Utility of ²¹¹At-trastuzumab for the Treatment of Metastatic Gastric Cancer in the Liver: Evaluation of a Preclinical α-Radioimmunotherapy Approach in a Clinically-relevant Mouse Model

Abstract

A liver metastasis from a primary gastric cancer (LMGC) is relatively common and results in an extremely poor prognosis due to a lack of effective therapeutics. We here demonstrate in a clinically-relevant mouse model that an α-radioimmunotherapy (α-RIT) approach with astatine-211-labeled-trastuzumab (²¹¹At-trastuzumab) has efficacy against LMGCs that are positive for human epidermal growth factor receptor 2 (HER2). Methods: ²¹¹At was produced in a cyclotron via a 209Bi (α, 2n) ²¹¹At reaction. ²¹¹At-trastuzumab was subsequently generated using a single-step labelling method. NCI-N87 cells (HER2-positive human GC cells) carrying a luciferase gene were intrasplenically transplanted into severe combined immunodeficiency mice to generate a HER2-positive LMGC model. A bio-distribution study was then conducted through the intravenous injection of ²¹¹At-trastuzumab (1 MBq) into these LMGC xenograft mice. In parallel with this experimental therapy, PBS, intact trastuzumab or ²¹¹At-non-specific human IgG (1MBq) were injected into control groups. The therapeutic efficacy was evaluated by monitoring tumor changes by chemiluminescence imaging. Monitoring of body weights, white blood cell counts, and serum markers of tissue damage were conducted at regular intervals. Microdosimetry using a CR39 plastic detector was also performed. Results: The biodistribution analysis revealed an increased uptake of ²¹¹At-trastuzumab in the metastasized tumors that reached approximately 12% of the injected dose per gram of tissue (%ID/g) at 24 hours. In contrast, its uptake to the surrounding liver was about 4%ID/g. The LMGCs in the mouse model reduced dramatically at 1 week after the single systemic injection of ²¹¹At-trastuzumab. No recurrences were observed in six of eight mice treated with this single injection and their survival time was significantly prolonged compared to the control groups, including the animals treated with ²¹¹At-non-specific antibodies. No severe toxicities or abnormalities in terms of body weight, white blood cell number, liver function, or kidney parameters were observed in the ²¹¹At-trastuzumab group. Microdosimetric studies further revealed that ²¹¹At-trastuzumab had been delivered at an 11.5- fold higher dose to the LMGC lesions compared to the normal liver. Conclusion: α-RIT with ²¹¹At-trastuzumab has considerable potential as an effective and safe therapeutic option for LMGC.