Cancer treatments have evolved significantly, moving towards more precise methods that specifically target cancer cells while sparing healthy tissue. One such innovative approach is the development of antibody-drug conjugates (ADCs). These therapies represent a promising advancement in oncology, combining the targeting ability of antibodies with the cell-killing power of chemotherapy. CEACAM5 ADC is a particular type of ADC designed to combat cancers that express a specific protein on their surface, offering a focused strategy for treatment.
What is CEACAM5 ADC
CEACAM5, or Carcinoembryonic Antigen-related Cell Adhesion Molecule 5, is a protein found on the surface of cells, often overexpressed in various cancer cells. Its high presence on malignant cells and low expression in normal epithelial tissues make it a potential target for cancer therapies. It functions as a cell adhesion protein and is part of the carcinoembryonic antigen (CEA) family.
An Antibody-Drug Conjugate (ADC) is a class of targeted therapy that combines the precise targeting of a monoclonal antibody with a potent chemotherapy drug. The antibody acts as a guidance system, specifically recognizing and binding to antigens on the surface of cancer cells. The chemotherapy drug is the payload, the cell-killing agent.
These two components are connected by a chemical linker, designed to be stable in the bloodstream, preventing the drug from being released prematurely. A CEACAM5 ADC uses an antibody that specifically binds to the CEACAM5 protein on cancer cells. This ensures the potent chemotherapy drug is delivered directly to tumor cells expressing CEACAM5, minimizing harm to healthy cells.
How CEACAM5 ADC Works Against Cancer
The mechanism of action for CEACAM5 ADC begins when the antibody component of the conjugate specifically recognizes and attaches to the CEACAM5 protein on a cancer cell. This binding is highly selective, ensuring the therapy targets the intended malignant cells.
Once the antibody-drug conjugate is bound to the CEACAM5 protein, the complex is drawn inside the cancer cell through a process called receptor-mediated endocytosis. This internalization brings the potent chemotherapy drug directly into the cellular environment where it can exert its effect.
Inside the cancer cell, the linker connecting the antibody to the drug is designed to break, typically in the acidic environment of the lysosome or by specific enzymes. This cleavage releases the active chemotherapy drug. The released drug then acts locally within the cancer cell, disrupting cellular processes, such as DNA replication or microtubule assembly, ultimately leading to the cancer cell’s death. This targeted delivery minimizes systemic toxicity and damage to healthy cells that do not express CEACAM5.
Cancers Targeted by CEACAM5 ADC
CEACAM5 is a protein frequently overexpressed in several cancer types, making it a suitable target for specific therapies. Its overexpression in a significant percentage of certain malignancies provides a rationale for targeting these diseases.
Cancers with high CEACAM5 levels include non-small cell lung cancer (NSCLC), gastric cancer, colorectal cancer (CRC), and pancreatic cancer. For instance, CEACAM5 is expressed in virtually all colorectal cancers, with about 90% showing high levels, while its expression in normal tissues is limited. It is overexpressed in about 90% of gastrointestinal, colorectal, and pancreatic cancers, and in gastric cancer, its expression can be assessed for prognosis. Studies have indicated that higher CEACAM5 expression in lung adenocarcinoma, for example, is linked to poor prognosis, further supporting its role as a therapeutic target.
Current Status and Future Outlook
Several CEACAM5 ADCs are currently in various stages of clinical development. Tusamitamab ravtansine (SAR408701) is one such CEACAM5-directed ADC that has been evaluated in clinical trials. This ADC consists of an anti-CEACAM5 antibody linked to a potent anti-microtubulin drug, DM4, via a cleavable linker.
While tusamitamab ravtansine showed promising preclinical activity in colorectal, lung, and gastric tumor models, a Phase 3 trial (CARMEN-LC03) in previously treated advanced non-squamous non-small cell lung cancer did not meet its primary endpoints of progression-free survival and overall survival. Despite this outcome, data from the study suggested a possible prognostic role for CEACAM5 expression in NSCLC patients, and the safety profile of tusamitamab ravtansine was considered favorable. Sanofi has discontinued the global clinical development program for tusamitamab ravtansine as a monotherapy for NSCLC, but continues to explore the potential of other CEACAM5-directed ADCs.
Research continues into CEACAM5 as a therapeutic target, with other ADCs and therapeutic modalities, such as CAR T-cells, also being investigated. The ongoing efforts aim to overcome challenges such as potential side effects and resistance mechanisms, with the goal of developing CEACAM5 ADCs that could become an important part of the cancer treatment landscape, potentially in combination with other therapies.