Locoregional therapy with α‐emitting trastuzumab against peritoneal metastasis of human epidermal growth factor receptor 2‐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 astatine‐211 (211At‐trastuzumab) is effective against human epidermal growth factor receptor 2 (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 s.c. 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 i.p. administration of 211At‐trastuzumab (1 MBq) was a more efficient means of delivery of 211At into metastatic tumors than i.v. injection; the maximum tumor uptake with i.p. administration was over 60% injected dose per gram of tissue (%ID/g) compared to approximately 18%ID/g with i.v. injection. Surprisingly, a single i.p. 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 another three mice. No bodyweight loss, leukocytopenia, or significant biochemical changes in liver or 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.

α‐particle therapy for synovial sarcoma in the mouse using an astatine‐211‐labeled antibody against frizzled homolog 10

“…The body weights of the mice tended to be lower in the groups treated with both 211 At‐OTSA101 and 90 Y‐OTSA101 compared to the control mice, but no severe body weight loss was observed in the RIT groups and all varied within a normal range. Although hematological toxicities were not examined in our current experiments, our previous study showed transient but recoverable leukocytopenia following the systemic administration of an α‐emitting antibody …”

“…Biodistribution studies were performed as described previously . Briefly, 111 In‐labeled OTSA101 ( 111 In‐OTSA101, 1 μCi) or 211 At‐OTSA101 (12.5 μCi) was injected into the tail veins of the SS xenograft mice.…”

“…18 The 211 At labeling of anti-FZD10 antibody (OTSA101) was also carried out following a previously described procedure. 14 respectively. Both the 111 In and 90 Y labeling were performed as described previously.…”

“…The remarkably high cell killing potency of 211 At derives from its high energy transfer within a short range of the α‐particle, which is considered to be stronger than that of a β‐particle . We have previously reported, also in a preclinical mouse model, that α‐RIT using 211 At‐labeled trastuzumab is highly effective against peritoneal metastases of gastric cancers that are positive for human epidermal growth factor receptor 2 (HER2) . Thus, we speculated that α‐RIT may be more beneficial than β‐RIT in the treatment of solid tumors, including STS and SS, which are often radio‐resistant or chemo‐resistant.…”

Prognostic Value of Pretreatment HER2 Status in Gastric Cancer Patients Treated with Postoperative Chemoradiotherapy

“…In addition, they reported that HER2 overexpression and/or amplification may be a molecular abnormality linked to this disease development. [21] In addition to the abovementioned studies, Li et al [22] investigated the effectiveness of locoregionally administered trastuzumab armed with astatine-211 (211At-trastuzumab) against HER2 (+) peritoneal metastasis of gastric cancer in a xenograft mouse model. They concluded that locoregionally administered 211At-trastuzumab significantly prolonged the survival time of HER2 (+) peritoneal metastasis of gastric cancer mice compared with control treatments.…”