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*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

3 Scopus citations

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.

Original languageEnglish
Article number13
JournalInflammation and Regeneration
Volume43
Issue number1
DOIs
StatePublished - Dec 2023

Keywords

  • Adverse effects
  • Albumin
  • Collagen-induced arthritis
  • CTLA4Ig
  • Inflammatory lesion-selective
  • Matrix metalloproteinase (MMP)
  • Protein engineering

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