Oncotarget

Research Papers:

Evaluation of a novel human IgG1 anti-claudin3 antibody that specifically recognizes its aberrantly localized antigen in ovarian cancer cells and that is suitable for selective drug delivery

Chiara Romani _, Emiliano Cocco, Eliana Bignotti, Daniele Moratto, Antonella Bugatti, Paola Todeschini, Elisabetta Bandiera, Renata Tassi, Laura Zanotti, Sergio Pecorelli, Enrico Sartori, Franco E. Odicino, Ario de Marco, Alessandro Davide Santin, Antonella Ravaggi and Stefania Mitola

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Oncotarget. 2015; 6:34617-34628. https://doi.org/10.18632/oncotarget.5315

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Abstract

Chiara Romani1, Emiliano Cocco2,3, Eliana Bignotti1, Daniele Moratto4, Antonella Bugatti5, Paola Todeschini1, Elisabetta Bandiera1, Renata Tassi1, Laura Zanotti1, Sergio Pecorelli1, Enrico Sartori1, Franco E. Odicino1, Ario de Marco6, Alessandro Davide Santin3, Antonella Ravaggi1, Stefania Mitola5

1“Angelo Nocivelli” Institute for Molecular Medicine, Division of Gynecologic Oncology, University of Brescia, Brescia, Italy

2Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, New Haven, CT, USA

3Department of Molecular and Translational Medicine, Brescia, Italy

4Laboratory of Genetic Disorders of Childhood, Angelo Nocivelli Institute for Molecular Medicine, Spedali Civili, Brescia, Italy

5Department of Pathology, University of Brescia, Brescia, Italy

6Department of Biomedical Science and Engineering, University of Nova Gorica, Vipava, Slovenia

Correspondence to:

Chiara Romani, e-mail: [email protected]

Keywords: claudins, tight junction, human antibody, therapeutic target

Received: April 24, 2015     Accepted: September 11, 2015     Published: September 21, 2015

ABSTRACT

Membrane protein claudin3 has been recently suggested as a marker for biologically aggressive tumors and a possible target for the therapeutic delivery of active anti-cancer compounds. Claudin3-binding molecules such as the Clostridium perfringens enterotoxin (CPE), CPE-related molecules, and murine and chimeric antibodies have shown promising antitumor efficacy in preclinical oncological settings. We first engineered a fully human anti-claudin3 IgG1 antibody (IgGH6) by fusing the human IgG1 Fc-domain to the anti-claudin3 scFvH6 previously isolated from a pre-immune phage display library. The construct was expressed in mammalian cells and specifically targeted claudin3 endogenously expressed on the surface of different human ovarian cancer cell lines. No detectable cross-reactivity with other homologous claudins was observed. The epitope recognized by IgGH6 is located within the minor extracellular domain of claudin3 and becomes accessible only in tumor cells characterized by incomplete junction formation. Confocal microscopy experiments demonstrated that IgGH6 was actively internalized in tumor cells after binding to native claudin3 and co-localized, likely within intracellular vesicles, with the C-CPE peptide. Preliminary results indicate that IgGH6 accumulated in vivo in free claudin3 ovarian carcinoma xenografts. For its selective uptake in tumor cells and its human nature, IgGH6 represents a valuable candidate for antibody-drug conjugate therapeutic applications in ovarian cancer patients.


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