Search Results (1,581)

Demyelinating diseases comprise a group of chronic and debilitating neurological disorders, with the destruction of the myelin sheath serving as the core pathological hallmark. The central pathogenesis involves immune-mediated damage to oligodendrocytes (Ols) and myelin breakdown, accompanied by a vicious cycle of neuroinflammation and impaired epigenetic repair. Current therapeutic strategies, including conventional immunomodulatory agents to targeted monoclonal antibodies, effectively control disease relapses but exhibit limited efficacy in promoting neural repair. Consequently, research focus is increasingly shifting towards neuroprotective and remyelination strategies. In this context, Emerging therapeutic promise stems primarily from two fronts: the advent of novel pharmaceuticals, such as remyelination-promoting drugs targeting oligodendrocyte maturation, interventions inhibiting epigenetic silencing, signal pathway inhibitors, and natural products derived from traditional Chinese medicine; the development of innovative technologies, including cell therapies, gene therapy, exosome and nanoparticle-based drug delivery systems, as well as extracellular protein degradation platforms. Nevertheless, drug development still faces challenges such as disease heterogeneity, limited blood–brain barrier penetration, long-term safety, and difficulties in translating findings from preclinical models. Future efforts should emphasize precision medicine, multi-target synergistic therapies, and the development of intelligent delivery systems, with the ultimate goal of achieving a paradigm shift from delaying disability progression to functional neural reconstruction. Full article

Background: The epithelial-to-mesenchymal transition (EMT) process is necessary for metastasis as it enables tumor cells’ migration and invasion. In the remote organ, tumor cells can develop into metastatic lesions or arrest their proliferation and become dormant, thus suspending metastatic development. EMMPRIN is a membrane glycoprotein, implicated in cell–cell interactions, proliferation, angiogenesis, and EMT. We asked whether neutralizing EMMPRIN with the new anti-EMMPRIN monoclonal antibody hMR18-mAb can inhibit EMT. Methods: We co-cultured tumor cell lines (breast carcinoma MCF-7, MDA-MB-231, or oral squamous cell carcinoma SCC-40) together with U937 monocytic-like cells, with or without hMR18-mAb or its negative control rabbit IgG. Results: We demonstrate that depending on the initial state of the cells along the epithelial–mesenchymal axis (E/M axis), co-culture enhanced the EMT process, whereas hMR18-mAb reversed this effect. The co-culture increased EMT-inducer cytokines in all cell lines (by 2.5-fold), while hMR18-mAb reduced them (by ~55–70% in the breast cancer cells and by 81% in the SCC-40 cells). The co-culture reduced E-cadherin (by 2-fold in MCF-7 and SCC-40 cells) and increased vimentin expression (by 2–3-fold in MDA-MB-231 and SCC-40), while hMR18-mAb reverted this effect. Co-culture enhanced proliferation, migration, and angiogenic potential of the tumor cells, while hMR18-mAb reduced these by ~20%, 30–44% and ~60–80%, respectively. Co-culture reduced the standard markers of dormancy (NR2F1, p21, p27) and stemness (SOX2, Nanog) (by 30–60% in MCF-7 and SCC-40), while hMR18-mAb elevated gene expression of these markers (by 1.5–3.5-fold) in all cell lines, pushing the cells towards dormancy. Conclusions: We conclude that EMMPRIN is a gatekeeper that prevents cells from entering dormancy, and that hMR18-mAb disrupts this effect. As it is the first antibody shown to induce dormancy in tumor cells and stop the development of metastases, this could become a new therapeutic strategy to prevent and treat metastasis. Full article

Background: Despite the growing importance of polypeptide-based drugs in clinical therapy, studies investigating the stability of their freeze-dried formulations remain scarce. Crystalline excipients, such as mannitol, are commonly used in freeze-dried formulations of chemically synthesized drugs, but they often negatively impact the long-term stability of biological macromolecules like monoclonal antibodies (mAbs). This study bridges this knowledge gap by evaluating the effects of crystalline and amorphous excipients, surfactants, and amino acid-based stabilizers on the long-term stability of freeze-dried formulations using model polypeptides, glucagon and insulin. Methods: The freeze-dried formulations were prepared with crystalline and amorphous excipients, surfactants, and amino acid-based stabilizers. The crystallization behavior of the excipients and the thermal stability of the formulations were thoroughly characterized using X-ray powder diffraction (XRPD) and differential scanning calorimetry (DSC). Results: The crystallization of mannitol was directly correlated with a significant reduction in the long-term stability of both model polypeptides. This detrimental effect mirrors the instability observed in mAbs formulations, indicating a common mechanism of protein destabilization induced by crystalline excipients, independent of molecular size. Conclusions: This study provides the first direct evidence that crystalline excipients pose a significant risk to the stability of freeze-dried polypeptides. These findings offer critical insights for the rational design of stable freeze-dried formulations, guiding industrial development strategies for polypeptide-based therapeutics. Full article

Background/Objectives: Therapeutic monoclonal antibodies, including bispecifics (t-mAbs), can interfere with serum protein electrophoresis (SPEP) and immunofixation electrophoresis (IFE), mimicking residual M-protein. We evaluated a mass spectrometry (MS; EXENT^®)-based workflow supported by an m/z reference library to discriminate drug from disease and assess concordance with IFE. Methods: Fifty-eight serum samples from 29 multiple myeloma patients were analyzed at baseline and after 3 months. Targeted enrichment of t-mAbs followed by MS enabled detection of peaks annotated through matching to a theoretical m/z panel and correlation with SPEP/IFE results. Results: Comparison of IFE versus MS showed 11/29 (38%) double positives, 15/29 (52%) double negatives, and 3/29 (10%) IFE−/MS+; no IFE+/MS− cases were observed. Using MS as a reference, IFE exhibited 78.6% sensitivity and 100% specificity. The m/z library enabled attribution of interference to linvoseltamab (n = 9), daratumumab (n = 6), and teclistamab (n = 3); in 16 patients treated with other bispecifics, no drug-related peaks were detected after 3 months. Longitudinal analysis discriminated therapeutic from endogenous immunoglobulins, identified baseline M-protein, and prevented false residual signals. Conclusions: MS (EXENT^®)-based characterization of t-mAbs improves response monitoring accuracy in multiple myeloma and supports integration of MS into routine laboratory practice. Full article

Diabetic nephropathy (DN) remains the leading cause of end-stage renal disease (ESRD) worldwide, primarily affecting individuals with Type 2 Diabetes Mellitus (T2DM). While traditional risk factors—such as hypertension, poor glycemic control, and dyslipidemia—are well known, recent research has illuminated the pivotal role of inflammation in DN pathogenesis. Inflammatory processes involving chemokines, cytokines, immune cell infiltration, and pro-fibrotic signaling pathways (e.g., NFκB, JAK/STAT) contribute significantly to glomerular and tubulointerstitial damage. Key immune players include macrophages and T lymphocytes, particularly CD4⁺ T cells, which correlate with disease severity and progression. Serum Amyloid A (SAA), an acute-phase reactant traditionally associated with Serum Amyloid A Amyloidosis (AA amyloidosis), has emerged as both a biomarker and active mediator of renal inflammation in DN. SAA promotes cytokine release, leukocyte recruitment, and extracellular matrix remodeling, contributing to glomerular and tubular injury. Elevated Saa3 expression in experimental models correlates with DN progression, while activation of the advanced glycation end products and the receptors for advanced glycation end products (AGE–RAGE) axis in podocytes enhances SAA upregulation and inflammatory signaling. Increasing evidence now indicates that SAA functions, not only as a marker of systemic inflammation, but also as a mechanistically significant driver of intrarenal injury, bridging metabolic dysregulation with sustained inflammatory and fibrotic signaling. Emerging therapeutic approaches—including interleukin 6 (IL-6) blockade, inhibition of AGE formation, targeted anti-fibrotic agents, and recently developed SAA-directed RNA or peptide therapeutics—underscore the therapeutic potential of modulating SAA activity in DN. Preclinical evidence further supports the efficacy of monoclonal antibodies, signaling inhibitors, and dietary anti-inflammatory compounds in mitigating renal injury. Collectively, these developments position SAA as a central mediator at the intersection of metabolic, inflammatory, and fibrotic pathways, highlighting its promise as both a diagnostic biomarker and a therapeutic target for early intervention in diabetic kidney disease. Full article

Multiple myeloma (MM) is a clonal malignancy of terminally differentiated plasma cells characterized by bone marrow infiltration and excessive production of monoclonal immunoglobulins, leading to end-organ damage such as osteolytic bone lesions. Despite substantial therapeutic progress achieved with proteasome inhibitors, immunomodulatory drugs, and anti-CD38 monoclonal antibodies, multiple myeloma remains incurable, and outcomes for triple-class-refractory patients remain dismal, with median survival below one year. Bispecific T cell engaging antibodies (TCEs) have recently emerged as a promising immunotherapeutic approach capable of redirecting cytotoxic T cells to eliminate malignant plasma cells. These engineered antibodies simultaneously engage CD3 on T cells and a tumor-associated antigen such as B cell maturation antigen (BCMA), G protein-coupled receptor family C group 5 member D (GPRC5D), or Fc receptor homolog 5 (FcRH5), thereby forming an immune synapse that triggers T cell activation, cytokine secretion, and perforin–granzyme-mediated apoptosis of the targeted B cell. This review summarizes the molecular design, mechanism of action, and clinical development of TCEs in MM, encompassing early bi-specific T cell engagers (BiTE) constructs such as AMG 420 and next-generation IgG-like molecules including teclistamab. Pivotal clinical trials have demonstrated overall response rates between 43% and 73%, accompanied by durable remissions and manageable safety profiles. Future directions include earlier-line integration, synergistic combinations with immunomodulatory or costimulatory agents, and the development of trispecific formats to overcome antigen escape and T cell exhaustion. Collectively, TCEs represent a paradigm shift toward durable, immune-mediated disease control in multiple myeloma. Full article

Rapid advancements in understanding how the immune system can eliminate tumors have quickly translated into breakthroughs in developing cancer therapeutics. Immune checkpoint inhibitors (ICIs) have shown great promise in several cancers; however, resistance can affect up to two-thirds of patients receiving ICIs. A significant limitation of the effectiveness of anti-PD-1 therapy centers around the insufficient levels of immune cells needed to recognize and kill cancer cells compared to the number of suppressive immune cells within the tumor microenvironment. Determining what is required to overcome the resistance to anti-PD-1 therapy in breast cancer remains a critical need. Our data demonstrate that IL-15 complexes injected intratumorally in combination with PD-1 blockade therapy induce regression of established luminal B mammary breast tumors. We show that IL-15 alone or in combination with anti-PD-1 drives changes in gene expression of pathways associated with TCR and co-stimulatory signaling, immune cell adhesion, and migration. Furthermore, we show that intratumoral injection of IL-15 complexes traffics to the tumor-draining lymph node, as evidenced by Light sheet microscopy, and colocalizes with the anti-PD-1 monoclonal antibody. We also identify the immune signatures, localization, and distribution of immune cells in regressing and non-regressing breast tumors. Full article

Atopic dermatitis is the most prevalent chronic inflammatory skin disease, posing a significant individual and healthcare burden. Traditionally managed with topical agents and broad immunosuppressants, the treatment landscape has shifted significantly in recent years. This review explores the transition from immunopathogenic understanding to personalized treatment strategies through advanced systemic therapies. We provide a thorough description of the current therapeutic arsenal, including approved monoclonal antibodies and Janus kinase (JAK) inhibitors, as well as experimental agents under clinical investigation. Key cytokines and receptors implicated in type 2 inflammation are explored alongside relevant intracellular signaling pathways. Special attention has been given to literature published from 2015 onwards. By synthesizing the latest scientific and clinical knowledge, this review aims to provide clinicians with practical guidance for navigating the evolving landscape of atopic dermatitis management and improving patient outcomes. Full article

Cellular senescence is an irreversible cell cycle arrest, triggered by stressors like telomere shortening, DNA damage, and oncogenic signaling. These cells, often referred to as ‘zombie cells’ because they cease dividing yet resist apoptosis, drive the Senescence-Associated Secretory Phenotype (SASP), releasing pro-inflammatory cytokines, chemokines, growth factors, and matrix-remodeling enzymes. While senescence is a protective mechanism against malignant proliferation, its persistence in tissues contributes to aging and age-related diseases (inflammaging). Recognizing this dual role forms the basis for developing therapies that bridge anti-aging, regenerative medicine, and oncology, as precise molecular regulatory mechanisms remain incompletely understood. This review interrelates these disciplines, focusing on targeted interventions against senescent cells (SnCs). These interventions include senolytics (agents that selectively eliminate SnCs) and senomorphics (agents that suppress the SASP), offering translational insights from anti-aging/aesthetic applications into integrated treatment models. The framework addresses cancer therapeutics via immunologic modalities such as monoclonal antibodies (mAbs) and CAR T-cell therapy, alongside nucleic acid-based therapeutics (mRNA and siRNA), and is used in combination with broad-spectrum therapeutics. The novelty lies in synthesizing these disparate fields, unified by cellular senescence as a central mechanistic target. Ultimately, the goal is to identify targets that induce tumor regression, mitigate age-related vulnerabilities, promote tissue homeostasis and regeneration, and improve quality of life and overall survival. Full article

Radiolabeled monoclonal antibodies represent a promising approach to integrate molecular imaging with immunotherapy for cancer diagnosis and treatment. These antibodies target immune checkpoints and tumor-associated antigens, enabling non-invasive visualization of tumor dynamics through PET and SPECT imaging. Evidence from preclinical and clinical studies suggests that such imaging can provide insights into antibody distribution, immune cell infiltration, and potential treatment responses within the tumor microenvironment. By combining diagnostic and therapeutic capabilities, antibody-based theranostics offer opportunities for personalized treatment planning and understanding mechanisms of resistance. This review highlights current advances in antibody-based molecular imaging, discusses challenges in translation, and explores future directions for integrating imaging with immuno-oncology strategies to improve patient outcomes. Radiolabeled antibodies allow non-invasive assessment of tumor–immune interactions, supporting adaptive treatment planning and bridging immunotherapy with molecular imaging. Full article

Gynecological cancers remain a major global health burden due to their high incidence, molecular heterogeneity, and frequent resistance to conventional therapies. Beyond well-established genetic alterations and targeted treatments, growing attention has been directed toward the role of cancer stem cells (CSCs), a rare tumor subpopulation with self-renewal, differentiation, and tumor-initiating capacities. CSCs are sustained by a specialized microenvironment, the cancer stem cell niche, where growth factors, cytokines, hypoxia, and stromal interactions converge to promote stemness, chemoresistance, and metastatic potential. In breast cancer, signaling axes such as EGFR, IGF, TGFβ, and HGF/c-Met critically regulate CSC expansion, particularly in aggressive subtypes like triple-negative tumors. In ovarian cancer, factors including HGF, VEGFA, IGF, and stromal-derived BMPs drive CSC plasticity and contribute to relapse after platinum therapy. Endometrial CSCs are supported by pathways involving TGFβ, BMP2, and Netrin-4/c-Myc signaling, while in cervical cancer, VEGF, IGF-1, Gremlin-1, and TGFβ-mediated circuits enhance stem-like phenotypes and drug resistance. Cytokine-driven inflammation, especially via IL-3, IL-6, IL-8, IL-10, and CCL5, further fosters CSC survival and immune evasion across gynecologic malignancies. Preclinical studies demonstrate that targeting growth factors and cytokine signaling, through monoclonal antibodies, receptor inhibitors, small molecules, or cytokine modulation, can reduce CSC frequency, restore chemosensitivity, and enhance immunotherapy efficacy. This review highlights the interplay between CSCs, growth factors, and cytokines as central to tumor progression and relapses, emphasizing their translational potential as therapeutic targets in precision oncology for gynecological cancers. Full article

CD44 variant (CD44v) isoforms are involved in promoting cancer metastasis, sustaining cancer stem cell (CSC) properties, and conferring resistance to therapeutic interventions. Consequently, the development of monoclonal antibodies (mAbs) targeting CD44v represents a crucial strategy for eliminating CD44v-positive cancer cells. Previously, an anti-CD44v6 mAb, C₄₄Mab-9 (mouse IgG₁, κ), was established. C₄₄Mab-9 recognizes explicitly the epitope encoded by the variant exon 6-encoded region of CD44 and applies to flow cytometry, western blotting, and immunohistochemistry. To assess the therapeutic potential, a mouse IgG_2a isotype of C₄₄Mab-9 (designated C₄₄Mab-9-mG_2a) was generated, and the in vitro and in vivo antitumor activities were evaluated using gastric and colorectal cancer cell lines. C₄₄Mab-9-mG_2a demonstrated specific binding to CD44v3–10-overexpressed Chinese hamster ovary cells (CHO/CD44v3–10), as well as gastric cancer (NUGC-4) and colorectal cancer (COLO201 and COLO205) in flow cytometry. C₄₄Mab-9-mG_2a exerted antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC) against CHO/CD44v3–10, NUGC-4, COLO201, and COLO205. Moreover, systemic administration of C₄₄Mab-9-mG_2a significantly inhibited tumor growth in CHO/CD44v3–10, NUGC-4, COLO201, and COLO205 xenografts compared with the control IgG_2a. These findings indicate that C₄₄Mab-9-mG_2a could be applied to the mAb-based therapy against CD44v6-positive tumors. Full article

Background: Rituximab, a monoclonal antibody targeting CD20, has revolutionized the management of B-cell lymphoproliferative disorders and some immune conditions, significantly improving disease control and patient survival. Beyond its indisputable therapeutic benefits, rituximab can cause serious pulmonary adverse events, particularly interstitial lung disease (R-ILD). Diagnosing R-ILD is challenging due to nonspecific clinical and imagistic features, and its true incidence is possibly underestimated. Methods: We conducted a systematic review to synthesize current evidence on R-ILD, focusing on its incidence, diagnostic approaches, management strategies and clinical outcomes. A comprehensive search of PubMed/MEDLINE was performed using the term “rituximab induced interstitial lung disease” through August 2025. Relevant abstracts were screened, and full-text articles meeting the inclusion criteria were analyzed. Results: A total of 40 studies were retained after the search and screening, including case reports, case series and cohort studies of R-ILD. This condition was identified in both malignant and autoimmune disorders receiving rituximab, more frequently for combination regimens. Radiological manifestations were heterogeneous, and ground-glass opacities were the dominant pattern. Most R-ILD cases were reversible, but progression to chronic interstitial disease and fatal outcomes are possible. Cohort studies demonstrated variability in incidence, reported instances of successful rituximab reintroduction and suggested a protective effect of prophylactic trimethoprim-sulfamethoxazole against opportunistic pneumonitis. Conclusions: Although rare, R-ILD is a clinically significant complication of rituximab therapy. Early recognition and multidisciplinary management are essential, as most patients respond to corticosteroids, while severe cases may progress to respiratory failure or fatal outcomes. Full article

Somatic embryogenesis (SE) is a morphogenetic pathway widely employed in the commercial micropropagation of plants. This route enables the generation of somatic embryos from somatic tissues, which give rise to complete (bipolar) plants that develop like zygotic embryos. SE can proceed via direct or indirect pathways, and both approaches have been adapted not only for large-scale clonal propagation but also for the regeneration of genetically modified plants. In this context, SE can be harnessed as a versatile platform for recombinant protein production, including vaccine antigens and therapeutic proteins, by combining plant tissue culture with genetic transformation strategies. Successful examples include non-model plants, as Daucus carota and Eleutherococcus senticosus expressing the cholera and heat-labile enterotoxin B subunits, respectively; Oryza sativa, Nicotiana tabacum, and Medicago sativa producing complex proteins such as human serum albumin (HSA), α₁-antitrypsin (AAT), and monoclonal antibodies. However, challenges remain in optimizing transformation efficiency, scaling up bioreactor-based suspension cultures, and ensuring proper post-translational modifications under Good Manufacturing Practice (GMP) standards. Recent advances in synthetic biology, modular vector design, and glycoengineering have begun to address these limitations, improving control over transcriptional regulation and protein quality. This review highlights the application of SE as a biotechnological route for recombinant protein production, discusses current challenges, and presents innovative strategies and perspectives for the development of sustainable plant-derived biopharmaceutical systems. Full article

The Japanese encephalitis virus (JEV) remains a major cause of viral encephalitis in Asia, and recent epidemiological shifts driven by the predominance of genotype I and the re-emergence of genotype V have renewed concerns regarding control efforts. Licensed vaccines have a reduced incidence of more than 90% in several endemic regions; however, evidence of reduced cross-neutralization against heterologous genotypes indicates that vaccines derived from genotype III strains may not fully match the evolving antigenic landscape. This review synthesizes current knowledge on vaccine performance, genotype-driven antigenic variation, and implications for future strain alignment. Emerging platforms, including mRNA, DNA, virus-like particles, and structure-guided recombinant antigens, have been evaluated for their potential to enhance cross-genotype breadth, scalability, and thermostability. We also summarize the progress in antiviral discovery targeting viral nonstructural proteins, host pathways, and monoclonal antibody development, along with immunomodulatory and neuroprotective strategies. Translational challenges, such as blood–brain barrier penetration, therapeutic timing, and durability of immunity, have been highlighted as key barriers to clinical application. By integrating molecular, immunological, and epidemiological evidence, this review outlines strategic directions for developing broad-spectrum vaccines and therapeutics capable of addressing the evolving genetic and ecological landscape of JEV. Full article