This week the BBC reported that a phase I clinical trial involving a monoclonal antibody experienced serious adverse events. The study, sponsored by a German biopharmaceutical company, TeGenero AG, involved TGN1412, an immunomodulatory humanized agonistic anti-CD28 monoclonal antibody that is being developed for the treatment of immunological diseases with a high unmet medical need including rheumatoid arthritis, multiple sclerosis and leukemias such as chronic lymphocytic leukemia (CLL).
The healthy volunteers were testing the anti-inflammatory drug at a research unit in the grounds of Northwick Park Hospital when they suffered a reaction leading to multiple organ failure. The six men who were treated with the drug remain in intensive care after being taken ill. Two men who received the placebo injection were unaffected. Those affected apparently reported splitting headaches, vomiting and hyperventilation before fainting and being taken to the intensive care unit where they remain. The reactions took place within hours of taking the first starting dose. Four of the patients have regained consciousness and were said to be responding. The other two patients remain critically ill.
As a result of the study events, the Medicines and Healthcare products Regulatory Agency (MHRA) were investigating whether the reactions were caused by a manufacturing problem, contamination, dosing error or a completely unrelated side effect in humans.
In oncology, monoclonal antibodies (mAB’s) are created by fusing or merging a cell that produces antibodies with a cancer cell. Antibodies are the foot soldiers of the immune system. Generally, mAB’s are antagonists which prevent something from happening as shown by Genentech’s suite of products Herceptin, Rituxan and Avastin, which inhibit critical pathways (Her-2, CD20 and VEGF respectively) associated with tumours. Another example is ImClone’s Erbitux which inhibits EGF, a pathway linked to colorectal and head and neck cancers.
TGN 1412 does the exact opposite – it’s an mAB agonist that boosts or stimulates the activity of CD28, an immune system protein that is present on the surface of white blood cells. The idea behind the concept was to stimulate the immune system to fight against the disease. Antibodies are proteins in the body that target and link specific shapes (the so-called antigens) on the surface of, various cells. Humanised agonistic anti-CD28 monoclonal antibody is an antibody that binds to the T-lymphocytes. By binding these cells, it is thought that the antibody can stimulate them to attack and kill the cancer cells.
Interestingly, a recently FDA approved drug called abatacept (Orencia) from BMS, appears to actually do the opposite of TGN 1412 in rheumatoid arthritis. This drug, a selective T-cell co-stimulatory modulator, inhibits T-cell (T-lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28 indirectly. This interaction then provides a co-stimulatory signal necessary for full activation of T-lymphocytes, which have been implicated in the pathogenesis of rheumatoid arthritis. So although the T-lymphocytes are stimulated in both cases, the mechanism of action on CD28 is very different from that of TGN1412. It remains to be seen whether this is relevant to the serious adverse events that occurred this week with TeGenaro’s agent.
The dramatic results of this week may lead the authorities to question whether it is appropriate and ethical to test such stimulatory drugs on healthy volunteers whose immune systems are already working effectively; it is possible that by stimulating CD28 above normal levels, it might push their immune systems into overdrive, hence increasing the risk of multi organ failure. Time will tell and it is critical that the MHRA gets the bottom of the issue expediently; it’s the very least the volunteers can expect, as well as a safe and speedy recovery.
Relevant Links:
TeGenero AG Statement
{EDIT: A subsequent post on this topic was added 2 years later HERE}.