In 2006 a near-fatal “cytokine storm” occurred in six healthy volunteers during the phase I clinical trial of TGN1412, a therapeutic superagonistic CD28-specific monoclonal antibody, signalling a failure of pre-clinical safety testing. Subsequently it was established that TGN1412 could stimulate a “cytokine storm” in vitro from human white blood cells but only if presented to the cells by immobilisation onto plastic or if the white blood cells were cultured over a monolayer of human endothelial cells. Data from the novel in vitro procedures suggests that the dose of TGN1412 given to the volunteers was close to the maximum immunostimulatory dose. In contrast to human white blood cells, TGN1412 was found not to be a superagonist in vivo or in vitro for white blood cells from the non-human primates used in the pre-clinical testing. The novel procedures are now being applied to emerging immunotherapeutics and to other therapeutics that have the potential to act upon the immune system.