Using the Allergic Immune System to Target Cancer

描述(由申请人提供)： 癌症免疫疗法寻求使用免疫系统来治疗或治愈癌症。这一领域大致可分为针对独特肿瘤抗原的主动T细胞免疫，或针对细胞表面肿瘤抗原的抗体的被动注射。其中，基因人源化的单抗的使用对临床肿瘤学产生了更显著的影响。所有用于治疗癌症患者的抗体都是伽马1亚型(LgG1)。这一标准在很大程度上是基于需要重新审查的历史数据。这项建议将探索通过接触过敏免疫系统的效应细胞来获得癌症治疗的高级抗体的可能性。这一假设将通过构建三种针对两种不同肿瘤抗原的人源化抗体来验证。抗体将通过改变其恒定区域而进一步重塑，使其成为epsilon抗体(IgE)。通过这样做，抗体将能够与肥大细胞、嗜酸性粒细胞和嗜碱性粒细胞结合，这些细胞都是过敏免疫系统的有效效应细胞。抗CD20和两种糖基化形式的MUC1的单抗将人源化。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，评估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物的临床效用，将评估它们根除小鼠肿瘤的能力。人类和小鼠的过敏性免疫系统之间存在着显著的差异，这可能低估了这些制剂在人类身上的真正价值。幸运的是，存在一种基因改变的小鼠，它的内源性小鼠免疫球蛋白E受体被删除，并被人类受体取代。肿瘤特异的人源化IgE抗体将被测试其治疗这些转基因小鼠移植瘤的能力。

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.