[Federal Register: May 10, 1999 (Volume 64, Number 89)] [Notices] [Page 25052-25053] From the Federal Register Online via GPO Access [wais.access.gpo.gov] [DOCID:fr10my99-90] ----------------------------------------------------------------------- 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. ----------------------------------------------------------------------- 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: jd212g@NIH.GOV). 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