Using the Allergic Immune System to Target Cancer

描述（由申请人提供）： 癌症免疫疗法旨在利用免疫系统来治疗或治愈癌症。该领域可以广泛地分为针对独特肿瘤抗原的主动T细胞免疫，或对细胞表面肿瘤抗原特异性的抗体的被动施用。在这两者中，基因人源化单克隆抗体的施用对临床肿瘤学产生了更显著的影响。用于治疗癌症患者的所有抗体都是γ 1同种型（IgG 1）。这一标准主要是基于历史数据，需要重新审查。该提议将探索通过参与过敏性免疫系统的效应细胞来获得用于癌症治疗的上级抗体的可能性。将通过构建对两种不同肿瘤抗原具有特异性的三种人源化抗体来测试该假设。抗体将通过改变其恒定区并使其成为特异性抗体（IgE）而进一步重塑。通过这样做，抗体将能够参与肥大细胞，嗜酸性粒细胞和嗜碱性粒细胞;所有过敏性免疫系统的有效效应细胞。针对CD 20和MUC 1的两种糖基化形式的单克隆抗体将被人源化。前者是治疗非霍奇金淋巴瘤的有效靶点，后者是治疗乳腺癌、胰腺癌、前列腺癌和多发性骨髓瘤的新靶点。一旦构建，将使用肥大细胞和嗜酸性粒细胞作为效应细胞评价抗体在体外介导肿瘤溶解的能力。为了更严格地评估这些新药剂的临床效用，将评估它们在小鼠中根除肿瘤的能力。人类和小鼠过敏性免疫系统之间存在显著差异，这可能低估了这些药物在人类中的真实的价值。幸运的是，存在一种基因改变的小鼠，其内源性小鼠IgE受体被删除并被人类受体取代。将测试肿瘤特异性人源化IgE抗体治疗这些转基因小鼠中植入肿瘤的能力。

DESCRIPTION (provided by applicant): Cancer Immunotherapy seeks to use the immune system to treat or cure cancer. This field may be broadly divided into active T cell immunization against unique tumor antigens, or passive administration of antibodies specific for cell surface tumor antigens. Of these two, administration of genetically humanized monoclonal antibodies has made more of a significant impact on clinical oncology. All of the antibodies used to treat cancer patients are of the gamma 1 isotype (lgG1). This standard is largely based on historical data that needs to be reexamined. This proposal will explore the possibility that superior antibodies for cancer therapeutics are possible by engaging effector cells of the allergic immune system. This hypothesis will be tested by construction of three humanized antibodies specific for two different tumor antigens. The antibodies will further be reshaped by changing their constant region and making them epsilon antibodies (IgE). By doing this, the antibodies will be able to engage mast cells, eosinophils and basophils; all potent effector cells of the allergic immune system. Monoclonal antibodies to CD20 and two glycosylated forms of MUC1 will be humanized. The former is a validated target in the treatment of non-Hodgkin's lymphomas and the latter a novel target in the treatment of breast, pancreatic and prostate cancer and multiple myeloma. Once constructed, the antibodies will be evaluated for their ability to mediate tumor lysis in vitro using mast cells and eosinophils as effector cells. To more rigorously evaluate the clinical utility of these novel agents, their ability to eradicate tumors in mice will be assessed. Significant differences exist between the human and mouse allergic immune system that may underestimate the real value of these agents in humans. Fortunately, a genetically altered mouse exists that has had the endogenous mouse receptor for IgE deleted and replaced by the human receptor. The tumor specific, humanized IgE antibodies will be tested for their ability to treat implanted tumors in these transgenic mice.