Case Study 1
If the Alcyomics Skimune® technology had been available the Northwick Park drug trial disaster, which resulted in catastrophic systemic organ failure in human subjects, would have been averted. Most of us remember vividly the drug trial conducted at the Northwick Park Hospital in London in 2006. This was an extreme example of what can go wrong when drugs are introduced to patients without the correct testing protocols.
The trial involved the experimental humanized monoclonal antibody TGN1412 which was a monoclonal antibody targeted towards CD28, a marker found on effector T cells.
The antibody had been tested vigorously in pre-clinical trials using Cynomolgus monkeys. However, the testing in monkeys was inappropriate due to the difference in receptor expression of CD28 on CD4+ memory T cells in this species compared to the human counterpart (Eastwood et al., 2010). This difference in expression meant the response observed in humans could not be observed by testing Cynomolgus monkeys. Administration of the antibody in humans, lead to binding to the CD28 receptor present on effector T cells and resulting in mass cytokine release, also known as cytokine release syndrome (CRS).
This extreme example demonstrates the need for more effective drug testing and human in vitro models. This is especially true when one considers the increasing number of biological drugs (e.g. monoclonal antibodies, biosimilars and cellular therapies) planned or in development.
The antibody is of course no longer on the market but Alcyomics signed a Material Transfer Agreement with NIBSC (The National Institute for Biological Standards and Control) and tested their analogue of the antibody, TGN1412, raised for in vitro testing, in order to alleviate this type of problem in the future.
Alcyomics tested the anti-CD28 antibody using the human in vitro skin explant assay Skimune®Mab. The result showed a grade III reaction with sub-epidermal damage in the skin (skin blistering). The data showed that the assay could have predicted and prevented the Northwick Park disaster.
Figure 1: TGN1412 positive Grade III response obtained from Skimune®Mab
A Grade III positive response was shown using Skimune®Mab assay to test the TGN1412 monoclonal antibody. Positive response indicated by damage between the dermal-epidermal junction (highlighted by black arrows).