@article {Ehlerding457, author = {Emily Ehlerding and Dawei Jiang and Shreya Goel and Reinier Hernandez and Justin Jeffery and Weibo Cai}, title = {Targeting angiogenesis for radioimmunotherapy with 177Lu}, volume = {58}, number = {supplement 1}, pages = {457--457}, year = {2017}, publisher = {Society of Nuclear Medicine}, abstract = {457Objectives: Increased angiogenesis is a marker of aggressiveness in many cancers. Targeted radionuclide therapy of these cancers with angiogenesis-targeting agents may curtail this increased blood vessel formation and slow the growth of tumors, both primary and metastatic. CD105, or endoglin, has a primary role in angiogenesis in a number of cancers, making this a widely-applicable target. Thus, targeted radionuclide therapy utilizing TRC105, a clinically used anti-CD105 antibody, holds promise in the treatment of most solid cancers, demonstrated here in a breast cancer model.Methods: The anti-CD105 antibody, TRC105 (TRACON Pharmaceuticals), was conjugated with diethylenetriaminepentaacetic acid (DTPA) for radiolabeling with 177Lu (t1/2: 6.65 days). Radiolabeling conditions and efficiencies were determined and quantified using iTLC. Balb/c mice were implanted with 4T1 mammary carcinoma cells in Matrigel in the lower flank and tumors were allowed to grow for 10 days, at which point therapies were administered. Four study groups were employed: 177Lu-only, TRC105 only, 177Lu-DTPA-TRC105 low dose, and 177Lu-DTPA-TRC105 high dose, outlined in table 1. Tumor sizes and mouse body weight were monitored until tumors reached 蠅500\% of the initial size, body weight dropped by 15\%, or hindlimb movement was impaired. Blood samples were also analyzed for markers of toxicity. Biodistribution studies of 177Lu-DTPA-TRC105 were also performed at 1 and 7 days post-injection. Ex vivo histology studies of various tissues were conducted at 1, 7, and 30 days post-injection of high dose 177Lu-DTPA-TRC105.Results: Successful radiolabeling yields of \>90\% of DTPA-TRC105 were achieved after 1 h incubation. Biodistribution studies indicated steady uptake of 177Lu-DTPA-TRC105 in 4T1 tumors between 1 and 7 days post-injection (17.4 {\textpm} 2.7 \%ID/g and 17.7 {\textpm} 6.7 \%ID/g, respectively; n = 3) and gradual clearance from other organs. Significant inhibition of tumor growth was observed in the high dose group, with a corresponding significant increase in survival (p\<0.001, all groups). In all study groups, mouse body weight did not decrease by more than 10\%, indicating the safety of the injected agents. Serum ALT quantification indicated steady levels and no damage to the liver (a primary clearance organ of the agent), confirmed with ex vivo histological analyses. Immunohistochemical staining of tumor tissues at various timepoints showed decreased vascularization and disrupted morphology after treatment with 177Lu-DTPA-TRC105.Conclusion: 177Lu-DTPA-TRC105, when administered at a sufficient dose, is able to curtail tumor growth and provide a significant survival benefit without off-target toxicity. Thus, this targeted agent holds promise to be combined with other treatment options in order to slow tumor growth and allow for greater therapeutic indices. Research Support: NIH, American Cancer Society, University of Wisconsin - Madison View this table:Table 1. Treatment groups}, issn = {0161-5505}, URL = {https://jnm.snmjournals.org/content/58/supplement_1/457}, eprint = {https://jnm.snmjournals.org/content}, journal = {Journal of Nuclear Medicine} }