Evaluation of therapeutic efficacy of 211At-labeled farletuzumab in an intraperitoneal mouse model of disseminated ovarian cancer

Introduction: Antibodies labeled with alpha-emitter astatine-211 have previously shown effective in intraperitoneal (i. p.) treatments of ovarian cancer. In the present work we explore the use of investigational farletuzumab, aimed at the folate receptor alpha. The aim was to evaluate the biodistribution and therapeutic effect of 211At-farletuzumab in invitro and in-vivo experiments and, using models for radiation dosimetry, to translate the findings to expected clinical result. The activity concentration used for therapy in mice (170 kBq/mL) was chosen to be in agreement with an activity concentration that is anticipated to be clinically relevant in patients (200 MBq/L). Methods: For biodistribution, using intravenous injections and mice carrying subcutaneous (s.c.) tumors, the animals were administered either 211At-farletuzumab (n = 16); or with a combination of 125I-farletuzumab and 211At-MX35 (n = 12). At 1, 3, 10 and 22 h, mice were euthanized and s.c.-tumors and organs weighted and measured for radioactivity. To evaluate therapeutic efficacy, mice were inoculated i.p. with 2x10(6) NIH:OVCAR-3 cells. Twelve days later, the treatments were initiated by i.p.-administration. Specific treatment was given by 211At-labeled farletuzumab (group A; n = 22, 170 kBq/mL) which is specific for OVCAR-3 cells. Control treatments were given by either 211Atlabeled rituximab which is unspecific for OVCAR-3 (group B; n = 22, 170 kBq/mL), non-radiolabeled farletuzumab (group C; n = 11) or PBS only (group D; n = 8). Results: The biodistribution of At-211-farletuzumab was similar to that with 125I as radiolabel, and also to that of At-211-labeled MX35 antibody. The tumor-free fraction (TFF) of the three control groups were all low (PBS 12%, unlabeled specific farletuzumab 9% and unspecific 211At-rituximab 14%). TFF following treatment with 211At-farletuzumab was 91%. Conclusion: The current investigation of intraperitoneal therapy with 211At-farletuzumab, delivered at clinically relevant At-211-mAb radioactivity concentrations and specific activities, showed a 6 to 10-fold increase (treated versus controls) in antitumor efficacy. This observation warrants further clinical testing.

Automated summary

The study aimed to evaluate the biodistribution and therapeutic effect of 211At-farletuzumab in vitro and in vivo, showing a 6 to 10-fold increase in antitumor efficacy compared to control groups. This observation suggests the potential for further clinical testing of intraperitoneal therapy with 211At-farletuzumab.