title: Understanding the Supersensitive Anti-Drug Antibody Assay: Unexpected High Anti-Drug Antibody Incidence and Its Clinical Relevance.
abstract: Numbers of biotherapeutic products in development have increased over past decade. Despite providing significant benefits to patients with unmet needs, almost all protein-based biotherapeutics could induce unwanted immunogenicity, which result in a loss of efficacy and/or increase the risk of adverse reactions, such as infusion reactions, anaphylaxis, and even life-threatening response to endogenous proteins. Recognizing these possibilities, regulatory agencies request that immunogenicity be assessed as part of the approval process for biotherapeutics. Great efforts have been made to reduce drug immunogenicity through protein engineering. Accordingly the immunogenicity incidence has been reduced from around 80% in murine derived products to 0-10% in fully human products. However, recent improvements in immunogenicity assays have led to unexpectedly high immunogenicity rates, even in fully human products, leading to new challenges in assessing immunogenicity and its clinical relevance. These new immunogenicity assays are becoming supersensitive and able to detect more of anti-drug antibodies (ADA) than with earlier assays. This paper intends to review and discuss our understanding of the supersensitive ADA assay and the unexpected high ADA incidence and its potential clinical relevance.
authors.affiliation: Immunogenicity Group, Department of Translational Medicine, Takeda Pharmaceutical USA, Inc., 35 Landsdowne Street, Cambridge, MA 02139, USA.
authors.forename: Sam
authors.identifier: 0000-0001-6616-0902
authors.initials: S
authors.lastname: Song
authors.affiliation: Immunogenicity Group, Department of Translational Medicine, Takeda Pharmaceutical USA, Inc., 35 Landsdowne Street, Cambridge, MA 02139, USA.
authors.forename: Lili
authors.identifier: 0000-0001-8031-6408
authors.initials: L
authors.lastname: Yang
authors.affiliation: Immunogenicity Group, Department of Translational Medicine, Takeda Pharmaceutical USA, Inc., 35 Landsdowne Street, Cambridge, MA 02139, USA.
authors.forename: William L
authors.identifier: 0000-0002-9989-0183
authors.initials: WL
authors.lastname: Trepicchio
authors.affiliation: Immunogenicity Group, Department of Translational Medicine, Takeda Pharmaceutical USA, Inc., 35 Landsdowne Street, Cambridge, MA 02139, USA.
authors.forename: Timothy
authors.identifier: 0000-0003-0696-5770
authors.initials: T
authors.lastname: Wyant
mesh_terms: D000906:Antibodies / Q000097:blood / Q000276:immunology*; D001688:Biological Products / Q000009:adverse effects* / Q000276:immunology*; D006801:Humans; D007118:Immunoassay / Q000379:methods; D004364:Pharmaceutical Preparations; D015203:Reproducibility of Results; D012680:Sensitivity and Specificity
chemical_list: D000906:Antibodies; D001688:Biological Products; D004364:Pharmaceutical Preparations