A Lesion-selective Albumin-CTLA4Ig As a Safe and Effective Treatment for Collagen-induced Arthritis

Overview

Journal Inflamm Regen

Publisher Biomed Central

Date 2023 Feb 17

PMID 36797799

Authors

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

Affiliations

Soon will be listed here.

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 IgG 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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