Claudin 18.2: A Promising Avenue in Modern Oncology

Claudin 18.2 is a protein found on the surface of stomach lining cells that has become one of the most actively pursued drug targets in gastrointestinal cancer. Normally locked away in the tight seals between stomach cells, it becomes exposed on the surface of tumor cells in a way that lets drugs reach it, and its near-total absence from other healthy tissues means therapies aimed at it have a built-in safety advantage. The first drug designed to attack this protein, zolbetuximab, reached patients in 2024, and a wave of next-generation treatments are now in clinical testing.

What Claudin 18.2 Actually Does in a Healthy Body

Claudins are a family of proteins that form the watertight junctions between cells lining your organs. Think of them as the molecular mortar between bricks in a wall. Claudin 18 comes in two versions. One version (isoform 1) appears in lung tissue. The other, isoform 2, is expressed almost exclusively in the stomach, where it helps gastric cells withstand the harsh acidic environment needed for digestion.¹ Under normal conditions, the protein sits buried within those tight junctions, essentially hidden from the bloodstream and from circulating immune cells. This matters enormously for drug design: a protein that the immune system cannot normally “see” is also a protein that a carefully designed drug can reach on cancer cells without causing collateral damage to healthy tissue elsewhere.

Why Cancer Makes the Protein Visible

When stomach cells become cancerous, the orderly architecture of the tissue breaks down. Tight junctions lose their structure, and claudin 18.2 that was once tucked between cells becomes exposed on the outer face of tumor cells. This molecular wardrobe malfunction turns a maintenance protein into a target that antibodies and immune cells can latch onto. The protein also turns up on cancers beyond the stomach, particularly tumors that have features resembling gastric tissue. Pancreatic cancers show positivity in roughly 15 to 22 percent of cases, biliary tract cancers in about 6 to 25 percent, and some rarer subtypes, like invasive mucinous lung adenocarcinoma and mucinous ovarian tumors, express it at even higher rates.²³ In colorectal cancer, by contrast, expression is rare, under 1 percent in one large survey.³

The common thread is gastric-type differentiation: the more a tumor’s biology resembles stomach lining, the more likely it is to carry claudin 18.2 on its surface. This observation has shaped which cancers researchers are now testing therapies against and has broadened the potential reach of claudin 18.2-directed drugs beyond stomach cancer alone.

Zolbetuximab and the Phase 3 Evidence

Zolbetuximab is a monoclonal antibody, a lab-made protein engineered to bind specifically to claudin 18.2 on tumor cells. Once it locks on, it triggers two immune-mediated killing pathways: it recruits natural killer cells to destroy the cancer cell directly, and it activates a cascade of blood proteins called complement that punch holes in the cell membrane.⁴ Phase 1 studies confirmed that patients retain enough natural killer cell and complement activity for these mechanisms to work throughout the dosing interval.⁵

The pivotal evidence came from the SPOTLIGHT trial, a large randomized study of patients with previously untreated, advanced gastric or gastroesophageal junction adenocarcinoma whose tumors expressed claudin 18.2. Adding zolbetuximab to standard chemotherapy reduced the risk of disease progression or death by 25 percent compared with chemotherapy alone. Median progression-free survival stretched from about 8.7 months to 10.6 months, and the risk of death also fell by 25 percent.⁶ Those numbers may look modest in absolute terms, about two extra months before the cancer progressed, but in advanced gastric cancer, where options have been limited for decades, a statistically robust survival benefit from a targeted agent represents a genuine shift in how the disease is treated.

Testing Tumors for Claudin 18.2

Not every gastric cancer patient benefits from zolbetuximab. The drug only works when the tumor has enough claudin 18.2 on its surface, and determining that requires a pathology test called immunohistochemistry. A pathologist stains a tissue sample with an antibody that lights up wherever claudin 18.2 is present, then scores the result by how intensely the protein stains and in what percentage of tumor cells. The threshold used in clinical practice is moderate-to-strong staining in at least 75 percent of the cancer cells.⁷

Getting an accurate score is trickier than it sounds. Several aspects of how the tissue sample is handled before staining, the specific antibody clone used, and how the pathologist interprets borderline cases can influence the result. Practical guidance for pathologists has been published to standardize the process, but this remains an area where testing quality can vary between hospitals.⁷

The Heterogeneity Problem

One of the biggest headaches with claudin 18.2 testing is that expression of the protein can vary within a single patient’s cancer. A biopsy taken from one part of a tumor might show high expression while another spot tests low. This is called intratumoral heterogeneity. Studies comparing the primary stomach tumor with its metastases in lymph nodes or other organs have found discordant results in roughly 18 to 20 percent of cases.⁸⁹ That means a patient classified as “negative” based on a single biopsy site could actually have claudin 18.2-positive disease elsewhere, and vice versa. This mismatch has real consequences: some patients who might benefit from targeted therapy could be missed, while others may receive it without the target being present on their most dangerous lesions.

Imaging to See the Whole Picture

Biopsy-based testing only samples a tiny fragment of the tumor. Researchers are working on PET imaging tracers that can map claudin 18.2 expression across the entire body in a single scan. One approach uses a radioactive tracer linked to a claudin 18.2 antibody. In preclinical models, the tracer showed uptake more than twice as high in tumors expressing the protein compared with those that did not.¹⁰ A first-in-human study of a different tracer demonstrated that PET imaging could safely reveal most claudin 18.2-positive lesions across the body.¹¹ If this technology matures, it could solve a lot of the heterogeneity problem by letting oncologists see which patients have enough target across all their disease sites to justify treatment, without relying on a single needle biopsy.

Beyond Zolbetuximab: Antibody-Drug Conjugates

Zolbetuximab kills by rallying the immune system, but a newer class of drugs takes a more direct approach. Antibody-drug conjugates, or ADCs, are essentially guided missiles: an antibody that recognizes claudin 18.2 is chemically linked to a potent cell-killing toxin. When the antibody binds to a tumor cell and gets pulled inside, the toxin is released internally and destroys the cell from within. CMG901, the most advanced claudin 18.2-directed ADC, uses the microtubule-disrupting agent MMAE as its warhead.¹²

In lab studies, CMG901 showed not only direct toxicity to cancer cells but also triggered the same immune-mediated killing seen with zolbetuximab, plus an additional trick called bystander killing, where the released toxin diffuses to nearby tumor cells that may not express the target themselves.¹² That bystander effect could be especially useful in heterogeneous tumors where not every cancer cell displays claudin 18.2. CMG901 has entered phase 1 clinical testing in patients with advanced gastric or gastroesophageal junction cancer and is now in phase 3 trials.¹³¹²

Bispecific Antibodies That Redirect T Cells

Another line of attack uses bispecific antibodies, engineered proteins with two arms: one grabs claudin 18.2 on the tumor cell, the other grabs a T cell, physically bringing killer immune cells into contact with cancer. AZD5863 is one such molecule, designed with a deliberately weak grip on T cells and a strong grip on the tumor target. This engineering choice is intentional. A gentler T cell engagement means less of the inflammatory cytokine storm that has plagued earlier bispecific antibodies in other cancers. In lab assays, AZD5863 killed tumor cells more effectively than a comparator molecule while triggering lower levels of inflammatory cytokines.¹⁴

A different bispecific, IBI389, takes a complementary tack. Beyond simply redirecting T cells, it appears to remodel the immune landscape around the tumor, increasing T cell infiltration into tissue that normally keeps immune cells out. In animal models, it also synergized with PD-1 blockade, a class of immunotherapy already in wide use, suggesting future combination strategies.¹⁵

CAR T Cells Against Solid Tumors

CAR T cell therapy, which has transformed the treatment of certain blood cancers, has been notoriously difficult to apply to solid tumors. Claudin 18.2 is one of the first solid-tumor targets where CAR T cells have shown real clinical traction. Satri-cel (also known as CT041) is a CAR T product in which a patient’s own T cells are extracted, genetically reprogrammed to recognize claudin 18.2, expanded in the lab, and infused back.

In a phase 1 trial enrolling 98 patients with heavily pretreated gastrointestinal cancers, about 39 percent had their tumors shrink meaningfully, and over 90 percent achieved at least disease stabilization. Median progression-free survival was roughly 4.4 months and median overall survival reached about 8.8 months.¹⁶ In gastric cancer specifically, the earlier interim data were even more encouraging, with response rates near 57 percent and a six-month survival rate over 80 percent.¹⁷

A randomized phase 2 trial then compared satri-cel against physician’s choice of chemotherapy in patients who had already failed at least two lines of treatment. Median progression-free survival nearly doubled, from about 1.8 months with standard care to 3.3 months with satri-cel, a statistically robust difference.¹⁸ These absolute numbers are still short by the standards of some other cancers, but in the third-line gastric cancer setting, where effective options barely exist, they represent meaningful progress. The safety profile was described as manageable, with cytokine release syndrome (an inflammatory reaction to T cell activation) occurring but decreasing in severity with subsequent infusions.¹⁷

Combining Claudin 18.2 Drugs with Checkpoint Inhibitors

One of the more exciting theoretical possibilities is pairing claudin 18.2-targeted therapies with PD-1 or PD-L1 checkpoint inhibitors. Checkpoint inhibitors work by removing the “brakes” that tumors place on the immune system, but they work best when the immune system is already active against the cancer. There is a hypothesis that claudin 18.2-targeted agents, whether antibodies, ADCs, bispecific molecules, or CAR T cells, could jump-start that immune activation, making checkpoint inhibitors more effective. Early mechanistic work supports the idea that these treatments may partially reverse the immunosuppressive microenvironment characteristic of gastric tumors, although direct clinical evidence of synergy remains limited so far.¹⁹ Multiple clinical trials combining these approaches are underway.

When Treatments Stop Working

Like virtually every targeted cancer therapy, claudin 18.2-directed treatments face resistance. Tumors are moving targets, and several escape routes have been identified. The cancer cells can reduce or lose claudin 18.2 expression altogether, making the drug unable to find its target. The cell’s internal machinery for pulling the antibody inside and breaking it down can malfunction, blunting ADC efficacy in particular. Some cells ramp up molecular pumps that eject the toxic payload before it can do damage. And the immunosuppressive environment within the tumor can limit drug delivery and shield cancer cells from immune attack.²⁰ Understanding these mechanisms is critical because it shapes how the field designs next-generation drugs and combination regimens intended to stay ahead of the tumor’s adaptations.

What Patients Report About Quality of Life on Zolbetuximab

A common fear when adding a new drug to chemotherapy is that side effects will make daily life worse. Data collected directly from patients in the SPOTLIGHT and GLOW trials showed that adding zolbetuximab to chemotherapy did not erode health-related quality of life compared with chemotherapy alone. Patients in both arms maintained roughly similar scores on physical functioning, emotional well-being, and global health status.²¹ Earlier data from the phase 2 FAST trial suggested that once chemotherapy ended and patients continued on zolbetuximab alone as maintenance, they reported better quality of life and lower symptom burden than those who had stopped active treatment, with a statistically significant advantage in the time before global health status worsened. The one area where zolbetuximab fared worse was nausea and vomiting, a known side effect of the drug.²²

Cost and Access Barriers in the Real World

Having a drug that works in trials and getting it to patients in daily practice are different challenges. A cost-effectiveness analysis conducted from the Chinese health-care perspective found that adding zolbetuximab to chemotherapy produced an incremental cost-effectiveness ratio well above conventional willingness-to-pay thresholds, concluding it would not be cost-effective in that setting at current pricing.²³ How those numbers translate to other health-care systems depends heavily on local pricing, insurance structures, and reimbursement policies, but the general reality is that novel targeted therapies carry high price tags that constrain access.

Beyond cost, a study examining adoption in community oncology practices in the United States identified four major barriers: limited awareness of the clinical trial data among practicing oncologists, inadequate infrastructure for biomarker testing (many community labs are not yet set up to run standardized claudin 18.2 staining), uncertainty about which patients are optimal candidates, and insurance coverage gaps.²⁴ These are familiar hurdles in precision oncology; they arose with earlier biomarker-directed drugs and are likely to crop up with every new claudin 18.2 therapy that reaches the market. Solving them will require coordinated effort between pathology labs, insurers, and the oncology community, especially outside major academic centers where expertise and infrastructure are more concentrated.

Other Tumors on the Radar

Although gastric cancer has been the primary battlefield, claudin 18.2’s expression in pancreatic, biliary, and certain lung and ovarian cancers has not gone unnoticed. One study found claudin 18.2 positivity in all five mucinous ovarian tumor samples tested and in four of five invasive mucinous lung adenocarcinomas, though these are small numbers from uncommon subtypes.² Pancreatic cancer, with its dire prognosis and limited treatment options, is a particularly compelling frontier. Early-phase trials of claudin 18.2-directed therapies in pancreatic adenocarcinoma are underway, though the lower and more variable expression rates in that disease compared with gastric cancer mean patient selection will be even more critical. Small bowel adenocarcinoma, another rare gastrointestinal malignancy, also shows claudin 18.2 expression in a meaningful subset of cases.²⁵ Whether the protein’s presence in these rarer settings translates into clinical benefit with targeted treatment is still an open question, but the biology provides a rationale for finding out.