What went horribly wrong in a London clinical trial?
The recent report by the MHRA on its investigation into the adverse effects in the TGN1412 trial1 concluded that an unpredicted biological action of the drug in humans is the most likely cause of the cytokine release syndrome seen in the trial participants.2 So do we have any idea on how could TGN1412 have induced a cytokine storm?
TGN1412 is a monoclonal antibody that targets the CD28 co-signaling molecule that is present on most human T-cells (>90% CD4+, ~50% CD8+).3 The antibody acts as a superagonist by binding the CD28 molecule at a site distinct from that bound by its normal ligand B7 and this effects a strong mitogenic activation of the T-cell.4 In the normal activation of T-cells, CD28 signalling is preceded by the initial triggering of the T-cell receptor for antigen (TCR) and this ensures the controlled activation of only T-cells specific for antigen in the immune response to pathogens.3 Interestingly, a similar mitogenic activation of T-cells can also be mediated by antibodies to the CD3 component of the TCR and previous clinical studies with these may shed some light on the TGN1412 trial.5,6
The primary use of anti-CD3 was to induce targeted immunosuppression in transplant recipients by the depletion of T-cells. However, initial studies using a mouse anti-CD3 antibody resulted in severe side-effects resembling the adverse effects reported in the TGN1412 trial that were ascribed to the potent mitogenic effect of these antibodies.6,7 Most interestingly, these mitogenic effects were mapped to the Fc region of the antibodies that mediated binding to the Fc-receptors (FcR) and resulted in the cross-linking of the antibodies and activation of the T-cells.7,8 This may be of particular relevance to the TGN1412 issue as the antibody used in the trial is reported to have an absolute requirement for its biological activity.2 Moreover, the requirement of both target antigen and FcR binding for the activation of T-cells may explain the lack of adverse effects in the animal models in the pre-clinical safety studies. On a more positive note, the initial problems with the anti-CD3 antibodies were overcome with the engineering of the Fc domains to minimize their FcR binding.7,8 and these antibodies are now being used clinically in transplant patients.
For immunologists the story does not end here as the studies on the engineered anti-CD3 antibodies experience shows both a qualitative and quantitative difference in the activation signals delivered by the various antibodies8 and suggest a possible link between tumor necrosis factor and the gastrointestinal inflammation observed in the clinical adverse effects that bears further examination.
Babraham Research Campus,