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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.

Atopic dermatitis is a chronic inflammatory skin disease affecting approximately 15-20% of children and 2-10% of adults worldwide. Epidermal barrier dysfunction and immune dysregulation are central to its pathogenesis, creating a self-perpetuating cycle in which barrier disruption exacerbates inflammation, which in turn further impairs skin barrier integrity. The OX40/OX40L axis, involving the co-stimulatory receptor OX40 expressed on T cells and its ligand OX40L on antigen-presenting cells, plays a critical role in sustaining T cell-driven inflammatory responses in AD. Despite recent therapeutic advances, many patients remain inadequately controlled, and key unmet needs persist. Inhibitors of the OX40/OX40L pathway represent a novel therapeutic approach by modulating multiple effector and memory T-cell subsets implicated in disease pathogenesis. Amlitelimab, an anti-OX40L monoclonal antibody, has demonstrated sustained efficacy and a favorable safety profile in phase IIa and IIb trials. Rocatinlimab, targeting OX40, has also shown promising results in a phase IIb study and has progressed into multiple phase III trials, with supportive top-line data. In contrast, telazorlimab has shown more modest efficacy and has not advanced to later-stage development. Next-generation agents, including IMG-007, STAR-0310, APG990, and APG279, have been engineered with extended half-lives and attenuated antibody-dependent cellular cytotoxicity to support longer dosing intervals and improve tolerability. While these findings are encouraging, direct comparative studies among agents and versus established therapies are lacking, and long-term efficacy and safety data are still needed. This narrative review explores the role of the OX40/OX40L axis in atopic dermatitis pathogenesis and critically evaluates emerging therapies targeting this pathway, aiming to inform their future integration into clinical practice.

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.

The rapid growth in the global aging population has intensified concerns regarding age-related diseases (ARDs), which pose substantial health and socioeconomic burdens. Current therapeutic strategies, such as small-molecule drugs, primarily target downstream pathophysiological manifestations, including inflammation, fibrosis, and metabolic imbalance, but have limited ability to address the underlying molecular causes of disease. Antisense oligonucleotides (ASOs) are emerging as a promising modality capable of precise, sequence-specific regulation of gene expression at the RNA level, offering the potential to directly modulate disease etiology. This review examines the relationship between major ARD categories and the hallmarks of aging and highlights recent research trends in ASO-based therapeutics. We explore the connections between hallmark aging processes and major ARDs, including neurodegenerative, cardiovascular, metabolic, and musculoskeletal disorders, emphasizing dysregulated genes that contribute to disease progression. Preclinical and clinical studies demonstrate that ASOs can offer targeted intervention against key pathological mechanisms such as protein aggregation, chronic inflammation, metabolic dysfunction, and tissue fibrosis by modulating gene expression. Despite their promise, major challenges remain, including poor tissue-specific delivery, limited penetration into certain tissues, and concerns around long-term safety. Emerging delivery strategies such as ligand conjugates and lipid nanoparticle systems are expanding the therapeutic reach of ASOs. By providing a programmable approach to precisely regulate pathogenic gene expression, ASOs have the potential to redefine the therapeutic landscape for ARDs in an aging society. This review provides an integrated perspective on these advances and their implications for future therapeutic development.

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.

Mammalian cell lines are the preferred host cells for the biopharmaceutical industry. Chinese hamster ovary (CHO) and human embryonic kidney 293 (HEK293) cells are frequently utilized in the production of recombinant therapeutic proteins (RTPs) owing to their capacity to facilitate appropriate protein folding and perform accurate post-translational modifications (PTMs). However, there are still some bottlenecks in the biopharmaceutical process using mammalian cells, including lower productivity, higher production cost and increased risk of contamination compared with bacterial or yeast expression systems. In addition to vector, media and bioprocess optimization, advances in host cell engineering including gene overexpression, knockout and knockdown have significantly advanced cell-line development. Besides targeting known genes and pathways, miRNA engineering and omics analysis are also employed to enhance mammalian cell culture performance. Optimization of cell engineering and production processes further drives the development of more efficient mammalian cell expression systems. This review systematically summarizes key achievements in cell engineering and offers insights into potential targets and pathways for improving therapeutic protein production in mammalian cells.

Subcutaneous autoinjectors serve as a convenient and user-friendly alternative to manual injection using prefilled syringes or handheld syringes, enhancing self-administration in decentralized care settings, patient compliance, and dosing accuracy. Autoinjectors consistently penetrate the skin to the same depth, and are, thus, expected to reduce variability in injection conditions as compared to more operator-dependent manual self-injection. Even with an established autoinjector platform, molecule-specific technical development requirements often preclude the availability of the automated device at the start of pivotal clinical studies. This necessitates manual injections during these studies and frequently subsequent pharmacokinetic comparability studies to transition to the autoinjector. A proposed Molecule-Independent Device Bridging Approach (MIDBA) aims to eliminate the need for dedicated pharmacokinetic comparability studies for each new monoclonal antibody developed with a previously validated autoinjector platform by referring to PK data from other mAbs with dosing volumes up to 2 mL. The rationale for this approach lies in the slow absorption rates of mAbs following SC injection, which is primarily influenced by the residence time in subcutaneous tissue and subsequent lymphatic drainage rather than the specifics of the injection method. A narrative review of clinical data from 29 pharmacokinetic comparability studies revealed that independent of the molecule and the injection device, comparable pharmacokinetic and tolerability profiles were achieved following manual and automated injection. The review supports the applicability of the MIDBA as a streamlined development pathway for autoinjector validation without molecule-specific pharmacokinetic studies. This framework is expected to present a novel methodology for efficient transition from manual to automated subcutaneous injections for biotherapeutics.

Background: Xeligekimab is a novel immunoglobulin G4 (IgG4) monoclonal antibody targeting interleukin-17A (IL-17A). In a phase III trial in patients with plaque psoriasis, xeligekimab showed efficacy and safety consistent with other IL-17A inhibitors, supporting its potential application in the treatment of spondyloarthritis.

Objective: This phase III trial aimed to investigate the efficacy and safety of xeligekimab in patients with radiographic axial spondyloarthritis (r-axSpA).

Methods: This was a phase III study conducted at multiple centers in China. Eligible patients were randomly assigned (1:1:1) to receive xeligekimab 100 mg, xeligekimab 200 mg, or placebo. Randomization was stratified by medication history (biologic-experienced vs. biologic-naïve) and weight (≥ 70 kg vs. < 70 kg). The primary endpoint was the proportion of patients achieving an Assessment of SpondyloArthritis International Society 20 (ASAS20) response at week 16. A key secondary endpoint was the ASAS40 response rate at the same time point.

Results: A total of 465 patients were recruited. A significantly higher proportion of patients receiving xeligekimab 200 mg (n = 114 (74.0%); p < 0.001, 95% confidence interval (CI) 28.5-48.4) and xeligekimab 100 mg (n = 102 (65.8%); p < 0.001, 95% CI 19.4-41.0) achieved an ASAS20 response compared to the placebo group (n = 56 (35.9%)) at week 16. Similarly, a significantly higher ASAS40 response rate was observed in the xeligekimab 100 mg group (n = 62 (40.0%); p < 0.001) and the xeligekimab 200 mg group (n = 64 (41.6%); p < 0.001) compared to placebo. Adverse events were similar across all groups, with serious adverse events occurring in 1.6% of the treatment group during the core treatment period. No unexpected safety signals were reported through week 48.

Conclusion: Xeligekimab demonstrated significant efficacy in improving the signs and symptoms of active r-axSpA in Chinese patients at week 16, with sustained effects observed through week 48 and no new safety signals identified.

Trial registration: ClinicalTrials.gov identifier: NCT05881785 (Date: 21 May 2023).