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 Müllerian-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 carcinomatosis, such as after cytoreductive surgery. Methods: DOTA-, DTPA- or deferoxamine mesylate-conjugated 16F12 mAb was radiolabeled with β-particle (¹⁷⁷Lu) or α-particle (²¹³Bi) emitters for therapeutic use and with ⁸⁹Zr for PET imaging. On the 13th postxenograft day, mice bearing intraperitoneal MISRII-positive AN3CA endometrial carcinoma cell xenografts were treated by conventional intraperitoneal radioimmunotherapy (IP-RIT) with 10 MBq of ¹⁷⁷Lu-16F12 or 12.9 MBq of ²¹³Bi-16F12 or by brief intraperitoneal radioimmunotherapy (BIP-RIT) using 50 MBq of ¹⁷⁷Lu-16F12 or 37 MBq of ²¹³Bi-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 ¹⁷⁷Lu- and ²¹³Bi-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 ¹⁷⁷Lu-16F12 was slightly more efficient in delaying tumor growth than IP-RIT with ²¹³Bi-16F12. Conversely, ²¹³Bi-16F12 was more efficient than ¹⁷⁷Lu-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 ²¹³Bi- and ¹⁷⁷Lu-16F12. Hematologic toxicity was more pronounced with ¹⁷⁷Lu-16F12 than with ²¹³Bi-16F12. SPECT/CT images (after BIP-RIT with ¹⁷⁷Lu-16F12) and PET/CT images (after injection of ⁸⁹Zr-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, ²¹³Bi-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-in-human study, thus making radiolabeled anti-MISRII mAbs a realistic theranostic option for the clinic.

Keywords: 177Lu; 213Bi; MISRII; ovarian; peritoneal carcinomatosis; radioimmunotherapy; targeted radiotherapy; theranostic.