Preclinical Activity of Sacituzumab Govitecan, an Antibody-Drug Conjugate Targeting Trophoblast Cell-Surface Antigen 2 (Trop-2) Linked to the Active Metabolite of Irinotecan (SN-38), in Ovarian Cancer

Elisabetta Perrone; Salvatore Lopez; Burak Zeybek; Stefania Bellone; Elena Bonazzoli; Silvia Pelligra; Luca Zammataro; Aranzazu Manzano; Paola Manara; Anna Bianchi; Natalia Buza; Joan Tymon-Rosario; Gary Altwerger; Chanhee Han; Gulden Menderes; Elena Ratner; Dan-Arin Silasi; Masoud Azodi; Pei Hui; Peter E. Schwartz; Giovanni Scambia; Alessandro D. Santin

doi:10.3389/fonc.2020.00118

Preclinical Activity of Sacituzumab Govitecan, an Antibody-Drug Conjugate Targeting Trophoblast Cell-Surface Antigen 2 (Trop-2) Linked to the Active Metabolite of Irinotecan (SN-38), in Ovarian Cancer

Elisabetta Perrone, Salvatore Lopez, Burak Zeybek, Stefania Bellone, Elena Bonazzoli, Silvia Pelligra, Luca Zammataro, Aranzazu Manzano, Paola Manara, Anna Bianchi, Natalia Buza, Joan Tymon-Rosario, Gary Altwerger, Chanhee Han, Gulden Menderes, Elena Ratner, Dan-Arin Silasi, Masoud Azodi, Pei Hui, Peter E. SchwartzGiovanni Scambia, Alessandro D. Santin

Yale University

Risultato della ricerca: Contributo in rivista › Articolo in rivista

3 Citazioni (Scopus)

Abstract

Background: Epithelial ovarian cancer (EOC) is the most lethal gynecologic malignancy. Sacituzumab govitecan (SG) is a novel antibody-drug-conjugate (ADC) targeting trophoblast-antigen-2 (Trop-2), a cell surface glycoprotein highly expressed in many epithelial tumors, to deliver SN-38, the active metabolite of irinotecan. This study aimed to evaluate Trop-2 expression in EOC tissues and the preclinical activity of SG against primary EOC cell lines and xenografts. Methods: Trop-2 expression was assessed in 90 formalin-fixed-paraffin-embedded tumors and nine primary tumor cell lines by immunohistochemistry (IHC) and flow cytometry, respectively. Trop-2 expression and cell viability after exposure to SG in primary tumor cell lines, non-targeting control ADC, and SG-parental antibody hRS7 were evaluated using flow-cytometry-based-assays. Antibody-dependent-cell-cytotoxicity (ADCC) against Trop-2+ and Trop-2– EOC cell lines was tested in vitro using 4 h Chromium-release-assays. In vivo activity of SG was evaluated against Trop-2+ EOC xenografts. Results: Moderate-to-strong staining was seen in 47% (42/90) of ovarian tumors by IHC while 89% (8/9) of the primary EOC cell lines overexpressed Trop-2 by flow cytometry. EOC Trop-2+ were significantly more sensitive to SG compared to control ADC (p < 0.05). Both SG and hRS7 mediated high ADCC activity against Trop-2+ cell lines. SG also induced significant bystander killing of Trop-2– tumor cells admixed with Trop-2+ EOC cells. In in vivo experiments SG treatment demonstrated impressive anti-tumor activity against chemotherapy-resistant EOC xenografts. Conclusion: SG demonstrates remarkable preclinical activity against biologically aggressive and chemotherapy-resistant EOC cell lines and a significant bystander effect against EOC cell lines with heterogenous Trop-2 expression. Clinical trials are warranted.

Lingua originale	English
pagine (da-a)	1-11
Numero di pagine	11
Rivista	Frontiers in Oncology
Volume	10
DOI	https://doi.org/10.3389/fonc.2020.00118
Stato di pubblicazione	Pubblicato - 2020

Keywords

Trop-2
antibody drug conjugate (ADC)
ovarian carcinoma
sacituzumab govitecan
target therapy

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Perrone, E., Lopez, S., Zeybek, B., Bellone, S., Bonazzoli, E., Pelligra, S., Zammataro, L., Manzano, A., Manara, P., Bianchi, A., Buza, N., Tymon-Rosario, J., Altwerger, G., Han, C., Menderes, G., Ratner, E., Silasi, D.-A., Azodi, M., Hui, P., ... Santin, A. D. (2020). Preclinical Activity of Sacituzumab Govitecan, an Antibody-Drug Conjugate Targeting Trophoblast Cell-Surface Antigen 2 (Trop-2) Linked to the Active Metabolite of Irinotecan (SN-38), in Ovarian Cancer. Frontiers in Oncology, 10, 1-11. https://doi.org/10.3389/fonc.2020.00118

@article{2ba7032889784207827803f3f6239a66,

title = "Preclinical Activity of Sacituzumab Govitecan, an Antibody-Drug Conjugate Targeting Trophoblast Cell-Surface Antigen 2 (Trop-2) Linked to the Active Metabolite of Irinotecan (SN-38), in Ovarian Cancer",

abstract = "Background: Epithelial ovarian cancer (EOC) is the most lethal gynecologic malignancy. Sacituzumab govitecan (SG) is a novel antibody-drug-conjugate (ADC) targeting trophoblast-antigen-2 (Trop-2), a cell surface glycoprotein highly expressed in many epithelial tumors, to deliver SN-38, the active metabolite of irinotecan. This study aimed to evaluate Trop-2 expression in EOC tissues and the preclinical activity of SG against primary EOC cell lines and xenografts. Methods: Trop-2 expression was assessed in 90 formalin-fixed-paraffin-embedded tumors and nine primary tumor cell lines by immunohistochemistry (IHC) and flow cytometry, respectively. Trop-2 expression and cell viability after exposure to SG in primary tumor cell lines, non-targeting control ADC, and SG-parental antibody hRS7 were evaluated using flow-cytometry-based-assays. Antibody-dependent-cell-cytotoxicity (ADCC) against Trop-2+ and Trop-2– EOC cell lines was tested in vitro using 4 h Chromium-release-assays. In vivo activity of SG was evaluated against Trop-2+ EOC xenografts. Results: Moderate-to-strong staining was seen in 47% (42/90) of ovarian tumors by IHC while 89% (8/9) of the primary EOC cell lines overexpressed Trop-2 by flow cytometry. EOC Trop-2+ were significantly more sensitive to SG compared to control ADC (p < 0.05). Both SG and hRS7 mediated high ADCC activity against Trop-2+ cell lines. SG also induced significant bystander killing of Trop-2– tumor cells admixed with Trop-2+ EOC cells. In in vivo experiments SG treatment demonstrated impressive anti-tumor activity against chemotherapy-resistant EOC xenografts. Conclusion: SG demonstrates remarkable preclinical activity against biologically aggressive and chemotherapy-resistant EOC cell lines and a significant bystander effect against EOC cell lines with heterogenous Trop-2 expression. Clinical trials are warranted.",

keywords = "Trop-2, antibody drug conjugate (ADC), ovarian carcinoma, sacituzumab govitecan, target therapy, Trop-2, antibody drug conjugate (ADC), ovarian carcinoma, sacituzumab govitecan, target therapy",

author = "Elisabetta Perrone and Salvatore Lopez and Burak Zeybek and Stefania Bellone and Elena Bonazzoli and Silvia Pelligra and Luca Zammataro and Aranzazu Manzano and Paola Manara and Anna Bianchi and Natalia Buza and Joan Tymon-Rosario and Gary Altwerger and Chanhee Han and Gulden Menderes and Elena Ratner and Dan-Arin Silasi and Masoud Azodi and Pei Hui and Schwartz, {Peter E.} and Giovanni Scambia and Santin, {Alessandro D.}",

year = "2020",

doi = "10.3389/fonc.2020.00118",

language = "English",

volume = "10",

pages = "1--11",

journal = "Frontiers in Oncology",

issn = "2234-943X",

publisher = "Frontiers Media SA",

}

Perrone, E, Lopez, S, Zeybek, B, Bellone, S, Bonazzoli, E, Pelligra, S, Zammataro, L, Manzano, A, Manara, P, Bianchi, A, Buza, N, Tymon-Rosario, J, Altwerger, G, Han, C, Menderes, G, Ratner, E, Silasi, D-A, Azodi, M, Hui, P, Schwartz, PE, Scambia, G & Santin, AD 2020, 'Preclinical Activity of Sacituzumab Govitecan, an Antibody-Drug Conjugate Targeting Trophoblast Cell-Surface Antigen 2 (Trop-2) Linked to the Active Metabolite of Irinotecan (SN-38), in Ovarian Cancer', Frontiers in Oncology, vol. 10, pagg. 1-11. https://doi.org/10.3389/fonc.2020.00118

Preclinical Activity of Sacituzumab Govitecan, an Antibody-Drug Conjugate Targeting Trophoblast Cell-Surface Antigen 2 (Trop-2) Linked to the Active Metabolite of Irinotecan (SN-38), in Ovarian Cancer. / Perrone, Elisabetta; Lopez, Salvatore; Zeybek, Burak et al.
In: Frontiers in Oncology, Vol. 10, 2020, pag. 1-11.

Risultato della ricerca: Contributo in rivista › Articolo in rivista

TY - JOUR

T1 - Preclinical Activity of Sacituzumab Govitecan, an Antibody-Drug Conjugate Targeting Trophoblast Cell-Surface Antigen 2 (Trop-2) Linked to the Active Metabolite of Irinotecan (SN-38), in Ovarian Cancer

AU - Perrone, Elisabetta

AU - Lopez, Salvatore

AU - Zeybek, Burak

AU - Bellone, Stefania

AU - Bonazzoli, Elena

AU - Pelligra, Silvia

AU - Zammataro, Luca

AU - Manzano, Aranzazu

AU - Manara, Paola

AU - Bianchi, Anna

AU - Buza, Natalia

AU - Tymon-Rosario, Joan

AU - Altwerger, Gary

AU - Han, Chanhee

AU - Menderes, Gulden

AU - Ratner, Elena

AU - Silasi, Dan-Arin

AU - Azodi, Masoud

AU - Hui, Pei

AU - Schwartz, Peter E.

AU - Scambia, Giovanni

AU - Santin, Alessandro D.

PY - 2020

Y1 - 2020

N2 - Background: Epithelial ovarian cancer (EOC) is the most lethal gynecologic malignancy. Sacituzumab govitecan (SG) is a novel antibody-drug-conjugate (ADC) targeting trophoblast-antigen-2 (Trop-2), a cell surface glycoprotein highly expressed in many epithelial tumors, to deliver SN-38, the active metabolite of irinotecan. This study aimed to evaluate Trop-2 expression in EOC tissues and the preclinical activity of SG against primary EOC cell lines and xenografts. Methods: Trop-2 expression was assessed in 90 formalin-fixed-paraffin-embedded tumors and nine primary tumor cell lines by immunohistochemistry (IHC) and flow cytometry, respectively. Trop-2 expression and cell viability after exposure to SG in primary tumor cell lines, non-targeting control ADC, and SG-parental antibody hRS7 were evaluated using flow-cytometry-based-assays. Antibody-dependent-cell-cytotoxicity (ADCC) against Trop-2+ and Trop-2– EOC cell lines was tested in vitro using 4 h Chromium-release-assays. In vivo activity of SG was evaluated against Trop-2+ EOC xenografts. Results: Moderate-to-strong staining was seen in 47% (42/90) of ovarian tumors by IHC while 89% (8/9) of the primary EOC cell lines overexpressed Trop-2 by flow cytometry. EOC Trop-2+ were significantly more sensitive to SG compared to control ADC (p < 0.05). Both SG and hRS7 mediated high ADCC activity against Trop-2+ cell lines. SG also induced significant bystander killing of Trop-2– tumor cells admixed with Trop-2+ EOC cells. In in vivo experiments SG treatment demonstrated impressive anti-tumor activity against chemotherapy-resistant EOC xenografts. Conclusion: SG demonstrates remarkable preclinical activity against biologically aggressive and chemotherapy-resistant EOC cell lines and a significant bystander effect against EOC cell lines with heterogenous Trop-2 expression. Clinical trials are warranted.

AB - Background: Epithelial ovarian cancer (EOC) is the most lethal gynecologic malignancy. Sacituzumab govitecan (SG) is a novel antibody-drug-conjugate (ADC) targeting trophoblast-antigen-2 (Trop-2), a cell surface glycoprotein highly expressed in many epithelial tumors, to deliver SN-38, the active metabolite of irinotecan. This study aimed to evaluate Trop-2 expression in EOC tissues and the preclinical activity of SG against primary EOC cell lines and xenografts. Methods: Trop-2 expression was assessed in 90 formalin-fixed-paraffin-embedded tumors and nine primary tumor cell lines by immunohistochemistry (IHC) and flow cytometry, respectively. Trop-2 expression and cell viability after exposure to SG in primary tumor cell lines, non-targeting control ADC, and SG-parental antibody hRS7 were evaluated using flow-cytometry-based-assays. Antibody-dependent-cell-cytotoxicity (ADCC) against Trop-2+ and Trop-2– EOC cell lines was tested in vitro using 4 h Chromium-release-assays. In vivo activity of SG was evaluated against Trop-2+ EOC xenografts. Results: Moderate-to-strong staining was seen in 47% (42/90) of ovarian tumors by IHC while 89% (8/9) of the primary EOC cell lines overexpressed Trop-2 by flow cytometry. EOC Trop-2+ were significantly more sensitive to SG compared to control ADC (p < 0.05). Both SG and hRS7 mediated high ADCC activity against Trop-2+ cell lines. SG also induced significant bystander killing of Trop-2– tumor cells admixed with Trop-2+ EOC cells. In in vivo experiments SG treatment demonstrated impressive anti-tumor activity against chemotherapy-resistant EOC xenografts. Conclusion: SG demonstrates remarkable preclinical activity against biologically aggressive and chemotherapy-resistant EOC cell lines and a significant bystander effect against EOC cell lines with heterogenous Trop-2 expression. Clinical trials are warranted.

KW - Trop-2

KW - antibody drug conjugate (ADC)

KW - ovarian carcinoma

KW - sacituzumab govitecan

KW - target therapy

KW - Trop-2

KW - antibody drug conjugate (ADC)

KW - ovarian carcinoma

KW - sacituzumab govitecan

KW - target therapy

UR - http://hdl.handle.net/10807/168132

U2 - 10.3389/fonc.2020.00118

DO - 10.3389/fonc.2020.00118

M3 - Article

SN - 2234-943X

VL - 10

SP - 1

EP - 11

JO - Frontiers in Oncology

JF - Frontiers in Oncology

ER -

Preclinical Activity of Sacituzumab Govitecan, an Antibody-Drug Conjugate Targeting Trophoblast Cell-Surface Antigen 2 (Trop-2) Linked to the Active Metabolite of Irinotecan (SN-38), in Ovarian Cancer

Abstract

Keywords

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