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Glucocorticoids (GCs) are efficacious drugs used for treating many inflammatory diseases, but the dose and duration of administration are limited because of severe side effects. We therefore sought to identify an approach to selectively target GCs to inflamed tissue. Previous work identified that anti–tumor necrosis factor (TNF) antibodies that bind to transmembrane TNF undergo internalization; therefore, an anti-TNF antibody-drug conjugate (ADC) would be mechanistically similar, where lysosomal catabolism could release a GC receptor modulator (GRM) payload to dampen immune cell activity. Consequently, we have generated an anti–TNF-GRM ADC with the aim of inhibiting pro-inflammatory cytokine production from stimulated human immune cells. In an acute mouse model of contact hypersensitivity, a murine surrogate anti–TNF-GRM ADC inhibited inflammatory responses with minimal effect on systemic GC biomarkers. In addition, in a mouse model of collagen-induced arthritis, single-dose administration of the ADC, delivered at disease onset, was able to completely inhibit arthritis for greater than 30 days, whereas an anti-TNF monoclonal antibody only partially inhibited disease. ADC treatment at the peak of disease was also able to attenuate the arthritic phenotype. Clinical data for a human anti–TNF-GRM ADC (ABBV-3373) from a single ascending dose phase 1 study in healthy volunteers demonstrated antibody-like pharmacokinetic profiles and a lack of impact on serum cortisol concentrations at predicted therapeutic doses. These data suggest that an anti–TNF-GRM ADC may provide improved efficacy beyond anti-TNF alone in immune mediated diseases while minimizing systemic side effects associated with standard GC treatment. Editor's summary: Glucocorticoids are an essential component of the inflammatory disease treatment toolbox, but their side effects limit long-term use. An alternative strategy to dampen inflammatory responses while avoiding side effects is thus urgently needed. Here, McPherson et al. developed an antibody-drug conjugate (ADC) of an anti-TNF antibody and a gluococorticoid receptor modulator (GRM) that, upon internalization in immune cells through transmembrane TNF, resulted in release of the GRM and attenuated inflammatory responses. The authors found that administration of a murine version of the anti–TNF-GRM ADC reduced disease severity in mice with contact hypersensitivity or arthritis better than an anti-TNF antibody alone. Moreover, a phase 1 study of the human anti–TNF-GRM ADC, ABBV-3373, showed favorable pharmacokinetics and safety. Together, these data support continued clinical development ABBV-3373 for immune-mediated inflammatory diseases. —Courtney Malo [ABSTRACT FROM AUTHOR]