AvidinOX-anchored biotinylated trastuzumab and pertuzumab induce down-modulation of ErbB2 and tumor cell death at concentrations order of magnitude lower than not-anchored antibodies
| Autor: | Barbara Leoni, Rita De Santis, Loredana Vesci, Caterina Chiapparino, Antonio Rosi, Anna Maria Anastasi, Fiorella Petronzelli, Ferdinando Maria Milazzo |
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| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Receptor ErbB-2 medicine.drug_class Apoptosis Breast Neoplasms Pharmacology Antibodies Monoclonal Humanized Monoclonal antibody 03 medical and health sciences 0302 clinical medicine ErbB2 pertuzumab Trastuzumab Antineoplastic Combined Chemotherapy Protocols Biomarkers Tumor Tumor Cells Cultured cancer Humans Medicine Panitumumab Biotinylation Epidermal growth factor receptor Cell Proliferation Cetuximab biology business.industry avidinOX Avidin 030104 developmental biology Oncology 030220 oncology & carcinogenesis Monoclonal biology.protein Female Pertuzumab business Research Paper Signal Transduction medicine.drug |
| Zdroj: | Oncotarget |
| ISSN: | 1949-2553 |
| DOI: | 10.18632/oncotarget.15145 |
| Popis: | // Ferdinando Maria Milazzo 1 , Anna Maria Anastasi 1 , Caterina Chiapparino 1 , Antonio Rosi 1 , Barbara Leoni 1 , Loredana Vesci 1 , Fiorella Petronzelli 1 , Rita De Santis 1 1 Biotech Products, Research and Development, Sigma-Tau SpA, 00071 Pomezia, Rome, Italy Correspondence to: Rita De Santis, email: rita.desantis@sigma-tau.it Keywords: avidinOX, trastuzumab, pertuzumab, ErbB2, cancer Received: December 23, 2016 Accepted: January 25, 2017 Published: February 07, 2017 ABSTRACT The oxidized version of Avidin, known as AvidinOX, was previously shown to link to tissue proteins upon injection or nebulization, thus becoming a stable receptor for biotinylated therapeutics. AvidinOX is currently under clinical investigation to target radioactive biotin to inoperable tumor lesions ( ClinicalTrials.gov NCT02053324). Presently, we show that the anti-ErbB2 monoclonal antibodies Trastuzumab and Pertuzumab can be chemically biotinylated while maintaining their biochemical and biological properties. By using several and diverse experimental conditions, we show that when AvidinOX is conjugated to tumor cells, low antibody concentrations of biotinylated Trastuzumab (bTrast) or Pertuzumab (bPert) prevent internalization of ErbB2, induce endoplasmic reticulum stress, cell cycle arrest and apoptosis leading to inhibition of proliferation and ErbB2 signaling. Moreover, we found that the treatment is able to induce down-modulation of ErbB2 thus bypassing the known resistance of this receptor to degradation. Interestingly, we show that AvidinOX anchorage is a way to counteract agonistic activities of Trastuzumab and Pertuzumab. Present data are in agreement with previous observations from our group indicating that the engagement of the Epidermal Growth Factor Receptor (EGFR) by AvidinOX-bound biotinylated Cetuximab or Panitumumab, leads to potent tumor inhibition both in vitro and in animal models. All results taken together encourage further investigation of AvidinOX-based treatments with biotinylated antibodies directed to the members of the EGFR family. |
| Databáze: | OpenAIRE |
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