Preclinical Assessment of Therapeutic Antibodies against Human CD40 and Human Interleukin-12/23p40 in a Nonhuman Primate Model of Multiple Sclerosis

Abstract

Background: 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). Objective: 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. Results: 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 (Callithrix jacchus). 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. Conclusion: 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.