Antibody-drug conjugates in colorectal cancer: advances, challenges, and prospectives
Lili Zeng1, Yuanlin Zhu2, Ke Zhang2
1Guizhou University Medical College, Guiyang 550025, Guizhou Province, China; NHC Key Laboratory of Pulmonary Immunological Diseases, Guizhou Provincial People's Hospital, Guiyang 550002, Guizhou Province, China; Key Laboratory for Cancer Prevention and Treatment of Guizhou Province, Guiyang 550002, Guizhou Province, China.
Abstract:
Antibody-drug conjugates (ADCs) represent an emerging class of targeted therapeutics with considerable potential in the management of colorectal cancer (CRC). By delivering highly potent cytotoxic agents to cancer cells via specific antibodies, ADCs enable precise tumor targeting while minimizing off-target toxicity. Recent advancements have identified several promising targets for ADC development in CRC, including human epidermal growth factor receptor 2 (HER2), carcinoembryonic antigen-related cell adhesion molecule 5 (CEACAM5), mesenchymal-epithelial transition factor (c-MET), epidermal growth factor receptor (EGFR), cadherin-17 (CDH17), and trophoblast cell surface antigen 2 (Trop-2). Clinical trials have demonstrated encouraging objective response rates and survival benefits with ADCs such as trastuzumab deruxtecan (T-DXd) and disitamab vedotin in patients with advanced CRC. Nonetheless, the clinical application of ADCs faces several challenges, including tumor heterogeneity leading to variable target expression, the emergence of diverse resistance mechanisms that limit long-term efficacy, and manageable but significant safety concerns. Future research should prioritize tumor-selective linker design, novel payload development, bispecific and dual-payload ADC platforms, and rational combination strategies to overcome resistance and further improve the therapeutic index of ADCs in CRC.
Insights
Antibody-drug conjugates (ADCs) show promise for colorectal cancer (CRC) treatment by targeting tumors precisely. Challenges like resistance and toxicity require further research for improved ADC therapies in CRC management.
Area of Science:
- Oncology
- Pharmacology
- Biotechnology
Background:
- Antibody-drug conjugates (ADCs) are emerging targeted therapies for colorectal cancer (CRC).
- ADCs deliver potent cytotoxic agents to cancer cells, enhancing tumor targeting and reducing off-target toxicity.
- Several targets are being explored for ADC development in CRC, including HER2, CEACAM5, c-MET, EGFR, CDH17, and Trop-2.
Purpose of the Study:
- To review the potential of ADCs in colorectal cancer management.
- To discuss promising ADC targets and clinical trial outcomes.
- To identify challenges and future research directions for ADCs in CRC.
Main Methods:
- Review of recent advancements in ADC technology for CRC.
- Analysis of clinical trial data for ADCs in advanced CRC.
- Identification of targets, resistance mechanisms, and safety concerns associated with ADCs.
Main Results:
- ADCs like trastuzumab deruxtecan (T-DXd) and disitamab vedotin show encouraging response rates and survival benefits in advanced CRC.
- Promising ADC targets identified include HER2, CEACAM5, c-MET, EGFR, CDH17, and Trop-2.
- Challenges include tumor heterogeneity, resistance mechanisms, and safety concerns.
Conclusions:
- ADCs hold significant potential for colorectal cancer treatment.
- Overcoming resistance and managing safety are crucial for clinical success.
- Future research should focus on novel ADC designs, payloads, and combination strategies to enhance efficacy and therapeutic index.
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