Search Results (695)

Machine learning is increasingly used to relate molecular descriptors, formulation variables, and biophysical measurements to aggregation, viscosity, solubility, and shelf-life outcomes. The evidence is promising but uneven. Most published datasets contain tens to a few hundred antibodies, use different assays and endpoint definitions, and rely mainly on internal validation. Direct evidence for bispecific antibodies, antibody–drug conjugates, mRNA–lipid nanoparticles, and viral vectors remains limited. This structured critical review evaluates what current models can support, how data and validation choices shape reported performance, and where claims exceed the available evidence. We searched PubMed through 30 June 2026 using predefined queries for machine learning, biopharmaceutical formulation, colloidal stability, advanced modalities, and shelf-life modelling. Studies were assessed by molecular diversity, formulation coverage, endpoint quality, split strategy, external validation, and decision relevance. The strongest current use cases are early antibody developability screening, high-concentration viscosity classification, formulation ranking within a defined experimental domain, and image-based particle classification. Long-term shelf-life prediction may benefit from hybrid kinetic and machine learning models, but real-time confirmation remains necessary. Progress will depend less on larger algorithms than on better labels, molecule-level validation, shared reference datasets, and clear uncertainty reporting. Full article

Background: Elranatamab, a bispecific antibody targeting BCMA and CD3, has demonstrated clinical activity in relapsed/refractory multiple myeloma. Real-world evidence regarding infectious complications and supportive care remains limited. We evaluated the early clinical activity, safety profile, infectious complications, and supportive care practices associated with relapsed/refractory multiple myeloma (RRMM). This study represents one of the first multicenter real-world evaluations of elranatamab in Türkiye. Methods: This multicenter retrospective study included 87 patients with relapsed/refractory multiple myeloma treated with elranatamab. Clinical characteristics, treatment responses, immune-mediated toxicities, infectious complications, and supportive care practices were assessed. Overall response rate (ORR), progression-free survival (PFS), and overall survival (OS) were evaluated. Multivariable analyses were performed to identify factors associated with treatment response and clinical outcomes. Results: At 3 months, ORR was 47.1% in the ITT population, 54.7% in the mITT population, and 83.7% among evaluable patients; corresponding 6-month ORRs were 31.0%, 42.2%, and 81.8%, respectively. The high proportion of patients without landmark response assessments primarily reflected insufficient follow-up, early death, or disease progression. Elevated LDH remained independently associated with lower response probability and inferior clinical outcomes. Cytokine release syndrome (CRS) occurred in 69% of patients, with grade ≥ 3 events in 5.7%, whereas immune effector cell-associated neurotoxicity syndrome (ICANS) was infrequent (4.6%) and no grade ≥ 3 events occurred. Grade ≥ 3 infections occurred in 39% of patients, including CMV events requiring antiviral treatment in 24.1%. No HBV reactivation occurred among patients receiving antiviral prophylaxis. Median PFS and OS were 8.1 and 10.6 months, respectively. Conclusions: Elranatamab demonstrated early clinical activity and a manageable safety profile in a heavily pretreated real-world RRMM population. Infectious complications, including CMV events, remained clinically relevant, emphasizing the importance of supportive care. Longer follow-up is needed to characterize long-term outcomes. Full article

Immune checkpoint inhibitors (ICIs) have significantly changed the treatment landscape of several gastrointestinal (GI) malignancies, particularly microsatellite instability-high (MSI-H) and mismatch repair-deficient (dMMR) tumors. However, most GI cancers remain resistant to current PD-1/PD-L1-based immunotherapy because of complex and highly suppressive tumor microenvironments characterized by immune stromal exclusion, myeloid-driven immune suppression, defective antigen presentation, and adaptive immune resistance mechanisms. Emerging evidence suggests that alternative inhibitory pathways, including lymphocyte activation gene-3 (LAG-3), T-cell immunoreceptor with immunoglobulin and ITIM domain (TIGIT), T-cell immunoglobulin and mucin-domain containing-3 (TIM-3), and V-domain Ig suppressor of T-cell activation (VISTA), contribute substantially to persistent T-cell dysfunction and resistance to checkpoint blockade. This review summarizes the immune landscape of GI malignancies and discusses the biological mechanisms underlying resistance to current ICIs. We highlight the evolving role of next-generation immune checkpoints, ongoing clinical development of novel inhibitors, and emerging combination strategies involving chemotherapy, anti-angiogenic therapy, radiation, bispecific antibodies, and tumor microenvironment modulation. In addition, we discuss current limitations in biomarker development and the growing role of circulating tumor DNA, spatial immune profiling, and multi-omics approaches in patient selection. Finally, we explore future directions aimed at improving precision immunotherapy and expanding durable responses across GI cancers. Full article

Relapsed/refractory multiple myeloma is marked by frequent triple-class refractoriness and poor survival, whereas bispecific antibodies targeting BCMA, GPRC5D, or FcRH5 show meaningful activity even in heavily pretreated and post-BCMA disease. This meta-analysis evaluates and compares the efficacy and safety of these agents in RRMM using direct and indirect evidence. We manually searched seven databases and identified 44 studies for quantitative analysis. Forest plots were created using R 4.1.1 software. Compared to Standard of care (SOC), the odds of Objective response rate (ORR) were higher with Talquetamab, Teclistamab, Elranatamab, and Linvoseltamab (5.73, 4.86, 3.84, and 2.63). PFS improved with Teclistamab (HR 0.50, 95% CI 0.36–0.55), Talquetamab (0.50, 0.36–0.55), Elranatamab (0.45, 0.36–0.55), and Linvoseltamab (0.23, 0.17–0.31). Linvoseltamab and Elranatamab showed numerically longer OS relative to SOC (HR 0.41, 0.24–0.70 and HR 0.58, 0.43–0.78, respectively), but numerically shorter OS with Teclistamab (HR 1.82, 1.37–2.42) and Talquetamab (HR 1.75, 1.20–2.57). In pooled single-arm data, Talquetamab had the highest ORR (72%) and CRS rate (68%); Teclistamab showed an ORR of 61% with a CRS rate of 61% and Linvoseltamab showed an ORR of 60% with a CRS rate of 51%. Cevostamab and Elranatamab had ORRs of 49% and 56% with CRS rates of 61% and 52%, respectively. In RRMM, all bispecific antibodies showed superior ORR along with improved PFS compared to SOC. Linvoseltamab and Elranatamab showed numerically longer OS relative to SOC, whereas Talquetamab and Teclistamab showed numerically shorter OS versus SOC, within the constraints of adjusted cross-trial comparisons. Full article

Introduction: Bispecific antibodies (BsAbs) are a promising and potent therapeutic intervention for relapsed or refractory (R/R) hematologic malignancies, including acute lymphoblastic leukemia (ALL), multiple myeloma (MM), and B-cell lymphomas. These recombinant molecules are designed to target two distinct antigens or epitopes. While BsAbs have shown significant efficacy in managing hematologic malignancies, toxicities must be carefully monitored and their safety profiles require further investigation. This meta-analysis investigates cardiovascular adverse effects associated with seven BsAbs across multiple clinical trials. Methods: A systematic literature review identified seven BsAbs, blinatumomab, elranatamab, epcoritamab, glofitamab, mosunetuzumab, talquetamab, and teclistamab, analyzing 25 clinical trials (Phase I–III) that included monotherapy regimens. The cardiovascular adverse events studied were arrhythmias, heart failure, blood pressure changes, and myocardial infarctions. A meta-analysis using the R meta package calculated proportions and 95% confidence intervals (CIs) and employed a random-effects model to assess heterogeneity. Results: Among 3215 patients, pooled analysis revealed significant findings with 13.6% cardiac arrhythmia (95% CI 10.1–18.2%, p = 0.05), 13.3% hypotension (95% CI 10–17.3%, p < 0.0001), 10.2% tachycardia (95% CI 7.6–13.5%, p = 0.0003), and 3.4% sudden death (95% CI 0–80%, p = 0.046). Less frequent events were hypertension (8%), acute myocardial infarction (1.5%), heart failure (1.4%), and atrial fibrillation (1.3%). Discussion: As BsAbs see increased use in R/R hematologic malignancies, cardiovascular complications must be closely monitored. This analysis highlights hypotension, cardiac arrhythmias, tachycardia, and sudden death as significant adverse effects. Although study heterogeneity and limited patient-level data may have influenced incidence estimates, these findings support routine cardiovascular monitoring and underscore the need for prospective studies to identify high-risk patients and optimize prevention and management strategies. Oncologists, cardiologists, and pharmacists should establish strategies for early detection and management to optimize patients’ outcomes. Full article

Background/Objectives: The treatment landscape of relapsed/refractory multiple myeloma (RRMM) has significantly evolved with the introduction of novel classes of agents and, more recently, of T-cell-redirecting therapies, including bispecific antibodies (BsAbs). It is essential to enhance and harmonize the therapeutic management of BsAbs within clinical practice. Methods: We performed a modified Delphi expert consensus study on the use of BsAbs targeting the B-Cell Maturation Antigen (BCMA) in patients with triple-class-exposed (TCE) RRMM. The study was conducted in April–November 2025 following established guidelines and best practices for defining consensus. The key phases in the use of anti-BCMA BsAbs were identified and explored. Results: Fifteen Italian hematologists with expertise in the care of TCE RRMM completed two Delphi rounds. Agreement (defined as ≥67% of panelists) was achieved on most of the topics evaluated. In particular, all panelists considered the step-up dosing phase feasible in an outpatient setting, under specific circumstances, and dosing de-escalation in responding patients to reduce the risk of adverse events. For most of them, anti-BCMA BsAb treatment is also feasible in several challenging subgroups, including frail patients (93% agreement) and those with high-risk cytogenetics (93%), extramedullary disease (93%), end-stage renal disease (86%), active plasma cell leukemia (79%), and central nervous system involvement (67%). In addition, agreement (93%) was reached on the possible sequential use of BCMA-targeting therapies, preferentially BsAbs following CAR-T, though a switch in the target antigen should primarily be considered. Conclusions: In this article, we address the main challenges related to the real-world use of anti-BCMA BsAbs in patients with TCE RRMM, offering expert recommendations to complement existing guidelines and support clinical practice. Full article

Bispecific antibodies (bsAbs) are engineered to recognize either two distinct antigens or two different epitopes on the same antigen within a single molecule. This design varies according to the intended indication and mechanism of action; the factors considered during design are critical determinants of antigen binding, pharmacological activity, productivity, and safety. In this review, bsAbs are classified into fragment-based formats and Fc-containing IgG-like formats, with the latter further divided into symmetric and asymmetric architectures. Based on this structural framework, we discuss how key design parameters—including valency, epitope geometry, affinity and binding kinetics, and linker architecture—influence avidity, immune synapse formation, receptor clustering, signaling modulation, and toxicity profiles. We further compare preclinical and clinical examples across representative target combinations, including CD19 × CD3, CD20 × CD3, BCMA × CD3, HER2 × HER2, and EGFR × MET, to illustrate how different molecular formats yield distinct therapeutic outcomes even when the target combinations are similar. By linking structural classification with mechanism-based interpretation and within-target comparisons, this framework relates individual design variables directly to their preclinical and clinical consequences. Finally, we describe how the energy-based molecular modeling platform Rosetta and the deep-learning-based structure-prediction system AlphaFold are applied to support interface optimization, chain-pairing control, epitope geometry prediction, and structure-guided candidate prioritization. Overall, this review can provide a structure–function framework for bsAb design by integrating key structural determinants, their functional consequences, and emerging AI-based predictive strategies to facilitate the selection of optimal molecular architectures for specific therapeutic applications. Full article

T-cell immunoreceptor with immunoglobulin and immunoreceptor tyrosine-based inhibitory motif (ITIM) domains (TIGIT) emerged as one of the most promising next-generation immune checkpoint targets following the success of programmed cell death protein 1 (PD-1), programmed death-ligand 1 (PD-L1), and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) blockade. TIGIT suppresses antitumor immunity through interaction with cluster of differentiation 155 (CD155), inhibition of CD226-mediated co-stimulation, and promotion of immunosuppressive regulatory T-cell (Treg) activity within the tumor microenvironment (TME). Strong preclinical evidence demonstrated that TIGIT blockade, particularly in combination with PD-1/PD-L1 inhibition, restored T-cell and natural killer (NK) cell function and produced durable antitumor responses in multiple tumor models, leading to rapid clinical development. Despite this compelling biological rationale, most late-stage clinical programs failed to reproduce early success. Although the phase II CITYSCAPE trial showed encouraging activity in PD-L1-high non-small cell lung cancer (NSCLC), subsequent phase III trials, including SKYSCRAPER-01, SKYSCRAPER-02, SKYSCRAPER-03, SKYSCRAPER-14, AdvanTIG-302, KEYVIBE, and STAR-221, failed to improve survival outcomes or meet primary endpoints. The notable exception was SKYSCRAPER-08 in esophageal squamous cell carcinoma, suggesting that TIGIT blockade may be effective only in selected biological contexts. This review critically examines the molecular biology of the TIGIT–CD155–CD226 axis, its role in immune regulation and tumor immune evasion, and the preclinical and clinical evidence supporting TIGIT-targeted therapy. Particular emphasis is placed on understanding the causes of clinical failure, including CD226 loss during T-cell exhaustion, checkpoint network redundancy, Fc-engineering uncertainty, immunosuppressive TMEs, inadequate biomarker-guided patient selection, and tumor-type-specific dependence on the TIGIT pathway. We also present original bioinformatics analyses demonstrating that broader checkpoint network signatures outperform TIGIT expression alone for patient stratification. Finally, we evaluate emerging solutions including biomarker-guided precision immunotherapy, Fc-optimized antibodies, bispecific checkpoint inhibitors, TIGIT-engineered chimeric antigen receptor T-cell (CAR-T) cells, radiotherapy combinations, and multi-checkpoint blockade. Collectively, current evidence suggests that the future of TIGIT-directed therapy lies not in universal checkpoint inhibition but in biologically informed, precision-guided immunotherapy strategies. Full article

Background: The treatment paradigm for relapsed/refractory (R/R) large B-cell lymphoma (LBCL) has undergone significant change with the advent of CD19-directed chimeric antigen receptor T-cell (CAR-T) therapies and CD20 × CD3 bispecific antibodies (BsAbs). Although both approaches have shown high response rates in single-arm studies, the absence of prospective randomized head-to-head comparisons has resulted in true clinical equipoise. Methods: A narrative synthesis was conducted, incorporating pivotal and updated phase 2 and 3 trial data, real-world evidence, and published meta-analyses. Results: In the second-line setting, CAR-T therapy demonstrates superior event-free survival, progression-free survival, and overall survival compared to standard-of-care chemo-transplant regimens. In the third-line setting, a pooled meta-analysis indicates significantly higher complete response rates for CAR-T compared with BsAbs, as well as superior 12-month progression-free survival. BsAbs provide immediate availability, greater accessibility, more favorable neurotoxicity profiles, and are feasible for frail or elderly patients. Real-world data show that BsAb complete response rates are consistently lower than those observed in clinical trials, whereas CAR-T real-world effectiveness closely aligns with pivotal trial outcomes. Emerging phase 3 data on fixed-duration and monotherapy bispecific regimens suggest that a genuine, if less mature, curative fraction may also be achievable among BsAb-treated complete responders. Conclusions: CAR-T therapy remains the standard of care for fit, eligible patients with R/R LBCL in second- and third-line settings with curative intent, providing superior depth and durability of response and a growing potential for long-term cure. BsAbs constitute a critical therapeutic alternative for patients ineligible for CAR-T, those with rapidly progressive disease, frail or elderly individuals, and as bridging strategies. A patient-centered, scenario-specific clinical decision framework is recommended. Full article

Acute myeloid leukemia (AML) is a heterogeneous hematologic malignancy characterized by the clonal expansion of myeloid blasts and the persistence of leukemic stem cells (LSCs) within a profoundly remodeled bone marrow (BM) microenvironment. Despite advances in molecular stratification and the introduction of targeted agents, long-term outcomes remain unsatisfactory, particularly in older and high-risk patients. Increasing evidence indicates that leukemogenesis and treatment resistance are critically sustained by a permissive immune milieu, in which LSCs, myeloid-derived suppressor cells, leukemia-associated macrophages, and dysfunctional T and NK cells shape an immunosuppressive “leukemic niche.” This evolving understanding has renewed interest in immune-based strategies capable of restoring effective antitumor immunity. Bispecific antibodies (bsAbs) are engineered molecules designed to engage AML-associated antigens while simultaneously recruiting and activating immune effector cells, most commonly T cells or NK cells. By promoting immune synapse formation independently of major histocompatibility complex expression and conventional co-stimulatory pathways, bsAbs can overcome several mechanisms of immune escape. In this review, we summarize the biological rationale for immunotherapy in AML, with a focus on the role of the BM microenvironment and immune dysregulation. We then discuss the structural and functional properties of IgG-like and non-IgG-like bsAbs, key antigenic targets such as CD33, CD123, CD70 and others, and the main T-cell- and NK-cell-engaging platforms under clinical investigation. Finally, we highlight emerging clinical data, principal toxicities, and the challenges of integrating bsAbs into existing treatment algorithms, including combinations with hypomethylating agents, BCL-2 inhibitors, and allogeneic stem cell transplantation. A deeper understanding of AML immune biology and antigen expression patterns will be essential to optimize bsAb design, maximize therapeutic benefit, and minimize on-target off-tumor toxicity. Full article

Background/Objectives: Teclistamab is a B-cell maturation antigen (BCMA)-directed bispecific antibody approved for relapsed or refractory multiple myeloma (RRMM). Although prior analyses have summarized teclistamab outcomes, some have included combination regimens or broader comparative studies. Given the expanding real-world experience with teclistamab, we conducted a systematic review and meta-analysis focused on teclistamab monotherapy in RRMM. Methods: We performed a systematic review and meta-analysis of clinical trials and retrospective real-world studies evaluating teclistamab monotherapy in RRMM. The primary endpoint was overall response rate (ORR). Secondary endpoints included complete response (CR), overall mortality rate (OMR), mortality due to multiple myeloma progression, teclistamab-attributed mortality, adverse event-related mortality, grade ≥3 cytokine release syndrome (CRS), grade ≥3 immune effector cell-associated neurotoxicity syndrome (ICANS), and other grade ≥3 adverse events. Pooled proportions were estimated using random-effects models. Results: Twelve studies including 761 patients were analyzed, comprising two clinical trials and ten real-world retrospective cohorts. The pooled ORR was 60.9%, and the pooled CR rate was 25.2%. The pooled OMR was 26.9%, with mortality due to myeloma progression of 23.9%, adverse event-related mortality of 8.1%, and teclistamab-attributed mortality of 3.3%. Severe (grade ≥3) CRS and ICANS were uncommon, with grade ≥3 events occurring in 1.7% and 3.1%, respectively. Grade ≥3 infections occurred in 28.3%. Common grade ≥3 hematologic adverse events included lymphopenia, neutropenia, anemia, and thrombocytopenia. Conclusions: Teclistamab monotherapy demonstrates meaningful clinical activity and a manageable immune toxicity profile in heavily pretreated RRMM. However, severe infections and hematologic toxicities remain important clinical considerations, supporting the need for close monitoring, infection prevention, and supportive care during therapy. Full article

Monoclonal antibodies are emerging as advanced therapies in companion-animal medicine, with approved or clinically evaluated applications in canine and feline osteoarthritis pain, canine atopic dermatitis, and selected infectious-disease and oncological settings. This critical narrative review integrates peer-reviewed studies, regulatory records, product information, and publicly available therapeutic-antibody sequence resources to examine target biology, species adaptation, Fc function, developability, and clinical implementation. Anti-NGF and anti-IL-31 products demonstrate the clinical value of long dosing intervals, whereas oncology and infectious-disease programmes remain subject to indication-specific efficacy and safety requirements. Canine and feline IgG subclasses, Fc-receptor and FcRn biology, incomplete feline framework resources, manufacturing economics, and owner-funded care all influence candidate design and deployment. Emerging bispecific antibodies, antibody–drug conjugates, VHHs, mRNA-based approaches, and AI-assisted strategies are most relevant when they address a defined veterinary use case. We propose a translational framework linking target validation, species-adapted engineering, species-matched assays, manufacturability, regulatory evidence, and real-world deployment. Full article

A single-chain variable fragment (scFv) is an engineered antibody derivative that retains antigen-binding specificity while having a much smaller size than an antibody, improved tissue penetration, and enhanced versatility for genetic manipulation. When an scFv is fused with diverse protein payloads, multifunctional biologics can be created for targeted delivery and therapy. Over the past decade, scFv fusion proteins have gained significant traction in oncology, where they have been incorporated into immunotoxins, immunocytokines, bispecific antibodies, Chimeric Antigen Receptor (CAR)-T cells constructs, and immune cell engagers. In addition, advances in blood–brain barrier (BBB)-targeting strategies have enabled the exploration of scFv-based therapeutics for neurodegenerative diseases, including Alzheimer’s disease and Parkinson’s disease. Despite promising preclinical and clinical outcomes, challenges such as structural instability, short half-life, immunogenicity, and manufacturing complexity remain. This review provides an in-depth and up-to-date overview of scFv fusion protein engineering and its therapeutic applications in cancer and neurodegenerative disorders. We also highlight the clinical translations and design principles of scFv fusion proteins. Full article

Pseudomonas aeruginosa is an important opportunistic pathogen associated with diverse healthcare-associated infections and increasing antimicrobial resistance. This systematic review evaluated antimicrobial treatment regimens, clinical outcomes, and pharmacokinetic/pharmacodynamic (PK/PD) considerations in P. aeruginosa infections. A systematic review was conducted according to PRISMA guidelines. PubMed/MEDLINE and the Cochrane Library were searched for studies published between January 2000 and March 2026. Data on antimicrobial therapies, clinical and microbiological outcomes, and PK/PD parameters were extracted. Study quality was assessed using the NHLBI quality assessment tool. Narrative synthesis was performed for all eligible studies, and a quantitative meta-analysis was conducted for studies with standardized outcome data. Of the 982 records identified, 249 studies met the inclusion criteria, and 34 were included in the quantitative meta-analysis. The evidence base was highly heterogeneous regarding study design, patient populations, infection types, and treatment regimens. Respiratory infections, particularly in cystic fibrosis patients, accounted for most studies. Quantitative synthesis showed no consistent superiority of any antimicrobial regimen (or combination of them), while treatment outcomes were influenced by infection characteristics, antimicrobial resistance patterns, and PK/PD factors. No universally superior antimicrobial regimen was identified for Pseudomonas aeruginosa infections. Some novel and promising treatment options have been identified, such as anti-Pseudomonas aeruginosa LPS monoclonal antibody panobacumab and inhaled Clostridium butyricum delivered via oxygen-driven nebulization. Two novel treatment modalities did not yield a clinically relevant effect, namely, the bispecific monoclonal antibody MEDI3902 (gremubamab) and the IC43 Pseudomonas aeruginosa vaccine. Treatment effectiveness appears to depend on clinical context, antimicrobial susceptibility, and PK/PD considerations, highlighting the need for further standardized research. Full article

Background/Objectives: Pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal malignancies because of aggressive tumor biology, pervasive therapeutic resistance, rapid adaptive reprogramming, and a profoundly immunosuppressive tumor microenvironment. This review summarizes recent advances in KRAS-targeted therapies, DNA damage response (DDR)-directed strategies, immune-redirection platforms, and tumor microenvironment modulation. Methods: We conducted a narrative review of peer-reviewed publications, clinical trial reports, trial registries, and selected conference data addressing emerging therapeutic strategies for PDAC. Results: KRAS-targeted therapies, including KRAS G12D-selective and multi-selective RAS(ON) inhibitors, have demonstrated substantial preclinical and emerging clinical activity while revealing diverse mechanisms of adaptive resistance. DDR-directed approaches are expanding beyond BRCA-mutated disease toward functional homologous recombination deficiency, replication stress, and synthetic lethality. In parallel, bispecific antibodies, T-cell engagers, and CAR-T-cell therapies have generated preliminary evidence of antitumor activity, although stromal exclusion, antigen heterogeneity, and immune suppression remain major barriers. These advances indicate that therapeutic resistance in PDAC is a dynamic process involving interconnected oncogenic, genomic, stromal, metabolic, and immune mechanisms. Conclusions: Future progress will require biologically informed treatment frameworks integrating complementary therapeutic modalities according to baseline tumor biology and treatment-induced adaptive states, supported by longitudinal biomarkers and rational clinical trial design. Full article