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SYD985, a novel duocarmycin-based HER2-targeting antibody-drug conjugate, shows promising antitumor activity in epithelial ovarian carcinoma with HER2/Neu expression.
- Source :
-
Gynecologic oncology [Gynecol Oncol] 2017 Jul; Vol. 146 (1), pp. 179-186. Date of Electronic Publication: 2017 May 01. - Publication Year :
- 2017
-
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.<br />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.<br />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.<br />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.<br /> (Copyright © 2017 Elsevier Inc. All rights reserved.)
- Subjects :
- Ado-Trastuzumab Emtansine
Adult
Aged
Animals
Antibodies, Monoclonal, Humanized pharmacology
Antibody-Dependent Cell Cytotoxicity
Antineoplastic Agents, Alkylating administration & dosage
Bystander Effect immunology
Carcinoma, Ovarian Epithelial
Cell Line, Tumor
Duocarmycins
Female
Humans
Immunotoxins immunology
Maytansine analogs & derivatives
Maytansine pharmacology
Mice
Mice, SCID
Middle Aged
Neoplasms, Glandular and Epithelial enzymology
Neoplasms, Glandular and Epithelial immunology
Ovarian Neoplasms enzymology
Ovarian Neoplasms immunology
Pyrrolidinones administration & dosage
Random Allocation
Receptor, ErbB-2 biosynthesis
Receptor, ErbB-2 genetics
Trastuzumab
Xenograft Model Antitumor Assays
Immunotoxins pharmacology
Indoles administration & dosage
Neoplasms, Glandular and Epithelial drug therapy
Ovarian Neoplasms drug therapy
Receptor, ErbB-2 immunology
Subjects
Details
- Language :
- English
- ISSN :
- 1095-6859
- Volume :
- 146
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- Gynecologic oncology
- Publication Type :
- Academic Journal
- Accession number :
- 28473206
- Full Text :
- https://doi.org/10.1016/j.ygyno.2017.04.023