Professor Shen Lin’s team tackles gastric cancer! The CLDN18.2 targeted ADC drug IBI343 Phase I study tops Nature Medicine.
Gastric cancer, as a “health killer” globally, is particularly rampant in East Asia. Data shows that in 2022, there were 358,700 new cases of gastric cancer in China, with 260,400 deaths, accounting for nearly 40% of the global total. Despite continuous advancements in medical technology, treatment remains challenging for patients with unresectable or metastatic gastric cancer and gastroesophageal junction (G/GEJ) adenocarcinoma, especially for those who are HER2-negative and have normal mismatch repair. The median overall survival for first-line treatment is only 10-15 months, dropping to 5-10 months for second-line treatment, and there are often “no options available” for third-line and beyond.
In this context, the discovery of the CLDN18.2 target brings new hope for gastric cancer treatment. This tight junction protein is abnormally expressed in about 80% of gastric cancers and 60% of pancreatic ductal adenocarcinomas, and upon malignant transformation, it is exposed on the surface of tumor cells, becoming a “target marker” for precise attack. Previously, anti-CLDN18.2 monoclonal antibodies have been approved in multiple countries, but antibody-drug conjugates (ADCs), as “precision missiles,” still have vast exploration space due to their dual advantages of “targeting + toxicity.”
On July 16, 2025, Professor Shen Lin’s team from Peking University Cancer Hospital published a significant study in the top international journal Nature Medicine, focusing on the self-developed novel CLDN18.2 targeted ADC drug IBI343, and announced the results of its Phase I clinical trial for the first time, injecting a “booster” into the treatment of advanced gastric cancer.
1. Unique Design of the “Next-Generation ADC”: Safer and More Precise
Unlike the first-generation ADCs that are prone to blood toxicity and fatal interstitial lung disease (ILD), IBI343 achieves multiple breakthroughs in design:
– More precise targeting: It uses a fully humanized anti-CLDN18.2 monoclonal antibody, coupled with site-specific glycosylation technology, to precisely link the topoisomerase inhibitor exatecan, maintaining a stable drug-antibody ratio (DAR) of 4, ensuring that the “munitions” are accurately delivered to tumor cells.
– More controllable toxicity: The innovative Fc segment silencing design significantly reduces antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC), lowering the risk of gastrointestinal toxicity and other side effects from the source.
2. Impressive Phase I Trial Data: Safety and Efficacy Both Meet Standards
This study is a multicenter, open-label trial (NCT05458219), covering dose escalation (0.3-10mg/kg) and expansion phases, including 211 patients, with core results as follows:
1. Safety: No fatal ILD, significantly reduced gastrointestinal toxicity
– The maximum tolerated dose (MTD) was determined to be 8mg/kg in the dose escalation phase, with only 2 cases of dose-limiting toxicity (grade 4 bone marrow suppression, grade 4 neutropenia with fever) in the 10mg/kg dose group.
– In the expansion phase (116 G/GEJ adenocarcinoma patients), 97.4% experienced treatment-related adverse events (TEAEs), but the incidence of grade ≥3 was only 66.4%, and no ILD was observed (significantly better than the 15.4% ILD incidence of similar drugs).
– Gastrointestinal side effects were significantly reduced: nausea occurred in 41.4% (only 1.7% grade ≥3), vomiting occurred in 25% (2.6% grade ≥3), far lower than the approved CLDN18.2 monoclonal antibody (nausea/vomiting incidence over 50%, grade ≥3 over 8%).
2. Efficacy: Significant Benefits for Patients with High CLDN18.2 Expression
The study found a high correlation between CLDN18.2 expression levels and efficacy, with the most pronounced effects in patients with high expression (2+/3+ ≥75%):
– In the 6mg/kg dose group (31 cases): confirmed objective response rate (ORR) of 29.0%, disease control rate (DCR) of 90.3%, median progression-free survival (PFS) of 5.5 months, and median overall survival (OS) of 10.8 months.
– In the 8mg/kg dose group (17 cases): confirmed ORR increased to 47.1%, DCR 88.2%, median PFS 6.8 months, and median OS not yet reached.
– Compared to traditional third-line chemotherapy (ORR 4%-11.2%, PFS 1.6-2.0 months), IBI343 monotherapy achieved a “qualitative leap” in efficacy.
3. Pharmacokinetics: Supports Administration Every 3 Weeks, Excellent Stability
IBI343 exhibits linear pharmacokinetic characteristics within the 0.3-10mg/kg dose range, with a half-life of about 2 weeks at the 6mg/kg dose, supporting intravenous infusion once every 3 weeks. Additionally, the drug’s stability is excellent, with an ADC to free toxic molecule (payload) ratio exceeding 100 times, and the drug-antibody ratio (DAR) remained stable within 21 days in rhesus monkey tests (compared to a 69% decrease in DAR for similar drugs).
3. Clinical Significance and Future Prospects
Based on the balance of safety and efficacy, the study ultimately determined 6mg/kg once every 3 weeks as the recommended Phase II dose (RP2D). Currently, a Phase III trial (G-HOPE-001, NCT06238843) evaluating IBI343 against chemotherapy has been initiated, which, if successful, is expected to rewrite the treatment guidelines for advanced gastric cancer.
In the future, the research team will explore three major directions:
1. Combination Therapy: Conduct trials combining IBI343 with immune checkpoint inhibitors to explore the synergistic effects of “ADC + immunotherapy” to further extend patient survival.
2. Sequential Therapy: Validate the subsequent treatment potential of IBI343 for patients who have previously received CLDN18.2 targeted therapy (in this study, one patient who had previously received anti-CLDN18.2 monoclonal antibody still achieved partial remission).
3. Biomarker Optimization: Standardize CLDN18.2 testing and explore its combined application with biomarkers such as HER2 and PD-L1 to accurately select the best beneficiary population.
Professor Shen Lin’s team’s research not only validates the value of CLDN18.2 as a core target for gastric cancer but also brings a “long-lasting, safe” new treatment option for patients with advanced gastric cancer through ADC technology innovation. With the advancement of the Phase III trial, IBI343 is expected to become a “new business card” for gastric cancer treatment in China.