Oncotarget

Research Papers:

Tetraspanin 8 (TSPAN 8) as a potential target for radio-immunotherapy of colorectal cancer

Aurelie Maisonial-Besset, Tiffany Witkowski, Isabelle Navarro-Teulon, Odile Berthier-Vergnes, Giovanna Fois, Yingying Zhu, Sophie Besse, Olivia Bawa, Arnaud Briat, Mercedes Quintana, Alexandre Pichard, Mathilde Bonnet, Eric Rubinstein, Jean-Pierre Pouget, Paule Opolon, Lydia Maigne, Elisabeth Miot-Noirault, Jean-Michel Chezal, Claude Boucheix and Francoise Degoul _

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Oncotarget. 2017; 8:22034-22047. https://doi.org/10.18632/oncotarget.15787

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Abstract

Aurelie Maisonial-Besset1,2,*,**, Tiffany Witkowski1,2,*,**, Isabelle Navarro-Teulon3,4,5, Odile Berthier-Vergnes6,7, Giovanna Fois2,8, Yingying Zhu9,10,11, Sophie Besse1,2, Olivia Bawa12, Arnaud Briat1,2, Mercedes Quintana1,2, Alexandre Pichard3,4,5, Mathilde Bonnet2,13, Eric Rubinstein9,10,11, Jean-Pierre Pouget3,4,5, Paule Opolon12, Lydia Maigne2,8, Elisabeth Miot-Noirault1,2, Jean-Michel Chezal1,2, Claude Boucheix9,10,11,*, Françoise Degoul1,2,*

1INSERM, U 1240, Clermont-Ferrand, France

2Université Clermont Auvergne, Imagerie Moléculaire et Thérapie Vectorisée, Clermont-Ferrand, France

3IRCM, Institut de Recherche en Cancérologie de Montpellier, Montpellier, France

4INSERM, U896, Montpellier, France

5Université Montpellier 1, Montpellier, France

6Université de Lyon 1, Lyon, France

7CNRS, UMR5534, Centre de Génétique et de Physiologie Moléculaires et Cellulaires, Villeurbanne, France

8CNRS/IN2P3, UMR6533, Laboratoire de Physique Corpusculaire (LPC), Clermont-Ferrand, France

9INSERM, UMR-S 935, Villejuif, France

10Université Paris-Sud 11, Orsay, France

11Université Paris Saclay, Saint-Aubin, France

12Gustave Roussy, Laboratoire de Pathologie Expérimentale, Villejuif, France

13INSERM U1071, Faculté de Médecine, Clermont Ferrand, France

*These authors have contributed equally to this work

**First co-authors

Correspondence to:

Françoise Degoul, email: [email protected]

Keywords: TSPAN8, radioimmunotherapy, colorectal cancer, dosimetry

Abbreviations: DOTA: 2,2’,2’’-(10-(2-((2,5-dioxopyrrolidin-1-yl)oxy)-2-oxoethyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid

Received: December 12, 2016    Accepted: January 24, 2017    Published: February 28, 2017

ABSTRACT

Tetraspanin 8 (TSPAN8) overexpression is correlated with poor prognosis in human colorectal cancer (CRC). A murine mAb Ts29.2 specific for human TSPAN8 provided significant efficiency for immunotherapy in CRC pre-clinical models. We therefore evaluate the feasability of targeting TSPAN8 in CRC with radiolabeled Ts29.2. Staining of tissue micro-arrays with Ts29.2 revealed that TSPAN8 espression was restricted to a few human healthy tissues. DOTA-Ts29.2 was radiolabeled with 111In or 177Lu with radiochemical purities >95%, specific activity ranging from 300 to 600 MBq/mg, and radioimmunoreactive fractions >80%. The biodistribution of [111In]DOTA-Ts29.2 in nude mice bearing HT29 or SW480 CRC xenografts showed a high specificity of tumor localization with high tumor/blood ratios (HT29: 4.3; SW480-TSPAN8: 3.9 at 72h and 120h post injection respectively). Tumor-specific absorbed dose calculations for [177Lu]DOTA-Ts29.2 was 1.89 Gy/MBq, establishing the feasibility of using radioimmunotherapy of CRC with this radiolabeled antibody. A significant inhibition of tumor growth in HT29 tumor-bearing mice treated with [177Lu]DOTA-Ts29.2 was observed compared to control groups. Ex vivo experiments revealed specific DNA double strand breaks associated with cell apoptosis in [177Lu]DOTA-Ts29.2 treated tumors compared to controls. Overall, we provide a proof-of-concept for the use of [111In/177Lu]DOTA-Ts29.2 that specifically target in vivo aggressive TSPAN8-positive cells in CRC.


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