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）被广泛应用于治疗多种自身免疫性和炎症性疾病；然而，全身性给药GCs与影响几乎每一个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，为克服这些不良反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的选择性达到其他核受体的100倍，并且在药理学实验（hERG、AMES）中未显示出体外安全性问题，并在小鼠接受脂多糖（LPS）挑战后显示出肿瘤坏死因子-α（TNF-α）释放的显著减少。通过组织蛋白酶可切割连接子特异性偶联的GC-ADCs在血浆中高度稳定，并在抗原阳性细胞中特异性释放GCs，这表明这些新型GCs可以作为ADC有效载荷用于治疗自身免疫性和炎症性疾病。