A novel interleukin-10 antibody graft to treat inflammatory bowel disease

IF 4.4 2区生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Structure Pub Date : 2025-01-10 DOI:10.1016/j.str.2024.12.010

Michael DiDonato, Carolina Turk Simpson, Todd Vo, Mark Knuth, Bernhard Geierstanger, Joanna Jamontt, David H. Jones, John W. Fathman, Donnie DeLarosa, Tobias Junt, Damien Picard, Ulrike Sommer, Morten Bagger, Eric Peters, Shelly Meeusen, Glen Spraggon

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Abstract

Inflammatory bowel disease (IBD) consists of chronic conditions that severely impact a patient’s health and quality of life. Interleukin-10 (IL-10), a potent anti-inflammatory cytokine has strong genetic links to IBD susceptibility and has shown strong efficacy in IBD rodent models, suggesting it has great therapeutic potential. However, when tested in clinical trials for IBD, recombinant human IL-10 (rhIL-10) showed weak and inconsistent efficacy due to its short half-life and pro-inflammatory properties that counteract the anti-inflammatory efficacy. Here we present an engineered, IL-10, antibody-graft therapeutic (GFT-IL10M) designed to rectify these issues. GFT-IL10M combines the half-life extension properties of a monoclonal IgG antibody with altered IL-10 cell-type selective signaling, retaining desirable signaling on monocytes while reducing unwanted signaling on T, natural killer (NK), and B cells. Our structural and biochemical results indicate that the altered IL-10 topology in GFT-IL10M leads to a predominantly anti-inflammatory profile, potentially altering cell-type specific signaling patterns and extending half-life.

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一种新型白细胞介素-10抗体移植治疗炎症性肠病

炎症性肠病（IBD）由严重影响患者健康和生活质量的慢性疾病组成。白细胞介素-10 （IL-10）是一种有效的抗炎细胞因子，与IBD易感性有很强的遗传联系，并在IBD啮齿动物模型中显示出很强的疗效，表明它具有很大的治疗潜力。然而，在IBD的临床试验中，重组人IL-10 （rhIL-10）表现出微弱且不一致的疗效，因为其半衰期短和促炎特性抵消了抗炎疗效。在这里，我们提出了一种工程化的IL-10抗体移植治疗（GFT-IL10M），旨在纠正这些问题。GFT-IL10M结合了单克隆IgG抗体的半衰期延长特性和改变的IL-10细胞型选择性信号，保留了单核细胞上所需的信号，同时减少了T细胞、自然杀伤细胞（NK）和B细胞上不需要的信号。我们的结构和生化结果表明，GFT-IL10M中IL-10拓扑结构的改变导致了主要的抗炎特征，可能改变细胞类型特异性信号模式并延长半衰期。

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来源期刊

Structure 生物-生化与分子生物学

CiteScore

8.90

自引率

1.80%

发文量

155

审稿时长

3-8 weeks

期刊介绍： Structure aims to publish papers of exceptional interest in the field of structural biology. The journal strives to be essential reading for structural biologists, as well as biologists and biochemists that are interested in macromolecular structure and function. Structure strongly encourages the submission of manuscripts that present structural and molecular insights into biological function and mechanism. Other reports that address fundamental questions in structural biology, such as structure-based examinations of protein evolution, folding, and/or design, will also be considered. We will consider the application of any method, experimental or computational, at high or low resolution, to conduct structural investigations, as long as the method is appropriate for the biological, functional, and mechanistic question(s) being addressed. Likewise, reports describing single-molecule analysis of biological mechanisms are welcome. In general, the editors encourage submission of experimental structural studies that are enriched by an analysis of structure-activity relationships and will not consider studies that solely report structural information unless the structure or analysis is of exceptional and broad interest. Studies reporting only homology models, de novo models, or molecular dynamics simulations are also discouraged unless the models are informed by or validated by novel experimental data; rationalization of a large body of existing experimental evidence and making testable predictions based on a model or simulation is often not considered sufficient.