Carcinoembryonic antigen-related cell adhesion molecule 5 peptide-MHC complex (CEACAM5-pMHC)

The Carcinoembryonic antigen-related cell adhesion molecule 5 (CEACAM5) peptide-MHC complex is a specialized immunological target consisting of a processed 9-10 amino acid peptide fragment of the CEA protein (such as the CAP-1 epitope, YLSGANLNL) bound within the groove of a Major Histocompatibility Complex (MHC) molecule, most commonly HLA-A*02:01. While the full CEACAM5 protein is a well-known cell surface glycoprotein involved in cell adhesion, the pMHC complex represents a target for T-cell receptor (TCR)-based immunotherapies that can recognize intracellularly derived antigens presented on the cell surface (Source: UniProt P06731). CEACAM5 is significantly overexpressed in a wide range of solid tumors, including over 90% of colorectal cancers, as well as pancreatic and lung adenocarcinomas, making this complex a high-priority target for redirecting T-cell cytotoxicity. Therapeutic strategies targeting the CEACAM5-pMHC complex include TCR-engineered T-cells (TCR-T) and Immune mobilizing monoclonal TCRs Against Cancer (ImmTACs), such as IMC-C103C, which act as bispecific bridges between the tumor-specific pMHC and CD3 on T-cells. These modalities offer a distinct advantage over traditional monoclonal antibodies by targeting the specific peptide-HLA signature that identifies a cell as malignant. However, a primary therapeutic challenge is the potential for on-target off-tumor toxicity, as CEACAM5 is expressed at lower levels in normal colonic mucosa and other glandular epithelia, necessitating careful affinity tuning of the TCR domains to ensure a wide therapeutic window (Source: PubMed PMID: 27532813).

Other names

CEA peptide-HLA complexCEACAM5-HLA-A*02:01 complexCarcinoembryonic antigen peptide-MHC complexCAP-1-HLA-A2 complexCEA-pMHC

The target is a specific peptide fragment (e.g., CAP-1) derived from the intracellular processing of the CEACAM5 protein, which is then presented by Major Histocompatibility Complex (MHC) Class I molecules (typically HLA-A*02:01) on the cell surface. Therapeutic agents such as T-cell receptor (TCR) engineered T-cells or bispecific TCR molecules (ImmTACs) bind specifically to this peptide-MHC complex. This binding facilitates the formation of an immunological synapse between the cancer cell and a cytotoxic T-lymphocyte, leading to the release of perforins and granzymes that induce apoptosis in the target tumor cell (Source: PubMed PMID: 32534479, ClinicalTrials.gov NCT04318106).