ETA2023 Poster Presentations Basic Thyroid Gland, Iodine & Autoimmunity Basic (9 abstracts)
Targeting interleukin-11 signaling, an emerging patholgical mediator in thyroid eye disease
James Swaney 1 , Toni Jun 2 , Eric Elliott 2 , Ivan Lu 2 , Shira Geller 2 , Merrick Chai 2 , Deborah Witherden 2 , Puneet Arora 2 , Rona Silkiss 3 & David King 2
1Lassen Therapeutics, Biology, San Diego, United States; 2Lassen Therapeutics, San Diego, United States; 3Silkiss Eye Surgery, Oakland, United States
Objectives: Thyroid eye disease (TED) is considered a fibroinflammatory disease with pathology related to both inflammatory and fibrotic disease processes. IL-11 is a fibroinflammatory cytokine that is linked to tissue fibrosis of the lung, skin, heart, kidney and liver. Recently, IL-11 was identified as a possible disease modifier in TED. IL-11 levels are increased in TED patient plasma, in correlation with disease severity, and IL-11 stimulates phenotypic switching of orbital tissue-derived cells to pro-fibrotic myofibroblasts. We have further evaluated the role of IL-11 in the activation of human TED patient derived orbital fibroblasts to determine if IL-11 may play a pathologic role. LASN01 is a fully human, clinical stage antibody to IL-11R which potently blocks IL-11 signaling and is an investigational therapeutic agent for fibroinflammatory diseases. We have investigated the ability of LASN01 to reverse IL-11 driven pathologies in TED.
Methods: Orbital adipose/connective tissue was obtained from control (n =2) and TED patients (n =7) following orbital decompression surgery and used to isolate orbital fibroblasts (OFs). The effects of IL-11R blockade with LASN01 on the release of hyaluronic acid, a driver of TED progression, cell proliferation, and collagen expression were examined in response to stimulation with IL-11 or other stimuli. Cellular expression/release of IL-11 and IL-11R were also compared between control cells and TED-derived orbital fibroblasts.
Results: IL-11 gene expression is increased in TED fibroblasts relative to control cells and is induced by fibroinflammatory mediators IL-1β and TGFβ. IL-11 induces proliferation of TED OFs as well as secretion of hyaluronan (HA). LASN01 can effectively block IL-11 induced proliferation and HA production by TED-derived OFs. Although some donor variability was observed, LASN01 can inhibit IGF-1 stimulation of orbital fibroblasts and may affect the pathway downstream of the FDA approved therapeutic agent, teprotumumab.
Conclusion: LASN01 has the potential for differentiated therapeutic efficacy through the inhibition the IL-11R and the inhibition of HA release and anti-fibrotic activity. LASN01 is worthy of further investigation as a potential treatment of TED.
Volume 92
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Endocrine Abstracts
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