Claudin 18.2 (CLDN18.2) has emerged as one of the most promising targets in solid tumor therapy, especially for gastric cancers. As of 2025, the global R&D landscape for CLDN18.2-targeted antibody-drug conjugates (ADCs) is expanding rapidly, with multiple candidates entering mid- to late-stage clinical trials.

Claudins are a family of integral membrane proteins that form tight junctions (TJs) in epithelial and endothelial tissues, regulating the passage of molecules through the paracellular space. They are widely expressed in tissues such as the stomach, pancreas, and lungs.

CLDN18.2 is a highly selective marker protein that is exclusively expressed in differentiated gastric mucosal membrane epithelial cells. Under normal physiological conditions, CLDN18.2 is shielded from epitope exposure. However, during malignant cellular transformation, alterations in cell polarity result in the exposure of CLDN18.2 epitopes on the cell surface, making it a viable target for molecular therapy.

Beyond gastric tissue, CLDN18.2 expression has been observed in pancreatic, esophageal, and lung cancers, suggesting potential applications beyond gastric malignancies.

Latest Clinical Advances in CLDN18.2-Targeted ADCs

To date, over 80 CLDN18.2-targeted agents are in clinical development globally, spanning monoclonal antibodies, bispecific antibodies, CAR-T therapies, and ADCs. Among them, zolbetuximab (Astellas) remains the only approved therapy, indicated for CLDN18.2-positive, HER2-negative GC/GEJC in combination with chemotherapy.

ADCs combine the targeting precision of antibodies with the cytotoxic potency of small-molecule drugs, enabling selective tumor killing while limiting systemic toxicity. There are several CLDN18.2-targeted ADCs under clinical trials, and at least five CLDN18.2-targeted ADCs have now advanced to Phase III clinical trials

SHR-A1904

Developed in China, SHR-A1904 couples a humanized anti-CLDN18.2 IgG1 antibody with a cleavable peptide-based linker and a DNA topoisomerase I inhibitor payload.

A Phase I trial led by Prof. Ruihua Xu (Sun Yat-sen University Cancer Center) and published in Nature Medicine (July 2025) showed encouraging efficacy in previously treated CLDN18.2-positive advanced GEA patients. [1]

At doses of 6.0 mg/kg and 8.0 mg/kg, the objective response rates (ORRs) were 24.2% and 25.0%, with median PFS of 5.6 and 5.8 months, respectively. Common adverse events included anemia, nausea, and leukopenia.

Figure 1.  Kaplan–Meier plots of PFS. [1]

Following these results, Phase III monotherapy (NCT06649292) and Phase Ib/III combination (NCT06350006) studies are underway.

IBI343

IBI343 is another next-generation, Fc-silent CLDN18.2-targeted ADC from China. It is consisted of a fully humanized anti-CLDN18.2 monoclonal antibody conjugated to exatecan via site-specific glycol conjugation and a cleavable linker with a drug-to-antibody ratio of 4.

A Phase I trial led by Prof. Lin Shen (Beijing Cancer Hospital), also published in Nature Medicine (July 2025), showed ORRs of 29% (6 mg/kg) and 47.1% (8 mg/kg), with median PFS of 5.5 and 6.8 months, respectively. [2]

Although higher-grade hematologic toxicities were more common at 8 mg/kg, the recommended Phase II dose was set at 6 mg/kg every three weeks. IBI343 has now progressed to an international Phase III trial (NCT06238843).

CMG901 (AZD0901)

CMG901 consists of an anti-Claudin 18.2 monoclonal antibody, a protease-degradable linker, and a cytotoxic small molecule monomethyl auristatin E (MMAE).

In Febrary 2023, AstraZeneca, KYM Biosciences Inc. and Lepu Biopharma Co., Ltd. have entered into a global exclusive licence agreement for CMG901. Under the licence agreement, AstraZeneca will be responsible for the research, development, manufacture and commercialisation of CMG901 globally.

At the 2024 ASCO Annual Meeting, updated results from CMG901 (AZD0901) studies were presented. Three dose groups—2.2 mg/kg, 2.6 mg/kg, and 3.0 mg/kg—showed confirmed objective response rates (ORR) of 48%, 24%, and 38%, respectively. Median progression-free survival (PFS) was 4.8, 3.3, and 9.9 months, while median overall survival (OS) reached 11.8, 11.5, and 11.1 months. These results highlight the robust efficacy of CMG901 in patients with heavily pretreated, CLDN18.2-high gastric cancer. Importantly, no new safety signals emerged with extended follow-up. [3]

Figure 2. Clinical results for CMG901, source: https://www.astrazeneca.com/ 

Currently, an international, multicenter Phase III trial (CTR20240730, NCT06346392) is underway. This study compares CMG901 monotherapy against investigator’s choice of second-line or later treatments in patients with CLDN18.2-positive advanced gastric cancer.

XNW27011

XNW27011 is a novel CLDN 18.2-targeting ADC with the TMALIN® linker, a proprietary TOP1i payload more potent than Dxd, and homogeneous DAR of 8. 

In a Phase 1/2 clinical trial for CLDN18.2-positive GC/GEJC, data presented at the 2025 ASCO Annual Meeting showed the drug produced a best overall response rate (BOR) of 46.7% and a disease control rate (DCR) of 88.0%. [4]

In May 2025, Astellas has inked a ~$1.54B licensing deal with Evopoint Biosciences to develop & commercialize XNW27011 globally, excl. Mainland China, Hong Kong, Macao, and Taiwan, signaling strong commercial confidence in its potential.

LM-302

Developed by LaNova Medicines (now part of CSPC), LM-302 became the first CLDN18.2 ADC licensed globally. It consists of a CLDN18.2-specific antibody linked to the cytotoxic agent monomethyl auristatin E (MMAE) through a cleavable VC-PAB linker. The FDA has granted Orphan Drug Designation for pancreatic cancer, GC/GEJC, and cholangiocarcinoma.

At the 2025 ASCO meeting, LaNova presented new clinical data on LM-302 in combination with the anti-PD-1 antibody toripalimab. Among 41 efficacy-evaluable patients, the combination achieved an ORR of 65.9% and a disease control rate (DCR) of 85.4%. In patients with CLDN18.2 expression ≥25% (n=32), the ORR increased to 71.9% and DCR to 96.9%. Subgroup analysis showed an ORR of 63.3% in patients with PD-L1 CPS <1, and 77.8% in those with CPS ≥1. [5]

Outlook

From a global perspective, CLDN18.2-targeted ADCs are redefining therapeutic strategies for gastric and GEJ cancers. Their ability to selectively deliver cytotoxic agents directly to tumor sites offers new hope for patients who have exhausted standard treatments.

As more candidates enter late-stage trials, future efforts are expected to focus on:

• · Refining patient selection and biomarker-driven enrollment.

• · Exploring combination regimens with immunotherapy.

• · Expanding indications to pancreatic and esophageal cancers.

With rapid clinical progress and strong industry momentum, CLDN18.2-targeted ADCs are poised to become a cornerstone in next-generation gastric cancer therapy—bringing new precision and hope to patients worldwide.

About Huateng Pharma

PEG linkers play a crucial role in the design of ADCs, ensuring stability, controlled release, and optimal therapeutic performance.  At Huateng Pharma, we supply high-quality PEG derivatives manufactured to GMP standards, supporting both research and commercial-scale needs. We also provide custom synthesis services to meet specific project requirements, including PEG linkers with tailored molecular weights, branching, and functional groups that may not be listed in our online catalog. With our expertise, we deliver flexible and reliable solutions to help our partners accelerate ADC innovation and achieve their unique quality specifications.

References:
[1] Ruan DY, Wu HX, Luo SX, Huang WW, Liang XJ, Niu ZX, Dang Q, Li HL, Pan ZY, Lu HX, Zhang YQ, Li XY, Xiao XY, Cai SR, Dong YG, Zhang J, Li Z, Lan HT, Wang X, Zhou Y, Liu L, Liu HL, Xu PS, Suo AL, Jia RN, Li YQ, Peng XD, Wang SC, Yu AA, Xie J, Qiu MZ, Xu RH. The antibody-drug conjugate SHR-A1904 for targeting CLDN18.2 in advanced gastric or gastroesophageal junction cancer: a phase 1 trial. Nat Med. 2025 Sep;31(9):3037-3046. doi: 10.1038/s41591-025-03781-w. Epub 2025 Jul 16. PMID: 40670772.
[2] Liu J, Yang J, Sun Y, Gong J, Yue J, Pan Y, Sun M, Song R, Xiao X, Tazbirkova A, Ruan J, Liu Z, Liu Z, Li Z, Sheng L, Qin Y, Ying J, Yu X, Zhang J, Mou Y, Lu C, Chen P, Li S, Li J, Qu X, Deng T, Du J, Zhou A, Li E, Yuan X, Liang X, Yu W, Morris M, Luo Y, Zhao X, Guo Y, Zhou H, Shen L. CLDN18.2-targeting antibody-drug conjugate IBI343 in advanced gastric or gastroesophageal junction adenocarcinoma: a phase 1 trial. Nat Med. 2025 Sep;31(9):3028-3036. doi: 10.1038/s41591-025-03783-8. Epub 2025 Jul 16. PMID: 40670773; PMCID: PMC12443601.
[3] Xu R,et al.Updates on Abstract 434420:A Phase 1 Trial of Claudin 18.2-Specific Antibody-Drug Conjugate CMG901 in Patients with Advanced Gastric/Gastroesophageal Junction Cancer.2024 ASCO Plenary Series.
[4] Jinming Yu et al. Efficacy and safety of XNW27011, a Claudin 18.2 targeting antibody drug conjugate with topoisomerase 1 inhibitor payload, in patients with Claudin 18.2 positive gastric/gastroesophageal junction cancer: Results from ongoing phase I/II study.. J Clin Oncol 43, 3034-3034(2025). DOI:10.1200/JCO.2025.43.16_suppl.3034
[5] Haiping Jiang,Mingzhu Huang,et al.Efficacy and safety of LM-302 (anti-claudin 18.2 ADC) in combination with anti-PD-1 therapy for advanced gastric, gastroesophageal junction cancer and esophageal adenocarcinoma: Early-phase study results.ASCO 2025