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Abstract Number: 1936

Bimekizumab Blocks T Cell-Mediated Osteogenic Differentiation of Periosteal Stem Cells: Coupling Pathological Bone Formation to IL-17A and IL-17F Signaling

Mittal Shah1,2, Ash Maroof1, Rawiya Al-Hosni2, Panagiotis Gikas3, Neil Gozzard1, Stevan Shaw1 and Scott Roberts1,2, 1UCB Pharma, Slough, United Kingdom, 2University College London, London, United Kingdom, 3The Royal National Orthopaedic Hospital, London, United Kingdom

Meeting: 2017 ACR/ARHP Annual Meeting

Date of first publication: September 18, 2017

Keywords: bone biology, cytokines, interleukins (IL), monoclonal antibodies and spondylarthritis

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Session Information

Date: Tuesday, November 7, 2017

Session Title: Biology and Pathology of Bone and Joint Poster II

Session Type: ACR Poster Session C

Session Time: 9:00AM-11:00AM

Background/Purpose: Structural tissue damage, as a result of pathological bone formation, is a major cause of disability in spondyloarthritis (SpA). A paucity of in vitro models that faithfully replicate human skeletal biology has impeded research into the cellular and molecular triggers for this osteoimmunologic phenomenon. Nevertheless, clinical and animal studies have defined IL-17 signaling as a key regulator of SpA disease; however, the role of IL-17 in bone pathology is poorly understood. IL-17-producing γδ-T cells have a critical function in periosteal bone formation for fracture repair,1 the periosteum has also been implicated in pathological bone formation in SpA disease progression.2 This study aimed to investigate IL-17 signaling in the context of pathological bone formation using a biomimetic human periosteum derived stem cell (hPDSC) model of osteogenic differentiation.

Methods: hPDSCs were obtained through enzymatic digestion of periosteal biopsies from patients undergoing orthopedic surgery. Expanded cultures were treated with recombinant human IL-17A, IL-17F, or both over 96h and expression of gene markers evaluated. hPDSCs were also stimulated using a biomimetic protocol in combination with IL‑17A and IL‑17F, or human Th17 and γδ-T-cell supernatants (SNs) (as a surrogate disease-like inflammatory milieu). Antibodies with strong-affinity to IL-17A, IL‑17F, or bimekizumab (a humanized monoclonal IgG1 antibody with strong affinity for both IL-17A and IL-17F) were used to define the role of these cytokines in the SNs. Expression of osteogenic markers and matrix mineralization was assessed to define in vitro bone formation.

Results: Under basal conditions IL-17A and IL-17F significantly up-regulated IL-6 expression and transiently enhanced the expression of the osteogenic transcription factor RUNX-2. When IL-17 cytokines were combined in a biomimetic protocol, both IL-17A and IL-17F promoted osteogenic differentiation. Following 9 days’ exposure, IL-17F enhanced the expression of most osteogenic markers to a greater extent than IL-17A alone. Conversely, IL-17A treatment resulted in elevated in vitro mineralization vs IL-17F. The SNs potently enhanced hPDSC osteogenic differentiation and mineralization. While IL-6 expression and in vitro bone formation were blocked by neutralization of IL-17A or IL-17F individually, dual neutralization with bimekizumab exhibited the greatest effect on most of the tested parameters.

Conclusion: These data show that both IL-17A and IL-17F enhance in vitro osteogenic differentiation and bone formation from hPDSCs. The source of these cytokines has not been established but may, for example, involve entheseal resident γδ-T cells. We propose that IL‑17A and IL-17F drive pathological bone formation resulting in enthesophytes at the enthesis/periosteum interface. Current therapeutics display limited efficacy in blocking enthesophyte formation, hence inhibition of both IL-17A and IL-17F with bimekizumab offers an attractive therapeutic strategy to prevent this debilitating feature of SpA.

References:

1Ono, et al. Nat Commun 2016;7:10928; 2Lories, et al. Arthritis Res Ther 2009;11:221


Disclosure: M. Shah, UCB Pharma, 3,UCB Pharma, 2; A. Maroof, UCB Pharma, 3,UCB Pharma, 9; R. Al-Hosni, None; P. Gikas, None; N. Gozzard, UCB Pharma, 3; S. Shaw, UCB Pharma, 3,UCB Pharma, 9; S. Roberts, UCB Pharma, 3.

To cite this abstract in AMA style:

Shah M, Maroof A, Al-Hosni R, Gikas P, Gozzard N, Shaw S, Roberts S. Bimekizumab Blocks T Cell-Mediated Osteogenic Differentiation of Periosteal Stem Cells: Coupling Pathological Bone Formation to IL-17A and IL-17F Signaling [abstract]. Arthritis Rheumatol. 2017; 69 (suppl 10). https://acrabstracts.org/abstract/bimekizumab-blocks-t-cell-mediated-osteogenic-differentiation-of-periosteal-stem-cells-coupling-pathological-bone-formation-to-il-17a-and-il-17f-signaling/. Accessed April 12, 2021.
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ACR Meeting Abstracts - https://acrabstracts.org/abstract/bimekizumab-blocks-t-cell-mediated-osteogenic-differentiation-of-periosteal-stem-cells-coupling-pathological-bone-formation-to-il-17a-and-il-17f-signaling/

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