Sialic acid-binding immunoglobulin-like lectin (Siglec) 8 in patients with eosinophilic disorders: Receptor expression and targeting using chimeric antibodies

JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY

卷:143

Article

Legrand, Fanny¹  Cao, Yun³  Wechsler, Joshua B.⁴  Zhu, Xiang^5,6  Zimmermann, Nives^5,6  Rampertaap, Shakuntala⁷  Monsale, Joseph⁷  Romito, Kimberly⁷  Youngblood, Bradford A.⁹  Brock, Emily C.⁹  Makiya, Michelle A.¹  Tomasevic, Nenad⁹  Bebbington, Christopher⁹  Maric, Irina⁸  Metcalfe, Dean D.²  Bochner, Bruce S.³  Klion, Amy D.¹ 

[1] NIAID, Lab Parasit Dis, Human Eosinophil Sect, 9000 Rockville Pike, Bethesda, MD 20892 USA

[2] NIAID, Mast Cell Biol Sect, Lab Allerg Dis, 9000 Rockville Pike, Bethesda, MD 20892 USA

[3] Northwestern Univ, Dept Med, Div Allergy & Immunol, Feinberg Sch Med, Chicago, IL 60611 USA

[4] Ann & Robert H Lurie Childrens Hosp Chicago, Div Pediat Gastroenterol Hepatol & Nutr, Chicago, IL 60611 USA

[5] Cincinnati Childrens Hosp Med Ctr, Div Allergy & Immunol, Cincinnati, OH 45229 USA

[6] Univ Cincinnati, Dept Pediat, Coll Med, Cincinnati, OH 45221 USA

[7] NIH, Dept Lab Med, Warren Magnusson Clin Ctr, Bldg 10, Bethesda, MD 20892 USA

[8] NIH, Hematol Sect, Dept Lab Med, Clin Ctr, Bldg 10, Bethesda, MD 20892 USA

[9] Allakos Inc, San Carlos, CA USA

关键词: Siglec-8;    eosinophil;    mast cell;    soluble receptor;    inhibitory receptor;    apoptosis;    hypereosinophilic syndrome;    eosinophilic gastrointestinal disease;    mastocytosis;    monoclonal antibody;   

DOI  :  10.1016/j.jaci.2018.10.066

来源: Elsevier

【 摘 要 】

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: We sought to characterize surface and soluble Siglec-8 (sSiglec-8) levels in normal donors (NDs) and eosinophilic donors (EOs) and assess the efficacy of anti-Siglec-8 antibodies in inducing eosinophil cell death in vitro. Methods: Eosinophil expression of Siglec-8 was assessed by using flow cytometry and quantitative PCR. Serum sSiglec-8 levels were measured by means of ELISA. Induction of eosinophil death by IgG(4) (chimeric 2E2 IgG(4)) and afucosylated IgG(1) (chimeric 2E2 IgG(1) [c2E2 IgG(1)]) anti-Siglec-8 antibodies was evaluated in vitro by using flow cytometry and in vivo in humanized mice. Results: Siglec-8 was consistently expressed on eosinophils from NDs and EOs and did not correlate with absolute eosinophil count or disease activity. sSiglec-8 levels were measurable in sera from most donors unrelated to absolute eosinophil counts or Siglec-8 surface expression. c2E2 IgG(1) and chimeric 2E2 IgG(4) were equally effective at inducing cell death (Annexin-V positivity) of purified eosinophils from NDs and EOs after overnight IL-5 priming. In contrast, killing of purified eosinophils without IL-5 was only seen in EOs, and natural killer cell-mediated eosinophil killing was seen only with c2E2 IgG(1). 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 EOs and NDs and represents a potential therapeutic target for eosinophilic disorders. Enhanced killing of eosinophils in the presence of IL-5 might lead to increased efficacy in patients with IL-5-driven eosinophilia.

【 授权许可】

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