Mechanism of Antibody Therapy in Human B Cell Lymphoma

人B细胞淋巴瘤抗体治疗机制

• 批准号: 6983124
• 负责人: WEN-KAI WENG
• 金额: $ 13.81万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-08-22 至 2008-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6983124
• 关键词: Mechanism; Antibody; Therapy; Human; Cell

DESCRIPTION (provided by applicant): Patients with B cell lymphoma usually require treatment with a combination of several cytotoxic chemotherapy agents to control their disease and usually need more than one course of treatment. Recently, the successful use of non-toxic monoclonal anti-CD20 antibody, rituximab, to treat B cell lymphoma has produced a great deal of excitement and new hope. However, the response rate is relatively low compared to chemotherapy and antibody treatment alone does not appear to be curative. If we can understand how monoclonal antibodies mediate their anti-tumor effect, it is possible to increase their efficacy by developing new ways to use them and design more effective antibodies based on what we learn. The hypothesis tested in this project is that monoclonal antibodies such as rituximab mediate their anti-lymphoma activity either by antibody-mediated killing and a direct anti-tumor effect on tumor cells. I plan to test this hypothesis through a systematic analysis of these mechanisms on primary tumor samples from rituximab-treated patients. Recently, we have shown evidence that antibody-dependent cellular cytotoxicity (ADCC) plays a major role in rituximab's anti-tumor effect. The specific aims of this project are designed to extend our previous finding: 1) To dissect the mechanism of antibody-mediated cytotoxicity induced by rituximab. 2) To analyze the direct effect of rituximab on lymphoma cells. 3) To characterize anti-CD20 variants with altered Fc that bind Fc receptor with higher affinity. 4) To define the mechanism of rituximab resistance. By this systematic analysis of primary tumor cells from rituximab-treated patients, we have a unique opportunity to learn how rituximab works in patients, and how treatment resistance develops. The knowledge generated from this project will help us to design better ways to use monoclonal antibodies and to develop new reagents to treat patients with B cell lymphoma.

描述（由申请人提供）：B细胞淋巴瘤患者通常需要联合使用几种细胞毒性化疗药物来控制病情，通常需要一个以上的疗程。近年来，无毒单克隆抗cd20抗体利妥昔单抗治疗B细胞淋巴瘤的成功应用给人们带来了极大的兴奋和新的希望。然而，与化疗相比，反应率相对较低，单独使用抗体治疗似乎无法治愈。如果我们能够了解单克隆抗体是如何介导它们的抗肿瘤作用的，就有可能通过开发新的方法来使用它们，并根据我们所了解的设计出更有效的抗体来提高它们的功效。本项目测试的假设是单克隆抗体如利妥昔单抗通过抗体介导的杀伤和对肿瘤细胞的直接抗肿瘤作用介导其抗淋巴瘤活性。我计划通过对利妥昔单抗治疗患者原发肿瘤样本的这些机制的系统分析来验证这一假设。最近，我们有证据表明抗体依赖性细胞毒性（ADCC）在利妥昔单抗的抗肿瘤作用中起主要作用。这个项目的具体目标是为了扩展我们之前的发现：