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

Integration of Omics Data Sources to Inform Mechanistic Modeling of Immune‐Oncology Therapies: A Tutorial for Clinical Pharmacologists

“…29 We note that this strategy has been already applied in QSP platform models of therapeutic protein antigenicity, where well-established bioinformatics approaches were used to predict T-cell epitopes and MHCII receptor binding affinities. [30][31][32][33] Quantitative assessment of antigenicity can be further informed by high-throughput ex vivo assays 16 used to determine naïve T-cell precursor frequencies, as demonstrated in our example. Single-cell sequencing of T-cell receptors may contribute further insight.…”

Immunogenicity in Clinical Practice and Drug Development: When is it Significant?

“…A Quantitative Systems Pharmacology (QSP) approach can open an avenue toward prediction of ADA impact on PK in patient populations; thus, enabling model‐informed management of immunogenicity. Following seminal work, a number of companies recognized that development of a QSP model of immunogenicity is a noncompetitive effort and formed a consortium . The immunogenicity simulator, referred to as the IG Simulator, developed by the IG QSP Consortium is one example of a QSP model, among others, that integrates literature‐based, mechanistic models of immune response and ADA synthesis with a physiologically‐based pharmacokinetic model of biologics ( Figure ).…”

“…Overview of the IG Simulator (Adapted from Kierzek et al ., 2019 CPT:PSP). The Quantitative Systems Pharmacology model includes mechanistic model of immune response and Simcyp Biologics physiologically‐based pharmacokinetic.…”

“…Following seminal work, 7 a number of companies recognized that development of a QSP model of immunogenicity is a noncompetitive effort and formed a consortium. 8 The immunogenicity simulator, referred to as the IG Simulator, developed by the IG QSP Consortium is one example of a QSP model, among others, 7,9 that integrates literature-based, mechanistic models of immune response and ADA synthesis with a physiologically-based pharmacokinetic model of biologics 10 (Figure 2). The simulator uses data on T-cell epitopes, MHC II affinities and patient HLA genotype as input, thereby enabling extrapolation from in vitro assays and bioinformatics to predictions of ADA incidence along with PK effects in patient populations.…”

Where Do PBPK Models Stand in Pharmacometrics and Systems Pharmacology?

“…Perhaps, as suggested by Bradshaw and co‐workers, we should use the term “quantitative systems pharmacokinetic” models instead of PBPK to better encompass their broad range of application . Examples of combining quantitative systems pharmacokinetic models with classic QSP models have been published and the integration of these complementary approaches can considerably expand their individual scope as suggested recently …”