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Treatment method using EGFR antibodies and SRC inhibitors and related formulations

A mammalian and compositional technology, applied in the field of EGFR-mediated diseases, can solve problems such as not combining with normal human tissues

Active Publication Date: 2013-06-12
LUDWIG INST FOR CANCER RES LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Epitope studies are supported by immunohistochemistry studies demonstrating that the 806 antibody binds to epitopes present in glioma as well as various epidermal cancers, but not normal human tissue

Method used

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  • Treatment method using EGFR antibodies and SRC inhibitors and related formulations
  • Treatment method using EGFR antibodies and SRC inhibitors and related formulations
  • Treatment method using EGFR antibodies and SRC inhibitors and related formulations

Examples

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Effect test

example 1

[0070] Enhanced potency of EGFR-specific antibodies following SRC inactivation or inhibition

[0071] Factors affecting the efficacy of therapeutic monoclonal antibodies (mAbs) against EGFR are still poorly understood, especially in glioma. The efficacy of two EFGR-specific mAbs (mAb806 and 528) was tested against U87MG-derived glioma xenografts expressing EGFR variants. Using this approach enabled changing EGFR forms while keeping the genetic background constant. These variants include the constitutively active mutant of EGFR de2-7EGFR (or EGFRvIII) expressed in gliomas.

[0072] The potency of mAbs correlates with the number of EGFRs, however the most important factor is receptor activation. While U87MG xenografts expressing de2-7EGFR responded to treatment, those displaying the death kinase de2-7EGFR were non-responsive. Modified de2-7EGFR, which is kinase active but deficient in autophosphorylation, also responded, suggesting that these mAbs act by blocking phosphate ...

Embodiment 2

[0191] Animal Therapeutic Study of Src Inhibitor Dasatinib and mAb806 Treatment

[0192] Animal treatment studies were performed to evaluate the in vivo effects of the anti-EGFR antibody mAb806 alone or in combination with the src inhibitor dasatinib. Use 1×10 6 U87MG.Δ2-7 SRC Eight-week-old female Balb / C nu nu mice were injected subcutaneously. U87MG.Δ2-7 SRC Cells express activated Src (Y529F mutation) and Δ2-7 mutant EGFR. Two tumors were prepared in each mouse by injecting these cells into each side of the right and left flanks. When the average tumor volume reaches about 80mm 3 start processing. Mice were treated in four treatment groups (consisting of 4-5 mice / group) 3 times a week for 2 weeks. The treatment groups were as follows: (1) Control - 100 μl diluent 4% DMSO / dH 2 O; (2) Dasatinib - 10 mg / kg agent dissolved in diluent; (3) mAb 806 - 1 mg; (4) mAb 8061 mg and Dasatinib 10 mg / kg.

[0193] Antibody. Src was detected using mouse monoclonal antibody v-Sr...

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Abstract

The present invention relates to the treatment of EGFR-mediated disease, particularly cancer by inhibiting or blocking EGFR and src in combination or simultaneously. The invention relates to treatment, prevention, or modulation of cancer, particularly EGFR-mediated disease, with one or more EGFR modulator and src inhibitor in combination. The invention further relates to the treatment of cancer with anti-EGFR antibodies and src inhibitors. Methods and compositions for treatment of cancer with the antibody anti-EGFR mAb806 in combination or series with a src inhibitor or src inhibitors are described.

Description

field of invention [0001] The present invention relates to the treatment of EGFR-mediated diseases, especially cancer. Methods of treating cancer using combinations of EGFR modulators, particularly EGFR antibodies and scr inhibitors, are provided. Methods and combinations of MAb806 antibody and scr inhibitor are provided. Background of the invention [0002] Targeted cancer therapy is designed to destroy the function of specific molecules required for cancer initiation and tumor growth, thereby killing or preventing the growth of cancer cells (Ji H et al. (2006) Cell Cycle 5(18): 2072-2076 Equb 2006 September 15). Such targeted cancer treatments may be more effective and less damaging to normal cells than traditional cytotoxic chemotherapy. A major effort in the field of targeted cancer therapy has been the development of agents targeting the epidermal growth factor receptor (EGFR). EGFR is a member of the closely related ErbB family of receptors, which includes EGFR (Er...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): A61K39/395A61P35/00
CPCA61K31/506C07K2317/30A61K39/39541A61K31/517A61K45/06A61P35/00A61P43/00A61K2300/00
Inventor W·卡夫尼F·福尔纳里T·G·约翰斯A·斯科特
Owner LUDWIG INST FOR CANCER RES LTD
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