Some aspects of the recombinantly expressed humanised superagonist anti-CD28 mAb, TGN1412 trial catastrophe lessons to safeguard mAbs and vaccine trials

Quality and safety considerations for recombinant biological medicines: A regulatory perspective

“…Rather, additional calculations based on pharmacokinetic/pharmacodynamic (PK/PD) data (e.g., target binding and receptor occupancy studies, concentration-response curves and exposure calculations) should be integrated into a PK/PD modelling approach in order to determine the Minimal Anticipated Biological Effect Level (MABEL), which is the anticipated dose level leading to a minimal biological effect level in humans. Using these techniques, the ESG and also Mehrishi et al [29] have noted that, at the starting dose used in the TGN1412 trial, perhaps 80-90% of all TGN1412 target molecules would have been occupied with drug.…”

Will advances in fish immunology change vaccination strategies?

“…Indeed, the same approach has been adopted with CD28, although the use of the B7 proteins is complicated by their ability to also bind the negative regulator CD152 (CTLA-4) on the T cell surface. However, a major lesson learnt from the use of anti-CD28 mAb in humans is that the dose is crucial and if too high can lead to a so-called ''cytokine storm'' with severe effects on the host [77,78].…”

T Cells Survey the Stability of the Self: A Testable Hypothesis on the Homeostatic Role of TCR-MHC Interactions

“…A large and uncontrollable increase in tissue cytokine concentrations occurred, leading to severe lymphopenia involving all mononuclear cells (CD4+ and CD8+ T cells and monocytes). We found that at the dose used in the trial nearly all (∼85%) the CD28 receptors would have been saturated in all the patients [92]. We are, therefore, inclined to interpret the trial disaster results as quite consistent with the law of mass action [92] and our HRT model for the following reasons: (1) the very high (saturating) concentration of the superagonist anti-CD28 monoclonal antibody was sufficient to ensure that the entire T cell system was activated by stimulating a single receptor; (2) consistent with the model’s prediction, the presence of a high concentration of a s-TCR ligand (anti-CD28 monoclonal antibody; TGN1412) perturbed the steady-state conditions.…”

“…We speculate that adjuvants are able to increase the local concentration of the B7 such that most CD28 receptors of the bystander, polyclonal helper T cells will be saturated and activated via this receptor alone. This way a limited and beneficial cytokine storm is generated [92]. Consistent with this, attenuated viruses have been successful generally because they retain enough of their structure to stimulate innate immunity, essentially serving as their own adjuvants.…”