A breakthrough novel method to resolve the drug and target interference problem in immunogenicity assays

Zoghbi, Jad; Xu, Yuanxin; Grabert, Ryan C.; Theobald, Valerie; Richards, Susan

doi:10.1016/j.jim.2015.08.002

Cited by 73 publications

(40 citation statements)

References 14 publications

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“…It is recommended in cases where drug tolerance is poor resulting in ADA assays with significant drug interference, the sponsor should provide the totality of the data and demonstrate a good faith effort to develop a drugtolerant assay by considering exploring acid dissociation, acid-capture-elution (ACE), solid-phase extraction with acid dissociation (SPEAD), precipitation and acid method (PANDA) [33] or an alternative assay format [34,35]. However, if acid dissociation is used, there is a risk of denaturing ADA due to pH treatment, or the potential to release the soluble target from the therapeutic:target complex [36].…”

Section: Drug Tolerancementioning

confidence: 99%

2017 White Paper on Recent Issues in Bioanalysis: A Global Perspective on Immunogenicity Guidelines & Biomarker Assay Performance (Part 3 – Lba: Immunogenicity, Biomarkers and PK Assays)

et al. 2017

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The 2017 11th Workshop on Recent Issues in Bioanalysis took place in Los Angeles/Universal City, California, on 3–7 April 2017 with participation of close to 750 professionals from pharmaceutical/biopharmaceutical companies, biotechnology companies, contract research organizations and regulatory agencies worldwide. WRIB was once again a 5-day, week-long event – a full immersion week of bioanalysis, biomarkers and immunogenicity. As usual, it was specifically designed to facilitate sharing, reviewing, discussing and agreeing on approaches to address the most current issues of interest including both small- and large-molecule analysis involving LC–MS, hybrid ligand-binding assay (LBA)/LC–MS and LBA approaches. This 2017 White Paper encompasses recommendations emerging from the extensive discussions held during the workshop, and is aimed to provide the bioanalytical community with key information and practical solutions on topics and issues addressed, in an effort to enable advances in scientific excellence, improved quality and better regulatory compliance. Due to its length, the 2017 edition of this comprehensive White Paper has been divided into three parts for editorial reasons. This publication (Part 3) covers the recommendations for large-molecule bioanalysis, biomarkers and immunogenicity using LBA. Part 1 (LC–MS for small molecules, peptides and small molecule biomarkers) and Part 2 (hybrid LBA/LC–MS for biotherapeutics and regulatory agencies’ inputs) are published in volume 9 of Bioanalysis, issues 22 and 23 (2017), respectively.

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Section: Drug Tolerancementioning

confidence: 99%

2017 White Paper on Recent Issues in Bioanalysis: A Global Perspective on Immunogenicity Guidelines & Biomarker Assay Performance (Part 3 – Lba: Immunogenicity, Biomarkers and PK Assays)

et al. 2017

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“…Alternative tests are therefore required to determine the true nature of interfering factors. Methods that can be applied to evaluate the nature of assay interfering factors include Protein A/G depletion, RF-specific blocker, and removal or blocking of drug target (23)(24)(25)(26)(27). The approach based on pre-adsorption and extraction of the preexisting antibody, e.g., using the abovementioned reagents, would have the advantage of clearly distinguishing reactivity due to antibody responses versus other assay interferents.…”

Section: Assay Strategies For Evaluating Potential Pre-existing Antibmentioning

confidence: 99%

Recommendations for the Assessment and Management of Pre-existing Drug-Reactive Antibodies During Biotherapeutic Development

Xue

Clements-Egan

Amaravadi

et al. 2017

AAPS J

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Abstract.Anti-drug antibodies (ADA) pose a potential risk to patient safety and efficacy and are routinely monitored during clinical trials. Pre-existing drug-reactive antibodies are present in patients without prior drug exposure and are defined by their ability to bind to a component of the drug. These pre-existing drug-reactive antibodies are frequently observed and could represent an adaptive immune response of an individual who has been previously exposed to antigens with structural similarities to the biotherapeutic. Clinical consequences of these antibodies can vary from no impact to adverse effects on patient safety, exposure, and efficacy, and are highly dependent on biotherapeutic modality, disease indications, and patient demographics. This paper describes how the immunogenicity risk assessment of a biotherapeutic integrates the existence of pre-existing drug-reactive antibodies, and provides recommendations for risk-based strategies to evaluate treatment-emergent ADA responses.

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“…Unfortunately, in some cases, these acidic conditions may exacerbate the drug target interference by disrupting drug-target complexes and releasing the accumulated target [14]. Acid treatment has also been reported to multimerize a monomeric target in a sample [28]. The target can then potentially bridge with the capture and detection reagents upon neutralization of the sample pH, leading to false-positive results in the ADA screening assay.…”

Section: Overview Of Ada Assaysmentioning

confidence: 99%

“…The effectiveness of PEG precipitation greatly depends on the hydrodynamic radius of the protein [31]. In a recent report, a monomeric drug target dimerized at acidic pH during the acid dissociation step of the bridging assay, leading to false-positive signal [28]. To circumvent the target interference and the low drug tolerance limit, excess drug was added to samples to saturate free ADAs and form drug-ADA complexes.…”

Section: Other Potential Mitigation Strategiesmentioning

confidence: 99%

Drug Target Interference in Immunogenicity Assays: Recommendations and Mitigation Strategies

Zhong

Clements-Egan

Gorovits

et al. 2017

AAPS J

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Abstract.Sensitive and specific methodology is required for the detection and characterization of anti-drug antibodies (ADAs). High-quality ADA data enables the evaluation of potential impact of ADAs on the drug pharmacokinetic profile, patient safety, and efficacious response to the drug. Immunogenicity assessments are typically initiated at early stages in preclinical studies and continue throughout the drug development program. One of the potential bioanalytical challenges encountered with ADA testing is the need to identify and mitigate the interference mediated by the presence of soluble drug target. A drug target, when present at sufficiently high circulating concentrations, can potentially interfere with the performance of ADA and neutralizing antibody (NAb) assays, leading to either false-positive or, in some cases, false-negative ADA and NAb assay results. This publication describes various mechanisms of assay interference by soluble drug target, as well as strategies to recognize and mitigate such target interference. Pertinent examples are presented to illustrate the impact of target interference on ADA and NAb assays as well as several mitigation strategies, including the use of anti-target antibodies, soluble versions of the receptors, target-binding proteins, lectins, and solid-phase removal of targets. Furthermore, recommendations for detection and mitigation of such interference in different formats of ADA and NAb assays are provided.

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A breakthrough novel method to resolve the drug and target interference problem in immunogenicity assays

Cited by 73 publications

References 14 publications

2017 White Paper on Recent Issues in Bioanalysis: A Global Perspective on Immunogenicity Guidelines & Biomarker Assay Performance (Part 3 – Lba: Immunogenicity, Biomarkers and PK Assays)

2017 White Paper on Recent Issues in Bioanalysis: A Global Perspective on Immunogenicity Guidelines & Biomarker Assay Performance (Part 3 – Lba: Immunogenicity, Biomarkers and PK Assays)

Recommendations for the Assessment and Management of Pre-existing Drug-Reactive Antibodies During Biotherapeutic Development

Drug Target Interference in Immunogenicity Assays: Recommendations and Mitigation Strategies

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