CEACAM5: From Classic Tumor Marker to Hot Target for Next-Generation ADCs/Bispecific Antibodies

It has been 60 years since CEACAM5 (also known as CEA, CD66e) was discovered in 1965. From its initial role as a serum tumor marker to its current status as a hot target for innovative therapies such as ADCs, bispecific antibodies, and CAR-T cells, it is experiencing a renaissance. Several CEACAM5-targeted drugs globally have entered clinical trials: Merck's M9140 has advanced to Phase III, and LaNova Medicines' LM-24C5 has entered Phase II. At the 2026 AACR Annual Meeting, next-generation drugs such as bispecific ADCs and site-specifically conjugated ADCs attracted significant attention, marking a new stage of differentiated and precision-targeted development for this marker.  

Unique Structural Characteristics of CEACAM5

CEACAM5 belongs to the CEACAM subfamily within the immunoglobulin superfamily. It is a cell adhesion molecule expressed on the cell membrane via a GPI anchor and can be released by GPI-PLC enzyme cleavage. Its structure includes one N-terminal IgV domain and six IgC2 domains (divided into three groups: A1-B1, A2-B2, and A3-B3), as well as a GPI anchor moiety. Its primary function is to mediate cell adhesion, inhibit colon cell differentiation and apoptosis, and prevent tumor cell death.

Schematic diagram of the structures of human CEACAM family members^[1]

Ideal Characteristics of CEACAM5: High Expression in Tumors and Low Expression in Normal Tissues

CEACAM5 expression is extremely low in normal adult tissues, restricted exclusively to the apical membrane side of epithelial cells such as those in the colon and esophagus. In contrast, it is significantly overexpressed in various solid tumors: approximately 80-90% of colorectal cancers, as well as a high proportion of pancreatic and gastric cancers. This makes it an ideal target for tumor therapy.  

Prevalence of CEACAM5 in human tumor and normal tissues^[2]

Challenges of Soluble CEACAM5 (sCEACAM5)

It is worth noting that tumor cells can actively shed CEACAM5 into the bloodstream, making it a commonly used clinical serum marker. Normal human serum levels are extremely low (<5 ng/mL)^[3], but the high levels of sCEACAM5 in the blood of tumor patients may competitively bind to therapeutic antibodies, reducing the effective dose at the tumor site—this is perhaps one of the major challenges in targeted drug development.

The Dual Pro-Tumorigenic Role of CEACAM5 (CEA) in Tumor Biology

CEACAM5 is not merely a marker, it actively participates in tumor progression. On the one hand, it enhances malignant phenotypes through cell adhesion and anti-apoptosis mechanisms. On the other hand, it inhibits NK cells, induces dendritic cell tolerance, and remodels the liver metastatic microenvironment, helping tumors achieve immune evasion and metastasis (Figure 3). These mechanisms explain why high CEACAM5 expression is closely correlated with tumor invasion, metastasis, and poor prognosis. They also highlight the significant therapeutic value of targeting CEACAM5 and blocking its interactions with soluble receptors and immune cells. Concurrently, this places higher demands on drug design, necessitating differentiated strategies tailored to the biological characteristics of different cancer types. 

CEA interacts with various immune and non-immune cells to promote tumor progression and metastasis^[4]

Current Status of CEACAM5-Targeted Drug Development

ADC Drugs: From Setbacks to Breakthroughs

Sanofi's Tusamitamab ravtansine (targeting the A3-B3 domain) failed to meet the primary endpoint of PFS in the Phase III CARMEN-LC03 clinical trial, showing no superior efficacy over docetaxel chemotherapy, and its global development has been terminated.

Next-Generation Innovative Drugs: Breakthroughs in Differentiated Design

Sanofi's setback did not dampen industry confidence: instead, it catalyzed the emergence of more differentiated and innovative drugs.

Merck's Precemtabart tocentecan (M9140) utilizes the TOP1 inhibitor exatecan. In a Phase I study for colorectal cancer, it achieved an ORR of 31% (at 2.8 mg/kg) and a median PFS of 6.9 months with a favorable safety profile, making it currently the most successful drug candidate.

Next-Generation ADCs: Differentiated Design  

While Merck is achieving success, the industry has not stopped exploring superior ADCs. At the 2026 AACR conference, Kivu Bioscience presented preclinical data for its next-generation CEACAM5 ADC—KIVU-305. This drug attempts to overcome the limitations of first-generation ADCs through three major technological innovations. In preclinical models, KIVU-305 demonstrated robust, target-specific anti-tumor activity across multiple colorectal, lung, and pancreatic cancer PDX models, and it was well-tolerated in non-human primates, showing potential to further expand the therapeutic window.  

Bispecific ADCs: Dual-Target Synergy to Overcome Heterogeneity and Drug Resistance  

To address tumor heterogeneity and single-target drug resistance, dual-target ADCs have emerged as another major hotspot. At AACR 2026, several studies on CEACAM5 bispecific ADCs attracted significant attention.

CEACAM5 × EGFR Bispecific ADC (RT023, Ruotuo Bio.): As illustrated in Figure 4, this drug employs a heterodimeric bispecific antibody structure (anti-CEACAM5 VHH + anti-EGFR Fab) conjugated with a novel TOP1 inhibitor linker-payload (DAR=6). Preclinical data indicate that RT023 exerts potent killing effects on CEACAM5 or EGFR single-positive and double-positive cells, with an internalization capability superior to that of the parental monoclonal antibodies. It is well-tolerated in cynomolgus monkeys (30 mg/kg) and demonstrates extremely high circulation stability (free toxin release <0.02%). The IND application for RT023 was accepted on June 12, 2026.  

Structure of RT023^[5]

CEACAM5 × CDH17 Bispecific ADC: Helixon and Haisco have independently developed bispecific ADCs targeting this combination, and their preclinical data corroborate one another. CDH17 and CEACAM5 are co-expressed in colorectal cancer (>95%) and gastric/pancreatic cancer (~80%). Furthermore, the loss of tumor cell polarity causes both targets to co-localize within the same membrane region, providing an ideal foundation for dual-targeting.

Other Novel Therapies

Overcoming Soluble Target Interference: The Key to Next-Generation Drug Development

Extensive clinical evidence indicates that the neutralizing effect of sCEACAM5 is a core obstacle limiting ADC efficacy. Multiple companies (such as Sichuan Kelun, Jiangsu Hengrui, and DAAN Biotherapeutics) have prioritized the avoidance of soluble target binding as a core technical metric. Developing antibodies that selectively bind to membrane-bound CEACAM5, while simultaneously evaluating both membrane-bound and sCEACAM5 binding early in the antibody screening process, are critical strategies for mitigating clinical development risks.
Notably, the CEACAM5 bispecific ADCs that emerged at AACR 2026 offer a completely novel approach: even if a portion of the drug is neutralized by sCEACAM5, it can still rely on the second target to internalize into tumor cells. This "double insurance" mechanism provides a more robust design to overcome the sCEACAM5 barrier.  

KACTUS: Empowering the Development of Next-Generation CEACAM5-Targeted Drugs

KACTUS provides a comprehensive matrix of recombinant CEACAM5 protein products, covering multiple species, various tags, different domains (N-A1-B2, A1-B2, A1-B1, A2-B2, A3-B3, etc.), full-length extracellular domains, and low-endotoxin versions. These offerings comprehensively support enterprises in the efficient development of next-generation candidate molecules.  

Product Data

The purity of Human CEACAM-5 is greater than 90% and the molecular weight of this protein is around 170-205 kDa as determined by SEC-MALS.

Loaded Anti-CEACAM-5 Antibody, hFc Tag on ProA-Biosensor can bind Human CEACAM-5, His Tag with an affinity constant of 6.95 nM as determined in BLI assay.

Immobilized Human CEACAM-5, His Tag at 1 μg/ml (100 μl/well) on the plate. Dose response curve for Anti-CEACAM5 Antibody, hFc Tag with the EC50 of 2.5ng/ml determined by ELISA.

Immobilized Biotinylated Human CEACAM-5 (499-685), His Avi Tag at 0.5μg/ml (100μl/well) on the streptavidin precoated plate (5μg/ml). Dose response curve for Anti-CEACAM-5 Antibody, hFc Tag with the EC50 of 3.6ng/ml determined by ELISA.

Immobilized Cynomolgus CEACAM-5, His Tag at 0.5μg/ml (100μl/well) on the plate. Dose response curve for Anti-CEACAM-5 Antibody, hFc Tag with the EC50 of 3.7ng/ml determined by ELISA.

Product List

References

1.    Han Z W, Lyv Z W, Cui B, et al. The old CEACAMs find their new role in tumor immunotherapy[J]. Investigational New Drugs, 2020, 38(6): 1888-1898.
2.    Decary S, Berne P F, Nicolazzi C, et al. Preclinical activity of SAR408701: a novel anti-CEACAM5–maytansinoid antibody–drug conjugate for the treatment of CEACAM5-positive epithelial tumors[J]. Clinical Cancer Research, 2020, 26(24): 6589-6599.
3.    Huang S C, Chang S C, Liao T T, et al. Detection and clinical significance of CEACAM5 methylation in colorectal cancer patients[J]. Cancer Science, 2024, 115(1): 270-282.
4.    Beauchemin N, Arabzadeh A. Carcinoembryonic antigen-related cell adhesion molecules (CEACAMs) in cancer progression and metastasis[J]. Cancer and Metastasis Reviews, 2013, 32(3): 643-671.
5.    Huang S, Zhou L, Cao J, et al. RT023, a first-in-class CEACAM5/EGFR targeted bispecific antibody drug conjugate (ADC) in colorectal cancer (CRC)[J]. Cancer Research, 2026, 86(7_Supplement): 1718-1718.