Epitope characterization of anti-drug antibodies—a tool for discovery and health: an overview of the necessity of early epitope characterization to avoid anti-drug antibodies and promote patient health

ABSTRACT

Introduction: The market for monoclonal antibody (mAb) therapies is growing rapidly as the pharmaceutical industry expands its development across a broad spectrum of diseases. Unfortunately, as shown in the recent failure of bococizumab by Pfizer, these treatments often stimulate the formation of problematic anti-drug antibodies (ADAs). ADAs can cause side effects and limit efficacy for many patients. To increase efficacy and decrease safety concerns from ADAs, immunogenicity characterization is needed early in the drug development process. Here, we present emerging techniques that hold promise to improve ADA assays and their potential applications to pharmaceutical development and personalized medicine.

Areas covered: This manuscript outlines the importance of epitope characterization to better understand immunogenicity and describes a strategy for using this information in treating patients taking mAb therapies.

Expert opinion: We propose using high-information assays to characterize epitopes to help mAb therapy engineering and potentially improve individual patient outcomes. To understand this, we will discuss three different aspects of ADAs: (1) the problem of ADAs and what is currently being done about them, (2) the current state of epitope characterization and how it is being utilized, and (3) how early epitope characterization can advance drug discovery and improve outcomes for patients taking mAb therapies.

KEYWORDS:

• Anti-drug antibodies
• drug discovery
• immunoassays
• mAb therapies
• immunogenicity assessment
• regulatory evaluation

Article highlights

• Anti-drug antibody assays historically have focused on binding or neutralization with increasing focus on improved sensitivity.

• High-throughput biosensors have emerged to identify epitopes for drug candidates. These biosensors can be used to compare immune repertoires of patients using mAb therapies to identify the epitopes of anti-drug antibodies.

• Epitope characterization of ADAs gathers important information on their biophysical characteristics and functional properties.

• Epitope characterization of ADAs improves safety and dosing.

• High-information assays improve both mAb therapy engineering and individual patient outcomes.

• HLA characterization and awareness of potential hypersensitivity reactions are important for applying mAb therapies to individual patients.

This box summarizes key points contained in the article.

Abbreviations

ABIRISK, aAnti-Biopharmaceutical Immunization: Prediction and Analysis of Clinical Relevance to Minimize the Risk; ADA, anti-drug antibody; bAb, binding ADAs; CLB, competitive ligand-binding; EMA, European Medicines Agency; ELISA, enzyme-linked immunosorbent assay; FDA, Food and Drug Administration; mAb, monoclonal antibody; nAbs, neutralizing antibodies; PCSK9, proprotein convertase subtilisin kexin type 9; RIPAs, radioimmunoprecipitation Assay; SPR, surface plasmon resonance.

Acknowledgments

We thank Alexis Horst, MA, for editing and review of this manuscript. We also thank Ron Weed for graphic design.

Disclosure statement

B Brooks has a financial interest in Carterra, Inc. Carterra sells instruments that are used for epitope binning and epitope mapping. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial relationships or otherwise to disclose.

Additional information

Funding

This article is funded by the Foundation for the National Institutes of Health (1R43AI132075-01).