RESUMO
The differentiation of therapeutic monoclonal antibodies in an increasingly competitive landscape requires optimization of clinical efficacy combined with increased patient convenience. We describe here the generation of MEDI5117, a human anti-interleukin (IL)-6 antibody generated by variable domain engineering, to achieve subpicomolar affinity for IL-6, combined with Fc (fragment crystallizable) engineering to enhance pharmacokinetic half-life. MEDI5117 was shown to be highly potent in disease-relevant cellular assays. The pharmacokinetics of MEDI5117 were evaluated and compared to those of its progenitor, CAT6001, in a single-dose study in cynomolgus monkeys. The antibodies were administered, either subcutaneously or intravenously, as a single dose of 5 mg/kg. The half-life of MEDI5117 was extended by approximately 3-fold, and clearance was reduced by approximately 4-fold when compared to CAT6001. MEDI5117 therefore represents a potential 'next-generation' antibody; future studies are planned to determine the potential for affinity-driven efficacy and/or less frequent administration.
Assuntos
Anticorpos Anti-Idiotípicos/farmacologia , Anticorpos Monoclonais/farmacologia , Anticorpos Monoclonais/farmacocinética , Interleucina-6/antagonistas & inibidores , Interleucina-6/imunologia , Macaca fascicularis/imunologia , Animais , Anticorpos Anti-Idiotípicos/administração & dosagem , Anticorpos Monoclonais/administração & dosagem , Células Cultivadas , Meia-Vida , Humanos , Interleucina-6/genética , Rim/citologia , Rim/metabolismo , Modelos Químicos , Mutagênese , Engenharia de Proteínas , Receptores de Interleucina/imunologia , Ressonância de Plasmônio de Superfície , Linfócitos T/metabolismo , Distribuição Tecidual , Fator A de Crescimento do Endotélio Vascular/metabolismoRESUMO
We describe the discovery of small molecule benzazepine derivatives as agonists of human peroxisome proliferator-activated receptor δ (PPARδ) that displayed excellent selectivity over the PPARα and PPARγ subtypes. Compound 8 displayed good PK in the rat and efficacy in upregulation of pyruvate dehydrogenase kinase, isozyme 4 (PDK4) mRNA in human primary myotubes, a biomarker for increased fatty acid oxidation.
Assuntos
Anilidas/síntese química , Benzazepinas/química , PPAR delta/agonistas , Anilidas/química , Anilidas/farmacocinética , Animais , Benzazepinas/síntese química , Benzazepinas/farmacocinética , Sítios de Ligação , Simulação por Computador , Hepatócitos/metabolismo , Humanos , Microssomos Hepáticos/metabolismo , PPAR alfa/agonistas , PPAR alfa/metabolismo , PPAR delta/metabolismo , PPAR gama/agonistas , PPAR gama/metabolismo , Proteínas Serina-Treonina Quinases/genética , Proteínas Serina-Treonina Quinases/metabolismo , Piruvato Desidrogenase Quinase de Transferência de Acetil , Ratos , Regulação para CimaRESUMO
Small molecule isoindoline and tetrahydroisoquinoline derivatives have been identified as selective agonists of human peroxisome proliferator-activated receptor δ (PPARδ. Compound 18 demonstrated efficacy in a biomarker for increased fatty acid oxidation, with upregulation of pyruvate dehydrogenase kinase, isozyme 4 (PDK4) in human primary myotubes.
