title: Identification of a novel CD40 ligand for targeted imaging of inflammatory plaques by phage display.
abstract: The CD40/CD40L dyad is deemed to play a central role in several inflammatory processes, including atherosclerosis. As CD40 is overexpressed in atherosclerotic lesions, it constitutes a promising candidate for targeted imaging approaches. Here we describe the design of a novel, selective peptide ligand for CD40 by phage display. A synthetic peptide corresponding with the phage insert NP31 displayed nanomolar affinity for CD40. Affinity was further enhanced by mutimeric presentation of NP31. An essential 11-mer peptide motif was identified by truncation and alanine scan studies. Enriched phage selectively bound human CD40 and homed to inflammatory joints in a murine model of rheumatoid arthritis. NP31 ablated VEGF and IL-6 transcriptional activation and partially inhibited IL-6 production by CD40L-activated endothelial cells. Notably, NP31 did not only alter the biodistribution profile of a streptavidin scaffold but also markedly increased accumulation of the carrier in atherosclerotic aortic lesions of aged ApoE(-/-) mice in a CD40-dependent manner. This potent and selective peptide ligand has potential for targeted imaging and drug delivery approaches in CD40-dependent inflammatory disorders such as atherosclerosis.
authors.affiliation: 2Department of Pathology, University Hospital Maastricht, Debeijelaan 25, 6229 HX Maastricht, The Netherlands. erik.biessen@mumc.nl.
authors.forename: Haixiang
authors.initials: H
authors.lastname: Yu
authors.forename: Filip
authors.initials: F
authors.lastname: Segers
authors.forename: Karen
authors.initials: K
authors.lastname: Sliedregt-Bol
authors.forename: Ilze
authors.initials: I
authors.lastname: Bot
authors.forename: Andrea M
authors.initials: AM
authors.lastname: Woltman
authors.forename: Peter
authors.initials: P
authors.lastname: Boross
authors.forename: Sjef
authors.initials: S
authors.lastname: Verbeek
authors.forename: Herman
authors.initials: H
authors.lastname: Overkleeft
authors.forename: Gijs A
authors.initials: GA
authors.lastname: van der Marel
authors.forename: Cees
authors.initials: C
authors.lastname: van Kooten
authors.forename: Theo J C
authors.initials: TJ
authors.lastname: van Berkel
authors.forename: Erik A L
authors.initials: EA
authors.lastname: Biessen
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001011:Aorta / Q000473:pathology; D001172:Arthritis, Rheumatoid / Q000175:diagnosis; D050197:Atherosclerosis / Q000378:metabolism / Q000473:pathology; D023201:CD40 Ligand / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D006801:Humans; D007249:Inflammation; D051379:Mice; D019151:Peptide Library; D011485:Protein Binding
chemical_list: D019151:Peptide Library; D023201:CD40 Ligand
keywords: CD154; atherosclerosis; autoimmune diseases