Use of the DAF Assay to Assess the
Functional Properties of Polyclonal
and Monoclonal Rh D Antibodies

Ducrot, T.; Beliard, R.; Glacet, A.; Klein, P.; Harbonnier, S.; Benmostefa, N.; Bourel, D.

doi:10.1159/000462017

Cited by 6 publications

(8 citation statements)

References 22 publications

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“…5 × 10 5 target RhD + RBCs were incubated with serial dilutions of anti-D mAbs in presence of NK cells at an E/T ratio of 3:1. ADCC was then quantified using the 2.7 diaminofluorene (DAF) assay, as previously described [25]. O.D.…”

Section: Adcc Analysismentioning

confidence: 99%

Effect of zinc on human IgG1 and its FcγR interactions

et al. 2012

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Section: Adcc Analysismentioning

confidence: 99%

Effect of zinc on human IgG1 and its FcγR interactions

et al. 2012

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“…These biological effects would typically include standard pharmacological and toxicological tests, in vivo biomarker (either target and/or mechanism biomarkers) studies, and dose–response studies in disease models. Routine in vitro pharmacological testing includes receptor binding affinity and occupancy experiments with human receptors or receptor‐bearing cells and other mechanism‐specific assays such as antibody‐dependant cell cytotoxicity (ADCC) assay [20]. In vivo testing may include PK–PD experiments to characterize the relationship between dose, exposure, and biomarker changes, and efficacy studies in appropriate disease models, when available.…”

Section: Proposed Approach By Emeamentioning

confidence: 99%

Use of pharmacokinetic/ pharmacodynamic modelling for starting dose selection in first‐in‐human trials of high‐risk biologics

Agoram

2009

Brit J Clinical Pharma

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WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• Recent regulatory guidance has highlighted the importance of using pharmacokinetic-pharmacodynamic (PK-PD) modelling in the selection of starting doses in first-in-human trials of high-risk biologics.• However, limited examples exist in literature illustrating this procedure. WHAT THIS STUDY ADDS• An interpretation of the recommended dose-selection methodology and the minimum anticipated biological effect level (MABEL) principle, contained in the updated European Medicines Agency guidance on risk-mitigation strategies for first-in-human studies, is presented.• Some literature and simulation-based examples of the application of PK-PD modelling principles to starting dose selection using in vitro and in vivo data under the MABEL paradigm are highlighted, along with the advantages and limitations of this approach. AIMSTo illustrate the use of pharmacokinetic-pharmacodynamic (PK-PD) models to select rational starting doses in clinical trials within the minimum anticipated biological effect level (MABEL) principle using literature data and through simulations. METHODSThe new European Medicines Agency guidance on starting dose selection of high-risk biologics was analysed considering the basic pharmacological properties and preclinical testing limitations of many biologics. The MABEL approach to dose selection was illustrated through simulations and through literature-reported examples on the selection of starting doses for biologics such as antibodies based on in vitro biomarker data, in vivo PK and PK-PD data. RESULTSLiterature reports indicating the use of preclinical pharmacological and toxicological data to select successfully safe starting doses in line with the MABEL principle are summarized. PK-PD model-based simulations of receptor occupancy for an anti-IgE antibody system indicate that the relative abundance of IgE in animal models and patients and the turnover rate of the IgE-antibody complex relative to the off-rate of the antibody from IgE are important determinants of in vivo receptor occupancy. CONCLUSIONSMechanistic PK-PD models are capable of integrating preclinical in vitro and in vivo data to select starting doses rationally in first-in-human trials. Biological drug-receptor interaction dynamics is complex and multiple factors affect the dose-receptor occupancy relationship. Thus, these factors should be taken into account when selecting starting doses.

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“…Three repeats were done for each point. Plates were incubated at 37 o C for 18-20 h, then samples of the supernatant were collected and free hemoglobin was assessed colorimetrically [5]. Hemolytic activity of MCA relative to antirhesus Ig activity taken as 100% was determined by the formula:…”

Section: Methodsmentioning

confidence: 99%

Effect of Producer Cell Line on Functional Activity of Anti-D Monoclonal Antibodies Destined for Prevention of Rhesus Sensitization

et al. 2009

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The ability of anti-D antibodies to cause antigen-specific immunosuppression depends on their interaction with low-affinity Fcgamma-receptors. Human monoclonal antibodies to D antigen of the rhesus system were investigated by antibody-dependent cytotoxicity assay in order to estimate their ability to induce hemolysis mediated by low-affinity Fcgamma receptors. We demonstrate that affinity of monoclonal antibodies to receptors of this type does not depend on primary structure of Fc-fragment, but depends on the producer cell line which expresses the antibodies. Monoclonal IgG1 antibodies interacting with FcgammaRIIa and FcgammaRIII lost this property, if they were secreted by human-mouse heterohybridoma, but not by human B-cell line. On the opposite, monoclonal antibodies that could not activate low-affinity Fcgamma receptors were highly active after human cells fusion with rat myeloma YB2/0. Hemolytic activity of IgG3 remained unchanged after fusion of human cells with rodent cells.

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Use of the DAF Assay to Assess the Functional Properties of Polyclonal and Monoclonal Rh D Antibodies

Cited by 6 publications

References 22 publications

Effect of zinc on human IgG1 and its FcγR interactions

Effect of zinc on human IgG1 and its FcγR interactions

Use of pharmacokinetic/ pharmacodynamic modelling for starting dose selection in first‐in‐human trials of high‐risk biologics

Effect of Producer Cell Line on Functional Activity of Anti-D Monoclonal Antibodies Destined for Prevention of Rhesus Sensitization

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