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National Institutes of Health, Public Health Service, DHHS.
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.
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.
Monoclonal Antibodies (MAbs) Define Human Cytochrome P450 Drug Metabolism
Harry V. Gelboin et al. (NCI)
Licensing Contact: Fatima Sayyid; 301/435-4521; firstname.lastname@example.org.
The application of the invention reported herein will be useful for reducing the incidence of adverse drug reactions (ADR) causing serious toxicity and mortality from certain drugs and toxicity from drug-drug interactions (DDI). The MAb system will be useful in the search for new drugs in Drug Discovery. The system engages the use of specific inhibitory monoclonal antibodies (MAbs) to identify, measure and quantitate the role of each human Cytochrome P450 in the metabolism of drugs, NCEs (new chemical entities) or xenobiotics that can be toxic to the human population. Hybridoma clones have been isolated that produce MAbs uniquely specific to human P450s 1A1, 1A2, 2A6, 2C8, 2C9, 2C9*2, 2C19, 2C family (8,9,18,19), 2D6, 2E1, and 3A4/5. The MAbs are highly inhibitory (80-90%) to the enzyme activity of the target P450 and thus the amount of inhibition of the metabolism of the substrate drug incubated with human liver microsomes defines the maximum contribution of the target P450 to the metabolism of the drug or other substrate. The MAbs also immunoblot the target P450 permitting the identification of the target P450 in cells and tissues. In stark contrast to other complex commonly used analytic systems that are selective, the MAb system is specific to the target P450 and is the basis for an extraordinary simple in vitro methodology. The microsome-MAb system (in vitro) defines the contribution of the target P450 to the metabolism of the substrate and identifies substrates metabolized by a single or multiple P450s and P450s catalyzing alternate metabolic pathways. Substrates metabolized by a single P450 or through a specific metabolic route can be used as a marker probe (in vivo) for examining the role of different P450 isoforms in the metabolism of drugs. They are also used for individual phenotyping for studying the genetic potential for individual drug metabolism. Additional applications include the study of polymorphic P450s to identify the metabolic consequences of the absence of a polymorphic P450 in an individual. The MAbs, listed below, are present in ascites fluid and are generally useful for all of the procedures described above. Some are also available in purified form.
|Human P450||Monoclonal antibody (MAb clone #)||DHHS reference No.|
|2C8, 9, 18, 19||1-68-11||B-043-1994/0|
Additionally, the following MAbs are non-inhibitory, but yield an Immunoblot:
|Human P450||Monoclonal antibody (MAb clone #)||DHHS reference No.|
These MAbs are further described in the following research articles:
Gelboin HV, Krausz KW, Gonzalez FJ, and Yang TJ (1999). Inhibitory Monoclonal Antibodies to Human Cytochrome P450 Enzymes: A New Avenue for Drug Discovery. Trends Pharmacol Sci 20(11):432-438.
Gelboin HV, Shou M, Goldfarb I, Yang TJ and Krausz KW (1998). Monoclonal Antibodies to Cytochrome P450 in Methods in Molecular Biology: Cytochrome P450 Protocols. (IR Phillips and EA Shephard, eds) pp 227-237, Humana Press Inc., Totowa, New Jersey.
Yang TJ, Krausz KW, Sai Y, Gonzalez FJ and Gelboin HV (1999). Eight Inhibitory Monoclonal Antibodies Define the Role of Individual P450s in Human Liver Microsomal Diazepam, 7-Ethoxycoumarin and Imipramine Metabolism. Drug Metab Dispos 27: 102-109.
Yang TJ, Sai Y, Krausz KW, Gonzalez FJ and Gelboin HV (1998a). Inhibitory Monoclonal Antibodies to Human Cytochrome P450 1A2: Analysis of Phenacetin o-Deethylation in Human Liver. Pharmacogenetics 8:375-382.
Sai Y, Yang TJ, Krausz KW, Gonzalez FJ and Gelboin HV (1999). An Inhibitory Monoclonal Antibody to Human Cytochrome P450 2A6 Defines its Role in the Metabolism of coumarin, 7-ethoxycoumarin and 4-nitroanisole in Human Liver. Pharmacogenetics 9:229-237.
Yang TJ, Krausz KW, Shou M, Yang SK, Buters JTM, Gonzalez FJ and Gelboin HV (1998b). Inhibitory Monoclonal Antibody to Human Cytochrome P450 2B6. Biochem Pharmacol 55:1633-1640.
Krausz KW, Goldfarb I, Yang TJ, Gonzalez FJ, and Gelboin HV (2000). An Inhibitory Monoclonal Antibody to Human Cytochrome P450 that Specifically Binds and Inhibits P450 2C9II, an Allelic Variant of P450 2C9 Having a Single Amino Acid Change Arg144 Cys. Xenobiotica 30:619-625.
Krausz KW, Goldfarb I, Buters JTM, Yang TJ, Gonzalez FJ, and Gelboin HV (2001). Monoclonal Antibodies Specific and Inhibitory to Human Cytochromes P450 2C8, 2C9, and 2C19. Drug Metab Dispos 29: 1410-1423.
Krausz KW., Yang TJ., Shou M, Gonzalez FJ and Gelboin, HV (1997). Inhibitory Monoclonal Antibodies to Human Cytochrome P450 2D6. Biochem Pharmocol. 54:15-17.
Gelboin HV, Krausz KW, Shou M, Gonzalez FJ and Yang TJ (1997). A Monoclonal Antibody Inhibitory to Human P450 2D6: A Paradigm for Use in Combinatorial Determination of Individual P450 Role in Specific Drug Tissue Metabolism. Pharmacogenetics 7:469-477.
Gelboin HV, Goldfarb I, Krausz KW, Grogan J, Korzekwa KR, Gonzalez FJ and Shou M (1996). Inhibitory and Noninhibitory Monoclonal Antibodies to Human Cytochrome P450 2E1. Chem Res Toxicl. 9:1023-1030.
Gelboin HV, Krausz KW, Goldfarb I, Buters JTM, Yang SK, Gonzalez FJ, Korzekwa KR and Shou M (1995). Inhibitory and Non Inhibitory Monoclonal Antibodies to Human Cytochrome P450 3A3/4. Biochem Pharmacol 50:1841-1850.Start Signature
Dated: June 5, 2004.
Steven M. Ferguson,
Director, Division of Technology Development and Transfer, Office of Technology Transfer, National Institutes of Health.
[FR Doc. 04-13890 Filed 6-18-04; 8:45 am]
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