SYD985, a novel duocarmycin-based HER2-targeting antibody-drug conjugate, shows promising antitumor activity in epithelial ovarian carcinoma with HER2/Neu expression

Gulden Menderes, Elena Bonazzoli, Stefania Bellone, Jonathan Black, Gary Altwerger, Alice Masserdotti, Francesca Pettinella, Luca Zammataro, Natalia Buza, Pei Hui, Serena Wong, Babak Litkouhi, Elena Ratner, Dan Arin Silasi, Gloria S. Huang, Masoud Azodi, Peter E. Schwartz, Alessandro D. Santin

Research output: Contribution to journalArticle

9 Citations (Scopus)

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 languageEnglish (US)
JournalGynecologic Oncology
DOIs
StateAccepted/In press - Feb 20 2017
Externally publishedYes

Fingerprint

Drug Delivery Systems
Carcinoma
Antibodies
Heterografts
Ovarian epithelial cancer
Lymphocytes
Cell Line
Ovarian Neoplasms
Neoplasms
Cell Proliferation

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 journalArticle

Menderes, G, Bonazzoli, E, Bellone, S, Black, J, Altwerger, G, Masserdotti, A, Pettinella, F, Zammataro, L, Buza, N, Hui, P, Wong, S, Litkouhi, B, Ratner, E, Silasi, DA, Huang, GS, Azodi, M, Schwartz, PE & Santin, AD 2017, 'SYD985, a novel duocarmycin-based HER2-targeting antibody-drug conjugate, shows promising antitumor activity in epithelial ovarian carcinoma with HER2/Neu expression', Gynecologic Oncology. https://doi.org/10.1016/j.ygyno.2017.04.023
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. / SYD985, a novel duocarmycin-based HER2-targeting antibody-drug conjugate, shows promising antitumor activity in epithelial ovarian carcinoma with HER2/Neu expression. In: Gynecologic Oncology. 2017.
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title = "SYD985, a novel duocarmycin-based HER2-targeting antibody-drug conjugate, shows promising antitumor activity in epithelial ovarian carcinoma with HER2/Neu expression",
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.",
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author = "Gulden Menderes and Elena Bonazzoli and Stefania Bellone and Jonathan Black and Gary Altwerger and Alice Masserdotti and Francesca Pettinella and Luca Zammataro and Natalia Buza and Pei Hui and Serena Wong and Babak Litkouhi and Elena Ratner and Silasi, {Dan Arin} and Huang, {Gloria S.} and Masoud Azodi and Schwartz, {Peter E.} and Santin, {Alessandro D.}",
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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

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U2 - 10.1016/j.ygyno.2017.04.023

DO - 10.1016/j.ygyno.2017.04.023

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JO - Gynecologic Oncology

JF - Gynecologic Oncology

SN - 0090-8258

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