Anti-Notch-1 Monoclonal Antibodies for Inducing Cellular Differentiation and Apoptosis
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.
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.
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 differentiation inducing agent is disclosed as is the hybridoma which produces these antibodies.
Bill Ronnenberg, JD-MIP, MS
FDA Technology Transfer Program
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Building WO1, Rm 4214
Silver Spring, MD 20993
OTT Reference No: E-176-1998/1
Updated: August 9, 2015