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Combination Therapy Using Anti-EGFR and Anti-HER2 Antibodies

a technology of anti-egfr and anti-her2 antibodies, which is applied in the direction of antibody medical ingredients, drug compositions, peptides, etc., can solve the problems of little information available regarding antibody efficacy, the difficulty of treating adenocarcinomas of the pancreas, and the prognosis remains poor, so as to prevent the dimerization of egfr, the effect of confirming the importance of communication

Inactive Publication Date: 2009-08-27
INST NAT DE LA SANTE & DE LA RECHERCHE MEDICALE (INSERM)
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The patent describes a combination of two antibodies, one targeting EGFR and one targeting HER2, that work synergistically to treat cancer. This combination is effective in cancers that overexpress EGFR but not HER2, and inhibits the growth of tumors in animals with low levels of HER2 expression. The combination treatment is particularly effective in pancreatic cancer, which has a high level of EGFR expression. The patent also explains the mechanism of action of the antibodies and how they can be used in combination to provide a more effective treatment for cancer.

Problems solved by technology

Although, as stated above, the therapeutic efficacy trastuzumab in breast carcinoma is well demonstrated, it is strictly limited and only approved for 30% of breast cancer patients whose tumor overexpress HER2.70% of the breast cancer patients do not or insufficiently respond to trastuzumab because their individual tumor do not overexpress or do not sufficiently express HER2.
Adenocarcinomas of the pancreas remain one of the most difficult malignancies to treat.
The incidence has steadily increased over the past four decades, and its prognosis is still dismal, despite tremendous efforts in early diagnosis and therapy.
However, little information is available concerning antibody efficacy and the actual function of EGFR and HER2 receptors in specific cancer tissue expressing low levels of at least one of these receptors, for example, pancreatic cancer, targeted by specific anti-ErbB antibodies, and up to date no clinical studies have evaluated the efficacy of targeting concurrently these two receptors in these tumors with suitable monoclonal antibodies.

Method used

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  • Combination Therapy Using Anti-EGFR and Anti-HER2 Antibodies
  • Combination Therapy Using Anti-EGFR and Anti-HER2 Antibodies
  • Combination Therapy Using Anti-EGFR and Anti-HER2 Antibodies

Examples

Experimental program
Comparison scheme
Effect test

example 1

In Vivo Tumor Growth Inhibition Study

[0133]All in vivo experiments were performed in compliance with the French guidelines for experimental animal studies (Agreement No. B34-172-27). Nude mice, 6-8-week-old female athymic NMRI mice and BALB / c athymic mice were purchased from Janvier, Le Genest (St Isle, France) and Charles Rivers Laboratories (L'Arbresle, France), respectively. BxPC-3 (3.5×106), MiaPaCa-2 (5×106) and SK-OV-3 (5×106) cells were injected subcutaneously (s.c.) in to the right flank of athymic NMRI (BxPC-3 model) and BALB / c (MiaPaCa-2 and SK-OV-3) nude mice. MiaPaCa-2 cells were suspending in 50% culture medium and 50% Matrigel (BD biosciences, Le Pont De claix, France). Tumor-bearing mice were randomized in the different treatment groups when the tumors reached an approximate volume indicated in each experiment. For the BxPC-3 model, effects of antibody treatments were studied on small tumor (experiment S) and on large tumor (experiment L). The mice were treated by int...

example 2

Immunocytochemical Analyses

[0134]Expression of receptors was analyzed in paraffin-embedded cells fixed in AFA (alcohol formol acetic acid). Analysis of EGFR expression was performed by using the EGFR pharmDx kit (DakoCytomation, Carpinteria, Calif., USA) according to the manufacturer's recommendations. Diaminobenzidine (Dakocytomation) was used as the chromogen, and the sections were lightly counterstained with hematoxylin. The primary antibody used for the detection of HER2 was a rabbit polyclonal antibody (Dakocytomation).

example 3

Immunoblotting Analysis

[0135]BxPC-3 and MiaPaCa-2 cells, plated at 106 cells for 24 h in Petri dishes were starved for two days in a medium without growth factors (SM medium) and treated with 10 Ng / ml of trastuzumab, matuzumab or both antibodies at a fixed 1:1 ratio (or controls without antibody). After a 48-h incubation, cells were incubated for 10 min in the SM medium with or without 100 ng / ml of EGF, washed twice, and lysed with buffer (CliniSciences SA, Montrouge France)-1-containing 100 NM PMSF, 100 mM sodium fluorure, 1 mM sodium orthovanate, and one complete protease inhibitor mixture tablet (Sigma, St Louis, Mo.). After electrophoresis on 8% SDS-PAGE under non-reducing conditions, the proteins were transferred to a polyvinylidene difluoride membranes (Millipore Co., Bedford, Mass.) which were saturated in PBS containing 0.1% Tween 20 and 5% nonfat dry milk and then incubated with the antibodies against the phosphorylated forms of EGFR and HER2, obtained from Cell Signaling T...

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Abstract

The invention relates to the combined use of anti-EGFR antibodies and anti-Her2 antibodies for the treatment of cancer, especially suitable for cancer expressing high levels of the EGFR type and low levels of HER2. The invention refers in particular monoclonal antibody “trastuzumab” (HERCEPTIN®) directed against the HER2 receptors the efficacy of which can be significantly increased in vivo when combined with monoclonal antibody “matuzumab” (hmAB 425, EMD 72000) directed against EGF receptors. The combination treatment is suitable for patients suffering from cancer having said receptor profile, preferably pancreatic cancer.

Description

FIELD OF THE INVENTION[0001]The invention relates to the combined use of an anti-EGFR (ErbB1) antibody and an anti-Her2 (ErbB2) antibody for the treatment of cancer. The invention furthermore relates to the treatment of tumor in an individual with said antibodies, wherein the tumor cells express high levels of the EGFR type and low or no significant levels of HER2. In particular, the invention refers to the combination treatment using monoclonal antibody trastuzumab” (HERCEPTIN®) directed against HER2 receptor and “matuzumab” (hmAb 425, EMD 72000) directed against EGF receptor, or another anti-EGFR antibody. The combination treatment is preferably suitable for patients suffering from a cancer, the tissue of which do not overexpress HER2 or express HER2 in low amounts, but do overexpress EGFR.BACKGROUND OF THE INVENTION[0002]Subclass I of the receptor tyrosine kinase (RTK) super family consists of ErbB receptors and comprises four members: EGFR / ErbB1, HER2 / ErbB2, ErbB3 and ErbB4. All...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K39/395A61P35/00
CPCA61K2039/507C07K2317/24C07K16/32C07K16/2863A61P35/00A61P43/00A61K39/395A61K39/39558A61K45/06A61K2039/505C07K2317/31
Inventor GILLIES, STEPHEN D.AZRIA, DAVIDLARBOURET, CHRISTELPELEGRIN, ANDRE
Owner INST NAT DE LA SANTE & DE LA RECHERCHE MEDICALE (INSERM)
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