Katharina Hartman

• Despite success, the use of therapeutic monoclonal antibodies (mAbs) in clinical settings has been complicated by the ability of the patient’s immune system to provoke an unwanted humoral immune response against the drug, generally through the formation of anti-drug antibodies (ADAs) – termed immunogenicity. ADA onset may compromise clinical efficacy and impact safety in patients. A fundamental area of immunogenicity research is investigating mAb-derived peptides processed by dendritic cells (DCs) and presented through major histocompatibility complex (MHC) class II receptors. These mAb-derived peptides, representing potential T cell engaging epitopes, orchestrate the immunogenicity cascade by directly influencing T cell activation leading to ADA production. The MHC-II-associated peptide proteomics (MAPPs) assay is a Roche-invented methodology to identify and quantify such potential T cell epitopes. As an integrated approach during preclinical drug development, MAPPs is used alongside other in vitro, in silico, and in vivo tools to address the risk of immunogenicity. This PhD work aims to extend the applications of MAPPs for the development of a tool for personalized healthcare (PHC) in the clinic with the purpose of identifying patients with a potential risk of immunogenicity prior to treatment in order to devise an ideal treatment plan (main aim 1). Moreover, since most MAPPs studies are currently restricted to HLA-DR as the dominant MHC-II genotype due to lack of satisfactory MHC-II receptor-precipitating reagents available, an immunoprecipitation strategy using the MAPPs assay alongside the advanced epitope–prediction algorithm NetMHCIIpan was developed to accommodate MHC-II pan receptors for improved predictability of potential T cell epitopes (main aim 2). Taken together, these reformed uses of the MAPPs assay will lead to an invaluable clinical tool for immunogenicity risk assessments that support personalized healthcare.