Immunogenicity assay cut point determination using nonparametric tolerance limit

Background: Currently, screening cut point (CP) calculated from an assay validation with replicates are applied to an immunogenicity study with nonreplicates, for which the antidrug antibodies rate is determined. IID treats the replicate of a sample as coming from another independent sample. AVE uses average results from each sample across runs but inter-assay variability is reduced. Therefore, we propose a random effect model (REM) for calculating CP. Materials & method: We investigate impact of noncompatibility design between validation and immunogenicity studies on CP and compare these methods. Conclusion: IID may not fit for use when replicates’ variability dominates all sources of uncertainty. REM considers covariance structure of repeated measurements. CP by REM is smaller than that by IID but larger than that by AVE.

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P4-075: LUMIPULSE® G TOTAL TAU TO β-AMYLOID 1-42 RATIO CUT-POINT DETERMINATION FOR AMYLOID ELIGIBILITY SCREENING

Alzheimer s & Dementia ◽

10.1016/j.jalz.2018.06.2478 ◽

2006 ◽

Vol 14 (7S_Part_27) ◽

pp. P1463-P1463

Author(s):

June Kaplow ◽

Manu Vandijck ◽

Roger Moonen ◽

Bart De Decker ◽

Jim Zhao ◽

...

Keyword(s):

Cut Point ◽

Total Tau ◽

Β Amyloid ◽

Point Determination

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Confirmatory cut point has limited ability to make accurate classifications in immunogenicity assays

Bioanalysis ◽

10.4155/bio-2019-0283 ◽

2020 ◽

Vol 12 (4) ◽

pp. 245-256

Author(s):

Robert J Kubiak ◽

Rosalinda HGP Arends ◽

Nancy Lee ◽

Meina Liang ◽

Jianchun Zhang ◽

...

Keyword(s):

Competitive Inhibition ◽

Cut Points ◽

Limited Ability ◽

Cut Point ◽

Confirmatory Assay ◽

Drug Naïve ◽

Point Determination ◽

Antidrug Antibodies ◽

Immunogenicity Assays

Aim: Competitive inhibition with excess unlabeled drug is used to confirm the presence of antidrug antibodies (ADA) in study samples. We evaluated specific and nonspecific responses from both drug-naive and drug-treated subjects to identify conditions required by the confirmatory assay to make accurate ADA classifications. Results: Nonspecific signal measured in drug-naive samples used to determine assay cut points was uniformly low and close to the screening cut point. Confirmatory assays performed on incurred study samples with nonspecific responses significantly above the level observed during cut point determination resulted in incorrect ADA classifications. Conclusion: Intensity of confirmatory response should be proportional to the screening response and therefore, to ensure accurate ADA classifications, the confirmatory responses cannot be considered as independent but need to be evaluated in relation to the screening responses.

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A bridging immunogenicity assay for anti-cabiralizumab antibodies: overcoming the low assay cut point and drug tolerance challenges

Bioanalysis ◽

10.4155/bio-2020-0300 ◽

2021 ◽

Author(s):

Long Yuan ◽

Carol R Gleason ◽

Dennis Stocker ◽

Li Li ◽

Jim X Shen ◽

...

Keyword(s):

Clinical Studies ◽

Drug Tolerance ◽

Normal Serum ◽

Acid Dissociation ◽

Reagent Concentration ◽

Acid Pretreatment ◽

Cut Points ◽

Cut Point ◽

Immunogenicity Assay ◽

Assay Conditions

Background: To support the clinical studies of cabiralizumab, an immunogenicity assay for detecting anti-cabiralizumab antibodies is required. Results: Strategies were developed to overcome two major bioanalytical challenges: poor drug tolerance of the anti-drug antibodies assay and very low cut point observed in the screening and confirmatory assays. By using acid dissociation (400 mM glycine solution at pH 2.0), drug tolerance of 200 μg/ml drug was achieved for both the screening and confirmatory assays. Effects of biological matrix (disease state vs normal serum) and assay conditions (capture/detector reagent concentration, minimum required dilution, acid pretreatment) on assay cut points were systematically evaluated. Conclusion: A bridging immunogenicity assay for detecting anti-cabiralizumab antibodies in human serum has been successfully developed, validated and applied to clinical studies.

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