PMID- 30488542 OWN - NLM STAT- MEDLINE DCOM- 20200504 LR - 20210109 IS - 1398-9995 (Electronic) IS - 0105-4538 (Print) IS - 0105-4538 (Linking) VI - 74 IP - 4 DP - 2019 Apr TI - Dupilumab reduces local type 2 pro-inflammatory biomarkers in chronic rhinosinusitis with nasal polyposis. PG - 743-752 LID - 10.1111/all.13685 [doi] AB - BACKGROUND: Chronic rhinosinusitis with nasal polyposis (CRSwNP) is a type 2-mediated inflammatory disease associated with significant clinical, social, and economic burdens and high unmet therapeutic need. Dupilumab, a fully human monoclonal antibody targeting the interleukin-4 receptor alpha (IL-4Ralpha) subunit, demonstrated efficacy and acceptable safety in CRSwNP and other type 2 diseases (eg, atopic dermatitis and asthma). We now report the local effects of dupilumab on type 2 inflammatory biomarkers in nasal secretions and nasal polyp tissues of patients with CRSwNP in a randomized, placebo-controlled, phase 2 trial (NCT01920893). METHODS: Cytokines, chemokines, and total immunoglobulin E (IgE) levels were measured using immunoassay techniques in nasal secretions and nasal polyp tissue homogenates of CRSwNP patients receiving dupilumab 300 mg or placebo weekly for 16 weeks. RESULTS: With dupilumab, type 2 biomarker concentrations decreased in nasal secretions (least squares mean area under the curve from 0 to 16 weeks for the change from baseline) vs placebo for eotaxin-3 (-30.06 vs -0.86 pg/mL; P = 0.0008) and total IgE (-7.90 vs -1.86 IU/mL; P = 0.022). Dupilumab treatment also decreased type 2 biomarker levels in nasal polyp tissues at Week 16 vs baseline for eosinophilic cationic protein (P = 0.008), eotaxin-2 (P = 0.008), eotaxin-3 (P = 0.031), pulmonary and activation-regulated chemokine (P = 0.016), IgE (P = 0.023), and IL-13 (P = 0.031). CONCLUSIONS: Dupilumab treatment reduced multiple biomarkers of type 2 inflammation in nasal secretions and polyp tissues of patients with CRSwNP, demonstrating that antagonism of IL-4Ralpha signaling suppresses IL-4-/IL-13-dependent processes, such as mucosal IgE formation, as well as the expression of chemokines attracting inflammatory cells to the nasal mucosa. CI - (c) 2018 The Authors. Allergy Published by John Wiley & Sons Ltd. FAU - Jonstam, Karin AU - Jonstam K AUID- ORCID: 0000-0002-0545-8008 AD - Division of ENT Diseases, Department of Clinical Sciences, Intervention and Technology, Karolinska Institute, Stockholm, Sweden. AD - Department of Ear, Nose and Throat Diseases, Karolinska University Hospital, Stockholm, Sweden. FAU - Swanson, Brian N AU - Swanson BN AD - Sanofi, Bridgewater, New Jersey. FAU - Mannent, Leda P AU - Mannent LP AD - Sanofi, Chilly-Mazarin, France. FAU - Cardell, Lars-Olaf AU - Cardell LO AUID- ORCID: 0000-0003-0538-9580 AD - Division of ENT Diseases, Department of Clinical Sciences, Intervention and Technology, Karolinska Institute, Stockholm, Sweden. AD - Department of Ear, Nose and Throat Diseases, Karolinska University Hospital, Stockholm, Sweden. FAU - Tian, Nian AU - Tian N AD - Sanofi, Bridgewater, New Jersey. FAU - Wang, Ying AU - Wang Y AD - Sanofi, Bridgewater, New Jersey. FAU - Zhang, Donghui AU - Zhang D AD - Sanofi, Bridgewater, New Jersey. FAU - Fan, Chunpeng AU - Fan C AD - Sanofi, Bridgewater, New Jersey. FAU - Holtappels, Gabriele AU - Holtappels G AD - Upper Airways Research Laboratory, Ghent University Hospital, Ghent, Belgium. FAU - Hamilton, Jennifer D AU - Hamilton JD AD - Regeneron Pharmaceuticals, Inc., Tarrytown, New York. FAU - Grabher, Annette AU - Grabher A AD - Sanofi, Berlin, Germany. FAU - Graham, Neil M H AU - Graham NMH AD - Regeneron Pharmaceuticals, Inc., Tarrytown, New York. FAU - Pirozzi, Gianluca AU - Pirozzi G AD - Sanofi, Bridgewater, New Jersey. FAU - Bachert, Claus AU - Bachert C AUID- ORCID: 0000-0003-4742-1665 AD - Division of ENT Diseases, Department of Clinical Sciences, Intervention and Technology, Karolinska Institute, Stockholm, Sweden. AD - Department of Ear, Nose and Throat Diseases, Karolinska University Hospital, Stockholm, Sweden. AD - Upper Airways Research Laboratory, Ghent University Hospital, Ghent, Belgium. LA - eng SI - ClinicalTrials.gov/NCT01920893 GR - Sanofi/International GR - Regeneron Pharmaceuticals, Inc./International PT - Clinical Trial, Phase II PT - Journal Article PT - Randomized Controlled Trial PT - Research Support, Non-U.S. Gov't DEP - 20190121 PL - Denmark TA - Allergy JT - Allergy JID - 7804028 RN - 0 (Antibodies, Monoclonal, Humanized) RN - 0 (Biomarkers) RN - 0 (Cytokines) RN - 0 (IL4 protein, human) RN - 0 (Interleukin-13) RN - 207137-56-2 (Interleukin-4) RN - 37341-29-0 (Immunoglobulin E) RN - 420K487FSG (dupilumab) SB - IM MH - Adult MH - Antibodies, Monoclonal, Humanized/*pharmacology MH - Biomarkers/blood MH - Chronic Disease MH - Cytokines/analysis MH - Humans MH - Immunoglobulin E/analysis MH - Inflammation/*prevention & control MH - Interleukin-13/antagonists & inhibitors/metabolism MH - Interleukin-4/antagonists & inhibitors/metabolism MH - Male MH - Middle Aged MH - *Nasal Polyps MH - Rhinitis/*pathology MH - Sinusitis/complications/*pathology PMC - PMC6590149 OTO - NOTNLM OT - biomarkers OT - dupilumab OT - nasal polyposis OT - nasal secretions OT - type 2 inflammation COIS- K. Jonstam is the sub-investigator of the study. B.N. Swanson, L. Mannent L, N. Tian, Y. Wang, D. Zhang, C. Fan, A. Grabher, and G. Pirozzi are employees of and may hold stock and/or stock options in Sanofi. L-O. Cardell is an associate investigator of the study. G. Holtappels has nothing to disclose. J.D. Hamilton and N.M.H. Graham are employees and shareholders of Regeneron Pharmaceuticals, Inc. C. Bachert is the principal investigator of the study. EDAT- 2018/11/30 06:00 MHDA- 2020/05/06 06:00 PMCR- 2019/06/24 CRDT- 2018/11/30 06:00 PHST- 2018/03/14 00:00 [received] PHST- 2018/09/20 00:00 [revised] PHST- 2018/10/08 00:00 [accepted] PHST- 2018/11/30 06:00 [pubmed] PHST- 2020/05/06 06:00 [medline] PHST- 2018/11/30 06:00 [entrez] PHST- 2019/06/24 00:00 [pmc-release] AID - ALL13685 [pii] AID - 10.1111/all.13685 [doi] PST - ppublish SO - Allergy. 2019 Apr;74(4):743-752. doi: 10.1111/all.13685. Epub 2019 Jan 21.