In vitro and in vivo activity of sacituzumab govitecan, an antibody-drug conjugate targeting trophoblast cell-surface antigen 2 (Trop-2) in uterine serous carcinoma.

Animals Antibodies, Monoclonal, Humanized / immunology Antibody-Dependent Cell Cytotoxicity Antigens, Neoplasm / biosynthesis Camptothecin / analogs & derivatives Cell Adhesion Molecules / biosynthesis Cell Line, Tumor Cystadenocarcinoma, Serous Female Flow Cytometry Humans Immunoconjugates / immunology Immunohistochemistry Mice Mice, SCID Molecular Targeted Therapy Random Allocation Tissue Array Analysis Uterine Neoplasms / drug therapy Xenograft Model Antitumor Assays

IMMU-132 Sacituzumab govitecan Uterine cancer Uterine serous carcinoma antibody drug conjugate (ADC)

Journal

Gynecologic oncology

ISSN: 1095-6859

Titre abrégé: Gynecol Oncol

Pays: United States

ID NLM: 0365304

Informations de publication

Date de publication:
02 2020

Historique:

received: 19 08 2019

revised: 02 11 2019

accepted: 10 11 2019

pubmed: 17 12 2019

medline: 6 5 2020

entrez: 17 12 2019

Statut: ppublish

Résumé

Uterine serous carcinoma (USC) is an aggressive variant of endometrial cancer with poor prognosis. Sacituzumab govitecan (SG) is a novel antibody-drug-conjugate (ADC) targeting trophoblast cell-surface antigen 2 (Trop-2), a transmembrane-calcium-signal-transducer, to deliver SN-38, the active metabolite of irinotecan. The objective of this study was to evaluate the expression of Trop-2 in USC and the preclinical activity of SG against primary USC cell-lines and xenografts. We used immunohistochemistry (IHC) and flow-cytometry-based assays to evaluate Trop-2 expression and cell-viability in USC tissue and primary tumor-cell-lines after exposure to SG, non-targeting control ADC, and naked antibody hRS7-IgG. Antibody-dependent-cell-cytotoxicity (ADCC) against Trop-2+ and Trop-2- USC cell-lines was evaluated in vitro using 4-hr-Chromium-release-assays. In vivo activity of SG was tested against Trop-2+ USC xenografts by intravenous administration of SG, control ADC, and hRS7. Trop-2 expression by IHC was detected in 95.1% of USC samples (99/104). Primary tumor cell-lines overexpressing Trop-2 were significantly more sensitive to SG when compared to control ADC (p <0.05). Both SG and hRS7 mediated ADCC in Trop2+ USC cell-lines while no cytotoxicity was detected against Trop-2- cells. SG induced significant bystander killing of Trop-2- tumors when admixed with Trop-2+ tumors. SG caused growth-inhibition and increased survival in SG treated mice harboring Trop-2+ xenografts when compared to controls (p <0.05). SG is remarkably active against USC overexpressing Trop-2 in vitro and in vivo. Our results combined with SG clinical responses recently reported against multiple chemotherapy resistant human tumors further support clinical development of SG in USC patients with advanced/recurrent disease.

Identifiants

DOI: 10.1016/j.ygyno.2019.11.018 PMID: 31839338

pubmed: 31839338

pii: S0090-8258(19)31669-5

doi: 10.1016/j.ygyno.2019.11.018

pii:

doi:

Substances chimiques

Antibodies, Monoclonal, Humanized 0

Antigens, Neoplasm 0

Cell Adhesion Molecules 0

Immunoconjugates 0

TACSTD2 protein, human 0

sacituzumab govitecan M9BYU8XDQ6

Camptothecin XT3Z54Z28A

Types de publication

Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

Pagination

430-438

Subventions

Organisme : NCI NIH HHS

ID : U01 CA176067

Pays : United States