Carcinoembryonic antigen (CEA) is a complex acidic glycoprotein. CEA belongs to the immunoglobulin family known as CEA-related cell adhesion molecules (CEACaMs), also known as CEACAM5. It is primarily found in adult cancer tissue and fetal gastrointestinal tissue, where it inhibits anoikis, differentiation, and cell polarization. CEA is a broad-spectrum tumor marker used as an aid in the diagnosis of common tumors, including colorectal cancer, lung cancer, breast cancer, esophageal cancer, gastric cancer, and metastatic liver cancer.

Structure and distribution of CEA

The CEACAM family is a cell membrane protein, which includes 12 family members. CEA is the first member of the CEACAM family. It binds to the membrane through glycosylphosphatidylinositol (GPI). Its structure contains 7 immunoglobulin-like domains, a variable (lgV)-like domain (N domain); followed by three repeating units, including six lgC-like domains (A1-B3); there is a 34-amino acid signal peptide in front of the lg domain.

(Data source: Han ZW, et al. Invest New Drugs. 2020)

CEA is produced in the gastrointestinal tract during the early stages of embryonic and fetal development (9 to 14 weeks), its serum levels decline during the second trimester, and remain very low in adulthood. In healthy adults, CEA is still produced in some tissues, primarily in the goblet cells and columnar epithelial cells of the colon, but also in the prostate, cervix, tongue, esophagus, stomach, and prostate.

(Data source: Uniprot)

Functions of CEA

CEACAM5 is highly expressed in most malignant tumors and is associated with tumor initiation, invasion, and metastasis. CEACAM5, through its immunoglobulin (Ig)-like domain, participates in homologous and heterologous cell-cell adhesion, which is crucial for maintaining tissue architecture and intercellular communication. CEA-CEA homologous interactions between tumor cells or tumor-stromal cells can directly influence tumor progression. Furthermore, heterologous interactions of CEA on tumor cells with death receptor 5 (DR5) or transforming growth factor-β receptor 1 (TGF-βR1) lead to reduced anoikis (cell death after detachment from the matrix) or resistance to TGF-β-mediated growth inhibition, respectively. These effects enhance tumor cell survival and, consequently, metastasis. CEA can heterologously bind to CEACAM1 on the surface of natural killer (NK) cells through its N domain, and this binding inhibits NK cell cytotoxicity in an MHC-independent manner.

(Data source: Beauchemin N, et al. Cancer Metastasis Rev. 2013)

Clinical value of CEA

Tumor prognosis assessment: If serum CEA levels continue to rise after treatment, it indicates a poor prognosis. If treatment is effective, the concentration will decrease to within the reference range. If the concentration decreases partially or not at all, it indicates poor treatment efficacy. Under normal circumstances, the reference range for human serum CEA is ≤5.0 ng/mL.

Targeted therapy of CEA: CEACAM5 plays a key role in malignant tumors. CEACAM5 plays an important role in the development of advanced cancer treatments such as antibody-drug conjugates (ADCs), bispecific antibodies (BsAbs), bispecific T cell engagers (BiTEs) and chimeric antigen receptor T cells (CAR-T).

Merck is developing a CEACAM5 ADC designed to deliver a cytotoxic topoisomerase 1 (TOP1) inhibitor payload to CEACAM5-expressing tumor cells. The TOP1 inhibitor payload enters the cell nucleus and disrupts DNA replication and repair, thereby killing CEACAM5-expressing tumor cells. The payload can also enter and kill neighboring tumor cells through a bystander effect. M9140 monotherapy is currently in a Phase 1, multicenter, open-label, first-in-human study in patients with advanced solid tumors.

(Data source: Merck official website)

The CEACAM5xCD47 bispecific antibody NILK-2401 targets CEACAM5-positive solid tumors and is designed to block the CD47 "don't eat me" signal, which allows tumor cells to evade immune surveillance by interacting with signal-regulatory protein alpha (SIRPa) on phagocytes. NILK-2401 initially binds to CEACAM5+ tumor cells, driven by the high-affinity anti-CEACAM5 arm. The low-affinity anti-CD47 arm co-binds and blocks CD47 binding to tumor cells. Tumor cells are killed through antibody-dependent cellular phagocytosis (ADCP) and antibody-dependent cytotoxicity (ADCC).

(Data source: Seckinger A, et al. Front Immunol. 2024)