¹¹¹In-DOTA-biotin pharmacokinetics after pretargeted intratumoral avidin in a human breast cancer mouse model

Abstract

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Objectives: Because biotin has an extremely high binding avidity for avidin, this combination has been used in pretargeting strategies to improve the tumor to normal tissue therapeutic index. To evaluate this pretargeting strategy as an alternative form of postoperative regional radiotherapy for breast cancer, and to establish the temporal conditions for implementing this strategy, pharmacokinetics were determined in a human breast cancer mouse model.

Methods: Female BALB/c athymic mice with bilateral human breast cancer xenografts (HBT 3477) were used to assess the pharmacokinetics of 20 μg ¹¹¹In-DOTA-biotin given iv at 0.5 or 2 hours after local injection of 200 μg avidin into the xenografts. Intratumoral saline was used as a control. Whole body and blood activities (% ID/g) over 4 hours and tissue activities at 0.5, 2 and 4 hours following ¹¹¹In-DOTA-biotin were measured. Subsets of the mice given ¹¹¹In-DOTA-biotin 0.5 or 2 hours after avidin or saline were imaged at 0.5, 2 and 4 hours after ¹¹¹In-DOTA-biotin, using a gamma camera.

Results: Xenograft uptake of ¹¹¹In was clearly observed on images of mice given ¹¹¹In-DOTA-biotin following intratumoral avidin, but not in mice following intratumoral saline. Avidin remained at the intratumoral site in sufficient amounts to capture subsequently administered ¹¹¹In-DOTA-biotin in high concentrations (% ID/g). Mean xenograft % ID/g was 9.0, 8.0, and 5.9 at 0.5, 2, and 4 hours, respectively, for the 0.5 hour avidin-biotin interval and 5.6 and 9.3 at 0.5 and 2 hours, respectively, for the 2 hour avidin-biotin interval. The ratios of median xenograft concentrations of ¹¹¹In-DOTA-biotin for the avidin to saline xenografts were 79.0 at 2 hours for the 2 hour avidin-biotin interval, and 27.5 at 4 hours for the 0.5 hour avidin-biotin interval. Because of xenograft accumulation of ¹¹¹In-DOTA-biotin after intratumoral avidin, whole body clearance was longer than blood clearance; whole body clearance was also longer in the mice given intratumoral avidin vs. saline. Therapeutic indices (ratio of xenograft to normal tissue cumulated activities) were greater than 3 : 1.

Conclusions: Pretargeted avidin and ¹¹¹In-DOTA-biotin provided favorable pharmacokinetics and therapeutic indices (xenograft : normal tissue). This pretargeting strategy shows potential for local radiotherapy, e.g., following breast cancer surgery or locally recurrent cancer.

Research Support (if any): Supported by NCI grant CA47829