The MYC family oncoproteins, including MYC, MYCN, and MYCL, are potent drivers of tumorigenesis across a broad range of human cancers, frequently linked to aggressive tumor behavior, poor prognosis, and therapy resistance. They function as master transcriptional regulators that orchestrate gene expression programs governing nearly all aspects of tumor development. Despite their pivotal oncogenic role, they have long been considered “undruggable” due to their intrinsically disordered structure, lack of enzymatic activity, and the difficulty of targeting their protein–DNA and protein–protein interactions with conventional small-molecule approaches. Recent advances are beginning to overcome these challenges through innovative molecular strategies that either directly inhibit MYC activity or exploit MYC regulatory networks. Importantly, the first direct MYC inhibitor evaluated in humans, OMO-103, recently demonstrated promising antitumor activity in phase I clinical trials. Indirect approaches have focused on suppressing MYC transcription, translation, or stability by targeting upstream signaling pathways, as well as by exploiting MYC-associated cofactor interactions and synthetic lethal vulnerabilities to improve therapeutic specificity. In this review, we highlight the multifaceted roles of MYC in different cancer types and provide a comprehensive overview of current therapeutic strategies targeting MYC with a particular focus on epigenetic modifiers and metabolic vulnerabilities.
Acute anterior uveitis (AAU) is the most common extra-musculoskeletal manifestation of radiographic axial spondyloarthritis (r-axSpA) and is an important consideration when selecting biological therapy. Although adalimumab (ADA) and infliximab are commonly used in patients with r-axSpA and AAU, direct comparative evidence, particularly between ADA and subcutaneous infliximab (IFX-SC), remains limited. The objective of this study was to compare the risk of AAU flare between ADA and IFX-SC in patients with r-axSpA and a history of AAU. This multicenter, head-to-head, randomized, open-label trial enrolled patients with r-axSpA and a documented AAU event within the preceding 2 years. Participants were randomly assigned (1:1) to receive ADA (40 mg every 2 weeks) or IFX-SC (intravenous 5 mg/kg induction followed by subcutaneous 120 mg every 2 weeks) and were followed for 48 weeks. The primary endpoint was AAU flare occurrence. Hazard ratios (HRs) were estimated using Cox proportional hazards models. Secondary endpoints included changes in best-corrected visual acuity (BCVA), r-axSpA disease activity and functional indices, and safety outcomes. Fifty-six patients were randomized (ADA, n = 28; IFX-SC, n = 28). During follow-up, one AAU flare episode occurred in each group. The adjusted HR of IFX-SC (vs ADA) for an AAU flare was 0.496 (95
Autoimmune diseases remain a major cause of chronic morbidity despite substantial advances in targeted immunomodulatory therapies. In many autoantibody-mediated conditions, disease refractoriness and relapse are driven by long-lived plasma cells, which are largely resistant to conventional immunosuppression and upstream B cell–directed strategies. CD38, a surface molecule highly expressed on plasmablasts and plasma cells and functionally involved in immunometabolic regulation, has emerged as a promising therapeutic target to overcome this limitation. Clinical interest in anti-CD38 therapy has been catalyzed by experience in plasma cell dyscrasias, where anti-CD38 monoclonal antibodies induce rapid and profound depletion of antibody-secreting cells. Over recent years, accumulating reports and early-phase studies have explored the repurposing of CD38-directed therapies in severe, treatment-refractory autoimmune diseases. The most compelling evidence has emerged in lupus nephritis and immune thrombocytopenia, with additional proof-of-concept data in autoimmune cytopenias and plasma cell–driven renal disorders such as immunoglobulin light chain (AL) amyloidosis. These experiences suggest that targeting CD38 can lead to meaningful clinical and immunological improvement, often accompanied by rapid reductions in pathogenic autoantibody production. However, the current evidence base remains heterogeneous and largely derived from small cohorts, case series, and early-phase trials, and important questions remain regarding durability of response, optimal treatment strategies, and long-term safety, particularly with respect to hypogammaglobulinemia and infection risk. We summarize the biological rationale for CD38 targeting in autoimmunity and plasma cell–driven immune-mediated diseases, critically appraise the emerging clinical evidence across disease settings, and discuss key challenges and future directions for integrating plasma cell–directed therapies into immunological disease management.
Continuous biologic therapy achieves psoriasis control but may be limited by cost, adherence burden, safety concerns, and patient preference. Evidence on outcomes after early, patient-driven discontinuation of secukinumab in routine practice is limited. The aim of this study was to describe clinical outcomes after voluntary secukinumab discontinuation among patients achieving predefined week-12 response targets and to explore factors associated with relapse. This prospective single-center cohort enrolled 172 adults with moderate-to-severe plaque psoriasis initiating secukinumab during 2022–2024. At week 12, patients achieving target response achievement 1 (TRA1: Psoriasis Area and Severity Index [PASI]75, Physician’s Global Assessment [PGA] 0/1, or body surface area [BSA] <3
CT-P16 (Vegzelma®) is a bevacizumab biosimilar approved for indications including non-squamous non-small cell lung cancer. We developed an integrated population pharmacokinetic model pooling data from two phase I studies in healthy subjects and one phase III study in patients with non-small cell lung cancer to (i) quantify the influence of the drug product on pharmacokinetic parameters within a single unified framework simultaneously evaluating CT-P16 against both EU-Avastin® and US-Avastin®; (ii) characterise covariate-driven exposure variability, including disease-status effects, across healthy subjects and patients with non-small cell lung cancer, and compare these effects with previously reported analyses of reference bevacizumab and other bevacizumab biosimilars; and (iii) contextualise simulated steady-state exposure under the approved 15 mg/kg every-3-weeks regime against a published exposure–response benchmark, thereby supporting a biosimilar assessment within the streamlined regulatory paradigm. Concentration data from one phase III trial (NCT03676192) and two phase I trials (NCT03247673; CT-P16 1.2) were pooled. The population pharmacokinetic analysis used nonlinear mixed-effects modelling in NONMEM® (Version 7.4) with first-order conditional estimation with interaction. Drug product (CT-P16, EU-Avastin®, US-Avastin®) and clinical/demographic covariates were evaluated by stepwise selection. Model adequacy was assessed by goodness-of-fit diagnostics, non-parametric bootstrap resampling (1000 replicates), and a visual predictive check. Steady-state exposure under 15 mg/kg every 3 weeks was simulated using both typical population-predicted profiles and the observed phase III patient covariate distribution with inter-individual variability. A total of 8058 serum concentrations from 834 subjects (phase I: 187 healthy male volunteers; phase III: 649 patients with non-small cell lung cancer) were analyzed. A two-compartment model with first-order elimination adequately described the pooled data. Body weight, sex, and disease status were retained as covariates on clearance; sex, baseline serum albumin, and disease status were retained on central volume of distribution. Drug product was not retained as a significant covariate, indicating no clinically meaningful difference between CT-P16 and either EU-Avastin® or US-Avastin®. The estimated body-weight exponent on clearance (0.369) was numerically indistinguishable from previously published values for reference bevacizumab (0.368 [11]) and for the bevacizumab biosimilar PF-06439535 (0.354 [24]). Across covariate-defined subgroups, the median simulated steady-state trough concentrations remained above the published progression-free-survival reference of 89.1 µg/mL. Within a unified population pharmacokinetic framework, CT-P16 demonstrated comparable pharmacokinetics to both EU-Avastin® and US-Avastin®, with no clinically meaningful drug-product effect on clearance or central volume of distribution. Covariate effects mirrored those reported for reference bevacizumab, and simulated steady-state exposures were generally consistent with a published progression-free-survival-based exposure benchmark at the median level across covariate-defined patient subgroups. These findings extend the totality of evidence supporting CT-P16 biosimilarity and illustrate how population pharmacokinetic modelling can quantitatively inform a streamlined biosimilar assessment in the era of reduced reliance on comparative clinical efficacy trials. NCT03247673; NCT03676192.
Advanced therapy medicinal products (ATMPs) promise transformative clinical potential, but their use remains limited by complex manufacturing, high prices, and fragmented market access. To explore the existing and potential regulatory pathways to increase access to ATMPs, we conducted a product-level analysis of ATMPs and biologic medicines submitted to the European Medicines Agency up to May 2026, and a review of regulatory pathways and policy frameworks. While certain scientific principles from biologic and biosimilar regulation, such as totality of evidence, fit-for-purpose data, and tailored approaches are transferable, the biosimilar pathway may not be suitable for certain ATMPs. Other approaches, including bio-hybrid applications or prior knowledge-based dossiers, may be better suited to support competitive entry and second-wave innovation. Tailored follow-on pathways, open and well governed platform technologies, and supportive industrial and data sharing policies, are key to facilitate the translation of the scientific promise of ATMPs into sustainable and equitable patient access.
Enzyme replacement therapy (ERT) is the standard treatment for patients with Pompe disease, a hereditary metabolic myopathy. While ERT in the home situation is increasingly common in adults with Pompe disease, experience in children remains limited due to higher dosing requirements and increased risk of infusion-associated reactions (IARs). We analysed the results of the in-hospital and home-based infusion programme applied in the Netherlands to children since 1999 to provide guidance. We studied hospital and home-based infusions administered to children with Pompe disease (i.e., classic infantile, atypical infantile, and childhood onset phenotypes) who started ERT between 1999 and 2022 and analysed the characteristics of patients and IARs. The IARs were graded by healthcare providers. A total of 11,898 infusions with recombinant human α -glucosidase (rhGAA) were administered in 52 Pompe patients (27 classic infantile, two atypical infantile and 23 childhood onset phenotypes). Of these, 5278 infusions (44.4
Ustekinumab biosimilars have expanded treatment options for moderate-to-severe plaque psoriasis, but pooled evidence is needed to determine whether they achieve therapeutic equivalence to reference ustekinumab during the initial randomized comparative period before protocol-defined switching. The aim of this systematic review was to assess the therapeutic equivalence of ustekinumab biosimilars versus reference ustekinumab during the pre-switch period in adults with moderate-to-severe plaque psoriasis. We searched PubMed, Embase, Scopus, Web of Science, Cochrane Central Register of Controlled Trials (CENTRAL), and trial registries from inception to 15 October 2025 for phase III randomized clinical trials comparing ustekinumab biosimilars or follow-on biologics with reference ustekinumab and reporting comparative data before switching. Data were extracted independently by two reviewers. Risk of bias was assessed using the Risk of Bias 2 (RoB 2) tool, and certainty of evidence was assessed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. Random-effects meta-analysis with Hartung–Knapp–Sidik–Jonkman 95
Uveal melanoma is the most common primary intraocular malignancy in adults and remains associated with poor outcomes once metastatic disease develops. Despite advances in local tumour control and molecular prognostication, effective systemic therapies capable of delivering durable benefit are limited. A range of gene-based therapeutic strategies have been explored in uveal melanoma, including immune-based approaches, gene-modified cell therapies and direct gene delivery. While these strategies have yielded important biological insights and modest clinical advances, their broader impact has been constrained by challenges related to delivery, tumour specificity, durability of effect and translational feasibility. This review surveys the current landscape of gene-based therapies investigated in uveal melanoma and synthesises lessons learned from these approaches, with a particular emphasis on the delivery platform as a determinant of therapeutic success. We examine the emerging potential of adeno-associated virus vectors as gene-delivery platforms for uveal melanoma, drawing on their safety profile and capacity for sustained transgene expression. We highlight the need for adaptation beyond native adeno-associated virus serotypes and discuss advances in capsid engineering, targeting strategies and control mechanisms that enable tumour-selective gene delivery. Finally, we consider translational challenges and future directions for integrating targeted adeno-associated virus-based approaches into therapeutic strategies for uveal melanoma.
Monoclonal antibodies (mAbs) have revolutionized therapeutic treatments by their ability to target specific antigens, leading to enhanced clinical outcomes over other drugs. They are one of the largest modalities within the growing biotherapeutics space and are indicated for a range of diseases. Though transformative, mAbs are still not readily accessible to many patients globally because of their high costs. An increasing number of mAbs are losing patent exclusivity, which has opened the door for the development of biosimilars that could drive down costs and ensure increased access to these life-saving drugs. Regulators approve biosimilars after conducting a rigorous evaluation similar to any other biologic medicine to ensure the safety, quality, and efficacy of these products. To establish biosimilarity, extensive comparative analytical and clinical studies of the biosimilar product with the approved reference product is a regulatory expectation. Growing acceptance from regulators to potentially waive clinical efficacy studies when robust evidence for similarity with reference product is established from analytical, functional, and pharmacokinetic/pharmacodynamic studies will have a major impact on reducing the time and cost of developing biosimilars. Comparative analytical assessment includes side-by-side analysis of the biosimilar with the reference product to demonstrate similarity regarding their physicochemical and functional characteristics. This is usually achieved by identifying product quality attributes (PQAs) that could impact clinical safety and efficacy and applying orthogonal analytical methods to characterize these attributes to identify any differences between the products. This review identifies the common PQAs studied for approved mAb biosimilars in the United States and the European Union through to the end of 2024. We have also compiled the data for the analytical methods used to characterize these attributes and identified a subset of methods universally used among biosimilar applicants. Finally, a brief overview of the risk-based analysis of attributes is summarized from the regulatory submissions.
Biosimilars are a critical strategy for improving access to high-cost biologics and ensuring the sustainability of healthcare systems worldwide. Over the past decade, China has transformed from a nascent market into one of the world's most active regions for biosimilar development. This review evaluates this transformation with a focus on regulatory evolution, approval dynamics, and global integration. We trace the development of China's biosimilar regulatory framework from the foundational 2015 Technical Guidelines to the current system of 19 technical and product-specific guidelines, highlighting the maturation of a stepwise, science-driven comparability paradigm aligned with international regulatory standards. Drawing on a systematic analysis of 83 biosimilars approved between 2019 and 2025, we analyze trends across molecular classes, therapeutic areas, and regulatory review pathways, illustrating how regulatory expectations and sponsor development strategies have evolved through representative case examples. Notably, the 2025 annual reports from both the US Food and Drug Administration and European Medicines Agency emphasize the increasing number of biosimilar approvals, therefore, we place China's approval experience in brief comparative context. Finally, we discuss China's expanding biosimilar development pipeline in the context of the forthcoming global biologics patent cliff and ongoing international initiatives to streamline biosimilar development, highlighting China's increasing integration into the global biopharmaceutical landscape.
BackgroundTherapeutic proteins such as adalimumab can elicit an antibody response. How dosing regimens impact immunogenicity remains ill-understood, especially with respect to the frequency of dosing.ObjectiveWe aimed to investigate the relationship between single versus multiple adalimumab doses and immunogenicity, in terms of anti-drug antibody production and skewing towards the non-inflammatory immunoglobulin G4 (IgG4) subclass.MethodsImmunoglobulin M, immunoglobulin G, and IgG4 anti-drug antibodies were analyzed in retrospective cohorts of healthy individuals and patients with rheumatoid arthritis, psoriatic arthritis, spondyloarthritis, or psoriasis, receiving one or multiple doses of adalimumab, using optimized drug-tolerant assays, newly developed in the case of IgG4.ResultsA single dose of adalimumab proved highly immunogenic, while repeated dosing, resulting in prolonged exposure to high antigen concentrations, led to attenuation of the anti-drug antibody response. Immunoglobulin G4 anti-drug antibodies developed earlier than previously reported with drug-sensitive assays, appearing as early as week 3, even after a single dose of adalimumab. Skewing towards IgG4 was nevertheless stronger with repeated dosing.ConclusionsRepeated high-dose adalimumab exposure can limit both the magnitude and inflammatory potential of the antibody response. These results highlight drug exposure as a factor modulating the immunogenicity of biologics.
The ever-increasing trend of antibiotic resistance necessitates new therapeutic strategies for fighting infection. Standing on decades of extensive research and development, monoclonal antibodies have great promise for treating antibiotic-resistant bacterial infections. In this comprehensive review of the field, we summarize the rapidly emerging field of monoclonal therapeutics that offer alternative approaches to target bacterial pathogens that pose critical concern to human health. Organizing the findings by species and by molecular target, we discuss antibodies that have demonstrated therapeutic potential as well as those that did not provide efficacy, highlighting new insights for the design and discovery of highly effective therapeutics for the future. Furthermore, we discuss the latest advances in molecular biology that have revolutionized the implementation, efficacy, and utility of monoclonal antibodies as therapeutics, and that continues to drive what will be an exciting era for antibacterial monoclonal antibodies.
Seasonal influenza epidemics and pandemics remain a persistent public health threat. A universal influenza vaccine is urgently needed. Such a vaccine must accommodate rapid viral evolution, strain diversity-including types A and B and their many subtypes-and the complexities of human immune history and biases. Messenger RNA (mRNA)-formulated lipid-nanoparticles have evolved from an emergency pandemic vaccine experiment into a versatile vaccine platform. This technology has demonstrated potential to address several critical challenges in developing a universal influenza vaccine, including rapid strain updates, the production of high-valent formulations, and the ability to target conserved antigens that may induce broader and longer-lasting protection. This review summarizes recent studies and applications of multivalent antigen selection strategies and self-amplifying and circular RNA vaccine platforms to develop mRNA influenza vaccines to achieve vaccine universality, with an emphasis on immune responses against conserved targets. We also review the latest advances in generating long-term mucosal immunity against influenza through optimized mRNA delivery. Finally, we discuss practical considerations for correlates of protection, manufacturing, and accessibility, pioneering mRNA vaccine candidates heading to clinical trials, and milestones that define vaccine "universality."
Antimicrobial resistance poses a critical and escalating threat to global public health, driven by the widespread and often unjustified use of antibiotics and the rapid dissemination of resistance determinants. With the antibiotic discovery pipeline largely depleted, alternative and complementary strategies are urgently needed to preserve the effectiveness of existing antimicrobials. Bacteriophages—viruses that specifically infect bacteria—have re-emerged as promising tools not only for direct bacterial eradication but also for reshaping bacterial evolutionary trajectories. This review examines the concept of phage-driven restoration of antibiotic susceptibility, focusing on evolutionary trade-offs that arise when bacteria adapt to phage pressure. Resistance to bacteriophages frequently involves modifications of surface structures, capsules, or efflux systems, changes that often incur fitness costs manifested as reduced virulence, impaired biofilm formation, or increased antibiotic sensitivity. Experimental studies and clinical case reports demonstrate that phage–antibiotic synergy can suppress bacterial growth more effectively than monotherapy, limit resistance emergence, and resensitize multidrug-resistant pathogens to previously ineffective antibiotics. Particular attention is given to mechanisms involving efflux pump targeting, capsule loss, biofilm disruption, and temperate phage–antibiotic interactions. In addition, emerging strategies that combine bacteriophages with CRISPR-Cas systems enable precise targeting and removal of resistance genes, offering a highly selective means to restore antibiotic efficacy and curb horizontal gene transfer. Together, these findings highlight bacteriophages as powerful evolutionary and therapeutic tools capable of giving antibiotics a “second chance”. Integrating phage-based approaches into antibiotic stewardship frameworks may represent a sustainable path forward in combating multidrug-resistant bacterial infections.
The therapeutic arsenal of immunosuppressive drugs in kidney transplantation has recently expanded with the introduction of biologics, approved or used off-label, that specifically target the immune system. Although therapeutic drug monitoring is well established for calcineurin inhibitors, its utility for biological immunosuppressants remains unclear. The objective of this narrative review was to evaluate whether biologics used to prevent or treat renal allograft rejection could be suitable candidates for therapeutic drug monitoring. This review provides (1) a comprehensive and up-to-date synthesis on the pharmacological targets of biologics used in kidney transplantation, (2) assesses the interindividual variability of the pharmacokinetics and pharmacokinetic/pharmacodynamic relationships of key biologics, including belatacept, tocilizumab, rituximab, basiliximab, alemtuzumab, eculizumab, ravulizumab, daratumumab, and imlifidase and (3) describes the analytical methods available for their quantification. This review underscores that, although none of these biologics currently meet all criteria for routine therapeutic drug monitoring, emerging clinical evidence indicates that individualized dosing could enhance both therapeutic outcomes and cost effectiveness. It also discusses future directions for improving pharmacokinetic/pharmacodynamic knowledge on biological therapies in kidney transplant recipients and places in perspective the potential of therapeutic drug monitoring to improve the benefit-risk ratio and cost effectiveness of these biologics.
B-cell maturation antigen (BCMA) directed CAR T-cell therapy has emerged as an innovative and effective treatment for patients with relapsed/refractory multiple myeloma, demonstrating high response rates and durable remissions. However, its use is associated with a broad spectrum of toxicities, ranging from well characterized common events to rarer, less well described complications. A comprehensive understanding of both common and rare toxicities is essential for timely recognition and management to prevent non-relapse mortality. Frequently observed toxicities include cytokine release syndrome, immune effector cell-associated neurotoxicity syndrome (ICANS), immune effector cell-associated hematotoxicity, and infections. In addition, less frequent adverse events have been reported, including non-ICANS neurotoxicity such as parkinsonian-like movement disorders, immune-mediated enterocolitis, hemophagocytic lymphohistiocytosis, and secondary malignancies. The timing and severity of these toxicities is variable and may be influenced by the extent of CAR T-cell expansion and persistence, as well as patient-specific factors. In this review, we summarize currently available evidence with respect to the safety profile of approved BCMA-targeted CAR T-cell therapies, emphasizing both common and rare toxicities, their possible underlying mechanisms, and management strategies.
Background 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. Objective To identify tumor site-specific genomic alterations associated with outcomes of nivolumab monotherapy in a nationwide real-world cohort. Methods 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. Results 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. Conclusions 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.
Over the past decade, recombinant protein therapeutics have moved from conventional biologics toward highly engineered, multifunctional versions. Enabled by innovations in synthetic biology, host cell engineering, and bioprocess optimization, proteins are increasingly viewed not only as drugs for replacement therapies but also as fully versatile platforms in innovative therapeutic approaches aiming at functional reprogramming. Advances in host systems, from optimized microbial strains to mammalian and plant-based platforms, have expanded the range of proteins that can be produced with high fidelity, scalability, and safety. In parallel, modular protein engineering has delivered next-generation formats, including bispecific antibodies, nanobodies, fusion proteins, and self-assembling biomaterials, broadening therapeutic applications across oncology, inflammation, metabolic disorders, and beyond. At the same time, regulatory frameworks are adapting to support accelerated approval of personalized and complex biologics, while decentralized and flexible manufacturing models begin to emerge. This review provides a 2025 update on the field of recombinant protein drugs, integrating advances in production platforms, protein engineering, and regulatory science, and outlining how these technologies are shaping the next generation of biologics.
The therapeutic potential of programmed cell death-1 (PD-1) agonism is increasingly recognized as a cornerstone for restoring immune tolerance in autoimmune diseases. However, while PD-1 antagonism has revolutionized oncology, a critical knowledge gap remains regarding optimal strategies to therapeutically harness PD-1 activation. This review provides a comprehensive analysis of the mechanical and molecular requirements for inducing PD-1 signaling, addressing the current lack of a unified framework for agonistic drug development. We first delineate the fundamental biology of PD-1 signaling in maintaining peripheral tolerance. We then evaluate four primary mechanistic strategies currently under investigation: (1) receptor dimerization and clustering; (2) membrane-proximal epitope binding; (3) modulation of antibody binding affinity; and (4) Fcγ-receptor crosslinking. Each mechanism is critically assessed for its ability to mimic natural ligand-induced inhibitory signaling, alongside its inherent translational limitations. Emerging data suggest that optimal PD-1 agonism is achieved not through high-affinity binding but rather through low-affinity antibodies targeting membrane-proximal epitopes. This approach appears to preserve essential ligand-engagement dynamics and to facilitate productive Fcγ-receptor-mediated scaffolding. By surveying recent advances in clinical trials and ongoing challenges, this work serves as a vital resource for researchers and clinicians. Refinement of these agonistic strategies is essential for the development of next-generation targeted immunotherapies capable of precision immune regulation in chronic autoimmunity.
