Related Experiment Video
Updated: Jun 13, 2025
09:44
Pretargeted Radioimmunotherapy Based on the Inverse Electron Demand Diels-Alder Reaction
Published on: January 29, 2019
10.1K
Optimizing the Therapeutic Index of sdAb-Based Radiopharmaceuticals Using Pretargeting.
Sophie Poty1, Laura Ordas2, Yana Dekempeneer3
1Institut de Recherche en Cancérologie de Montpellier, Université de Montpellier, INSERM, U1194, Équipe labellisée Ligue contre le cancer, Montpellier, France; and sophie.poty@u-bourgogne.fr jean-pierre.pouget@inserm.fr.
Summary
Pretargeting reduces kidney retention of single-domain antibodies for radionuclide therapy. This approach improved survival and reduced kidney toxicity in pancreatic cancer models compared to conventional methods.
Area of Science:
- Oncology
- Radiochemistry
- Immunotherapy
Background:
- Single-domain antibodies (sdAbs) show promise for molecular imaging and targeted radionuclide therapy (TRT).
- Renal excretion and retention of sdAbs pose challenges for effective TRT, potentially leading to kidney toxicity.
- Fibroblast activation protein alpha (FAP) is a target overexpressed in various cancers, including pancreatic ductal adenocarcinoma (PDAC).
Purpose of the Study:
- To develop and validate a click-chemistry-based pretargeting strategy to reduce kidney retention of a FAP-targeted sdAb (4AH29) for 177Lu-TRT.
- To optimize pretargeting parameters, including sdAb-injected mass and lag time, for improved therapeutic index.
- To evaluate the efficacy and safety of the pretargeting approach in a PDAC patient-derived xenograft (PDX) model.
Main Methods:
- A FAP-targeted sdAb (4AH29) was modified with trans-cyclooctene (TCO) moieties for click chemistry.
- Pretargeting parameters were optimized in healthy mice and FAP-positive U87MG xenografts.
- A pilot TRT study was conducted in a PDAC PDX model using the optimized pretargeting approach (4AH29-TCO + [177Lu]Lu-DOTA-PEG7-tetrazine) and compared to conventional TRT ([177Lu]Lu-DOTA-4AH29).
Main Results:
- TCO modification did not alter the pharmacokinetic profile of 4AH29.
- Optimized pretargeting (200 µg 4AH29-TCO, 8-h lag time) resulted in a 5-fold higher kidney therapeutic index compared to conventional TRT.
- Pretargeting treatment led to prolonged survival in PDAC PDX mice and showed no observed kidney morphologic changes, unlike the conventional TRT group.
- FAP expression was confirmed in the tumor microenvironment of the PDAC PDX model.
Conclusions:
- Click-chemistry-based pretargeting effectively mitigates kidney retention of sdAbs for 177Lu-TRT, enhancing the therapeutic index.
- The pretargeting strategy demonstrated improved survival and reduced kidney toxicity in a preclinical PDAC model.
- Clinical translation of this pretargeting approach is warranted to overcome limitations associated with sdAb pharmacokinetics and improve TRT safety and efficacy.
- Limitations in current preclinical models (stroma, FAP expression) impacted tumor absorbed dose and survival benefit, highlighting the need for more representative models.
