Fit-for-purpose Non-clinical Immunogenicity Assessment to Support PK Data Interpretation – A Case Study

Purpose

• The scope and extent of preclinical immunogenicity testing required to support dose-range finding (DRF) and GLP toxicology (Tox) studies remain topics of active discussion, with strategies varying based on biotherapeutic modality and risk assessment. This case study examines a recombinant human protein administered to rats and monkeys in DRF studies, highlighting the development of a targeted MSD ligand-binding assay (LBA) based pharmacokinetics (PK) method. A customized anti-drug antibody (ADA) assay was also developed and optimized to aid in interpreting PK data.

• During initial ADA assay development, certain challenges were encountered, including high background signals, variability in negative controls, and a low positive control (LPC) level failure rate exceeding 1%. Consequently, a streamlined, fit-for-purpose approach was adopted to define a screening cut point and establish preset LPC/sensitivity levels, with confirmatory and titration cut points excluded. ADA response levels were then estimated based on signal to-negative control (S/NC) ratios derived from the screening assay