ACS Pharmacology and Translational Science最新文献

{"title":"A Computational Glucoregulatory Model of Liver and Glucagon for the Evaluation of Therapeutics","authors":"Xun Gong,&nbsp;Ali A. Alizadehmojarad,&nbsp;Marco Machado,&nbsp;Sungyun Yang and Michael S. Strano*,&nbsp;","doi":"10.1021/acsptsci.5c00177","DOIUrl":"https://doi.org/10.1021/acsptsci.5c00177","url":null,"abstract":"<p >Computational models of the glucoregulatory system constitute a powerful tool for preclinical evaluation and mechanistic insight into therapeutics. However, in the case of diabetes, there is a dearth of physiological models capable of accurately describing the hormone glucagon, which is important for the study and design of new classes of therapeutics, such as glucose-responsive glucagon (GRG). In this work, we construct a physiological compartment model, IMPACT 2.0, which integrates a refined liver submodel and explicit whole-body glucagon kinetics. Key mechanistic enhancements include glucose transporter dynamics, receptor binding, and hepatic glycogen metabolism, allowing for the improved prediction of glucose excursions in response to both insulin- and glucagon-based therapeutics. Model validation against experimental data from healthy and diabetic rats demonstrated accurate glucose predictions following insulin and glucagon administration. Sensitivity analysis was used to evaluate our model’s identifiability in the case of insulin or glucagon subcutaneous injections. By comparing diabetic and healthy model fits, we found that 16 of the 37 fitting parameters were significantly different between the health states. Additionally, we applied IMPACT 2.0 to evaluate a recently developed GRG based on controlled release via a microneedle patch, illustrating its utility in mechanistic drug design and bridging in vitro characterization with physiological outcomes. By offering a physiologically detailed and validated framework for glucagon and liver metabolism, IMPACT 2.0 is an improved pharmacokinetic and pharmacodynamic model that will be valuable for accelerating drug discovery, optimizing GRG formulations, and informing the design of closed-loop insulin and glucagon therapeutics.</p>","PeriodicalId":36426,"journal":{"name":"ACS Pharmacology and Translational Science","volume":"8 9","pages":"2983–2995"},"PeriodicalIF":3.7,"publicationDate":"2025-08-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145036533","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Hypoxia, Psychedelics, and Terminal Lucidity: A Perspective on Neuroplasticity and Neuropsychiatric Disorders","authors":"Junjie Zhang,&nbsp;Xiubo Du,&nbsp;Xinying Li,&nbsp;Xinyou Lv and Xiaohui Wang*,&nbsp;","doi":"10.1021/acsptsci.5c00440","DOIUrl":"https://doi.org/10.1021/acsptsci.5c00440","url":null,"abstract":"<p >Hypoxia and psychedelics, despite their distinct origins, both induce altered states of consciousness and promote neuroplasticity, suggesting a shared underlying mechanism relevant to neuropsychiatric treatment and neurological recovery. Terminal lucidity, the transient resurgence of cognitive function in late-stage dementia, highlights the brain’s latent capacity for rapid reorganization, a phenomenon that may be driven by transient hypoxia. Similarly, acute intermittent hypoxia and pharmacological agents like HypoxyStat, which modulate oxygen availability, have emerged as potential strategies for enhancing neural adaptability. This perspective explores the hypothesis that controlled reductions in oxygen availability─whether through psychedelics, near-death experiences, meditation, holotropic breathwork, or hypoxia therapies─trigger calcium signaling pathways that promote synaptogenesis and the formation of new neural circuits. Rather than restoring damaged connections, this process may enable functional rerouting, thereby supporting cognitive resilience and behavioral compensation in conditions such as stroke, Alzheimer’s disease, and psychiatric disorders. By integrating insights from psychedelic research, hypoxia-based therapies, and neuroplasticity studies, we propose a unifying framework that leverages altered oxygen homeostasis as a novel therapeutic strategy for neuropsychiatric and neurodegenerative diseases.</p>","PeriodicalId":36426,"journal":{"name":"ACS Pharmacology and Translational Science","volume":"8 9","pages":"2848–2854"},"PeriodicalIF":3.7,"publicationDate":"2025-08-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145036530","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Hyperfiltration and Elevated Fractional Excretion of Magnesium in Children with Cystic Fibrosis","authors":"Elena K. Schneider-Futschik,&nbsp;Courtney B. Munro,&nbsp;Danni Li,&nbsp;Sarath Ranganathan and Catherine Quinlan*,&nbsp;","doi":"10.1021/acsptsci.5c00330","DOIUrl":"https://doi.org/10.1021/acsptsci.5c00330","url":null,"abstract":"<p >Several critical knowledge gaps exist in understanding and managing renal function in pediatric patients with cystic fibrosis (CF). A limited amount of data demonstrates hyperfiltration in CF, yet it is unknown how these changes in relation to intravenous (IV) aminoglycosides and evolves into chronic kidney disease in CF. Similarly, there is limited information on the fractional excretion of magnesium (FEMg) in relation to acute kidney injury induced by IV aminoglycosides. The PIANO–CF trial was a single-center study conducted at a pediatric hospital in Australia, looking at young children with CF who were admitted for IV aminoglycoside therapy. In relation to IV aminoglycoside therapy, the study evaluated the estimated glomerular filtration rate, serum magnesium, FEMg, and urine creatinine (UCr). For children with CF admitted for IV aminoglycosides, estimated glomerular filtration rate indicated hyperfiltration in 87% at baseline and 81% post-IV aminoglycosides. A significant increase in FEMg was observed with treatment, with a mean increase of 2.6% (<i>p</i> = 0.0143). FEMg values increased significantly with tobramycin administration (<i>p</i> = 0.0024 and <i>p</i> = 0.0021). Hyperfiltration rates in young children with CF were high at ∼80%. It is not known what the resulting effect of hyperfiltration has on susceptibility to acute kidney injury or the development of chronic kidney disease in CF. Finally, given the high rates of FEMg, renal wasting of magnesium in CF warrants further study.</p>","PeriodicalId":36426,"journal":{"name":"ACS Pharmacology and Translational Science","volume":"8 9","pages":"3199–3206"},"PeriodicalIF":3.7,"publicationDate":"2025-08-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145036438","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A Difluorinated Derivative of ARC-111 Suppresses Intrahepatic Cholangiocarcinoma Growth via Targeting Topoisomerase I","authors":"Yin-Peng Bai,&nbsp;Mi Zhang,&nbsp;Jian-Hua Liu,&nbsp;Gui-Sha Chen,&nbsp;Cheng-Jie Yang,&nbsp;Nan Deng,&nbsp;Chan-Yuan Chen,&nbsp;Zhi-Ping Wang,&nbsp;Chuan-Rui Xu,&nbsp;Zhi-Jun Zhang,&nbsp;Lei Li*,&nbsp;Li-Zeng Peng,&nbsp;Min Liu and Ying-Qian Liu*,&nbsp;","doi":"10.1021/acsptsci.5c00114","DOIUrl":"https://doi.org/10.1021/acsptsci.5c00114","url":null,"abstract":"<p >Intrahepatic cholangiocarcinoma (ICC) has limited treatment options and a poor prognosis. Thus, novel therapeutics are urgently needed. Topoisomerase I (Top I), an essential DNA regulatory enzyme, is commonly upregulated in malignancies and contributes to their aggressive growth. ARC-111 derivative <b>YCJ-02</b> is a new synthesized Top I inhibitor with a structure different from camptothecin, but its potential for ICC treatment is not clear. In this study, we investigated the potential of <b>YCJ-02</b> to inhibit the growth of ICC cells in vitro and verified its antitumor activity in vivo by using an AKT/NICD-induced ICC preclinical mouse model. We found that Top I was overexpressed in human ICC tissues and cell lines and knockdown of Top I inhibited ICC cell growth. Consistently, Top I inhibitor <b>YCJ-02</b> blocked the proliferation of ICC cells and showed superior cytotoxic activity compared to reference drugs ARC-111, topotecan, and SN-38. Mechanistically, <b>YCJ-02</b> arrested the cell cycle at the G2/M phase and elevated p21 expression. Subsequently, apoptosis was induced, characterized by increased Bax, Bad, and cleaved caspase3 and decreased Bcl-2. <b>YCJ-02</b> also induced DNA damage, as shown with increased γ-H2AX. Interestingly, DNA relaxation assay and Western blotting showed that <b>YCJ-02</b> not only functions as a Top I poison but also promotes its degradation via a ubiquitin/26S proteasome pathway. Critically, <b>YCJ-02</b> dramatically suppressed AKT/NICD-induced ICC growth in mice and decreased the expression of Top I. Together, this study demonstrates that <b>YCJ-02</b> is an effective Top I inhibitor with high potency in inhibiting ICC growth and merits further preclinical evaluation.</p>","PeriodicalId":36426,"journal":{"name":"ACS Pharmacology and Translational Science","volume":"8 9","pages":"2936–2952"},"PeriodicalIF":3.7,"publicationDate":"2025-08-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145036433","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Insights into the Expression, Structure, and Function of the Thromboxane A2 Receptor in Vascular Biology","authors":"Robert Eckenstaler,&nbsp; and ,&nbsp;Ralf A. Benndorf*,&nbsp;","doi":"10.1021/acsptsci.5c00378","DOIUrl":"https://doi.org/10.1021/acsptsci.5c00378","url":null,"abstract":"<p >The thromboxane A₂ receptor is known for its role in platelet aggregation. In platelets, loss or gain-of-function of the thromboxane A₂ receptor may therefore lead to bleeding disorders or prothrombotic conditions. However, the thromboxane A₂ receptor is also expressed in many other cell types and tissues and is thought to contribute to a broad range of other pathophysiological processes, such as pulmonary hypertension and cancer cell metastasis. In endothelial cells, the thromboxane A₂ receptor is an important player in the pathogenesis of endothelial dysfunction, one of the main contributors to the development of hypertension and atherosclerosis-related diseases. In this review, we provide insight into the genomic structure and expression, protein structure and function of the thromboxane A₂ receptor, with a particular focus on vascular (patho)physiology and recent findings regarding the involvement of thromboxane A₂ receptor signaling in the pathogenesis of endothelial dysfunction and cardiovascular disease. In addition, we provide an overview of clinically relevant polymorphisms within the thromboxane A₂ receptor gene (<i>TBXA2R</i>) and their influence on gene expression, protein structure, and receptor pathophysiology.</p>","PeriodicalId":36426,"journal":{"name":"ACS Pharmacology and Translational Science","volume":"8 9","pages":"2887–2907"},"PeriodicalIF":3.7,"publicationDate":"2025-08-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145036371","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Spermine-Functionalized Multiepitope Signaling Peptide Nanovaccine to Stimulate the Systemic Immunity against Pneumonia","authors":"Arivalagan Ponbharathi,&nbsp;Sivaraj Mehnath,&nbsp;Chithaiyan Kamaladevi Sowndharya,&nbsp;Kannaiyakumar Dharshini,&nbsp;Ammavasi Chandran Ambigaibalan and Murugaraj Jeyaraj*,&nbsp;","doi":"10.1021/acsptsci.5c00328","DOIUrl":"https://doi.org/10.1021/acsptsci.5c00328","url":null,"abstract":"<p >Pneumonia is a high-risk chronic respiratory infection with serious morbidity and mortality rates. Existing vaccines have a poor immune response; vaccine efficiency is limited to the specific serotypes, indicating an urgent need to develop an effective vaccine. The study pursues to design multiepitope signaling peptide nanovaccine using the YSIRK-G/S motif, B/T-cell epitope, and surface modification of the dextran (Dex), functionalized with spermine. It improves the higher load of signaling peptide motif (SPM), pH-responsive delivery, immune cell targeting, endosomal escape, higher antigenicity, and immune activation. The surface modification of dextran enhances nanoparticle uptake, and spermine functionalization regulates particle aggregation. Spermine-modified acetalated dextran nanoparticles (AcDx-Sp NPs) show a higher loading of SPM and uniform spherical morphology with a size range of 105 nm. After impregnation of SPM, the nanovaccine was stable and maintained the structural integrity for 3 days in both PBS and DMEM. In acidic pH conditions, the nanovaccine destabilized to release SPM in 65% in 5 days; at pH 5.0, AcDx was degraded into Dex, providing endosomal escape and releasing the SPM. In vitro studies show the activation of dendritic cells (DCs) and upregulation up to a 200-fold increase in pro-inflammatory cytokine compared to SPM. Comparatively, mice after immunization elicited higher antibody titers and stimulated the robust CD4⁺ and CD8⁺ T-cell responses, alongside strong IgA and IgG production. Serum bacterial neutralization assay confirms the high amount of antibody production, and it is able to neutralize the bacteria, which was confirmed through confocal and HRTEM analysis. This potent neutralization capability underscores the therapeutic promise of these antibodies for controlling bacterial pathogenesis. Overall, nanovaccine was potentially targeting the antigen-presenting cells (APCs), inherent adjuvant function, and peptides providing systemic immunity.</p>","PeriodicalId":36426,"journal":{"name":"ACS Pharmacology and Translational Science","volume":"8 9","pages":"3182–3198"},"PeriodicalIF":3.7,"publicationDate":"2025-08-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145036475","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Photoactivatable Cisplatin-Combretastatin-BODIPY Pt(IV) Prodrug for Dual-Action Light-Controlled Chemotherapy","authors":"Daniil V. Spector,&nbsp;Georgy Karetnikov,&nbsp;Anna Bubley,&nbsp;Roman A. Akasov,&nbsp;Yulia A. Isaeva,&nbsp;Tatiana V. Egorova,&nbsp;Alexander G. Martynov,&nbsp;Dmitry Bunin,&nbsp;Dmitry A. Skvortsov,&nbsp;Daria Ipatova,&nbsp;Alexander S. Erofeev,&nbsp;Petr V. Gorelkin,&nbsp;Vugara Mamed-Nabizade,&nbsp;Vasilii S. Kolmogorov,&nbsp;Alexander N. Vaneev,&nbsp;Igor A. Rodin,&nbsp;Mikhail F. Vokuev,&nbsp;Yuri K. Grishin,&nbsp;Vitaly A. Roznyatovsky,&nbsp;Vita N. Nikitina,&nbsp;Elena K. Beloglazkina and Olga O. Krasnovskaya*,&nbsp;","doi":"10.1021/acsptsci.5c00442","DOIUrl":"https://doi.org/10.1021/acsptsci.5c00442","url":null,"abstract":"<p >Herein, we designed, synthesized, and studied the activity of a novel dual-action red light-activatable Pt(IV) prodrug <b>BDP-Pt-CA4</b> with a BODIPY fluorophore and CA4 in axial positions, capable of light-controlled release of two chemotherapeutic drugs: cisplatin and combretastatin A4 (CA4). To the best of our knowledge, this is the first example of a dual-action photoactive Pt(IV)-CA4 prodrug that releases two antiproliferative agents upon red light irradiation. The aim of this work was to demonstrate light-induced release of CA4 and cisplatin from the prodrug, occurring strictly on demand to reduce the overall toxicity of the drug and minimize the damaging effect on normal tissues. In addition to <i>in vitro</i> evidence of light-induced release of two chemotherapeutic agents, a controllable release of both drugs inside cancer cells was also proven. For the first time, a light-induced release of the tubulin polymerization inhibitor from a photoactivatable prodrug was observed via quantification of subtle changes in the mechanistic properties of cell surfaces via single-cell low-stress scanning ion conductance microscopy (SICM). Our results clearly demonstrate a perspective for photoactive Pt(IV) prodrugs, confirming an ability to release the platinum agent “on demand”, and to act as light-controlled dual-action chemotherapy.</p>","PeriodicalId":36426,"journal":{"name":"ACS Pharmacology and Translational Science","volume":"8 9","pages":"3296–3313"},"PeriodicalIF":3.7,"publicationDate":"2025-08-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145036265","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Target Engagement Studies and Kinetic Live-Cell Degradation Assays Enable the Systematic Characterization of Histone Deacetylase 6 Degraders","authors":"Maria Hanl,&nbsp;Felix Feller,&nbsp;Irina Honin,&nbsp;Kathrin Tan,&nbsp;Martina Miranda,&nbsp;Linda Schäker-Hübner,&nbsp;Nico Bückreiß,&nbsp;Matthias Schiedel,&nbsp;Michael Gütschow,&nbsp;Gerd Bendas and Finn K. Hansen*,&nbsp;","doi":"10.1021/acsptsci.5c00247","DOIUrl":"https://doi.org/10.1021/acsptsci.5c00247","url":null,"abstract":"<p >Histone deacetylase 6 (HDAC6) is an important drug target for the treatment of cancer, inflammation, and neurodegenerative disorders. In recent years, the development of proteolysis-targeting chimeras (PROTACs) has emerged to achieve the chemical knockdown of HDAC6. Consequently, there is an urgent need to develop efficient methods for target engagement studies and to enable a thorough characterization of the degradation efficiency and kinetics of HDAC6 PROTACs. In this work, we present a simple NanoBRET assay to assess HDAC6 cellular target engagement using a HeLa^{HDAC6–HiBiT} cell line that stably expresses the LgBiT protein. For this purpose, we successfully designed, synthesized, characterized, and utilized the cell permeable TAMRA-based fluorescent ligand <b>5</b>. The key advantage of this NanoBRET assay using HeLa^{HDAC6–HiBiT} cells is the endogenously tagged HDAC6, allowing us to study binding of inhibitors in a near-native environment. Furthermore, we succeeded in establishing a system for kinetic live cell monitoring of HDAC6 degradation. The analysis of the degradation kinetics of a set of HDAC6 PROTACs provided detailed insights into their degradation efficiency and will be helpful for the development of improved HDAC6 degraders in the future.</p>","PeriodicalId":36426,"journal":{"name":"ACS Pharmacology and Translational Science","volume":"8 9","pages":"3074–3089"},"PeriodicalIF":3.7,"publicationDate":"2025-08-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145036660","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Design and Synthesis of Novel Pirfenidone Analogues for Targeting Fibroblast Differentiation via Transforming Growth Factor-β/Smad Pathway Using In Vitro and In Vivo Models","authors":"Laxman D. Nandawadekar,&nbsp;Vaishnavi Kambhampati,&nbsp;Sai Kiran Kunuru,&nbsp;Madhusudhana Kuncha,&nbsp;Sai Balaji Andugulapati* and D. Srinivasa Reddy*,&nbsp;","doi":"10.1021/acsptsci.5c00280","DOIUrl":"https://doi.org/10.1021/acsptsci.5c00280","url":null,"abstract":"<p >Pulmonary fibrosis is a progressive interstitial lung disease characterized by excessive extracellular matrix (ECM) deposition, resulting in impaired respiratory function. Due to the limited efficacy of current antifibrotic therapies, there is an urgent need to develop novel agents or optimize existing drugs. In this study, a series of pirfenidone (PFD) derivatives were rationally designed and synthesized with targeted modifications at the third position of the core scaffold to enhance antifibrotic efficacy. A total of 30 derivatives (100 μM) were screened using a TGF-β-induced differentiation model, leading to the identification of hit compounds with superior activity compared to PFD (500 μM). Selected candidates were further validated both in vitro (LL29 and DHLF cells) and in the bleomycin (BLMN)-induced pulmonary fibrosis mouse model. In vitro, compounds <b>6a</b> and <b>10b</b> (50 and 100 μM) demonstrated robust suppression of fibrotic markers, as confirmed by RT-qPCR and immunofluorescence, indicating a dose-dependent antifibrotic effect. In vivo, BLMN administration significantly increased the lung index and fibrotic marker expression. In contrast, compounds <b>6a</b> and <b>10b</b> significantly downregulated the expression of fibrotic markers (including FN1, α-SMA, and collagen1α1). Histopathological analysis revealed that compound <b>10b</b> effectively mitigated BLMN-induced alveolar wall thickening and collagen deposition, and significantly restored lung function in a dose-dependent manner, outperforming the PFD group. Mechanistic studies further indicated that <b>10b</b> exerts its effects through modulation of the SMAD3/SMAD7 signaling pathway. Additionally, compound <b>10b</b> exhibited a pharmacokinetic profile comparable to PFD. Collectively, these findings support compound <b>10b</b> as a promising antifibrotic candidate with strong potential for clinical translation.</p>","PeriodicalId":36426,"journal":{"name":"ACS Pharmacology and Translational Science","volume":"8 9","pages":"3101–3125"},"PeriodicalIF":3.7,"publicationDate":"2025-08-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145036268","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cross-Species Extrapolation of Neonatal Fc Receptor (FcRn) Binding Affinity to Predict Monoclonal Antibody Pharmacokinetics in Humans Using Physiologically Based Pharmacokinetic Modeling (PBPK): Are We There Yet?","authors":"Salih Benamara,&nbsp;Carla Troisi,&nbsp;Florence Gattacceca,&nbsp;Erik Sjögren,&nbsp;Laurent Nguyen and Donato Teutonico*,&nbsp;","doi":"10.1021/acsptsci.5c00356","DOIUrl":"https://doi.org/10.1021/acsptsci.5c00356","url":null,"abstract":"<p >Physiologically based pharmacokinetic (PBPK) modeling is a useful tool during drug development due to its ability to extrapolate pharmacokinetics (PK) between species and populations. For monoclonal antibodies (mAbs), these models can be used to support dose selection, especially for first-in-human (FIH) trials. In the PBPK model for biologics in the software PK-Sim, salvaging from endosomal degradation via the neonatal fragment crystallizable receptor (FcRn) is a critical process for the systemic clearance of mAbs. However, high variability is associated with in vitro measurements of the dissociation constant (<i>K</i>_d) for FcRn (<i>K</i>_{d_FcRn}) in human. Furthermore, predicting affinity for FcRn in human presents a significant challenge due to the lack of a standardized methodology. In this paper, we evaluated different predictors of the <i>K</i>_d for FcRn (<i>K</i>_{d_FcRn}) in humans to enhance the precision of mAbs PK projections for FIH trials. A database comprising PK profiles for 27 mAbs was constructed across different species. Plasma concentration–time courses for each drug and species were used to develop a PBPK model for each compound, by estimating the <i>K</i>_{d_FcRn} for each species. Cross-species correlations were established to explore extrapolation performances of <i>K</i>_{d_FcRn} from animals to humans. As an alternative to using animal data, a direct prediction approach, based on the median of the 27 human <i>K</i>_{d_FcRn} values, was assessed. When considering a prediction error of 100% (2-fold deviation), both the extrapolation from preclinical species and the direct approach based on the median human value accurately predict at least 80% of the <i>K</i>_{d_FcRn} values within the prediction interval.</p>","PeriodicalId":36426,"journal":{"name":"ACS Pharmacology and Translational Science","volume":"8 9","pages":"3207–3220"},"PeriodicalIF":3.7,"publicationDate":"2025-08-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145036231","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}