Oncotarget

Research Papers:

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

Ferdinando Maria Milazzo, Anna Maria Anastasi, Caterina Chiapparino, Antonio Rosi, Barbara Leoni, Loredana Vesci, Fiorella Petronzelli and Rita De Santis _

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Oncotarget. 2017; 8:22590-22605. https://doi.org/10.18632/oncotarget.15145

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Abstract

Ferdinando Maria Milazzo1, Anna Maria Anastasi1, Caterina Chiapparino1, Antonio Rosi1, Barbara Leoni1, Loredana Vesci1, Fiorella Petronzelli1, Rita De Santis1

1Biotech 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.


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