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Research ArticleTheranostics

Radiolabeled Antibodies Against Müllerian-Inhibiting Substance Receptor, Type II: New Tools for a Theranostic Approach in Ovarian Cancer

Emmanuel Deshayes, Riad Ladjohounlou, Pierre Le Fur, Alexandre Pichard, Catherine Lozza, Vincent Boudousq, Samuel Sevestre, Marta Jarlier, Roxana Kashani, Joanna Koch, Jane Sosabowski, Julie Foster, Nicolas Chouin, Frank Bruchertseifer, Alfred Morgenstern, Pierre-Olivier Kotzki, Isabelle Navarro-Teulon and Jean-Pierre Pouget
Journal of Nuclear Medicine August 2018, 59 (8) 1234-1242; DOI: https://doi.org/10.2967/jnumed.118.208611
Emmanuel Deshayes
1Institut de Recherche en Cancérologie de Montpellier (IRCM), INSERM, Université de Montpellier, Institut Régional du Cancer de Montpellier (ICM), Montpellier, France
2Institut régional du Cancer de Montpellier, Montpellier, France
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Riad Ladjohounlou
1Institut de Recherche en Cancérologie de Montpellier (IRCM), INSERM, Université de Montpellier, Institut Régional du Cancer de Montpellier (ICM), Montpellier, France
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Pierre Le Fur
1Institut de Recherche en Cancérologie de Montpellier (IRCM), INSERM, Université de Montpellier, Institut Régional du Cancer de Montpellier (ICM), Montpellier, France
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Alexandre Pichard
1Institut de Recherche en Cancérologie de Montpellier (IRCM), INSERM, Université de Montpellier, Institut Régional du Cancer de Montpellier (ICM), Montpellier, France
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Catherine Lozza
1Institut de Recherche en Cancérologie de Montpellier (IRCM), INSERM, Université de Montpellier, Institut Régional du Cancer de Montpellier (ICM), Montpellier, France
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Vincent Boudousq
1Institut de Recherche en Cancérologie de Montpellier (IRCM), INSERM, Université de Montpellier, Institut Régional du Cancer de Montpellier (ICM), Montpellier, France
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Samuel Sevestre
1Institut de Recherche en Cancérologie de Montpellier (IRCM), INSERM, Université de Montpellier, Institut Régional du Cancer de Montpellier (ICM), Montpellier, France
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Marta Jarlier
2Institut régional du Cancer de Montpellier, Montpellier, France
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Roxana Kashani
3Centre for Molecular Oncology, Barts Cancer Institute, Queen Mary University of London, London, United Kingdom
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Joanna Koch
3Centre for Molecular Oncology, Barts Cancer Institute, Queen Mary University of London, London, United Kingdom
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Jane Sosabowski
3Centre for Molecular Oncology, Barts Cancer Institute, Queen Mary University of London, London, United Kingdom
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Julie Foster
3Centre for Molecular Oncology, Barts Cancer Institute, Queen Mary University of London, London, United Kingdom
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Nicolas Chouin
4Nantes-Angers Cancer Research Center CRCINA, University of Nantes, INSERM UMR1232, CNRS-ERL6001, Nantes, France
5Oniris, AMaROC Unit, Nantes, France; and
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Frank Bruchertseifer
6Directorate for Nuclear Safety and Security, Joint Research Centre, European Commission, Karlsruhe, Germany
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Alfred Morgenstern
6Directorate for Nuclear Safety and Security, Joint Research Centre, European Commission, Karlsruhe, Germany
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Pierre-Olivier Kotzki
1Institut de Recherche en Cancérologie de Montpellier (IRCM), INSERM, Université de Montpellier, Institut Régional du Cancer de Montpellier (ICM), Montpellier, France
2Institut régional du Cancer de Montpellier, Montpellier, France
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Isabelle Navarro-Teulon
1Institut de Recherche en Cancérologie de Montpellier (IRCM), INSERM, Université de Montpellier, Institut Régional du Cancer de Montpellier (ICM), Montpellier, France
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Jean-Pierre Pouget
1Institut de Recherche en Cancérologie de Montpellier (IRCM), INSERM, Université de Montpellier, Institut Régional du Cancer de Montpellier (ICM), Montpellier, France
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  • FIGURE 1.
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    FIGURE 1.

    (A) Schematic representation of BIP-RIT approach, showing mean activity per whole mouse body at different time points after BIP-RIT (50 MBq) and IP-RIT (10 MBq) with 177Lu-16F12 (n = 7 mice/group). (B and C) Merged whole-body SPECT/CT images of mice bearing AN3CA endometrial carcinoma cell tumor xenografts at 24 h after BIP-RIT (B) or IP-RIT (C).

  • FIGURE 2.
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    FIGURE 2.

    Therapeutic efficacy of 177Lu-16F12 (A and B) and 213Bi-16F12 (C and D) after IP-RIT (A and C) and BIP-RIT (B and D). Tumor mass (mean ± SD) was calculated at days 10, 20, and 30 after treatment. *P < 0.05 between therapeutic group and NaCl controls, between 213Bi-16F12 and 177Lu-16F12, or between IP-RIT and BIP-RIT (n = 7 mice per group).

  • FIGURE 3.
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    FIGURE 3.

    Tissue distribution of 177Lu-16F12 (A and B) and 213Bi-16F12 (C and D). Data are mean (±SD) %IA/g after IP-RIT (A and C) or %RA/g after BIP-RIT (B and D) (n = 4 mice/group).

  • FIGURE 4.
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    FIGURE 4.

    Time–activity curves (not corrected for decay) for blood (A) and AN3CA endometrial carcinoma cell tumor xenografts (B) measured with 177Lu-16F12 and for blood (C) and tumor (D) measured with 213Bi-16F12. Fitting of distribution (with 95% confidence intervals) using mono- or biexponential components is shown on A–C but, for sake of clarify, not on D.

  • FIGURE 5.
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    FIGURE 5.

    Incorporated therapeutic 177Lu-16F12 activity over time for tumors (A), blood (B), liver (C), and kidneys (D) after IP-RIT or BIP-RIT, with mean absorbed dose shown in key.

  • FIGURE 6.
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    FIGURE 6.

    Incorporated therapeutic 213Bi-16F12 activity over time for tumors (A), blood (B), liver (C), and kidneys (D) after IP-RIT or BIP-RIT, with mean absorbed dose shown in key.

  • FIGURE 7.
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    FIGURE 7.

    (A) Hematologic toxicity. White blood cell count, hemoglobin level, and weight were monitored in healthy mice at various times from days 0 to 36 after IP-RIT and BIP-RIT with 177Lu-16F12 or 213Bi-16F12 and expressed as ratio relative to treatment with NaCl control. (B) Whole-body PET/CT images of mice bearing subcutaneous AN3CA cell tumor xenografts in right flank at 24, 48, 72, and 96 h after injection of 89Zr-16F12C.

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    TABLE 1

    Absorbed Doses After 177Lu-16F12 IP-RIT or BIP-RIT

    IP-RITBIP-RIT
    SiteAbsorbed dose (Gy/MBq)*Absorbed dose, therapy (Gy)Absorbed dose (Gy/MBq)*Absorbed dose, therapy (Gy)
    Blood1.347 ± 0.30513.5 ± 3.00.086 ± 0.0424.3 ± 2.1
    Tumor0.560 ± 0.1905.6 ± 2.10.050 ± 0.0162.5 ± 1.0
    Liver0.973 ± 0.2449.7 ± 2.40.054 ± 0.0302.7 ± 1.5
    Kidneys0.717 ± 0.1717.2 ± 1.70.066 ± 0.0273.3 ± 1.3
    Lungs0.461 ± 0.1584.6 ± 1.60.031 ± 0.0211.5 ± 1.1
    Spleen0.899 ± 0.3599.0 ± 3.60.045 ± 0.0312.2 ± 1.5
    Heart0.388 ± 0.1083.9 ± 1.10.024 ± 0.0181.2 ± 0.9
    Bones0.183 ± 0.0631.8 ± 0.60.014 ± 0.0080.7 ± 0.4
    Stomach0.170 ± 0.0211.7 ± 0.20.011 ± 0.0040.6 ± 0.2
    Small intestine0.178 ± 0.0451.8 ± 0.40.008 ± 0.0030.4 ± 0.1
    Large intestine0.056 ± 0.0150.6 ± 0.10.004 ± 0.0030.2 ± 0.1
    Carcass0.248 ± 0.0942.5 ± 0.90.016 ± 0.0070.8 ± 0.3
    Bone marrow0.456 ± 0.1224.6 ± 1.20.029 ± 0.0171.5 ± 0.8
    • ↵* Corresponds to absorbed dose per unit of injected activity (MBq) during therapy.

    • Data are mean ± SD.

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    TABLE 2

    Absorbed Doses After 213Bi-16F12 IP-RIT or BIP-RIT

    IP-RITBIP-RIT
    SiteAbsorbed dose (Gy/MBq)*Absorbed dose, therapy (Gy)Absorbed dose (Gy/MBq)*Absorbed dose, therapy (Gy)
    Blood0.126 ± 0.0291.63 ± 0.370.013 ± 0.0100.49 ± 0.37
    Tumor0.169 ± 0.2272.18 ± 2.950.081 ± 0.0813.00 ± 2.98
    Liver0.042 ± 0.0110.55 ± 0.150.004 ± 0.0030.17 ± 0.10
    Kidneys0.106 ± 0.0151.37 ± 0.200.010 ± 0.0130.38 ± 0.47
    Lungs0.043 ± 0.0170.55 ± 0.220.004 ± 0.0020.16 ± 0.09
    Spleen0.046 ± 0.0230.60 ± 0.300.008 ± 0.0100.30 ± 0.36
    Heart0.038 ± 0.0190.49 ± 0.250.003 ± 0.0020.12 ± 0.07
    Bones0.013 ± 0.0080.17 ± 0.100.002 ± 0.0030.08 ± 0.10
    Stomach0.047 ± 0.0290.61 ± 0.370.006 ± 0.0070.24 ± 0.24
    Small intestine0.045 ± 0.0090.59 ± 0.110.004 ± 0.0030.15 ± 0.10
    Large intestine0.028 ± 0.0150.37 ± 0.190.003 ± 0.0030.10 ± 0.11
    Carcass0.033 ± 0.0310.42 ± 0.400.005 ± 0.0090.20 ± 0.33
    Bone marrow0.050 ± 0.0120.65 ± 0.150.005 ± 0.0040.20 ± 0.15
    • ↵* Corresponds to absorbed dose per unit of injected activity (MBq) during therapy.

    • Data are mean ± SD.

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Journal of Nuclear Medicine: 59 (8)
Journal of Nuclear Medicine
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Radiolabeled Antibodies Against Müllerian-Inhibiting Substance Receptor, Type II: New Tools for a Theranostic Approach in Ovarian Cancer
Emmanuel Deshayes, Riad Ladjohounlou, Pierre Le Fur, Alexandre Pichard, Catherine Lozza, Vincent Boudousq, Samuel Sevestre, Marta Jarlier, Roxana Kashani, Joanna Koch, Jane Sosabowski, Julie Foster, Nicolas Chouin, Frank Bruchertseifer, Alfred Morgenstern, Pierre-Olivier Kotzki, Isabelle Navarro-Teulon, Jean-Pierre Pouget
Journal of Nuclear Medicine Aug 2018, 59 (8) 1234-1242; DOI: 10.2967/jnumed.118.208611

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Radiolabeled Antibodies Against Müllerian-Inhibiting Substance Receptor, Type II: New Tools for a Theranostic Approach in Ovarian Cancer
Emmanuel Deshayes, Riad Ladjohounlou, Pierre Le Fur, Alexandre Pichard, Catherine Lozza, Vincent Boudousq, Samuel Sevestre, Marta Jarlier, Roxana Kashani, Joanna Koch, Jane Sosabowski, Julie Foster, Nicolas Chouin, Frank Bruchertseifer, Alfred Morgenstern, Pierre-Olivier Kotzki, Isabelle Navarro-Teulon, Jean-Pierre Pouget
Journal of Nuclear Medicine Aug 2018, 59 (8) 1234-1242; DOI: 10.2967/jnumed.118.208611
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Keywords

  • targeted radiotherapy
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  • 213Bi
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  • Ovarian
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