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Published on: May 4, 2017
Identification of CD66c as a potential target in gastroesophageal junction cancer for antibody-drug conjugate
Peng Zhang1,2,3,4, Changjuan Tao5, Hanfei Xie6
1Department of Gastric Surgery, Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, China.
Background:
Gastroesophageal junction (GEJ) cancer exhibits unique biological characteristics and currently lacks specific targeted therapies. Given the clinical efficacy of antibody-drug conjugates (ADCs) in solid tumor treatment, we aimed to identify a novel ADC target and suitable payload for GEJ-targeted therapy.
Methods:
In this study, we conducted bioinformatic analyses of multi-omics data, including transcriptomics, proteomics, and phosphoproteomics, to identify CD66c as a promising ADC target for GEJ cancer. We then engineered a CD66c-directed antibody-drug conjugate (CD66c-DXd) incorporating a GGFG linker. The preclinical efficacy of CD66c-DXd was determined in multi GEJ xenograft models.
Results:
Proteomic analyses of 103 cases of GEJ cancer revealed that CD66c expression was significantly higher in tumoral tissues compared to normal tissues. Proteomic and phosphoproteomic analyses identified deruxtecan (DXd) as a potentially potent payload for ADCs targeting GEJ cancer. Furthermore, high CD66c expression in GEJ was associated with a significantly lower proportion of plasma cells. The drug-to-antibody ratio (DAR) of CD66c-DXd was determined to be 3.6. CD66c-DXd effectively and selectively ablated multiple human GEJ cell lines (OE-19, OE33 and SK-GT-4) without affecting non-malignant cells (GES-1) in vitro. Eventually, CD66c-DXd mediated potent and durable tumor regression in vivo with excellent safety profiles.
Conclusions:
This preclinical study provides a strong rationale for the further development of CD66c-DXd as promising therapeutic candidates to treat advanced GEJ cancer. Additionally, the study demonstrates the robustness of the multi-omics data in identifying novel potential ADC targets and payloads.
Insights
Researchers identified CD66c as a novel target for gastroesophageal junction (GEJ) cancer therapy. A CD66c-directed antibody-drug conjugate (ADC), CD66c-DXd, showed potent preclinical efficacy and safety in GEJ cancer models.
Area of Science:
- Oncology
- Molecular Biology
- Drug Development
Background:
- Gastroesophageal junction (GEJ) cancer lacks specific targeted therapies.
- Antibody-drug conjugates (ADCs) show promise in solid tumor treatment.
Purpose of the Study:
- Identify a novel ADC target and payload for GEJ cancer.
- Evaluate the preclinical efficacy of a CD66c-directed ADC.
Main Methods:
- Multi-omics data analysis (transcriptomics, proteomics, phosphoproteomics) to identify CD66c.
- Engineering of a CD66c-directed ADC (CD66c-DXd) with deruxtecan (DXd) payload.
- Preclinical evaluation in GEJ xenograft models.
Main Results:
- CD66c was significantly overexpressed in GEJ tumors compared to normal tissues.
- CD66c-DXd demonstrated selective ablation of GEJ cancer cells in vitro and potent tumor regression in vivo.
- CD66c-DXd exhibited favorable safety profiles in preclinical models.
Conclusions:
- CD66c-DXd is a promising therapeutic candidate for advanced GEJ cancer.
- Multi-omics data robustly identified novel ADC targets and payloads.
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