Antibody Immunotherapy to a Pro-apoptotic Tumor Antigen

针对促凋亡肿瘤抗原的抗体免疫疗法

基本信息

批准号：
6469453
负责人：
KENNETH L ROCK
金额：
$ 28.3万
依托单位：
UNIV OF MASSACHUSETTS MED SCH WORCESTER
依托单位国家：
美国
项目类别：
财政年份：
2002
资助国家：
美国
起止时间：
2002-07-15 至 2005-06-30
项目状态：
已结题

项目摘要

DESCRIPTION (PROVIDED BY APPLICANT): The basis of this grant is our discovery of a novel tumor antigen (p40) that has several features, which make it an attractive candidate as a target for antibody-based immunotherapy of certain cancers. These features include: (1) Tumor specific expression; (2) Broad expression on many different tumors; (3) Antibody binding inhibits tumor proliferation and induces apoptosis. The objective of this grant is to develop and evaluate monoclonal antibodies against this tumor antigen for immunotherapy. Our underlying hypothesis is that tumor specific monoclonal antibodies which block proliferation and cause tumor cells to die have the potential to treat cancers. An important feature of our anti-tumor monoclonal antibody selected for these studies is that it reacts with (and is anti-proliferative and pro-apoptotic for) both murine and human tumors. Therefore, we can evaluate its ability to treat both murine and human tumors. The goal of the first Aim is to clone and characterize the p40 gene. The rationale for this objective is that it will allow us to define the molecular structure of this antigen. Moreover, it will provide an important tool to explore the function of this antigen. Our experimental approach will be to probe cDNA expression libraries with anti-ligand reagents or to probe libraries with oligonucleotides based on the amino acid sequence of p40. The goal of the second aim is to define which human tumors express the p40 antigen and to assess how these tumors are affected by the anti-p40 mAb. The obvious importance of this objective is that this data will determine the kinds of tumors that are candidates for immunotherapy with the anti-p40 mAb. Our experimental approach is to analyze expression of the p40 antigen in a variety of biopsies and surgically-resected tumors by immunohistochemistry. We will also examine whether p40 is expressed in any normal tissues. The effects of the mAb on cell proliferation and apoptosis of p40 positive cells will be examined in vitro. Finally, we will determine whether tumors can extinguish the expression the p40 antigen, and if so, how this loss of expression affects the malignant phenotype of the tumor. The goal of the third aim is to test whether the anti-p40 antibody can cause regression of or cure established cancers in an animal model. Our experimental approach will be to inject the anti-p40 mAb into mice bearing transplanted tumors. In one set of experiments we will test the efficacy of immunotherapy on mice transplanted with syngeneic tumors. In another set of experiments, we will test the effect of p40 on human tumors transplanted into immunodeficient mice.

描述（由申请人提供）：这项资助的基础是我们的发现一种新型肿瘤抗原 (p40) 的研究，具有多种特征，使其成为作为某些基于抗体的免疫治疗靶点的有吸引力的候选者癌症。这些特征包括：（1）肿瘤特异性表达； (2) 广义在许多不同的肿瘤上表达； (3)抗体结合抑制肿瘤增殖并诱导细胞凋亡。这笔赠款的目标是发展并评估针对该肿瘤抗原的单克隆抗体免疫疗法。我们的基本假设是肿瘤特异性单克隆阻止增殖并导致肿瘤细胞死亡的抗体具有治疗癌症的潜力。我们的抗肿瘤单克隆抗体的一个重要特征为这些研究选择的抗体是它与（并且是对小鼠和人类肿瘤具有抗增殖和促凋亡作用。因此，我们可以评估其治疗小鼠和人类肿瘤的能力。第一个目标是克隆和表征 p40 基因。这这一目标的基本原理是，它将允许我们定义分子该抗原的结构。此外，它将提供一个重要的工具探索该抗原的功能。我们的实验方法是使用抗配体试剂探测 cDNA 表达文库或探测文库具有基于p40氨基酸序列的寡核苷酸。的目标第二个目标是确定哪些人类肿瘤表达 p40 抗原并评估这些肿瘤如何受到抗 p40 mAb 的影响。显而易见的这一目标的重要性在于，这些数据将决定适合使用抗 p40 mAb 进行免疫治疗的肿瘤。我们的实验方法是分析p40抗原在多种细胞中的表达通过免疫组织化学进行活检和手术切除的肿瘤。我们将还检查 p40 是否在任何正常组织中表达。的影响 mAb对细胞增殖和p40阳性细胞凋亡的影响将被检测体外。最后，我们将确定肿瘤是否可以消灭 p40 抗原的表达，如果是，这种表达缺失如何影响肿瘤的恶性表型。第三个目标的目的是测试是否抗 p40 抗体可以使已形成的癌症消退或治愈动物模型。我们的实验方法是将抗 p40 mAb 注射到携带移植肿瘤的小鼠。在一组实验中，我们将测试免疫疗法对移植同基因肿瘤的小鼠的疗效。在另一组实验，我们将测试p40对人类肿瘤的作用移植到免疫缺陷小鼠体内。