A Pharmacokinetic and Pharmacodynamic Model of an IL-12 Anchored-Drug Conjugate for the Treatment of Solid Tumors.

IL-12 mediates innate and adaptive immune responses and has demonstrated therapeutic antitumor 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 pharmacokinetic (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 injection of mANK-101. When compared with nonanchored IL-12, mANK-101 exhibited a distinct PK profile. Specifically, mANK-101 treatment was associated with a significant ninefold increase in the systemic terminal volume of distribution (Vd). Furthermore, linear mixed-effects models provided evidence that CD8+ T-cell infiltration and increased serum IFN-γ levels were correlated with tumor regression after a single dose of mANK-101. In addition, PK/pharmacodynamic modeling confirmed a link between systemic IL-12 and serum IFN-γ. The model also suggests that the anchored IL-12 drug conjugate is expected to prolong the absorption half-life (115 hours vs. 8 hours for the unanchored drug) with durable local retention and limited systemic absorption. In addition, serum IFN-γ may be a surrogate marker for drug activity. The PK modeling predictions may also contribute to determining the optimal clinical dose and schedule of mANK-101 and other anchored drug conjugates in patients with solid tumors.