Abstract Background Mirikizumab, an anti-interleukin-23 p19 IgG4 monoclonal antibody, is approved for treatment of moderately to severely active ulcerative colitis (UC).1 Although prior studies defined transcriptional patterns modulated by mirikizumab therapy in UC,2 they lack cellular resolution and spatial context, limiting insight into mucosal remodelling in therapeutic responses. This study used spatial transcriptomics to delineate molecular- and cellular-based tissue archetype features associated with clinical response to mirikizumab in colon biopsies of patients with UC. Methods In the phase 2 AMAC study (NCT02589665), patients with UC were randomized to receive intravenous placebo (PBO) or 1 of 3 mirikizumab induction doses of 50, 200, or 600 mg. Mucosal biopsies were collected at baseline and week 12 and formalin-fixed paraffin-embedded blocks (n = 41) from 11 patients randomized to PBO or mirikizumab 200 mg induction (mirikizumab responders n = 3, mirikizumab nonresponders n = 3, PBO responders n = 2, and PBO nonresponders n = 3) were profiled using the 10x Genomics Xenium spatial transcriptomics platform. Spatial clustering was used to identify transcriptionally and spatially coherent tissue niches, achieving stable niche resolution across 9 spatial domains. Each niche was subsequently annotated by cell type based on single-cell RNA sequencing data (TAURUS).3 Results Analysis of distinct tissue niches revealed that transcriptional profiles aligned with signatures previously described in bulk transcriptomics studies,2 mapping them spatially in colonic tissue (Fig. 1A). Cell-type composition assessment revealed clear differences linked to therapeutic response to mirikizumab induction treatment. In mirikizumab responders, IgG⁺ plasma cells were more prevalent at baseline and declined by 81% after treatment (Fig. 1B). In contrast, IgG+ plasma cells in mirikizumab nonresponders increased substantially (7.8-fold), while there was minimal increase (29%) in PBO responders. Cycling stromal cells showed a similar pattern, with a 37% reduction in mirikizumab responders. Conversely, tuft cells increased by 1.5-fold after mirikizumab treatment in responders (Fig. 1B). However, this group also showed the highest baseline tuft cell abundance among all groups. Conclusion Spatial transcriptomics profiling demonstrates that mirikizumab reduces tissue inflammation by plasma cell and stromal response normalization, as well as by epithelial restitution, suggesting multifaceted mucosal healing in induction responders. These spatially characterized signatures provide insight into mucosal remodelling in mirikizumab responders and may inform the development of cellular markers for precision medicine in UC management. References: 1. Sandborn WJ, Ferrante M, Bhandari BR, et al. Efficacy and safety of continued treatment with mirikizumab in a phase 2 trial of patients with ulcerative colitis. Clin Gastroenterol Hepatol. 2022;20(1):105-115.e114. 2. Steere B, Schmitz J, Powell N, et al. Mirikizumab regulates genes involved in ulcerative colitis disease activity and anti-TNF resistance: results from a phase 2 study. Clin Transl Gastroenterol. 2023;14(7):e00578. 3. Thomas T, Friedrich M, Rich-Griffin C, et al. A longitudinal single-cell atlas of anti-tumour necrosis factor treatment in inflammatory bowel disease. Nat Immunol. 2024;25(11):2152-2165. Conflict of interest: Fernandes, Nadia: No conflict of interest Sharma, Osheen: No conflict of interest Ma, Christopher: Consulting fees: AbbVie, Alimentiv, Amgen, Anaptys Bio, AVIR Pharma Inc, Bristol Myers Squibb, Celltrion, Domain Therapeutics, Eupraxia, Eli Lilly, Ferring, Forte Biosciences, Fresenius Kabi, Gilead, Janssen, McKesson, Merck, Mirador Therapeutics, Pendopharm, Pfizer, Roche, Sanofi, Takeda, Tillotts Pharma Speaker’s fees: AbbVie, Amgen, AVIR Pharma Inc, Alimentiv, Bristol Myers Squibb, Eli Lilly, Ferring, Fresenius Kabi, Janssen, Merck, Organon, Pendopharm, Pfizer, Sanofi, Takeda, Tillotts Pharma Royalties: Springer Publishing Research Support: AbbVie, Eli Lilly, Ferring, Pfizer Yarur, Andres: Personal Fees: Consultant for Takeda, Pfizer, Roche, Merck, Abbvie, Eli Lilly. Bristol Myers Squibb, Celltrion, Johnson and Johnson. Deepak, Parakkal: Parakkal Deepak has received research support under a sponsored research agreement unrelated to the data in the abstract from AbbVie, Johnson and Johnson, Sanofi, Merck, Teva, Direct Biologics, Tr1x, Boehringer Ingelheim, Bristol Myers Squibb, Pfizer, Prometheus Biosciences, Takeda Pharmaceuticals, Roche Genentech, Eli Lilly, AstraZeneca, Spyre and Agomab, has received consulting fees from Johnson and Johnson, Abbvie, Merck, Sobi, Celltrion, Fresenius Kabi, Asahi Kasei Pharma, Sandoz and CorEvitas, LLC and has served on the board of the Srategic Alliance for Intercultural Advocacy in GI. Jain, Dhawal: Dhawal Jain is an employee and shareholder of Eli Lilly and Company Pellanda, Paola: employees and shareholder of Eli Lilly and Company. Maier, Sebastian: Employee and shareholder of Eli Lilly and Company Uhlig, Holm: Research support from Eli Lilly for this project. Research support or consultancy fees from J&J, Bristol Myers Squibb BMS. No stocks or share options. Reinisch, Walter: Personal Fees: WR has served as a speaker for AbbVie, Alfasigma, Celltrion, Ferring, JNJ, Galapagos Medice, Lilly, MSD, Roche, Pfizer, Sobi, Takeda, as a consultant for AbbVie, Agomab, Alfasigma, Alvotech, Amgen, Anaptys Bio, AOP Orphan, Boehringer Ingelheim, Bristol Myers Squibb, Calyx, Celltrion, Eli Lilly, Galapagos, Gilead, Index Pharma, Janssen, Medahead, Merck, Microbiotica, Pfizer, Sanofi, Teva, Takeda as an advisory board member for AbbVie, Alfasigma, Amgen, Boehringer Ingelheim, Bristol Myers Squibb, Celltrion, Galapagos, JNJ, Pfizer, Teva and has received research funding from AbbVie, JNJ, Sandoz, Sanofi, Takeda. Dendrou, Calliope: No conflict of interest Friedrich, Matthias: Received speaker and/or consultancy fees from EliLilly, Quell Therapeutics, Ono Pharma, Foghorn and received research funding from EliLilly. Steere, Boyd: Employee and shareholder of Lilly
Fernandes et al. (Thu,) studied this question.