2. Academic Validation
  3. EV20/NMS-P945, a Novel Thienoindole Based Antibody-Drug Conjugate Targeting HER-3 for Solid Tumors

EV20/NMS-P945, a Novel Thienoindole Based Antibody-Drug Conjugate Targeting HER-3 for Solid Tumors

  • Pharmaceutics. 2021 Apr 2;13(4):483. doi: 10.3390/pharmaceutics13040483.
Emily Capone 1 2,  Rossano Lattanzio 1 2,  Fabio Gasparri 3,  Paolo Orsini 3,  Cosmo Rossi 2,  Valentina Iacobelli 4,  Vincenzo De Laurenzi 1 2,  Pier Giorgio Natali 5,  Barbara Valsasina 3,  Stefano Iacobelli 5,  Gianluca Sala 1 2
Affiliations

Affiliations

  • 1 Department of Innovative Technologies in Medicine & Dentistry, University of Chieti-Pescara, 66100 Chieti, Italy.
  • 2 Center for Advanced Studies and Technology (CAST), Via Polacchi 11, 66100 Chieti, Italy.
  • 3 Nerviano Medical Sciences Srl, 20014 Milan, Italy.
  • 4 Department of Gynecology and Obstetrics, Catholic University, 00168 Rome, Italy.
  • 5 MediaPharma s.r.l., Via della Colonnetta 50/A, 66100 Chieti, Italy.
PMID: 33918158 DOI: 10.3390/pharmaceutics13040483
Abstract

HER-3 is becoming an attractive target for antibody-drug conjugate (ADC)-based therapy. Indeed, this receptor and its ligands are found to be overexpressed in several malignancies, and re-activation of its downstream signaling axis is known to play a critical role in modulating the sensitivity of targeted therapeutics in different tumors. In this study, we generated a novel ADC named EV20/NMS-P945 by coupling the anti-HER-3 antibody EV20 with a duocarmycin-like derivative, the thienoindole (TEI) NMS-P528, a DNA minor groove alkylating agent through a peptidic Cleavable Linker. This ADC showed target-dependent cytotoxic activity in vitro on several tumor cell lines and therapeutic activity in mouse xenograft tumor models, including those originating from pancreatic, prostatic, head and neck, gastric and ovarian Cancer cells and melanoma. Pharmacokinetics and toxicological studies in monkeys demonstrated that this ADC possesses a favorable terminal half-life and stability and it is well tolerated. These data support further EV20/NMS-P945 clinical development as a therapeutic agent against HER-3-expressing malignancies.

Keywords

HER-3; antibody–drug conjugates; duocarmycin; targeted therapy.

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