Glucocorticoids (GCs) are excellent anti-inflammatory drugs but are dose-limited by on-target toxicity. We sought to solve this problem by delivering GCs to immune cells with antibody–drug conjugates (ADCs) using antibodies containing site-specific incorporation of a non-natural amino acid, novel linker chemistry for in vitro and in vivo stability, and existing and novel glucocorticoid receptor (GR) agonists as payloads. We directed fluticasone propionate to human antigen-presenting immune cells to afford GR activation that was dependent on the targeted antigen. However, mechanism of action studies pointed to accumulation of free payload in the tissue culture supernatant as the dominant driver of activity and indeed administration of the ADC to human CD74 transgenic mice failed to activate GR target genes in splenic B cells. Suspecting dissipation of released payload, we designed an ADC bearing a novel GR agonist payload with reduced permeability which afforded cell-intrinsic activity in human B cells. Our work shows that antibody-targeting offers significant potential for rescuing existing and new dose-limited drugs outside the field of oncology.

中文翻译：

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抗CD74抗体药物的开发与免疫细胞靶向糖皮质激素的结合。

糖皮质激素（GCs）是出色的抗炎药，但受靶标毒性限制剂量。我们试图通过使用包含非天然氨基酸的位点特异性掺入的抗体，用于体外和体内稳定性的新型接头化学以及现有的和新型的抗体，通过抗体-药物偶联物（ADC）将GC递送至免疫细胞来解决此问题糖皮质激素受体（GR）激动剂作为有效载荷。我们将丙酸氟替卡松导向人抗原呈递免疫细胞，以提供依赖于靶向抗原的GR激活。然而，作用机理研究指出，游离有效载荷在组织培养上清液中的积累是活性的主要驱动力，实际上向人CD74转基因小鼠施用ADC未能激活脾脏B细胞中的GR靶基因。考虑到释放的有效载荷的耗散，我们设计了一种ADC，该ADC带有一种新型GR激动剂有效载荷，具有降低的渗透性，可在人B细胞中提供细胞内在活性。我们的工作表明，靶向抗体为在肿瘤学领域之外拯救现有和新的剂量受限药物提供了巨大的潜力。