Cleaved kininogen as a biomarker for bradykinin release in hereditary angioedema Zonne L.M. Hofman, MSc, Steven de Maat, PhD, Chiara Suffritti, PhD, Andrea.

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Cleaved kininogen as a biomarker for bradykinin release in hereditary angioedema Zonne L.M. Hofman, MSc, Steven de Maat, PhD, Chiara Suffritti, PhD, Andrea Zanichelli, PhD, Cassandra van Doorn, MSc, Silvie A.E. Sebastian, BSc, Nora Veszeli, PhD, Dorottya Csuka, PhD, Thomas Renné, PhD, Gerard Pasterkamp, PhD, Marco Cicardi, PhD, Henriette Farkas, PhD, C. Erik Hack, PhD, Coen Maas, PhD Journal of Allergy and Clinical Immunology Volume 140, Issue 6, Pages 1700-1703.e8 (December 2017) DOI: 10.1016/j.jaci.2017.07.012 Copyright © 2017 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 1 Assay development. Western blot (reduced) (A) or immunoassay of purified HK and cHK (B). C, Immunoassay of (activated) NPP (1:32 dilution) with or without DXS. D and E, Immunoassay behavior with a range of cHK in plasma (1:32 dilution) and accompanying Western blot (reduced). F, Immunoassay principle. Data represent β mean ± SD of 3 separate experiments; replicates were analyzed with the Mann-Whitney t test. Journal of Allergy and Clinical Immunology 2017 140, 1700-1703.e8DOI: (10.1016/j.jaci.2017.07.012) Copyright © 2017 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 2 cHK levels in patients with C1-INH-HAE. A, Hungarian cohort. B, Italian cohort. C, Paired analysis of remission and attack. Blue lines: increases (28/33), red lines: decreases (5/33). D, Samples in inhibitor tubes. E, Paired analysis of samples in sodium citrate or inhibitor tubes. Open circles, remission; red, attack; green, controls. Sample dilutions described in this article's Methods section in the Online Repository at www.jacionline.org. Kruskal-Wallis test (Fig 2, A, B, and D) and Wilcoxon matched-pairs signed rank test (Fig 2, C and E). Journal of Allergy and Clinical Immunology 2017 140, 1700-1703.e8DOI: (10.1016/j.jaci.2017.07.012) Copyright © 2017 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E1 DXS enhances detection of purified cHK, whereas enzyme inhibitors in sample dilution buffer prevent contact activation. Detection of cHK in NPP and activated NPP by Western blot (reduced) (A) or immunoassay (1:32) (B). C, Immunoassay of purified (c)HK ± DXS. Enzyme inhibitors block DXS-triggered contact activation, determined by chromogenic assay (D) or (c)HK Western blot (reduced) (E). Data represent mean ± SD; replicates were analyzed with Mann-Whitney t test. Images represent 3 separate experiments. Journal of Allergy and Clinical Immunology 2017 140, 1700-1703.e8DOI: (10.1016/j.jaci.2017.07.012) Copyright © 2017 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E2 Cleaved high molecular weight kininogen (cHK) detection in plasma between the range of 20% and 100%. Plasma samples with increasing levels of cHK were prepared by mixing NPP with fully activated NPP in the presence of enzyme inhibitors. A, Immunoassay (1:128 dilution). B, Corresponding Western blot in the same sample range (reduced). Data represent mean ± SD of 3 separate experiments. Journal of Allergy and Clinical Immunology 2017 140, 1700-1703.e8DOI: (10.1016/j.jaci.2017.07.012) Copyright © 2017 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E3 Assembly of (cleaved) high molecular weight kininogen on dextran sulfate improves assay sensitivity. A, Western blot (reduced) of “input” NPP and products that are captured by VhH-D1. B, Densitometric quantification of HK and light-chain fragments (normalized for “input” signals). C, Detection of cHK by immunoassay (1:64 dilution) in NPP, or kininogen-depleted plasma (ΔHK). When cHK levels are low, HK acts as a signal amplifier. Data represent mean ± SD of 3 separate experiments. Journal of Allergy and Clinical Immunology 2017 140, 1700-1703.e8DOI: (10.1016/j.jaci.2017.07.012) Copyright © 2017 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E4 cHK detection in C1-INH-HAE patient plasma samples with hexadimethrine bromide. Data points represent patient or control plasma sample, lines indicate medians. Samples were analyzed at 1:32 dilution, in the presence of 8 μg/mL DXS, to overcome hexadimetrine bromide. Kruskal-Wallis test was used for multiple comparison. Journal of Allergy and Clinical Immunology 2017 140, 1700-1703.e8DOI: (10.1016/j.jaci.2017.07.012) Copyright © 2017 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E5 Correlation of cHK levels with C1-INH activity, complement parameters, and yearly angioedema attack frequency. Comparison of cHK detection by immunoassay or Western blot (nonreduced). Plasma cHK levels of patients with C1-INH-HAE or healthy controls are plotted against C1-INH function (A), C1-INH antigen level (B), C4 (C) or C1q (levels expressed as a percentage of normal values) (D), yearly angioedema attack frequency (E), and previously determined cHK levels previously analyzed by Western blot in the Italian cohort (F).E3 Correlation was calculated with Spearman r. Journal of Allergy and Clinical Immunology 2017 140, 1700-1703.e8DOI: (10.1016/j.jaci.2017.07.012) Copyright © 2017 American Academy of Allergy, Asthma & Immunology Terms and Conditions