Abstract A141: Preclinical pharmacokinetic (PK) and tumor growth inhibition (TGI) modeling for mANK-101, an anchored murine interleukin-12 (IL-12) complex for intratumoral administration for solid cancer

Abstract

Abstract Introduction – Murine ANK-101 (mANK-101) is a stable complex composed of a modified murine IL-12 cytokine with aluminum hydroxide at a 1:10 ratio designed for intratumoral delivery to established solid cancers. The objective of this work was to build a preclinical PK/PD/TGI model to gain a better mechanistic understanding of the pharmacology of mANK-101 and potential impact on therapeutic efficacy. Methods - Data were collected from in vivo studies measuring PK, intratumoral immune cells and tumor growth inhibition (TGI) in a CT26 syngeneic mouse model treated with mANK-101. A PK model was derived from Momin et al. [1], the surrogacy potential of immune cells was assessed via a statistical model and subsequently a mathematical model linking immune cell activation to TGI was developed. Results – A two-compartment PK model was established to take into account both the intratumoral depot effect of mANK-101 and the release into the peripheral circulation for mIL12 from the mANK-101 complex. CD8+ T-cell infiltration was found to be a surrogate biomarker for anti-tumor activity and was subsequently used to link PD-TGI. The model was able to capture various doses and schedules of mANK-101 at different starting tumor volumes on therapeutic responses. Conclusions – A PK-PD-TGI model was developed that links the release of mIL12 from mANK-101 to immune cell-activation through to tumor growth inhibition thus providing a causal understanding of the mechanism of action. The model could potentially form the basis of a translational model to assist in designing first-in-man dose and schedule.