Abstract 5343: Experimental targeted alpha-particle therapy against liver metastasis of HER2-positive gastric cancer in mice

Abstract

Abstract Gastric cancer (GC) is one of the common cancer type and a leading cause of cancer-related death worldwide. Liver metastasis of gastric cancer (LMGC) is often found in GC patients and a fatal condition that is hard to be cured. HER2 overexpression is detected in a subset of about 10-20% of GC. HER2-targeting antibody trastuzumab has been used clinically for the treatment against advanced GC positive for HER2. Recently, targeted alpha-particle therapy has emerged as a new therapeutic option of cancer. Radionuclide astatine-211 is produced by cyclotron and emits alpha-particle at its decay with about 7 hours-half-life. Alpha-particle beam induces irreparable DNA damages to kill the cells. Here we investigated the therapeutic efficacy and toxicities of At-211-armed trastuzumab in a mouse model of LMGC positive for HER2. Trastuzumab was conjugated with At-211 to produce alpha-emitting antibodies targeting HER2 ([At-211]-trastuzumab). To generate a mouse LMGC model, we injected luciferase-labelled HER2-positive human metastatic NCI-N87 GC cells into splenic vein of severe combined immunodeficiency mice. Bio-distribution data showed that the maximum uptake of [At-211]trastuzumab in the liver metastatic GC tumors was approximately 12% of injected dose per tissue gram at 24 hours after injection. [At-211]trastuzumab was excreted mostly in the urine. For experimental therapeutics, a single dose of systemic injection of [At-211]trastuzumab (1 MBq) significantly reduced a tumor burden in the liver to extend the survival of model mice significantly compared to controls. Transient leukocytopenia was observed in mice received 1 MBq of [At-211]trastuzumab at 5-7 days after injection. No body weight loss was so far found in the mice treated with [At-211]trastuzumab. No Biochemical abnormalities for Liver and kidney function were found. These data suggest that targeted alpha-particle therapy using [At-211]trastuzumab is effective for LMGC. Citation Format: Sumitaka Hasegawa, Huizi Keiko Li. Experimental targeted alpha-particle therapy against liver metastasis of HER2-positive gastric cancer in mice [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5343.