Research ArticleOncology

Development of 64Cu-NOTA-Trastuzumab for HER2 Targeting: A Radiopharmaceutical with Improved Pharmacokinetics for Human Studies

Sang-Keun Woo, Su Jin Jang, Min-Jung Seo, Ju Hui Park, Byoung Soo Kim, Eun Jung Kim, Yong Jin Lee, Tae Sup Lee, Gwang Il An, In Ho Song, Youngho Seo, Kwang Il Kim and Joo Hyun Kang
Journal of Nuclear Medicine January 2019, 60 (1) 26-33; DOI: https://doi.org/10.2967/jnumed.118.210294

Article Figures & Data

Figures

  • FIGURE 1.
    FIGURE 1.

    64Cu-NOTA-trastuzumab PET images in HER2-positive tumor model. Right 2 columns display PET images after cold trastuzumab pretreatment (n = 2), and left 3 show nonblocking images (n = 3). Arrows indicate BT-474 tumors.

  • FIGURE 2.
    FIGURE 2.

    64Cu-NOTA-trastuzumab PET image quantification of nonblocking group (A) and cold trastuzumab–pretreated group (B) in HER2-positive tumor model. 64Cu-NOTA-trastuzumab specificity was suggested by blocking experiments with excess of unlabeled trastuzumab.

  • FIGURE 3.
    FIGURE 3.

    64Cu-NOTA-trastuzumab PET and immunohistochemistry in orthotopic HER2-positive BT-474 breast tumor model. Tumor uptake of 64Cu-NOTA-trastuzumab was clearly visible at 6 h and peaked at 51 h, and autoradiogram of frozen section prepared from removed tumor revealed high accumulation in area where HER2-positive cells were detected by immunohistochemistry. IHC = immunohistochemistry.

  • FIGURE 4.
    FIGURE 4.

    Biodistribution of 64Cu-NOTA-trastuzumab in normal mice (A) and HER2-positive tumor–bearing mice (B). At 2, 6, 24, 48, and 72 h after injection of 64Cu-NOTA-trastuzumab, both mice were euthanized, and radioactivity in organs was measured (n = 4).

  • FIGURE 5.
    FIGURE 5.

    Average blood radioactivity concentration vs. time after intravenous injection of 64Cu-NOTA-trastuzumab in nude mice with or without BT-474 tumor xenografts. Data are mean ± SD.

  • FIGURE 6.
    FIGURE 6.

    (A) Acquired CT and PET images. (B) Time–activity curve evaluated by segmented PET image data at 6 time points. (C) Calculated residence time in each organ and tumor. (D) Energy map generated from Monte Carlo simulation.

  • FIGURE 7.
    FIGURE 7.

    64Cu-DOTA-trastuzumab exhibited higher absorbed dose than 64Cu-NOTA-trastuzumab in heart, liver, and spleen (12).

Tables

  • TABLE 1

    Blood Radioactivity Parameters After 64Cu-NOTA-Trastuzumab* in Mice With and Without BT-474 Tumors

    ParameterWith tumorWithout tumorP
    C0 (%ID/mL)46.8 ± 7.5248.7 ± 4.640.605
    t1/2,λz (h)135 ± 41.1190 ± 40.20.041
    AUC0–72 h (%ID⋅h/mL)1,354 ± 1661,480 ± 1240.167
    Vz (mL)4.74 ± 0.7864.69 ± 0.4610.892
    Cl (mL/h)0.0254 ± 0.005380.0176 ± 0.002890.011
    Last MRT (h)31.0 ± 0.51231.6 ± 0.3900.051

    • ↵* Dose, 100 μg/150–180 μCi/head.

    • C0 = blood concentration extrapolated to time zero; t1/2,λz = terminal elimination half-life; AUC0–72 h = area under blood concentration–time curve from 0 to 72 h; Vz = volume of distribution at terminal phase; Cl = systemic clearance; MRT = mean retention time.

    • Data are mean ± SD.

  • TABLE 2

    64Cu S Values Calculated Using Monte Carlo Simulation with CT Image

    SiteBrainHeartLungLiverKidneyStomachSpleenBladderTumor
    Brain1.87E−013.39E−052.34E−059.14E−064.02E−068.93E−064.71E−061.38E−064.00E−06
    Heart2.41E−051.05E−011.13E−031.97E−041.64E−054.17E−052.29E−054.30E−061.08E−05
    Lung2.23E−051.07E−031.32E−015.70E−043.23E−055.28E−052.86E−057.40E−061.86E−05
    Liver1.26E−052.08E−045.90E−042.12E−024.49E−055.56E−043.33E−041.23E−052.89E−05
    Kidney4.51E−062.16E−052.80E−054.06E−056.77E−021.08E−041.63E−042.55E−053.06E−04
    Stomach4.95E−063.97E−054.56E−055.67E−049.71E−056.92E−028.32E−042.02E−052.47E−05
    Spleen4.56E−061.74E−052.51E−053.30E−041.43E−048.22E−042.43E−012.24E−052.06E−05
    Bladder1.78E−066.84E−066.93E−061.07E−052.58E−052.26E−051.89E−051.13E−011.85E−05
    Tumor9.09E−062.65E−053.20E−055.90E−054.59E−044.74E−053.11E−054.61E−053.28E−01
  • TABLE 3

    67Cu S Values Calculated Using Monte Carlo Simulation with CT Image

    SiteBrainHeartLungLiverKidneyStomachSpleenBladderTumor
    Brain8.54E−021.30E−051.18E−056.75E−065.01E−064.97E−062.61E−061.31E−064.41E−06
    Heart1.23E−051.38E−014.79E−041.49E−041.19E−052.43E−059.16E−064.70E−061.21E−05
    Lung1.22E−055.17E−041.79E−015.47E−041.56E−052.46E−051.66E−054.74E−061.81E−05
    Liver8.11E−061.45E−045.02E−042.76E−022.43E−054.04E−042.13E−046.01E−062.57E−05
    Kidney4.46E−061.31E−051.45E−052.67E−058.33E−025.66E−051.02E−041.83E−052.81E−04
    Stomach5.35E−062.22E−052.42E−054.11E−045.88E−058.54E−023.14E−041.07E−052.35E−05
    Spleen4.15E−061.31E−051.38E−052.09E−041.00E−043.23E−043.07E−011.30E−051.69E−05
    Bladder1.80E−065.20E−063.45E−066.35E−061.74E−051.11E−051.35E−051.30E−011.70E−05
    Tumor3.03E−069.70E−061.04E−051.57E−051.80E−041.59E−051.17E−051.33E−054.01E−01

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