Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 1 de 1
Filtrar
Mais filtros

Base de dados
Ano de publicação
Tipo de documento
Intervalo de ano de publicação
1.
Bioconjug Chem ; 29(7): 2357-2369, 2018 07 18.
Artigo em Inglês | MEDLINE | ID: mdl-29923706

RESUMO

Glucocorticoids (GCs) are excellent anti-inflammatory drugs but are dose-limited by on-target toxicity. We sought to solve this problem by delivering GCs to immune cells with antibody-drug conjugates (ADCs) using antibodies containing site-specific incorporation of a non-natural amino acid, novel linker chemistry for in vitro and in vivo stability, and existing and novel glucocorticoid receptor (GR) agonists as payloads. We directed fluticasone propionate to human antigen-presenting immune cells to afford GR activation that was dependent on the targeted antigen. However, mechanism of action studies pointed to accumulation of free payload in the tissue culture supernatant as the dominant driver of activity and indeed administration of the ADC to human CD74 transgenic mice failed to activate GR target genes in splenic B cells. Suspecting dissipation of released payload, we designed an ADC bearing a novel GR agonist payload with reduced permeability which afforded cell-intrinsic activity in human B cells. Our work shows that antibody-targeting offers significant potential for rescuing existing and new dose-limited drugs outside the field of oncology.


Assuntos
Anticorpos Monoclonais/uso terapêutico , Antígenos de Diferenciação de Linfócitos B/imunologia , Linfócitos B/metabolismo , Sistemas de Liberação de Medicamentos/métodos , Glucocorticoides/administração & dosagem , Antígenos de Histocompatibilidade Classe II/imunologia , Imunoconjugados/uso terapêutico , Animais , Anti-Inflamatórios/uso terapêutico , Linfócitos B/efeitos dos fármacos , Desenvolvimento de Medicamentos , Estabilidade de Medicamentos , Fluticasona/administração & dosagem , Humanos , Camundongos , Camundongos Transgênicos , Receptores de Glucocorticoides/agonistas
SELEÇÃO DE REFERÊNCIAS
Detalhe da pesquisa