Research Advances Related to CLDN18.2 Target

The following article is transferred from Xiamen Spacegen.Co.,Ltd （SpaceGen cancer research newsletter）

Background - Claudin18.2 Protein

The CLDN protein family consists of at least 27 transmembrane proteins, which can be classified into two types: classical and non-classical, based on their sequence. CLDN18 belongs to the non-classical type. The protein expressed by CLDN18 undergoes splice modifications, resulting in two subtypes: CLDN18.1 and CLDN18.2. CLDN18.2 is a highly selective marker protein that is primarily expressed in differentiated gastric mucosal epithelial cells in normal tissues. However, in cases of tissue malignancy, CLDN18.2 shows corresponding expression, particularly in digestive tract tumors such as gastric cancer, pancreatic cancer, esophageal cancer, bile duct cancer, and gallbladder cancer. The presence of CLDN18.2 has also been detected in ovarian cancer and lung cancer tissues [1-4].

According to statistics, approximately 33% to 37% of patients with solid tumors exhibit high expression of CLDN18.2. Additionally, a study has shown that among gastric cancer patients, approximately 16% to 73% of individuals tested positive for CLDN18.2 expression [5].

CLDN18.2 and Gastric Cancer

Currently, there is significant variation in the reported positivity rates of Claudin18.2 protein in gastric cancer patients, which could be attributed to differences in ethnicity, reagents, and detection criteria. Rohde et al. [6], using the CLAUDETECT™18.2 assay with the same positivity criteria, found a positive expression rate of 52% in Japanese gastric cancer patients. Dottermusch et al. [7], using an anti-Claudin18.2 antibody from ABCAM to detect a Caucasian population, utilized a tissue scoring system as the criteria for positive expression and reported a 42.2% positivity rate in gastric cancer cases. Baek et al. [8], in a Korean population using the ABCAM anti-Claudin18.2 antibody, employed a semi-quantitative scoring method with a score of 3 (51% to 100% staining) as the criteria for positive expression, and according to this standard, 29.4% of patients showed positive expression. Xu et al. [9], in their study of 105 advanced gastric signet ring cell carcinoma patients' pathological specimens, demonstrated a positive expression rate of Claudin18.2 of 95.2% (100/105), significantly higher than that of ordinary gastric adenocarcinoma patients. Among the specimens, 64.8% (68/105) showed moderate to high levels of expression of Claudin18.2, and in 21.0% (22/105) of the specimens, the expression level of Claudin18.2 was even ≥90%. The above studies suggest a high positive expression rate of Claudin18.2 in gastric cancer patients, and the expression rate and intensity are positively correlated with malignancy. CLDN18.2 is applicable to the treatment of many gastric adenocarcinoma patients.

CLDN18.2 and Pancreatic Cancer

In addition to its stable high expression in various gastric cancer tissues, CLDN18.2 is also aberrantly expressed in pancreatic cancer tissues [11]. Kojima et al. [12] found that CLDN18 can transcriptionally regulate the tight junction molecules in normal human pancreatic ductal epithelial cells through the protein kinase C signaling pathway. In pancreatic cancer tissues, CLDN18.2 can be induced by PKC activators and DNA methylation modifications. Studies have shown [13] that gemcitabine (GEM) can upregulate the expression of CLDN18.2 in pancreatic cancer cells, enhancing zolbetuximab-induced antibody-dependent cellular cytotoxicity (ADCC). For gemcitabine-resistant pancreatic cancer types, zolbetuximab can slow tumor growth and reduce metastasis, thereby prolonging survival. This further supports the potential use of zolbetuximab as a monotherapy or in combination with gemcitabine for pancreatic cancer patients expressing CLDN18.2.

Research on Other Targeted Drugs

Claudin18.2, as a pan-cancer target, exhibits abnormal expression in various epithelial tumors and has become one of the hot targets in cancer research. Current researches on targeting Claudin18.2 encompass almost all mainstream approaches including monoclonal antibodies, bispecific antibodies, CAR-T cells, and antibody-drug conjugates (ADC). There are high expectations for Claudin18.2, and it has the potential to become the next "PD-1".

Osemitamab is a second-generation Claudin18.2-targeted antibody currently under development worldwide. It is a highly affinity-optimized humanized monoclonal antibody against Claudin18.2. Osemitamab is designed to exhibit enhanced antibody-dependent cell-mediated cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC).

Detection Methods

Currently, the primary method for protein expression detection of CLDN18.2 is immunohistochemistry (IHC). There are two main sources of well-established detection antibodies: CLAUDETECT (Ganymed, Germany) used in the FAST study and Abcam (Cambridge, USA). The CLAUDETECT antibody has a slightly higher positive detection rate compared to the antibodies from Abcam. It's worth noting that different studies may have different thresholds for determining positivity for Claudin18.2.

Currently, the detection methods used in clinical studies for Claudin18.2 are primarily based on immunohistochemistry (IHC). However, there are different criteria for defining the positive threshold in clinical research, and there is currently no unified standard. In China, most of the registered products for Claudin18.2 detection utilize the immunohistochemistry methodology.

Summary

Claudin18.2 is widely distributed on the surface of various cancer cells and represents a potential solution. Combining its targeting with other therapeutic targets may offer additional benefits for a broader range of patients.

Reference：

[1] Antican—cer Res, 2019, 39(12):6973—6979.

[2] The AdV Med 0ncol, 2022, 14: 17588359221083049.

[3] Clin Cancer Res, 2008, 14(23): 7624—7634.

[4] Hi-stol Histopathol, 2022, 37(10): 1031-1040.

[5] Cancers (Basel). 2020 Mar 18;12(3):711.

[6] Jap J Clin Oncol, 2019, 49(9): 870-876.

[7] Virchows Arch, 2019, 475: 563-571.

[8] Anti‐cancer Research, 2019, 39 (12): 6973-6979.

[9] Gastrointest Oncol, 2020, 11(6): 1431-1439.

[10] Research progress of transmembrane protein CLDN18.2 in cancer targeted therapy

[11] Hi-stol Histopathol, 2022, 37(10): 1031-1040

[12] Ann N Y Acad Sci, 2012, 1257: 85—92

[13] Oncoimmunology. 2018 Nov 10;8(1):e1523096.

[14] The biological role of CLDN18 in the progression of hepatocellular carcinoma and its prognostic value

[15] Biomark Res. 2022 May 31;10(1):38.

[16] FDA website

[17] Research progress of CLDN18.2 in gastric cancer

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