Locoregional therapy with α-emitting trastuzumab against peritoneal metastasis of HER2-positive gastric cancer in mice

Abstract

Peritoneal metastasis of gastric cancer (PMGC) is incurable and thus has an extremely poor prognosis. We have found however that locoregionally administered trastuzumab armed with a radionuclide astatine-211 (²¹¹At)-emitting α-particle (²¹¹At-trastuzumab) is effective against HER2-positive PMGC in a xenograft mouse model. We first observed that ²¹¹At-trastuzumab can specifically bind and effectively kill NCI-N87 (N87) cells, which are HER2-positive human metastatic GC cells, both in vitro and in subcutaneous tumors. We established a PMGC mouse model using N87 xenografts stably expressing luciferase to test α-particle radioimmunotherapy with ²¹¹At-trastuzumab against PMGC. Biodistribution analysis in this PMGC mouse model revealed that the intraperitoneal administration of ²¹¹At-trastuzumab (1 MBq) was a more efficient means of delivery of ²¹¹At into metastatic tumors than intravenous injection; the maximum tumor uptake with intraperitoneal administration was over 60 percent injected dose per gram (%ID/g) compared to about 18%ID/g with intravenous injection. Surprisingly, a single intraperitoneal injection of ²¹¹At-trastuzumab (1 MBq) was sufficient to completely eradicate intraperitoneally disseminated HER2-positive GC xenografts in two of six treated mice by inducing DNA double-strand breaks, and to drastically reduce the tumor burden in three further mice. No body weight loss, leukocytopenia or significant biochemical changes in liver and kidney function were observed in the treatment group. Accordingly, locoregionally administered ²¹¹At-trastuzumab significantly prolonged the survival time of HER2-positive PMGC mice compared with control treatments. Our results provide a proof-of-concept demonstration that locoregional therapy with ²¹¹At-trastuzumab may offer a new treatment option for HER2-positive PMGC.

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