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

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 ß-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.

Localized Irradiation of Cell Membrane by Auger Electrons Is Cytotoxic Through Oxidative Stress-Mediated Nontargeted Effects.

AIMS: We investigated whether radiation-induced nontargeted effects are involved in the cytotoxic effects of anticell surface monoclonal antibodies labeled with Auger electron emitters, such as iodine 125 (monoclonal antibodies labeled with (125)I [(125)I-mAbs]). RESULTS: We showed that the cytotoxicity of (125)I-mAbs targeting the cell membrane of p53(+/+) HCT116 colon cancer cells is mainly due to nontargeted effects. Targeted and nontargeted cytotoxicities were inhibited in vitro following lipid raft disruption with Methyl-ß-cyclodextrin (MBCD) or filipin or use of radical oxygen species scavengers. (125)I-mAb efficacy was associated with acid sphingomyelinase activation and modulated through activation of the AKT, extracellular signal-related kinase ½ (ERK1/2), p38 kinase, c-Jun N-terminal kinase (JNK) signaling pathways, and also of phospholipase C-γ (PLC-γ), proline-rich tyrosine kinase 2 (PYK-2), and paxillin, involved in Ca(2+) fluxes. Moreover, the nontargeted response induced by directing 5-[(125)I]iodo-2'-deoxyuridine to the nucleus was comparable to that of (125)I-mAb against cell surface receptors. In vivo, we found that the statistical significance of tumor growth delay induced by (125)I-mAb was removed after MBCD treatment and observed oxidative DNA damage beyond the expected Auger electron range. These results suggest the involvement of nontargeted effects in vivo also. INNOVATION: Low-energy Auger electrons, such as those emitted by (125)I, have a short tissue range and are usually targeted to the nucleus to maximize their cytotoxicity. In this study, we show that targeting the cancer cell surface with (125)I-mAbs produces a lipid raft-mediated nontargeted response that compensates for the inferior efficacy of non-nuclear targeting. CONCLUSION: Our findings describe the mechanisms involved in the efficacy of (125)I-mAbs targeting the cancer cell surface. Antioxid. Redox Signal. 25, 467-484.