Background
ZW171 is a clinical-stage humanized bispecific T-cell engager (TCE) molecule in a 2+1 antibody format that incorporates two single chain variable fragments (scFvs) that bind to the extracellular domain (ECD) of MSLN, and one fragment antigen binding domain (Fab) that binds to CD3. Binding of the molecule to CD3 on T-cells and MSLN on tumor cells results in the formation of a trimolecular complex(CD3-ZW171-MSLN), or a tetramolecular complex (CD3-ZW171-MSLN-MSLN) due to ZW171’s ability to bind to two MSLN molecules. This mechanism of action mimics the standard immune synapse, triggering T cell activation and killing of MSLN+ tumor cells. A Quantitative System Pharmacology (QSP) model was developed for ZW171 to facilitate the selection of an optimal ZW171 starting dose for phase 1 clinical study.
Methods
The human QSP model was developed by a stepwise approach: (1) an in vitro binding model (including cis-avidity of ZW171 (i.e. accumulated binding strength of ZW171 to two MSLN molecules) and the ability of ZW171 to crosslink between MSLN+ tumor cells and T-cells); (2) a two compartment (central and peripheral) in vivo cynomolgus monkey model; and (3) a three compartment (central, peripheral and tumor) in vivo human model. The in vitro model was used to capture cytotoxicity data and establish criteria for starting and efficacious doses in the clinic. The in vivo human model was constructed to determine the ZW171 doses at which the criteria outlined in the in vitro models were met.
Results
In the QSP model, the effective trimer per cell (TPC) was derived based on the binding kinetics of ZW171 to MSLN protein on tumor cells and CD3 receptor on T cells, serving as a driver for pharmacologic activity. The effective trimer per cell (TPC) that leads to various levels of the observed in vitro cytotoxicity was assessed to establish the criteria for the starting dose. By utilizing the estimated human PK parameters of ZW171 and incorporating the literature data for the numbers of T cells and MSLN-expressing cells, the doses required to achieve different levels of TPC at maximum in circulation after the first dose was evaluated and used to determine the starting dose.
Conclusions
A fit-for-purpose QSP model was developed for ZW171 to facilitate the determination of starting dose in the first-in-human (FIH) clinical study. This approach led to greater confidence in determining the starting dose for the ZW171 Phase 1 clinical study, expected to commence in the second half of 2024.