AK002, a Humanized Sialic Acid-Binding Immunoglobulin-Like Lectin-8 Antibody that Induces Antibody-Dependent Cell-Mediated Cytotoxicity against Human Eosinophils and Inhibits Mast Cell-Mediated Anaphylaxis in Mice.
Anaphylaxis
/ immunology
Animals
Antibodies, Monoclonal, Humanized
/ immunology
Antibody-Dependent Cell Cytotoxicity
/ immunology
Antigens, CD
/ immunology
Antigens, Differentiation, B-Lymphocyte
/ immunology
Basophils
/ immunology
Eosinophils
/ immunology
Humans
Lectins
/ immunology
Mast Cells
/ immunology
Mice
N-Acetylneuraminic Acid
/ immunology
Receptors, IgG
/ immunology
AK002
Anaphylaxis
Antibody-dependent cell-mediated cytotoxicity
Eosinophils
Mast cells
Sialic acid-binding immunoglobulin-like lectin-8
Journal
International archives of allergy and immunology
ISSN: 1423-0097
Titre abrégé: Int Arch Allergy Immunol
Pays: Switzerland
ID NLM: 9211652
Informations de publication
Date de publication:
2019
2019
Historique:
received:
07
05
2019
accepted:
19
06
2019
pubmed:
12
8
2019
medline:
5
11
2019
entrez:
12
8
2019
Statut:
ppublish
Résumé
Pathologic accumulation and activation of mast cells and eosinophils are implicated in allergic and inflammatory diseases. Sialic acid-binding immunoglobulin-like lectin (Siglec)-8 is an inhibitory receptor selectively expressed on mast cells, eosinophils and, at a lower extent, basophils. When engaged with an antibody, Siglec-8 can induce apoptosis of activated eosinophils and inhibit mast cell activation. AK002 is a humanized, non-fucosylated IgG1 anti-Siglec-8 antibody undergoing clinical investigation for treatment of allergic, inflammatory, and proliferative diseases. Here we examine the human tissue selectivity of AK002 and evaluate the in vitro, ex vivo, and in vivo activity of AK002 on eosinophils and mast cells. The affinity of AK002 for Siglec-8 and CD16 was determined by biolayer interferometry. Ex vivo activity of AK002 on human eosinophils from blood and dissociated human tissue was tested in apoptosis and antibody-dependent cell-mediated cytotoxicity (ADCC) assays. The in vivo activity of a murine precursor of AK002 (mAK002) was tested in a passive systemic anaphylaxis (PSA) humanized mouse model. AK002 bound selectively to mast cells, eosinophils and, at a lower level, to basophils in human blood and tissue and not to other cell types examined. AK002 induced apoptosis of interleukin-5-activated blood eosinophils and demonstrated potent ADCC activity against blood eosinophils in the presence of natural killer cells. AK002 also significantly reduced eosinophils in dissociated human lung tissue. Furthermore, mAK002 prevented PSA in humanized mice through mast cell inhibition. AK002 selectively evokes potent apoptotic and ADCC activity against eosinophils and prevents systemic anaphylaxis through mast cell inhibition.
Identifiants
pubmed: 31401630
pii: 000501637
doi: 10.1159/000501637
pmc: PMC6878738
doi:
Substances chimiques
AK002
0
Antibodies, Monoclonal, Humanized
0
Antigens, CD
0
Antigens, Differentiation, B-Lymphocyte
0
Lectins
0
Receptors, IgG
0
SIGLEC8 protein, human
0
N-Acetylneuraminic Acid
GZP2782OP0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
91-102Subventions
Organisme : NIAID NIH HHS
ID : R01 AI132963
Pays : United States
Informations de copyright
© 2019 The Author(s)Published by S. Karger AG, Basel.
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