Claudin18.2 is one of the most popular targets at present. Innovative drugs developed on this target include monoclonal antibody, double antibody, CAR-T and ADC, which almost contain the most promising and popular forms of biological innovative drugs at present. Even among the classic targets that have been developed for many years, not many can win this "honor". This article mainly introduces ADC drugs targeting Claudin18.2.
Claudin18.2: An Ideal Drug Target
Claudins (CLDN) are a class of tight junction proteins in human normal tissues. Claudin has 4 transmembrane domains, and is an important molecule that is closely connected to cells. It is involved in physiological processes such as the regulation of paracellular permeability and conductance, and it forms a paracellular barrier, controlling the flow of molecules between cells.
The Claudins family contains at least 27 transmembrane proteins, which are important components and functional structures of tight cell junctions. Among them, Claudin18 has two isomers, Claudin18.1 and Claudin18.2, and Claudin18.2 is mainly used for indications of gastric cancer and pancreatic cancer.
Figure 1. Model structure of claudin protein
Claudin18.2 is abnormally activated and overexpressed in various primary malignant tumors such as breast cancer, colon cancer, liver cancer, head and neck cancer, bronchial cancer and non-small cell lung cancer, especially in digestive system malignant tumors, including gastric cancer (70% ), pancreatic cancer (50%), esophageal cancer (30%), etc. Claudin18.2 is involved in the proliferation, differentiation and migration of tumor cells. However, Claudin 18.2 is almost not expressed in normal tissues. It has excellent specificity.
Claudin18.2 is highly expressed in various malignant tumors such as gastric cancer and pancreatic cancer. The number of patients with gastric cancer ranks fourth among all malignant tumors, and the related mortality rate ranks third. However, compared with lung cancer, there are very few targeted drugs approved for gastric cancer. The approved indications are only the "old" target HER2 and anti-angiogenesis inhibitor VEGFR2, which represents a large demand for targeted treatment for gastric cancer.
The positive rate of HER2 target in gastric cancer patients is only 10%-15%, while Claudin18.2 is highly expressed in gastric cancer, with a positive rate of more than 60%. For gastric cancer patients, Claudin18.2 is an ideal drug target. In one study, Claudin18.2 protein was found to be present in 69% of ovarian cancer cells in patients with gastric cancer that had spread to the ovaries. This means that the Claudin18.2 target is equally effective for most patients with advanced cancer that has metastasized.
Claudin18.2 is almost born for targeted drugs. Not only its excellent targeting properties, but also aimed at the blank space in the current treatment of gastric cancer and pancreatic cancer, its market value is immeasurable. Therefore, the development of drugs targeting Claudin18.2 is expected to provide effective treatment for more patients, which also makes Claudin18.2 a popular target in the diagnosis and treatment of various solid tumors such as gastric cancer and pancreatic cancer. Various treatment methods such as monoclonal antibody, double antibody, ADC, CAR-T and other innovative therapies.
ADC drugs targeting Claudin18.2
According to PharmSnap database, there are currently 92 drugs in development targeting Claudin 18.2. As can be seen from the top five countries in terms of R&D popularity, China leads the R&D layout of Claudin 18.2 target with 81.4% (70 drugs in development), followed by the United States with 10.46% (9 drugs in development), followed by Germany, the Czech Republic and the United Kingdom. Therefore, we can see that the research and development enthusiasm of Claudin 18.2 target is weak in Europe.
Here we will introduce 11 ADC drugs targeting Claudin18.2.
Table 1: ADC drugs targeting Claudin18.2
CMG901 is a Claudin 18.2 antibody-drug conjugate jointly developed by Keymed Biosciences and Lepu Biopharma, which consists of a Claudin 18.2-specific antibody, a cleavable linker and a toxic load, monomethyl auristatin E (MMAE).
CMG901 was approved by the FDA in March 2021 to carry out Phase I clinical trials for gastric cancer and gastroesophageal junction adenocarcinoma, and in April 2022 it was granted Orphan Drug Designation and Fast Track Designation by the FDA.
On September 8, 2022, according to the official website of CDE, Keymed Biosciences’s Claudin 18.2 ADC CMG901 is planned to be included in breakthrough therapy for Claudin 18.2-positive advanced gastric cancer that has failed or cannot be tolerated by first-line or above treatment.
SHR-A1904 is a Claudin18.2 ADC drug developed by Hengrui. It is developing two indications for advanced pancreatic cancer and advanced solid tumors, both of which are in Phase I clinical trials.
RC118 for injection is an innovative ADC independently developed by RemeGen, which is used for the treatment of patients with locally advanced unresectable or metastatic malignant solid tumors positive for Claudin 18.2 expression.
In December 2022, the phase I clinical study of RemeGen RC118 showed good safety and tolerability. The company's phase I clinical study of RC118 for injection in Australia and China is progressing smoothly, showing good safety and tolerability. RC118 was granted two orphan drug qualifications by the FDA on December 8, 2022, with indications for gastric cancer (including gastroesophageal junction cancer) and pancreatic cancer.
SYSA1801 is an anti-Claudin-18.2 fully human monoclonal antibody-MMAE drug conjugate developed by CSPC Megalith Biopharmaceutical Co. Ltd. Preclinical in vitro and in vivo animal experiments have shown that SYSA1801 can effectively target tumor cells through anti-Claudin-18.2 antibody and endocytosis. Introducing MMAE toxin into tumor cells to treat cancer.
On July 28, 2022, the company signed an exclusive agreement with Elevation Oncology of the United States on the innovative SYSA1801 (Claudin 18.2-ADC).
Under the terms of the agreement, CSPC Megalith Biopharmaceutical Co. Ltd. received an initial payment of US$27 million and is entitled to receive up to $148 million in potential development and regulatory milestone payments and up to $1.02 billion in potential sales milestone payments, as well as a sales commission of up to double-digit percentages based on annual net sales in the licensed territories.
LM-302 is an ADC of Claudin 18.2 with first-in-class potential independently developed by LaNova Medicines. It was granted clinical implicit approval by CDE on October 14, 2021, and is currently undergoing Phase 1 clinical trials in patients with advanced solid tumors in both China and the United States.
In May 2022, LaNova Medicines and Turning Point Therapeutics reached an exclusive licensing cooperation on LM-302 with an expected total value of over US$1 billion.
According to the agreement, Turning Point Therapeutics will make an initial payment of US $25 million to LaNova Medicines for exclusive rights to develop and commercialize LM-302 in countries and regions around the world, with the exception of China and Korea. LaNova Medicines will be eligible to receive milestone payments of up to $1 billion, including $195 million for R&D milestones. And upon successful commercialization of LM-302, it is entitled to receive a gradient royalty of a single - to double-digit percentage of net sales from Turning Point Therapeutics.
SKB315 is an ADC drug targeting Claudin 18.2 developed by Sichuan Kelun-Biotech Biopharmaceutical Co., Ltd.. The product was approved for clinical trials in November 2021 and is currently in the early stages of clinical trials.
On July 26, 2022, the company and Merck signed a drug authorization agreement with cumulative milestone payments of no more than US$901 million. According to professionals, the authorized product is SKB315.
ATG-022 is an antibody-drug conjugate (ADC) targeting tumor-associated antigen (TAA) Claudin 18.2 independently developed and developed by Antengene Corporation.
At the AACR meeting in 2022, the staff of Antengene announced the in vivo efficacy of ATG-022 in xenografts derived from gastric cancer patients (Figure 2) . The data show that ATG-022 has low nanomolar affinity for Claudin 18.2 and potent anti-tumor activity in vitro and in vivo.
Figure 2. Efficacy of ATG-022 in PDX model
On March 14, 2023, NMPA has approved the Phase I clinical trial application of ATG-022 for the treatment of patients with advanced or metastatic solid tumors, and patient recruitment is currently underway. On March 29, 2023, Antengene announced that the phase I CLINCH study aimed at evaluating ATG-022 monotherapy in patients with advanced or metastatic solid tumors has completed the administration of the first patient.
Claudin18.2 is a promising and valuable target, which is an ideal addition to the current blank field of targeted cancer therapy. Claudin18.2 is abnormally activated and over-expressed in a variety of primary malignancies such as breast cancer, colon cancer, liver cancer, head and neck cancer, bronchial cancer and non-small cell lung cancer, especially in digestive system malignancies, including gastric cancer (70%), pancreatic cancer (50%), esophageal cancer (30%), etc. Claudin18.2 showed high expression in gastric cancer, pancreatic cancer and other malignant tumors. In gastric cancer, for example, HER-2 is positive in less than 20% of patients with gastric cancer, while Claudin18.2 is positive in more than 50% of related cancers.
Therefore, CLDN18.2 may be the second most important target for gastric cancer after HER-2, and there are many different types of products under research, such as monoclonal antibody, double antibody, ADC and CAR-T. Although there is no drug on the market at this stage, many companies around the world have deployed different therapies and strive to occupy a place in this market. Looking forward to seeing the successful launch of Claudin18.2 targeted innovative drugs as soon as possible to benefit more patients.
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. Cao, W., Xing, H., Li, Y. et al. Claudin18.2 is a novel molecular biomarker for tumor-targeted immunotherapy. Biomark Res 10, 38 (2022). https://doi.org/10.1186/s40364-022-00385-1
.Jinxia Chen, Zhiyuan Xu, Can Hu, Shengjie Zhang, Mengli Zi, Li Yuan and Xiangdong Cheng, Targeting CLDN18.2 in cancers of the gastrointestinal tract: New drugs and new indications, Frontiers in oncology (2023), 13, 1132319.
. Ref ZL-1211 Exhibits Robust Antitumor Activity by Enhancing ADCC and Activating NK Cell–mediated Inflammation in CLDN18.2-High and -Low Expressing Gastric Cancer Models | Cancer Research Communications | American Association for Cancer Research (aacrjournals.org) .
. Antengene Announces Publication of Five Posters at the 2022 American Association for Cancer Research(AACR)Annual Meeting.
. Chang song Qi, Jifang Gong, Jian Li, Dan Liu, Yanru Qin, etc.,Claudin18.2-specific CAR T cells in gastrointestinal cancers: phase 1 trial interim results, Nature Medicine | VOL 28 | June 2022 | 1189–1198.
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