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The target is a peptide-MHC complex consisting of the ALNEQIARL peptide, derived from the kinetochore protein NDC80 (also known as HEC1), presented on the Human Leukocyte Antigen (HLA)-A*02:01 molecule. NDC80 is a critical component of the outer kinetochore, essential for stable microtubule-kinetochore attachment and proper chromosome segregation during mitosis. While NDC80 is expressed at low levels in most healthy tissues, it is significantly overexpressed in a wide variety of hematologic and solid tumors, making its derived peptides attractive targets for immunotherapy. The ALNEQIARL epitope was identified via mass spectrometry as a broadly presented, non-immunogenic ligand shared across multiple cancer types. Therapeutic strategies targeting this complex include T-cell receptor (TCR)-mimic chimeric antigen receptor (CAR) T-cells and TCR-engineered T-cells, which are designed to recognize the specific peptide-HLA conformation and induce tumor cell lysis. Experimental agents like the NDC80-clC CAR T-cell have demonstrated high sensitivity and specificity in preclinical models of leukemia and solid tumors.
T-cell mediated cytotoxicity via TCR-mimic recognition of the peptide-MHC complex
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