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

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journal contribution
posted on 30.03.2022, 04:46 by Q Cao, C Huang, H Yi, AJ Gill, A Chou, Michael FoleyMichael Foley, Christopher Hosking, Kimhour LimKimhour Lim, Cristina TriffonCristina Triffon, Y Shi, XM Chen, CA Pollock
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.

Funding

This work was supported by the National Health and Medical Research Council (NHMRC APP1142793) . QC was supported by Australian Postgraduate Award for PhD study.

History

Publication Date

22/02/2022

Journal

JCI Insight

Volume

7

Issue

4

Article Number

143018

Pagination

19p.

Publisher

American Society for Clinical Investigation

ISSN

2379-3708

Rights Statement

© 2022, Cao et al. This is an open access article published under the terms of the Creative Commons Attribution 4.0 International License.

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