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Method for target identification using intracellular antibodies, and for high-throughput screening of drug candidates

Reference

86236-01

Patents status

French patent application FR0404433 filed on April 27, 2004 and entitled “Method For Identifying A Ligand Capable Of Selectively Modulating A Functional Cascade Involving A Target, And Uses Thereof For High-Throughput Screening Of Molecules Of Interest”

Inventors

Piona DARIAVACH
Pierre MARTINEAU

commercial status

Research agreement, non exclusive licenses

Laboratory

Institut de Recherche en Cancérologie de Montpellier (IRCM, INSERM U896), Montpellier, France.

Description

CONTEXT

Discovery of new medicaments involves developing methods for high-throughput screening of libraries of molecules which are effective, i.e. which make it possible to isolate, from a restricted number of selected molecules (hits), molecules which are active in vivo on the pathology intended to be treated (leads).
In fact, functional tests (in vitro in cell culture or in vivo in an appropriate animal model) which make it possible to verify the activity of the hits selected during the screening are not generally adaptable to high-throughput. Since most eukaryotic proteins are multifunctional and involved in several functional cascades, the molecules isolated must be capable of specifically modulating the property of interest of the target without affecting its other activities, the modulation of which could have detrimental effects for the cell. Consequently, the screening must be highly specific in order to restrict to a maximum the number of hits identified, so that only a small number of them have to be tested in functional tests in vivo.

TECHNICAL DESCRIPTION

The present invention relates to a method based on the use of Intracellular Antibodies for identifying a ligand capable of selectively modulating a functional cascade involving a target molecule, and also to uses thereof for high-throughput screening of molecules of interest, in an Antibody Displacement Assay.

DEVELOPMENT STAGE

Antibodies have the advantage of recognizing any region of a protein, specifically and with a high affinity. In particular, they can recognize the surface sites of this protein and are therefore very advantageous for specifically inhibiting the regions of proteins involved in functional cascades via protein-protein interactions. We describe here a screening method based on an Antibody Displacement Assay for identifying antibody mimotopes with the same properties, in particular in terms of affinity/specificity for the target. We have shown that the scFv antibody fragment G4G11 directed against the SH2 domains of Syk tyrosine kinase is capable of specifically inhibiting the liberation of allergic mediators by mast cells (Dauvilliers et al., 2002, J. Immunology, 169: 2274-2283). We screened a library of 3000 molecules using the scFv G4G11; among the 10 molecules selected for their ability to inhibit the binding of G4G11 to Syk, at least one named C-13 was an active molecule in vivo, inhibiting FcepsilonRI-induced mast cell degranulation and the anaphylactic shock in mice (Mazuc et al., 2008, J. Allergy and Clinical Immunology, 122: 188-194). As expected, C-13 does not affect the kinase activity of Syk.

BENEFITS

This invention offers a new approach for the selection of new drug-like candidates, by isolating small molecules that act as mimotopes of an antibody in terms of selectivity for a specific metabolic pathway.

INDUSTRIAL APPLICATIONS

The generic approach reported in this invention has shown its proof of concept with the Syk model and the identification of efficient anti-allergic drugs. This method may be used for the treatment of any other pathology or metabolic pathway.

For further information, please contact us (Ref 86236-01)        

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