RT Journal Article
SR Electronic
T1 Guiding dose selection of monoclonal antibodies using a new parameter (AFTIR) for characterizing ligand binding systems
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 432500
DO 10.1101/432500
A1 Sameed Ahmed
A1 Miandra Ellis
A1 Hongshan Li
A1 Luca Pallucchini
A1 Andrew M Stein
YR 2019
UL http://biorxiv.org/content/early/2019/02/06/432500.abstract
AB Guiding the dose selection for monoclonal antibody oncology drugs is often done using methods for predicting the receptor occupancy of the drug in the tumor. In this manuscript, previous work on characterizing target inhibition at steady state using the AFIR metric was extended to include a "target-tissue" compartment and the shedding of membrane-bound targets. A new potency metric AFTIR was derived (Averarge Free Tissue target to Initial target ratio at steady state) and it depends on four key quantities: the equilibrium binding constant, the fold-change in target expression at steady state after binding to drug, the biodistribution of target from circulation to target tissue, and the average drug concentration in circulation. The AFTIR metric has been useful for guiding dose selection, for rapidly performing sensitivity analyses, and for building intuition for more complex target mediated drug disposition models. In particular, reducing the complex, physiological model to four key parameters needed to predict target inhibition helps to highlight the particular parameters that are most important to estimate in future experiments and further guide drug development. #ddct #phmx #cpt