THERE鈥橪L be nowhere for diseased and cancerous cells to hide when a revolutionary new breed of drugs starts coming after them. The new drugs鈥攚hich will only destroy diseased cells鈥攁re being touted as the biggest breakthrough since the late C茅sar Milstein discovered monoclonal antibodies in the 1980s.
Monoclonal antibodies can seek out and destroy diseased cells. It has taken two decades for these designer antibodies to make the grade as 鈥渕agic bullet鈥� drugs, but 10 are now on sale to treat diseases including breast cancer, leukaemia and arthritis.
The new drugs, called monoclonal T-cell receptors or mTCRs, could do even better because they can detect and destroy all diseased or cancerous cells, not just the 10 to 15 per cent targeted by monoclonal antibodies. 鈥淚t鈥檚 a new chapter in drug discovery, and we think that potentially it could be as big as monoclonal antibodies,鈥� says Bent Jakobsen, chief scientific officer at the British company Avidex in Abingdon, Oxfordshire, which is developing mTCRs. Another company, Sunol Molecular in Florida, is also developing the drugs.
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Between them, the body鈥檚 antibodies and T cells spot all abnormal protein fragments, called antigens, produced by diseased cells. But they don鈥檛 spot the same ones. Antibodies only recognise antigens if they鈥檙e part of a whole protein straddling the membrane of a diseased cell (see Diagram).
T cells, on the other hand, spot protein fragments called peptides displayed like tiny molecular ID cards on the surface of all cells. These peptides are the shredded remains of proteins from within the cell. By inspecting each peptide as it鈥檚 presented by the cell, T cells can tell whether the protein it came from should be there. If the peptide is abnormal or comes from an invader, the cell is destroyed. T-cell receptors (TCRs) are the molecular tweezers that the T cells use to sample the peptides.
Avidex and Sunol have broken new ground by creating artificial T-cell receptors that can exist independently from the T cells. 鈥淲e managed to re-engineer them so there鈥檚 no difference between them and the ones on T cells,鈥� says Jakobsen.
Starting with human T cells, the researchers at Avidex extract the genes that manufacture the receptor. They then shuttle these genes into E. coli bacteria, causing the bugs to start churning out identical copies of the receptor protein in potentially limitless amounts. This process mimics the one used for creating monoclonal antibodies, which is why the mass-produced receptors have been dubbed 鈥渕onoclonal TCRs鈥�.
But how do you find the right receptor to clone? One approach is to screen T cells from patients with breast cancer, say, to find ones that have already targeted diseased cells. Genes from these cells can then be extracted and cloned. Another approach is to mutate receptor genes until mTCRs emerge that bind to particular target cells.
Both Avidex and Sunol have already discovered mTCRs that bind to cancer cells. Avidex has just begun testing its mTCRs to see how long they survive in animals. To turn them into 鈥渕agic bullets鈥�, the mTCRs will have to carry a backpack of toxins or radioactive isotopes, just as drugs based on monoclonal antibodies do now.
It could be a couple of years before mTCRs are tested in people, but rival companies that sell monoclonal antibodies are already watching with interest. 鈥淲e鈥檇 view it as complementary, because mTCRs attack different targets to antibodies,鈥� says Richard Bungay, head of communications at Celltech, a company in Slough.
鈥淚t does look interesting, but it took 20 years for antibodies to make it,鈥� adds Bungay. He thinks that it may take quite a while for researchers to develop mTCRs that can stick as firmly to their targets as antibodies.