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Research Article

A bridging immunogenicity assay for monoclonal antibody: case study with SHR-1222

    Dan Zhang

    State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 501 Haike Road, Shanghai 201203, PR China

    Nano Science and Technology Institute, University of Science and Technology of China, Suzhou 215123, PR China

    Authors contributed equally

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    ,
    Changyong Yang

    Research Center and School of Chemistry and Chemical Engineering, Southeast University, Nanjing 211189, PR China

    Province Hi-Tech Key Laboratory for Biomedical Research, Southeast University, Nanjing 211189, PR China

     Preclinical department, Hengrui Medicine Co., Ltd., Jiangsu, Lianyungang 222047, PR China

    Authors contributed equally

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    ,
    Xiaoyan Chen

    State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 501 Haike Road, Shanghai 201203, PR China

    ,
    Xiuli Li

    **Author for correspondence: Tel./Fax: +86–21–20231977;

    E-mail Address: xli@simm.ac.cn

    State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 501 Haike Road, Shanghai 201203, PR China

    &
    Dafang Zhong

    *Author for correspondence: Tel./Fax: +86–21–50800738;

    E-mail Address: dfzhong@simm.ac.cn

    State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 501 Haike Road, Shanghai 201203, PR China

    Published Online:https://doi.org/10.4155/bio-2017-0289

    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 Lewiecki EM. Monoclonal antibodies for the treatment of osteoporosis. Expert Opin. Biol. Ther. 13(2), 183–196 (2013).
    • 2 Paszty C, Turner CH, Robinson MK. Sclerostin: a gem from the genome leads to bone-building antibodies. J. Bone Miner. Res. 25(9), 1897–1904 (2010).
    • 3 Zhong ZD, Dinnogen S, Hokom M et al. Identification and inhibition of drug target interference in immunogenicity assays. J. Immunol. Methods 355(1–2), 21–28 (2010).
    • 4 Goupille P. Immunogenicity of biopharmaceuticals: which consequences during the treatment of rheumatoid arthritis. Rev. Med. Intern. 37(5), 343–349 (2016).
    • 5 Wang Yow-Ming C, Jawa V, Ma Mark. 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 Gunn George R, Evans C, Yang Eric. Immunogenicity and biomarkers: bioanalytical challenges and considerations. Bioanalysis 9(22), 1729–1732 (2017).
    • 7 Hoofring SA, Lopez R, Hock MB et al. 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 Patton A, Mullenix MC, Swanson SJ, Koren E. 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 Recknor CP, Recker RR, Benson CT et al. 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 Partridge MA, Pham J, Dziadiv O et al. 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 Mire-Sluis AR, Barrett YC, Devanarayan V et al. 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 Wadhwa M, Knezevic I, Kang HN, Thorpe R. Immunogenicity assessment of biotherapeutic products: an overview of assays and their utility. Biologicals 43(5), 298–306 (2015).
    • 14 Thway TM. Fundamentals of large-molecule protein therapeutic bioanalysis using ligand-binding assays. Bioanalysis 8(1), 11–17 (2016).
    • 15 Menendez AT. Strategic selection and development of immunogenicity binding methods. Bioanalysis 4(12), 1491–1508 (2012).
    • 16 Bütikofer L, Lemaillet G, Faust H. Strategies to estimate and improve drug tolerance in anti-drug antibody assays. Bioanalysis 4(16), 1999–2012 (2012).
    • 17 Sloan JH, Conway RG, Pottanat TG et al. 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 Zoghbi J, Xu Y, Grabert R, Theobald V, Richards S. 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 Spriggs Franklin P, Duriga N, Rathi Alok, Qu Qiang. Resolution of matrix interference: quantitative and quasi-quantitative ligand-binding assays case studies. Bioanalysis 6(8), 1093–1101 (2014).
    • 20 Carrasco-Triguero Montserrat, Mahood C, Milojic-Blair M et al. Overcoming soluble target interference in an anti-therapeutic antibody screening assay for an antibody drug conjugate therapeutic. Bioanalysis 4(16), 2013–2026 (2012).
    • 21 Dai S, Schantz A, Clements-Egan A, Cannon M, Shankar G. 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.