Intralesional radiolabeled human monoclonal IgM in human tumor xenografts

Background and purpose: Intralesional (i.l.) administration of radiolabeled human monoclonal IgM could provide a new method for increasing the radiation dose delivered to a tumor without exceeding normal tissue tolerance. Materials and methods: Nude mice with subcutaneous human head and neck squamous cell carcinoma nodules were injected either intralesionally or intravenously with a tumor-reactive human monoclonal IgM (CR4E8) labeled with indium-111 (111In) or yttrium-90 (90Y). Groups of mice were sacrificed at different time points and their tumors and major organs were excised and counted for radioactivity. Additional mice that were treated with i.l. 90Y-labeled CR4E8 were sacrificed at the same time points for tumor autoradiography. Serial whole-body gamma camera images were obtained from additional mice treated with i.l. 111In-labeled CR4E8. Intralesionally administered 111In-labeled irrelevant IgM (CH-1B9) and 90Y-aggregate served as specificity controls. Results: Intralesional administration of radiolabeled IgM resulted in prolonged high tumor radioactivity with little normal tissue uptake, with kidney and liver having the highest values. The biodistribution of i.l. CR4E8 was similar whether labeled with 111In or 90Y. Tumor uptake of i.l. irrelevant IgM appeared to be lower and tumor retention appeared to be shorter. Intravenous administration of tumor-reactive IgM resulted in very low tumor radioactivity with high liver and moderate spleen uptake. The i.l. administration of 90Y-aggregate produced prolonged high tumor radioactivity with little normal tissue uptake, with bone having the highest value. Tumor autoradiographs demonstrated that the radiolabeled IgM diffused through the tumor over time while the 90Y-aggregate remained localized at the injection site. Gamma camera scintigraphy corroborated the results of the biodistribution studies. Conclusions: Intralesional but not intravenous administration of 111In- or 90Y-labeled human IgM results in high tumor radioactivity with low normal tissue exposure. Myelotoxicity is not anticipated to be the dose-limiting normal tissue toxicity of this treatment. Further development of human IgM for the i.l. treatment of human malignancies appears to be warranted