Publisher Correction: Quantitative and organisational changes in mature extracellular matrix revealed through high-content imaging of total protein fluorescently stained in situ

Holdsworth, Gill; Bon, Hélène; Bergin, Marianne; Qureshi, Omar; Paveley, Ross A.; Atkinson, John; Huang, Linghong; Tewari, Roohi; Twomey, Breda M.; Johnson, Timothy S.

doi:10.1038/s41598-017-16513-z

Cited by 3 publications

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“…To measure effects of activity of anti-gremlin antibodies on BMP signaling, HEK- ID1 luciferase reporter cells 41 were plated in poly-D-lysine coated 96-well plates in assay media (Dulbecco’s Modified Eagle Medium [DMEM] with 0.5% fetal bovine serum [FBS], 1X L-glutamine, and 1X non-essential amino acids) and incubated at 37°C, 5% CO 2 until adhered. Antibody was prepared in assay media and titrated threefold across the plate.…”

Section: Methodsmentioning

confidence: 99%

Discovery of ginisortamab, a potent and novel anti-gremlin-1 antibody in clinical development for the treatment of cancer

Davies,

Dedi,

Jones

et al. 2023

mAbs

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Gremlin-1, a high-affinity antagonist of bone morphogenetic proteins (BMP)-2, −4, and −7, is implicated in tumor initiation and progression. Increased gremlin-1 expression, and therefore suppressed BMP signaling, correlates with poor prognosis in a range of cancer types. A lack of published work using therapeutic modalities has precluded the testing of the hypothesis that blocking the gremlin-1/BMP interaction will provide benefits to patients. To address this shortfall, we developed ginisortamab (UCB6114), a first-in-class clinical anti-human gremlin-1 antibody, currently in clinical development for the treatment of cancer, along with its murine analog antibody Ab7326 mouse immunoglobulin G1 (mIgG1). Surface plasmon resonance assays revealed that ginisortamab and Ab7326 mIgG1 had similar affinities for human and mouse gremlin-1, with mean equilibrium dissociation constants of 87 pM and 61 pM, respectively. The gremlin-1/Ab7326 antigen-binding fragment (Fab) crystal structure revealed a gremlin-1 dimer with a Fab molecule bound to each monomer that blocked BMP binding. In cell culture experiments, ginisortamab fully blocked the activity of recombinant human gremlin-1, and restored BMP signaling pathways in human colorectal cancer (CRC) cell lines. Furthermore, in a human CRC – fibroblast co-culture system where gremlin-1 is produced by the fibroblasts, ginisortamab restored BMP signaling in both the CRC cells and fibroblasts, demonstrating its activity in a relevant human tumor microenvironment model. The safety and efficacy of ginisortamab are currently being evaluated in a Phase 1/2 clinical trial in patients with advanced solid tumors (NCT04393298).

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Section: Methodsmentioning

confidence: 99%

Discovery of ginisortamab, a potent and novel anti-gremlin-1 antibody in clinical development for the treatment of cancer

Davies,

Dedi,

Jones

et al. 2023

mAbs

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SIRT1: a promising therapeutic target in type 2 diabetes mellitus

Mihanfar

Akbarzadeh

Darband

et al. 2021

Archives of Physiology and Biochemistry

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Spontaneous Extracellular Matrix Accumulation in a Human in vitro Model of Renal Fibrosis Is Mediated by αV Integrins

Bon

Hales

Lumb

et al. 2019

Nephron

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Background: Tubulointerstitial fibrosis is a key feature of chronic kidney diseases leading to renal failure. It is characterised by the infiltration of fibroblasts and aberrant accumulation of extracellular matrix (ECM) proteins, which are associated with progressive loss of renal function. Integrins play a major role in fibrosis, but the mechanisms through which they do this are not fully understood. Objective: Using a complex cell system, we test the hypothesis that integrins are pro-fibrotic via regulation of functional interactions between tubular epithelial cells and renal fibroblasts. Method: Contact co-culture of human primary renal proximal tubular epithelial cells and renal fibroblasts promoted the spontaneous accumulation of a mature ECM rich in interstitial collagens, which was considerably in excess of that seen in the individual mono-cultures. Both cell types persisted throughout the culture and were capable of expressing multiple ECM components. Results: While ECM accumulation was inhibited by the clinically proven anti-fibrotic, nintedanib, and was partially abrogated by transforming growth factor β neutralisation, its levels did not return to basal, indicating additional pathways were implicated in the pro-ECM response. Application of anti-integrin blocking antibodies and small molecules demonstrated a major role of the αV integrins in the ECM accumulation during fibroblast: epithelial cell interactions. Conclusion: Integrin-mediated pathways can facilitate the spontaneous accumulation of ECM during fibroblast: epithelial cell interactions, and this direct renal co-culture assay system could provide a translational in vitro assay for investigating novel pathways involved in the pro-ECM response and the screening of renal anti-fibrotic agents.

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Publisher Correction: Quantitative and organisational changes in mature extracellular matrix revealed through high-content imaging of total protein fluorescently stained in situ

Abstract: A correction to this article has been published and is linked from the HTML version of this paper. The error has been fixed in the paper.

Cited by 3 publications

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Discovery of ginisortamab, a potent and novel anti-gremlin-1 antibody in clinical development for the treatment of cancer

Discovery of ginisortamab, a potent and novel anti-gremlin-1 antibody in clinical development for the treatment of cancer

SIRT1: a promising therapeutic target in type 2 diabetes mellitus

Spontaneous Extracellular Matrix Accumulation in a Human in vitro Model of Renal Fibrosis Is Mediated by αV Integrins

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