Glucocorticoid-based immunology antibody-drug conjugates: linker, warhead, and targeting strategies for anti-inflammatory drug development.

Abstract

Glucocorticoids (GCs) are effective anti-inflammatory agents, but systemic glucocorticoid receptor (GR) activation limits prolonged treatment. Immunology antibody-drug conjugates (iADCs) seek to concentrate GR agonist activity in selected cell populations while limiting systemic payload exposure. This review examines GC- and glucocorticoid receptor modulator (GRM)-based iADCs from a medicinal chemistry perspective, emphasizing the evolution of steroidal payloads and their integration with linker chemistry and antibody targeting. Dexamethasone-, budesonide-, and fluticasone propionate-derived conjugates illustrate how payload potency, hydrophobicity, metabolic stability, and available attachment sites shape linker selection and release strategies. Engineered GRM payloads introduce amine handles, phosphate prodrugs, or metabolically labile groups to address specific constraints in conjugation, solubility, formulation, or systemic exposure. We compare reported phosphate, pyrophosphate, peptide, and self-immolative linker systems, distinguishing proposed release mechanisms from those supported by experimental evidence. We also consider how target expression, antibody internalization, conjugation chemistry, and drug-to-antibody ratio influence delivery and developability. The progression from ABBV-3373 to ABBV-154 highlights the importance of controlling aggregation and conjugate stability for subcutaneous administration. Their clinical development, including the discontinuation of ABBV-154, underscores the need to establish differentiated benefit-risk profiles in patients. Emerging programs further motivate coordinated optimization of payload pharmacology, linker behavior, formulation, and translational biomarkers. GC/GRM-based iADCs remain investigational, and improved targeting or molecular properties alone do not establish clinical superiority.

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