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

被引：31

作者：

Puerto-Camacho, Pilar ^{[1
]}

Teresa Amaral, Ana ^{[1
]}

Lamhamedi-Cherradi, Salah-Eddine ^{[2
]}

Menegaz, Brian A. ^{[2
]}

Castillo-Ecija, Helena ^{[3
]}

Luis Ordonez, Jose ^{[1
]}

Dominguez, Saioa ^{[4
]}

Jordan-Perez, Carmen ^{[1
]}

Diaz-Martin, Juan ^{[1
]}

Romero-Perez, Laura ^{[1
]}

Lopez-Alvarez, Maria ^{[1
]}

Civantos-Jubera, Gema ^{[1
]}

Jose Robles-Frias, Maria ^{[1
]}

Biscuola, Michele ^{[1
]}

Ferrer, Cristina ^{[4
]}

Mora, Jaume ^{[3
]}

Cuglievan, Branko ^{[2
]}

Schadler, Keri ^{[2
]}

Seifert, Oliver ^{[5
]}

Kontermann, Roland ^{[5
]}

Pfizenmaier, Klaus ^{[5
]}

Simon, Laureano ^{[4
]}

Fabre, Myriam ^{[4
]}

Carcaboso, Angel M. ^{[3
]}

Ludwig, Joseph A. ^{[2
]}

de Alava, Enrique ^{[1
]}

机构：

[1] Univ Seville, Inst Biomed Sevilla IBiS, Virgen Rocio Univ Hosp, CIBERONC,CSIC, Seville, Spain

[2] Univ Texas MD Anderson Canc Ctr, Dept Sarcoma Med Oncol, 1901 East Rd,Bldg 4SCBR2-1042, Houston, TX 77054 USA

[3] Hosp St Joan Deu Barcelona, Pediat Hematol & Oncol, Inst Recerca St Joan Deu, Barcelona, Spain

[4] Oncomatryx, Bilbao, Spain

[5] Univ Stuttgart, IZI, Stuttgart, Germany

来源：

CLINICAL CANCER RESEARCH | 2019年 / 25卷 / 07期

关键词：

TUMOR-CELL PLASTICITY; SOLID TUMORS; OPEN-LABEL; IDENTIFICATION; HETEROGENEITY; MARKER; BREAST; TRC105; GENE; BEVACIZUMAB;

D O I：

10.1158/1078-0432.CCR-18-0936

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

Purpose: Endoglin (ENG; CD105) is a coreceptor of the TGF beta family that is highly expressed in proliferating endothelial cells. Often coopted by cancer cells, ENG can lead to neoangiogenesis and vasculogenic mimicry in aggressive malignancies. It exists both as a transmembrane cell surface protein, where it primarily interacts with TGF beta, 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. Experimental Design: We characterized the expression pattern of transmembrane ENG, sENG, and MMP14 in pre-clinical 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.

引用

页码：2228 / 2240

页数：13

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