Biologics : Targets & Therapy最新文献

[This corrects the article DOI: 10.2147/BTT.S454058.].

Purpose: Subcutaneous tocilizumab (SC-TCZ) is approved for rheumatoid arthritis (RA) management. During Severe Acute Respiratory Syndrome CoronaVirus 2 (SARS-CoV2) pandemics, experiences of intravenous (IV)-to-SC TCZ switch in RA patients spread. We aimed to determine SC-TCZ maintenance, efficacy and safety in IV-to-SC TCZ switchers, combining a single center, retrospective cohort study and a systematic literature review (SLR).

Patients and methods: We included RA patients undergoing IV-to-SC TCZ switch (2015-2024); patients were grouped and evaluated according to maintenance of SC-TCZ ("Go on SC" group, GoS) or returning to IV-TCZ within 12 months (T2) ("Back IV" group, BI). SC-TCZ maintenance, disease activity, adverse events (AEs) were evaluated; a univariate regression analysis was performed to evaluate factors associated with a successful switch. The SLR was performed in accordance with PRISMA 2.0 guidelines and registered in PRSPERO (ID CRD42024523714), to search for relevant articles regarding maintenance of SC-TCZ after IV-to-SC switch, efficacy (assessed both clinically and with clinimetric tools) and safety of this strategy, as well as predictors of a successful IV-to-SC switch.

Results: According to the success of SC-TCZ switch (T2), SC-TCZ maintenance rate was 43.3% (13/30 patients). A switch back to IV-TCZ was more likely if patients had higher baseline GH score (OR 1.05, 95% CI 1.01-1.10), and less likely if the IV-to-SC switch was agreed with treating physician (0.03, 0.00-0.21). At first visit after baseline, the mean DAS28 value diminished in GoS (-0.3) versus BI (+0.5), p < 0.001. No treatment-related serious AEs were reported. The SLR retrieved 12 articles (3626 patients), including 2 open-label randomized controlled trials (RCTs) and 10 observational studies. By the end of follow-up, SC-TCZ maintenance in our cohort was lower than in other experiences (25.9% versus 78.7%), but with a longer follow-up (up to 4.5 years).

Conclusion: Intravenous to subcutaneous tocilizumab switch is an effective and safe option in rheumatoid arthritis management, especially in the case of a shared decision.

Tumor-to-tumor metastasis (TTM) is a rare phenomenon characterized by the metastasis of one malignant tumor into another histologically different tumor. While breast and lung cancers are prevalent among women globally, TTM involving breast cancer metastasizing to lung adenocarcinoma is exceptionally uncommon. Herein, we report a rare case of Luminal B breast cancer metastasizing to EGFR exon 19 deletion-mutated lung adenocarcinoma. The patient achieved prolonged disease-free survival following comprehensive treatment, including surgical resection, chemotherapy, EGFR-tyrosine kinase inhibitor (TKI) therapy, and endocrine therapy. This case highlights the importance of molecular profiling in guiding personalized therapeutic strategies for TTM, particularly when actionable mutations are present.

Background: Malaria is a major global health issue, which significantly affects developing countries, including Indonesia. Plasmodium falciparum, the leading cause of malaria mortality, is increasingly resistant to standard treatments. The antimalarial properties of compounds derived from Streptomyces sp. have been demonstrated in several in vivo and in vitro studies, although their exact mechanism of action remains unclear. This study explores Streptomyces sp. metabolites as potential antimalarials targeting PfDHODH and PfDPCK, essential enzymes for P. falciparum survival.

Methods: A comprehensive in silico screening was employed, including phylogenetic analysis of PfDHODH and PfDPCK, network protein analysis, identification and preparation of Streptomyces sp. bioactive compounds, structural preparation of target enzymes, molecular docking and visualization, antimalarial efficacy prediction, assessment of drug-likeness and toxicity, and molecular dynamics simulations.

Results: Phylogenetic analysis confirmed that PfDHODH and PfDPCK are distinct from human proteins, reducing off-target risks. Network analysis identified nine proteins linked to PfDHODH and one for PfDPCK. From 27 Streptomyces sp. bioactive compounds, caboxamycin, bisanhydroaklavinone, napyradiomycin A1, and gardenomycin A showed the strongest binding to target enzymes. These compounds occupied the active sites of PfDHODH and PfDPCK, mirroring control ligands (FMN, Opera1). PASS analysis indicated strong antiprotozoal potential for bisanhydroaklavinone and gardenomycin A. Toxicity analysis revealed bisanhydroaklavinone's mutagenicity and carcinogenicity risks, while napyradiomycin A1 showed moderate hepatotoxicity. Nonetheless, molecular dynamics confirmed stable interactions, highlighting their promise as antimalarial candidates. However, their toxicity profiles warrant further investigation to ensure safe therapeutic application.

Conclusion: PfDHODH and PfDPCK were identified as selective targets in P. falciparum. Four Streptomyces-derived compounds showed strong binding, stability, and promising antimalarial potential with acceptable predicted toxicity, warranting further evaluation. However, only caboxamycin and gardenomycin show potential for antimalarial drug development, with acceptable predicted toxicity profiles, making them suitable candidates for in vitro and in vivo testing prior to clinical evaluation.

Although numerous biologic and targeted synthetic disease-modifying antirheumatic drugs (b/tsDMARDs) are available, substantial number of rheumatic patients fail to achieve therapeutic goals with sequential monotherapy. Dual biologic therapy (DBT) may overcome treatment resistance by concomitantly inhibiting multiple inflammatory pathways. In rheumatoid arthritis, DBT shows moderate efficacy improvements but consistently higher serious infection rates compared to monotherapy, particularly with rituximab and JAK inhibitor combination-based regimens. In psoriatic arthritis, studies demonstrate possible benefits especially with combinations targeting alternate pathways, eg, apremilast with biologics or IL-17/IL-23 inhibitors with TNF blockers, though safety concerns exist. The multi-domain nature of PsA makes DBT particularly attractive in achieving global disease control. In axSpA, evidence of efficacy is also limited but encouraging in treatment-refractory disease. However, major research gaps persist. Data remain limited and largely heterogeneous, with limited disease-specific studies and a paucity of randomized controlled trials (RCTs). Most available reports derive from small case series or single-center experiences, limiting the generalizability of findings. Geographic variation further complicates interpretation, as infection risk, treatment accessibility, and pharmacovigilance capacity differ markedly between developed and resource-limited regions. Therefore, this narrative review aims to summarize current evidence while emphasizing the unmet clinical and research needs surrounding DBT, highlighting the necessity for systematic reviews, large-scale registries, and context-specific studies to inform safe and equitable clinical application worldwide. While DBT may be beneficial in carefully selected patients with treatment-refractory disease, current evidence does not consistently demonstrate increased efficacy. Thus, DBT should be reserved for refractory cases where benefits outweigh risks.

Objective: To evaluate the effectiveness of belimumab in different joint and skin phenotypes of systemic lupus erythematosus (SLE).

Methods: The BeRLiSS-JS 2.0 is a decade-long observational study including adult SLE patients from 14 Italian Centers treated with belimumab (intravenous/subcutaneous) stratified by articular (nondeforming nonerosive arthritis -NDNE-, Jaccoud's arthropathy, Rhupus) and cutaneous phenotypes (acute -ACLE-, subacute -SCLE-, and chronic cutaneous lupus erythematosus -CCLE-, and nonspecific manifestations). Outcome variables measured every 6 months up to 36 months included Disease Activity Score-28 joints (DAS28) and Cutaneous Lupus Erythematosus Disease Area and Severity Index (CLASI) scores, remission rates (DAS28<2.6; CLASI-A=0), and prednisone intake (mg/day).

Results: Of 443 patients, 221 (49.9%) had NDNE, 30 (6.8%) Jaccoud's arthropathy, 21 (4.7%) rhupus, 112 (25.3%) had ACLE, 54 (12.2%) SCLE, and 18 (4.1%) CCLE. At 6 months a significant decrease of DAS28 was observed in NDNE (p<0.001) and by CLASI-A in ACLE and SCLE (both p<0.001). Non-specific cutaneous manifestations did not improve significantly. CLASI-D scores remained stable over 36 months. Remission rates were higher in NDNE and ACLE patients (at 6 months: NDNE 59.6%, Jaccoud's 18.8%, rhupus 30.3% - p=0.002; at 18 months: ACLE 75.9%, SCLE 56.4%, CCLE 33.3% - p=0.018). Daily prednisone dosage decreased in all organ-specific phenotypes, but more pronouncedly in patients with NDNE, ACLE, and SCLE. Higher baseline CLASI-A and DAS28 and CLASI-D were associated with lower remission rates.

Conclusion: Treatment with belimumab was associated with reduced disease activity and increased remission especially in NDNE and ACLE patients. Glucocorticoid-sparing effect was also found.

Statins have provided the first line treatment for hypercholesterolemia for over two decades with the addition of ezetimibe if low-density lipoprotein (LDL) cholesterol targets are not achieved with statins alone. However, treatment with statins and other oral small molecules is often insufficient to attain the target levels of LDL cholesterol. This review describes the monoclonal antibodies (mAbs) that have been produced to overcome the residual cardiovascular risk related to uncontrolled LDL cholesterol. In recent years the mAbs, alirocumab and evolocumab, targeting proprotein convertase subtilisin/kexin type 9 (PCSK9) have become established worldwide as an additional treatment for patients not achieving LDL cholesterol goals on statins and ezetimibe, or sometimes as an alternative treatment in those with statin intolerance. They have been shown to be safe and effective in reducing cardiovascular events in patients at high cardiovascular risk. More recently, four new mAbs targeting PCSK9 have been developed and approved in China. Some of these mAbs offer the benefit of less frequent subcutaneous dosing and some are humanized mAbs and it remains to be seen whether their efficacy will be retained with long term use. New drug targets were identified to potentially reduce elevated triglyceride levels and the mAb angiopoietin-like 3 (ANGPTL3) inhibitor, evinacumab, was found to be effective in reducing LDL cholesterol in patients with homozygous familial hypercholesterolemia (FH) and has been approved for that indication. SHR-1918 is another mAb targeting ANGPTL3 being developed in China which may also be effective to treat homozygous FH. These drugs are expensive and may not be suitable for a wider indication and there are antisense oligonucleotides and small interfering RNA treatments in development which may prove more cost effective. Another mAb at an early stage of development is MAR001 targeting angiopoietin-like 4 (ANGPTL4). The role for this remains to be established.

The TRAIL-DR5 signaling axis exhibits a pronounced "double-edged sword" nature in cardiovascular diseases, embodying both deleterious and protective roles. On one hand, it contributes to pathology by promoting cardiomyocyte apoptosis and enhancing inflammatory responses, thereby driving the progression of conditions such as myocardial ischemia-reperfusion injury, atherosclerotic plaque destabilization, and heart failure. On the other hand, under specific contexts, TRAIL-DR5 signaling can exert protective effects through mechanisms including the regulation of angiogenesis, suppression of inflammation, and facilitation of tissue repair. This functional dichotomy likely stems from cell-type specificity, dynamic microenvironmental changes, and crosstalk with other signaling pathways-such as NF-κB, MAPK, and autophagy-related processes. This review systematically examines the molecular mechanisms underlying TRAIL-DR5 signaling and its multifaceted involvement in acute myocardial infarction, heart failure, atherosclerosis, and atrial fibrillation. Furthermore, it explores targeted therapeutic strategies, including: DR5 agonists (such as monoclonal antibodies and small molecule compounds) for selective clearance of pathological cells; inhibitors (for instance, soluble DR5-Fc fusion proteins and siRNAs) to block deleterious signaling; and combination therapies (eg, with kinase inhibitors) to achieve synergistic efficacy. We propose that future investigations should prioritize the development of highly specific biomarkers, the refinement of targeted delivery systems, and a deeper mechanistic understanding of cellular and disease-stage heterogeneity. Such advances will be essential to propel the field from broad-spectrum treatments toward precision interventions, offering innovative solutions for complex cardiovascular disorders.

Purpose: Irisin, an exercise-induced myokine, promotes the browning of white adipose tissue. Over a decade of research has expanded its functions to include the amelioration of metabolic disorders and protection of neural, skeletal, muscular, cardiac, and renal systems. Exogenous administration of irisin has been demonstrated to mimic the beneficial effects of exercise, showing therapeutic potential for a range of conditions including obesity, diabetes, Alzheimer's disease, osteoporosis, sarcopenia, myocardial ischemia, and chronic kidney disease. Irisin emerges as a promising circulating biomarker for assessing health status. By offering a quantitative, data-driven perspective from macro to micro scales, bibliometrics serves as a crucial decision-support tool for irisin research. It facilitates the mapping of the intellectual landscape, pinpoints knowledge gaps and underinvestigated niches, and tracks the temporal evolution of research fronts, thereby guiding future investigative priorities.

Patients and methods: Publications were retrieved from the Web of Science Core Collection (WoSCC) using the search strategy "Topic = irisin", covering the period from its discovery in 2012 to 2024. After applying language (English-only) and type (article/review) filters, VOSviewer, CiteSpace and R package "bibliometrix" was used to conduct the bibliometric analysis.

Results: This bibliometric analysis was conducted on a total of 2412 articles sourced from 78 countries. China emerged as the leading contributor, ranking first among the corresponding authors' countries. The primary research institutions identified were the Egyptian Knowledge Bank, Firat University, and Harvard University. The most locally cited authors were Mantzoros CS and Spiegelman BM, while Aydin S was recognized as the most relevant author. The most frequently occurring keywords included "exercise", "obesity", and "FNDC5". The latest trend topics identified were "neuroinflammation", "ferroptosis", "chronic kidney disease", and "cognition".

Conclusion: This bibliometric study delineates irisin's emerging clinical translational prospects, thereby providing evidence-based guidance for prioritizing research on irisin's therapeutic targeting and biomarker validation across multidisciplinary clinical contexts.

Lupus erythematosus panniculitis (LEP) is a rare and serious skin lesion associated with systemic lupus erythematosus (SLE). In the past, the management of LEP has followed the treatment guidelines for SLE, which is based on the administration of high doses of hormones together with immunosuppressants, with no treatment plans specific for LEP. However, the long-term use of high hormone doses and immunosuppressants can exacerbate skin breakage and calcification. Telitacicep is an approved biological agent demonstrating significant therapeutic efficacy in immune system disorders. We report a case of lupus erythematosus panniculitis in which the patient's clinical symptoms and laboratory test results improved after treatment with a combination of steroids, cyclophosphamide, and the biologic agent Telitacicept. The condition was significantly controlled and alleviated. This report highlights the successful application of Telitacicept in the treatment of lupus panniculitis, providing valuable insights for future management of this condition.