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Updated: May 26, 2025
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Pretargeted Radioimmunotherapy Based on the Inverse Electron Demand Diels-Alder Reaction
Published on: January 29, 2019
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Optimizing peptide nucleic acid-based pretargeting for enhanced targeted radionuclide therapy.
Mohamed Altai1, Ábel Nagy2, Pauline Granit2
1Division of Oncology and Pathology, Department of Clinical Sciences, Lund University, Lund, Sweden; Lund University Cancer Centre (LUCC), Lund University, Lund, Sweden.
Summary
This study optimized a peptide nucleic acid (PNA) pretargeting system for cancer therapy. The enhanced system improved tumor targeting and reduced off-target radiation, leading to delayed disease progression and extended survival in HER2+ models.
Area of Science:
- Bioconjugation Chemistry
- Radiopharmaceutical Therapy
- Molecular Imaging and Targeted Therapy
Background:
- Radiolabeled monoclonal antibodies (mAbs) are used for cancer treatment but face challenges with long circulation times, leading to off-target toxicity.
- Pretargeting strategies aim to improve tumor-to-background ratios and reduce radiation exposure to healthy tissues.
- Previous PNA-based pretargeting concepts showed limited efficacy with mAb vectors.
Purpose of the Study:
- To re-engineer and optimize a peptide nucleic acid (PNA)-based pretargeting system for enhanced cancer therapy.
- To develop novel PNA-conjugated trastuzumab (T) as a primary targeting agent for HER2-expressing tumors.
- To evaluate the in vivo performance and therapeutic efficacy of the optimized PNA pretargeting system.
Main Methods:
- Functionalization of trastuzumab (T) with a 9-mer PNA probe (HP9) using FcIII-based crosslinking (T-FcIII-HP9) and glyco-engineering click chemistry (T-gly-HP9).
- Development of a complementary 9-mer PNA probe (HP16) as a radionuclide-carrying secondary agent.
- In vitro assessment of HER2-binding and cell surface accumulation, followed by in vivo evaluation of pharmacokinetics, tumor uptake, and therapeutic efficacy in HER2+ tumor models.
Main Results:
- Trastuzumab-PNA conjugates (T-FcIII-HP9 and T-gly-HP9) retained HER2-binding affinity.
- T-gly-HP9 demonstrated superior in vivo pharmacokinetics and tumor uptake compared to T-FcIII-HP9.
- Pretargeted therapy with [177Lu]-HP16 significantly delayed disease progression and extended survival in HER2+ tumor models, comparable to direct [177Lu]-trastuzumab administration.
Conclusions:
- The optimized PNA-based pretargeting system exhibits excellent in vivo targeting characteristics and therapeutic efficacy.
- This novel approach holds significant potential for improving the treatment of disseminated cancers, particularly HER2-positive malignancies.
- The refined PNA pretargeting strategy offers a promising alternative to conventional mAb-based radiopharmaceutical therapies.
