Targeted Delivery of LXR Agonist Using a Site-Specific Antibody Drug Conjugate
Targeted Delivery of LXR Agonist Using a Site-Specific Antibody Drug Conjugate
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DOI：
10.1021/acs.bioconjchem.5b00203
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发表时间：
2015-11-01
影响因子：
4.7
通讯作者：
Kazane, Stephanie A.
中科院分区：
文献类型：
--
作者：
Lim, Reyna K. V.;Yu, Shan;Kazane, Stephanie A.
肝脏 X 受体 (LXR) 激动剂因其诱导逆转胆固醇转运和抑制炎症的能力而被探索作为动脉粥样硬化和其他疾病的潜在治疗方法。然而，这种治疗潜力受到了过度脂肪生成介导的肝脏靶向不良反应的阻碍。在此，我们报告了一种新型位点特异性抗体药物偶联物（ADC），它可以选择性地将 LXR 激动剂递送至单核细胞/巨噬细胞，同时不伤害肝细胞。非天然氨基酸对乙酰基苯丙氨酸 (pAcF) 被位点特异性整合到抗 CD 11a IgG 中，该 IgG 与几乎所有单核细胞和巨噬细胞上表达的淋巴细胞功能相关抗原 1 (LFA-1) 的 α 链成分结合。氨氧基修饰的 LXR 激动剂通过稳定的组织蛋白酶 B 可裂解的肟键与抗 CD11a IgG 缀合，形成化学成分确定的 ADC。抗 CD11a IgG-LXR 激动剂 ADC 诱导 LXR。体外（EC50-27 nm）在人 THP-1 单核细胞/巨噬细胞中特异性激活，但在肝细胞中没有显着影响，表明有效负载递送是 CD11a 介导的。此外，与传统合成 LXR 激动剂 T0901317 (Tularik) 相比，ADC 表现出更高倍数的激活（3 倍）。这种新型 ADC 代表了一种根本不同的策略，它使用组织靶向来克服 LXR 激动剂的局限性，有望用于治疗动脉粥样硬化。
Liver X receptor (LXR) agonists have been explored as potential treatments for atherosclerosis and other diseases based on their ability to induce reverse cholesterol transport and suppress inflammation. However, this therapeutic potential has been hindered by on-target adverse effects in the liver mediated by excessive lipogenesis. Herein, we report a novel site-specific antibody drug conjugate (ADC) that selectively delivers a LXR agonist to monocytes/macrophages while sparing hepatocytes. The unnatural amino acid para-acetylphenylalanine (pAcF) was site-specifically incorporated into anti-CD 11a IgG, which binds the alpha-chain component of the lymphocyte function-associated antigen 1 (LFA-1) expressed on nearly all monocytes and macrophages. An aminooxy-modified LXR agonist was conjugated to anti-CD11a IgG through a stable, cathepsin B cleavable oxime linkage to afford a chemically defined ADC. The anti-CD11a IgG-LXR agonist ADC induced LXR. activation specifically in human THP-1 monocyte/macrophage cells in vitro (EC50-27 nm), but had no significant effect in hepatocytes, indicating that payload delivery is CD11a-mediated. Moreover, the ADC exhibited higher-fold activation compared to a conventional synthetic LXR agonist T0901317 (Tularik) (3-fold). This novel ADC represents a fundamentally different strategy that uses tissue targeting to overcome the limitations of LXR agonists for potential use in treating atherosclerosis.