Biologics : Targets & Therapy最新文献

Oral manifestations are a frequent yet underrecognized feature of systemic lupus erythematosus (SLE), contributing substantially to patient morbidity and reduced quality of life. They are insufficiently represented in clinical outcome measures and therapeutic guidelines, despite their clinical relevance. We report the case of a 39-year-old woman with SLE who developed severe, refractory tongue ulcers and glossodynia persisting for three years, unresponsive to hydroxychloroquine (HCQ), azathioprine (AZA), colchicine, methotrexate (MTX), and glucocorticoids (GC). Belimumab was discontinued due to gastrointestinal intolerance and lack of efficacy on oral lesions. The patient was subsequently treated with anifrolumab 300 mg intravenously every four weeks. After the first infusion, oral ulcers resolved, arthritis improved, and corticosteroids were discontinued. Within three months, the tongue lesions had completely healed, enabling unrestricted oral intake and full resumption of professional activities. Clinical remission was maintained on anifrolumab and hydroxychloroquine alone at four months of follow-up. This case highlights the therapeutic challenge of refractory oral lesions in SLE, a manifestation not adequately addressed in current EULAR (2023 update) or ACR (2025) guidelines. While conventional immunosuppressants such as azathioprine, methotrexate, and mycophenolate mofetil remain options, their efficacy for isolated oral lesions is limited. Emerging evidence, including case reports and small series, suggests that anifrolumab may provide significant benefit for mucosal involvement. The key learning point is that refractory tongue involvement may represent a dominant and treatment-resistant manifestation of SLE, yet it can respond to targeted biologic therapy such as anifrolumab and our report adds to this growing body of evidence. Prospective comparative studies and registry analyses are required to define anifrolumab's effectiveness specifically for refractory oral manifestations and to compare outcomes with other biologics.

Chronic migraine (CM) is a disabling neurological disorder for which calcitonin gene-related peptide (CGRP)-targeted monoclonal antibodies, such as erenumab, provide effective prophylaxis. Although generally well tolerated, rare neuromuscular complications resembling ocular myasthenia gravis (MG) have been reported. A 46-year-old woman with CM achieved marked improvement with erenumab for over three years before developing diplopia and intermittent ptosis. Laboratory and imaging studies were unremarkable, but clinical suspicion for MG led to pyridostigmine therapy, resulting in rapid improvement. Brief episodes of dysarthria occurred but resolved within one month. Symptoms disappeared after discontinuation of erenumab and continued pyridostigmine. On re-initiation of erenumab, the patient maintained migraine control without recurrence of MG-like symptoms. This case illustrates a rare, late-onset, reversible MG-like complication of erenumab. Clinicians should remain alert to ocular manifestations even as delayed adverse effects of anti-CGRP therapy.

Purpose: Blockade of the PD-L1/PD-1 pathway combined with chemotherapy has demonstrated significant survival benefits as first‑line therapy for esophageal squamous cell carcinoma (ESCC). However, comprehensive benefit-risk comparisons among approved agents remain limited. This study conducted an indirect comparison of serplulimab versus other anti-PD-1/PD-L1 antibodies plus chemotherapy in treatment-naïve ESCC patients.

Patients and methods: A systematic review with matching-adjusted indirect comparisons (MAICs) was conducted using individual patient data (IPD) from ASTRUM-007 and aggregate data (AgD) from seven comparator trials, including CheckMate 648, ESCORT-1st, GEMSTONE-304, JUPITER-06, KEYNOTE-590, ORIENT-15, and RATIONALE-306. IPD were reweighted to match key baseline characteristics. Hazard ratios (HRs) for overall survival (OS) and progression-free survival (PFS) were estimated using the Bucher method. Subgroup analyses were further explored using Bayesian network meta-analysis.

Results: Eight Phase 3 randomized controlled trials comprising 4,702 patients were included. After adjusting for baseline imbalances, serplulimab demonstrated comparable efficacy to other PD-1/PD-L1 inhibitors. The pooled adjusted OS HR was 0.98 (95% CI, 0.87-1.11), with numerically favorable OS versus nivolumab (HR, 0.76; 95% CI 0.47-1.24) and comparable OS versus pembrolizumab (HR, 0.93; 95% CI, 0.71-1.22) and camrelizumab (HR, 0.93; 95% CI, 0.70-1.24). The pooled adjusted PFS HR was 0.91 (95% CI, 0.81-1.02), significantly favoring serplulimab over nivolumab (HR, 0.56; 95% CI, 0.33-0.96), with favorable trends versus pembrolizumab (HR, 0.83; 95% CI, 0.63-1.10) and sugemalimab (HR, 0.86; 95% CI, 0.63-1.16). Subgroup analyses suggested greater relative benefit in women and patients with locally advanced disease. Grade 3-5 treatment-related adverse events occurred in 52.9% of serplulimab-treated patients, comparable to other PD-1/PD-L1 inhibitors (range, 47.4%-71.9%).

Conclusion: This indirect comparison provides comparative benefit-risk evidence to inform first‑line treatment selection for locally advanced or metastatic ESCC. Serplulimab plus chemotherapy demonstrated a clinically meaningful PFS benefit, comparable OS after matching, and a manageable safety profile consistent with the PD-1/PD-L1 inhibitor class.

Background: Previous studies have demonstrated that numerous medicine and food homology (MFH) possess the potential to regulate purine metabolism disorders, promote uric acid excretion, and alleviate hyperuricemia symptoms. Examples include CS (Chaenomeles speciosa (Sweet) Nakai), SR (Smilax glabra Roxb.) and PL (Pueraria montana var. lobata).

Methods: Metabolomics was employed to analyze the compositional changes in medicinal and edible extracts before and after fermentation. Network pharmacology and molecular docking studies were further utilized to elucidate the interactions between these differential metabolites and the core targets of hyperuricemia. In vitro enzyme activity assays were conducted to confirm the therapeutic effects.

Results: A total of 283, 248, and 18 differential metabolites were identified in CS,SR and PL samples, respectively. Among these, 54 significantly upregulated differential metabolites were selected for screening. Based on these metabolites, 53 HUA-related targets were identified for CS, SR and PL. Functional enrichment analysis revealed their roles in inflammatory stress and uric acid production pathways, particularly the MAPK signaling pathway and purine metabolism regulated by XDH. Additionally, other targets in the purine metabolism pathway, such as ADA, PNP, AMPD3, and IMPDH2, were co-regulated. Enzyme activity assays indicate that fermented MFH more effectively inhibits XOD, thereby regulating the conversion of xanthine and hypoxanthine into uric acid. Molecular docking revealed two significantly upregulated compounds in CS; and five in PL; and four in SR. exhibit strong binding to XOD.

Conclusion: These findings provide theoretical support for FMFH as a potential effective component in preventing and treating hyperuricemia. Our research demonstrates that FMFH targets multiple pathways associated with hyperuricemia, offering a promising approach for preventing this condition.

Background: The FDA's October 2025 guidance proposes waiving Phase 3 comparative efficacy studies for biosimilars when analytical and pharmacokinetic similarity are demonstrated.

Methods: We conducted a net present value (NPV) analysis comparing traditional biosimilar development pathways (with Phase 3 comparative efficacy studies) to streamlined pathways utilizing FDA's Phase 3 waiver framework. The model incorporates industry-benchmarked cost data (Phase 3 studies: $20-28M), development timelines (Phase 3 duration: 1-3 years). Economic outcomes were evaluated across three monoclonal antibody biosimilar programs representing high-, moderate-, and lower-complexity scenarios. Sensitivity analysis evaluated parameter variation across realistic ranges.

Results: Waiving Phase 3 studies reduces development costs by $25 million per program (18% reduction) and shortens timelines by 1.5 years (21% reduction). Risk-adjusted NPV improves by $25 million (29%), and minimum viable peak sales threshold decreases from $300 million to $250 million.

Conclusion: Phase 3 waivers can substantially reduce development costs (~$25M average), accelerate timelines (~1.5 years), and improve NPV (~25-29%) for well-characterized monoclonal antibody biosimilars meeting FDA's analytical similarity and pharmacokinetic equivalence criteria. Economic benefits are conditional on robust analytical data, regulatory approval of waiver requests, and appropriate product selection (Tier 1/2/3 classification). Real-world realization requires post-implementation surveillance of FDA approval patterns, achieved cost reductions, and timeline compression beginning 2026-2027.

Background: Janus kinase (JAK) inhibitors are highly effective at inducing remission in moderate-to-severe ulcerative colitis (UC). Because JAK inhibitors are small molecules, they can be administered orally, are rapidly absorbed, and have a rapid onset of action. However, potential adverse events, such as serious infections, opportunistic infections, herpes zoster infections, venous thrombosis, and cardiovascular events have been identified. To avoid the side effects associated with the long-term administration of JAK inhibitors, switching to biologics may be considered, even if remission is maintained with JAK inhibitors (positive switch).

Case report: Case 1: A 53-year-old man with steroid-dependent UC achieved rapid symptomatic improvement and complete mucosal healing on upadacitinib. Due to recurrent common colds and concerns regarding long-term adverse events, he underwent a positive switch to ustekinumab. Clinical and endoscopic remission have been maintained for one year. Case 2: A 36-year-old woman with refractory UC achieved clinical remission and mucosal healing with filgotinib following inadequate response to vedolizumab and corticosteroids. Given her desire for pregnancy and the potential risks of long-term JAK inhibitor use, she was switched to ustekinumab, which is considered safe during pregnancy. Remission has been maintained for one year.

Conclusion: In two UC patients who achieved mucosal healing with a JAK inhibitor, remission was successfully maintained after switching to ustekinumab. These cases suggest that a positive switch may be a reasonable option for patients who respond to JAK inhibitors but have concerns about long-term safety. Additional cases are required to better define the clinical role of this strategy.

Teclistamab is the first bispecific antibody targeting B-cell maturation antigen (BCMA) approved for the treatment of relapsed or refractory multiple myeloma. Its significant efficacy as monotherapy, particularly in the Phase 1/2 MajesTEC-1 trial, has been also confirmed in the context of combination therapies. Early safety events are dominated by grade 1 or 2 cytokine release syndrome. Risk of infection is now better characterized and can be managed through systematic prophylaxis. Notably, real-world studies have confirmed its efficacy and safety, notably in patients under-represented or ineligible for clinical trials (elderly, with renal impairment or central nervous system involvement). Mechanisms of resistance to teclistamab including target loss and T-cell environment are increasingly understood. Consequently, several strategies to overcome immune escape or antigen loss are currently being evaluated in clinical trials. The use of teclistamab in earlier lines of treatment and in combination may yield better results and is evaluating but ongoing Phase 3 clinical trials.

Chronic refractory wounds exhibit a complex etiology characterized by prolonged healing and pathological chronic inflammation, which pose significant challenges to wound recovery and may increase the risk of cancer over time. In recent years, the autophagy mechanism has emerged as a focal point of research. This process is regulated by nutritional status, growth factors, and cellular stress. Autophagy facilitates the removal of damaged organelles and misfolded proteins, recycles nutrients, contributes to immune defense, and aids in the elimination of pathogens. Endothelial autophagy is particularly crucial in the healing of chronic refractory wounds. It may be activated under conditions of ischemia, hypoxia, inflammation, and infection, thereby inhibiting cell proliferation and tissue repair while assisting cells in maintaining homeostasis and managing various stressors. Consequently, investigating the autophagic mechanisms in vascular endothelial cells during chronic refractory wound healing is essential for the development of novel wound treatment strategies.

Summary: Osteoarthritis (OA) and rheumatoid arthritis (RA) are chronic diseases characterized by persistent inflammation and autoimmune responses that affect the joints and other organs. Scientific evidence indicates that the therapeutic effects of mesenchymal stem cells (MSCs) are mediated through the release of soluble factors and extracellular vesicles (EVs), particularly exosomes. The release of microRNAs from MSCs holds substantial potential for cell-free treatment in OA and RA.

Methods: A comprehensive search was conducted on Web of Science, PubMed, Scopus, and Google Scholar to identify relevant publications until 24 March 2024. The systematic review aimed at illuminating the current understanding of MSC-derived exosomal microRNAs, the origin of MSCs, potential mechanisms of action, and their therapeutic implications in managing OA and RA.

Results: A total of fifty-five articles (OA, n= 41 and RA, n= 14) were deemed eligible for inclusion in this study. Regardless of MSC origin, exosomal miRNAs could induce anti-inflammatory, protective, and chondroregenerative potential in in vitro and in vivo models of OA by targeting different signaling pathways. Fourteen studies have highlighted the role of MSC-derived exosomal miRNAs in modulating immune responses, reducing pro-inflammatory cytokine production, and potentially ameliorating synovial inflammation and joint symptoms associated with RA. To suppress joint inflammation and preserve cartilage, miR-140, miR-92a-3p, and miR-136-5p emerged as leading candidates for OA because they help restore the anabolic/catabolic balance and modulate key signaling pathways. For RA, the most effective candidates were miR-146a, miR-150-5p and miR-205-5p that target innate and adaptive immune signaling and synoviocyte activation, with NF-κB modulators such as miR-361-5p offering overlap across both diseases.

Conclusion: The mounting body of preclinical evidence supports that MSC-exosomal-miRNAs present a promising solution for OA and RA as a novel therapeutic strategy. However, human studies and more clinical trials are warranted.

[This corrects the article DOI: 10.2147/BTT.S326422.].