Radiotherapy-Conditioned Antibody–Drug Conjugate Activity: Molecular Mechanisms, Therapeutic Windows and Organ-Specific Toxicity
5 affiliations
- 1Department of Clinical Anatomy, Mazovian University in Płock, 09-402 Płock, Poland
- 2VARIA Research Laboratory, 09-402 Płock, Poland
- 3VARIANTIS Research Laboratory, 09-402 Płock, Poland
- 4Faculty of Health Sciences, Mazovian University in Płock, 09-402 Płock, Poland
- 5Faculty of Medicine, Collegium Medicum, Mazovian University in Płock, 09-402 Płock, Poland
Abstract
Antibody–drug conjugate (ADC) activity depends on accessible targets, tissue distribution, payload release, cellular susceptibility, and host immunity. Radiotherapy (RT) can modify these determinants, creating a time- and tissue-dependent radiation-conditioned ADC state. This critical narrative review integrates mechanistic and clinical evidence, distinguishing intact ADC–RT experiments from studies of isolated components, ADCs without RT, and engineered platforms. Direct preclinical studies support selected target-conditioning, payload, and immune interactions, but do not establish a class-wide effect. We organize the evidence into four overlapping, potentially competing biological windows: targeting, radiosensitization, immune priming, and normal-tissue injury. The framework links mechanisms to schedule comparisons, measurements, and organ-specific constraints. Delivery-mediated interactions require altered exposure; response-mediated effects may occur at comparable exposure. Clinical evidence is predominantly observational and heterogeneous in the drug, irradiated site, fractionation, overlap, and follow-up. Feasibility reports involving trastuzumab deruxtecan and the association between trastuzumab emtansine and radionecrosis after stereotactic radiosurgery require a separate interpretation. Biological susceptibility also differs from later injury detection. Prospective studies should compare durable tumor control, treatment continuity, and acute and delayed toxicity, using selected mechanistic substudies. The framework is hypothesis-generating and does not establish a universal treatment sequence.
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BibTeX
@article{landfald2026radiotherapyconditioned,
title = {{Radiotherapy-Conditioned Antibody–Drug Conjugate Activity: Molecular Mechanisms, Therapeutic Windows and Organ-Specific Toxicity}},
author = {Ingrid C. Landfald and Łukasz Olewnik and Magdalena Ciechanowska and Maciej Kornatowski},
journal = {Cancers},
year = {2026},
month = nov,
doi = {10.3390/cancers18213554},
url = {https://www.mdpi.com/2072-6694/18/21/3554},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Radiotherapy-Conditioned Antibody–Drug Conjugate Activity: Molecular Mechanisms, Therapeutic Windows and Organ-Specific Toxicity
AU - Ingrid C. Landfald
AU - Łukasz Olewnik
AU - Magdalena Ciechanowska
AU - Maciej Kornatowski
PY - 2026
DA - 2026/11/05
JO - Cancers
DO - 10.3390/cancers18213554
UR - https://www.mdpi.com/2072-6694/18/21/3554
AB - Antibody–drug conjugate (ADC) activity depends on accessible targets, tissue distribution, payload release, cellular susceptibility, and host immunity. Radiotherapy (RT) can modify these determinants, creating a time- and tissue-dependent radiation-conditioned ADC state. This critical narrative review integrates mechanistic and clinical evidence, distinguishing intact ADC–RT experiments from studies of isolated components, ADCs without RT, and engineered platforms. Direct preclinical studies support selected target-conditioning, payload, and immune interactions, but do not establish a class-wide effect. We organize the evidence into four overlapping, potentially competing biological windows: targeting, radiosensitization, immune priming, and normal-tissue injury. The framework links mechanisms to schedule comparisons, measurements, and organ-specific constraints. Delivery-mediated interactions require altered exposure; response-mediated effects may occur at comparable exposure. Clinical evidence is predominantly observational and heterogeneous in the drug, irradiated site, fractionation, overlap, and follow-up. Feasibility reports involving trastuzumab deruxtecan and the association between trastuzumab emtansine and radionecrosis after stereotactic radiosurgery require a separate interpretation. Biological susceptibility also differs from later injury detection. Prospective studies should compare durable tumor control, treatment continuity, and acute and delayed toxicity, using selected mechanistic substudies. The framework is hypothesis-generating and does not establish a universal treatment sequence.
SN - 2072-6694
ER -