86/90Y-based theranostics of breast cancer in a preclinical model

539 Objectives: Angiogenesis is one of the hallmarks of cancer, enabling increased tumor growth and metastasis. Therefore, imaging of angiogenesis may enable sensitive detection of tumors, and therapy targeted to angiogenic vessels can greatly reduce tumor burden of both primary and disseminated disease. CD105 is highly expressed on angiogenic vessels in a number of cancers, making it a widely-applicable target for both imaging and therapy with a chimeric CD105-targeted monoclonal antibody, TRC105. The use of the theranostic pair 86Y/90Y enables accurate tracking and therapy with the same chemical entity, Y-DTPA-TRC105. Methods: The chimeric anti-CD105 antibody, TRC105 (TRACON Pharmaceuticals) was conjugated with diethylenetriaminepentaacetic acid (DTPA) for radiolabeling with two isotopes of yttrium: 86Y (t1/2: 14.7 h, a positron emitter) and 90Y (t1/2: 64 h, a higher energy beta-emitter). Serial PET imaging with the positron-emitting 86Y-DTPA-TRC105 was conducted to map the biodistribution and investigate the pharmacokinetics of the tracer in 4T1 tumor-bearing mice. For therapeutic studies, four groups were employed: 90Y-DTPA-TRC105 (120 µCi, 45 µg), 90Y-DTPA-IgG (an isotype control, 120 µCi, 45 µg), TRC105 only (45 µg), and PBS only. Tumor growth and mouse body weight were monitored for 14 days. Blood analyses were performed in the treatment group at 0, 7, and 14 days post-injection, and histological analysis also compared tumors and main organs pre- and post-therapy. Cherenkov luminescence imaging was also performed for the 90Y-injected mice throughout the course of the study to qualitatively map the biodistribution of 90Y-DTPA-TRC105. Estimation of radiation doses from 90Y-DTPA-TRC105 was also enabled through the analysis of 86Y-DTPA-TRC105 PET data and OLINDA. Results: High uptake of 86Y-DTPA-TRC105 was found in 4T1 tumors, increasing over time (from 2.3 ± 0.6 %ID/g at 30 min p.i. to 9.1 ± 1.1 %ID/g at 48 h, n=4), with the liver showing the highest off-target accumulation, at 7.1 ± 0.9 %ID/g at 48 h p.i. Ex vivo biodistribution studies further verified this trend, with tumor uptake of 7.2 ± 0.41 %ID/g. Radiation extrapolation to an adult human female revealed a whole-body effective dose of 0.57 ± 0.02 mSv/MBq from 90Y-DTPA-TRC105, via analysis of the 86Y-DTPA-TRC105 PET data. Cherenkov imaging demonstrated persistent uptake of 90Y-DTPA-TRC105 in the 4T1 tumors throughout the entire study. In therapeutic studies, 90Y-DTPA-TRC105 was found to slow tumor growth relative to the control groups, with significantly smaller (p<0.05) tumor volumes at 10 days p.i. However, high doses to the liver (the clearance organ for antibody-based agents, 0.079 ± 0.008 mSv/MBq) limited the amount of radioactivity that could be administered. Histological analysis of ex vivo tissues revealed significant damage to the treated tumors; at the same time, noticeable damage was evident in the liver and clearance organs as well. Conclusions: The use of the theranostic pair of 86/90Y allows PET imaging and treatment of CD105-expressing angiogenic tumors. While promising therapeutic outcomes were achieved, the treatment with 90Y-DTPA-TRC105 requires further optimization to minimize off-target doses.