ValCitGlyPro-dexamethasone antibody conjugates selectively suppress the activation of human monocytes.
ValCitGlyPro-dexamethasone antibody conjugates selectively suppress the activation of human monocytes.
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ValCitGlyPro-地塞米松抗体缀合物选择性抑制人单核细胞的活化。
DOI：
10.1039/d3md00336a
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发表时间：
2023
影响因子：
4.1
通讯作者：
Tumey,LNathan
中科院分区：
文献类型：
--
作者：
Howe,JustinM;Fang,Siteng;Watts,KelseyA;Xu,Fanny;Benjamin,SamanthaR;Tumey,LNathan
糖皮质激素（GCs）在治疗自身免疫性和炎症性疾病方面是有效的，但也有明显的副作用，其中许多副作用是由非免疫细胞介导的。因此，人们对使用抗体药物偶联物（ADC）技术将GCs特异性递送到免疫细胞，从而最大限度地减少脱靶副作用的兴趣迅速增长。在此，我们报道了抗cd11a、抗cd38和抗tnf α adc将地塞米松递送至单核细胞的研究。我们发现抗cd11a和抗cd38被单核细胞迅速内化，而抗tnf α的摄取依赖于LPS的预激活。利用这些抗体连接到一个新的连接系统，ValCitGlyPro-Dex (VCGP-Dex)，有效地释放地塞米松在溶酶体分解代谢。该连接体依靠溶酶体组织蛋白酶在ValCit序列后裂解，从而释放GlyPro-Dex物种，该物种经历快速自我牺牲形成地塞米松。在单核细胞系（THP1）和人PBMCs中，携带这种连接物载荷的单核细胞靶向adc有效地抑制了lps诱导的NFκB激活和细胞因子释放。抗tnf α _vcgp - dex和抗cd38_vcgp - dex特别有效，在3-10 μg mL−1浓度下抑制lps诱导的PBMCs中IL-6释放的~ 60-80%。相比之下，相应的同型对照ADC（抗rsv）和相应的裸抗体（抗cd38和抗tnf α）只能适度抑制lps诱导的IL-6（0-30%）。综上所述，这些结果进一步证明了糖皮质激素adc选择性抑制免疫反应的能力，并强调了两个靶点（CD38和TNFα）在开发新型免疫抑制adc方面的潜力。
Glucocorticoids (GCs) are effective in treating autoimmune and inflammatory disorders but come with significant side effects, many of which are mediated by non-immunological cells. Therefore, there is rapidly growing interest in using antibody drug conjugate (ADC) technology to deliver GCs specifically to immune cells, thereby minimizing off-target side effects. Herein, we report the study of anti-CD11a, anti-CD38, and anti-TNFα ADCs to deliver dexamethasone to monocytes. We found that anti-CD11a and anti-CD38 were rapidly internalized by monocytes, while uptake of anti-TNFα depended on pre-activation with LPS. Using these antibodies were attached to a novel linker system, ValCitGlyPro-Dex (VCGP-Dex), that efficiently released dexamethasone upon lysosomal catabolism. This linker relies on lysosomal cathepsins to cleave after the ValCit sequence, thereby releasing a GlyPro-Dex species that undergoes rapid self-immolation to form dexamethasone. The resulting monocyte-targeting ADCs bearing this linker payload effectively suppressed LPS-induced NFκB activation and cytokine release in both a monocytic cell line (THP1) and in human PBMCs. Anti-TNFα_VCGP-Dex and anti-CD38_VCGP-Dex were particularly effective, suppressing ∼60–80% of LPS-induced IL-6 release from PBMCs at 3–10 μg mL−1 concentrations. In contrast, the corresponding isotype control ADC (anti-RSV) and the corresponding naked antibodies (anti-CD38 and anti-TNFα) resulted in only modest suppression (0–30%) of LPS-induced IL-6. Taken together, these results provide further evidence of the ability of glucocorticoid-ADCs to selectively suppress immune responses, and highlight the potential of two targets (CD38 and TNFα) for the development of novel immune-suppressing ADCs.