There is increasing interest in the use of radiolabeled antibodies (Abs ) for cancer therapy. This proposalfocuses on the use of radionuclides emitting low energy electrons (LEEs), which includes both Auger electrons andlower-energy conversion electrons, for therapy of micrometastases of B-cell tumors, including non-Hodgkin'slymphoma, chronic lymphocytic leukemia, acute lymphocytic leukemia, and multiple myeloma. High-energy (3-particles, which have been most widely used for cancer therapy, are probably not optimal for therapy of microscopictumor, because of the long pathlength of the radiation emitted, which means that only a very small fraction of the totalenergy is deposited in the cells to which the Ab has bound. For this reason, the level of non-specific toxicity isrelatively high. In contrast, low energy electrons can deliver a toxic dose to the target cell while producing relativelylittle non-specific toxicity. These radionuclides can also be potentially used to treat patients with extensive bonemarrow involvement, who cannot be treated with [3-particle emitters due to the hematologic damage that would occur.Radionuclides that emit such LEEs include 125I, inln, 67Ga, and most of the other 'imaging' radionuclides. Ourexperiments have demonstrated that, if high density antigens are used as targets, tumor cells can be efficiently killed,and that effective therapy can be obtained in a mouse xenograft model. This proposal is to continue previous studieswith B-cell lymphoma, using anti-CD74, which is an effective Ab due to the high level of Ab uptake per cell. Since67Ga has greater potency per decay than ''in, we will first attempt to develop better conjugation methods for 67Ga.Using the optimal LEE emitter (either iuln or 67Ga), we will test combined therapy with various other agents,including: 1) Unconjugated (naked) Abs that are therapeutic themselves, namely anti-CD20; 2) Anti-CD20 andantiCD22 Ab conjugated to (3-particle emitters, which may be more effective at treating macroscopic tumor masses; 3)Radiation sensitizers, including agents that inhibit repair of radiation damage. Several animal tumor models will betested, using tumors of various histological types: a systemic model in which tumor cells are injected i.v.; and a s.c.model. The long-term goal is the development of a new form of cancer therapy.
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