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BRIEF RESEARCH REPORT article

Front. Immunol.
Sec. Inflammation
Volume 15 - 2024 | doi: 10.3389/fimmu.2024.1471168
This article is part of the Research Topic Bradykinin and Histamine Mediated Angioedema View all 5 articles

Hereditary angioedema plasma proteomics following specific plasma kallikrein inhibition with lanadelumab

Provisionally accepted
Daniel J Sexton Daniel J Sexton 1Anton Kichev Anton Kichev 2Salomé Juethner Salomé Juethner 3Dave Yeung Dave Yeung 1Amanda MacDonald Amanda MacDonald 1Ezequiel Anokian Ezequiel Anokian 2Bin Li Bin Li 1*
  • 1 Takeda Development Centers Americas, Lexington, United States
  • 2 Clarivate PLC, Barcelona, Spain
  • 3 Takeda Pharmaceuticals USA Inc., Lexington, United States

The final, formatted version of the article will be published soon.

    Introduction: Plasma proteomics analyses was performed to identify novel disease state biomarkers of hereditary angioedema due to C1 inhibitor deficiency (HAE-C1INH) and investigate the biological consequences of specific plasma kallikrein inhibition with lanadelumab. Methods: Affinity proteomic analyses were performed using plasma from healthy controls (n=30) and patients with HAE-C1INH before (baseline, n=125) and after 6 months of treatment with lanadelumab (300 mg every 2 weeks, n=112) using the SomaScan platform. Results: Relative plasma levels for several proteins differed significantly between controls and patients with HAE-C1INH, and between matched baseline and post-treatment samples from patients with HAE-C1INH. As expected, C1 inhibitor and complement C4 were significantly lower (P<1.10e-39 false discovery rate [fdr], P<6.6e-25 fdr, respectively) in HAE-C1INH baseline plasma versus controls. Cleaved high-molecular-weight kininogen, a biomarker of excess kallikrein-kinin system (KKS) activation, was higher in HAE-C1INH baseline plasma versus controls (P<6.7e-6 fdr) and was reduced in HAE-C1INH plasma after lanadelumab treatment. Of 1041 identified proteins that differed significantly (P<0.05) from controls and HAE-C1INH baseline plasma, 120 proteins were no longer different between controls and patients with HAE-C1INH after 6 months of lanadelumab treatment. Canonical pathway and local network analyses of HAE-C1INH plasma proteomics suggest dysregulation in KKS, coagulation, cell adhesion, and connective tissue degradation that approach that of healthy controls following treatment with lanadelumab. Conclusion: Proteomic analyses of plasma from patients with HAE-C1INH before and after treatment with lanadelumab compared with healthy controls confirmed known HAE-C1INH biomarkers and identified additional potential biomarkers of plasma kallikrein dysregulation for further investigation.

    Keywords: Kallikrein-Kinin System, Lanadelumab, Bradykinin, antibody inhibitor of protease, hereditary angioedema

    Received: 31 Jul 2024; Accepted: 26 Nov 2024.

    Copyright: © 2024 Sexton, Kichev, Juethner, Yeung, MacDonald, Anokian and Li. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

    * Correspondence: Bin Li, Takeda Development Centers Americas, Lexington, United States

    Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.