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Method of treating cancer with anti-neurotrophin agents

A neurotrophic protein and cancer technology, applied in the field of oncology and neurotrophic protein, can solve unsatisfactory problems

Inactive Publication Date: 2003-05-28
CEPHALON INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Antibodies against specific trk receptors have been shown to be less ideal than small molecules for this purpose (LeSauteur et al., Nature Biotech., 1996, 14, 1120)

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment Embodiment 1

[0053] EXAMPLES Example 1: Neutralization of trk receptors by anti-NGF

[0054] Antibodies were injected into PC-3 and / or TSU-pr1 xenografts previously shown to respond to CEP-751 (Dionne et al., Clin. Canc. Res., 1998, 4, 187- 1898). The following experiments were performed to confirm the neutralizing ability of anti-neurotrophin antibodies.

[0055]Anti-NGF antibody reduces ligand-stimulated trk autophosphorylation in NIH3T3-trkA cells. NGF (10 ng / ml) and various concentrations of antibodies were pre-incubated in 6 ml tissue culture medium. The NGF / antibody mixture was added to NIH3T3-trkA cells. Trk protein was immunoprecipitated from lysates using the pan-Trk antibody CEP-21, and samples were probed on immunoblots with anti-phosphotyrosine antibody 4G10. Optical density scan values ​​(integer OD units) are as follows (as displayed by NGF (10ng / ml) / anti-NGF (μg / ml)): - / - channel, 0.3; + / - channel, 6.5; 0.001 mg / ml, 5.0; 0.01 mg / ml, 4.5; 0.1 mg / ml, 2.5; 1.0 mg / ml, 3.1; ...

Embodiment 2

[0055]Anti-NGF antibody reduces ligand-stimulated trk autophosphorylation in NIH3T3-trkA cells. NGF (10 ng / ml) and various concentrations of antibodies were pre-incubated in 6 ml tissue culture medium. The NGF / antibody mixture was added to NIH3T3-trkA cells. Trk protein was immunoprecipitated from lysates using the pan-Trk antibody CEP-21, and samples were probed on immunoblots with anti-phosphotyrosine antibody 4G10. Optical density scan values ​​(integer OD units) are as follows (as displayed by NGF (10ng / ml) / anti-NGF (μg / ml)): - / - channel, 0.3; + / - channel, 6.5; 0.001 mg / ml, 5.0; 0.01 mg / ml, 4.5; 0.1 mg / ml, 2.5; 1.0 mg / ml, 3.1; 10.0 mg / ml, 2.1; 100 mg / ml, 1.1. Thus, in cells treated with 10 ng / ml NGF for 5 minutes, anti-NGF (Pepro Tech, Inc., 500-P85) at a concentration of 100 μg / ml reduced trk phosphorylation by approximately 80% relative to no anti-NGF treatment. Example 2: Neutralization of trk receptors by anti-NT-3

[0056] Anti-NT-3 antibody reduces ligand-stimula...

Embodiment 3

[0057] The following examples show the results of experiments on the antitumor activity of the antibodies of the present invention. The tumor models used in these experiments were prostate and pancreatic cancer xenografts in nude mice, which are well known to those skilled in the art as preferred preclinical animal models that correlate with in vivo clinical outcomes. Recent references showing the specific relevance of these xenograft models to corresponding human diseases include Plonowski et al., Cancer Res., 1999, 59, 1947, Joseph et al., Cancer Res., 1997, 57, 1054, Pinski et al. , Int. J. Cancer, 1993, 55, 963, Gao et al., Cancer Res., 1998, 58, 1391, and Tan et al., Tumor Biology, 1985, 6, 89. Example 3: Inhibition of PC-3 Prostate Cancer Xenograft Growth by Neurotrophin Antibodies

[0058] The following neurotrophin antibodies were used: anti-NGF (Pepro Tech 500-P85), anti-BDNF (Pepro Tech 500-P84), anti-NT-3 (Pepro Tech 500-P82), anti-NT-4 / 5 (Pepro Tech 500- P83). A...

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PUM

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Abstract

A method of treating or preventing cancer by administering to a mammal a therapeutically effective amount of at least one anti-neurotrophin agent is described. The anti-neurotrophin agent is preferably an anti-neurotrophin antibody, an antisense molecule directed to a neurotrophin, a small organic molecule which binds a neurotrophin, or a dominant-negative mutation of a trk receptor that binds a neurotrophin. This method is particularly preferred for the treatment of prostate or pancreatic cancer. The anti-neurotrophic agents neutralize NGF, BDNF, NT-3, NT-4 / 5, NT-6 or NT-7 and include humanized antibodies as well as fragments thereof.

Description

field of invention [0001] The present invention relates to the field of oncology and is directed to methods of treating or preventing cancer, especially prostate and pancreatic cancer. The present invention also relates to the field of neurotrophins, and the use of anti-neurotrophins agents, such as antibodies, in the treatment or prevention of cancer and / or pain. Background of the invention [0002] Neurotrophin (NT) belongs to a subfamily of specific neurotrophin factors, including four well-known structurally and functionally related proteins: nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT -3) and neurotrophin-4 / 5 (NT-4 / 5). Two additional NTs, neurotrophin-6 (NT-6) and neurotrophin-7 (NT-7), have recently been discovered. Neurotrophins bind and activate specific cell surface membrane receptors with tyrosine kinase activity. These receptors are known as trk receptors and are classified according to subtype as trkA, trkB and trkC....

Claims

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Application Information

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IPC IPC(8): C12N5/06A61K31/7088A61K39/395A61K45/00A61K48/00A61P1/18A61P13/08A61P25/00A61P25/04A61P35/00A61P43/00C07K16/22
CPCC07K16/22A61K2039/505A61P1/18A61P13/08A61P25/00A61P25/04A61P35/00A61P43/00
Inventor 卡伦·J·布奇科维奇克雷格·A·迪翁希拉·J·米克尼奥茨基布鲁斯·A·鲁杰里
Owner CEPHALON INC
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