A Double‐Blind, Phase I, Single Ascending Dose Study to Assess the Safety, Pharmacokinetics, and Pharmacodynamics of BOS161721 in Healthy Subjects

Abstract

The purpose of this study was to assess the safety, tolerability, pharmacokinetics, pharmacodynamics, and immunogenicity of BOS161721, a humanized immunoglobulin G1 triple mutation (M252Y/S254T/T256E) monoclonal antibody that inhibits interleukin‐21 (IL‐21) bioactivity. This randomized, single‐center, double‐blind, placebo‐controlled study randomized healthy volunteers 3:1 to single ascending intravenous and subcutaneous doses of BOS161721 (range 1–240 mg) or placebo. BOS161721 and placebo groups had similar rates of adverse events, mostly mild; none led to study discontinuation. There were no clinically significant findings in physical examination, vital signs, or laboratory assessment. In the pooled BOS161721 population, four subjects (8.5%) tested antidrug antibody‐positive predose, and seven (14.9%) postdose. Absolute CD4+ lymphocyte count remained normal throughout follow‐up. BOS161721 administered subcutaneously was absorbed slowly, with a median time to maximum concentration (Tmax) of 144 hours across doses (range 1–15 days) and a mean apparent terminal elimination half‐life of 80–87 days for doses ≥ 30 mg. Area under the concentration‐time curve from time zero to infinity (AUC0‐inf) and maximum observed concentration (Cmax) were linear across doses > 10 mg. Subcutaneous bioavailability was 64%. Phosphorylated signal transducer and activator of transcription 3 (pSTAT3) decreased dose‐dependently with threshold characteristics at doses of ≥ 10 mg. Downregulation in BATF, IL6, LAG3, and SOCS3 genes caused by IL‐21 stimulation was reversed dose‐dependently. BOS161721 was well‐tolerated across doses, suppressed IL‐21‐induced pSTAT3 dose‐dependently, and reversed downregulation of genes critical to tolerance induction and T‐cell exhaustion induced by IL‐21. Further clinical studies are ongoing in patients with systemic lupus erythematosus, in which IL‐21 has a pathogenetic role.

Translational Approach for Predicting Human Pharmacokinetics of Engineered Therapeutic Monoclonal Antibodies with Increased FcRn-Binding Mutations

“…Motavizumab-YTE showed a half-life of around 80 days whereas motavizumab without YTE mutations showed a half-life of only 20–30 days in humans. Based on this impressive report, several engineered mAbs with mutations to increase FcRn binding were evaluated in clinical studies [ 17 – 19 ]. In particular, these mutations have been frequently applied to therapeutic anti-virus antibodies [ 20 – 22 ].…”

Translatability of findings from cynomolgus monkey to human suggests a mechanistic role for IL-21 in promoting immunogenicity to an anti-PD-1/IL-21 mutein fusion protein

“…To determine what types of adverse events could potentially manifest as a result of an anti-IL-21 neutralizing antibody, a comprehensive literature search of compounds blocking IL-21 signaling was carried out. Several anti-IL-21 antibodies (12,13) and an anti-IL-21R antibody (14) were identified and available clinical data were assessed. Overall, a decrease or loss of IL-21 signaling was well-tolerated, but theory and some studies suggested that loss of IL-21 signaling could cause immunosuppression relative to placebo.…”

Tissue‐resident memory T cells and lung immunopathology

“…Furthermore, the blockade of IL‐21 function ameliorated CD8 + T cell‐mediated lung fibrosis after bleomycin administration in mice 217 . A human monoclonal antibody, avizakimab, that can inhibit IL‐21 bioactivity, is currently in phase 2 clinical trials for systemic lupus erythematosus (SLE) 218 (NCT03371251). It would be worth exploring the utility of IL‐21 mAb to prevent chronic lung pathology including lung fibrosis following viral infection.…”