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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 4

I-body AD-114 mitigates the upregulation of TGF-β1 and lysyl oxidase-like 2 in FA-induced kidney fibrosis.

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I-body AD-114 mitigates the upregulation of TGF-β1 and lysyl oxidase-lik...
Representative images of (A) TGF-β1–stained and (C) lysyl oxidase-like 2–stained (LOXL2-stained) kidney section. Quantitation of (B) TGF-β1 and (D) LOXL2 immunohistochemical staining. Original magnification: ×200 in all. Statistical analysis was performed using 1-way ANOVA followed by Tukey’s multiple comparisons test. Results are presented as mean ± SEM. **P < 0.01. n = 6–8.

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