Journal
ONCOTARGET
Volume 6, Issue 33, Pages 34617-34628Publisher
IMPACT JOURNALS LLC
DOI: 10.18632/oncotarget.5315
Keywords
claudins; tight junction; human antibody; therapeutic target
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Funding
- Regione Lombardia (Network-Enabled Drug Design)
- NIH [R01 CA154460-01, U01 CA176067-01A1]
- Deborah Bunn Alley Foundation
- Tina Brozman Foundation
- Discovery to Cure Foundation
- Ministero della Salute [RF-2010-2313497]
- Guido Berlucchi Foundation
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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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