Anti-Drug Antibodies: A Challenge for Biopharmaceutical Development
Anti-Drug Antibodies: A Challenge for Biopharmaceutical Development
Therapeutic antigens can give an unwanted immune response. This reaction leads to the production of anti-drug antibodies (ADAs). ADA assays are designed to detect and quantify antibodies produced by individuals in response to the administered drug. These assays help identify if a drug is immunogenic and if patients are developing antibodies that may impact drug efficacy and safety.
The clinical effects of ADAs could range from no measurable clinical effect to very harmful adverse events. The most common problem is loss of efficacy when ADAs bind the drug and neutralize its activity or increase the elimination. Understanding immunogenicity and its potential impact on PK and/or PD helps researchers and clinicians make informed decisions about dosing regimens, patient management, and risk mitigation strategies.
The immunogenicity multi-tier analytical workflow demands substantial resources and time. Alternative more resource-efficient approaches have been suggested from cross-industry bioanalytical communities (e.g., at the European Bioanalytical Forum Workshop in September 2023). These suggestions include:
- Can an assay signal be used instead of titer determination for assessment of the magnitude of an ADA response?
The many dilutions of each sample in a titer assay give a low sample throughput per plate. Several studies have shown a correlation between signal-to-noise (S/N) and titer in samples in clinical studies. S/N also has been reported to have better precision and ability to detect potentially low avidity ADA compared to titer.
- Is the confirmation step needed?
The screening and confirmation steps are based on the same assay and a statistical correlation of the results has been shown in multiple studies. Results indicate that similar conclusions could be obtained by removing the confirmation step and instead having a lower cut-off in the screening assay.
If any of these alternative approaches are to be used, the sponsor must consult regulatory bodies early in the drug development program and a suitable justification must be provided.
References
Assay signal as an alternative to titer for assessment of magnitude of an antidrug antibody response. Manning et al., Bioanalysis (2017) 9(23), 1849–1858. https://pubmed.ncbi.nlm.nih.gov/29020795/
Comparison of Titer and Signal to Noise (S/N) for Determination of Anti‑drug Antibody Magnitude Using Clinical Data from an Industry Consortium. Manning et al., The AAPS Journal (2022) 24: 81. https://doi.org/10.1208/s12248-022-00728-8
Anti‑drug Antibody Magnitude and Clinical Relevance Using Signal to Noise (S/N): Bococizumab Case Study. McCush et al., The AAPS Journal (2023) 25:85. https://doi.org/10.1208/s12248-023-00846-x
Correlation of screening and confirmatory results in tiered immunogenicity testing by solution-phase bridging assays. Kubiak et al., Journal of Pharmaceutical and Biomedical Analysis 74 (2013) 235–245. https://pubmed.ncbi.nlm.nih.gov/23245256/
Confirmatory cut point has limited ability to make accurate classifications in immunogenicity assays. Kubiak et al., Bioanalysis 2020 Feb;12(4):245-256. https://doi.org/10.4155/bio-2019-0283
A strategic approach to nonclinical immunogenicity assessment: a recommendation from the European Bioanalysis Forum. Laurén et al., Bioanalysis 2021 Apr;13(7):537-549. https://pubmed.ncbi.nlm.nih.gov/33729007/
European Bioanalysis Forum recommendation on singlicate analysis for ligand binding assays: time for a new mindset. Barfield et al., Bioanalysis 2020;12(5):273–84.
