Protein differences to blame?
2006-03-19 19:33
London - Differences between a cell signalling protein in humans and animals may explain the unexpectedly severe reaction in six young men given a new drug in a clinical trial in Britain, an expert said on Sunday.
The previously healthy men were the first humans to receive
the drug, designed to treat leukaemia and chronic inflammation
disorders.
Shortly after they were given the treatment last
week, they suffered massive inflammation and excruciating pain.
Two are still critically ill, one is on organ support and
the other three are recovering.
Doctors are baffled about what went wrong in the trial of
the antibody drug TGN1412, made by the privately-owned German
company TeGenero AG, which had previously been tested in
laboratories and on rabbits and monkey.
TGN1412 belongs to a class of drugs known as monoclonal
antibodies, which specifically bind to target molecules. TGN1412
targets an immune system protein called CD28.
Dr David Glover, a drug industry consultant with extensive
experience of antibody treatments, said the protein the drug
targets may not be the same in all species.
False reassuring results
"I suspect the antibody was designed to work against human
CD28 and because it was designed to work best in humans its
performance in different animals may fall short of what you
might have expected in humans," Glover said in an interview.
"That is why the animal testing may have falsely provided
reassuring results. It could be one of the explanations."
Dr Thomas Hanke, the chief scientific officer at TeGenero
said in a statement last week that tests on animals had not
produced drug related adverse advents, nor drug-related deaths.
CD28 is a protein on the surface of some white blood cells
that plays a part in activating them for an immune response.
Hanke said TGN1412 was designed to activate its target protein
- rather than blocking it as many antibody drugs do.
In the British trial, the administration of the drug was
followed by a massive inflammation reaction.
The trial was being run by US drug research company
Parexel International Corp. <PRXL.O> on behalf of TeGenero AG.
Benefits
Ray Nobel, a medical ethicist who sits on a committee at
University College London, said Phase 1 trials, in which new
compounds are tested on healthy volunteers, are a fundamental
part of the ethical process.
Glover said no one should lose sight of the benefits of
antibody drugs. He said the focus should not be on antibody
treatments in general, or stopping clinical trials.
The breast cancer drug Herceptin, made by the Swiss
pharmaceutical Roche <ROG.VX>, is an antibody treatment.
It
attaches itself to the HER2 receptor on the cancer cells and
blocks them from receiving growth signal.
Eighteen antibody products have been approved for sale and
their combined worldwide sales reached $14bn last year.
However Glover said trials of drugs targeting the protein
CD28 should be reviewed.
"Should we stop doing trials that are directed against the
target CD28? I think the answer is yes, until more is known
about what it going on," he said.
The Medicines Healthcare products Regulatory Agency (MHRA)
is conducting and enquiry into what went wrong. Results are
expected in weeks.