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

Figure 7

Aggregation could contribute to ADA production by inducing the presentation of high affinity epitopes that may not be present in nonaggregated TPP. Simulated levels of TPP in endosome, epitope in endosome, MHC II-peptide complex on cell surface, and ADA production are shown for ((a)–(d)) original internalization rate (IR₀) and two low affinity epitopes for hypothetical nonaggregated TPP, ((e)–(h)) 16.6IR₀ and two low affinity epitopes for hypothetical aggregated form, and ((i)–(l)) IR₀ and inclusion of a high affinity third epitope for hypothetical aggregated form. The predicted dissociation constant (, unit: nM) for binding of each epitope to MHC II is indicated. ADA production has the same definition and dose and IR₀ have the same values as in Figure 4.