213Bi-radioimmunotherapy defeats early-stage disseminated gastric cancer in nude mice

The alpha-emitter Bi-213 is characterized by a high relative biological effectiveness. Bi-213-immunoconjugates targeting tumor-specific d9-E-cadherin have been proven to effectively kill tumor cells in a murine peritoneal carcinomatosis model. The aim of the present study was to optimize the efficacy of Bi-213-radioimmunotherapy for disseminated gastric cancer in a mouse model of early- and advanced-stage disease and to evaluate the long-term toxicity of Bi-213-immunoconjugates. For that purpose, nude mice were treated with different activities of Bi-213-d9 monoclonal antibody (MAb) targeting d9-E-cadherin or unspecific Bi-213-d8MAb at days 1 or 8 after inoculation of HSC45-M2 gastric cancer cells expressing mutant d9-E-cadherin. Therapeutic efficacy was evaluated by monitoring survival for up to 300 days. Long-term toxicity was evaluated by the survival of tumor-free mice injected with Bi-213-immunoconjugates, kidney function parameters and histopathological examination of kidneys. We showed that survival was significantly prolonged following treatment of mice with Bi-213-immunoconjugates (0.37-22.2 MBq) at day 1 after tumor cell inoculation (P < 0.002). Therapy with 1.85 MBq of Bi-213-d9MAb was most successful, defeating early-stage disease in 87% of all cases. Treatment at day 8 after tumor cell inoculation was less efficient. Long-term nephrotoxicity could only be observed following application of 22.2 MBq of Bi-213-d9MAb, the highest activity applied in the therapy trials. As treatment with 1.85 MBq Bi-213-d9MAb showed excellent therapeutic efficacy without any signs of acute or chronic toxicity, radioimmunotherapy with the alpha-emitter Bi-213 is a promising concept for treatment of early peritoneal carcinomatosis.