Targeting angiogenesis for radioimmunotherapy with a 177Lu-labeled antibody
- 783 Downloads
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.
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.
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.
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.
KeywordsAngiogenesis Radioimmunotherapy Lutetium-177 (177Lu) CD105 Endoglin Cancer
Compliance with ethical standards
This work was supported, in part, by the University of Wisconsin – Madison, the National Institutes of Health (NIBIB/NCI 1R01CA169365, 1R01EB021336, P30CA014520, 5T32GM08349, T32GM008505), the National Science Foundation (DGE-1256259) and the American Cancer Society (125246-RSG-13-099-01-CCE).
Conflicts of interest
C.P. Theuer is the CEO of TRACON Pharmaceuticals. No potential conflicts of interest were disclosed by the other authors.
All applicable international, national, and/or institutional guidelines for the care and use of animals were followed.
- 3.Burstein HJ, Chen Y-H, Parker LM, Savoie J, Younger J, Kuter I, et al. VEGF as a marker for outcome among advanced breast cancer patients receiving anti-VEGF therapy with bevacizumab and vinorelbine chemotherapy. Clin Cancer Res. 2008;14(23):7871–7. doi: 10.1158/1078-0432.ccr-08-0593.CrossRefPubMedPubMedCentralGoogle Scholar
- 7.Carbone C, Moccia T, Zhu C, Paradiso G, Budillon A, Chiao PJ, et al. Anti-VEGF treatment–resistant pancreatic cancers secrete proinflammatory factors that contribute to malignant progression by inducing an EMT cell phenotype. Clin Cancer Res. 2011;17(17):5822–32. doi: 10.1158/1078-0432.ccr-11-1185.CrossRefPubMedPubMedCentralGoogle Scholar
- 8.Miyata Y, Sagara Y, Watanabe S-i, Asai A, Matsuo T, Ohba K, et al. CD105 is a more appropriate marker for evaluating angiogenesis in urothelial cancer of the upper urinary tract than CD31 or CD34. Virchows Arch. 2013;463(5):673–9. doi: 10.1007/s00428-013-1463-8.CrossRefPubMedPubMedCentralGoogle Scholar
- 15.Duffy AG, Ulahannan SV, Cao L, Rahma OE, Makarova-Rusher OV, Kleiner DE, et al. A phase II study of TRC105 in patients with hepatocellular carcinoma who have progressed on sorafenib. United European Gastroenterol J. 2015;3(5):453–61. doi: 10.1177/2050640615583587.CrossRefPubMedPubMedCentralGoogle Scholar
- 16.Gordon MS, Robert F, Matei D, Mendelson DS, Goldman JW, Chiorean EG, et al. An open-label phase Ib dose-escalation study of TRC105 (anti-endoglin antibody) with bevacizumab in patients with advanced cancer. Clin Cancer Res. 2014;20(23):5918–26. doi: 10.1158/1078-0432.ccr-14-1143.CrossRefPubMedPubMedCentralGoogle Scholar
- 18.Gudkov VS, Shilyagina YN, Vodeneev AV, Zvyagin VA. Targeted radionuclide therapy of human tumors. Int J Mol Sci. 2016;17(1). doi: 10.3390/ijms17010033.
- 19.Fahey F, Zukotynski K, Capala J, Knight N; Organizing Committee, Contributors, and Participants of NCI/SNMMI Joint Workshop on Targeted Radionuclide Therapy. Targeted radionuclide therapy: proceedings of a joint workshop hosted by the National Cancer Institute and the Society of Nuclear Medicine and Molecular Imaging. J Nucl Med. 2014;55(2):337–48. doi: 10.2967/jnumed.113.135178.CrossRefPubMedPubMedCentralGoogle Scholar
- 21.Li X-F, Kinuya S, Yokoyama K, Koshida K, Mori H, Shiba K, et al. Benefits of combined radioimmunotherapy and anti-angiogenic therapy in a liver metastasis model of human colon cancer cells. Eur J Nucl Med Mol Imaging. 2002;29(12):1669–74. doi: 10.1007/s00259-002-0997-9.CrossRefPubMedPubMedCentralGoogle Scholar
- 22.Lee H-J, Yoon C, Park DJ, Kim Y-J, Schmidt B, Lee Y-J, et al. Inhibition of vascular endothelial growth factor A and hypoxia-inducible factor 1α maximizes the effects of radiation in sarcoma mouse models through destruction of tumor vasculature. Int J Radiat Oncol Biol Phys. 2015;91(3):621–30. doi: 10.1016/j.ijrobp.2014.10.047.CrossRefPubMedPubMedCentralGoogle Scholar
- 23.Lee S-Y, Hong Y-D, Pyun M-S, Felipe PM, Choi S-J. Radiolabeling of monoclonal anti-vascular endothelial growth factor receptor 1 (VEGFR 1) with 177Lu for potential use in radioimmunotherapy. Appl Radiat Isot. 2009;67(7-8):1185–9. doi: 10.1016/j.apradiso.2009.02.006.CrossRefPubMedPubMedCentralGoogle Scholar
- 24.Ashrafi SA, Hosseinimehr SJ, Varmira K, Abedi SM. Radioimmunotherapy with 131I-bevacizumab as a specific molecule for cells with overexpression of the vascular endothelial growth factor. Cancer Biother Radiopharm. 2012;27(7):420–5. doi: 10.1089/cbr.2012.1224.CrossRefPubMedPubMedCentralGoogle Scholar
- 29.Sabet A, Biersack H-J, Ezziddin S. Advances in peptide receptor radionuclide therapy. Semin Nucl Med. 2016;46(1):40–6. doi: 10.1053/j.semnuclmed.2015.09.005.
- 30.Ehlerding EB, England CG, McNeel DG, Cai W. Molecular imaging of immunotherapy targets in cancer. J Nucl Med. 2016;57(10):1487–92. doi: 10.2967/jnumed.116.177493.
- 31.Al-Ejeh F, Shi W, Miranda M, Simpson PT, Vargas AC, Song S, et al. Treatment of triple-negative breast cancer using anti-EGFR-directed radioimmunotherapy combined with radiosensitizing chemotherapy and PARP inhibitor. J Nucl Med. 2013;54(6):913–21. doi: 10.2967/jnumed.112.111534.CrossRefPubMedPubMedCentralGoogle Scholar
- 32.Wagner JY, Schwarz K, Schreiber S, Schmidt B, Wester HJ, Schwaiger M, et al. Myeloablative anti-CD20 radioimmunotherapy +/− high-dose chemotherapy followed by autologous stem cell support for relapsed/refractory B-cell lymphoma results in excellent long-term survival. Oncotarget. 2013;4(6):899–910. doi: 10.18632/oncotarget.1037.CrossRefPubMedPubMedCentralGoogle Scholar
- 33.Press OW, Unger JM, Rimsza LM, Friedberg JW, LeBlanc M, Czuczman MS, et al. Phase III randomized intergroup trial of CHOP plus rituximab compared with CHOP chemotherapy plus (131)iodine-tositumomab for previously untreated follicular non-Hodgkin lymphoma: SWOG S0016. J Clin Oncol. 2013;31(3):314–20. doi: 10.1200/JCO.2012.42.4101.CrossRefPubMedPubMedCentralGoogle Scholar
- 34.Blakkisrud J, Løndalen A, Martinsen ACT, Dahle J, Holtedahl JE, Bach-Gansmo T, et al. Tumor-absorbed dose for non-Hodgkin lymphoma patients treated with the anti-CD37 antibody radionuclide conjugate 177Lu-lilotomab satetraxetan. J Nucl Med. 2017;58(1):48–54. doi: 10.2967/jnumed.116.173922.CrossRefPubMedPubMedCentralGoogle Scholar
- 35.Frost SHL, Frayo SL, Miller BW, Orozco JJ, Booth GC, Hylarides MD, et al. Comparative efficacy of (177)Lu and (90)Y for anti-CD20 pretargeted radioimmunotherapy in murine lymphoma xenograft models. PLoS One. 2015;10(3):e0120561. doi: 10.1371/journal.pone.0120561.CrossRefPubMedPubMedCentralGoogle Scholar