovir. Descriptions of the inventions may be found in Rodriguez et al., J. Medicinal Chemistry 37:3389 3399 (1994) and Marquez et al., J. Medicinal Chemistry 39:3739-3747 (1996).