Peptide-HLA class I complexes derived from melanoma-associated antigens (pHLA-MAA complexes)

Peptide-HLA class I complexes derived from melanoma-associated antigens (MAAs) are specialized molecular targets that represent the presentation of intracellular tumor proteins on the cell surface (Kavraki Lab, https://kavrakilab.org/research/structural-modeling-of-peptide-hla-complexes/). These complexes are formed when proteins such as gp100, MART-1, or MAGE-A4 are degraded by the proteasome into short peptides, which are then loaded onto Human Leukocyte Antigen (HLA) Class I molecules and transported to the plasma membrane (NIH, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5509013/). This mechanism allows the immune system, specifically CD8+ T cells, to monitor the internal state of the cell and identify malignant transformations. In melanoma, these complexes are highly relevant because the tumor is often immunogenic and expresses a variety of well-characterized antigens (NIH, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11346541/). Therapeutic intervention targeting these complexes has led to significant clinical breakthroughs, most notably with the approval of tebentafusp for uveal melanoma (NIH, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8634511/). Tebentafusp is a bispecific protein that uses a high-affinity T-cell receptor (TCR) domain to bind the gp100 peptide-HLA-A*02:01 complex and an anti-CD3 domain to recruit T cells for tumor lysis (MDPI, https://www.mdpi.com/2072-6694/11/7/971). Other modalities include TCR-engineered T cells (TCR-T) and TCR-mimic antibodies, which are designed to overcome the limitations of traditional antibodies that cannot target intracellular proteins (NIH, https://pubmed.ncbi.nlm.nih.gov/39787441/). However, the high specificity required to distinguish these complexes from similar ones in healthy tissues is a major safety hurdle, as evidenced by historical cases of fatal cross-reactivity (NIH, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4936055/).

Other names

Melanoma-associated antigen-HLA complexesMHC-peptide complexes in melanomaTumor-associated antigen-HLA class I complexespHLA-I complexespMHC complexesMelanoma immunopeptidome

Drugs targeting these complexes primarily function through T-cell redirection or adoptive cell transfer. Bispecific T-cell engagers (e.g., tebentafusp) bridge the pHLA complex on tumor cells with the CD3 receptor on T cells, inducing polyclonal T-cell activation and cytolysis. TCR-engineered T-cell therapies (e.g., afamitresgene autoleucel) involve the infusion of patient T cells modified to express a high-affinity TCR specific for the pHLA complex. TCR-mimic (TCRm) antibodies bind the complex like a TCR and can trigger antibody-dependent cellular cytotoxicity (ADCC) or be used as the targeting domain in CAR-T cells.