Compounds and methods for modulating adhesion molecule function

a cadherin-mediated process and compound technology, applied in the direction of antibody medical ingredients, peptide/protein ingredients, drug compositions, etc., can solve the problems of limited use of skin patches, hydrophobic molecules, and undesirable cell adhesion levels, so as to prevent pregnancy, inhibit synaptic stability, and increase vasopermeability

Inactive Publication Date: 2007-08-30
ADHEREX TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The formation of such junctions gives rise to physical and permeability barriers that restrict the free passage of cells and other biological substances from one tissue compartment to another.
Although cell adhesion is required for certain normal physiological functions, there are situations in which the level of cell adhesion is undesirable.
In addition, permeability barriers arising from cell adhesion create difficulties for the delivery of drugs to specific tissues and tumors within the body.
However, the use of skin patches has been limited to small, hydrophobic molecules because of the epithelial and endothelial cell barriers.
Similarly, endothelial cells render the blood capillaries largely impermeable to drugs, and the blood / brain barrier has hampered the targeting of drugs to the central nervous system.
In addition, many solid tumors develop internal barriers that limit the delivery of anti-tumor drugs and antibodies to inner cells.
However, such methods are often inefficient, due to low endogenous transport rates or to the poor functioning of a carrier protein with drugs.
While improved efficiency has been achieved using a variety of chemical agents that disrupt cell adhesion, such agents are typically associated with undesirable side-effects, may require invasive procedures for administration and may result in irreversible effects.

Method used

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  • Compounds and methods for modulating adhesion molecule function
  • Compounds and methods for modulating adhesion molecule function
  • Compounds and methods for modulating adhesion molecule function

Examples

Experimental program
Comparison scheme
Effect test

example 1

Preparation of Representative Modulating Agents

[0202] This Example illustrates the solid phase synthesis of representative peptide modulating agents.

[0203] The peptides were synthesized on a 431A Applied Biosystems peptide synthesizer using p-Hydroxymethylphenoxymethyl polystyrene (HMP) resin and standard Fmoc chemistry. After synthesis and deprotection, the peptides were de-salted on a Sephadex G-10 column and lyophilized. The peptides were analyzed for purity by analytical HPLC, and in each case a single peak was observed. Peptides were made as stock solutions at 10 to 25 mg / mL in dimethylsulfoxide (DMSO) or water and stored at −20° C. before use.

example 2

Disruption of the Ability of Mouse Cerebellar Neurons to Extend Neurites

[0204] N-cadherin and N-CAM are established as CAMs that can regulate neurite outgrowth (Doherty and Walsh, Curr. Op. Neurobiol. 4:49-55, 1994; Williams et al., Neuron 13:583-594, 1994; Hall et al., Cell Adhesion and Commun. 3:441-450, 1996; Doherty and Walsh, Mol. Cell. Neurosci. 8:99-111, 1996; Saffell et al., Neuron 18:231-242, 1997). Neurons cultured on monolayers of 3T3 cells that have been transfected with cDNAs encoding N-cadherin or N-CAM extend longer neurites than neurons cultured on the untransfected parental 3T3 cells (commonly referred to as the control 3T3 cells). It has been determined that the neurite response stimulated by transfected N-CAM and N-cadherin initially depends upon a trans homophilic binding interaction between the transfected CAM in the 3T3 cell and the corresponding CAM in the neuron. This Example illustrates the use of representative modulating agents to disrupt neurite outgrowt...

example 3

Modulating Agent Binding to N-Cadherin

[0213] This Example illustrates the ability of a representative modulating agent to bind to N-cadherin.

[0214] The peptide H-WLKIDPVNGQI-OH (SEQ ID NO:13) was passed over flow cells coated with an N-cadherin-Fc chimera or human IgG1 at a concentration of either 250, 500 or 1000 μg / ml. FIG. 7 is a graph illustrating the association of the peptide to the flow cell coated with the N-cadherin Fc chimera, with the binding to the control flow cell (coated with human IgG1) automatically subtracted.

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Abstract

Modulating agents and methods for enhancing or inhibiting cadherin-mediated functions are provided. The modulating agents comprise at least an HAV binding motif, an analogue or peptidomimetic thereof, or an antibody or fragment thereof that specifically binds to such a motif. Modulating agents may additionally comprise one or more cell adhesion recognition sequences recognized by cadherins and / or other adhesion molecules. Such modulating agents may, but need not, be linked to a targeting agent, drug and / or support material.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS [0001] This application is a continuation of U.S. Ser. No. 10 / 956,748 filed Oct. 1, 2004; which is a continuation of U.S. Ser. No. 10 / 193,653 filed Jul. 10, 2002, now U.S. Pat. No. 6,806,255; which is a continuation of U.S. Ser. No. 09 / 351,048 filed Jul. 9, 1999, now U.S. Pat. No. 6,472,368; which is a continuation-in-part of U.S. Ser. No. 09 / 113,977, filed Jul. 10, 1998, now U.S. Pat. No. 6,277,824.TECHNICAL FIELD [0002] The present invention relates generally to methods for modulating cadherin-mediated processes, and more particularly to the use of modulating agents comprising a cadherin cell adhesion recognition sequence, or an antibody that specifically recognizes such a sequence, for inhibiting or enhancing functions such as cell adhesion. BACKGROUND OF THE INVENTION [0003] Cell adhesion is a complex process that is important for maintaining tissue integrity and generating physical and permeability barriers within the body. All tissues ar...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K38/12A61K38/00C12N15/09A61K39/395A61K47/48A61P17/02A61P25/00A61P35/00A61P43/00C07K7/06C07K7/64C07K14/705C07K16/18
CPCA61K38/12A61P17/02A61P25/00A61P35/00A61P43/00C07K7/06C07K7/64C07K14/705
Inventor DOHERTY, PATRICKBLASCHUK, ORESTGOUR, BARBARA
Owner ADHEREX TECH
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