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: 7267083
• 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 2009-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7267083
• 关键词: Adverse effects; Affinity; Antibodies; Antibody Therapy; Antigens; B-Cell Lymphomas; B-Lymphocytes; Binding; Biopsy; Cells; Classification; Cytotoxic Chemotherapy; Diagnosis; Disease; Effector Cell; Fc Receptor; Follicular Lymphoma; Human; Immunoglobulin G; Knowledge; Learning; Lymphoma; Mediating; Modality; Monoclonal Antibodies; Monoclonal Antibody CD20; Natural Killer Cells; Non-Hodgkin' s Lymphoma; North America; Pathway interactions; Patients; Play; Primary Neoplasm; Radiation therapy; Rate; Reagent; Resistance; Resistance development; Role; Sampling; Signal Transduction; Signal Transduction Pathway; Specimen; Testing; Time; Variant; Work; antibody-dependent cell cytotoxicity; base; chemotherapy; cytotoxicity; design; humanized monoclonal antibodies; killings; macrophage; neoplastic cell; next generation; response; rituximab; tositumomab; tumor

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疾病，通常需要一个以上的疗程。近年来，无毒的抗CD 20单克隆抗体利妥昔单抗治疗B细胞淋巴瘤的成功给人们带来了极大的兴奋和新的希望。然而，与化疗相比，应答率相对较低，并且单独的抗体治疗似乎不具有治愈性。如果我们能够了解单克隆抗体如何介导其抗肿瘤作用，那么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更有效的抗体来提高它们的功效。在该项目中检验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来介导其抗淋巴瘤活性。我计划通过对利妥昔单抗治疗患者的原发性肿瘤样本进行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着重要作用。这个项目的具体目标是为了扩展我们以前的发现： 1)探讨利妥昔单抗诱导抗体介导细胞毒作用的机制。 2)分析利妥昔单抗对淋巴瘤细胞的直接作用。 3)表征Fc改变的抗CD20变体，其以更高亲和力结合Fc受体。 4)明确利妥昔单抗耐药的机制。 通过对利妥昔单抗治疗患者的原发性肿瘤细胞进行系统分析，我们有一个独特的机会来了解利妥昔单抗如何在患者中起作用，以及如何产生耐药性。从这个项目产生的知识将帮助我们设计更好的方法来使用单克隆抗体和开发新的试剂来治疗B细胞淋巴瘤患者。