Siglec-8 in eosinophilic disorders: receptor expression and targeting using chimeric antibodies.

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Siglec-8 in eosinophilic disorders: receptor expression and targeting using chimeric antibodies.

J Allergy Clin Immunol. 2018 Dec 10;:

Authors: Legrand F, Cao Y, Wechsler J, Zhu X, Zimmermann N, Rampertaap S, Monsale J, Romito K, Youngblood BA, Brock EC, Makiya M, Tomasevic N, Bebbington C, Maric I, Metcalfe DD, Bochner BS, Klion AD

Abstract
BACKGROUND: Sialic acid-binding immunoglobulin-like lectin (Siglec)-8 is selectively expressed on eosinophils, mast cells and basophils, and, when engaged on eosinophils, can cause cell death.
OBJECTIVE: To characterize surface and soluble Siglec-8 levels in normal (ND) and eosinophilic (EO) subjects and assess the efficacy of anti-Siglec-8 antibodies in inducing eosinophil cell death in vitro.
METHODS: Eosinophil expression of Siglec-8 was assessed using flow cytometry and quantitative PCR. Serum soluble Siglec-8 levels were measured by ELISA. Induction of eosinophil death by IgG4 (c2E2 IgG4) and afucosylated IgG1 (c2E2 IgG1) anti-Siglec-8 antibodies was evaluated in vitro by flow cytometry and in vivo in humanized mice.
RESULTS: Siglec-8 was consistently expressed on eosinophils from ND and EO and did not correlate with absolute eosinophil count (AEC) or disease activity. Soluble Siglec-8 levels were measurable in serum from most donors, unrelated to AEC or Siglec-8 surface expression. c2E2 IgG1 and c2E2 IgG4 were equally effective at inducing cell death (Annexin-V positivity) of purified eosinophils from ND and EO after overnight IL-5 priming. In contrast, killing of purified eosinophils without IL-5 was only seen in EO subjects, and NK-mediated eosinophil killing was seen only with c2E2 IgG1. Finally, treatment of humanized mice with anti-Siglec antibody led to robust depletion of IL-5-induced eosinophilia in vivo.
CONCLUSIONS: Siglec-8 is highly expressed on blood eosinophils from EO and ND and represents a potential therapeutic target for eosinophilic disorders. Enhanced killing of eosinophils in the presence of IL-5 may lead to increased efficacy in patients with IL-5-driven eosinophilia.

PMID: 30543818 [PubMed - as supplied by publisher]

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