A lesion-selective albumin-CTLA4Ig as a safe and effective treatment for collagen-induced arthritis.

IF 5 3区 医学 Q2 IMMUNOLOGY
Fu-Yao Jiang, Yan-Zhu Zhang, Yuan-Hong Tai, Chien-Yu Chou, Yu-Ching Hsieh, Ya-Chi Chang, Hsiao-Chen Huang, Zhi-Qin Li, Yuan-Chin Hsieh, I-Ju Chen, Bo-Cheng Huang, Yu-Cheng Su, Wen-Wei Lin, Hsin-Chieh Lin, Jui-I Chao, Shyng-Shiou F Yuan, Yun-Ming Wang, Tian-Lu Cheng, Shey-Cherng Tzou
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引用次数: 1

Abstract

Background: CTLA4Ig is a dimeric fusion protein of the extracellular domain of cytotoxic T-lymphocyte protein 4 (CTLA4) and an Fc (Ig) fragment of human IgG1 that is approved for treating rheumatoid arthritis. However, CTLA4Ig may induce adverse effects. Developing a lesion-selective variant of CTLA4Ig may improve safety while maintaining the efficacy of the treatment.

Methods: We linked albumin to the N-terminus of CTLA4Ig (termed Alb-CTLA4Ig) via a substrate sequence of matrix metalloproteinase (MMP). The binding activities and the biological activities of Alb-CTLA4Ig before and after MMP digestion were analyzed by a cell-based ELISA and an in vitro Jurkat T cell activation assay. The efficacy and safety of Alb-CTLA4Ig in treating joint inflammation were tested in mouse collagen-induced arthritis.

Results: Alb-CTLA4Ig is stable and inactive under physiological conditions but can be fully activated by MMPs. The binding activity of nondigested Alb-CTLA4Ig was at least 10,000-fold weaker than that of MMP-digested Alb-CTLA4Ig. Nondigested Alb-CTLA4Ig was unable to inhibit Jurkat T cell activation, whereas MMP-digested Alb-CTLA4Ig was as potent as conventional CTLA4Ig in inhibiting the T cells. Alb-CTLA4Ig was converted to CTLA4Ig in the inflamed joints to treat mouse collagen-induced arthritis, showing similar efficacy to that of conventional CTLA4Ig. In contrast to conventional CTLA4Ig, Alb-CTLA4Ig did not inhibit the antimicrobial responses in the spleens of the treated mice.

Conclusions: Our study indicates that Alb-CTLA4Ig can be activated by MMPs to suppress tissue inflammation in situ. Thus, Alb-CTLA4Ig is a safe and effective treatment for collagen-induced arthritis in mice.

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病变选择性白蛋白ctla4ig作为一种安全有效的治疗胶原性关节炎的药物。
背景:CTLA4Ig是细胞毒性t淋巴细胞蛋白4 (CTLA4)细胞外结构域的二聚体融合蛋白和人IgG1的Fc (Ig)片段,已被批准用于治疗类风湿性关节炎。然而,CTLA4Ig可能会引起不良反应。开发CTLA4Ig的病变选择性变体可以提高安全性,同时保持治疗的有效性。方法:我们通过基质金属蛋白酶(MMP)底物序列将白蛋白连接到CTLA4Ig的n端(称为Alb-CTLA4Ig)。采用细胞酶联免疫吸附法(ELISA)和体外Jurkat T细胞活化法分析MMP消化前后Alb-CTLA4Ig的结合活性和生物活性。在小鼠胶原性关节炎实验中,研究了Alb-CTLA4Ig治疗关节炎症的疗效和安全性。结果:Alb-CTLA4Ig在生理条件下稳定且无活性,但可被MMPs充分激活。未消化的Alb-CTLA4Ig的结合活性比mmp消化的Alb-CTLA4Ig的结合活性弱至少1万倍。未消化的Alb-CTLA4Ig不能抑制Jurkat T细胞的激活,而mmp消化的Alb-CTLA4Ig在抑制T细胞方面与常规CTLA4Ig一样有效。在炎症关节中将Alb-CTLA4Ig转化为CTLA4Ig治疗小鼠胶原性关节炎,其疗效与常规CTLA4Ig相似。与常规CTLA4Ig相比,Alb-CTLA4Ig不抑制处理小鼠脾脏的抗菌反应。结论:我们的研究表明,Alb-CTLA4Ig可被MMPs激活,原位抑制组织炎症。因此,Alb-CTLA4Ig是一种安全有效的治疗小鼠胶原性关节炎的药物。
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来源期刊
CiteScore
11.10
自引率
1.20%
发文量
45
审稿时长
11 weeks
期刊介绍: Inflammation and Regeneration is the official journal of the Japanese Society of Inflammation and Regeneration (JSIR). This journal provides an open access forum which covers a wide range of scientific topics in the basic and clinical researches on inflammation and regenerative medicine. It also covers investigations of infectious diseases, including COVID-19 and other emerging infectious diseases, which involve the inflammatory responses. Inflammation and Regeneration publishes papers in the following categories: research article, note, rapid communication, case report, review and clinical drug evaluation.
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