Room: Karl Dean Ballroom A1
Purpose: Targeted radiotherapy treatments have shown promise in many trials. However, the beta-emitting isotope, â?¹â?°Y, cannot be quantitatively imaged using common methods. Therefore, using the positron-emitting isotope, â?¸â?¶Y, allows tracking of the therapeutic entity and development of theranostic agents. Herein, we present PET imaging and radioimmunotherapy of murine breast cancer models using a chimeric antibody targeted to angiogenic vessels.
Methods: Diethylenetriaminepentaacetic acid (DTPA) was conjugated to the anti-CD105 antibody TRC105 for radiolabeling with yttrium: â?¸â?¶Y (half-life: 14.7 h, positron-emitter) and â?¹â?°Y (half-life: 64 h, beta-emitter). Longitudinal PET imaging with â?¸â?¶Y-DTPA-TRC105 allowed quantitative evaluation of tracer pharmacokinetics in 4T1 tumor-bearing mice. For therapeutic studies, four groups were employed: â?¹â?°Y-DTPA-TRC105 (120 ÂµCi, 45 Âµg), â?¹â?°Y-DTPA-IgG (isotype control, 120 ÂµCi, 45 Âµg), TRC105 only (45 Âµg), and PBS only. Mice were monitored throughout the study through measurement of body weight, tumor volume, and blood markers. After the therapeutic study, histological evaluation was performed for major organs. Cherenkov imaging enabled qualitative mapping of â?¹â?°Y-DTPA-TRC105. Dosimetric extrapolation to an adult human female was performed using OLINDA/EXM.
Results: High, persistent uptake of â?¸â?¶Y-DTPA-TRC105 was found in 4T1 tumors (9.1 Â± 1.1 %ID/g, 48 h, n=4), while the liver was the off-target organ with the highest tracer accumulation (7.1 Â± 0.9 %ID/g). Ex vivo gamma-counting studies verified these trends as well. In therapeutic studies, animals injected with â?¹â?°Y-DTPA-TRC105 had significantly smaller (p<0.05) tumor volumes than other groups at 10 days post-injection; however, high doses to the liver, 0.079 Â± 0.008 mSv/MBq, limited the radioactivity that could be administered. Histological evaluations revealed notable damage to treated tumors; additionally, analysis of off-target organs suggested toxicity as well.
Conclusion: The use of the theranostic pair â?¸â?¶Y/â?¹â?°Y allows PET imaging and treatment of CD105-expressing tumors. While promising therapeutic outcomes were achieved, treatment with â?¹â?°Y-DTPA-TRC105 requires further optimization to minimize off-target doses.
Funding Support, Disclosures, and Conflict of Interest: This work was supported, in part, by the University of Wisconsin - Madison, the National Institutes of Health (P30CA014520, T32CA009206, T32GM008505), and the American Cancer Society (125246-RSG-13-099-01-CCE).