An antibody that inhibits TGF-β1 release from latent extracellular matrix complexes attenuates the progression of renal fibrosis

IF 6.7 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY
Justin W. Jackson, Frederick C. Streich Jr., Ajai Pal, George Coricor, Chris Boston, Christopher T. Brueckner, Kaleigh Canonico, Christopher Chapron, Shaun Cote, Kevin B. Dagbay, Francis T. Danehy Jr., Mania Kavosi, Sandeep Kumar, Susan Lin, Christopher Littlefield, Kailyn Looby, Rohan Manohar, Constance J. Martin, Marcie Wood, Agatha Zawadzka, Stefan Wawersik, Samantha B. Nicholls, Abhishek Datta, Alan Buckler, Thomas Schürpf, Gregory J. Carven, Mohammed Qatanani, Adam I. Fogel
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引用次数: 0

Abstract

Inhibitors of the transforming growth factor–β (TGF-β) pathway are potentially promising antifibrotic therapies, but nonselective simultaneous inhibition of all three TGF-β homologs has safety liabilities. TGF-β1 is noncovalently bound to a latency-associated peptide that is, in turn, covalently bound to different presenting molecules within large latent complexes. The latent TGF-β–binding proteins (LTBPs) present TGF-β1 in the extracellular matrix, and TGF-β1 is presented on immune cells by two transmembrane proteins, glycoprotein A repetitions predominant (GARP) and leucine-rich repeat protein 33 (LRRC33). Here, we describe LTBP-49247, an antibody that selectively bound to and inhibited the activation of TGF-β1 presented by LTBPs but did not bind to TGF-β1 presented by GARP or LRRC33. Structural studies demonstrated that LTBP-49247 recognized an epitope on LTBP-presented TGF-β1 that is not accessible on GARP- or LRRC33-presented TGF-β1, explaining the antibody’s selectivity for LTBP-complexed TGF-β1. In two rodent models of kidney fibrosis of different etiologies, LTBP-49247 attenuated fibrotic progression, indicating the central role of LTBP-presented TGF-β1 in renal fibrosis. In mice, LTBP-49247 did not have the toxic effects associated with less selective TGF-β inhibitors. These results establish the feasibility of selectively targeting LTBP-bound TGF-β1 as an approach for treating fibrosis.
抑制 TGF-β1 从潜伏细胞外基质复合物中释放的抗体可减轻肾脏纤维化的进展。
转化生长因子-β(TGF-β)通路抑制剂是一种很有潜力的抗纤维化疗法,但同时抑制所有三种 TGF-β 同源物的非选择性疗法存在安全隐患。TGF-β1 与潜伏相关肽非共价结合,而潜伏相关肽又与大型潜伏复合物中的不同呈现分子共价结合。潜伏的 TGF-β 结合蛋白(LTBPs)将 TGF-β1 呈现在细胞外基质中,而 TGF-β1 则通过两种跨膜蛋白(糖蛋白 A 重复为主蛋白(GARP)和富亮氨酸重复蛋白 33(LRRC33))呈现在免疫细胞上。在这里,我们描述了 LTBP-49247 这种抗体,它能选择性地结合并抑制由 LTBPs 呈现的 TGF-β1 的活化,但不能结合由 GARP 或 LRRC33 呈现的 TGF-β1。结构研究表明,LTBP-49247 能识别由 LTBP 呈递的 TGF-β1 上的表位,而由 GARP 或 LRRC33 呈递的 TGF-β1 上的表位则无法识别,这就解释了该抗体对 LTBP 复合物 TGF-β1 的选择性。在两种不同病因的啮齿动物肾脏纤维化模型中,LTBP-49247 可减轻纤维化的进展,这表明了 LTBP 呈递的 TGF-β1 在肾脏纤维化中的核心作用。在小鼠体内,LTBP-49247 不会产生与选择性较低的 TGF-β 抑制剂相关的毒性作用。这些结果证明了选择性靶向与 LTBP 结合的 TGF-β1 作为治疗肾纤维化方法的可行性。
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来源期刊
Science Signaling
Science Signaling BIOCHEMISTRY & MOLECULAR BIOLOGY-CELL BIOLOGY
CiteScore
9.50
自引率
0.00%
发文量
148
审稿时长
3-8 weeks
期刊介绍: "Science Signaling" is a reputable, peer-reviewed journal dedicated to the exploration of cell communication mechanisms, offering a comprehensive view of the intricate processes that govern cellular regulation. This journal, published weekly online by the American Association for the Advancement of Science (AAAS), is a go-to resource for the latest research in cell signaling and its various facets. The journal's scope encompasses a broad range of topics, including the study of signaling networks, synthetic biology, systems biology, and the application of these findings in drug discovery. It also delves into the computational and modeling aspects of regulatory pathways, providing insights into how cells communicate and respond to their environment. In addition to publishing full-length articles that report on groundbreaking research, "Science Signaling" also features reviews that synthesize current knowledge in the field, focus articles that highlight specific areas of interest, and editor-written highlights that draw attention to particularly significant studies. This mix of content ensures that the journal serves as a valuable resource for both researchers and professionals looking to stay abreast of the latest advancements in cell communication science.
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