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  • Journal article
    Pavlidis S, Takahashi K, Kwong FNK, Xie J, Hoda U, Sun K, Elyasigomari V, Agapow P, Loza M, Baribaud F, Chanez P, Fowler SJ, Shaw DE, Fleming LJ, Howarth PH, Sousa AR, Corfield J, Auffray C, De Meulder B, Knowles R, Sterk PJ, Guo Y, Adcock IM, Djukanovic R, Chung KF, U-BIOPRED study groupet al., 2019,

    "T2-high" in severe asthma related to blood eosinophil, exhaled nitric oxide and serum periostin

    , European Respiratory Journal, Vol: 53, ISSN: 0903-1936

    BACKGROUND: Type-2 (T2) immune responses in airway epithelial cells (AECs) classifies mild-moderate asthma into a T2-high phenotype. We examined whether currently-available clinical biomarkers can predict AEC-defined T2-high phenotype within U-BIOPRED cohort. METHODS: The transcriptomic profile of AECs obtained from brushings of 103 patients with asthma and 44 healthy controls was obtained and gene set variation analysis used to determine the relative expression score of T2 asthma using a signature from IL-13-exposed AECs. RESULTS: 37% of asthmatics (45% non-smoking severe asthma, n=49, 33% of smoking or ex-smoking severe asthma, n=18 and 28% mild-moderate asthma, n=36) were T2-high using AEC gene expression. They were more symptomatic with higher levels of nitric oxide in exhaled breath (FeNO) and of blood and sputum eosinophils but not of serum IgE or periostin. Sputum eosinophilia correlated best with the T2-high signature. FeNO (≥30 ppb) and blood eosinophils (≥300/µL) gave a moderate prediction of T2-high asthma. Sputum IL-4, IL-5 and IL-13 protein levels did not correlate with gene expression. CONCLUSION: T2-high severe asthma can be predicted to some extent from raised levels of FeNO, blood and sputum eosinophil counts, but serum IgE or serum periostin were poor predictors. Better bedside biomarkers are needed to detect T2-high.

  • Journal article
    Hersh CP, Adcock IM, Celedon JC, Cho MH, Christiani DC, Himes BE, Kaminski N, Mathias RA, Meyers DA, Quackenbush J, Redline S, Steiling KA, Tabor HK, Tobin MD, Wurfel MM, Yang IV, Koppelman GHet al., 2019,

    High-throughput sequencing in respiratory, critical care, and sleep medicine research. An Official American Thoracic Society Workshop Report

    , Annals of the American Thoracic Society, Vol: 16, Pages: 1-16, ISSN: 2329-6933

    High-throughput, “next-generation” sequencing methods are now being broadly applied across all fields of biomedical research, including respiratory disease, critical care, and sleep medicine. Although there are numerous review articles and best practice guidelines related to sequencing methods and data analysis, there are fewer resources summarizing issues related to study design and interpretation, especially as applied to common, complex, nonmalignant diseases. To address these gaps, a single-day workshop was held at the American Thoracic Society meeting in May 2017, led by the American Thoracic Society Section on Genetics and Genomics. The aim of this workshop was to review the design, analysis, interpretation, and functional follow-up of high-throughput sequencing studies in respiratory, critical care, and sleep medicine research. This workshop brought together experts in multiple fields, including genetic epidemiology, biobanking, bioinformatics, and research ethics, along with physician-scientists with expertise in a range of relevant diseases. The workshop focused on application of DNA and RNA sequencing research in common chronic diseases and did not cover sequencing studies in lung cancer, monogenic diseases (e.g., cystic fibrosis), or microbiome sequencing. Participants reviewed and discussed study design, data analysis and presentation, interpretation, functional follow-up, and reporting of results. This report summarizes the main conclusions of the workshop, specifically addressing the application of these methods in respiratory, critical care, and sleep medicine research. This workshop report may serve as a resource for our research community as well as for journal editors and reviewers of sequencing-based manuscript submissions in our research field.

  • Journal article
    Frent SM, Chapman KR, Larbig M, Mackay A, Fogel R, Gutzwiller FS, Shen S, Patalano F, Banerji D, Kostikas K, Wedzicha JAet al., 2019,

    Capturing exacerbations of chronic obstructive pulmonary disease with EXACT: A sub-analysis of FLAME

    , American Journal of Respiratory and Critical Care Medicine, Vol: 199, Pages: 43-51, ISSN: 1073-449X

    Rationale: Chronic obstructive pulmonary disease (COPD) exacerbations accelerate lung function decline, reduce quality of life, and increase mortality. A subset of patients (n=457) from the FLAME study used the EXAcerbations of COPD Tool (EXACT®) to capture symptom-defined exacerbations. Objectives: To evaluate the effect of indacaterol/glycopyrronium (IND/GLY) versus salmeterol/fluticasone (SFC) on symptom-defined exacerbations measured using EXACT, and to assess differences between these events and exacerbations requiring healthcare resource use (HCRU). Methods: All patients in FLAME used an e-Diary to record and detect symptom deteriorations; HCRU-related exacerbations were confirmed by investigators. In patients using the EXACT questionnaire, the onset, recovery and magnitude of symptom-defined exacerbations were identified by changes in total scores relative to baseline. We analyzed the annualized rate and time-to-first symptom-defined (EXACT) exacerbation, and assessed differences between symptom-defined and HCRU events in terms of number, severity and concordance. Measurements and Main Results: A non-significant 17% reduction in the annualized rate of symptom-defined (EXACT) exacerbations (rate ratio: 0.83, 95% CI: 0.60, 1.14, P = 0.242) and a numerically longer time to first symptom-defined exacerbation were observed with IND/GLY versus SFC (HR 0.76, 95% CI: 0.56, 1.03, P = 0.075). These results were consistent with data from the overall FLAME population. 23.5% of symptom-defined (EXACT) events corresponded to HCRU events, and 22.2% of HRCU events were captured by EXACT (kappa index 0.24, 95% CI: 0.15, 0.33). Conclusions: Regardless of the exacerbation definition used, our findings support the use of LABA/LAMAs as the preferred treatment option for patients at risk of future exacerbations.

  • Conference paper
    Ritchie AI, Donaldson GC, El-Emir E, Calverley PM, Vestbo J, Wedzicha JAet al., 2019,

    The British Lung Foundation Early COPD Consortium - Recruitment and Results from an Initial Pilot

    , International Conference of the American-Thoracic-Society, Publisher: AMER THORACIC SOC, ISSN: 1073-449X
  • Conference paper
    Wiseman DJ, Kamal F, Finney L, Ritchie AI, Gent J, Edwards MR, Johnston SL, Donaldson GC, Openshaw PJ, Wedzicha JAet al., 2019,

    Respiratory Syncytial Virus (RSV) Detection Is Associated with an Increased Inflammatory Response in Stable (non-Exacerbating) Chronic Obstructive Pulmonary Disease (COPD) Patients

    , International Conference of the American-Thoracic-Society, Publisher: AMER THORACIC SOC, ISSN: 1073-449X
  • Journal article
    Zhu J, Message SD, Mallia P, Kebadze T, Contoli M, Ward CK, Barnathan ES, Mascelli MA, Kon OM, Papi A, Stanciu LA, Edwards MR, Jeffery PK, Johnston SLet al., 2019,

    Bronchial mucosal Interferon-α/β and pattern recognition receptor expression in experimental rhinovirus-induced asthma exacerbations

    , Journal of Allergy and Clinical Immunology, Vol: 143, Pages: 114-125.e4, ISSN: 0091-6749

    BACKGROUND: The innate immune system senses viral infection via pattern recognition receptors (PRRs) leading to type I interferon (IFN) production: their roles in rhinovirus (RV)-induced asthma exacerbations in vivo are uncertain. OBJECTIVES: To compare bronchial mucosal type I IFN and PRR expression at baseline and following RV infection in atopic asthmatic and control subjects. METHODS: Immunohistochemistry was used to detect expression of IFN-α, IFN-β and the PRRs, toll-like receptor (TLR)-3, melanoma-differentiation-associated gene-5 (MDA-5) and retinoic-acid-inducible protein-I (RIG-I) in bronchial biopsies from 10 atopic asthmatics and 15 non-asthmatic non-atopic controls at baseline and on day four and six weeks following RV infection. RESULTS: We observed IFN-α/β deficiency in bronchial epithelium at three time points in asthma in vivo. Lower epithelial IFN-α/β expression was related to greater virus load, worse airway symptoms, airway hyperresponsiveness (AHR) and reductions in lung function during RV infection. We found lower frequencies of bronchial subepithelial monocytes/macrophages expressing IFN-α/β in asthma during infection. IFN deficiency at baseline was not accompanied by deficient PRR expression in asthma. Both epithelial and subepithelial PRR expression was induced during RV infection. RV infection increased numbers of subepithelial IFN/PRRs-expressing inflammatory cells were related to greater virus load, AHR and reductions in lung function. CONCLUSIONS: Bronchial epithelial IFN-α/β expression and numbers of subepithelial IFN-α/β-expressing monocytes/macrophages during infection were both deficient in asthma. Lower epithelial IFN-α/β expression was associated with adverse clinical outcomes following RV infection in vivo. Increases in subepithelial cells expressing IFN/PRRs during infection were also related to greater virus load/illness severity.

  • Journal article
    Shrine N, Portelli MA, John C, Soler Artigas M, Bennett N, Hall R, Lewis J, Henry AP, Billington CK, Ahmad A, Packer RJ, Shaw D, Pogson ZEK, Fogarty A, McKeever TM, Singapuri A, Heaney LG, Mansur AH, Chaudhuri R, Thomson NC, Holloway JW, Lockett GA, Howarth PH, Djukanovic R, Hankinson J, Niven R, Simpson A, Chung KF, Sterk PJ, Blakey JD, Adcock IM, Hu S, Guo Y, Obeidat M, Sin DD, van den Berge M, Nickle DC, Bossé Y, Tobin MD, Hall IP, Brightling CE, Wain LV, Sayers Iet al., 2019,

    Moderate-to-severe asthma in individuals of European ancestry: a genome-wide association study

    , Lancet Respiratory Medicine, Vol: 7, Pages: 20-34, ISSN: 2213-2600

    BACKGROUND: Few genetic studies that focus on moderate-to-severe asthma exist. We aimed to identity novel genetic variants associated with moderate-to-severe asthma, see whether previously identified genetic variants for all types of asthma contribute to moderate-to-severe asthma, and provide novel mechanistic insights using expression analyses in patients with asthma. METHODS: In this genome-wide association study, we used a two-stage case-control design. In stage 1, we genotyped patient-level data from two UK cohorts (the Genetics of Asthma Severity and Phenotypes [GASP] initiative and the Unbiased BIOmarkers in PREDiction of respiratory disease outcomes [U-BIOPRED] project) and used data from the UK Biobank to collect patient-level genomic data for cases and controls of European ancestry in a 1:5 ratio. Cases were defined as having moderate-to-severe asthma if they were taking appropriate medication or had been diagnosed by a doctor. Controls were defined as not having asthma, rhinitis, eczema, allergy, emphysema, or chronic bronchitis as diagnosed by a doctor. For stage 2, an independent cohort of cases and controls (1:5) was selected from the UK Biobank only, with no overlap with stage 1 samples. In stage 1 we undertook a genome-wide association study of moderate-to-severe asthma, and in stage 2 we followed up independent variants that reached the significance threshold of p less than 1 × 10-6 in stage 1. We set genome-wide significance at p less than 5 × 10-8. For novel signals, we investigated their effect on all types of asthma (mild, moderate, and severe). For all signals meeting genome-wide significance, we investigated their effect on gene expression in patients with asthma and controls. FINDINGS: We included 5135 cases and 25 675 controls for stage 1, and 5414 cases and 21 471 controls for stage 2. We identified 24 genome-wide significant signals of association with moderate-to-severe asthma, including several signals in innate or adaptive im

  • Conference paper
    Finney L, Fenwick PS, Kemp S, Bakhsoliani E, Belchamber KBR, Edwards MR, Donaldson GC, Donnelly L, Mallia P, Johnston SL, Wedzicha JAet al., 2019,

    Interferon Response to Human Rhinovirus Is Impaired in Alveolar Macrophages but Not Bronchial Epithelial Cells in Chronic Obstructive Pulmonary Disease

    , International Conference of the American-Thoracic-Society, Publisher: AMER THORACIC SOC, ISSN: 1073-449X
  • Journal article
    Garcia-Marcos L, Edwards J, Kennington E, Aurora P, Baraldi E, Carraro S, Gappa M, Louis R, Moreno-Galdo A, Peroni DG, Pijnenburg M, Priftis KN, Sanchez-Solis M, Schuster A, Walker S, Blakey J, Compton C, Fleming L, Fowler S, Gaillard E, Gibson F, Glenn Crater G, Niven R, Roberts A, Ryan D, Seppala U, Usmani O, van der Schee M, van Sont Jet al., 2018,

    Priorities for future research into asthma diagnostic tools: A PAN-EU consensus exercise from the European asthma research innovation partnership (EARIP)

    , Clinical and Experimental Allergy, Vol: 48, Pages: 104-120, ISSN: 0954-7894

    The diagnosis of asthma is currently based on clinical history, physical examination and lung function, and to date, there are no accurate objective tests either to confirm the diagnosis or to discriminate between different types of asthma. This consensus exercise reviews the state of the art in asthma diagnosis to identify opportunities for future investment based on the likelihood of their successful development, potential for widespread adoption and their perceived impact on asthma patients. Using a two-stage e-Delphi process and a summarizing workshop, a group of European asthma experts including health professionals, researchers, people with asthma and industry representatives ranked the potential impact of research investment in each technique or tool for asthma diagnosis and monitoring. After a systematic review of the literature, 21 statements were extracted and were subject of the two-stage Delphi process. Eleven statements were scored 3 or more and were further discussed and ranked in a face-to-face workshop. The three most important diagnostic/predictive tools ranked were as follows: “New biological markers of asthma (eg genomics, proteomics and metabolomics) as a tool for diagnosis and/or monitoring,” “Prediction of future asthma in preschool children with reasonable accuracy” and “Tools to measure volatile organic compounds (VOCs) in exhaled breath.”.

  • Journal article
    Farne H, Groves H, Gill S, stokes I, Mccolloch S, karoly E, Trujillo-Torralbo M, Johnston S, Mallia P, Tregoning Jet al., 2018,

    Comparative metabolomic sampling of upper and lower airways by four different methods to identify biochemicals that may support bacterial growth

    , Frontiers in Cellular and Infection Microbiology, Vol: 8, ISSN: 2235-2988

    Bacteria need nutrients from the host environment to survive, yet we know little about which biochemicals are present in the airways (the metabolome), which of these biochemicals are essential for bacterial growth and how they change with airway disease. The aims of this pilot study were to develop and compare methodologies for sampling the upper and lower airway metabolomes and to identify biochemicals present in the airways that could potentially support bacterial growth. Eight healthy human volunteers were sampled by four methods: two standard approaches - nasal lavage and induced sputum, and two using a novel platform, synthetic adsorptive matrix (SAM) strips—nasosorption and bronchosorption. Collected samples were analyzed by Ultrahigh Performance Liquid Chromatography-Tandem Mass Spectroscopy (UPLC-MS/MS). Five hundred and eighty-one biochemicals were recovered from the airways belonging to a range of metabolomic super-pathways. We observed significant differences between the sampling approaches. Significantly more biochemicals were recovered when SAM strips were used, compared to standard sampling techniques. A range of biochemicals that could support bacterial growth were detected in the different samples. This work demonstrates for the first time that SAM strips are a highly effective method for sampling the airway metabolome. This work will assist further studies to understand how changes in the airway metabolome affect bacterial infection in patients with underlying airway disease.

  • Journal article
    Grigg J, Nibber A, Paton JY, Chisholm A, Guilbert TW, Kaplan A, Turner S, Roche N, Hillyer E, Price DB, van Aalderen WMC, Murray CS, Phipatanakul W, Sonnappa S, Hoe TO, Martin RJ, Papi A, Szefler SJ, Skinner D, McQueen RB, Usmani OSet al., 2018,

    Matched cohort study of therapeutic strategies to prevent preschool wheezing/asthma attacks

    , JOURNAL OF ASTHMA AND ALLERGY, Vol: 11, ISSN: 1178-6965
  • Journal article
    Owen J, Kamila S, Shrivastava S, Carugo D, Bernardino de la Serna J, Mannaris C, Pereno V, Browning R, Beguin E, McHale AP, Callan JF, Stride Eet al., 2018,

    The Role of PEG-40-stearate in the Production, Morphology, and Stability of Microbubbles.

    , Langmuir

    Phospholipid coated microbubbles are currently in widespread clinical use as ultrasound contrast agents and under investigation for therapeutic applications. Previous studies have demonstrated the importance of the coating nanostructure in determining microbubble stability and its dependence upon both composition and processing method. While the influence of different phospholipids has been widely investigated, the role of other constituents such as emulsifiers has received comparatively little attention. Herein, we present an examination of the impact of polyethylene glycol (PEG) derivatives upon microbubble structure and properties. We present data using both pegylated phospholipids and a fluorescent PEG-40-stearate analogue synthesized in-house to directly observe its distribution in the microbubble coating. We examined microbubbles of clinically relevant sizes, investigating both their surface properties and population size distribution and stability. Domain formation was observed only on the surface of larger microbubbles, which were found to contain a higher concentration of PEG-40-stearate. Lipid analogue dyes were also found to influence domain formation compared with PEG-40-stearate alone. "Squeezing out" of PEG-40-stearate was not observed from any of the microbubble sizes investigated. At ambient temperature, microbubbles formulated with DSPE-PEG(2000) were found to be more stable than those containing PEG-40-stearate. At 37 °C, however, the stability in serum was found to be the same for both formulations, and no difference in acoustic backscatter was detected. This could potentially reduce the cost of PEGylated microbubbles and facilitate simpler attachment of targeting or therapeutic species. However, whether PEG-40-stearate sufficiently shields microbubbles to inhibit physiological clearance mechanisms still requires investigation.

  • Conference paper
    Moore AJS, Dean LSN, Fraceto LF, Lima R, Tetley TDet al., 2018,

    THE EFFECTS OF A NOVEL POLY(EPSILON-CAPROLACTONE) NANOCAPSULE CONTAINING THE PESTICIDE ATRAZINE ON HUMAN ALVEOLAR EPITHELIUM

    , Winter Meeting of the British-Thoracic-Society, Publisher: BMJ PUBLISHING GROUP, Pages: A20-A21, ISSN: 0040-6376
  • Conference paper
    Finney LJ, Belchamber KBR, Kemp SV, Fenwick P, Mallia P, Donaldson G, Johnston SL, Donnelly L, Wedzicha JAet al., 2018,

    HUMAN RHINOVIRUS IMPAIRS THE INNATE IMMUNE RESPONSE TO BACTERIA IN MACROPHAGES IN CHRONIC OBSTRUCTIVE PULMONARY DISEASE

    , Winter Meeting of the British-Thoracic-Society, Publisher: BMJ PUBLISHING GROUP, Pages: A9-A9, ISSN: 0040-6376
  • Conference paper
    Fei L, Fraser J, Padmanaban V, Boniface A, Wyman E, Maguire M, Stone M, Elkin S, Mallia Pet al., 2018,

    FRAILTY IN HOSPITALISED COPD PATIENTS

    , Winter Meeting of the British-Thoracic-Society, Publisher: BMJ PUBLISHING GROUP, Pages: A170-A170, ISSN: 0040-6376
  • Journal article
    Cowie MR, Gallagher AM, Simonds AK, 2018,

    Treating central sleep apnoea in heart failure: is pull better than push?

    , European Journal of Heart Failure, Vol: 20, Pages: 1755-1759, ISSN: 1388-9842
  • Journal article
    Loeckx M, Rabinovich RA, Demeyer H, Louvaris Z, Tanner R, Rubio N, Frei A, De Jong C, Gimeno-Santos E, Rodrigues FM, Buttery SC, Hopkinson NS, Busching G, Strassmann A, Serra I, Vogiatzis I, Garcia-Aymerich J, Polkey MI, Troosters Tet al., 2018,

    Smartphone-based physical activity telecoaching in chronic obstructive pulmonary disease: Mixed-methods study on patient experiences and lessons for implementation

    , JMIR mHealth and uHealth, Vol: 6, ISSN: 2291-5222

    Background: Telecoaching approaches can enhance physical activity (PA) in patients with chronic obstructive pulmonary disease (COPD). However, their effectiveness is likely to be influenced by intervention-specific characteristics.Objective: This study aimed to assess the acceptability, actual usage, and feasibility of a complex PA telecoaching intervention from both patient and coach perspectives and link these to the effectiveness of the intervention.Methods: We conducted a mixed-methods study based on the completers of the intervention group (N=159) included in an (effective) 12-week PA telecoaching intervention. This semiautomated telecoaching intervention consisted of a step counter and a smartphone app. Data from a project-tailored questionnaire (quantitative data) were combined with data from patient interviews and a coach focus group (qualitative data) to investigate patient and coach acceptability, actual usage, and feasibility of the intervention. The degree of actual usage of the smartphone and step counter was also derived from app data. Both actual usage and perception of feasibility were linked to objectively measured change in PA.Results: The intervention was well accepted and perceived as feasible by all coaches present in the focus group as well by patients, with 89.3% (142/159) of patients indicating that they enjoyed taking part. Only a minority of patients (8.2%; 13/159) reported that they found it difficult to use the smartphone. Actual usage of the step counter was excellent, with patients wearing it for a median (25th-75th percentiles) of 6.3 (5.8-6.8) days per week, which did not change over time (P=.98). The smartphone interface was used less frequently and actual usage of all daily tasks decreased significantly over time (P<.001). Patients needing more contact time had a smaller increase in PA, with mean (SD) of +193 (SD 2375) steps per day, +907 (SD 2306) steps per day, and +1489 (SD 2310) steps per day in high, medium, and low contact

  • Journal article
    Li F, Xu M, Wang M, Wang L, Wang H, Zhang H, Chen Y, Gong J, Zhang JJ, Adcock IM, Chung KF, Zhou Xet al., 2018,

    Roles of mitochondrial ROS and NLRP3 inflammasome in multiple ozone-induced lung inflammation and emphysema

    , Respiratory Research, Vol: 19, ISSN: 1465-9921

    BackgroundMitochondrial damage leading to oxidant stress may play an important role in the pathogenesis of airflow obstruction and emphysema. NLPR3 inflammasome can be activated by mitochondrial ROS (mtROS) and other stimuli. We examined the importance of mtROS and NLRP3 inflammasome and their interactions in multiple ozone-induced lung inflammation and emphysema.MethodsC57/BL6 mice were exposed to ozone (2.5 ppm, 3 h) or filtered air twice a week over 6 weeks. MitoTEMPO (20 mg/kg), an inhibitor of mtROS, and VX765 (100 mg/kg), an inhibitor of caspase-1 activity, were administered by intraperitoneal or intragastric injection respectively 1 h prior to each ozone exposure for 6 weeks.ResultsOzone-exposed mice had increased bronchoalveolar lavage (BAL) total cells and levels of IL-1β, KC and IL-6, augmented lung tissue inflammation scores, enhanced oxidative stress with higher serum 8-OHdG concentrations, emphysema with greater mean linear intercept (Lm), airway remodeling with increased airway smooth muscle mass and airflow limitation as indicated by a reduction in the ratio of forced expiratory volume at 25 and 50 milliseconds to forced vital capacity (FEV25/FVC, FEV50/FVC). Both MitoTEMPO and VX765 reduced lung inflammation scores, cytokine levels, oxidative stress and increased mitochondrial fission proteins. VX765 also attenuated emphysema, airway remodeling and airflow limitation. MitoTEMPO inhibited the increased expression of mitochondrial complex II and IV and of NLPR3 while VX765 inhibited the expression and activity of NLRP3 and caspase-1 pathway in the lung.ConclusionsBoth mtROS and NLRP3 inflammasome play a role in ozone-induced lung inflammation while only NLRP3 is involved in ozone-induced emphysema.

  • Journal article
    Compte M, Lykke Harwood S, Munoz IG, Navarro R, Zonca M, Perez-Chacon G, Erce-Llamazares A, Merino N, Tapia-Galisteo A, Cuesta AM, Mikkelsen K, Caleiras E, Nunez-Prado N, Aznar MA, Lykkemark S, Martinez-Torrecuadrada J, Melero I, Blanco FJ, Bernardino de la Serna J, Zapata JM, Sanz L, Alvarez-Vallina Let al., 2018,

    A tumor-targeted trimeric 4-1BB-agonistic antibody induces potent anti-tumor immunity without systemic toxicity

    , Nature Communications, Vol: 9, ISSN: 2041-1723

    The costimulation of immune cells using first-generation anti-4-1BB monoclonal antibodies (mAbs) has demonstrated anti-tumor activity in human trials. Further clinical development, however, is restricted by significant off-tumor toxicities associated with FcγR interactions. Here, we have designed an Fc-free tumor-targeted 4-1BB-agonistic trimerbody, 1D8N/CEGa1, consisting of three anti-4-1BB single-chain variable fragments and three anti-EGFR single-domain antibodies positioned in an extended hexagonal conformation around the collagen XVIII homotrimerization domain. The1D8N/CEGa1 trimerbody demonstrated high-avidity binding to 4-1BB and EGFR and a potent in vitro costimulatory capacity in the presence of EGFR. The trimerbody rapidly accumulates in EGFR-positive tumors and exhibits anti-tumor activity similar to IgG-based 4-1BB-agonistic mAbs. Importantly, treatment with 1D8N/CEGa1 does not induce systemic inflammatory cytokine production or hepatotoxicity associated with IgG-based 4-1BB agonists. These results implicate FcγR interactions in the 4-1BB-agonist-associated immune abnormalities, and promote the use of the non-canonical antibody presented in this work for safe and effective costimulatory strategies in cancer immunotherapy.

  • Journal article
    Simonds AK, 2018,

    Happy ever after? A new assessment tool for long-term noninvasive ventilation: the S-3-NIV questionnaire

    , EUROPEAN RESPIRATORY JOURNAL, Vol: 52, ISSN: 0903-1936

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