Mark Stroh(1), Jason Sagert(1), Bjorn L. Millard(2), Lin Lin(2), Joshua F. Apgar(2), John M. Burke(2), and W. Michael Kavanaugh(1)
(1) CytomX, South San Francisco, California, USA; (2) Applied BioMath, Lincoln, MA, USA
Objective: Probody™ therapeutics (Pb-Txs) are masked monoclonal antibody (mAb) prodrugs designed to be preferentially activated by tumor-associated proteases. The peptide mask inhibits binding of the Pb-Tx in healthy tissues and, when removed by tumor-associated proteases, releases an active mAb. The aim of this study is to develop a quantitative systems pharmacology (QSP) model that integrates Pb-Tx and system properties for controlling Pb-Tx distribution. The Pb-Txs evaluated in this investigation were directed against activated leukocyte cell adhesion molecule (ALCAM; CD166), which is highly expressed in both tumors and healthy tissue.
Methods: A QSP Pb-Tx model was developed, calibrated against cynomolgus monkey pharmacokinetic (PK) data, and used to project human PK and pharmacodynamics (PD). Whole blood was collected from cynomolgus monkeys at various timepoints up to 21 days post-dose following administration of anti-CD166 Pb-Txs with varying mask and substrate characteristics. Dose levels investigated included 3, 5, and 10 mg/kg administered either as a single dose or as two doses administered three weeks apart. Models were implemented using KroneckerBio v. 0.4 (https://github.com/kroneckerbio) and expressed as a system of ordinary differential equations with the following form:
dx/dt=k+Ax+B (x⊗x)
where k is a vector of 0th order rate constants, A is an n by n matrix of 1st order rate constants, and B is a n by n matrix of second order rate constants. Parameter estimation and simulations were performed using MATLAB v. 2015b (Mathworks, Natick MA).
Results: The QSP Pb-Tx model was developed to capture events both at the Pb-Tx and the compartmental levels. The QSP Pb-Tx model has provisions that are unique to the Pb-Tx as well as those that are shared with other mAb pharmacology models. Elements shared with mAb pharmacology models include those governing mAb distribution both in the systemic compartment (1, 2) and in the tumor (3), including those governing receptor binding, and receptor and receptor-drug complex endocytosis. These events in turn occur downstream of Pb-Tx administration, distribution, and activation by proteases(4).
The QSP Pb-Tx model adequately described monkey PK data following administration of six Pb-Txs of different mask strength and protease substrate cleavability. The QSP Pb-Tx model suggested decreasing importance of target-mediated drug disposition with increasing mask strength, and captured the corresponding, observed trends of decreasing systemic clearance. Simulations in humans suggested increasing levels of activated Pb-Tx in tumor in comparison to simulated exposures following administration of the corresponding, unprotected parental mAb. The QSP Pb-Tx model suggested an optimal mask strength for maximizing tumor receptor-mediated uptake. Simulations further suggested that the Pb-Tx would circulate predominantly as the masked, intact species. Under physiologically-relevant conditions, QSP Pb-Tx model simulations did not project significant tumor flux of activated Pb-Tx to the systemic compartment.
Conclusions: The QSP Pb-Tx model captures the determinants of Pb-Tx PK/PD, allowing for customizable Pb-Tx distribution even with a broadly-expressed target like CD166.
References:
[1]. Gibiansky L, Gibiansky E. Target-mediated drug disposition model: approximations, identifiability of model parameters and applications to the population pharmacokinetic-pharmacodynamic modeling of biologics. Expert Opin Drug Metab Toxicol. 2009;5(7):803-12.
[2]. Wang W, Wang EQ, Balthasar JP. Monoclonal antibody pharmacokinetics and pharmacodynamics. Clin Pharmacol Ther. 2008;84(5):548-58.
[3]. Jain RK. Physiological barriers to delivery of monoclonal antibodies and other macromolecules in tumors. Cancer Res. 1990;50(3 Suppl):814s-9s.
[4]. Desnoyers LR, Vasiljeva O, Richardson JH, Yang A, Menendez EE, Liang TW, et al. Tumor-specific activation of an EGFR-targeting probody enhances therapeutic index. Sci Transl Med. 2013;5(207):207ra144.
Reference: PAGE 27 (2018) Abstr 8530 [www.page-meeting.org/?abstract=8530]
Poster: Drug/Disease Modelling - Oncology