Development of Novel Glucocorticoids for Use in Antibody–Drug Conjugates for the Treatment of Inflammatory Diseases

Glucocorticoids
(GCs) are widely used to treat a variety of autoimmune
and inflammatory diseases; however, systemic delivery of GCs is associated
with side effects that affect essentially every organ system, reflecting
the nearly ubiquitous expression of the glucocorticoid receptor (GR).
Targeted delivery of GCs to diseased tissues using antibody-glucocorticoid
conjugates (GC-ADCs) offers a therapeutic alternative to overcome
these adverse effects. Herein, we describe novel classes of GCs that
exhibited greater potency than dexamethasone and budesonide, a 100-fold
selectivity toward the GR over other nuclear receptors, and no in vitro safety liability in pharmacology assays (hERG,
AMES) and that demonstrated a substantial reduction in tumor necrosis
factor-α (TNF-α) release in mice challenged with lipopolysaccharide
(LPS). The site-specific conjugated GC-ADCs via cathepsin-cleavable
linkers were highly stable in plasma and specifically released GCs
in antigen-positive cells, suggesting that these novel GCs can serve
as ADC payloads to treat autoimmune and inflammatory diseases.