Research ArticleBasic Science Investigation

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

Huizi Keiko Li, Yukie Morokoshi, Satoshi Kodaira, Tamon Kusumoto, Katsuyuki Minegishi, Hiroaki Kanda, Kotaro Nagatsu and Sumitaka Hasegawa
Journal of Nuclear Medicine October 2021, 62 (10) 1468-1474; DOI: https://doi.org/10.2967/jnumed.120.249300

Article Figures & Data

Figures

  • Figure
  • FIGURE 1.
    FIGURE 1.

    Biodistribution of 211At-trastuzumab in LMGC mouse model. (A) %ID/g for 211At in blood, organs, and tumor tissues at 1, 3, and 24 h after intravenous injection of 211At-trastuzumab (1 MBq). Data represent mean ± SD (n = 5 for each time point). (B) %ID of 211At in feces and urine of mice. Five animals were used at each time point. Data represent mean (n = 5).

  • FIGURE 2.
    FIGURE 2.

    α-RIT with 211At-trastuzumab in LMGC mouse model. (A) Treatment schema. (B) Representative chemiluminescence images of LMGC lesions in model mice on day before (day 0) and 1, 4, and 8 wk after treatment. Mice were treated with phosphate-buffered saline (PBS), trastuzumab (10 μg), 211At-HuIgG (1 MBq, 10 μg), or 211At-trastuzumab (1 MBq, 10 μg). Color scale indicates chemiluminescence intensity per pixel. i.v. = intravenous; WBC = white blood cell.

  • FIGURE 3.
    FIGURE 3.

    Results of 211At-trastuzumab α-RIT in LMGC mouse model. (A) Waterfall plot of percentage tumor chemiluminescence intensity change in each mouse at 28 d after treatment. Tumor chemiluminescence intensity at day 0 was set as baseline (n = 8 in each group). (B) Relative chemiluminescence intensity of tumor in each mouse. Chemiluminescence intensity at day 0 was considered to be 100% (n = 8 in each group). (C) Kaplan–Meier survival curves for LMGC mice. *P < 0.05 vs. control. **P < 0.05 vs. trastuzumab. ***P < 0.05 vs. 211At-HuIgG (n = 8 in each group). (D) Histopathologic analysis by hematoxylin and eosin staining of LMGC lesions that were untreated and were treated for 3 h with α-RIT. Scale bars = 50 μm. Percentages of necrosis in tumors are shown at right. Two (for untreated) or 5 (for treated with 211At-trastuzumab) mice were used. Data represent mean ± SD. PBS = phosphate-buffered saline.

  • FIGURE 4.
    FIGURE 4.

    Toxicity evaluation of 211At-trastuzumab α-RIT in LMGC mouse model. (A and B) Body weights (A) and white blood cell counts (B) of LMGC mice after treatment are shown. Plots are interrupted if mouse reached endpoint. Data represent mean ± SD. (C) Glutamic oxaloacetic transaminase (GOT), glutamic pyruvate transaminase (GPT), blood urea nitrogen (BUN), and creatinine (CRE) levels measured up to 30 d after 211At-trastuzumab α-RIT. Data for each mouse are shown in graph. (D) Histopathologic analysis by hematoxylin and eosin staining of mouse liver and stomach in animals that were untreated or treated with 211At-trastuzumab for 3 h with α-RIT, respectively. Scale bars = 50 μm. PBS = phosphate-buffered saline; UT = untreated mice.

  • FIGURE 5.
    FIGURE 5.

    Microdosimetry. (A) Microscopic images of sectioned sample of mouse liver tissue, including metastasized tumors, and contour map of α-particle track density at binned positions (ΔX, ΔY) with 50-μm intervals at 24 h after treatment. Scale bars = 2 mm. (B) Estimated local absorbed dose per frozen section at tumor and normal liver regions at 24 h after treatment.

Tables

  • TABLE 1

    Absorbed Doses at 24 Hours after Intravenous Injection of 211At-Trastuzumab (1 MBq)

    TissueAbsorbed dose (Gy)
    Whole blood10.11
    Heart2.96
    Lung4.39
    Salivary glands1.61
    Thyroid (neck)2.95
    Liver2.88
    Pancreas0.85
    Stomach5.79
    Small intestine1.20
    Large intestine0.66
    Kidney2.90
    Muscle0.27
    Bone0.87
    Tumor4.58

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