Constructs for anti-CD20 Directed Therapeutics

该项目的重点是利用两种不同的机制来改善基于抗体的免疫疗法，用于治疗CD 20阳性非霍奇金淋巴瘤。前两个具体目标将集中于开发抗CD 20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。 虽然很快就会有两种FDA批准的用于CD 20 + NHL的放射免疫治疗药物，但它们提供了利用专门设计为放射性同位素载体的试剂取得成功的机会。在第一个具体目标中，我们将开发用于成像淋巴瘤的分子工程抗体片段，建立在我们工程化CEA抗体的成功经验基础上，专注于双抗体和微抗体，它们应提供更快的靶向， 并且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以利用正电子发射同位素的一般较短的半衰期。虽然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，我们假设它们将显示出改善的性能，因为淋巴瘤与血管供应的关系不同。用于肿瘤成像的试剂的改进并不 仅作为B细胞淋巴瘤的显像剂是有价值的，而且还将在给定的患者中验证靶抗原是否存在于一系列新的免疫导向治疗剂中。第二个目标集中在放射免疫偶联物的治疗方面，通过分子工程定义改进放射免疫治疗的最佳特性。抗体的所需特征可能与成像不同，因为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。在这个项目中，我们将进行RituxanIL-2融合蛋白的实验室和临床研究，该融合蛋白具有显著的临床前治疗活性，通过利用抗体的肿瘤定位能力来激活淋巴细胞中IL-2的细胞效力。在最后一个具体目标中，我们将进行人源化（去免疫化）抗CD 20 - 1 L2免疫细胞因子的临床试验，以确定这种新试剂在复发性B细胞淋巴瘤治疗中的活性。这一目标将为额外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内源性免疫系统可用于破坏淋巴瘤的机制。这些研究报告将 这对于理解基于免疫系统的淋巴瘤以及人类其它恶性肿瘤的有效治疗剂的最佳开发所必需的免疫机制是重要的。

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.