BioDrugs最新文献

Adoptive cell therapies involving chimeric antigen receptor (CAR)-T cells have been demonstrated to be efficient treatments for hematologic malignancies and have successfully completed clinical translation. While traditional ex vivo T-cell engineering is still limited by challenges such as time-consuming processes, high costs, and poor controllability, as an emerging strategy, in vivo T-cell engineering involves the generation of functional effector T cells directly within patients through several injections of delivery vectors, which can reach cell therapies in days, further reducing costs and increasing scalability. This review logically outlines the technical development and application of in vivo T-cell engineering, with a particular focus on innovations in delivery systems, in which we elaborate on the mechanism and latest advances in viral vector platforms and RNA-based platforms. Furthermore, we analyzed the delivery platforms of multiple therapeutic candidates and their available data, discussing their therapeutic efficacy and safety profiles in both animal models and clinical applications. Although some challenges remain in solid tumor targeting, precise regulation, and manufacturing, increasing preclinical and clinical data have revealed the immense therapeutic potential of in vivo programming strategies across a broad spectrum of diseases.

In recent years, substantial progress has been achieved in the development of novel therapeutic options for inflammatory bowel disease (IBD). Despite these advances, a significant proportion of patients continue to experience either primary nonresponse or secondary loss of response to biologic agents or small-molecule therapies. In addition, many patients present with heterogeneous and often difficult-to-manage extraintestinal manifestations, highlighting the persistent unmet needs in IBD management. Consequently, multiple therapeutic strategies have been explored to overcome these challenges and to improve long-term disease control. Among emerging approaches, advanced combination therapy (ACT)-defined as the concomitant use of monoclonal antibodies and/or oral small-molecule agents with distinct mechanisms of action-has attracted increasing interest in recent years. ACT aims to enhance therapeutic efficacy, address complex disease phenotypes, and potentially prevent or delay treatment failure. In this review, we summarize the currently available evidence on how to optimally apply combination therapeutic strategies in IBD. Key aspects discussed include the rationale for selecting agents with complementary mechanisms of action, the hypothetical timing and duration of combination treatment, and the clinical criteria that may guide the selection of specific ACT algorithms. Evidence derived from real-world studies and completed randomized clinical trials, including the landmark VEGA trial, is critically reviewed. Furthermore, we present data from ongoing clinical trials-both industry- and investigator-initiated-as well as emerging research on bispecific therapeutic molecules in IBD, which combine two molecular targets within a single compound. Together, these data provide a comprehensive overview of the current and future role of ACT in IBD management.

While mammalian-derived extracellular vesicles (EVs) face significant challenges in clinical translation due to scalability, cost, and safety, plant-derived EVs (PDEVs) have emerged as a promising alternative. This review focuses on EVs derived from hemp (Cannabis sativa L.), or HEVs, a particularly compelling source that combines the general benefits of PDEVs, such as improved safety and scalability, with a unique, inherent therapeutic cargo. HEVs are naturally enriched with a potent mix of cannabinoids, terpenes, and flavonoids, which may enhance therapeutic outcomes through synergistic interactions-a phenomenon known as the 'entourage effect.' Preclinical studies already demonstrate their potential, showing significant anti-cancer effects against aggressive tumors like glioblastoma, along with neuroprotective and anti-inflammatory properties. However, the critical challenge hindering their clinical application is the lack of standardized, GMP (Good Manufacturing Practice)-compliant manufacturing protocols to address the inherent biochemical variability of the source material. Overcoming these obstacles will be vital to unlocking the potential of HEVs as a novel, scalable frontier in nanomedicine.

Background: Dostarlimab, a PD-1 inhibitor, was initially approved in Europe in 2021 for advanced or recurrent mismatch repair-deficient/microsatellite instability-high (dMMR/MSI-H) endometrial cancer. The phase III RUBY trial later demonstrated improved survival with dostarlimab plus chemotherapy, leading to EU approval in this indication in 2023. However, real-world data on the use of dostarlimab in routine clinical practice remain limited.

Objective: This study aimed to describe patients' characteristics, survival, and safety outcomes of dostarlimab plus chemotherapy in this population.

Patients and methods: We used the French National Health Data System (SNDS) to include all patients with uterine corpus cancer who received dostarlimab through the French early access program between 27 September 2023 and 30 June 2024, with follow-up until 30 November 2025. Overall survival (OS), time to treatment discontinuation (TTD), and real-world progression-free survival (rwPFS; i.e. subsequent treatment, palliative care, or death) were estimated using the Kaplan-Meier method. Safety outcomes were identified using hospitalization diagnoses and outpatient dispensing, and their prevalence was reported per 1000 person-months (PM).

Results: The cohort included 644 patients with dMMR/MSI-H endometrial cancer (median age 71 years), most with metastatic disease (73.3%). At baseline, 22.2% of patients were obese, 20.0% had cardiovascular disease, and 20.2% had diabetes. During follow-up (median [IQR]: 18.8 months [10.8-21.9]), 264 patients (41.0%) died. Median OS was not reached, and the 1-year OS probability was 72.8% (95% CI 69.5-76.3). TTD and rwPFS were lower, with median of 8.6 and 9.7 months, and 1-year survival probabilities of 35.7% (95% CI 32.2-39.6) and 44.4% (95% CI 40.7-48.4), respectively. Apart from unspecific potential immune-related adverse events (AEs; 193.6/1000 PM), hematologic AEs were the most frequent (23.8/1000 PM), mainly anemia (18.9/1000 PM), followed by digestive AEs (14.0/1000 PM).

Conclusions: This first real-world study of dostarlimab plus chemotherapy in advanced or recurrent endometrial cancer involved an older, more comorbid, and less selected population with more advanced disease than in RUBY. Survival outcomes were less favorable, but the safety profile was comparable.

Engineered virus-like particles (eVLPs) have emerged as a promising class of delivery systems for genome editing agents. By combining the efficient cellular entry of viral vectors with the safety advantages of nonviral platforms, eVLPs enable transient delivery of ribonucleoproteins such as Cas9, base editors, and prime editors. Successive design strategies, from rational engineering to directed optimization, have progressively improved particle assembly, cargo stability, and editing efficiency. In parallel, pseudotyping approaches have expanded the versatility of eVLPs for cell-type-specific targeting. Recent preclinical studies highlight their potential across diverse applications, ranging from monogenic disease models to complex disorders, and support their advancement toward clinical translation. This review summarizes the structural and production principles of eVLPs, surveys key advances in their development, and discusses therapeutic opportunities and future challenges for their application in genome editing.

Background: Patients with immune-mediated inflammatory diseases are routinely transitioned from originator biologics to biosimilars to reduce healthcare costs. While barriers related to patient and practitioner beliefs and knowledge are well-documented, less focus has been placed on system-level factors that may hinder biosimilar uptake.

Aims: This review aims to identify system-level factors that impact biosimilar brand transitions for treatment of immune-mediated inflammatory diseases, as reported by key stakeholders involved in real-world brand changes.

Methods: A scoping review was conducted following the Arksey and O'Malley framework and was reported in line with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines for scoping reviews (PRISMA-ScR). A comprehensive search was performed in APA PsycInfo, Embase, PubMed, Scopus, and Web of Science, and databases for major conferences in rheumatology, dermatology, and gastroenterology. Data from relevant studies were extracted and summarized onto a structured coding sheet before being synthesized.

Results: Of 2301 articles screened, 47 journal articles and five conference abstracts were included. Most studies were conducted in the United States and focused primarily on rheumatology. Barriers and facilitators were organized into four overarching themes. These were regulatory and approval processes (e.g., tendering practices, interchangeability policies, prescriber guidelines), healthcare system policies and incentives (including quotas, insurance coverage, reimbursement mechanisms, and rebates), infrastructure and logistics (such as supply chain considerations and storage requirements), and communication and education (including media and expert influence and the involvement of patient organizations).

Conclusions: Multiple components of the healthcare system play a role in successful biosimilar transitions. Leveraging regulations, policies, infrastructure, and communication before, during, and after transition offers a practical blueprint for managing brand changes across health systems and therapies.

Antibody-drug conjugates (ADCs) have emerged as an efficacious and promising treatment for advanced gynecologic cancers. These agents are an innovative treatment strategy that combines a monoclonal antibody, a linker, and a cytotoxic payload. Currently, three ADCs have received Food and Drug Administration (FDA) approval for use in gynecologic malignancies: mirvetuximab soravtansine, tisotumab vedotin, and trastuzumab deruxtecan. The demonstrable efficacy of these therapeutic agents has catalyzed rapid advancements in the field, prompting investigations into novel antigen targets such as cadherin-6 and B7H4, varying payloads, and innovative construction designs in both preclinical and clinical settings. While enthusiasm for ADCs is substantial, their clinical utility is tempered by significant side effects, such as ocular toxicities and pneumonitis, that necessitate specialized management expertise. Furthermore, the inherent complexities of these drugs and their mechanisms of action underscore the need for further research into the relevance of biomarkers, methods of therapy resistance, and the potential for re-utilization of payloads and targets later in the disease course. This review focuses on the mechanisms of action of ADCs, their developmental trajectory, successes in gynecologic cancers, emerging areas of investigation, the prospective landscape, and current challenges in the field.

Spider venom has emerged as a promising source of neuroactive compounds with potential applications in the treatment of complex neurological disorders. With over 53,000 described species and more yet to be studied, spiders possess one of the most chemically diverse venoms in the animal kingdom. This diversity has evolved through ecological adaptation, enabling spiders to paralyze and manipulate the nervous systems of a wide range of prey. These same mechanisms, which target ion channels, neurotransmitter receptors, and signaling enzymes, coincide with pathways implicated in human neurologic diseases. By examining the structure-function relationships of spider venom components, this review highlights how venom compounds can modulate neuronal excitability, synaptic transmission, inflammation, and neurodegeneration. Evidence of therapeutic relevance is found in diseases such as Alzheimer's disease, Parkinson's disease, epilepsy, stroke, erectile dysfunction, and anxiety, where specific spider-derived components have demonstrated potential disease-modifying effects. Furthermore, by integrating molecular action with disease relevance and ecological context, this review proposes a shift in how spider venom is viewed-not simply as a source of isolated toxins, but as a platform for next-generation therapeutics. This integration of ecological, molecular, and therapeutic dimensions not only synthesizes current knowledge but also charts a path for future interdisciplinary research by revealing critical translational gaps and offering strategies to bridge them toward effective neurotherapeutics.

Background: HLX26 is a novel, recombinant humanized anti-LAG-3 IgG4 monoclonal antibody that exhibits high affinity for LAG-3 and demonstrates that it can block LAG-3 and its ligand interaction and activate T cells in preclinical in vitro studies.

Objective: These two phase I, dose-escalation studies evaluated the safety, tolerability, pharmacokinetics profile, and preliminary efficacy of HLX26 monotherapy, or in combination with serplulimab (PD-1 inhibitor), in patients with advanced/metastatic solid tumors or lymphomas.

Patients and methods: Adult patients with advanced/metastatic solid tumors that have failed or deemed clinically unsuitable for standard therapy, or lymphoma received different doses of HLX26 alone (at 60, 150, 300, 500, and 800 mg administered every 3 weeks [Q3W]) in the HLX26-001 study, or HLX26 plus serplulimab (HLX26 at 500, 800, and 1600 mg plus serplulimab (300 mg) administered Q3W) in the HLX26-002 study, respectively. The primary end points for both studies were the dose-limiting toxicities (DLT) and maximum tolerable dose (MTD).

Results: As of 18 August 2023, with a median follow-up duration of 12.8 months, 26 patients were screened for the HLX26-001 study, 18 of whom were enrolled. As of 31 August 2023, with a median follow up duration of 6.0 months, 14 patients were screened for the HLX26-002 study, 9 of whom received HLX26 plus serplulimab. No DLT was observed, and the MTD was not reached for both studies. In the HLX26-001 study, 17 (94.4%) patients experienced at least one treatment-emergent adverse event (TEAE), most commonly proteinuria (n = 6, 33.3%) and hypercholesterolemia (n = 5, 27.8%). In the HLX26-002 study, all nine (100.0%) patients experienced TEAEs that were all treatment-related and predominantly mild in severity.

Conclusions: HLX26 was well-tolerated and safe at various doses as a single agent, and in combination with serplulimab for patients with advanced solid tumors and warrants further investigation.

Trial registration: HLX26-001-ClinicalTrials.gov: NCT05078593; HLX26-002-ClinicalTrials.gov: NCT05400265.