Development of a cyst-targeted therapy for polycystic kidney disease using an antagonistic dimeric IgA monoclonal antibody against cMET.

IF 10.6 1区医学 Q1 CELL BIOLOGY

Cell Reports Medicine Pub Date : 2025-09-16 Epub Date: 2025-09-05 DOI:10.1016/j.xcrm.2025.102335

Margaret F Schimmel, Bryan C Bourgeois, Alison K Spindt, Sage A Patel, Tiffany Chin, Gavin E Cornick, Yuqi Liu, Thomas Weimbs

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引用次数: 0

Abstract

Polycystic kidney disease (PKD) is characterized by the development of fluid-filled kidney cysts and relentless progression to renal failure. Current treatments have adverse effects and limited efficacy, enhancing the need for improved therapeutics. Here, we provide a proof of concept for the use of dimeric immunoglobulin A (IgA) (dIgA) monoclonal antibodies (mAbs) to target epithelial-enclosed cysts, by exploiting their ability to transcytose via the polymeric immunoglobulin receptor highly expressed on renal cyst-lining cells. We engineered an antagonistic dIgA mAb against the cell mesenchymal-epithelial transition (cMET) receptor, a driver of cyst progression, and demonstrated its specific binding and inhibition of cMET in vitro. In vivo studies in PKD rodent models showed efficient targeting of the mAb to renal cyst lumens and its ability to slow disease progression without apparent adverse effects. This study presents an intriguing avenue for developing antibody-based therapies for PKD and similar diseases by repurposing existing immunoglobulin G (IgG) mAbs into dIgA mAbs for superior targeting to epithelial-enclosed compartments.

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利用抗cMET二聚体IgA单克隆抗体治疗多囊肾病的研究进展

多囊肾病（PKD）的特点是发展为充满液体的肾囊肿和无情的进展到肾功能衰竭。目前的治疗方法有不良反应且疗效有限，因此需要改进治疗方法。在这里，我们提供了使用二聚体免疫球蛋白a (IgA) （dIgA）单克隆抗体（mab）靶向上皮封闭囊肿的概念证明，利用它们通过肾囊肿衬里细胞上高度表达的聚合免疫球蛋白受体转糖的能力。我们设计了一种针对细胞间充质上皮转化（cMET）受体的拮抗dIgA单抗，该受体是囊肿进展的驱动因素，并在体外证明了其对cMET的特异性结合和抑制。在PKD啮齿动物模型中进行的体内研究表明，单抗可有效靶向肾囊肿管腔，并具有减缓疾病进展而无明显不良反应的能力。这项研究提出了一种有趣的途径，通过将现有的免疫球蛋白G （IgG）单克隆抗体改造成dIgA单克隆抗体，以更好地靶向上皮封闭区室，开发基于抗体的治疗PKD和类似疾病的方法。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Cell Reports Medicine Biochemistry, Genetics and Molecular Biology-Biochemistry, Genetics and Molecular Biology (all)

CiteScore

15.00

自引率

1.40%

发文量

231

审稿时长

40 days

期刊介绍： Cell Reports Medicine is an esteemed open-access journal by Cell Press that publishes groundbreaking research in translational and clinical biomedical sciences, influencing human health and medicine. Our journal ensures wide visibility and accessibility, reaching scientists and clinicians across various medical disciplines. We publish original research that spans from intriguing human biology concepts to all aspects of clinical work. We encourage submissions that introduce innovative ideas, forging new paths in clinical research and practice. We also welcome studies that provide vital information, enhancing our understanding of current standards of care in diagnosis, treatment, and prognosis. This encompasses translational studies, clinical trials (including long-term follow-ups), genomics, biomarker discovery, and technological advancements that contribute to diagnostics, treatment, and healthcare. Additionally, studies based on vertebrate model organisms are within the scope of the journal, as long as they directly relate to human health and disease.