In Silico Technologies
iTope™ – Peptide/MHC Class II Binding
A necessary step in the induction of helper CD4+ T cell responses to a peptide is binding to MHC class II. iTope™ is a proprietary in silico molecular modelling technology which models the binding of peptides to 34 MHC class II alleles. The contribution of individual amino acids to peptide binding can be determined for each allele, and this provides information on the precise location of the core 9mer sequences that interact with the MHC class II binding groove.
iTope™ provides a useful low resolution first step in evaluating the immunogenicity potential of biologics prior to a high resolution EpiScreen™ analysis. For T cell epitopes already identified using EpiScreen™ T cell epitope mapping, iTope™ determines the core 9mer sequences that can be used to enable the design of ‘deimmunised’ sequence variants in which T cell epitopes are mutated to disrupt binding.
TCED™ – T Cell Epitope Database™
Data from large scale EpiScreen™ T cell epitope mapping studies over several years has enabled the development of a database of “real” helper CD4+ T cell epitopes. Novel test sequences can be analysed for homology to known T cell epitopes in the TCED™ enabling the rapid and accurate in silico identification of T cell epitopes in protein sequences. Furthermore, homology to peptides in the TCED™ that do not contain T cell epitopes provides a valuable source of sequences that are used as ‘building blocks’ to generate non-immunogenic therapeutic proteins and antibodies (Composite Proteins and Composite Human Antibodies).
Preclinical Prediction of Immunogenicity – Combined TCED™/iTope™
Whilst iTope™ alone provides a low resolution evaluation of the immunogenic potential of biologics, the combination of TCED™/iTope™ analysis provides a significant improvement. TCED™ and iTope™ are used in combination to test protein sequences in order to identify matches to previously screened sequences (TCED™) and to determine binding to MHC class II (iTope™). Using this combined method sequences within the test protein are identified that have a high probability of containing T cell epitopes. If required, such sequences can then be tested in vitro by EpiScreen™. The combined TCED™/iTope™ is typically used for rapid analysis of multiple sequence (for example, from recombinant antibody leads) in order to identify sequences with the lowest probability of containing T cell epitopes.