Specificity and selectivity evaluations of ligand binding assay of protein therapeutics against concomitant drugs and related endogenous proteins

Lee, Jean; Ma, Hongjin

doi:10.1208/aapsj0902018

Cited by 39 publications

(16 citation statements)

References 16 publications

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“…For example, validations to support clinical trials in patient populations should typically include the use of disease-state matrix for selectivity testing, since matrix factors that bias results could differ between these individuals and healthy volunteers. Matrix from autoimmune conditions such as rheumatoid arthritis or inflammatory conditions such as sepsis and viral infection may be more likely to affect LBA readouts (5).…”

Section: Selectivitymentioning

confidence: 99%

Large Molecule Specific Assay Operation: Recommendation for Best Practices and Harmonization from the Global Bioanalysis Consortium Harmonization Team

Stevenson

Kelley

Gorovits

et al. 2013

AAPS J

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Abstract. The L2 Global Harmonization Team on large molecule specific assay operation for protein bioanalysis in support of pharmacokinetics focused on the following topics: setting up a balanced validation design, specificity testing, selectivity testing, dilutional linearity, hook effect, parallelism, and testing of robustness and ruggedness. The team additionally considered the impact of lipemia, hemolysis, and the presence of endogenous analyte on selectivity assessments as well as the occurrence of hook effect in study samples when no hook effect had been observed during pre-study validation.

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Section: Selectivitymentioning

confidence: 99%

Large Molecule Specific Assay Operation: Recommendation for Best Practices and Harmonization from the Global Bioanalysis Consortium Harmonization Team

Stevenson

Kelley

Gorovits

et al. 2013

AAPS J

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“…The specific interferences for PK assays can be caused by catabolic species of the drug, analogs of the endogenous proteins, heterophilic antibodies, human antianimal antibodies, rheumatoid factors, soluble ligands, antidrug antibodies, high-dose hook effect, etc. [34][35][36][37][38]. For biomarker assays, specific matrix effects can be additionally caused by endogenous molecules with similar structure to the target analyte (e.g., homologous family members, isoforms and precursor proteins) [39] or their natural ligands and the analogs of the ligands.…”

Section: Parallelism and Matrix Effectsmentioning

confidence: 99%

“…The specific reagents are designed, confirmed and selected with the assistance of other technologies (e.g., western blots, surface plasmon resonance, HPLC, LC-MS/MS, etc.) [26,36]. The specificity test protocol currently in use is in a learnand-confirm approach [25,26].…”

Section: Parallelism and Specificitymentioning

confidence: 99%

Parallelism Experiments to Evaluate Matrix Effects, Selectivity and Sensitivity in Ligand-Binding Assay Method Development: Pros and Cons

Bennett

2017

Bioanalysis

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Parallelism is an essential experiment characterizing relative accuracy for a ligandbinding assay (LBA). By assessing the effects of dilution on the quantitation of endogenous analyte(s) in matrix, selectivity, matrix effects, minimum required dilution, endogenous levels of healthy and diseased populations and the LLOQ are assessed in a single experiment. This review compares and discusses all available approaches that can be used to assess key assay parameters for pharmacokinetic and biomarker LBAs, as well as the advantages and disadvantages of each approach. This review also summarizes a systematic approach that can apply to guide endogenous LBA method development and optimization with a suggested way to interpret parallelism data.

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“…Lack of selectivity can result in binding inhibition or enhancement. The results can appear as an over-or underestimation of the analyte concentration (17). Matrix components that cause interference may be dependent on the health status and populations as well as sample collection.…”

Section: Selectivity and Parallelismmentioning

confidence: 99%

“Fit-for-Purpose” Method Validation and Application of a Biomarker (C-terminal Telopeptides of Type 1 Collagen) in Denosumab Clinical Studies

Wang

Lee

Burns

et al. 2009

AAPS J

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Abstract. Biomarkers are used to study drug effects, exposure-response relationships, and facilitate early decision making during development. Denosumab, a fully human monoclonal antibody against receptor activator of nuclear factor-κB ligand, profoundly inhibits bone resorption. C-terminal telopeptides of type I collagen (CTx), a bone resorption biomarker, provides early indications of denosumab effectiveness and informs protracted clinical outcomes (e.g., bone mineral density). Because of the dynamic relationship between denosumab and CTx, a precise and robust assay was desired. Thus, we adopted a fit-for-purpose approach to modify and validate a commercial CTx diagnostic kit to meet the intended applications of a quantitative pharmacodynamic biomarker for denosumab development. Seven standards were prepared to replace five calibrators provided in the kit. Three quality controls (QC) and two sample controls were used to characterize and monitor assay performance. Robotic workstations were used for standard and QC preparation and assay execution. Method validation experiments were conducted with rigor and procedures similar to those used for drug bioanalysis. The method demonstrated a linear range of 0.0490-2.34 ng/mL with four-parameter logistic regression. Inter-assay total error of validation samples in serum was ≤26.7%. Extensive tests were conducted on selectivity in sera from target populations, specificity, stability, parallelism, and dilutional linearity. Applications to samples from numerous clinical studies confirmed that the CTx method was reliable, robust, and fit for use as an early indicator of denosumab effectiveness. Refinement supported the confidence for use in pharmacokinetic/pharmacodynamic modeling, dose selections, correlation to clinical effects, and formulation bioequivalence work.KEY WORDS: bone resorption marker; commercial immunoassay kit; method validation; pharmacodynamic (PD) biomarker; serum C-terminal telopeptides of type 1 (CTx).

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Specificity and selectivity evaluations of ligand binding assay of protein therapeutics against concomitant drugs and related endogenous proteins

Cited by 39 publications

References 16 publications

Large Molecule Specific Assay Operation: Recommendation for Best Practices and Harmonization from the Global Bioanalysis Consortium Harmonization Team

Large Molecule Specific Assay Operation: Recommendation for Best Practices and Harmonization from the Global Bioanalysis Consortium Harmonization Team

Parallelism Experiments to Evaluate Matrix Effects, Selectivity and Sensitivity in Ligand-Binding Assay Method Development: Pros and Cons

“Fit-for-Purpose” Method Validation and Application of a Biomarker (C-terminal Telopeptides of Type 1 Collagen) in Denosumab Clinical Studies

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