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A single-domain i-body, AD-114, attenuates renal fibrosis through blockade of CXCR4
Qinghua Cao, … , Xin-Ming Chen, Carol A. Pollock
Qinghua Cao, … , Xin-Ming Chen, Carol A. Pollock
Published January 11, 2022
Citation Information: JCI Insight. 2022;7(4):e143018. https://doi.org/10.1172/jci.insight.143018.
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Research Article Nephrology Therapeutics

A single-domain i-body, AD-114, attenuates renal fibrosis through blockade of CXCR4

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Abstract

The G protein–coupled CXC chemokine receptor 4 (CXCR4) is a candidate therapeutic target for tissue fibrosis. A fully human single-domain antibody-like scaffold i-body AD-114-PA600 (AD-114) with specific high binding affinity to CXCR4 has been developed. To define its renoprotective role, AD-114 was administrated in a mouse model of renal fibrosis induced by folic acid (FA). Increased extracellular matrix (ECM) accumulation, macrophage infiltration, inflammatory response, TGF-β1 expression, and fibroblast activation were observed in kidneys of mice with FA-induced nephropathy. These markers were normalized or partially reversed by AD-114 treatment. In vitro studies demonstrated AD-114 blocked TGF-β1–induced upregulated expression of ECM, matrix metalloproteinase-2, and downstream p38 mitogen-activated protein kinase (p38 MAPK) and PI3K/AKT/mTOR signaling pathways in a renal proximal tubular cell line. Additionally, these renoprotective effects were validated in a second model of unilateral ureteral obstruction using a second generation of AD-114 (Fc-fused AD-114, also named AD-214). Collectively, these results suggest a renoprotective role of AD-114 as it inhibited the chemotactic function of CXCR4 as well as blocked CXCR4 downstream p38 MAPK and PI3K/AKT/mTOR signaling, which establish a therapeutic strategy for AD-114 targeting CXCR4 to limit renal fibrosis.

Authors

Qinghua Cao, Chunling Huang, Hao Yi, Anthony J. Gill, Angela Chou, Michael Foley, Chris G. Hosking, Kevin K. Lim, Cristina F. Triffon, Ying Shi, Xin-Ming Chen, Carol A. Pollock

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Figure 6

Late administration of AD-114 attenuates FA-induced renal fibrosis and improves kidney function in the therapeutic mouse model.

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Late administration of AD-114 attenuates FA-induced renal fibrosis and i...
Mice were dosed daily with negative i-body, AD-114, and AMD3100 from days 7–21. (A) Representative images of H&E and Masson’s trichrome staining. (B) Representative images of COL-1– and COL-4–stained kidney sections. (C) Quantitative analysis of tubulointerstitial fibrosis from Masson’s trichrome staining using ImageJ software. (D) Quantitation of COL-1 and COL-4 immunohistochemical staining. (E) A 24-hour urine was collected at day 21, and urinary albumin and creatinine levels were detected for UACR calculation. To differentiate the preventative study, the groups targeted for therapeutic intervention are prefaced by “T/.” Original magnification: ×200 in all. Statistical analysis was performed using 1-way ANOVA followed by Tukey’s multiple comparisons test. Results were presented as mean ± SEM. *P < 0.01, **P < 0.01. n = 6–8.

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