Abstract 104: Preclinical microPET/CT imaging of 89Zr-Df-SGN-35 in mice bearing xenografted CD30 expressing and non-expressing tumors

Abstract

Abstract Introduction: Positron emission tomography (PET) imaging is a non-invasive tool to quantitatively describe the drug distribution in vivo. To answer the question whether radiolabeled antibody-drug conjugates (ADCs) can be utilized as PET imaging probes, and to explore PET imaging sensitivity for detecting antigen expression, we conducted preclinical microPET/CT imaging studies with radiolabeled SGN-35 in SCID mice bearing tumors with varying levels of CD30 expression. Methods: SGN-35 was either directly labeled with 124Iodine or conjugated with the chelator desferrioxamine (DFO) and subsequently labeled with 89Zirconium. Karpas 299, TF1-α, and Daudi were selected as the representative high (CD30high), low (CD30low) and negative (CD30neg) CD30 expressing tumor cell lines, respectively. Expression of CD30 and receptor copy number on each cell line was confirmed by quantitative FACS assay. One mouse from each CD30 expression group was administered a single IV bolus dose of either 124I-SGN-35 (0.5 mg/kg) or 89Zr-Df-SGN-35 (1 mg/kg), and serially imaged 0 - 2 hours (dynamic scan), and at 4, 24, 48, 72, 96 and 144 hours (10 min static scans). An additional 3 mice with CD30high and CD30low tumors, and 2 mice with CD30neg tumors, were dosed and imaged at 72, 96 and 144 hours (10 min static scans). Blood samples (10 μL) were taken from mice at 0, 4, 24, 48, 72, 96 hours and by cardiac puncture at 144 hours for pharmacokinetic (PK) analysis. Additional mice (n=4 per group) were sacrificed at 72 and 144 hours to determine tissue biodistribution via gamma counting. Results: The elimination of 124I-SGN-35 and 89Zr-Df-SGN-35 followed 2-compartment PK, and the calculated elimination T1/2 was 3.6-3.9 days. In mice bearing CD30high tumors with ∼291,000 CD30 copies per cell, the tumor:blood ratio of 124I-radioactivity after a dose of 124I-SGN-35 fell from 1.24 after 72 hours to 0.78 after 144 hours, whereas after a dose of 89Zr-Df-SGN-35, mean tumor:blood ratio of 89Zr-radioactivity increased from 7.38 at 72 hours to 15.05 (157.5 %ID/g) at 144 hours. The 124I-radioactivity and 89Zr-radioactivity tumor:blood ratio in the CD30neg tumors was 0.2 and 0.5 after 144 hours, respectively. The tumor:blood ratio of 89Zr-radioactivity continued to increase from 0.57 after 72 hours to 0.90 (13.4 %ID/g) at 144 hours after a dose of 89Zr-Df-SGN-35 in TF1-α (CD30low) tumor bearing mice. Conclusions: These results indicate that 89Zr-Df-SGN-35 retains the specific anti-CD30 immune-reactivity and PK of the parent SGN-35 molecule. 89Zr labeling generated superior imaging results compared with 124I labeling. With respect to specificity, a favorable tumor:blood ratio was observed in the CD30high tumor bearing mice in contrast to the lack of accumulation of 89Zr-radioactivity in the CD30 negative tumors. The accumulation of 89Zr-radioactivity in CD30low TF1-α tumors suggests that 89Zr-Df-SGN-35 is a very sensitive CD30 targeted PET/CT imaging agent. Citation Format: Aaron Moss, Jean Gudas, Tina Albertson, Nancy Whiting, Che-Leung Law. Preclinical microPET/CT imaging of 89Zr-Df-SGN-35 in mice bearing xenografted CD30 expressing and non-expressing tumors. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 104. doi:10.1158/1538-7445.AM2014-104