In the field of gastrointestinal (GI) cancer treatment, target research remains the core direction for breaking through efficacy bottlenecks. CDH17 has emerged as a "rising star" in pharmaceutical R&D due to its unique expression profile in tumor cells, offering new possibilities for the precise treatment of prevalent GI cancers such as gastric and colorectal cancer.
01 An Innate "Tumor-Targeting Biomarker"
The biological characteristics of CDH17 (cadherin-17) naturally make it an ideal target for targeted therapy, primarily due to its stark contrast of being "hidden in normal tissues but exposed in tumor tissues."
In healthy individuals, CDH17 is highly confined to the lateral membrane of intestinal epithelial cells and concealed within tight junctions. This "hidden" distribution prevents access by antibody-based drugs, fundamentally avoiding damage to normal tissues and ensuring treatment safety. In GI cancers, however, CDH17 expression undergoes a dramatic shift: its levels significantly increase, with overexpression observed in 50–90% of gastric, colorectal, and other GI cancers. Moreover, it relocates from the lateral membrane to the surface of cancer cells, becoming fully exposed and accessible to drugs.
This differential expression between normal and tumor tissues is CDH17's key competitive advantage. It enables drugs to act like "precision missiles," selectively recognizing and binding to CDH17 on cancer cells while sparing normal intestinal cells, perfectly aligning with the "high efficacy, low toxicity" principle of targeted therapy.
02 A Key Driver of GI Cancer Progression
CDH17 is not merely a biomarker; it also functions as a "functional driver" in the initiation, progression, and drug resistance of GI cancers, further underscoring the clinical significance of targeting it.
In tumor proliferation and invasion, CDH17 disrupts tissue stability by interfering with intercellular junctions. Normally, CDH17 helps maintain intestinal epithelial integrity via binding to adjacent cells. In cancer cells, however, its aberrant expression weakens cell adhesion, enabling tumor cells to detach from the primary site, invade surrounding tissues, and metastasize.
In angiogenesis, CDH17 indirectly regulates vascular endothelial growth factor (VEGF) expression. By promoting VEGF secretion, it accelerates the formation of tumor blood vessels, supplying oxygen and nutrients to support rapid cancer growth.
Critically, CDH17 is linked to therapy resistance. Clinical studies show that CDH17 expression is often upregulated in GI cancer cells resistant to chemotherapy (e.g., fluorouracil, platinum-based drugs). It reduces drug sensitivity by modulating drug transporter activity or apoptosis-related proteins, leading to treatment failure. Targeting CDH17 may thus reverse resistance, offering new options for refractory patients.
03 CDH17 Drug Development: Notable Progress
With growing recognition of CDH17's potential, numerous companies have advanced drug candidates, several of which show promising results at various stages of development.
Lide Biotech: Their LBL-054-CD3, a bispecific T-cell engager targeting CDH17 and CD3, demonstrates high CDH17 affinity and no cross-reactivity with other cadherins. It exhibits potent tumor-killing activity in CDH17-positive cells, with no toxicity to CDH17-negative cells. Meanwhile, LBL-054-ADC, using a proprietary linker-payload platform, shows high stability, rapid internalization, and optimized drug-antibody ratio (DAR=6), with strong efficacy in preclinical models.
Huadong Medicine: HDM2017, an ADC targeting CDH17 with a topoisomerase I inhibitor (DAR=4), received FDA IND approval in September 2025 for Phase I trials. Preclinical data show robust antitumor effects in colorectal, pancreatic, and gastric cancer models.
Yizheng Biotech: YL217, a CDH17-targeting ADC, has entered Phase I clinical trials, showing potential for GI cancers due to CDH17's high specificity in these tumors.
Mabwell Biotech: 7MW4911, an ADC using site-specific conjugation (DAR=4), exhibits excellent efficacy in GI cancer models, including multidrug-resistant cases, and is currently in preclinical development.
Simcere Pharma: SCR-A008, an ADC with a humanized anti-CDH17 antibody and novel topoisomerase I inhibitor (DAR=8), shows promising results in CDH17-positive solid tumor models.
Lanova Medical: LM-350, developed on a next-generation ADC platform, demonstrates strong tumor suppression in xenograft models, including chemotherapy-resistant colorectal cancer, and has FDA IND clearance.
VelaBio: VBC108, a bispecific ADC targeting CDH17 and CLDN18.2, leverages dual-target synergy to overcome treatment limitations in GI cancers, supported by strong preclinical data.
Bioray Biotech: BR116, an ADC with a humanized antibody and innovative topoisomerase I inhibitor (DAR=4), shows good safety in primates and plans to submit an IND in 2025.
Bio-Thera Solutions: BSI-721, an ADC with a fully human anti-CDH17 antibody and MMAE payload, inhibits tumor growth in high and medium CDH17-expression models, with ongoing IND-enabling studies.
SOTIO Biotech: SOT109, an ADC with a fully human CDH17 antibody and topoisomerase I inhibitor, is expected to submit an IND in Q2 2026, targeting the >90% of GI cancers expressing CDH17.
04 Opportunities and Challenges
Despite rapid progress, clinical translation of CDH17-targeted therapies faces challenges but also holds significant opportunities.
Key challenges include tumor heterogeneity (varying CDH17 expression among patients) requiring companion diagnostics, and off-target toxicity control to minimize impact on normal tissues.
Opportunities arise from the high unmet need in advanced GI cancer, where current therapies offer limited survival benefits. Advances in ADC and bispecific antibody technologies may enhance efficacy-e.g., ADC bystander effects could target CDH17-low cells, while bispecific drugs engage multiple targets.
With improved diagnostics and deeper research, CDH17-targeted therapies are poised to become a vital component in GI cancer treatment, especially for advanced and resistant cases.
05 Conclusion
From basic research to drug development, CDH17 has established a comprehensive R&D pipeline, opening new avenues for GI cancer therapy. While challenges such as tumor heterogeneity and drug specificity remain, current progress is promising.
As technology and research advance, CDH17-targeted drugs are expected to evolve, offering hope for improved survival and quality of life for GI cancer patients, ultimately becoming a cornerstone of oncology treatment.
References:
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3.Kim JS,Park JY,Lee JH,et al.CDH17 as a potential therapeutic target for colorectal cancer:association with tumor progression and chemoresistance[J].International Journal of Oncology,2021,59(2):387-398.
4.Official announcements from Lide Biotech, Huadong Medicine, Yizheng Biotech, etc.
