Biologics : Targets & Therapy最新文献

Purpose: This review examines recent advances in monoclonal antibody (mAb) manufacturing, focusing on process optimization, cost reduction strategies, and emerging technologies. The analysis addresses critical challenges in current manufacturing processes while evaluating innovative solutions to improve production efficiency and economic viability.

Methods: We conducted a comprehensive analysis of recent literature on mAb manufacturing, examining traditional batch processing, continuous processing, and hybrid systems. The review evaluates cost optimization strategies, including media development and process integration, while assessing the impact of emerging technologies, such as machine learning and advanced analytics, on manufacturing efficiency.

Results: Recent studies demonstrate that continuous processing can achieve up to 35% cost savings compared to traditional batch processing to meet an annual production demand of 100-500 kg, though this gain diminishes at larger scales. Hybrid facilities show accelerated break-even points, reaching profitability 2-2.5 years earlier than traditional facilities. Advanced media optimization strategies, incorporating novel tripeptide delivery methods, have demonstrated up to 35% improvement in mAb titers. Integration of machine learning and advanced analytics has significantly enhanced process control and optimization capabilities.

Conclusion: The evolution of mAb manufacturing technologies offers promising pathways for improving production efficiency and reducing costs. Scale-dependent considerations remain crucial in selecting optimal manufacturing strategies, while emerging technologies present new opportunities for process optimization. Future developments in continuous processing, advanced analytics, and cell line engineering will be essential in meeting growing global demand while ensuring economic viability and accessibility of mAb therapeutics.

Background: Glioblastoma is a highly aggressive brain tumor, and the transition from the proneural to mesenchymal subtype is associated with more aggressive and therapy-resistant features. However, the signaling pathways and genes involved in this transition remain largely undefined.

Methods: We utilized patient-derived xenograft (PDX) samples of glioblastoma, specifically PDX-L14, which exhibit both negative and overexpressed FOSL1 expression. mRNA expression profiles were assessed by RNA sequencing in these samples, followed by gene ontology (GO) analysis, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis, and Gene Set Enrichment Analysis (GSEA). Validation of the hub genes was performed using qPCR and immunohistochemistry assays.

Results: Differentially expressed genes (DEGs) between FOSL1 overexpression groups were predominantly involved in ferroptosis, immune response, angiogenesis, vascular mimicry, autophagy, epithelial-mesenchymal transition (EMT), cancer cell stemness, temozolomide (TMZ) resistance, and NF-κB signaling. Downregulated DEGs were associated with TMZ resistance, glioma proliferation, RNA processing, and Wnt/β-catenin signaling. Key enrichment pathways, including NF-κB, Want, and BMP, are all critical for maintaining glioma stemness. FOSL1 was found to regulate RNA processing and ubiquitination. Notably, 8 upregulated (ITGA5, SDC1, PHLDB2, TNFRSF8, ADAM8, TLR7, STEAP3, and POU3F2) and 4 downregulated (IFIT1, FBXO16, ARL3, and BEX1) genes were identified, with implications for glioblastoma prognosis.

Conclusion: This transcriptome investigation emphasizes the diverse functions of FOSL1 in different biological processes and signaling networks during the shift from proneural to mesenchymal state in glioblastoma.

Neuromyelitis optica spectrum disorders (NMOSD) are primarily autoimmune diseases mediated by B cells and AQP4-IgG antibodies, typically affecting the optic nerves and spinal cord, and are characterised by high relapse rates and significant disability. We present two cases of NMOSD patients who also had systemic lupus erythematosus (SLE), with one case additionally complicated by myasthenia gravis (MG). Both patients initially received first-line treatment with corticosteroids; however, no clinical improvement was observed; As a result, the treatment was switched to the dual-target biologic agent, Telitacicept. Following the administration of Telitacicept, both patients demonstrated significant improvements in clinical symptoms, daily functional abilities, and imaging findings. This report highlights the successful use of Telitacicept in treating NMOSD complicated by other autoimmune diseases, which may serve as an important reference for the management of NMOSD.

Background: The increasing prominence of biosimilars in healthcare delivery has created the need for robust financial evaluation methods to assess development opportunities. Unlike traditional generic drugs, biosimilars require substantial investments ($100-250 million) and longer development timelines (6-8 years), necessitating sophisticated evaluation approaches.

Methods: This study presents a comprehensive Net Present Value (NPV) analysis framework specifically designed for biosimilar development projects. Our framework incorporates key technical, regulatory, and commercial factors through a risk-adjusted NPV methodology, validated through case studies of three monoclonal antibody biosimilar development programs.

Results: The analysis reveals that successful projects require minimum peak sales of $250-300 million to achieve a positive NPV, with market share and manufacturing efficiency serving as critical value drivers. Cost analysis shows that clinical development represents the largest share (57%) of total development costs.

Conclusion: The framework demonstrates that early market entry, manufacturing optimization, and market share achievement are key success factors, whereas technical complexity and competitive intensity significantly influence risk-adjusted returns.

Introduction: Autologous platelet concentrates (APC) are widely used in the infiltrative treatment of knee osteoarthritis (OA) to enhance tissue healing and relieve pain. Aim of this study was to identify predictive biomarkers for clinical outcomes in patients with grade I knee OA.

Methods: A panel of growth factors (GFs) and cytokines was determined in peripheral blood (PB) and APC. The Numeric Pain Rating Scale (NPRS) was used as a clinical readout before and after the APC infiltration.

Results: A lower white blood cell (WBC) count and higher Monocyte-chemoattractant Protein-1 levels in PB were associated with APC-induced pain relief. Platelet-derived Growth Factor (PDGF) levels in APC were significantly higher in OA patients displaying a larger NPRS reduction, independent of platelet count. Finally, the simultaneous determination of PDGF, Vascular Endothelial Growth Factor, and Macrophage Inflammatory Protein-1α in APC discriminated OA patients with very poor or no response.

Conclusion: Platelet-released GFs rather than platelet counts may predict clinical outcomes in grade 1 knee OA.

Background: This study investigates the role of DNA topoisomerase IIα (TOP2A) in retinoblastoma (RB), focusing on its involvement in epithelial-mesenchymal transition (EMT) and the potential of TOP2A inhibition as a therapeutic strategy.

Methods: We analyzed TOP2A expression in RB tissues using public gene expression databases (GSE97508, GSE110811, and GSE172170) and conducted functional assays in human RB cell lines (Y79 and WERI-Rb-1) modified to knock down or overexpress TOP2A. Assessments included cell proliferation, migration, invasion, and EMT marker expression via RT-PCR and Western blot. Additionally, we evaluated the effects of TOP2A modulation in subcutaneous and liver metastasis mouse xenograft models.

Results: TOP2A was significantly overexpressed in RB tissues (p < 0.0001). In vitro, TOP2A knockdown inhibited RB cell proliferation, migration, and invasion, and reversed EMT marker expression (p < 0.05), while TOP2A overexpression enhanced these oncogenic processes. In vivo, TOP2A knockdown or inhibition significantly reduced tumor growth and metastasis in both subcutaneous and liver metastasis models (p < 0.05). Combination therapy with TOP2A and EMT inhibitors further enhanced anti-tumor effects, significantly reducing tumor burden and metastatic lesions (p < 0.01).

Conclusion: TOP2A is pivotal in RB pathogenesis and progression, primarily by regulating EMT. Its inhibition not only curtails RB cell proliferation and metastasis but also reverses EMT, underscoring its potential as a therapeutic target. This study lays the groundwork for further exploration of TOP2A-targeted therapies in RB.

Although adjuvant endocrine therapy (ET) greatly lowers the risk of recurrence and mortality in hormone receptor (HR)-positive early-stage breast cancer (EBC), more than 20% of patients may experience relapses within 10 years, often manifesting as incurable distant metastases. To improve outcomes, ovarian function suppression (OFS) with gonadotropin-releasing hormone agonists (GnRHa) added to tamoxifen or aromatase inhibitors like exemestane have shown significant disease-free survival (DFS) and, in some cases, overall survival (OS) benefits. CDK4/6 inhibitors, a cornerstone in metastatic HR-positive, HER2-negative breast cancer (MBC), are now being explored in EBC. Trials with abemaciclib and ribociclib have shown promise in high-risk EBC. For BRCA-mutant patients, the PARP inhibitor olaparib, as demonstrated in the OlympiA trial, significantly improved invasive DFS and OS when used as adjuvant therapy for one year. Conversely, de-escalation strategies are also emerging. Recent studies suggest that younger premenopausal women with low-risk disease may safely interrupt ET after 18-30 months to pursue pregnancy. Additionally, genomic tumor profiling is widely utilized to decide on aggressiveness of adjuvant therapy of EBC. These advancements reflect a shift toward personalized adjuvant therapy, integrating targeted treatments like CDK4/6 inhibitors and PARP inhibitors, optimizing ET with OFS, and balancing efficacy with quality of life through de-escalation strategies. This tailored approach aims to improve long-term outcomes for HR-positive EBC patients.

Purpose: Aortic valve disease (AVD) is a common condition that leads to pressure and/or volume overload in the left ventricle. Aortic valve replacement is the standard treatment, as no pharmacological therapies are currently available. The incidence of AVD is increasing in developed countries, making the discovery of new biomarkers for early detection crucial. The importance of mitochondria in heart function is well established, and various cardiovascular pathologies are associated with mitochondrial dysfunction. In this cross-sectional study, we evaluated for the first time the role of mitochondria in AVD, aiming to identify new pathways involved in the disease and discover potential biomarkers.

Patients and methods: We recruited 17 patients diagnosed with AVD and scheduled for aortic valve replacement, and 22 healthy controls. Plasma levels of peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1α) and mitochondrial open reading frame of the 12S rRNA type-c peptide (MOTS-c) were measured by ELISA.

Results: We observed significantly reduced levels of both proteins in patients, suggesting that substantial mitochondrial dysfunction occurs in AVD patients, independent of sex or age, but directly related to the disease.

Conclusion: Mitochondria may represent a promising target for studying new pathways involved in AVD. We propose PGC1α and MOTS-c as potential plasma biomarkers for AVD detection. Further studies, including early-stage patients, are necessary to confirm the significance of our findings.

Bronchial asthma is a complex and heterogeneous disease with ongoing airway inflammation and increased airway responsiveness. Key characteristics of the disease include persistent airway inflammation, airway hyperresponsiveness, and airway remodeling. Asthma's chronic and recurrent characteristics contribute to airway remodeling and inflammation, which can exacerbate lung damage. Presently, inflammation is predominantly managed with corticosteroids, yet there is a notable absence of treatments specifically addressing airway remodeling. The phosphoinositide 3-kinase (PI3K) signaling pathway is integral to the processes of inflammation, airway remodeling, and immune responses. Pharmacological agents targeting this pathway are currently undergoing clinical evaluation. This review elucidates the role of PI3K in the immune responses, airway inflammation, and remodeling associated with asthma, examining its underlying mechanisms. Furthermore, we synthesize the existing literature on the therapeutic potential of PI3K inhibitors for asthma management, emphasizing immune modulation, airway inflammation, and remodeling, including drug development and ongoing clinical trials. Lastly, we explore how various PI3K-targeted therapies may enhance efficacy and improve tolerance.

Introduction: The integration of anti-HER2 targeted therapy with chemotherapy has demonstrated an increase in pathologic complete response rates (pCR) in patients with HER2-positive early-stage breast cancer (EBC). This study presents real-world data on the use of trastuzumab with or without pertuzumab, in combination with anthracycline and taxanes-based chemotherapy regimen.

Methods: We conducted a retrospective analysis of patients with HER2-positive EBC who underwent neoadjuvant chemotherapy (NACT), treated between January 2014 and September 2021. The regimen included four cycles of doxorubicin and cyclophosphamide (AC), followed by four cycles of docetaxel every three weeks, with anti-HER2 therapy administered alongside docetaxel. Outcomes assessed included pCR, 3-year disease-free survival (DFS), and surgical outcomes.

Results: During the study period, 484 consecutive patients with HER2-positive EBC, median age of 47 (range, 21-80) years, were enrolled. (64.7%) of patients received dual anti-HER2 therapy, while 35.3% received single-agent trastuzumab. The overall pCR rate was 44.2%, with a higher rate (55.6%) in hormone receptor (HR)-negative patients compared to HR-positive patients (39.8%), p=0.002. Although dual therapy resulted in a higher pCR rate (46.6%) compared to trastuzumab alone (39.8%), the difference was not statistically significant (p=0.15). The estimated 3-year DFS was 86.1% with dual therapy and 83.1% with trastuzumab alone (p=0.37). Further stratification revealed superior 3-year DFS in node-negative disease (96.4%) compared to node-positive disease (82.3%), p=0.0021. Patients who achieved pCR had a significantly better 3-year DFS (89.3%) compared to those with residual disease (82.2%), p=0.0177. Rate of breast conserving surgery (BCS) was lower (15.2%) among patients who received trastuzumab alone, compared to 26.5% among those who received dual anti-HER2 [Odds Ratio (OR)= 0.50, 95% Confidence Interval (CI), 0.30-0.80, p=0.005].

Conclusion: Dual anti-HER2 therapy did not significantly enhance DFS but was associated with higher BCS rates, highlighting its potential to improve surgical outcomes.