Antibody-Drug Conjugates for Breast Cancer Treatment: Emerging Agents, Targets and Future Directions
Abstract
:1. Introduction
2. Structure and Evolution of ADCs
2.1. The Structure of ADCs
2.2. First-Generation ADCs
2.3. Second-Generation ADCs
2.4. Third-Generation ADCs
3. ADCs Targeting HER2 in Breast Cancer
3.1. T-DM1
3.2. T-DXd
3.3. Other ADCs Targeting HER2
4. Emerging Targets of ADCs in Breast Cancer
4.1. Trop2
4.2. PTK7
4.3. ROR1 and ROR2
4.4. B7-H3
4.5. gpNMB
4.6. FRα
4.7. HER3
4.8. CA6
5. Challenges and Future Directions in ADCs
5.1. Challenges in ADCs
5.2. Future Directions
6. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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ADCs | Antibodies | Payloads | Representative Trials | Phase | Approval |
---|---|---|---|---|---|
T-DM1 | Trastuzumab | DM1 | EMILIA (NCT00829166) | III | Yes |
KATHERINE (NCT01772472) | III | ||||
ATEMPT (NCT01853748) | II | ||||
KATE2 (NCT02924883) | II | ||||
KATE3 (NCT04740918) | III | ||||
Astefania (NCT04873362) | III | ||||
T-DXd | Trastuzumab | DXd | DESTINY breast-03 (NCT03529110) | III | Yes |
DESTINY breast-09 (NCT04784715) | III | ||||
NCT02564900 | I | ||||
DESTINY breast-04 (NCT03734029) | III | ||||
DESTINY breast-07 (NCT04538742) | I/II | ||||
DESTINY breast-08 (NCT04556773) | Ib | ||||
RC48 | Hertuzumab | MMAE | NCT02881190 | I | Yes |
NCT03052634 | Ib | ||||
SYD985 | Trastuzumab | Duocarmycin | TULIP (NCT03262935) | III | Not yet |
A166 | Trastuzumab | Duostain-5 | NCT03602079 | I | Not yet |
ARX788 | anti-HER2 monoclonal antibody with the modified heavy chain Ala114 | Amberstatin | NCT03255070 | I | Not yet |
Targets | ADCs | Antibodies | Payloads | Representative Trials | Phase | Approval |
---|---|---|---|---|---|---|
Trop2 | SG | Sactizumab | SN-38 | ASCENT(NCT02574455) | III | Yes |
TROPiCS-02 (NCT03901339) | III | |||||
Trop2 | Dato-DXd | Datopotamab | DXd | TROPION-PanTumor01 (NCT03401385) | I | Not yet |
TROPION Breast01 (NCT05104866) | III | |||||
TROPION Breast02 (NCT05374512) | III | |||||
Trop2 | SKB264 | Anti-Trop2 | Topoisomerase I inhibitor | NCT05347134 | III | Not yet |
NCT05445908 | II | |||||
NCT04152499 | I/II | |||||
PTK7 | Cofetuzumab pelidotin | Cofetuzumab | Au0101 | NCT02222922 | I | Not yet |
ROR1 | NBE-002 | Anti-ROR1 | PNU-159682 | NCT04441099 | I/II | Not yet |
ROR2 | CAB-ROR2-ADC | Anti-ROR2 | Undisclosed | NCT03504488 | I | Not yet |
B7-H3 | MCG018 | Anti-B7-H3 | Duocarmycin | NCT03729596 | I | Not yet |
gpNMB | CDX-011 | Glembatumumab | MMAE | EMERGE (NCT01156753) | II | Not yet |
NCT00704158 | I/II | |||||
METRIC (NCT01997333) | II | |||||
FRα | MORAB-202 | Anti-FRα | Eribulin | NCT04300556 | I/II | Not yet |
HER3 | HER3-DXd | Patritumab | DXd | NCT02980341 | I/II | Not yet |
NCT04610528 | I | |||||
CA6 | SAR566658 | DS6 | DM4 | NCT02984683 | II | Not yet |
Adverse Events | Frequency in T-DM1 [79] | Frequency in T-DXd [38] | Frequency in SG [52,80] |
---|---|---|---|
Thrombocytopenia | 14.3% | 4.3% | 14% |
Neutropenia | 2.4% | 20% | 26% |
Anemia | 3.8% | 8.6% | 11% |
Fatigue | 2.4% | 6% | 9% |
ILD | - | 15.5% (Grade 3:1%) | - |
Drop of LVEF (left ventricular ejection fraction) | 2% (Grade 3: 0.7%) | 1.6% (Grade 0.5%) | - |
Increase in ALT | 15% | - | - |
Nausea | - | 7.6% | 6% |
Vomit | - | 4.3% | 6% |
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Yang, T.; Li, W.; Huang, T.; Zhou, J. Antibody-Drug Conjugates for Breast Cancer Treatment: Emerging Agents, Targets and Future Directions. Int. J. Mol. Sci. 2023, 24, 11903. https://doi.org/10.3390/ijms241511903
Yang T, Li W, Huang T, Zhou J. Antibody-Drug Conjugates for Breast Cancer Treatment: Emerging Agents, Targets and Future Directions. International Journal of Molecular Sciences. 2023; 24(15):11903. https://doi.org/10.3390/ijms241511903
Chicago/Turabian StyleYang, Tinglin, Wenhui Li, Tao Huang, and Jun Zhou. 2023. "Antibody-Drug Conjugates for Breast Cancer Treatment: Emerging Agents, Targets and Future Directions" International Journal of Molecular Sciences 24, no. 15: 11903. https://doi.org/10.3390/ijms241511903