[Federal Register Volume 64, Number 89 (Monday, May 10, 1999)]
[Notices]
[Pages 25052-25053]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 99-11659]


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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 invention listed below is owned by an agency of the U.S. 
Government and is 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.

ADDRESSES: Licensing information and a copy of the U.S. patent 
application referenced below may be obtained by contacting J.R. Dixon, 
Ph.D., at the Office of Technology Transfer, National Institutes of 
Health, 6011 Executive Boulevard, Suite 325, Rockville, Maryland 20852-
3804 (telephone 301/496-7056 ext 206; fax 301/402-0220; E-Mail: 
[email protected]). A signed Confidential Disclosure Agreement is required 
to receive a copy of any patent application.

SUPPLEMENTARY INFORMATION: .

Title: ``Monoclonal Antibodies Specific for Human Thymidylate 
Synthase''--Prognosticator of Breast and Colorectal Cancer Survival

    Inventors: Drs. Patrick G. Johnston (NCI), Carmen J. Allegra (NCI), 
Bruce A. Chabner (NCI) and Chi-Ming Liang (NCI).
    DHHS Ref. No.: E-137-90/0 [= USPA SN: 07/690,841--Filed April 24, 
1991].
    The fluoropyrimidines are an important group of antineoplastic 
agents that are widely used in the treatment of gastrointestinal 
tumors, breast tumors, and epithelial tumors of the upper aerodigestive 
tract. Thymidylate synthase (``TS'') catalyzes the methylation of 
deoxyurdine monophasphate (``dUMP'') to deoxythymidine monphosphate 
(``dTMP''). The de novo synthesis of dTMP is an essential step in the 
synthesis of pyrimidine nucleotides and DNA biosynthesis. Thymidylate 
synthase (``TS'') enzyme inhibition is one of the main biochemical 
events underlying the antineoplastic action of the fluropyrimidines 5-
fluorouracil (``5-FU'') and fluorodeoxyuridine (``FudR'').
    The clinical importance of Thymidylate synthase (``TS'') has been 
noted by several investigators who have demonstrated in vivo as well as 
in vitro that TS enzyme levels in neoplastic cells rise rapidly when 
cells are exposed to 5-fluorouracil. Thus, the ability of a tumor to 
acutely over express the TS enzyme may play a key role in the 
development of tumor resistance and may represent an important 
protective mechanism in response to this drug.
    The quantitation and detection of TS in human tissues has 
traditionally been performed by enzymatic biochemical assays that 
either measure catalytic activity or measure the amount of radiolabeled 
FdUMP binding to TS following extraction of the enzyme from cells and 
tissue. These assays have several limitations when applied to the 
measurement of TS activity in human tissue samples. While the assays 
have the required sensitivity for quantitating enzyme in vitro 
malignant cells in culture, they lack adequate sensitivity to measure 
the lower levels of enzyme activity in human tumors. Recently, 
monoclonal antibodies have been developed to human thymidylate synthase 
that have the required sensitivity and specificity to detect and 
quantitate thymidylate synthase enzyme in formalin-fixed tissue 
sections. These monoclonal antibodies to TS provide a method for 
determining the prognosis of a patient afflicted with breast cancer or 
with primary colorectal cancer by measuring the level of TS expression 
in biopsy tissue samples by using these antibodies specific to 
thymidylate synthase.
    These monoclonal antibodies further provide a method for predicting 
the benefit of chemotherapy for a patient afflicted with breast cancer. 
The aforementioned methodology is derived from the discovery that high 
thymidylate synthase expression is associated with a poor prognosis in 
node-positive, but not in node-negative breast cancer patients. 
Further, with some 2,500 patients, thymidylate synthase expression was 
not found to be correlated with other prognostic factors including 
tumor size, ER status, PR Status, tumor grade, vessel invasion, and 
histology.
    The expression of TS is also an important independent 
prognosticator of disease-free survival and overall survival in 
patients with colorectal cancer. In a study of the prognostic 
importance of the level of thymidylate synthase (``TS'') expression in 
patients with primary colorectal cancer, the level of TS expression in 
the primary rectal cancers of 294 of 801 patients was 
immunohistochemically assessed with the TS-106 monoclonal antibodies. 
Forty-nine percent of patients whose tumors had low TS levels were 
disease free at 5 years compared with 27% of patients with high levels 
of TS. Moreover, 60% of patients with low TS

[[Page 25053]]

levels were alive after 5 years compared with 40% of patients with high 
TS levels. The level of TS expression remained prognostic for both 
disease-free survival and survival independent of the stage of disease 
and other pathologic characteristics evaluated.
    The present invention relates to monoclonal antibodies that are 
specific for the protein thymidylate synthase, and TS-106 hybridoma 
producing these monoclonal antibodies. The invention further relates to 
methods of detection and diagnostic kits to test for the presence of 
thymidylate synthase.
    The above mentioned invention is available for licensing, including 
any foreign intellectual property rights, on an exclusive or non-
exclusive basis.

    Dated: April 29, 1999.
Jack Spiegel,
Director, Division of Technology Development and Transfer, Office of 
Technology Transfer.
[FR Doc. 99-11659 Filed 5-7-99; 8:45 am]
BILLING CODE 4140-01-M