Targeting CLDN18.2 in cancers of the gastrointestinal tract: New drugs and new indications

Chen, Jinxia; Hu, Can; Zhang, Shengjie; Zi, Mengli; Li, Yuan; Cheng, Xiuzhen

doi:10.3389/fonc.2023.1132319

Cited by 22 publications

(16 citation statements)

References 103 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…T cell engagers (TCEs) hold great promise as a therapeutic modality, enabling the redirection of T cells toward specific tumor antigens. AMG910, developed on AMGEN's HLE platform, represents the pioneering clinical entry of a CLDN18.2-targeting TCE [ 45 ]. In our study, we successfully developed a tri-specific TCE, DR30318, which exhibited simultaneous binding to CLDN18.2, HSA and CD3 in vitro affinity assays.…”

Section: Discussionmentioning

confidence: 99%

DR30318, a novel tri-specific T cell engager for Claudin 18.2 positive cancers immunotherapy

Ma,

Zhou,

Duan

et al. 2024

Cancer Immunol Immunother

View full text Add to dashboard Cite

Background Claudin 18.2 (CLDN18.2) is a highly anticipated target for solid tumor therapy, especially in advanced gastric carcinoma and pancreatic carcinoma. The T cell engager targeting CLDN18.2 represents a compelling strategy for enhancing anti-cancer efficacy. Methods Based on the in-house screened anti-CLDN18.2 VHH, we have developed a novel tri-specific T cell engager targeting CLDN18.2 for gastric and pancreatic cancer immunotherapy. This tri-specific antibody was designed with binding to CLDN18.2, human serum albumin (HSA) and CD3 on T cells. Results The DR30318 demonstrated binding affinity to CLDN18.2, HSA and CD3, and exhibited T cell-dependent cellular cytotoxicity (TDCC) activity in vitro. Pharmacokinetic analysis revealed a half-life of 22.2–28.6 h in rodents and 41.8 h in cynomolgus monkeys, respectively. The administration of DR30318 resulted in a slight increase in the levels of IL-6 and C-reactive protein (CRP) in cynomolgus monkeys. Furthermore, after incubation with human PBMCs and CLDN18.2 expressing cells, DR30318 induced TDCC activity and the production of interleukin-6 (IL-6) and interferon-gamma (IFN-γ). Notably, DR30318 demonstrated significant tumor suppression effects on gastric cancer xenograft models NUGC4/hCLDN18.2 and pancreatic cancer xenograft model BxPC3/hCLDN18.2 without affecting the body weight of mice.

show abstract

Section: Discussionmentioning

confidence: 99%

DR30318, a novel tri-specific T cell engager for Claudin 18.2 positive cancers immunotherapy

Ma,

Zhou,

Duan

et al. 2024

Cancer Immunol Immunother

View full text Add to dashboard Cite

show abstract

“…( 27 – 30 ). Claudin18 also has different effects in tumors, acting as a tumor suppressant in gastric and lung cancers, but playing a promoting role in other gastrointestinal tumors, such as pancreatic cancer, colorectal cancer, and esophageal cancer ( 31 ). At present, only a few articles have elucidated the mechanism of action of Claudin18 in different tumors, which needs further summary.…”

Section: The Double-edged Sword Role Of Claudin18 In Cancersmentioning

confidence: 99%

“…In the normal esophageal squamous epithelium, Claudin18 is not expressed, but the expression of Claudin18 in the columnar epithelium of Barrett’s esophagus is doubled, and Claudin18 can reduce the permeability of tightly junction H + ions, prevent its attack and destroy the esophageal squamous epithelium, thereby promoting tumorigenesis ( 38 ). Claudin18.2 is mainly regulated by the hypomethylation gene sequence CpG island promoter and the transcription factor cAMP-response element blinding protein (CREB) in its genetic coding sequence ( 8 ), and its overexpression may be related to signaling pathways, like PKC pathway, ERK/MAPK pathway, and HER2/HER3 pathway, which promote the proliferation of tumor cells ( 31 , 39 , 40 ). In addition, the high expression of Claudin18.2 can regulate cell polarity, disrupt the tight junctions of tumor cells, change the adhesion and plasticity of tumor cells, increase their ability to metastasize and infiltration, and increase the degree of malignancy of tumors ( 41 ).…”

Section: The Double-edged Sword Role Of Claudin18 In Cancersmentioning

confidence: 99%

Dark horse target Claudin18.2 opens new battlefield for pancreatic cancer

Xu,

Jia,

et al. 2024

Front. Oncol.

View full text Add to dashboard Cite

Pancreatic cancer is one of the deadliest malignant tumors, which is a serious threat to human health and life, and it is expected that pancreatic cancer may be the second leading cause of cancer death in developed countries by 2030. Claudin18.2 is a tight junction protein expressed in normal gastric mucosal tissues, which is involved in the formation of tight junctions between cells and affects the permeability of paracellular cells. Claudin18.2 is highly expressed in pancreatic cancer and is associated with the initiation, progression, metastasis and prognosis of cancer, so it is considered a potential therapeutic target. Up to now, a number of clinical trials for Claudin18.2 are underway, including solid tumors such as pancreatic cancers and gastric cancers, and the results of these trials have not yet been officially announced. This manuscript briefly describes the Claudia protein, the dual roles of Cluadin18 in cancers, and summarizes the ongoing clinical trials targeting Claudin18.2 with a view to integrating the research progress of Claudin18.2 targeted therapy. In addition, this manuscript introduces the clinical research progress of Claudin18.2 positive pancreatic cancer, including monoclonal antibodies, bispecific antibodies, antibody-drug conjugates, CAR-T cell therapy, and hope to provide feasible ideas for the clinical treatment of Claudin18.2 positive pancreatic cancer.

show abstract

“…The special feature of tumors is the high expression of this protein in the malignant tissue. Its exposure as an extracellular anchor makes it an ideal target for immunotherapy in digestive system cancers[ 93 ]. Also, lymphocyte activation gene-3 is a type of immune checkpoint receptor protein.…”

Section: Future Perspectivesmentioning

confidence: 99%

Immunotherapy of gastric cancer: Present status and future perspectives

Triantafillidis,

Konstadoulakis,

Papalois

2024

World J Gastroenterol

View full text Add to dashboard Cite

In this editorial, we comment on the article entitled “Advances and key focus areas in gastric cancer immunotherapy: A comprehensive scientometric and clinical trial review (1999-2023),” which was published in the recent issue of the World Journal of Gastroenterology . We focused on the results of the authors’ bibliometric analysis concerning gastric cancer immunotherapy, which they analyzed in depth by compiling the relevant publications of the last 20 years. Before that, we briefly describe the most recent data concerning the epidemiological parameters of gastric cancer (GC) in different countries, attempting to give an interpretation based on the etiological factors involved in the etiopathogenesis of the neoplasm. We then briefly discuss the conservative treatment (chemotherapy) of the various forms of this malignant neoplasm. We describe the treatment of resectable tumors, locally advanced neoplasms, and unresectable (advanced) cases. Special attention is given to modern therapeutic approaches with emphasis on immunotherapy, which seems to be the future of GC treatment, especially in combination with chemotherapy. There is also a thorough analysis of the results of the study under review in terms of the number of scientific publications, the countries in which the studies were conducted, the authors, and the scientific centers of origin, as well as the clinical studies in progress. Finally, an attempt is made to draw some con-clusions and to point out possible future directions.

show abstract

Targeting CLDN18.2 in cancers of the gastrointestinal tract: New drugs and new indications

Cited by 22 publications

References 103 publications

DR30318, a novel tri-specific T cell engager for Claudin 18.2 positive cancers immunotherapy

DR30318, a novel tri-specific T cell engager for Claudin 18.2 positive cancers immunotherapy

Dark horse target Claudin18.2 opens new battlefield for pancreatic cancer

Immunotherapy of gastric cancer: Present status and future perspectives

Contact Info

Product

Resources

About