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Antibody antagonists of ve-cadherin without adverse effects on vascular permeability

a technology of vecadherin and anti-vecadherin, which is applied in the field of anti-vecadherin anti-antagonizers without adverse effects on vascular permeability, can solve the problems of vascular leak syndrome, hemorrhage and death, and disturbance of normal vasculature integrity

Inactive Publication Date: 2008-12-18
IMCLONE SYSTEMS
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

"The present invention is about an antibody that can inhibit the formation of new blood vessels (angiogenesis) and the growth and spread of tumors (tumor metastasis) by targeting a molecule called VE-cadherin. The antibody can also inhibit the formation of new adherens junctions without affecting existing ones. The antibody is safe and can be administered to mammals without causing any significant side effects. The invention also includes a method for using the antibody in gene therapy to treat cell proliferative disorders associated with vascularization. The antibody can be administered as a single chain antibody, humanized, chimerized, bispecific, or fused to a heterologous polypeptide. The invention also provides a nucleic acid that encodes the antibody."

Problems solved by technology

For example, administering certain anti-cadherin antibodies in amounts sufficient to prevent or inhibit angiogenesis have resulted in disturbances in the integrity of normal vasculature with resultant vascular leak syndromes, hemorrhage and death.

Method used

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  • Antibody antagonists of ve-cadherin without adverse effects on vascular permeability
  • Antibody antagonists of ve-cadherin without adverse effects on vascular permeability
  • Antibody antagonists of ve-cadherin without adverse effects on vascular permeability

Examples

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example 1

Methods

[0078]Monoclonal Antibody Preparation: Lewis rats (6-8 week old females) were injected subcutaneously (s.c.) with 0.1 ml of protein or peptide mixed in Freund's complete adjuvant using a 25-gauge needle. Rats were boosted every 2-3 weeks with antigen and bled via the tail vein every week. After 3 booster immunizations or when sera titers reach maximal levels, mice were sacrificed by CO2 inhalation. Spleens were recovered from sacrificed animals for monoclonal antibody generation by conventional techniques.

[0079]Antibody Screening: Hybridoma supernatants were screened in by an enzyme-linked immunosorbent assay (ELISA) to identify antibodies which bound to VE-cadherin.

[0080]Junction Formation / Ca Switch Assay: The junction formation assay was developed based on a modification of the calcium switch assay (Gumbiner, B., & Simons, K., Cell Biol. 102:457-468 (1986)). Transfectant CHO cells or endothelial cells expressing VE-cadherin are plated onto glass slides and allowed to form a...

example 2

VE-Cadherin Monoclonal Antibodies That Inhibit Adherens Junction Formation Without Disrupting Existing Junctions

[0084]Two groups of Lewis rats were immunized with either a mixture of four KLH-coupled peptides having sequences from the N-terminal domain 1 of murine VE-cadherin (FIG. 2) or with affinity-purified soluble mouse VE-cadherin (smVEC-Ig) which had been expressed in CHO cells. This immunogen encompasses the entire extracellular region of mouse VE-cadherin fused to human Fc chain. The resulting hybridoma clones were tested for production of antibodies with binding activity to VE-cadherin using a conventional ELISA format. This screening identified twenty (20) rat anti-murine VE-cadherin antibodies, 10 from each of the originally immunized groups of rats.

[0085]Several properties of these monoclonal antibodies were examined and the results are summarized in Tables 1 and 2.

[0086]The 20 candidate VE-cadherin antibodies were tested in the “calcium-switch” and “permeability” assays...

example 3

E4B9 Cross Reacts with Human VE-Cadherin

[0087]The murine epitope sequence recognized by antibody E4B9 shares 100% homology with human VE-cadherin, so this antibody was examined to determine if it cross-reacts with human VE-cadherin. Western-blot analysis of several VE-cadherin expressing human and murine cell indicated that E4B9 indeed cross-reacts with human VE-cadherin (FIG. 6). This finding facilitates development of a “humanized” E4B9 antibody and its success in the preclinical development since its anti-tumor activity can be tested extensively in several mouse models.

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Abstract

The murine epitope sequence recognized by antibody E4B9 shares 100% homology with human VE-cadherin, so this antibody was examined to determine if it cross-reacts with human VE-cadherin. Western-blot analysis of several VE-cadherin expressing human and murine cells indicated that E4B9 indeed cross-reacts with human VE-cadherin. (FIG. 6). This finding facilitates development of a “humanized” E4B9 antibody and its success in the preclinical development since its anti-tumor activity can be tested extensively in several mouse models.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS[0001]The present application is a divisional application of U.S. patent application Ser. No. 10 / 040,128 filed Jan. 2, 2002, which is a continuation of U.S. application Ser. No. 09 / 540,967 filed Mar. 31, 2000, now abandoned, the contents of which are incorporated herein by reference.FIELD OF THE INVENTION[0002]The present invention relates to antibody antagonists of VE-cadherin that inhibit formation new of adherens junctions without disrupting the integrity of existing junctions. Such antibodies are useful to prevent angiogenesis in a variety of disease conditions, including, for example, to prevent neovascularization of tumors. These antibodies are also useful for treating endothelial cell proliferative disorders.BACKGROUND OF THE INVENTION[0003]Many diseases are associated with an abnormal proliferation of blood vessels. The process of forming new blood vessels is termed angiogenesis. Under normal or non-pathologic conditions angiogenesis oc...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K39/395A61P9/00C12N15/02A61K48/00A61P19/02A61P27/00A61P27/02A61P27/06A61P35/00A61P35/02A61P35/04A61P37/00C07K16/18C07K16/28C07K19/00C12N5/10C12N5/20C12N15/13C12P21/08
CPCA61K48/00C07K2317/34C07K16/2896A61K2039/505A61P19/02A61P27/00A61P27/02A61P27/06A61P35/00A61P35/02A61P35/04A61P37/00A61P9/00
Inventor LIAO, FANGHICKLIN, DANIEL J.BOHLEN, PETER
Owner IMCLONE SYSTEMS
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