Prior activation of human T-cells could be the reason for the severe adverse reactions triggered by TeGenero's monoclonal antibody TGN1412 in a Phase I trial at London's Northwick Park Hospital last March.
The hypothesis is based on research by a team from Imperial College London, King's College London and the Cambridge-based Babraham Institute. It offers a possible explanation as to why the 'cytokine storm' that left six healthy volunteers in intensive care after taking TGN1412 did not occur in animal studies, even though cynomolgus monkeys were given 500 times the dose administered to humans.
The therapeutic potential of TGN1412 rested on its ability to activate immune-mediating T-cells by binding to the CD28 antigen on these cells. The theory was that, by targeting CD28, TGN1412 could overstimulate the rogue T-cells responsible for the autoimmune response in chronic inflammatory conditions such as rheumatoid arthritis, leukaemia and multiple sclerosis, making these cells "burn out and die", the researchers noted.
This process was complicated, however, when the T-cells were 'memory cells' - meaning they had already been activated or altered in the past by infection or illness. Some 50% of adult human T-cells are memory cells, whereas animal models - such as those used to calculate the dose for human exposure to TGN1412 - have few memory T-cells, as they are deliberately kept in a sterile environment where they are shielded from infections, the research team pointed out.
When the scientists artificially stimulated the CD28 antigen on memory T-cells and injected them into healthy mice, the cells immediately migrated from the bloodstream into organs where there was no infection, such as the heart, kidney and gut, causing significant tissue damage. This could explain why a drug that appeared relatively safe in animals had a disastrous effect in humans, as the more prevalent memory T-cells "lost their sense of direction and started migrating into several areas of the body they were not supposed to go", they suggested.
The study, led by Dr Federica Marelli-Berg from the Department of Immunology at Imperial College London, was presented at the Club de la Transplantation conference in Cernay la Ville, France. Last year an independent Expert Scientific Group convened by the UK government in the wake of the TeGenero study recommended a number of additional safeguards for first-in-man trials of potentially higher-risk compounds, such as information sharing, regulatory access to independent expertise and a conservative approach to drug dosing.
