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    Research Grants Awarded

    Anti-HER2/neu IgE for the Therapy of Breast Cancer

    Study Section:
    Treatment

    Scientific Abstract:
    Despite considerable advancement in cancer therapy, relapse is still a major problem in the management of breast cancer. The prognosis for breast cancer patients is particularly poor in those bearing tumors overexpressing HER2/neu (nearly 30% of patients). Although treatment of patients with advanced breast cancer using the humanized anti-HER2/neu antibody (IgG1) Trastuzumab (also known as Herceptin) leads to an objective response in patients with tumors overexpressing HER2/neu, this response is limited to a partial tumor regression in a subset of patients. The present proposal seeks to develop a novel anti-HER2/neu antibody composed of the variable region of Herceptin and the human Fc epsilon constant regions (anti-HER2/neu IgE). We hypothesize that the anti-HER2/neu IgE will target the tumor and in so doing activate the innate immune response resulting in an acute inflammation in the tumor microenvironment with subsequent tumor destruction. The presence of dead tumor cells would allow the effective uptake and presentation of tumor antigens by antigen presenting cells (APCs) resulting in an efficient priming of the adaptive (cellular and humoral) immune response. We also hypothesize that immunocomplexes composed of anti-HER2/neu IgE and soluble HER2/neu antigen would be able to target APCs resulting in an efficient antigen internalization and presentation with the subsequent immune activation. We propose three specific aims: 1) To construct and express the humanized anti-HER2/neu IgE; 2) To evaluate the properties of the anti-HER2/neu IgE in vitro; 3) To evaluate the properties of the anti-HER2/neu IgE in vivo. To construct the anti-HER2/neu IgE we will genetically fuse the cDNA encoding the variable regions of Herceptin to the DNA encoding the human kappa (light chain) and epsilon (heavy chain) constant regions. The resulting humanized antibody will be expressed in mammalian cells. We will test the ability of the antibody to bind antigen and also study its ?Herceptin-like activity? by testing its ability to inhibit the proliferation of human breast cancer cells. We will also study the binding of the antibody to human Fc epsilon receptor as well as its ability to internalize and process HER2/neu in APCs. The in vivo properties will be evaluated in transgenic mice expressing human Fc epsilon receptor alpha chain. We will study the pharmacokinetics of the antibody and its ability to target and eliminate HER2/neu expressing tumors. We will also test the efficacy of anti-HER2/neu IgE to enhance the immune response of HER2/neu protein vaccination. In summary, the anti-HER2/neu IgE will be capable of a two-pronged attack against cancer cells, through their direct destruction and through the orchestration of a robust tumor specific immune response directed not only against HER2/neu, but also against a wide range of other tumor antigens. We anticipate that our studies will have a significant impact in the prevention and treatment of breast cancer.

    Lay Abstract:
    Despite considerable advancement in cancer therapy, relapse is still a major problem in the clinical management of breast cancer and once the disease is disseminated it is practically incurable. The prognosis for breast cancer patients is particularly poor in those bearing tumors that express a protein called HER2/neu (nearly 30% of patients). In fact, patients with tumors expressing HER2/neu respond less to conventional therapies and die earlier than those bearing HER2/neu negative tumors. Although the treatment of patients with advanced breast cancer using the anti-HER2/neu antibody Trastuzumab (also known as Herceptin, Genentech Inc., San Francisco, CA) leads to an objective response in patients with HER2/neu positive tumors, this response is generally limited to a partial tumor regression in a small number of patients. Most of the advanced breast cancer patients that respond initially eventually develop resistance to the treatment and will succumb to the disease. Therefore, improved therapies are still needed. The goal of this proposal is to develop an anti-HER2/neu antibody named ?anti-HER2/neu IgE?. This novel antibody will act as a ?magic bullet? that will target HER2/neu positive tumors and in so doing create an inflammatory response which would result in tumor destruction. In addition, the anti-HER2/neu IgE will be able to ?teach? the patient?s immune system to learn that breast cancer cells are ?foreign? and should be destroyed. These mechanisms of action are different to those described for Trastuzumab. To accomplish our goal we have three specific aims: 1) To construct the anti-HER2/neu IgE antibody; 2) To evaluate the properties of the anti-HER2/neu IgE in cancer cells; and 3) To evaluate the properties of the anti-HER2/neu IgE in animal models. If encouraging results are found the proposed antibody can be used directly in humans. In summary, the anti-HER2/neu IgE will be a novel therapeutic capable of a two-pronged attack against breast cancer cells through their direct destruction and through the orchestration of a robust tumor specific immune response. Importantly, the resulting immune response should be directed not only against the targeted molecule (HER2/neu), but also against a wide range of other proteins expressed on the surface of breast cancer cells. We anticipate that our studies will have a significant impact in the eradication of HER2/neu positive breast cancer, including those resistant to Trastuzumab. In addition, the anti-HER2/neu IgE may also be used as a ?potentiator? to enhance the efficacy of future breast cancer vaccines. In both cases the proposed approach is expected significantly contribute to a decrease in the human and economic cost associated with breast cancer. It is expected that the anti-HER2/neu IgE will represent the starting point for a new generation of breast cancer therapeutics.