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EGFR antigen-binding molecules and uses thereof

a technology of antigen-binding molecules and antigen-binding molecules, which is applied in the field of antigen-binding molecules, can solve the problems of heterogeneous tumors, on the cellular and/or molecular level, and patients are exposed to the risks and discomforts of unneeded therapies, and are even from the same tissue or organ

Inactive Publication Date: 2009-01-15
VENTANA MEDICAL SYST INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The patent describes methods for studying the status of EGFR regulation in biological samples, which can help predict the aggressiveness of EGFR-positive neoplasms and the effectiveness of EGFR-targeted therapies. The methods involve using antigen-binding molecules that specifically bind to the intracellular regulatory domain of EGFR. The patent also describes peptides derived from the EGFR regulatory domain, which can be used to make RD-binding molecules. These RD-binding molecules can recognize specific epitopes within the peptides and can be useful in studying EGFR regulation.

Problems solved by technology

However, it is now apparent that tumors, even from the same tissue or organ, are heterogeneous on the cellular and / or molecular level.
This unpredictability confounds treatment selection and may expose patients to the risks and discomforts of unneeded therapies.

Method used

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  • EGFR antigen-binding molecules and uses thereof
  • EGFR antigen-binding molecules and uses thereof
  • EGFR antigen-binding molecules and uses thereof

Examples

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Effect test

example 1

An Exemplary Monoclonal Antibody Specific for EGFR Regulatory Domain

[0135]This Example describes an exemplary RD-binding molecule; more particularly a monoclonal antibody that binds an epitope in the EGFR inhibitory subdomain. This antibody has the added advantage that it will identify not only full-length EGFR, but also truncated mutant forms of EGFR, which have been shown to be constitutively activated (Pedersen et al., Ann. Oncol., 12(6):745-60, 2001).

[0136]A computer program (DNASTAR™, Madison, Wis.) was used for the selection of immunogenic peptide sequences within the EGFR intracellular domain. The program examined the input protein sequence for short (e.g., less than 20 contiguous amino acids) sequences that likely had a high probability for producing an antibody response in animals immunized with immunogens including such short sequences.

[0137]One identified short sequence was LDNPDYQQDFFPKEAKPNG (L2G Peptide; SEQ ID NO: 2), which, by computer analysis, had high antigenicity...

example 2

Exemplary Methods for Immunohistochemical Staining of Tissue with EGFR-Specific Antibodies

[0142]Immunohistochemistry is the well-known method and variations on such methods are readily determined with routine experimentation by those of ordinary skill in the art (see, e.g., Dabbs, Diagnostic Immunohistochemistry, Churchill Livingstone, 2002). Exemplary methods for detecting in FFPE tissue by manual IHC an EGFR RD-binding molecule (e.g., monoclonal antibody clone 5B7) or an antigen-binding molecule specific for the EGFR extracellular domain (e.g., monoclonal antibody clone 3C6) are provided in the following table:

Step #Manual IHC Assay0Fresh tissue is placed in a fixative (such as, 10% neutral buffered formalin)for approximately 12-48 hours at room temperature. Then, the tissue isdehydrated through graded alcohols (e.g., 50% to 70% to 90% to 95% to100% EtOH) for 1-2 hours at each grade, and infiltrated with a clearingreagent (such as, xylene) for 3-5 hours at room temperature. The cl...

example 3

Antibody Specific for EGFR Regulatory Domain Epitope Unexpectedly does not Substantially Bind to Some EGFR-Positive Tissues

[0145]This Example demonstrates that RD-binding molecules, such as clone 5B7, exhibited differential binding to EGFR-positive tissues (as detected by an antibody specific for the EGFR external domain). As described in more detail below, but without being limited to a single theory, this differential binding is believed to be due to the differential expression of EGFR regulatory proteins (e.g., SOCS proteins like SOCS1 or SOCS3) in EGFR-positive tissues. Such regulatory proteins, when directly associated with the EGFR regulatory domain, mask the epitopes of RD-binding molecules.

[0146]A. Normal Human Tissues

[0147]The staining by IHC of antibodies specific for the EGFR regulatory domain (i.e., clone 5B7) and external domain (i.e., clone 3C6) in FFPE 30 normal human tissues were compared. Tissue arrays were obtained from USBiomax (Igamsville, Md.; Cat. No. FDA801). ...

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Abstract

Disclosed herein are antigen-binding molecules, such as antibodies, that specifically recognize a portion of the EGFR C-terminal (intracellular) regulatory domain that interacts with one or more regulatory molecules (such as Suppressor of Cytokine Signaling (“SOCS”) proteins). In certain normal or neoplastic cells and / or tissues, this region is inaccessible to the disclosed antigen-binding molecules. Thus, such antigen-binding molecules are useful at least to interrogate the regulated state of EGFR, predict the response of a cancer patient to EGFR inhibitor therapies, and / or predict the aggressiveness of neoplasms.

Description

CROSS REFERENCE TO RELATED APPLICATIONS[0001]This application claims priority to U.S. Provisional Application Nos. 60 / 949,792 filed Jul. 13, 2007 and 60 / 988,196 filed Nov. 15, 2007, herein incorporated by reference.FIELD OF THE DISCLOSURE[0002]This disclosure concerns antigen-binding molecules, such as antibodies, specific for a portion of the intracellular domain of epidermal growth factor receptor (“EGFR”) and uses of such antigen-binding molecules, for instance, as cancer prognostics and / or as indicators for particular (e.g., EGFR inhibitor) cancer therapies.BACKGROUND[0003]Cancer is a generic name for a wide range of cellular malignancies characterized by unregulated growth, lack of differentiation, and the ability to invade local tissues and metastasize. These neoplastic malignancies affect, with various degrees of prevalence, every tissue and organ in the body. Historically, cancers have been diagnosed using conventional histological and clinical features of the affected tissu...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K39/00C07K14/00G01N1/30G01N33/566
CPCC07K16/2863C07K2317/33C07K2317/34G01N2800/52G01N2333/71G01N2500/02G01N33/57484A61P35/00
Inventor POWELL, WILLIAM C.KIVI, LINDA WILLOUGHBYROCHE, PATRICK C.GOOCH, GARYGAIRE, FABIEN
Owner VENTANA MEDICAL SYST INC
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