A pharmacokinetic and pharmacodynamic model of an interleukin-12 (IL-12) anchored-drug conjugate for the treatment of solid tumors

Abstract Interleukin-12 (IL-12) mediates innate and adaptive immune responses and has demonstrated therapeutic anti-tumor activity but clinical development has been hindered by a narrow therapeutic window. We generated a novel IL-12 anchored-drug conjugate by physiochemical linking of murine IL-12 to aluminum hydroxide (alum). The complex was designed to utilize alum as a scaffolding for durable retention of IL-12 within the tumor microenvironment as a strategy to increase the therapeutic window. To better define the systemic PK profile of the anchored IL-12 (mANK-101), a model-based assessment tool was developed to describe the systemic PK profile and downstream signaling factors following intratumoral (IT) injection of mANK-101. When compared to non-anchored IL-12, mANK-101 exhibited a distinct PK profile. Specifically, mANK-101 treatment was associated with a significant 9-fold increase in the systemic terminal volume of distribution (Vd). Furthermore, linear mixed-effects models provided evidence that CD8+ T cell infiltration and increased serum interferon gamma (IFNG) levels were correlated with tumor regression after a single dose of mANK-101. In addition, PK/PD modeling confirmed a link between systemic IL-12 and serum IFNG. The model also suggests that anchored IL-12 drug conjugate is expected to prolong the absorption half-life (115 h vs 8 h for the unanchored drug) with durable local retention and limited systemic absorption. In addition, serum IFNG may be a surrogate marker for drug activity. The PK modeling predictions may also contribute to determining the optimal clinical dose and schedule of ANK-101 and other anchored drug conjugates in patients with solid tumors.