Search Results (1,263)

Bispecific antibody–drug conjugates (bsADCs) are being developed to address limitations of conventional ADCs, including heterogeneous antigen expression, insufficient tumor–normal discrimination, and suboptimal intracellular trafficking. This review evaluates bsADCs from a preclinical-to-clinical translational perspective and defines the evidence needed to justify the added complexity of bispecific design. A structured search of PubMed/MEDLINE, Embase, Web of Science, Scopus, clinical-trial registries, and major oncology conference proceedings was conducted through 29 July 2026. Dual-antigen bsADCs were classified as coverage-oriented, co-expression-dependent, trafficking-assisted, or multifunctional, while biparatopic ADCs were considered mechanistically related comparators. Dual recognition can broaden tumor coverage, enhance avidity-dependent selectivity, improve intracellular trafficking, or add biological functions. These effects depend on target-pair biology, molecular format, valency, epitope geometry, arm affinity, linker–payload properties, drug-to-antibody ratio, pharmacokinetics, normal-tissue exposure, manufacturability, and biomarker feasibility. Clinically, izalontamab brengitecan supports the feasibility of selected architectures, whereas MEDI4276 and TQB2102 illustrate how complete molecular design shapes therapeutic index. We propose an integrated translational framework and functional design parsimony, defined as selecting the least complex ADC architecture capable of achieving the intended biological and translational objective. Bispecificity should be used only when it provides a demonstrable advantage over a simpler ADC design. Full article

Background: Breast cancer is the most common malignancy among women. The HER2-low subgroup represents one of its prevalent subtypes; however, due to its unique characteristics, it presents challenges in diagnosis and treatment, complicating clinical management. This narrative review aims to synthesize evidence regarding the epidemiology, diagnosis, treatment, and prognosis of this subgroup. Methods: In this narrative review, following a search of PubMed, Web of Science, Scopus, and Google Scholar databases and the evaluation of 91 studies, findings were synthesized qualitatively and descriptively. Additionally, cohort studies, systematic reviews, and meta-analyses were utilized to explore associations and summarize prognostic trends. Results: The prevalence of HER2-low varied between 30% and 65% across different populations, with most studies reporting an association with hormone receptor (HR)-positive status and age over 50 years. Diagnostic challenges primarily stemmed from poor inter-pathologist agreement and laboratory variability. However, emerging technologies such as artificial intelligence (AI) and radiomics have shown promising results in diagnosis. Therapeutically, trastuzumab deruxtecan (T-DXd) demonstrated efficacy with response rates ranging from 21% to 62%; nevertheless, cross-resistance to antibody–drug conjugates (ADCs) and high drug costs remain significant barriers. Patient prognosis and survival, beyond HER2 status, depended on factors such as HR status, Ki-67 index, lymph node involvement, and treatment response. Conclusions: HER2-low tumors constitute a distinct, highly prevalent subgroup with specific clinical features, necessitating differentiated diagnostic and therapeutic approaches. Despite the efficacy of T-DXd, obstacles such as intragroup heterogeneity, treatment resistance, high costs, and the lack of standardized diagnostic criteria persist. Therefore, attention to molecular profiling, standardization of diagnostic methods, and the development of cost-effective strategies are essential for equitable access to treatment. Full article

Treatment for locally advanced and recurrent cervical cancer has advanced substantially with immune checkpoint inhibitors, induction chemotherapy, bevacizumab, and antibody-drug conjugates. However, subgroup analyses of major phase III trials suggest that cervical adenocarcinoma (AC) may respond differently from squamous cell carcinoma (SCC). Therefore, novel treatment strategies based on the distinct biological characteristics of AC are needed. This review aimed to evaluate the efficacy of current treatments for AC by examining histology-specific subgroup analyses from major clinical trials and to identify potential therapeutic strategies for AC. We also reviewed ongoing AC-focused clinical trials of novel molecularly targeted agents and combination therapies for advanced or recurrent disease. A structured search of PubMed and ClinicalTrials.gov through 1 June 2026, identified studies of advanced or recurrent cervical adenocarcinoma. Randomized trials, prospective studies, and histology-specific subgroup analyses were included, while case reports, preclinical studies, and SCC-only studies were excluded. Survival and response outcomes were extracted, with histology-specific findings considered exploratory. AC exhibits distinct molecular and immunological features compared with SCC, including frequent alterations in ERBB2/3, KRAS, PIK3CA, PTEN, ARID1A, and STK11 and a relatively immune-cold tumor microenvironment. HPV-independent AC, particularly gastric-type adenocarcinoma, shows aggressive clinical behavior and resistance to conventional therapies. Although bevacizumab, immune checkpoint inhibitors, and tisotumab vedotin have improved outcomes in cervical cancer, evidence specific to AC remains limited because most pivotal trials predominantly enrolled SCC or reported combined AC/adenosquamous subgroups. Emerging strategies targeting HER2, CLDN18.2, TROP2, Nectin-4, FAK, PI3K/AKT/mTOR, and ROS1 may provide new therapeutic opportunities for AC. AC represents a biologically heterogeneous disease distinct from SCC, supporting treatment strategies based on histology and molecular characteristics. Future AC-specific clinical trials and molecular stratification according to HPV association, histological subtype, and actionable alterations are needed to establish biomarker-driven personalized therapy, particularly for treatment-resistant HPV-independent AC. Full article

Background/Objectives: Androgen receptor pathway inhibitor (ARPI) intensification in metastatic hormone-sensitive prostate cancer has changed the population reaching metastatic castration-resistant prostate cancer (mCRPC), and the optimal sequence of subsequent therapies is uncertain. Methods: The study presents a narrative review of phase II/III trials reporting radiographic progression-free survival (rPFS) or overall survival (OS) in mCRPC, including congress data, to June 2026, graded on a five-level evidence hierarchy. Results: No prospective sequencing trial has been reported. CARD (cabazitaxel versus an ARPI switch after docetaxel; OS HR 0.64) remains the clearest sequencing dataset. Alpha-controlled OS benefit for PARP inhibitors is established in the PROfound cohort A (HR 0.69) and in the TALAPRO-2 all-comer population (HR 0.80); larger BRCA-specific estimates are exploratory, and BRCA OS in TRITON3 was not improved (HR 0.91). ¹⁷⁷Lu-PSMA-617 improved rPFS versus an ARPI switch in PSMAfore, but intention-to-treat OS did not differ (HR 0.91) amid 60% crossover; no taxane-controlled trial has shown an OS advantage, and in preliminary PLUDO data, OS favoured docetaxel first (HR 1.64), a difference potentially confounded by asymmetric crossover. Conclusions: We propose a hypothesis-generating four-track framework stratified by homologous recombination repair status and PSMA-PET expression; treatment choice remains individualised. Full article

Background: Sacituzumab govitecan (SG) and datopotamab deruxtecan (Dato-DXd) are TROP2-directed antibody–drug conjugates with topoisomerase I inhibitor payloads but distinct recognized adverse-event profiles. Comparative reporting patterns for these agents remain incompletely characterized. Methods: We analyzed a case-level line listing downloaded from the U.S. Food and Drug Administration (FDA) Adverse Event Monitoring System (AEMS; formerly the FDA Adverse Event Reporting System [FAERS]) Public Dashboard on 7 July 2026. Reports listing SG or Dato-DXd among suspect product names or active ingredients were assigned mutually exclusively. Prespecified toxicity phenotypes and individual MedDRA Preferred Terms (PTs) were compared using reporting proportions, comparative reporting odds ratios (RORs), false-discovery-rate correction, and multivariable logistic regression. A breast cancer-restricted analysis with crude RORs and 95% CIs was also performed. Results: The cohort comprised 6368 distinct Case IDs (SG, 5714; Dato-DXd, 654). Compared with SG, Dato-DXd reports were enriched for mucositis/stomatitis (18.3% vs. 1.3%; ROR, 17.61; adjusted reporting odds ratio [aROR], 20.04) and ocular toxicity (10.9% vs. 0.9%; ROR, 13.26; aROR, 13.98). The aRORs for Dato-DXd versus SG were 0.11 for hematologic cytopenia, 0.12 for neutropenia/febrile neutropenia, 0.11 for diarrhea/colitis, and 0.57 for infection/sepsis. Exact interstitial lung disease/pneumonitis showed reporting enrichment with Dato-DXd in the unadjusted analysis (ROR, 3.12), but the comparative reporting association was attenuated after adjustment (aROR, 1.44; 95% CI, 0.87–2.39). Overall gastrointestinal reporting was similar, and the breast cancer-restricted crude RORs were directionally consistent with the full-cohort comparisons. Conclusions: SG and Dato-DXd showed distinct adverse-event reporting profiles. SG reports were characterized by relative enrichment of hematologic and diarrheal events, whereas Dato-DXd reports were enriched for mucosal and ocular events. These findings are hypothesis-generating reporting comparisons and should not be interpreted as incidence estimates, causal associations, or conventional head-to-head safety estimates. Full article

Aim: Antibody-drug conjugates (ADCs) are an emerging class of anti-cancer therapies, designed to specifically target cancer cells while minimizing impact on healthy tissues; however, they are associated with a broad spectrum of toxicities. The goal of this paper is to review the current knowledge about ADC-associated oral toxicities with a focus on the oral mucosa. Methods: A literature search of PubMed and Google Scholar from inception through June 2026 was conducted, supplemented by official FDA pharmaceutical drug information. The review encompasses oral mucosal toxicity, dry mouth, xerostomia, and dysgeusia associated with ADCs. Findings were qualitatively assessed and compared with established guidelines for cancer therapy-associated mucositis. Results: ADC-associated oral mucosal toxicity (OMT) presents as erosions or ulcers, often causing moderate to severe pain. OMT typically occurs early in ADC treatment, with high prevalence rates and varying severity, depending on the ADC type, dose, and treatment cycles. ADC-associated dry mouth can worsen OMT, and ADC-associated dysgeusia may complicate oral intake. OMT management involves a multidisciplinary approach, focusing on basic oral care, pain management, and adequate oral intake tailored to severity. Limited evidence is available regarding steroid-based mouthwashes and cryotherapy, and their efficacy is unclear. Severe OMT may require ADC therapy adjustments, such as dose reduction, cycle spacing, or temporary discontinuation. Conclusions: ADC-associated oral toxicities manifest in various tissues. These toxicities may arise from on-target, off-target, or immune-mediated mechanisms. They require a multidisciplinary approach for management. Further research is needed to establish effective protocols for the prevention and treatment of ADC-associated oral toxicities. Full article

Cholangiocarcinoma (CCA) remains an aggressive malignancy characterized by late-stage diagnosis, substantial molecular heterogeneity, and limited therapeutic options. Advances in molecular characterization have identified actionable alterations and expanded systemic treatment beyond conventional cytotoxic chemotherapy. This review examines three clinically relevant and mechanistically distinct targeted strategies in advanced CCA. Pemigatinib, a selective fibroblast growth factor receptor 1–3 (FGFR1–3) inhibitor, targets oncogenic signaling driven by FGFR2 fusions or rearrangements, which occur predominantly in intrahepatic CCA. Zanidatamab, a bispecific human epidermal growth factor receptor 2 (HER2)-directed antibody targeting two extracellular HER2 domains, provides a therapeutic approach for HER2-positive biliary tract cancers (BTCs). Ivosidenib, a selective inhibitor of mutant isocitrate dehydrogenase 1 (IDH1m), suppresses production of the oncometabolite D-2-hydroxyglutarate and targets the associated metabolic and epigenetic dysregulation in IDH1-mutant CCA. The review integrates the molecular rationale and pivotal clinical evidence supporting these therapies with their safety profiles, mechanisms of acquired resistance, biomarker selection, and therapeutic positioning. Particular attention is given to tumor heterogeneity and the tumor microenvironment as determinants of treatment response and resistance, as well as to emerging strategies involving next-generation inhibitors, antibody–drug conjugates, immunotherapy, rational combinations, and longitudinal molecular monitoring. Collectively, the clinical development of pemigatinib, zanidatamab, and ivosidenib demonstrates the therapeutic value of matching actionable molecular alterations with mechanism-based treatments, while highlighting the need to overcome resistance and optimize treatment sequencing to achieve more durable benefit in advanced CCA. Full article

Artificial intelligence (AI) is reshaping molecular oncology by making complex biological data tractable and by extending the reach of precision drug discovery. Its emerging value is particularly evident at the interface of immunoengineering and targeted therapy, where computational models can help prioritize tumor-selective antigens, predict neoantigen immunogenicity, optimize engineered receptors, support antibody and antibody–drug conjugate design, guide small-molecule discovery, refine genome-editing strategies, and anticipate treatment response. Across these applications, the central promise is not automation for its own sake, but a wider therapeutic window in which tumor control is increased while off-target toxicity is reduced. Yet the translational gap remains substantial. Many models are still preclinical, external validation is limited, and clinical implementation remains uncommon. This Commentary follows representative methods across a therapeutic continuum that now extends from target discovery and therapeutic engineering to imaging, liquid biopsy, resistance forecasting, combination selection, and drug repurposing. We argue that clinical value will depend on closed-loop workflows in which multimodal predictions are experimentally validated, externally tested, and longitudinally updated to guide the next therapeutic decision. Full article

Background/Objectives: Conjugation of polyethylene glycol (PEG) to L-asparaginase (ASP) reduces immunogenicity and prolongs the half-life of this biological drug used to treat acute lymphoblastic leukemia (ALL). However, some patients develop anti-drug antibodies (anti-ASP and anti-PEG), which may impair efficacy through neutralization or faster elimination and may cause hypersensitivity reactions. Their clinical impact remains debated, partly due to variability in analytical methods and cut-points often defined by statistical rather than clinical outcomes. Methods: To address this issue, we used two assays to measure anti-PEG antibodies in 27 sera from 25 children with ALL who showed reactions to PEG-ASP—either clinical allergy with reduced ASP activity (n = 18) or allergic-like reactions without major activity loss (n = 9)—and in 25 sera from 19 children with ALL but without clinically relevant reactions. Sera from 16 healthy children were used as controls. This design enabled assessment of sensitivity and specificity using clinically relevant cut-points. Results: Anti-PEG IgG (but not IgM), measured by ELISA, correlated with reduced drug activity, showing 83% sensitivity and 91% specificity. We also developed a surface plasmon resonance (SPR) assay, capable of detecting simultaneously both anti-PEG and anti-ASP antibodies and analyzing binding kinetics. ROC analysis of SPR data showed 78% sensitivity and 94% specificity. Conclusions: Overall, these findings highlight the importance of clinically defined cut-points, support a key role of anti-PEG antibodies in hypersensitivity with reduced drug activity, and suggest that measuring anti-PEG antibodies may help guide therapeutic decisions. Full article

Background/Objectives: Bispecific antibody–drug conjugates (bispecific ADCs) are among the most rapidly advancing antibody therapeutic modalities, with only one product (BL-B01D1) currently approved for marketing worldwide to date. In this study, we investigated several critical quality attributes (CQAs) of a glyco-site-specific antibody–drug conjugate (ADC) targeting two distinct epitopes of HER2. Methods: We established quality control methods for the assessment of mispaired species, conjugation site, drug-to-antibody ratios (DARs), charge variants, residual free drugs, residual β1,4-galactosyltransferase I (GalT) enzyme, relative binding activity, and cell proliferation inhibition activity. Conclusions: An analytical method suite was developed for the bispecific ADC to comprehensively characterize and appropriately control its critical quality attributes, thereby guiding the research, development, and manufacturing process optimization of the ADC product and ensuring its safety, efficacy, and quality consistency. Full article

Background: Anthracyclines have historically remained a cornerstone of treatment for early HER2-positive breast cancer. However, the emergence of dual HER2 blockade, antibody–drug conjugates, and response-adapted treatment strategies has changed the clinical context in which anthracycline use is considered. Whether anthracyclines continue to provide sufficient oncologic benefit to justify their additional cardiovascular toxicity remains uncertain. Objectives: This study aims to evaluate the contemporary role of anthracyclines in early HER2-positive breast cancer by synthesizing direct comparative evidence and contextual evidence from prospective de-escalation studies. Design: It involves a systematic review with narrative synthesis. Data Sources and Methods: PubMed, the Web of Science, and CENTRAL were searched for prospective studies published from January 2000 to 31 May 2026. A meta-analysis was initially planned, but only three clinically heterogeneous trials directly compared anthracycline-containing and anthracycline-free regimens. Direct comparative and contextual de-escalation evidence was therefore synthesized separately using a narrative approach. Results: Twelve studies were included. BCIRG-006, TRAIN-2, and TRYPHAENA provided direct comparative evidence; nine additional prospective trials provided contextual evidence on anthracycline-sparing or treatment de-escalation strategies. Direct comparisons generally indicated greater cardiac toxicity with anthracycline-containing regimens, although severe events were uncommon and cardiotoxicity definitions varied. Contextual studies supported the feasibility of contemporary anthracycline-sparing approaches in selected populations but did not provide direct estimates of the effect of anthracycline exposure. Conclusions: Anthracycline-containing regimens appear to confer greater cardiac risk than anthracycline-free regimens, but comparative evidence remains limited. The available evidence supports selective rather than routine anthracycline use, with treatment decisions guided by the anticipated oncologic benefit, cardiovascular risk, tumor characteristics, treatment setting, and patient preferences. Registration: PROSPERO CRD420261296599; registered on 29 January 2026. Full article

Aptamers are short nucleic acid molecules that bind to targets with high specificity. Recognized as “chemical antibodies”, they offer distinct advantages including strong programmability and ease of synthesis and chemical modification. Heterobifunctional targeted degraders were developed to address the challenges posed by traditionally “undruggable” targets and acquired drug resistance. The degraders recruit endogenous cellular degradation machinery to catalyze the removal of disease-associated proteins, thereby overcoming the limitations of conventional occupancy-driven inhibition. The fusion of aptamers with these degradation modalities has given rise to integrated platforms such as aptamer–proteolysis-targeting chimeras (PROTACs), aptamer–lysosome-targeting chimeras (LYTACs), and aptamer–autophagosome-tethering compounds (ATTECs). These conjugates combine the precise targeting ability of aptamers with the event-driven, catalytic nature of degradation technologies. As such, they not only expand the druggable target space to include intracellular proteins, membrane proteins, and pathogenic aggregates but also hold significant therapeutic potential in areas ranging from oncology and neurodegenerative disorders to infections and inflammatory diseases. Furthermore, degradation can be spatially and temporally controlled through receptor-mediated delivery or photo-switchable mechanisms. In this review, we provide a comprehensive summary of recent progress in studies on aptamer-based heterobifunctional degraders, with an emphasis on their design principles, biomedical applications, and therapeutic prospects. Full article

Metastatic breast cancer (MBC) remains incurable because of tumor evolution. Despite advances in targeted therapies—CDK4/6 inhibitors, PIK3 inhibitors, HER2-directed agents, and antibody–drug conjugates—median overall survival is modest, with resistance emerging in nearly all patients. From an evolutionary perspective, standard continuous maximum tolerated dose (MTD) therapy may create intense selective pressure that reduces treatment-sensitive cells and, in some incurable and resistance-prone settings, could permit competitive release of resistant clones. While MTD remains the guideline-endorsed standard of care in many metastatic settings and has produced substantial survival gains, the eco-evolutionary framework highlights a potential trade-off rather than a categorical failure of MTD. Cancer is not just a genetic disease but an evolving ecosystem where cell populations compete for limited resources. Resistant cells typically carry a fitness cost—slower growth in the absence of treatment—creating an exploitable vulnerability. By preserving treatment-sensitive cells through dose modulation or treatment holidays (adaptive therapy), we can harness competitive suppression to control resistant populations and prolong disease control, potentially doubling time to progression compared to continuous MTD. This primer translates these ideas into plain language for clinical trial application. We explain four core eco-evolutionary principles every breast oncologist should know, review emerging evidence from adaptive therapy trials in breast and other cancers, and discuss practical implementation strategies to incorporate into future trials. The goal is not cure through eradication, but long-term control through evolutionary management. These evolution-informed strategies may, in selected contexts, help delay resistance and prolong disease control, and represent a complementary framework that warrants prospective testing. Full article

Autoimmune diseases encompass nearly 100 distinct conditions characterized by dysregulated immune responses against self-antigens, resulting in tissue damage, chronic inflammation, and substantial morbidity. Over recent decades, the global burden of autoimmune diseases has increased, while their therapeutic management has undergone a paradigm shift from broad, nonspecific immunosuppression toward targeted biologic therapies. Among these, antibody-based therapeutics, including monoclonal antibodies targeting cytokines, cell-surface molecules, and co-stimulatory pathways, have transformed the treatment of numerous systemic and organ-specific autoimmune disorders. Nevertheless, important challenges remain, including primary non-response, secondary loss of efficacy related to immunogenicity or disease adaptation, increased susceptibility to infections, and mechanistic redundancy among therapeutic targets. This review provides a comprehensive overview of the cellular and molecular mechanisms underlying antibody-based therapies, summarizes major therapeutic target classes across autoimmune diseases, and examines their clinical and mechanistic limitations. Emerging therapeutic platforms, including bispecific antibodies, antibody–drug conjugates (ADCs), novel Fc-engineering, and cellular approaches such as CD19-targeted chimeric antigen receptor (CAR)-T therapy, are also discussed. Finally, antigen-specific immunotherapies designed to restore antigen-specific immune tolerance while preserving systemic host defense are explored. These approaches may represent an important next frontier in the treatment of autoimmune diseases, moving beyond broad systemic immune modulation toward more selective and durable immune control. Full article

CD97 is an adhesion G-protein-coupled receptor encoded by ADGRE5 that integrates extracellular signals (including cell adhesion, ligand binding, and mechanical stimulation) with intracellular signal transduction. Recent structural studies have further elucidated tethered/intramolecular agonist (TIA)/Stachel recognition and engagement of the seven-transmembrane domain (7TMD), activation-associated 7TMD conformational changes, and G-protein coupling, including the structural basis for the preferential coupling of CD97 to G13. Currently, antibody–drug conjugates (ADCs) targeting CD97 are supported by in vitro proof-of-concept evidence, whereas chimeric antigen receptor (CAR) strategies have shown antitumor activity in animal models of glioblastoma (GBM) and acute myeloid leukemia (AML). Existing research indicates that CD97 is involved in maintaining stem-like states, invasion and metastasis, metabolic adaptation, and stress survival in certain tumors, and its function varies depending on tumor type and cellular environment. Because CD97 is also expressed in normal immune cells and various nonhematopoietic tissues, systemic targeted therapy may be limited by on-target/off-tumor toxicity. This article reviews the latest advances in CD97 structure and signal transduction, and explores its tumor-related functions, biomarker value, evidence for ADC and CAR-related therapies, as well as early exploratory directions involving RNA-mediated downregulation and structure-guided interventions. Full article