ArticleBioanalysis2025
Refined ADA testing strategy to overcome sRANKL interference in denosumab/FKS518 immunogenicity assessment.
Article in Bioanalysis, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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Abstract
backgroundFresenius Kabi developed FKS518, a fully human monoclonal antibody biosimilar to denosumab, that inhibits osteoclast activation by targeting the receptor activator of nuclear factor kappa-Β ligand (RANKL). RANKL exists as a trimeric soluble protein (sRANKL) with high affinity for denosumab. Post-dose, sRANKL levels can rise due to drug-target complex accumulation, creating a risk of interference in bridging anti-drug antibodies (ADA) assays, particularly after acid dissociation.
methodsWe evaluated sRANKL interference in the ADA bridging assay and, to competitively block sRANKL, we introduced a specificity tier by adding osteoprotegerin (OPG). This approach enabled reanalysis of previously ADA-positive samples to confirm whether signals represented true ADA responses or artifacts caused by sRANKL interference.
resultsAcid dissociation significantly exacerbated target interference, resulting in ADA positivity rates of ~96-98% in clinical studies. Introducing a specificity tier corrected incidence to ≤3.9%. OPG incorporation did not change the minimum required dilution (MRD) of the assay and did not affect signals for negative/positive control, confirming assay integrity. DISCUSSION: These findings underscore the importance of early interference assessment and mitigation. A multi-tiered strategy, encompassing screening, confirmatory, and specificity tiers, provided a robust solution applicable to programs facing similar challenges.
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