[Federal Register Volume 64, Number 232 (Friday, December 3, 1999)]
[Notices]
[Pages 67925-67926]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 99-31343]


-----------------------------------------------------------------------

DEPARTMENT OF HEALTH AND HUMAN SERVICES

National Institutes of Health


Government-Owned Invention; Availability for Licensing: ``Novel 
Method and Composition to Induce Apoptosis in Tumor Cells''

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, 
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: Invention Title: ``Anti-Notch-1 Monoclonal 
Antibodies for Inducing Cellular Differentiation and Apoptosis'' 
Inventors: Drs. Lucio L Miele (U.S.F.D.A.) and Chana Y. Fuchs 
(U.S.F.D.A.) USPA SN: 60/124,119--Filed with the U.S.P.T.O. March 12, 
1999
    Apoptosis or programmed cell death is caused by many anti-tumor 
drugs and by radiation therapy. These treatment modalities cause 
apoptosis in tumor cells and in many normal cells in the body. As 
cancer cells progress towards more aggressive forms, they often become 
highly resistant to drug or radiation-induced apoptosis, generally 
through the loss of function p53, a gene which can trigger apoptosis in 
response to DNA damage. Thus, novel strategies to induce apoptosis in 
tumor cells, especially p53-deficient cells, is an attractive and an 
active area of research.
    Notch-1 is expressed at high levels in several human tumors. 
However, its function in tumor cells has not been characterized. So 
far, its role in maintaining tumor cell survival has not been 
identified. Using a model constituted by a p53-deficient mouse leukemia 
cell line, PHS scientists found that: (1) Antisense synthetic DNA 
oligonucleotides and stable incorporation of an antisense gene (a model 
for gene therapy) targeting notch-1, when given together with a 
differentiation-inducing antitumor drug, cause the cells to respond by 
massive apoptosis rather than differentiation; (2) stable incorporation 
of an antisense notch-1 gene increases apoptosis in these cells even in 
the absence of any antitumor drugs. This suggests that antisense notch-
1 treatment, by antisense oligonucleotides or by gene therapy, may be 
used alone or together with anti-cancer drugs to cause apoptosis in 
tumor cells.
    The notch gene belongs to a family of epidermal growth factor 
(``EGF'') like homeotic genes, which encode transmembrane proteins with 
a variable number of cystgeine-rich EGF-like repeats in the 
extracellular region. Four notch genes have been described in mammals, 
which include notch-1, notch-2, notch-3, and notch-4 (Int-3), which 
have been implicated in the differentiation of the nervous system and 
other structures. The EGF-like proteins Delta and Serrate have been 
identified as ligands of notch-1.
    Mature notch proteins are heterodimeric receptors derived from the 
cleavage of notch pre-proteins into an extracellular subunit 
(NEC) containing multiple EGF-Like repeats and a 
transmembrane subunit including intracellular region (Ntm). 
Notch activation results from the binding of ligands expressed by 
neighboring cells, and signaling from activated notch involves network 
of transcription regulators.
    Alteration of notch-1 signaling or expression may contribute to 
tumorigenesis. Deletions of the extracellular portion of human notch-1 
are associated with about 10% of the cases of T-Cell acute 
lymphoblastic leukemia. Truncated forms of notch-1 cause T-Cell 
lymphomas when introduced into mouse bone marrow stem cells and are 
onogenic in rat kidney cells. The human notch-1 gene is in a 
chromosomal region (9q34)

[[Page 67926]]

associated with hematopoietic malignancies of lymphoid, myeloid, and 
erythroid lineage. Additionally, strikingly increased expression of 
notch-1 has been documented in a number of human tumors including 
cervical cancer, colon tumors, lung tumors, and pre-neoplastic lesions 
of the uterine cervix.
    Notch antisense oligonucleotides (or other molecules that interfere 
with the expression or function of notch) could be therapeutically 
administered to treat or prevent tumors. It has not been found that 
administration of notch antisense oligonucleotides alone is effective 
as an anti-neoplastic treatment. The present invention has overcome 
this problem by combining the administration of a cell differentiation 
agent with an antibody that antagonizes the function of a notch protein 
and hence interferes with the expression or function of a notch protein 
(such as the notch-1 protein). This combination of approaches has 
unexpectedly been found to induce apoptosis in neoplastic cells, and 
provide a useful therapeutic application of this technology.
    In particular the tumor cell is one that is characterized by 
increased activity or increased expression of a notch protein, such as 
a notch-1 or notch-2 protein. Examples of tumor types that over express 
notch-1 include cervical cancer, breast cancer, colon cancer, melanoma, 
seminoma, lung cancer and hematopoietic malignancies, such as erythroid 
leukemia, myeloid leukemia, (such as chronic or acute myelogenous 
leukemia), neuroblastoma and medulloblastoma. The differentiation 
inducing agent to which the cell is exposed can be selected from a 
broad variety of agents, including retinoids, polar compounds (such as 
hexamethylene bisacetanmide), short chain fatty acids, organic acids, 
Vitamin D derivatives, cyclooxygenase inhibitors, arachidonate 
metabolism inhibitors, ceramides, diacylglycerol, cyclic nucleotide 
derivatives, hormones, hormone antagonists, biologic promoters of 
differentiation, and derivatives of any of these agents.

Technology

    This invention provides compositions, pharmaceutical compositions, 
and methods for stimulating/increasing cell differentiation, and is 
particularly related to the treatment of tumors which have increased 
notch-1 expression. A polyclonal and/or monoclonal antibody generated 
against human Notch-1 Epidermal Growth Factor (``EGF'') that recognizes 
an extracellular epitope of notch-1 and that stimulates target cell 
differentiation in the presence of an effect amount of differentiation 
inducing agent is disclosed as is the hybridoma which produces these 
antibodies. At a time during which differentiation has been promoted, 
and the cell is susceptible to interference with the anti-apoptosis 
effect of notch, the function of the notch protein is disrupted. 
Disruption of notch function can be achieved, for example, by the 
expression of antisense oligonucleotides that specifically interfere 
with expression of the notch protein on the cell, or by monoclonal 
antibodies that specifically bind to notch and inactivate it. This 
technology represents a novel method to induce apoptosis in tumor 
cells.
    The above mentioned Invention is available, including any available 
foreign intellectual property rights, for licensing.

    Dated: November 24, 1999.
Jack Spiegel,
Director, Division of Technology Development & Transfer, Office of 
Technology Transfer.
[FR Doc. 99-31343 Filed 12-2-99; 8:45 am]
BILLING CODE 4140-01-P