EV20-Sap, a novel anti-HER-3 antibody-drug conjugate, displays promising antitumor activity in melanoma
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Emily Capone1,*, Francesco Giansanti2,*, Sara Ponziani2,3, Alessia Lamolinara4, Manuela Iezzi4, Annamaria Cimini2,5,6, Francesco Angelucci2, Rossana La Sorda3, Vincenzo De Laurenzi1, Pier Giorgio Natali3, Rodolfo Ippoliti2, Stefano Iacobelli1,3 and Gianluca Sala1,3
1Department of Medical, Oral and Biotechnological Sciences, University of Chieti-Pescara, Chieti, Italy
2Department of Life, Health and Environmental Sciences, University of L'Aquila, Coppito (AQ) Italy
3MediaPharma s.r.l., Via della Colonnetta, Chieti, Italy
4Department of Medicine and Aging Science, Center of Excellence on Aging and Translational Medicine (CeSi-Met), G. D’Annunzio University, Chieti-Pescara, Italy
5Sbarro Institute for Cancer Research and Molecular Medicine and Center for Biotechnology Temple University, Philadelphia, USA
6National Institute for Nuclear Physics (INFN), Gran Sasso National Laboratory (LNGS), Assergi, Italy
*These authors have contributed equally to this work
Gianluca Sala, email: [email protected]
Stefano Iacobelli, email: [email protected]
Keywords: HER-3, antibody-drug conjugate, melanoma, saporin, target therapy
Received: June 22, 2017 Accepted: August 08, 2017 Published: September 08, 2017
Melanoma is the most biologically aggressive skin cancer of well established constitutive and induced resistance to pharmacological treatment. Despite the recent progresses in immunotherapies, many advanced metastatic melanoma patients still face a significant mortality risk. The aggressive nature of this disease sustains an urgent need for more successful, effective drugs. HER-3 - one of the four member of the tyrosin kinase epidermal growth factor receptors (EGFRs) family- is frequently overexpressed in solid tumors, including melanoma. Moreover, up-regulation of HER-3 and its ligand NRGβ-1 are associated with poor prognosis, thus suggesting this receptor as a suitable target for cancer therapy. Several monoclonal antibodies targeting HER-3 are currently available, but preliminary results from clinical testing of these agents reveal a modest efficacy. Thus, a substantial improvement over this immunotherapeutic approach could be offered by an anti-HER-3 based Antibody-Drug Conjugate (ADC). In the present paper, we describe the generation of an ADC obtained by coupling the HER-3 targeting antibody EV20 linked to the plant toxin Saporin (Sap). In vitro, this ADC displays a powerful, specific and target-dependent cytotoxic activity which correlates with the degree of expression and internalization of HER-3 on tumor cells. Furthermore, in a murine melanoma model, EV20-Sap treatment leads to a significant reduction of the number of pulmonary metastasis.
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