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

Abstract : We have developed the 16F12 mouse monoclonal antibody (mAb), which targets the M ¨ ullerian-inhibiting substance receptor, type II (MISRII), expressed by ovarian tumors. Here, we assessed in preclinical models the possibility of using radiolabeled 16F12 in a theranostic approach for small-volume ovarian peritoneal carcino-matosis, such as after cytoreductive surgery. Methods: DOTA-, DTPA-or deferoxamine mesylate-conjugated 16F12 mAb was ra-diolabeled with β-particle (177 Lu) or α-particle (213 Bi) emitters for therapeutic use and with 89 Zr for PET imaging. On the 13th post-xenograft day, mice bearing intraperitoneal MISRII-positive AN3CA endometrial carcinoma cell xenografts were treated by conventional intraperitoneal radioimmunotherapy (IP-RIT) with 10 MBq of 177 Lu-16F12 or 12.9 MBq of 213 Bi-16F12 or by brief intraperitoneal radio-immunotherapy (BIP-RIT) using 50 MBq of 177 Lu-16F12 or 37 MBq of 213 Bi-16F12. For BIP-RIT, 30 min after injection of the radiolabeled mAbs, the peritoneal cavity was washed to remove the unbound radioactivity. The biodistribution of 177 Lu-and 213 Bi-16F12 mAbs was determined and then used for dose assessment. Hematologic toxicity was also monitored. Results: The 16F12 mAb was satisfactorily radiolabeled for both therapy and imaging. IP-RIT with 177 Lu-16F12 was slightly more efficient in delaying tumor growth than IP-RIT with 213 Bi-16F12. Conversely, 213 Bi-16F12 was more efficient than 177 Lu-16F12 in BIP-RIT. The biodistribution analysis showed that the tumor-to-blood uptake ratio was significantly higher with BIP-RIT than with IP-RIT for both 213 Bi-and 177 Lu-16F12. Hemato-logic toxicity was more pronounced with 177 Lu-16F12 than with 213 Bi-16F12. SPECT/CT images (after BIP-RIT with 177 Lu-16F12) and PET/CT images (after injection of 89 Zr-16F12 in the tail vein) showed focal uptake at the tumor site. Conclusion: Radiolabeled 16F12 could represent a new theranostic tool for small-volume ovarian peritoneal carcinomatosis. Specifically, 213 Bi-16F12-based BIP-RIT could be proposed to selected patients as an alternative adjuvant treatment immediately after cytoreductive surgery. An anti-MISRII mAb is currently being used in a first-inhuman study, thus making radiolabeled anti-MISRII mAbs a realistic theranostic option for the clinic.
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Emmanuel Deshayes, Riad Ladjohounlou, Pierre Le Fur, Alexandre Pichard, Catherine Lozza, et al.. Radiolabeled Antibodies Against Müllerian-Inhibiting Substance Receptor, Type II: New Tools for a Theranostic Approach in Ovarian Cancer. Journal of Nuclear Medicine, Society of Nuclear Medicine, 2018, 59 (8), pp.1234 - 1242. ⟨10.2967/jnumed.118.208611⟩. ⟨inserm-01885063⟩

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