Targeting angiogenesis for radioimmunotherapy with a 177Lu-labeled antibody.

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 DTPA for radiolabeling with 177Lu (t 1/2 6.65 days). Balb/c mice were implanted with 4T1 mammary carcinoma cells, and five study groups were used: 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 by body weight measurements and analysis of blood markers. Biodistribution studies of 177Lu-DTPA-TRC105 were also performed at 1 and 7 days after injection. Ex vivo histology studies of various tissues were conducted at 1, 7, and 30 days after 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 after 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 group), the body weights of the mice did not decrease by more than 10%, indicating the safety of the injected agents. Serum alanine transaminase levels remained nearly constant indicating no damage to the liver (a primary clearance organ of the agent), and this was confirmed by 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 could be used in combination with other treatment options to slow tumor growth allowing the other agents to be more effective.

Absence of the Vitamin D Receptor Inhibits Atherosclerotic Plaque Calcification in Female Hypercholesterolemic Mice.

Epidemiological and clinical data suggest adverse cardiovascular outcomes with respect to vitamin D deficiency. Here, we explored the effects of vitamin D in atherosclerotic plaque calcification in vivo by utilizing vitamin D receptor (Vdr)-deficient mice in an Apoe-/- background. Animals were fed a high-fat diet (HFD) for either 12 or 18 weeks and then examined for atherosclerotic plaque development. In order to prevent calcium deficiency, Vdr-/- and Apoe-/- ;Vdr-/- animals were fed a high-calcium rescue diet prior to initiation of the HFD feeding and supplemented with high-calcium water during HFD feeding. Although calcium supplementation improved bone mass in Vdr-/- and Apoe-/- ;Vdr-/- mice, neither strain was fully rescued. Systemic inflammatory responses observed in the absence of VDR were exaggerated in Apoe-/- mice. Whereas, hyperlipidemic profiles seen in Apoe-/- mice were ameliorated in the absence of VDR. Micro-computed tomography (µCT) analysis revealed that six out of eight Apoe-/- animals developed atherosclerotic plaque calcification following 12 weeks of HFD feeding and 100% of the mice developed plaque calcification after 18 weeks. In contrast, although atherosclerotic lesions were evident in Apoe-/- ;Vdr-/- mice at 12 and 18 weeks of HFD challenge, none of these animals developed plaque calcification at either time point. The active vitamin D hormone, 1,25(OH)2 D3 likely increased calcification in aortic smooth muscle cells perhaps by directly modulating expression of Alpl, Rankl, and Opg. Our data suggest that the absence of VDR inhibits atherosclerotic plaque calcification in hypercholesterolemic Apoe-/- mice, providing additional insight into the role of vitamin D in atherosclerotic plaque calcification. J. Cell. Biochem. 118: 1050-1064, 2017. © 2016 Wiley Periodicals, Inc.