Therapeutic Effectiveness of T Cell Receptor mimic (TCRm) Antibodies in Breast Ca

描述(申请人提供)：美国癌症协会每年公布在美国被诊断为浸润性乳腺癌并死于浸润性乳腺癌的女性人数惊人。与所有癌症一样，早期治疗成功率较高，治疗方案因疾病进展而异。尽管我们相当重视治愈或改善这种疾病，但我们的知识基础仍然存在严重差距，阻碍了开发更有效的晚期癌症治疗形式。重要的是，几项研究还表明，老年妇女不太可能选择手术或放射治疗，这显著降低了她们的存活率(《外科档案》，2006年10月)。 通过与乳腺癌细胞表面特定靶点结合的单抗摧毁乳腺癌细胞，显示出作为一种新的治疗方式的巨大前景。然而，很明显，肿瘤细胞表面特有的靶点可能是有限的。主要组织相容性复合体(MHC)I类系统可以被认为是自然界的蛋白质组扫描芯片，因为它不断地处理细胞内的蛋白质，并在细胞表面呈现多肽。根据最近的研究，我们发现与正常细胞相比，多肽-MHC-I类靶标在癌细胞表面的独特表达。这些肿瘤特异性多肽-MHC复合体是抗体结合的靶标，但对多肽-MHC复合体具有识别特异性的抗体并不常见。我们已经开发了一种技术来产生抗体，这种抗体可以模拟T细胞受体(TCR)的结合特异性，被指定为TCRm。我们已经确定了一种TCRm，它可以在体外结合并介导肿瘤细胞的死亡，并在体内导致肿瘤缩小。 在这项第一阶段的研究中，我们将通过在异种移植小鼠模型中完全表征小鼠3.2G1TCRm的抗肿瘤特性来扩展我们先前的观察。我们将测定hCG(抗原)和GVL多肽-人类白细胞抗原A2表位的表达频率。然后我们将确定治疗效果以及靶向密度和TCRm介导的肿瘤缩小之间的关系。其具体目的是：1)建立hCG抗原和GVL多肽-HLA-A2表位在乳腺癌细胞中的频率；2)确定3.2G1TCRm介导的抗肿瘤活性的普遍性。我们期待这项研究的结果将导致TCRMS作为一类新的癌症治疗药物的开发。此外，这些研究有望验证GVL多肽HLA-A2表位用于癌症免疫治疗。最后，这项研究的结果将用于提交STTR第二阶段申请，以进行嵌合和/或人源化3.2G1TCRm的临床前开发，作为乳腺癌的一种新治疗方式。 与公共健康相关：美国癌症协会每年公布美国被诊断为浸润性乳腺癌并死于浸润性乳腺癌的女性人数惊人。重要的是，研究表明，老年女性不太可能选择传统疗法，这显著降低了她们的存活率。因此，为了减少乳腺癌的死亡和痛苦，新的治疗方式是必要的。这项提议旨在检测一类识别乳腺癌细胞新靶点的新型抗体的抗肿瘤特性。这些研究的完成有望导致开发用于治疗乳腺癌的新的治疗性抗体。

DESCRIPTION (provided by applicant): The American Cancer Society announces annually the staggering number of women that are diagnosed with and die from invasive breast cancer in the United States. As with all cancers, treatment success rates are higher in early stages and treatment options vary with disease progression. Despite considerable focus on curing or ameliorating this disease, there are still critical gaps in our knowledge base that hinder the development of more effective forms of treatment for later-stage cancer. Importantly, several studies have also shown that older women are less likely to choose surgery or radiation, decreasing their survival rates significantly (Archives of Surgery, October 2006). Destruction of breast cancer cells by monoclonal antibodies that bind to specific targets on their surface shows great promise as a new treatment modality. However, it has become apparent that targets unique to the surface of tumor cells may be limited. The Major Histocompatability Complex (MHC) class I system can be thought of as nature's proteomic scanning chip because it continuously processes intracellular protein and presents peptides on the surface of cells. From recent studies, we show unique expression of peptide-MHC class I targets on the surface of cancer cells compared to normal cells. These tumor-specific peptide-MHC complexes represent targets for antibody binding however, antibodies that have recognition specificity for peptide-MHC complexes are not common. We have developed technology to generate antibodies that mimic the binding specificity of T cell receptors (TCR) designated as TCRm. We have identified a TCRm that can bind to and mediate tumor cell death in vitro and cause tumor shrinkage in vivo. In this Phase I study, we will extend our earlier observations by fully characterizing the murine 3.2G1TCRm's anti-tumor properties in a xenograft mouse model. We will determine the expression frequency for hCG ( antigen and the GVL peptide-HLA-A2 epitope. We will then determine the therapeutic effectiveness and the relationship between target density and TCRm- mediated tumor shrinkage. The Specific Aims are: 1) to establish the frequency of hCG antigen and the GVL peptide-HLA-A2 epitope in breast cancer cells and 2) to determine the generality of anti-tumor activity mediated by the 3.2G1 TCRm. We expect that the results from this study will lead to the development of TCRms as a novel class of agents for cancer treatment. Moreover, these studies are expected to validate the GVL peptide HLA-A2 epitope for cancer immunotherapy. Finally, the results from this study will be used to submit an STTR phase II application to carry out the pre-clinical development of the chimeric and/or humanized 3.2G1 TCRm as a novel treatment modality for breast cancer. PUBLIC HEALTH RELEVANCE: The American Cancer Society announces annually the staggering number of women that are diagnosed with and die from invasive breast cancer in the United States. Importantly, studies have shown that older women are less likely to choose traditional therapies, decreasing their survival rates significantly. As such, new treatment modalities are necessary to reduce the death and suffering from breast cancer. This proposal aims to examine the anti-tumor properties of a new class of antibodies that recognize novel targets on breast carcinoma cells. Completion of these studies is expected to lead to development of new therapeutic antibodies for the treatment of breast cancer.