Heart of the Matter: Solving the Titin Toxicity Challenge in HLA-A*02:01 Immunotherapy

New immunotherapy drugs can be very effective, but also: extremely toxic!

Preventing side effects is therefore one of the most important milestones to achieve beforeIND submission and the major hurdle in early drug development.

What if HLA peptide targeted therapies are recognizing peptides from Titin, one of the major proteins expressed in muscular tissues and most importantly myocardiocytes?
This has been observed for TCR Tcell therapies against an A*01:01-restricted TCR against MAGEA3, a cancer testis antigen otherwise a clean target. In HLA-Compass, we can find this HLA A*01:01-restricted epitope easily when using the safety predictors.

However, knowledge about Titin epitope from the more relevant HLA A*02:01 allele, which 80% of drug developers are targeting as it is found in 50% of caucasian population, is scarse: IMDB knows 8, the Ligandome Atlas does not feature any A*02:01 heart tissue.

That’s why we recently released a deeply characterized, high quality A*02:01 immunopeptidomics dataset into HLA-Compass which features 21 A*02:01-restricted Titin epitopes among 25k total unique peptides.
We hope this dataset will be valuable to prevent heart toxicities in future TCR and TCR-mimic therapies and will allow accelerated IND submission of save therapeutic modalities.

precisionmedicine cancer cellandgenetherapy cancervaccine drugsafety drugdevelopment