Randomized, double-blind, placebo-controlled trial of CCR9-targeted leukapheresis treatment of ulcerative colitis patients

Eberhardson, Michael; Karlén, Per; Linton, Ludvig; Jones, Philip C.; Lindberg, Annelie; Kostalla, Martina Jones; Lindh, Erik; Odén, Anders; Glise, Hans; Winqvist, Ola

doi:10.1093/ecco-jcc/jjw196

Cited by 12 publications

(8 citation statements)

References 42 publications

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“… 45 This led to a subsequent double-blind placebo-controlled trial of leukapheresis to deplete CCR9 + monocytes in ulcerative colitis, which was associated with improvement in the endoscopic Mayo score compared with placebo ( Table 2 ). 56 …”

Section: Ccr9 and Ccl25mentioning

confidence: 99%

Chemokines and Chemokine Receptors as Therapeutic Targets in Inflammatory Bowel Disease; Pitfalls and Promise

Trivedi

Adams

2018

Journal of Crohn's and Colitis

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The principal targets for anti-chemokine therapy in inflammatory bowel disease (IBD) have been the receptors CCR9 and CXCR3 and their respective ligands CCL25 and CXCL10. More recently CCR6 and its ligand CCL20 have also received attention, the expression of the latter in enterocytes being manipulated through Smad7 signalling. These pathways, selected based on their fundamental role in regulating mucosal immunity, have led to the development of several therapeutic candidates that have been tested in early phase clinical trials with variable clinical efficacy. In this article, we appraise the status of chemokine-directed therapy in IBD, review recent developments, and nominate future areas for therapeutic focus.

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Section: Ccr9 and Ccl25mentioning

confidence: 99%

Chemokines and Chemokine Receptors as Therapeutic Targets in Inflammatory Bowel Disease; Pitfalls and Promise

Trivedi

Adams

2018

Journal of Crohn's and Colitis

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“…MST experiments were performed in the Centre for Macromolecular Interactions at Harvard Medical School. Curve fit formula: CCR9 QTY -Fc versus CCL25~8 (Eberhardson et al, 2017) 37.2 AE 15.7…”

Section: Microscale Thermophoresismentioning

confidence: 99%

QTY Code-designed Water-soluble Fc-fusion Cytokine Receptors Bind to their Respective Ligands

Hao

Jin²,

Zhang

et al. 2020

QRB Discovery

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Cytokine release syndrome (CRS), or ‘cytokine storm’, is the leading side effect during chimeric antigen receptor (CAR)-T therapy that is potentially life-threatening. It also plays a critical role in viral infections such as Coronavirus Disease 2019 (COVID-19). Therefore, efficient removal of excessive cytokines is essential for treatment. We previously reported a novel protein modification tool called the QTY code, through which hydrophobic amino acids Leu, Ile, Val and Phe are replaced by Gln (Q), Thr (T) and Tyr (Y). Thus, the functional detergent-free equivalents of membrane proteins can be designed. Here, we report the application of the QTY code on six variants of cytokine receptors, including interleukin receptors IL4Rα and IL10Rα, chemokine receptors CCR9 and CXCR2, as well as interferon receptors IFNγR1 and IFNλR1. QTY-variant cytokine receptors exhibit physiological properties similar to those of native receptors without the presence of hydrophobic segments. The receptors were fused to the Fc region of immunoglobulin G (IgG) protein to form an antibody-like structure. These QTY code-designed Fc-fusion receptors were expressed in Escherichia coli and purified. The resulting water-soluble fusion receptors bind to their respective ligands with Kd values affinity similar to isolated native receptors. Our cytokine receptor–Fc-fusion proteins potentially serve as an antibody-like decoy to dampen the excessive cytokine levels associated with CRS and COVID-19 infection.

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“…By blocking physiologic CCL25/CCR9 interactions using CCL25‐conjugated Sepharose beads, intestinal inflammation was found to be alleviated in IBD patients by selectively deleting CCR9+ monocytes 22,23 . Similarly, in a clinical trial for ulcerative colitis, CCL25‐conjugated Sepharose beads have been found to decrease the number of circulating HLA‐DR hi inflammatory monocytes with no obvious adverse side effect 24 . Recently, IECs were found to serve as a major source of a novel CCR2 ligand: PC3‐secreted microprotein (PSMP), which mediates the infiltration of Ly6C hi monocytes into colon, resulting in colitis development.…”

Section: Crosstalk Between Iecs and Imφsmentioning

confidence: 99%

Macrophage orchestration of epithelial and stromal cell homeostasis in the intestine

Cao

Mertens

Sivanathan

et al. 2022

Journal of Leukocyte Biology

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The intestinal tract is a complex ecosystem where numerous cell types of epithelial, immune, neuronal, and endothelial origin coexist in an intertwined, highly organized manner. The functional equilibrium of the intestine relies heavily on the proper crosstalk and cooperation among each cell population. Furthermore, macrophages are versatile, innate immune cells that participate widely in the modulation of inflammation and tissue remodeling. Emerging evidence suggest that macrophages are central in orchestrating tissue homeostasis. Herein, we describe how macrophages interact with epithelial cells, neurons, and other types of mesenchymal cells under the context of intestinal inflammation, followed by the therapeutic implications of cellular crosstalk pertaining to the treatment of inflammatory bowel disease.

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Randomized, double-blind, placebo-controlled trial of CCR9-targeted leukapheresis treatment of ulcerative colitis patients

Abstract: This clinical induction trial using CCL25-tailored leukapheresis demonstrates a safe and effective removal of activated monocytes with a clinical effect in patients with ulcerative colitis.

Cited by 12 publications

References 42 publications

Chemokines and Chemokine Receptors as Therapeutic Targets in Inflammatory Bowel Disease; Pitfalls and Promise

Chemokines and Chemokine Receptors as Therapeutic Targets in Inflammatory Bowel Disease; Pitfalls and Promise

QTY Code-designed Water-soluble Fc-fusion Cytokine Receptors Bind to their Respective Ligands

Macrophage orchestration of epithelial and stromal cell homeostasis in the intestine

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