Sialic acid–binding immunoglobulin-like lectin (Siglec) 8 in patients with eosinophilic disorders: Receptor expression and targeting using chimeric antibodies - 06/06/19
, Yun Cao, MS b, Joshua B. Wechsler, MD c, Xiang Zhu, PhD d, Nives Zimmermann, MD d, Shakuntala Rampertaap, MT/ASCP e, Joseph Monsale, MT/ASCP e, Kimberly Romito, MT/ASCP e, Bradford A. Youngblood, PhD f, Emily C. Brock, MSc f, Michelle A. Makiya, MSc a, Nenad Tomasevic, PhD f, Christopher Bebbington, PhD f, Irina Maric, MD g, Dean D. Metcalfe, MD h, Bruce S. Bochner, MD b, Amy D. Klion, MD a, ⁎ 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 |
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 IgG4 (chimeric 2E2 IgG4) and afucosylated IgG1 (chimeric 2E2 IgG1 [c2E2 IgG1]) 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 IgG1 and chimeric 2E2 IgG4 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 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 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.
Le texte complet de cet article est disponible en PDF.Graphical abstract |
Key words : Siglec-8, eosinophil, mast cell, soluble receptor, inhibitory receptor, apoptosis, hypereosinophilic syndrome, eosinophilic gastrointestinal disease, mastocytosis, monoclonal antibody
Abbreviations used : 7-AAD, ADCC, AEC, CHO, c2E2 IgG4, c2E2 IgG1, EAD, EO, EoE, EPX, GM, HES, IRB, ND, NK, Siglec, SM, sSiglec-8, VLA4
Plan
| Supported in part by the Division of Intramural Research, National Institute of Allergy and Infectious Diseases/National Institutes of Health (NIH). Development of the soluble Siglec-8 ELISA in the Bochner laboratory was supported in part by NIH grant AI097073. Collection of patient specimens/data at the Ann & Robert H. Lurie Children's Hospital funded by the American Partnership for Eosinophilic Diseases (APFED) and Buckeye Foundation. J.B.W. is funded by K08 1K08DK097721-01. Anti–Siglec-8 antibodies and funding for N.Z. for this project were provided by Allakos, Inc. |
|
| Disclosure of potential conflict of interest: B. A. Youngblood, E. C. Brock, N. Tomasevic, and C. Bebbington are full-time employees of Allakos, Inc. B. S. Bochner has current consulting and scientific advisory board arrangements with Allakos, Inc, and owns stock in Allakos, Inc; is a coinventor on existing Siglec-8–related patents and thus might be entitled to a share of royalties received by Johns Hopkins University on the potential sales of such products; and is a cofounder of Allakos, Inc, which makes him subject to certain restrictions under university policy (the terms of this arrangement are being managed by the Johns Hopkins University and Northwestern University in accordance with their conflict of interest policies). The rest of the authors declare that they have no relevant conflicts of interest. |
Vol 143 - N° 6
P. 2227 - juin 2019 Retour au numéro
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