Pharmacokinetic immunoassay methods in the presence of soluble target

Verch, Thorsten; Chilewski, Shannon D; Bouaraphan, Silikhone; Yarovoi, Helen; Yin, Kuo‐Chang; Chen, Dave; Washabaugh, Michael W.

doi:10.1016/j.jim.2010.07.014

Cited by 19 publications

(7 citation statements)

References 22 publications

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“…Due to its ease of access, plasma remains the gold standard matrix for basic PK characterization and constitutes the central point of reference for the assessment of drug distribution, clearance and thus half‐life 1 . Depending on drug binding to plasma proteins 7 and/or circulating soluble targets, 8,9 either the total drug concentration in plasma or its free fraction should be used for PK. The distribution of most drugs will change if its unbound fraction is altered.…”

Section: Ten Parameters Of Interest To Reach the Drugs' Sites Of Actimentioning

confidence: 99%

“…in infections and particularly in malignancies continuously changing expression patterns. Additionally, PK evaluation based on total plasma concentrations can be biased by plasma protein binding 7 or the presence of shed and circulating soluble targets 8,9 . In these cases, the unbound drug fraction in plasma can be more informative, not least because it can change over time.…”

Section: Introductionmentioning

confidence: 99%

“…Additionally, PK evaluation based on total plasma concentrations can be biased by plasma protein binding 7 or the presence of shed and circulating soluble targets. 8,9 In these cases, the unbound drug fraction in plasma can be more informative, not least because it can change over time. In view of these elements, drug quantification at the different sites of action will probably foster a more precise evaluation of concentration-effect relationships and minimize the impact of its modulators.…”

mentioning

confidence: 99%

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Approaching sites of action of drugs in clinical pharmacology: New analytical options and their challenges

Longuespée

Theile

Fresnais

et al. 2020

Brit J Clinical Pharma

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Clinical pharmacology is an important discipline for drug development aiming to define pharmacokinetics (PK), pharmacodynamics (PD) and optimum exposure to drugs, i.e. the concentration-response relationship and its modulators. For this purpose, information on drug concentrations at the anatomical, cellular and molecular sites of action is particularly valuable. In pharmacological assays, the limited accessibility of target cells in readily available samples (i.e. blood) often hampers mass spectrometry-based monitoring of the absolute quantity of a compound and the determination of its molecular action at the cellular level. Recently, new sample collection methods have been developed for the specific capture of rare circulating cells, especially for the diagnosis of circulating tumour cells. In parallel, new advances and developments in mass spectrometric instrumentation now allow analyses to be scaled down to the cellular level. Together, these developments may permit the monitoring of minute drug quantities and show their effect at the cellular level. In turn, such PK/PD associations on a cellular level would not only enrich our pharmacological knowledge of a given compound but also expand the basis for PK/PD simulations. In this review, we describe novel concepts supporting clinical pharmacology at the anatomical, cellular and molecular sites of action, and highlight the new challenges in mass spectrometry-based monitoring. Moreover, we present methods to tackle these challenges and define future needs. K E Y W O R D S clinical pharmacology, mass spectrometry, personalized medicine, review, sites of action 1 | INTRODUCTION Clinical pharmacology studies the relevant parameters of drug fate (pharmacokinetics, PK) and efficacy (pharmacodynamics, PD) in humans in order to establish the dose-response and concentrationresponse relationship. It also defines intraindividual and interindividual modulators of these relationships, leading to different effectiveness, safety and dose requirements. Monitoring drug concentrations and effects is therefore of considerable importance during drug development, starting with the very first clinical trials. 1 Clinical pharmacology clarifies mechanisms of both beneficial and adverse drug effects in order to get closer to drug effectiveness monitoring. A drug's site of action can be defined at different scales: anatomical (the compartment the drug has to reach, e.g. tissues), cellular (the

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Section: Ten Parameters Of Interest To Reach the Drugs' Sites Of Actimentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

mentioning

confidence: 99%

See 1 more Smart Citation

Approaching sites of action of drugs in clinical pharmacology: New analytical options and their challenges

Longuespée

Theile

Fresnais

et al. 2020

Brit J Clinical Pharma

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“…Thus, in assays where target interference is anticipated or known to be an issue, an anti-ID mAb might be less appealing than pAbs as an assay detection reagent, but this would need to be evaluated on a case-by-case basis. 18 CDR-specific pAbs are typically affinity purified using the CDR of a rhumAb. In general, CDRspecific pAbs can tolerate interference from soluble target better than anti-ID mAbs because they comprise a mixture of antibodies with different specificities, subclasses and affinities; however, CDR-specific pAbs may not have good lot-to-lot consistency in reagent performance.…”

Section: Generating Mab 10c4mentioning

confidence: 99%

Generation and characterization of a unique reagent that recognizes a panel of recombinant human monoclonal antibody therapeutics in the presence of endogenous human IgG

Wang

Quarmby

et al. 2013

mAbs

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Pharmacokinetic (PK) and immunohistochemistry (IHC) assays are essential to the evaluation of the safety and efficacy of therapeutic monoclonal antibodies (mAb) during drug development. These methods require reagents with a high degree of specificity because low concentrations of therapeutic antibody need to be detected in samples containing high concentrations of endogenous human immunoglobulins. Current assay reagent generation practices are labor-intensive and time-consuming. Moreover, these practices are molecule-specific and so only support one assay for one program at a time. Here, we describe a strategy to generate a unique assay reagent, 10C4, that preferentially recognizes a panel of recombinant human mAbs over endogenous human immunoglobulins. This "panel-specific" feature enables the reagent to be used in PK and IHC assays for multiple structurally-related therapeutic mAbs. Characterization revealed that the 10C4 epitope is conformational, extensive and mainly composed of non-CDR residues. Most key contact residues were conserved among structurally-related therapeutic mAbs, but the combination of these residues exists at low prevalence in endogenous human immunoglobulins. Interestingly, an indirect contact residue on the heavy chain of the therapeutic appears to play a critical role in determining whether or not it can bind to 10C4, but has no affect on target binding. This may allow us to improve the binding of therapeutic mAbs to 10C4 for assay development in the future. Here, for the first time, we present a strategy to develop a panel-specific reagent that can expedite the development of multiple clinical assays for structurally-related therapeutic mAbs.

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“…Consequently, it is important to determine what forms are measured with a given LBA, especially if the concentration of soluble drug target is not negligible compared to the drug concentration at the time point of measurement. 12 There is still an ongoing debate about what form of the drug is the most relevant to measure. 13 Anti-idiotypic antibodies that bind to the paratope of the therapeutic antibody typically interfere with drug-target binding and are therefore inhibitory.…”

Section: Introductionmentioning

confidence: 99%

Generation by phage display and characterization of drug-target complex-specific antibodies for pharmacokinetic analysis of biotherapeutics

Harth

Haaf

Loew

et al. 2018

mAbs

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Anti-idiotypic antibodies play an important role in pre-clinical and clinical development of therapeutic antibodies, where they are used for pharmacokinetic studies and for the development of immunogenicity assays. By using an antibody phage display library in combination with guided in vitro selection against various marketed drugs, we generated antibodies that recognize the drug only when bound to its target. We have named such specificities Type 3, to distinguish them from the anti-idiotypic antibodies that specifically detect free antibody drug or total drug. We describe the generation and characterization of such reagents for the development of ligand binding assays for drug quantification. We also show how these Type 3 antibodies can be used to develop very specific and sensitive assays that avoid the bridging format.Abbreviations: BAP: bacterial alkaline phosphatase; CDR: complementarity-determining regions in VH or VL; Fab: antigen-binding fragment of an antibody; HRP: horseradish peroxidase; HuCAL®: Human Combinatorial Antibody Libraries; IgG: immunoglobulin G; LBA: ligand binding assay; LOQ: limit of quantitation; NHS: normal human serum; PK: pharmacokinetics; VH: variable region of the heavy chain of an antibody; VL: variable region of the light chain of an antibody.

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Pharmacokinetic immunoassay methods in the presence of soluble target

Cited by 19 publications

References 22 publications

Approaching sites of action of drugs in clinical pharmacology: New analytical options and their challenges

Approaching sites of action of drugs in clinical pharmacology: New analytical options and their challenges

Generation and characterization of a unique reagent that recognizes a panel of recombinant human monoclonal antibody therapeutics in the presence of endogenous human IgG

Generation by phage display and characterization of drug-target complex-specific antibodies for pharmacokinetic analysis of biotherapeutics

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