RT Journal Article
T1 Preclinical Efficacy of Endoglin-Targeting Antibody-Drug Conjugates for the Treatment of Ewing Sarcoma.
A1 Puerto-Camacho, Pilar
A1 Amaral, Ana Teresa
A1 Lamhamedi-Cherradi, Salah-Eddine
A1 Menegaz, Brian A
A1 Castillo-Ecija, Helena
A1 Ordóñez, José Luis
A1 Domínguez, Saioa
A1 Jordan-Perez, Carmen
A1 Diaz-Martin, Juan
A1 Romero-Pérez, Laura
A1 Lopez-Alvarez, Maria
A1 Civantos-Jubera, Gema
A1 Robles-Frías, María José
A1 Biscuola, Michele
A1 Ferrer, Cristina
A1 Mora, Jaume
A1 Cuglievan, Branko
A1 Schadler, Keri
A1 Seifert, Oliver
A1 Kontermann, Roland
A1 Pfizenmaier, Klaus
A1 Simón, Laureano
A1 Fabre, Myriam
A1 Carcaboso, Ángel M
A1 Ludwig, Joseph A
A1 de Álava, Enrique
AB 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.
YR 2018
FD 2018-11-12
LK http://hdl.handle.net/10668/13173
UL http://hdl.handle.net/10668/13173
LA en
DS RISalud
RD Apr 6, 2025