Generic anti-drug antibody assay with drug tolerance in serum samples from mice exposed to human antibodies

Stubenrauch, Kay; Mackeben, Klaus; Vogel, Rudolf; Heinrich, Joachim

doi:10.1016/j.ab.2012.08.022

Cited by 15 publications

(12 citation statements)

References 11 publications

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“…Anti-drug antibodies (ADA) were analyzed with a generic ADA assay in streptavidin-coated 96 well microplates as described by Stubenrauch et al (19). In this sandwich-ELISA, ADAs are converted to immune complexes by pre-incubation with excess drug.…”

Section: Methodsmentioning

confidence: 99%

Neonatal Immune Tolerance Induction to Allow Long-Term Studies With an Immunogenic Therapeutic Monoclonal Antibody in Mice

Piccand

Bessa

Schick

et al. 2015

AAPS J

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Abstract. The purpose of this study is to test the feasibility of neonatal immune tolerance induction in mice to enable long-term pharmacokinetic studies with immunogenic therapeutic monoclonal antibodies (mAb). Neonatal immune tolerance was induced by transfer of a mAb to neonatal mice via colostrum from nursing mother mice treated with two subcutaneous doses of a tolerogen starting within the first 24 h after delivery. Adalimumab and efalizumab were administered as tolerogens at various dose levels. Tolerance induction was evaluated in the offspring after reaching adulthood at 8 weeks of age. After a single intravenous injection of the same mAb as used for tolerance induction, the pharmacokinetics of the mAb and formation of anti-drug antibodies (ADA) in plasma were assessed using ELISA. Tolerance induction to adalimumab was achieved in a maternal dose-dependent manner. Adalimumab immunetolerant offspring showed a slower adalimumab clearance (4.24±0.32 mL/day/kg) as compared to the control group (12.09±3.81 mL/day/kg). In the control group, accelerated clearance started 7 days after adalimumab dosing, whereas immune-tolerant offspring showed a log-linear terminal concentration-time course. In the offspring, the absence of predose ADA levels was indicative of successful tolerance induction. The second test compound efalizumab was not immunogenic in mice under our experimental conditions. Overall, the present study demonstrated the suitability of neonatal immune tolerance induction for a 4-week single dose study in adult mice with a human therapeutic mAb that is otherwise immunogenic in laboratory animals.

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Section: Methodsmentioning

confidence: 99%

Neonatal Immune Tolerance Induction to Allow Long-Term Studies With an Immunogenic Therapeutic Monoclonal Antibody in Mice

Piccand

Bessa

Schick

et al. 2015

AAPS J

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“…The CIC assay used in the present study detects in vivo formed CICs consisting of ADAs in complex with hIgG independent of test substance target and IgG subtype specificity. 21,47 In comparison, the standard bridging ADA assay detects monomeric ADAs not in complex with test substance. The ADA and CIC assays have been shown to complement each other well, as the CIC assay has higher drug tolerance, whereas the ADA assay has better sensitivity at low or absent exposure.…”

Section: Discussionmentioning

confidence: 99%

Formation and Glomerular Deposition of Immune Complexes in Mice Administered Human Antibodies: Evaluation of Dose, Frequency, and Biomarkers

et al. 2020

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Administration of human protein–based drugs to animals often leads to formation of antidrug antibodies (ADAs) that may form circulating immune complexes (CICs) with the dosed protein. Circulating immune complexes can activate and bind complement (cCICs), and if large amount of CICs or cCICs is formed, the clearance mechanism potentially becomes saturated, which can lead to immune complex (IC) deposition and inflammation. To obtain a better understanding of the underlying factors, including the relationship between different dose regimes on IC formation and deposition and identification of possible biomarkers of IC deposition and IC-related pathological changes in kidneys, BALB/c and C57BL/6J mice were administered with human anti-tumor necrosis factor α (aTNFα, adalimumab) or a humanized anti-TNP (aTNP) antibody for 13 weeks. Particularly, ADA, CIC, cCIC formation, IC deposition, and glomerulonephritis were observed in C57BL/6J administered with aTNFα, whereas the immunologic response was minor in BALB/c mice administered with aTNFα and in BALB/c and C57BL/6J mice administered aTNP. Changing dose levels or increasing dosing frequency of aTNFα on top of an already-established CIC and cCIC response did not lead to substantial changes in CIC, cCIC formation, or IC deposition. Finally, no association between the presence of CICs or cCIC in plasma and glomerular IC deposition and/or glomerulonephritis was observed.

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“…ADA assays typically use drug-specific reagents that require substantial time and resources to prepare and characterize. Generic ADA assays that can be applied to all human monoclonal antibody therapeutics have been reported for nonclinical applications [ 36 , 37 ]. These “off-the-shelf” assays require minimal assay optimization and can be used for early candidate selection studies right up to IND-enabling GLP studies.…”

Section: Generic Ada Assay Methodologiesmentioning

confidence: 99%

“…Immune-complex assays have been used to measure immunogenicity in mouse and cynomolgus monkey studies [ 36 , 37 ]. The assays used anti-human constant region antibodies to capture the drug and anti-mouse or anti-cynomolgus IgG species-specific antibodies to detect the drug-ADA complex.…”

Section: Generic Ada Assay Methodologiesmentioning

confidence: 99%

Emerging Technologies and Generic Assays for the Detection of Anti-Drug Antibodies

Partridge

Purushothama

Elango

et al. 2016

Journal of Immunology Research

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Anti-drug antibodies induced by biologic therapeutics often impact drug pharmacokinetics, pharmacodynamics response, clinical efficacy, and patient safety. It is critical to assess the immunogenicity risk of potential biotherapeutics in producing neutralizing and nonneutralizing anti-drug antibodies, especially in clinical phases of drug development. Different assay methodologies have been used to detect all anti-drug antibodies, including ELISA, radioimmunoassay, surface plasmon resonance, and electrochemiluminescence-based technologies. The most commonly used method is a bridging assay, performed in an ELISA or on the Meso Scale Discovery platform. In this report, we aim to review the emerging new assay technologies that can complement or address challenges associated with the bridging assay format in screening and confirmation of ADAs. We also summarize generic anti-drug antibody assays that do not require drug-specific reagents for nonclinical studies. These generic assays significantly reduce assay development efforts and, therefore, shorten the assay readiness timeline.

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Generic anti-drug antibody assay with drug tolerance in serum samples from mice exposed to human antibodies

Cited by 15 publications

References 11 publications

Neonatal Immune Tolerance Induction to Allow Long-Term Studies With an Immunogenic Therapeutic Monoclonal Antibody in Mice

Neonatal Immune Tolerance Induction to Allow Long-Term Studies With an Immunogenic Therapeutic Monoclonal Antibody in Mice

Formation and Glomerular Deposition of Immune Complexes in Mice Administered Human Antibodies: Evaluation of Dose, Frequency, and Biomarkers

Emerging Technologies and Generic Assays for the Detection of Anti-Drug Antibodies

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