Considerations for the sensible use of rodent models of inflammatory disease in predicting efficacy of new biological therapeutics in the clinic.
Successful therapeutics for treating autoimmune and inflammatory diseases must be able to significantly dampen, and ideally reverse, the complex processes involved in the manifestation of inflammatory pathology in intact tissues and organs. Studies on human cells and tissues - both normal and diseased - are obviously critical for moving forward with a particular therapeutic strategy, but these types of studies are oftentimes limited in their complexity and usually fail to fully replicate the biology of the intact inflammatory environment and disease process. It is for this reason that development of a new drug generally relies on data generated from in vivo animal models that have been created to mimic aspects of the complex disease process in whole organs and whole animals. Although the intact animal model of disease provides the opportunity for key elements involved in inflammatory processes to be investigated in natural surroundings, the primary trigger for inflammatory activation in animal models is, by necessity, artificial and, of course, differs from the natural pathogenesis driving disease in humans. Despite the artificial way of inducing inflammatory responses, animal models of disease have proven invaluable for providing insight into the potential efficacy of new drugs, particularly when careful consideration has been given to ensure that the model system under study resembles the inflammatory pathway expected in human disease. The most common artificial approaches for stimulating inflammatory diseases in mice are quite varied, and range from overexpression or targeted deletion of genes in transgenic or knockout animals, immunization of animals with putative autoantigens, all the way to synthetic, chemical challenges. None of these artificial systems or triggers is wholly perfect at mimicking the complexity of human autoimmune and inflammatory diseases, but animal disease model data is an important, and very necessary, step in the path of drug development. This review will focus on the critical aspects of disease modeling in animals that should be considered when embarking on drug discovery programs, with particular attention on three of the major inflammatory diseases - rheumatoid arthritis, multiple sclerosis and asthma. We will discuss the use of rodent models in predicting the outcomes of currently approved medicines with a focus on biological therapeutics, and will highlight ongoing clinical trials where there appears to be strong correlation between animal models and the initial indication of clinical efficacy.
Arnett
Heather A
HA
Amgen, Inc., Department of Inflammation, Seattle, Washington 98119, USA.
Viney
Joanne L
JL
D000818:Animals; D000888:Antibodies, Anti-Idiotypic; D000911:Antibodies, Monoclonal / Q000627:therapeutic use; D061067:Antibodies, Monoclonal, Humanized; D001172:Arthritis, Rheumatoid / Q000188:drug therapy* / Q000209:etiology; D001249:Asthma / Q000188:drug therapy* / Q000209:etiology; D001688:Biological Products / Q000627:therapeutic use*; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical; D006801:Humans; D051379:Mice; D009103:Multiple Sclerosis / Q000188:drug therapy* / Q000209:etiology; D000069442:Natalizumab; D000069444:Omalizumab; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors