Abstract
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.
| Original language | English (US) |
|---|---|
| Journal | Gynecologic Oncology |
| DOIs | |
| State | Accepted/In press - Feb 20 2017 |
| Externally published | Yes |
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Keywords
- Ado-trastuzumab emtansine
- Antibody-drug conjugate
- HER2
- Ovarian serous carcinoma
- SYD985
- T-DM1
ASJC Scopus subject areas
- Oncology
- Obstetrics and Gynecology
Cite this
SYD985, a novel duocarmycin-based HER2-targeting antibody-drug conjugate, shows promising antitumor activity in epithelial ovarian carcinoma with HER2/Neu expression. / Menderes, Gulden; Bonazzoli, Elena; Bellone, Stefania; Black, Jonathan; Altwerger, Gary; Masserdotti, Alice; Pettinella, Francesca; Zammataro, Luca; Buza, Natalia; Hui, Pei; Wong, Serena; Litkouhi, Babak; Ratner, Elena; Silasi, Dan Arin; Huang, Gloria S.; Azodi, Masoud; Schwartz, Peter E.; Santin, Alessandro D.
In: Gynecologic Oncology, 20.02.2017.Research output: Contribution to journal › Article
}
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.
PY - 2017/2/20
Y1 - 2017/2/20
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
UR - http://www.scopus.com/inward/record.url?scp=85018438727&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85018438727&partnerID=8YFLogxK
U2 - 10.1016/j.ygyno.2017.04.023
DO - 10.1016/j.ygyno.2017.04.023
M3 - Article
JO - Gynecologic Oncology
JF - Gynecologic Oncology
SN - 0090-8258
ER -