Journal Article

A Quantitative Systems Pharmacology Consortium Approach to Managing Immunogenicity of Therapeutic Proteins

Deng, Rong, Narula, Jatin, Giorgi, Mario, Zhou, Lian, Thalhauser, Craig J., Van Der Walt, Jan‐Stefan, Veldman, Geertruida M., Small, Ben G., Kalvass, J. Cory, Tourdot, Sophie, Yamada, Akihiro, Figueroa, Isabel, Ribba, Benjamin, Yokoo, Sachiko, Benson, Neil, Chen, Xiaoying, Sayama, Hiroyuki, Lavé, Thierry, Quarmby, Valerie, Gulati, Abhishek, Dhanikula, Renu S., Swat, Maciej J., Kierzek, Andrzej M., Leil, Tarek A., Dickinson, Gemma L., Jones, Hannah M., Ferrante, Andrea, Gadkar, Kapil, Graaf, Piet H., Mohan, Krithika, Walker, Michael, Nijsen, Marjoleen, Chelliah, Vijayalakshmi, Gokemeijer, Jochem, Hickling, Timothy P.

2019

Overview

[...]as the immune status of a patient or comedications change, a drug that had not appeared immunogenic for many years of treatment could begin to induce an immune response. [...]a marketed drug may exhibit IG for the first time in a new and sensitive target population, such as patients with an autoimmune disease or children. [...]bioinformatic approaches provide a good basis for screening and optimizing compounds, but they cannot be used to manage IG once a protein therapeutic has entered human trials. The most frequent application of PBPK is the prediction of DDIs and the confidence in this approach is such that regulators accept simulations as a substitute for clinical trials and as the basis for label statements. [...]although DDIs still cannot be “engineered out” completely, they can be predicted and managed effectively through virtual trial simulation using models with sufficient mechanistic detail. The QSP model used in the IG Simulator has sufficient mechanistic detail to integrate diverse inputs, including bioinformatics predictions of MHC II binding to antigenic peptides, in vitro cell‐based assays and clinical measurements of compound concentrations, and ADA titers. [...]a detailed simulation of complex immune system interactions allows for

• Publisher: John Wiley & Sons, Inc,John Wiley and Sons Inc,Wiley
• Subject: Binding sites / Bioinformatics / Biological products / Clinical trials / Consortia / Drug dosages / Engineering / FDA approval / Immune system / Patients / Pharmacology / Physiology / Proteins