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 journalArticlepeer-review

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

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

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