Title:Pitfalls and Solutions for the Validation of Novel Drugs in Animal Models of Disease
Volume: 8
Issue: 2
Author(s): Zoe Johnson, Christine A. Power and Amanda E. I. Proudfoot
Affiliation:
Keywords:
Antibodies, chemokines, drug development, inflammation, inhibitors, pre-clinical pharmacology, rodent models,
toxicology
Abstract: Aberrant cell recruitment is a hallmark of inflammatory responses, a complex process orchestrated by a unique
interplay of adhesion, chemotactic and pro-inflammatory molecules. To date there are only two marketed drugs that block
cell migration, interestingly both for Multiple Sclerosis (MS). Tysabri/Natalizumab, a humanized monoclonal antibody
against the cellular adhesion molecule VLA-4 was the first to be approved for the treatment of MS. A second inhibitor of
migration, Gilenya/fingolimod entered the market last year, having received FDA approval in 2010. There are many more
drugs targeting cellular recruitment in preclinical and clinical development, reflecting the promise that lies behind
inhibiting this process as treatment for a range of inflammatory diseases. Confirmation of efficacy of the compound/drug
in vivo is an important part of the drug development process and is essential for drugs that have a novel mechanism of
action. Additionally, toxicological tests to determine the safety of the drug are a pre-requisite for successful IND filing. In
pre-clinical development studies, drugs are preferentially tested for efficacy in rodent species such as mice, however in
order for these tests to be relevant, the compound has to show cross-reactivity with the target in the test species, which can
be a major hurdle for some target classes including chemokines. Not only do such tests rely on compound cross-reactivity,
but differences in biology, in particular of the immune system between rodents and humans, can cause additional
problems for drug development. In this review, we discuss, in the context of cell migration and inflammation, the
problems that arise during pre-clinical testing in vivo, including strategies to mitigate these risks.
