TY - JOUR
T1 - Preclinical efficacy of endoglin-targeting antibody–drug conjugates for the treatment of Ewing sarcoma
AU - Puerto-Camacho, Pilar
AU - Amaral, Ana Teresa
AU - Lamhamedi-Cherradi, Salah Eddine
AU - Menegaz, Brian A.
AU - Castillo-Ecija, Helena
AU - Ordóñez, José Luis
AU - Domínguez, Saioa
AU - Jordan-Perez, Carmen
AU - Diaz-Martin, Juan
AU - Romero-Pérez, Laura
AU - Lopez-Alvarez, Maria
AU - Civantos-Jubera, Gema
AU - Robles-Frías, María José
AU - Biscuola, Michele
AU - Ferrer, Cristina
AU - Mora, Jaume
AU - Cuglievan, Branko
AU - Schadler, Keri
AU - Seifert, Oliver
AU - Kontermann, Roland
AU - Pfizenmaier, Klaus
AU - Simón, Laureano
AU - Fabre, Myriam
AU - Carcaboso, Ángel M.
AU - Ludwig, Joseph A.
AU - de Álava, Enrique
N1 - Publisher Copyright:
© 2018 American Association for Cancer Research.
PY - 2019/4/1
Y1 - 2019/4/1
N2 - Purpose: Endoglin (ENG; CD105) is a coreceptor of the TGFb 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 TGFb, and as a soluble matricellular protein (sENG) when cleaved by matrix metal-loproteinase 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. Experimental Design: 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. Results: 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. Conclusions: Taken together, these studies demonstrate potent preclinical activity of first-in-class anti-ENG ADCs as a nascent strategy to eradicate Ewing sarcoma.
AB - Purpose: Endoglin (ENG; CD105) is a coreceptor of the TGFb 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 TGFb, and as a soluble matricellular protein (sENG) when cleaved by matrix metal-loproteinase 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. Experimental Design: 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. Results: 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. Conclusions: Taken together, these studies demonstrate potent preclinical activity of first-in-class anti-ENG ADCs as a nascent strategy to eradicate Ewing sarcoma.
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U2 - 10.1158/1078-0432.CCR-18-0936
DO - 10.1158/1078-0432.CCR-18-0936
M3 - Article
C2 - 30420447
AN - SCOPUS:85064161843
SN - 1078-0432
VL - 25
SP - 2228
EP - 2240
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 7
ER -