Biologics : Targets & Therapy最新文献

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.

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.].

Purpose: Data regarding treatment switch from the originator infliximab (IFX) to GP-1111 in inflammatory bowel disease (IBD) are limited. Only a few studies have examined the financial aspects of biosimilar use, none of them regarding GP-1111. The study aimed to evaluate the long-term efficacy and safety of the IFX biosimilar GP-1111 in patients with IBD who underwent a nonmedical switch from the original IFX in real-life settings. Further, it investigated the switch from a health economics perspective.

Patients and methods: A prospective cohort study was conducted on patients with IBD who were on maintenance IFX treatment and who switched to the IFX biosimilar GP-1111 due to financial constraints, with a 1-year follow-up period. Clinical and laboratory parameters were measured at baseline and at weeks 8, 16, and 52 and serum IFX levels were measured at baseline and at week 24. Statistical analyses were performed using the paired t-test, Pearson's chi-square test, Kaplan-Meier survival curves, Cox proportional hazard regression models, and univariate linear model.

Results: This study included 142 patients (95 with Crohn's disease and 47 with ulcerative colitis). The average serum IFX level remained within the therapeutic range from baseline (3.2 ± 2.3 μg/mL) to week 24 (3.7 ± 2.7 μg/mL, p = 0.106). The corticosteroid-free remission (S-SFR) rates were stable (baseline: 69.7%, follow-up: 72.9%, p = 0.58). The 1-year treatment persistence rate was 83.1%. The adverse events included allergic reactions (IR: 6.3 per 100 patient-years) and paradoxical reactions (IR: 2.4 per 100 patient-years). Based on the estimated cost analysis, biosimilar use could lead to significant savings, with a total of 201.9 million HUF (514,000 €).

Conclusion: The IFX biosimilar GP-1111 was safe and effective against IBD in real-world settings. The average serum IFX levels and S-SFR rates remained stable, while no identifiable factors leading to treatment discontinuation were observed. Biosimilar use has a cost advantage with a reassuring safety profile.

[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.