TGN1412 (Theralizumab): A Case Study in Immunomodulation, Clinical Trial Catastrophe, and Regulatory Evolution

1. Executive Summary

TGN1412, also known under development names such as Theralizumab and CD28-SuperMAB, was an investigational humanized IgG4 monoclonal antibody designed to act as a superagonist of the CD28 receptor on T-lymphocytes.[1] Its intended therapeutic applications were in B-cell chronic lymphocytic leukemia (B-CLL) and rheumatoid arthritis, based on the premise that targeted CD28 stimulation could modulate aberrant immune responses.[1] However, TGN1412 is infamously remembered for the catastrophic events of its first-in-human (FIH) Phase 1 clinical trial conducted in March 2006 at Northwick Park Hospital, London. In this trial, six healthy male volunteers experienced an immediate and severe systemic inflammatory response, characterized as a cytokine release syndrome (CRS), leading to multi-organ failure and life-threatening complications, despite receiving a dose approximately 500 times lower than that found to be safe in preclinical animal studies.[1]

The unpredicted severity of the adverse events stemmed primarily from critical species-specific differences in the expression and function of the CD28 receptor on key T-cell populations, particularly CD4+ effector memory T-cells, between the cynomolgus macaques used for preclinical safety testing and humans.[6] These primate cells lacked CD28 expression on the crucial effector memory T-cell subset that was highly responsive in humans, rendering the animal model non-predictive for the type of immunotoxicity observed.