Investigating the Mechanisms of Short- and Long-term Responses to IL-23 Inhibition Using Tildrakizumab in Moderate to Severe Plaque Psoriasis Using High-definition Multiomics
Conditions: Psoriasis
Sponsor: University Hospital Schleswig-Holstein

 
 
 
 
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Investigating the mechanisms of short- and long-term responses to IL-23 
inhibition using Tildrakizumab in moderate to severe plaque psoriasis using 
high-definition multiomics  
Kurzantrag  
Version 1.1, 09.10.2025 
 
Sponsor 
Institute for Inflammation Medicine (CCIM) 
of the University of Lübeck  
Sponsor (representative) 
UKSH/University of Lübeck 
Represented by Director of Institute 
Prof. Dr. med. Diamant Thaçi 
Principal Investigator 
Prof. Dr. med. Diamant Thaçi 
Protocol written  
Sadegh Mousavi 
Dr. Yask Gupta 
PD Dr. rer. nat. Tatiana Sezin 
Inga Catharina Brouer 
In collaboration with 
 
 
 

 
 
 
 
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Protocol Synopsis 
Study title 
Investigating the mechanisms of short- and long-term responses to IL-
23 inhibition using Tildrakizumab in moderate to severe plaque 
psoriasis using high-definition multiomics 
Hypothesis 
Define the mechanisms underlying the short- and the long-lasting 
effects of IL-23 targeting in plaque PsO, by characterizing the 
longitudinal effects of IL-23 inhibition on the ratio of Trm/Treg cells in the 
skin of moderate to severe plaque PsO patients. 
Objectives 
HDST (Visium HD) and HDSP (MICS) are used to characterize the early 
(2 weeks) and late (16 weeks) molecular effects of treatment with 
tildrakizumab on the skin of three patients with moderate to severe 
plaque psoriasis. Non-lesional and lesional skin samples taken at the 
start of treatment with tildrakizumab will be used, as well as healed skin 
adjacent to the original sampling sites at week 2 and week 16 after the 
start of treatment with tildrakizumab. The same samples will be 
examined using Visium HD and the MACSima imaging system.  
Study design 
This is a retrospective, exploratory study using material from our existing 
biobank (Excellence cluster, ‘Clinical Demonstrator 1’) in patients with 
moderate-to-severe plaque psoriasis who received Tildrakizumab 
treatment.  
Sample size 
3 patients 
Study site 
location 
The study will be conducted at the Institute for Inflammation Medicine at 
the University of Lübeck, Lübeck, Germany 
 
 
 

 
 
 
 
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Table of contents 
Protocol Synopsis ............................................................................................................ 2 
Protokollsynopse ........................................................ Fehler! Textmarke nicht definiert. 
List of abbreviations ......................................................................................................... 4 
1. 
Background ............................................................................................................. 5 
2. 
Study Purpose ......................................................................................................... 6 
3. 
Study Methodology.................................................................................................. 6 
4. 
Signatures ............................................................................................................... 8 
5. 
References .............................................................................................................. 9 
 

 
 
 
 
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List of abbreviations 
 
HDST 
high-definition spatial transcriptomics 
mDCs  
myeloid dendritic cells  
pDCs  
plasmacytoid dendritic cells 
PsO 
Psoriasis 
UKSH       University Medical Center Schleswig-Holstein 
   
 
 

 
 
 
 
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1. Background 
Psoriasis (PsO), a chronic inflammatory skin disease that affects up to 2-3% of the western 
population (1) and ~125 million people worldwide (2). It is marked by the presence of red, scaly 
plaques that are commonly seen in its plaque-type form that accounts for over 80% of all PsO 
cases (3). Its development is driven by a complex interplay of genetic and environmental 
factors, and involves both keratinocytes, and innate and adaptive immune cells (4). Early 
activation of keratinocytes, leads to activation of plasmacytoid dendritic cells (pDCs), that in 
turn release IFN-α– and stimulate myeloid dendritic cells (mDCs) to produce interleukin (IL)-
23 (5). The IL-23 cytokine, composed of the IL-12/23p40 subunit, which is shared with IL-12, 
and the IL-23p19 subunit, is crucial in sustaining the inflammatory response in plaque PsO by 
activating distinct subsets of IL-17-producing lymphoid cells such as CD4+ helper T cells 
(Th17), cytotoxic CD8+ T cells (Tc17), γδ T cells, and innate lymphoid cells (ILC3) (6). In the 
presence of IL-23, these IL-17 producing cells expand clonally and secrete large amounts of 
IL-17, in particular, the IL-17A and IL-17F cytokines that drive the key pathological features in 
plaque PsO (7). Elevated IL-17 levels promote keratinocyte proliferation, angiogenesis, 
upregulation of adhesion molecules on endothelial cells, and immune cell recruitment into the 
skin. This, in turn, leads to a feedforward inflammatory loop, amplifying keratinocyte 
hyperproliferation and sustaining the disease pathology (8). While mDCs are the main 
producers of IL-23, other cell types, such as, macrophages, also contribute to IL-23 production 
(9). These additional sources may play a role in the pathogenesis and persistence of psoriatic 
lesions, further highlighting the complexity of PsO-related inflammation. 
Targeted therapies like ustekinumab, which inhibit the IL-12/23p40 subunit, have proven 
effective in treating plaque PsO. Furthermore, evidence from tissue expression and genetic 
studies indicates that the therapeutic impact of these agents is largely due to their ability to 
block IL-23, rather than IL-12 (10), underscoring the significance of the IL-23 pathway. 
Furthermore, a head to head comparison suggests that IL-23p19 inhibitors like guselkumab 
and risankizumab offer superior efficacy over TNF inhibitors such as adalimumab (11) and IL-
17A inhibitors like secukinumab (12). Nevertheless, IL-17A inhibitors, including secukinumab 
and ixekizumab, exhibit a faster onset of action compared to IL-23p19 inhibitors in the 
treatment of plaque PsO (13). 
Tildrakizumab is a high-affinity, humanized, IgG1/κ monoclonal antibody that selectively binds 
to the (IL)-23p19 subunit but does not bind to human IL-12 or the IL‐12/23p40 subunit (18). 
Importantly, treatment effects that were achieved over the first 16 weeks of treatment were 
maintained through 52 weeks of treatment with doses of 100 and 200 mg Tildrakizumab (19). 
Upon cessation of treatment, the rate of relapse was low during a 20‐week nontreatment period 

 
 
 
 
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(19), suggesting that Tildrakizumab might have beneficial effect in clearing Trm cells and 
expanding Treg cells in the skin in plaque PsO patients.   
Global spatial transcriptomics (ST) revolutionized the study of drug effects within tissues by 
charting the spatial organization of cells while preserving their native cellular context (20). 
Furthermore, it permitted studying cell-cell interactions and eliminated the biases associated 
with cell dissociation and recovery, especially in extracellular matrix-rich tissues, like skin (21). 
Though conventional spatial profiling methods captured spatial data in intact tissues, they often 
relied on pre-selected markers and lacked adequate resolution (22). The recently established 
cutting edge high-definition spatial transcriptomics (HDST) approach (10x Genomics) 
overcomes these limitations by combining spatial barcoding with high-resolution RNA 
sequencing (23). Using this novel technology, we can now map precise localization of gene 
expression at every 2 μm achieving a single-cell resolution (22,23). In addition to HDST, spatial 
proteomics methods such as MICS also known as MACSima Imaging Cyclic Staining 
technology (Miltenyi Biotec) enabled the immunofluorescent imaging of hundreds of protein 
targets across a single specimen at subcellular resolution, and offered new insights into cellular 
complexity of the skin in response to treatment (24,25). By integrating data from these state-
of-the-art technologies, we aim to study the short (2 weeks after initiation of treatment) and the 
long-term effects (16 weeks after initiation of treatment) of Tildrakizumab treatment on the 
cellular composition and activation in the skin of plaque PSO patients, especially  of Trm and 
Treg cells. 
2. Study Purpose 
This study aims to define the mechanisms underlying both short- and long-term effects of IL-
23 inhibition in patients with moderate-to-severe plaque psoriasis during treatment with 
Tildrakizumab. Specifically, the study will investigate longitudinal changes in the ratio of tissue-
resident memory T cells (Trm) to regulatory T cells (Treg) in lesional, non-lesional, and 
resolved skin. In addition, the study will assess spatial and temporal alterations in IL-23 source 
and target cells using high-definition spatial transcriptomics (Visium HD) and high-dimensional 
spatial proteomics (MACSima MICS). 
3. Study Methodology 
The study will use HDST (Visium HD) and HDSP (MACSima Imaging Cyclic Staining – MICS) 
to analyze early (2 weeks) and late (16 weeks) molecular effects of Tildrakizumab treatment 
in the skin of three moderate-to-severe plaque psoriasis patients using previously collected 

 
 
 
 
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biopsies from our existing biobank. Sections will be subjected to spatial transcriptomic analysis 
using Visium HD and multiplex imaging with the MACSima system.  
4. Biobank 
The biological samples used in this project originate from the Clinical Demonstrator 1 Biobank, 
which is registered under file number 2023-800. It is confirmed that the patients, from whom 
the materials are derived, have consented to the use of their biological samples within the 
scope of project 2023-800. The use of the samples is carried out exclusively in accordance 
with the purposes described in the consent form and in compliance with applicable data 
protection regulations. 
 

 
 
 
 
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5. Signatures 
 
 
 

 
 
 
 
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6. References 
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(Heidelb) 11, 1053–1064 (2021). 
2. EClinicalMedicine. The burden of psoriasis: a call for awareness. eClinicalMedicine 38, 
(2021). 
3. Kimmel, G. W. & Lebwohl, M. Psoriasis: Overview and Diagnosis. Evidence-Based 
Psoriasis 1–16 (2018) doi:10.1007/978-3-319-90107-7_1. 
4. Enamandram, M. & Kimball, A. B. Psoriasis Epidemiology: The Interplay of Genes and 
the Environment. Journal of Investigative Dermatology 133, 287–289 (2013). 
5. Nestle, F. O. et al. Plasmacytoid predendritic cells initiate psoriasis through interferon-
α production. J Exp Med 202, 135–143 (2005). 
6. Krueger, J. G. et al. IL-23 past, present, and future: a roadmap to advancing IL-23 
science and therapy. Front Immunol 15, 1331217 (2024). 
7. Blauvelt, A. & Chiricozzi, A. The Immunologic Role of IL-17 in Psoriasis and Psoriatic 
Arthritis Pathogenesis. Clin Rev Allergy Immunol 55, 379–390 (2018). 
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disease. Immunity 50, 892–906 (2019). 
9. Łukasik, Z., Gracey, E., Venken, K., Ritchlin, C. & Elewaut, D. Crossing the boundaries: 
IL-23 and its role in linking inflammation of the skin, gut and joints. Rheumatology (Oxford) 
60, iv16–iv27 (2021). 
10. Di Cesare, A., Di Meglio, P. & Nestle, F. O. The IL-23/Th17 Axis in the 
Immunopathogenesis of Psoriasis. Journal of Investigative Dermatology 129, 1339–1350 
(2009). 
11. Gordon, K. B. et al. A Phase 2 Trial of Guselkumab versus Adalimumab for Plaque 
Psoriasis. New England Journal of Medicine 373, 136–144 (2015). 
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Lancet 394, 831–839 (2019). 
13. Gottlieb, A. B. et al. Indirect comparisons of ixekizumab versus three interleukin-23 p19 
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17. Dikiy, S. & Rudensky, A. Y. Principles of regulatory T cell function. Immunity 56, 240–
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