Toxicologic Pathology最新文献

{"title":"Applications of Cell-Based Protein Array Technology to Preclinical Safety Assessment of Biological Products.","authors":"Axel Vicart, Cam Holland, Kathryn Fraser, Frederic Gervais, Mark Aspinall-O'Dea, Nick Brown, Kirk Siddals, Géraldine Greiner, Vinicius Carreira, Elizabeth Galbreath, Maggie Willer, Saravanan Kaliyaperumal, Charles Wood, Tim MacLachlan, Elizabeth Clark","doi":"10.1177/01926233241311259","DOIUrl":"10.1177/01926233241311259","url":null,"abstract":"<p><p>Off-target evaluation is essential in preclinical safety assessments of novel biotherapeutics, supporting lead molecule selection, endpoint selection in toxicology studies, and regulatory requirements for first-in-human trials. Off-target interaction of a therapeutic antibody and antibody derivatives has been historically assessed via the Tissue Cross-Reactivity (TCR) study, in which the candidate molecule is used as a reagent in immunohistochemistry (IHC) to assess binding of the candidate molecule to a panel of human tissue sections. The TCR approach is limited by the performance of the therapeutic as an IHC reagent, which is often suboptimal to outright infeasible. Furthermore, binding of the therapeutic in IHC conditions typically has poor in vitro to in vivo translation and lacks qualitative data of the identity of putative off-targets limiting the decisional value of the data. More recently, cell-based protein arrays (CBPA) that allow for screening against a large portion of the human membrane proteome and secretome have emerged as a complement, and likely a higher value alternative, to IHC-based off-target assessment. These arrays identify specific protein interactions and may be useful for testing nontraditional antibody-based therapeutic formats that are unsuitable for TCR studies. This article presents an overview of CBPA technologies in the context of TCR and off-target assessment studies. Selected case examples and strategic considerations covering a range of different modalities are presented.</p>","PeriodicalId":23113,"journal":{"name":"Toxicologic Pathology","volume":" ","pages":"31-44"},"PeriodicalIF":1.4,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143053717","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Thank You to Reviewers.","authors":"","doi":"10.1177/01926233251315826","DOIUrl":"https://doi.org/10.1177/01926233251315826","url":null,"abstract":"","PeriodicalId":23113,"journal":{"name":"Toxicologic Pathology","volume":"53 1","pages":"159"},"PeriodicalIF":1.4,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143516852","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Characterizing Antisense Oligonucleotide-Induced Histopathology Findings in Spinal Cord of Mauritius Cynomolgus Monkeys by Molecular Localization Investigation.","authors":"Valérie Dubost, Kuno Wuersch, Kelley Penraat, Eric Johnson, Anja Wekkeli, Ramprasad Ramakrishna, Aline Piequet, Géeraldine Greiner, Magali Jivkov, Esther Erard, Regine Hansen, Dominique Brees, Andreas Hartmann, Kamal Kumar Balavenkatraman, Jairo Nunes","doi":"10.1177/01926233241311277","DOIUrl":"10.1177/01926233241311277","url":null,"abstract":"<p><p>The safety of a 2'-<i>O</i>-methoxyethyl antisense oligonucleotide (ASO) was investigated in Mauritius cynomolgus monkeys in a 41-week Good Laboratory Practice (GLP) toxicity study after multiple intrathecal (IT) administrations. Histopathological examination revealed ectopic formation of lymphoid follicles in the spinal cord (SC) at the injection site at all doses and the presence of granular material in neurons of the SC in high-dose animals. The granular material was seen in all the segments of the SC, but mainly in the lumbar segment and persisted at the end of the 26-week recovery period, while the lymphoid follicles showed a reversibility trend. Findings associated with repeated IT administration of ASOs have been described in nonhuman primate (NHP) toxicity studies, specifically in the brain, but findings in the SC are rarely reported. In the present study, we report a high incidence of findings in the SC compared to brain, especially in the lumbar segment in proximity to IT injection sites. An extensive panel of immunohistochemistry markers showed that the ectopic lymphoid follicle formation (LFF) had a cellular composition and organization consistent with tertiary lymphoid structure (TLS) without associated axonal damage in the adjacent nervous tissue. In situ hybridization with an miRNA probe complementary to the ASO revealed that the granular material represented a dose-dependent ASO accumulation in the cytoplasm of neurons without inducing cell death or apoptosis. Glial and ependymal cells in the SC also showed dose-dependent accumulation of the ASO preceding detection of granular material by hematoxylin and eosin (H&E). Based on these molecular localization data, the presence of LFF in SC suggests a chronic local immune activation. Considering the absence of neuronal dysfunction or injury and transient clinical signs previously reported with other 2'-<i>MOE</i> ASOs, the presence of TLS and ASO was considered non-adverse.</p>","PeriodicalId":23113,"journal":{"name":"Toxicologic Pathology","volume":" ","pages":"95-106"},"PeriodicalIF":1.4,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143068182","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"European Society of Toxicologic Pathology-Pathology 2.0 Mass Spectrometry Imaging Special Interest Group: Mass Spectrometry Imaging in Diagnostic and Toxicologic Pathology for Label-Free Detection of Molecules-From Basics to Practical Applications.","authors":"Enrico Vezzali, Michael Becker, Fernando Romero-Palomo, Marjolein van Heerden, Caroline Chipeaux, Gregory Hamm, Dinesh S Bangari, Thomas Lemarchand, Barbara Lenz, Bogdan Munteanu, Bhanu Singh, Celine Thuilliez, Seong-Wook Yun, Andrew Smith, Rob Vreeken","doi":"10.1177/01926233241311269","DOIUrl":"10.1177/01926233241311269","url":null,"abstract":"<p><p>Mass Spectrometry Imaging (MSI) is a powerful tool to understand molecular pathophysiology and therapeutic and toxicity mechanisms, as well as for patient stratification and precision medicine. MSI, a label-free technique offering detailed spatial information on a large number of molecules in different tissues, encompasses various techniques including Matrix-Assisted Laser Desorption Ionization (MALDI), Desorption Electrospray Ionization (DESI), and Secondary Ion Mass Spectrometry (SIMS) that can be applied in diagnostic and toxicologic pathology. Given the utmost importance of high-quality samples, pathologists play a pivotal role in providing comprehensive pathobiology and histopathology knowledge, as well as information on tissue sampling, orientation, morphology, endogenous biomarkers, and pathogenesis, which are crucial for the correct interpretation of targeted experiments. This article introduces MSI and its fundamentals, and reports on case examples, determining the best suited technology to address research questions. High-level principles and characteristics of the most used modalities for spatial metabolomics, lipidomics and proteomics, sensitivity and specific requirements for sample procurement and preparation are discussed. MSI applications for projects focused on drug metabolism, nonclinical safety assessment, and pharmacokinetics/pharmacodynamics and various diagnostic pathology cases from nonclinical and clinical settings are showcased.</p>","PeriodicalId":23113,"journal":{"name":"Toxicologic Pathology","volume":" ","pages":"130-158"},"PeriodicalIF":1.4,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143190356","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Points to Consider From the ESTP Pathology 2.0 Working Group: Overview on Spatial Omics Technologies Supporting Drug Discovery and Development.","authors":"Kerstin Hahn, Bettina Amberg, Josep M Monné Rodriguez, Mieke Verslegers, Byunghak Kang, Hans Wils, Chandra Saravanan, Dinesh S Bangari, Simon Y Long, Sameh A Youssef, Benedek Pesti, Johanna Schaffenrath, Alberto Valdeolivas, Nadine Kumpesa, José A Galván, Marion Richardson, Nicolas Giroud, Leo Kunz, Inês Berenguer Veiga, Michael Bscheider, Precious Cramer, Sizun Jiang, Robert Kreutzer, Enrico Vezzali, Seong-Wook Yun, Sven Rottenberg, Bjoern Jacobsen","doi":"10.1177/01926233241311258","DOIUrl":"10.1177/01926233241311258","url":null,"abstract":"<p><p>Recent advances in bioanalytical and imaging technologies have revolutionized our ability to assess complex biological and pathological changes within tissue samples. Spatial omics, a rapidly evolving technology, enables the simultaneous detection of multiple biomolecules in tissue sections, allowing for high-dimensional molecular profiling within tissue microanatomical contexts. This offers a powerful opportunity for precise, multidimensional exploration of complex disease pathophysiology. The Pathology 2.0 working group within the European Society of Toxicologic Pathology (ESTP) includes a subgroup dedicated to spatial omics technologies. Their primary goal is to raise awareness about these emerging technologies and their potential applications in discovery and toxicologic pathology. This review provides an overview of commonly used, commercially available platforms for transcriptomic, proteomic, and multiomic analysis, discussing technical aspects and illustrative examples of their applications. To harness the power of spatial omics for translational drug discovery and human safety risk assessment, we emphasize the important role of pathologists at every stage of the workflow-from hypothesis generation to sample preparation, data analysis, and interpretation. Spatial omics technologies offer novel opportunities in target discovery, lead selection, preclinical assessment, and clinical development in compound development.</p>","PeriodicalId":23113,"journal":{"name":"Toxicologic Pathology","volume":" ","pages":"107-129"},"PeriodicalIF":1.4,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143391787","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Trends and Challenges of the Modern Pathology Laboratory for Biopharmaceutical Research Excellence.","authors":"Sílvia Sisó, Anoop Murthy Kavirayani, Suzana Couto, Birgit Stierstorfer, Sunish Mohanan, Caroline Morel, Mathiew Marella, Dinesh S Bangari, Elizabeth Clark, Annette Schwartz, Vinicius Carreira","doi":"10.1177/01926233241303898","DOIUrl":"10.1177/01926233241303898","url":null,"abstract":"<p><p>Pathology, a fundamental discipline that bridges basic scientific discovery to the clinic, is integral to successful drug development. Intrinsically multimodal and multidimensional, anatomic pathology continues to be empowered by advancements in molecular and digital technologies enabling the spatial tissue detection of biomolecules such as genes, transcripts, and proteins. Over the past two decades, breakthroughs in spatial molecular biology technologies and advancements in automation and digitization of laboratory processes have enabled the implementation of higher throughput assays and the generation of extensive molecular data sets from tissue sections in biopharmaceutical research and development research units. It is our goal to provide readers with some rationale, advice, and ideas to help establish a modern molecular pathology laboratory to meet the emerging needs of biopharmaceutical research. This manuscript provides (1) a high-level overview of the current state and future vision for excellence in research pathology practice and (2) shared perspectives on how to optimally leverage the expertise of discovery, toxicologic, and translational pathologists to provide effective spatial, molecular, and digital pathology data to support modern drug discovery. It captures insights from the experiences, challenges, and solutions from pathology laboratories of various biopharmaceutical organizations, including their approaches to troubleshooting and adopting new technologies.</p>","PeriodicalId":23113,"journal":{"name":"Toxicologic Pathology","volume":" ","pages":"5-20"},"PeriodicalIF":1.4,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142824202","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Characterization of Pulmonary Pathology in the Golden Syrian Hamster Model of COVID-19 Using Micro-Computed Tomography.","authors":"Julita A Ramirez, Micah D Dunlap, Reyna Prosnitz, Anderson Watson, Mary K Montgomery, Matthew Gutman, Timothy M Coskran, Samantha L Levinson, Katharine Yang, Isis Kanevsky, Shambhunath Choudhary","doi":"10.1177/01926233241300451","DOIUrl":"https://doi.org/10.1177/01926233241300451","url":null,"abstract":"<p><p>The Golden Syrian hamster is a well-characterized rodent model for severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2)-associated pneumonia. We sought to characterize the pulmonary disease course during SARS-CoV-2 infection (strain USA-WA1/2020) in the hamster model using micro-computed tomography (micro-CT) and compare radiologic observations with histopathologic findings. We observed a range of radiologic abnormalities, including ground glass opacities (GGOs), consolidations, air bronchograms, and pneumomediastinum. The appearance, distribution, and progression of these abnormalities in hamsters were similar to those observed in the lungs of coronavirus disease 2019 (COVID-19) patients by clinical CT and chest X-rays, and correlated with clinical signs and weight loss during the course of disease. Histopathological analysis of infected hamsters revealed lung pathology characteristic of COVID-19 pneumonia, and we observed a strong association between CT and histopathologic scorings. We also analyzed accumulation of air in the thoracic cavity by both manual and automated threshold-based segmentation and found that automated analysis significantly decreases the time needed for data analysis. Data presented here demonstrate that micro-CT imaging can be a major tool in preclinical investigative studies using animal models by providing early and detailed assessment of disease severity and outcomes.</p>","PeriodicalId":23113,"journal":{"name":"Toxicologic Pathology","volume":" ","pages":"1926233241300451"},"PeriodicalIF":1.4,"publicationDate":"2024-12-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142781005","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Session 5: Protein Degraders.","authors":"Kiran Palyada, Renee Hukkanen, Stephanie Leuenroth-Quinn, Allison Vitsky, Richard Peterson, Katie Stamp, Clare Hoover, Laurie Volak","doi":"10.1177/01926233241300452","DOIUrl":"10.1177/01926233241300452","url":null,"abstract":"<p><p>The so-called undruggable space is an exciting area of potential growth for drug development. Undruggable proteins are defined as those unable to be targeted via conventional small molecule drugs. New modalities are being developed to potentially target these proteins. Targeted protein degradation (TPD) is one such new modality, which over the last two decades has moved from academia to industry. TPD makes use of the endogenous degradation machinery present in all cells, in which E3 ubiquitin ligases mark proteins for degradation via ubiquitin attachment. This session explored the challenges and perspectives of using protein degraders as novel therapeutic agents. The session began with a general introduction to the modality, followed by considerations in evaluating their on- and off-target toxicities including data from an IQ Consortium working group survey. Unique absorption, distribution, metabolism, and excretion (ADME) properties of degrader molecules were presented in relation to their effect on drug development and nonclinical safety assessment. The role of transgenic models in evaluating hemotoxicity associated with cereblon-based therapies was then discussed. A case study to derisk dose-limiting thrombocytopenia was also presented. Finally, a regulatory perspective on the challenges of having toxicity associated with protein degraders was presented.</p>","PeriodicalId":23113,"journal":{"name":"Toxicologic Pathology","volume":" ","pages":"553-565"},"PeriodicalIF":1.4,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142807216","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Neuropathological Findings in Nonclinical Species Following Administration of Adeno-Associated Virus (AAV)-Based Gene Therapy Vectors.","authors":"Brad Bolon, Elizabeth Buza, Elizabeth Galbreath, Joan Wicks, Francesca Cargnin, Juliette Hordeaux","doi":"10.1177/01926233241300314","DOIUrl":"10.1177/01926233241300314","url":null,"abstract":"<p><p>Adeno-associated virus (AAV) gene therapy vectors are an accepted platform for treating severe neurological diseases. Test article (TA)-related and procedure-related neuropathological effects following administration of AAV-based vectors are observed in the central nervous system (CNS) and peripheral nervous system (PNS). Leukocyte accumulation (mononuclear cell infiltration > inflammation) may occur in brain, spinal cord, spinal nerve roots (SNRs), sensory and autonomic ganglia, and rarely nerves. Leukocyte accumulation may be associated with neuron necrosis (sensory ganglia > CNS) and/or glial changes (microgliosis and/or astrocytosis in the CNS, increased satellite glial cellularity in ganglia and/or Schwann cellularity in nerves). Axonal degeneration secondary to neuronal injury may occur in the SNR (dorsal > ventral), spinal cord (dorsal and occasionally lateral funiculi), and brainstem centrally and in nerves peripherally. Patterns of AAV-associated microscopic findings in the CNS and PNS differ for TAs administered into brain parenchyma (where tissue at the injection site is affected most) versus TAs delivered into cerebrospinal fluid (CSF) or systemically (which primarily impacts sensory ganglion neurons and their processes in SNR and spinal cord). Changes related to the TA and procedure may overlap. While often interpreted as adverse, AAV-associated neuronal necrosis and axonal degeneration of limited severity generally do not preclude clinical testing.</p>","PeriodicalId":23113,"journal":{"name":"Toxicologic Pathology","volume":" ","pages":"489-505"},"PeriodicalIF":1.4,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142819284","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Session 4: mRNA and Self-Amplifying RNA (saRNA): Opportunities for Disease Prevention and Therapy.","authors":"Rani S Sellers, Lila Ramaiah, Sue-Jean Hong, Prashant Nambiar, Eric Jacquinet, Shan Naidu","doi":"10.1177/01926233241298572","DOIUrl":"10.1177/01926233241298572","url":null,"abstract":"<p><p>The unprecedented speed of developing vaccines against the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), responsible for the COVID-19 pandemic, has propelled mRNA technologies into the public eye. The versatility of mRNA technology, often referred to as \"plug and play,\" offers immense promise for rapidly updating vaccines to address newer variants of respiratory diseases and combat emerging infectious diseases and lethal pathogens, such as the Ebolavirus. However, the potential applications of mRNA technology extend well beyond prophylactic vaccines. This session explored the two primary mRNA platforms: nonreplicating mRNA and self-amplifying mRNA (variably referred to as saRNA, samRNA, or SAM). Presentation topics were on current research efforts aimed at broadening the applications of mRNA modalities beyond vaccines. Topics included opportunities for delivering mRNA via intra-tumoral and inhalational routes, immunological and systemic inflammatory responses elicited by these modalities, and regulatory considerations involved in the development and licensing of these technologies.</p>","PeriodicalId":23113,"journal":{"name":"Toxicologic Pathology","volume":" ","pages":"545-552"},"PeriodicalIF":1.4,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11673298/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142693617","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}