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- Title
A lesion-selective albumin-CTLA4Ig as a safe and effective treatment for collagen-induced arthritis.
- Authors
Jiang, Fu-Yao; Zhang, Yan-Zhu; Tai, Yuan-Hong; Chou, Chien-Yu; Hsieh, Yu-Ching; Chang, Ya-Chi; Huang, Hsiao-Chen; Li, Zhi-Qin; Hsieh, Yuan-Chin; Chen, I-Ju; Huang, Bo-Cheng; Su, Yu-Cheng; Lin, Wen-Wei; Lin, Hsin-Chieh; Chao, Jui-I; Yuan, Shyng-Shiou F.; Wang, Yun-Ming; Cheng, Tian-Lu; Tzou, Shey-Cherng
- 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.
- Publication
Inflammation & Regeneration, 2023, Vol 43, Issue 1, p1
- ISSN
1880-8190
- Publication type
Article
- DOI
10.1186/s41232-023-00264-8