Antibody Immunotherapy to a Pro-apoptotic Tumor Antigen

针对促凋亡肿瘤抗原的抗体免疫疗法

• 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
• 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
• 来源: https://reporter.nih.gov/project-details/6469453
• 关键词: SCID mouse; antigen antibody reaction; antineoplastics; apoptosis; biopsy; cell line; cell proliferation; clinical research; complementary DNA; disease /disorder model; drug design /synthesis /production; flow cytometry; gene expression; genetic library; human tissue; immunocytochemistry; molecular cloning; monoclonal antibody; neoplasm /cancer immunotherapy; neoplasm /cancer remission /regression; neoplastic cell; nonhuman therapy evaluation; northern blottings; polymerase chain reaction; tumor antigens

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）：本补助金的基础是我们的发现 一种新的肿瘤抗原（p40），具有几个特征，使其成为一种新的肿瘤抗原。 作为基于抗体的免疫疗法的靶点的有吸引力的候选物 癌的这些特征包括：（1）肿瘤特异性表达;（2）广泛表达;（3）肿瘤特异性表达;（4）肿瘤特异性表达。 在许多不同肿瘤上表达;（3）抗体结合抑制肿瘤 增殖并诱导凋亡。该补助金的目的是发展 并评估针对这种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抗体 阻断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是 选择用于这些研究的抗体的一个重要特征是，它与 抗增殖和促细胞凋亡）。 因此，我们可以评估其治疗小鼠和人肿瘤的能力。 第一个目标是克隆和表征p40基因。的 这一目标的基本原理是，它将使我们能够定义分子 这种抗原的结构。此外，它将提供一个重要工具， 探讨该抗原的功能。我们的实验方法是 用抗配体试剂探测cDNA表达文库或探测文库 与基于p40的氨基酸序列的寡核苷酸结合。的目标 第二个目的是确定哪些人肿瘤表达p40抗原， 评估抗p40 mAb如何影响这些肿瘤。明显的 这一目标的重要性在于，这些数据将决定 肿瘤是用抗p40 mAb进行免疫治疗的候选者。我们 实验方法是分析p40抗原在各种 活检和切除肿瘤的免疫组化。我们将 并检测p40是否在正常组织中表达。的影响 将检测mAb对p40阳性细胞的细胞增殖和凋亡的影响 体外最后，我们将确定肿瘤是否可以消灭 表达p40抗原，如果是这样，这种表达的损失如何影响p40抗原的表达。 肿瘤的恶性表型。第三个目标是测试 抗-p40抗体可以引起癌症的消退或治愈 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 免疫治疗对移植有同基因肿瘤的小鼠的功效。在 在另一组实验中，我们将测试p40对人类肿瘤的影响。 移植到免疫缺陷小鼠体内。