title: Prevention of experimental autoimmune encephalomyelitis in the common marmoset (Callithrix jacchus) using a chimeric antagonist monoclonal antibody against human CD40 is associated with altered B cell responses.
abstract: Inhibition of CD40-CD40 ligand interaction is a potentially effective approach for treatment of autoimmune diseases, such as multiple sclerosis. We have investigated this concept with a chimeric antagonist anti-human CD40 mAb (ch5D12) in the marmoset monkey experimental autoimmune encephalomyelitis (EAE) model. Marmosets were immunized with recombinant human myelin oligodendrocyte glycoprotein (rMOG) and treated from the day before immunization (day -1) until day 50 with either ch5D12 (5 mg/kg every 2-4 days) or placebo. On day 41 after the induction of EAE, four of four placebo-treated monkeys had developed severe clinical EAE, whereas all animals from the ch5D12-treated group were completely free of disease symptoms. High serum levels of ch5D12 associated with complete coating of CD40 on circulating B cells were found. At necropsy placebo- and ch5D12-treated animals showed similar MOG-specific lymphoproliferative responses in vitro, but ch5D12 treatment resulted in strongly reduced anti-MOG IgM Ab responses and delayed anti-MOG IgG responses. Most importantly, treatment with ch5D12 prevented intramolecular spreading of epitope recognition. Postmortem magnetic resonance imaging and immunohistologic analysis of the CNS showed a markedly reduced lesion load after ch5D12 treatment. In conclusion, the strong reduction of clinical, pathological, and radiological aspects of EAE by ch5D12 treatment in this preclinical model points to a therapeutic potential of this engineered antagonist anti-CD40 mAb for multiple sclerosis.
authors.affiliation: Tanox Pharma B.V., Amsterdam, The Netherlands.
authors.forename: L
authors.initials: L
authors.lastname: Boon
authors.forename: H P
authors.initials: HP
authors.lastname: Brok
authors.forename: J
authors.initials: J
authors.lastname: Bauer
authors.forename: A
authors.initials: A
authors.lastname: Ortiz-Buijsse
authors.forename: M M
authors.initials: MM
authors.lastname: Schellekens
authors.forename: S
authors.initials: S
authors.lastname: Ramdien-Murli
authors.forename: E
authors.initials: E
authors.lastname: Blezer
authors.forename: M
authors.initials: M
authors.lastname: van Meurs
authors.forename: J
authors.initials: J
authors.lastname: Ceuppens
authors.forename: M
authors.initials: M
authors.lastname: de Boer
authors.forename: B A
authors.initials: BA
authors.lastname: 't Hart
authors.forename: J D
authors.initials: JD
authors.lastname: Laman
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D001402:B-Lymphocytes / Q000276:immunology*; D019013:CD40 Antigens / Q000276:immunology* / Q000378:metabolism; D023201:CD40 Ligand / Q000378:metabolism; D002144:Callithrix; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology / Q000517:prevention & control* / Q000628:therapy; D006801:Humans; D007114:Immunization; D008213:Lymphocyte Activation; D009185:Myelin Proteins; D018992:Myelin-Associated Glycoprotein / Q000276:immunology; D063308:Myelin-Oligodendrocyte Glycoprotein; D011993:Recombinant Fusion Proteins / Q000494:pharmacology; D013997:Time Factors
chemical_list: D000911:Antibodies, Monoclonal; D019013:CD40 Antigens; C571326:MOG protein, human; D009185:Myelin Proteins; D018992:Myelin-Associated Glycoprotein; D063308:Myelin-Oligodendrocyte Glycoprotein; D011993:Recombinant Fusion Proteins; D023201:CD40 Ligand