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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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 188-194.e3 (July 2008) DOI: 10.1016/j.jaci.2008.04.026 Copyright © 2008 American Academy of Allergy, Asthma & Immunology Terms and Conditions

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 2008 122, 188-194.e3DOI: (10.1016/j.jaci.2008.04.026) Copyright © 2008 American Academy of Allergy, Asthma & Immunology Terms and Conditions

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 2008 122, 188-194.e3DOI: (10.1016/j.jaci.2008.04.026) Copyright © 2008 American Academy of Allergy, Asthma & Immunology Terms and Conditions

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 2008 122, 188-194.e3DOI: (10.1016/j.jaci.2008.04.026) Copyright © 2008 American Academy of Allergy, Asthma & Immunology Terms and Conditions

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 2008 122, 188-194.e3DOI: (10.1016/j.jaci.2008.04.026) Copyright © 2008 American Academy of Allergy, Asthma & Immunology Terms and Conditions

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 2008 122, 188-194.e3DOI: (10.1016/j.jaci.2008.04.026) Copyright © 2008 American Academy of Allergy, Asthma & Immunology Terms and Conditions

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 2008 122, 188-194.e3DOI: (10.1016/j.jaci.2008.04.026) Copyright © 2008 American Academy of Allergy, Asthma & Immunology Terms and Conditions