Research Center for Macromolecules and Biomaterials, National Institute for Materials Science (NIMS), 1-1 Namiki, Tsukuba 305-0044, Japan.
Graduate School of Pure and Applied Sciences, University of Tsukuba, 1-1-1 Tennodai, Tsukuba 305-8577, Japan.
Int J Mol Sci. 2023 Nov 7;24(22):16036. doi: 10.3390/ijms242216036.
Apoptotic cells' phosphoserine (PS) groups have a significant immunosuppressive effect. They inhibit proinflammatory signals by interacting with various immune cells, including macrophages, dendritic cells, and CD4 cells. Previously, we synthesized PS-group-immobilized polymers and verified their immunomodulatory effects. Despite its confirmed immunomodulatory potential, the PS group has not been considered as a payload for antibody-drug conjugates (ADCs) in a targeted anti-inflammatory approach.
We conducted this research to introduce an apoptotic-cell-inspired antibody-drug conjugate for effective immunomodulation.
Poly(2-hydroxyethyl methacrylate--2-methacryloyloxyethyl phosphorylserine) (p(HEMA--MPS)) was synthesized as a payload using RAFT polymerization, and goat anti-mouse IgG was selected as a model antibody, which was conjugated with the synthesized p(HEMA--MPS) via 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide/-Hydroxysuccinimide (EDC/NHS) reaction. The antibody-binding affinity, anti-inflammatory potential, and cytotoxicity measurements were evaluated.
We successfully synthesized ADCs with a significant anti-inflammatory effect and optimized the antibody-polymer ratio to achieve the highest antibody-binding affinity.
We successfully introduced p(HEMA--MPS) to IgG without decreasing the anti-inflammatory potential of the polymer while maintaining its targeting ability. We suggest that the antibody-polymer ratio be appropriately adjusted for effective therapy. In the future, this technology can be applied to therapeutic antibodies, such as Tocilizumab or Abatacept.
凋亡细胞的磷酸丝氨酸（PS）基团具有显著的免疫抑制作用。它们通过与各种免疫细胞（包括巨噬细胞、树突状细胞和 CD4 细胞）相互作用来抑制促炎信号。以前，我们合成了 PS 基团固定化聚合物，并验证了它们的免疫调节作用。尽管已证实其具有免疫调节潜力，但 PS 基团尚未被认为是靶向抗炎方法中抗体药物偶联物（ADC）的有效载荷。
我们进行这项研究是为了引入一种受凋亡细胞启发的抗体药物偶联物，以实现有效的免疫调节。
使用 RAFT 聚合合成了聚（2-羟乙基甲基丙烯酸酯-2-甲基丙烯酰氧基乙基磷酸丝氨酸）（p（HEMA-MPS））作为有效载荷，选择山羊抗小鼠 IgG 作为模型抗体，通过 1-乙基-3-（3-二甲基氨基丙基）碳二亚胺/-羟基琥珀酰亚胺（EDC/NHS）反应将合成的 p（HEMA-MPS）与抗体偶联。评估了抗体结合亲和力、抗炎潜力和细胞毒性测量。
我们成功合成了具有显著抗炎作用的 ADC，并优化了抗体-聚合物比例以实现最高的抗体结合亲和力。
我们成功地将 p（HEMA-MPS）引入 IgG 而不降低聚合物的抗炎潜力的同时保持其靶向能力。我们建议适当调整抗体-聚合物比例以实现有效治疗。在未来，这项技术可以应用于治疗性抗体，如托珠单抗或阿巴西普。
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