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1.
Bioanalysis ; 8(6): 519-31, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-26915587

RESUMO

BACKGROUND: The bioanalytical strategy for antibody-drug conjugates (ADC) includes multiple integrated measurements of pharmacologically relevant ADC. METHODS & RESULTS: Three ligand-binding assays were validated for the measurement of total antibody, active ADC and total ADC. Accuracy and precision demonstrate %bias from -8 to 14%, %CV from 3 to 11% and total error from 3 to 21%, with >98% samples meeting incurred sample reanalysis criteria. Each assay met stability, selectivity, dilutional integrity, carry over and specificity criteria with no interference from associated metabolite/impurity. Given the active ADC assay sensitivity to payload, active ADC was used to assess drug to antibody ratio. DISCUSSION & CONCLUSION: Implementation of a microfluidic automated platform enabled high throughput sample analysis of multiple analytes with minimal sample processing.


Assuntos
Imunoensaio , Imunoconjugados/análise , Anticorpos Monoclonais/química , Meia-Vida , Imunoensaio/normas , Imunoconjugados/farmacocinética , Lignanas , Preparações Farmacêuticas/química , Controle de Qualidade
2.
Bioanalysis ; 7(13): 1569-82, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26226308

RESUMO

BACKGROUND: The bioanalytical strategy for antibody-drug conjugates (ADC) includes numerous measurements integrally designed to provide comprehensive characterization of PK, PD and immunogenicity. This manuscript describes the utilization of reagents specifically tailored to an ADC with a microtubule polymerization inhibitor payload and cathepsin B cleavable linker. METHODS: The PK strategy includes the evaluation of physiological levels of total antibody, active ADC, total ADC, antibody-conjugated payload and unconjugated payload. These data are evaluated in the context of target and antidrug antibody levels to elucidate bioactive ADC. RESULTS & CONCLUSION: Herein, we discuss how this strategy has been applied and present our preliminary observations. Continuously evolving to meet pipeline demands, the integrated bioanalytical data will provide critical insights into the exposure-response relationship.


Assuntos
Anticorpos Monoclonais/imunologia , Imunoconjugados/imunologia , Anticorpos Monoclonais/química , Humanos , Imunoconjugados/química
3.
J Immunol Methods ; 419: 18-24, 2015 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-25728474

RESUMO

Bioanalytical data from early human studies conducted in normal volunteers are often used for building pharmacokinetic/pharmacodynamic models that can predict outcomes of future studies in diseased patients. Thus, it is important to develop and validate reliable and accurate bioanalytical assays that instill confidence that the intended therapeutic species (total or free) are being measured. Assays quantifying the free therapeutic species, the partially bound (for multivalent therapeutics) and unbound species, require much more characterization than assays that quantify the total therapeutic species. We have developed an immunoassay to measure free BMS-962476, an Adnectin protein therapeutic against soluble proprotein convertase subtilisin kexin (PCSK)-9, and performed an in-depth characterization of the accuracy of this assay with the assistance of modeling. The experimental data correlates with modeled data within 15% at all clinically relevant levels of PCSK9 in normal and diseased populations.


Assuntos
Anticorpos Anti-Idiotípicos/imunologia , Anticorpos Monoclonais/imunologia , Imunoensaio/métodos , Modelos Imunológicos , Algoritmos , Anticorpos Anti-Idiotípicos/metabolismo , Anticorpos Monoclonais/metabolismo , Cinética , Ligantes , Polietilenoglicóis/metabolismo , Polietilenoglicóis/farmacologia , Pró-Proteína Convertase 9 , Pró-Proteína Convertases/antagonistas & inibidores , Pró-Proteína Convertases/imunologia , Pró-Proteína Convertases/metabolismo , Ligação Proteica , Proteínas/imunologia , Proteínas/metabolismo , Proteínas/farmacologia , Reprodutibilidade dos Testes , Serina Endopeptidases/imunologia , Serina Endopeptidases/metabolismo
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