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 - Funding Information:
This work was supported in part by R01 CA154460-01 and U01 CA176067-01A1 grants from NIH, and grants from the Deborah Bunn Alley Foundation, the Tina Brozman Foundation, the Discovery to Cure Foundation and the Guido Berlucchi Foundation to A.D. Santin. This investigation was also supported by NIH Research Grant CA-16359 from the NCI to A.D. Santin.
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
VL - 146
SP - 179
EP - 186
JO - Gynecologic Oncology
JF - Gynecologic Oncology
SN - 0090-8258
IS - 1
ER -