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

Inhibition of CD40-CD40 ligand interaction is a potentially effective appro ach for treatment of autoimmune diseases, such as multiple sclerosis. We ha ve 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 oligode ndrocyte 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 placeb o. On day 41 after the induction of EAE, four of four placebo-treated monke ys had developed severe clinical EAE, whereas all animals from the ch5D12-t reated group were completely free of disease symptoms. High serum levels of ch5D12 associated with complete coating of CD40 on circulating B cells wer e found. At necropsy placebo- and ch5D12-treated animals showed similar MOG -specific lymphoproliferative responses in vitro, but ch5D12 treatment resu lted in strongly reduced anti-MOG IgM Ab responses and delayed anti-MOG IgG responses. Most importantly, treatment with ch5D12 prevented intramolecula r spreading of epitope recognition. Postmortem magnetic resonance imaging a nd immunohistologic analysis of the CNS showed a markedly reduced lesion lo ad 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 anta gonist anti-CD40 mAb for multiple sclerosis.