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.
Highlights
The approvals of the first recombinant human protein and the first therapeutic monoclonal antibody (Muromonab-CD3, OKT3, 1985) symbolized the start of the new biotherapeutic era
They found the low concentration drug was associated with high titer of anti-drug antibodies (ADA) and had a 14.5 times higher odds ratio (OR) (p = 0.006) to develop gadolinium positive Gd+ lesions and a nine times higher OR (p = 0.01) to have a relapse compared to normal serum natalizumab concentrations
The very high ADA positive rate seen in recent reports relative to the low ADA positive rate seen in earlier reports suggests the ADA positive rate in earlier studies may have been underestimated due to the low assay sensitivity and low drug tolerance
Summary
The approvals of the first recombinant human protein (insulin, 1982) and the first therapeutic monoclonal antibody (Muromonab-CD3, OKT3, 1985) symbolized the start of the new biotherapeutic era. The ADA response is directed to the administrated biotherapeutic and to its endogenous counterpart protein and may elicit a life-threatening response in particular if the endogenous protein is unique and nonredundant and has a vital life function [6, 14]. In recognition of these possibilities, the regulatory agencies request that a biotherapeutic’s immunogenicity be assessed and a determination of its characteristics relative to any induced clinical consequences be done as part of the approval process for biotherapeutics. This paper intends to review and understand the supersensitive ADA assay and examine the unexpected high ADA positive incidence and the potential clinical relevance of a high ADA positive incidence
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