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A novel druglike spleen tyrosine kinase binder prevents anaphylactic shock when administered orally  Elsa Mazuc, MSc, Bruno O. Villoutreix, PhD, Odile.

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Presentation on theme: "A novel druglike spleen tyrosine kinase binder prevents anaphylactic shock when administered orally  Elsa Mazuc, MSc, Bruno O. Villoutreix, PhD, Odile."— Presentation transcript:

1 A novel druglike spleen tyrosine kinase binder prevents anaphylactic shock when administered orally 
Elsa Mazuc, MSc, Bruno O. Villoutreix, PhD, Odile Malbec, MSc, Thomas Roumier, PhD, Sébastien Fleury, Jean-Paul Leonetti, PhD, David Dombrowicz, PhD, Marc Daëron, MD, PhD, Pierre Martineau, PhD, Piona Dariavach, PhD  Journal of Allergy and Clinical Immunology  Volume 122, Issue 1, Pages e3 (July 2008) DOI: /j.jaci Copyright © 2008 American Academy of Allergy, Asthma & Immunology Terms and Conditions

2 Fig 1 Binding of C-13 to Syk in vitro. A, The C-13 pocket (mesh representation) was predicted through theoretical means and validated by mutagenesis. The figure illustrates C-13 docked into this newly identified Syk cavity located next to scFv G4G11 epitope. B, Binding of G4G11 to Syk in ADA in the presence of C-13 (▪). Binding of C-13 to Syk measured using fluorescence spectroscopy (○). C, Binding of G4G11 to Syk mutants in ADA. Data shown are representative of at least 2 experiments. Significant inhibition with C-13 versus DMF: ∗∗P < .01. Journal of Allergy and Clinical Immunology  , e3DOI: ( /j.jaci ) Copyright © 2008 American Academy of Allergy, Asthma & Immunology Terms and Conditions

3 Fig 2 C-13 impairs FcεRI-induced mast cell activation. A, Immunoprecipitations performed on RBL-2H3 cell lysates were analyzed by immunoblotting with the indicated antibodies. In vitro kinase activities of Syk, Btk, and Lyn immunoprecipitates were examined. RBL-2H3 (B) and BMMCs (C) cell lysates were subjected to electrophoresis and proteins were analyzed by immunoblotting. These representative data are from at least 2 experiments. DNP, Dinitrophenyl. Journal of Allergy and Clinical Immunology  , e3DOI: ( /j.jaci ) Copyright © 2008 American Academy of Allergy, Asthma & Immunology Terms and Conditions

4 Fig 3 C-13 inhibits FcɛRI-mediated calcium release and degranulation. A, FACS analysis of IgE-mediated calcium flux in RBL-2H3 cells. B, β-hexosaminidase release measurement in RBL-2H3 cells. β-hexosaminidase release (C) and TNF-α titration (D) in BMMCs. E, FACS analysis of surface expression of FcɛRI in RBL-2H3 cells (0 = 0.25% DMF). These representative data are from 3 experiments. Significant inhibition with C-13 versus DMF: ∗∗P < .01 and ∗P < .05. DNP, Dinitrophenyl. Journal of Allergy and Clinical Immunology  , e3DOI: ( /j.jaci ) Copyright © 2008 American Academy of Allergy, Asthma & Immunology Terms and Conditions

5 Fig 4 In vivo studies on BALB/c mice. A-C, PSA response. A, Temperature change. B, Quantification of Evans blue extravasation. C, Photograph representing dye extravasation following oral administration of 130 mg/kg C-13 or irrelevant chemical (IR); carrier (T); nontreated animal (NT). D, PCA response: quantification of Evans blue extravasation. Four to 5 mice were used per condition. Data shown are representative of 3 experiments. Significant inhibition with C-13 versus irrelevant chemical (∗∗P < .01) versus carrier + dinitrophenyl (DNP)-KLH (∗P < .05). Journal of Allergy and Clinical Immunology  , e3DOI: ( /j.jaci ) Copyright © 2008 American Academy of Allergy, Asthma & Immunology Terms and Conditions

6 C-13 had no toxic effect on mast cells
C-13 had no toxic effect on mast cells. The viability of BMMCs treated with DMF, C-13, or staurosporine was evaluated immediately (day 0) and after 5 days culture (day 5; n = 3). Journal of Allergy and Clinical Immunology  , e3DOI: ( /j.jaci ) Copyright © 2008 American Academy of Allergy, Asthma & Immunology Terms and Conditions

7 In vivo and in vitro effects of C-13 on neutrophils and B cells
In vivo and in vitro effects of C-13 on neutrophils and B cells. A, Neutrophil recruitment into the peritoneal cavity after thioglycollate (or vehicle) injection in the presence of B pertussis toxin (where indicated; n = 4). B, Anti-IgM–induced B-cell proliferation in vitro. C, Serum immunoglobulin concentration 12 days after trinitrophenyl (TNP)-KLH immunization (n = 4). PTX, B pertussis toxin. Journal of Allergy and Clinical Immunology  , e3DOI: ( /j.jaci ) Copyright © 2008 American Academy of Allergy, Asthma & Immunology Terms and Conditions

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