Anti-drug Antibody Validation Testing and Reporting Harmonization

Abstract

Evolving immunogenicity assay performance expectations and a lack of harmonized anti-drug antibody validation testing and reporting tools have resulted in significant time spent by health authorities and sponsors on resolving filing queries. Following debate at the American Association of Pharmaceutical Sciences National Biotechnology Conference, a group was formed to address these gaps. Over the last 3 years, 44 members from 29 organizations (including 5 members from Europe and 10 members from FDA) discussed gaps in understanding immunogenicity assay requirements and have developed harmonization tools for use by industry scientists to facilitate filings to health authorities. Herein, this team provides testing and reporting strategies and tools for the following assessments: (1) pre-study validation cut point; (2) in-study cut points, including procedures for applying cut points to mixed populations; (3) system suitability control criteria for in-study plate acceptance; (4) assay sensitivity, including the selection of an appropriate low positive control; (5) specificity, including drug and target tolerance; (6) sample stability that reflects sample storage and handling conditions; (7) assay selectivity to matrix components, including hemolytic, lipemic, and disease state matrices; (8) domain specificity for multi-domain therapeutics; (9) and minimum required dilution and extraction-based sample processing for titer reporting. Graphical Abstract

Trends in industrialization of biotherapeutics: a survey of product characteristics of 89 antibody-based biotherapeutics

“…Generation of immune response among patients receiving immunotherapy is a very complex and multifactorial process. 107 , 108 In addition to the type of the antibody, other factors such as molecular sequence features (e.g., presence or absence of T- and B-cell immune epitopes, stability/aggregation of the molecule under physiological conditions), manufacturing processes, formulation, aggregates already present at the time of drug administration, route of administration, product presentation, as well as genetic and disease history of the patients including presence of preexisting antibodies, can play significant roles. 26 , 109 Furthermore, the real-life experience on immunogenicity of a given antibody-based biotherapeutic product, outside of the clinical trial setting, may be different than the % ADAs reported in the package inserts or BLA reviews.…”

The Impact of Immunogenicity on the Pharmacokinetics, Efficacy, and Safety of Sotatercept in a Phase III Study of Pulmonary Arterial Hypertension

“…The assessment justified an in‐study cutoff point approach for STELLAR ADA sample analyses. In‐study cutoff points were derived statistically from baseline samples of the study population and applied for STELLAR sample testing with a false‐positive rate of 7.1%, which is within the regulatory‐acceptable range of 2%–11% 24 . Therefore, the methodology for sotatercept immunogenicity evaluation was deemed adequate.…”

Association between genetic variants and development of antibodies to infliximab: A cross-sectional study in Chinese patients with Crohn’s disease

“…ATI was detected by a bridging ELISA method. The analytical method was validated according to current industry practice ( Myler et al, 2021 ). Plasma samples and controls were diluted in glycine (100 mM, pH 2.5) at a minimum dilution of 1:20 for 30 min at RT in a shaker.…”