RADIOIMMUNOTHERAPY AND BONE MARROW TRANSPLANTATION IN HEMATOLOGIC MALIGNANCY

该项目将专注于临床的开发和生产 用三种单独的药物进行人体试验所需的试剂 放射性标记单抗在骨髓定位中的应用 移植。骨髓移植是最有效的方法之一。 然而，治疗各种白血病和淋巴瘤的方法，在 在某些情况下，患者的疾病并不是由前 移植疗法。一般说来，病人是用大剂量治疗的。 化疗和分次全身放射治疗是一部分 他们在移植前的调理方案。有无线电标记的 在该项目中开发的单抗将用于 努力补充分次全身放射治疗 以提高长期无病间隔时间。 该项目将开发三种不同的单抗。一 针对抗原CD33，针对抗原CD45， 一种是针对CD20抗原的。CD33是一种常见的抗原 在急性髓系白血病的绝大多数细胞上。这个 因此，放射性标记抗体将被用作 急性髓系白血病患者的预适应方案 接受骨髓移植的患者，以及其他患有 VCD33阳性疾病包括慢性粒细胞白血病和 肌发育异常疾病。 正在开发的第二种抗体是抗CD45抗体。CD45是 在几乎所有的造血细胞上都有发现，因此代表了一个目标 对于不仅适用于急性髓系白血病患者的临床试剂， 但淋巴细胞白血病的患者也是如此。第三种抗体 研制了一种识别发现的共同抗原的抗CD20抗体 B细胞系的正常和恶性淋巴细胞。大多数淋巴瘤 是B细胞起源的，表达CD20，并将作为靶点 这种放射性标记抗体的患者群体。 放射性标记工作的重点将是使用重金属同位素。 Y-90作为一种将大剂量辐射输送到 累及肿瘤部位和骨髓。Y-90可能比 碘由于其更高的比活度，更长的贝塔范围 发射，缺乏高能伽马，以及寻骨能力。 抗CD20抗体也将是分子工程的重点。 以改善其生物分布，从而提高其临床应用价值。 一种双功能抗体分子构建体，其分子量为 大约8万人将是最初设计的建筑。进一步 分子构建体将包括针对后续位点特异性的抗体 修饰和融合蛋白。 最后一个方面是应用更好的螯合剂来保持 标记在单抗上的放射性金属。这些试剂将集中在 以分子DOTA为代表的大环类化合物。 这种DOTA络合物的进一步修饰将被评估为潜在的 治疗白血病和白血病的临床实用试剂 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.