Abstract

Trimer formation is key to the pharmacology of the bispecific ATG-101 but is difficult to measure. ATG-101 is a bispecific antibody that crosslinks tumor-expressed PD-L1 to T-cell-expressed 4-1BB, thereby selectively activating T-cells infiltrating solid tumors while inhibiting immune checkpoints. The molecule is designed in a 2+2 format that requires crosslinking to initiate 4-1BB activity, and thus does not act as a superagonist unlike other comparator molecules (e.g., Urelumab). Therefore, the pharmacologically active complex that corresponds to efficacy consists of the drug bound to both PD-L1 and 4-1BB (i.e., “trimers”). The formation of this trimeric complex is subject to various factors, including binding affinity to each target, avidity effects between the two targets, the density of target receptors, the E:T ratio, etc. We used modeling to predict trimer formation in tumors. While difficult to measure directly, these trimeric complexes can be predicted using mechanistic modeling. Once calibrated and benchmarked to preclinical in vitro and in vivo data, simulations of trimer formation can be used to translate these findings to guide clinical dosing strategies (Betts & van der Graaf, 2020) rather than relying on exposure metrics.