CSL (Australia)

IntroductionSarcoidosis is a multisystem chronic inflammatory disorder of unknown etiology that primarily affects the lungs and currently has no cure. Macrophages are central to granuloma formation, and βc cytokines tightly regulate their activation and function. This study investigates the role of the βc receptor in granuloma development and evaluates βc antagonism as a potential therapeutic strategy for sarcoidosis.MethodsWe utilized an in vitro model of human granuloma formation using sarcoidosis patient human peripheral blood mononuclear cells (PBMCs) and an in vivo vimentin-induced pulmonary sarcoidosis model in unique humanized βc transgenic (hβcTg) mice to assess the efficacy of βc antagonism in reducing granuloma formation and evaluate the underlying mechanism of action.ResultsAnti-βc receptor antibody, CSL311, significantly reduced the formation of human granulomas from PBMCs exposed to purified protein derivative and decreased the pro-inflammatory cytokine production by the granulomas. Mechanistically, CSL311 inhibited hyperactivation of mTOR signaling and reduced lipid droplet formation in granuloma macrophages. In hβcTg mice challenged with vimentin, CSL311 effectively reduced both granuloma size and immune cell infiltration in the lung. RNA sequencing analysis of lung tissue further showed that CSL311 treatment suppressed the activation of vimentin-induced inflammatory, fibrotic, and lipid metabolic pathways.ConclusionWe identified that βc cytokines are critical regulators in driving inflammatory and metabolic processes that lead to granuloma formation in sarcoidosis. Precisely targeting the βc receptor effectively disrupts these pathogenic networks and offers a promising new strategy for mitigating sarcoidosis immunopathology.

The extent of alien taxa impacts on river ecosystem health is unclear, but their frequency continues to rise. We investigated 1) the prevalence of including alien taxa in common bioindicators used in river bioassessment, 2) the effect of alien taxa on the richness and abundance of natives, and 3) whether including alien taxa in bioassessment tools increased their sensitivity to river degradation. In the 17 countries analyzed fish represented the greatest number of alien species (1726), followed by macrophytes (925), macroinvertebrates (556), and diatoms (7). Yet, alien species are only distinguished from natives in some fish and macrophyte indices. In addition, the analyses of 8 databases with fish, macroinvertebrate, or macrophyte data showed that abundance of alien taxa was associated with different stressors and pressures resulting in river degradation, and had a significant effect on native community composition. When alien species were accounted for, there was a strong negative correlation between the values of a fish index with alien richness and abundance while when alien taxa was not or only partially considered the results varied. Thus, we recommend: 1) Include specific metrics for alien species in biological quality indices. 2) Increase the investigation of alien taxa of small organisms (e.g. diatoms, small benthic invertebrates). 3) Eliminate sites with confirmed biological invasions for use as reference sites. 4) Remove alien from calculations of total richness and diversity. 5) Identify to the species level in biomonitoring programs. 6) Avoid legislation and management that protect alien species. 7) Encourage behaviors that prevent alien invasions of aquatic biota.

Asthma-COPD overlap (ACO) is characterized by patients exhibiting features of both asthma and COPD. Currently, there is no specific treatment for ACO. This study aimed to investigate the therapeutic potential of targeting CD131, a shared receptor subunit for IL-3, IL-5 and GM-CSF, in ACO development and in preventing acute viral exacerbations. A two-hit mouse model of ACO was established by house dust mite (HDM) allergen sensitization to model asthma, and elastase treatment to model emphysema. In a separate model, human rhinovirus 1b (RV1b) was used to induce an acute asthma exacerbation. A neutralizing antibody against CD131 was used to block CD131 in vivo signalling. Mice exposed to HDM and elastase developed cardinal features for asthma and COPD, including airway hyperreactivity (AHR) and emphysema. A mixed granulocytic inflammatory profile was identified in the lungs, including expansion of monocyte-derived macrophages, neutrophils and eosinophils. RT-qPCR analysis detected heightened gene expression of Mmp12, Il5 and Il13. Transcriptomic analysis further revealed pathway enrichment for type 2 inflammation and macrophage activation. Blockade of CD131 effectively reduced the lung inflammation and prevented the development of AHR, airway fibrosis and emphysema. Interestingly, pathway enrichment for Th1 response and interferon production detected in the model was not affected by the treatment. Consistently, CD131 antagonism prevented RV1b-induced asthma exacerbation without compromising RV1b clearance. CD131 signalling coordinates multiple pathological pathways that drive airway inflammation and lung remodelling in ACO. Hence, CD131 antagonism represents a novel approach to combating the immunopathology in the complex ACO setting.

Garadacimab, an activated factor XII (FXIIa) inhibitor monoclonal antibody, is being evaluated for the long‐term prophylaxis of hereditary angioedema. Here, we report the results from a two‐part, phase 1, open‐label, single ascending dose study assessing the pharmacokinetics (PK), pharmacodynamics, safety, and tolerability after subcutaneous (SC) and intravenous (IV) administration of garadacimab in healthy Japanese and White participants. Part 1 assessed garadacimab PK after SC administration of a 200 mg dose in weight‐matched White and Japanese participants, and 600 mg dose in Japanese participants. Part 2 assessed 3 and 10 mg/kg IV doses in Japanese participants. Follow‐up for safety was over 84 days post‐dose. Overall, 37 participants received garadacimab dosing and 36 completed the study, with one participant lost to follow‐up. Following SC administration, time to maximum plasma concentration (tmax) occurred at 7 days post‐dose, and garadacimab exposure, based on maximum plasma concentration (Cmax) and area under the plasma concentration–time curve (AUC), increased less than 3‐fold when tripling the dose. PK was comparable between Japanese and White participants, with geometric mean ratios for Cmax and AUC close to 100%. Following IV administration, tmax occurred at the end of infusion, and garadacimab exposure increased in a dose‐proportional manner. Inhibition of FXIIa‐mediated kallikrein activity versus baseline was observed in all participants receiving the SC and IV doses. No anti‐drug antibodies against garadacimab were reported. Consistent with pivotal phase 3 (VANGUARD) outcomes, no safety concerns and no difference in the safety profile of garadacimab were observed between healthy Japanese and White participants.

Increased vascular endothelial growth factor B (VEGF-B) expression in patients with diabetic kidney disease (DKD) is associated with increased lipid deposition in glomerular podocytes. Reducing VEGF-B activity in animal models of DKD using an anti-VEGF-B antibody improved histological evidence of glomerular injury and reduced albuminuria; effects attributed to prevention of ectopic lipid deposition in the kidney. CSL346 is a novel humanized monoclonal antibody that binds VEGF-B with high affinity. Targeting VEGF-B in patients with type 2 diabetes mellitus may improve DKD progression markers. An international, randomized, double-blind, placebo-controlled, phase 2a study (NCT04419467) assessed CSL346 (8 mg/kg or 16 mg/kg subcutaneously every 4 weeks for 12 weeks) in participants with type 2 diabetes mellitus and a urinary albumin-to-creatinine ratio (UACR) ≥150 mg/g (17.0 mg/mmol), and eGFR >20 mL/min/1.73m2. Efficacy, safety/tolerability, pharmacokinetics, and pharmacodynamics of CSL346 were evaluated. The primary analysis compared the change from baseline in log-transformed UACR between the two CSL346 dose groups combined versus placebo at Week 16. In total, 114 participants were randomized. CSL346 did not significantly reduce UACR compared with placebo at Week 16 (combined CSL346 group difference from placebo 95% confidence interval]: 4.0% [-14.7, 26.8]). Furthermore, no effect was seen in participant subgroups (degree of kidney impairment or sodium-glucose cotransporter 2 [SGLT2] inhibitor use) or on urinary biomarkers reflecting proximal tubular injury. CSL346 was generally well tolerated; however, diastolic blood pressure was significantly higher with CSL346 16 mg/kg versus placebo from Week 2 onwards, with differences ranging from +3.8 to +5.3 mmHg (P = 0.002 at Week 16). CSL346 did not reduce UACR compared with placebo at 16 weeks in participants with type 2 diabetes mellitus and DKD, and was associated with an increase in diastolic blood pressure.

The intricate dynamics of local liquid-gas interactions in agitated bioreactors poses a difficulty in understanding the mechanistic relationships among critical operational design parameters and cellular growth, especially for large-scale pharmaceutical production. Traditional computer models have advanced the understanding of such complex interactions. Their implementation is, however, associated with considerable computational costs, power and wall-clock time, to effectively simulate dynamic multiphase phenomena existing within bioreactors. This study explores a novel modeling approach that leverages high-resolution Large Eddy Simulation (LES) and the Lattice Boltzmann Method (LBM) to simulate turbulent flows within an industrial bioreactor. This approach allows the practical simulation of millions of bubbles modeled individually in a computationally accelerated manner. The model performance was evaluated with the experimental data obtained at various working volumes, aeration and agitation conditions. A further comparison with a conventional Reynolds-averaged Navier–Stokes method also provided comparable results. Furthermore, to complement the root-cause analysis conducted experimentally, a detailed model was developed to comprehend the underlying mechanisms for cell death, incorporating changes in individual bubble sizes due to various mass exchanges, fluid-gas forces and hydrodynamic pressure. Additionally, the model provided in-depth insights into other technical considerations for a proposed change in the sparger design at elevated gassing flow rates, including oxygen transfer rate, bubble breakup rate and impeller flooding transitions.

In the version of the article initially published, in the "Toxicity analysis" section, "Nine patients (25%) discontinued all therapy as a result of AEs" has been corrected to "Five patients (13.8%)…". In the fifth paragraph of the Discussion, "9 patients (25%) discontinued therapy as a result of AEs" has been removed and "25%" has been changed to "13.8%" in the text "Of note is a higher rate of AE-related treatment discontinuation of 13.8%". These changes have been made to the HTML and PDF versions of the article.

To characterize the effects of CSL112 (human APOA1 [apolipoprotein A1]) on the APOA1 exchange rate (AER) and the relationships with specific HDL (high-density lipoprotein) subpopulations when administered in the 90-day high-risk period post-acute myocardial infarction. A subset of patients (n=50) from the AEGIS-I (ApoA-I Event Reducing in Ischemic Syndromes I) study received either placebo or CSL112 post-acute myocardial infarction. AER was measured in AEGIS-I plasma samples incubated with lipid-sensitive fluorescent APOA1 reporter. HDL particle size distribution was assessed by native gel electrophoresis followed by fluorescent imaging and detection of APOA1 and SAA (serum amyloid A) by immunoblotting. CSL112 infusion increased AER peaking at 2 hours and returning to baseline 24 hours post-infusion. AER correlated with cholesterol efflux capacity (r=0.49), HDL-cholesterol (r=0.30), APOA1 (r=0.48), and phospholipids (r=0.48; all P<0.001) over all time points. Mechanistically, changes in cholesterol efflux capacity and AER induced by CSL112 reflected HDL particle remodeling resulting in increased small HDL species that are highly active in mediating ABCA1 (ATP-binding cassette transporter 1)-dependent efflux, and large HDL species with high capacity for APOA1 exchange. The lipid-sensitive APOA1 reporter predominantly exchanged into SAA-poor HDL particles and weakly incorporated into SAA-enriched HDL species. Infusion of CSL112 enhances metrics of HDL functionality in patients with acute myocardial infarction. This study demonstrates that in post-acute myocardial infarction patients, HDL-APOA1 exchange involves specific SAA-poor HDL populations. Our data suggest that progressive enrichment of HDL with SAA may generate dysfunctional particles with impaired HDL-APOA1 exchange capacity, and that infusion of CSL112 improves the functional status of HDL with respect to HDL-APOA1 exchange. URL: https://www. gov; Unique identifier: NCT02108262.