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Compositions and methods for modulating vascular development

Inactive Publication Date: 2007-02-08
GENENTECH INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0031] In one preferred embodiment, the pathological condition associated with angiogenesis is a cancer. In another preferred embodiment, the pathological condition associated with angiogenesis is an intraocular neovascular disease. In yet another preferred embodiment, the EGFL7 antagonist is co-administered with another anti-angiogenic agent, such as an anti-VEGF antibody including bevacizumab. The present invention also provides a method of enhancing the efficacy of an anti-angiogenic agent treatment in a subject having a pathological condition associated with angiogenesis, comprising administering to the subject an EGFL7 antagonist in combination with the anti-angiogenic agent. Such a method will be useful in treating cancers or intraocular neovascular diseases, especially those diseases or stages of the diseases that responded poorly to a treatment with the anti-angiogenic agent alone. The anti-angiogenic agent can be any agent capable of reducing or inhibiting angiogenesis, including VEGF antagonists such as anti-VEGF antibody. When treating tumor, the EGFL7 antagonist alone or in combination with an anti-angiogenic agent can be further combined with a chemotherapy regime comprising one or more chemotherapeutic agents. Radioactive therapy can also be combined for enhanced efficacy.

Problems solved by technology

Loss of EGFL7 function caused significant vascular defects in animal embryos, and reduced tumor growth.

Method used

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  • Compositions and methods for modulating vascular development
  • Compositions and methods for modulating vascular development
  • Compositions and methods for modulating vascular development

Examples

Experimental program
Comparison scheme
Effect test

example 1

Cloning of EGFL7

[0318] EGFL7 was identified and cloned in an effort to discover novel human secreted and transmembrane proteins, particularly those involved in the regulation of vascular development. Details of the cloning and expression of human EGFL7 are described in, for example, patent application US20030224948A1 (wherein EGFL7 is identified as PRO1449). Briefly, whole mount in situ hybridization screens were performed to identify secreted factors and receptors that are enriched in mouse embryonic vasculatures. By way of signal sequence prediction and extracellular domain homology searching, hundreds of human and mouse cDNAs representing putative secreted factors and receptors were identified and collected. Using the mouse cDNAs as templates, riboprobes were generated and in situ hybridizations were performed on whole mouse embryos ranging from E7.5 to E14.5. This developmental time window was chosen because it encompasses many key stages in vasculogenesis and angiogenesis. Amo...

example 2

Expression of EGFL7

[0326] To elucidate the expression pattern of EGFL7, whole mount in situ hybridization, immunofluorescent staining and radioactive in situ hybridization were carried out on mouse and zebrafish embryos as well as mouse and human tissue sections.

[0327] Zebrafish and Mouse Strains

[0328] Mouse embryos were harvested from timed-pregnant CD-1 mice. Tüebingen long fin (TL) wild-type zebrafish line, ˜30 hpf cloche (Clom39) homozygous mutant embryos and their wild-type siblings were used in the expression and activity studies described herein below. Adult zebrafish and embryos were maintained as previously described (Westerfield 1993 Zebrafish Book).

[0329] Radioactive in situ Hybridization

[0330] Tissues were processed for in situ hybridization by a method described previously. Phillips et al. (1990) Science 250:290-4. 33P-UTP-labelled RNA probes were generated as described. Melton et al. (1984) Nucleic Acids Research 12:7035-56. EGFL7 sense and antisense probes were s...

example 3

Phenotypic Analysis of Animals with Reduced EGFL7 Activity

[0343] A. Vascular Defects in the EGFL7 Knockdown Zebrafish

[0344] In a recent report, conditioned medium containing the recombinant EGFL7 protein is shown to inhibit smooth muscle cell (SMC) migration in vitro. Soncin et al. EMBO J. 22:5700-5711 (2003). However, its in vivo function has not been defined. To uncover the in vivo biological function of EGFL7, the model organism zebrafish was used because of the availability of tools to study vasculogenesis and angiogenesis, and the ease to manipulate gene expression in embryos. Fishman et al. Circulation Research 74:757-63 (1994); Weinstein et al. Cardiovascular Research 31 :E17-24 (1996); Dooley et al. Current Opinion in Genetics &Development 10:252-6(2000); Nasevicius & Ekker Nature Genetics 26:216-20 (2000). Furthermore, it was found that Egfl8 was expressed in a subset of blood vessels and peripheral nerves in mouse embryos, making it a potential redundant factor for EGFL7...

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Abstract

The present invention provides methods of using EGFL7 antagonist to modulate vascular development. Also provided herein are methods of screening for modulators of EGFL7 activity. Furthermore, methods of treatment using EGFL7 antagonists are provided.

Description

RELATED APPLICATIONS [0001] This application is a continuation of International Application No. PCT / US2005 / 013658, filed Apr. 14, 2005, which claims the benefit of U.S. Provisional Application No. 60 / 562,054, filed Apr. 14, 2004.FIELD OF THE INVENTION [0002] The present invention relates generally to compositions and methods that are useful for modulating vascular development. Specifically, the present invention relates to EGF-like domain 7 (EGFL7), a novel endothelial cell-derived secreted factor. The present invention further relates to the diagnosis and treatment of conditions and diseases associated with angiogenesis. BACKGROUND OF THE INVENTION [0003] Development of a vascular supply is a fundamental requirement for many physiological and pathological processes. Actively growing tissues such as embryos and tumors require adequate blood supply. They satisfy this need by producing pro-angiogenic factors, which promote new blood vessel formation via a process called angiogenesis. ...

Claims

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Application Information

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IPC IPC(8): A61K39/395A61K31/7088C07K16/22
CPCA61K31/7088C07K16/22A61K2039/505A61P17/00A61P17/06A61P27/00A61P27/02A61P27/06A61P29/00A61P35/00A61P35/04A61P37/06A61P43/00A61P9/00A61P9/10A61K39/395
Inventor FILVAROFF, ELLENYE, WEILANPARKER, LEON H. IVHONGO, JO-ANNE S.SCHMIDT, MAIKE
Owner GENENTECH INC
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