Therapy of Small Subcutaneous B-Lymphoma Xenografts with Antibodies Conjugated to Radionuclides Emitting Low-Energy Electrons

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Abstract
Purpose: Radionuclides emitting low-energy electrons (Auger and conversion electrons of <50 keV) are potentially useful for cancer therapy when conjugated to an antibody, because they can irradiate the cell to which they bind while producing relatively little irradiation of surrounding cells and tissues. We showed previously the ability of such antibody conjugates to treat micrometastatic, disseminated human B-lymphoma in a severe combined immunodeficient mouse model using an anti-CD74 antibody. In this study, we have evaluated the ability of such conjugates to treat s.c. tumors.Experimental Design: Severe combined immunodeficient mice were injected s.c. with Raji, Daudi, or RL B-lymphoma human tumor cells. Antibodies to CD74, CD20, or HLA-DR were radiolabeled with 111In or 125I and injected i.v. at various times starting at day 5, and tumor growth was monitored. Controls included the testing of unlabeled antibodies, labeled nonreactive antibodies, and a combination of the two.Results: Therapy of s.c. B-lymphoma was more difficult than therapy of tumor cells that had been injected i.v. Although large, macroscopic tumors were not effectively treated, therapy was effective on s.c. Daudi tumors on day 36 after injection of this slowly growing tumor, with an 111In anti-CD74 antibody given in two doses. An anti-CD20 antibody labeled with either 111In or 125I was able to effectively treat s.c. RL tumors when given as late as day 16 after tumor inoculation. The largest tumors that were effectively treated were macroscopic thin discs (<2 mm in diameter) growing on the mesentery.Conclusion: These results extend previous evidence that antibody conjugates with emitters of low-energy electrons can be effective therapeutic agents for micrometastatic cancer.

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