Claudin 18.2 is a target for IMAB362 antibody in pancreatic neoplasms

Abstract

The majority of pancreatic neoplasms are characterized by a generally lethal progress within a short period of time after primary diagnosis and the mortality of patients is expected to increase further. Due to lack of efficient screening programs and moderate response to treatments, novel compounds for treatment are needed. We investigated the CLDN18.2 expression in affected patients as in vitro feasibility study for a potential treatment with the novel antibody IMAB362. Therefore, we analyzed the expression of CLDN18.2 in normal pancreatic tissues (N 5 24), primary lesions (N 5 202), metastases (N 5 84) and intra-individually matched samples (N 5 48) of patients with pancreatic ductal adenocarcinoma (PDAC), neuroendocrine neoplasia (NEN) and acinar cell carcinoma. A standardized method for evaluation by immunohistochemistry was developed. The specific staining was evaluated by two independent raters and analysis of staining intensities (range 0-31) and relative proportions of tumor cells were performed. One hundred three (59.2%) samples of primary PDAC were found positive. The vast majority of positive samples were characterized to highly express CLDN18.2: 54.6% (N 5 95) with staining intensities of 21. NEN were positive in 20% of cases (all 21). Metastases of pancreatic neoplasms were also frequently found positive with comparable high rates (69.4% of lymph node and 65.7% of liver metastases). The rate of CLDN18.2 positivity is high in pancreatic neoplasms whereby the expression is not limited to the primaries but is also maintained upon metastasis. Thus, a considerable number of patients with pancreatic neoplasms would be in principle eligible for a CLDN18.2-targeting approach.Pancreatic ductal adenocarcinoma (PDAC), representing >80% of all pancreatic neoplasms, is the seventh most frequent cancer in Europe and is the fourth most frequent cause of cancer related deaths in the European Union (EU).1-3 The prevalence of pancreatic neoplasms is 1-5/10,000 in both, the EU and the United States. 4,5 In contrast to all major cancers, however, the mortality rate of PDAC is expected to increase further. 6 No effective screening programs for early detection of pancreatic neoplasms are available and patients lack specific clinical symptoms at early stages. Thus, most PDAC patients are diagnosed at an advanced stage of the disease and are not suitable for resection with curative intent. For systemic palliative treatment cytotoxic agents are administered. The majority of patients are treated with gemcitabine, whereas patients with a good performance status undergo polychemotherapy with 5-FU/irinotecan/oxaliplatin (FOLFORINOX).3,7 Chemosensitivity of PDAC is moderate 8 and targeted therapeutics are of high interest. Although various compounds have been tested, only erlotinib, an epidermal growth factor receptor tyrosine kinase inhibitor, received approval by the European Medicines Agency (EMA) and Food and Drug Administration (FDA) for the treatment of patients with metastatic disease in combination with gemcitabine. The ...

Mucin 5B, carbonic anhydrase 9 and claudin 18 are potential theranostic markers of gallbladder carcinoma

“…In particular, CLDN18 seems to be important for avoiding paracellular permeability of cations, including H + , which is the smallest cation and one of the most damaging for oesophageal and gastric epithelia, in which CLDN18 expression is high . Previous studies have shown CLDN18 expression in pancreatic preneoplasia and biliary intraepithelial neoplasia, whereas it has been shown that, for pancreatic cancer, the expression of this protein is increased and conserved in advanced stages of the disease . However, in our study, CLDN18 expression was observed in metaplastic cells, strongly suggesting that CDLN18 deregulation arises before the onset of dysplastic lesions, and therefore earlier in the histological progression than previously thought.…”

Aberrantly activated claudin 6 and 18.2 as potential therapy targets in non‐small‐cell lung cancer

“…The level of protein expression was manually scored (J.M. and P.M.) by determining the signal intensity using a 4‐grade scale: negative (0), weak (1), moderate (2) and strong (3) as previously described . The fraction of stained tumor cells was evaluated as follows: <1% positive cells (0), 1–9% (1), 10–50% (2) and >50% (3).…”

“…For the analysis of the CLDN18.2 expression, sections were stained with the diagnostic monoclonal mouse anti-CLDN18.2 antibody aGC182, which was developed to be CLDN18.2-specific and not crossreacting with CLDN18.1. 27 The sections were treated for 15 min at 95 C with a Tris-ethylenediaminetetraacetic acid (EDTA, pH 9.0) epitope retrieval solution and cooled down at room temperature (RT) for 10 min. Endogenous peroxidases were quenched with 3% H 2 O 2 in tris-buffered saline (TBS) for 5 min.…”

“…and P.M.) by determining the signal intensity using a 4-grade scale: negative (0), weak (1), moderate (2) and strong (3) as previously described. 27,34,35,37,38 The fraction of stained tumor cells was evaluated as follows: <1% positive cells (0), 1-9% (1), 10-50% (2) and >50% (3). One score was set for the duplicate cores on the arrays representing the same tumor sample.…”

Anti-Claudin Antibodies as a Concept for Development of Claudin-Directed Drugs

“…In primary gastric cancers and their metastases, CLDN-18.2 is expressed on the outer cell membrane and thus is available for mAb binding (Sahin et al, 2008) (Table 1). CLDN-18.2 was expressed in $80% of advanced gastroesophageal cancers and overexpressed in $40% (Singh et al, 2017); in addition, CLDN-18.2 was expressed in 54.6% of pancreatic cancers (Wöll et al, 2014). A phase III trial of IMAB362 for advanced gastroesophageal cancer (NCT03504397) commenced in 2017.…”