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.

糖皮质激素（GCs）广泛用于治疗多种自身免疫性和炎症性疾病；然而，糖皮质激素的系统递送与影响几乎所有器官系统的副作用相关，这反映了糖皮质激素受体（GR）的几乎普遍表达。利用抗体-糖皮质激素偶联物（GC-ADCs）将GCs靶向递送至病变组织，为克服这些不良效应提供了一种治疗替代方案。本文描述了新型GCs，其效力优于地塞米松和布地奈德，对GR的选择性高达100倍，且在药理学检测（hERG、AMES）中未显示出体外安全性风险。这些新型GCs在脂多糖（LPS）挑战小鼠模型中显著降低了肿瘤坏死因子-α（TNF-α）的释放。通过组织蛋白酶-c可切割连接子特异性偶联的GC-ADCs在血浆中高度稳定，并能在抗原阳性细胞中特异性释放GCs，这表明这些新型GCs可作为ADC载体治疗自身免疫性和炎症性疾病。