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Updated: Sep 17, 2025
Pretargeted Radioimmunotherapy Based on the Inverse Electron Demand Diels-Alder Reaction
Published on: January 29, 2019
Single atom engineering for radiotherapy-activated immune agonist prodrugs
Zexuan Ding1, Xiaozhe Yin2, Yuedan Zheng3
1Changping Laboratory, Beijing, China.
Abstract:
Immunotherapy has revolutionized cancer treatment by leveraging the body's immune system to combat malignancies. However, on-target, off-tumour (OTOT) toxicity poses significant challenges, often leading to the failure of clinical trials for the development of immunotherapeutic drugs. The molecular engineering of clinically relevant, tumour-selective prodrugs, activated in a targeted way, could help minimize systemic toxicity while maximizing anti-tumour efficacy. Here, we propose a Single Atom Engineering for Radiotherapy-Activated Prodrug (SAE-RAP) technique for the development of radiotherapy-activatable small-molecule immune agonist prodrugs. We show that introducing a single oxygen atom into the TLR7/8 agonist R848 significantly reduces the EC50 value by over 4000-fold, hence mitigating severe side effects following systemic administration. In preclinical tumour mouse models, exposure to radiotherapy removes the protective mask provided by the oxygen atom and locally rescues the activity of the prodrugs, triggering anti-tumour immunity and limiting the growth of primary and distal tumours. The SAE-RAP technique may be further utilized for developing radiotherapy-activated prodrugs for next-generation combination therapies that transcend traditional limitations.
Insights
This study introduces a novel radiotherapy-activated prodrug strategy to enhance cancer immunotherapy. By engineering prodrugs with a single atom mask, researchers minimized toxicity and improved anti-tumour efficacy in preclinical models.
Area of Science:
- Oncology
- Immunology
- Radiochemistry
Background:
- Immunotherapy shows promise in cancer treatment but faces challenges due to on-target, off-tumour toxicity.
- Developing tumour-selective prodrugs activated in a targeted manner is crucial for minimizing systemic side effects and maximizing anti-tumour activity.
Purpose of the Study:
- To introduce a Single Atom Engineering for Radiotherapy-Activated Prodrug (SAE-RAP) technique.
- To develop radiotherapy-activatable small-molecule immune agonist prodrugs for targeted cancer therapy.
Main Methods:
- Molecular engineering of TLR7/8 agonist R848 by introducing a single oxygen atom as a protective mask.
- Preclinical evaluation in tumour mouse models using radiotherapy to activate the prodrug.
Main Results:
- The engineered prodrug showed a >4000-fold reduction in EC50, significantly mitigating systemic toxicity.
- Radiotherapy successfully removed the oxygen mask, locally rescuing prodrug activity and triggering anti-tumour immunity.
- Inhibition of primary and distal tumour growth was observed in preclinical models.
Conclusions:
- The SAE-RAP technique offers a promising strategy for developing targeted, radiotherapy-activatable immune agonist prodrugs.
- This approach can minimize systemic toxicity and enhance anti-tumour efficacy in cancer immunotherapy.
- SAE-RAP holds potential for next-generation combination cancer therapies.
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