Human Leukocyte Antigen A*02 (HLA-A*02) (HLA-A*02)

Human Leukocyte Antigen A*02 (HLA-A*02) is a polymorphic MHC class I molecule that plays a central role in the immune system by presenting intracellular peptides to CD8+ T cells [1, 9]. In the context of novel logic-gated cell therapies, HLA-A*02 serves as a critical safety gate or ligand for an engineered inhibitory receptor known as a blocker [1, 3]. This blocker is designed to recognize the specific HLA-A*02 allele on the surface of healthy cells, delivering a potent inhibitory signal that overrides any activating signals from a chimeric antigen receptor (CAR) or T-cell receptor (TCR) [5]. This mechanism ensures that the therapeutic cells remain inactive when encountering normal tissues that express the germline HLA-A*02 allele, thereby preventing off-tumor toxicity [1, 5].\n\nThe therapeutic utility of HLA-A*02 as a target arises from the phenomenon of Loss of Heterozygosity (LOH) in cancer, where tumor cells frequently lose one of their HLA alleles to evade immune detection [1, 5]. By targeting an activating antigen (like CEA) while simultaneously gating the therapy with an HLA-A*02 blocker, the treatment can selectively destroy tumor cells that have lost the HLA-A*02 allele while sparing healthy cells that retain it [3, 5]. This AND-NOT logic gate approach is currently being evaluated in clinical trials, such as the EVEREST-1 trial for A2B530, to treat solid tumors like colorectal and lung cancer [5]. The specificity of the blocker for HLA-A*02 is paramount to avoid off-target inhibition or unintended toxicity, making it a cornerstone of precision immunotherapy [1, 6].

Other names

HLA-A2MHC class I antigen A*02Tmod blocker ligandHLA-I-gated safety switch ligand

Logic-gated inhibition (AND-NOT gate) where an engineered inhibitory receptor (blocker) on a cell therapy binds to the HLA allele on healthy cells to prevent off-tumor toxicity, while the absence of the allele on tumor cells (due to LOH) allows for selective tumor killing.