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 ( 211 At-trastuzumab) has efficacy against LMGCs that are positive for human epidermal growth factor receptor 2 (HER2). Methods: 211 At was produced in a cyclotron via a 209 Bi (α, 2n) 211 At reaction. 211 Attrastuzumab 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 211 At-trastuzumab (1 MBq) into these LMGC xenograft mice. In parallel with this experimental therapy, PBS, intact trastuzumab or 211 At-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 4 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 211 At-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 211 At-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 211 At-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 211 At-trastuzumab group. Microdosimetric studies further revealed that 211 At-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.

Computational Nanomaterials Design: towards the Realization of Nanoparticle use in Radiotherapy Case Study 2: Adsorption states of At on Au (111) Surface

“…To take advantage of this new treatment, the use of astatine in radiotherapy research has been gaining in recent years. Astatine has a shorter half-life than other α particle emitters which makes it less likely to stay active for long periods of time in the patient's body, but not so short that it is not logistically viable to be used [2][3][4][5][6][7][8][9].…”

Effective Treatment of Human Breast Carcinoma Xenografts with Single-Dose211At-Labeled Anti-HER2 Single-Domain Antibody Fragment

“…Indeed, the cytotoxicity of iso-211 At-SAGMB-5F7 (D 0 5 1.313 kBq/mL) was higher than that determined for 211 At-trastuzumab (1.7 kBq/mL) under similar conditions on the same BT474 cell line (28). Therapeutic responses after 211 At-trasuzumab treatment have been observed in various animal models; however, except for a recent study (33), these have involved direct delivery into a tumor-compromised compartment (6,34). After intrathecal delivery, regional differences in therapeutic effectiveness against carcinomatous meningitis were observed with 211 At-trasuzumab, suggesting that inhomogeneous distribution of the labeled mAb had occurred (6).…”

Alpha‐emitters and targeted alpha therapy in cancer treatment

“…The biological effect of 211 At‐trastuzumab was twice as great as that of external radiation therapy [41], and 211 At‐trastuzumab inhibited the growth of HER2‐positive tumor cells. Another study showed that 211 At‐trastuzumab extended median survival without posing a severe risk of harm in the treatment of liver metastases from primary gastric cancer [62].…”