Combination Therapy Using Anti-EGFR and Anti-HER2 Antibodies

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...

AI Technical Summary

Benefits of technology

[0082]A method for improving the efficacy of the treatment of cancer that expresses HER2 and preferably overexpresses EGFR with an anti-HER2 antibody, wherein said cancer does not overexpress HER2 or expresses HER2 in low levels or levels that are not sufficient to respond significantly to said anti-HER2 antibody treatment alone; the method comprising administering to an individual an anti-HER2 antibody, which, when given alone, does not or not significantly inhibit HER2 dimerization and / or HER2 / EGFR heterodimerization, and an anti-EGFR antibody, which, when given alone, significantly inhibits EGFR dimerization and / or EGFR / HER2 heterodimerization.

[0094]Despite a high EGFR expression in the pancreatic BxPC-3 cell line, matuzumab (EMD7200) is not or only little effective on tumor growth inhibition used alone at a dose of 50 or 200 μg / injection, confirming the absence of correlation between EGFR expression and curative efficacy of anti-EGFR antibodies. This can be illustrated with a second in vivo pancreatic cancer model (MiaPaca) where mice are treated with 50 μg / injection of EMD72000 twice a week for four weeks. The anti-tumor activity of the combination, however, is much stronger than the negligible anti-tumor activity of the antibodies used as single components alone. With regard to decreased tumor volume and in vitro viability studies, the effect of the combined antibodies is clearly synergistic in the BxPC-3 model and not a mere additive effect calculated from the efficacies of the single components. This effect is particularly striking during the four-week treatment period, where no tumor progression can be observed in the combined treatment group. Similar efficacy of this treatment can be observed on both small and large pancreatic tumors.

[0113]The therapeutic approach of this invention includes as a specific embodiment the administration of further therapeutically effective agents, which support the desired effect, e.g. tumor toxicity or cytostatic efficacy, or diminish or prevent undesired side effects. Thus the invention includes the combination of such agents with the pharmaceutical composition defined and claimed above and below, wherein said agents may be other ErbB receptor antagonists, VEGF receptor antagonists, cytokines, cytokine-immunoconjugates, anti-angiogenic agents, anti-hormonal agents, or cytotoxic agents in general. It is also an object of this invention to combine the compositions as defined herein with radiotherapy according to known methods.

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.

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