title: Agonistic and antagonistic properties of CD40 mAb G28-5 are dependent on binding valency.
abstract: CD40 functional responses can be triggered by binding of mAb G28-5. Here we show that G28-5 induces partial CD40 responses and functions as a partial antagonist of natural CD40 ligand, gp39, by preventing gp39 binding. Fab fragments of G28-5 retain inhibitory activity but lose crosslinking-dependent stimulatory activity. The synergistic interaction of CD40 signals with PMA or CD20 show differential requirements for CD40 crosslinking and different sensitivity to cyclosporine A, suggesting that CD40 receptor may use different effector mechanisms for synergy with calcium-dependent CD20 signals or with calcium-independent signals from PMA. Activation of NF-kappa B occurred in RAJI cells by G28-5 or by gp39 treatment, and was CD40 crosslinking-dependent. These results suggest that activation of NF-kappa B is involved in some CD40 receptor signals and may be related to CD40 effects on stimulation or inhibition of apotosis.
authors.affiliation: Bristol-Myers Squibb, Pharmaceutical Research Institute, Seattle, WA 98121, USA.
authors.forename: J A
authors.initials: JA
authors.lastname: Ledbetter
authors.forename: L S
authors.initials: LS
authors.lastname: Grosmaire
authors.forename: D
authors.initials: D
authors.lastname: Hollenbaugh
authors.forename: A
authors.initials: A
authors.lastname: Aruffo
authors.forename: S G
authors.initials: SG
authors.lastname: Nadler
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D001402:B-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*; D001483:Base Sequence; D023201:CD40 Ligand; D002352:Carrier Proteins; D002478:Cells, Cultured; D016572:Cyclosporine / Q000494:pharmacology*; D005434:Flow Cytometry; D008562:Membrane Glycoproteins / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D008969:Molecular Sequence Data; D016328:NF-kappa B / Q000187:drug effects / Q000378:metabolism; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*
chemical_list: D000911:Antibodies, Monoclonal; D002352:Carrier Proteins; D008562:Membrane Glycoproteins; D016328:NF-kappa B; D023201:CD40 Ligand; D016572:Cyclosporine