Assessment and Reporting of the Clinical Immunogenicity of Therapeutic Proteins and Peptides—Harmonized Terminology and Tactical Recommendations

Abstract

Abstract. Immunogenicity is a significant concern for biologic drugs as it can affect both safety and efficacy. To date, the descriptions of product immunogenicity have varied not only due to different degrees of understanding of product immunogenicity at the time of licensing but also due to an evolving lexicon that has generated some confusion in the field. In recent years, there has been growing consensus regarding the data needed to assess product immunogenicity. Harmonization of the strategy for the elucidation of product immunogenicity by drug developers, as well as the use of defined common terminology, can benefit medical practitioners, health regulatory agencies, and ultimately the patients. Clearly, understanding the incidence, kinetics and magnitude of anti-drug antibody (ADA), its neutralizing ability, cross-reactivity with endogenous molecules or other marketed biologic drugs, and related clinical impact may enhance clinical management of patients treated with biologic drugs. To that end, the authors present terms and definitions for describing and analyzing clinical immunogenicity data and suggest approaches to data presentation, emphasizing associations of ADA development with pharmacokinetics, efficacy, and safety that are necessary to assess the clinical relevance of immunogenicity.

Assessment of human antihuman antibodies to eculizumab after long‐term treatment in patients with paroxysmal nocturnal hemoglobinuria

“…This analysis provides sufficient evidence to support long-term lack of immunogenicity of commercial eculizumab in the treatment of PNH [8]. Moreover, these findings are consistent with shorterterm studies in which HAHAs were infrequent, occurring in 2% (3/196) of patients [9].…”

Immunogenicity of Antibody Drug Conjugates: Bioanalytical Methods and Monitoring Strategy for a Novel Therapeutic Modality

“…Each offers unique advantages (as discussed in "ADA DOMAIN SPECIFICITY STRATEGY"), and diverse approaches have been followed to assess and describe immunogenicity data for different ADC molecules (see Table I). A recent white paper suggests harmonized definitions and terminology to describe product immunogenicity (2). A similar effort may eventually come about with regard to immunogenicity assessment for ADCs.…”

“…Accordingly, sponsor organizations are tasked with monitoring the immunogenicity of their therapeutic proteins and providing a thorough evaluation of this information to clinicians in the product label. This may include information on ADA prevalence and the impact of ADA on clinical safety and efficacy (2).…”

Evaluating and Reporting the Immunogenicity Impacts for Biological Products—a Clinical Pharmacology Perspective

“…It is worth noting that clinical studies reported in the literature and conducted by individual institutions often relied on in-house assay methods for measuring not only the ADA but also the drug concentrations. A cross-study comparison of immunogenicity data in the literature may not be as informative as within-study comparisons because the immunogenicity results are highly dependent on the assay methodology used (3,9). As such, almost all prescribing information of biological products cautioned that comparison of incidence of ADA across products may be misleading.…”