<i>Background:</i> Proinflammatory cytokines, such as interleukin (IL)-12 and IL-23, and costimulatory molecules on antigen-presenting cells (APC), such as CD40, are critical to autoreactive T cell activation by APC, and hence, are considered relevant targets of therapy for immune-mediated inflammatory diseases (IMID). <i>Objective:</i> The current review discusses the preclinical evaluation of two novel immunotherapeutic monoclonal antibodies (mAbs), one directed against human IL-12/23p40 and the other against CD40. As the antibodies only recognize their target molecule in primates, the efficacy could not be tested in rodent models. <i>Results:</i> As a preclinical IMID model for the in vivo evaluation of both mAbs, we have used the experimental autoimmune/allergic encephalomyelitis (EAE) model in common marmoset monkeys <i>(Callithrix jacchus).</i> Both mAbs show beneficial activities in the EAE model when administered early in disease development as well as after the onset of brain inflammation. The treatment effects were evaluated using a combination of quantitative magnetic resonance imaging and a series of ex vivo and immunopathological evaluations. <i>Conclusion:</i> The promising effects during ongoing disease in a relevant preclinical IMID model illustrate the potential of these two antibodies as treatment of IMID, in particular for multiple sclerosis on which disease EAE has been modeled.