DHES0815A, a novel antibody-drug conjugate targeting HER2/neu, is highly active against uterine serous carcinomas in vitro and in vivo

Joan Tymon-Rosario, Department of Obstetrics, Gynecology, Reproductive Sciences Yale University School of Medicine, CT 06520, USA.
Elena Bonazzoli, Department of Obstetrics, Gynecology, Reproductive Sciences Yale University School of Medicine, CT 06520, USA.
Stefania Bellone, Department of Obstetrics, Gynecology, Reproductive Sciences Yale University School of Medicine, CT 06520, USA.
Aranzazu Manzano, Department of Obstetrics, Gynecology, Reproductive Sciences Yale University School of Medicine, CT 06520, USA.
Silvia Pelligra, Department of Obstetrics, Gynecology, Reproductive Sciences Yale University School of Medicine, CT 06520, USA; Gynecologic Oncology Unit, Women Wealth Area, Department of Woman and Child Health and Public Health, Fondazione Policlinico Universitario "Agostino Gemelli" IRCCS, Rome, Italy.
Adele Guglielmi, Department of Obstetrics, Gynecology, Reproductive Sciences Yale University School of Medicine, CT 06520, USA.
Barbara Gnutti, Department of Obstetrics, Gynecology, Reproductive Sciences Yale University School of Medicine, CT 06520, USA.
Nupur Nagarkatti, Department of Obstetrics, Gynecology, Reproductive Sciences Yale University School of Medicine, CT 06520, USA.
Burak Zeybek, Department of Obstetrics, Gynecology, Reproductive Sciences Yale University School of Medicine, CT 06520, USA.
Paola Manara, Department of Obstetrics, Gynecology, Reproductive Sciences Yale University School of Medicine, CT 06520, USA.
Luca Zammataro, Department of Obstetrics, Gynecology, Reproductive Sciences Yale University School of Medicine, CT 06520, USA.
Justin Harold, Department of Obstetrics, Gynecology, Reproductive Sciences Yale University School of Medicine, CT 06520, USA.
Dennis Mauricio, Department of Obstetrics, Gynecology, Reproductive Sciences Yale University School of Medicine, CT 06520, USA.
Natalia Buza, Department of Pathology, Yale University School of Medicine, CT 06520, USA.
Pei Hui, Department of Pathology, Yale University School of Medicine, CT 06520, USA.
Gary Altwerger, Department of Obstetrics, Gynecology, Reproductive Sciences Yale University School of Medicine, CT 06520, USA.
Gulden Menderes, Department of Obstetrics, Gynecology, Reproductive Sciences Yale University School of Medicine, CT 06520, USA.
Elena Ratner, Department of Obstetrics, Gynecology, Reproductive Sciences Yale University School of Medicine, CT 06520, USA.
Mitchell Clark, Department of Obstetrics, Gynecology, Reproductive Sciences Yale University School of Medicine, CT 06520, USA.
Vaagn Andikyan, Department of Obstetrics, Gynecology, Reproductive Sciences Yale University School of Medicine, CT 06520, USA.
Gloria S. Huang, Department of Obstetrics, Gynecology, Reproductive Sciences Yale University School of Medicine, CT 06520, USA.
Dan-Arin Silasi, Gynecologic Oncology, Obstetrics and Gynecology, Mercy Hospital St. Louis, MO 63141, USA.
Masoud Azodi, Department of Obstetrics, Gynecology, Reproductive Sciences Yale University School of Medicine, CT 06520, USA.Follow
Peter E. Schwartz, Department of Obstetrics, Gynecology, Reproductive Sciences Yale University School of Medicine, CT 06520, USA.
Alessandro D. Santin, Department of Obstetrics, Gynecology, Reproductive Sciences Yale University School of Medicine, CT 06520, USA. Electronic address: alessandro.santin@yale.edu.

Document Type

Article

Publication Title

Gynecologic oncology

Abstract

OBJECTIVE: Uterine serous carcinoma (USC) is an aggressive histologic variant of endometrial cancer which portends a poor prognosis. DHES0815A is a novel antibody-drug-conjugate (ADC) which binds specifically to HER2 overexpressing tumors at a distinct epitope from that bound by trastuzumab and pertuzumab after which it delivers the toxic payload, PBD-MA, a DNA mono-alkylating agent. The objective of this study was to evaluate the preclinical activity of DHES0815A against primary USC cell lines and xenografts. METHODS: Twelve primary USC cell lines were assessed by immunohistochemistry (IHC) for HER2 protein expression and for C-erbB2 gene amplification using fluorescent in situ hybridization (FISH) analysis. Cell viability and bystander killing in USC cell lines after exposure to DHES0815A, the non-targeted ADC, and the unconjugated antibody (i.e. MHES0488A) were evaluated using flow cytometry-based-assays. In vivo activity of DHES0815A was tested against HER2/neu overexpressing USC xenografts. RESULTS: High HER2/neu protein expression was seen in 25% (3/12) of the primary USC cell lines. USC cell lines overexpressing HER2/neu were significantly more sensitive to DHES0815A when compared to the non-targeted control ADC (p < 0.001). DHES0815A did not induce significant bystander killing of HER2/neu negative tumors when admixed with HER2/neu positive tumors. DHES0815A caused growth-inhibition and increased survival in USC HER2/neu overexpressing xenografts when compared to controls (p < 0.01). CONCLUSIONS: DHES0815A is both highly selective and toxic to USC tumors overexpressing HER2/neu both in vitro and in vivo. HER2-directed ADCs, alone or in combination with other HER2/neu targeted agents may represent a novel treatment option for patients with tumors harboring HER2/neu overexpression refractory to trastuzumab and traditional chemotherapy.

First Page

334

Last Page

341

DOI

10.1016/j.ygyno.2021.08.014

Publication Date

11-1-2021

Identifier

34452746 (pubmed); NIHMS1735666 (mid); PMC8722447 (pmc); 10.1016/j.ygyno.2021.08.014 (doi); S0090-8258(21)01313-5 (pii)

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