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Updated: Feb 24, 2026
Pretargeted Radioimmunotherapy Based on the Inverse Electron Demand Diels-Alder Reaction
Published on: January 29, 2019
Targeting angiogenesis for radioimmunotherapy with a 177Lu-labeled antibody
Emily B Ehlerding1, Saige Lacognata2, Dawei Jiang2
1Department of Medical Physics, University of Wisconsin - Madison, 1111 Highland Avenue, Madison, WI, 53705, USA.
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.
Insights
Targeted radionuclide therapy using 177Lu-DTPA-TRC105 effectively inhibits tumor growth and improves survival. This angiogenesis-targeting agent demonstrates safety and potential for combination cancer treatment.
Area of Science:
- Oncology
- Radiopharmaceutical Therapy
- Cancer Biology
Background:
- Increased angiogenesis is a hallmark of aggressive cancers.
- CD105 (endoglin) is a key target for anti-angiogenesis strategies.
- Targeted radioimmunotherapy offers a potential approach to inhibit tumor growth.
Purpose of the Study:
- To evaluate the efficacy and safety of 177Lu-DTPA-TRC105 for targeted radionuclide therapy.
- To assess the anti-tumor activity and survival benefit of 177Lu-DTPA-TRC105 in a preclinical cancer model.
Main Methods:
- Conjugation of anti-CD105 antibody TRC105 with DTPA for 177Lu radiolabeling.
- Administration of 177Lu-DTPA-TRC105 to mice bearing 4T1 mammary carcinoma.
- Monitoring of tumor growth, survival, toxicity (body weight, blood markers), and biodistribution.
Main Results:
- 177Lu-DTPA-TRC105 showed steady tumor uptake and gradual clearance from other organs.
- Significant tumor growth inhibition and increased survival were observed in the high-dose group.
- The agent demonstrated safety, with no significant toxicity or off-target effects on liver function.
Conclusions:
- 177Lu-DTPA-TRC105 effectively curtails tumor growth and improves survival at sufficient doses.
- The targeted agent is well-tolerated, showing no significant off-target toxicity.
- 177Lu-DTPA-TRC105 holds promise for combination therapy to enhance treatment efficacy.
