Alpha radioimmunotherapy using 213Bi-anti MISRII mAb in ovarian cancer

Hypothesis: We assessed in vitro the therapeutic efficacy of the newly developed anti-MISRII mAbs (16F12 and 12G4) labelled with 213Bi in the therapy of ovarian cancer. In vivo, we explored their potential use during brief intraperitoneal radioimmunoptherapy (BIP-RIT). Methods: In vitro, clonogenic survival of SK-OV-3 cells expressing MISRII receptor were evaluated. Briefly, SK-OV-3 cells (donor cells) were incubated for 90 min with increasing activities (0- 0.5MBq/mL) of anti MISRII 213Bi-16F12, 213Bi-12G4 mAbs or irrelevant 213Bi-Rituximab. We used the standard medium transfer protocol between donor cells and recipient cells (grown in non-radioactive medium previously incubated for 2h with donor cells) to evaluate bystander cytotoxic effects.Uptake of radioactivity per cell together with appropriate cellular S-values were determined for absorbed dose assessment. Radiation-induced biological effects were measured in both donor and recipient cells as the yield of DNA double strand breaks (DSBs) through immunofluorescent detection of gamma-H2AX and 53BP1. In vivo we assessed in nude mice bearing intraperitoneal 2-3 mm SK-OV-3 MSIRII tumors nodules the biodistribution of radiolabeled antibodies (IP-RIT, 0- 2.96MBq; 37MBq/mg) or BIP-RIT (5.5-12.9MBq; 37MBq/ mg). BIP-RIT consisted of intraperitoneal injection of radiolabeled mAbs followed by washing of the peritoneal xenograft cavity with saline solution. After, the biodistribution of radiolabeled antibodies was investigated after IP and BIP-RIT. Results: In vitro we showed the strong efficacy of 213Bi-12G4 and 213Bi-16F12 mAbs. Bystander cytotoxicity was measured in all recipient cells for the three radiolabeled mAbs. In agreement with DNA DSBs formation, uptake of radioactivity by donor cells was shown to be higher for 213Bi-16F12 than for 213Bi-12G4. DNA DSBs yield was lower in recipient cells and preliminary results indicate that their complexity might be lower than the one measured in donor cells. In vivo, maximum tolerated activity of 213Bi-16F12 was about 2.9MBq and 12.9MBq after IP-RIT and BIP-RIT, respectively. Moderate hematological toxicity was observed in groups treated with the highest amount of activity. Biodistribution studies indicated that the tumor-blood uptake ratio was 1.4 and 6.3 one hour after IP and BIP-RIT, respectively. This ratio was decreased to 0.2 and 3.7, three hours post treatment, respectively. Therapeutic efficacy of 213Bi-12G4 and 213Bi-16F12 mAbs after IP-RIT and BIP-RIT is ongoing. Conclusions: In vitro, we showed the strong therapeutic efficacy of anti-MISRII 213Bi-16F12 mAb against ovarian cancer cells. We also showed that bystander effects were involved. In vivo, the feasibility of BIP-RIT using high activities of 213Bi-mAbs was demonstrated. We are now assessing its therapeutic efficacy using 213Bi-16F12.

LADJOHOUNLOU Riad;  PICHARD Alexandre;  BOUDOUSQ Vincent;  CHOUIN N;  BRUCHERTSEIFER Frank;  MORGENSTERN Alfred;  NAVARRO-TEULON Isabelle;  POUGET Jean-Pierre; 

2016-01-05

SPRINGER

JRC98149

1619-7070,   

https://publications.jrc.ec.europa.eu/repository/handle/JRC98149,