Anti-drug antibodies (ADA) reduce the efficacy of immunotherapies in multiple sclerosis (MS) and are associated with increased disease progression risk. Blood biomarkers predicting immunogenicity to biopharmaceuticals represent an unmet clinical need. Patients with relapsing remitting (RR)MS were recruited before (baseline), three, and 12 (M12) months after commencing interferon-beta treatment. Neutralising ADA-status was determined at M12, and patients were stratified at baseline according to their M12 ADA-status (ADA-positive/ADA-negative). Patients stratified as ADA-positive were characterised by an early dampened response to interferon-beta (prior to serum ADA detection) and distinct proinflammatory transcriptomic/proteomic peripheral blood signatures enriched for \'immune response activation\' including phosphoinositide 3-kinase-γ and NFκB-signalling pathways both at baseline and throughout the treatment course, compared to ADA-negative patients. These immunogenicity-associated proinflammatory signatures significantly overlapped with signatures of MS disease severity. Thus, whole blood molecular profiling is a promising tool for prediction of ADA-development in RRMS and could provide insight into mechanisms of immunogenicity.

Hyaluronan (HA) is a glycosaminoglycan that forms a gel-like barrier in the subcutaneous (SC) space, limiting bulk fluid flow and the dispersion of SC-administered therapeutics. Recombinant human hyaluronidase PH20 (rHuPH20) facilitates the rapid delivery of co-administered therapeutics by depolymerizing HA in the SC space. Administration of rHuPH20 can induce the formation of anti-rHuPH20 antibodies, or anti-drug antibodies (ADAs), with the potential to bind endogenous PH20 hyaluronidase in the adult testes and epididymis. Using a variety of relevant animal models and multiple dose regimens of rHuPH20 across the full spectrum of animal development, we demonstrated that rHuPH20 administration resulted in the formation of ADAs. Although these ADAs can bind both the recombinant rHuPH20 enzyme and recombinant versions of animal model-specific hyaluronidases, they had no impact on fertility parameters (as measured by sperm concentration and motility, litter size, and litter viability) or fetal development. We present the result of our nonclinical studies in order of the developmental lifecycle, beginning with adults. Toxicology studies that extend beyond the standard package are also presented. These studies demonstrate the favorable safety profile of rHuPH20 and ADAs in nonclinical models. Additionally, we identified substantial safety margins for therapeutically relevant doses of rHuPH20.

UNASSIGNED: The efficacy of anti-TNF therapy in Crohn\'s disease (CD), such as infliximab, is often compromised by the development of anti-drug antibodies (ADAs). The genetic variation HLA-DQA1*05 has been linked to the immunogenicity of biologics, influencing ADA formation. This study investigates the correlation between HLA-DQA1*05 and ADA formation in CD patients treated with infliximab in a Chinese Han population and assesses clinical outcomes.
UNASSIGNED: In this retrospective cohort study, 345 infliximab-exposed CD patients were genotyped for HLADQ A1*05A > G (rs2097432). We evaluated the risk of ADA development, loss of infliximab response, adverse events, and treatment discontinuation among variant and wild-type allele individuals.
UNASSIGNED: A higher percentage of patients with ADAs formation was observed in HLA-DQA1*05 G variant carriers compared with HLA-DQA1*05 wild-type carriers (58.5% vs 42.9%, P = 0.004). HLA-DQA1*05 carriage significantly increased the risk of ADAs development (adjusted hazard ratio = 1.65, 95% CI 1.18-2.30, P = 0.003) and was associated with a greater likelihood of infliximab response loss (adjusted HR = 2.55, 95% CI 1.78-3.68, P < 0.0001) and treatment discontinuation (adjusted HR = 2.21, 95% CI 1.59-3.06, P < 0.0001). Interestingly, combined therapy with immunomodulators increased the risk of response loss in HLA-DQA1*05 variant carriers.
UNASSIGNED: HLA-DQA1*05 significantly predicts ADAs formation and impacts treatment outcomes in infliximab-treated CD patients. Pre-treatment screening for this genetic factor could therefore be instrumental in personalizing anti-TNF therapy strategies for these patients.

Aim: An assay to detect anti-tocilizumab antibodies in the presence of high levels of circulating target and drug is needed for immunogenicity assessment in comparative clinical studies. Methods: An assay was developed and validated using a combination of blocking agents and dilutions to overcome target interference challenges. Results: No false-positive signal was detected in serum samples spiked with 350-500 ng/ml of IL-6 receptor. As low as 50 ng/ml of positive control antibodies could be detected in the presence of either 500 ng/ml of IL-6 or 250 μg/ml of the drug product. Assay also demonstrated high sensitivity, selectivity and precision. Conclusion: A robust, easy to perform immunogenicity assay was developed and validated for detecting anti-tocilizumab antibodies.
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Measurement of anti-drug antibodies (ADA) to assess the incidence of ADA in a clinical trial is a critical step in immunogenicity assessment during the development of a protein therapeutic. We developed novel graphical approaches to illustrate clinical trial ADA data for the PD-L1 inhibitor atezolizumab (Tecentriq) that included a systematic analysis of the impact of the timing of ADA sampling and ADA assay drug tolerance on reported ADA incidence. We found that approaches used across the industry for ADA incidence analysis provide a limited view of immunogenicity in oncology studies, where ADA detection may be confounded by both drug dosage and patient attrition. Moreover, these approaches can miss important temporal information about the immune response. Our results demonstrated that the methodology of ADA assessment for the atezolizumab program was specifically designed to capture most ADA responses to ensure accurate reporting of ADA incidence. We further showed that the use of sparse sampling and/or ADA test methods with insufficient drug tolerance may result in a significant underreporting of ADA incidence. We conclude that the comparison of ADA incidence between different drugs can be highly misleading and that a test method with appropriate sensitivity in the presence of the drug and a clinical sampling scheme that is aligned with ADA responses to a drug is required to accurately report ADA incidence.

[This corrects the article DOI: 10.3389/fimmu.2024.1345473.].

UNASSIGNED: Asthma is a major global disease affecting adults and children, which can lead to hospitalization and death due to breathing difficulties. Although targeted monoclonal antibody therapies have revolutionized treatment of severe asthma, some patients still fail to respond. Here we critically evaluate the literature on biologic therapy failure in asthma patients with particular reference to anti-drug antibody production, and subsequent loss of response, as the potential primary cause of drug failure in asthma patients.
UNASSIGNED: Encouragingly, asthma in most cases responds to treatment, including the use of an increasing number of biologic drugs in moderate to severe disease. This includes monoclonal antibody inhibitors of immunoglobulin E and cytokines, including interleukin 4, 5, or 13 and thymic stromal lymphopoietin. These limit mast cell and eosinophil activity that cause the symptomatic small airways obstruction and exacerbations.
UNASSIGNED: Despite humanization of the antibodies, it is evident that benralizumab; dupilumab; mepolizumab; omalizumab; reslizumab and tezepelumab all induce anti-drug antibodies to some extent. These can contribute to adverse events including infusion reactions, serum sickness, anaphylaxis and potentially disease activity due to loss of therapeutic function. Monitoring anti-drug antibodies (ADA) may allow prediction of future treatment-failure in some individuals allowing treatment cessation and switching therefore potentially limiting disease breakthrough.

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Bispecific antibodies, including bispecific IgG, are emerging as an important new class of antibody therapeutics. As a result, we, as well as others, have developed engineering strategies designed to facilitate the efficient production of bispecific IgG for clinical development. For example, we have extensively used knobs-into-holes (KIH) mutations to facilitate the heterodimerization of antibody heavy chains and more recently Fab mutations to promote cognate heavy/light chain pairing for efficient in vivo assembly of bispecific IgG in single host cells. A panel of related monospecific and bispecific IgG1 antibodies was constructed and assessed for immunogenicity risk by comparison with benchmark antibodies with known low (Avastin and Herceptin) or high (bococizumab and ATR-107) clinical incidence of anti-drug antibodies. Assay methods used include dendritic cell internalization, T cell proliferation, and T cell epitope identification by in silico prediction and MHC-associated peptide proteomics. Data from each method were considered independently and then together for an overall integrated immunogenicity risk assessment. In toto, these data suggest that the KIH mutations and in vitro assembly of half antibodies do not represent a major risk for immunogenicity of bispecific IgG1, nor do the Fab mutations used for efficient in vivo assembly of bispecifics in single host cells. Comparable or slightly higher immunogenicity risk assessment data were obtained for research-grade preparations of trastuzumab and bevacizumab versus Herceptin and Avastin, respectively. These data provide experimental support for the common practice of using research-grade preparations of IgG1 as surrogates for immunogenicity risk assessment of their corresponding pharmaceutical counterparts.

OBJECTIVE:  Pediatric uveitis is a rare but sight-threatening condition. Prompt and adequate treatment is crucial to preserve vision and avoid long-term complications. In cases that are resistant to corticosteroids and disease-modifying anti-rheumatic drugs (DMARDs), anti-tumor necrosis (anti-TNF) biologic agents are usually added. In this study, we report our experience with adalimumab (ADA) anti-TNF use in this group of patients.
METHODS:  This is a retrospective observational study conducted in a tertiary pediatric uveitis clinic, in Manchester Royal Eye Hospital. All patients were pediatric patients (aged 2-18 years old) under follow-up during the period of six months. The patients\' data were analyzed according to the diagnosis, age of onset of uveitis, systemic medications used before and concomitantly with ADA, duration of uveitis before starting ADA, its effect, and time to notice the therapeutic effect in controlling inflammation. Finally, cases were reviewed for the development of anti-drug antibodies.
RESULTS:  Forty-two patients were included in the study. Idiopathic uveitis was diagnosed in 47.6% of patients and 40.5% of patients were associated with juvenile idiopathic arthritis (JIA). Most (97.6%) of patients were using topical steroids before starting ADA and 95.2% continued using steroids after established ADA use, but systemic steroid use was reduced from 33.3% to 14.3%. The most common non-biologic DMARD used before ADA was methotrexate (MTX) (90.5%). One-third of the patients started ADA between 6 and 12 months after the diagnosis of uveitis, while this percentage dropped to 9.5% the year after diagnosis. Seventy-eight percent of patients acquired complete clinical control of inflammation on ADA use. Almost 78.6% of patients showed a full response in less than six months. In eight patients who were not controlled or were transiently controlled on ADA, three patients had positive anti-drug antibodies. In one patient, antidrug antibodies were identified after 12 years of ADA use, and in another, after 4 years.
CONCLUSIONS:  Adalimumab is an effective, well-tolerated drug in children with uveitis refractory to non-biologic DMARD therapy. DMARDs were usually used alongside ADA in this cohort and few patients had confirmed ADA antibodies.