Title:
EPHA2, HYPOPROLIFERATIVE CELL DISORDERS AND EPITHELIAL AND ENDOTHELIAL RECONSTITUTION
Document Type and Number:
WIPO Patent Application WO2004092343
Kind Code:
A3
Abstract:
The present invention relates to methods and compositions designed for the treatment, management, or prevention of a hypoproliferative cell disorder, especially those disorders relating to the destruction, shedding, or inadequate proliferation of epithelial and/or endothelial cells, particularly interstitial cystitis (IC) and lesions associated with inflammatory bowel disease (IBD). The methods of the invention comprise the administration of an effective amount of one or more agents that are antagonists of EphA2. In certain embodiments, the EphA2 antagonistic agent of the invention decreases EphA2endogenous ligand binding, upregulates EphA2 gene expression and/or translation, increases EphA2 protein stability or protein accumulation, decreases EphA2 cytoplasmic tail phosphorylation, promotes EphA2 kinase activity (other than autophosphorylation or ligandmediated EphA2 signaling), increases proliferation of EphA2 expressing cells, increases survival of EphA2 expressing cells, and/or maintains/reconstitutes epithelial and/or endothelial cell layer integrity. The invention also provides pharmaceutical compositions comprising one or more EphA2 antagonistic agents of the invention either alone or in combination with one or more other agents useful for therapy for a hypoproliferative cell disorder. Diagnostic methods and methods for screening for therapeutically useful agents are also provided.
Inventors:
KIENER PETER A (US)
KINCH MICHAEL S (US)
LANGERMANN SOLOMON (US)
KINCH MICHAEL S (US)
LANGERMANN SOLOMON (US)
Application Number:
PCT/US2004/011481
Publication Date:
December 01, 2005
Filing Date:
April 12, 2004
Export Citation:
Assignee:
MEDIMMUNE INC (US)
KIENER PETER A (US)
KINCH MICHAEL S (US)
LANGERMANN SOLOMON (US)
KIENER PETER A (US)
KINCH MICHAEL S (US)
LANGERMANN SOLOMON (US)
International Classes:
A61K38/00; A61K38/19; A61K39/395; A61K48/00; C07K14/715; C07K16/28; C12N; (IPC1-7): A61K39/395; A61K38/00; A61K48/00
Domestic Patent References:
| WO2001012172A1 | 2001-02-22 |
Foreign References:
| US6927203B1 | 2005-08-09 |
Other References:
CHENG N. ET AL: "Blockade of EphA receptor tyrosine kinase activation inhibits vascular endothelial cell growth factor-induced angiogenesis", MOL. CANCER RES., vol. 1, no. 1, 1 November 2002 (2002-11-01), pages 2 - 11, XP002992331
BRANTLEY D.M. ET AL: "Soluble Eph A receptors inhibit tumor angiogenesis and progression in vivo", ONCOGENE, vol. 21, no. 45, 10 October 2002 (2002-10-10), pages 7011 - 7026, XP002992332
GRIFFIOEN A.W. ET AL: "Angiogenesis: potentials for pharmacologic intervention in the treatment of cancer, cardiovascular diseases, and chronic inflammation", PHARMACOL. REV., vol. 52, no. 2, 2000, pages 237 - 268, XP001012605
CARLES-KINCH K. ET AL: "Antibody targeting of the EphA tyrosine kinase inhibits malignant cell behaviour", CANCER RES., vol. 62, no. 10, 15 May 2002 (2002-05-15), pages 2840 - 2847, XP002309753
POTLA ET AL: "Reduced expression of EphrinA1 (EFNA1) inhibits three-dimensional growth of HT29 colon carcinoma cells", CANCER LETT., vol. 175, no. 2, 25 January 2002 (2002-01-25), pages 187 - 195, XP002992333
See also references of EP 1618184A4
BRANTLEY D.M. ET AL: "Soluble Eph A receptors inhibit tumor angiogenesis and progression in vivo", ONCOGENE, vol. 21, no. 45, 10 October 2002 (2002-10-10), pages 7011 - 7026, XP002992332
GRIFFIOEN A.W. ET AL: "Angiogenesis: potentials for pharmacologic intervention in the treatment of cancer, cardiovascular diseases, and chronic inflammation", PHARMACOL. REV., vol. 52, no. 2, 2000, pages 237 - 268, XP001012605
CARLES-KINCH K. ET AL: "Antibody targeting of the EphA tyrosine kinase inhibits malignant cell behaviour", CANCER RES., vol. 62, no. 10, 15 May 2002 (2002-05-15), pages 2840 - 2847, XP002309753
POTLA ET AL: "Reduced expression of EphrinA1 (EFNA1) inhibits three-dimensional growth of HT29 colon carcinoma cells", CANCER LETT., vol. 175, no. 2, 25 January 2002 (2002-01-25), pages 187 - 195, XP002992333
See also references of EP 1618184A4
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