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Anti-egfr antibody therapy based on an increased copy number of the egfr gene in tumor tissues

Inactive Publication Date: 2008-04-02
MERCK PATENT GMBH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The molecular mechanisms underlying the responsiveness or reactivity of EGFR-expressing cancer cells to anti-EGFR mAbs are unclear

Method used

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  • Anti-egfr antibody therapy based on an increased copy number of the egfr gene in tumor tissues
  • Anti-egfr antibody therapy based on an increased copy number of the egfr gene in tumor tissues
  • Anti-egfr antibody therapy based on an increased copy number of the egfr gene in tumor tissues

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0110] Example 1: Patients and Treatment with Anti-EGFR Monoclonal Antibodies

[0111] Ospedale Niguarda Ca'Granda enrolled patients in a clinical trial for the treatment of EGFR-expressing mCRC with the anti-EGFR moAbs panitumumab or cetuximab, and in these patients we demonstrated radiologically-documented tumor sensitivity to this therapy or Tolerability was evaluated in 31 patients (Table 1). Patient selection was based on the availability of sufficient tumor tissue for the current study. All patients had EGFR-expressing mCRC, manifested as ≥1% EGFR-staining malignant cells, as per clinical protocol (Cunningham et al., 2004, N EngI J Med 351:337-345), in the central laboratory Assessed by IHC with DAKO EGFRPharmDX kit. Cetuximab (chimeric IgG1 moAb; Erbitux  , Merck, Milan, Italy) and panumumab (whole human IgG2 moAb; Amgen, Thousand Oaks, CA, USA) both target the ligand-binding domain of EGFR. In addition to the lower incidence of fusion reactions observed with intac...

Embodiment 2

[0112] Example 2: Mutation Analysis

[0113] DNA was extracted from paraffin-embedded samples. 10 slices were prepared for each patient. Additional representative sections were deparaffinized, stained with hematoxylin-eosin, and subjected to detailed morphological analysis. The area showing tumor tissue was marked, and the tissue was extracted with 0.2M NaOH / 1 mM EDTA, which was then neutralized with 100 mM Tris-TE. After extraction, the DNA was purified using the Qiagen PCR purification kit (cat# 28104) according to the manufacturer's instructions. Exon-specific primers and sequencing primers were designed with Primer3 software (http: / / frodo.wi.mit.edu / cgi-bin / primer3 / primer3_www.cgi) and supplied by Invitrogen TM analyze. The primer sequences are: Forward, reverse and sequencing primers for each exon are as follows:

[0114] EGFR-Ex18

[0115] GCTGAGGTGACCCTTGTCTC;ACAGCTTGCAAGGACTCTGG;TGGAGCCTCTTACACCCAGT;

[0116] EGFR-Ex19

[0117] CCCAGTGTCCCTCACCTTC;CCACACAGCAAAG...

Embodiment 3

[0129] Example 3: Analysis of the EGFR gene by fluorescence in situ hybridization (FISH)

[0130]Tissue sections were processed according to the protocol used for the Her2 FISH detection kit (Dakocytomation, Glostrup, DK). The samples were placed in the pretreatment solution at 96°C for 30 minutes, and then digested with trypsin solution for 30 minutes at room temperature. Two-color, two-target FISH assays were performed using the LSI EGFR Spectrum Orange / CEP7 SpectrumGreen Probe (Vysis, Downers Grove, IL). Briefly, tissue sections were overlaid with 10 μL of probe solution, incubated with co-denatured EGFR and CEP7 probes at 75°C for 5 min, and hybridized overnight at 37°C. Both co-denaturation and hybridization were performed sequentially in a microprocessor-controlled system (Hybridizer, Dakocytomation, Glostrup, DK). Stringent washes after hybridization were performed in a 65°C water bath for 10 minutes. After washing twice and drying at room temperature for 15 minutes,...

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Abstract

The invention relates to an individualized and personalized diagnosis and therapy of cancer based on specific molecular alterations which occur in specific tumor tissue of specific tumor patient populations. The therapy and diagnostic is based on the findings that proliferation and tumor growth of specific EGFR bearing tumor tissue expressing an amplified EGFR gene copy number may be abolished by anti-EGFR antibodies, while other individual molecular alterations such as mutations occurring in tumor tissues are unaffected by the same anti-EGFR antibody treatment.

Description

technical field [0001] The present invention relates to the diagnosis and treatment of tumors expressing high levels of epithelial growth factor receptor (EGFR) by anti-EGFR antibodies. The present invention additionally relates to individualized and individualized diagnosis and treatment of EGFR-expressing cancers on the basis of specific molecular alterations occurring in specific tumor tissues of specific tumor patient populations. This treatment and diagnosis is based on the discovery that anti-EGFR antibodies can inhibit the proliferation and tumor growth of tumor tissue with a specific EGFR that exhibits an amplified EGFR gene copy number, while the tumor tissue that occurs in tumor tissue Other individual molecular changes, such as specific gene mutations, were not affected by the same anti-EGFR antibody treatment. Background technique [0002] Biomolecules, such as monoclonal antibodies (MAbs) or other proteins / peptides, as well as small chemical compounds that dire...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C12Q1/68C07K16/28
CPCC12Q2600/156C07K2317/21C07K16/2863C12Q1/6886A61K39/39541A61K39/00C12Q2600/106A61K2039/505C07K2317/73C07K2317/24A61K2039/55A61K2300/00G01N33/53G01N33/57407G01N33/68
Inventor S·谢纳M·莫罗尼G·马拉皮塞A·萨尔托雷-比安基S·韦罗内塞M·甘巴库尔塔S·本韦努蒂F·迪尼科兰托尼奥A·巴尔代利
Owner MERCK PATENT GMBH
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