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1.
Anal Chem ; 86(17): 8776-84, 2014 Sep 02.
Artigo em Inglês | MEDLINE | ID: mdl-25010922

RESUMO

Quantitation of therapeutic monoclonal antibodies (mAb) using liquid chromatography-tandem mass spectrometry (LC-MS/MS) for pharmacokinetic (PK) studies is becoming an essential complement to traditional antibody-based ligand binding assays (LBA). Here we show an automated method to perform LC-MS/MS-based quantitation, with IgG1 conserved peptides, a heavy isotope labeled mAb internal standard, and anti-human Fc enrichment. All reagents in the method are commercially available with no requirement to develop novel assay-specific reagents. The method met traditional quantitative LC-MS/MS assay analytical characteristics in terms of precision, accuracy, and specificity. The method was applied to the pharmacokinetic study of a mAb dosed in cynomolgus monkey, and the results were compared with the immunoassay data. This methodology has the potential to benefit and accelerate the early biopharmaceutical development process, particularly by enabling PK analysis across species and candidate molecules with minimal method development.


Assuntos
Anticorpos Monoclonais/farmacocinética , Análise Química do Sangue/instrumentação , Peptídeos/análise , Espectrometria de Massas em Tandem , Sequência de Aminoácidos , Animais , Anticorpos Monoclonais/sangue , Cromatografia Líquida de Alta Pressão , Avaliação Pré-Clínica de Medicamentos , Ensaio de Imunoadsorção Enzimática , Meia-Vida , Imunoglobulina G/metabolismo , Imunoprecipitação , Marcação por Isótopo , Macaca fascicularis , Dados de Sequência Molecular , Peptídeos/química
2.
Mol Cancer Ther ; 9(8): 2344-53, 2010 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-20663931

RESUMO

Cyclin-dependent kinases (CDK) are key positive regulators of cell cycle progression and attractive targets in oncology. SCH 727965 inhibits CDK2, CDK5, CDK1, and CDK9 activity in vitro with IC(50) values of 1, 1, 3, and 4 nmol/L, respectively. SCH 727965 was selected as a clinical candidate using a functional screen in vivo that integrated both efficacy and safety parameters. Compared with flavopiridol, SCH 727965 exhibits superior activity with an improved therapeutic index. In cell-based assays, SCH 727965 completely suppressed retinoblastoma phosphorylation, which correlated with apoptosis onset and total inhibition of bromodeoxyuridine incorporation in >100 tumor cell lines of diverse origin and background. Moreover, short exposures to SCH 727965 were sufficient for long-lasting cellular effects. SCH 727965 induced regression of established solid tumors in a range of mouse models following intermittent scheduling of doses below the maximally tolerated level. This was associated with modulation of pharmacodynamic biomarkers in skin punch biopsies and rapidly reversible, mechanism-based effects on hematologic parameters. These results suggest that SCH 727965 is a potent and selective CDK inhibitor and a novel cytotoxic agent.


Assuntos
Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia , Quinases Ciclina-Dependentes/antagonistas & inibidores , Piperidinas/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Compostos de Piridínio/farmacologia , Antineoplásicos/efeitos adversos , Antineoplásicos/química , Antineoplásicos/farmacologia , Compostos Bicíclicos Heterocíclicos com Pontes/efeitos adversos , Compostos Bicíclicos Heterocíclicos com Pontes/química , Linhagem Celular Tumoral , Óxidos N-Cíclicos , Relação Dose-Resposta a Droga , Flavonoides/química , Flavonoides/farmacologia , Humanos , Indolizinas , Fosforilação/efeitos dos fármacos , Piperidinas/efeitos adversos , Piperidinas/química , Poli(ADP-Ribose) Polimerases/metabolismo , Inibidores de Proteínas Quinases/efeitos adversos , Inibidores de Proteínas Quinases/química , Compostos de Piridínio/efeitos adversos , Compostos de Piridínio/química , Proteína do Retinoblastoma/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
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