Introduction to CLDN18.2
Claudin18.2 (CLDN18.2) protein, an isomer of claudin18, a member of the tight junction protein family, is a highly selective biomarker with limited expression in normal tissues and is often aberrantly expressed during the occurrence and development of various primary malignancies, such as gastric/gastroesophageal junction (GC/GEJ) cancer, breast cancer, colon cancer, liver cancer, head and neck cancer, bronchial cancer, and non-small cell lung cancer. CLDN18.2 is involved in the proliferation, differentiation and migration of tumor cells. Recent studies have found CLDN18.2 expression to be a potential specific marker for the diagnosis and treatment of these tumors.
Figure 1: Claudin protein structure diagram
Progress in targeted therapy for CLDN18.2
Therapeutics for CLDN18.2 are currently in the development stage, including monoclonal antibodies, antibody-drug conjugates (ADCs), bispecific/trispecific antibodies, and CAR-T cell therapies.
1. Monoclonal antibody against claudin18.2
1. Zortuximab: the world's first approved CLDN18.2 targeted therapy drug
Zolbetuximab (VYLOY™) is a monoclonal antibody targeting CLDN18.2 developed by Astellas Pharmaceutical Group and approved in Japan for the treatment of patients with CLDN18.2-positive, unresectable, advanced or recurrent gastric cancer. It is a chimeric monoclonal antibody that specifically binds to CLDN18.2 and binds to CLDN18.2 on the surface of cancer cells by intravenous injection, activating two immune system pathways, antibody-dependent cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC), to induce cancer cell death. The approval was based on the results of two phase III clinical trials, SPOTLIGHT and GLOW, which demonstrated that zolbetuximab plus chemotherapy significantly improved progression-free survival (PFS) and overall survival (OS) compared with placebo plus chemotherapy.
Table 1: Summary of zobetuximab clinical trials
Chinese name: zotuximab
英文名称：Zolbetuximab
Product name: Vyloy
Target: CLDN18.2
Approved for listing in Japan: Approved for listing in Japan on March 27, 2024, and not approved for listing in other countries
Approved for marketing in China: On August 1, 2023, the Center for Drug Evaluation (CDE) of the National Medical Products Administration (NMPA) of China accepted the Marketing Authorization Application (BLA) for zolbetuximab for the treatment of patients with gastric cancer or gastroesophageal junction (GEJ) adenocarcinoma.
Approved indications in Japan: CLDN18.2 positive, unresectable, advanced or recurrent gastric cancer
R&D manufacturer: Astellas Pharmaceutical Group
Price: Not yet announced, the Japan version is expected to be announced in August 2024 (July 2024)
2. 奥塞米单抗(Osemitamab):FDA授予其孤儿药称号
Osemimab (TST001) is a high-affinity humanized monoclonal antibody targeting CLDN18.2, a pan-tumor target that is expressed in a variety of epithelial tumors, especially gastric cancer and pancreatic cancer. In pancreatic cancer, high expression of Claudin 18.2 is detected in up to 50%-60% of patients. It was developed by Director Yang Zhi and researcher Zhu Hua of Peking University Cancer Hospital. The drug has shown potent anti-tumor activity in xenograft trials, and multiple clinical trials are ongoing.
Preliminary data presented at the ESMO Congress 2022 show that Osemitamab in combination with capecitabine and oxaliplatin has great potential in the first-line treatment of patients with locally advanced or metastatic gastric/GEJ cancer!
The results showed that at a median follow-up of 65 days, 15 patients were evaluable, with a partial response (PR) rate of 73.3% (n = 11) and a disease control rate of up to 100% (n = 15)! This means that all patients with advanced pancreatic cancer have different degrees of shrinkage or stable control after treatment with the new treatment regimen!
Figure 2: Data graph of TST001 in combination with capecitabine and oxaliplatin in the first-line treatment of locally advanced or metastatic gastric cancer
2. Antibody-drug conjugates (ADCs)
Antibody-drug conjugates (ADCs) are a powerful class of anti-cancer therapeutics that deliver highly cytotoxic molecules directly to cancer cells. Many patients with solid tumors and hematologic malignancies have been treated with ADCs.
1. CMG901(AZD0901)
CMG901 is an investigational antibody-drug conjugate targeting Claudin18.2 by Keynova-B. CMG901 is an ADC targeting CLDN 18.2 and consists of three parts: a monoclonal antibody targeting CLDN18.2, a cleavable linker, and a potent cytotoxic payload (MMAE). CMG901 binds to Claudin18.2-positive cells through its monoclonal antibody moiety. Upon binding, CMG901 is internalized into lysosomes by tumor cells and releases cytotoxic payloads, leading to cell cycle arrest and tumor cell apoptosis. Mechanism of action studies have shown that CMG901 can cause tumor cell death through a variety of mechanisms. Preclinical studies have shown that CMG901 is effective in killing gastric cancer cells and is much more effective against tumors than zobetuximab analogues or CMG901-unconjugated antibodies. CMG901 has also demonstrated good tolerability and a favorable safety profile in preclinical studies. CMG-901 has been approved by the FDA for a Phase I clinical trial (NCT04805307) in patients with GC/GEJ cancer.
2. SYSA-1801
SYSA-180 is a CDLN18.2 ADC product developed by CSPC, which is composed of a monoclonal antibody (mAb) targeting CLDN18.2 and a monomethyl auristatin E (MMAE) combined with a DAR of 2 through a cleavable linker. SYSA-1801 is a fully human mAb plus MMAE drug conjugate targeting CLDN18.2. It is usually a tight junction protein expressed only on the gastric mucosa and is overexpressed in the stomach, pancreas, esophagus, ovaries, lungs, and other solid tumors. SYSA1801 has excellent in vitro and in vivo activity and a good safety profile against gastric, pancreatic, and lung cancers, indicating that it is a promising drug with good efficacy in clinical trials. SYSA-1801 has been approved for clinical trials (NCT05009966, CTR20211879) by the United States FDA and the China CDE, respectively, for the treatment of patients with CLDN18.2-expressing GC/GEJ cancer and PC.
3. RC118
RC118 is an innovative antibody-drug conjugate (ADC) independently developed by Remegen. RC118 consists of a recombinant humanized anti-CLDN18.2 monoclonal antibody and monomethyl auristatin E (MMAE), a potent tubulin binder with a half-maximum inhibitory concentration (IC50) in the sub-nanomolar range as a cytotoxic payload, and these factors bind to each other at an optimized drug-antibody ratio via protease-cleavable linkers. In December 2022, Remegen's innovative antibody-drug conjugate RC118 was granted two orphan drug designations by the United States Food and Drug Administration for the treatment of gastric cancer (including gastroesophageal junction cancer) and pancreatic cancer.
III. Bispecific/Trispecific Antibodies against Claudin18.2
1. 格瑞妥单抗（AMG-910）
AMG-910 is an Extended Half-Life (HLE) BiTE (Bispecific T Cell Engager) antibody designed to engage CD3-positive T cells and CLDN18.2-expressing tumor cells. By binding to CLDN18.2 on tumor cells and CD3 on T cells, AMG-910 redirects tumor cell lysis to kill tumor cells. Currently, a phase I clinical study in patients with CLDN18.2-positive GC and GEJ adenocarcinoma is underway (NCT04260191). The trial is intended for patients aged 18 years with histologically or cytologically confirmed non-resectable CLDN18.2-positive GC/GEJ adenocarcinoma.
2.Q-1802
Q-1802 is a bispecific antibody targeting programmed death-ligand 1 (PD-L1) and CLDN18.2. It binds to CLDN18.2 and mediates antibody-dependent cell-mediated cytotoxicity against tumor cells. On the other hand, the antibody portion that recognizes PD-L1 blocks PD-1 signaling and activates innate and adaptive immunity. Animal studies have shown that Q-1802 can accurately target tumor tissues and has a potent efficacy in killing tumor cells, revealing novel therapeutic candidates for advanced solid tumors with CLDN18.2 expression. A phase I clinical trial (NCT04856150) has been initiated in patients with advanced solid tumors with results yet to be determined.
4. CAR-T cell therapy
1. CT041: The first CAR-T cell therapy for CLDN18.2
CT041 is an autologous CAR-T cell therapy targeting CLDN18.2, developed by CARsgen, which is the world's first autologous CAR-T product candidate for CLDN18.2 independently developed by CARsgen. Since its debut in 2019, CT041 has shown promising prospects for the treatment of digestive system tumors with its remarkable efficacy. In 2022, CT041 achieved positive results in multiple clinical trials, especially in the subgroup of gastric/esophageal junction cancer, with an objective response rate of up to 60%, and the majority of patients were stable with varying degrees of tumor shrinkage. It is currently in a phase II clinical trial. CT041 has shown positive efficacy in the treatment of CLDN18.2-positive gastrointestinal tumors with a manageable safety profile.
2.LY011
LY011 is an anti-CLDN18.2 third-generation CAR-T cell product prepared from allogeneic T lymphocytes that have been genetically modified to target tumor-associated antigen (TAA) CLDN18.2 using lentiviral vector technology with potential immunostimulatory and antitumor activity. After administration, LY011 specifically recognizes and binds to CLDN18.2-expressing tumor cells, thereby mediating the killing of CLDN18.2-expressing tumor cells through specific cytotoxic T lymphocytes (CTLs). Currently, two phase I clinical trials (NCT04966143 and NCT04977193) are underway in patients with CLDN18.2-positive PC and advanced GC. According to the report on January 31, 2021, 4 patients with advanced malignant solid tumors (3 cases of gastric cancer and 1 case of pancreatic cancer) have completed the DLT observation period and received their first dose of drug therapy. According to the RECIST 1.1 evaluation criteria, the best efficacy among the 4 subjects was 2 with remission (PR) and 2 with stable disease (SD). At the time of publication, the overall ORR was 50.0% and the overall disease control rate (DCR) was 100%.
3. LCAR-C18S
LCAR-C18S is a CAR-T cell therapy targeting CLDN18.2 developed by Nanjing Legend Biotechnology Co., Ltd. The therapy has entered a phase I clinical trial (NCT04467853, also known as BM2L201910) for the treatment of GC and PC to determine its safety, tolerability, and efficacy. In addition, other companies have developed additional drug candidates that are in preclinical or early clinical studies with clinical results yet to be published.
Summary
Therapeutics targeting CLDN18.2 are developing rapidly, involving a variety of types such as monoclonal antibodies, ADCs, and CAR-T cell therapies. These drugs have shown good efficacy and safety in clinical trials, indicating that CLDN18.2 targeted therapy will bring new hope to patients with malignant tumors such as gastric cancer.
Tips: The medical content involved in this article is a general application suggestion, which is for learning and reference only, and the final opinion is subject to the diagnosis of the clinician.