Naked cuticle homolog 1 (NKD1)-derived peptide presented by HLA-A*02:01 (NKD1/HLA-A*02:01 complex)

The target is a specific peptide derived from the Naked cuticle homolog 1 (NKD1) protein, presented on the cell surface by the Human Leukocyte Antigen A*02:01 (HLA-A2) molecule. NKD1 is a negative regulator of the canonical Wnt signaling pathway and is characterized as an oncofetal antigen, meaning it is expressed during embryonic development but is largely absent in healthy adult tissues [1, 8]. In certain malignancies, particularly microsatellite stable (MSS) metastatic colorectal cancer, the fetal Wnt developmental program is reactivated, leading to the overexpression of NKD1 and the subsequent presentation of its derived peptides on HLA-A2 [2, 3]. This peptide-MHC complex serves as a highly specific tumor-associated antigen that can be targeted by engineered T-cell receptor (TCR) therapies or TCR-mimic antibodies [14]. By targeting an intracellular protein through its surface-presented peptide, this approach bypasses the limitations of traditional CAR-T therapies that require surface-expressed proteins. Current therapeutic development focuses on TCR-T cell products that recognize this complex to induce potent, antigen-dependent cytotoxicity against tumor cells while sparing healthy tissues [2, 3].

Other names

NKD1-A2 complexNKD1-derived peptide-MHC complexFetal WNT-associated antigen NKD1 peptideOncofetal protein 1 (OFP1) peptide-HLA complex

Engineered T-cell receptors (TCRs) or TCR-mimic antibodies specifically recognize the NKD1-derived peptide in the context of HLA-A*02:01 on the tumor cell surface, leading to T-cell activation, inflammatory cytokine production, and direct cytotoxic lysis of the cancer cell [2, 3].