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Immunopeptidomics
The human leukocyte antigen (HLA) complex represents an important component of adaptive immune reactions and an attractive target for specialized immunotherapy, i.e. with genetically engineered T cells (TCR T cells), soluble TCR receptors and TCR-mimic antibodies. The first ever therapy against HLA peptides was approved in 2022, Immunocore’s Kimmtrak, a soluble TCR targeting a gp100 peptide on the surface of melanoma cells.
More recently, Adaptimmune’s TCR T cell therapy against an HLA-presented MAGEA4 peptide was approved against synovial sarcoma. A growing number of additional investigational therapeutics is in clinical development mainly in the US and in China.
The peptides presented by HLA complexes are anchored in the pocket through interactions within certain amino acids of the peptide sequence, typically at position 2 and 9 of the nine-mer peptide.
Some HLA allele-specific motifs representing the frequency of certain amino acids at certain positions are shown below:
Due to the high variability of peptides in different samples and the different physico-chemical properties of these different sets of peptides, immunopeptidomics, i.e. the study of the HLA-presented peptides, represents a challenging research area and requires highly specialized companies such as Alithea.
HLA peptides are typically isolated via a multi-step procedure starting from cell and tissue lysate, incubation with affinity resin, to elution of HLA peptides in acidic condition. These eluted peptides require an additional purification step over C18 resin before UHPLC-MS analysis with highly sensitive mass spectrometers.
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