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Inhalation exposure to multi-walled carbon nanotubes (MWCNT) in mice results in inflammation, fibrosis and the promotion of lung adenocarcinoma; however, the molecular basis behind these pathologies is unknown. This study determined global mRNA and miRNA profiles in whole blood from mice exposed by inhalation to MWCNT that correlated with the presence of lung hyperplasia, fibrosis, and bronchiolo-alveolar adenoma and adenocarcinoma. Six-week-old, male, B6C3F1 mice received a single intraperitoneal injection of either the DNA-damaging agent methylcholanthrene (MCA, 10 µg g-1 body weight) or vehicle (corn oil). One week after injections, mice were exposed by inhalation to MWCNT (5mgm-3, 5 hours per day, 5 days per week) or filtered air (control) for a total of 15days. At 17months post-exposure, mice were euthanized and examined for the development of pathological changes in the lung, and whole blood was collected and analyzed using microarray analysis for global mRNA and miRNA expression. Numerous mRNAs and miRNAs in the blood were significantly up- or down-regulated in animals developing pathological changes in the lung after MCA/corn oil administration followed by MWCNT/air inhalation, including fcrl5 and miR-122-5p in the presence of hyperplasia, mthfd2 and miR-206-3p in the presence of fibrosis, fam178a and miR-130a-3p in the presence of bronchiolo-alveolar adenoma, and il7r and miR-210-3p in the presence of bronchiolo-alveolar adenocarcinoma, among others. The changes in miRNA and mRNA expression, and their respective regulatory networks, identified in this study may potentially serve as blood biomarkers for MWCNT-induced lung pathological changes. [ABSTRACT FROM AUTHOR]

Toll‐like receptor (TLR)7 is a pattern recognition receptor that critically contributes to the pathogenesis of systemic lupus erythematosus (SLE). DS‐7011a is an anti‐TLR7 monoclonal antibody that prevents TLR7 from signaling. The aim of this first‐in‐human, double‐blind, randomized, and placebo‐controlled study was to evaluate the safety, pharmacokinetics, immunogenicity, and pharmacodynamics of single ascending intravenous (IV) and subcutaneous (SC) doses of DS‐7011a in healthy subjects (HS) (NCT05203692). On day 1, 80 HS received DS‐7011a or placebo 6:2 in 10 cohorts (7 treated IV and 3 SC) of 8 each and were followed for 8 weeks until day 57. Safety was evaluated by recording treatment‐emergent adverse events (TEAEs), pharmacokinetics by measuring plasma DS‐7011a, immunogenicity by measuring plasma anti‐drug antibodies (ADAs), and pharmacodynamics by evaluating the suppression of interleukin‐6 production ex vivo in whole blood. DS‐7011a was safe and well tolerated across all cohorts. TEAEs were mostly mild in severity and not drug‐related. DS‐7011a exposure increased with the dose but was not dose proportional, as the elimination of lower doses was accelerated by target‐mediated drug disposition. Terminal half‐life was about 15‐17 days and Tmax upon SC administration was about 5 days. DS‐7011a induced ADAs in about half of HS but with no impact on clinical findings and pharmacokinetics. Pharmacodynamic (PD) response also increased with the dose and at the higher doses was of large extent (>90%), early onset, and lasting duration. DS‐7011a showed favorable safety, pharmacokinetics, immunogenicity, and PD properties that support its development for the treatment of SLE. [ABSTRACT FROM AUTHOR]