title: Depletion of major pathogenic cells in asthma by targeting CRTh2.
abstract: Eosinophilic inflammation and Th2 cytokine production are central to the pathogenesis of asthma. Agents that target either eosinophils or single Th2 cytokines have shown benefits in subsets of biomarker-positive patients. More broadly effective treatment or disease-modifying effects may be achieved by eliminating more than one inflammatory stimulator. Here we present a strategy to concomitantly deplete Th2 T cells, eosinophils, basophils, and type-2 innate lymphoid cells (ILC2s) by generating monoclonal antibodies with enhanced effector function (19A2) that target CRTh2 present on all 4 cell types. Using human CRTh2 (hCRTh2) transgenic mice that mimic the expression pattern of hCRTh2 on innate immune cells but not Th2 cells, we demonstrate that anti-hCRTh2 antibodies specifically eliminate hCRTh2+basophils, eosinophils, and ILC2s from lung and lymphoid organs in models of asthma andNippostrongylus brasiliensisinfection. Innate cell depletion was accompanied by a decrease of several Th2 cytokines and chemokines. hCRTh2-specific antibodies were also active on human Th2 cells in vivo in a human Th2-PBMC-SCID mouse model. We developed humanized hCRTh2-specific antibodies that potently induce antibody-dependent cell cytotoxicity (ADCC) of primary human eosinophils and basophils and replicated the in vivo depletion capacity of their murine parent. Therefore, depletion of hCRTh2+basophils, eosinophils, ILC2, and Th2 cells with h19A2 hCRTh2-specific antibodies may be a novel and more efficacious treatment for asthma.
authors.affiliation: Department of Immunology.
authors.forename: Tao
authors.initials: T
authors.lastname: Huang
authors.affiliation: Department of Antibody Engineering.
authors.forename: Meredith
authors.initials: M
authors.lastname: Hazen
authors.affiliation: Department of Antibody Engineering.
authors.forename: Yonglei
authors.initials: Y
authors.lastname: Shang
authors.affiliation: Department of Immunology.
authors.forename: Meijuan
authors.initials: M
authors.lastname: Zhou
authors.affiliation: Department of Immunology.
authors.forename: Xiumin
authors.initials: X
authors.lastname: Wu
authors.affiliation: Department of Immunology.
authors.forename: Donghong
authors.initials: D
authors.lastname: Yan
authors.affiliation: Department of Immunology.
authors.forename: Zhonghua
authors.initials: Z
authors.lastname: Lin
authors.affiliation: Department of Pathology.
authors.forename: Margaret
authors.initials: M
authors.lastname: Solon
authors.affiliation: Department of Protein Chemistry.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Luis
authors.affiliation: Department of Pathology.
authors.forename: Hai
authors.initials: H
authors.lastname: Ngu
authors.affiliation: Department of Biochemical and Cellular Pharmacology.
authors.forename: Yongchang
authors.initials: Y
authors.lastname: Shi
authors.affiliation: Department of Immunology.
authors.forename: Arna
authors.initials: A
authors.lastname: Katewa
authors.affiliation: Department of Biomarker Discovery OMNI.
authors.forename: David F
authors.initials: DF
authors.lastname: Choy
authors.affiliation: Department of Biomarker Discovery OMNI.
authors.forename: Nandhini
authors.initials: N
authors.lastname: Ramamoorthi
authors.affiliation: Department of Protein Chemistry.
authors.forename: Erick R
authors.initials: ER
authors.lastname: Castellanos
authors.affiliation: Department of Immunology.
authors.forename: Mercedesz
authors.initials: M
authors.lastname: Balazs
authors.affiliation: Department of Immunology.
authors.forename: Min
authors.initials: M
authors.lastname: Xu
authors.affiliation: Department of Immunology.
authors.forename: Wyne P
authors.initials: WP
authors.lastname: Lee
authors.affiliation: Department of Protein Chemistry.
authors.forename: Marissa L
authors.initials: ML
authors.lastname: Matsumoto
authors.affiliation: Department of Protein Engineering, Genentech Inc., South San Francisco, California, USA.
authors.forename: Jian
authors.initials: J
authors.lastname: Payandeh
authors.affiliation: Department of Biomarker Discovery OMNI.
authors.forename: Joseph R
authors.initials: JR
authors.lastname: Arron
authors.affiliation: Department of Antibody Engineering.
authors.forename: Jo-Anne
authors.initials: JA
authors.lastname: Hongo
authors.affiliation: Department of Biochemical and Cellular Pharmacology.
authors.forename: Jianyong
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Antibody Engineering.
authors.forename: Isidro
authors.initials: I
authors.lastname: Hötzel
authors.affiliation: Department of Pathology.
authors.forename: Cary D
authors.initials: CD
authors.lastname: Austin
authors.affiliation: Department of Immunology.
authors.forename: Karin
authors.initials: K
authors.lastname: Reif
mesh_terms: D000818:Animals; D061067:Antibodies, Monoclonal, Humanized / Q000276:immunology; D000920:Antibody-Dependent Cell Cytotoxicity; D001249:Asthma / Q000628:therapy*; D001491:Basophils / Q000166:cytology; D016207:Cytokines; D004195:Disease Models, Animal; D004804:Eosinophils / Q000166:cytology; D006801:Humans; D007113:Immunity, Innate; D008168:Lung / Q000166:cytology / Q000276:immunology; D008214:Lymphocytes / Q000166:cytology; D008221:Lymphoid Tissue / Q000166:cytology / Q000276:immunology; D051379:Mice; D016513:Mice, SCID; D008822:Mice, Transgenic; D018418:Th2 Cells / Q000166:cytology*
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D016207:Cytokines