title: Whole-molecule antibody engineering: generation of a high-affinity anti-IL-6 antibody with extended pharmacokinetics.
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.
authors: MedImmune Ltd., Milstein Building, Granta Park, Cambridge CB1 6GH, UK.
authors: Donna K
authors: DK
authors: Finch
authors: Matthew A
authors: MA
authors: Sleeman
authors: Jacques
authors: J
authors: Moisan
authors: Franco
authors: F
authors: Ferraro
authors: Sara
authors: S
authors: Botterell
authors: Jamie
authors: J
authors: Campbell
authors: Duncan
authors: D
authors: Cochrane
authors: Simon
authors: S
authors: Cruwys
authors: Elizabeth
authors: E
authors: England
authors: Steven
authors: S
authors: Lane
authors: Elizabeth
authors: E
authors: Rendall
authors: Monisha
authors: M
authors: Sinha
authors: Craig
authors: C
authors: Walker
authors: Gareth
authors: G
authors: Rees
authors: Michael A
authors: MA
authors: Bowen
authors: Amy
authors: A
authors: Schneider
authors: Meina
authors: M
authors: Liang
authors: Raffaella
authors: R
authors: Faggioni
authors: Michael
authors: M
authors: Fung
authors: Philip R
authors: PR
authors: Mallinder
authors: Trevor
authors: T
authors: Wilkinson
authors: Roland
authors: R
authors: Kolbeck
authors: Tristan
authors: T
authors: Vaughan
authors: David C
authors: DC
authors: Lowe
mesh_terms: D000818:Animals; D000888:Antibodies, Anti-Idiotypic / Q000008:administration & dosage / Q000494:pharmacology*; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology*; D002478:Cells, Cultured; D006207:Half-Life; D006801:Humans; D015850:Interleukin-6 / Q000235:genetics / Q000276:immunology*; D007668:Kidney / Q000166:cytology / Q000378:metabolism; D008252:Macaca fascicularis / Q000276:immunology*; D008956:Models, Chemical; D016296:Mutagenesis; D015202:Protein Engineering; D018123:Receptors, Interleukin / Q000276:immunology; D020349:Surface Plasmon Resonance; D013601:T-Lymphocytes / Q000378:metabolism; D014018:Tissue Distribution; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D000093242:Interleukin-6 Inhibitors
chemical_list: D000888:Antibodies, Anti-Idiotypic; D000911:Antibodies, Monoclonal; D015850:Interleukin-6; D018123:Receptors, Interleukin; D042461:Vascular Endothelial Growth Factor A; D000093242:Interleukin-6 Inhibitors; C467484:VEGFA protein, human