Determination of IL-23 Pharmacokinetics by Highly Sensitive Accelerator Mass Spectrometry and Subsequent Modeling to Project IL-23 Suppression in Psoriasis Patients Treated with Anti-IL-23 Antibodies

The pro-inflammatory cytokine interleukin (IL)-23 is a key modulator of the immune response, making it an attractive target for the treatment of autoimmune disease. Correspondingly, several monoclonal antibodies against IL-23 are either in development or approved for autoimmune indications such as psoriasis. Despite being a clinical validated target, IL-23 pharmacokinetics (e.g., IL-23 synthesis and elimination rates) and the degree of target suppression (i.e., decrease in free “active” IL-23) associated with clinical efficacy are not well understood, primarily due to its ultra-low circulating levels and the lack of sensitive and accurate measurement methods. In the current work, this issue was overcome by using accelerator mass spectrometry (AMS) to measure the concentration and pharmacokinetics of human recombinant [14C]-IL-23 following an intravenous trace-dose in cynomolgus monkeys. IL-23 pharmacokinetic parameters along with clinical drug exposure and IL-23 binding affinities from four different anti-IL-23 antibodies (ustekinumab, tildrakizumab, guselkumab, and risankizumab) were used to build a pharmacokinetics/pharmacodynamics (PK/PD) model to assess the time course of free IL-23 over one year in psoriasis patients following different dosing regimens. The predicted rank order of reduction of free IL-23 was consistent with their reported rank order of Psoriasis Area and Severity Index (PASI) 100 scores in clinical efficacy trials (ustekinumab < tildrakizumab < guselkumab < risankizumab), thus demonstrating the utility of highly sensitive AMS for determining target pharmacokinetics to inform PK/PD modeling and assessing target suppression associated with clinical efficacy.