TY - JOUR
T1 - [64Cu]Cu-NOTA-Trastuzumab and [89Zr]Zr-DFO-Trastuzumab in Xenografts with Varied HER2 Expression
AU - Simó, Cristina
AU - Shmuel, Shayla
AU - Vanover, Alex
AU - Pereira, Patrícia M.R.
N1 - Publisher Copyright:
© 2024 The Authors. Published by American Chemical Society.
PY - 2024/12/2
Y1 - 2024/12/2
N2 - Positron emission tomography (PET) has potential as a complementary technique to biomarker analysis, especially for human epidermal growth factor receptor 2 (HER2)-expressing tumors characterized by high heterogeneity. In this study, zirconium-89 (89Zr) and copper-64 (64Cu) labeled trastuzumab were employed to monitor varying levels of tumoral HER2 expression. Additionally, we studied the use of the cholesterol-depleting lovastatin as a pharmacological approach to enhance cell-surface HER2 expression in tumors with moderate to low HER2 levels, aiming to increase antibody accumulation in these tumor types. Both 89Zr- and 64Cu-labeled trastuzumab effectively monitor HER2 expression levels in xenografts exhibiting varying HER2 expression. No significant difference in tumor uptake was observed between 89Zr- or 64Cu-labeled trastuzumab, and tumor uptake for both radioimmunoconjugates positively correlated with HER2 protein levels. These findings underscore the potential of PET to monitor HER2 protein levels across heterogeneous tumors. Furthermore, our results suggest that further optimization of statin dosing and timing could offer a promising strategy to enhance trastuzumab accumulation in HER2-high, HER2-moderate, and HER2-low tumors.
AB - Positron emission tomography (PET) has potential as a complementary technique to biomarker analysis, especially for human epidermal growth factor receptor 2 (HER2)-expressing tumors characterized by high heterogeneity. In this study, zirconium-89 (89Zr) and copper-64 (64Cu) labeled trastuzumab were employed to monitor varying levels of tumoral HER2 expression. Additionally, we studied the use of the cholesterol-depleting lovastatin as a pharmacological approach to enhance cell-surface HER2 expression in tumors with moderate to low HER2 levels, aiming to increase antibody accumulation in these tumor types. Both 89Zr- and 64Cu-labeled trastuzumab effectively monitor HER2 expression levels in xenografts exhibiting varying HER2 expression. No significant difference in tumor uptake was observed between 89Zr- or 64Cu-labeled trastuzumab, and tumor uptake for both radioimmunoconjugates positively correlated with HER2 protein levels. These findings underscore the potential of PET to monitor HER2 protein levels across heterogeneous tumors. Furthermore, our results suggest that further optimization of statin dosing and timing could offer a promising strategy to enhance trastuzumab accumulation in HER2-high, HER2-moderate, and HER2-low tumors.
KW - Cu-labeled trastuzumab
KW - Zr-labeled trastuzumab
KW - HER2
KW - Immuno-PET
KW - statin
UR - http://www.scopus.com/inward/record.url?scp=85208249947&partnerID=8YFLogxK
U2 - 10.1021/acs.molpharmaceut.4c00777
DO - 10.1021/acs.molpharmaceut.4c00777
M3 - Article
C2 - 39471823
AN - SCOPUS:85208249947
SN - 1543-8384
VL - 21
SP - 6311
EP - 6322
JO - Molecular Pharmaceutics
JF - Molecular Pharmaceutics
IS - 12
ER -