title: The Role of Aggregates of Therapeutic Protein Products in Immunogenicity: An Evaluation by Mathematical Modeling.
abstract: Therapeutic protein products (TPP) have been widely used to treat a variety of human diseases, including cancer, hemophilia, and autoimmune diseases. However, TPP can induce unwanted immune responses that can impact both drug efficacy and patient safety. The presence of aggregates is of particular concern as they have been implicated in inducing both T cell-independent and T cell-dependent immune responses. We used mathematical modeling to evaluate several mechanisms through which aggregates of TPP could contribute to the development of immunogenicity. Modeling interactions between aggregates and B cell receptors demonstrated that aggregates are unlikely to induce T cell-independent immune responses by cross-linking B cell receptors because the amount of signal transducing complex that can form under physiologically relevant conditions is limited. We systematically evaluate the role of aggregates in inducing T cell-dependent immune responses using a recently developed multiscale mechanistic mathematical model. Our analysis indicates that aggregates could contribute to T cell-dependent immune response by inducing high affinity epitopes which may not be present in the nonaggregated TPP and/or by enhancing danger signals to break tolerance. In summary, our computational analysis is suggestive of novel insights into the mechanisms underlying aggregate-induced immunogenicity, which could be used to develop mitigation strategies.
authors.affiliation: Pharmacokinetics, Dynamics and Metabolism-New Biological Entities, Pfizer, Andover, MA 01810, USA.
authors.forename: Liusong
authors.initials: L
authors.lastname: Yin
authors.affiliation: Pharmacokinetics, Dynamics and Metabolism-New Biological Entities, Pfizer, Cambridge, MA 02138, USA.
authors.forename: Xiaoying
authors.initials: X
authors.lastname: Chen
authors.affiliation: Pharmacokinetics, Dynamics and Metabolism-New Biological Entities, Pfizer, Cambridge, MA 02138, USA.
authors.forename: Abhinav
authors.initials: A
authors.lastname: Tiwari
authors.affiliation: Pharmacokinetics, Dynamics and Metabolism-New Biological Entities, Pfizer, San Diego, CA 92121, USA.
authors.forename: Paolo
authors.initials: P
authors.lastname: Vicini
authors.affiliation: Pharmacokinetics, Dynamics and Metabolism-New Biological Entities, Pfizer, Andover, MA 01810, USA.
authors.forename: Timothy P
authors.initials: TP
authors.lastname: Hickling
mesh_terms: D000911:Antibodies, Monoclonal / Q000737:chemistry / Q000494:pharmacology*; D000936:Antigen-Antibody Complex / Q000737:chemistry / Q000276:immunology; D001402:B-Lymphocytes / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D003198:Computer Simulation; D016207:Cytokines / Q000737:chemistry / Q000494:pharmacology*; D003713:Dendritic Cells / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D000939:Epitopes / Q000737:chemistry / Q000276:immunology; D006801:Humans; D007111:Immunity, Cellular / Q000187:drug effects; D056724:Immunity, Humoral / Q000187:drug effects; D007141:Immunoglobulin Fc Fragments / Q000737:chemistry / Q000494:pharmacology*; D018448:Models, Immunological; D066329:Protein Aggregates / Q000187:drug effects* / Q000276:immunology; D011947:Receptors, Antigen, B-Cell / Q000737:chemistry / Q000276:immunology; D011993:Recombinant Fusion Proteins / Q000737:chemistry / Q000494:pharmacology*; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000166:cytology / Q000187:drug effects / Q000276:immunology
chemical_list: D000911:Antibodies, Monoclonal; D000936:Antigen-Antibody Complex; D016207:Cytokines; D000939:Epitopes; D007141:Immunoglobulin Fc Fragments; D066329:Protein Aggregates; D011947:Receptors, Antigen, B-Cell; D011993:Recombinant Fusion Proteins