Extension of the in vivo half-life of endostatin and its improved anti-tumor activities upon fusion to a humanized antibody against tumor-associated glycoprotein 72 in a mouse model of human colorectal carcinoma

Abstract

Endostatin is an endogenous angiogenesis inhibitor that exhibits potential anti-tumor efficacy in various preclinical animal models. However, its relatively short in vivo half-life and the long-term, frequent administration of high doses limit its widespread clinical use. In this study, we evaluated whether a fusion protein of murine endostatin (mEndo) to a humanized antibody against tumor-associated glycoprotein 72 (TAG-72), which is highly expressed in several human tumor tissues including colon cancer, can extend the serum half-life and improve the anti-tumor efficacy of endostatin by targeted delivery to the tumor mass. The fusion protein (3E8-mEndo) and mEndo showed improved anti-angiogenic activity in vitro and in vivo, predominantly by interfering with pro-angiogenic signaling triggered by vascular endothelial growth factor (VEGF). Moreover, in mice treated with 3E8-mEndo, we observed a markedly prolonged serum half-life and significantly inhibited tumor growth. The improved anti-tumor activity of 3E8-mEndo can be partially explained by increased local concentration in the tumor mass due to targeted delivery of 3E8-mEndo to implanted colon tumors. Collectively, our data clearly indicate that tumor-targeting antibody fusions to endostatin are a powerful strategy that improves the poor pharmacokinetic profile and anti-tumor efficacy of endostatin.

Matricryptins Network with Matricellular Receptors at the Surface of Endothelial and Tumor Cells

“…Endostatin has been fused to the proapoptotic domain (BH3) of the BAX protein (Chura-Chambi et al, 2014 ), to tumor necrosis factor-related apoptosis-inducing ligand (Zheng et al, 2013 ) and one of its anti-angiogenic sequences to an heptapeptide inhibitor of MMPs (Qiu et al, 2013 ). Endostatin has also been fused to protein sequences targeting it to tumors and/or tumor vasculature such as humanized antibodies against tyrosine kinase-type receptor HER2 (Shin et al, 2011 ) or against tumor-associated glycoprotein 72 highly expressed in human tumor tissues (Lee et al, 2015 ), the RGD integrin-binding sequence (Jing et al, 2011 ), and a liver-targeting peptide (circumsporozoite protein CSP I-plus (Ma et al, 2014 ; Bao et al, 2015 ).…”

Delisheng induces antiproliferation and apoptosis effects in Hep3B cells via modulation of angiogenic proteins

“…Furthermore, ES suppressed the expression of VEGF, matrix metalloproteinases, fibroblast growth factor and cell adhesion molecule ( 37 , 38 ). Certain previous studies revealed that tumor growth was inhibited in transgenic mice overproducing ES ( 39 , 40 ). Based on the results of the present study, the upregulation of ES and downregulation of VEGF and OPN may be responsible for the anticancer effect of Delisheng on Hep3B cells.…”

Recombinant Endostatin as a Potential Radiosensitizer in the Treatment of Non-Small Cell Lung Cancer

“…Collectively, these studies fall under a large blanket of experimental findings that show RE’s effect on the vascular endothelium and successfully served as a validation of the original work by O’Reilly and colleagues [ 38 ]. Importantly, anti-angiogenic drugs like RE target rapidly proliferating tumour-associated endothelial cells rather than relatively dormant endothelial cells in healthy tissue, making them less toxic than chemotherapeutic agents [ 82 ].…”