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###### Department of Health and Human Services

###### National Institutes of Health

# 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: 301/496-7057; fax: 301/402-0220. A signed Confidential Disclosure Agreement will be required to receive copies of the patent applications.

## Treatment of Cancer Using Metal Coordinating Compounds That Kill Multi-Drug Resistant Cancer Cells

*Description of Invention:*                     One of the major hindrances to successful cancer chemotherapy is the development of multi-drug resistance (MDR) in cancer cells. MDR is frequently caused by the increased expression or activity of ABC transporter proteins in response to the toxic agents used in chemotherapy. Research has generally been directed to overcoming MDR by inhibiting the activity of ABC transporters. However, compounds that inhibit ABC transporter activity often elicit strong and undesirable side-effects, restricting their usefulness as therapeutics.                

                    In an alternative approach to reducing the debilitating effects of MDR during cancer therapy, scientists at the NIH have identified a family of compounds                           ( print page 38441)                        whose activities are enhanced, rather than decreased, in MDR cancer cells. Particular embodiments of these “MDR-selective compounds” include certain metal coordinating compounds. Recent evidence suggests that these MDR-selective compounds can be used to kill cancer cells that overexpress ABC transporters or to re-sensitize multi-drug resistant cancer cells to chemotherapeutics. Furthermore, the effectiveness of these compositions in killing MDR cancer cells correlates directly with the level of ABC transporter expression. Importantly, MDR-selective compounds are not inhibitors of ABC transporters, thereby reducing the likelihood of undesirable side-effects during treatment. Thus, MDR-selective compounds represent a powerful strategy for treating multi-drug resistant cancers as a direct chemotherapeutic and as agents that can re-sensitize MDR cancer cells for treatment with additional chemotherapeutic agents.                

### Applications

      - Treatment of cancers associated with multi-drug resistance, either alone or in combination with other therapeutics.
      - Re-sensitization of multi-drug resistant cancer cells to chemotherapeutic agents.

### Advantages

      - MDR-selective compounds capitalize on one of the most common drawbacks to cancer therapies (MDR) by using it as an advantage for treating cancer.
      - The compositions do not inhibit the function of ABC transporters, reducing the chance of side-effects during treatment.
      - The effects of MDR-selective compounds correlate with the level of ABC transporter expression, allowing healthy cells which do not express high levels of ABC transporters to better survive treatment.

*Development Status:*                     Preclinical stage of development.                

*Patent Status:*                     U.S. Provisional Application No. 61/182,511 (HHS Reference No. E-157-2009/0-US-01).                

*Inventors:*                     Gergely Szakacs                     *et al.*                     (NCI).                

### *For More Information, See*

      - C Hegedus et al.                      Interaction of ABC multidrug transporters with anticancer protein kinase inhibitors: substrates and/or inhibitors? Curr Cancer Drug Targets. 2009 May;9(3):252-272.                
      - MD Hall et al.                      Synthesis, activity, and pharmacophore development for isatin-beta-thiosemicarbazones with selective activity toward multidrug-resistant cells. J Med Chem. 2009 May 28;52(10):3191-3204.                
      - U.S. Patent Application Publication 20080214606 A1 (U.S. Patent Application 11/629,233).

*Licensing Status:*                     Available for licensing.                

*Licensing Contact:*                     David A. Lambertson, Ph.D.; 301-435-4632;                     *lambertsond@mail.nih.gov*.                

*Collaborative Research Opportunity:*                     The Institute of Enzymology is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize MDR-selective compounds. Please contact John D. Hewes, Ph.D. at 301-435-3121 or                     *hewesj@mail.nih.gov*                     for more information.                

## Non Toxic Peptide Treatment for Dyslipidemic and Vascular Disorders

*Description of Invention:*                     Dyslipidemia and vascular disorders such as hyperlipidemia, hypercholesterolemia, HDL deficiency, coronary heart disease, atherosclerosis, or thrombic stroke, have become major health concerns in recent years. Various approaches to treating these diseases have led to mixed success with some undesirable side effects. Long term administration of some regimens aimed at reducing cholesterol levels in cells can lead to persistent hypertriglyceridemia; a condition that is characterized by chronically high triglycerides in the blood. Other approaches, such as using peptides to stimulate the efflux of lipids from cells, are also associated with high toxicity, which has limited their use.                

This technology uses peptide and peptide analogues with multiple amphipathic alpha helical domains that have the dual ability to promote lipid efflux from cells and stimulate lipoprotein lipase activity, without inducing toxicity. It consists of motifs that mimick apolipoprotein A-I (apoA-I), the most abundant protein constituent of high density lipoproteins (HDLs) that is capable of inducing cellular lipid efflux, and motif resembling apolipoprotein C-II (apoC-II), a known activator of lipoprotein lipase. Peptides constructed with these structural domains are capable of stimulating lipid efflux and activating lipoprotein lipase, leading to a reduced incidence of hypertriglyceridemia. Unlike previous methods, some amphipathic peptides cause transient hypertriglyceridema in mice that lasts for less than 8 hours. Mice treated with these modified peptides have shown preserved liver function as they have failed to express increased levels of biomarkers for liver damage and prevent hypertriglyceridemia. Furthermore, treated mice show a reduced level of pro-atherogenic lipoproteins. This technology demonstrates specific control of lipid efflux and transport; a desirable property that gives it a significant advantage for treating or preventing a vast range of vascular diseases and their dyslipidemic precursors.

This technology also encompasses a method for identifying non-cytotoxic peptides that promote lipid efflux from cells and activates lipoprotein lipase.

### Applications and Advantages

      - Peptide treatment of dyslipidemic and vascular disorders.
      - Transient hypertriglyceridemia with no reported toxicity.
      - Method of identifying therapeutic non-cytotoxic peptides.

*Development Status:*                     Pre-clinical.                

*Inventor:*                     Alan T. Remaley and Marcelo Amar (NHLBI).                

*Publication:*                     AT Remaley, F Thomas, JA Stonik, SJ Demosky, SE Bark, EB Neufeld, AV Bocharov, TG Vishnyakova, AP Patterson, TL Eggerman, S Santamarina-Fojo, HB Brewer. Synthetic amphipathic helical peptides promote lipid efflux from cells by an ABCA1-dependent and an ABCA1-independent pathway. J Lipid Res. 2003 Apr;44(4):828-836.                

*Patent Status:*                     U.S. Provisional Application No. 60/045,213 filed 15 Apr 2008 (HHS Reference No. E-138-2008/0-US-01); PCT Application No. PCT/US2009/040560 filed 14 Apr 2009 (HHS Reference No. E-138-2008/0-PCT-02).                

*Licensing Status:*                     Available for licensing.                

*Licensing Contact:*                     Fatima Sayyid, M.H.P.M.; 301-435-4521;                     *sayyidf@mail.nih.gov*.                

## Methods for Treating or Ameliorating Fibrosis by Inhibiting the Interaction Between IL-21 Receptor (IL-21R) and IL-21

*Description of Invention:*                     This invention includes methods for treating or ameliorating fibrosis by inhibiting the interaction between IL-21 Receptor (IL-21R) and IL-21 using either anti-IL21R monoclonal antibodies (or binding fragments of anti-IL-21R mAbs), anti-IL21 monoclonal antibodies (or binding fragments of anti-IL-21 mAbs) or soluble IL-21R (or binding fragments of IL-21R). It is believed that the TH2 immune response, induced by IL-21, plays a major role in the pathogenesis of tissue fibrosis. Antagonism of IL-21R by anti-IL-21R monoclonal antibodies or the sequestration of IL-21 by soluble IL-                          ( print page 38442)                        21R or anti-IL-21 monoclonal antibodies has been demonstrated to reduce TH2 immune responses associated with fibrosis in animal models.                

The causes of chronic tissue fibrosis are diverse and the market for a therapeutic that targets fibrosis is large. Fibrosis is associated with diverse causes which include: genetic diseases (such as cystic fibrosis); autoimmune diseases (such as scleroderma); chronic viral infections (such as hepatitis), parasitic infections (such as schistosomiasis); and occupational exposures to causative agents (such as asbestosis). Additionally, many cases of tissue fibrosis are idiopathic.

*Application:*                     The treatment or amelioration of tissue fibrosis.                

*Inventors:*                     Thomas A. Wynn (NIAID); Deborah A Young; Mary Collins; and Michael J. Grusby.                

*Relevant Publication:*                     J Pesce                     *et al.*                     The IL-21 receptor augments Th2 effector function and alternative macrophage activation. J Clin Invest 2006 Jul;116(7):2044-2055.                

*Patent Status:*                     U.S. patent application no. 11/402,885 (priority date April 14, 2005) and international patent applications including European patent application No. EP06/0750009 (HHS Reference No. E-250-2005).                

*Licensing Status:*                     Available for non-exclusive licensing.                

*Licensing Contact:*                     Surekha Vathyam, Ph.D.; 301-435-4076;                     *vathyams@mail.nih.gov*.                

*Collaborative Research Opportunity:*                     The National Institute of Allergy and Infectious Diseases is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize this invention. Please contact Nicole Mahoney at 301-435-9017 or                     *mahoneyn@niaid.nih.gov*                     for more information.                

## Use of Discoidin Domain Receptor 1 (DDR1) and Agents That Affect the DDR1/Collagen Pathway

*Description of Invention:*                     Dendritic cells (DCs) are pivotal antigen-presenting cells for initiation of an immune response. Indeed, dendritic cells provide the basis for the production of an effective immune response to a vaccine, particularly for antigens wherein conventional vaccination is inadequate. DCs are also important in the production on an immune response to tumor antigens.                

The present invention discloses methods of using the receptor tyrosine kinase discoidin domain receptor 1 (DDR1) to facilitate the maturation/differentiation of DCs or macrophages. Activating agents of DDR1 may be useful in the induction of highly potent, mature DCs or highly differentiated macrophages from DC precursors, such as monocytes. Use of this method may enhance the antigen presenting capabilities of the immune system, leading to a more effective overall immune response.

*Inventor:*                     Teizo Yoshimura (NCI).                

### Relevant Publications

                    1. H Kamohara                     *et al.*                     Discoidin domain receptor 1 isoform-a (DDR1a) promotes migration of leukocytes in three-dimensional collagen lattices. FASEB J. 2001 Dec;15(14):2724-2726.                

                    2. W Matsuyama                     *et al.*                     Interaction of discoidin domain receptor 1 isoform b (DDR1b) with collagen activates p38 mitogen-activated protein kinase and promotes differentiation of macrophages. FASEB J. 2003 Jul;17(10):1286-1288.                

*Patent Status:*                     U.S. Application No. 10/507,385 filed 09 Sep 2004 (HHS Reference No. E-083-2002/2-US-02).                

*Licensing Status:*                     Available for licensing.                

*Licensing Contact:*                     Betty B. Tong, Ph.D.; 301-594-6565;                     *tongb@mail.nih.gov*.                

Dated: July 28, 2009.

Richard U. Rodriguez,

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

[FR Doc. E9-18504 Filed 7-31-09; 8:45 am]

BILLING CODE 4140-01-P