Development of Anti-CD74 Antibody-Drug Conjugates to Target Glucocorticoids to Immune Cells
Development of Anti-CD74 Antibody-Drug Conjugates to Target Glucocorticoids to Immune Cells
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DOI：
10.1021/acs.bioconjchem.8b00312
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发表时间：
2018-07-01
影响因子：
4.7
通讯作者：
Zielstorff, Mark
中科院分区：
文献类型：
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作者：
Brandish, Philip E.;Palmieri, Anthony;Zielstorff, Mark
糖皮质激素（GC）是优秀的抗炎药，但剂量有限的靶向毒性。我们试图通过用抗体药物偶联物（ADC）将GC递送至免疫细胞来解决这个问题，所述抗体药物偶联物使用含有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类抗原呈递免疫细胞，以提供依赖于靶抗原的GR激活。然而，作用机制研究指出，游离有效负载在组织培养上清液中的积累是活性的主要驱动因素，并且实际上，将ADC施用至人CD 74转基因小鼠未能激活脾B细胞中的GR靶基因。怀疑释放的有效载荷的耗散，我们设计了具有降低的渗透性的携带新型GR激动剂有效载荷的ADC，其在人B细胞中提供细胞内在活性。我们的工作表明，抗体靶向为拯救肿瘤学领域以外的现有和新的剂量限制药物提供了巨大的潜力。
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.