BioPharm (United Kingdom)

Fibrotic tissues are characterized by excessive crosslinking between extracellular matrix (ECM) proteins, rendering them more resistant to degradation. Although increased crosslinking of ECM is thought to play an important role for progression of tissue fibrosis, enhanced ECM crosslinking has not yet been targeted therapeutically in systemic sclerosis (SSc). Here, we investigated the role of transglutaminase 2 (TG2), a central crosslinking enzyme, in the activation of SSc fibroblasts. We assessed TG2 expression and activity using TG2 staining, Western blotting, and TG2 activity assays. We inhibited TG2 in fibroblasts cultured under standard 2-dimensional conditions and in a 3-dimensional full-thickness equivalent skin model using monoclonal inhibitory anti-TG2 antibodies. TG2 expression was increased in the skin of patients with SSc compared with healthy controls, with levels particularly high in patients with SSc-associated interstitial lung disease. TG2 expression and TG2 activity were also increased in SSc dermal fibroblasts. Moreover, the levels of circulating TG2 in the plasma samples from SSc patients were increased versus samples from healthy controls. Anti-TG2 antibodies did not show consistent antifibrotic effects across different fibroblast cell lines under 2-dimensional culture conditions; however, anti-TG2 antibodies effectively reduced transforming growth factor β-induced dermal thickening, myofibroblast differentiation, and collagen accumulation in the 3-dimensional full-thickness model of human skin. We provide the first evidence, to our knowledge, that inhibition of TG2 might be a potential antifibrotic approach in SSc. Our findings have translational potential as anti-TG2 antibodies are currently evaluated in a phase II clinical trial in chronic allograft injury and would thus be available for clinical studies in SSc (ClinicalTrials.gov identifier: NCT04335578).

<div>AbstractPurpose:<p>We assessed the relationship between cluster of differentiation-22 (CD22) expression and outcomes of inotuzumab ozogamicin versus standard of care (SC) in INO-VATE (NCT01564784).</p>Patients and Methods:<p>Adults with relapsed/refractory B-cell precursor CD22-positive (by local or central laboratory) acute lymphoblastic leukemia were randomized to inotuzumab ozogamicin (<i>n</i> = 164) or SC (<i>n</i> = 162). Outcomes were analyzed by baseline CD22 positivity (percentage of leukemic blasts CD22 positive, ≥90% vs. <90%) and CD22 receptor density [molecules of equivalent soluble fluorochrome (MESF), quartile analysis].</p>Results:<p>Most patients had high (≥90%) CD22 positivity per central laboratory. The response rate was significantly higher with inotuzumab ozogamicin versus SC. Minimal/measurable residual disease negativity, duration of remission (DoR), progression-free survival, and overall survival (OS) were significantly better with inotuzumab ozogamicin versus SC in patients with CD22 positivity ≥90%. Fewer patients had CD22 positivity <90%; for whom, response rates were higher with inotuzumab ozogamicin versus SC, but DoR and OS appeared similar. Similar trends were evident in quartile analyses of CD22 MESF and CD22 positivity per local laboratory. Among inotuzumab ozogamicin–responding patients with subsequent relapse, decrease in CD22 positivity and receptor density was evident, but not the emergence of CD22 negativity. Rates of grade ≥3 hematologic adverse events (AEs) were similar and hepatobiliary AEs rate was higher for inotuzumab ozogamicin versus SC. No apparent relationship was observed between the rates of hematologic and hepatic AEs and CD22 expression.</p>Conclusions:<p>Inotuzumab ozogamicin demonstrated a favorable benefit–risk profile versus SC in patients with higher and lower CD22 expression. Patients with high CD22 expression and normal cytogenetics benefited the most from inotuzumab ozogamicin therapy.</p></div>

Abstract BACKGROUND AND AIMS Chronic kidney disease (CKD) is likely to significantly affect the lives of patients and their carers, including increasing the economic burden. The relationship between CKD progression and these life impacts remains poorly characterized. The patient, carer and economic burden (PaCE) CKD study aims to enhance understanding of patient and carer experiences of CKD, including financial impact. METHOD In-depth, semi-structured, qualitative interviews were conducted with 20 patients with CKD and 19 informal carers in Australia, France, Germany, Italy, the UK and the USA. Participants were asked about their experiences with CKD and the associated economic burden. A quantitative online survey is ongoing, with 150–200 patients and 75–100 carers anticipated to participate per country. A Work Productivity and Activity Impairment (WPAI) questionnaire for patients and caregivers is being used to understand and estimate the financial burden of CKD on patients and caregivers. Patients are also being asked about their disease background, including the stage of CKD and treatment history. RESULTS In total, 20 patients and 19 carers participated in the qualitative interviews, with at least 3 patients and 3 carers included from each country. Eleven patients were male. Most patients were 75 years old or younger (18/20; overall range 30–81 years, overall mean 61.7 years). Patients reported their CKD stages: 3/20 stage 5; 2/20 stage 4–5; 2/20 stage 4; 2/20 stage 3–4; 8/20 stage 3; 1/20 stage 2; and 2/20 unknown. A third of patients underwent dialysis (7/20), including at least one patient from each country. Nine patients were working full- or part-time. Carers were 30–90 years old (mean 55.1 years), predominantly women (13/19) and were primarily relatives of the patient (8/19 partner, 5/19 daughter/son, 2/19 daughter-/son-in-law). More than half of the carers were employed (13/19 employed, 5/19 unemployed/retired, 1/19 unknown). Carer support varied between 4 and 35 h/week. Support included activities of daily living, visits to the hospital and emotional/psychological support; support was noted as more critical for patients with later-stage CKD. The degree of financial burden experienced by patients and carers varied between countries, potentially reflecting differences in local healthcare systems; however, the impact of reduced work hours on finances was consistent across all countries. Both patients and carers reported a loss of work hours, and in some cases, participants reported that they had to stop working. Patients who were employed reported lower productivity, and carers reported taking days off work without pay. Expenses related to the cost of managing CKD, including dietary needs, medical aids and hospital transport, further increased the economic burden. The extent of these impacts varied depending on the severity of CKD. Results from the quantitative survey will be presented at the congress. CONCLUSION Responses from qualitative interviews suggest that CKD increases the financial burden for both patients and carers, particularly as the disease progresses. When combined with data from the quantitative survey, these findings will provide important insights into the economic burden of CKD for patients and carers.

Abstract Background and Aims Anaemia is a common complication in patients with chronic kidney disease (CKD) and is associated with increased mortality, cardiovascular complications, reduced quality of life and increased use of healthcare resources. Mathematical modelling based on robust epidemiological and clinical data is a useful approach for predicting the future burden of disease and the impact of different intervention scenarios; this is important for health service planning. This analysis uses a microsimulation model, Inside ANEMIA of CKD, to predict the effects of a hypothetical intervention scenario that reduces the prevalence of anaemia of CKD on related healthcare costs in the USA from 2020 to 2025. Method A virtual cohort representing the US population was created within the Inside ANEMIA of CKD microsimulation model framework using demographics and epidemiological data drawn from the US Census Bureau, the Centers for Disease Control and Prevention, and the National Health and Nutrition Examination Survey. In the cohort, virtual individuals were ascribed an age–sex-stratified CKD status (defined by estimated glomerular filtration rate and albuminuria levels, as per international guidelines) and anaemia status (defined by haemoglobin level as mild, moderate or severe, as per WHO criteria) based on US prevalence data. Key comorbidities (type 2 diabetes, heart failure and hypertension) were also assigned, reflecting US-specific population statistics. Healthcare costs related to CKD and anaemia of CKD were taken from the published literature. The study modelled the effects on healthcare costs of a hypothetical intervention scenario in which the prevalence of moderate and severe anaemia is reduced by 20% per year from 2020 to 2025 compared with no intervention (baseline). In each scenario (i.e. intervention or baseline), the modelling analysis estimated healthcare costs related to CKD and anaemia (including inpatient, outpatient, pharmacy costs) for patients with moderate or severe anaemia of CKD. The model did not adjust for the potential costs of the intervention. Results Preliminary results predict that, with the hypothetical intervention, there could be 1.40 million fewer patients with moderate or severe anaemia of CKD in the USA in 2025 compared with no intervention (1.45 million versus 2.85 million). This represents a 49% reduction in cases of moderate or severe anaemia of CKD in 2025 with the intervention versus no intervention. The intervention is projected to lead to a reduction of approximately US$18 billion in annual direct healthcare costs in 2025 for patients with moderate or severe anaemia of CKD compared with no intervention (US$26 billion versus US$44 billion). Conclusion The Inside ANEMIA of CKD microsimulation model predicts that a hypothetical intervention which reduces the prevalence of moderate and severe anaemia of CKD would reduce direct healthcare costs. This suggests that interventions effective at reducing the prevalence of anaemia of CKD would help to reduce the economic burden on healthcare services.

The delivery of biotherapeutic molecules (antibodies, proteins, peptides) and nucleic acids via the respiratory route has presented challenges for regulatory approval, due in part to a lack of understanding of the expected pathology, mechanisms of toxicity, and immunogenicity induced by the inhalation route. Although the first inhaled biotherapeutic was approved some time ago (Dornase Alfa, Pulmozyme; Genetech, 1993), no other inhaled biotherapeutics have been marketed for the treatment of human disease other than the inhaled insulins (Exubera; Pfizer, 2006 and Afrezza; Mannkind Corporation, 2014). As a result, scientific knowledge within the toxicologic pathology community is fragmented with precious little publicly available data. Therefore, one of the aims of this special edition was to generate a collection of manuscripts that pathologists and toxicologists could refer in order to understand the pathology, mechanisms of toxicity, immunogenicity, and challenges associated with the development of inhaled biotherapeutics.

Abstract Developmental defects affecting the heart and aortic arch arteries are a key phenotype observed in DiGeorge syndrome patients and are caused by a microdeletion on chromosome 22q11. Heterozygosity ofTBX1, one of the deleted genes, is expressed throughout the pharyngeal arches and is considered a key component for the arch artery defects.Pax9is expressed in the pharyngeal endoderm and is downregulated inTbx1mutant mice. We show here thatPax9deficient mice are born with complex cardiovascular malformations affecting the outflow tract and aortic arch arteries with failure of the 3rdand 4thpharyngeal arch arteries to form correctly. Transcriptome analysis indicated thatPax9andTbx1may function together, and mice double heterozygous forTbx1/Pax9presented with a significantly increased incidence of interrupted aortic arch when compared toTbx1heterozygous mice. Using a novelPax9Creallele we demonstrated that the site of thisTbx1-Pax9genetic interaction is in the pharyngeal endoderm, therefore revealing that aTbx1/Pax9-controlled signalling mechanism emanating from the pharyngeal endoderm is required for critical tissue interactions during normal morphogenesis of the pharyngeal arch artery system.Summary statementPax9is required for outflow tract and aortic arch development, and functions together withTbx1in the pharyngeal endoderm for 4tharch artery formation.