Targeting interleukin-11 signaling, an emerging patholgical mediator in thyroid eye disease

James Swaney; Toni Jun; Eric Elliott; Ivan Lu; Shira Geller; Merrick Chai; Deborah Witherden; Puneet Arora; Rona Silkiss; David King

doi:10.1530/endoabs.92.PS1-10-01

PS1-10-01

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Endocrine Abstracts (2023) 92 PS1-10-01 | DOI: 10.1530/endoabs.92.PS1-10-01

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

Err

Author affiliations

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.