Gene and cell therapies have been gaining popularity with market approvals by the US Food and Drug Administration, European Medicines Agency, and other regulatory bodies. Adeno-associated viral vector gene therapies approved for rare inherited diseases and chimeric antigen receptor T-cell therapies approved as a novel modality for hematological anti-cancer therapies have led the way in a new paradigm of drug discovery and development. Previously incurable diseases such as hemophilia A and B have now been effectively treated via adeno-associated viral vector-mediated gene therapy, and chimeric antigen receptor T-cell therapies have provided cures for lymphomas in patients refractory to all previous treatments demonstrating the great promise of these agents. Immunogenicity is a major factor hampering the efficacy and eligible population of gene therapies as well as creates a safety risk for some individuals. Inherent attributes of adeno-associated viral vector gene and autologous chimeric antigen receptor T-cell therapies present a unique set of factors that can influence immunogenicity to the drug compared to widely used small-molecule or biologic drugs. This review outlines immunogenicity concerns of gene and cell therapy, and their clinical manifestations. We detail mechanisms by which these therapies can trigger innate, humoral, and cellular immunity. Additionally, we give an in-depth discussion of in silico, in vitro, and in vivo immunogenicity screening methods that have been applied in gene and cell therapy development, and the utility of each.
Peripherally administered therapeutics for neurological indications are challenged with anatomical and physiological barriers that limit their ability to access their site of action in the central nervous system (CNS). This is particularly true for complex therapeutics such as antibodies, immunotherapeutics, and gene therapies. The blood-brain barrier is the specialized structure that functionally regulates the ability of blood constituents to access the CNS. Blood-brain barrier delivery technologies for protein therapeutics have been established in pre-clinical models and are beginning to be verified in clinical studies. Technologies reliant on the transcellular pathway across the blood-brain barrier utilize the receptor-mediated transcytosis mechanism. Research into the use of lipid nanoparticles (LNPs) to deliver complex therapeutics has tremendously expanded in recent years. Lipid nanoparticles represent a compelling alternative to viral vectors for the delivery of various gene therapy modalities, including messenger RNA, small interfering RNA, and antisense oligonucleotides. Functionalization of LNPs with blood-brain barrier-penetrant moieties is being explored as a means to enable CNS delivery of LNP-based therapeutics. The recent innovations and validation of LNP-based delivery systems have hastened the fulfillment of the promise of facile CNS-targeted gene therapies. This review focuses on functional aspects of the blood-brain barrier and how they relate to recent advances in LNP technologies for CNS delivery, as well as their potential impact on gene therapy.
We studied alpha-glucosidase activity in plasma and leukocytes after an infusion of 40 mg/kg of recombinant alglucosidase alpha in patients with classic infantile Pompe disease to assess the pharmacokinetics and identify potential surrogate efficacy markers of gene therapy in patients on enzyme replacement therapy. Samples were collected by pharmacokinetic curves (n = 5) and random samples (n = 21 patients). Alpha-glucosidase activity was measured in plasma (substrate 4-methylumbelliferyl-α-D-glucopyranoside, MU) and leukocytes (substrate glycogen, Gn, and MU). Plasma peak concentration occurred at the end of the infusion, reaching concentrations > 5000 and > 100,000 times higher than the control and untreated patient levels, with a median half-life of 3.1 h (1.3-4.2 h). In leukocytes, plasma peak concentration occurred 24 h after the start of enzyme replacement therapy; plasma peak concentration did not exceed the control level (0.7 [Gn] and 0.9 [MU] times higher than controls). The estimated half-life was 2-4 days. Seven days after enzyme replacement therapy, median enzyme activity was 1.3 times higher than the control levels in plasma and within the control range in leukocytes; after 14 days, median values in plasma and leukocytes were below the control level. These findings suggest alpha-glucosidase activity in plasma and leukocytes may serve as an efficacy marker for gene therapy studies in patients with classic infantile Pompe disease receiving enzyme replacement therapy. Similar studies with next-generation enzyme replacement therapy are advised.
Biopharmaceuticals add value in the treatment of many diseases but different health systems in Europe face clinical and economic challenges with introducing them. Joint efforts across Europe are therefore essential to ensure their sustainable and equitable use. However, to date few cross-national comparative studies have assessed their introduction. This study aimed to assess the availability of health authority data and variation in the early diffusion of biopharmaceuticals across Europe. A cross-sectional study was undertaken to analyze the diffusion of 17 biopharmaceuticals, approved between 2015 and 2019, among European countries between 2015 and 2022. The study assessed data availability, diffusion rates measured as accumulated defined daily doses per 1000 inhabitants, as well as relative rankings between countries during the first 4 years following market authorization. Twenty countries and two regions out of 31 European countries provided data on biopharmaceutical utilization for out-of-hospital care, 15 provided wholesaler data, and 14 provided hospital data. Certain countries and regions contributed data in multiple categories, while six did not provide any data. Diffusion rates were assessed for 17 countries and two regions, which showed appreciable variation, with secukinumab and erenumab being introduced in most countries and follitropin delta and tildrakizumab in the least number of countries. Germany, Austria, and Norway demonstrated the highest early diffusion rates, while Lithuania, Romania, and Latvia had the lowest. This study revealed a substantial variation between European countries and regions in the early diffusion of biopharmaceuticals and the availability of data to monitor their use. The reasons behind these patterns require further investigation to support European countries in optimizing the use of biopharmaceuticals to reach an equitable and cost-effective use of medicines across Europe.
Golimumab is a safe and effective treatment for patients with rheumatoid arthritis. Biosimilars to the reference product (RP; Simponi®) may make treatment more accessible. The aim of this study was to assess the efficacy of AVT05, a golimumab biosimilar, and RP, each used in combination with methotrexate, in participants with moderate-to-severe rheumatoid arthritis. This was a 52-week, randomized, double-blind, two-arm, parallel-group, active-controlled study. Participants were randomized 1:1 to receive AVT05 (n = 251) or RP (n = 251), 50 mg subcutaneously once every 4 weeks to Week 12 inclusive. Randomization was stratified by the baseline Disease Activity Score-28 for Rheumatoid Arthritis using C-Reactive Protein (DAS28-CRP) [≤ 5.1 and > 5.1]. The primary endpoint was the change from baseline in DAS28-CRP at Week 16. At Week 16, responder participants (DAS28-CRP decreased by > 0.6 from baseline and disease activity DAS28-CRP ≤ 5.1) initially enrolled in the AVT05 arm continued to receive AVT05 every 4 weeks. Responder participants initially randomized to RP were re-randomized 1:1 to either continue receiving RP or switch to AVT05. Non-responders were discontinued from the study drug. Change from baseline in DAS28-CRP response criteria at weeks 4, 8, 12, 24, 32, 40, 48, and 52 and percentage of subjects achieving American College of Rheumatology 20/50/70 at weeks 4, 8, 12, 16, 24, 32, 40, 48, and 52 were assessed as secondary endpoints. Safety and immunogenicity endpoints were also assessed. At Week 16, the least squares mean (standard error) change from baseline in DAS28-CRP in AVT05 and RP was - 2.89 (0.058) and - 2.98 (0.058), respectively. The two-sided 95% confidence interval of the least squares mean difference (0.09; standard error 0.082) was entirely contained within the prespecified equivalence margin of - 0.6, 0.6 (- 0.07, 0.25), supporting a demonstration of comparative efficacy. Two sensitivity analyses (one [S1] without exclusion of any data because of intercurrent events, and one [S2] excluding data following intercurrent events or relevant protocol deviations) supported the robustness of the primary endpoint estimates (S1 95% confidence interval - 0.07, 0.25; S2 95% confidence interval - 0.07, 0.25). There were no notable differences in subgroup analyses. Secondary efficacy analyses were consistent with the primary endpoint, including in participants who switched treatments. Overall safety profiles showed no clinically meaningful differences between treatments, including in participants who switched treatments. Immunogenicity profiles were comparable between treatment arms at all timepoints, including in participants who switched treatments. Analysis of the change in DAS28-CRP from baseline to Week 16 supported the assessment of comparative efficacy between AVT05 and RP golimumab. Secondary efficacy endpoints were consistent with this, including in participants who switched. AVT05 had a safety and immunogenicity profile similar to that observed for RP at all timepoints, including in participants who switched treatments. The trial is registered at ClinicalTrials.gov (ClinicalTrials.gov identifier: NCT05842213) and the EU Clinical Trials Register (EudraCT Number: 2022-001825-63).
To evaluate the impact of demand- and supply-side policies on the biosimilar market penetration and identify effective strategies for promoting biosimilar uptake in eight high-income countries. We analyzed biosimilar market penetration for infliximab, rituximab, and trastuzumab in six European countries-France, Germany, Italy, Spain, Sweden, and the UK-and two Asian countries-Japan and South Korea. Biosimilar market penetration was measured using two indicators: biosimilar market share and the time required for biosimilars to reach the majority point (> 50% market share). Policies were categorized into demand- and supply-side measures, and weights were applied to reflect the extent and timing of policy implementation. Spearman correlation examined the relationship between policy implementation and biosimilar market penetration. Sweden, Italy, and the UK showed the highest biosimilar market shares, adopting various demand-side policies, while Japan and South Korea exhibited slower biosimilar adoption with fewer or no demand-side policies. Biosimilars in most European countries reached the majority point within 5-6 quarters, while projections for Japan and South Korea exceeded 30 quarters. Correlation analysis revealed that adoption of demand-side policies was significantly associated with higher market share (rs = 0.69, p < 0.001) and shorter time to reach the majority point (rs = - 0.62, p < 0.01). In contrast, supply-side policies showed a weaker and less consistent association. Demand-side policies, such as financial incentives and prescribing guidelines, are significantly associated with rapid and widespread biosimilar adoption, while supply-side policies had limited impact. Policymakers should prioritize demand-side measures to improve biosimilar uptake and reduce healthcare expenditures effectively.
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.
Denosumab is a fully human monoclonal antibody (IgG2) k subclass that targets and binds with high affinity and specificity to receptor activator of nuclear factor-κB ligand (RANKL). Gedeon Richter's denosumab RGB-14-P and RGB-14-X are proposed biosimilar drug products to the reference medicinal products Prolia® and Xgeva® (marketing authorisation holder: Amgen Europe B.V. in the European Union [EU] and Amgen Inc. in USA, respectively). The present study demonstrates the structural, physico-chemical and functional similarity between RGB-14 and reference drug products marketed in the EU and US. Using an extensive, state-of-the-art analytical and functional panel of 38 methods ensured the comprehensive characterisation of the biosimilar and reference drug products. To assess biosimilarity, physico-chemical and biological functional tests were performed using multiple orthogonal techniques, in addition to the in-depth comparison of the primary and higher-order structures of the therapeutic proteins. It has been demonstrated that the primary and higher order structures of RGB-14-P and RGB-14-X drug products are identical or highly similar to those of EU/US Prolia® and Xgeva®. The purity profiles of the biosimilar and reference products were similar. Only minor differences were observed in glycosylation patterns and charge variant profiles. A wide range of bioassays was used demonstrating similarity in terms of potency, ligand and receptor binding. Additionally, during comprehensive analysis of the reference product data as the function of expiry dates, shifts were revealed in certain quality parameters, although these did not impact the biological activity of the products. The extensive analytical and functional similarity assessment study provides robust evidence that the structure and function of RGB-14-P and RGB-14-X are highly similar to those of EU/US Prolia® and Xgeva®.
Bispecific antibodies (BsAbs) that bind two distinct antigenic epitopes represent a new therapeutic paradigm. However, their clinical benefits and global regulatory status remain uncertain. In this cross-sectional analysis, BsAbs data from the US Food and Drug Administration (FDA), European Medicines Agency (EMA), Chinese National Medical Products Administration (NMPA), and Japanese Pharmaceuticals and Medical Devices Agency (PMDA) were identified up to December 31, 2025. BsAb indications, supporting trials (pivotal and confirmatory), and regulatory approval statuses were analyzed. Clinical benefits based on improved efficacy endpoints, and approval time lags among agencies, were compared. Twenty BsAbs and 33 BsAb indications were identified. Of 33 indications, 27 were oncology and six were non-oncology. Among oncology indications, only six (6/27, 22.2%) demonstrated benefits with improvements in overall survival (OS) and/or quality of life (QoL). The remaining 21 (21/27, 77.8%) oncology BsAb indications showed benefits based on surrogate endpoints. All six non-oncology indications showed benefits based on true endpoints without surrogacy. Among the 38 supporting trials for oncology indications, the majority (36/38, 94.7%) were pivotal trials, while only two (2/38, 5.3%) were confirmatory trials. Most of these trials (32/38, 84.2%) recruited relapsed/refractory patients. Of 20 BsAbs, 12 received initial approval from the FDA, five from EMA, two from NMPA, and one from PMDA. FDA-approved BsAbs obtained EMA approvals with a median lag of 82.5 days, whereas approvals in China and Japan were delayed by a median of 602 and 455 days, respectively. Most oncology BsAb indications remain without OS or QoL benefits. The FDA approved the largest number of BsAbs. Regulatory approval time lags in NMPA and PMDA are substantially longer than those in EMA.
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. 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. 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). 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. 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. HLX26-001-ClinicalTrials.gov: NCT05078593; HLX26-002-ClinicalTrials.gov: NCT05400265.
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. 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. 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. 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). 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.
AVT05, a recombinant, human, immunoglobulin G1қ monoclonal antibody, is a biosimilar to Simponi®. The purpose of this study was to investigate the pharmacokinetic (PK) similarity, safety, tolerability, and immunogenicity between AVT05 and US-licensed and European Union (EU)-approved reference product (RP) golimumab (US-RP and EU-RP, respectively) in healthy adult participants. Three hundred and thirty-six healthy male and female participants aged 18-55 years were randomized in a 1:1:1 ratio to AVT05, US-RP, or EU-RP. Participants received a single 50 mg/0.5 mL subcutaneous injection on Day 1 and were followed until Day 75. The primary PK endpoints were maximum serum concentration (Cmax) and area under the serum concentration-time curve from time zero to infinity (AUC0-inf). Pharmacokinetic similarity was demonstrated if the 90% confidence intervals for the geometric mean ratio for both AUC0-inf and Cmax were entirely contained within the prespecified margins of 80.00% and 125.00% for all six pairwise treatment comparisons. Secondary endpoints were additional PK parameters (area under the concentration-time curve from time zero to the last quantifiable concentration, time to Cmax, terminal elimination rate constant, terminal elimination half-life, apparent volume of distribution, and apparent clearance), safety, tolerability, and immunogenicity. Demographic and baseline characteristics were balanced between the treatment groups. The 90% confidence intervals for the geometric means ratio for the protein-adjusted primary PK parameters were entirely contained within the prespecified margins of 80.00% and 125.00% (Cmax [AVT05/US-RP 89.45, 106.75; AVT05/EU-RP 92.33, 110.15; EU-RP/US-RP 88.64, 105.92]; AUC0-inf [AVT05/US-RP 94.35, 108.40; AVT05/EU-RP 98.46, 113.13; EU-RP/US-RP 89.36, 102.76]), supporting the demonstration of PK similarity. The secondary PK parameters were also comparable between the treatment arms. The mean serum golimumab concentrations through Day 75 post-dose were similar between treatment arms. Overall, 66.1% of participants experienced at least one treatment-emergent adverse event (TEAE) during the study period. The frequency of TEAEs was comparable across the treatment arms. The majority of TEAEs were mild to moderate in severity. There were two serious TEAEs reported (one [0.9%] each in AVT05 and EU-RP arms), neither of which was considered treatment related. Local administration site reactions were mild in severity and observed in 6.1%, 10.8%, and 5.5% of participants in the AVT05, EU-RP, and US-RP arms, respectively. Overall, 87 (75.7%), 92 (82.9%), and 89 (80.9%) participants in the AVT05, EU-RP, and US-RP arms, respectively, were anti-drug antibody positive; among those 66 (57.4%), 68 (61.3%), and 61 (55.5%) participants, respectively, were neutralizing antibody positive at least once during the study. The primary PK parameters (AUC0-inf and Cmax) were slightly lower in antidrug antibody-positive participants compared with antidrug antibody-negative participants. Following single-dose administration, the study supported a demonstration of PK similarity between AVT05 and EU-RP and US-RP in healthy participants. Safety, tolerability, and immunogenicity profiles were comparable between the treatment arms. The trial is registered at ClinicalTrials.gov (CT.gov identifier: NCT05632211).
Only a minority of patients with advanced gastric cancer (GC) or esophagogastric junction (EGJ) adenocarcinoma derive durable benefit from anti-programmed cell death 1 (PD-1) therapy. However, reliable biomarkers for real-world clinical decision-making remain limited. To identify tumor site-specific genomic alterations associated with outcomes of nivolumab monotherapy in a nationwide real-world cohort. We conducted a retrospective nationwide analysis using Japan's Center for Cancer Genomics and Advanced Therapeutics (C-CAT) registry, including patients with GC and EGJ cancer adenocarcinoma treated with nivolumab monotherapy (July 2019-April 2024). Primary endpoints were time to treatment failure (TTF) and overall survival (OS), defined as the interval from nivolumab initiation to death from any cause; objective response rate (ORR) was secondary. Gene-level alteration indicators were derived from vendor-reported tumor-only panel calls across multiple platforms and filtered for clonal hematopoiesis of indeterminate potential (CHIP)-like variants (variant allele frequency < 0.05). Multivariable models adjusted for age and sex were fitted separately for GC and EGJ cancer. Variant pathogenicity was based on available panel annotations; therefore, gene-level results should be interpreted as exploratory findings. Among 798 patients with GC and 114 patients with EGJ cancer adenocarcinoma, median TTF/OS/ORR were 3.98 months/20.2 months/11.7% in GC and 4.80 months/24.7 months/14.9% in EGJ cancer adenocarcinoma. In GC, ASXL1 mutation remained independently associated with longer TTF (hazard ratio [HR] 0.59, 95% confidence interval [CI] 0.37-0.94) after adjustment and CHIP filtering. For OS, microsatellite instability-high [MSI-H] (HR 0.16, 95% CI 0.04-0.70) and FANCG (HR 0.37, 95% CI 0.16-0.87) were associated with longer OS, whereas CDH1 (HR 1.51, 95% CI 1.10-2.05) was associated with shorter OS. In EGJ cancer adenocarcinoma, NTRK1 mutation correlated with longer TTF (HR 0.31, 95% CI 0.10-0.98) and MUTYH with shorter OS (HR 5.68, 95% CI 2.04-15.81), both exploratory. In this large Japanese real-world cohort, genomic associations with nivolumab outcomes differed by tumor site. In gastric cancer, ASXL1 mutation was associated with prolonged treatment benefit under PD-1 blockade, while CDH1 and FANCG showed exploratory associations with OS. These findings warrant further validation in prospective and platform-controlled analyses.
Conditionally activatable antibodies represent a promising strategy to improve the therapeutic index of antibody-based drugs by restricting their activity to disease sites, thereby minimizing systemic toxicity. These engineered platforms leverage disease-associated cues-such as protease activity, pH, redox gradients, or other microenvironmental factors-to modulate antigen binding or effector function in a spatially and temporally controlled manner. In this review, we categorize recent advances in activatable antibody technologies into three principal strategies: (1) masking domains or peptides that block target recognition until removed by disease-specific triggers, (2) structural rearrangement by fusing external domains to antibodies to regulate access to the paratope, and (3) payload activation approaches in antibody-drug conjugates. We summarize key design principles, representative examples, and their preclinical or clinical development status, highlighting strengths, limitations, and translational challenges. Special attention is given to linker chemistry, trigger specificity, and pharmacokinetic considerations that influence therapeutic performance. Finally, we discuss emerging trends, including multi-input activation systems and integration with next-generation modalities such as bispecific antibodies and immune cell engagers, which could further refine target selectivity and broaden therapeutic applications. This overview highlights representative advances to guide the rational design of future activatable antibody platforms and to accelerate their progression toward clinical use.
This study examines the monoclonal antibody innovation landscape through patent activity and market data. A dedicated dataset was constructed by linking multiple sources (Antibody Society, Orange Book, Ark Patent Intelligence, US Patent and Trademark Office, PATSTAT, Purple Book, US Veterans Affairs, US-FDA, and ORBIS), covering patents registered between 1986 and 2019. Data analysis comprised six components: (i) a general description of the dataset, (ii) an examination of monoclonal antibody patents and approval trends, (iii) an analysis of therapeutic indications, (iv) a characterization of patent holders and producers through descriptive and network analyses, (v) an assessment of shareholder influence, including common-ownership patterns, and (vi) an evaluation of monoclonal antibody prices. The dataset included 63 monoclonal antibodies, 1732 unique patents, 89 active pharmaceutical ingredients, 34 producers, and 214 therapeutic indications, of which 36.5% were single indication, while the average number of secondary indications was 3.78. Roche, Johnson & Johnson, Eli Lilly, Amgen, and Novartis led reference medicine production, while Amgen and Pfizer were notable in biosimilars, with only five companies producing both. Shareholders such as BlackRock, UBS, Vanguard, and JPMorgan exerted strong market influence in monoclonal antibody production. Prices were extremely high, averaging US$127,430 per course or year (s = US$142,509), with 42.1% of monoclonal antibodies priced above US$100,000. While monoclonal antibodies have transformed modern medicine and improved safety and effectiveness, their persistently high prices, reinforced by market concentration and financial investor influence, raise serious concerns for equity and social welfare.
Osteoarthritis is a prevalent condition among middle-aged and elderly populations characterized primarily by the progressive degeneration of articular cartilage. Despite advances in medical technology, the complexity of osteoarthritis pathogenesis presents significant challenges in halting or reversing cartilage degradation. Recently, mesenchymal stem cells and their secretome have emerged as promising regenerative therapies for osteoarthritis. Mesenchymal stem cells not only differentiate into chondrocytes to repair cartilage defects but also maintain chondrocyte homeostasis by interacting with existing chondrocytes and modulating synovial inflammation. Additionally, the proteins and bioactive molecules contained within the mesenchymal stem cell secretome offer multifaceted therapeutic benefits. However, challenges such as the limited survival and integration of transplanted mesenchymal stem cells, potential for unwanted differentiation, and variable efficacy of the secretome persist. Hydrogels, which mimic the chemical and mechanical properties of the extracellular matrix, are frequently utilized as carriers for mesenchymal stem cells and their secretome in osteoarthritis treatments. This review explores the current applications of mesenchymal stem cells and their secretome in osteoarthritis therapy, proposing innovative strategies to overcome these existing treatment limitations.
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.
Anti-CD20 monoclonal antibodies are gaining clinical relevance in the nephrology community due to their demonstrated efficacy and favorable safety profiles across short-, medium-, and long-term use. Initially developed for hematologic malignancies and multiple sclerosis, B-cell depletion therapies are now being investigated across a broader spectrum of autoimmune diseases, including glomerulopathies, both with and without associated podocytopathy. Recent advances have led to the development of novel anti-CD20 agents that are being used not only as potential alternatives to corticosteroids but also as adjunctive therapies in complex clinical settings. However, their efficacy is not uniform across all conditions, whether used for induction therapy, relapse management, or as rescue treatment following first-line therapy failure. A thorough understanding of their mechanisms of action, along with the potential for resistance and therapeutic failure, is essential for advancing precision medicine in this field. This review provides a molecular and clinical overview, incorporating pharmacokinetic and pharmacodynamic insights into the most widely used and emerging anti-CD20 monoclonal antibodies in nephrology. It serves as a practical guide to understand how these agents' function, why they may fail, and what alternative strategies should be considered in cases of adverse reactions or inadequate response. Finally, it highlights their evolving role in precision therapy, both as monotherapy in podocytopathies and as part of a multi-targeted treatment approach for glomerular diseases with systemic involvement.
Programmed Cell Death Protein 1 (PD-1) / Programmed Cell Death Ligand 1 (PD-L1) inhibitors have revolutionized cancer immunotherapy but are limited by low response rates and drug resistance. Interleukin-2 (IL-2), a potent T-cell activator, is clinically restricted due to regulatory T cell (Treg) activation and severe systemic toxicity. PD1-IL2 bispecific drugs, integrating PD-1 blockade and engineered IL-2 variants (IL-2v) into a single molecule, precisely regulate tumor microenvironment immunity to overcome these limitations. This review summarizes their latest progress, including the synergistic mechanism of PD-1/PD-L1 and IL-2 signaling, molecular designs (e.g., βγ-biased IL-2v and Innovent's α-biased IBI363), and 'cis delivery' for targeted activation. Preclinical and clinical data (e.g., IBI363) show encouraging anti-tumor activity and improved safety in advanced tumors, benefiting PD-1-resistant patients. Challenges remain, such as unclear mechanisms, drug resistance, and long-term safety. Future advancements rely on optimized molecular design, combination therapies, and predictive biomarkers, driving PD1-IL2 bispecific drugs toward more precise and effective tumor immunotherapy for broader patient populations.
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. This study aimed to describe patients' characteristics, survival, and safety outcomes of dostarlimab plus chemotherapy in this population. 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). 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). 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.