T-cell receptors, like antibodies, have long been recognised as possible therapeutics as they are used by the immune system to recognise abnormal body cells, such as cancer cells or cells infected by virus.
They could also offer a novel therapeutic approach to autoimmune diseases where intracellular protein markers of such diseases have been identified by, for example, genomics or proteomics companies.
There are now more than 12 monoclonal antibody products registered as drugs and over 200 are in clinical trials. Until now, however, attempts to isolate and produce soluble, stable and high affinity TCRs for the use in antibody-like products have not been successful and this has hampered the development of TCRs for therapeutic uses.
Current monoclonal antibodies available or in late trials in the United States include Rituxan (rituximab) a nonradioactive bound monoclonal antibody recently approved by the US Food and Drug Administration (FDA), Zevalin, (ibritumomab tiuxetan) an investigative drug from the makers of Rituxin with yttrium-90 radiolabel, Bexxar (tositumomab), the first radio labelled antibody is in phase III trials and is receiving wider distribution and publicity prior to approval and Oncolym (131I Lym-1), another radio labelled antibody in phase III trials in the US.
Until now, attempts to isolate and produce soluble, stable and high affinity TCRs for the use in antibody-like products have not been successful and this has hampered the development of TCRs for therapeutic uses.
Peptides derived from almost all proteins, including disease-associated proteins, can be presented on the cell surface as peptide human leukocyte antigen (pHLA) complexes. T cells specifically recognise pHLA with their clonally rearranged T-cell receptors (TCRs).
Avidex scientists, along with researchers from Cardiff University displayed ten different human TCRs on the surface of bacteriophage, stabilised by a nonnative interchain disulfide bond.
Results of the study, published online in the journal Nature Biotechnology, in a paper entitled 'Directed evolution of human T cell receptors with picomolar affinities by phage display,' revealed the high-affinity TCRs specific for two different pHLAs: the human T-cell lymphotropic virus type 1 (HTLV-1) and the tumour-associated peptide antigen-HLA-A demonstrated high specificity and sensitivity for targeting of cell-surface pHLAs.
The T cell mediated immune response is specifically triggered by the interaction between TCRs and the 'peptide antigen', a structure at the surface of the antigen-presenting cell (APC) that combines the antigen and the HLA complex (human leukocyte antigen).
Peptide antigens play a key role in the onset of many diseases and represent the most comprehensive range of potential therapeutic targets including intracellular, cell-surface-expressed or secreted targets.
Dr Bent Jakobsen, chief scientific officer of Avidex said that the affinities (KDs) of natural TCRs for antigens were extremely low. He added that the binding half-lives of natural TCRs, were in the range of only a few seconds. They were insufficient to enable stable cell-surface adhesion of a soluble TCR, as would be required for therapeutic use.
He added: "Our recent breakthrough has produced monoclonal human TCRs with picomolar affinities, representing a million-fold improvement over the affinity of natural TCRs. Avidex's technology can be applied to any TCR and can be used to screen phage libraries of 1010 variants."
"These extremely high-affinity TCRs exhibit reduced cross-reactivity and are exquisitely specific for the antigen they recognise," he added.
The therapeutic potential of monoclonal antibodies (MAbs) has been investigated for more than 20 years and is expected to grow at a compound annual growth rate (CAGR) of 34.1 per cent to $11.4 billion (€8.7 billion) by 2011.
A major reason for the lengthy period between their original discovery and pharmaceutical applications has been the need to reduce adverse immune reactions by patients to the MAbs themselves. Thus, MAbs needed to be "humanised" to reduce such reactions.