Monoclonal Antibodies Specific And Inhibitory To Human Cytochrome P450 2C8, 2C9, 2C18 And 2C19 - New Avenues For Drug Discovery
Description of Invention:
The cytochrome P450 family of enzymes has primary responsibility for the metabolism of xenobiotic drugs and non-drug carcinogens and environmental chemicals, as well as some endobiotics. This laboratory has isolated monoclonal antibodies (MAbs) that are specific to and inhibit the ten major human cytochrome P450s (CYPs) that are responsible for the metabolism of most drugs. The MAb based analytic system identifies the P450s responsible for metabolism of a drug and is thus an entirely new system for Drug Discovery. Drug-drug toxicity can be due to drug partners competing for an individual P450 and be a cause of drug toxicity. Certain drugs given to genetically polymorphic individuals that are defective in a specific P450 can cause serious toxicity to the defective individual. In one case 6-10% of the world population are missing an important P450 (2D6).
The 2C family of cytochrome P450s metabolizes a very large and extensive number of drugs which include tolbutamide, S-Warfarin, mephenytoin, diazepam and taxol. The invention reports the production of inhibitory MAbs to the P450 2C family. The invention describes MAb 5-1-5 and 281-1-1 that specifically inhibit CYP 2C8, MAb 292-2-3 that specifically inhibits CYP 2C9, and MAb 592-2-5 that specifically inhibits both CYP 2C9 and 2C18. MAb 5-7-5 specifically inhibits CYP 2C9, 2C18, and 2C19. In addition MAb 1-68-11 previously reported specifically inhibits all four members of the 2C family, 2C8, 2C9, 2C18 and 2C19. The MAbs may be used as diagnostic probes identifying the single or several P450s responsible for a drugs metabolism and also yield important information on inter-individual differences. The MAb system identifies and characterizes the P450 based metabolism of drugs currently in use and drugs in the screening and development stages of Drug Discovery.
Inventors:
Harry V. Gelboin (NCI) Frank J. Gonzalez (NCI) Kristopher W. Krausz (NCI)
Cancer -Diagnostics-In Vitro-MAb Based Cancer -Diagnostics Cancer -Research Materials Internal Medicine-Diagnostics Internal Medicine-Research Materials
For Additional Information Please Contact: Fatima Sayyid M.H.P.M.
NIH Office of Technology Transfer
6011 Executive Blvd, Suite 325
Rockville, MD 20852-3804
Phone: (301) 435-4521
Email: sayyidf@mail.nih.gov
Fax: (301) 402-0220
