Immunostimulatory antibodies: challenging the drug testing paradigm.

The recently failed first-in-man clinical trial of TGN1412 raises concerns about whether the existing drug testing paradigm is suited to the safety assessment of drugs based on immunostimulatory antibodies that have complex and novel mechanisms of action. In particular, there is a need to consider whether animal studies are relevant and, if so, how the resulting information can be used to best inform clinical studies. The preclinical testing of TGN1412 is considered in relation to the selection of a suitable test species, deficiencies in an understanding of the similarities and differences between human and other primate immune functioning and species extrapolation. It is concluded that more emphasis should be placed on the development and use of in vitro and computational methods to identify potentially important species differences in the activity of immunostimulatory antibodies. Such approaches are useful with regards to species extrapolation, mechanistic studies and the design of both preclinical tests in animals and clinical studies in humans.