Pritzker School for Molecular Engineering, University of Chicago, Chicago, IL 60637, USA.
Committee on Immunology, University of Chicago, Chicago, IL 60637, USA.
Cell Rep Med. 2024 Jan 16;5(1):101345. doi: 10.1016/j.xcrm.2023.101345. Epub 2023 Dec 20.
Immunogenic biologics trigger an anti-drug antibody (ADA) response in patients that reduces efficacy and increases adverse reactions. Our laboratory has shown that targeting protein antigen to the liver microenvironment can reduce antigen-specific T cell responses; herein, we present a strategy to increase delivery of otherwise immunogenic biologics to the liver via conjugation to a synthetic mannose polymer, p(Man). This delivery leads to reduced antigen-specific T follicular helper cell and B cell responses resulting in diminished ADA production, which is maintained throughout subsequent administrations of the native biologic. We find that p(Man)-antigen treatment impairs the ADA response against recombinant uricase, a highly immunogenic biologic, without a dependence on hapten immunodominance or control by T regulatory cells. We identify increased T cell receptor signaling and increased apoptosis and exhaustion in T cells as effects of p(Man)-antigen treatment via transcriptomic analyses. This modular platform may enhance tolerance to biologics, enabling long-term solutions for an ever-increasing healthcare problem.
免疫原性生物制剂会在患者体内引发抗药物抗体（ADA）反应，从而降低疗效并增加不良反应。我们的实验室已经表明，将蛋白质抗原靶向肝脏微环境可以减少抗原特异性 T 细胞反应；在此，我们提出了一种通过与合成甘露糖聚合物 p(Man)缀合将其他具有免疫原性的生物制剂递送至肝脏的策略。这种递药方式导致抗原特异性滤泡辅助 T 细胞和 B 细胞反应减少，从而减少 ADA 的产生，并且在随后给予天然生物制剂时仍能维持。我们发现，p(Man)-抗原治疗会削弱针对重组尿酸酶的 ADA 反应，而重组尿酸酶是一种高度免疫原性的生物制剂，这与半抗原免疫优势或 T 调节细胞的控制无关。通过转录组分析，我们发现 p(Man)-抗原治疗会导致 T 细胞中 T 细胞受体信号转导增加、细胞凋亡和衰竭增加。通过这种模块化平台可以增强对生物制剂的耐受性，为日益增长的医疗保健问题提供长期解决方案。
