The Role of Aggregates of Therapeutic Protein Products in Immunogenicity: An Evaluation by Mathematical Modeling

Figure 3

Schematic highlighting of the potential role of aggregates in T cell-dependent ADA production. A recapitulation of our system-level model for T cell-dependent ADA production [47, 48]. At the subcellular level, TPP are internalized into endosome of APC, such as dendritic cells (DC), and then degraded into antigenic peptides. Epitopes derived from TPP could be loaded onto MHC II and presented on the surface of APC. Aggregates could contribute to enhanced ADA production by having increased internalization or degradation rate or number and affinity of epitopes generated (indicated by thick red arrows). At the cellular level, danger signal (DS) maturated DC activate T cells which in turn activate B cells to generate ADA. Aggregates could enhance the DS to maturate DC (see red arrow). At the whole-body level, aggregated and nonaggregated TPP are absorbed from the injection site into plasma and will be distributed into periphery, eliminated, or captured by B cells through BCR binding.