Constructs for anti-CD20 Directed Therapeutics

抗 CD20 定向治疗的构建体

• 批准号: 6992458
• 负责人: ANDREW A. RAUBITSCHEK
• 金额: $ 16.79万
• 依托单位: BECKMAN RESEARCH INSTITUTE/CITY OF HOPE
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-09-02 至 2009-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6992458
• 关键词: CD antigens; bioimaging /biomedical imaging; biotechnology; chimeric proteins; clinical research; clinical trial phase I; clinical trial phase II; computed axial tomography; cytokine; human therapy evaluation; hybrid antibody; immunologic substance development /preparation; interleukin 2; laboratory mouse; monoclonal antibody; neoplasm /cancer immunotherapy; neoplasm /cancer radioimmunotherapy; nonHodgkin' s lymphoma; nonhuman therapy evaluation; patient oriented research; pharmacokinetics; positron emission tomography; protein engineering; radionuclides; therapy design /development; tissue /cell culture; xenotransplantation

This Project focuses on improving antibody based immunotherapy for the treatment of CD20-positive Non-Hodgkin's Lymphoma utilizing two different mechanisms. The first two specific aims will focus on the development of anti-CD20 antibodies as carriers of radioactivity for the purpose of achieving better imaging and more effective treatment of NHL. Although there are soon to be two FDA approved radioimmunotherapeutics for CD20+ NHL, they offer the opportunity to build on their success with reagents specifically designed as carriers of radioisotopes. In the first specific aim, we will develop molecularly engineered antibody fragments for imaging lymphoma, building on our successful experience with engineering CEA antibodies, focusing on diabodies and minibodies which should provide both faster targeting and more rapid clearance from the blood stream thereby providing better images of sites of lymphomatous disease. With the advent of PET scanners, faster targeting reagents are required to take advantage of the general shorter half lives of positron emitting isotopes. Although these agents are being evaluated in solid tumors, this will be the first time they will be investigated in lymphomas, where we hypothesize that they will show improved performance given the different relationship of lymphomas to the vascular supply. Refinements in reagents used for tumor imaging are not only worthwhile as imaging agents in B cell lymphoma but also will verify in the given patient whether the target antigen is present for a range of novel immune directed therapeutics. The second aim focuses on the therapeutic aspect of radioimmunoconjugates, defining by molecular engineering the optimal characteristics for improved radioimmunotherapy. The desired features of the antibody are likely to be different than that for imaging since a longer residence time at the tumor site is needed for better therapeutic applications. The third specific aim deals with the utilizing antibodies to carry immunologic agents to sites of tumor. The success of Rituxan in the treatment of lymphoma confirms the important role of the immune system as an anti-cancer therapeutic. In this project we will conduct laboratory and clinical studies of a RituxanlL-2 fusion protein which has significant pre-clinical therapeutic activity, by harnessing the tumor localization capabilities of the antibody to the cellular potency of IL2 in activating lymphocytes. In the last specific aim, we will conduct clinical trials of a humanized (delmmunized) antiCD20-1L2 immunocytokine to determine the activity of this novel reagent in the treatment of relapsed B cell lymphoma. This aim will provide an important opportunity for additional translational research as the patient studies will allow an in depth exploration of the mechanisms by which the endogenous immune system can be harnessed to destroy lymphoma. These studies will be important for understanding the immune mechanisms necessary for optimal development of effective immune system based therapeutics for lymphoma as well as for other malignancies in humans.

该项目的重点是利用两种不同的机制改进基于抗体的免疫疗法，用于治疗 CD20 阳性非霍奇金淋巴瘤。前两个具体目标将集中于开发抗CD20抗体作为放射性载体，以实现更好的成像和更有效的NHL治疗。 尽管很快就会有两种 FDA 批准的 CD20+ NHL 放射免疫治疗药物，但它们提供了利用专门设计为放射性同位素载体的试剂在其成功基础上再接再厉的机会。在第一个具体目标中，我们将基于我们在工程 CEA 抗体方面的成功经验，开发用于成像淋巴瘤的分子工程抗体片段，重点关注双抗体和微型抗体，它们应提供更快的靶向性 更快速地从血流中清除，从而提供淋巴瘤疾病部位的更好图像。 随着 PET 扫描仪的出现，需要更快的靶向试剂来利用正电子发射同位素普遍较短的半衰期。尽管这些药物正在实体瘤中进行评估，但这将是它们首次在淋巴瘤中进行研究，我们假设考虑到淋巴瘤与血管供应的不同关系，它们将表现出更好的性能。用于肿瘤成像的试剂的改进并没有 仅值得作为 B 细胞淋巴瘤的显像剂，而且还将在特定患者中验证是否存在针对一系列新型免疫定向疗法的靶抗原。第二个目标侧重于放射免疫缀合物的治疗方面，通过分子工程定义改进放射免疫疗法的最佳特性。抗体的所需特征可能与成像的特征不同，因为为了更好的治疗应用需要在肿瘤部位更长的停留时间。第三个具体目标涉及 利用抗体将免疫剂携带到肿瘤部位。 Rituxan 在淋巴瘤治疗中的成功证实了免疫系统作为抗癌治疗的重要作用。在该项目中，我们将利用抗体的肿瘤定位能力与 IL2 激活淋巴细胞的细胞效力，对 RituxanlL-2 融合蛋白进行实验室和临床研究，该融合蛋白具有显着的临床前治疗活性。在最后一个具体目标中，我们将进行人源化（去免疫化）抗CD20-1L2免疫细胞因子的临床试验，以确定这种新型试剂在治疗复发性B细胞淋巴瘤中的活性。这一目标将为更多的转化研究提供重要的机会，因为患者研究将允许深入探索利用内源性免疫系统来消灭淋巴瘤的机制。这些研究将 对于了解最佳开发有效的基于免疫系统的淋巴瘤以及人类其他恶性肿瘤疗法所必需的免疫机制非常重要。