What are the therapeutic candidates targeting CLDN18.2?

Introduction to CLDN18.2

CLDN18.2 is a splice variant of claudin‐18, a member of a family that regulates tight junctions between epithelial cells. Over the past several years, it has emerged as a promising molecular target in multiple cancers due to its unique expression pattern and cellular functions.

Biological Role and Importance

CLDN18.2 plays a critical role in maintaining the barrier function of gastric epithelial cells by contributing to the formation and maintenance of tight junctions. Under normal physiological conditions, the protein is expressed only on differentiated gastric mucosal cells where it helps to regulate paracellular permeability and maintain cell polarity. However, upon malignant transformation, the tissue architecture and polarity are often disrupted; this leads to disordered localization and over‐expression of CLDN18.2 on the surface of tumor cells. The importance of targeting CLDN18.2 is further heightened as its expression is largely tissue restricted in normal cells yet becomes readily accessible on malignant cells. This selective abnormal expression makes it a valuable biomarker for targeted therapies and may reduce off‐target effects during treatment.

Expression in Cancer Types

In the cancer setting, CLDN18.2 is most notably associated with gastric cancer. However, its overexpression or ectopic activation has also been documented in several other malignancies including pancreatic, esophageal, ovarian, lung, colon, hepatic, head and neck cancers, and even certain subtypes of gastroesophageal junction adenocarcinoma. The tight linkage between the loss of normal tissue architecture, the emergence of invasive tumor properties, and the resultant exposure of CLDN18.2 epitopes on the cell surface has been a pivotal discovery. In clinical settings, immunohistochemical assessments have revealed significant expression levels in patients with advanced disease, thereby providing a rationale for targeting CLDN18.2 with monoclonal antibodies, bispecific agents, and cell therapies.

Current Therapeutic Candidates

There is a diverse array of candidates in development, spanning multiple therapeutic modalities. These include classical monoclonal antibodies, small‐molecule inhibitors (albeit fewer in number compared to antibody therapeutics), and more innovative platforms such as antibody–drug conjugates (ADCs), bispecific antibodies, and CAR-T cell therapies. The candidates have progressed from preclinical exploration to rigorous clinical evaluation across various phases.

Monoclonal Antibodies

Monoclonal antibodies represent the most mature group of therapeutics targeting CLDN18.2. The rationale behind these antibodies is to bind with high affinity and specificity to the extracellular domain of CLDN18.2 on tumor cells, thereby triggering immune effector mechanisms like antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC).

• Zolbetuximab (also known as IMAB362) is perhaps the best-known monoclonal antibody targeting CLDN18.2. It was designed specifically to bind the CLDN18.2 epitope on the cell surface. Zolbetuximab has already been evaluated in multiple clinical trials in patients with advanced gastric and gastroesophageal junction cancers and has demonstrated significant improvements in progression-free survival (PFS) and overall survival (OS) when combined with chemotherapy in various phase II and III trials. It is considered a benchmark candidate in this field and has paved the way for other antibody-based strategies.

• Other anti-CLDN18.2 antibody candidates include those that are in earlier development stages or have been explored in collaborative or licensing agreements. Patent disclosures and synapse-sourced documents mention multiple anti-CLDN18.2 antibody candidates that have been engineered to improve their binding specificity, pharmacokinetic profiles, and to limit cross-reactivity with closely related isoforms (such as CLDN18.1). Some patents describe panels of monoclonal antibodies along with engineered Fc regions to enhance immune effector cell engagement. These candidates are designed with the hope of achieving improved safety and efficacy profiles while expanding the clinical utility beyond gastric cancers.

• In addition, candidates such as AB011 from CARsgen have been announced as monoclonal antibodies that received investigational new drug (IND) clearance in China. These newer molecules exhibit high selectivity, and some are being developed in combination with immune checkpoint inhibitors (e.g., atezolizumab) to potentially improve clinical outcomes for patients with CLDN18.2-positive solid tumors.

The literature stresses that the antibody approach benefits from the low toxicity inherent to monoclonal antibodies while also providing a versatile platform for modifications such as Fc engineering, conjugation to cytotoxic payloads, and multi-specific designs to engage other immune cells.

Small Molecule Inhibitors

While small molecule inhibitors have revolutionized many areas of oncology, there is relatively less focus on developing small molecules targeting CLDN18.2 directly. The molecular structure of claudins and the nature of their cell–cell junction interactions have favored the development of large proteins like antibodies. That said, some research efforts are underway to explore whether small molecule compounds can be designed to interfere with CLDN18.2’s function or modulate its expression.

• Small molecules in this context may act as modulators that stabilize or downregulate CLDN18.2 expression, or even prevent its ligand interactions that might contribute to tumor progression. However, the specific mechanism of action for many of these compounds is under preclinical evaluation, and to date, there is limited clinical data relative to antibody-based therapies.

• In addition, there is emerging interest in identifying compounds using structure-based design or high-throughput screening methodologies. Such small molecules may compete with therapeutic antibodies or act synergistically when combined with antibody drug conjugates or immune therapies. These candidates can be designed to mimic critical binding motifs on CLDN18.2 and potentially disrupt signaling pathways that support cell adhesion and metastasis. Although promising in concept, these inhibitors remain in the early probe/lead optimization stage.

Other Innovative Therapies

Other innovative therapeutic modalities have expanded the armamentarium of CLDN18.2-targeting candidates beyond conventional antibodies. These include:

• Antibody–drug Conjugates (ADCs): ADCs combine the specificity of monoclonal antibodies with potent cytotoxic drugs. ADCs targeting CLDN18.2, for example, CMG901 and SYSA1801, have been evaluated in early-phase clinical studies. These conjugates deliver cytotoxic payloads directly to the tumor cells, thereby improving the therapeutic index by limiting systemic exposure of the cytotoxic agent. Clinical data reported improvement in objective response rates and disease control, especially in tumors with high levels of CLDN18.2 expression.

• Bispecific Antibodies: Bispecific antibodies are designed to engage two antigens simultaneously. In the case of CLDN18.2, bispecific formats may link T cells (via CD3 binding) to cancer cells expressing CLDN18.2, thereby redirecting the immune system toward the tumor and bypassing some immune suppressive mechanisms. Although fewer details are available, some patents and early-phase studies refer to bispecific molecules that provide dual engagement mechanisms.

• CAR-T Cell Therapies: Chimeric antigen receptor T-cell (CAR-T) therapy has emerged as a revolutionary treatment for hematologic malignancies and is now being adapted for solid tumors. CLDN18.2-targeting CAR-T cells have been developed to treat solid tumors, particularly gastric and pancreatic cancers. Several early-phase clinical trials are evaluating the safety and efficacy of CLDN18.2-CAR-T therapies. These approaches reprogram patient-derived T cells to specifically recognize tumor cells expressing CLDN18.2. Preliminary data from trials have shown promising objective response rates while maintaining manageable toxicity profiles. For instance, investigator-initiated studies involving CT041 demonstrated efficacy and safety in CLDN18.2-positive digestive system malignancies even though hematologic toxicity and cytokine release syndrome were observed and carefully managed.

• Other cell-based therapies: In addition to CAR-T cells, other immune cell redirection approaches such as CAR-NK (Natural Killer) cells or T-cell engagers using platforms like the “2+1” T-cell engager (e.g., AnTenGagerTM) are being explored. These strategies are designed to combine the cytotoxic potential of effector cells with the targeting specificity of CLDN18.2 binding moieties. Although the majority of these candidates are in preclinical development or early-phase clinical trials, they provide additional avenues particularly if challenges related to the tumor microenvironment can be overcome.

Clinical Trials and Development Status

Therapeutic candidates targeting CLDN18.2 are being evaluated in a variety of clinical trials that span from early to advanced phases, helping to further refine safety, dosing, and efficacy. The clinical development and trial design strategies have been informed by both the earlier promising results and the inherent challenges in treating solid tumors.

Phase I/II/III Trials

• Phase I Trials: Early-phase studies have primarily focused on establishing the safety, tolerability, pharmacokinetics, and recommended phase II dosing of various anti-CLDN18.2 candidates. CAR-T therapies targeting CLDN18.2, for instance, have been tested in a controlled setting to assess toxicity profiles and the feasibility of adoptively transferred cells in patients with advanced gastric cancers. Additionally, preliminary results from ADCs such as those conjugated with monomethyl auristatin E (MMAE) targeting CLDN18.2 have been included in phase I dose-escalation cohorts, showing evidence of manageable adverse events and initial signals of antitumor activity.

• Phase II Trials: Candidate therapies such as zolbetuximab have progressed into phase II trials where they have been evaluated in combination with chemotherapy regimens. These studies are designed to assess the efficacy in terms of progression-free survival and overall response in patients with advanced or metastatic disease. In many trials, patients are selected based on immunohistochemical criteria demonstrating high levels of CLDN18.2 expression, ensuring that the benefits are maximized while reducing off-target exposure.

• Phase III Trials: The most advanced candidates, particularly the monoclonal antibody zolbetuximab, have reached phase III evaluation. Large-scale randomized controlled trials – such as the SPOTLIGHT and GLOW trials – have demonstrated statistically significant improvements in PFS and OS when zolbetuximab is added to standard-of-care chemotherapy regimens. These pivotal trials have set the benchmark by which future CLDN18.2-targeted therapies will be measured.

The synapse-sourced documents indicate that the United States and Europe continue to host significant clinical activity in this field, while China remains at the forefront of CLDN18.2 development with a large proportion of therapeutic candidates in clinical evaluation. Not only are traditional antibody therapies being tested, but next-generation modalities, including bispecifics and CAR-T cells, have begun to show promising early results.

Key Findings and Outcomes

Clinical trial data from these studies have provided several promising outcomes:

• Monoclonal antibodies like zolbetuximab have shown improved survival outcomes when combined with chemotherapy. For instance, the SPOTLIGHT trial indicated a significant reduction in the risk of disease progression, while the GLOW study reported prolonged overall survival rates in CLDN18.2-positive patients.

• ADC candidates have demonstrated robust anti-tumor responses even in tumors refractory to standard chemotherapy. The delivery of potent cytotoxins directly to CLDN18.2-expressing cells helps to mitigate systemic toxicity while improving tumor-killing efficacy.

• CAR-T therapies have proven that cell-based approaches can induce a durable immune response in a subset of patients with advanced solid tumors. Despite challenges such as cytokine release syndrome, early-phase studies report manageable toxicity and promising response rates, indicating that with proper patient monitoring and optimized dosing strategies, these therapies could fill an unmet clinical need.

• Bispecific antibodies and other innovative T cell recruiting agents have begun to display encouraging preclinical and early clinical results, though robust long-term outcome data remain pending. Their unique ability to simultaneously engage tumor cells and immune effector cells may create an immune synapse that is both rapid and effective, particularly in CLDN18.2-expressing cancers.

Overall, the clinical data gathered across various trials underscore both the promise of targeting CLDN18.2 and the variability of response among different modalities. The diversity of therapeutic candidates offers a portfolio-wide advantage in addressing multiple resistance mechanisms and improving patient outcomes.

Challenges and Future Directions

Despite the promising advancements in the development of CLDN18.2-targeted therapies, there are several challenges and opportunities that need to be addressed to further optimize these strategies.

Current Challenges in Targeting CLDN18.2

• Heterogeneous Expression: One major challenge is the heterogeneity of CLDN18.2 expression across different tumors and even within the same tumor. Differences in immunohistochemical assessment and grading thresholds can lead to variability in patient selection, affecting trial outcomes. Standardizing detection methods and cut-off values for positive expression is therefore critical.

• Resistance Mechanisms: Tumors are notorious for developing resistance to targeted therapies through a variety of mechanisms including antigen loss, changes in the tumor microenvironment, and alterations in downstream signaling cascades. For therapeutic candidates such as monoclonal antibodies and ADCs, overcoming antigen modulation or adaptive resistance is an ongoing challenge.

• Toxicity and Off-target Effects: Although CLDN18.2 expression is largely confined to gastric mucosa under normal conditions, inadvertent toxicity due to low-level expression in other tissues remains a concern. This is especially true when using immune-activating therapies like CAR-T cells, which may lead to on-target off-tumor effects that must be carefully managed.

• Manufacturing and Scalability: For cell-based therapies, including CLDN18.2-targeted CAR-T treatments, manufacturing complexities, quality control, and scalability issues are significant hurdles that could impact widespread clinical adoption.

• Optimization of Combination Modalities: Many current trials are evaluating combination therapies (for example, adding checkpoint inhibitors to CLDN18.2-targeted therapy) in order to overcome intrinsic limitations of single-agent treatment. Determining the optimal doses and sequences remains an area requiring careful clinical investigation.

Future Prospects and Research Directions

• Improved Patient Stratification: Next-generation diagnostic tools such as liquid biopsies, ctDNA analyses, and advanced imaging techniques are expected to improve patient stratification by more precisely identifying those with high CLDN18.2 expression. Tailoring therapies to patient-specific expression patterns is likely to increase therapeutic efficacy and reduce unnecessary toxicity.

• Next-Generation Therapeutic Formats: The evolution of antibody engineering, including the development of multispecific antibodies, Fc-engineered variants, or oligoclonal mixtures, holds promise for enhancing antitumor activity. These formats may provide a combinatorial approach to improve receptor internalization, enhance immune cell activation, and overcome resistance.

• Integration of Immunomodulators: Future strategies may increasingly rely on combining CLDN18.2-targeted therapies with immunomodulators such as checkpoint inhibitors or novel immune agonists. Early data from combination trials suggest that such regimens may boost anti-tumor immunity while minimizing toxicity through dose adjustments.

• Expanding Beyond Gastric Cancer: Although gastric cancer remains one of the primary indications, the expression of CLDN18.2 in multiple other tumor types offers an opportunity to broaden clinical indications. Future trials will likely explore its expression and therapeutic responsiveness in pancreatic, esophageal, ovarian, lung, and colon cancers.

• Enhanced Delivery Platforms: In the realm of cell-based therapies, technological advances in CAR-T cell engineering—including improvements in persistence, reduced exhaustion, and novel methods of in vivo expansion—will likely lead to more effective treatments for solid tumors. The integration of these strategies with modified dosing schedules and supportive immune therapies could address several current limitations.

• Small Molecule Modulators and ADC Optimization: Research is also underway to optimize ADC design by fine-tuning linker chemistry and payload selection, as well as developing small molecule agents that can modulate CLDN18.2 function. The convergence of medicinal chemistry and structural biology might eventually yield small molecules that either enhance the efficacy of other modalities or act as stand-alone agents in cases where antibody formats face resistance.

• Regulatory Interactions and Biomarker-Driven Trials: Future clinical success will depend on close collaboration with regulatory authorities to establish robust endpoints and biomarker-based inclusion criteria in clinical trials. Adaptive trial designs and real-time monitoring of treatment responses based on CLDN18.2 expression could further accelerate the development and approval of these therapeutic candidates.

Conclusion

In summary, the field of therapeutics targeting CLDN18.2 represents one of the most dynamically evolving areas in oncology. CLDN18.2’s restricted expression in normal tissues and its aberrant exposure in several cancers make it a highly attractive target for precision therapy.

The current therapeutic candidates can be broadly grouped into three main categories:

• Monoclonal antibodies such as zolbetuximab have emerged as the frontrunners with extensive clinical validation in phase III trials and have demonstrated clear clinical benefits when combined with chemotherapy. Numerous next-generation antibody candidates are also under investigation to improve specificity and safety.

• Small molecule inhibitors, though less advanced relative to antibody modalities, are being investigated through structure-based design and high-throughput screening to modulate CLDN18.2 function or regulate its expression. These efforts remain largely exploratory and represent an opportunity for future development.

• Other innovative therapies—most notably ADCs, bispecific antibodies, and CAR-T cell therapies—are expanding the therapeutic landscape. ADCs deliver potent cytotoxic agents directly to tumor cells, bispecific antibodies engage immune cells directly toward CLDN18.2-positive tumors, and CAR-T cell therapies are reprogramming patient T cells to recognize and destroy malignant cells. Early clinical results indicate that these modalities can produce disease control with manageable toxicity profiles.

Clinical trials across different phases have provided encouraging safety and efficacy data. Early-phase trials have focused on dosing, safety, and immune engagement, while phase III studies with agents like zolbetuximab have definitively demonstrated survival benefits for CLDN18.2-positive gastric and gastroesophageal cancers. Nevertheless, challenges such as heterogeneous expression, tumor resistance mechanisms, potential off-target effects, and manufacturing constraints especially for cell therapies remain hurdles that the field is actively addressing.

Future directions include enhanced patient stratification via next-generation biomarkers, the development of next-generation multispecific therapeutic formats, better integration of immunomodulatory agents, and a broader exploration of CLDN18.2-targeted treatment in additional cancer types. Researchers are also focusing on optimizing combination regimens and overcoming inherent resistance mechanisms to further improve long-term outcomes.

In conclusion, targeting CLDN18.2 stands as a paradigmatic example of precision oncology where a deep molecular understanding has led to the development of diverse therapeutic candidates. The field is progressing rapidly with promising early to late-phase clinical data, though further research is needed for long-term durability and to expand indications. Through continued innovation and collaborative efforts between academia, industry, and regulatory bodies, CLDN18.2-targeted therapies have significant potential to transform the management of several solid tumors and deliver meaningful clinical benefits to patients.

This detailed review from multiple perspectives underlines the importance of both the current advances and the future challenges. The convergence of various therapeutic approaches—from monoclonal antibodies with proven clinical outcomes, through innovative cell-based therapies, to emerging small molecule strategies—demonstrates a robust and diversified pipeline. As these candidates continue to be refined through rigorous clinical trials and real-world evidence, they offer hope for a future where targeted therapy against CLDN18.2 can be integrated seamlessly into personalized cancer treatment strategies, ultimately improving patient survival and quality of life.