Constructs for anti-CD20 Directed Therapeutics

本项目致力于利用两种不同的机制改进基于抗体的免疫疗法来治疗CD20阳性的非霍奇金淋巴瘤。前两个具体目标将集中在开发抗CD20抗体作为放射性载体，以实现更好的成像和更有效的治疗非霍奇金淋巴瘤。 尽管FDA很快就会批准两种治疗CD20+NHL的放射免疫疗法，但它们提供了利用专门设计的放射性同位素载体的试剂来发展其成功的机会。在第一个具体目标中，我们将根据我们在设计CEA抗体方面的成功经验，开发用于淋巴瘤成像的分子工程抗体片段，重点放在应该提供更快靶向的恶性肿瘤和微体上。 更快地从血流中清除，从而提供更好的淋巴瘤疾病部位的图像。 随着PET扫描仪的出现，需要更快的靶向试剂来利用发射正电子的同位素一般较短的半衰期。虽然这些药物正在实体肿瘤中进行评估，但这将是它们第一次在淋巴瘤中进行研究，我们假设，鉴于淋巴瘤与血管供应的不同关系，它们的性能将有所改善。用于肿瘤成像的试剂中的改进并不是 仅作为B细胞淋巴瘤的显像剂是有价值的，但也将在给定的患者中验证目标抗原是否存在于一系列新的免疫导向疗法中。第二个目标集中在放射免疫结合物的治疗方面，通过分子工程定义改进放射免疫治疗的最佳特征。抗体的所需特征可能与成像不同，因为为了更好的治疗应用，需要在肿瘤部位停留更长的时间。第三个具体目标涉及 利用抗体将免疫试剂携带到肿瘤部位。Rituxan在治疗淋巴瘤方面的成功证实了免疫系统作为抗癌疗法的重要作用。在这个项目中，我们将通过利用针对IL2激活淋巴细胞的细胞效力的抗体的肿瘤定位能力，对具有显著临床前治疗活性的RituxanlL-2融合蛋白进行实验室和临床研究。在最后一个特定目标中，我们将进行人源化(去免疫)抗CD20-1L2免疫细胞因子的临床试验，以确定这种新试剂在治疗复发B细胞淋巴瘤中的活性。这一目标将为进一步的转译研究提供重要机会，因为患者研究将允许深入探索利用内源性免疫系统摧毁淋巴瘤的机制。这些研究将是 这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治疗方法所需的免疫机制非常重要。

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.