OtherBASIC SCIENCE INVESTIGATIONS

Imaging of Tumor Angiogenesis Using 99mTc-Labeled Human Recombinant Anti-ED-B Fibronectin Antibody Fragments

Dietmar Berndorff, Sandra Borkowski, Dieter Moosmayer, Francesca Viti, Beate Müller-Tiemann, Stephanie Sieger, Matthias Friebe, Christoph S. Hilger, Luciano Zardi, Dario Neri and Ludger M. Dinkelborg
Journal of Nuclear Medicine October 2006, 47 (10) 1707-1716;

Article Figures & Data

Figures

  • FIGURE 1. 
    FIGURE 1. 

    Synthesis scheme of 99mTc labeling of L19-Hi20.

  • FIGURE 2. 
    FIGURE 2. 

    Schematic drawings show domain structure and potential 99mTc acceptor sites of antibody derivatives that were investigated in this study. Derivatives consist of VL and VH domains of L19 scFv. Using a bifunctional chelator, L19 can be labeled indirectly with 99mTc (potential 99mTc acceptor sites suitable for indirect labeling are indicated by triangles). By insertion of the peptide sequence (His)6 and (Gly)3-Cys-Ala in L19-His and AP39, respectively, these molecules can be labeled directly with 99mTc (potential 99mTc acceptor sites suitable for direct labeling are indicated by asterisks).

  • FIGURE 3. 
    FIGURE 3. 

    Representative SE-HPLC chromatograms (radiation detection) of 99mTc-AP39 (A), 99mTc-L19-His (B), and 99mTc-L19-Hi20 (C).

  • FIGURE 4. 
    FIGURE 4. 

    Comparison of 99mTc-L19 derivatives in F9 tumor–bearing nude mice with regard to tumor uptake up to 24 h after injection (A), blood clearance up to 24 h after injection (B), and organ uptake at 3 h after injection (C). All data are presented as mean ± SD (n = 3).

  • FIGURE 5. 
    FIGURE 5. 

    Scintigraphic images (posterior) of 99mTc-AP39 in F9 tumor–bearing mice 3 h (A), 5 h (B), and 24 h (C) after injection.

  • FIGURE 6. 
    FIGURE 6. 

    Scintigraphic images (posterior) of 99mTc-L19-His in F9 tumor–bearing mice 5 h (A) and 24 h (B) after injection.

  • FIGURE 7. 
    FIGURE 7. 

    Scintigraphic images (posterior) of 99mTc-L19-Hi20 in F9 tumor–bearing mice 5 h (A) and 24 h (B) after injection.

Tables

  • TABLE 1

    Biodistribution of 99mTc-AP39 in F9 Tumor–Bearing Mice

    Biodistribution time (h)
    Tissue0.2513524
    Uptake (%ID/g)
     Spleen5.1 ± 0.72.0 ± 0.30.7 ± 0.20.6 ± 0.10.2 ± 0.0
     Liver5.1 ± 0.22.5 ± 0.31.1 ± 0.21.1 ± 0.20.3 ± 0.0
     Kidneys48.2 ± 4.221.8 ± 2.58.6 ± 0.67.9 ± 0.42.6 ± 0.4
     Lung6.9 ± 1.73.1 ± 0.21.2 ± 0.01.1 ± 0.20.8 ± 1.0
     Bone*2.8 ± 0.92.3 ± 0.31.6 ± 0.21.7 ± 0.10.8 ± 0.2
     Heart4.1 ± 1.31.8 ± 0.20.7 ± 0.20.4 ± 0.00.2 ± 0.0
     Brain0.4 ± 0.00.1 ± 0.00.1 ± 0.0NDND
     Thyroid3.4 ± 0.62.0 ± 0.21.3 ± 0.11.3 ± 0.70.8 ± 0.4
     Muscle*0.8 ± 0.10.6 ± 0.00.6 ± 0.20.2 ± 0.00.1 ± 0.0
     Stomach†1.7 ± 0.11.4 ± 0.01.1 ± 0.11.0 ± 0.00.4 ± 0.1
     Intestine‡1.6 ± 0.11.4 ± 0.01.3 ± 0.21.6 ± 0.50.3 ± 0.0
     Uterus2.5 ± 0.82.0 ± 0.51.4 ± 0.72.8 ± 1.21.3 ± 0.7
     Ovaries13.0 ± 1.87.6 ± 2.24.3 ± 1.42.7 ± 0.90.9 ± 0.1
     Tumor5.2 ± 2.56.1 ± 2.08.3 ± 3.28.7 ± 5.52.8 ± 1.4
     Blood14.4 ± 0.93.9 ± 0.81.3 ± 0.11.0 ± 0.10.2 ± 0.0
    Excretion (%ID)
     Urine22.7 ± 3.946.7 ± 4.448.8 ± 6.752.5 ± 2.064.5 ± 6.5
     FecesNDND0.4 ± 0.10.6 ± 0.54.8 ± 1.0
    Tumor/tissue ratio
     T/spleen1.0 ± 0.33.1 ± 0.612.4 ± 7.314.8 ± 11.411.5 ± 4.5
     T/liver1.0 ± 0.42.4 ± 0.57.8 ± 4.08.3 ± 6.28.1 ± 3.6
     T/kidneys0.1 ± 0.00.3 ± 0.11.0 ± 0.41.1 ± 0.81.0 ± 0.4
     T/lung0.8 ± 0.52.0 ± 0.76.8 ± 2.68.3 ± 6.57.5 ± 5.9
     T/muscle6.8 ± 3.410.5 ± 3.213.6 ± 2.638.5 ± 28.925.3 ± 11.2
     T/blood0.4 ± 0.21.6 ± 0.26.4 ± 2.99.0 ± 6.517.2 ± 6.8
     T/intestine3.3 ± 1.34.3 ± 1.36.9 ± 3.66.9 ± 6.98.9 ± 3.7

    • ↵* Tissue aliquot only.

    • ↵† Without content.

    • ↵‡ With content.

    • ND = not detectable; T = tumor.

    • All data are presented as mean ± SD (n = 3).

  • TABLE 2

    Biodistribution of 99mTc-L19-His in F9 Tumor–Bearing Mice

    Biodistribution time (h)
    Tissue0.2513524
    Uptake (%ID/g)
     Spleen5.5 ± 0.62.7 ± 0.71.8 ± 0.21.2 ± 0.20.8 ± 0.2
     Liver6.1 ± 0.73.4 ± 0.44.3 ± 0.33.4 ± 0.72.5 ± 0.7
     Kidneys87.5 ± 5.2124.7 ± 6.3145.1 ± 22.3117.0 ± 12.972.4 ± 11.3
     Lung10.4 ± 1.85.2 ± 1.04.0 ± 1.24.1 ± 2.92.0 ± 0.6
     Bone*4.6 ± 0.95.4 ± 1.02.9 ± 1.53.4 ± 0.73.1 ± 0.9
     Heart5.2 ± 0.22.3 ± 0.21.1 ± 0.10.7 ± 0.10.4 ± 0.1
     Brain0.4 ± 0.10.2 ± 0.00.1 ± 0.00.1 ± 0.00.1 ± 0.0
     Thyroid4.9 ± 1.52.9 ± 0.12.7 ± 1.32.7 ± 1.11.1 ± 0.0
     Muscle*0.5 ± 0.20.6 ± 0.10.6 ± 0.10.4 ± 0.10.3 ± 0.1
     Stomach†2.0 ± 0.21.7 ± 0.12.1 ± 0.21.7 ± 0.31.1 ± 0.2
     Intestine‡1.4 ± 0.11.8 ± 0.22.4 ± 0.51.9 ± 0.81.2 ± 0.7
     Uterus3.2 ± 1.74.7 ± 1.34.9 ± 1.22.7 ± 0.84.4 ± 2.4
     Ovaries27.2 ± 18.810.2 ± 2.16.0 ± 1.06.9 ± 1.02.8 ± 0.5
     Tumor6.3 ± 2.08.4 ± 0.89.4 ± 1.48.1 ± 2.05.7 ± 2.0
     Blood18.7 ± 2.04.3 ± 0.11.7 ± 0.30.9 ± 0.10.2 ± 0.1
    Excretion (%ID)
     Urine10.8 ± 3.314.8 ± 5.420.9 ± 5.521.3 ± 4.964.5 ± 6.5
     FecesNDND0.2 ± 0.30.6 ± 0.34.8 ± 1.0
    Tumor/tissue ratio
     T/spleen1.2 ± 0.43.3 ± 1.15.3 ± 0.77.0 ± 2.36.6 ± 1.0
     T/liver1.1 ± 0.42.5 ± 0.52.2 ± 0.52.4 ± 0.62.3 ± 0.2
     T/kidneys0.1 ± 0.00.1 ± 0.00.1 ± 0.00.1 ± 0.00.1 ± 0.0
     T/lung0.6 ± 0.11.7 ± 0.42.5 ± 0.82.5 ± 1.22.9 ± 0.9
     T/muscle12.4 ± 1.415.5 ± 4516.4 ± 4.223.0 ± 9.522.9 ± 6.6
     T/blood0.4 ± 0.12.0 ± 0.25.7 ± 0.59.5 ± 2.623.6 ± 8.3
     T/intestine4.5 ± 1.74.8 ± 0.94.0 ± 0.74.9 ± 2.24.9 ± 1.4

    • ↵* Tissue aliquot only.

    • ↵† Without content.

    • ↵‡ With content.

    • ND = not detectable; T = tumor.

    • All data are presented as mean ± SD (n = 3).

  • TABLE 3

    Biodistribution of 99mTc-L19-Hi20 in F9 Tumor–Bearing Mice

    Biodistribution time (h)
    Tissue0.2513524
    Uptake (%ID/g)
     Spleen4.9 ± 0.54.1 ± 0.72.8 ± 1.01.4 ± 0.20.5 ± 0.1
     Liver10.5 ± 2.17.1 ± 0.14.7 ± 0.63.4 ± 0.51.7 ± 0.2
     Kidneys33.5 ± 2.426.6 ± 0.715.2 ± 1.310.9 ± 0.43.0 ± 0.6
     Lung9.4 ± 1.46.2 ± 0.65.0 ± 1.82.6 ± 0.81.3 ± 0.5
     Bone*4.0 ± 0.44.2 ± 0.63.6 ± 0.52.9 ± 0.51.0 ± 0.1
     Heart4.7 ± 1.53.3 ± 0.41.6 ± 0.31.1 ± 0.10.2 ± 0.0
     Brain0.4 ± 0.10.3 ± 0.00.1 ± 0.00.1 ± 0.0ND
     Thyroid3.5 ± 1.44.3 ± 1.21.9 ± 0.83.2 ± 1.10.7 ± 0.1
     Muscle*0.8 ± 0.20.7 ± 0.00.5 ± 0.10.5 ± 0.10.2 ± 0.0
     Stomach†1.9 ± 0.12.5 ± 0.21.6 ± 0.11.5 ± 0.10.6 ± 0.1
     Intestine‡1.6 ± 0.23.3 ± 0.24.4 ± 1.14.2 ± 1.80.9 ± 0.4
     Uterus2.1 ± 0.84.9 ± 1.53.8 ± 2.43.1 ± 0.91.6 ± 0.7
     Ovaries7.6 ± 4.18.4 ± 0.44.4 ± 0.83.6 ± 0.91.0 ± 0.2
     Tumor3.5 ± 0.66.8 ± 1.97.7 ± 2.17.6 ± 0.64.0 ± 2.6
     Blood16.1 ± 1.79.5 ± 0.24.3 ± 0.62.8 ± 0.30.4 ± 0.0
    Excretion (%ID)
     Urine19.1 ± 2.427.1 ± 6.038.8 ± 4.441.8 ± 4.057.8 ± 3.0
     FecesNDND2.6 ± 1.37.3 ± 6.118.6 ± 4.0
    Tumor/tissue ratio
     T/spleen0.7 ± 0.11.7 ± 0.43.1 ± 1.45.4 ± 1.27.7 ± 5.7
     T/liver0.4 ± 0.11.0 ± 0.31.6 ± 0.42.2 ± 0.32.4 ± 1.9
     T/kidneys0.1 ± 0.00.3 ± 0.10.5 ± 0.20.7 ± 0.11.4 ± 1.0
     T/lung0.4 ± 0.01.1 ± 0.21.6 ± 0.53.1 ± 0.74.5 ± 4.9
     T/muscle4.8 ± 1.89.7 ± 3.117.5 ± 8.515.5 ± 2.125.7 ± 13.5
     T/blood0.2 ± 0.10.7 ± 0.21.8 ± 0.52.7 ± 0.49.4 ± 6.4
     T/intestine2.2 ± 0.42.1 ± 0.51.9 ± 0.82.0 ± 0.88.4 ± 2.8

    • ↵* Tissue aliquot only.

    • ↵† Without content.

    • ↵‡ With content.

    • ND = not detectable; T = tumor.

    • All data are presented as mean ± SD (n = 3).

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