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A novel allergen-adjuvant conjugate suitable for specific immunotherapy of respiratory allergy  Lucia Filì, PhD, Alessandra Vultaggio, MD, Elisa Cardilicchia,

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Presentation on theme: "A novel allergen-adjuvant conjugate suitable for specific immunotherapy of respiratory allergy  Lucia Filì, PhD, Alessandra Vultaggio, MD, Elisa Cardilicchia,"— Presentation transcript:

1 A novel allergen-adjuvant conjugate suitable for specific immunotherapy of respiratory allergy 
Lucia Filì, PhD, Alessandra Vultaggio, MD, Elisa Cardilicchia, PhD, Cinzia Manuelli, MS, Andrea Casini, MS, Francesca Nencini, MS, Laura Maggi, PhD, Sara Pratesi, MS, Giulia Petroni, MS, Francesca Boscaro, MS, Antonio Guarna, MS, Ernesto G. Occhiato, MS, Sergio Romagnani, MD, Enrico Maggi, MD, Paola Parronchi, MD  Journal of Allergy and Clinical Immunology  Volume 132, Issue 1, Pages e6 (July 2013) DOI: /j.jaci Copyright © 2013 American Academy of Allergy, Asthma & Immunology Terms and Conditions

2 Fig 1 Preparation and characterization of nDer p 2–Conj. A, Covalent bond of SA-26E (left) to lysine residues of nDer p 2 (right). B, Conjugation ratios between SA-26E and nDer p 2 and percentages of unbound allergen (P) and allergen linked to adenine fragments (P+1, P+2, P+3, and P+4). C, Mass spectrometric analysis of nDer p 2–Conj. Journal of Allergy and Clinical Immunology  , e6DOI: ( /j.jaci ) Copyright © 2013 American Academy of Allergy, Asthma & Immunology Terms and Conditions

3 Fig 2 nDer p 2–Conj acts as a TLR7 ligand and activates innate immune cells. A, NF-κB–dependent luciferase activity of stimulated human TLR7 (hTLR7)–, human TLR8 (hTLR8)–, or mouse TRL7 (mTLR7)–expressing HEK293 cells (mean ± SE, 5 experiments). B, Mean ± SE cytokine concentrations in supernatants of purified CD14+ or BDCA-4+ cells (10 healthy donors). ns, Not significant. *P < .05, **P < .005, and ***P < .0005. Journal of Allergy and Clinical Immunology  , e6DOI: ( /j.jaci ) Copyright © 2013 American Academy of Allergy, Asthma & Immunology Terms and Conditions

4 Fig 3 nDer p 2–Conj redirects human allergen-specific TH2 cells to the TH1/TH0 profile. A, IL-4 and IFN-γ intracellular expression (mean ± SE) by CD3+CD4+ T cells from polyclonally stimulated TCLs (10 donors). B, Cytokine mRNA expression by TCLs (7 donors). Medians and 25th and 75th percentiles are shown in boxes; minimum and maximum values are shown as whiskers. C, Percentages of nDer p 2–specific TCCs exhibiting the indicated phenotype (2 donors). D, GATA-3 and T-bet mRNA expression in TCLs (7 donors). Medians and 25th and 75th percentiles are shown in boxes; minimum and maximum values are shown as whiskers. E, IL-4+, IFN-γ+, or double-positive T-cell blasts of polyclonally stimulated CD4+CRTH2+ derived TCLs (4 donors). A representative case is shown (donor 1). F, IL-4 and IFN-γ intracellular expression in polyclonally stimulated blasts from nDer p 2– or nDer p 2–Conj–derived TCLs plus isotype control or anti–IL-12 and anti–IFN-α mAbs (2 donors). *P < .05 and **P < .005. ns, Not significant. Journal of Allergy and Clinical Immunology  , e6DOI: ( /j.jaci ) Copyright © 2013 American Academy of Allergy, Asthma & Immunology Terms and Conditions

5 Fig 4 nDer p 2–Conj exhibits reduced ability to stimulate human basophils. CD63 expression (mean ± SE) by circulating basophils after activation with nDer p 2 or nDer p 2–Conj is shown (4 HDM-sensitive donors). *P < .05 and **P < .005. Journal of Allergy and Clinical Immunology  , e6DOI: ( /j.jaci ) Copyright © 2013 American Academy of Allergy, Asthma & Immunology Terms and Conditions

6 Fig 5 Effects of nDer p 2–Conj in a mouse model of allergic airway sensitization. A, Cell counts (mean ± SE) in Diff-Quick–stained BALF after intratracheal challenge. Eo, Eosinophils; L, lymphocytes; MΦ, macrophages. B, Congo Red–stained and hematoxylin-counterstained lung tissue sections (×400 magnification, 1 representative case). C, Eosinophil infiltration in lung compartments. ALV, Alveolar; PB, peribronchial; PV, perivascular. D, Lung cytokine mRNA expression. E, Cytokine levels in supernatants of nDer p 2–stimulated lung-derived mononuclear cells. F, Serum IgE, IgG1, and IgG2a levels (OD; mean ± SE). N = 12 mice per group; 2 experiments. ns, Not significant. *P < .05 and **P < .005. Journal of Allergy and Clinical Immunology  , e6DOI: ( /j.jaci ) Copyright © 2013 American Academy of Allergy, Asthma & Immunology Terms and Conditions

7 Fig E1 Synthetic route to compound SA-26E. III, 6-Amino-9-benzyl-2-mercapto-9H-purin-8-ol; IVa, 4-(6-amino-9-benzyl-8-hydroxy-9H-purin-2-ylsulfanyl)-butyric acid ethyl ester; Va, 4-(6-amino-9-benzyl-8-hydroxy-9H-purin-2-ylsulfanyl)-butyric acid; SA-26E, 4-(6-amino-9-benzyl-8-hydroxy-9H-purin-2-ylsulfanyl)-butyric acid 2,5-dioxo-pyrrolidin-1-yl ester. The single compounds were obtained, as described in the Methods section in this article's Online Repository. Journal of Allergy and Clinical Immunology  , e6DOI: ( /j.jaci ) Copyright © 2013 American Academy of Allergy, Asthma & Immunology Terms and Conditions

8 Fig E2 SA-26E triggers TLR7 at high concentrations. NF-κB–dependent luciferase activity of free SA-26E–stimulated human and mouse TLR7-expressing HEK293 cells (mean ± SE, 5 experiments). Journal of Allergy and Clinical Immunology  , e6DOI: ( /j.jaci ) Copyright © 2013 American Academy of Allergy, Asthma & Immunology Terms and Conditions

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