This publication used Flow Cytometry in the course of research, as well as UWCCC’s Small Animal Imaging & Radiotherapy Facility (SAIRF), and Experimental Pathology Laboratory (EPL).
Purpose
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 for targeted radioimmunotherapy.
Methods
The anti-CD105 antibody, TRC105 (TRACON Pharmaceuticals), was conjugated with diethylenetriaminepentaacetic acid (DTPA) for radiolabeling with 177Lu (t1/2: 6.65 days). Balb/c mice were implanted with 4T1 mammary carcinoma cells, and five study groups were employed: 177Lu-only, TRC105 only, 177Lu-DTPA-IgG (a nonspecific antibody), 177Lu-DTPA-TRC105 low dose, and 177Lu-DTPA-TRC105 high dose. Toxicity of the agent was monitored through body weight measurements and analysis of blood markers. 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
Biodistribution studies indicated steady uptake of 177Lu-DTPA-TRC105 in 4T1 tumors between 1 and 7 days post-injection (14.3 ± 2.3 %ID/g and 11.6 ± 6.1 %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 most study groups (all except the nonspecific IgG), 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.
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.