Abstract
Aim: SHR-1222 is a humanized monoclonal antibody targeted to soluble sclerostin. To support the preclinical study of SHR-1222 in cynomolgus monkeys, a method for the detection of anti-drug antibodies is required. Results: A bridging immunogenicity method for the detection of anti-SHR-1222 antibodies was developed and validated. In the method, minimal required dilution, normalization factor and confirmatory cut point were 1:20, 4.35 and 10.45%, respectively. The method was successfully applied to evaluate a multiple-dose toxicity study in monkeys. Conclusion: The proposed method allows for the detection of anti-SHR-1222 antibodies in preclinical studies and aids in the interpretation of pharmacokinetic changes in certain animals. The soluble targets interference on anti-drug antibody detection can be blocked or decreased by the therapeutic drug.
Papers of special note have been highlighted as: • of interest; •• of considerable interest
References
- 1 . Monoclonal antibodies for the treatment of osteoporosis. Expert Opin. Biol. Ther. 13(2), 183–196 (2013).
- 2 . Sclerostin: a gem from the genome leads to bone-building antibodies. J. Bone Miner. Res. 25(9), 1897–1904 (2010).
- 3 Identification and inhibition of drug target interference in immunogenicity assays. J. Immunol. Methods 355(1–2), 21–28 (2010).
- 4 . Immunogenicity of biopharmaceuticals: which consequences during the treatment of rheumatoid arthritis. Rev. Med. Intern. 37(5), 343–349 (2016).
- 5 . Immunogenicity and PK/PD evaluation in biotherapeutic drug development: scientific considerations for bioanalytical methods and data analysis. Bioanalysis 6(1), 79–87 (2014). •• Illustrates key challenges with regard to understanding the relationship between anti-drug antibody (ADA) and pharmacokinetic/pharmacodynamic.
- 6 . Immunogenicity and biomarkers: bioanalytical challenges and considerations. Bioanalysis 9(22), 1729–1732 (2017).
- 7 Immunogenicity testing strategy and bioanalytical assays for antibody–drug conjugates. Bioanalysis 5(9), 1041–1055 (2013). • Indicates that anti-drug antibody produced in the subject would change the therapeutic pharmacokinetic profile.
- 8 . An acid dissociation bridging ELISA for detection of antibodies directed against therapeutic proteins in the presence of antigen. J. Immunol. Methods 304(1), 189–195 (2005).
- 9 The effect of discontinuing treatment with blosozumab: follow-up results of a phase 2 randomized clinical trial in postmenopausal women with low bone mineral density. J. Bone Miner. Res. 30(9), 1717–1725 (2015). • Indicates that the therapeutic targeted to sclerostin may lead to sclerostin elevation in the subject.
- 10 Minimizing target interference in PK immunoassays: new approaches for low-pH-sample treatment. Bioanalysis 5(15), 1897–1910 (2013). • Develops two low-pH-sample-pretreatment techniques to minimize target interference.
- 11 US FDA. Guidance for Industry: Assay Development and Validation for Immunogenicity Testing of Therapeutic Protein Products (2016). www.fda.gov/downloads/Drugs/Guidances/UCM192750.pdf. • Guidance article provides experimental and statistical methodologies for the validation of critical performance characteristics of antitherapeutic antibody immunoassays.
- 12 Recommendations for the design and optimization of immunoassays used in the detection of host antibodies against biotechnology products. J. Immunol. Methods 289(1–2), 1–16 (2004).
- 13 . Immunogenicity assessment of biotherapeutic products: an overview of assays and their utility. Biologicals 43(5), 298–306 (2015).
- 14 . Fundamentals of large-molecule protein therapeutic bioanalysis using ligand-binding assays. Bioanalysis 8(1), 11–17 (2016).
- 15 . Strategic selection and development of immunogenicity binding methods. Bioanalysis 4(12), 1491–1508 (2012).
- 16 . Strategies to estimate and improve drug tolerance in anti-drug antibody assays. Bioanalysis 4(16), 1999–2012 (2012).
- 17 An innovative and highly drug-tolerant approach for detecting neutralizing antibodies directed to therapeutic antibodies. Bioanalysis 8(20), 2157–2168 (2016). •• Provides details of affinity capture elution bridging immunogenicity assay format.
- 18 . A breakthrough novel method to resolve the drug and target interference problem in immunogenicity assays. J. Immunol. Methods 426, 62–69 (2015). •• Provides details of precipitation and acid dissociation immunogenicity assay format.
- 19 . Resolution of matrix interference: quantitative and quasi-quantitative ligand-binding assays case studies. Bioanalysis 6(8), 1093–1101 (2014).
- 20 Overcoming soluble target interference in an anti-therapeutic antibody screening assay for an antibody drug conjugate therapeutic. Bioanalysis 4(16), 2013–2026 (2012).
- 21 . Development of a method that eliminates false-positive results due to nerve growth factor interference in the assessment of fulranumab immunogenicity. AAPS J. 16(3), 464–477 (2014). • Provides details to improve target interference.