C11-conjugated soft glucocorticoid antibody–drug conjugates for precision immunomodulation
- 1School of Pharmacy and Pharmaceutical Sciences, Binghamton University PO Box 6000 Binghamton NY 13902-6000 USA +1 (845)234 9113
Abstract
Glucocorticoids (GCs) are highly effective therapies for inflammatory diseases, but their clinical use is severely limited by systemic toxicities. To address this liability, we developed a modular antibody–drug conjugate (ADC) platform for targeted delivery of GC to immune cells, thereby minimizing systemic exposure to free GC. The platform integrates three key design features: (i) fluticasone furoate (FF), a potent metabolically soft glucocorticoid; (ii) a legumain-cleavable AsnAsnGlyPro self-immolative linker for lysosome-selective payload release; and (iii) C11 hydroxyl conjugation to enhance resistance to serum esterase-mediated hydrolysis. ADCs targeting TNFα, CD38, and CD11a exhibited nanomolar potency in glucocorticoid-responsive reporter assays and excellent serum stability enabled by the C11 conjugation. Across all three targets, the ADCs displayed nanomolar potency in glucocorticoid-responsive reporter assays, achieving over 50-fold selectivity over non-targeting isotype controls. Functional assays in primary bone marrow-derived macrophages (BMDMs) and THP-1 cells confirmed potent inhibition of NF-κB signaling and pro-inflammatory cytokine secretion (IL-6, IL-8). Extensive stability assays in human and mouse serum revealed that the C11-conjugated constructs are highly resistant to premature cleavage. These findings establish a robust, highly stable soft glucocorticoid ADC platform for targeted immunosuppression with the potential to improve the safety and efficacy of glucocorticoid therapy for inflammatory diseases.
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BibTeX
@article{yaseen2026c11conjugated,
title = {{C11-conjugated soft glucocorticoid antibody–drug conjugates for precision immunomodulation}},
author = {Aiman A. Yaseen and Daniel J. Cohen and Anqi Zhang and L. Nathan Tumey},
journal = {RSC medicinal chemistry},
year = {2026},
month = oct,
doi = {10.1039/d6md00649c},
url = {https://europepmc.org/article/PMC/PMC13728932},
note = {CC BY-NC},
}
RIS
TY - JOUR
TI - C11-conjugated soft glucocorticoid antibody–drug conjugates for precision immunomodulation
AU - Aiman A. Yaseen
AU - Daniel J. Cohen
AU - Anqi Zhang
AU - L. Nathan Tumey
PY - 2026
DA - 2026/10/14
JO - RSC medicinal chemistry
DO - 10.1039/d6md00649c
UR - https://europepmc.org/article/PMC/PMC13728932
AB - Glucocorticoids (GCs) are highly effective therapies for inflammatory diseases, but their clinical use is severely limited by systemic toxicities. To address this liability, we developed a modular antibody–drug conjugate (ADC) platform for targeted delivery of GC to immune cells, thereby minimizing systemic exposure to free GC. The platform integrates three key design features: (i) fluticasone furoate (FF), a potent metabolically soft glucocorticoid; (ii) a legumain-cleavable AsnAsnGlyPro self-immolative linker for lysosome-selective payload release; and (iii) C11 hydroxyl conjugation to enhance resistance to serum esterase-mediated hydrolysis. ADCs targeting TNFα, CD38, and CD11a exhibited nanomolar potency in glucocorticoid-responsive reporter assays and excellent serum stability enabled by the C11 conjugation. Across all three targets, the ADCs displayed nanomolar potency in glucocorticoid-responsive reporter assays, achieving over 50-fold selectivity over non-targeting isotype controls. Functional assays in primary bone marrow-derived macrophages (BMDMs) and THP-1 cells confirmed potent inhibition of NF-κB signaling and pro-inflammatory cytokine secretion (IL-6, IL-8). Extensive stability assays in human and mouse serum revealed that the C11-conjugated constructs are highly resistant to premature cleavage. These findings establish a robust, highly stable soft glucocorticoid ADC platform for targeted immunosuppression with the potential to improve the safety and efficacy of glucocorticoid therapy for inflammatory diseases.
SN - 2632-8682
ER -