Henlius (2696.HK) recently presented the preclinical data of HLX403, its novel anti-CDH17 antibody-drug conjugate (ADC) at the ADC Asia Congress 2026. This candidate, developed using the company's proprietary Hanjugator™ ADC platform, demonstrated differentiated advantages that highlight its potential as a best-in-class ADC for gastrointestinal (GI) cancers.
Gastrointestinal (GI) cancers represent one of the largest global cancer burdens, accounting for more than 5 million new cases and approximately 3.7 million deaths annually1. Among these, colorectal and gastric cancers consistently rank among the leading contributors to cancer incidence and mortality worldwide, while pancreatic cancer is characterized by an aggressive phenotype and extremely poor prognosis, rendering it one of the most lethal solid tumors. Despite recent advances in targeted therapy and immunotherapy that have improved outcomes for certain patient subsets, a substantial proportion of individuals with GI malignancies—particularly those with advanced or metastatic disease—continue to confront a paucity of effective therapeutic options, limited durability of clinical benefit, and the emergence of acquired resistance. These persistent challenges underscore a critical and ongoing unmet medical need in this field2. Antibody–drug conjugates (ADCs) have rapidly emerged as a promising strategy in gastrointestinal cancers, delivering targeted cytotoxicity to tumor-associated antigens such as HER2, Claudin18.2, CDH17 and c-MET. They demonstrate potent anti-tumor activity with manageable safety, offering new avenues for precision therapy3.
Cadherin-17 (CDH17), a member of the cadherin family protein, is normally restricted to gastrointestinal epithelial tight junctions. In malignancies, loss of cell polarity exposes CDH17 on the tumor surface. CDH17 is highly expressed in gastric, colorectal, and pancreatic cancers and correlates with poor prognosis. Its selective expression makes CDH17 an attractive therapeutic target, particularly for antibody-drug conjugates in GI cancers4-5.
The preclinical data presented at the conference highlight the molecule's key attributes:
1. Superior Antibody Performance and Specificity
- High Affinity and Specificity: The antibody component of this ADC demonstrates nanomolar binding affinity to CDH17, with no off-target binding to other members of the cadherin family and exhibits a clean profile in MPA assays.
2. Differentiated Linker-Payload Platform (Hanjugator™)
- Highly Hydrophilic Design: The proprietary hydrophilic linker-payload platform confers excellent druggability and developability.
- Potent Anti-tumor Activity and Significantly Enhanced Bystander Effect: The payload exhibits anti-tumor activity comparable to DXd, while the ADC demonstrates a 19.7-fold stronger bystander killing effect than deruxtecan-based ADCs, a key feature for addressing tumor heterogeneity.
3. Robust In Vivo Anti-tumor Activity & Potential to Overcome Drug Resistance
- Superior to Deruxtecan: Demonstrated superior efficacy compared to deruxtecan analogues across multiple cell line-derived xenograft (CDX) models, including SNU-16 gastric cancer cells and GP2D colorectal cancer cells.
- Potential to Overcome Drug Resistance: Showed robust anti-tumor activity in a Fruquintinib-resistant, KRAS-mutant colorectal cancer patient-derived xenograft (PDX) model.
- Efficacious in Low-Expressing Tumors: Achieved >100% tumor growth inhibition (TGI) with a single dose (3 mpk or 6 mpk) in a gastric cancer PDX model with low CDH17 and low PD-L1 expression.
4. Potential Best-in-Class Safety and Tolerability
- Best-in-Class Tolerability Profile: In non-human primate (NHP) toxicology studies, the highest non-severely toxic dose (HNSTD) was established at 40 mg/kg (Q3W x 3), representing one of the highest levels reported for ADCs against the same target.
- Favorable CMC Profile: Exhibits a high antibody titer (>8 g/L) and an overall favorable CMC profile.
In conclusion, Henlius' CDH17 ADC HLX403 has demonstrated potent anti-tumor activity in preclinical studies, along with a best-in-class tolerability profile in NHPs. It may help overcome therapeutic challenges, including tumor heterogeneity and drug resistance, offering a potentially improved ADC option for patients with gastrointestinal cancers. A first-in-human clinical trial for this molecule is expected to commence in the third quarter of 2026.
References
1. Danpanichkul P, et al. Epidemiology of gastrointestinal cancers: a systematic analysis from the Global Burden of Disease Study 2021. Gut. 2024 Dec 10;74(1):26-34.
2. Singh A. Global burden of five major types of gastrointestinal cancer. Prz Gastroenterol. 2024;19(3):236-254.
3. Ntellas P, Chau I. Expanding the potential of antibody-drug conjugates in gastrointestinal malignancies: beyond HER2 targets. ESMO Gastrointest Oncol. 2025;8:100154.
4. Ge J, et al. A clinicopathological study on the expression of cadherin-17 and caudal-related homeobox transcription factor (CDX2) in human gastric carcinoma. Clin Oncol (R Coll Radiol). 2008 May;20(4):275-83.
5. Ito R, et al. Clinicopathological significant and prognostic influence of cadherin-17 expression in gastric cancer. Virchows Arch. 2005 Oct;447(4):717-22.
