The Impact of Immunogenicity on the Pharmacokinetics, Efficacy, and Safety of Sotatercept in a Phase III Study of Pulmonary Arterial Hypertension.

Sotatercept, a soluble fusion protein comprising the extracellular domain of activin receptor type IIA linked to the Fc portion of human IgG1, is a first-in-class activin signaling inhibitor under development for the treatment of pulmonary arterial hypertension (PAH). We evaluated antidrug antibody (ADA) development and determined the effects of immunogenicity on the pharmacokinetics (PKs), efficacy, and safety of sotatercept in STELLAR, a multicenter, double-blind phase III trial (NCT04576988) wherein participants with PAH were randomized 1:1 to receive sotatercept (starting dose 0.3; target dose 0.7 mg/kg) or placebo subcutaneously every 3 weeks in combination with background therapies for ≤ 72 weeks. ADA-positive (ADA-POS) participants were identified and characterized for neutralizing antibodies (NAbs). PKs, efficacy, and safety were evaluated by ADA and NAb status. Of 162 evaluable participants, 42 (25.9%) were ADA-POS through week 24, of whom 11 (6.8%) were also NAb-POS. Median onset of ADAs was 3.29 weeks (interquartile range (IQR): 3.14-6.14), and median duration was 6 weeks (IQR: 3.14-17.86). No clinically meaningful differences were found across subgroups that were ADA-NEG, ADA-POS/NAb-NEG, and ADA-POS/NAb-POS, in terms of PKs (sotatercept trough concentration over time, mean postdose trough concentration at the end of treatment, and clearance), efficacy (changes from baseline in 6-minute walk distance, pulmonary vascular resistance, and N-terminal pro-B-type natriuretic peptide levels), and safety (incidence of hypersensitivity, anaphylactic reactions, and administration site reactions). We conclude that ADA incidence from sotatercept treatment was 25.9% and did not meaningfully affect the PKs, efficacy, or safety of sotatercept in participants with PAH.

Soil bacterial communities associated with multi-nutrient cycling under long-term warming in the alpine meadow.

Introduction: The functions of terrestrial ecosystems are mainly maintained by bacteria, as a key component of microorganisms, which actively participate in the nutrient cycling of ecosystems. Currently, there are few studies have been carried out on the bacteria contributing to the soil multi-nutrient cycling in responding to climate warming, which hampers our obtainment of a comprehensive understanding of the ecological function of ecosystems as a whole. Methods: In this study, the main bacteria taxa contributing to the soil multi-nutrient cycling under the long-term warming in an alpine meadow was determined based onphysichemical properties measurement and high-throughput sequencing, and the potential reasons that warming altered the main bacteria contributing to the soil multi-nutrient cycling were further analyzed. Results: The results confirmed that the bacterial ß-diversity was crucial to the soil multi-nutrient cycling. Furthermore, Gemmatimonadetes, Actinobacteria, and Proteobacteria were the main contributors to the soil multi-nutrient cycling, and played pivotal roles as keystone nodes and biomarkers throughout the entire soil profile. This suggested that warming altered and shifted the main bacteria contributing to the soil multi-nutrient cycling toward keystone taxa. Discussion: Meanwhile, their relative abundance was higher, which could make them have the advantage of seizing resources in the face of environmental pressures. In summary, the results demonstrated the crucial role of keystone bacteria in the multi-nutrient cycling under the climate warming in the alpine meadow. This has important implications for understanding and exploring the multi-nutrient cycling of alpine ecosystems under the global climate warming.