Biologics : Targets & Therapy最新文献

Fecal microbiota transplantation (FMT) has evolved from a niche therapy to a cornerstone in the treatment of recurrent Clostridioides difficile infection (rCDI). Initially introduced in the 1950s, its relevance has surged with the emergence of virulent and antibiotic-resistant C. difficile strains. In recent years, the FDA approved two standardized microbiota-based therapeutics-Rebyota™ (fecal microbiota, live-jslm) and Vowst™ (fecal microbiota spores, live-brpk)-for rCDI prevention. Multiple pivotal trials support the efficacy and safety of both traditional FMT and the FDA-approved prescription FMTs, with sustained response rates surpassing 80% in select populations. In parallel, live biotherapeutic products (LBPs)-donor independent, well-defined microbial consortia produced in laboratory setting are under development. Examples include VE303 and NTCD-M3, a single non-toxigenic C. difficile strain (M3). Beyond the FDA approved therapeutics, conventional FMT is gaining traction as a potential treatment for severe or fulminant CDI, especially in patients not responding to antibiotics and ineligible for surgery. Investigational indications include decolonizing multidrug-resistant organisms and treatment of noninfectious conditions such as inflammatory bowel disease, irritable bowel syndrome, liver disease, and metabolic syndrome. Given the differing pathophysiology of these conditions, a tailored approach supported by rigorous clinical trials is essential. Although there is a growing shift, particularly in the United States, toward the use of FDA-approved FMTs, global practices remain heterogeneous, with conventional FMT still widely employed. Meanwhile, regulatory pathways and clinical guidelines for microbiota-derived biologics and live biotherapeutic products continue to evolve. In this manuscript, we provide an update on the emerging use of FDA-approved prescription microbiota-derived therapeutics for the prevention of rCDI, review data on investigational agents including both donor dependent and donor independent microbial products, and summarize current evidence on the use of conventional FMT for indications beyond prevention of rCDI.

Purpose: This study aimed to explore the effect of activated growth factor (AGF) in anabolic-catabolic regulation pathway in an experimental osteoarthritis (OA) rat model. This investigation was predicated on the critical need for a disease-modifying osteoarthritis drug, seeking to determine if AGF could restore chondral homeostasis by reversing the catabolic-dominant state that defines OA pathology. This is the first study to compare AGF with platelet-rich plasma (PRP) and diclofenac sodium in vivo.

Methods: Fifty-six male Wistar rats were randomly allocated into seven groups (n = 8 per group); normal control (NC), negative control (OA induced, saline-treated), positive control with platelet-rich plasma (PRP) (OA induced + PRP), positive control diclofenac (OA induced + Diclofenac sodium), AGF 0.1 ng/mL (OA induced + AGF with TGF-β at 0.1 ng/mL), AGF 1 ng/mL (OA induced + AGF with TGF-β at 1 ng/mL), AGF 10 ng/mL (OA induced + AGF with TGF-β at 10 ng/mL). Cartilage anabolic-catabolic status was assessed by measuring matrix metalloproteinases (MMP-1, MMP-13), a-disintegrin and metalloproteinase with thrombospondin motifs-4 (ADAMTS-4), SMAD3, aggrecan, and collagen type II (Col2) expression via ELISA and Western blot. Key inflammatory mediators (TNF-α, IL-1β, NF-κB) and histopathological changes were also evaluated.

Results: AGF treatment demonstrated superior efficacy in modulating anabolic-catabolic balance compared to OA controls and PRP. AGF dose-dependently and significantly decreased MMP-1, MMP-13, and ADAMTS-4 levels. Conversely, AGF significantly increased SMAD3 phosphorylation, aggrecan synthesis, and Col2 expression, surpassing the effects of PRP. The 10 ng/mL AGF group showed the most pronounced chondroprotective and anabolic effects, often restoring parameters towards normal levels. Furthermore, AGF significantly reduced TNF-α, IL-1β, and NF-κB levels, and diminished inflammatory cell infiltration, with the 10 ng/mL dose being comparable or superior to Diclofenac in these anti-inflammatory/anti-catabolic effects. PRP showed moderate benefits, generally less than AGF formulations.

Conclusion: Platelet-derived AGF, as an advanced mode of PRP, effectively regulates the anabolic-catabolic processes in OA cartilage. It achieved this by significantly inhibiting key catabolic enzymes and pro-inflammatory mediators, while concurrently promoting crucial anabolic signaling pathways and extracellular matrix synthesis. These findings highlight AGF's substantial therapeutic potential as a disease-modifying biological agent for OA.

Introduction: Ovarian cancer (OC) ranks among the most lethal and aggressive gynecological malignancies. Identifying novel molecular targets is crucial for improving early diagnosis and developing effective therapies. Despite advancements in immunotherapy, its efficacy in OC remains limited due to the absence of well-defined immune-related molecular targets.

Methods: This study offers a comprehensive analysis of YTHDF1, combining multi-omics-based bioinformatics approaches with in vitro and in vivo experimental validation to elucidate its functional role and significance in the progression and treatment of OC.

Results: Our findings reveal that YTHDF1 is significantly upregulated in OC and correlates with poor clinical outcomes. Functional assays confirmed its oncogenic properties, while pathway analyses highlight its involvement in critical tumor-promoting signaling pathways. Importantly, we identified a potential link between YTHDF1 expression and the tumor immune landscape, suggesting its role in modulating immune cell infiltration and driving immunosuppression. Additionally, both computational and in vivo evidence underline the relevance of YTHDF1 in influencing immunotherapeutic responsiveness and chemosensitivity in OC. Mechanistically, we discovered for the first time that YTHDF1 can be encapsulated within tumor-derived exosomes, contributing to the polarization of macrophages toward the immunosuppressive M2a phenotype.

Discussion: These findings position YTHDF1 as a promising prognostic biomarker and therapeutic target for OC. Its role in shaping an immunosuppressive microenvironment and mediating chemoresistance underscores its potential in enhancing immunotherapy and improving chemotherapy outcomes.

The "biologic era" in the management of juvenile idiopathic arthritis (JIA) has begun in the year 2000, with the publication of the randomized controlled trial on etanercept. In the subsequent years, there has been continued progress, marked by the availability of new therapeutic agents and the shift towards early aggressive interventions. In addition, a more rational therapeutic approach has been fostered by the promulgation of therapeutic recommendations and guidelines. In parallel with the growing use of the novel biologic disease-modifying antirheumatic drugs (bDMARDs) in the real world of clinical practice, additional information has been gained about their effectiveness and safety. Furthermore, the role of the various bDMARDs in the management of the different JIA categories and of the main disease complications and comorbidities has been scrutinized. Innovative management strategies, such as the step-down and the treat-to-target, have been proposed to maximize the therapeutic benefits through the optimal combination of the newer and conventional medications. However, despite this progress several unmet needs remain, including the lack of well-established criteria for medication discontinuation after the attainment of sustained disease remission and of effective alternatives for patients who respond inadequately to the contemporary therapeutic modalities. The research agenda also calls for the search for reliable early predictors of therapeutic response that foster personalization of treatment and increase its precision. The aim of this Review is to summarize the evidence obtained in the past 5 years in the field of biologic therapy for JIA and to discuss the remaining gaps and the future perspectives of the use of these medications.

Brodalumab is a monoclonal antibody that targets interleukin-17 receptor A (IL-17RA), offering a novel approach to treating moderate-to-severe psoriasis. By blocking IL-17RA, brodalumab inhibits the activity of multiple pro-inflammatory IL-17 isoforms, including IL-17A, IL-17F, and IL-17C, which are critical in the pathogenesis of psoriasis. This review synthesizes data from Phase I-IV clinical trials and real-world studies to provide a comprehensive overview of brodalumab's efficacy, safety, and clinical role in the treatment of moderate-to-severe psoriasis. Clinical trial data consistently demonstrate its rapid onset of action, high rates of skin clearance, and durability of response. Real-world evidence supports its effectiveness in treatment-resistant cases and among patients with previous biologic failures. Safety considerations include the need for monitoring suicidality, although no causal relationship has been confirmed. Despite being one of the most effective biologic agents available for psoriasis, brodalumab remains underutilized, highlighting the need for improved awareness of its potential clinical advantages. Further research is warranted to better define its role in treatment algorithms and to assess long-term outcomes in broader patient populations.

Objective: The present study was designed to determine the anti-inflammatory and antioxidant effects of dulaglutide (DUL) on doxorubicin (DOX) -induced acute kidney injury (AKI).

Methods: Twenty-eight male rats were randomly allocated into four groups: the negative control group (received Distilled water), the positive control group (received Distilled water and a single dose of DOX), DUL 0.2 mg/kg group (received DUL 0.2 mg/kg twice weekly and single dose of DOX), and DUL 0.6 mg/kg group (received DUL 0.2 mg/kg twice weekly and single dose of DOX). All DOX doses (20 mg/kg) were given at day 13th of the study and all treatments were administered intraperitoneally for 14 days. On day fifteenth, the rats were sacrificed, and blood was collected to measure the complete blood count (CBC), Neutrophile/Lymphocyte Ratio (NLR), Monocyte/Lymphocyte Ratio (MLR), And Platelet/Lymphocyte Ratio (PLR), C-reactive protein (CRP), blood urea nitrogen (BUN), and serum creatinine (SCr). The right kidney was used for histopathological examination, while the left kidney was homogenized to assess the renal tissue levels of malondialdehyde (MDA), total antioxidant capacity (TAOC), interleukin-1beta (IL-1β), tumor necrosis factor-alpha (TNF-α), kidney injury molecule-1 (KIM-1), and neutrophil gelatinase-associated lipocalin (NGAL).

Results: DOX induces acute kidney injury was demonstrated by significant elevations in BUN, SCr, and CRP levels. DUL significantly lowered the levels of BUN, SCr, and CRP, and reduced the levels of blood inflammation markers, including NLR and MLR. Additionally, it resulted in a significant reduction in the renal tissue levels of MDA, IL-1β, and TNF-α, while the level of TAOC was significantly elevated. These findings were supported by histopathological assessments.

Conclusion: The present study indicates that DUL mitigates doxorubicin-induced kidney damage by reducing oxidative stress and inflammation.

Hidradenitis suppurativa (HS), a chronic inflammatory condition, features recurrent, painful lesions in the perineal area, severely impairing patients' quality of life. Despite its clinical significance, HS pathogenesis remains incompletely understood, and effective treatments are scarce. Interleukin-1 receptor-associated kinase 4 (IRAK4) is located downstream of IL-1R/TLR in the IL-1R/TLR signaling pathway, which is upstream of the end products of the pathway. IRAK4-targeted drugs can potentially block this pathway, reducing cytokine secretion and alleviating HS symptoms. This paper comprehensively reviews IRAK4 and its family members' physiological functions, systematically examines the IRAK family's roles in the IL-1R/TLR pathway, with a focus on IRAK4, analyzes IRAK4's specific role in HS, strengthening the theoretical basis for using IRAK4-targeted drugs. The text also covers representative drugs of the major biologics currently used in the treatment of HS and describes the IRAK4 inhibitor Zimlovisertib and the IRAK4 degrader KT-474, along with a discussion of the current status of drugs that inhibit IRAK4 in the treatment of HS and the challenges they face.

Hemophilia A and B, caused by deficiencies of coagulation factors VIII or IX, result in impaired thrombin generation with consequent spontaneous or trauma-related bleeding, particularly hemarthroses. Although prophylactic factor replacement therapy remains the global standard of care for hemophilia, it has significant limitations, including intravenous administration, breakthrough bleeding, inhibitor development, and deteriorating arthropathy despite prophylaxis. Marstacimab, an IgG1 monoclonal antibody targeting tissue factor pathway inhibitor (TFPI), represents a novel non-factor approach. Marstacimab restores thrombin generation via the extrinsic pathway, bypassing intrinsic pathway deficiencies and offering prophylactic benefit independent of inhibitor status. Clinical evaluation across Phase 1b/2 and Phase 3 (BASIS) trials and ongoing extension studies has demonstrated robust efficacy. In Phase 3, marstacimab reduced annualized bleed rates by 91.6% compared with episodic treatment and was non-inferior to factor prophylaxis. Bleed control was sustained though zero-bleed outcomes were not uniformly achieved. Pharmacokinetic data support once-weekly fixed dosing independent of body weight, simplifying administration and potentially improving adherence. Across all studies, marstacimab demonstrated a favorable safety profile. Injection site reactions were the most common adverse events, while anti-drug antibodies, including neutralizing types, were transient and without clinical impact. Marstacimab, the first FDA-approved anti-TFPI antibody for prophylaxis in hemophilia A and B without inhibitors, addresses key unmet needs, particularly for hemophilia B patients lacking subcutaneous (SC) prophylaxis options. Its novel mechanism, ease of administration, and sustained efficacy position it as a significant therapeutic advance. Marstacimab's exact role in the hemophilia treatment armamentarium is yet to be established with the availability of coming real-world experience data. The long-term studies remain essential to fully demonstrate its role, especially in populations with inhibitors and in the context of evolving non-factor therapies. This review summarises currently available clinical data and contextualises these in light of other treatments in hemophilia.