Major Histocompatibility Complex Class I: Difference between revisions

A recent study called ''Targeting a neoantigen derived from a common TP53 mutation'' describes the means by which T Cell Receptor mimic (TCRm) antibodies were created a new class of immunotherapy. TP53, tumor protein 53, is a tumor suppressor gene, and is the most commonly mutated protein in cancers. Most [[P53]] is located inside the cell, the largest concentration is in the nucleus, which makes it difficult to find a treatment for TP53. Scientists have been struggling to design a drug to target this inactivated tumor suppressor gene. However, a  small percentage is degraded by proteasomes and is present on the cell surface by MHC, Human Leukocyte Antigen (HLA). The most frequent mutation in the TP53 gene is a substitution from Arginine to Histidine at codon 175 (R175H). Most mutations within this gene occur as single-nucleotide variants at positions nearest to the DNA-binding domain. Using an HLA TP53 complex researchers discovered that neoantigen p53R175H is displayed by HLA:A2 on the cell surface at very low density. These peptide-HLA (pHLA) complexes are naturally ligands for T-cell receptors (TCRs). The advantage of using TCRm’s for immunotherapies is that they are easier to graft into different therapuetic formats and are an off the shelf ready to use therapy. Specifically, researchers developed a bispecific antibody constructed from H2 and an antiCD3 antibody,  (H2- scDb) that can activate T cells even when the pHLA complex is expressed at very low, endogenous levels. This promising research shows that MHC I can be a key player in the fight against cancers caused by p53 mutations. <ref>DOI: 10.1126/science.abc8697</ref>. See below for interactive figures from this research.

The video above depicts the 3D structure of the pHLA (p53R175H/HLA-A*02:01) that is bound to an H2-Fab fragment (PDB 6W51). The Fab fragment is colored according to its heavy chains (dark blue) and light chains (cyan). The Fab fragment is bound to the C terminus of the pHLA complex, where HLA-A*02:01 is colored gray and the β2 microglobulin is colored in gold. Sandwiched in between alpha helices of HLA are nine amino acids that are part of p53R175H shown light green.