Discovery, Function, and Therapeutic Targeting of Siglec-8 - PubMed (original) (raw)

Review

doi: 10.3390/cells10010019.

John Leung 1, Rustom Falahati 1, Jason Williams 1, Julia Schanin 1, Emily C Brock 1, Bhupinder Singh 1, Alan T Chang 1, Jeremy A O'Sullivan 2, Robert P Schleimer 2, Nenad Tomasevic 1, Christopher R Bebbington 1, Bruce S Bochner 2

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Review

Discovery, Function, and Therapeutic Targeting of Siglec-8

Bradford A Youngblood et al. Cells. 2020.

Abstract

Siglecs (sialic acid-binding immunoglobulin-like lectins) are single-pass cell surface receptors that have inhibitory activities on immune cells. Among these, Siglec-8 is a CD33-related family member selectively expressed on human mast cells and eosinophils, and at low levels on basophils. These cells can participate in inflammatory responses by releasing mediators that attract or activate other cells, contributing to the pathogenesis of allergic and non-allergic diseases. Since its discovery in 2000, initial in vitro studies have found that the engagement of Siglec-8 with a monoclonal antibody or with selective polyvalent sialoglycan ligands induced the cell death of eosinophils and inhibited mast cell degranulation. Anti-Siglec-8 antibody administration in vivo to humanized and transgenic mice selectively expressing Siglec-8 on mouse eosinophils and mast cells confirmed the in vitro findings, and identified additional anti-inflammatory effects. AK002 (lirentelimab) is a humanized non-fucosylated IgG1 antibody against Siglec-8 in clinical development for mast cell- and eosinophil-mediated diseases. AK002 administration has safely demonstrated the inhibition of mast cell activity and the depletion of eosinophils in several phase 1 and phase 2 trials. This article reviews the discovery and functions of Siglec-8, and strategies for its therapeutic targeting for the treatment of eosinophil- and mast cell-associated diseases.

Keywords: AK002; Siglec-8; eosinophils; glycan ligands; lirentelimab; mast cells; monoclonal antibodies.

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Conflict of interest statement

B.A.Y., J.L., R.F., J.W., J.S., E.C.B., B.S., A.T.C., N.T., and C.R.B. are current or former employees of and/or own stock and/or stock options from Allakos, Inc. J.A.O. has nothing to disclose. R.P.S. and B.S.B. receive remuneration for serving on the scientific advisory board of Allakos, Inc. and own stock in Allakos. B.S.B. receives publication-related royalty payments from Elsevier and UpToDate. R.P.S. and B.S.B. are co-inventors on existing Siglec-8–related patents and thus may be entitled to a share of royalties received by Johns Hopkins University during development and potential sales of such products. Schleimer and Bochner are also co-founders of Allakos, Inc. which makes them subject to certain restrictions under University policy. The terms of this arrangement are being managed by Johns Hopkins University and Northwestern University in accordance with their conflict of interest policies.

Figures

Figure 1

Figure 1

Summary of the in vitro and in vivo functions of Siglec-8 on eosinophils and mast cells. (Left) Eosinophil-specific activity of Siglec-8 mAbs or glycan-ligands. (Right) Mast cell-specific activity of Siglec-8 mAbs. (Bottom) Anti-inflammatory activity of targeting both eosinophils and mast cells with Siglec-8 mAbs. ADCC, antibody-dependent cellular cytotoxicity; AKC, atopic keratoconjunctivitis; CSU, chronic spontaneous urticaria; EG/EoD, eosinophilic gastritis/eosinophilic duodenitis; ISM, indolent systemic mastocytosis.

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