Trastuzumab-Doxorubicin Conjugate Provides Enhanced Anti-Cancer Potency and Reduced Cardiotoxicity — Oak Academic Publishing
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Trastuzumab-Doxorubicin Conjugate Provides Enhanced Anti-Cancer Potency and Reduced Cardiotoxicity
Texas Therapeutics Institute, Brown Foundation Institute of Molecular Medicine, the University of Texas Health Science Center at Houston, Houston, USA
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Division of Cardiovascular Medicine, Department of Internal Medicine, University of Texas Health Science Center, Houston, USA
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Texas Therapeutics Institute, Brown Foundation Institute of Molecular Medicine, the University of Texas Health Science Center at Houston, Houston, USA
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Texas Therapeutics Institute, Brown Foundation Institute of Molecular Medicine, the University of Texas Health Science Center at Houston, Houston, USA
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Division of Cardiovascular Medicine, Department of Internal Medicine, University of Texas Health Science Center, Houston, USA.
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Texas Therapeutics Institute, Brown Foundation Institute of Molecular Medicine, the University of Texas Health Science Center at Houston, Houston, USA
1 Texas Therapeutics Institute, Brown Foundation Institute of Molecular Medicine, the University of Texas Health Science Center at Houston, Houston, USA
2 Division of Cardiovascular Medicine, Department of Internal Medicine, University of Texas Health Science Center, Houston, USA
3 Texas Therapeutics Institute, Brown Foundation Institute of Molecular Medicine, the University of Texas Health Science Center at Houston, Houston, USA
4 Texas Therapeutics Institute, Brown Foundation Institute of Molecular Medicine, the University of Texas Health Science Center at Houston, Houston, USA
5 Division of Cardiovascular Medicine, Department of Internal Medicine, University of Texas Health Science Center, Houston, USA.
6 Texas Therapeutics Institute, Brown Foundation Institute of Molecular Medicine, the University of Texas Health Science Center at Houston, Houston, USA
Since trastuzumab monotherapy for treatment of breast cancer with HER2/ErbB2 over-expression has been shown to have limited efficacy, combined treatment of trastuzumab with chemotherapy is widely practiced in clinic. However, certain combination treatments of trastuzumab and chemotherapy ( i.e . doxorubicin) are not recommended due to high risk of cardiotoxicity. Antibody-drug conjugates (ADCs) offer selective delivery of cytotoxic agents into targeted cancer cells, thereby allowing for reduced general cellular cytotoxicity caused by chemotherapeutic agents through antibody mediated specific recognition of tumor antigens. In this study, we constructed a trastuzumab-doxorubicin conjugate (T-Dox) using a thioether linkage and characterized both biophysical stability and anti-cancer potency of the T-Dox using a panel of HER2 expressing cancer cell lines. The T-Dox conjugate showed significantly improved anti-cancer potency in comparison with trastuzumab. The results demonstrated for the first time that there were significant differences in the uptake of T-Dox among high HER2 expression cancer cells and higher T-Dox uptake also showed stronger anti-cancer potency. Similar to trastuzumab, T-Dox selectively bound to HER2 overexpressing cancer cells and low HER2 expression cells had no detectable uptake of T-Dox. Consistent to the uptake data, human cardiomyocyte cells had no detectable HER2 expression and T-Dox showed minimal cytotoxic effects. On the contrary, a treatment with combination of trastuzumab and doxorubicin showed severe cytotoxicity to human cardiomyocytes (>90% cell death after 3 day exposure). This study demonstrated that trastuzumab conjugated with doxorubicin (T-Dox) can provide valuable alternative to the combination treatment with doxorubicin and trastuzumab for high HER2 expressing cancer patients.
KeywordsAntibody Drug ConjugateADCTrastuzumabDoxorubicinCardiotoxicityHER2/ErbB2 Internalization
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