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Suppression of Ongoing Disease in a Nonhuman Primate Model of Multiple Sclerosis by a Human-Anti-Human IL-12p40 Antibody¹

Bert A. ’t Hart^2,*,,, Herbert P. M. Brok^*, Ed Remarque^¶, Jacqueline Benson^||, George Treacy^||, Sandra Amor^*,, Rogier Q. Hintzen^,, Jon D. Laman^,, Jan Bauer^# and Erwin L. A. Blezer^**

^* Department of Immunobiology, Biomedical Primate Research Center, Rijswijk, The Netherlands; Departments of Immunology and Neurology, Erasmus Medical Center, Rotterdam, The Netherlands; Multiple Sclerosis Center, Erasmus, The Netherlands; ^¶ Department of Parasitology, Biomedical Primate Research Center, Rijswijk, The Netherlands; ^|| Department of Discovery and Preclinical Development, Centocor, Malvern, PA 19335; ^# Division of Neuroimmunology, Brain Science Institute, Medical University Vienna, Austria; and ^** Department of Experimental In Vivo Nuclear Magnetic Resonance, Image Sciences Institute, University Medical Center, Utrecht, The Netherlands

IL-12p40 is a shared subunit of two cytokines with overlapping activities in the induction of autoreactive Th1 cells and therefore a potential target of therapy in Th1-mediated diseases. We have examined whether ongoing disease in a nonhuman primate model of multiple sclerosis (MS) can be suppressed with a new human IgG1 Ab against human IL-12p40. Lesions developing in the brain white matter were visualized and characterized with standard magnetic resonance imaging techniques. To reflect the treatment of MS patients, treatment with the Ab was initiated after active brain white matter lesions were detected in T₂-weighted images. In placebo-treated control monkeys we observed the expected progressive increase in the total T₂ lesion volume and markedly increased T₂ relaxation times, a magnetic resonance imaging marker of inflammation. In contrast, in monkeys treated with anti-IL-12p40 Ab, changes in the total T₂ lesion volume and T₂ relaxation times were significantly suppressed. Moreover, the time interval to serious neurological deficit was delayed from 31 ± 10 to 64 ± 20 days (odds ratio, 0.312). These results, in a disease model with high similarity to MS, are important for ongoing and planned trials of therapies that target IL-12 and/or IL-23.

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