Search Results (96)

The landscape of first-line treatment for metastatic non-small cell lung cancer (NSCLC) without actionable driver mutations is rapidly evolving, currently dominated by pembrolizumab-based regimens. This review discusses the unique molecular characteristics of cemiplimab, a newer anti-PD-1 antibody, and defines its optimal positioning against established standards. Cemiplimab is a fully human IgG4 monoclonal antibody distinguished by two key features: an engineered hinge-region mutation that prevents Fab-arm exchange, ensuring exceptional molecular stability which minimizes anti-drug antibody (ADA) risks associated with unstable molecules; and a unique interaction with PD-1 glycosylation sites, potentially enhancing binding efficacy. These structural advantages may be particularly relevant in histologies like squamous NSCLC, where accumulating somatic mutations drive high neoantigen loads and heightened immune responses, creating an environment historically prone to ADA formation. Based on data from the pivotal EMPOWER-Lung program, we highlight cemiplimab’s exceptional promise in specific populations. Firstly, in the EMPOWER-Lung 1 trial, cemiplimab monotherapy demonstrated extraordinary survival benefits in a pre-specified analysis of the distinct “ultra-high” PD-L1 expression subgroup (TPS ≥90%), potentially surpassing historical benchmarks. Secondly, cemiplimab displays consistent, robust efficacy in challenging-to-treat squamous histology, both as monotherapy for patients with high PD-L1 expression and in combination with chemotherapy for patients with PD-L1 < 50%. In conclusion, cemiplimab establishes a unique therapeutic niche for patients with squamous histology and ultra-high PD-L1 expression, likely driven by its distinct structural stability and reduced immunogenicity. Full article

Background: Vedolizumab and ustekinumab are increasingly used off-label in pediatric inflammatory bowel disease (IBD) unresponsive or refractory to anti–TNFα therapy. Despite their increasing use in clinical practice, evidence in the pediatric population remains limited, especially regarding therapeutic exposure thresholds and the clinical utility of therapeutic drug monitoring (TDM). Methods: We report a series of five pediatric cases with Crohn’s disease or ulcerative colitis treated with ustekinumab or vedolizumab after anti-TNFα failure. Trough drug concentrations, anti-drug antibodies (ADAs), clinical scores (PCDAI/PUCAI), biomarkers (fecal calprotectin, C-reactive protein), and endoscopic findings were assessed longitudinally. Results: In all cases, we observed recurrent discordance between clinical indices (PCDAI/PUCAI), biochemical markers, and endoscopic activity. Clinical improvement frequently correlated with trough concentrations above commonly cited adult-derived reference ranges (>15 µg/mL for vedolizumab; >3 µg/mL for ustekinumab), although this alignment was not uniform across patients. Notably, one patient developed high-titre ADAs with undetectable ustekinumab levels, yet remained clinically stable, suggesting substantial interindividual variability in pharmacokinetics, immunogenicity, and disease control. Conclusions: Ustekinumab and vedolizumab are promising off-label options for pediatric refractory IBD. In this case series, TDM contributed to the interpretation of pharmacokinetic variability and immunogenicity, offering contextual insights that may support dose adjustments and therapeutic decision-making. Integrating TDM with clinical, biochemical, and endoscopic monitoring may improve optimize individualized treatment in this complex and vulnerable patient group. Full article

Background/Objectives: There is limited data regarding the association of anti-drug antibody (ADA) levels with the efficacy of anti-tumor necrosis factor (anti-TNF) therapy in patients with inflammatory bowel disease (IBD). We aimed to investigate the association between antibody to adalimumab (ATA) and antibody to infliximab (ATI) levels and treatment failure in IBD. Methods: This single-center, retrospective cohort study included consecutive IBD patients with ADA evaluated with a drug-tolerant assay between September 2012 and February 2023. A time-to-event analysis was performed for treatment failure, defined as the need for drug discontinuation due to primary non-response, loss of response, a serious adverse event, or an IBD-related surgery. Patients were followed from first positive ADA until treatment failure or the end of the follow-up (May 2024). Results: The study population consisted of 134 patients with IBD [n = 58 (43%) on adalimumab; n = 86, (64%) with Crohn’s disease]. Multiple COX regression analysis identified higher ADA levels to be associated with treatment failure (HR: 1.034, 95%CI: 1.024–1.045, p < 0.001). A ROC analysis identified an ATA and ATI level threshold of 5.2 U/mL (AUC: 0.705; 95%CI: 0.569–0.841; p = 0.003; sensitivity: 64%; specificity: 82%) and 8.8 U/mL (AUC: 0.809; 95%CI: 0.713–0.906; p < 0.001; sensitivity: 69%; specificity: 93%), respectively, to distinguish patients with or without treatment failure. Conclusions: In this large retrospective cohort study, higher levels of ADA were associated with treatment failure to anti-TNF therapy in IBD. Moreover, we identified ATA and ATI level thresholds of 5.2 U/mL and 8.8 U/mL, respectively, to be associated with treatment failure. Full article

Background and Objectives: Crohn’s Disease (CD) is a chronic inflammatory condition often treated with anti-TNF agents such as infliximab (IFX) and adalimumab (ADA). This study compares the efficacy, immunogenicity, and pharmacokinetics of IFX and ADA over a 54-week period. Materials and Methods: A prospective, multicentre cohort study was conducted involving 72 patients with active CD (Crohn’s disease activity index, CDAI > 150), who received treatment with either IFX (n = 42) or ADA (n = 30). Results: By week 54, treatment discontinuation occurred in 31% of IFX-treated patients (13/42) and 37% of ADA-treated patients (11/30), with no significant difference between groups (p = 0.612). Among those who completed the study, clinical remission (CDAI ≤ 150) was achieved in 65% of the IFX group and 95% of the ADA group (OR = 8.10; 95% CI = 1.10–20.11; p = 0.049). Loss of clinical response was more frequent in the IFX group (31%) than in the ADA group (10%), with an OR of 0.25 (95% CI: 0.06–0.97; p = 0.045). Fibrinogen levels declined in both groups, with a greater reduction observed in ADA-treated patients. The area under the ROC curve (AUC) for fibrinogen in distinguishing remission from active disease was 0.608 for IFX and 0.711 for ADA. Anti-drug antibodies were detected more frequently in IFX-treated patients (16.7%, 7/42) compared to those receiving ADA (6.7%, 2/30). Conclusions: Treatment with ADA demonstrated superior efficacy compared to IFX in maintaining clinical remission in CD, which was paralleled by a more effective normalization of fibrinogen levels (Clinical trial: GET-CRO-2010-01). Full article

Background: Antibodies have the unique ability to recognize antigens and to be recognized as antigens by other antibodies, creating a balanced network that regulates the humoral part of the immune system. An antibody that uniquely identifies another antibody of a given specificity as its antigen is referred to as an anti-idiotypic antibody. Methods: A descriptive literature review was conducted using the PubMed database, including publications up to 2025. Results: This review examines the formation mechanisms of anti-idiotypic antibodies, their functional attributes, and their importance in diverse pathologies. A key focus is their capacity to neutralize pathogenic autoantibodies, offering a novel strategy for treating autoimmune diseases. Conversely, the generation of anti-Id Abs against therapeutic monoclonal antibodies (anti-drug antibodies) represents a significant challenge for biologic therapy, a complication addressed in a dedicated section on detection methods. Furthermore, consideration is given to the application of anti-Id Abs as innovative tools for vaccine design, particularly in oncology. By mimicking tumor-associated antigens, anti-Id Abs can induce a potent, targeted immune response against cancer with minimal side effects, presenting an alternative to conventional chemotherapy and radiation. Conclusions: Anti-Id Abs hold significant therapeutic promise. Their ability to selectively suppress pathogenic autoantibodies allows for precise immune intervention without broad immunosuppression. Additionally, their utility extends to vaccine development for various diseases. Further research into anti-Id Abs will deepen our understanding of immune regulation and open new avenues for targeted therapies. Full article

Background: The development of anti-drug antibodies (ADAs) and resulting immune complexes are key mechanisms behind the secondary loss of response to adalimumab in Crohn’s disease (CD). Despite their clinical importance, routine immunogenicity assays are limited, underscoring the need for alternative predictive approaches. Objective: This study aimed to develop interpretable artificial neural network (ANN) models to predict immune complex formation and estimate serum adalimumab levels using routinely available clinical and laboratory data from CD patients. Methods: A prospective analysis was performed on 58 CD patients on maintenance adalimumab. Immune complexes and serum adalimumab were measured via ELISA and lateral flow assays. ANN and ensemble regression models were trained on demographic, clinical, and inflammatory data, with performance evaluated by five-fold cross-validation. Interpretability was enhanced using Garson’s algorithm and permutation importance. Results: The ANN-based classification model accurately predicted ADA immune complex formation, achieving an accuracy of 77.47% and an area under the curve (AUC) of 82.63%. The main predictive variables included extraintestinal manifestations, perianal disease, disease behavior, and age at diagnosis. For estimating serum adalimumab levels measured by ELISA, the model performed modestly (accuracy 59.89%, AUC 79.72%), incorporating factors such as Montreal classification, perianal disease, C-reactive protein, immunosuppressant use, and disease duration. Conclusions: Interpretable ANN models robustly predict anti-adalimumab immune complexes and, to a lesser extent, serum adalimumab, using clinically available data, including perianal disease. This proof-of-concept study is limited by the relatively small, single-center dataset (n = 58), which may affect model generalizability and increase the risk of overfitting. External validation in larger and multicenter cohorts is required before clinical implementation. Full article

Inflammatory bowel disease, encompassing ulcerative colitis and Crohn’s disease, is characterised by chronic immune-mediated inflammation and variable treatment response. Loss of drug efficacy due to underexposure, pharmacokinetic variability, and immunogenicity remains a key challenge. Therapeutic drug monitoring, using drug levels and anti-drug antibody measurements, is an important strategy for optimising the treatment of inflammatory bowel disease. It helps ensure adequate dosing and can distinguish between pharmacokinetic and mechanistic drug failure. Most evidence pertains to infliximab and adalimumab. Multiple factors influence drug pharmacokinetics, affecting both target drug levels and the doses required to achieve them. These include inflammatory burden, bodyweight, age, disease phenotype, and route of administration, all of which are important considerations for individualising treatment in inflammatory bowel disease. This narrative review explores how special clinical situations—acute severe ulcerative colitis, perianal fistulising Crohn’s disease, hypoalbuminaemia, extremes of body composition, pregnancy, paediatrics, and advanced age—alter drug pharmacokinetics and influence the utility and interpretation of therapeutic drug monitoring in inflammatory bowel disease. Full article

Background: Biological therapy is frequently used for the treatment of inflammatory bowel disease (IBD); however, the long-term efficacy of anti-tumor necrosis factor-alpha (TNF−α) therapies, such as infliximab (IFX) and adalimumab (ADA), is often compromised by the development of antidrug antibodies (AIFX and AADA, respectively). While several individual factors are known to contribute to immunogenicity, the complex, interactive effects of various clinical variables have not been fully elucidated in a real-world setting. Methods: We conducted a hierarchical logistic regression analysis on a retrospective cohort of 153 pediatric and adult IBD patients receiving IFX or ADA therapy to identify clinical factors and their interactions associated with AIFX/AADA positivity. The analysis progressively incorporated demographic, disease-related, and treatment-related variables, culminating in a model that included two- and three-way interaction terms. Results: Our final model demonstrated modest predictive power, with a Nagelkerke R² of 0.287, explaining less than 30% of the variance in antibody positivity using readily available clinical data (AUC of 0.806, 71.0% sensitivity and 77.6% specificity). Key predictors included the type of biological therapy (IFX vs. ADA) and the duration of treatment, with IFX therapy being a significant independent predictor (OR = 6.940, p = 0.004) for antibody positivity. Importantly, we identified novel three-way interactions, revealing that the combined effect of age at disease onset, IBD subtype, and biological therapy type significantly influences antibody formation (p = 0.042), particularly in childhood-onset ulcerative colitis patients treated with IFX. A similar interaction was found for treatment duration, IBD subtype, and therapy type (p = 0.042), where the risk of antibody positivity with IFX increased significantly with treatment length, particularly in UC patients. Conclusions: This study highlights that the combination of routine clinical variables in IBD offers a data-driven, mechanistically insightful framework, supporting the prediction of AIFX/AADA positivity to a modest extent. This framework requires prospective and external validation before clinical implementation. Full article

Background/Objectives: The development of anti-drug antibodies (ADA) significantly diminishes the clinical efficacy of infliximab (IFX) in Crohn’s disease (CD). This study aimed to develop and validate an interpretable machine learning (ML) framework for predicting ADA risk during IFX induction therapy using multidimensional clinical and laboratory data. Methods: We conducted a retrospective analysis of 606 CD patients who initiated IFX induction between January 2023 and August 2024 at the Sixth Affiliated Hospital of Sun Yat-sen University. Predictor selection was performed through univariate analysis and least absolute shrinkage and selection operator (LASSO) regression, with significant features further evaluated via multivariate logistic regression. Seven ML models were developed and evaluated mainly based on area under the curve (AUC), F1 score, and Brier score. Model interpretability was enhanced using SHapley Additive exPlanations (SHAP). Results: Among the 606 CD patients, 145 (23.93%) developed ADA during IFX induction. Independent predictors included serum trough levels of IFX (TLI), erythrocyte sedimentation rate (ESR), history of delayed treatment, prior exposure to anti-TNF agents, and concomitant use of immunosuppressants (IMM). The XGBoost algorithm outperformed others, with an AUC of 0.899, accuracy of 0.851, F1 score of 0.640, and Brier score of 0.102 in validation. SHAP analysis identified TLI and ESR as the most influential predictors, with history of delayed treatment and prior exposure to anti-TNF agents showing moderate impact, while concomitant use of IMM was associated with a protective effect. Conclusions: We developed an interpretable ML model that effectively predicts ADA formation in CD patients undergoing IFX induction therapy, facilitating early risk stratification and personalized treatment planning. This approach integrates advanced analytics with clinical practice to support precision medicine in CD management. Full article

Objectives: To assess the association between serum concentrations of adalimumab (ADL) and etanercept (ETN) and the occurrence of a flare in rheumatoid arthritis (RA) patients who are tapering methotrexate (MTX) or their TNF inhibitor. In addition, we explored the impact of tapering MTX on immunogenicity in patients with longstanding ADL use. Methods: ADL and ETN serum concentrations and anti-drug antibodies (ADAs) quantified with a drug-tolerant assay were determined in all RA patients who participated in the TARA trial. Within the TARA trial, two tapering strategies were compared, namely gradually tapering MTX followed by tapering a TNF-inhibitor (ADL or ETN) or vice versa. Results: In the current analysis, 111 RA patients who strictly followed the tapering strategy and had >3 blood samples were included, of them 41% tapered ADL and 59% tapered ETN. Both ADL and ETN concentrations decreased during tapering and stopping, but ADL was longer detectable after cessation compared to ETN. If MTX was tapered first, more ADAs against ADL were detectable in the serum, but it did not affect the serum concentrations. Conclusions: Our data showed that the majority of flares occur when the median serum concentration of ADL and ETN falls below 1 mg/L. If MTX is tapered first, there is a notable increase in the detection of ADAs, but this does not impact the median ADL serum concentration. Full article

Background/Objectives: Pharmacogenetics examines genome variability and its influence on drug efficacy and toxicity, forming the foundation for personalized medicine. Patients with inflammatory bowel disease (IBD) treated with azathioprine with thiopurine S-methyltransferase (TPMT) deficiency are at an increased risk of drug-related toxic effects. Variability in the HLA-DQA1 and DQB1 alleles may lead to an inadequate therapeutic response. This study aimed to determine the significance of TPMT and HLA-DQ Allelic Variants in therapy optimization planning. Methods: A retrospective study was conducted to determine TPMT gene polymorphism and the presence of HLA-DQA1 and HLA-DQB1 alleles in children diagnosed with IBD and treated at the Institute for Child and Youth Health Care of Vojvodina in May 2023. Results: The study included 104 children with a mean age of 13.71 ± 3.1 years, with a balanced gender distribution. A TPMT mutation was identified in only one child. The most common HLA-DQA1 alleles were *01 (49%) and *05 (28.8%), while the most frequent allele at the HLA-DQB1 locus was 03 (15.4%). The presence of the HLA-DQA105 allele was associated with the development of anti-drug antibodies against anti-TNF therapy (RR: 1.23; 95% CI: 1.03–1.50), while the presence of HLA-DQA101 was significantly more frequent in children on optimized therapeutic regimens (RR: 1.63; 95% CI: 1.13–2.10). Conclusions: Prior to the initiation of azathioprine therapy, TPMT genotyping should be performed to prevent adverse effects and ensure optimal drug dosing. Identification of the HLA-DQA105 and HLA-DQA101 alleles plays an important role in the planning of biological therapy regimens, including decisions on dose escalation or interval shortening. Full article

Background/Objectives: Gaucher disease type 1 is an autosomal recessive lysosomal storage disorder caused by pathogenic variants in the GBA1 gene. Although enzyme replacement therapy has improved patient outcomes, there is limited long-term real-world data on taliglucerase alfa. This study aimed to evaluate the long-term efficacy and safety of taliglucerase alfa in both treatment-naïve and previously treated patients with Gaucher disease type 1 over a 10-year period. Methods: This prospective, single-centre cohort study involved 29 patients (13 treatment-naïve and 16 previously treated with imiglucerase) who received taliglucerase alfa from 2015 to 2024. Clinical, hematological, visceral, skeletal, and biochemical parameters were assessed at baseline and at 12, 60, and 120 months. Biomarkers included chitotriosidase and glucosylsphingosine. Safety was evaluated through adverse event reporting and anti-drug antibody testing. Results: Hemoglobin and platelet counts improved or remained stable in all patients. By 60 months, liver volume had normalised in treatment-naïve patients (mean reduction: 23.1%), while spleen volume had decreased by up to 47.3%. Lyso-Gb1 levels decreased by 86.1% in patients who had not previously received treatment and by 59.5% overall, with a strong correlation to adherence. Bone mineral density improved in most cases. 137 adverse events were reported, 24% of which were mild infusion-related reactions. Anti-drug antibody developed in two patients, including one with a reduced therapeutic response. Conclusions: Taliglucerase alfa offers sustained long-term clinical, hematological and biochemical benefits in both treatment-naïve and previously treated Gaucher disease type 1 patients, with a favorable safety profile. Glucosylsphingosine proved to be a highly sensitive biomarker for monitoring therapeutic efficacy and detecting treatment response. Full article

Biological drugs have revolutionized the treatment of many chronic diseases, starting with cancer. They normally consist of antibodies that are also effectively used to treat several autoimmune diseases, including psoriasis. These products, called biologics, work by selectively blocking the activity of certain targets, mainly cytokines, which play a crucial role in the pathogenic and inflammatory processes involved in a particular disease. Unfortunately, a reduction in response to these biological treatments may occur over time, and this phenomenon is often due to the development of antibodies against the therapeutic antibodies. The immune responses directed to these therapeutics range from transient anti-drug antibodies (ADA) formation, with no clinical significance, to the generation of high titers and persistence of ADA, causing loss of efficacy. Considering the costs associated with the use of biological drugs, there is growing interest in identifying biomarkers that can predict clinical response to personalize treatments. Full article

Serum sickness-like reaction (SSLR) is a rare immune-mediated condition that typically affects the skin and joints after exposure to certain drugs, infections, or vaccines. Although it shares clinical similarities with serum sickness (SS), SSLR differs in its underlying mechanisms, histopathology, and causes. Despite its generally benign and self-limiting nature, SSLR is frequently misdiagnosed and may lead to unnecessary hospitalization. This narrative review summarizes current knowledge on epidemiology, pathophysiology, clinical features, diagnosis, treatment, and long-term considerations related to SSLR. The condition is most often associated with antibiotics, monoclonal antibodies, and vaccines, particularly in pediatric populations. Its pathogenesis remains incompletely understood, but proposed mechanisms include immune complex formation, altered drug metabolism, lymphocyte toxicity, and the development of anti-drug antibodies. Diagnosis is primarily clinical, although novel diagnostic tools are emerging. Management involves discontinuation of the offending agent and supportive care, such as antihistamines or nonsteroidal anti-inflammatory drugs (NSAIDs) in mild cases, and corticosteroids in more severe cases. Long-term management, especially in cases requiring potential re-exposure to the causative agent, remains challenging. Skin testing and graded oral challenges appear promising within a structured clinical framework. Increased awareness of SSLR is essential for timely recognition and appropriate care, and further research is needed to elucidate its mechanisms and inform evidence-based management strategies. Full article

Background/Objectives: Adalimumab and Infliximab are biologics used to treat autoimmune diseases. Monitoring drug and anti-drug antibody (ADA) levels in patients helps optimize treatment. However, current quantitation methodologies for drug and total (free and drug-bound) ADAs often involve multi-step workflows. Automated systems can streamline the process. The i-Tracker chemiluminescent immunoassays (CLIA) are cartridge-based kits for quantifying serum levels of drugs such as Adalimumab, Infliximab, and associated ADAs. Herein, we aimed to establish performance characteristics of the i-Tracker Adalimumab, Infliximab, and total ADAs in serum on the random-access analyzer IDS-iSYS and to compare patient results with an electrochemiluminescent immunoassay (ECLIA)-based reference method. Methods: Remnant serum specimens, calibration material, or spiked serum were used to evaluate assay linearity, precision, functional sensitivity, and accuracy on the IDS-iSYS analyzer and to perform the method comparison. Results: The assays displayed linearity, accuracy, and up to 8% imprecision across clinically relevant analyte ranges. Compared to the reference method, the drug assays exhibited a strong linear fit (correlation coefficient > 0.95) with <±1.0 µg/mL mean bias. The total anti-Adalimumab assay demonstrated over 85% qualitative agreement. The total anti-Infliximab assay, however, showed higher detection rate of ADAs in Infliximab-treated patient specimens, yielding < 60% negative agreement with the reference method. Although i-Tracker total ADA assays exhibited drug sensitivity, they still detected ADAs in supratherapeutic drug concentrations. Conclusions: The i-Tracker assays demonstrated robust analytical performance, suggesting potential for clinical application. The method comparison underscored functional differences with the reference method, an important consideration when transitioning assay formats for monitoring Adalimumab- and Infliximab-treated patients. Full article