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Tanox Pharma B.V., Amsterdam, The Netherlands;
Department of Immunobiology, Biomedical Primate Research Center, Rijswijk, The Netherlands;
Department of Neuroimmunology, Institute of Brain Research, University of Vienna, Vienna, Austria;
Division of Immunological and Infectious Diseases, Netherlands Central Organization for Applied Scientific Research Prevention and Health, Leiden, The Netherlands;
¶ Imaging Science Institute, University Medical Center, Utrecht, The Netherlands;
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Division of Experimental Immunology, Faculty of Medicine, Catholic University of Leuven, Belgium;
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Department of Immunology, Erasmus University, Rotterdam, The Netherlands; and
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Academic Hospital Dijkzigt, Dijkzigt, The Netherlands
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.
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