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.

Trial registration: ClinicalTrials.gov NCT02277717.

Keywords: Ado-trastuzumab emtansine; Antibody-drug conjugate; HER2; Ovarian serous carcinoma; SYD985; T-DM1.

Conflict of interest statement

Conflict Of Interest Statement: The authors declare no conflict of interest or previous publication. All of the authors fulfill the conditions required for authorship.

Copyright © 2017 Elsevier Inc. All rights reserved.

Figures

Figure 1

HER2/neu expression in representative EOC cell lines by flow cytometry: A) HER2 3+ cell line. B) HER2 2+ cell line. C) HER2 1+/0 cell line.

Figure 2

ADCC results (mean ± SD) of SYD985, T-DM1, Trastuzumab and ADC isotype control in a representative HER2 3+ expressing cell line (KRCH31, panel A), a representative 2+ HER2 expressing cell line [OVA5, panel B] and a representative 1+/0 HER2 expressing cell line (OVA3, panel C).

Figure 3

IC50 dose response curves of SYD985, T-DM1 and ADC isotype control in all EOC cell lines tested in vitro (i.e., HER2 3+ cell lines, p = <0.0001, HER2 2+ cell lines, p = <0.0001 and HER2 1+ cell lines, p = <0.0001) at 3 days.

Figure 4

A) Cytotoxicity induced on HER2 3+ EOC cells (KRCH31), HER2 1+/0 USC cells (ARK-4), and KRCH31/ARK-4 co-cultures with 1μg/ml of SYD985. A significant increase of killing of HER2 1+/0 USC cells was detected when compared to control (p= 0.001) after treatment with SYD985. B) Cytotoxicity induced on HER2 3+ EOC cells (KRCH31), HER2 1+/0 USC cells (ARK-4), and KRCH31/ARK-4 co-cultures with 1μg/ml of SYD995 (T-DM1). No significant increase of killing of HER2 1+/0 USC cells was detected when compared to control (p= 0.29) after treatment with T-DM1. C) Cytotoxicity induced on HER2 3+ EOC cells (KRCH31), HER2 1+/0 USC cells (ARK-4), and KRCH31 /ARK-4 co-cultures with 1μg/ml of SYD989 (isotype control ADC). No significant increase of killing of HER2 1+/0 USC cells was detected when compared to control (p= 0.51) after treatment with isotype control ADC.

Figure 5

Antitumor activity of SYD985 compared to T-DM1 and ADC isotype control in EOC xenograft tumor models with OVA10 (HER2/neu 3+). Mice were treated with a single dose administered intravenously as described in Methods. A significant difference in tumor growth inhibition was detected in SYD985-treated groups at the dose of 3mg/kg and 10 mg/kg when compared to the other treatment groups.

Figure 6

Overall survival in mice inoculated with EOC xenografts with OVA10 (HER2/neu 3+) after treatment with vehicle, single injection SYD985 (3mg/kg and 10mg/kg), and single injection T-DM1 (10mg/kg) and ADC isotype control. Significantly prolonged overall survival with SYD985 10 mg/kg treated group was detected when compared to the other treatment groups.