BioDrugs最新文献

{"title":"Frequency of Biological Drug Use in Older Patients with Immune-Mediated Inflammatory Diseases: Results from the Large-Scale Italian VALORE Distributed Database Network.","authors":"Federica Soardo, Andrea Spini, Giorgia Pellegrini, Giorgio Costa, Clément Mathieu, Chiara Bellitto, Luca L'Abbate, Ylenia Ingrasciotta, Olivia Leoni, Martina Zanforlini, Domenica Ancona, Paolo Stella, Anna Cavazzana, Angela Scapin, Sara Lopes, Valeria Belleudi, Stefano Ledda, Paolo Carta, Paola Rossi, Lucian Ejlli, Ester Sapigni, Aurora Puccini, Rita Francesca Scarpelli, Giovambattista De Sarro, Alessandra Allotta, Sebastiano Addario Pollina, Roberto Da Cas, Giampaolo Bucaneve, Antea Maria Pia Mangano, Francesco Balducci, Carla Sorrentino, Ilenia Senesi, Marco Tuccori, Rosa Gini, Stefania Spila-Alegiani, Marco Massari, Silvana Anna Maria Urru, Annalisa Campomori, Gianluca Trifirò","doi":"10.1007/s40259-025-00716-2","DOIUrl":"10.1007/s40259-025-00716-2","url":null,"abstract":"<p><strong>Background: </strong>Limited real-world data on biological drug use in older patients with immune-mediated inflammatory diseases (IMIDs) exist despite these drugs carrying serious risks in this population.</p><p><strong>Objective: </strong>We aimed to describe the frequency and persistence of biological drug use in older patients (≥ 65 years) with IMID, including inflammatory bowel diseases (IBDs), psoriatic arthritis/psoriasis, rheumatoid arthritis (RA), and ankylosing spondylitis, in a large Italian population.</p><p><strong>Methods: </strong>A retrospective cohort study using the VALORE distributed claims database network from 13 Italian regions in the years 2010-2022 was performed. Older patients with IMID receiving biological drugs were included. Yearly prevalence of biological drug use and treatment persistence among incident users, from first dispensing to discontinuation/switching to another drug, was measured. Multivariable logistic regression was employed to identify treatment discontinuation predictors.</p><p><strong>Results: </strong>The prevalence of biological drug use in older patients with IMID increased dramatically from 2010 (0.44 per 1000 residents) to 2022 (2.48 per 1000 residents). Overall, 25,284 incident users of biological drugs were identified, with a female/male ratio of 1.6 and a mean age of 71.0 (standard deviation ± 5.2) years. The median duration of follow-up was 4.2 (2.5-6.6) years, and the most common indication for use was RA (n = 8371; 33.1%). Overall, biological drug persistence was 54.4% at 1 year from treatment start. The highest persistence rates were found for vedolizumab and ustekinumab in patients with IBD (ulcerative colitis, 68.1% and 76.2%, respectively; Crohn's disease, 69.6% and 88.1%, respectively). Polypharmacy, advanced age, and female sex were identified as predictors of treatment discontinuation.</p><p><strong>Conclusions: </strong>This study documented a significant rise in biological drug use among older patients with IMID in Italy over the last decade. Around 50% of users discontinued treatment after the first year, with even higher rates observed in very old patients with polypharmacy. These findings highlight potential concerns about the use of biological therapies in older patients and underscore the urgent need for large-scale cohort studies to address the current knowledge gaps regarding their safety and effectiveness in this vulnerable population.</p>","PeriodicalId":9022,"journal":{"name":"BioDrugs","volume":" ","pages":"499-512"},"PeriodicalIF":5.4,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12031992/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143778801","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Real-World Evidence on the Effectiveness and Safety of Spesolimab in the Treatment of Generalized Pustular Psoriasis Flares: A Case Series.","authors":"Martim Luz, M Ribeiro, M Alpalhão, A M Silva, J Alves, C Brito, P Filipe, Tiago Torres","doi":"10.1007/s40259-025-00717-1","DOIUrl":"https://doi.org/10.1007/s40259-025-00717-1","url":null,"abstract":"","PeriodicalId":9022,"journal":{"name":"BioDrugs","volume":"39 3","pages":"513-516"},"PeriodicalIF":5.4,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143964450","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"First-in-Human Study on Tolerability, Pharmacokinetics, and Pharmacodynamics of Single Escalating Doses of HEC88473, a Novel Dual GLP-1 and FGF21 Receptor Agonist in Healthy and Obese Chinese Subjects.","authors":"Hong Zhang, Qianqian Li, Hong Chen, Lingfeng Guo, Jing Li, Can Xie, Jiangyu Yan, Yanhua Ding","doi":"10.1007/s40259-025-00715-3","DOIUrl":"10.1007/s40259-025-00715-3","url":null,"abstract":"<p><strong>Background: </strong>HEC88473 is a novel long-acting dual agonist of glucagon-like peptide 1 (GLP-1) and fibroblast growth factor 21 (FGF21) receptors. It is a Fc fusion protein containing a fibroblast growth factor 21 and a GLP-1 moiety, fused to the N-terminal and C-terminal of the Fc fragment, respectively.</p><p><strong>Objectives: </strong>This study aimed to evaluate the clinical safety, tolerability, pharmacokinetics, and pharmacodynamics of HEC88473.</p><p><strong>Methods: </strong>The clinical safety, tolerability, pharmacokinetics, and preliminary pharmacodynamics of HEC88473 (0.5-62.9 mg) were evaluated in a phase I, single-ascending dose trial with healthy and obese subjects. Serum glucose, lipid, and adiponectin levels were evaluated.</p><p><strong>Results: </strong>HEC88473 was slowly absorbed and metabolized into Fc-GLP-1 and Fc-FGF21 after dosing. In healthy participants, the median times to observed maximum serum concentration of HEC88473, Fc-GLP-1, and Fc-FGF21 were all in the range of 12.00-14.00 h, and their geomean half-lives were 16.2-22.6, 66.5-119.5, and 28.4-41.6 h, respectively. Their systemic exposure increased slightly more than proportionally to the dose. In healthy subjects, serum glucose decreased from baseline (day 1) in the oral glucose tolerance test at days 3 and 7 after HEC88473 administration with doses ≥ 5.1 mg, and the largest reduction occured in the 47.6-mg dose group, which was -1.829 mmol/L after baseline and placebo adjustment. At doses of ≥ 10.2 mg, adiponectin levels showed an upward trend with the dose and treatment time, and the average percentage increase of adiponectin from baseline was up to 90.71% in the 62.9-mg dose group. At doses of ≥ 17.0 mg, triglyceride levels showed a significant reduction from baseline in a certain dose-dependent manner, and the average percentage of triglyceride decrease from baseline was up to - 43.01% in the 62.9-mg dose group. HEC88473 was well tolerated, with the majority of treatment-related adverse events being gastrointestinal disorders of mild severity.</p><p><strong>Conclusions: </strong>HEC88473 is well tolerated in healthy and obese subjects, and it shows glucose-lowering and lipid-lowering efficacies. The data support further clinical evaluations of HEC88473 for the treatment of metabolic diseases.</p><p><strong>Clinical trial registration: </strong>This study was registered at ClinicalTrials.gov (registration number: NCT05943886).</p>","PeriodicalId":9022,"journal":{"name":"BioDrugs","volume":" ","pages":"477-486"},"PeriodicalIF":5.4,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143771219","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Understanding IgM Structure and Biology to Engineer New Antibody Therapeutics.","authors":"Johannes Buchner, Roberto Sitia, Hristo L Svilenov","doi":"10.1007/s40259-025-00720-6","DOIUrl":"https://doi.org/10.1007/s40259-025-00720-6","url":null,"abstract":"<p><p>Immunoglobulin M (IgM) antibodies are an essential and conserved part of adaptive immunity. IgMs assemble into pentamers and hexamers that bind to antigens with high avidity. Pentamers incorporate a small protein called J-chain (JC) that is important for their transcytosis via the poly-immunoglobulin receptor (pIgR). IgM antibodies can efficiently activate complement and interact with different Fc receptors (FcμR, Fcα/μR, pIgR) that trigger distinct effector functions and biodistribution. Even if these features have made the clinical use of IgM attractive over the past decades, there are currently no approved therapeutic IgMs on the market. In this review, we summarize the recent advances in the knowledge of IgM biogenesis and structure and discuss the therapeutic opportunities of IgM over IgG arising from high avidity, target clustering, binding to distinct IgM receptors, complement activation, transcytosis, and protein engineering opportunities. In addition, we summarize possibilities and outstanding challenges in the production of therapeutic IgM, including available technologies for IgM purification. Finally, we review recent preclinical and clinical data showing that IgM outperforms IgG in various in vitro assays but still fails to pass through clinical trials successfully. Challenges remain for IgM development, such as the need for a better understanding of IgM biology to facilitate a smoother transition from the preclinic to successful clinical trials.</p>","PeriodicalId":9022,"journal":{"name":"BioDrugs","volume":"39 3","pages":"347-357"},"PeriodicalIF":5.4,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12031937/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143972473","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Interrogation of Structure-Activity Relationships in Charge Variants of Therapeutic IgG2s Enabled by Free-Flow Isoelectric Focusing Fractionation.","authors":"Lingyu Wang, Yajun Zeng, Wenyuan Gao, Pengcheng Shen, Ping Han, Zhongli Zhang","doi":"10.1007/s40259-025-00718-0","DOIUrl":"https://doi.org/10.1007/s40259-025-00718-0","url":null,"abstract":"<p><strong>Background: </strong>Recombinant immunoglobulin G2 (IgG2) antibodies are effective neutralization agents or antagonists with high medical value because of their high specificity, long half-life, and absent effector functions. During biopharmaceutical process development, charge heterogeneity and bioactivity alternation related to charge variation should be investigated to understand the structure-activity relationship (SAR) in therapeutic antibodies. Isoelectric focusing can provide fine resolution for the charge heterogeneity profiling of IgG2, while ion exchange chromatography cannot achieve effective separation of IgG2 charge variants. In-depth investigation of charge heterogeneity requires a fractionation tool to enrich and isolate acidic and basic variants.</p><p><strong>Objectives: </strong>This study aims to investigate the structural origins and functional implications of charge heterogeneity in two therapeutic IgG2 antibodies, including an anti-receptor activator of nuclear factor κ-B ligand (RANKL) biosimilar of denosumab and an innovative anti-CD73 IgG2 (H-mab), using free-flow isoelectric focusing (FF-IEF).</p><p><strong>Methods: </strong>Charge variants of denosumab and H-mab were fractionated using FF-IEF, followed by characterization of isolated IgG2 charge variants to establish the SAR between charge-related antibody modifications and bioactivities. The investigation incorporated in silico 3D modeling of the FcRn-IgG2 Fc complex and the CD73-Fab complex to facilitate the SAR interrogation of these two IgG2s.</p><p><strong>Results: </strong>The acidic charge variants of denosumab were driven primarily by N-glycan sialylation and deamidation in the Fc region, showing negligible effects on biological functions except for a reproducible reduction in FcRn binding affinity. In contrast, the basic charge variants of H-mab were associated with D₉₉-succinimide formation in the heavy chain complementarity-determining region 3 (CDR3), significantly impairing binding and enzymatic inhibition activities.</p><p><strong>Conclusions: </strong>This study underscores the irreplaceable role of FF-IEF in both biosimilar and innovative therapeutic pipelines, highlighting the importance of monitoring charge heterogeneity and understanding SAR in therapeutic IgG2 antibodies.</p>","PeriodicalId":9022,"journal":{"name":"BioDrugs","volume":" ","pages":""},"PeriodicalIF":5.4,"publicationDate":"2025-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143965614","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Switching from Adalimumab Reference Product to and Among Adalimumab Biosimilars Outside the USA: Insights for US Clinicians.","authors":"John R P Tesser, Aline Charabaty, Adelaide A Hebert","doi":"10.1007/s40259-025-00719-z","DOIUrl":"https://doi.org/10.1007/s40259-025-00719-z","url":null,"abstract":"<p><p>Ten adalimumab biosimilars have been introduced in the United States (USA) since 2023, while adalimumab biosimilars have been available for several years in other countries. These experiences of biosimilar uptake outside the USA can inform US-based healthcare professionals on switching in real-life practice settings. Considerations include how healthcare professionals might meaningfully address patient concerns about outcomes to improve patient satisfaction. A search of the MEDLINE database was used to identify publications on switching to and among adalimumab biosimilars in an ex-US setting, with no restriction on publication language and using a time frame of 1 January 2017 through 12 December 2023, coinciding with the European Union approval of the first adalimumab biosimilar, adalimumab-atto, in March 2017. This narrative review aims to provide insights into the efficacy and safety of transitioning to and among adalimumab biosimilars in adult patients from clinical studies but also, more importantly, using real-world evidence (RWE) from outside the USA. Overall, RWE suggested that efficacy and outcomes were consistent in patients who underwent switching from the reference product (RP) across various immune-mediated inflammatory diseases when compared to patients who did not switch from the RP. The ex-US RWE of RP and biosimilar adalimumab switches generally reflected the experiences observed in clinical trials; however, RWE findings elucidated several challenges to biosimilar uptake, including patient education, provider training, and supportive policies.</p>","PeriodicalId":9022,"journal":{"name":"BioDrugs","volume":" ","pages":""},"PeriodicalIF":5.4,"publicationDate":"2025-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143957123","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Interleukin-23 versus Interleukin-17 Inhibitors in Preventing Incidental Psoriatic Arthritis in Patients with Psoriasis: A Real-World Comparison From the TriNetX US Collaborative Network.","authors":"Sebastian Yu, An-Ping Huo, Yu-Hsun Wang, James Cheng-Chung Wei","doi":"10.1007/s40259-025-00705-5","DOIUrl":"10.1007/s40259-025-00705-5","url":null,"abstract":"<p><strong>Background: </strong>Psoriatic arthritis (PsA) is a common comorbidity in patients with psoriasis (PsO) that leads to significant disease burden. Biologic therapies targeting the interleukin (IL)-23/IL-17 axis have been widely used for PsO, but their comparative effectiveness in preventing PsA remains unclear.</p><p><strong>Objective: </strong>The study objective was to compare the occurrence of developing incidental PsA among PsO patients treated with interleukin-23 inhibitors (IL23is) or interleukin-17 inhibitors (IL17is).</p><p><strong>Methods: </strong>A retrospective cohort study was conducted using real-world data from the TriNetX US Collaborative Network, including 53 healthcare organizations. Adult PsO patients treated with IL23is or IL17is between January 2019 and June 2022 were identified. Cox regression analysis was used to assess the risk of PsA incidence, with hazard ratios (HRs) and 95% confidence intervals (CIs) reported. Subgroup analyses were performed based on age, sex, and ethnicity. Sensitivity analyses included comparisons with tumor necrosis factor (TNF) inhibitors (TNFis) to ensure robustness.</p><p><strong>Results: </strong>A total of 4,580 PsO patients were included in the study, with 2,273 receiving IL23is and 2,307 receiving IL17is. Treatment with IL23is was associated with a significantly lower incidence of PsA compared to IL17is (HR = 0.60, 95% CI 0.44-0.82, P = 0.001). This reduction in risk was particularly notable in the 41- to 65-year age group (HR = 0.42, 95% CI 0.27-0.64, P < 0.001) and among females (HR = 0.57, 95% CI 0.38-0.86, P = 0.007). Subgroup analyses based on ethnicity revealed varying outcomes, with White patients showing a significant risk reduction (HR = 0.55, 95% CI 0.38-0.79, P = 0.001) but no significant risk reduction was observed in Black or African American patients (HR = 1.37, 95% CI 0.37-5.13, P = 0.637). Sensitivity analyses comparing IL23is and TNFis confirmed the robustness of the findings.</p><p><strong>Conclusion: </strong>IL23is are associated with a lower risk of PsA incidence compared to IL17is in PsO patients, particularly in specific age, sex, and ethnic groups. These findings suggest that IL23is may be more suitable for PsO patients at high risk of PsA and could inform potential updates to treatment guidelines. Further research should focus on refining therapeutic strategies by incorporating patient-specific factors such as comorbidities, ethnicity, and genetic predispositions, which could optimize biologic selection and enhance PsA prevention efforts in clinical practice.</p>","PeriodicalId":9022,"journal":{"name":"BioDrugs","volume":" ","pages":"297-306"},"PeriodicalIF":5.4,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11906553/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143057813","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Comparative Structure Activity Relationship Characterization of the Biosimilar BAT1806/BIIB800 to Reference Tocilizumab.","authors":"Yujie Liu, Jianhua Xie, Zhuxiang Li, Xiong Mei, Di Cao, Shengfeng Li, Linda Engle, Suli Liu, Hans C Ebbers, Cuihua Liu","doi":"10.1007/s40259-024-00698-7","DOIUrl":"10.1007/s40259-024-00698-7","url":null,"abstract":"<p><strong>Background: </strong>BAT1806/BIIB800 (Tofidence™/tocilizumab-bavi), a biosimilar of tocilizumab, demonstrated a high degree of analytical and functional similarity to reference tocilizumab (TCZ) in a comprehensive comparative analytical assessment. Minor differences with respect to TCZ were observed for some attributes and this study assessed the potential impact of these differences through structure activity relationship characterization.</p><p><strong>Methods: </strong>Structure activity relationship studies were conducted to assess glycation, glycosylation, charge variants, hydrophobicity, oxidation, and deamidation differences, using a range of investigative techniques. Structure activity relationship studies were performed on one lot each of BAT1806/BIIB800 and TCZ (European Union sourced only) except for glycation, where additional lots sourced from China and the USA were used.</p><p><strong>Results: </strong>Average total glycated protein content of BAT1806/BIIB800 was higher than TCZ (10.08% vs 1.19%); however, biological activity, including target binding and functional potency, was unaffected. Stress-induced glycation of BAT1806/BIIB800 and TCZ also did not affect the biological activity of the products despite up to 60% total glycation content. Minor differences were observed between BAT1806/BIIB800 and TCZ in glycosylation, charge variants, hydrophobicity, oxidation, and deamidation without a relevant impact on interleukin-6 receptor binding, Fc-receptor binding, and effector functions. In forced degradation studies, oxidation and deamidation trends were comparable between the two products.</p><p><strong>Conclusions: </strong>Comparative structure activity relationship characterization of BAT1806/BIIB800 and TCZ indicated that there are no relevant differences in quality attributes between BAT1806/BIIB800 and reference TCZ. Observed differences between BAT1806/BIIB800 and TCZ had no functional impact on BAT1806/BIIB800. The results support the conclusion that BAT1806/BIIB800 is similar to TCZ.</p>","PeriodicalId":9022,"journal":{"name":"BioDrugs","volume":" ","pages":"307-320"},"PeriodicalIF":5.4,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11906491/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143565900","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"State-of-the-Art Liver Cancer Organoids: Modeling Cancer Stem Cell Heterogeneity for Personalized Treatment.","authors":"Julien Giron-Michel, Maël Padelli, Estelle Oberlin, Hind Guenou, Jean-Charles Duclos-Vallée","doi":"10.1007/s40259-024-00702-0","DOIUrl":"10.1007/s40259-024-00702-0","url":null,"abstract":"<p><p>Liver cancer poses a global health challenge with limited therapeutic options. Notably, the limited success of current therapies in patients with primary liver cancers (PLCs) may be attributed to the high heterogeneity of both hepatocellular carcinoma (HCCs) and intrahepatic cholangiocarcinoma (iCCAs). This heterogeneity evolves over time as tumor-initiating stem cells, or cancer stem cells (CSCs), undergo (epi)genetic alterations or encounter microenvironmental changes within the tumor microenvironment. These modifications enable CSCs to exhibit plasticity, differentiating into various resistant tumor cell types. Addressing this challenge requires urgent efforts to develop personalized treatments guided by biomarkers, with a specific focus on targeting CSCs. The lack of effective precision treatments for PLCs is partly due to the scarcity of ex vivo preclinical models that accurately capture the complexity of CSC-related tumors and can predict therapeutic responses. Fortunately, recent advancements in the establishment of patient-derived liver cancer cell lines and organoids have opened new avenues for precision medicine research. Notably, patient-derived organoid (PDO) cultures have demonstrated self-assembly and self-renewal capabilities, retaining essential characteristics of their respective in vivo tissues, including both inter- and intratumoral heterogeneities. The emergence of PDOs derived from PLCs serves as patient avatars, enabling preclinical investigations for patient stratification, screening of anticancer drugs, efficacy testing, and thereby advancing the field of precision medicine. This review offers a comprehensive summary of the advancements in constructing PLC-derived PDO models. Emphasis is placed on the role of CSCs, which not only contribute significantly to the establishment of PDO cultures but also faithfully capture tumor heterogeneity and the ensuing development of therapy resistance. The exploration of PDOs' benefits in personalized medicine research is undertaken, including a discussion of their limitations, particularly in terms of culture conditions, reproducibility, and scalability.</p>","PeriodicalId":9022,"journal":{"name":"BioDrugs","volume":" ","pages":"237-260"},"PeriodicalIF":5.4,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11906529/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142999412","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Primary and Acquired Resistance to Immunotherapy with Checkpoint Inhibitors in NSCLC: From Bedside to Bench and Back.","authors":"Annapaola Mariniello, Maxime Borgeaud, Marc Weiner, Daniele Frisone, Floryane Kim, Alfredo Addeo","doi":"10.1007/s40259-024-00700-2","DOIUrl":"10.1007/s40259-024-00700-2","url":null,"abstract":"<p><p>Immunotherapy with checkpoint inhibitors has become the cornerstone of systemic treatment for non-oncogene addicted non-small-cell lung cancer. Despite its pivotal role, a significant proportion of patients-approximately 70-85%-either exhibit primary resistance to PD-1 blockade or develop acquired resistance following an initial benefit, even in combination with chemotherapy and/or anti-CTLA-4 agents. The phenomenon of primary and acquired resistance to immunotherapy represents a critical clinical challenge, largely based on our incomplete understanding of the mechanisms of action of immunotherapy, and the resulting lack of accurate predictive biomarkers. Here, we review the definitions and explore the proposed mechanisms of primary and acquired resistance, including those related to the tumor microenvironment, systemic factors, and intrinsic tumor characteristics. We also discuss translational data on adaptive changes within tumor cells and the immune infiltrate following exposure to checkpoint inhibitors. Lastly, we offer a comprehensive overview of current and emerging therapeutic strategies designed to prevent primary resistance and counteract acquired resistance.</p>","PeriodicalId":9022,"journal":{"name":"BioDrugs","volume":" ","pages":"215-235"},"PeriodicalIF":5.4,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11906525/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143424768","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}