ABSTRACT
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.
Subject(s)
Antibodies, Anti-Idiotypic/pharmacology , Antibodies, Monoclonal/pharmacology , Antibodies, Monoclonal/pharmacokinetics , Interleukin-6/antagonists & inhibitors , Interleukin-6/immunology , Macaca fascicularis/immunology , Animals , Antibodies, Anti-Idiotypic/administration & dosage , Antibodies, Monoclonal/administration & dosage , Cells, Cultured , Half-Life , Humans , Interleukin-6/genetics , Kidney/cytology , Kidney/metabolism , Models, Chemical , Mutagenesis , Protein Engineering , Receptors, Interleukin/immunology , Surface Plasmon Resonance , T-Lymphocytes/metabolism , Tissue Distribution , Vascular Endothelial Growth Factor A/metabolismABSTRACT
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.
Subject(s)
Anilides/chemical synthesis , Benzazepines/chemistry , PPAR delta/agonists , Anilides/chemistry , Anilides/pharmacokinetics , Animals , Benzazepines/chemical synthesis , Benzazepines/pharmacokinetics , Binding Sites , Computer Simulation , Hepatocytes/metabolism , Humans , Microsomes, Liver/metabolism , PPAR alpha/agonists , PPAR alpha/metabolism , PPAR delta/metabolism , PPAR gamma/agonists , PPAR gamma/metabolism , Protein Serine-Threonine Kinases/genetics , Protein Serine-Threonine Kinases/metabolism , Pyruvate Dehydrogenase Acetyl-Transferring Kinase , Rats , Up-RegulationABSTRACT
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.
