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Aims: This study describes the pharmacokinetic (PK)/target engagement (TE) relationship of tozorakimab, an anti‐interleukin (IL)‐33 antibody, by building a mechanistic population PK/TE model using phase 1 biomarker data. Methods: The analysis included tozorakimab PK and TE in serum assessed in 60 tozorakimab‐treated participants, including healthy adults and patients with mild chronic obstructive pulmonary disease. Scenarios evaluated three dose frequencies (once every 2, 4 or 6 weeks) administered subcutaneously at seven doses of tozorakimab (30, 60, 90, 120, 150, 300 or 600 mg). For each dose, simulations were performed with 5000 virtual individuals to predict systemic TE. Inhibition of IL‐33/soluble ST2 (sST2) complex levels at trough PK at steady state was assessed in each dosing scenario. The PK/TE modelling analyses were performed using a nonlinear mixed‐effect modelling approach. Results: The final two‐compartment PK model with tozorakimab binding IL‐33 in the central compartment adequately described the systemic PK and TE of tozorakimab at population and individual levels. The mean PK parameter estimates of absorption rate, central volume of distribution and clearance were 0.48 (90% confidence interval [CI]: 0.40–0.59, 1/day), 12.64 (90% CI: 8.60–18.62, L) and 0.87 (90% CI: 0.65–1.16, L/day), respectively. Consistent with the observed value, tozorakimab bioavailability was 45%. For all three dose frequencies, predicted inhibition of systemic IL‐33/sST2 levels was more than 95% at doses greater than 90 mg. Conclusions: The PK/TE model reliably quantified the relationship between PK and systemic TE of tozorakimab, with potential utility for predicting clinical dose–response relationships and supporting clinical dose selection. [ABSTRACT FROM AUTHOR]

Tozorakimab is a human monoclonal antibody that neutralizes interleukin (IL)‐33. IL‐33 is a broad‐acting epithelial "alarmin" cytokine upregulated in lung tissue of patients with chronic obstructive pulmonary disease (COPD). This first‐in‐human, phase I, randomized, double‐blind, placebo‐controlled study (NCT03096795) evaluated the safety, tolerability, pharmacokinetics (PKs), immunogenicity, target engagement, and pharmacodynamics (PDs) of tozorakimab. This was a 3‐part study. In part 1, 56 healthy participants with a history of mild atopy received single escalating doses of either intravenous or subcutaneous tozorakimab or placebo. In part 2, 24 patients with mild COPD received multiple ascending doses of subcutaneous tozorakimab or placebo. In part 3, 8 healthy Japanese participants received a single intravenous dose of tozorakimab or placebo. The safety data collected included treatment‐emergent adverse events (TEAEs), vital signs, and clinical laboratory parameters. Biological samples for PKs, immunogenicity, target engagement, and PD biomarker analyses were collected. No meaningful differences in the frequencies of TEAEs were observed between the tozorakimab and placebo arms. Three tozorakimab‐treated participants with COPD experienced treatment‐emergent serious adverse events. Subcutaneous or intravenous tozorakimab demonstrated linear, time‐independent PKs with a mean half‐life of 11.7–17.3 days. Treatment‐emergent anti‐drug antibody frequency was low. Engagement of tozorakimab with endogenous IL‐33 in serum and nasal airways was demonstrated. Tozorakimab significantly reduced serum IL‐5 and IL‐13 levels in patients with COPD compared with placebo. Overall, tozorakimab was well tolerated, with a linear, time‐independent serum PK profile. Additionally, biomarker studies demonstrated proof of mechanism. Overall, these data support the further clinical development of tozorakimab in COPD and other inflammatory diseases. [ABSTRACT FROM AUTHOR]

IL-33 is a tissue-derived cytokine that induces and amplifies eosinophilic inflammation and has emerged as a promising new drug target for asthma and allergic disease. Common variants at IL33 and IL1RL1, encoding the IL-33 receptor ST2, associate with eosinophil counts and asthma. Through whole-genome sequencing and imputation into the Icelandic population, we found a rare variant in IL33 (NM_001199640:exon7:c.487-1G>C (rs146597587-C), allele frequency = 0.65%) that disrupts a canonical splice acceptor site before the last coding exon. It is also found at low frequency in European populations. rs146597587-C associates with lower eosinophil counts (β = -0.21 SD, P = 2.5×10–16, N = 103,104), and reduced risk of asthma in Europeans (OR = 0.47; 95%CI: 0.32, 0.70, P = 1.8×10–4, N cases = 6,465, N controls = 302,977). Heterozygotes have about 40% lower total IL33 mRNA expression than non-carriers and allele-specific analysis based on RNA sequencing and phased genotypes shows that only 20% of the total expression is from the mutated chromosome. In half of those transcripts the mutation causes retention of the last intron, predicted to result in a premature stop codon that leads to truncation of 66 amino acids. The truncated IL-33 has normal intracellular localization but neither binds IL-33R/ST2 nor activates ST2-expressing cells. Together these data demonstrate that rs146597587-C is a loss of function mutation and support the hypothesis that IL-33 haploinsufficiency protects against asthma. [ABSTRACT FROM AUTHOR]

Understanding the underlying mechanisms that cause and exacerbate allergic asthmatic disease is of great clinical interest. Clinical studies have revealed that allergies and viral respiratory illnesses are strongly linked to the inception and exacerbation of asthma, and suggest the possibility that there are interactive inflammatory mechanisms. Recent work has revealed a number of mechanisms of virus and allergen cross-talk that may play a role in the pathophysiology of allergic asthma, including (1) deficiency in virus-induced interferon responses, (2) defective epithelial barrier function, (3) increased release of epithelium-derived cytokines (e.g., thymic stromal lymphopoietin (TSLP), interleukin (IL)-25, IL-33), (4) dysregulation of lymphocytes [e.g., innate lymphoid cells (ILCs), regulatory T cells (Tregs)], and (5) altered activation of purinergic receptors. One or more of these processes may provide targets for new therapeutics to treat allergic asthma and prevent disease exacerbation. [ABSTRACT FROM AUTHOR]

Extracellular nucleotides can act as important intercellular signals in diverse biological processes, including the enhanced production of factors that are key to immune response regulation. One receptor that binds extracellular adenosine triphosphate released at sites of infection and injury is P2X7, which is an ionotrophic receptor that can also lead to the formation of a non-specific pore, activate multiple mitogen-activated protein kinases (MAPKs), and stimulate the production of immune mediators including interleukin family members and reactive oxygen species (ROS). In the present report, we have investigated the signaling mechanisms by which P2X7 promotes monocytic cell mediator production and induces transcription factor expression/phosphorylation, as well as how receptor-associated pore activity is regulated by intracellular trafficking. We report that P2X7 stimulates ROS production in macrophages through the MAPKs ERK1/2 and the nicotinamide adenine dinucleotide phosphate oxidase complex, activates several transcription factors including cyclic-AMP response element-binding protein and components of the activating protein-1 complex, and contains specific sequences within its intracellular C-terminus that appear critical for its activity. Altogether, these data further implicate P2X7 activation and signaling as a fundamental modulator of macrophage immune responses. [ABSTRACT FROM AUTHOR]