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Targeting angiogenesis for radioimmunotherapy with a 177Lu-labeled antibody

  • Emily B. Ehlerding
  • Saige Lacognata
  • Dawei Jiang
  • Carolina A. Ferreira
  • Shreya Goel
  • Reinier Hernandez
  • Justin J. Jeffery
  • Charles P. Theuer
  • Weibo Cai
Original Article

Abstract

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.

Keywords

Angiogenesis Radioimmunotherapy Lutetium-177 (177Lu) CD105 Endoglin Cancer 

Notes

Compliance with ethical standards

Financial support

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.

Ethical approval

All applicable international, national, and/or institutional guidelines for the care and use of animals were followed.

Supplementary material

259_2017_3793_MOESM1_ESM.docx (2.1 mb)
ESM 1 (DOCX 2104 kb).

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Copyright information

© Springer-Verlag GmbH Germany 2017

Authors and Affiliations

  • Emily B. Ehlerding
    • 1
  • Saige Lacognata
    • 2
  • Dawei Jiang
    • 2
  • Carolina A. Ferreira
    • 3
  • Shreya Goel
    • 4
  • Reinier Hernandez
    • 1
  • Justin J. Jeffery
    • 5
  • Charles P. Theuer
    • 6
  • Weibo Cai
    • 1
    • 2
    • 3
    • 4
  1. 1.Department of Medical PhysicsUniversity of Wisconsin – MadisonMadisonUSA
  2. 2.Department of RadiologyUniversity of Wisconsin – MadisonMadisonUSA
  3. 3.Department of Biomedical EngineeringUniversity of Wisconsin – MadisonMadisonUSA
  4. 4.Department of Materials Science and EngineeringUniversity of Wisconsin – MadisonMadisonUSA
  5. 5.Small Animal Imaging FacilityUniversity of Wisconsin – MadisonMadisonUSA
  6. 6.TRACON Pharmaceuticals, Inc.San DiegoUSA

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