RADIOIMMUNOTHERAPY AND BONE MARROW TRANSPLANTATION IN HEMATOLOGIC MALIGNANCY

该项目将专注于临床的开发和生产 进行人体试验所需的试剂， 放射性标记的单克隆抗体在骨髓中的应用 移植 骨髓移植是目前最有效的 然而，治疗各种白血病和淋巴瘤的方法， 在某些情况下，病人的疾病不是由预先的 移植治疗 一般来说，患者接受高剂量治疗 化疗以及分次全身放射治疗作为 移植前的预处理方案 放射性标记 本项目开发的单克隆抗体将用于 全身分次放射治疗 以改善长期无病间隔。 该项目将开发三种不同的单克隆抗体。 一 一种针对抗原CD 33，一种针对抗原CD 45， 一种针对抗原CD 20。 CD 33是一种常见的抗原， 对绝大多数急性髓细胞性白血病细胞的影响。 的 因此，放射性标记的抗体将用作 急性髓细胞白血病的预处理方案 接受骨髓移植的患者，以及其他 VCD 33阳性疾病，包括CML患者和 骨髓增生异常疾病 正在开发的第二种抗体是抗CD 45抗体。 cd 45是 在几乎所有造血细胞上都有发现，因此代表了一个靶点， 不仅用于急性髓细胞白血病患者的临床试剂， 还有淋巴细胞白血病患者。 第三抗体 开发了一种抗CD 20抗体，它识别一种常见的抗原， 对B细胞系的正常和恶性淋巴细胞的作用。 大多数淋巴瘤 是B细胞来源的，表达CD 20，将作为靶细胞。 该放射性标记抗体的患者人群。 放射性标记的工作将集中在使用重金属同位素 钇-90作为一种手段，提供显着剂量的辐射， 包括肿瘤部位和骨髓 钇-90可以优选于 碘由于其比活度更高，β范围更长， 发射、缺乏高能伽马射线和骨寻找能力。 抗CD 20抗体也将是分子工程的重点， 以改善其生物分布，从而提高其临床实用性。 一种双功能抗体分子构建体，其分子量为 大约80，000个将是最初设计的结构。 进一步 分子构建体将包括用于随后的位点特异性的抗体， 修饰和融合蛋白。 最后一个方面将是应用更好的螯合剂来保持 放射性金属附着在单克隆抗体上。 试剂将集中在 以分子DOTA为例的大环类化合物。 这种DOTA螯合物的进一步修饰将被评估为潜在的 用于临床治疗白血病的试剂， 本研究涵盖的淋巴瘤。

This project will focus on the development and production of the clinical reagents necessary to carry out human trials with three separate radiolabeled monoclonal antibodies in the setting of bone marrow transplantation. Bone marrow transplantation is one of the most effective ways of dealing with a variety of leukemias and lymphomas, however, in certain cases, the disease of the patient is not irradicated by the pre- transplant therapy. In general, patients are treated with high dose chemotherapy as well as fractionated total body radiation therapy as part of their conditioning regimen prior to transplant. The radiolabeled monoclonal antibodies developed in this project will be used for supplementaing the fractionated total body radiation therapy in an effort to improve long term disease free intervals. The project will develop three different monoclonal antibodies. One directed against the antigen CD33, one directed against the antigen CD45, and one directed against the antigen CD20. CD33 is a common antigen found on the vast majority of cells in acute myelogenous leukemia. The radiolabeled antibody will therefore be used as an adjunct to the conditioning regimen for patients with acute myelogenous leukemia undergoing bone marrow transplantation, as well as other patients with VCD33 positive disease including those patients with CML and myuelodysplastic disorders. The second antibody being developed is an anti-CD45 antibody. CD45 is found on almost all hematopoietic cells and therefore represents a target for clinical reagents for not only patient with acute myelogenous leukemia, but patients with lymphocytic leukemias as well. The third antibody developed is an anti-CD20 antibogy which recognized a common antigen found on normal and malignant lymphocytes of the B-cell lineage. Most lymphomas are of the B-cell origin and express CD20 and will serve as the target patient population for this radiolabeled antibody. The radiolabeling effort will focus on using the heavy metal isotope Yttrium-90 as a means of delivering significant doses of irradiation to involved tumor sites and bone marrow. Yttrium-90 may be preferred over iodine because of its higher specific activity, longer range of beta emission, absence of high energy gamma, and bone seeking capabilities. The anti-CD20 antibody will also be the focus of molecular engineering in order to improve it's biodistribution and therefore it's clinical utility. A bi-functional antibody molecular construct with a molecular weight of approximately 80,000 will be the initial construct engineered. Further molecular constructs will include antibodies for subsequent site specific modification and fusion proteins. The final aspect will be to apply better chelating agents for holding the radiometal attached to the monoclonal antibody. The reagents will focus on compounds of the macrocyclic class exemplified by the molecular DOTA. Further modification of this DOTA chelate will be evaluated as potential reagents for clinical utility in the treatment of the leukemias and lymphomas covered under this study.