Tumour endothelial marker 1/endosialin-mediated targeting of human sarcoma

Publication date: February 2018
Source:European Journal of Cancer, Volume 90
Author(s): Y. Guo, J. Hu, Y. Wang, X. Peng, J. Min, J. Wang, E. Matthaiou, Y. Cheng, K. Sun, X. Tong, Y. Fan, P.J. Zhang, L.E. Kandalaft, M. Irving, G. Coukos, C. Li
BackgroundTumour endothelial marker 1 (TEM1/endosialin/CD248) is a tumour-restricted cell-surface protein expressed by human sarcomas. We previously developed a high-affinity human single-chain variable fragment (scFv)-Fc fusion protein (78Fc) against TEM1 and demonstrated its specific binding to human and mouse TEM1.Patient and methodsClinical sarcoma specimens were collected between 2000 and 2015 at the Hospital of the University of Pennsylvania, as approved by the institutional review board and processed by standard formalin-fixed paraffin embedded techniques. We analysed TEM1 expression in 19 human sarcoma subtypes (n = 203 specimens) and eight human sarcoma–cell lines. Near-infrared (NIR) imaging of tumour-bearing mice was used to validate 78Fc binding to TEM1⁺ sarcoma in vivo. Finally, we tested an immunotoxin conjugate of anti-TEM1 78Fc with saporin (78Fc-Sap) for its therapeutic efficacy against human sarcoma in vitro and in vivo.ResultsTEM1 expression was identified by immunohistochemistry in 96% of human sarcomas, of which 81% expressed TEM1 both on tumour cells and the tumour vasculature. NIR imaging revealed specific in vivo targeting of labelled 78Fc to TEM1⁺ sarcoma xenografts. Importantly, 78Fc-Sap was effective in killing in vitro TEM1⁺ sarcoma cells and eliminated human sarcoma xenografts without apparent toxicity in vivo.ConclusionTEM1 is an important therapeutic target for human sarcoma, and the high-affinity TEM1-specific scFv fusion protein 78Fc is suitable for further clinical development for therapeutic applications in sarcoma.



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