Inquiry Basket
Loading ......
The maintenance of physiological barriers and the regulation of paracellular permeability are fundamental requirements for the survival and homeostasis of multicellular organisms. These critical functions are governed by tight junctions, highly complex intercellular adhesion structures located at the most apical region of polarized epithelial and endothelial cells. The primary structural and functional determinants of these tight junctions are a family of tetraspanin transmembrane proteins known as claudins. Comprising over two dozen identified members in humans, claudins dictate the size and charge selectivity of the paracellular pore. While many claudins exhibit broad expression across various tissues, identifying members with highly restricted, tissue-specific profiles has become a major focal point in modern oncology. Among these, Claudin-18 (CLDN18) has rapidly emerged as a highly compelling biomarker and a pristine target for therapeutic intervention, particularly situated at the intersection of biomolecular interactions and advanced drug discovery.
The biological uniqueness of CLDN18 lies in its precise genetic regulation and the generation of two distinct splice variants: CLDN18.1 and CLDN18.2. These isoforms are generated through the alternative splicing of the first exon of the CLDN18 gene, resulting in proteins that differ significantly in their N-terminal sequences and, most importantly, in their first extracellular loop (ECL1). This subtle structural variation dictates a remarkably strict tissue-specific expression pattern in healthy adult humans.
CLDN18.1 is predominantly expressed in the ciliated epithelial cells of the respiratory tract, playing a critical role in maintaining alveolar fluid homeostasis and lung barrier function. Conversely, the CLDN18.2 isoform is exclusively restricted to the differentiated epithelial cells of the gastric mucosa. In normal, healthy gastric tissue, CLDN18.2 is deeply embedded within the tight junction complexes of the gastric pits and glands. In this physiological state, the protein is largely shielded from the systemic circulation and inaccessible to large macromolecules, including therapeutic antibodies, providing a natural protective mechanism against autoimmune targeting.
Figure 1. Structure of claudins (CLDNs)
(Source: Łukaszewicz-Zając M, et al. 2023)
The transition of CLDN18.2 from an inaccessible physiological barrier component to a highly vulnerable tumor antigen is a fascinating process driven by malignant transformation. During the pathogenesis of gastric adenocarcinoma, neoplastic cells undergo profound morphological and epigenetic changes. A hallmark of this transformation is the loss of apical-basal cell polarity and the catastrophic disruption of normal tight junction architecture.
As the tight junctions degrade, the CLDN18.2 proteins that were previously sequestered are dispersed across the entire surface of the malignant cell. This spatial redistribution effectively "unmasks" the extracellular loops of CLDN18.2, suddenly exposing them to the systemic circulation and making them readily accessible to targeted biotherapeutics. Furthermore, while strictly confined to the stomach in healthy individuals, aberrant, ectopic expression of CLDN18.2 is frequently observed in a significant percentage of pancreatic adenocarcinomas, esophageal carcinomas, and cholangiocarcinomas. This ectopic expression in highly lethal gastrointestinal malignancies underscores its value not just as a gastric cancer target, but as a broader oncological biomarker. The high prevalence of CLDN18.2 in these difficult-to-treat tumors, combined with its absence in normal tissues outside the stomach, creates an exceptionally wide and favorable therapeutic window.
The exploitation of CLDN18.2 has catalyzed a wave of innovative drug discovery efforts, moving from basic biomolecular interaction studies to advanced clinical therapeutics. Because the target is a membrane-bound protein with exposed extracellular loops, it is highly amenable to various antibody-based modalities. The most advanced therapeutic approach involves the use of engineered, naked monoclonal antibodies. These immunoglobulins are meticulously designed to bind with high affinity and absolute specificity to the ECL1 domain of the CLDN18.2 isoform, ensuring no cross-reactivity with the lung-specific CLDN18.1 isoform to prevent pulmonary toxicity.
Once bound to the tumor cell surface, these antibodies primarily mediate their cytotoxic effects through the recruitment of the host's innate immune system. They trigger robust Antibody-Dependent Cellular Cytotoxicity (ADCC), recruiting natural killer (NK) cells to release perforin and granzymes directly into the tumor cell. Simultaneously, they activate Complement-Dependent Cytotoxicity (CDC), initiating the complement cascade that culminates in the formation of the membrane attack complex and subsequent bacterial-like lysis of the cancer cell. The efficacy of these mechanisms is highly dependent on the density of CLDN18.2 expressed on the tumor surface, highlighting the importance of precise molecular binding.
Figure 2. CLDN18.2 expression in neoplastic and non-neoplastic gastric cells
(Source: Dottermusch M, et al. 2019)
Beyond naked monoclonal antibodies, the pristine specificity of CLDN18.2 is being leveraged for next-generation immunotherapies, specifically Bispecific T-cell Engagers and Chimeric Antigen Receptor T-cell (CAR-T) therapies. Bispecific antibodies are engineered to simultaneously bind CLDN18.2 on the tumor cell and the CD3 receptor on circulating cytotoxic T-lymphocytes. This physically bridges the T-cell to the tumor, forming an artificial immunological synapse that forces T-cell activation and targeted tumor lysis, bypassing the traditional, often compromised, major histocompatibility complex (MHC) presentation pathways of the tumor.
Simultaneously, CLDN18.2-directed CAR-T cell therapy is showing immense promise, particularly in the realm of solid tumors where cellular therapies have historically struggled. Autologous T-cells are genetically reprogrammed ex vivo to express a synthetic receptor featuring a single-chain variable fragment (scFv) specifically tuned to the CLDN18.2 ECL1 domain. Upon infusion, these engineered cells act as a living drug, capable of actively seeking out CLDN18.2-positive metastases, penetrating the dense desmoplastic stroma characteristic of pancreatic and gastric cancers, and initiating a profound, localized anti-tumor response. The development of these advanced modalities represents a pinnacle in translating complex biomolecular interactions into highly specific, localized drug delivery systems.
The successful clinical implementation of any CLDN18.2-targeted therapy is inextricably linked to robust, reliable companion diagnostics. Because CLDN18.2 expression is not universal across all gastrointestinal tumors, and its expression levels can be highly heterogeneous even within a single tumor mass, precise patient stratification is mandatory. Immunohistochemistry (IHC) utilizing highly validated, isoform-specific monoclonal antibodies has become the gold standard for clinical screening.
Pathologists evaluate tissue biopsies to determine both the intensity of the membrane staining and the percentage of tumor cells exhibiting positivity. Establishing standardized clinical cutoff values—such as requiring a specific percentage of tumor cells to demonstrate moderate to strong membrane staining—is critical for identifying the patient cohorts most likely to achieve a durable response. This rigorous diagnostic screening ensures that targeted therapies are administered safely and efficiently, maximizing clinical benefit while minimizing unnecessary exposure for patients with target-negative disease.
Figure 3. Mechanisms of action of the various classes of developmental claudin 18.2-targeted therapies
(Source: Nakayama I, et al. 2024)
References
| Target | Cat. No. | Product Name | Host | Isotype | Application | |
| CLDN18 | DPAB-DC2137 | Anti-CLDN18 (aa 196-261) polyclonal antibody | Mouse | WB, ELISA | Inquiry | |
| CABT-L1246 | Rabbit Anti-Human Claudin 18 monoclonal antibody, clone 45I25M26 | Rabbit | IgG | ICC, IHC-P, IF, WB | Inquiry | |
| CABT-CS565 | Human Anti-Human Claudin 18.2 (Zolbetuximab) Monoclonal antibody, clone Zolbetuximab | Human | IgG1 | ELISA | Inquiry | |
| DCABH-200380 | Anti-CLDN18 monoclonal antibody | Rabbit | IgG | WB, ELISA | Inquiry | |
| DPABH-19864 | Anti-CLDN18 (aa 143-192) polyclonal antibody | Rabbit | IgG | WB | Inquiry | |
| DPABH-19088 | Anti-CLDN18 (aa 212-261) polyclonal antibody | Rabbit | IgG | WB | Inquiry | |
| CABT-Z509R | Rabbit Anti-Human CLDN18.2 Polyclonal Antiboody | Rabbit | IgG | WB, IHC-P, FC | Inquiry | |
| CABT-Z510R | Rabbit Anti-Human CLDN18.1 Polyclonal Antiboody | Rabbit | IgG | WB, FC | Inquiry | |
| CABT-Z508H | Recombinant Human Anti-Human CLDN18.2 Monoclonal Antiboody, clone E21D | Human | IgG1 | WB | Inquiry | |
| CABT-Z512H | Human Anti-Human CLDN18.2 (Zolbetuximab) Monoclonal Antiboody, clone IMAB362 [Biosimilar] | Human | IgG1 | ELISA | Inquiry |
| Target | Cat. No. | Product Name | Expression System | Tag/Conjugate | Application | |
| CLDN18 | DAG-WT1229 | Recombinant Human Claudin 18.2 VLP | HEK293 cells | N/A | ELISA, SPR | Inquiry |
Loading ......
