Expression-Dependent Tumor Pretargeting via Engineered Avidity
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View abstract on PubMed
Summary
This summary is machine-generated.Engineered a novel binding platform for cancer therapy that uses avidity-driven specificity for precise tumor targeting, improving selectivity and reducing side effects in pretargeted radioligand therapy.
Area Of Science
- Biotechnology
- Oncology
- Molecular Engineering
Background
- Selective delivery of cancer therapeutics to tumor cells is crucial but limited by the lack of truly specific biomarkers.
- Non-specific binding to healthy tissues causes on-target, off-tumor toxicity, restricting therapeutic windows.
Purpose Of The Study
- To engineer an advanced binding platform for expression-dependent tumor targeting, enhancing selectivity in cancer therapy.
- To develop a system that relies on avidity rather than binary biomarker presence for improved targeting.
Main Methods
- Engineered affibodies targeting carcinoembryonic antigen-related cell adhesion molecule 5 (CEACAM5) and folate receptor 1 (FolR1) with varied monomeric affinities.
- Constructed bispecific, trivalent proteins by tethering affibodies to a nanobody for pretargeted radioligand therapy.
- Evaluated expression-dependent targeting and selectivity in mixed cell cultures.
Main Results
- Achieved expression-dependent targeting with affibodies to CEACAM5 (110 nM affinity) and FolR1 (250 nM affinity).
- Demonstrated over 25-fold differentiation between high and low FolR1-expressing cells using a bispecific, trivalent construct.
- Developed a size-efficient bivalent molecule with similar selectivity and minimal inhibition by soluble antigen.
Conclusions
- Avidity-driven specificity enables precise, expression-dependent tumor targeting, overcoming limitations of traditional biomarker-based approaches.
- The engineered platform offers enhanced selectivity and reduced susceptibility to soluble antigen interference for improved cancer therapeutics.
- This work provides new design principles for advanced tumor targeting strategies in pretargeted radioligand therapy.
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