Research ArticleTheranostics

Characterization of Site-Specifically Conjugated Monomethyl Auristatin E– and Duocarmycin-Based Anti-PSMA Antibody–Drug Conjugates for Treatment of PSMA-Expressing Tumors

Susanne Lütje, Danny Gerrits, Janneke D. Molkenboer-Kuenen, Ken Herrmann, Giulio Fracasso, Marco Colombatti, Otto C. Boerman and Sandra Heskamp
Journal of Nuclear Medicine March 2018, 59 (3) 494-501; DOI: https://doi.org/10.2967/jnumed.117.196279

Article Figures & Data

Figures

  • FIGURE 1.
    FIGURE 1.

    (A) Binding of 111In-D2B, 111In-D2B-DAR2-duocarmycin, 111In-D2B-DAR4-duocarmycin, 111In-D2B-DAR2-MMAE, and 111In-D2B-DAR4-MMAE to PSMA-expressing LS174T-PSMA cells. No significant difference in immunoreactivity in any of the 5 agents was observed. (B–F) Internalization kinetics of 111In-D2B (B), 111In-D2B-DAR2-duocarmycin (C), 111In-D2B-DAR4-duocarmycin (D), 111In-D2B-DAR2-MMAE (E), and 111In-D2B-DAR4-MMAE (F) in LS174T-PSMA cells. Binding and internalization are presented as percentage of added activity after 48 h of incubation (mean ± SD).

  • FIGURE 2.
    FIGURE 2.

    Representative small-animal SPECT/CT images of mice with subcutaneous LS174T-PSMA xenografts on right flank. Images were acquired 3 d after injection of 111In-D2B (17.8 MBq) (A), 111In-D2B-DAR2-duocarmycin (22.1 MBq) (B), 111In-D2B-DAR4-duocarmycin (20.8 MBq) (C), 111In-D2B-DAR2-MMAE (17.2 MBq) (D), and 111In-D2B-DAR4-MMAE (15.2 MBq) (E).

  • FIGURE 3.
    FIGURE 3.

    (A) Biodistribution of 111In-D2B, 111In-D2B-DAR2-duocarmycin, 111In-D2B-DAR4-duocarmycin, 111In-D2B-DAR2-MMAE, and 111In-D2B-DAR4-MMAE in PSMA-expressing LS174T-PSMA tumors and healthy organs at 3 d after injection (n = 5 mice per group). (B) Tumor-to-organ ratios of all 4 agents and control agent 111In-D2B. (C) Tumor uptake per mouse and targeting agent.

  • FIGURE 4.
    FIGURE 4.

    Tumor size of individual mice in each group after treatment with PBS (A), D2B (B), D2B-DAR2-duocarmycin (C), D2B-DAR4-duocarmycin (D), D2B-DAR2-MMAE (E), or D2B-DAR4-MMAE (F) (5 mg/kg).

  • FIGURE 5.
    FIGURE 5.

    (A) Kaplan–Meier survival plot of mice with subcutaneous LS174T-PSMA tumors treated with PBS, D2B, D2B-DAR2-duocarmycin, D2B-DAR4-duocarmycin, D2B-DAR2-MMAE, or D2B-DAR4-MMAE. (B) Tumor-doubling time.

Tables

  • TABLE 1

    Biodistribution at 3 Days After Injection

    Organ111In-D2B111In-D2B-DAR2-duocarmycin111In-D2B-DAR4-duocarmycin111In-D2B-DAR2-MMAE111In-D2B-DAR4-MMAE
    Blood12.2 ± 1.111.4 ± 0.910.3 ± 1.518.6 ± 4.78.8 ± 2.2
    Muscle1.1 ± 0.31.2 ± 0.10.9 ± 0.21.2 ± 0.30.7 ± 0.3
    Tumor75.1 ± 8.187.7 ± 15.470.7 ± 15.1119.7 ± 37.462.1 ± 21.1
    Lung7.1 ± 1.18.6 ± 2.37.0 ± 1.214.3 ± 5.75.9 ± 1.7
    Spleen6.5 ± 1.04.2 ± 0.54.1 ± 0.44.9 ± 1.32.7 ± 0.5
    Kidney5.0 ± 0.64.2 ± 0.54.1 ± 0.46.5 ± 1.57.0 ± 1.7
    Liver4.9 ± 0.55.0 ± 1.27.4 ± 2.44.9 ± 1.34.8 ± 1.3
    Small intestine2.6 ± 0.62.4 ± 0.82.0 ± 0.53.7 ± 1.21.6 ± 0.5
    Salivary gland3.7 ± 0.42.9 ± 0.22.9 ± 0.44.5 ± 1.02.7 ± 0.5
    Adrenal gland4.1 ± 1.34.0 ± 0.93.8 ± 0.56.0 ± 1.83.1 ± 0.7

    • Data are mean ± SD (n = 5 mice per group).

Back to top

In this issue

Print
Download PDF
Article Alerts
Email Article
Citation Tools
Bookmark this article

Jump to section

Keywords