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