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Updated: Dec 5, 2025
Targeted Antibody Blocking by a Dual-Functional Conjugate of Antigenic Peptide and Fc-III Mimetics DCAF
Published on: September 17, 2019
cIRCR201-dPBD, a Novel Pyrrolobenzodiazepine Dimer-Containing Site-Specific Antibody-Drug Conjugate Targeting c-Met
Byeongkwi Min1,2, Jonghwa Jin3, Hyeree Kim1,4
1Department of Health Sciences and Technology, Samsung Advanced Institute for Health Sciences and Technology, Sungkyunkwan University, Seoul 06355, Republic of Korea.
Abstract:
c-Met, as a receptor expressed on the cell membrane, contributes to the growth and metastasis of tumors, as well as angiogenesis, mainly through the hepatocyte growth factor (HGF)/c-Met axis during tumor progression. Although several c-Met inhibitors, including small molecules and monoclonal antibody inhibitors, are currently being investigated, their clinical outcomes have not been promising. Development of an antibody-drug conjugate (ADC) against c-Met could be an attractive therapeutic strategy that would provide superior antitumor efficacy with broad-spectrum c-Met expression levels. In the present study, site-specific drug-conjugate technology was applied to develop an ADC using the human-mouse cross-reactive c-Met antibody and a prodrug pyrrolobenzodiazepine (PBD). The toxin payload was uniformly conjugated to the light-chain C-terminus of the native cIRCR201 antibody (drug-to-antibody ratio = 2), as confirmed using LC-MS. Using a high-throughput screening system, we found that cIRCR201-dPBD exhibited varying sensitivities depending on the expression levels of c-Met, and it induced receptor-mediated endocytosis and toxin-mediated apoptosis in 47 different cancer cell lines. cIRCR201-dPBD also showed significant antitumor activity on the MET-amplified cancer cells using in vivo xenograft models. Therefore, cIRCR201-dPBD could be a promising therapeutic strategy for tumors with c-Met expression.
Insights
A novel antibody-drug conjugate targeting c-Met (HGF/c-Met axis) shows promise for cancer therapy. This c-Met ADC demonstrated significant antitumor activity in preclinical models, offering a potential new treatment strategy.
Area of Science:
- Oncology
- Molecular Biology
- Drug Development
Background:
- The hepatocyte growth factor (HGF)/c-Met signaling pathway is crucial for tumor growth, metastasis, and angiogenesis.
- Existing c-Met inhibitors have shown limited clinical success, necessitating novel therapeutic approaches.
Purpose of the Study:
- To develop and evaluate a novel antibody-drug conjugate (ADC) targeting c-Met for cancer treatment.
- To assess the efficacy of the c-Met ADC, cIRCR201-dPBD, in preclinical cancer models.
Main Methods:
- Site-specific drug conjugation technology was used to create cIRCR201-dPBD, an ADC targeting c-Met.
- The ADC's efficacy was evaluated in 47 cancer cell lines with varying c-Met expression levels and in vivo xenograft models.
Main Results:
- cIRCR201-dPBD demonstrated dose-dependent sensitivity based on c-Met expression levels.
- The ADC induced receptor-mediated endocytosis and toxin-mediated apoptosis in cancer cells.
- Significant antitumor activity was observed in MET-amplified cancer cells in vivo.
Conclusions:
- cIRCR201-dPBD is a promising therapeutic candidate for cancers expressing c-Met.
- The development of c-Met targeted ADCs represents a viable strategy for improving cancer treatment outcomes.
