TY - JOUR
T1 - SYD985, a novel duocarmycin-based HER2-targeting antibody-drug conjugate, shows promising antitumor activity in epithelial ovarian carcinoma with HER2/Neu expression
AU - Menderes, Gulden
AU - Bonazzoli, Elena
AU - Bellone, Stefania
AU - Black, Jonathan
AU - Altwerger, Gary
AU - Masserdotti, Alice
AU - Pettinella, Francesca
AU - Zammataro, Luca
AU - Buza, Natalia
AU - Hui, Pei
AU - Wong, Serena
AU - Litkouhi, Babak
AU - Ratner, Elena
AU - Silasi, Dan Arin
AU - Huang, Gloria S.
AU - Azodi, Masoud
AU - Schwartz, Peter E.
AU - Santin, Alessandro D.
N1 - Publisher Copyright:
© 2017 Elsevier Inc.
PY - 2017/7
Y1 - 2017/7
N2 - Background Epithelial ovarian cancer (EOC) is an aggressive and heterogeneous disease. < 10% of EOC demonstrate HER2/neu 3 + receptor over-expression. However, moderate to low (i.e., 2 + and 1 +) HER2/neu expression is reported in up to 50% of EOC. The objective of this study was to compare the anti-tumor activity of SYD985, a novel HER2-targeting antibody-drug conjugate (ADC), to trastuzumab emtansine (T-DM1) in EOC models with differential HER2/neu expression. Methods The cytotoxicity of SYD985 and T-DM1 was evaluated using ten primary EOC cell lines with 0/1 +, 2 +, and 3 + HER2/neu expression in antibody-dependent cellular cytotoxicity (ADCC), proliferation, viability and bystander killing experiments. Finally, the in vivo activity of SYD985 and T-DM1 was also studied in ovarian cancer xenografts. Results SYD985 and T-DM1 induced similar ADCC in the presence of peripheral blood lymphocytes (PBL) against EOC cell lines with differential HER2/neu expression. In contrast, SYD985 was 3 to 42 fold more cytotoxic in the absence of PBL when compared to T-DM1 (p < 0.0001). Unlike T-DM1, SYD985 induced efficient bystander killing of HER2/neu 0/1 + tumor cells when admixed with HER2/neu 3 + EOC cells. In vivo studies confirmed that SYD985 is significantly more active than T-DM1 against HER2/neu 3 + EOC xenografts. Conclusions SYD985 is a novel ADC with remarkable activity against EOC with strong (3 +) as well as moderate to low (i.e., 2 + and 1 +) HER2/neu expression. SYD985 is more potent than T-DM1 in comparative experiments and unlike T-DM1, it is active against EOC demonstrating moderate/low or heterogeneous HER2/neu expression.
AB - Background Epithelial ovarian cancer (EOC) is an aggressive and heterogeneous disease. < 10% of EOC demonstrate HER2/neu 3 + receptor over-expression. However, moderate to low (i.e., 2 + and 1 +) HER2/neu expression is reported in up to 50% of EOC. The objective of this study was to compare the anti-tumor activity of SYD985, a novel HER2-targeting antibody-drug conjugate (ADC), to trastuzumab emtansine (T-DM1) in EOC models with differential HER2/neu expression. Methods The cytotoxicity of SYD985 and T-DM1 was evaluated using ten primary EOC cell lines with 0/1 +, 2 +, and 3 + HER2/neu expression in antibody-dependent cellular cytotoxicity (ADCC), proliferation, viability and bystander killing experiments. Finally, the in vivo activity of SYD985 and T-DM1 was also studied in ovarian cancer xenografts. Results SYD985 and T-DM1 induced similar ADCC in the presence of peripheral blood lymphocytes (PBL) against EOC cell lines with differential HER2/neu expression. In contrast, SYD985 was 3 to 42 fold more cytotoxic in the absence of PBL when compared to T-DM1 (p < 0.0001). Unlike T-DM1, SYD985 induced efficient bystander killing of HER2/neu 0/1 + tumor cells when admixed with HER2/neu 3 + EOC cells. In vivo studies confirmed that SYD985 is significantly more active than T-DM1 against HER2/neu 3 + EOC xenografts. Conclusions SYD985 is a novel ADC with remarkable activity against EOC with strong (3 +) as well as moderate to low (i.e., 2 + and 1 +) HER2/neu expression. SYD985 is more potent than T-DM1 in comparative experiments and unlike T-DM1, it is active against EOC demonstrating moderate/low or heterogeneous HER2/neu expression.
KW - Ado-trastuzumab emtansine
KW - Antibody-drug conjugate
KW - HER2
KW - Ovarian serous carcinoma
KW - SYD985
KW - T-DM1
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U2 - 10.1016/j.ygyno.2017.04.023
DO - 10.1016/j.ygyno.2017.04.023
M3 - Article
AN - SCOPUS:85018438727
SN - 0090-8258
VL - 146
SP - 179
EP - 186
JO - Gynecologic Oncology
JF - Gynecologic Oncology
IS - 1
ER -