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Updated: Nov 3, 2025
Pretargeted Radioimmunotherapy Based on the Inverse Electron Demand Diels-Alder Reaction
Published on: January 29, 2019
Targeting a Radiosensitizing Antibody-Drug Conjugate to a Radiation-Inducible Antigen
Calvin D Lewis1,2, Abhay K Singh1, Fong-Fu Hsu3
1Department of Radiation Oncology, School of Medicine, Washington University in St. Louis, St. Louis, Missouri.
Purpose:
We recently discovered that anti-TIP1 antibody activates endocytosis in cancer cells, which facilitates retention of antibody and dissociation of a conjugated drug. To improve the pharmacokinetics and cancer specificity of radiosensitizing drugs, we utilized antibody-drug conjugates (ADCs) that bind specifically to radiation-inducible antigen, TIP1, on non-small cell lung cancer (NSCLC). This approach exploits the long circulation time of antibodies to deliver a radiosensitizing drug to cancer each day during radiotherapy.
Experimental Design:
Antibodies to TIP1 were prioritized based on affinity, cancer-specific binding, and internalization. The lead antibody, 7H5, was conjugated with a cytotoxic drug MMAE because of its ability to radiosensitize cancer. Cytotoxicity, colony formation, and tumor growth studies were performed with 7H5-VcMMAE in combination with radiation.
Results:
7H5 showed a high affinity to recombinant TIP1 protein and radiation-inducible TIP1 on the cancer cell surface. 7H5 undergoes endocytosis in NSCLC cells in vitro. We obtained an average drug-to-antibody ratio (DAR) of 4.25 for 7H5-VcMMAE. A 70% reduction in viable cells was observed following 7H5-VcMMAE treatment compared with 7H5 alone in both A549 and H1299 cells. 7H5-VcMMAE sensitized NSCLC cells to radiation, thereby significantly decreasing the surviving fraction. The ADC combined with radiation showed a prolonged delay in tumor growth and improved survival in A549 and H1299 tumor models.
Conclusions:
Targeting radiation-inducible TIP1 with a radiosensitizing ADC is a promising strategy to enhance the therapeutic efficacy of NSCLC. This novel approach of targeting with ADCs to radiation-inducible antigens will lead to clinical trials in lung cancer patients treated with radiotherapy.
Insights
Antibody-drug conjugates targeting TIP1 enhance radiosensitizing drug delivery for non-small cell lung cancer (NSCLC). This approach improves drug retention and cancer specificity, leading to delayed tumor growth and increased survival.
Area of Science:
- Oncology
- Pharmacology
- Immunotherapy
Background:
- Radiotherapy is a cornerstone in non-small cell lung cancer (NSCLC) treatment.
- Improving drug delivery and specificity of radiosensitizing agents remains a challenge.
- Antibody-drug conjugates (ADCs) offer a targeted approach to drug delivery.
Purpose of the Study:
- To develop and evaluate an antibody-drug conjugate (ADC) targeting the radiation-inducible antigen TIP1 on NSCLC cells.
- To assess the efficacy of a TIP1-targeting ADC in combination with radiotherapy.
- To improve the pharmacokinetics and cancer specificity of radiosensitizing drugs.
Main Methods:
- Prioritization of anti-TIP1 antibodies based on affinity, cancer-specific binding, and internalization.
- Conjugation of the lead antibody (7H5) with a radiosensitizing drug (MMAE) to create 7H5-VcMMAE.
- In vitro and in vivo studies evaluating cytotoxicity, radiosensitization, colony formation, and tumor growth in NSCLC models.
Main Results:
- The anti-TIP1 antibody 7H5 demonstrated high affinity and specific binding to TIP1 on NSCLC cells, with efficient endocytosis.
- 7H5-VcMMAE showed significant cytotoxicity and radiosensitizing effects on NSCLC cells in vitro.
- Combination therapy with 7H5-VcMMAE and radiation resulted in prolonged tumor growth delay and improved survival in preclinical NSCLC models.
Conclusions:
- Targeting radiation-inducible TIP1 with a radiosensitizing ADC is a promising strategy for enhancing NSCLC therapeutic efficacy.
- This novel ADC approach targeting radiation-inducible antigens holds potential for clinical application in NSCLC patients undergoing radiotherapy.
- Further clinical trials are warranted to validate this approach in lung cancer patients.
