RADIOIMMUNOTHERAPY AND BONE MARROW TRANSPLANTATION IN HEMATOLOGIC MALIGNANCY

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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.