Summary of Confirmation Cut Point Discussions

Smith, Holly W.; Moxness, Michael; Marsden, Robin

doi:10.1208/s12248-011-9263-z

Cited by 18 publications

(12 citation statements)

References 4 publications

(3 reference statements)

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“…Mire-Sluis et al recommend a confirmatory step during immunogenicity assessment of a biotherapeutic that ascertains the specificity of the initial screening response (16,17) to be biotherapeutic specific. The specificity step usually involves the depletion of the antibody signal by adding an excess amount of biotherapeutic (5)(6)(7)(8)(9)13,18).…”

Section: Discussionmentioning

confidence: 99%

Statistical and Bioanalytical Considerations for Establishing a Depletion Criterion for Specificity Testing During Immunogenicity Assessment of a Biotherapeutic

Driscoll

Zhou

Moxness

et al. 2013

AAPS J

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Abstract. Immunogenicity assessment of fully human monoclonal antibody-based biotherapeutics requires sensitive and specific ligand binding assays. One of the components of specificity is the depletion of signal by a relevant biotherapeutic that is commonly based on an arbitrary depletion criterion of inhibition of the original response or reduction of the signal below the screening assay cut point (ACP). Hence, there is a need to develop a statistically derived physiologically relevant specificity criterion. We illustrate an optimization approach to determine the concentration of biotherapeutic required for the specificity evaluation. Naïve donor sample sets with and without circulating drug and antitherapeutic/drug antibody (ADA) were prepared. Next, a depletion cut point (DCP) using naïve and ADA-containing donor sets with the optimized biotherapeutic concentration was evaluated. A statistically derived design of experiment was used to establish a validated DCP. A reliable DCP requires naïve (no ADA) donors treated only with an optimized concentration of biotherapeutic. The additional DCPs generated using two distinct concentrations of ADA-spiked sample sets led to a physiologically irrelevant criterion that was not necessarily representative of real-time samples. This increased the risk of false positives or negatives. In this study, well-defined bioanalytical and statistical methods were employed to validate a DCP to confirm the presence of biotherapeutic specific ADA in human serum samples. A physiologically relevant and effective strategy to confirm specificity in immune reactive samples, especially those that are close to the ACP, is proposed through this study.

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Section: Discussionmentioning

confidence: 99%

Statistical and Bioanalytical Considerations for Establishing a Depletion Criterion for Specificity Testing During Immunogenicity Assessment of a Biotherapeutic

Driscoll

Zhou

Moxness

et al. 2013

AAPS J

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“…Assay signals from a panel of samples from study drug-naive breast cancer patients were used for the determination of the assay cut-point factor, which in conjunction with the negative control was used to calculate the cut-point for each assay run. Cut-point factors with a false-positive rate set at 5% were determined using statistical methodology described elsewhere [ 15 , 16 ]. A sample with an assay signal at or above the cut-point was considered as having screened positive.…”

Section: Methodsmentioning

confidence: 99%

“…Binding was measured with and without the study drug (lipegfilgrastim or pegfilgrastim) in solution phase, and the ratio of binding signal was calculated and expressed as a percentage of signal inhibition. A cut-point with a false-positive rate set at 1% was determined for each drug using commercially available serum samples from treatment-naive cancer patients in accordance with statistical methods [ 15 , 16 ]. Samples were identified as confirmed-positive if the percentage of signal inhibition was greater than or equal to the confirmatory cut-point for lipegfilgrastim (28.5%) or pegfilgrastim (28.2%).…”

Section: Methodsmentioning

confidence: 99%

“…Binding signals were determined in the presence of unlabeled filgrastim, the PEG portion of lipegfilgrastim (cPEG), or glycosylated G-CSF (glycoG-CSF; Granocyte®; Chugai Pharma), which is an analog of endogenous G-CSF. The cut-points (% signal inhibition) for binding specificity were determined statistically (with false-positive rate set at 1%), using commercially available serum samples from treatment-naive cancer patients in accordance with statistical methodology [ 15 , 16 ], to be 22.0% for filgrastim, 19.4% for cPEG, and 17.5% for glycoG-CSF.…”

Section: Methodsmentioning

confidence: 99%

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Immunogenicity Assessment of Lipegfilgrastim in Patients with Breast Cancer Receiving Chemotherapy

Zou

Buchner

Roberge

et al. 2016

Journal of Immunology Research

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Lipegfilgrastim is a long-acting, once-per-cycle, glycopegylated recombinant granulocyte colony-stimulating factor (G-CSF) used to prevent neutropenia in patients receiving myelosuppressive chemotherapy. This integrated analysis examined the immunogenicity of lipegfilgrastim and its potential clinical impact in two double-blind randomized studies (phases II and III) of patients with breast cancer receiving chemotherapy. Serum samples were analyzed using sequential assays for screening, confirmation, antibody titer, and characterization of antidrug antibodies (ADA). Neutropenia-related efficacy measures were reviewed for each ADA-positive patient. Among 255 patients receiving lipegfilgrastim (154 in phase II, 101 in phase III) and 155 patients receiving pegfilgrastim (54 in phase II, 101 in phase III), the incidence of treatment-emergent ADA was low and similar between the lipegfilgrastim (phase II: 1.3%; phase III: 1.0%) and pegfilgrastim (phase II: 1.9%; phase III: 1.0%) arms. None of the treatment-emergent ADA-positive samples exhibited neutralizing activity against lipegfilgrastim, pegfilgrastim, or glycosylated G-CSF in a cell-based neutralizing antibody assay. No changes were observed in neutropenia-related efficacy measures among ADA-positive patients, and no treatment-related hypersensitivity or anaphylaxis occurred. These results indicate that there is no apparent impact of ADA on lipegfilgrastim efficacy and safety.

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“…The potential positives from the screening assay are then tested with a confirmatory assay and the confirmed positives are titrated and/or tested with a neutralizing antibody assay. One way to confirm the potential positives obtained in the screening assay is to test the samples with the same assay in the presence of drug concentrations which exhibit specific signal inhibition with the assay positive control antibodies (Shankar et al, 2008;Swanson and Chirmule, 2009;Smith et al, 2011). The confirmation CP is the percentage of signal suppression at or above which the sample is confirmed positive.…”

Section: Evaluating Confirmation Of Ada Positive Samples By Drug Inhimentioning

confidence: 99%

Addressing drug effects on cut point determination for an anti-drug antibody assay

Barbosa

Gleason

Phillips

et al. 2012

Journal of Immunological Methods

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Summary of Confirmation Cut Point Discussions

Cited by 18 publications

References 4 publications

Statistical and Bioanalytical Considerations for Establishing a Depletion Criterion for Specificity Testing During Immunogenicity Assessment of a Biotherapeutic

Statistical and Bioanalytical Considerations for Establishing a Depletion Criterion for Specificity Testing During Immunogenicity Assessment of a Biotherapeutic

Immunogenicity Assessment of Lipegfilgrastim in Patients with Breast Cancer Receiving Chemotherapy

Addressing drug effects on cut point determination for an anti-drug antibody assay

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