Targeted Delivery of an Antibody–Mutant Human Endostatin Fusion Protein Results in Enhanced Antitumor Efficacy

Shin, Sungwon; Cho, Hyun-Mi; Merchan, Jaime R.; Zhang, Jin; Kovacs, Krisztina; Jing, Yawu; Ramakrishnan, Sundaram; Rosenblatt, Joseph D.

doi:10.1158/1535-7163.mct-10-0804

Cited by 15 publications

(21 citation statements)

References 49 publications

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“…Endostatin oligomers effectively stimulate the motility of endothelial cells that can be a strategy in enhancing anti-tumor activity of rEs. 96 A point mutation in rhEs at position 125 (P125A) is another way that enhance the anti-angiogenic activity of Es and support proper localization of rEs into tumor tissue. The synthetic peptide corresponding to the sequence 93–133 of Es displayed a pro-angiogenic activity, enhanced migration of the endothelial cell and neovascularization.…”

Section: Clinical Application Challengesmentioning

confidence: 99%

The Challenges of Recombinant Endostatin in Clinical Application: Focus on the Different Expression Systems and Molecular Bioengineering

Mohajeri¹,

Sanaei

Kiafar³

et al. 2017

Adv Pharm Bull

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Angiogenesis plays an essential role in rapid growing and metastasis of the tumors. Inhibition of angiogenesis is a putative strategy for cancer therapy. Endostatin (Es) is an attractive anti-angiogenesis protein with some clinical application challenges including; short half-life, instability in serum and requirement to high dosage. Therefore, production of recombinant endostatin (rEs) is necessary in large scale. The production of rEs is difficult because of its structural properties and is high-cost. Therefore, this review focused on the different expression systems that involved in rEs production including; mammalian, baculovirus, yeast, and Escherichia coli (E. coli) expression systems. The evaluating of the results of different expression systems declared that none of the mentioned systems can be considered to be generally superior to the other. Meanwhile with considering the advantages and disadvantage of E. coli expression system compared with other systems beside the molecular properties of Es, E. coli expression system can be a preferred expression system for expressing of the Es in large scale. Also, the molecular bioengineering and sustained release formulations that lead to improving of its stability and bioactivity will be discussed. Point mutation (P125A) of Es, addition of RGD moiety or an additional zinc biding site to N-terminal of Es , fusing of Es to anti-HER2 IgG or heavy-chain of IgG, and finally loading of the endostar by PLGA and PEG- PLGA nanoparticles and gold nano-shell particles are the effective bioengineering methods to overcome to clinical changes of endostatin.

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Section: Clinical Application Challengesmentioning

confidence: 99%

The Challenges of Recombinant Endostatin in Clinical Application: Focus on the Different Expression Systems and Molecular Bioengineering

Mohajeri¹,

Sanaei

Kiafar³

et al. 2017

Adv Pharm Bull

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“…Similarly, Fc- or anti-HER2 antibody fusion to endostatin showed prolonged half-lives in circulation. For example, the elimination half-life (t 1/2 ) of the anti-HER2-endostatin fusion protein (40.2 ± 2.7 h) is ~10 times longer than that of endostatin (3.75 ± 2.18 h) in normal mice [22]. Antibody fusion did not adversely affect the anti-angiogenic activities of endostatin.…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2015

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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.

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“…The prolactin antagonist-ES fusion protein is a bifunctional protein, which inhibits both breast cancer cell proliferation and endothelial cell proliferation, exhibiting greater tumor inhibitory effects than prolactin antagonist and ES treated individually or in combination [29]. Targeting of ES using anti-HER2 antibody and human ES fusion protein could improve antitumor activity of either anti-HER2 antibody and/or ES and provides the versatile approach that could be applied to other tumor targets with alternative antibody specificities [30]. ZBP-ES, engineered by adding 9 extra amino acid residues MGGSHHHHH to the N-terminus of ES, showed increased thermodynamic stability and biological activity than the wild type ES [27], and was approved as anti-cancer drug in China.…”

Section: Discussionmentioning

confidence: 99%

Genetically engineered endostatin-lidamycin fusion proteins effectively inhibit tumor growth and metastasis

Jiang

Shang

et al. 2013

BMC Cancer

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BackgroundEndostatin (ES) inhibits endothelial cell proliferation, migration, invasion, and tube formation. It also shows antiangiogenesis and antitumor activities in several animal models. Endostatin specifically targets tumor vasculature to block tumor growth. Lidamycin (LDM), which consists of an active enediyne chromophore (AE) and a non-covalently bound apo-protein (LDP), is a member of chromoprotein family of antitumor antibiotics with extremely potent cytotoxicity to cancer cells. Therefore, we reasoned that endostatin-lidamycin (ES-LDM) fusion proteins upon energizing with enediyne chromophore may obtain the combined capability targeting tumor vasculature and tumor cell by respective ES and LDM moiety.MethodsIn this study, we designed and obtained two new endostatin-based fusion proteins, endostatin-LDP (ES-LDP) and LDP-endostatin (LDP-ES). In vitro, the antiangiogenic effect of fusion proteins was determined by the wound healing assay and tube formation assay and the cytotoxicity of their enediyne-energized analogs was evaluated by CCK-8 assay. Tissue microarray was used to analyze the binding affinity of LDP, ES or ES-LDP with specimens of human lung tissue and lung tumor. The in vivo efficacy of the fusion proteins was evaluated with human lung carcinoma PG-BE1 xenograft and the experimental metastasis model of 4T1-luc breast cancer.ResultsES-LDP and LDP-ES disrupted the formation of endothelial tube structures and inhibited endothelial cell migration. Evidently, ES-LDP accumulated in the tumor and suppressed tumor growth and metastasis. ES-LDP and ES show higher binding capability than LDP to lung carcinoma; in addition, ES-LDP and ES share similar binding capability. Furthermore, the enediyne-energized fusion protein ES-LDP-AE demonstrated significant efficacy against lung carcinoma xenograft in athymic mice.ConclusionsThe ES-based fusion protein therapy provides some fundamental information for further drug development. Targeting both tumor vasculature and tumor cells by endostatin-based fusion proteins and their enediyne-energized analogs probably provides a promising modality in cancer therapy.

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Targeted Delivery of an Antibody–Mutant Human Endostatin Fusion Protein Results in Enhanced Antitumor Efficacy

Cited by 15 publications

References 49 publications

The Challenges of Recombinant Endostatin in Clinical Application: Focus on the Different Expression Systems and Molecular Bioengineering

The Challenges of Recombinant Endostatin in Clinical Application: Focus on the Different Expression Systems and Molecular Bioengineering

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

Genetically engineered endostatin-lidamycin fusion proteins effectively inhibit tumor growth and metastasis

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