title: Modulation of the CD40-CD40 ligand interaction using human anti-CD40 single-chain antibody fragments obtained from the n-CoDeR phage display library.
abstract: CD40 plays a central regulatory role in the immune system and antibodies able to modulate CD40 signalling may consequently have a potential in immunotherapy, in particular for treatment of lymphomas and autoimmune disease like multiple sclerosis. As a first step to achieve this goal, we describe the selection and characterization of a novel set of fully human anti-CD40 antibody fragments (scFv) from a phage display library (n-CoDeR). In order to determine their biological potential, these antibody fragments have been analysed for their ability to promote B-cell activation, rescue from apoptosis and to block the CD40-CD40 ligand (CD40L) interaction. The selected cohort of human scFv could be subcategorized, each expressing a distinct functional signature. Thus scFv were generated that induced B-cell proliferation, rescued B cells from apoptosis and blocked the CD40-CD40L interaction to different extents. In particular, one of the scFv clones (F33) had the ability to abrogate completely this interaction. The epitope recognition patterns as well as individual rate constants were also determined and the affinity was shown to vary from low to high nanomolar range. In conclusion, this panel of human anti-CD40 scFv fragments displays a number of distinct properties, which may constitute a valuable source when evaluating candidates for in vivo trials.
authors.affiliation: Department of Immunotechnology, Lund University, Lund, Sweden.
authors.forename: Peter
authors.initials: P
authors.lastname: Ellmark
authors.forename: Camilla
authors.initials: C
authors.lastname: Ottosson
authors.forename: Carl A K
authors.initials: CA
authors.lastname: Borrebaeck
authors.forename: Ann-Christin
authors.initials: AC
authors.lastname: Malmborg Hager
authors.forename: Christina
authors.initials: C
authors.lastname: Furebring
mesh_terms: D000918:Antibody Specificity; D017209:Apoptosis / Q000276:immunology; D001402:B-Lymphocytes / Q000276:immunology; D001667:Binding, Competitive; D019013:CD40 Antigens / Q000276:immunology*; D023201:CD40 Ligand / Q000276:immunology*; D002455:Cell Division / Q000276:immunology; D018604:Epitope Mapping; D006801:Humans; D007128:Immunoglobulin Fragments / Q000276:immunology*; D008213:Lymphocyte Activation; D019151:Peptide Library; D016133:Polymerase Chain Reaction / Q000379:methods
chemical_list: D019013:CD40 Antigens; D007128:Immunoglobulin Fragments; D019151:Peptide Library; D023201:CD40 Ligand