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ABSTRACT
The surge in the clinical use of therapeutic antibodies has reshaped the landscape of pharmaceutical therapy for many diseases, including rare and challenging conditions. However, the administration of exogenous biologics could potentially trigger unwanted immune responses such as generation of anti-drug antibodies (ADAs). Real-world experiences have illuminated the clear correlation between the ADA occurrence and unsatisfactory therapeutic outcomes as well as immune-related adverse events. By retrospectively examining research involving immunogenicity analysis, we noticed the growing emphasis on elucidating the immunogenic epitope profiles of antibody-based therapeutics aiming for mechanistic understanding the immunogenicity generation and, ideally, mitigating the risks. As such, we have comprehensively summarized here the progress in both experimental and computational methodologies for the characterization of T and B cell epitopes of therapeutics. Furthermore, the successful practice of epitope-driven deimmunization of biotherapeutics is exceptionally highlighted in this article.
Abbreviations
| ADA | = | Anti-drug antibody |
| mAb | = | Monoclonal antibody |
| TP | = | Therapeutic protein |
| FR | = | Framework |
| CDR | = | Complementarity-determining region |
| MDB | = | Multi-domain biotherapeutic |
| VHH | = | Heavy-chain variable domain |
| Ti | = | T cell-independent |
| Td | = | T cell-dependent |
| Tfh | = | Follicular helper T lymphocyte |
| BCR | = | B cell receptor |
| TCR | = | T cell receptor |
| TCE | = | T cell epitope |
| BCE | = | B cell epitope |
| IgM | = | immunoglobulin M |
| PEG | = | Polyethylene glycol |
| MHC | = | Major histocompatibility complex |
| HLA | = | Human leukocyte antigen |
| APC | = | Antigen-presenting cell |
| DC | = | Dendric cell |
| Nab | = | Neutralizing antibody |
| TNF | = | Tumor necrosis factor |
| HCDR | = | Complementarity-determining region of heavy chain |
| LCDR | = | Complementarity-determining region of light chain |
| LFR | = | Framework of light chain |
| EPO | = | Erythropoietin |
| PBMC | = | Peripheral blood mononuclear cell |
| FVIII | = | Factor VIII |
| HAS | = | Human serum albumin |
| VNAR | = | Shark variable domain |
| ELISA | = | Enzyme-linked immunosorbent assay |
| ELISpot | = | Enzyme-linked immunosorbent spot |
| MAPPs | = | MHC-associated peptide proteomics |
| ADCC | = | antibody-dependent cell-mediated cytotoxicity |
| Fab | = | Antigen binding fragment |
| unAA | = | Unnatural amino acids |
| HA | = | Hemagglutinin |
| Fc | = | Crystallizable fragment |
| DDA | = | Domain detection assay |
| DCA | = | Domain competition assay |
| TIC | = | Targeted immunocytokine |
| MS | = | Mass spectrometry |
| IL | = | Interleukin |
| IFN | = | Interferon |
| IL-21 R | = | Interleukin-21 receptor |
| LBA | = | Ligand binding assay |
| pAb | = | Polyclonal antibody |
| pBCE | = | Polyclonal B cell epitope |
| BD | = | Binding domain |
| SPR | = | Surface plasmon resonance |
| AGAL | = | α-galactosidase A |
| HER2 | = | Human epidermal growth factor receptor 2 |
| DMS | = | Deep mutational scanning |
| RBD | = | Receptor-binding domain |
| HDX | = | Hydrogen-deuterium exchange |
| PROTEX | = | The proteolytic excision/extraction |
| FPOP | = | Fast photochemical oxidation of proteins |
| NMR | = | Nuclear magnetic resonance |
| EM | = | Electron microscopy |
| EMPEM | = | Electron microscopy polyclonal epitope mapping |
| nsEMPEM | = | negative staining Electron microscopy polyclonal epitope mapping |
| IEDB | = | The Immune Epitope Database |
| AUC | = | Area under the curve |
| GLP-1 | = | Glucagon-like peptide-1 |
Disclosure statement
All author(s) are currently employed by Takeda Pharmaceutical Company Limited and may hold stocks of the company.