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

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

doi:10.1186/s41232-023-00264-8

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

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^*

^*此作品的通信作者

研究成果: Article › 同行評審

4 引文斯高帕斯（Scopus）

摘要

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.

原文	English
文章編號	13
期刊	Inflammation and Regeneration
卷	43
發行號	1
DOIs	https://doi.org/10.1186/s41232-023-00264-8
出版狀態	Published - 12月 2023

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10.1186/s41232-023-00264-8

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Jiang, F. Y., Zhang, Y. Z., Tai, Y. H., Chou, C. Y., Hsieh, Y. C., Chang, Y. C., Huang, H. C., Li, Z. Q., Hsieh, Y. C., Chen, I. J., Huang, B. C., Su, Y. C., Lin, W. W., Lin, H. C., Chao, J. I., Yuan, S. S. F., Wang, Y. M., Cheng, T. L., & Tzou, S. C. (2023). A lesion-selective albumin-CTLA4Ig as a safe and effective treatment for collagen-induced arthritis. Inflammation and Regeneration, 43(1), 文章 13. https://doi.org/10.1186/s41232-023-00264-8

@article{106be45fd93e4b11ad07a2fc255bc9a6,

title = "A lesion-selective albumin-CTLA4Ig as a safe and effective treatment for collagen-induced arthritis",

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.",

keywords = "Adverse effects, Albumin, CTLA4Ig, Collagen-induced arthritis, Inflammatory lesion-selective, Matrix metalloproteinase (MMP), Protein engineering",

author = "Jiang, {Fu Yao} and Zhang, {Yan Zhu} and Tai, {Yuan Hong} and Chou, {Chien Yu} and Hsieh, {Yu Ching} and Chang, {Ya Chi} and Huang, {Hsiao Chen} and Li, {Zhi Qin} and Hsieh, {Yuan Chin} and Chen, {I. Ju} and Huang, {Bo Cheng} and Su, {Yu Cheng} and Lin, {Wen Wei} and Lin, {Hsin Chieh} and Chao, {Jui I.} and Yuan, {Shyng Shiou F.} and Wang, {Yun Ming} and Cheng, {Tian Lu} and Tzou, {Shey Cherng}",

note = "Publisher Copyright: {\textcopyright} 2023, The Author(s).",

year = "2023",

month = dec,

doi = "10.1186/s41232-023-00264-8",

language = "English",

volume = "43",

journal = "Inflammation and Regeneration",

issn = "1880-9693",

publisher = "BioMed Central Ltd.",

number = "1",

}

Jiang, FY, Zhang, YZ, Tai, YH, Chou, CY, Hsieh, YC, Chang, YC, Huang, HC, Li, ZQ, Hsieh, YC, Chen, IJ, Huang, BC, Su, YC, Lin, WW, Lin, HC , Chao, JI, Yuan, SSF, Wang, YM, Cheng, TL & Tzou, SC 2023, 'A lesion-selective albumin-CTLA4Ig as a safe and effective treatment for collagen-induced arthritis', Inflammation and Regeneration, 卷 43, 編號 1, 13. https://doi.org/10.1186/s41232-023-00264-8

TY - JOUR

T1 - A lesion-selective albumin-CTLA4Ig as a safe and effective treatment for collagen-induced arthritis

AU - Jiang, Fu Yao

AU - Zhang, Yan Zhu

AU - Tai, Yuan Hong

AU - Chou, Chien Yu

AU - Hsieh, Yu Ching

AU - Chang, Ya Chi

AU - Huang, Hsiao Chen

AU - Li, Zhi Qin

AU - Hsieh, Yuan Chin

AU - Chen, I. Ju

AU - Huang, Bo Cheng

AU - Su, Yu Cheng

AU - Lin, Wen Wei

AU - Lin, Hsin Chieh

AU - Chao, Jui I.

AU - Yuan, Shyng Shiou F.

AU - Wang, Yun Ming

AU - Cheng, Tian Lu

AU - Tzou, Shey Cherng

PY - 2023/12

Y1 - 2023/12

N2 - 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.

AB - 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.

KW - Adverse effects

KW - Albumin

KW - CTLA4Ig

KW - Collagen-induced arthritis

KW - Inflammatory lesion-selective

KW - Matrix metalloproteinase (MMP)

KW - Protein engineering

UR - http://www.scopus.com/inward/record.url?scp=85148511773&partnerID=8YFLogxK

U2 - 10.1186/s41232-023-00264-8

DO - 10.1186/s41232-023-00264-8

M3 - Article

AN - SCOPUS:85148511773

SN - 1880-9693

VL - 43

JO - Inflammation and Regeneration

JF - Inflammation and Regeneration

IS - 1

M1 - 13

ER -

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

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