The dual IGF-1R/IR blocker, Linsitinib, modulates human orbital fibroblast activity and proliferation
- 1Molecular Thyroid Research Laboratory, Department of Medicine I, Johannes Gutenberg-University (JGU) Medical Center , ,
- 2Sling Therapeutics , , ,
Abstract
Aim: The insulin-like growth factor-1 receptor (IGF-1R) and its downstream signaling pathways drive proliferation, survival, and extracellular matrix production, representing key therapeutic targets in thyroid eye disease (TED). This novel in vitro study investigated the inhibitory effects of the dual IGF-1R/insulin receptor small-molecule inhibitor Linsitinib on orbital target cell activity, proliferation, and survival.
Methods: Human orbital fibroblasts (OF) were pre-treated with increasing doses of Linsitinib and stimulated with 100 ng/mL IGF-1 to quantify hyaluronic acid (HA) and pro-collagen in supernatants via ELISA. Intracellular protein kinase B (AKT) phosphorylation at Serine 473 was quantified in cell lysates. Additionally, an equimolar comparison between Linsitinib and the anti-IGF-1R monoclonal antibody Teprotumumab was performed in IGF-1R-expressing cells. Proliferation was assessed both microscopically and by tetrazolium assay, while apoptosis was evaluated by caspase-3/7 activity.
Results: Linsitinib markedly suppressed IGF-1-induced HA and pro-collagen secretion, with TED OF showing significantly greater sensitivity and exclusive morphological evidence of apoptosis compared to control OF. Linsitinib effectively inhibited IGF-1-induced AKT phosphorylation to baseline levels in OF. Equimolar comparison in IGF-1R-expressing cells demonstrated that Linsitinib outperformed Teprotumumab in inhibiting cell proliferation across most tested concentrations, whereas Teprotumumab showed higher potency only at the lowest concentrations. While Teprotumumab failed to induce cell death, Linsitinib triggered robust activity of the apoptosis markers caspase-3/7. Morphologically, in contrast to Teprotumumab, Linsitinib induced dose-dependent changes characterized by cellular contraction and formation of gaps in the monolayer.
Conclusion: Linsitinib reverses OF activation through intracellular kinase blockade while outperforming Teprotumumab in equimolar comparison. These findings highlight the role of Linsitinib as a potent, dual-targeted therapy for TED.
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BibTeX
@article{luffy2026dual,
title = {{The dual IGF-1R/IR blocker, Linsitinib, modulates human orbital fibroblast activity and proliferation}},
author = {Maximilian Luffy and Stefanie Wagner and Jan Wolf and Anna-Lena Ganz and Xaver Michels and Ryan Zeidan and Jeffrey D. Kent and Raymond S. Douglas and George J. Kahaly},
journal = {Frontiers in immunology},
year = {2026},
month = oct,
doi = {10.3389/fimmu.2026.1920590},
url = {https://europepmc.org/article/PMC/PMC13673414},
note = {CC BY},
}
RIS
TY - JOUR
TI - The dual IGF-1R/IR blocker, Linsitinib, modulates human orbital fibroblast activity and proliferation
AU - Maximilian Luffy
AU - Stefanie Wagner
AU - Jan Wolf
AU - Anna-Lena Ganz
AU - Xaver Michels
AU - Ryan Zeidan
AU - Jeffrey D. Kent
AU - Raymond S. Douglas
AU - George J. Kahaly
PY - 2026
DA - 2026/10/02
JO - Frontiers in immunology
DO - 10.3389/fimmu.2026.1920590
UR - https://europepmc.org/article/PMC/PMC13673414
AB - Aim: The insulin-like growth factor-1 receptor (IGF-1R) and its downstream signaling pathways drive proliferation, survival, and extracellular matrix production, representing key therapeutic targets in thyroid eye disease (TED). This novel in vitro study investigated the inhibitory effects of the dual IGF-1R/insulin receptor small-molecule inhibitor Linsitinib on orbital target cell activity, proliferation, and survival. Methods: Human orbital fibroblasts (OF) were pre-treated with increasing doses of Linsitinib and stimulated with 100 ng/mL IGF-1 to quantify hyaluronic acid (HA) and pro-collagen in supernatants via ELISA. Intracellular protein kinase B (AKT) phosphorylation at Serine 473 was quantified in cell lysates. Additionally, an equimolar comparison between Linsitinib and the anti-IGF-1R monoclonal antibody Teprotumumab was performed in IGF-1R-expressing cells. Proliferation was assessed both microscopically and by tetrazolium assay, while apoptosis was evaluated by caspase-3/7 activity. Results: Linsitinib markedly suppressed IGF-1-induced HA and pro-collagen secretion, with TED OF showing significantly greater sensitivity and exclusive morphological evidence of apoptosis compared to control OF. Linsitinib effectively inhibited IGF-1-induced AKT phosphorylation to baseline levels in OF. Equimolar comparison in IGF-1R-expressing cells demonstrated that Linsitinib outperformed Teprotumumab in inhibiting cell proliferation across most tested concentrations, whereas Teprotumumab showed higher potency only at the lowest concentrations. While Teprotumumab failed to induce cell death, Linsitinib triggered robust activity of the apoptosis markers caspase-3/7. Morphologically, in contrast to Teprotumumab, Linsitinib induced dose-dependent changes characterized by cellular contraction and formation of gaps in the monolayer. Conclusion: Linsitinib reverses OF activation through intracellular kinase blockade while outperforming Teprotumumab in equimolar comparison. These findings highlight the role of Linsitinib as a potent, dual-targeted therapy for TED.
SN - 1664-3224
ER -