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IL-17A complexes with therapeutic antibodies exhibit distinct size distributions, potentially contributing to clinically observed immunogenicity
No full textMonoclonal antibodies are established as promising treatment options for a broad range of patients suffering from severe diseases. In some cases, the formation of anti-drug antibodies (ADA) may limit their clinical use and potentially affect safety and efficacy for patients. Despite extensive research, some factors contributing to the immunogenicity of some therapeutic antibodies remain poorly understood. In particular, the immunogenicity potential associated with multivalent antibody formats targeting oligomeric protein antigens has thus far received insufficient attention. Large, target-related immune complexes (TRICs) may be formed that can trigger Fc-mediated downstream effects and have the potential to contribute to the development of an ADA response. Here, we present experimental evidence highlighting the roles of epitope, paratope, and binding geometry in defining the composition and size distribution of TRICs formed by four clinical anti-IL-17 monoclonal antibodies with IL-17A, a homodimeric cytokine. Our findings underscore the importance of conducting in-depth biophysical analyses of TRICs formed by therapeutic antibody candidates targeting multivalent protein antigens, to develop safer and more efficacious treatments
A centenarian single nucleotide polymorphism in collagen gene COL25A1 promotes longevity in C. elegans.
No full textBefore human genome sequencing, a genome-wide study of sibling centenarian pairs identified a longevity-associated locus on chromosome 4. Here, we mapped the genes in this locus and identified a collagen gene, COL25A1. Introducing an SNP linked to longevity that changes a serine predicted to be phosphorylated to leucine in COL25A1, into col-99, the C. elegans ortholog, extended lifespan. These col-99(gk694263[S106L]) SNP-mutants exhibited enhanced innate immune-related transcriptional responses, and their lifespan extension was abolished by inhibiting the p38 MAPK pathway. YAP-1, a transcriptional co-activator responsive to extracellular matrix changes, was essential for this longevity. Mechanistically, we find that this SNP modifies furin-mediated cleavage of this transmembrane collagen in vitro, and expressing the cleaved extracellular domain of COL-99 alone was sufficient to prolong C. elegans' lifespan. These findings reveal a potential mechanism by which a human centenarian-associated SNP in COL25A1 influences furin cleavage and shedding of the collagen ectodomain to promote healthy longevity
Meeting Report Session 3: Neurobiomarkers STP 44th Annual Symposium 2025 Development and Utility of Neurobiomarkers in Nonclinical Toxicology Studies.
No full textThe objective of the third session (Neurobiomarkers) in the 2025 Society of Toxicologic Pathology (STP) symposium was to provide an overview of different types of existing neural biomarkers, highlight the value of novel biomarkers to detect and/or predict nervous system changes in preclinical species, and provide perspectives on their translational potential. These biomarkers can also help evaluate the efficacy of new drugs, monitor neurological diseases, and better characterize neuropathology findings. The lectures in this session featured distinguished experts in their respective scientific disciplines such as electrophysiology, molecular pathology tools to characterize pathology lesions in the visual pathways, fluid-based biomarkers, the use of MRI imaging to visualize test article delivery to the CNS of monkeys, and quantifying DRG changes using techniques like stereology, micro-CT, and nano-CT. In this session, there was also a presentation about immunohistochemical stains performed to evaluate ketamine-induced neurotoxicity in neonatal Sprague Dawley rats as a model for pediatric anesthesia. The integration of neural biomarkers in nonclinical studies in conjunction with a dedicated histopathology evaluation provides the necessary scientific data to better predict and derisk neurotoxicity in clinical studies
Harnessing glutamine-117 plasticity toward structure-based identification of triazole IL-17 inhibitors
No full textThe proinflammatory cytokine IL-17 is crucial for host defense but has also been linked to various inflammatory and autoimmune diseases. Antibody-based IL-17 inhibitors like secukinumab (Cosentyx) have demonstrated clinical success in psoriasis, psoriatic arthritis, and ankylosing spondylitis, sparking efforts to develop orally bioavailable small molecule alternatives. However, most small molecule IL-17 inhibitors failed in preclinical and clinical stages due to safety concerns and other challenges. This work describes the discovery of a 1,2,4-triazole scaffold that acts as an amide bioisostere. Its unique vector toward the Trp90 pocket, a key cavity for ligand binding, required the development of novel motifs. A structure-based library approach, considering the high plasticity of the Gln117 side chain, yielded structurally diverse Trp90 pocket binding motifs. The X-ray structures of the most potent hits guided subsequent optimization, resulting in triazole-based IL-17 inhibitors with low nanomolar cellular activity, which are promising leads for further development
Open problems in ageing science: a roadmap for biogerontology.
No full textThe field of ageing science has gone through remarkable progress in recent decades, yet many fundamental questions remain unanswered or unexplored. Here we present a curated list of 100 open problems in ageing and longevity science. These questions were collected through community engagement and further analysed using Natural Language Processing to assess their prevalence in the literature and to identify both well-established and emerging research gaps. The final list is categorised into different topics, including molecular and cellular mechanisms of ageing, comparative biology and the use of model organisms, biomarkers and the development of therapeutic interventions. Both long-standing questions and more recent and specific questions are featured. Our comprehensive compilation is available to the biogerontology community on our website ( www.longevityknowledge.app ). Overall, this work highlights current key research questions in ageing biology and offers a roadmap for fostering future progress in biogerontology
A sex-adjusted 7-biomarker clinical aging clock for translational preventative medicine.
No full textBiological aging clocks capture heterogeneous rates of aging in individuals and transform current medical practice toward translational preventive medicine. Here, we developed a clinical aging clock based on routine blood biochemistry markers from 59,741 healthy samples in a Southeast Asian cohort. We established a novel correction method to address the systematic skew in predictions from first-generation clocks. This correction improved the accuracy of age-acceleration predictions for disease risks and enhanced interpretability for disease-driven and organ-specific aging processes without relying on mortality data. Based on only seven biomarkers, our clock accurately predicts both self-reported and physician-annotated ICD health data, indicating an increased hazard ratio. Importantly, the clock is robust even in the presence of acute infections or transient immune activation. To demonstrate the multi-ethnic generalizability of our biological age clock, we validated our approach using data from both the NHANES and UK Biobank cohorts. Our approach demonstrates the feasibility of a simple, robust, and interpretable clinical aging clock with potential for real-world implementation in personalized health monitoring and preventive care
Scaffold Hopping with Generative Reinforcement Learning.
No full textScaffold hopping-the design of novel scaffolds for existing lead candidates-is a multifaceted and nontrivial task, for medicinal chemists and computational approaches alike. Generative reinforcement learning can iteratively optimize desirable properties of de novo designs, thereby offering opportunities to accelerate scaffold hopping. Current approaches confine the generation to a predefined molecular substructure (e.g., a linker or scaffold) for scaffold hopping. This confined generation may limit the exploration of the chemical space and require intricate molecule (dis)assembly rules. In this work, we aim to advance reinforcement learning for scaffold hopping, by allowing "unconstrained", full-molecule generation. This is achieved via the RuSH (Reinforcement Learning for Unconstrained Scaffold Hopping) approach. RuSH steers the generation toward the design of full molecules having a high three-dimensional and pharmacophore similarity to a reference molecule, but low scaffold similarity. In this first study, we show the flexibility and effectiveness of RuSH in exploring analogs of known scaffold-hops and in designing scaffold-hopping candidates that match known binding mechanisms. Finally, the comparison between RuSH and two established methods highlights the benefit of its unconstrained molecule generation to systematically achieve scaffold diversity while preserving optimal three-dimensional properties
A cooperative release of mitochondrial DNA from platelets and neutrophils drives an interferon signature in systemic sclerosis.
No full textMitochondria are organelles with a hypomethylated circular genome. Mitochondrial DNA (mtDNA) in the systemic circulation has been implicated in inflammation. This study investigates the role of circulating DNA in systemic sclerosis (SSc) and the cellular mechanisms governing its release.Total DNA was isolated from plasma of healthy individuals and SSc patients. Copy numbers were analyzed for mtDNA (ATP-6) and GAPDH abundance by qPCR. mtDNA was isolated from HC and SSc patients. Neutrophils and platelets were incubated with SSc patients' plasma and mtDNA, and NET formation was assessed by SytoxGreen and immunostainings. Platelets were tested for mtDNA release propensity. DNA oxidation was evaluated by MitoSOX Red staining in vitro and 8-OHdG ELISA of patient plasma. Plasma IFN type 1 and CXCL4 were measured by ELISA. IFN signaling activation capacity was evaluated utilizing THP1 reporter cells and confirmed by a whole blood bulk RNA transcriptomic analysis.Median plasma mtDNA levels were 152-fold higher in SSc patients compared to healthy controls (HC), while nDNA levels were similar. mtDNA from SSc plasma was highly oxidized. SSc-derived mtDNA efficiently promoted its own release by NETosis, most potently in SSc patient neutrophils, and by platelet activation. Oxidized mtDNA from SSc platelets in complex with CXCL4 further stimulated mtDNA release in both neutrophils and platelets. mtDNA plasma concentrations correlated with type I IFN concentrations in SSc patient blood, and SSc blood exhibited elevated interferon-stimulated gene (ISG) expression. SSc plasma-derived mtDNA induced IFN signaling and NET formation via endosomal TLR, cGAS/STING and the JAK/STAT pathway. The type I IFN pathway further promoted NETosis and mtDNA release since IFN receptor (IFNAR) and Janus kinase (JAK) inhibition antagonized the proNETotic effects of IFN.SSc plasma is characterized by highly abundant mtDNA, which drives feedback loops amplifying its own release from both neutrophils and platelets. Thus, mtDNA contributes to inflammation and tissue damage in SSc
Beyond Liquid Chromatography: Cyclic Ion Mobility Spectrometry for Phosphorothioate Diastereomer Separation in siRNA
No full textPhosphorothioate (PS) modifications in small interfering RNA (siRNA) moieties enhance stability and therapeutic efficacy but introduce diastereomeric heterogeneity, complicating structural characterization. Conventional chromatographic methods, such as ion-pair reversed-phase liquid chromatography, provide limited resolution of complex stereoisomer systems, necessitating alternative analytical approaches. In this work, we systematically evaluate cyclic ion mobility spectrometry (cIMS) for the separation and identification of PS diastereomers by investigating oligonucleotide systems with varying chain length and PS linkage patterns that mimic the metabolic diversity in siRNA therapeutics. Our results demonstrate that cIMS effectively separates diastereomers in short (5-mer) to medium-length (9-mer) oligonucleotides, with separation efficiency influenced by charge state and salt adduction. Higher charge states enhance resolution by narrowing conformational distributions and enabling increased numbers of cIMS passes, while sodium and potassium adducts improve separation by promoting distinct gas-phase conformers. However, as system size increases (15-mer), the relative influence of terminal diastereomers on the overall structure diminishes, leading to a reduced separation efficiency and ultimately preventing the resolution of long-chain siRNAs. Comparisons between experimental and computationally predicted collisional cross sections (CCS) underscore both the potential and limitations of CCS-based diastereomer assignment, emphasizing the need for refined computational models or orthogonal validation methods. These findings highlight cIMS as a powerful and complementary tool for the structural characterization of stereochemically complex oligonucleotide therapeutics, providing valuable insights for siRNA drug development
Redefining the Therapeutic Frontier in Autoimmune Disease
No full textThe treatment of autoimmune rheumatic diseases is entering a transformative era. Traditional immunosuppressive strategies, while effective for many, often fall short in patients with severe and refractory disease. Recent advances in the treatment landscape are redefining therapeutic possibilities, offering not just disease control but the potential for durable remission for these patients. At the forefront of this paradigm shift is the application of chimeric antigen receptor (CAR) T cell therapy—originally developed for hematologic malignancies—to severe, treatment-refractory autoimmune conditions. A landmark case report from Erlangen University followed by a case series from the same group demonstrated that autologous CD19-targeted CAR-T cells induced sustained, drug-free remission in patients with systemic lupus erythematosus (SLE), accompanied by a profound reshaping of the B cell compartment and normalization of immune signatures (Mougiakakos et al. 2021, Mackensen et al 2022). Emerging data suggests that CAR-T cells can eliminate autoreactive B cells and restore immune tolerance in autoimmune indications beyond SLE, in idiopathic inflammatory myopathies and systemic sclerosis (Schett et al. 2024). Emerging data from formal clinical trials evaluating CD19 CAR-T also suggest transformational efficacy in SLE (Morand et al, 2025) and other autoimmune diseases