The eosinophil surface receptor epidermal growth factor–like module containing mucin- like hormone receptor 1 (EMR1): A novel therapeutic target for eosinophilic.

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The eosinophil surface receptor epidermal growth factor–like module containing mucin- like hormone receptor 1 (EMR1): A novel therapeutic target for eosinophilic disorders Fanny Legrand, PhD, PharmD, Nenad Tomasevic, PhD, Olga Simakova, PhD, Chyi-Chia Richard Lee, MD, PhD, Zengfang Wang, PhD, Mark Raffeld, MD, Michelle A. Makiya, MS, Varghese Palath, PhD, John Leung, BS, Mark Baer, PhD, Geoffrey Yarranton, PhD, Irina Maric, MD, Christopher Bebbington, PhD, Amy D. Klion, MD Journal of Allergy and Clinical Immunology Volume 133, Issue 5, Pages 1439-1447.e8 (May 2014) DOI: 10.1016/j.jaci.2013.11.041 Copyright © 2014 Terms and Conditions

Fig 1 EMR1 is expressed exclusively on eosinophils. A and B, Representative staining of eosinophils with anti-EMR1 antibody in bone marrow (Fig 1, A) and blood (Fig 1, B) from a subject with HES. FITC, Fluorescein isothiocyanate; FSC, forward scatter; PE, phycoerythrin; SSC, side scatter. C-E, Absence of EMR1 expression on cells other than eosinophils in bone marrow (Fig 1, C) and peripheral blood (Fig 1, D) and in cell lines (Fig 1, E). The CHOK1SV cell line (CHO cells transfected with EMR1) is shown as a positive control. Journal of Allergy and Clinical Immunology 2014 133, 1439-1447.e8DOI: (10.1016/j.jaci.2013.11.041) Copyright © 2014 Terms and Conditions

Fig 2 EMR1 is expressed late in eosinophil development. A and B, Surface expression of IL-5Rα, but not EMR1, is detected on CD34+ cells in bone marrow from a patient with HES (Fig 2, A) and on purified CD34+ cells isolated from peripheral blood (Fig 2, B). FITC, Fluorescein isothiocyanate; PE, phycoerythrin; SSC, side scatter. C and D, In vitro differentiation of CD34+ cells. Fast Green/Neutral Red staining of cultured CD34+ cells 2 days before (Fig 2, C) and 21 days after (Fig 2, D) the addition of IL-5 is shown. The arrow indicates a mature eosinophil with bilobed red nucleus and green secondary granules. E, Surface expression of EMR1 and CD34 as a function of time. Δmfi, Change in mean fluorescence intensity. F and G, mRNA expression as a function of time for EPX, MBP, and EDN (Fig 2, F, left axis); ECP (Fig 2, F, right axis); EMR1 and Siglec-8 (Fig 2, G, left axis); and IL-5RA (Fig 2, G, right axis). Journal of Allergy and Clinical Immunology 2014 133, 1439-1447.e8DOI: (10.1016/j.jaci.2013.11.041) Copyright © 2014 Terms and Conditions

Fig 3 EMR1 expression on tissue eosinophils. A-C, Skin biopsy specimen from a subject with HES. Frozen section stained with antibody to EMR1 (Fig 3, A) is shown. Adjacent paraffin-embedded sections stained with antibody to EPX (Fig 3, B) and hematoxylin and eosin (Fig 3, C) showing eosinophilic infiltration and degranulation are also presented. The arrows indicate representative eosinophils (Fig 3, C). Fig 3, A and B, Original magnification ×600 and ×100 (Fig 3, C). D-I, Nasal polyp biopsy specimen. Immunofluorescence staining of EMR1 in red (Fig 3, D and G), EPX (Fig 3, E) or CD68 (Fig 3, H) in green, and an overlay (Fig 3, F and I) showing EMR1 staining on eosinophils and not on macrophages is shown. Original magnification ×640. Journal of Allergy and Clinical Immunology 2014 133, 1439-1447.e8DOI: (10.1016/j.jaci.2013.11.041) Copyright © 2014 Terms and Conditions

Fig 4 EMR1 expression in eosinophils is correlated with AECs. A, Surface expression of EMR1 on eosinophils in whole blood expressed as the change in mean fluorescence intensity (Δmfi) in healthy donors (ND), untreated subjects with eosinophilia (EOS), and treated subjects with eosinophilia (EOS Rx). GMs with 95% CIs are indicated by horizontal lines. *P < .05 versus healthy donors. B-D, Correlation of surface expression of EMR1 (Δmfi), plasma levels of sEMR1 (in picograms per milliliter), and EMR1 mRNA levels (expressed as arbitrary units relative to 18S rRNA) with AECs. An AEC of less than 500/mm3 is indicated by gray shading. Each symbol represents data for an individual donor. Healthy donors are indicated by open circles, eosinophilic subjects receiving no treatment are indicated by black circles, and eosinophilic subjects receiving therapy are indicated by gray circles. Journal of Allergy and Clinical Immunology 2014 133, 1439-1447.e8DOI: (10.1016/j.jaci.2013.11.041) Copyright © 2014 Terms and Conditions

Fig 5 In vitro killing of peripheral blood eosinophils with afucosylated anti-EMR1 mAb (c1E7). A, Eosinophil (target) cell death after 4 hours of incubation with c1E7 or afucosylated isotype control (Iso) and autologous NK cells (effector; effector/target ratio of 5:1). B, Lack of eosinophil or NK cell death after 4 hours of incubation with antibody alone. Each symbol represents data for an individual subject. Eosinophilic subjects (EOS; n = 4) are indicated by black circles, and healthy donors (ND; n = 4) are indicated by open circles. CM, Culture medium; ns, not significant. **P < .01, Wilcoxon t test. Journal of Allergy and Clinical Immunology 2014 133, 1439-1447.e8DOI: (10.1016/j.jaci.2013.11.041) Copyright © 2014 Terms and Conditions

Fig 6 Eosinophil depletion over time after intravenous administration of a single 5 mg/kg dose of afucosylated anti-EMR1 mAb in 2 cynomolgus monkeys. Each panel shows the data for an individual monkey (CYNO 10-65c in A and CYNO 10-66c in B). The AEC (left axis) at each time point is represented by dark columns, and the white blood cell count (right axis) is indicated by open circles connected by a dashed gray line. I.V., Intravenous. Journal of Allergy and Clinical Immunology 2014 133, 1439-1447.e8DOI: (10.1016/j.jaci.2013.11.041) Copyright © 2014 Terms and Conditions

Fig E1 In vitro differentiation of CD34+ cells. A, Representative dot plots of EMR1/Siglec-8 and EMR1/IL-5Rα surface expression at day 4. B, Overlay of EMR1 staining at days 4 and 24. C, Representative dot plots of Siglec-8 and IL-5Rα surface expression on EMR1+ cells at day 24. FSC, Forward scatter; PE, phycoerythrin; SSC, side scatter. Journal of Allergy and Clinical Immunology 2014 133, 1439-1447.e8DOI: (10.1016/j.jaci.2013.11.041) Copyright © 2014 Terms and Conditions

Fig E2 In vitro modulation of EMR1 in response to IL-5 stimulation. A and B, Surface expression of EMR1 and CD69 on purified eosinophils after 2 hours of stimulation (n = 14, 6 healthy donors and 8 patients with HES). C, EMR1 mRNA upregulation by IL-5 after 6 hours of stimulation (n = 13, 4 healthy donors and 9 patients with HES). CM, Culture medium; Δmfi, change in mean fluorescence intensity. *P < .05, **P < .01, and ***P < .001. Journal of Allergy and Clinical Immunology 2014 133, 1439-1447.e8DOI: (10.1016/j.jaci.2013.11.041) Copyright © 2014 Terms and Conditions

Fig E3 Cytofluorimetric gating for the determination of eosinophil cell death induced by NK cells in the presence of afucosylated anti-EMR1 antibody (c1E7). Results shown are from 1 representative experiment. NK cell–mediated killing assays were performed with purified eosinophils at an effector/target ratio of 5:1. The cells were incubated together for 4 hours and washed before addition of Annexin V–FITC. After exclusion of cell debris and doublets, the percentage of Annexin V+ cells was determined in the eosinophil (Eo) and effector NK (NK) cell gates. FITC, Fluorescein isothiocyanate; FSC, forward scatter; SSC, side scatter. Journal of Allergy and Clinical Immunology 2014 133, 1439-1447.e8DOI: (10.1016/j.jaci.2013.11.041) Copyright © 2014 Terms and Conditions

Fig E4 Levels of eosinophil granule proteins (ECP, MBP, EPO, and EDN) in plasma samples from the 4 monkeys at all time points. Journal of Allergy and Clinical Immunology 2014 133, 1439-1447.e8DOI: (10.1016/j.jaci.2013.11.041) Copyright © 2014 Terms and Conditions