Please cite this article in press as: B.A. ‘t Hart, et al., Improvement of preclinical animal models for autoimmune-mediated disorders via reverse translation of failed therapies, Drug Discov Today (2014), http://dx.doi.org/10.1016/j.drudis.2014.03.023 Drug Discovery Today  Volume 00, Number 00  April 2014 REVIEWS Improvement of preclinical animal models for autoimmune-mediated disorders via reverse translation of failed therapies Bert A. ‘t Hart 1,2,3 , S. Anwar Jagessar 1,3 , Yolanda S. Kap 1,3,4 , Krista G. Haanstra 1 , Ingrid H.C.H.M. Philippens 1 , Che Serguera 6 , Jan Langermans 5 and Michel Vierboom 1 1 Biomedical Primate Research Centre, Department of Immunobiology, Rijswijk, The Netherlands 2 University of Groningen, Department of Neuroscience, University Medical Center, Groningen, The Netherlands 3 MS Center ErasMS, Rotterdam, The Netherlands 4 Erasmus Medical Center Rotterdam, Department of Immunology, Rotterdam, The Netherlands 5 Department of Animal Science, Biomedical Primate Research Centre, 2288 GJ Rijswijk, The Netherlands 6 MIRCen, CEA, Fontenay-aux-Roses, France The poor translational validity of autoimmune-mediated inflammatory disease (AIMID) models in inbred and specific pathogen-free (SPF) rodents underlies the high attrition of new treatments for the corresponding human disease. Experimental autoimmune encephalomyelitis (EAE) is a frequently used preclinical AIMID model. We discuss here how crucial information needed for the innovation of current preclinical models can be obtained from postclinical analysis of the nonhuman primate EAE model, highlighting the mechanistic reasons why some therapies fail and others succeed. These new insights can also help identify new targets for treatment. The past few decades have been an era of enormous progress in our mechanistic understanding of AIMID. Much of the research into the processes underlying the initiation and progression of AIMID has been obtained in EAE, the elected preclinical model of multiple sclerosis (MS), most often induced in rodents. In several cases, new knowledge obtained in EAE has been successfully translated into effective treatments for patients with MS, such as small molecules (e.g. fingolimod), cytokines (interferon b) or various monoclonal antibodies (mAbs) [1]. Examples of mAbs showing significant clinical efficacy include natalizumab, targeting anti-a4b1 integrin; anti-CD52 (alemtuzumab), targeting a glycoprotein expressed on all mature lymphocytes; and several mAbs against CD20 (ritux- imab, ofatumumab and ocrelizumab), targeting a surface molecule that is broadly expressed in the B cell lineage. However, the translation of a pathogenic mechanism discovered in an animal model into a safe and effective treatment for patients often fails; a problem that is sometimes referred to as ‘the valley of death’ [2,3]. The limited predictive validity of the currently used animal models for the safety and efficacy evaluation of a new therapeutic biological agent in the clinic is the Achilles heel of preclinical research [4,5]. For this reason, new research programs funded by the European Commission, such as Horizon 2020 and Innovative Medicine Initiative 2, stimulate the generation of better predictive animal models for preclinical research as a priority strategy that should help the drug development industry to cross the valley of death. However, how can scientists working in preclinical research be expected to improve their animal models when they do not know why and where they fail? In this review, we postulate that such strategic information can be obtained from a critical ‘postclinical’ analysis of the reasons why some treatments succeed in the clinic, where others fail. We discuss examples from work in the field of MS where such strategic information has been obtained from ‘reverse transla- tion analysis’ of failed and successful therapeutic mAbs in well- validated nonhuman primate (NHP) models of the disease. Although the discussion is focused on MS and its elected animal model EAE, we envisage that this strategy could serve as a tem- plate for several types of treatment in a broader range of auto- immune inflammatory disorders, such as rheumatoid arthritis (RA), diabetes and others. MS and EAE MS is an enigmatic autoimmune inflammatory disease that targets the human central nervous system (CNS), comprising the brain Reviews  POST SCREEN Corresponding author: ‘t Hart, B.A. (hart@bprc.nl) 1359-6446/06/$ - see front matter ß 2014 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.drudis.2014.03.023 www.drugdiscoverytoday.com 1