Carbonic anhydrase IX peptide-MHC class I complex (CAIX/MHC-I)

Carbonic anhydrase IX (CAIX) is a transmembrane enzyme that is highly overexpressed in clear cell renal cell carcinoma (ccRCC) due to the loss of the von Hippel-Lindau (VHL) tumor suppressor gene and subsequent stabilization of hypoxia-inducible factors [1, 2]. The CAIX peptide-MHC class I complex is a specialized therapeutic target consisting of intracellularly processed CAIX fragments, such as the HLA-A*02:01-restricted peptide LLALVFGLL, presented on the cell surface [3, 4]. Unlike traditional monoclonal antibodies that bind to the folded extracellular domain of CAIX, therapies targeting this complex—such as TCR-engineered T-cells (TCR-T) and TCR-like antibodies—mimic the natural immune recognition system to identify and eliminate malignant cells [5]. This target is particularly valuable in the context of ccRCC, where CAIX expression is nearly universal and serves as a hallmark of the disease [6]. However, clinical application is complicated by the potential for on-target, off-tumor toxicity, as CAIX is also expressed at lower levels in normal tissues like the bile duct epithelium and gastric mucosa [7]. Furthermore, because the target is an MHC-restricted complex, its use is limited to patients with specific human leukocyte antigen (HLA) genotypes [8].

Other names

CA9 peptide-HLA complexG250 peptide-MHC complexHLA-A*02:01/CAIX(LLALVFGLL) complexCarbonic anhydrase 9 peptide-MHC complex

Recognition of the CAIX-derived peptide presented on MHC Class I by engineered T-cell receptors or TCR-like binders, triggering cytotoxic T-lymphocyte mediated lysis of the tumor cell.