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Preclinical Efficacy of Endoglin-Targeting Antibody–Drug Conjugates for the Treatment of Ewing Sarcoma

2018; American Association for Cancer Research; Volume: 25; Issue: 7 Linguagem: Inglês

10.1158/1078-0432.ccr-18-0936

1557-3265

Pilar Puerto‐Camacho, Ana Teresa Amaral, Salah-Eddine Lamhamedi-Cherradi, Brian A. Menegaz, Helena Castillo‐Ecija, José Luis Ordóñez, Saioa Domínguez, Carmen Jordán-Pérez, Juan Dı́az-Martı́n, Laura Romero‐Pérez, María López-Álvarez, Gema Civantos-Jubera, María José Robles‐Frías, Michele Biscuola, Cristina Suárez Ferrer, Jaume Mora, Branko Cuglievan, Keri Schadler, Oliver Seifert, Roland E. Kontermann, Klaus Pfizenmaier, Laureano Simón, Myriam Fabre, Ángel M. Carcaboso, Joseph A. Ludwig, Enrique de Álava,

Sarcoma Diagnosis and Treatment

Endoglin (ENG; CD105) is a coreceptor of the TGFβ family that is highly expressed in proliferating endothelial cells. Often coopted by cancer cells, ENG can lead to neo-angiogenesis and vasculogenic mimicry in aggressive malignancies. It exists both as a transmembrane cell surface protein, where it primarily interacts with TGFβ, and as a soluble matricellular protein (sENG) when cleaved by matrix metalloproteinase 14 (MMP14). High ENG expression has been associated with poor prognosis in Ewing sarcoma, an aggressive bone cancer that primarily occurs in adolescents and young adults. However, the therapeutic value of ENG targeting has not been fully explored in this disease.We characterized the expression pattern of transmembrane ENG, sENG, and MMP14 in preclinical and clinical samples. Subsequently, the antineoplastic potential of two novel ENG-targeting monoclonal antibody-drug conjugates (ADC), OMTX503 and OMTX703, which differed only by their drug payload (nigrin-b A chain and cytolysin, respectively), was assessed in cell lines and preclinical animal models of Ewing sarcoma.Both ADCs suppressed cell proliferation in proportion to the endogenous levels of ENG observed in vitro. Moreover, the ADCs significantly delayed tumor growth in Ewing sarcoma cell line-derived xenografts and patient-derived xenografts in a dose-dependent manner.Taken together, these studies demonstrate potent preclinical activity of first-in-class anti-ENG ADCs as a nascent strategy to eradicate Ewing sarcoma.