Recent results of cancer radioimmunotherapy (using radiolabeled antibodies) have been encouraging, especially for B-cell lymphoma. However, the selection of the optimal Ab and radionuclide remains uncertain. While high energy beta-emitters, which have been widely used, can kill large tumor masses, the radiation dose delivered is primarily due to the cross-fire from neighboring cells and such radiation is unable to efficiently and specially kill single cells in vitro. This of course represents a significant clinical problem, since it implies that single cells or small clusters of cells cannot be effectively targeted by RAIT. Radioisotopes emitting Auger and conversion electrons, which are very low energy electrons, are potentially able to kill single target cells if sufficient radioactivity is delivered intracellularly. The investigators have characterized an Ab, LL1, anti-MHC class II invariant chain (CD74), which reacts with B-cell lymphomas and is internalized by cells in large amounts, approximately 107 Ab molecules internalized per cell per day. The investigators have demonstrated that this Ab conjugated to 111 In or 99mTc, which are Auger electron-emitters, kills B-cell lymphoma cells specifically and efficiently. Conjugates with 125I are also effective, but only if a residualizing form of 125I is used (which is trapped in lysosomes after catabolism of the Ab to which it was attached). Conjugates with beta-particle emitters, 131 I and 90Y, are also able to kill cells specifically, although with a higher level of non-specific toxicity. The investigators propose herein to further test, in a more quantitative assay, the ability of these conjugates to kill tumor cells, in order to select the optimal isotope. In addition to in vitro studies, toxicity in vivo will also be evaluated, using nude or SCID mice bearing human tumor xenografts. Preliminary data shows effective therapy of systemic B cell lymphoma in SCID mice by 111In-LL1. Since the antigen recognized is also expressed on melanomas and carcinoma cells, after induction by interferon-gamma, these target cells will also be tested. They will also attempt to extend these experiments to other Abs, particularly those that react with high-density antigens, labeled to a high specific activity. This study may lead to the development of more effective radio-conjugates for the therapy of cancer and other diseases. Also, it will provide basic information about the toxic effects of intracellular (really lysosomal) radionuclides.
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