To allow the exploitation of molecular immunological technologies to develop commercially interesting recombinant reagents for tumour diagnosis and therapy.
Using conventional radio- and chemotherapy, only limited success has been achieved, in terms of increased five-year survival times, over the past 25 years, for most cancer patient categories. Thus, the demand for new treatment modalities is overwhelming, and the potential market for new anticancer therapeutics is huge. The prospects for cancer immunotherapy rely on the identification of tumour-associated cell surface antigens and their specific recognition, e.g. by cytotoxic T Lymphocytes (CTL). Antigens recognized by tumour-specific CTL consist of peptides derived from endogenous proteins and presented by human major histocompatibility (HLA) class I molecules, ideally only on tumour cells. Several such polypeptides have been described in the past two years, e.g. in melanomas. However, despite their exquisite specificity, CTL have a number of shortcomings as compared to soluble molecules, in particular with respect to production, handling and general applicability. These difficulties may now be overcome by replacing tumour-specific CTL with recombinant receptor molecules (e.g. antibodies) recognizing HLA/peptide complexes. With phage display, such reagents can be made completely in vitro, bypassing the immune system and immunization procedures, and allowing in vitro tailoring of the receptor's specificity and affinity. As T cell receptors (TCR) are the recognition molecules of CTL, their soluble counterparts are the favoured molecular format for such reagents. However, the expression of TCR as soluble molecules was difficult and phage display libraries were not available.
In order to overcome these problems, five European groups, with expertise in complementing areas of molecular immunology, will cooperate to use robot technology for large-scale selection from phage display libraries of recombinant TCR that interact with HLA class I molecules complexed with peptides derived from melanoma-associated antigens. We want to exploit this fundamental strategy of the immune system for making recombinant reagents with great potential for tumour diagnosis and therapy. By employing robot technology we will be able to screen the enormous diversity on both sides of this recognition system (HLA/peptides and TCR) to select large numbers of interacting molecules. As a starting point, we will focus the selection of recombinant TCR on a small set of HLA class I alleles which are known to efficiently present melanoma-associated peptides. We will then expand the set of antigens (epitopes) to other HLA class I alleles as well as additional melanoma-associated peptides.
Melanoma-peptide/HLA complexes, TCR, phage display libraries, robot technology
Funding SchemeCSC - Cost-sharing contracts