BioWorld International Correspondent
LONDON - More than 12 products based on monoclonal antibodies are available as drugs in the clinic, and more than 200 are in clinical trials. But a small biotech company in the UK now has developed a technology that could make it possible to achieve the same ends with the equivalent molecules on T cells.
Avidex, of Oxford, UK, said it can select specific monoclonal T-cell receptors (TCRs). James Noble, Avidex CEO, said: "This opens up significant new [avenues for] the treatment of major diseases, such as autoimmune diseases, viral diseases and cancer."
The monoclonal TCRs bind with high affinity to their target molecules, unlike natural TCRs, which normally bind for only a few seconds. The molecules also are fully human. Furthermore, they have the advantage that, unlike antibodies or related technologies, they can bind to proteins expressed within cells, making it difficult for tumors to avoid being targeted.
Researchers from Avidex reported their work in the Feb. 20, 2005, issue of Nature Biotechnology in a paper titled "Directed evolution of human T-cell receptors with picomolar affinities by phage display." The company has applied for patents to protect its intellectual property rights relating to monoclonal TCRs.
Neill MacKenzie, chief business officer of Avidex, told BioWorld International, "It is encouraging that a small UK biotech company can still deliver a major novel technology."
The company hopes to receive the go ahead to carry out Phase I trials in patients with cancer for one of its products by this time next year. The drug will deliver a cytokine to cells displaying an antigen found only in cancer cells.
MacKenzie described Avidex's advance as the "ying" that complements the "yang" of monoclonal antibodies.
Since the original discovery of monoclonal antibodies more than 25 years ago, scientists have developed more refined methods enabling them to produce specific monoclonal antibodies with specialized characteristics.
Not one, however, has managed to do the same on a large scale for the equivalent molecules on T cells, which form the other arm of the immune system - until now.
All cellular proteins naturally are broken down within the cell into fragments, or peptides. Those peptides appear on the cell's surface held in molecules called human leukocyte antigen (HLA) complexes.
T cells become activated when the receptors on their surface bind to the peptides held by the HLA molecules. As with B cells and antibodies, there is an infinite variety of T cells, each with T-cell receptors, capable of binding to all possible peptide antigens.
The cell-mediated immune response triggered in that way can lead to cell division and activation, so that a clone of cells develops that is capable of recognizing and killing body cells such as cancer cells or cells infected with a virus.
T-cell receptors have three parts: an intracellular domain, a transmembrane domain and an extracellular domain. The latter comprises two paired polypeptide chains, both of which have constant and variable regions (like antibodies). Those chains are involved in binding the TCR to the peptide/HLA complex target on the surface of cells.
Avidex now has developed a way of manufacturing only the extracellular domain of any desired monoclonal TCR. The company inserts the genes encoding the two chains of the desired TCR into separate Escherichia coli. The bacteria are allowed to grow and manufacture the polypeptide chains. With the addition of some disulphide bonds to hold the two chains together, the polypeptides fold into the correct conformation. Luckily, those that fold correctly are soluble, while those that do not precipitate out.
In order to maximize the binding capabilities of the TCRs required, Avidex introduces random mutations into the binding site of the desired TCR. That approach generates a library of TCRs, available as a phage display, and it then is possible to select those with high affinity for the peptide/HLA complex in question.
"This has enabled us to improve the affinity of the manufactured TCRs by a million-fold over that of natural TCRs," MacKenzie said.
So far, Avidex has manufactured high-affinity TCRs that bind to telomerase and NY-ESO, which are both markers for many types of cancer cells. The company also has a TCR for the human T-cell lymphotropic virus Type I, thus proving, MacKenzie said, that it is possible to produce such a TCR that recognizes a viral target.