In this article, we summarize the phase 1 trial of IBI343, reported in Nature Medicine (July 2025), focusing on its structural innovations, safety, efficacy, and position within the landscape of Claudin18.2-targeted ADCs.
Drug Profile: Molecular Design of IBI343
IBI343 is a fully humanized anti-CLDN18.2 monoclonal antibody conjugated to exatecan, a DNA topoisomerase I inhibitor, via a site-specific glycan conjugation at N297. This design ensures a stable drug-to-antibody ratio (DAR) of 4, minimizing premature payload release in circulation.
Importantly, IBI343 employs an Fc-silenced IgG1 backbone, reducing antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC), thereby mitigating on-target gastrointestinal toxicities that often complicate CLDN18.2 therapies:contentReference[oaicite:1]{index=1}.
Trial Design
This phase 1 study (NCT05458219) enrolled 127 patients with advanced gastric/GEJ adenocarcinoma. Key features:
- Population: 19 in dose escalation, 108 in expansion
- Dosing: 0.3–10 mg/kg intravenously every 3 weeks
- RP2D determined: 6 mg/kg Q3W
- CLDN18.2 stratification: low (<40%), moderate (40–74%), high (≥75%) expression assessed by Ventana CLDN18 (43-14A) IHC assay
Safety Profile
Safety outcomes were as follows:
- TEAEs in 97.4% of patients
- Grade ≥3 TEAEs in 66.4%; treatment-related AEs in 52.6%
- Most common: decreased WBC (67.2%), anemia (64.7%), neutropenia (58.6%)
- Notably, no interstitial lung disease (ILD) was observed
Compared with earlier ADCs, gastrointestinal adverse events were relatively mild, reflecting the benefit of Fc-silencing technology.
Efficacy Results
Among high-expression patients (≥75% CLDN18.2):
- 6 mg/kg: ORR 29.0%, DCR 90.3%, median PFS 5.5 months
- 8 mg/kg: ORR 47.1%, DCR 88.2%, median PFS 6.8 months
In moderate expression (40–74%), ORR was 38.8%. No responses were seen in the low-expression group (1–39%).
Clinical Pharmacology and PK
IBI343 demonstrated linear PK over 0.3–10 mg/kg, with a half-life of ~2 weeks, supporting Q3W dosing. DAR stability limited payload dissociation, yielding a strong correlation (r ≥0.85) between ADC and total antibody exposures.
This feature allows total antibody concentration to serve as a surrogate marker, simplifying exposure–response analyses in clinical development.
Clinical Significance
IBI343 showed a favorable balance of efficacy and tolerability, particularly at 6 mg/kg Q3W, while the 8 mg/kg cohort demonstrated higher ORR but increased toxicity. This underscores the need for dose optimization.
Given its Fc-silenced design and exatecan payload, IBI343 may provide therapeutic benefit in patients resistant to zolbetuximab and represents a next-generation ADC with improved pharmacologic stability.
My Perspective
IBI343 highlights the potential of rational ADC engineering to overcome limitations of earlier therapies. My key takeaways are:
- Biomarker-driven therapy: High CLDN18.2 expression remains the key determinant of response.
- Resistance strategies: Exatecan payload may overcome resistance to prior chemotherapies, extending therapeutic reach.
- Comparative advantage: Compared to SHR-A1904, IBI343 appears to offer reduced gastrointestinal toxicity, enhancing patient tolerability.
- Next steps: Phase 2/3 trials must establish OS benefit and evaluate combination regimens with chemotherapy or immunotherapy.
Overall, IBI343 represents a leading candidate in the Claudin18.2 ADC space and will likely shape future treatment strategies for gastric and GEJ cancers.
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This article was edited by the Morningglorysciences team.
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