MHC-Associated Peptide Proteomics (MAPPs) as a Tool for Assessment of Immunogenicity Risk Potential of Therapeutic Monoclonal Antibodies

Biotherapeutic monoclonal antibodies (mAbs) can elicit unwanted immune responses in patients, potentially leading to anti-drug antibody (ADA) formation, reduced efficacy, or safety concerns. The major histocompatibility complex (MHC)-associated peptide proteomics (MAPPs) assay enables the identification of naturally presented human leucocyte antigen (HLA) class II peptides and provides a mechanistic readout of antigen processing and presentation. In this study, we applied a high-sensitivity MAPPs workflow using magnetic bead-based HLA-DR/DP/DQ immunoprecipitation and high-resolution mass spectrometry (HRMS) to assess the immunogenicity risk of six marketed mAbs across a panel of 10 HLA-typed donors. Peptide length distribution and MHC motif deconvolution were used as quality control measures. The number and clustering of drug-derived peptides were compared across antibodies and donors and correlated with reported clinical ADA incidence. The results highlight the value of MAPPs for early-stage candidate selection and HLA-aware risk stratification.