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1.
Bioanalysis ; 15(6): 343-359, 2023 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-37026566

RESUMO

Background: An antibody specific to small-molecule inhibitor-bound TNF has enabled the development of target occupancy biomarker assays to support the development of novel treatments for autoimmune disorders. Materials & methods: ELISAs were developed for inhibitor-bound and total TNF to determine the percentage of TNF occupancy in samples from stimulated blood. Inhibitor-saturated samples allowed measurement of total and inhibitor-bound TNF in a single electrochemiluminescence immunoassay. Results: TNF occupancy was proportional to inhibitor concentration in plasma samples. An electrochemiluminescence method for inhibitor-bound TNF was validated for use as a potential clinical occupancy biomarker assay. Conclusion: Development of these assays has allowed measurement of a target occupancy biomarker, which has supported progression of the first small-molecule inhibitors of TNF.


Assuntos
Anticorpos , Ensaio de Imunoadsorção Enzimática
2.
Bioanalysis ; 13(21): 1617-1625, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34601974

RESUMO

As the number of therapeutic modalities expand, and the field of scientific research evolves toward finding treatment solutions for complex and rare disease, an ability to demonstrate efficacy through biomarker end points in clinical development studies is becoming increasingly important. Implementing flow cytometry in a clinical setting is challenging and many sponsor organizations take a hybrid approach, developing complex analytical methods internally before identifying and forming partnerships with contract research organizations to conduct the formal analytical method validation and sample bioanalysis. Ensuring that these interactions are effective is critical to the delivery of high-quality, impactful clinical data. This paper provides a review of the recommendations, challenges and solutions for the implementation of decision-making flow cytometry end points effectively utilizing the Sponsor Contract Research Organization interaction.


Assuntos
Citometria de Fluxo , Biomarcadores/análise , Humanos , Relatório de Pesquisa
3.
J Pharmacol Toxicol Methods ; 104: 106874, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32446729

RESUMO

INTRODUCTION: Several compounds from a neuroscience project induced convulsions in animals, at low exposure levels via a hypothetical off-target mechanism. A set of in vitro and in vivo experiments were conducted in order to 1) identify the mechanism behind convulsions; 2) characterize the convulsions, 3) detect premonitory signs that could be monitored clinically, and 4) assess the development of tolerance after repeat dosing. METHODS: Patch clamp assays were conducted on 12 different ion channels (e.g. sodium, potassium, calcium, AMPA, NMDA, GABAA and purinergic receptors) known to be associated with seizures, to identify the off-target culprit. A multiphase study was conducted with UCB-A and UCB-B in Beagle dogs telemetered for video EEG/EMG monitoring to further characterize the convulsive pattern. First, both compounds were administered by intravenous constant infusion (dose: 5 mg/kg/h) over 2 h. Thereafter, the same dogs received a daily oral administration of UCB-A (8 mg/kg/day) for 7 days. RESULTS: Compounds inducing convulsions showed strong inhibitory activity on GABAA channels (IC50 values <10 µM), whereas compounds with partial or no inhibitory effect on these channels did not induce seizures. In EEG experiments, convulsions were preceded by premonitory clinical signs (e.g. tremors, myoclonic jerks) and morphological EEG abnormalities (e.g. sharp waves, spike and wave patterns), confirming their CNS origin. No attenuation of the seizurogenic effects was observed over the 7-day treatment period. DISCUSSION: A well-designed set of experiments including electrophysiological assays on seizure-related ion channels and EEG/EMG assessment in telemetered dogs allowed a proper seizure liability risk assessment, leading to a rapid no go decision for the two most advanced leads.


Assuntos
Canais Iônicos/efeitos dos fármacos , Medição de Risco/métodos , Convulsões/induzido quimicamente , Animais , Células CHO , Cricetulus , Cães , Eletroencefalografia , Fenômenos Eletrofisiológicos , Feminino , Células HEK293 , Humanos , Concentração Inibidora 50 , Canais Iônicos/metabolismo , Chumbo , Masculino , Camundongos , Técnicas de Patch-Clamp , Ratos , Convulsões/fisiopatologia , Telemetria
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