Search Results (653)

Inherited platelet function disorders (IPFD) are characterized by normal platelet count and morphology but impaired function due to pathogenic variants in genes encoding membrane receptors, granule constituents, or intracellular signaling proteins. Glanzmann’s thrombasthenia, the most representative IPFD, results from ITGA2B or ITGB3 mutations that disrupt the αIIbβ3 integrin complex, producing severe mucocutaneous bleeding. Advances in molecular genetics have expanded the IPFDs landscape to include defects in other platelet receptors (Glycoprotein (GP)-VI, P2Y₁₂, and thromboxane A₂[TxA₂]-R), signaling mediators (RASGRP2, FERMT3, G-protein regulators, PLC, and TxA₂ pathway enzymes), and granule biogenesis disorders such as Hermansky–Pudlak and Chediak–Higashi syndromes. High-throughput sequencing technologies, including long-read approaches, have greatly improved diagnostic yield and clarified genotype–phenotype correlations. Clinically, bleeding severity varies from mild to life-threatening, and management relies on antifibrinolytics, desmopressin, or platelet transfusion; recombinant activated factor VII and hematopoietic stem cell transplantation are reserved for selected cases. Emerging strategies such as gene therapy and bispecific antibodies that link platelets and coagulation factors represent promising advances toward targeted and preventive treatment. A better knowledge of the clinical features and understanding molecular pathogenesis of IPFDs not only enhances diagnostic precision and therapeutic options but also provides key insights into platelet biology, intracellular signaling, and the broader mechanisms of human hemostasis. Full article

Blood cancer is characterized by the uncontrolled growth of blood cells in the bone marrow or in the lymphatic system. Chemotherapy is still considered the first line of treatment in several types of blood cancer despite its adverse effects. Recent advances in understanding the pathology and genomic changes in these cancers have led to the discovery of novel drug targets and the development of new therapeutic agents. In this review, we will discuss the mechanisms of action and clinical utility of several classes of targeted therapy used in blood cancers, including inhibitors of different types of tyrosine kinase enzymes (BCR-ABL, FLT3 and BTK), BCL-2 inhibitors, phosphoinositide 3-kinase inhibitors, nuclear export inhibitors, immune therapies (monoclonal antibodies, radioimmunoconjugates, chimeric antigen receptor T-cells, immune checkpoint inhibitors, and bispecific antibodies), and proteasome-dependent drugs (proteasome inhibitors and proteolysis targeting chimeras). Further advances in identifying distinct molecular subgroups in blood cancers will offer more opportunities for novel targeted therapies and more personalized medicine approaches. Full article

Treatment paradigms for B-cell lymphomas have evolved significantly in the last decades. Nevertheless, the widespread clinical use of immunotherapy has demonstrated that it invariably leads to the development of resistance. This review outlines the underlying molecular mechanisms of resistance associated with emerging immunotherapeutic strategies, including Chimeric Antigen Receptor (CAR) T cell therapy and bispecific antibodies (BsAbs). In high-grade B-cell lymphomas, nearly 50% of patients progress following CAR T treatment due to host-related factors affecting CAR T cell proliferation and persistence, as well as tumor-intrinsic factors, such as loss of CD19 epitope expression, trogocytosis, and other genomic alterations (e.g., CD19 mutations, chromothripsis, APOBEC mutational activity, and deletions of RHOA). Additional genomic and epigenetic events, including mutations, alternative splicing of CD19, and aberrant promoter methylation, further contribute to resistance. BsAbs, representing an off-the-shelf T-cell-redirecting strategy, have recently shown promising single-agent efficacy with a manageable toxicity profile, predominantly characterized by T cell overactivation syndromes. Similarly to CAR T cell therapy, BsAb resistance arises through diverse mechanisms, such as antigen loss, T cell dysfunction (exhaustion and regulatory T cell activation), tumor-intrinsic alterations (e.g., TP53 mutations and MYC amplifications), and immunosuppressive influences from the tumor microenvironment. These findings underscore the complexity of immune evasion in B-cell lymphomas and highlight the ongoing need to optimize immunotherapeutic strategies and develop combination approaches to overcome resistance. Full article

Follicular lymphoma management is rapidly evolving with advanced cellular therapies. This review examines the optimal sequencing of autologous stem cell transplantation (autoSCT), allogeneic stem cell transplantation (alloSCT), and CAR T-cell therapy. AutoSCT is a crucial intervention for chemosensitive relapsed FL, prolonging progression-free survival, though not typically curative. AlloSCT, offering a potential cure via a graft-versus-lymphoma effect, carries significant risks like graft-versus-host disease and non-relapse mortality, thus primarily serving as a salvage option for high-risk or treatment-refractory cases after other modalities, including autoSCT. CAR T-cell therapy, utilizing genetically modified T cells targeting CD19, has revolutionized relapsed/refractory FL. Products like axicabtagene ciloleucel, tisagenlecleucel, and lisocabtagene maraleucel have demonstrated high response rates and durable remissions even in heavily pretreated patients with high-risk features. This potent therapy is increasingly considered a bridge between autoSCT and alloSCT, expanding treatment options. Additionally, bispecific antibodies such as mosunetuzumab, epcoritamab and odrenextamab provide convenient off-the-shelf options, exhibiting strong efficacy and favorable safety. However, their impact on subsequent CAR-T outcomes, especially with CD19-targeting bispecifics, remains an area of ongoing investigation and uncertainty. The complex interplay of these therapies necessitates individualized decisions, emphasizing patient characteristics and disease-specific factors to optimize outcomes in FL. Further research into predictive biomarkers and refined treatment algorithms is crucial for future management. Full article

Background. The dense hyaluronan (HA)-rich stroma in solid tumors can prevent effective tumor growth inhibition by hindering drug delivery and immune cell infiltration. However, the degradation of HA alone by systemic delivery of hyaluronidase has not shown significant improvement of tumor growth inhibition. Objectives/Methods. In this study, we targeted hyaluronan degradation by using antibody–enzyme (AbEn) molecules by fusing antibodies to a recombinant human hyaluronidase (HYAL). Results. The AbEn molecules were stable, retained both antigen-binding and enzymatic activities, and demonstrated a prolonged serum half-life of 132 h in rodent models. In the HA-rich colorectal cancer model, the cancer-associated fibroblast (CAF)-directed AbEn, TAVO423 (FAP × LRRC15 × HYAL trispecific antibody) achieved greater intratumoral HA depletion resulting in superior tumor growth inhibition compared to untargeted HYAL. Furthermore, the combination of TAVO423 in combination with other solid tumor cell targeting modalities such as 5-fluorouracil (5-FU), anti-PD-L1 monoclonal antibody, a PD-L1 × CD3 bispecific T-cell engager (TCE), and a CD318-targeting antibody–drug conjugate (ADC) all demonstrated enhanced tumor growth inhibition (TGI) values of 49–67% as compared to the respective monotherapy TGI values of 1–28%. In addition, TAVO423 improved the antitumor response of a 5T4 × CD3 TCE with an increase in TGI from 73% to 92% in an in vivo HA-rich pancreatic cancer model. The CAF-targeted HA degradation mediated by TAVO423 also reversed immune exclusion by increasing the density of CD8⁺ tumor-infiltrating lymphocytes (TILs) by 6–9-fold and synergized with PD-1 blockade to enhance TGI from 33% to 51% in an in vivo immunocompetent EMT-6 breast cancer model. Conclusions. These findings demonstrated the broad potential of the modular AbEn platform for targeted HA degradation to overcome barrier entry in stromal HA-rich solid tumors. Full article

The COVID-19 pandemic, caused by SARS-CoV-2, has profoundly affected global health and the economy. The emergence of variants with spike mutations, particularly within the receptor-binding domain (RBD), has reduced the efficacy of many neutralizing antibodies (nAbs), and recent variants, including KP.3 and other circulating strains, show partial escape from infection- or vaccine-induced immunity. To overcome this, developing broad-spectrum nAbs that target the conserved S2 subunit of the spike protein is crucial. Unlike the highly mutable RBD, the S2 region remains structurally conserved, providing a promising foundation for universal protection. Deeper insight into S2 structure and function, together with advances in bispecific antibody design, could facilitate the development of next-generation therapeutics resilient to viral evolution. This review examines the structural evolution of the SARS-CoV-2 spike, focusing on the therapeutic potential of S2-targeting antibodies and strategies to overcome antibody resistance. Full article

More than a decade after its discovery, advances have been made in understanding the oncogenic role of mutant CALR in BCR::ABL1-negative myeloproliferative neoplasms (MPNs). Disease biology has proven to be distinct from other MPN subtypes, with meaningful differences that have created opportunities for therapeutic targeting of CALR-mutant clones. Among the approaches under investigation, immunotherapy has advanced furthest into clinical development and holds promise. Several strategies are now being explored, including monoclonal antibodies directed against the CALR neoepitope, T-cell–redirecting bispecific antibodies, precision antibody–drug conjugates, vaccination approaches, and CAR T-cell therapies. Early-phase clinical trials with fully human anti-CALR monoclonal antibodies (e.g., INCA033989) have shown very promising hematologic and molecular responses with manageable toxicity. In preclinical models, bispecific antibodies and CAR T-cell therapy offer additional avenues to exploit the selective cell-surface localization of mutant CALR. By contrast, vaccination strategies have so far demonstrated limited clinical efficacy, and their potential in clinical practice remains challenging. At the same time, the complexity of CALR-driven disease raises key questions, including whether anti-CALR therapies can shift treatment goals beyond thrombotic risk reduction, how best to monitor clonal burden, and how to address immune escape. In this review, we highlight the latest therapeutic advances in CALR-mutated MPNs while outlining the critical unmet needs that will shape the future of care for these patients. Full article

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers, characterized by a dense and immunosuppressive tumor microenvironment. With the limited actions of drugs and conventional monovalent antibodies, the success of existing cancer therapies is restricted so far. Recently, bispecific antibodies (BsAbs) have emerged as a promising therapeutic platform, capable of overcoming the limitations of current PDAC treatments by engaging T cells and delivering drugs to multiple targets in a selective manner. Furthermore, the recruitment of additional payloads expands their therapeutic potential, offering more selective drug delivery and presenting new possibilities for treating PDAC. However, a limited number of relevant studies and a lack of comprehensive research have hindered trials for the development of BsAbs and bispecific antibody-drug conjugates (BsADCs) in PDAC therapeutics. This review aims to provide the characteristics of BsAbs and BsADCs and their recent applications in PDAC treatment. Additionally, frequent targets of PDAC treatments will be discussed to suggest how to design BsAbs and BsADCs for PDAC treatments. Full article

Burkitt lymphoma (BL) is a rare, aggressive B-cell lymphoma that is characterized by rapid tumor proliferation and frequent extra-nodal involvement. While prompt diagnosis and initiation of highly intensive chemotherapy results in cure rates over 90% in children and adolescents, outcomes in adults are more modest, as comorbidities and advancing age may compromise treatment tolerability. In recent years, intermediate-intensity regimens have been developed for BL. These are highly effective in patients of all ages and associated with significantly less treatment-related toxicity compared to traditional high-dose chemotherapy. This was demonstrated in a recent randomized study of dose-intensive R-CODOX-M/R-IVAC compared to the reduced-intensity DA-EPOCH-R regimen, which was associated with equivalent outcomes but with significantly fewer side effects. Regardless of the chemotherapy platform, CNS involvement at baseline predicts a significantly inferior outcome, and the development of an optimal approach for these patients is an area of unmet need in BL therapeutics. Patients with relapsed or refractory disease following frontline therapy have very short survival times, as currently available salvage options are largely ineffective. In this regard, novel agents such as anti-CD19 CAR-T cells and bi-specific antibodies are under development in BL. It is hoped that progress in novel drug development, alongside improved understanding of BL biology, to further elucidate its genetic and epigenetic vulnerabilities, will lead to improved outcomes for patients in the future. Full article

Prostate cancer is the most frequently diagnosed solid-organ malignancy in men worldwide. Metastatic castration-resistant prostate cancer represents a rapidly fatal, end-stage form of the disease for which current therapies remain palliative rather than curative. The advent of chimeric antigen receptor (CAR) T-cell therapy has revolutionized the treatment of refractory hematologic malignancies, and a growing number of studies are now exploring its potential in solid tumors. In this review, we first provide a concise overview of current immunotherapeutic strategies for prostate cancer, including checkpoint inhibitors, vaccine-based approaches, and bispecific antibodies. We then focus on the most recent and promising developments in CAR-T cell therapy for this malignancy. Specifically, we examine the key tumor-associated antigens targeted in prostate cancer-directed CAR-T cell therapy and summarize findings from preclinical research as well as ongoing and completed clinical trials. Finally, we discuss the main challenges that limit the efficacy of CAR-T therapy in prostate cancer, such as antigen heterogeneity, immunosuppressive tumor microenvironments, on-target/off-tumor toxicity, limited T-cell persistence, and inefficient trafficking to metastatic lesions, and outline potential strategies to overcome these barriers. Our aim is to define a translational roadmap for advancing CAR-T therapy toward clinical application in patients with metastatic castration-resistant prostate cancer. Full article

This review analyzed approximately 115 peer-reviewed studies published between 2010 and 2025, focusing on molecular subtyping and circulating tumor DNA (ctDNA)-guided approaches in Diffuse Large B-Cell Lymphoma (DLBCL). Evidence was synthesized from retrospective cohorts, prospective clinical trials, and translational studies, highlighting how molecular heterogeneity, clonal evolution, and the tumor microenvironment complicate classification and treatment. While molecular subtypes such as MCD, BN2, EZB, A53, and ST2 have improved prognostication, their routine use in clinical practice remains limited due to cost, complexity, and restricted access to sequencing platforms. Tumor-informed ctDNA assays show promise for minimal residual disease (MRD) monitoring and adaptive therapy, yet their predictive power for CAR-T therapy, bispecific antibodies, and checkpoint inhibitors is still incompletely understood. Overall, the literature converges on the need for integrated strategies combining ctDNA, molecular subtyping, and immune microenvironment analysis to personalize frontline therapy. Full article

Bispecific peptides represent an emerging therapeutic platform in immunotherapy, offering simultaneous engagement of two distinct molecular targets to enhance specificity, functional synergy, and immune modulation. Their compact structure and modular design enable precise interaction with protein–protein interfaces and shallow binding sites that are otherwise difficult to target. This review summarizes current design strategies of bispecific peptides, including fused, linked, and self-assembled architectures, and elucidates their mechanisms in bridging tumor cells with immune effector cells and blocking immune checkpoint pathways. Recent developments highlight their potential applications not only in oncology but also in autoimmune and infectious diseases. Key translational challenges, including proteolytic stability, immunogenicity, delivery barriers, and manufacturing scalability, are discussed, along with emerging peptide engineering and computational design strategies to address these limitations. Bispecific peptides offer a versatile and adaptable platform poised to advance precision immunotherapy and expand therapeutic options across immune-mediated diseases. Full article

Background/Objectives: This study comprehensively characterized the O- and N-glycosylation profiles of bispecific antibodies (BsAbs) via advanced analytical techniques to evaluate their structural and functional implications. Methods: High-resolution MS revealed O-xylosylation at Ser468 within the (G4S)4 linker peptide, which was identified as xylose with a molecular weight of 132.042 Da. HILIC-HPLC analysis of N-glycosylation revealed glycan species engineered to eliminate Fc effector functions. O-glycosylation analysis via β-elimination followed by high-performance anion-exchange chromatography with pulsed amperometric detection (HPAEC-PAD) identified xylose as the predominant glycan. Results: O-xylosylation does not affect the binding of BsAbs to either antigen Programmed Death-1 (PD-1) or Vascular Endothelial Growth Factor (VEGF). Notably, O-xylosylation interactions with mannose receptor represent the first discovery highlighting potential immunomodulatory roles. Conclusions: This study highlights the critical importance of monitoring comprehensive glycosylation characterization during the development of BsAb with (G4S)n linkers to ensure optimal therapeutic efficacy, safety, and reduced immunogenic potential. Full article

Background: Macular edema (ME) secondary to retinal vein occlusion (RVO) is a significant cause of vision impairment. Many patients show suboptimal responses to anti-vascular endothelial growth factor (anti-VEGF) monotherapy, prompting the exploration of alternative treatments. Faricimab is a bispecific antibody that targets VEGF-A and angiopoietin-2. We report 9-month real-world outcomes of switching to faricimab in therapy-resistant RVO-associated ME. Methods: In this retrospective study at a single tertiary center, patients with persistent or recurrent ME despite prior treatments (ranibizumab, aflibercept, or dexamethasone implant) were switched to faricimab. All eyes received a loading phase of four monthly faricimab injections, followed by a treat-and-extend regimen individualized per response. Key outcomes included best-corrected visual acuity (BCVA, logMAR), the central subfield thickness (CST, μm), and the intraretinal fluid (IRF) status on optical coherence tomography, assessed from the baseline (month 0, mo0) through the loading phase (mo1–mo3) and at month 9 (mo9). Results: Nineteen eyes (19 patients, mean age 64.8 years) were analyzed. The median BCVA improved from 0.20 to 0.00 logMAR by month 3 (p < 0.01) and was maintained at month 9. The median CST decreased from 325 μm at the baseline to 285 μm at month 3 (p < 0.01) and remained at 285 μm at month 9. IRF was present in 100% of eyes at the baseline, 26% at month 3, and 26% at month 9 (p < 0.01 for the baseline vs. month 9). Among eyes previously on anti-VEGF therapy (n = 14), the median treatment interval increased from 45.50 days at the baseline to 56.50 days at month 9 (p = 0.01; δ = 0.86). No intraocular inflammation or other adverse events were observed in this cohort over nine months. Conclusions: In this retrospective series, switching to faricimab was associated with improvements in vision and retinal anatomy that were maintained over 9 months; injection intervals were extended in a subset of eyes. These exploratory findings warrant confirmation in larger, controlled studies to define long-term effectiveness, safety, and dosing strategies. Full article

Drug delivery to the brain faces a critical obstacle in the form of the blood–brain barrier (BBB), which severely limits therapeutic options for Alzheimer’s disease (AD). Transferrin receptor 1 (TfR1) is abundantly expressed in brain capillary endothelial cells, offering a potential pathway for circumventing this barrier. Physiologically, TfR1 binds to iron-laden transferrin, leading to cellular uptake through clathrin-mediated endocytosis. Within acidic endosomes, the iron is released, and the receptor–apotransferrin complex recycles to the cell surface for further rounds of transport. Furthermore, studies in AD mouse models have demonstrated that TfR1 expression in brain microvessels remains stable, highlighting its suitability as a delivery target even in disease conditions. Based on this, various drug delivery strategies targeting TfR1 have been developed, including bispecific antibodies, antibody fragments, ligand conjugates, and nanoparticle-based carriers. While these approaches hold great promise, they face practical limitations such as competition with endogenous transferrin, receptor saturation, and inefficient intracellular trafficking. This review details the current understanding of TfR1-mediated BBB transport mechanisms, evaluates emerging delivery platforms, and argues that TfR1 represents an accessible gateway for brain-targeted therapeutics in AD. The insights presented will be of interest to researchers in molecular biology, pharmacology, and drug development. Full article