Evaluation of therapeutic efficacy of (211)At-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 (211)At-farletuzumab in in-vitro 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 (211)At-farletuzumab (n = 16); or with a combination of (125)I-farletuzumab and (211)At-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 2 × 10(6) NIH:OVCAR-3 cells. Twelve days later, the treatments were initiated by i.p.-administration. Specific treatment was given by (211)At-labeled farletuzumab (group A; n = 22, 170 kBq/mL) which is specific for OVCAR-3 cells. Control treatments were given by either (211)At-labeled 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 (211)At-farletuzumab was similar to that with (125)I as radiolabel, and also to that of (211)At-labeled MX35 antibody. The tumor-free fraction (TFF) of the three control groups were all low (PBS 12%, unlabeled specific farletuzumab 9% and unspecific (211)At-rituximab 14%). TFF following treatment with (211)At-farletuzumab was 91%. CONCLUSION: The current investigation of intraperitoneal therapy with (211)At-farletuzumab, delivered at clinically relevant (211)At-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.