[Federal Register Volume 69, Number 118 (Monday, June 21, 2004)]
[Notices]
[Pages 34376-34377]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 04-13890]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

National Institutes of Health


Government-Owned Inventions; Availability for Licensing

AGENCY: National Institutes of Health, Public Health Service, DHHS.

ACTION: Notice.

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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.

Monoclonal Antibodies (MAbs) Define Human Cytochrome P450 Drug 
Metabolism

    Harry V. Gelboin et al. (NCI)
    Licensing Contact: Fatima Sayyid; 301/435-4521; 
[email protected].
    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.

 Inhibitory Monoclonal Antibodies (MAbs) to Human Liver Cytochrome P450s
------------------------------------------------------------------------
                                      Monoclonal
           Human P450                antibody (MAb    DHHS reference No.
                                   clone )
------------------------------------------------------------------------
1A1.............................               1-7-1        B-043-1994/0
1A2.............................             *26-7-5        E-122-1998/0
2A6.............................           *151-45-4        E-150-1998/0
2B6.............................           *49-10-20        B-043-1994/1
2C8, 9, 18, 19..................             1-68-11        B-043-1994/0
2C8.............................            *281-1-1        E-077-1999/0
2C9*1,*2,*3.....................           1763-15-5        E-077-1999/0
2C9*2...........................            1292-2-3        E-077-1999/0
2C19............................             1-7-4-8        E-200-2001/0
2D6.............................     *512-1-8 50-1-3        E-046-1997/0
2E1.............................             1-73-18        E-185-1995/0
3A4/5...........................              3-29-9       E-185-1995/0
------------------------------------------------------------------------
*Also Immunoblots.


[[Page 34377]]

    Additionally, the following MAbs are non-inhibitory, but yield an 
Immunoblot:

------------------------------------------------------------------------
                                      Monoclonal
           Human P450                antibody (MAb    DHHS reference No.
                                   clone )
------------------------------------------------------------------------
2E1.............................            2-106-12        E-185-1995/0
3A4.............................             275-1-2        E-185-1995/0
------------------------------------------------------------------------

    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.

    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]
BILLING CODE 4140-01-P