Antibody-Drug Conjugates in Solid Tumor Oncology and the Frontier of Precision Immunosuppression: A Mechanistic, Translational, and Clinical Review
- 1College of Medicine, Alfaisal University, Riyadh 11533, Saudi Arabia
- 2Research Center, King Faisal Specialist Hospital and Research Center, Jeddah 21499, Saudi Arabia
Abstract
Antibody-drug conjugates (ADCs) have transitioned from clinically marginal agents into a defining therapeutic class for solid tumor oncology. In DESTINY-Breast03, trastuzumab deruxtecan achieved a four-fold progression-free survival advantage over trastuzumab emtansine, attributable not to antibody engineering but to the linker-payload axis: a cleavable peptide linker and a topoisomerase I payload with bystander activity. Sacituzumab govitecan extends the same logic to Trop-2-positive disease via extracellular payload release, and the framework now spans breast, urothelial, gynecologic, lung, gastric, and colorectal cancers, with enfortumab vedotin plus pembrolizumab displacing platinum chemotherapy as first-line therapy for urothelial cancer in EV-302 (median overall survival 31.5 versus 16.1 months). This review synthesizes ADC biology along three analytical axes. The mechanistic axis links each linker-payload-DAR configuration to a specific tumor-biology barrier: vascular limitation, which delivers approximately 0.1% of the administered dose to tumor tissue; the binding-site barrier, which concentrates exposure at the perivascular margin; and antigen mosaicism, which defeats internalization-dependent killing. The translational axis examines resistance as a coordinated failure across antigen modulation, trafficking, efflux, apoptotic execution, and lysosomal processing. The clinical axis traces the platform's migration toward earlier-line and curative-intent settings. We close by examining whether the ADC delivery architecture translates to precision immunosuppression in autoimmune disease, where the glucocorticoid receptor modulator ADC ABBV-154 met placebo-controlled efficacy endpoints in rheumatoid arthritis but was discontinued because its benefit-risk profile did not differentiate it from existing biologic therapies.
Related
- Antibody-drug conjugates in precision oncology
- C11-conjugated soft glucocorticoid antibody–drug conjugates for precision immunomodulation
- From Unmet Medical Need to Drug Candidate: A Translational Therapeutic Development Roadmap Illustrated by Dual-Payload Antibody–Drug Conjugates
- 133 In vitro comparison of the stability and biotransformation of sac-TMT and control antibody-drug conjugates in human plasma
- From Payload‐First Toward Dual‐Mechanism Antibody–Drug Conjugates
BibTeX
@article{masoud2026antibodydrug,
title = {{Antibody-Drug Conjugates in Solid Tumor Oncology and the Frontier of Precision Immunosuppression: A Mechanistic, Translational, and Clinical Review}},
author = {Ibraheem Masoud and Nada Saed Homod Al Shaer and Ahmad Masoud and Ahmad Al Jandali and Abdulrahman Aldahash and Abdullah Jabri and Mohamed Alsharif and Fareeha Arshad and Itika Arora and Mohammed Imran Khan and Ahmed Yaqinuddin},
journal = {International Journal of Molecular Sciences},
year = {2026},
month = jun,
doi = {10.3390/ijms27125196},
url = {https://doi.org/10.3390/ijms27125196},
note = {CC BY},
}
RIS
TY - JOUR
TI - Antibody-Drug Conjugates in Solid Tumor Oncology and the Frontier of Precision Immunosuppression: A Mechanistic, Translational, and Clinical Review
AU - Ibraheem Masoud
AU - Nada Saed Homod Al Shaer
AU - Ahmad Masoud
AU - Ahmad Al Jandali
AU - Abdulrahman Aldahash
AU - Abdullah Jabri
AU - Mohamed Alsharif
AU - Fareeha Arshad
AU - Itika Arora
AU - Mohammed Imran Khan
AU - Ahmed Yaqinuddin
PY - 2026
DA - 2026/06/09
JO - International Journal of Molecular Sciences
DO - 10.3390/ijms27125196
UR - https://doi.org/10.3390/ijms27125196
AB - Antibody-drug conjugates (ADCs) have transitioned from clinically marginal agents into a defining therapeutic class for solid tumor oncology. In DESTINY-Breast03, trastuzumab deruxtecan achieved a four-fold progression-free survival advantage over trastuzumab emtansine, attributable not to antibody engineering but to the linker-payload axis: a cleavable peptide linker and a topoisomerase I payload with bystander activity. Sacituzumab govitecan extends the same logic to Trop-2-positive disease via extracellular payload release, and the framework now spans breast, urothelial, gynecologic, lung, gastric, and colorectal cancers, with enfortumab vedotin plus pembrolizumab displacing platinum chemotherapy as first-line therapy for urothelial cancer in EV-302 (median overall survival 31.5 versus 16.1 months). This review synthesizes ADC biology along three analytical axes. The mechanistic axis links each linker-payload-DAR configuration to a specific tumor-biology barrier: vascular limitation, which delivers approximately 0.1% of the administered dose to tumor tissue; the binding-site barrier, which concentrates exposure at the perivascular margin; and antigen mosaicism, which defeats internalization-dependent killing. The translational axis examines resistance as a coordinated failure across antigen modulation, trafficking, efflux, apoptotic execution, and lysosomal processing. The clinical axis traces the platform's migration toward earlier-line and curative-intent settings. We close by examining whether the ADC delivery architecture translates to precision immunosuppression in autoimmune disease, where the glucocorticoid receptor modulator ADC ABBV-154 met placebo-controlled efficacy endpoints in rheumatoid arthritis but was discontinued because its benefit-risk profile did not differentiate it from existing biologic therapies.
SN - 1422-0067
SN - 1661-6596
ER -