Ablynx (Belgium)

Disease of a subgroup of patients with atopic dermatitis (AD) does not show sufficient improvement with current systemic therapies, highlighting the heterogeneity of the chronic inflammatory skin disease and the need for novel treatments. In this study, we investigated the pathogenic contribution of the IL-22/IL-22 receptor (IL-22RA1) axis to AD skin inflammation in in vitro, ex vivo, and in vivo models to evaluate the therapeutic potential of blocking this axis. IL22RA1 expression in AD skin was assessed by in situ hybridization. Inhibition of the IL-22/IL-22R signaling cascade was evaluated in a human AD in vitro model (3-D skin equivalents) and a phorbol 12-myristate 13-acetate (aka TPA) mouse model using temtokibart, a humanized antibody directed against IL-22RA1. IL22RA1 was highly expressed in the epidermis of lesional AD skin versus nonlesional control skin; expression correlated positively with epidermal thickness and negatively with the barrier integrity marker loricrin. IL-22 stimulation in 3-D skin equivalents induced a specific molecular signature associated with lack of terminal differentiation, altered lipid metabolism, and increased immune response. Inhibition of IL-22RA1 with temtokibart showed significant improvements in skin barrier integrity at the histologic and molecular levels. IL-22RA1 inhibition in a skin inflammation mouse model with Zymo, a surrogate murine anti-IL-22RA1 monoclonal antibody for temtokibart, reduced local expression of Cxcl1 and S100a9. These findings suggest that the IL-22/IL-22RA1 axis functionally contributes to AD pathogenesis. Thus, blocking IL-22RA1 represents a potentially valuable new therapeutic option.

This paper presents SignBuddy, the result of ongoing co-created sign language processing research. Mostsign language processing research is performed by hearing, non-signing researchers. Even though co-creation efforts have recently increased, technical research still often fails to mention if (and how) co-creation was involved in the research process. SignBuddy is a co-created research tool developed through apartnership between the Flemish Sign Language Centre, a deaf-led organisation, and Ghent University. While respecting elemental concepts of co-creation - i.e. (i) defining common goals and (ii) building a formal and sustainable relationship between users/consumers and researchers/developers and respectingthe five lessons in co-creation - the platform successfully supported the development of the first fully scalable sign-to-text dictionary search system, built into the Flemish Sign Language–Dutch onlinedictionary. SignBuddy functions as a crowdsourcing interface for in-the-wild collection of modelevaluation data, gathering example queries for quantitative performance analysis and user feedback forqualitative assessment. This human evaluation allows us to shape the application based on the end-users'needs. Addressing the need for models that support large dictionaries (over ten thousand signs), we propose a scalable one-shot sign language recognition method and achieve state-of-the-art results. Beyond the co-created application itself, this work provides insights into the co-creation process - clarifying roles, shared goals, and responsibilities - and offers conclusions to guide future co-created sign language processing research.

Nanobody molecules are single-domain antibodies derived from stable and fully functional heavy-chain-only (VHH) camelid antibodies. Due to their small size, approximately 15 kDa, their tissue distribution differs from that of conventional antibodies. This study investigates the whole-body pharmacokinetics (WBPK) and specific binding of half-life extended VHHs (HLE-VHHs) using dynamic whole-body immunoPET imaging in nonhuman primates. A HLE-VHH targeting the IL-6 receptor (CD126-VHH) and its nontargeting control (IRR-VHH) were evaluated in vivo after zirconium-89 radiolabeling. We compared microdoses (0.18 ± 0.11 mg/kg, n = 2) and/or pharmacological doses (coinjection, 3.19 ± 0.02 mg/kg, n = 2) of IRR-VHH, alongside microdoses of CD126-VHH (0.25 ± 0.14 mg/kg, n = 2). Initial dynamic whole-body PET scans (240 min) were followed by static PET scans on days 1, 7, and 14. We validated an image-derived input function against the arterial blood sampling method for kinetic modeling. [89Zr]IRR-VHHs showed predominantly vascular distribution from day 0 to day 14, with comparable activity patterns and tissue distribution between microdose and pharmacological dose administrations. Early [89Zr]CD126-VHH distribution mirrored the nonspecific IRR-VHH pattern, showing strong correlation (R2 = 0.87, slope = 1.1) in uptakes of organs, normalized to blood (standard uptake value ratio, SUVR) values at day 0. Interestingly, by days 7 and 14, [89Zr]CD126-VHH exhibited higher uptake in bone marrow, spleen, liver, and kidneys, suggesting specific binding. The distribution of [89Zr]IRR-VHH in these organs was assumed to reflect the nonspecific uptake of VHHs and was used to estimate the specific binding of [89Zr]CD126-VHH. The specific binding of [89Zr]CD126-VHH was similarly estimated using either the arterial input function or the image-derived input function (R2 = 0.997, p < 0.0001). In plasma, the shorter elimination half-life of [89Zr]CD126-VHH (2.0-1.8 days) compared to microdose [89Zr]IRR-VHH (5.1-5.0 days) or pharmaco-dose [89Zr]IRR-VHH (4.9-4.8 days) suggested target-mediated drug disposition. This study demonstrates the potential of immunoPET for evaluating the target-mediated drug disposition and WBPK of VHH molecules in vivo, providing valuable insights into VHH-based therapeutic strategies.

Binding of the surrogate light chain (SLC) to the heavy chain (HC) of the pre-B cell receptor (preBCR) is an important quality control checkpoint during B cell development as roughly 50% of the rearranged HCs are defective. Unlike the regular light chain (LC), the SLC is a hetero-dimer of VpreB and λ5, both containing unstructured extensions, the unique regions. The molecular mechanisms that underlie the complex assembly processes which give rise to the final pre-BCR is not fully understood. Here we show, via reconstitution of the pre-BCR in vitro and in cells that λ5 plays a key role in the pre-BCR assembly. During SLC assembly, a β-strand, located between the λ5 domain and the unique region, induces structure in the largely unfolded VpreB, creating a high affinity complex. In addition, association of λ5 with the unstructured HC CH1 domain is required for its folding. This is essential for pre-BCR assembly and its release from the endoplasmic reticulum (ER). Finally, the unique region of λ5 plays a pivotal role in the antigen interaction of the SLC-HC complex. Together, our results reveal a multi-step mechanism for SLC and pre-BCR assembly, governed by association-induced folding reactions required for structural integrity and function.

Abstract Synaptic dysfunction arises early in Alzheimer’s disease (AD) and contributes to cognitive decline. Yet, plasma biomarkers to evaluate synaptic functioning remains underexplored. We developed a novel immunoassay to detect the synaptic marker SNAP25 in plasma, aiming to evaluate the association of plasma SNAP25 with AD progression. Participants who were cognitively unimpaired or had subjective cognitive decline (CU or SCD Aβ+/Aβ-), mild cognitive impairment (MCI Aβ+), and AD dementia were included from multiple cohorts (n=884). Plasma SNAP25 levels were higher in all Aβ+ groups (p&lt;0.01), from the CU/SCD stages onward, and levels increased more steeply over time in SCD Aβ+ than in SCD Aβ- individuals (βtime*amyloid status 0.08±0.02, p&lt;0.001). Among SCD, higher baseline and steeper increases in plasma SNAP25 were associated with cognitive decline (both βtime*SNAP25 –0.02±0.01, p&lt;0.001) and an increased risk of progression to MCI or dementia (HR 1.94 [95%CI 1.42–2.65], p&lt;0.001). Among Aβ-, baseline plasma SNAP25 predicted Aβ status conversion to Aβ+ over four years with AUC 0.71 [0.57–0.85]. In conclusion, plasma SNAP25 emerges as a promising blood-based synaptic biomarker for prognosis and progression in the preclinical AD stages.

BackgroundPost‐translational modifications of tau, such as acetylation, are emerging as key mechanisms in tau pathology. Tau acetylation at lysine 174 (AcTau174) is elevated in primary neurons with frontotemporal dementia (FTD)‐linked mutations and in early Alzheimer’s disease (AD) brain tissue. However, the utility of AcTau174 as a cerebrospinal fluid (CSF) biomarker across dementias is unknown, including in FTD, where AD‐type tau CSF biomarkers are typically not elevated. We investigated the diagnostic and prognostic potential of AcTau174 in a well‐characterized clinical cohort.MethodUsing our in‐house developed Simoa assay, we measured AcTau174 in CSF samples from the Amsterdam Dementia Cohort (109 non‐neurodegenerative controls, 52 FTD, 145 AD, 97 mild cognitive impairment due to AD (MCI‐AD), and 31 dementia with Lewy bodies (DLB)).ResultAcTau174 levels were elevated in all dementia groups compared to controls, with a stepwise increase from controls to MCI‐AD (2.2‐fold) to AD dementia (3.5‐fold, Figure 1). The strongest increase compared to controls was observed in the FTD group, wherein AcTau174 distinguished FTD from controls with a high area under the curve (AUC) accuracy of 0.95 (95%CI:0.92;0.99), significantly outperforming CSF pTau181 (AUC=0.65, 95%CI:0.55;0.75) and CSF Tau (AUC=0.83, 95%CI:0.75;0.91). AcTau174 showed high accuracy for differentiating AD (AUC=0.98, 95%CI:0.96;0.99) and MCI‐AD (AUC=0.89, 95%CI:0.84;0.93) from controls (Figure 2). In FTD, AcTau174 correlated with MMSE (ρ=‐0.29, p =0.039), and in AD with the frontal assessment battery score (ρ=‐0.35, p =0.0001). In FTD, higher baseline CSF AcTau174 was associated with a faster rate of decline in MMSE over time (β=‐1.64, 95%CI:‐2.61;‐0.87, p =0.0014, Figure 3), which was not observed for CSF pTau181 or Tau. Higher baseline CSF AcTau174 also predicted faster MMSE decline within AD (β=‐1.66, 95%CI:‐2.44;‐0.90, p <0.0001) and MCI‐AD (β=‐0.67, 95%CI:‐1.09;‐0.27, p =0.002, Figure 3).ConclusionCSF AcTau174 shows great diagnostic value across neurodegenerative dementias and is strongly associated with clinical progression. In FTD, where trials are limited by clinical heterogeneity and lack of fluid biomarkers, AcTau174 may aid in identifying patients at risk of rapid decline, supporting trial enrichment and more targeted intervention strategies. Its predictive capacity for MMSE decline highlights its potential as a progression biomarker, both for patient monitoring and therapeutic development.