A BARF1-specific mAb as a new immunotherapeutic tool for the management of EBV-related tumors

R. Turrini, A. Merlo, D. Martorelli, D.A. Faè, R. Sommaggio, I.M. Montagner, V. Barbieri, O. Marin, P. Zanovello, R. Dolcetti, A. Rosato

Research output: Contribution to journalArticle

3 Citations (Scopus)

Abstract

The use of monoclonal antibodies (mAb) for the diagnosis and treatment of malignancies is acquiring an increasing clinical importance, thanks to their specificity, efficacy and relative easiness of use. However, in the context of Epstein-Barr virus (EBV)-related malignancies, only cancers of B-cell origin can benefit from therapeutic mAb targeting specific B-cell lineage antigens. To overcome this limitation, we generated a new mAb specific for BARF1, an EBV-encoded protein with transforming and immune-modulating properties. BARF1 is expressed as a latent protein in nasopharyngeal (NPC) and gastric carcinoma (GC), and also in neoplastic B cells mainly upon lytic cycle induction, thus representing a potential target for all EBV-related malignancies. Considering that BARF1 is largely but not exclusively secreted, the BARF1 mAb was selected on the basis of its ability to bind a domain of the protein retained at the cell surface of tumor cells. In vitro, the newly generated mAb recognized the target molecule in its native conformation, and was highly effective in mediating both ADCC and CDC against BARF1-positive tumor cells. In vivo, biodistribution analysis in mice engrafted with BARF1-positive and -negative tumor cells confirmed its high specificity for the target. More importantly, the mAb disclosed a relevant antitumor potential in preclinical models of NPC and lymphoma, as evaluated in terms of both reduction of tumor masses and long-term survival. Taken together, these data not only confirm BARF1 as a promising target for immunotherapeutic interventions, but also pave the way for a successful translation of this new mAb to the clinical use. © 2017 The Author(s). Published with license by Taylor & Francis Group, LLC © 2017, © Riccardo Turrini, Anna Merlo, Debora Martorelli, Damiana Antonia Faé, Roberta Sommaggio, Isabella Monia Montagner, Vito Barbieri, Oriano Marin, Paola Zanovello, Riccardo Dolcetti, and Antonio Rosato.
Original languageEnglish
Article numbere1304338
Number of pages10
JournalOncoImmunology
Volume6
Issue number4
DOIs
Publication statusPublished - 2017

Fingerprint

Human Herpesvirus 4
Monoclonal Antibodies
Neoplasms
B-Lymphocytes
Turnera
Antibody-Dependent Cell Cytotoxicity
Cell Lineage
Licensure
Centers for Disease Control and Prevention (U.S.)
Lymphoma
Stomach
Carcinoma
Antigens
Proteins

Keywords

  • ADCC
  • BARF1
  • CDC
  • Epstein–Barr virus
  • immunotherapy
  • monoclonal antibody
  • CD16 antigen
  • CD56 antigen
  • Epstein Barr virus antigen 1
  • luciferase
  • membrane protein
  • animal experiment
  • antibody dependent cellular cytotoxicity
  • antibody specificity
  • Article
  • controlled study
  • cytolysis
  • dot hybridization
  • drug distribution
  • enzyme linked immunosorbent assay
  • Epstein Barr virus infection
  • flow cytometry
  • immunomodulation
  • long term survival
  • mouse
  • nasopharynx carcinoma
  • nonhuman
  • stomach carcinoma
  • tumor growth
  • virus carcinogenesis

Cite this

A BARF1-specific mAb as a new immunotherapeutic tool for the management of EBV-related tumors. / Turrini, R.; Merlo, A.; Martorelli, D.; Faè, D.A.; Sommaggio, R.; Montagner, I.M.; Barbieri, V.; Marin, O.; Zanovello, P.; Dolcetti, R.; Rosato, A.

In: OncoImmunology, Vol. 6, No. 4, e1304338, 2017.

Research output: Contribution to journalArticle

Turrini, R. ; Merlo, A. ; Martorelli, D. ; Faè, D.A. ; Sommaggio, R. ; Montagner, I.M. ; Barbieri, V. ; Marin, O. ; Zanovello, P. ; Dolcetti, R. ; Rosato, A. / A BARF1-specific mAb as a new immunotherapeutic tool for the management of EBV-related tumors. In: OncoImmunology. 2017 ; Vol. 6, No. 4.
@article{a94b7d7bff3a4510b33fe26fb9cc3b89,
title = "A BARF1-specific mAb as a new immunotherapeutic tool for the management of EBV-related tumors",
abstract = "The use of monoclonal antibodies (mAb) for the diagnosis and treatment of malignancies is acquiring an increasing clinical importance, thanks to their specificity, efficacy and relative easiness of use. However, in the context of Epstein-Barr virus (EBV)-related malignancies, only cancers of B-cell origin can benefit from therapeutic mAb targeting specific B-cell lineage antigens. To overcome this limitation, we generated a new mAb specific for BARF1, an EBV-encoded protein with transforming and immune-modulating properties. BARF1 is expressed as a latent protein in nasopharyngeal (NPC) and gastric carcinoma (GC), and also in neoplastic B cells mainly upon lytic cycle induction, thus representing a potential target for all EBV-related malignancies. Considering that BARF1 is largely but not exclusively secreted, the BARF1 mAb was selected on the basis of its ability to bind a domain of the protein retained at the cell surface of tumor cells. In vitro, the newly generated mAb recognized the target molecule in its native conformation, and was highly effective in mediating both ADCC and CDC against BARF1-positive tumor cells. In vivo, biodistribution analysis in mice engrafted with BARF1-positive and -negative tumor cells confirmed its high specificity for the target. More importantly, the mAb disclosed a relevant antitumor potential in preclinical models of NPC and lymphoma, as evaluated in terms of both reduction of tumor masses and long-term survival. Taken together, these data not only confirm BARF1 as a promising target for immunotherapeutic interventions, but also pave the way for a successful translation of this new mAb to the clinical use. {\circledC} 2017 The Author(s). Published with license by Taylor & Francis Group, LLC {\circledC} 2017, {\circledC} Riccardo Turrini, Anna Merlo, Debora Martorelli, Damiana Antonia Fa{\'e}, Roberta Sommaggio, Isabella Monia Montagner, Vito Barbieri, Oriano Marin, Paola Zanovello, Riccardo Dolcetti, and Antonio Rosato.",
keywords = "ADCC, BARF1, CDC, Epstein–Barr virus, immunotherapy, monoclonal antibody, CD16 antigen, CD56 antigen, Epstein Barr virus antigen 1, luciferase, membrane protein, animal experiment, antibody dependent cellular cytotoxicity, antibody specificity, Article, controlled study, cytolysis, dot hybridization, drug distribution, enzyme linked immunosorbent assay, Epstein Barr virus infection, flow cytometry, immunomodulation, long term survival, mouse, nasopharynx carcinoma, nonhuman, stomach carcinoma, tumor growth, virus carcinogenesis",
author = "R. Turrini and A. Merlo and D. Martorelli and D.A. Fa{\`e} and R. Sommaggio and I.M. Montagner and V. Barbieri and O. Marin and P. Zanovello and R. Dolcetti and A. Rosato",
note = "Export Date: 14 February 2018 Correspondence Address: Rosato, A.; Department of Surgery, Oncology and Gastroenterology, Oncology and Immunology Section, University of Padova, Via Gattamelata 64, Italy; email: antonio.rosato@unipd.it",
year = "2017",
doi = "10.1080/2162402X.2017.1304338",
language = "English",
volume = "6",
journal = "OncoImmunology",
issn = "2162-4011",
publisher = "Taylor and Francis Inc.",
number = "4",

}

TY - JOUR

T1 - A BARF1-specific mAb as a new immunotherapeutic tool for the management of EBV-related tumors

AU - Turrini, R.

AU - Merlo, A.

AU - Martorelli, D.

AU - Faè, D.A.

AU - Sommaggio, R.

AU - Montagner, I.M.

AU - Barbieri, V.

AU - Marin, O.

AU - Zanovello, P.

AU - Dolcetti, R.

AU - Rosato, A.

N1 - Export Date: 14 February 2018 Correspondence Address: Rosato, A.; Department of Surgery, Oncology and Gastroenterology, Oncology and Immunology Section, University of Padova, Via Gattamelata 64, Italy; email: antonio.rosato@unipd.it

PY - 2017

Y1 - 2017

N2 - The use of monoclonal antibodies (mAb) for the diagnosis and treatment of malignancies is acquiring an increasing clinical importance, thanks to their specificity, efficacy and relative easiness of use. However, in the context of Epstein-Barr virus (EBV)-related malignancies, only cancers of B-cell origin can benefit from therapeutic mAb targeting specific B-cell lineage antigens. To overcome this limitation, we generated a new mAb specific for BARF1, an EBV-encoded protein with transforming and immune-modulating properties. BARF1 is expressed as a latent protein in nasopharyngeal (NPC) and gastric carcinoma (GC), and also in neoplastic B cells mainly upon lytic cycle induction, thus representing a potential target for all EBV-related malignancies. Considering that BARF1 is largely but not exclusively secreted, the BARF1 mAb was selected on the basis of its ability to bind a domain of the protein retained at the cell surface of tumor cells. In vitro, the newly generated mAb recognized the target molecule in its native conformation, and was highly effective in mediating both ADCC and CDC against BARF1-positive tumor cells. In vivo, biodistribution analysis in mice engrafted with BARF1-positive and -negative tumor cells confirmed its high specificity for the target. More importantly, the mAb disclosed a relevant antitumor potential in preclinical models of NPC and lymphoma, as evaluated in terms of both reduction of tumor masses and long-term survival. Taken together, these data not only confirm BARF1 as a promising target for immunotherapeutic interventions, but also pave the way for a successful translation of this new mAb to the clinical use. © 2017 The Author(s). Published with license by Taylor & Francis Group, LLC © 2017, © Riccardo Turrini, Anna Merlo, Debora Martorelli, Damiana Antonia Faé, Roberta Sommaggio, Isabella Monia Montagner, Vito Barbieri, Oriano Marin, Paola Zanovello, Riccardo Dolcetti, and Antonio Rosato.

AB - The use of monoclonal antibodies (mAb) for the diagnosis and treatment of malignancies is acquiring an increasing clinical importance, thanks to their specificity, efficacy and relative easiness of use. However, in the context of Epstein-Barr virus (EBV)-related malignancies, only cancers of B-cell origin can benefit from therapeutic mAb targeting specific B-cell lineage antigens. To overcome this limitation, we generated a new mAb specific for BARF1, an EBV-encoded protein with transforming and immune-modulating properties. BARF1 is expressed as a latent protein in nasopharyngeal (NPC) and gastric carcinoma (GC), and also in neoplastic B cells mainly upon lytic cycle induction, thus representing a potential target for all EBV-related malignancies. Considering that BARF1 is largely but not exclusively secreted, the BARF1 mAb was selected on the basis of its ability to bind a domain of the protein retained at the cell surface of tumor cells. In vitro, the newly generated mAb recognized the target molecule in its native conformation, and was highly effective in mediating both ADCC and CDC against BARF1-positive tumor cells. In vivo, biodistribution analysis in mice engrafted with BARF1-positive and -negative tumor cells confirmed its high specificity for the target. More importantly, the mAb disclosed a relevant antitumor potential in preclinical models of NPC and lymphoma, as evaluated in terms of both reduction of tumor masses and long-term survival. Taken together, these data not only confirm BARF1 as a promising target for immunotherapeutic interventions, but also pave the way for a successful translation of this new mAb to the clinical use. © 2017 The Author(s). Published with license by Taylor & Francis Group, LLC © 2017, © Riccardo Turrini, Anna Merlo, Debora Martorelli, Damiana Antonia Faé, Roberta Sommaggio, Isabella Monia Montagner, Vito Barbieri, Oriano Marin, Paola Zanovello, Riccardo Dolcetti, and Antonio Rosato.

KW - ADCC

KW - BARF1

KW - CDC

KW - Epstein–Barr virus

KW - immunotherapy

KW - monoclonal antibody

KW - CD16 antigen

KW - CD56 antigen

KW - Epstein Barr virus antigen 1

KW - luciferase

KW - membrane protein

KW - animal experiment

KW - antibody dependent cellular cytotoxicity

KW - antibody specificity

KW - Article

KW - controlled study

KW - cytolysis

KW - dot hybridization

KW - drug distribution

KW - enzyme linked immunosorbent assay

KW - Epstein Barr virus infection

KW - flow cytometry

KW - immunomodulation

KW - long term survival

KW - mouse

KW - nasopharynx carcinoma

KW - nonhuman

KW - stomach carcinoma

KW - tumor growth

KW - virus carcinogenesis

U2 - 10.1080/2162402X.2017.1304338

DO - 10.1080/2162402X.2017.1304338

M3 - Article

VL - 6

JO - OncoImmunology

JF - OncoImmunology

SN - 2162-4011

IS - 4

M1 - e1304338

ER -