Generation of a novel Antibody-Drug Conjugate targeting endosialin: potent and durable antitumor response in sarcoma.

Emily Capone,Enza Piccolo,Paolo Ciufici,Imma Fichera,Daniela Barcaroli,Gianluca Sala,Stefano Iacobelli,Arturo Sala,Vincenzo De Laurenzi,Valentina Iacobelli

doi:10.18632/oncotarget.19499

Abstract

The endosialin/CD248/TEM1 receptor is expressed on the cell surface of tumor-associated stroma cells as well as in sarcoma and neuroblastoma cells. This receptor is emerging as an attractive molecule in diagnostics and therapeutics because of its expression across the stroma of many human tumors, the low to absent expression in normal tissues and accessibility from the vascular circulation. In this study, we present evidence of the preclinical efficacy of a novel Antibody-Drug Conjugate (ENDOS/ADC). It consists of a humanized endosialin monoclonal antibody, named hMP-E-8.3, conjugated to a potent duocarmycin derivative. In endosialin expressing cancer cell lines, this ENDOS/ADC showed a powerful, specific and target-dependent killing activity. High expression levels of endosialin in cells correlated with efficient internalization and cytotoxic effects in vitro. Efficacy studies demonstrated that ENDOS/ADC treatment led to a long-lasting tumor growth inhibition of a cell line-based model of human osteosarcoma. Taken together, our results demonstrate that endosialin is an attractive target in sarcoma and suggest that ENDOS/ADC has the potential to be developed into a bio-therapeutic agent for these malignancies.

Highlights

IntroductionEndosialin (aka Tumor endothelial marker 1) is a cell surface protein encoded by the CD248 gene in humans, belonging to a family of C-type lectin transmembrane receptors
Endosialin is a cell surface protein encoded by the CD248 gene in humans, belonging to a family of C-type lectin transmembrane receptors
Efficacy studies demonstrated that ENDOS/antibody-drug conjugate (ADC) treatment led to a long-lasting tumor growth inhibition of a cell linebased model of human osteosarcoma

Summary

Introduction

Endosialin (aka Tumor endothelial marker 1) is a cell surface protein encoded by the CD248 gene in humans, belonging to a family of C-type lectin transmembrane receptors. Endosialin expression is essentially restricted to activated cells of the mesenchymal lineage, including pericytes and myofibroblasts during embryogenesis [1,2,3]. In a large series of 514 www.impactjournals.com/oncotarget human sarcomas including undifferentiated pleomorphic sarcomas, rhabdomyosarcoma, synovial sarcomas, adult fibrosarcoma/spindle cell sarcoma and leiomyosarcomas, more than half of the tumours displayed endosialin on neoplastic sarcoma cells, whereas, in the remaining cases endosialin expression was restricted to pericytes and stromal fibroblasts [9]. In epithelial neoplasms of other lineages, including colorectal, breast, histiocytomas, highly invasive glioblastoma, anaplastic astrocytomas, and metastatic melanomas, expression of endosialin was confined to pericytes and stromal fibroblasts [8, 10, 11]

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