AbbVie Bioresearch Center Worcester, MA, United States
Julian Panés, MD, PhD1, Bram Verstockt, MD2, Valerie Pivorunas, PhD3, James Butler, PhD4, Naim Mahi, PhD4, Melanie Ruzek, PhD3, Thierry Sornasse, PhD5, James Fann, PhD3, Feng Hong, PhD3, Xiaohong Cao, PhD6, Nizar Smaoui, PhD4, Justin Wade Davis, PhD4, Jasmina Kalabic, PhD7, Alexandra Song, PhD8, Heath Guay, PhD3, Azucena Salas, MD9, Nick Kennedy, MD10, Tariq Ahmad, MD10, Severine Vermeire, MD, PhD11 1Hospital Clínic de Barcelona, IDIBAPS, CIBERehd, Barcelona, Catalonia, Spain; 2University Hospitals Leuven, Catholic University of Leuven, Leuven, Liege, Belgium; 3AbbVie Bioresearch Center, Worcester, MA; 4AbbVie Inc., North Chicago, IL; 5AbbVie, Redwood City, CA; 6AbbVie Cambridge Research Center, Cambridge, MA; 7AbbVie Deutschland GmbH & Co. KG, Ludwigshafen, Nordrhein-Westfalen, Germany; 8AbbVie, Inc., North Chicago, IL; 9Hospital Clinic de Barcelona, IDIBAPS, CIBERehd, Barcelona, Catalonia, Spain; 10Royal Devon and Exeter NHS Foundation Trust, Exeter, England, United Kingdom; 11University Hospitals Leuven, Leuven, Brussels Hoofdstedelijk Gewest, Belgium
Introduction: We report residual mechanisms associated with non-response to adalimumab(ADA) in Crohn’s disease(CD) and ulcerative colitis(UC) patients(pts) in both standard and higher induction regimens.
Methods: SERENE-CD response was defined as clinical remission(CR;Crohn's Disease Activity Index < 150) and/or >50% decrease in Simple Endoscopic Score for Crohn's Disease (SES-CD) from baseline (BL) or, if BL SES-CD=4, ≥2-point reduction from BL. SERENE-UC response was defined as CR, Full Mayo score ≤2 with no subscore >1. Levels of 184 plasma proteins(Olink Inflammation and Immune response panels) were measured at BL and Wks2, 4, 8, and 12 in SERENE-CD and Wks2, 4, and 8 in SERENE-UC responders vs non-responders across standard and higher induction regimens. RNAseq evaluated changes in whole blood gene expression in responders vs non-responders at Wk12(SERENE-CD) or Wk8(SERENE-UC).
Results: In SERENE-UC, 85 blood proteomic analytes differentially expressed in responders and non-responders, including OSM, IL-6, and IL-17A, were identified at Wk8. STRING network analysis highlighted IL-17 signaling and Th17 differentiation pathways in SERENE-UC non-responders at Wk8. Parallel RNAseq whole blood gene expression and KEGG enrichment analysis showed IL-17 signaling pathway was modulated in SERENE-UC pts achieving CR, whereas no change was observed in non-responders.
In SERENE-CD, 23 blood proteomic analytes differentially expressed in responders and non-responders were identified at Wk12. STRING network analysis identified regulation of immune cells, chemotaxis, and T cell cytokine production. SERENE-CD non-responders had persistent elevation of IL-6 and OSM vs responders at Wk12, similar to SERENE-UC non-responders at Wk8. RNAseq whole blood gene expression and KEGG enrichment analysis on SERENE-CD responders vs non-responders at Wk12 identified activation and degranulation of immune cells and immune cell-mediated immunity as main differentially regulated pathways.
Discussion: Blood proteomic and transcriptomic analyses of responders and non-responders at Wk12(SERENE-CD) or Wk8(SERENE-UC) of ADA treatment identified shared and distinct residual mechanisms of non-response. IL-17 signaling and Th17 differentiation pathways were associated with non-response to ADA in UC pts, while mechanisms associated with non-response to ADA in CD pts included regulation of immune cells, chemotaxis, and T cell cytokine production. Shared features of non-response to ADA in UC and CD pts included elevation of OSM and IL-6.